BASIC DOCUMENTS TUBERCULOSIS CONTROL
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TUBERCULOSIS CONTROL - extracted text
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HEALTH PROGRAMS DEVELOPMENT
MATERNAL AND CHILD HEALTH PROGRAM
PAHO/WHO
BASIC DOCUMENTS
CONTROL
TUBERCULOSIS
DECEMBER 1987
A
la
PAN AMERICAN HEALTH ORGANIZATION
WORLD HEALTH ORGANIZATION
■
!
■
CONTENTS
4
1.
Miller, J. W.
2.
Styblo, K. State of the art:
IUAT, 53 (3): 141-154, 1978.
3.
Styblo, K.; Meijer, J.
Recent advances :*in tuberculosis epidemiology
with regard to formulation or readjustment of control programmes. Bull.
UIAT, 53 (4): 283-294, 1978.
4.
ten Dam, H. G.; Pio, A.
Epidemiological research in tuberculosis
control. PAHO/WHO Epidemiological Bulletin 5 (1): 8-13, 1984.
5.
PAHO. Epidemiological assessment of tuberculosis. Trends in some coun
tries of the Americas. PAHO/WHO Epid. Bulletin 8 (3-4): 1-5, 1987.
6.
Stott H. et al. Tuberculosis control - current situation,
the views of workers involved in tuberculosis control
throughout the world. WHO/TB/82.133.
7.
Chaulet, P.
Treatment
WHO/TB/83.141 Rev. 2.
8.
Luelmo F. BCG vaccination.
1982.
9.
WHO.
Efficacy of infant BCG immunization.
PAHO/EPI Newsletter 8(6):
2-3, 1986 and WHO Weekly Epid. Record 61 (28): 216-218, 1986.
The natural history of primary tuberculosis WHO/TB/84.144.
of
I. Epidemiology of tuberculosis.
tuberculosis:
case
holding
Bull.
Summary of
programmes
until
cure.
Am. Rev. Resp. Dis., 125 (3) Part 2: 70-72,
Recommended publications
1.
Toman, K. Tuberculosis: Case-finding and chemotherapy.
answers. WHO, Geneva, 1979.
2.
PAHO/WHO. Tuberculosis control: A manual on methods and procedures for
integrated programs. PAHO Sc. Pub. 498, 1986.
Questions and
I
WORLD HEALTH ORGANIZATION
WHO/TB/84.144
ENGLISH ONLY
ORGANISATION MONDIALE DE LA SANTfi
1 June 1984
THE NATURAL HISTORY OF PRIMARY TUBERCULOSIS
by
Fred. J.W. Miller, Honorary Physician, Children's Department,
Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom
TABLE OF CONTENTS
Page
1.
Introduction
2
2.
Paths and sites' of infection
2
3.
Concept of primary infection
3
4.
The evolution and healing of the primary complex
5.
The risks of pulmonary primary infection
4
6.
Complications and timetable
5
6.1
The primary focus
5
6.2
The regional nodes
6
6.3
Haematogenous dissemination
7
. .
3
7.
Regional differences in clinical manifestations
8.
The relationship with chronic pulmonary tuberculosis
9.
Extrapulmonary primary infection
10
10.
Conelusion
11
11.
Bibliography
16
12.
Terminology
19
9
. .
9
With the permission of the publishers the tables and figures have been
reproduced from Tuberculosis in Children, F.J.W. Miller, Medicine in the
Tropics Series, Churchill-Livingstone, Edinburgh, 1982.
The issue of this document does not constitute
formal publication. It should not be reviewed,
abstracted or quoted without the agreement of
the World Health Organization. Authors alone
are responsible for views expressed in signed
articles.
Ce document ne constitue pas une publication.
II ne doit faire I’objet d'aucun compte rendu ou
r6sum6 ni d’aucune citation sans I’autorisation de
I’Organisation Mondiale de la Sante. Les opinions
exprimdes dans les articles signds n’engagent
que leurs auteurs.
WHO/TB/84.144
page 2
The Natural History of Primary Tuberculosis
1.
Introduction
To describe the natural history of any infection it is necessary to
observe a sufficient number of subjects from the time of infection through the
evolution of the relationship of the infective agent and the human host until
either the infective agent overcomes the host or the defences of the host
contain and then eliminate the infection. • With some infections these
processes are rapid and a matter of days or weeks.
With others such as
tuberculosis or syphilis the relationship, unless altered by treatment, is
prolonged and must be considered in years or even decades if the full story is
to be obtained.
If the moment of infection can also pass undetected because it may not be
marked by any acute change in clinical state the task is even more
difficult.
This is also the situation with tuberculosis.
Furthermore, in
describing the relationship between the invading organism and the human host
it is necessary to remember that the power of the host to '‘resist", that is to
prevent the multiplication of the invading organisms i.id ultimately to
eliminate them is not constant throughout life but varies with many factors,
three of special importance being age at infection, nutritional state and the
effect of other infective conditions.
Thus the evolution and outcome of the
infection are influenced by many variables which must be taken into account
when attempting to describe the natural history and assess the risk of damage
to, or even death of, the host.
The observation that the mammalian immune process reacts in a different
manner to the second invasion of the tissues with Mycobacterium tuberculosis
than it does to the first was made by Koch (1891).
fSince
‘*
then the concept of
primary infection which is to be described has grown slowly asJ a result of the
observations of many workers in different parts of the world who studied
tuberculosis either in the laboratory or by clinical experience before
chemotherapy became available.
C
Outstanding in the shaping of the concepts
were Gohn (1912), Ranke (1917), Rich and McCordock (1929) and Wallgren (1938
(a) and (b), 1948).
2.
Paths and sites of primary infection
Pulmonary tuberculosis is the classic example of an airborne infection.
When a person with open pulmonary tuberculosis coughs, especially if the cough
is forcible or explosive, many droplets of different sizes containing tubercle
bacilli are ejected.
The smallest are invisible, evaporate almost instantly
to still smaller droplet nuclei and become dispersed in the air moving as the
air itself moves.
If the coughing takes place in a confined and unventilated
space the number of droplet nuclei increases with repeated coughing and the
chance that some may be inhaled by other persons also increases.
Droplet
nuclei are important because they persist in the air after the infective
person has left the room and owing to their size (less than KLA) they can
penetrate to the smallest bronchioles and reach the subpleural space.
(Riley 1982)
Occasionally, human droplets containing bacilli may be introduced to a
small wound or abrasion in the skin or on a mucous membrane and this becomes
the site of a primary focus (Miller 1953).
Infection has even been recorded
following immersion in contaminated water (S£n£cal 1950).
WHO/TB/84.144
page 3
The spread of M. bovis is also initially by droplets expelled as the cow
coughs.
in this way infection may spread to the lungs of the cow-herds and
the milk can become contaminated.
If this milk is then consumed without
pasteurisation or boiling infection may be lodged in the tonsils, in the
oro pharynx or in the alimentary tract.
3.
Concept of primary infection
Wherever and whenever tubercle bacilli (M. tuberculosis or M. bovis) first
lodge in the tissues of a human host the invasion initiates a sequence of
events which is always the same although they may differ in degree with
certain characteristics of the host, principally with age and nutrition,
The
events which follow are also related in time so that it is possible to
describe a "time-table” (Wallgren 1948, and Figure 2).
After infection some bacilli remain at the site of entry, and others are
carried in the lymph flow to the nearest lymph nodes,
Bacilli then multiply
in both sites and as the defense mechanism of the host comes into play,
"tubercles” form so that a lesion develops at the point of entry and the
regional nodes enlarge,
Wherever its site, the lesion (focus) and nodes
together form the primary complex,
Gradually, the nodes further in the line
of lymph drainage also become involved,
As this occurs small numbers of
organisms are disseminated in the blood stream.
Some 4-8 weeks after first infection, most people develop "sensitivity”
to tuberculo-protein and the defense mechanisms accelerate.
The degree of
sensitivity developed varies with age and nutrition and probably with the
weight
J ‘ of infection.
---- The phenomenon is used in the tuberculin test to detect
whether or not an individual has been infected at some time previous to the
test.
In most children or young adults these defense mechanisms are
sufficient to contain and then slowly to heal the tuberculous process in both
the focus and the nodes without the development of clinical illness,
But the
infection can be progressive and complications can arise from either the
primary focus or the nodes if the body defenses are insufficient.
The
organisms disseminated in the blood stream can also form tuberculous seedings
in distant organs such as brain, bones or kidney and if extension occurs in
any of these sites clinical illness can result.
Organisms can remain dormant
both in the primary complex or in disseminated seedings and if the balance
reached between organism and host is at any time tipped in favour of the
former, then active tuberculous lesions may arise even years after the initial
infection.
4.
The evolution and healing of the primary complex
The evolution of the pulmonary primary lesion from the time of infection
to healing was worked out in detail by Sweany (1941) and Medlar (1948) by the
examination o f primary foci of known duration in both human tissues and
animals, the latter being produced experimentally.
The first response to the presence of tubercle bacilli is serous exudate
and the collection of polymorphonuclear leucocytes.
This is followed within
48 hours by monocytes and by mononuclear epitheloid cells of local origin the
number of which steadily increase until about the end of the second week when
giant cells begin to form and small numbers of lymphocytes appear.
About
this time the cells in the centre of the tubercle die and undergo the change
known as caseation.
This central area increases as the tubercle becomes
larger and ultimately forms the grey-white nodule so characteristic of
tuberculosis.
At some time during the second month the number of lymphocytes
quickly increases forming a zone around the developing tubercle.
This change
appears to coincide with the development of tuberculin sensitivity.
WHO/TB/84.14 4
page 6
the caseous material enter the pleurae there is also the danger that a
tuberculous empyema will develop,
This complication usually occurs within
six months of infection.
If the focus extends without rupturing into the pleural sac, it might
open into a bronchus [Fig. l.A (iii)].
If the contents are then coughed up a
cavity, sometimes^a tension cavity, is the result.
Except occasionally in
infants cavitation was uncommon in European countries between 1930 and 1960
but still occurs in children of all ages in countries of Africa and South-East
Asia.
It may also be the beginning of spread to other parts of the lung and
part of the mechanism of spread which causes the extensive pulmonary
involvement so common in malnourished children in Africa (Carter 1954).
Like
pleural effusion this type of cavitation tends to occur within a few months of
infection [Fig. 2].
Sometimes the primary focus remains almost unchanged in periods of
equilibrium with the host’s powers of resistance, or periods of extension and
periods of healing may alternate so that the focus comes to have a laminated
appearance.
Such a round shadow (coin or numular shadow) can persist for
many months until it is calcified, or opening into a bronchus, the caseous
material is coughed up and the radiological shadow disappears [Fig. l.A (iv)].
6.2
The regional nodes
When the primary focus is in a lung the regional nodes draining it are
situated at the junction of the bronchi supplying the same
pulmonary segment.
and at the broncho-pulmonary nodes at the root of the lung,
These in turn
dram into paratracheal nodes.
These nodes enlarge as their contents become
caseous and may soften to form what amounts to an abscess.
As the nodes lie
in relation to both bronchi and to blood vessels either structure can be
eroded by the tuberculous process or, in very young children,
the bronchi may
be compressed.
When a bronchus becomes eroded by tuberculous
endobronchitis
the contents of the nodes may leak or be extruded into the lumen.
When this
andSrhAPne\the
dePends uPon the physical state of the caseous material
nd the number of viable organisms it contains.
The possibilities are shown
m Figure l.B (i-iv).
The extent of lung involved depends on the order of
the bronchus eroded - whether segmented, lobar or that involving a whole lung.
(i) Hyperinflation.
When the bronchi is partly but incompletely
obstructed so that during inspiration some air can pass into the
lung beyond, but on expiration the obstruction is complete, the
segment of lung beyond the block becomes over distended [Fig. l.B
(i)J.
This ball-valve obstruction can affect a segment, a lobe or
a complete lung.
This situation by its very nature is unstable
and transient and the bronchus either b1ocks completely or the
material is coughed up.
(ii) Collapse. If complete obstruction occurs and the air beyond is
absorbed then the lung distal to the obstruction collapses as the
pressure falls [Fig. l.B (ii)].
(in) Collapse-consolidation. More usual than either over-inflation or
complete absorption-collapse is the situation when some of the
stents of the node have leaked into the bronchus and are inhaled
further into the lung beyond,
The contents contain tuberculin and
varying numbers of bacilli and seC UP an inflammatory reaction in
the distal lung - the two extremes of reaction are first a
non-specific exudation with few if any tubercles [Fig. l.B (iii))
or secondly, the beginning of a progressive tuberculous
broncho-pneumonia [Fig. l.B (iv)].
The first of these two
WHO/TB/84.144
page 7
extremes is the most common type of segmental lesion formerly seen
in Europe whilst the second appears to be a stage in the
development of the progressive pulmonary tuberculosis of African
children (Fig. l.B (iv)].
The segmental consolidations may leave permanent structural changes in
the affected lobe or segment of lung and its bronchi.
These changes shown
diagrammatically in Fig. l.C (i-iv)) are:
(i) Bronchial stricture by scarring at the point where the wall of the
bronchus was eroded by the tuberculous node.
(ii) Cylindrical bronchiectasis in the shrunken lobe or segment which
failed to reexpand after bronchial obstruction.
(iii) Bronchiectasis in a shrunken lobe or segment which has been the
site of consolidation and then slow healing by fibrosis and
contracture.
(iv) Sometimes the healed fibrotic area may appear simply as linear
scarring on an X-ray film.
Segmental lesions occur most frequently between three and nine months
after primary infection and can remain as radiological shadows for months
without any noticeable change in the child’s condition.
If, however, the
number of bacilli is sufficient to overcome resis*- -je then, as already
stated, progressive tuberculous broncho-pneumonia is the result.
Caseous nodes about the carina can also ulcerate forwards and leak or
rupture through the posterior wall of the pericardium into tne pericardial sac
and there set up a pericarditis which may be serous [Fig. l.C (v)j or adherent
obliterating the cavity.
Posteriorly the oesophagus can be involved and the
contents of the node discharged into its lumen and later if an adherent scar
remains it may be the beginning of an oesophageal pouch.
6.3
Haematagenous dissemination
. During the formation of the primary complex and for some time afterwards
bacilli escape intermittantly into the blood stream and are carried to other
parts of the body. . There is good evidence that this can happen without the
development of clinical illness.
Thus choroidal tubercles were seen in six
of one hundred consecutive children with asymptomatic primary infections.
Monbrun and Lavat (1949) and Webster (1942) and Munro (1944) recorded the
intermittent discharge of bacilli in the urine without any symptoms of renal
disease.
Tubercles have also been found in the livers of persons accidently
killed following a recent primary infection.
Although this intermittent spread does produce scattered seedings the
important point is whether any of these small lesions continue to enlarge and
damage tissue as in bone disease or by rupturing into a cavity cause
widespread reaction as occurs when a subcortical lesion in the brain (Rich
focus) leaks into the subarachnoid space and tuberculous meningitis follows.
Blood spread can
<
also take place within the lungs and probably occurs
both through the pulmonary
circulation
. veins and general
-- -----1 or by local spread
through small vessels,
Small tubercles known as Simon foci appear
particularly at the apices (Simon 1943).
It is possible that after a long
interval these foci might sometimes again become active and give rise to
chronic pulmonary lesions.
WHO/TB/84.144
page 10
ofthe radiological findings, 93 of the children had evidence of an old
primary complex in the same segment or lobe as the recent progressive
disease. The same situation must arise in adolescents.
Further evidence also pointing to the reactivation of primary pulmonary
lesions (endogenous exacerbation) was found in long-term BCG trials in
populations in America and the United Kingdom. During these studies, over the
years when the risk of infection was steadily falling, the incidence of active
pulmonary tuberculosis in the infected unvaccinated group was greater than in
either the unvaccinated uninfected or the vaccinated group (Medical Research
Council, 1963, 1977; Ferebee and Palmer, 1965).
In countries where pulmonary tuberculosis is prevalent in adults and the
risk of infection is high many cases of pulmonary tuberculosis must be caused
by exogenous reinfection in persons who have previously had a primary
infection. Thus the total morbidity of pulmonary tuberculosis in adults in
any community comprises three components, endogenous exacerbation of former
primary infections, the progressive primary infections of adult life and
exogenous reinfection in persons who have healed a previous primary
infection. The proportion which each of these contributes to the total
morbidity from pulmonary tuberculosis varies from community to community and
the annual risk of infection in each. As this risk declines the proportion of
cases due to endogenous exacerbation will increase.
9.
Extrapulmonary primary infection [Fig. 3}
The distribution of 66 extra pulmonary lesions
seen in the course of
clinical work with children in the North-East of England between 1948 and 1960
is shown in Figure 3. The sites of primary infection were in the conjunctiva,
on the face and forehead, in the mouth and oro-pharynx, on the forearms and
knees, legs and feet, These are sites which, in children, are often subject
to minor trauma and also to contamination by dust or fluids which might
contain tubercle bacilli or to droplet infection from adults.
Milk was previously a ccommon source of infection
2^.. and still is in certain
areas. "
The infecting organism is then either
bovis
or, by
by human
human "
- --- M.
- ---- j or,
contamination
----- M. tuberculosis, and the primary lesion is in the tonsil or the
oro-pharynx, or the
-- intestine
----------or in both. But other foods, cutlery or dental
instruments contaminated by M. tuberculosis can produce lesions in the
same
sites.
Except when the primary focus is in the intestine the clue to its
position is given by the site of the group of enlarged superficial regional
nodes
of the complex. T.._
...
The 1lymph
drainage from
the lesion
isJ dCC
«
•
m Lite
X C X 11 XS
accurate so the
lesion must be sought in the area drained by the nodes involved, Any small
ulcer or scab in the area should be suspected and investigated.*
In this way,
the origin of superficial tuberculosis lymphadenitis is explained and fits
into the picture of primary infection (Miller 1953, Miller and Cashman, 1958).
Most regional nodes enlarge slowly and painlessly but occasionally
the
onset may be swift with high fever and much perinodal oedema so that the
individual nodes cannot be recognized. Whatever the type of onset most nodes
sooner or later soften to form superficial abscesses which may be drained or
discharged . However, calcification can occur and then the node may remain
dormant for many years before finally softening.
Whilst the primary lesion is forming, bacilli escape into the blood
stream and are seeded just as in pulmonary primary lesions so that the risk of
haematogenous lesions exists wherever the primary complex forms.
WHO/TB/84.144
page 11
For intestinal primary infection, the regional nodes are deep in the
nuesentery and their presence can only be suspected if they cause an omental
roll,* ;adhesions between loops of gut or, rupturing, an effusion with abdominal
swelling. The mesenteric nodes, like others, may calcify and remain dormant
for years.
10.
Conelus ion
In this short description of the evolution and natural history of primary
tuberculosis infection, an attempt has been made to view tuberculosis as a
general disease and to relate all its manifestations in time and in relation
to the age and nutrition of the human host. It is in fact a plea that the
relationship of the tubercle bacillus and the human host can only be
understood if it is seen to_ begin
with the primary infectioni or first invasion
.
of the host and if it is regarded as a general disease and not as a medical,
surgical or dermatological problem depending upon the hospital department or
the 'specialist’ which the patient happens to reach.
WHO/TB/84.14 4
page 12
Table 1
Incidence (per cent* of complications of untreated primary tuberculous infection at different ages
Age at
infection
(years)
Author
0-2
0-2
0-5
0-5
0-5
0-5
0-7
0-7
Meningitis
and
miliary
Pleural
effusion
Segmental
lesion
Asymptomatic
converter
Routine test
16
0
23
5.7
Asymptomatic
conveners
Observation
at contact
clinic
Estimated
converters
Asymptomatic
converters
Erythema
nodosum
Routine
testing in
longitudinal
survey
2.6
2.6
11.4
0.9
5
1.3
Number
observed
Payne(1959)
England
Myers (1940'*
Source
69
209
America
Payne (1959)
England
Davies <19611
London
114
Cammock & Miller
(1953' England
Lotte & Rouillon
(I960? France
Holmdahl (1950)
Sweden
Miller et al
(1960) England
1020
74
314
657
99
%
4.8
2.6
3.5
1.5
3
1.9
3.8
12.7
6
0
2
23
Polarization of manifestations of tuberculosis
Manifestation
Size of primary infection
Amount of caseation
Size of regional nodes
Sensitivity phenomenon
Erythema nodosum
Phlyctenular
conjunctivitis
Pleural effusion
Abdominal asdtes
Tuberculosis of central
nervous system
(including tuberculomata)
Degree of skin sensitivity
Frequency of multiple
lesions
Frequency of primary
cavitation
'Temperate’
‘Tropical’
+
+++
+++
+++
+++
3.5
9.2
— Not recorded or not applicable.
Table
Pulmonary
Skeletal tuberculosis
3
WHO/TB/84.144
page 13
A
HJCUS ANO COMPi IC AT IONS
9 Owout nodrt
Primxy co
Foev* *nd
8
Ruptuie ol fucut into
Enlarged locus
twoochui cavitation
sometimes laminated
’round' or Com'
sharlow
MEOIAS1 INAi IRECIONALI NODES ANO COMPLICATIONS
Incomplete
bronchial obstruction
(Ball valve)
Inflation of middle
and lower lobes.
C.
Ruptuit ol locus mho
plcuial spacv with
cifusion, setous occ.
purulent.
Collapsed right
lower lobe after
complete bronchial
obstruction
Without
consolidation
Collapse after
partial
consolidation
segmental
lesion
Erosion into
Pericardial effusion post rupture
of node through percaidium
bronchus,
■nhalauon.and
areas of Tub.
bioncho
pneumonia
SEQUELAE OF BRONCHIAL COMPLICATIONS
ii
ii
iii
1
Si'Clurr of
Cylindrical
bronchiectasis in a<ea
of old collapse
WeOflt shadow with
fibrosis and
bronchiectasis
lollowiiiq contracture
of s«7nenta< lesion
Lmeai scai of fibrosis
following segmental
lesion
Fig. 1 The compGcations ind sequelae of Pulmonary primary tuberculous
infection
WHO/TB/84.144
page 14
EVOLUTION ANO TIMETABLE OF
UNTREATED PRIMARY TUBERCULOSIS
IN CHILDREN
Cornplicitiont of focut
1. Effusion
2. Cavitation
1 Coin shadow
Complications of nodes
1. Extension into tvonchui
2 Consolidation
X Hyperinflation
Rupture of
subcorneal
tuberculoma
MENINGITIS OR MILIARY
m 4% of children infected
under 5 years of age.
Mott cbitd'tn
b»ccxT>« tuberculin
t»n$itiv«
Most after 5 years
BRONCHIAL EROSION
A minority of children
I
eaperience:
I
1. Febrile illness
2. Erythema Nodosum
X Phlyctenular Conjunctivitis j
PRIMARY COMPLEX
Proflrettivt Healing
Mott cetet
Uncommon under 5
26% of cases within 3 months
75% of cases within 6 months
Incidence decreases
m age increated
BONE LESION
N------ 1
2
3
infection
_ACOUIRED RESISTANCE
12 moniM
Most within
3 YMI
Resistance reduced:
1. Early infection
(esp. in first year)
2. Malnutrition
X Repeated infections:
measles, whooping cough
streptococcal infections
4. Steroid therapy
;
!
Development
of Complex
h---------- ------------------- X
GRf ATEST RISK Of LOCAL 4 DISSEMINATED LESIONS *
Hl.
LATE
COMPLICATIONS
Renal & Skin
OiminiShinC risk
bui sial poaeie
90% m I«m 2 years
2 Evolution and Timetable of untreated primary tuberculous infection
@|©l
i
’
WHO/TB/84.144
page 15
Eye
Middle ear (6)
Face and Scalp (14) —
Tonsil (12)—
Mouth (8) —’
...... Postauricular (1)
...... Preauricular (10)
.............. Occipital (1)
............. Cervical (31)
............ Submental (3)
•♦It:::.'.'.'
......... Axilla (5)
Arm and Hand (5)
-\Groin (15)
Anus (1) —
Buttock (1)
Leg and Foot (13)
PRIMARY FOCI
A
REGIONAL NODES
Fig. 3 Distribution of primary foci and regional nodes in 66 children with primary
infection on skin or mucous membranes
WHO/TB/84.144
page 16
3i b1iography
Barnefollouin.yb 1? K’
Bacteriol°gical and X-Ray status of tuberculosis
following primary infection acquired during adolescence or later.
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Obstetrics and Gynaecology of British Empire 62:162.
Cammock RM, Miller FJW
Journal of
1953 Tuberculosis in young children.
Carter FS, 1954 Primary tuberculosis in African children
m Childhood 29:213.
Lancet 1:158.
Archives Disease
Dastur DK, Udani PM, 1966 Pathology and pathogenesis of
tuberculosis
encephalopa thy. Acta Neuropathologica 6:311.
Davies PDB, 1961 The natural history of tuberculosis in
children.
Tubercle (London) 42:Supp.
Ferebee SH, Palmer CE, 1965 The epidemiological bonus.
Respiratory Diseases 91:104.
American Review
Gohn A, 1912
r* " Der Primare Lungenherd bei der Tuberkulose
der Kinder.
Uban
.. und
-- 1 Schwarzenberg, Berlin und Vienna.
Granger J, Collins C, Yates M, 1722
1982 Z
Bacteriological survey of tuberculosis
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Community Health 36:157.
Holmdahl K, ]1950
-- Course
“
and prognosis in primary tuberculosis with erythema
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Koch R, J"1891’ Fortsetzung
der Mitteilung uber ein Heilmittel g
*
gegen Tuberkulose.
Deutsch. Med. Woch. 17, 101, 1189 Translated by Pinner 1948 Tubercle
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Levy LF, 1973 Tuberculoma
’
of brain in Malawi, Rhodesia and Zambia.
Journal Medical Science 4:399.
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Lotte A, Rouillon A, I960 Enquete sur la chimioprophylaxie et 1„ vl.lu.iu
la chimioch£rapie
pr^coce des tuberculoses primaires de 1’enfant et de 1’adolescent.
Bulletin Institut National d’Hygiene (Paris) 15:No. 5.
Medlar EM, 1948 Pathogenesis <of minimal pulmonary tuberculosis.
Review Tuberculosis 58:583.
American
Medical Research Council 1963 BCG and vole bacillus vaccines in the prevention
ot tuberculosis in adolescence and early adult life. 3rd Report by
Tuberculosis Vaccines Clinical Trials Committee. British Medical
Journal 1:973.
Medical Research Council 1977 Tuberculosis Vaccines Clinical Trials Committee.
BCG and vole bacillus vaccines in the prevention of tuberculosis in
adolescence and early adult life.
British Medical Journal 3:293.
WHO/TB/84.144
page 17
Miller FJW, 1953 Recognition of primary tuberculosis infection of skin and
mucosae. Lancet 1:5.
Miller FJW, 1982 Tuberculosis in children.
Churchill Livingstone, Edinburgh.
Miller FJW, Cashman Joan M, 1958 The origin of peripheral tuberculosis
lymphadenitis. Lancet 1:268.
Miller FJW, Court SDM, Walton WS, Knox EG, 1960 Growing up in Newcastle
upon Tyne. Oxford University Press, London.
Miller FJW, Seal RME, Taylor MD, 1963 Tuberculosis in children.
J A Churchill, London.
Monbrun A, Lavat J, 1949 Expose du rapport:
ophtalmoscopie et dissemination
tuberculeuse. Bulletin Socidt^ Ophtalmologie, Paris Supp 3:796.
Morrison JB, 1970 Resorption of calcification in primary pulmonary
tuberculosis. Thorax 25:643.
Munro WT, 1944 Tubercle bacilluria in the child.
Journal 51:101.
Edinburgh Medical
Myers JA, 1940 Tuberculosis among children and young adults.
Springfield, Illinois.
Charles C. Thomas
Payne M, 1959 Study of the natural history of primary tuberculosis in
children with particular reference to the prevention of morbidity
and mortality. MD Thesis University of Durham, England.
Ranke KE, 1917 Primare, sekundare und tertiare Tuberkulose des Menschen.
Mtinchener Medizinische Wochenschrift 64:305.
Rich AR, McCordock HA, 1929 An enquiry concerning the role of allergy,
immunity and other factors of importance in the pathogenesis of human
tuberculosis. Bulletin of Johns Hopkins Hospital 44:273.
Riley RL, 1982 Disease Transmission and contagion control.
Respiratory Diseases 125: Part 2:16.
American Review
Sdn^cal P. 1950 Primary pulmonary tuberculosis in two children in association
with a fall into sewage contaminated water. Acta Tuberculosea
Scandinavica 24:3.
Simon G, 1943 Some problems in connection with the early X Ray changes in
adult-pulmonary tuberculosis. British Journal Radiology 16:217.
SnaithLM, Barns TEC, 1962 Fertility in pelvic tuberculosis.
Sweany HC, 1941 The age-morphology of primary tubercles.
Springfield, Illinois.
Lancet 1:712.
Charles C. Thomas,
WHO/TB/84.144
page 18
Ustvedt HJ,
infection.
-...
re^a^^on between renal tuberculosis and primary
Tubercle (London) 28:22.
Ustvedt HJ, Ostensen IW, 1?
1951 The relation between tuberculosis of the skin
and primary infection.
... Tubercle (London) 32:36.
Wadla ^Clinical aKd 1969 Spinal n’eninSitidis with radiculomyelopathy
tt p
i 1
Radiological.
Radiological. Journal Neurological Sciences 8:239.
I Pathology and Pathogenesis.
Journal Neurological Sciences 8:261.
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1:359.
b) Pulmonary tuberculosis, Relation of childhood Lancet
infection
to the disease in adults. Lancet 1:417.
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'time-table' of tuberculosis.
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Tubercle (London) 29:245.
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WHO/TB/84.144
page 19
Terminology
Primary focus;
A primary focus is the cellular and structural change occurring in
response to the presence and multiplication of M. tuberculosis (or
M. bovis) at the site of first implantation into the tissues of the host:
the usual site for M. tuberculosis is in a lung and for M. bovis in the
oro-pharynx or intestinal
’
tract.
Primary complex;
The primary focus and associated lymphadenitis.
Tubercle;
When M. tuberculosis or M. bovis invades human tissue the first visible
response is by polymorphonuclear cells. The.*,
The.* widii
within 48 hours monocytes
and epitheloid cells appear and increase in numbers. U
’ / i__ about 7 days
'
Within
some lymphocytes can be seen but, unless the body has been previously
sensitised to tuberculin large numbers do not appear until the second
month. Meanwhile from the third week giant cells begin to form.
This aggregation of cells is the basic let ■*.*i of tuberculosis and is
known as a tubercle.
Caseation:
From about the 10-14 day after infection the cells in the central part of
the developing tubercle begin to lose their outlines and become
amorphous. This death of cells is a reflection of the relationship
between the local multiplication of organisms and the resistance of the
host but the central area of caseation is part of the tubercle. The
caseous area can continue to enlarge and may merge with that of other
tubercles if the pathological process extends.
The caseous material is grey-white in colour and it is this which gives
the macroscopic tubercle its characteristic appearance.
Exogenous reinfection;
The production of a Ituberculous
'
“
‘lesion by a new infection, from another
source outside
the
body
in
a
person
who- has
had1 a primary infection and
.
-- -has remained tuberculin sensitive.
Endogenous exacerbation;
The reactivation of an <old
* * and apparently healed tuberculous lesion
derived from the primary focus, the associated adenitis or the
haematogenous seedings thereof, The term endogenous reinfection is
sometimes used to describe the same process.
Segmental lesion:
The involvement of a pulmonary segment, lobe or whole lung secondary to
bronchial erosion with the aspiration of material from the affected
nodes. The term is descriptive of the extent of pulmonary involvement
and does not denote the histological changes in the affected area.
WHO/TB/84.144
page 20
Hyperinflation (sometimes called obstructive emphysema).
The hyperinflation of a pulmonary segment, lobe or whole lung resulting
from incomplete bronchial obstruction having a ball-valve effect allowing
air to enter but not to leave the affected segment or lobe.
Tension cavity:
If a caseous lesion opens into a bronchus the contents may be coughed up
and a cavity results; . sometimes the communication between cavity and
bronchus will allow air to enter on inspiration but impedes the flow
during expiration. These cavities radiologically appear to be thin
walled and translucent and may quickly disappear with treatment.
ARTICLES
STATE OF THE ART
I. - EPIDEMIOLOGY OF TUBERCULOSIS
K.Styblo*
The main aim of this paper is to summarise, in a simple way, recent studies on the epidemiology of
tuberculosis to give us a better understanding of the way in which tuberculosis behaves and maintains
itself in the community. These studies are also relevant to the planning of programmes for tuberculosis
control in developing countries and for eradication of the disease in developed ones.
The following items will be discussed:
1) The natural interactions between the tubercle bacillus and a human population.
2) Epidemiological indices for evaluation of the overall tuberculosis situation and its trend.
3) The so-called «natural» trend of tuberculosis in developed and developing countries.
4) Impact of present control measures on the tuberculosis situation.
5) Recent, present and future situation of tuberculosis in developed and developing countries.
6) Use of the two basic tools for planning an efficient tuberculosis programme in developing countries
and eradication of tuberculosis in developed countries.
In the present paper only the first two items will be considered. The remaining four will be dealt
b^^!97g^r' J*
211 d myself at the World Conference of the IUAT to be held in Brussels in SeptemIn order to make the present paper easier to understand and more readable, I have tried to keep it as
short as possible. More detailed information on some topics of the paper is given in the appendices. A
comprehensive study «Recent advances in epidemiological research)) will shortly be published in «Ad
vances in Tuberculosis Research)) (1).
1. Natural Interactions between the Tubercle Bacillus and a Human Population
The natural interactions between the tubercle bacillus and a human population can only be studied if
there is no man-made interference. Therefore, post-war routine statistics from developed countries can
not be used for studying this subject, as there has been uninterrupted interference, especially from che
motherapy, which has influenced one or more parameters.**
*
Director Tuberculosis Surveillance Research Unit of the IUAT, P.O.B. 146, The Hague, The Netherlands.
** A parameter is defined as a «constant» indicating the numerical value which links two variables (see below) together.
Parameters are constant under natural conditions only, i.e. without man-rpade interference. They may depend to
some extent upon socio-economic conditions.
Examples of parameters: a «contagiow$» parameter refers to the average number of persons infected with tubercle
bacilli during one year by one source of infection. The disease ratio expresses the proportion of cases in which in
fection with tubercle bacilli leads to the development of a source of infection.
N.B. The other expression to be clarified is the term wvariablex. Such quantities are not constant but vary with
time in a given population and among various population groups. Two important variables in tuberculosis epidemio
logy are prevalence and incidence.
Bulletin of the International Union Against Tuberculoaia, VoL 53, No. 3, 1978.
An extensive study of morbidity in contacts (more than 8,000 intimate and I 1.000casual contacts)
was recently carried out in British Columbia and Saskatchewan (Canada) (7). Tuberculosis was rare in
intimate contacts of culture-negative sources, and no cases of tuberculosis were observed among casual
contacts of culture-negative sources. Disease rates were also substantially lower (0.8% for whites and
2.3% for Indians) among intimate contacts of culture-positive cases than among intimate contacts of
smear-positive sources (5.9% and 8.2% respectively).
These observations confirm once more that the bacillary status of the patient decides the extent to
which he can transmit tubercle bacilli to other hosts. For the purpose of this study, patients with smear
positive tuberculosis will be considered as sources of infection, and other patients will not.
(iii) The ^contagious) parameter is computed as:
annual tuberculosis infection rate (%)
innn
prevalence of sources of infection (per 100,000)x
Some estimates of the «contagious» parameter are given in Appendix II.
Our best estimate is that about 10 persons are infected, on average, with tubercle bacilli during one
year by one unknown smear-positive case of pulmonary tuberculosis.
1.2
DEVELOPMENT OF INFECTIOUS TUBERCULOSIS FOLLOWING INFECTION WITH TUBERCLE BACILLI
The risk resulting from tuberculous infection is greater for persons not previously infected than for
those who have been previously infected with virulent tubercle bacilli. We shall refer to the disease fol
lowing primary infection as «primary» tuberculosis. The disease which occurs in those previously infec
ted with tubercle bacilli will, for our purpose, be called «secondary» tuberculosis*. In epidemiological
studies it is necessary to adopt a precise working distinction between «primary» and «secondary» pul
monary tuberculosis. Dr. Holm has suggested the following:
(a) Any pulmonaiy tuberculosis developing and being diagnosed during the first five years following
primary infection is classified as «primary» tuberculosis.
(b) Any pulmonary tuberculosis diagnosed more than five years after primary infection is classified
as wsecondaryw tuberculosis.
(a) «Primary) Tuberculosis
If the annual tuberculosis infection rate is high, as it was in developed countries before World War II
and still is in many developing countries at present, «primary» tuberculosis occurs mostly among chil
dren. If the risk of infection is low, a low rate of «primary» tuberculosis will occur among children as
well as adults.
Extensive information on the bacteriological status of children suffering from «primary» tuberculosis
is available in many developed countries where BCG vaccination has not been practised. All the statistics
show that few children with «primary» tuberculosis develop bacillary pulmonary tuberculosis (in Norway
2.6%; in Denmark 4.9%; in The Netherlands 0.9% — based on cases reported during the period 19511968); and very few children develop smear-positive (infectious) tuberculosis which is considered to be
the most important source of infection.
However, much less is known about the development of the disease, and especially its bacteriological
status, if the primary infection occurs during adolescence. As regards higher age-groups, very little is
known.
Information from X-ray and tuberculin surveys carried out in Saskatchewan since 1955 made it pos
sible to study the breakdown risk in persons who acquired primary infection during adolescence and
♦
This nomenclature is used for brevity’s sake.
meaning here.
The terms «primary» and «secondary» tuberculosis have no clinical
the programme should be primarily focused on decreasing the sources of infection (case-finding and
treatment).
P auU tS WhlCh WaS observed in 1116 1960s, has been ably reviewed by Canetti (14). Re.• s,.e s jave now
J some statistical evidence on the relative importance ofcndogc?. a<-tIva'1°n and exogenous re-infection for secondary tuberculosis. Reference is made toSutheriana s review (J).
We have also collected some direct evidence on the role of endogenous exacerbation and exogenous
re-infection (Appendix III).
On the basis of the anatomical, bacteriological, statistical and epidemiological studies there is reliable
evi ence t at exogenous re-infection does play a role m the pathogenesis of bacillary pulmonary tuber016 10 6 °f exogenous re*infection becomes evident only if the tuberculosis infection
13J
THE FATE OF THOSE SUFFERING FROM INFECTIOUS TUBE RCULOSIS
It is of great epidemiological interest to know the natural history of infectious pulmonary tuberculo
sis, i.e. the chances of recovery and death from the disease in the absence of chemotherapy. There is an
e*Pres.sl0n or this in the lethality, by which is meant that proportion of the number of notified patients
who die of pulmonary tuberculosis.
xx
tOj^j
cases not given chemotherapy were obtained from several sources.
io^ind i
i U ,s.tudled the occurrence of pulmonary tuberculosis in Denmark during the period 19251934 and its lethality during an observation period of 8 years. A total of 17,189 men and 22,190 women
were notified as having pulmonary tuberculosis (bacillary and non-bacillary) during the period under
study. She produced a simple survival table, for males and females separately (Table 1). By placing the
((sumvorsa (i.e. those who had not died of pulmonary tuberculosis) in relation to those who had died in
the 2nd, 3rd 4th, etc. years of observation, she arrived at the lethality percentages. Putting the original
total of notified cases at 1000, as in an ordinary life table, and by means of the lethality percentage, and
calculating how many of these were left after the 2nd, 3rd, etc. observation years, she obtained the surviAccording to this table after the expiry of the Sth year after notification, over half of the cases did
not die from pulmonary tuberculosis. It must be stressed, however, that the study refers to both bactenologicaily confirmed and unconfirmed cases together for all ages. For open (bacteriologically con
firmed) cases the lethality was higher than that given in Table 1, namely about 65% for men and 66% for
women at 4 years of follow-up.
Springett in Great Britain recorded the fate of 571 cases of bacillary pulmonary tuberculosis notified
cnc^e Pr^<hemotherapy Period (before 1947) (21). After the expiry of the 4th year after notification
ba^lH 1116 patientS Were dead’ 26<7£> Were wcured>> and
remaining 19% were still excreting tubercle
Rutledge and Crouch (22) analysed the fate of 1,229 sputum-positive patients admitted to a sanato
rium in the United States and found that 66% were dead at 4 years.
In India, a longitudinal study was conducted in the 1960s in order to observe the natural history of
pulmonary tuberculosis under the socio-economic conditions existing in an area that was not yet benefitUng from any of the active control measures - such as BCG vaccination and chemotherapy (23). Of the
178 bacteriologically confirmed cases found at the first survey, 126 could be followed up at three sub
sequent surveys carried out over the five following years. At the end of the 5-year period. 49% were
dead, 33% were «cured» and 18% remained sputum-positive.
Thus, one can conclude that about two-thirds of the patients suffering from smear-positive tuberculo
sis will die from tuberculosis, in the absence of chemotherapy, during 4-5 years after die diagnosis of the
disease.
I
2. Epidemiological Indices for Evaluation of the Overall Tuberculosis Situation
Two epidemiological indices are currently considered the most relevant for assessing the tuberculosis
problem and its trend in a given community:
The incidence of tuberculous patients excreting tubercle bacilli demonstrable by direct smear exami
nation.
The annual tuberculosis infection rate (the risk of tuberculous infection).
2.1
THE INCIDENCE OF TUBERCULOUS PATIENTS EXCRETING TUBERCLE BACILLI DEMONSTRABLE BY
DIRECT SMEAR EXAMINATION
Theoretically, the incidence of tuberculous patients excreting tubercle bacilli demonstrable by direct
smear examination is a good epidemiological index which reflects the magnitude of the tuberculosis pro
blem in a given community, and if observed over several consecutive years it also shows the trend in the
tuberculosis problem. However, its reliability is limited, to a larger or smaller extent, by several factors:
The incidence rate is closely related to the quality and extent of case-finding activities and bacriological examination.
- A number of cases are never notified either through error or because the disease may have healed
spontaneously without any medical interference.
- The calendar trend in the total incidence of smear-positive cases is an underestimate of the trend
of the recent tuberculous disease, because in middle-aged and elderly persons cases keep appear
ing due to endogenous exacerbation.
- When the incidence in a country becomes low, the index may be unreliable because it is based on
very small numbers.
-
In fact, the first current epidemiological index — the incidence of tuberculous patients excreting tu
bercle bacilli demonstrable by direct smear examination - is not used at present in most developed
countries. The currently reported notification data in most developed countries are particularly defi
cient in bacteriological examination, as they do not report whether patients are smear-positive and/or
culture-positive, or even whether such an examination has been performed (24).
On the other hand, most of the developing countries have been trying to follow the WHO recommen
dation and focus attention on smear-positive cases of pulmonary tuberculosis. However, in nearly all de
veloping countries there is still a large and varying proportion of undiagnosed cases, so that notification
data on the number of new smear-positive cases give inadequate information on the tuberculosis situa
tion and its trend.
2.2 THE ANNUAL TUBERCULOSIS INFECTION RATE (THE RISK OF TUBERCULOUS INFECTION)
There is now general agreement that the annual tuberculosis infection rate is the best single indicator
for evaluating the tuberculosis problem and its trend in developed and developing countries. It is an in
dex which expresses the attacking force of tuberculosis within the community and, unlike mortality and
notification rates, is independent of the procedures and of the intensity of the tuberculosis programme.
To obtain reliable estimates of the annual tuberculosis infection rates and changes in a particular
period, several tuberculin surveys are required at intervals, each in a representative sample of non-BCGvaccinated subjects of the same age, tested by the same technique.
The advantage of summarising the tuberculosis position in a country in terms of tuberculosis infec
tion rates in particular years is that these rates provide a readily intelligible measure of the impact of tu
berculosis on the conununity at different times. This approach also facilitates comparisons of the tuber
culosis situation in different countries. Moreover, knowledge of the trend of annual tuberculosis infec
tion rates enables comprehensive predictions to be made, both of the prevalence of tuberculous infection
and of the expected incidence of tuberculosis in die population at different ages. This provides guidance
on the likely magnitude of the tuberculosis problem in a country during the following ten to fifteen years.
In develop1 ng countries, where the risk of infection is still high, a relatively small sample of children
would sulhce for the estimation of the tuberculosis infection rate, of the order of 3.000 to 4,000 child
ren aged about 10 years. Care should be taken to exclude from the sample children who have already
had BCG vaccination.
However, in countries where the prevalence of tuberculous infection is low. and has been decreasing
rapidly it will be necessary to test many more unvaccinatcd children with BCG, e.g. 15.000 to 20.000
aged 15 years. A simple method of survey would be to pick a sufficient number of schools at random
and test all children in these schools in the chosen age-group every five years. The most convenient
approach would be to test about one-fifth of the selected schools each year, so that about 800 children
couU t y
eaCh year in a devel0Ping country, and about 3,000 to 4,000 each year in a developed
One considerable problem in interpreting the results of a tuberculin survey is how to assess what con
stitutes tuberculous infection and what constitutes other mycobacterial infection in countries where the
latter infection is present. Methods have been developed which allow, to some extent, separation and es
timation of that proportion of the population infected with virulent tubercle bacilli.
In countries where BCG vaccination has been obligatory at birth for more than 10 years, the level of
tuberculin sensitivity in young children provides no guide to the risk of infection, because sensitivity fol
lowing natural infection cannot be separated from sensitivity following BCG vaccination. The only way
of overcoming this difficulty is to select a representative sample of new-born children, to defer BCG vac
cination of this group for (say) six years, and to assess the development of tuberculin sensitivity during
this period in this unvaccinated group. Arrangements for chemoprophylaxis for any of the group who
acquired a tuberculous infection would ensure that the above procedure was ethically acceptable.
♦ * *
The topics under 3 to 6 of this paper will be presented at the World Conference of the 1UAT, in Brussels,
Belgium, in September 1978.
Table 1
SURVIVAL TABLE FOR CONSUMPTIVES IN RESPECT OF DEATHS FROM
PULMONARY TUBERCULOSIS. 1925-1934.
Males
Average period
of observation
Total
notified
cases
Of which died of 1000
notified
___ Total
(years)
0.5
1.5
2.5
3.5
4.5
5.5
6.5
7.5
17,189
12,065
10,923
10380
10,030
9,793
9,662
9,569
Females
%
Sur
vived
Died
No.
5124
1142
543
350
237
131
93
72
29.8
9.4
5.0
3.4
2.4
1.3
1.0
0.8
1000
702
636
604
583
569
562
556
298
66
32
21
14
7
6
4
Total
notified
cases
22,190
15,555
13,897
13,110
12,650
12,355
12,194
12,087
Of which died of 1000
notified
___ Total
No.
%
Sur Died
vived
6635
1658
787
460
295
161
107
53
1000
701
626
591
570
557
550
545
29.9
10.7
5.7
3.5
2.3
1.3
0.9
0.4
299
75
36
21
13
7
5
2
Source of information: Lindhardt, Marie: The statistics of pulmonary tuberculosis in Denmark, 19251934. A statistical investigation on the occurrence of pulmonary tuberculosis in the period 1925-1934,
worked out on the basis of the Danish National Health Service file of notified cases and of deaths. Ejnar
Munksgaard, Copenhagen 1939 (p. 100).
REFERENCES
(1)
(2)
(3)
tt'S ,U=XV£.^
(4)
mk^o7^‘A’: EP,deni,oI°Sical ^nds in low-prcvalence countries. Bull Int Un Tuberc, 49:128-
(5)
b“‘'»■h'»'
°fpUlmOnary '^erculosis in relation to sputum
status.
(6)
Hertzberg.C.; The infectiousness of human tuberculosis, pp. 57-89. E. Munksgaard, Copenhagen,
(7)
Bu7lmWUn Tuberc ^O ^l'oS
K" ContaCtS ofcases of active Pulmonary tuberculosis.
(8)
(9)
I-
Ew” T^rX w'eVSSjS?: R :
°f “b“d' b““
,967-
entas of chemo.
(10) Sutherland,
I. and Payers,
BuU
Int Un'Tuberc,
SO-iosi
"1915^ ass0clatl0n of the risk of tuberculous infection with age.
J).. 11 T - . w t
.
(11) Barnett, G.D. anrStybloV' ~
xm ^*2*SK
(12) British Medical Research Council:
( } ?o°Xh °'i U'db/Ck’ EErickaon-P A-: Epidemiolo^cal basis of tubemulosis^cation 10
BuS W?d?H^SOrg,41?95jei3r;S19069‘UberCU1°SiS “ ‘1'e POpU'ati°n °f 3 '“-Prevalence area.’
(16)
G D'’ G^;ybowski>S. and Styblo, K.: Present risk of developing active tuberculosis in Sas
c^Jl ^vac^ordlngu,!oprevioustuberculin andx’ray status. Bull Int Un Tuberc 45-51-74 197]
‘ ’ 3SK&ii^W- ■*** H““ T"b"“'“sT.&Xuo vol:
(,8) RepoSrUC76J974d|96P,hii'P’R'N': Dedine of d16 Olbe,culosis ePid'mic in Alaska. Public Health
‘21,)°) as&'HteBiSr'
mwi- e- ’*«**»o—x -uchhe. .f
Marie;, The statistics of pulmonary tuberculosis in Denmark, 1925-1934 A statistical
nn thpEt a °n the occunence of pulmonary tuberculosis in the period 1925-1934 worked out
E. MunksgTarlCopeZgenJ^
°fnOtified
311(1 °f deaths-’ PP' 76->01'
(21) berlleS,e52:7V3H87 J^r31 r'SU'tS dUn’ng 1113 introduction
chemotherapy for tuberculosis. Tu-
®>
<m>
°f s°“,h
'
Appendix I
HOW TO ESTIMATE THE ANNUAL TUBERCULOSIS INFECTION RATES
There are two steps in assessing the annual tuberculosis infection rates:
a) Estimation of the percentage decrease in the annual risk of infection using Appendix Table C of
TSRU Report No. 1 (2).
Appendix Table 1 shows a part of this table. The percentage decrease in the annual tuberculosis in
fection rates can be estimated if two or more prevalence figures are available for subjects of the same
age. If the prevalence of infection in children aged, say, 10 years was, for instance, 14.0% in 1972, and
11.0% in 1977, entry 26 in the table is divided by 5 (the interval in years between the later (1977) and
the earlier (1972) surveys) to give the approximate annual percentage decrease, which is about 5% in this
case. The approximate annual percentage decrease is needed for use in Appendix Table B of TSRU (2).
Appendix Table 1
Decrease in infection risk corresponding to various percentages infected by the same age
at two different surveys (from TSRU (2), Appendix Table C, p. 104)
Percentage of persons
already infected at the
time of
the
earlier
survey
7.0.
7.5
8.0
9.0
10.0
11.0
12.0
13.0
14.0
etc.
the later survey
6.5
7.0
7.5
8.0
9.0
10.0
11.0
12.0
8
15
22
34
45
55
64
73
81
7
14
26
37
47
57
65
73
7
19
30
40
49
58
66
12
23
33
43
51
59
11
21
30
39
47
10
19
28
36
9
18
26
9
17
8
Divide the entry in the table by the interval in years between the surveys to obtain
the approximate annual percentage decrease for use in Appendix Table B.
b) Using the estimate of the percentage decrease, Appendix Table B of the same report provides direct
assessments of the risk of tuberculous infection in two calendar years, namely the year in which the pre
valence of tuberculous infection was determined, and a few years earlier (Appendix Table 2). In the
above-mentioned case one consults Appendix Table B for children aged 10 years, 3rd column (5% annual
decrease in risk of infection each year). The Table indicates the following annual tuberculosis infection
rates:
1972: 1.09% (and in 1962: 1.78%)
1977: 0.84% (and in 1967: 1.38%)
u j 6 w? <
5-’:
(o(
..
—
S
Appendix Table 2
•.k/ia?3- PrCrCe"l^C .risks of tubcrculous infection corresponding to the percentage
alngdy mfected by tire age of 10.5 years (from TSRU (2), Appendix Table B. p 92)
Approximate percentage decrease in risk of infection each year
1
Percentage already
infected
Risk
this
year
1.0
1.5
etc.
11.0
12.0
13.0
14.0
etc.
Source of information:
3
Risk
10
years
ago
Risk
this
year
0.10
0.08
0.12
0.09
0.14
0.15
1.05
1.15
1.25
1.35
1.27
1.38
1.49
0.94
1.03
1.12
1.16
1.21
5
Risk
10
years
ago
Risk
this
year
7... 13
Risk
10
years
ago
0.11
0.07
0.16
0.11
0.12
0.18
1.27
0.84
0.92
1.00
1.09
1.38
1.51
1.65
1.78
1.39
1.51
1.64
etc.
Bleiker, M.A.: T “
Int. Tuberc. 49, 128-135’1974? trends in low prevalence countries, Bull. Un.
Appendix II
SOME ESTIMATES OF THE «CONTAG1OUS» PARAMETER
'■“ <■'» i-' pAppendix Table 3
Relationship between the annual tubercU)osis infection rates and mortality from tuberculosis
(all forms) (from Styblo, 1)
‘vuiuMi
Year
The annual
tuberculosis
infection rate
(1)
1922
1925
1928
1931
1934
1937
Death rate from
tuberculosis
(all forms)*
per 10.000
(2)
0)/(2)
Infections
per death
(3)/ (4)**
Infections per
source of infection
(3)
(4)
11.5
10.0
8.8
7.1
5.6
4.8
52.3
51.3
49.7
52.4
56.4
56.0
13.1
12.8
12.4
13.1
14.1
14.0
53.0
13.2
602
513
437
372
316
269
J 921-1938
” RatioMonalhy':'Pre^Ieicetf ‘sn^r^^^
The annual tuberculosis infection rate was 602 per 10,000 in 1922 and decreased to 269 per 10.000
in 1937. The average death rate from tuberculosis (all fonns) per 10,000 was 1 1.5 for 1921-1923. and
gradually decreased to 4.8 for 1936-1938. The third column of Appendix Table 1 gives the proportions
between the annual tuberculosis infection rates and death rates from tuberculosis from 1922, 1925,...
1937, ranging from 49.7 to 56.4. In order to obtain estimates for the «contagious» parameter concern
ing prevalence (and not mortality),estimates related to mortality rates (column 3 of Appendix Table 3)
were divided by four, as mortality from tuberculosis was assumed to be one-quarter of the prevalence of
smear-positive cases. The estimates derived from mortality (the last column of Appendix Table 3) indi
cate that about 13 persons (ranging between 12 and 14) were infected with tuberculosis during one year
by one source of infection in the Dutch community in the period 1921-1938.
The «contagious» parameter may depend, to some extent, on various socio-economic conditions; one
should therefore attempt to obtain values for different populations. Sutherland and Payers (10) calcu
lated annual tuberculosis infection rates for Lesotho and Uganda. The annual infection rates at age 10
years, applied in 1960, were 410 per 10,000 for Lesotho and 220 per 10,000 for Uganda. These rales
were related to the prevalences of smear-positive cases of pulmonary tuberculosis observed in the original
WHO surveys carried out in Lesotho in 1957 and Uganda in 1958. It was estimated that about 14 per
sons in Lesotho and 10 persons in Uganda were infected with tuberculosis by one source of infection (1).
Appendix HI
SOME DIRECT EVIDENCE ON THE ROLE OF ENDOGENOUS EXACERBATION AND
EXOGENOUS RE-INFECTION
1) The present very low risk of tuberculous infection in a number of developed countries enables us to
measure the effect of endogenous exacerbation, provided that the tuberculin status of the population is
known before the development of bacillary tuberculosis.
A large and representative segment of the Danish population, a total of over 626,000 persons aged 1544 years, was examined by a standardised technique in 1950-1952. The examination consisted of a single
Mantoux test (10 TU RT22) and a 35-mm photofluorogram. Horwitz, Wilbeck and Erickson reported
the risk of developing respiratory tuberculosis during the first 12 years of follow-up (15). Among the
286,000 natural reactors with no X-ray lesion, the annual rate of 23 per 100,000 was observed (bacillary
and non-bacillary cases together).
The risk of developing bacillary pulmonary tuberculosis among those with aprevious positive tubercu
lin; negative X-ray» was studied in Saskatchewan (Canada) during 1960-1969 (16). In 621 (67%) adults
with new active pulmonary tuberculosis reported during the period under study, full information was
available on the previous tuberculin and X-ray status. (The intervals between the earliest «positive» tu
berculin test result and the diagnosis of bacillary pulmonary tuberculosis were as follows: more than 5
years - 71%; 4-5 years - 10%; less than 4 years - 19%.) The probable average annual risk of develop
ing bacillary pulmonary tuberculosis in those with ((previous positive tuberculin; negative X-ray» was
approximately 15 per 100,000.
In The Netherlands in 1973-1975, the incidence of bacillary pulmonary tuberculosis cases among
those aged 65-74 years was 14 per 100,000, and in persons aged 75 years or more it was 25 per 100,000.
It may be assumed that nearly all subjects aged 65 years and over in the early 1970s must have been in
fected with virulent tubercle bacilli during their childhood or young adulthood because tin risk of tuber
culous infection was very high at the end of the last century and during the first two decades of this cen
tury. The role of exogenous re-infection in The Netherlands in the early 1970s can be disregarded, as it is
estimated that only 30 persons per 100,000 were re-infected annually with tubercle bacilli at that time.
Thus, the incidence rate of 14 per 100,000 among those aged 65-74, and 25 per 100,000 in subjects aged
75 years or more was to a large extent due to endogenous exacerbation.
Thus there is no doubt that in man, long after the last infection with virulent tubercle bacilli, there
still exists a risk, a small one. of developing bacillary pulmonary tuberculosis. In the past, it was not pos
sible to measure reliably the level of this risk because of a considerable and changing risk of exogenous
re-infection. The role of the latter risk can be disregarded at present.
The observations mentioned above suggest that the annual risk of endogenous exacerbation causing
bacillary pulmonary tuberculosis is, on average, between 15 and 25 per 100,000 natural reactors.
2) An observation showing the impact of the high levels of tuberculosis infection rates (and the role of
exogenous re-^ifection) on the magnitude of the tuberculosis problem in the respective populations, and
the close relationship between these two variables, will be mentioned.
The observation concerns Eskimos in Alaska, Greenland and the North-West Territories of Canada.
The annual incidence rates of tuberculosis among the native population were extremely high in all three
circumpolar areas in the early 1950s, in the order of 2.0% of new (mostly bacteriologically confirmed)
cases of tuberculosis each year (17). The annual tuberculosis infection rate in Alaska estimated by
Comstock and Philip (18) was, at that time, as high as 25% (!), so that the vast majority of all Eskimos
were infected in childhood.
The dramatic decreases in mortality and morbidity rates observed after the introduction of effective
control measures in the early 1950s have been preceded, naturally, by a sharp decrease in the tuberculo
sis infection rates. However, die decreases in the incidence of tuberculous disease did not occur only
among children and young adults but at all ages, i.e. also in persons previously infected. Thus, the same
number of infected subjects aged, say, 35 years or more, in the North-West Territories of Canada pro
duced 0.6% bacillary cases each year during 1966-1968, whereas the incidence was only 0.35% each year
in 1972-1974 (17, Figure 1). In Greenland, the rates in the same age-group fell from nearly 3.0% in
1955-1957 to less than 1.0% in 1963-1965 (19). Also, in Alaska a sharp decrease in the number of new
cases of tuberculosis can be observed, namely from 762 in 1952-1954 to 119 in 1970-1972 (by'84%) in
those aged 25-44, and from 436 to 116 (by 73%) in those aged 45 years or more, during the same period
of observation (17).
There is no doubt that the higher risk of infection in the early period must have contributed substan
tially, by exogenous re-infection, to the higher morbidity at that time.
Figure 1
Incidence of bacillary pulmonary tuberculosis (rate per 10,000) by age among Eskimos in the
North-West Territories of Canada in two time periods: 1966-68 and 1972-74
(Grzybowski et al., 17)
RATE
PER 10.000
130
120 ■
110
100 ■
90 ■
80 •
70 -
60 -
1966 - 68
50 ■
40 ■
1969 - 74
30 20 ■
10 ■
0
0 "r--------10
20
30
AGE IN YEARS
40
50
RECENT ADVANCES IN TUBERCULOSIS EPIDEMIOLOGY WITH REGARD
TO FORMULATION OR RE ADJUSTMENT OF CONTROL PROGRAMMES
K. STYBLO and J. MEIJER*
Recent epidemiological studies on tuberculosis, particularly those conducted by the Tuberculosis
Surveillance Research Unit, help us to understand better the way in which tuberculosis behaves and
maintains itself in the community. We shall mention sudies which are related to the following items:
- the so-called «natural» trend of tuberculosis,
• the epidemiological situation of tuberculosis in the middle of this century, at present and after
the turn of this century,
• impact of the present control measures on the tuberculosis situation.
- use of the basic tools for tuberculosis control at present and in future.
We cannot deal with the subjects in detail. A comprehensive report is shortly to be published in
wAdvances in Tuberculosis Research)) (1).
1. The «naturab> trend of tuberculosis
Figure 1 shows that tuberculosis mortality in Czechoslovakia, the Netherlands and Norway has
Rate per
100.000 popul.
400 —
CZECH COUNTRIES
300 —
NORWAY
200 —
THE NETHERLANDS
150 —
100 —
90 BO 70 60 50 —
40 —
r
1900
T
1905
1910
1920
I
I
I
1915
1925
1930
1935
1940
Figure 1. Tuberculosis death rates from all forms of tuberculosis in Czech countries, the Netherlands
and Norway, 1900 -1940.
• Koninklijke Nederland** Central# Verenlfling Tot Bestrijding Der Tuberculose (KNCV), P.O.B. 146, The
Hague, The Netherlands.
1
The annual tuberculotit infection rate indicate* the proportion of the population being infected or rein
fected in the cour*e of one year.
Bulletin of the Intemitionil Union Atxlnrt TubercuJotix. Volume 53, No. 4, December 1978.
been decreasing from at least the turn of this century. This was the case in most other developed
countnes during that period.
The observed decrease was 4-5% annually. It was not connected with mass BCG vaccination,
chemotherapy or mass radiographic surveys as these measures did not exist at that time. Improve
ment of socio-economic conditions, general anti-tuberculosis measures and treatment, including iso
lation in sanatoria, all may have played some part in the decline of tuberculosis but one cannot
assess their relative contributions. Ifwecall thisobserved declining trend «natural», it is only because
we have no better word to indicate that it was probably not brought about by specific anti-tuberculosis measures.
xt P16 saiPe decrease is mirrored by the trend in the annua! infection rare1 which is shown for the
Netherlands for the period 1920 to 1940 (Fig. 2).
Annual infection
rale (per cent)
- 10
-
8
7
-
6
- 5
ANNUAL INFECTION RATES
-
4
3
2
Rate per
100.000 popul.
150
130 Z
100 —
MORTALITY RATES
1
80 70 60 50 —
40 30
20
10
1920
r
I
1925
T
1930
I
1935
1940
Figure 2. Annual tuberculosis infection rates and tuberculosis death rates in the Netherlands,
1920'1940:
The mortality rate fell by 5.7%, and the infection rate by 5.4% per year between 1920 and 1940.
We have introduced the annual infection rate in this context because we cannot use mortalitv sta
tistics when discussing the «natural» trend of tuberculosis in developing countries.
Table 1. Estimated number of persons infected with tubercle bacilli in the Netherlands in 1910
1920........... 1970 and 1975.
Year
No. of infected/year
(per J00,000population)
1910
1920
1930
1940
1950
1960
1970
1975
11,310
6,690
3,920
2,080
530
133
45
25
The third curve shows similar figures to be expected in the year 2005. Only 25% of those aged
70 years will have been previously infected and about 50% of those aged 80 years.
The percentage of infected subjects for the years 1945, 1975 and 2005 given per age group in
Figure 5 can also be expressed in terms of the general population. The upper part of Figure 6 shows
the composition of the general population in the Netherlands in 1975, by age. The lower part of
per cent
100 —i
80 —
60 —
1945
40 —
1975
20 —
0
0
2005
I
10
I
20
r
30
I
40
T
so
T
60
T
70
"1
80 years
Figure 5. Estimated prevalence (per ct.) of tuberculous infection, by age-groups in 1945, 1975
and 2005, the Netherlands.
Figure 6 shows that between 1945 and 1975, the proportion of the total population infected with
tubercle bacilli fell from 59% to 26%. In the year 2005, the proportion of infected is expected to
be 5%.
In our opinion, similar trends may be expected in other developed countries.
per cent
30 —|
25 —
20 —
15 —
10 —
5 —
0 -1
0-14
25-34
15-24
35-44
45-54
55-64
> 75 years
65-74
per cent
26
24 —
22 —
20 —
18 —■
COMPOSITION OF THE GENERAL
POPULATION BY AGE
16 —
14 —
12 —
10 —
8 —
INFECTED IN 1945
(59 % of the total
population)
6 —
INFECTED IN 1975
(26 % ot the total
population)
4 —
INFECTED IN 2005
(5% of the total
population)-^
2 —
0
T
0
T
10
T
T
20
T
T
30
* r
40
T 1
r
50
60
T
T
70
*
I
80 years
Figure 6. F'
'
infection per 100.000 ^tFn In 1945F975and 2005. 7/,e bands'
There is evidence that in some developing countries a moderate decrease has occurred in the
tuberculosis infection rate but, in others, the risk remains nearly'consent
I or decreases very slowly.
narl^1iannUal ,nfe!:lJOvn rale ^mains constant, die proportions of the population infected'
I at a
particular age remain the same for each cohort.
on tuberculosis mortality. The main
these countries comes from the results
the'uend*
?S-ing *as.rePeated several years afler the WHO survey, so
often there waTli de f Jnv H
arevirtualTy no ' am’r
""?•
lnterval can be estimated. Figure 3 shows that
we'; now' hat" 7^ i"^"'On ra‘eS; in
C°U"‘
‘h-
are taken up a decrease J//
and K. Stybfo’s article, ibidem,
7a.
h
'/,n SUch countries specific control measures
Urban d‘S,ricU: See Fi8ure 2 of M' A’ B!eiker
Risk of T0
infection (per cent)
• LESOTHO
INDONESIA
KENITRA
UGANDA
ZAIRE
■-----FES
SURINAM
1
VENEZUELA •
0.5 —
ARGENTINA
THE NETHERLANDS
0.1 —
0.05 —
0.01
I
1950
1
1
1 I
1955
1
1
1
1950
i
I
I
I
I I I I
1965
1
I I
|
I
I
1970
1975
iigiire 3. Estimated annual risk of tuberculous infection, 1950 • 1971 or 1975
Z
°f lubeKulosis in the
of this century, at present and after
We shall focus on the size of the tuberculosis problem and on its trend. We shall do (his not bv
fhl^h n8hd u,a’ SUCh.aS ln?.ldence flEU,es from differentcountries, as these data are not always relb
culosis p^bkm^nd'.ts"^^
tUberCU,°SiS infeCli°n rate as *= ind« of the size of the tuberWe now
on ^annual infection rates and their trends in 6 countries or areas, as
shown
in have information on
snown in Figure 4. Two main conclusions are drawn:
have no data on the impact of control measures on
the tuberculosis situation for developing counInes. So we will only discuss developed countries.
per cent
40 —i
COMPOSITE AFRICAN AGE DISTRIBUTION (ECA)
35 —
30 —
25 —
20 —
per cent
42 —
15 —
40 —
10 —
38 —
5 —
36 —
0—
34 —
0-14
15-24
25-34
35-44
45-54
55-64
65-74
> 75 years
32 —
30 —
28 —
26 —
24 —
22 —
20 —
COMPOSITION OF THE GENERAL
"AFRICAN" POPULATION
18 —
16 —
14 —
12 —
10 —
INFECTED BEFORE 1980
(45 % of the total
population)^
8—
6 —
4 —
INFECTED IN 2010
(28% of the total
population)
2—
0
„°
1
’»
1
2<>
1
30
1
40
I
50
I
M
I
70
I
80 years
L-rn«h;Mn tr.yi’1g.t0 assess l,1ie imPact of specific control measures in developed countries one has to
mCP.
m’nd 116 <<natlIraI,> decline, which has already been mentioned P The effects’of control
measures are • so to speak - superimposed on the «natural» trend.
r
The two basic tools used for tuberculosis control are
BCG vaccination and case-finding/treatmcnt.
3.1. BCG vaccina tion
unv^c^nVted children6 Ardirec' effe5tS Of BCG’<ven at ages 15‘29 yeais- on tuberculosis among the
K-?!
f vacclnated parents. The trend in the incidence rates of tuberculosis fall
S dZ oVthe ^eago d^ a%d 5;14tin the Ne*eriands where mass
va
eadv 1950\ (F o o t,
d r 33
‘n N°™Jay where “ had been given to school-leavers since the
arty 1950 s (Fig. 9, shown for children aged 04 years only). We have also made a theoretical
pros™,.
Rate per
100,000 popul.
100 —
80 70 60 50 —
NORWAY
age 0-4 years •
40 -
\/
30
/\
20
THE NETHERLANDS
age 0-4 year?
10 —
8 7 6 -
5 —
4 -
3
2-----1951
r~r
1953
r « r >“r * r •I I T
1955
1957
1959
1961
^rland^O]95/a!%n63f luberculo5is (a" forms> in chi'dren
1963
1965
1977
0 - 4 years. Norway and the
The main error in the postulate that BCG vaccination would have a considerable impact on the
transmission of infection is due to the incorrect assumption that a case of tuberculosis prevented
by BCG vaccination is identical with a prevented source of infection. However, more than 95'#
of tuberculosis cases in children, and 75% of cases in subjects aged 15-29 years which should have
been prevented by BCG vaccination, are zmeat-negative. As the high protection induced by BCG
vaccination is limited in time, the vast majority of newly developed smear-positive cases of pulmo
nary tuberculosis among the general population cannot be prevented by mass BCG vaccination;
3.2. Case-finding/Treatment
The most powerful weapon in tuberculosis control is case-finding and chemotherapy, It is
considered as an entity, as case-finding is a preliminary to treatment and cure.
It is easy to measure the effect of chemotherapy in a group of bacillary patients. But what is its
effect on the overall tuberculosis situation? In other words: to what extent do case-finding and
chemotherapy influence the infection rate? This is more difficult to answer as the trend in the
tuberculosis infection rate mirrors several factors: (I) the «natural» trend; (2) some effect of BCG
vaccination; and (3) the effects of case-finding and chemotherapy. Even if we observe those deve
loped countries where no mass BCG vaccination was done, we shall not be able to estimate the
«pure» effect of case-finding/treatment but can only make an intelligent guess.
Our best estimate is that case-finding and treatment in developed countries during the last two or
three decades may have accelerated the decrease of the problem by 7-3% annually. This percentage
superimposed on the 4-5% annual «natural» decrease results in a total decrease in the tuberculosis
infection rate of about 11-13% each year, as shown previously (Fig. 4). Such a decrease was observed
both in developed countries with and those without a mass fcG programme.
4. Use of the basic tools for tuberculosis control at present and in the future (here we return to the
separa te presen ta tion for developed and developing coun tries)
The two basic tools used for tuberculosis control are BCG vaccination and case-finding/treatment.
In developed countries mass BCG vaccination will be discontinued when its complcations out
weigh its benefits. In the Netherlands with no BCG vaccination, the present annual rate of the
disease is about 4 per 100,000 in children aged 0-14 years. In this situation, mass BCG might do
more harm than good.
Chemoprophylaxis is not discussed in our contribution, as we think that it will have a very limited
use in future. It will continue to be given to converters in high risk groups, such as contacts of
smear-positive sources.
We shall not go into the subject of chemotherapy. There is evidence that at least in some deve
loped countries, the results of chemotherapy observed under routine conditions are nearly as good
as those obtained in controlled clinical trials (3,4). However, we would point out the danger of the
disappearing know-how on chemotherapy among the medical profession.
Diagnosis of the continuously decreasing number of new cases of tuberculosis will remain the
most difficult problem. Physicians will «forget» tuberculosis in their daily practice because they will
seldom see it. In some developed countries, three-quarters of the general population are at present
uninfected and thus tuberculin-negative. Such countries should introduce wide usage of the Mantoux
test into the daily work of some hospital departments and other health services.
It seems unavoidable that some persons with symptoms caused by tuberculosis will seek medical
advice too late or not seek it at all. Also, in a proportion of cases, the doctor’s delay in diagnosing
tuberculosis may be considerable.
•
It goes without saying that mass indiscriminate radiography will have no place in any future
tuberculosis programme.
OO*)
In developing countries, case-finding and treatment of smear-positive cases of tuberculosis at all
ages and direct mass BCG vaccination of children should both be applied as widely as possible.
These two tools must be used for several decades.
Experience shows that mass BCG vaccination at birth is not feasible in most developing coun
tries. At present, single direct BCG vaccination at school-entrance age will probably be the policy
of choice.
At present, the situation regarding case-finding of persons with smear-positive pulmonary tuber
culosis is very unsatisfactory, and intensive operational research in this field is urgently needed.
However, even an improvement in identification of smear-positive cases, for instance from 30 to
50%, will considerably increase the impact of the control measures on the overall tuberculosis
situation.
As to chemotherapy programmes, Table 2 shows that in some developing countries quiescence
of the disease was achieved in only 60-65% of all patients (5). The fatality rate was about 10-16%,
and the proportion of chronic bacillary excretors remained high (about 25%). In many developing
countries, the success rates may be even worse. Fox estimates that they can fall to levels of the order
of 50%, if the relapsed cases are taken into account (6).
Evidently, long-term chemotherapy of tuberculosis is beyond the resources of nearly all develop
ing countries. We would plead for reduction of the cost of rifampicin so that short-course chemo
therapy might be widely applied in most developing countries.
Table 2. Fate of bacillary cases of tuberculosis when treated under mass chemotherapy programmes
in certain developing countries.
Bacteriology
Country
Taiwan
Korea
Kenya
India
No. of
cases
237
288
’ 739
292
Year
1968
1968
1968
1974
Duration of
follow-up
Percent
died
%Pos.
%Neg.
2 years
1.5-2 years
> 1 year
1 year
10.5
11.1
15.6
9.6
24.1
26.0
21.5
27.0
65.4
62.9
62.9
63.4
Source of information: Grzy bowski, S. et al.
We had only 25 minutes to deal with a very large subject and therefore this presentation has to
be considered as an abstract. For those who are interested in this subject, we would refer to the
forthcoming report in ((Advances in Tuberculosis Research)) (1).
REFERENCES
1.
2.
3.
STYBLO K. Recent advances in epidemiological research in tuberculosis. Advances in tuberculosis re
search. In press.
STYBLO K. & MEIJER J. Impact of BCG vaccination programmes in children and young adults on the
tuberculosis problem. Tubercle, 57: 17 (1976).
BAAS M.A. ET AL. Surveillance of diagnostic and treatment measures. The Netherlands. Proceedings of
the XXIVth World Conference of the International Union Against Tuberculosis, Brussels 5-9 September,
1 978. Bulletin of the International Union Against Tuberculosis. In preparation.
4.
XXIVth World ContwerKeoTXVntV1 h’380!?/'?
tr.eatrnent measur«. Bavaria. Proceedings of the
ment programmes’
of pulmonary tuberculosis under various treat-
5.
6.
sy&K’S’2 *
Epidemiological Bulletin
fl
-.
PAN
HEALTH ORGAMZAHON
■■ AMERICAN
j
- . ' •
■ . .
f
-i
•■:
1
i= ®|
Vol. 5, No. 1, 1984
••'••.a
.:kw
Epidemiological Research in Tuberculosis Control
Introduction
Growing concern is being expressed about the fact
that the tuberculosis control programs introduced in
developing countries, now some 20 years ago, ap
parently fail to produce a noteworthy reduction of
the problem (1). Although it is generally recognized
that these programs still have many shortcomings,
there is a conviction that they will reduce transmis
sion and thus cause a gradual decline.
The implied assumption that the trend of the tu
berculosis problem is a suitable indicator of the
achievements of a tuberculosis program perhaps
should not be accepted uncritically. In Europe and
North America a decline in tuberculosis set in long
before the introduction of any specific antituber
culosis measures. A pronounced change in the de
clining trend of the risk of infection was observed in
the mid-1940s in many developed countries, with
the discovery and widespread use of streptomycin
for the treatment of tuberculosis. Whereas this no
doubt caused a reduction in case-fatality, it should
be noted that the ensuing reduction in the risk of in
fection also coincided with the upsurge in socioeco
nomic development after World War II. Then the
rate of decline jumped suddenly from 3-5% to 1014% a year, and this rate has been almost constant
until now (2). Some discrepancies in this pattern
have been observed. In the Netherlands, the sudden
change took place a few years before the discovery of
chemotherapy; one explanation advanced is that the
decrease was caused by the compulsory pasteuriza
tion of milk enforced by law in 1940 (3). In Finland
8
two abrupt changes were observed, one from 3.5%
to 8.5% in the mid-1940s, and a second, doubling
the rate of decline, to 16% in 1966
No plausible
explanation has yet been found for this observation.
Before chemotherapy, certain measures were ap
plied which probably had some effect in limiting the
spread of infection, such as the early diagnosis by
radiography and the isolation of patients in hospi
tals. Artificial pneumothorax might have had bacte
riological benefits too. It is impossible to separate by
retrospective analysis the epidemiological impact of
these measures from that of the continuous improve
ments in the standard of living for the period. No
estimates of the risk of infection are available before
1910, but the steadily declining mortality curve does
not show any change attributable to the introduction
of a specific intervention. For instance, in England
there was a gradual increase in the annual rate of
decline in mortality from tuberculosis during the
period 1851-1946 of almost 1 % to 2 % but no modifi
cation in this trend was seen when the tuberculosis
services were established and developed (5).
In some developing countries, especially in Latin
America, in the Western Pacific ridge, and the oilproducing Arab states, a modest annual decrease, in
the rate of 2-5%, of the tuberculosis problem is pro
bably occurring. These are countries with an inter
mediate level of socioeconomic development. Thus
the attribution of all the credit for the decline to the
tuberculosis programs, either in developed or in de
veloping countries, is largely unwarranted.
A distinction must be made between epidemiolog
ical surveillance and program evaluation. Whereas
creased by about 25% in spite of the fact that case
finding improved consistently during the period
(16). The project provided extensive case-finding
facilities, but no other treatment was made available
than the standard regimens of one year’s duration
recommended by the national tuberculosis program.
Several of the more affluent developing countries
have witnessed a decline in the tuberculosis prob
lem, but invariably the coverage and quality of the
health system has been quite high and extensive use
has been made of X-ray and cultures for the diag
nosis of tuberculosis, at least in the urban areas. And
even then, the question of how much the decline is
actually produced by the program and how much oc
curs as a result of general socioeconomic develop
ment is difficult to answer.
All developing countries, for social reasons, must
give priority to affording immediate relief from suf
fering. Still, in formulating programs to attain the
latter objective they would wish to select techniques
and strategies that are also propitious to achieving a
gradual reduction of the program and thus a durable
social benefit. Any reduction in the risk of infection
would have a relatively rapid effect on the incidence
of childhood tuberculosis, a problem given little at
tention so far, which is not directly alleviated by the
basic case-finding and treatment programs. Current
programs notably appear not to eliminate intrafamil
iar transmission of infection. Quantitative informa
tion on the magnitude of the problem in children,
and on the epidemiological significance of infection
in childhood, is badly needed.
The Impact of Various Control Measures
BCG Vaccination
It seems scarcely worth discussing this subject at a
moment when serious doubts have been raised about
the efficacy of BCG, but its potential epidemiolog
ical impact retains its interest. Extrapolating from
findings in Europe, in particular from a large trial in
England, it seemed that BCG vaccination not only
could reduce considerably the incidence of tuber
culosis in adolescents and young adults but also prevent an appreciable proportion of new sources of in
fection. Observations in other areas, however, did
not substantiate this point of view. In the BCG trials
in the United States, and very much so in the trial in
India, new infectious cases of tuberculosis almost en
tirely occurred in the already infected population;
during the first two and one-half years of the follow
up of the trial in India only some 4% of the cases of
infectious tuberculosis had been potentially prevent
able. Thus, even mass vaccination with an effective
vaccine could not possibly produce a significant im
mediate impact. A sustained vaccination program
could produce an impact in the long run if the pro
tection from BCG were appreciable and long lasting.
This matter still needs to be studied, but it should be
clear already that especially vaccination of the new
born will not prevent many sources of infection in
situations where infectious tuberculosis is mainly a
disease of late adulthood. The current priority is to
investigate the protective effect of BCG vaccination
against childhood tuberculosis in tropical and sub
tropical areas. Especially since young children do
not benefit directly from efforts to detect and treat
infectious pulmonary tuberculosis, BCG vaccination
retains its potentially important role in the control of
tuberculosis in children. A comprehensive program
has been started by WHO to evaluate the effective
ness of BCG vaccination programs in young chil
dren and to identify and quantity factors and de
terminants that may influence the efficacy of BCG,
including the characteristics of various strains of
Mycobacterium tuberculosis, the role of exogenous rein
fection, the host response, and environmental myco
bacteria.
Passive Case-finding by Microscopy,
Followed by Treatment
Currently this is the main control measure applied
in developing countries. Microscopy fairly reliably
gives a positive result if there are large amounts of
bacilli in the sputum. Therefore it is considered that
microscopy can discover, and subsequent chemo
therapy will remove, the most important sources of
infection. This in turn should reduce the risk of in
fection and thus the number of new cases arising
among the noninfected. The question is—how
much?
The matter appears to be an intricate one. In de
veloped countries, with extensive case-finding ac
tivities and almost maximum treatment results,
there has been a decline in the risk of infection in the
order of 12-14% per year, of which some 7-9% have
been attributed to the control program. The part
played in this rather modest reduction^ in the
transmission of infection by the diagnosis of self
2
The reduction is considered very modest when compared with the
effectiveness of other public health programs such as smallpox and
measles immunization and chlorination of municipal water supplies, by
which the transmission of infection is reduced by almost 100% in one
year.
11
reporting smear-positive patients and their treat
ment is unknown. In developed countries many per
sons were treated on radiological evidence or when
their sputum was positive on culture only. A signifi
cant proportion of these cases would have become
smear-positive if left untreated, within a relatively
short period of time. The removal of these potential
sources of infection may have had a far larger epi
demiological impact than that of the self-reporting
established sources.
In the European countries disease used to occur
relatively shortly after infection, so that a reduction
in the risk of infection was soon to be followed by a
reduction in incidence. Thus, the removal of sources
of infection had a noticeable indirect effect. How
ever, if a small reduction in the risk of infection is
obtained in a situation where both the prevalence of
infection is high and the interval between infection
and disease is long, there may not be any measur
able impact on the incidence for several decades.
Thus the effect on the epidemiological situation of
passive case-finding by microscopy .and treatment
may be very small. It therefore appears of great in
terest to conduct prospective studies of the relative
epidemiological merits of diagnosing and treating
different categories of pulmonary tuberculosis, and
to study the effect of introducing different case
finding strategies and diagnostic techniques.
Once an infectious case of tuberculosis has been
detected it remains to be treated effectively if a
source of infection is to be removed. In developing
countries treatment often remains deficient, and this
obviously further reduces the epidemiological im
pact of the program. In actual fact, the impact may
be less than suggested by the proportion of patients
cured; defective treatment may prolong the infec
tiousness together with the life of the patient. It
would appear difficult to study this matter in isola
tion, but one attempt in Madanapalle, India, tended
to show that an extended inefficient treatment pro
gram in fact produces an increase, both in the preva
lence of tuberculosis and the risk of infection (17),
which seemed, in epidemiological terms, worse than
not to treat at all. Surveillance of tuberculosis infec
tion among contacts of patients may provide infor
mation on this matter.
Awareness and Motivation
An inherent weakness of the passive “case-find
ing” method is that it relies entirely on patients having to be aware of the fact that they are ill and being
12
sufficiently motivated to seek relief at the right ad
dress. In these respects the situation in developing
countries is on the whole much less favorable than it
used to be in technically advanced countries. Only a
fraction of the patients come to the attention of the
competent health services. Moreover those who are
positive only on culture remain undiagnosed until
they possibly become smear-positive. Follow-up is
therefore essential.
Increasing the awareness and motivation through
health education, but also by providing adequate
relief for respiratory complaints other than tuber
culosis, may bring about significant improvements
in the effectiveness of case-finding, especially if the
quality of microscopy is high and can be comple
mented with culture examination. The development
of primary health care, and in particular of active
community participation, offers new prospects for
achieving adequate levels of awareness and moti
vation. The returns of efforts in this field may be
studied in comparison with those of further improve
ments in the specific control measures.
Smear and Culture Examination
Any diagnostic test discovers severe cases of dis
ease more readily than mild cases. For this reason
microscopy appears an acceptable technique in pro
grams relying on passive case-finding, and probably
also if a hard screening test is applied. Still, when the
prevalence of tuberculosis among symptomatics is
low, the method not only becomes impractical, but
would also produce false results, as was demon
strated in Papua New Guinea, where among high
landers 1,400 smears would have to be examined to
find one positive result, and the chance of this one
being tuberculosis would be as little as 1.1% (Id).
With increased awareness and motivation the effec
tiveness of microscopy as a diagnostic test will di
minish as the prevalence of disease among those ex
amined reduces, and the yield of case-finding actual
ly may not noticeably increase unless a more sen
sitive diagnostic measure is introduced. It has been
demonstrated that if health education shortens ‘‘pa
tient’s delay” in diagnosis, “doctor’s delay” in
creases to the extent that the overall effect is negligi
ble (19). Studies on the sensitivity and specificity of
smear microscopy as compared with culture exami
nation need to be carried out under different pro
gram situations, preferably in connection with stu
dies on the epidemiological significance of the vari
ous categories of patients.
X-ray Examination
In developed countries X-ray examination has
been used for two distinct purposes: diagnosis and
mass screening. Although not strictly pathogno mon
ic, X-ray examination proved a suitable test in
serious cases of disease, but in mild and early cases
both sensitivity and specificity are much reduced.
The latter results in a low effectiveness in pop
ulations where the prevalence is low, as was con
firmed in mass screening in developed countries.
Diagnostic use of X-ray examination was not rec
ommended as a priority for developing countries,
since in passive case-finding approximately similar
results can be obtained with sputum microscopy,
which is much cheaper. Also mass X-ray screening
was considered incompatible with a situation in
which the first felt need of the population, i.e., diag
nosis for persons with symptoms, and adequate treat
ment for patients, is not yet satisfied.
As a diagnostic facility at the referral level of the
general health service, X-ray examination makes it
possible to examine patients whose sputum is nega
tive on smear examination, and thus to obtain fur
ther information in cases with unexplained chest
symptoms. If adequate treatment facilities have been
established at the community level, X-ray examina
tion of high-risk groups would make it possible to
discover at least a large proportion of the prevalence
cases. Obviously the relative inefficiency of mass
X-ray observed in developed countries should not be
extrapolated to developing countries, but the matter
should be examined under local circumstances.
Conclusion
Reviewing the epidemiological basis for tuber
culosis control in the light of more recent observa
tions, a number of approximations and plain gaps in
knowledge appear to call for prospective quantitative
epidemiological research into several issues. In par
ticular the concept that control measures aimed at
attaining the primary social target of control will also
bring about a reduction of the problem, seems Vvorth
investigating. The relative importance of alternative
measures will become relevant when developing
countries will have the opportunity of extending con
trol beyond the first priority stage, which is likely to
occur with the widespread effective coverage of pri
mary health care. Practical methods for program
evaluation and surveillance need to be described if
the situation in developing countries is to be duly ap
preciated in the future.
References
(1) Resolution WHA33.26. Thirty-third World Health As
sembly, 1980.
Sty bio, K. Recent advances in epidemiological research in
tuberculosis. Adv. Tuberc. Res. 1980; 20:1-63.
.
Styblo, K. [and others). The transmission of tuberculo
sis bacilli. Its trend in a human population. Bull. Ini. Union
Tuberc. 1969; 42:5-104.
(4) Tuberculosis Surveillance Research Unit (TSRU). Estimates of the risk of tuberculosis infection in Finland, 19211980. 1982. Unpublished document.
(5) Heaf, F.; Rusby, N. L. Recent advances!in respiratory
tuberculosis, 4th ed. London: Churchill; 1948. p. 12-13.
(6) Shimao, T. Tuberculosis in the world: tuberculosis prev
alence survey. Bull. Int. Union Tuberc. 1982; 57:126-132.
f/9 Roelsgaard, E. [and others). Tuberculosis in tropical
Africa. Bull. World Health Organ. 1964; 30(4):459-518.
(8) National Tuberculosis Institute, Bangalore. Tuberculosis
in a rural population of South India: a five-year epidemiological
study. Bull. World Health Organ. 1974; 51 (5):473-488.
(9) Baily, G. V. Tuberculosis prevention trial, Madras. Ind.
J. Med. Res. 1980; 72 Suppl.: 1-74.
(J0) Styblo, K. The relationship between the annual risk of
tuberculous infection and the incidence of smear-positive pul
monary tuberculosis. 1982. Unpublished document.
(JJ) ten Dam, H. G.; Hitze, K. L. Determining the preva
lence of tuberculosis infection in populations with non-specific
Sensiliv’ty’ Bu,L Wor,d Health Organ. 1980; 58(3):
(J 2) Meijer, J. [and others). Identification of sources of in
fection. Bull. Int. Union Tuberc. 1971; 45:5-50.
(13) Grzybowski. S. [and others). Tuberculosis in eskimos.
Tubercle. 1976; 57, Suppl.:51-558.
(14) British Thoracic Association. Effectiveness of BCG vac
cination in Great Britain in 1978. Br. J. Dis. Chest. 1980; 74:
215-227.
(15) ten Dam, H. G.; Pfo, A. Pathogenesis of tuberculosis
and effectiveness of BCG vaccination. Tubercle. 1982; 63:225233.
(16) Tripathy, S. P. Personal communication.
(17) Frimodt-M^ller, J. Domiciliary tuberculosis chemotherapy in rural south India. Ind. J. Med. Res. 1981; 73(4) Suppl.:
1 -80.
(18) Pust, R. E. Public health practice. World Health Forum.
1982; 3(l):78-80.
(79) Aoki, M. [and others]. Studies on patient’s delay, doc
tor s delay and total delay of tuberculosis case-finding in Japan.
Tuberculosis Surveillance Research Unit (TSRU). 1982. Un
published document.
(Source: H. G. ten Dam, Scientist, and A. Pfo,
Chief, Tuberculosis and Respiratory
Infections Unit, WHO, Geneva.)
13
1
^Epidemiological Bullet!
$
1
ISSN 0256-1859
Vol. 8, No. 3-4,191
Epidemiological Assessment of Tuberculosis.
Trends in Some Countries of the Americas
Introduction
The continuity of the tuberculosis transmission
chain that keeps the disease endemic in the popula
tion depends on multiple factors. Prominent among
them are the prevalence of sources of infection,
mainly, cases of bacillary pulmonary tuberculosis;
the number of persons infected by each case; and the
probability of infected individuals contracting the
disease as a result of infection.
The number of infected persons per case depends
on the site and type of tuberculosis and the behavior
of the patient. The number of exposed persons and
the degree of exposure, which -in turn depend on
population density and type of housing, also influ
ence the number of infected persons. The probabil
ity of contracting the disease depends mainly on the
infecting dose and on the immune status of the host,
and therefore, on age, sex, nutrition and concomi
tant diseases. In relation to the latter it is well known,
for example, that diabetes and the use of corticoste
roids increase the risk of acquiring the disease. Sim
ilarly, infection with human immunodeficiency virus
(HIV) significantly increases the risk of contracting
tuberculosis (usually about 10%), among infected
persons. Infection with HIV interferes with the cellu
lar immune mechanism responsible for destroying
mycobacteria. In developed countries such as the
United States of America, the age group infected
with tuberculosis and infected with HI Vdo not over
lap much; in developing countries, however, both
infections have greater prevalence in young adults,
which could bring about an increase in tuberculosis
if HI V infection spreads. In Brazil, 17% of the AIDS
cases are discovered through tuberculosis.
In developed countries, improvement of socio
economic conditions contributed to a gradual
reduction of approximately 5% annually of endemic
disease; and when control measures such as diagno
sis, treatment, vaccination and chemoprophylaxis
were added, this reduction reached 14% annually in
countries with better health programs(Z). The
decrease in mortality from tuberculosis in the coun
tries of nothern Europe and the United States of
America began at the end of last century, long before
chemotherapy. In less developed countries, how
ever, the effect of socioeconomic development is
much smaller and a decrease in endemic disease does
not occur without an effective control program. This
control program must have enough coverage and
quality to be able to break the transmission chain.
Although the latter goal is more difficult to attain,
the impact of such a program may be greater in a
developing country. In developed countries the dis
ease occurs among the aged population, as a conse
quence of old infections, and cannot be prevented by
the principal control activities.
IN THIS ISSUE...
• Epidemiological Assessment of Tuberculosis
Trends in Some Countries of the Americas
• Epidemiological Activities in the Countries
• Acquired Immunodeficiency Syndrome
• AIDS Surveillance in the Americas
• Progress in Epidemiology
°
Co.ursc on Gerontology, Geriatrics, and
Administration of Services for the Elderly
• Diseases Subject to International Health Regulations
• Calendar of Meetings
• To our Readers
1
Epidemiological Indicators
In general, evaluation of thestatus of tuberculosis
is based on a combination of estimates of three
indicators, i.e., risk of infection, incidence, and
mortality, along with knowledge of socioeconomic
and sanitary conditions in the country and the
quality and coverage of program activities. The
most frequently used indicators are discussed below.
Risk ofinfection, or the probability of an individ
ual being infected in a year. Obtaining this indicator
requires prevalence studies of infection, with tuber
culin tests in representative samples of the child
population, repeated at several years intervals. This
is the most useful indicator; however, vaccination
with BCG, infections with nontuberculous myco
bacteria and the mobility of the population make its
obtention difficult.
Case incidence, especially of smear positive pul
monary tuberculosis in young adults. This indicator
is useful only when the case detection program
achieves good coverage, its intensity is maintained
relatively constant, and there is good reporting and
quality of registration .
Mortality. This indicator is greatly affected by the
program for case finding and treatment, and usually
decreases more rapidly than transmission. In the
absence of control measures its trend is similar to
that of the risk of infection and incidence. It is useful
as an indicator in countries with high mortality
where mortality reduction is a priority objective.
Current Situation and Trends in Incidence and
Mortality
In 1983 an analysis of the information available on
annual reported incidence of new cases and mortal
ity from tuberculosis in countries of the Americas
with more than 100,000 population was performed at
the PAHO/WHO Regional Office. The work was
done with the cooperation of the WHO Collaborat
ing Center for Tuberculosis Epidemiology in Santa
Fe, Argentina. The resulting document was distrib
uted to countries with the request that they provide
the Collaborating Center, on a regular basis, with
annually updated information on reported cases by
age, site and bacteriology; and on mortality by age.
With those data a second document(2) was pre
pared, on which this paper is based.
In general, for the population of the developed
countries in the Region—Canada and the United
States of America—annual reductions of nearly 6%
in the risk of becoming ill from tuberculosis are
estimated. These countries lack an “active” control
program with national coverage, but have ample
2
resources for highly effective diagnosis and treat
ment in addition to the historical trend resulting
from their socioeconomic development. In recent
years reported incidence in the United States has
stabilized at 10% above expected figures. The two
most important factors affecting this trend are the
immigration of persons with a greater prevalence of
infection and risk of becoming ill—from countries
of Southeast Asia and Latin America—and the
rapid spread of infection with HIV.
In countries of Latin America the trend varies
according to the level of development, quality of the
health care system, and coverage and quality of
control measures. The average reduction is esti
mated at 6% annually. There is a latent period of
several years between improvement or deterioration
of program activities and its reflection in the indica
tors. Hence a program with improved organization
will initially produce an increase in reported cases—
especially smear positive—followed by a reduction
in mortality and a stabilization of reporting, then a
reduction in incidence, greater among young people.
It should be reiterated that the epidemiological indi
cators cannot be interpreted independently of oper
ational factors of the programs, especially with
respect to data obtained from the notification
registries.
Trend differences in Latin America can be illus
trated by the tuberculosis situation in some coun
tries (Figure I). Cuba, for example, has a good
health care delivery system and a well-organized
tuberculosis control program; coverage of practi
cally 100% ofchildren with BCG; case finding among
patients with respiratory symptoms who consult the
general health services, through sputum smear and
culture; and treatment with high compliance. The
result has been an annual reduction of incidence of
9.6% since 1978, and juvenile tuberculous meningitis
has not been observed for 10 years. The incidence
level reached is similar to that in Canada and the
United States, although the average age of cases is
lower.
On the other hand, Costa Rica, with a much
slower reduction—approximately 6% annually in
incidence before 1975 and around 9% annually in
mortality—has also reached very low levels. This is
partly explained by an effective, ongoing program,
although of limited coverage in some areas due to
lack of integration of symptomatic case finding into
the social security health services system. From 1977
to 1983 sharp increases in reporting and a continued
decline in mortality were observed; this can be
interpreted as an increase in diagnoses—in large
measure through immigration due to political
instability in Central America—followed by good
treatment of the cases detected. A reactivation of the
Figure 1. Reported incidence of tuberculosis (per 100,000 popu
lation) in Brazil, Canada, Chile, Costa Rica, Cuba and the
United States of America, 1974-1986.
>
so
g’
o
a
100
90
80
■
»
70
■
60
■
50
-
40
.
30
-
Brazil
Chile
ex:
Costa Rica
20
probably a good reflection of the national trend
(Figure 2). The annual risk of infection is estimated
at approximately 0.9%, ranging from 0.2% in the
south to 2% in the north of the country.
In Chile the intensity of case finding efforts has
increased yearly. This may be observed through the
annual number of sputum smears performed in the
country for diagnosis of tuberculosis. Treatment has
also improved, currently utilizing an abbreviated
scheme of seven months including just one month of
daily treatment with completely supervised adminis
tration. As a result of the real reduction in incidence
and greater case-finding efforts, the reported inci
dence decreased gradually by 5.6% annually from
1976 to 1985, while the yield, as measured by the
proportion of positive sputum smears, decreased
rapidly. Mortality decreased by 9.9% annually
between 1981 and 1985.
United States
10
Canada
Cuba
Figure 2. Tuberculosis mortality (per 100,000 population) in
Argentina, Brazil, Chile, Ecuador, Peru and Uruguay,
1974-1985.
5
1 975
1980
30
1985
Peru
Years
20
Ecuador
program, currently in progress, should give rise to a
new peak in the detection of cases.
In Brazil the existent program, which had less
than 600 health services units and approximately
23,000 specialized beds, was gradually merged into
the general health services of the States in the 1970s.
Currently approximately 4,000 health services units
are incorporated into an integrated program, with
less than 3,000 specialized beds, almost all in general
or chest hospitals. At the same time, notification
increased from 47,000 cases in 1974 to 88,000 in 1984
and stabilized at an estimated 80% of the real inci
dence that can be detected with the technology
available in the country. Information at the national
level represents an average of the trends and levels of
the problem, as well as of the coverage and quality of
information, in the individual States. An average
minimum reduction in real incidence of 6%annually
can be assumed; mortality in state capitals, on the
other hand, is declining by 11% annually, which is
s5 io
g
Brazil
Chile
9
8
I 7
§
al
Argentina
6
5
4
3
Uruguay
2
1
1975
1980
1 98 5
Years
3
It is more difficult to interpret data from countries
where the program and the information systems are
inefficient. In Mexico, for example, it is estimated
that less than half the cases ^re reported; 10 years ago
the number of reported cases was almost the same as
the number of deaths registered by the vital statistics
system. The increase in reported cases is not due to
extension of the program but to the incorporation of
the cases treated by the Social Security health care
system into the reports of the services of the Ministry
of Health. The 7% annual reduction in reported
cases from 1974 to 1978, when there were no changes
in the program, may be real; however, this would not
be true for real incidence rates which are probably
much higher.
In countries with high incidence such as Haiti,
Bolivia, Paraguay and Peru, the problems of cover
age of the health infrastructure coincide with the
scarcity of resources for tuberculosis control activi
ties. This is the case especially with respect to the
provision of drugs, and supervision of services with
integrated actions necessary to maintain case find
ing and assure compliance with treatment. As a
result the reported incidence, although high, is much
lower than.the real incidence. In addition, interrup
tion of treatment for lack of drugs or abandonment
by patients produces a large number of drug
resistant cases which survive a long time and con
tribute to maintenance of the transmission chain.
Changes in incidence in these countries are basically
due to variations in case finding intensity and com
pleteness of registration. This is observed especially
in Haiti.
In spite of the limitations described, mortality
seems to be decreasing continuously in most coun
tries, reflecting gradual improvements in treatment
and, in general, in the quality of the tuberculosis
program and the health care systems in the Region
(Figure 2).
The age distribution of tuberculosis incidence
rates illustrates another aspect of the problem (Fig
ure 3). Although the magnitude of the rate depends
greatly on diagnostic coverage, it shows the risk
accumulated in countries by age cohorts. In devel
oped countries incidence increases in proportion to
age, as a result of risk accumulated over a lifetime,
and exposure to greater risks in prior decades. In
developing countries the risk of infection is high and
the “pooT’of uninfected is rapidly exhausted, which
explains the peak incidence of disease among young
adults. In Venezuela the curve by age is similar to
that of a developed country, whereas in Argentina
there is still a peak among the young. In Venezuela
the older age groups were exposed to greater risks
than in Argentina, but that situation has been re-
4
Figure 3. Reported incidence of tuberculosis (per 100,000 popu
lation) by age-groups in Argentina (1984), Chi!e(1980 and 1982)
and Venezuela (1984).
140
Venezuela
1084
Chll*
1880
-20
§ 00
Chit*
1082
§ 80
2
s
S’ 60
Q
40
ArQantina
1084
20
0
0
10
20
30
40
50
60
70
80
Age in years
versed in the last 40 years. In Chile the curve by age is
changing; the risk is high but has rapidly diminished
in recent years.
Conclusions
Appropriate analysis of the data on incidence and
mortality, accompanied whenever possible by
information on the risk of tuberculosis infection or
the prevalence of infection among children, allows
measurement of the long-term result of tuberculosis
control measures as well as the effect of nonspecific
factors, including socioeconomic development and
development of the health care system. For most of
Latin America, levels of annual reductions close to
those of developed countries of the Region have
been achieved through organized control programs.
The average reduction is estimated at 6% annually at
the very least, which would reduce real rates by half
in 11 years and the absolute number of cases in 18
years. These estimates refer to real incidence, since
observed incidence depends on operational factors
and will probably increase as coverage of the pro
gram improves and new diagnostic methods become
available. A real increase in many countries is also
possible, if HIV infection spreads rapidly.
Given that data interpretation should lead to pro
gram improvement and should be made in relation
to programs, PAHO/WHO has assigned priority
for next year to developing a system of evaluation of
90
program operations through periodic information
from countries, similar to that already existing for
epidemiological information. The basis for this sys
tem will be discussed, in November 1987, by a work
ing group which will propose basic indicators on
coverage and quality of interventions—BCG vac
cines, case finding and treatment—and criteria to
assess strategies, resources and intermediate activi
ties for national and international use.
References
(/) Styblo, K. Epidemiology of Tuberculosis. VEB Gustav
Fischer Verlag Jena. 1984.
(2) Pan American Health Organization. Tuberculosis: Inc!'
dencia y Mortalidad. PNSP/87-11. Washington. D.C.. 1987.
(Source: Tuberculosis, Maternal and Child Health
Program, PAHO.)
WORLD HEALTH ORGANIZATION
WHO/TB/82.133
ORGANISATION MONDIALE DE LA SANT£
ENGLISH ONLY
TUBERCULOSIS CONTROL - CURRENT SITUATION
SUMMARY OF THE VIEWS OF WORKERS INVOLVED
IN TUBERCULOSIS CONTROL PROGRAMMES THROUGHOUT THE WORLD1
by
H. Stott (Consultant), A. Pio (Chief Medical Officer),
J. Leowski (Medical Officer and H. G. ten Dam (Scientist),
Tuberculosis and Respiratory Infections Unit
WHO, Geneva, Switzerland
TABLE OF CONTENTS
page
1.
Introduction
2
2.
Epidemiology
2
3.
The impact of control measures
4
4.
Case-finding and treatment
6
5.
BCG vaccination
12
6.
The National Tuberculosis Programme
13
7.
Principal reasons for failures in the National Tuberculosis
Control Programmes
17
8.
Research
20
9.
List of Working and Background Papers
21
10.
Other references
22
11.
Acknowledgment
23
12.
Tables
24
^Background paper presented at the Study Group on Tuberculosis Control, a Joint
IUAT/WH0 Meeting, Geneva, 14-18 September 1981 (document WHO/1UAT/JSG/BP/8I.1)
The issue of this document does not constitute
formal publication. It should not be reviewed,
abstracted or quoted without the agreement of
the World Health Organization. Authors alone
are responsible for views expressed in signed
articles.
Ce document ne constitue pas une publication.
II ne doit faire 1‘objet d'aucun compte rendu ou
rgsumd ni d'aucune citation sans I’autonsation de
I’Organisation Mondiale de la Sante. Les opinions
exprimees dans les articles signds n’engagent
que leurs auteurs.
WHO/TB/82.133
page 2
1.
INTRODUCTION
The ninth report of the 1974 WHO Expert Committee on Tuberculosis 1 reviewed the current
tuberculosis control measures, particularly in developing countries,
Specific recommendations
were made for the utilization of the technical methods available in the diagnostic, curative
and preventive fields in the development of effective national tuberculosis programmes.
It was emphasized that the formulation of a control programme should be guided by a clear
understanding of the epidemiological, operational, economic and social aspects of the
local situation.
Many of the conclusions of this report are still valid and alterations
to the main recommendations of the report in the light of present knowledge are in emphasis
rather than radical change.
The one outstanding advance is the general introduction of
rifampicin and the development of short-course chemotherapy.
Tuberculosis still remains a major health problem in all developing countries, the
estimated annual incidence of the disease is 200 cases per 100 000 inhabitants with the
prevalence usually twice as high.
Even in many developed countries the annual case load
in the older age groups is considerable and tuberculosis and its sequelae remain important
causes of death.
Since the report of the Expert Committee, advances have been made in the epidemiological,
case-finding and chemotherapeutic fields.
Furthermore, with the increasing attention paid
to primary health care, culminating in the international conference at Alma Ata in 1978 ,
further emphasis has been laid on the necessity of integrating national tuberculosis program
mes with the general health services.
In the light of these advances and changes in emphasis
the centenary of the anniversary of the discovery of the tubercle bacillus by Robert Koch
has been
-- taken as an opportunity to review the tuberculosis situation.
The present paper summarizes the views of workers throughout the world who are involved
in tuberculosis control programmes.
It reviews the technical advances made in the last
decade and their influence on the tuberculosis control measures recommended in the ninth
report.
It examines the development of measures to control pulmonary tuberculosis,
particularly in developing countries, and the integration of the programme into the national
health
services.
----- —
---- It assesses the impact of the programme on the tuberculosis situation
and identifies the difficulties encountered in its implementation.
2.
EPIDEMIOLOGY
To provide an idea of the magnitude of the tuberculosis problem and its trend it is
customary to resort to epidemiological indices and health statistics,
A matter to be
considered is how well such indicators actually reflect the probl em.
Annual tuberculosis infection rate
The annual tuberculosis infection rate is derived from the results of: tuberculin tests
in representative samples of unvaccinated subjects .
It
It is
is generally
generally agreed
agreed that
that this
this rate
is the best single indicator for evaluating the tuberculosis situation and its trend within
the community.
It expresses the attacking force of tuberculosis within the population and
although highly relevant to developed countries it is particularly useful in developing
countries, where, unlike mortality and notification rates, it is not directly linked with
the availability and accuracy of local statistics and can be established much more reliably
than the incidence of smear-positive cases.
The risk of tuberculosis infection indicates the proportion of the population which
will be primarily infected (or reinfected in those who have been previously infected)
with tubercle bacilli in the course of one year, and it is expressed as a percentage or as
a rate.
The estimated annual risk of tuberculosis infection in most developed countries
is of the order of 1 to 3 per
1000..
.
In contrast, in the developing countries it ranges
from 1Z to 57..
It has been demonstrated that there is an almost constant ratio between
the risk of infection and incidence of smear-positive tuberculosis and it has been calculated
WHO/TB/82.133
page 3
that in developing countries a 17. annual risk of tuberculosis infection corresponds to about
0 smear-positive cases per 100 000 general population.
For the three billion people
iving at present (1982) in developing countries there are four to five million highly
infectious cases at a conservative estimate developing each year and 2 to 2.25 million
deaths from tuberculosis.
To estimate.the trend of the annual risk of infection several tuberculin surveys
are required at intervals (e.g. of five years), each in a representative sample of non-BCG
vaccinated subjects of the same age and tested by the same technique.
Information on
It^^ bp!
? ^•1uC?d?n *
°f hieh-Prevalenc* ^d low-prevalence countries.
It has
established that m
in some
«
*low-prevalence countries, where as many as 75Z to 802
nF
t-K been
n established
of the population are uninfected with the tubercle bacillus, the risk of infection is
decreasing by approximately 11-13Z per annum.
I..
In contrast in many of the higher
prevalence countries there has been no evidence of any appreciable change or only a slow
decrease in the annual risk over a number of years.
clear that even when there is very little transmission of infection in children
and young adults, a substantial case-load of new infectious cases may occur in the older
age groups,
It is also clear that estimates of the tuberculous infection rate are
difficult or impossible in areas with a very high BCG coverage in infants
Notification of tuberculosis
of ne^cases6 re^13^0" ,is/de^uately covered by the health services, annual notification
Such va
’s
a' T PI0Vlde
indications °f ^e tuberculosis problem.
uch uas the situation m many developed countries in the first half of this century
ven today, morbidity data for developed countries still give a fair picture of the
Indeed an incrfa "b*" tUberCul°sia becomes rare underdiagnosis and undernotification occur.
La
8 Percentage of patients is not being diagnosed until autopsy.
A variety
cannot easily be made°S1’
^^tln8.a^ bei?S used, so that comparisons between countries
wou?d afford com “ kN • " partlCular> information on bacteriological confirmation, which
L°
their iS
?
geae5ally deficient.
As for mortality data, these largely
reveal important enidL’ ^10ns> c^"ges in diagnosis, notifications after death) and can
These «shortcomings
’
*
of notifications obviously also apply to developing countries, but
with the added drawback that
many cases may remain undetected and thus unnotified.
Indeed
in many developing countries as
undiagnosed and i^ mosttbree"<Jua5ters °f
smear-positive cases remain
-- of most
the facilities°
majority of cases
]
because of lack
culture
^ris^vident
^.CUlbUre °nly Cannot be ^gnosed
It
is
new eases of tuberculosis is
Incom^te evident,
r* therefore,
. • the developing
•
A gradual
improvement
of smear-positive cases may be expected in
countries
; ' in case-finding
--- > and as it is gradually
In these
majority of cases uitb symptoms will be diagnosed
a^d
„
..J treated,
hese circumstances the number of cases identified will be j
gradually
increased
and
notifications will then provide a more reliable yardstick of the
tuberculosis problem and
its trend.
Newly registered cases of tuberculosis for different years, by WHO regions, are shown
in Table 1.
In p--any one year well over one million new cases were reported, which is only
a small fraction of the estimated inumber of new cases but already a considerable case-load.
There is a lack of consistency in the reporting of
: new cases in almost all WHO regions, so
that no meaningful comparison can be made.
^0/18/82.133
page 4
In the <developed
’
countries the incidence of tuberculosis in children is low because of
the greatly
p
’ reduced risk of infection.
In developing countries, however, this age group
is still
— Il at a high risk, but since
svmntnmc <- K
, . c®se"finding is usually based on sputum examination of
persons with y^P
s, tuberculosis in children may pass unnoticed since it is often not
detectable in this
Tw”ay'
Notlflcatlons for men were higher than for women (58X and 427.
respectively) .
inis tendency has been confirmed in prevalence surveys.
Deaths from tuberculosis for different years are given in Table 2.
The apparent
decrease is largely due fto the
■'
data from the developed countries only, since they are
r
"predominant
.--------- aTnon
8 the reporting countries.
IIn the developing countries the death toll
----of tuberculosis
t
' be
’ many times higher than
------- j must
T . --- 1 su88as^e^ by the figures presented.
Still,
even the reported
.--- -- data
--- 1 are most disquieting considering that tuberculosis is easily
treated.
3.
THE IMPACT OF CONTROL MEASURES
The technical imeasures available for the control of tuberculosis
are case-finding
combined with treatment, BCG vaccination, and preventive treatment,
The
impact which
these measures may have on the tuberculosis situation
can only be estimated for countries
where the relevant data are available.
The impact of case-finding and treatment can reliably be assessed in countries where
a reasonable knowledge of the "natural
trend of tuberculosis has been obtained, no mass
BCG vaccination
. was carried out.
• case“finking has been intensive for many years and
estimate inathneen
SUCCessfuI in the whole Population.
It was possible to
of Which z.7
Conditions that the annual decrease is of the order of 12% to 13%,
to intensi-Je °
"
tO the natural downward trend prior to chemotherapy and 7% to 8%
bacteriolnoi CaSe~f"ndln8.an£ effective treatment of all diagnosed cases, with and without
oacteriological confirmation .
A sudden elimination of the sources of infection, ulv'..
uuluuui
with the I
introduction
of chemotherapy,
should have brought about a large reduction in the risk of infection in
----a short period of
time, followed.by a gradual decrease.
This, however, was not observed,
the probable
exp anation being that the level of the risk of infection was already low and the imple
already low and the impl
mentation of effective chemotherapy gradual.
Thus, the decline must have been chiefly
due to the result of active case-finding.
Of particular interest is that the decline
ppears self perpetuating, i.e. the decrease in the risk of infection causes a reduction
in the number of sources of infection and vice-versa.
If elimination of the sources of
infection would merely affect the uninfected population, its impact would only be observed
ob
3a1?"2 rerlOd Of tlmeHowever, the effect seems to be much wider, for it has been
iZ-H
several developed countries, where even now the large majority of elderly people
infected, that the incidence among them also declined with the risk of infection.
England 11: wfs shown that over the last 25 years there has been more than a
old decrease in the incidence of tuberculosis among tuberculin-positive adolescents,
his suggests that, unless the risk of infection is extremely low, disease is to a large
extent the result of exogenous reinfection in the infected population.
If this were so,
a reduction of the infectious pool would be of benefit to the entire population.
It
would probably.cause an immediate reduction in the incidence of infectious, smear-positive,
cases m the higher age-groups, and thus a self-perpetuating decline of the tuberculosis
problem.
This has.been verified among the Eskimo population, in which an intensive
programme resulted in a sharp decline in all age groups.
Tuberculosis control strategi
es
m developing countries should be reviewed in this light.
In many developing countries the case-finding and treatment measures carried out are
unsatisfactory.
It has been estimated that only about a quarter of smear positive cases
are known to the treatment services and therefore there is considerable room for improvement
in case-finding.
Eyen^a 30!! to 50X improvement in the identification of smear-positive
cases and their treatment would considerably increase the impact of control
.,
,
,
.
.
'
------- ---wi.nul measures on the
overall tuberculosis situation.
WHO/TB/82.133
page 5
As regards chemotherapy, it has been estimated that the success
success rate
rate in
in programme
programme
conditions from potentially highly effective regimens prescribed
for one
one year
year may
may be
be of
of
-- 1 for
t^e
°f 607’ t?
with a fatality rate of 10% to 15%, resulting in a residue of
about 25% of chronic bacillary excretors.
The most important reason for this high
failure rate is in the large number of patients who stop treatment prematurely and/or
are irregular in the self-administration of their drugs.
This is principally the
result of a failure in the careful supervision which is required to ensure that the patients
actually receive their chemotherapy.
Substantially reducing the period for which patients
have to be treated by using short-course chemotherapy may thus have a considerable impact
f*
on the tuberculosis situation.
Short-course
regimens are likely to be more acceptable to
patients and will allow the staff more time, than would otherwise be the case, to devote
to the supervision of patients for the relatively short period of treatment.
Further,
even if patients default before completing the "short” ccourse,, it is known that as high a
proportion as 80% of smear-positive patients can be cured
— with
---1 as little as three months
intensive, supervised treatment.
The question is what might be the rate of decline in the risk of infection if the
minimum programme of case-finding by microscopy and one-year standard chemotherapy were
implemented adequately on a national scale.
The application of these measures no doubt
eliminates sources of infection, but the question of how far this reduced transmission of
infection is difficult to answer in developing countries.
In connexion with the objective of the programme aimed at reducing the human suffering
caused by tuberculosis, young children benefit less than adults from such diagnosis and
treatment programmes since child tuberculosis may pass almost unnoticed because children
rarely produce bacteriologically positive sputum.
Serious forms of childhood tuberculosis,
such as miliary tuberculosis and tuberculous meningitis, often will be undetected or
detected too late for treatment to be effective.
The need for preventing tuberculosis by
vaccination in young children is therefore particularly cogent.
BCG vaccination will directly reduce the incidence of disease, its effectiveness being
the product of the actual efficacy of the vaccination and the vaccination coverage.
In
the general population the impact will be limited since BCG vaccination is only applicable
in the non-infected population.
Whereas BCG vaccination may prevent very serious forms of tuberculosis such as
tuberculous meningitis and miliary tuberculosis, it will prevent only a very small
proportion of cases of smear-positive pulmonary tuberculosis.
This form, which is the main
source of infection, is relatively rare in children and adolescents.
Consequently BCG
vaccination, certainly when given to the newborn, will not substantially influence the
chain of transmission, especially if the risk of tuberculous infection is high and has
not been decreasing.
F*
‘ most developing
'
Since in
countries the prevalence of infection in
the older age groups is high, the vast majority of new jsmear-positive cases among the
general population cannot be prevented by mass vaccination.
___________
Systematic
vaccination
1
of
infants and revaccination later in life might only have an effect
the---olderr age-groups
-- - in -after a long period of time.
Providing preventive treatment to healthy persons who are likely to become tuberculosis
patients if not treated, would be an effective way of both preventing suffering and reducing
transmission.
Antituberculosis treatment is attended with certain undesirable side
effects, the risk of which, however, is small.
In the treatment of patients, therefore,
the disadvantages largely outweigh the benefits, and most side effects are reversible if
detected in time, which is likely when treatment is supervised,
The matter is different
when treatment is given as a preventive measure.
At the centre of the problem is that most new cases of infectious tuberculosis do not
emanate from an easily recognized population at risk; so-called "high-risk” groups do not
contribute more than a small proportion of all new cases in developing countries,
For
preventive treatment to be effective as a control measure, therefore, it would have to be
administered on a mass scale to large populations at a relatively low risk.
The cost of
WHO/TB/82.133
page 6
P
g arame
is still true for developing and probably for developed countries.
particularW1inet?rntrKe\PreVuntiVe treatment has a r°le
i" tuberculosis control.
Even in develo ’
h-8h
8ro'Jps’ for examPle infected contacts or silicotics.
selec ivl
'P 8
Wlth 8reat financial resources there could be a place for
proXe htX^XitJ: Sh°Uld’
that the -se-finding/treatment
4.
CASE-FINDING AND TREATMENT
The object of tuberculosis control is to break the chain of
of infection.
The most efficient iway of doing this is to detect the sources of transmission
infection as early as
possible and render them1 non-mfectious by chemotherapy.
Case finding
Case-finding is not an end to itself but is a
preliminary to treatment and cure.
It
is a crucial part in the tuberculosis
control programme; however, it is important that
expansion of a <case-finding programme does
not proceed ahead of the ability of the service
to deliver effective
---- J chemotherapy and to cure the cases found.
.Diagnosis of cases.
Bacteriology plays
a key role in diagnosing new cases of tuberculosis
(and, of course, in the control of their
chemotherapy).
The demonstration of tubercle
bacilli is conclusive and with few exceptions is r---necessary to establish the tuberculous
aetiology of abnormalities found on chest radiographs^
. »
Radiographic appearances are
subject to wide observer variation and if used as C
the sole criterion for diagnosis result
in a substantial proportion of persons being unnecessarily treated’
countries radiography can only play a subsidiary role in the routine In developing
diagnosis and
management of pulmonary tuberculosis because it is costly in t
terms
of staff and equipment,
and rs not readily available to the majority of the population.
’
in some of these countries where as many as half of the adult However, it is still
cases being treated for
coinr-ry tU^!rculosis are diagnosed by radiographic means only
countries radiography is a most useful ancillary to bacteriological In economically favoured
examination,
bacteriol^icaU
ldenti^in^ active case® °f Pulmonary tuberculosis
who particularly
------- are
g
y negative and who may become positive if not treated.
The 1
•
followed by identification
drugs.
In developed countries these
facilities are universally utilized but priorities
have to be set for developing countries,
Examination of direct smears is of first
importance, since it is relatively simple,
not
costly and detects those cases of pulmonary
tuberculosis which are the most infectious,
It has been estimated that each smear
positive case whilst undiagnosed infects <■
at least one person per month.
When smear
examinations are carried out in small, mu]
Itipurpose laboratories, bright field microscopy
technithe ^eh11-Neelsen (ZN) method should be used since capital
used since capital
are low and the
technique fairly easy.
a ]
1However in specialized laboratories with costs
large
flow
of specimens
^“e^ndttimate^y^s^::^^
6
miCrOSC
°
Py
advi
”
ble
” efficient?
-J a day) fluorescence microscopy is
Although the identification of the most infectious
community is a first
f
priority, examination by culture is smear-positive cases in the
increase the number .of cases found and identify cases in a useful examination for it will
a less advanced state of disease.
The Expert Committee recommended that in developing countries
"culture
------ » services should be
provided only when a
PrOp°hrtion °f the swear-positive cases in the country
are being discovered and treated hy chemotherapy".
However, there is currently some
'
difference of opinion in
-.1 emphasis and it is now increasingly felt that even in the absence
WHO/TB/82.133
page 7
of a fully satisfactory smear service, there is a need for culture facilities not only at
a central level but in some laboratories at an intermediate level.
Sensitivity tests are mainly of value in developing countries for epidemiological and
surveillance purposes and normally should be carried out only at the central specialized
laboratory.
Routine sensitivity tests at the start of treatment in patients who have not
had previous chemotherapy impose an unrealistic burden on the laboratory services and can
seldom be justified by the benefit they confer.
However where more advanced bacteriological
facilities are available, in a few developing and all developed countries, they are useful
in deciding on a suitable drug regimen for patients who have failed on chemotherapy.
The tuberculin test has virtually lost its use in the diagnosis of tuberculosis in
view of thf widespread BCG vaccination of infants and children, but.
useful
but uau
can suiil
still prove
prove useful
in areas where BCG vaccination has not been done on a wide scale and in certain individual
circumstances.
In developed countries, where the incidence of genuine infection due to a.typical
mycobacteria is almost ten times that in developing countries bacteriological identification
tests are of crucial importance in the diagnosis of atypical infections.
For extra-pulmonary tuberculosis the use of radiography and histological facilities
are frequently required.
The development of a specific serological test would ba
particularly useful in the diagnosis of extra-pulmonary tuberculosis and might also prove
helpful in pulmonary disease.
Methods of case-finding.
In the majority of low-prevalence countries, where treatment
services are highly developed and effective, case-finding programmes, based on bacteriological
and radiographic examinations, may have a high priority particularly in high risk groups such
as immigrants, foreign workers, and among old persons in homes and hostels and in jails.
In developing countries the great majority of cases are identified when they present
themselves at health facilities often with far advanced tuberculosis and in a highly
infectious state.
This passive method of case-finding yields only about a quarter of the
smear-positive cases in the community and in order that there should be any impact on the
tuberculosis situation more active case-finding measures to identify the large number of
undiagnosed cases need to be pursued.
. . The only active case-finding measure used on a large scale in the past has been mass
miniature radiography (MMR) but this has been virtually abandoned, except in certain high
risk groups in developed countries, largely because it contributes a very limited number of
infectious cases and is very expensive.
It has been estimated that the cost of detecting
a smear positive case through mobile MMR examination of the general population is about 50
times higher than identification of a case by the examination of sputum smears from
symptomatic patients attending health facilities.
However, there are still a few countries
where mobile mass radiography is currently being carried out at regular intervals.
In view of the fact that it iu’as generally believed that tuberculosis patients failed
to attend for treatment at health units, there has
-- been
--- * ari increasing interest in recent
years in actively searching in the community for "tuberculosis suspects" who have
chronic respiratory symptoms (a cough for one month or more) and examining them bacteriologically by smear (or by smear and culture).
Several methods of identifying such
tuberculosis suspects in the community have been investigated in Kenya.
It was found that
the proportion of suspects with a chronic cough in the general population was
was 5.0Z,
5.0Z, (pot
dissimilar to the 4?1Z reported from Uganda , 3.52 from Upper Volta5, 6.67. from Burma6 and
J.b/. rrom Indonesia ).
The most productive of the methods investigated, which yielded 702
ot the total estimated number of smear-positive cases and 652 of all culture-positive cases
in the area, was a time-consuming and cumbersome procedure of interrogating household heads
or suspects living in the household.
This involved house-to-house visiting and is
usually impractical to undertake on a large scale in the great majority of developing
countries, although it is practised in Korea.
WHO/TB/82.133
page 8
A much more practical and manageable method
• i •
, W?S interr°gation of community elders on
several separate occasions for
suspects within their communities (containing about 1000
persons) which produced 43Z of all «
‘ ‘
smear-positive and 40Z of all culture-positive cases
but which contained
—J a high proportion of previously
treated cases.
This suggested that
the elders knew and remembered old cases but were less
aware of subjects with common
symptoms such as a chronic cough.
-p.«. -«»
3- alluf0r> surprisingly, over three-quarters of the tuberculosis
clairaed that during the
previous '•*
■’
T
year they had attended one or more peripheral
health units for
on several “cession:
I^h:
respiratory
symptoms c~ « 1-st one occasion, and the great majority
circumstances it
it was possible that the problem was to
ensure that susnects’vh In these circumstances
units were /
Presented themselves with chronic respiratory'symptoms to these
f!™e? thls flndrng and demonstrated a singular failure of the
staff of rhece
:: :x“
their burden
’
“a-
-r r:;::
’
SPeClal Procedure> ^^ver simple, is an increase to
There was additional evidence from these
studies that suspects who failed to obtain
relief at the periphery, then attended the better
* staffed and better equipped district
hospital.
Accordingly, a series
«
“
of" further
investigations were undertaken involving the
screening of outpatients for
J <suspects in several district hospitals.
This is relatively
easily organized for there are better resources available
, namely on-the-spot facilities
or microscopic and radiographic examination and often
a chest clinic with better trained
staff to make a diagnosis and initiate treatment,
This approach was encouraging and
productive, for the proportion of suspects with
a chronic cough among outpatients aged
six years or more was 2.7Z and the yield of c
smear-positive cases from them was 2Z to 5Z,
house-L^n, y?hd ■r°m SUaPeCts obtained by actively searching'in'the' co^unity
same district was 1Z.
Similar findings’havr’bee/reported
from other de
•ame dlStrict was
Similar findings have been reported
er developing countries which indicate2 that
CllCnorfc crroonorl
that the
the oroDortinn
proportion D
off suspects
screened
from outpatients attending health facilities
ranges from 2Z to 10Z and the yield of cases
from 1Z to 10Z.
The approach through the district hospital <
outpatients is, however, unlikely to
provide by itself full coverage of the community.
.
This presents a dilemma for to obtain
the poPulation sonie activities must also be carried out in the periphery,
at the perinher3
emP1Oyed have yet to be determined but it does mean that the staff
ti.herr.n
•
r nlot:ivated to remember to take the trouble to identify
berculosis suspects and arrange for the examination of their sputum.
A further case-finding method investigated was the examination of all cases of
RegTster7 ^n'i^eas5 ^^ed °ver a period of several years in the District Tuberculosis
a full address f
\
U?de\take provided the register is well maintained and contains
refei- afdr“S for each P^^nt) and entails the tracing and examination of only a
resistIn!ybfcillP-r-°ntS;
“
t0
3
°f identifyinS chronic excretors of
natienrs h '
C0'?n,unlty- over three-quarters of the bacteriologically positive
resistant
”lns _ rest s tant to isoniazid; however, less than one-fifth had strains
lln“ a S
streptomycin.
The examination of their contacts was almost wholly
p o uctive but it might be useful if contacts of newly diagnosed smear-positive
cases
were examined.
A useful approach to case-finding, being evaluated in Hong Kong,
has been to increase
the <awareness
---of the medical profession, of all cadres of medical staff and of the
community (by a publicity campaign, posters, television and radio) of the importance of chronic
symptoms referrable *■''
to ‘the
respiratory
■v~---“
r system.
WHO/TB/82.133
page 9
In most populations in developing and developed countries, there are individuals and
groups for whom the risk of tuberculous infection and disease are greater than for
others.
The identification of these groups is particularly important because it is more
economical and more operationally feasible to concentrate case-finding efforts on them.
An important high priority group is the contacts of smear-positive cases, others are health
staff exposed to infection in wards and laboratories, patients who have had tuberculosis
and have been inadequately treated or persons with radiographic abnormalities in the lung,
especially if these are large and recently detected.
Particularly relevant to developed
countries are migrant groups, elderly subjects and patients with special concomitant
diseases (such as diabetes, pulmonary chest diseases, silicotics and patients on steroids).
In summary, it is concluded that the present methods of case-finding in developing
countries are generally unsatisfactory and produce only about a quarter of the smear
positive cases in the community.
Greater attention needs to be paid to the identification
of symptomatics in the community and among outpatients and the examination of their sputum.
It has been demonstrated that if carried out systematically, an active policy in the
community is potentially capable of identifying two-thirds of all smear-positive patients in
the population.
Chemotherapy
The Ninth report of the WHO Expert Committee emphasized the importance of giving
adequate chemotherapy free of charge to every patient with infectious pulmonary tuberculosis.
Certain general principles were formulated, namely that patients should be treated on an
ambulatory basis with careful supervision to ensure the regular administration of drugs for
a year and that the benefits of prolonging chemotherapy beyond a year were small.
In
selecting regimens to be used, consideration should be given to the relative efficiency,
toxicity, acceptability and cost of the drugs.
These principles are equally relevant
seven years later.
The main drugs for national tuberculosis programmes available in 1974 were isoniazid,
streptomycin, p-aminosalicyclic acid (PAS) and thioacetazone.
Recommended for general use
in national tuberculosis programmes was the combination of isoniazid (300 mg) and
thioacetazone (150 mg) in one daily dose for patients weighing 35 kg or more, an effective,
inexpensive (Table 3) and widely used regimen for those countries in which the level of
toxicity is acceptable.
Streptomycin is frequently administered daily for the first month
or two of treatment.
Recommended for those countries where fully supervised intermittent
chemotherapy is feasible, and carrying the benefit of overcoming undetected irregularity,
was a highly effective twice-weekly combination of streptomycin (1 g or 0.75 g) plus
isoniazid (in a single dose of approximately 15 mg per kg body weight) given together
twice a week; with 5-10 mg of pyridoxine to prevent peripheral neuritis.
It was, however,
recognized that there was a need for fully oral standard intermittent regimens which could
be administered under supervision by non-medical auxiliary health workers.
It should be
recognized that the figures for the efficacy of the various regimens shown in Table 3 are
based on the results of controlled studies and are optimal results, and, in practice,
frequently fall far short of these.
A review of the current methods employed for the treatment of tuberculosis in the
developed countries shows that isoniazid, rifampicin, streptomycin, ethambutol and pyrazinamide
are used in various combinations, often for periods of nine months or less.
In many
countries some, and sometimes all the patients are still being treated initially in hospital
for periods up to three months and sometimes even for considerably longer.
In developing countries patients are often treated on an ambulatory basis from the
start of chemotherapy, but often the first month or two is spent in hospital to cover the
period during which streptomycin is given.
Usually treatment is prescribed for one year
but in some countries it is standard procedure to prescribe it for as long as 18 months and
occasionally for two years.
The standard regimen in many countries is the combination of
isoniazid and thioacetazone, often with the addition of streptomycin for an initial period
WHO/TB/82.133
page 10
of one to three months,
However in other countries, where thioacetazone is unacceptable
because of its incidence of side effects, it has been replaced as a companion drug to
isoniazid by PAS ((Na)' or ethambutol.
In a few countries fully supervised intermittent
chemotherapy is standardJ treatment and in a few others short-course chemotherapy with
isoniazid, rifampicin, streptomycin and pyrazinamide for six months has recently been
introduced.
Shore / Pyrazlnamlda as an important bactericidal drug has led to the introduction of
the leneehSefrer'r'anSa oShort‘course chemotherapy ’ was primarily developed to shorten
devel 8 h °f Sta'?dard 12-m°r1th treatment because of the difficulties, particularly in
The
C°Untries! of maintaming patients on regular treatment for one year or more.
"her
U-Se J’681"’6115 have a mode of action which differ essentially from that of the
to oLeT6"
"• Standard len8th regions.
In standard chemotherapy it was necessary
select companion drugs for isoniazid which would prevent the emergence of drug
InSshnrrCe’
thKioacetazone> PAS a"d ethambutol - drugs with a bacteriostatic action,
re
^“7 ^emotherapy the aim is to select combinations of bactericidal drugs which
thMb
a
r
8’ nan!ely rlfa“Picin> Pyrazinamide, isoniazid and streptomycin and
thereby producing a more rapid cure.
!
Shown.1"/a series of controlled studies that a six month regimen of a
combinatron of rsomazid (300 mg), rifampicin (450-600 mg) plus streptomycin (1 g) for an
intensive phase of two months (2SHR) followed by a 4-month continuation phase of isoniazid
plus rifampicin (HR) is a highly effective r--1-- ’
’ '
isoniazid
(Table rP1Ckne ad -r1- '
smear-positive pulmonary tuberculosis
(Table
The addition
addition of
of pyrazinamide
pyrazinamide (1.5
(1.5 -- 2.0 g) to the initial 2-month phase (2SHRZ)
rnn
-a 3).
achieved hy P^ent:/a?d the e£ficacy of the re8imen.
High levels of success were
for Deriodsenf
1 combination for two months was followed in the continuation phase
115 me/k ?
a
-r of
°f six
S1X n,OnthS
(a) streptomycin (1 g) , isoniazid
months by a c°”binati°a
(150 me) nlus iPyr-Z1”r^nn(3’i S- glVen twice-weekly
or (b) thioacetazone
drug r fam i “Onlazld.(30° ’’g) 8lven dally (TH).
In bot£ ?hese regimens the expensive
If !he
a
: Waf ?1Ven °nly fOr the firSt tWO rnonths> a mai°r eco"°“y in drug cost,
thus reducing
phase were reduced from two months to one month (1SHRZ)
of the r ■ 8
C0St and the duratlon of daily streptomycin injections, the efficacy
eight monfhV
COrresPond!n81y reduced bV ab°ut 10Z for each of the six month and
eight month regimens, respectively (Table 3).
With an initial month h
Sorter courses of chemotherapy, namely 4-month regimens,
T2SHR7? Joia
K P
Of strePtoraycln> isoniazid, rifampicin and pyrazinamide
( SHRZ) followed in the continuation phase by isoniazid in combination with rifampicin
and/or pyrazinamide have proved to be disappointing in smear-positive disease.
the
can
S^O^t’c°?rse chemotherapy has several advantages over courses of standard lengthnP3tientS a"d
^ff^rts
drugs- the total auanr r^r!
I
attendance and
administration of
th 8
a
1 quantlty of dru8 used ls less
therefore there is less toxicity
par? lf the drV3 «ere given for longer periods and the cost is lower, and because of the
bs n d
1ZlnS
f6Ct °f th£ drU8S in the
Phase °f treatment, patients who
abscond early are less
less likely
likely to
to relapse
relapse than
than on standard regimens.
Intermittent chemotherapy.
LWith
‘2_*. the introduction of rifampicin there have been
further advances in regimens for supervised intermittent c
: chemotherapy.
A fully oral
twice-weekly regimen of rifampicin (600 mg) plus isoniazid
------- J in high dosage (15 mg/kg) has
been investigated.
The regimen given for
one year, was preceded by a short daily phase
of the two drugs given in conventional
dosage plus streptomycin for two weeks and was found
to be highly effective (Table 3). The same regimen given once-weekjy was also very promising
and required only 64 doses in the year.
Immunologically adverse reactions to rifampicin
(the flu syndrome) were very uncommon in these regimens.
WHO/TB/82.133
page 11
Intermittent regimens have been shown to be highly effective also in short-course
chemotherapy.
In Hong Kong, a fully supervised regimen of streptomycin (1 g),
ri ampicm (600 mg), isoniazid (15 mg/kg) and pyrazinamide (2-2.5 g) given together
three times a week for four months and followed by twice-weekly streptomycin plus
isoniazid plus pyrazinamide (3-4 g) for a further two months, was found to have a high success
rate and when the twice-weekly regimen was given
( ‘
* the continuation phase for four months
in
instead of two, the efficacy was increased to virtually 100%.
Indeed, in Hong Kong, a
regimen of streptomycin (1 g) plus isoniazid (15 m^.''
>g/kg) plus pyrazinamide (2-2.5 g) three
times a week for nine months cured 95% of the patients.
Cost of the drug regimens.
IIn considering the applicability of chemotherapy, cost is
an important factor affecting the choice,
For some short-course regimens the cost is
principally due to rifampicin but pyrazinamide is also a
relatively expensive drug.
There
is a surprisingly wide variation in the price difference
of a drug in different parts of the
world even when it is marketed by one company (Table 4).
These differences are irrespective
of
, costs of transportation and distribution.
Nevertheless, it should be recognized that
ne actual cost of drugs does not necessarily reflect the total cost of administering a
regimen.
There are other important considerations indirectly affecting the cost of treat
ment, nameiy its acceptability to patients, toxicity, whether it requires injections and its
ability tQ sterilize lesions rapidly and thus ensure a substantial cure rate in persons
defaulting from treatment early.
In developed countries, where the cost of drugs is not of such great importance
(although it may be by no means a negligible factor), it seems likely that, on the basis of
current findings, 6-9 month regimens containing rifampicin, isoniazid and pyrazinamide
will be used for patients with smear-positive disease.
For those patients negative on smear
but positive on culture the duration of treatment with these drugs may be anything from four
to six months and for those who are consistently negative on smear and culture (about half
the patients coming under treatment) it could be three months or perhaps even two.
However,
the time periods for patients with smear-negative disease need further clarification.
an initial pnase as possible and the choice for the continuation phase may well be the
relatively cheap standard combination of isoniazid plus thioacetazone or possibly isoniazid
mieht’weJ
h3nd ^ere.is the ability
organize full supervision, the choice
ght well be a fully supervised twice-weekly regimen for the continuation phase.
It is
however necessary for each country to decide its own policy of chemotherapy and which
regimens are appropriate, maybe in different parts of the country, to its programme conditions.
making preatme^ reg£mensneed for retreatment should be avoided as far as possible by
making every effort to ensure the highest standards of primary treatment.
In general drugs
for retreatment are available only in small quantities in the developing countries.
toxic andaLuanvatnien^ntaining ethionamide and cycloserine are expensive and
toxic and usually require hospital treatment.
In countries where the resources permit,
considered SS tSS
f1
COmm°nly usedA very important factor to be
oe"Sr " 1
sh?rkt-course ^gimens for primary treatment is that relapses which
occur i~
th^ thS iLS S 7 T
organisms fully sensitive to the drugs administered and
that the patients can
can be
the same combination of drugs.
be effectively
effectively retreated
retreated with
with the
l£-e_ventlve treatment.
practice, isoniazid by itself is conventionally administered
In practice
s a chemoprophylactic for a period of six months or more.
However, it is possible that
A hiX1Cln admilnl?,:ered for considerably shorter periods might prove equally as effective.
chSS
speculative possibility is that immunotherapy, either by itself or together with
chemoprophylaxis, might prove a successful preventive treatment.
S
WHO/TB/82.133
page 12
5.
BCG VACCINATION
BCG vaccination was introduced in most developing countries as
a a time when it was the only tuberculosis control method applicabl an emergency measure
e on a national scale.
negaJive1-nnoDularrartetWKt:h 3
Camp?ign to cover the entire eligible’-’tuberculin
. P P Iatlon> which was followed in many countries by an i
integrated programme, to
exXLWlth the birth.rateM°re "cently BCG vaccination has been inciuded
in the
-age group eit^\On lmn?niZftion? which
reaching a high coverage in the lowest
mainly in’instit
Vacclnatl?8 the newborn, in countries where deliveries take place
health care s
“
£ lntenslve efforts through child welfare clinics and primary
neaith care services to reach the young infants.
F
y
Direct vaccination with freeze-dried
vaccine by the intradermal method is the normal
procedure and coverage in the various age
groups and in different countries varies widely
ranging from 30X to over 90Z.
cI"j!Zel^SC^nvt.rieS Spe':ial.att?ntion was ®iven to.providing BCG vaccination before
adolescence, alone or by revaccination in c
*
‘
cases where vaccination of the newborn was also
, and childhood
adolescents and young adults appeared the group most susceptible
to developing tuberculosis.
The protective effect of BCG vaccination remained a matter of controversy.
The
information obtained in the newborn and
young children appeared very favourable, but results
in adolescents and adults obtained in a series of carefully planned and executed controlled
trials were contradictory,
The results of the latest BCG trial in south India obviously
weigh heavily in the balance,
trial was carefully designed and took account of all
technological developments and results of
research on BCG vaccination carried out in the
previous twenty years.
’The
7"
complete absence of a protective effect has prompted1 a
reappraisal of the mechanism of- protection
r-------- 1 afforded by BCG1 .
""
There is no suggestion
that the trial methodology, nutrition, freeze-drying or <
quality or strain of vaccine used
had any influence
----- * on the efficiency of vaccination in thea south India study.
The first explanation that comes to mind is sensitization with environmental
mycobactena.
Indeed in the trial area this kind of sensitization was massive, but one
would have expected that it might have caused a reduction in the protective effect of BCG
vaccination, not a complete elimination.
In the trial area a 1high prevalence of tuberculosis infection appeared to be accompanied
by an unexpectedly low incidence of bacteriologically
j confirmed tuberculosis among those
recently infected.
In contrast, the incidence ramong those already infected, particularly
among adult men, was exceptionally high,
The lack of protection from BCG might: be related
to this unusual epidemiological pattern.
The pattern observed possibly could be explained
from infection in the area being predominantly with1 a "south Indian variant" of the
tubercle bacillus.
’ variant, first studied some 20 years ago, had been found in some
This
3 ago, had been found in
75% of the isolates from patients in Madras.
- -------- It has several unusual characteristics, a
striking one being that it is of low virulence in the g *
--------- —
guinea pig, unlike the ordinary
tubercle bacillus.
It has therefore been suggested that the’organism may be fully
infectious but may only rarely lead to disease soon after infection, though it might cause
disease later.
The tuberculin sensitivity induced by BCG vaccination in the trial population appeared
to have waned considerably within a few years.
This may point to an unusual immune
response.
Further indications of this are the unexpected age dependence of tuberculosis
as well as the high incidence of leprosy in the trial area.
WHO/TB/82.133
page 13
Another hypothesis is that the low effectiveness of BCG vaccination observed in
south India could be the result of the disease diagnosed being predominantly of the
exogenous superinfection type.
Whereas BCG vaccination may protect uninfected persons
against primary and evolutive tuberculosis, as well as against endogenous reactivation,
it cannot be expected to protect uninfected persons if their eventual disease were of the
exogenous reinfection type: at the time of reinfection the level of immunity would be
that derived from the primary infection, whether BCG had been given before this or not,
so that controls and vaccinated subjects would have the same risk of disease from
exogenous reinfection.
A study group on BCG vaccination policies
considered whether modifications were to
be made in current BCG vaccination policies in the light of present knowledge.
It was
stressed that the Indian trial was not designed to establish the effect of BCG in infants
and young children.
The evidence available on the effect of BCG vaccination in these age
groups is very favourable.
Some hypotheses that explain the lack of effect in older age
groups, such as a high prevalence of infection with environmental mycobacteria, do not apply
to infants.
In practice BCG vaccination is being applied most often in the newborn and young
infants, and this policy is being adopted more and more with the introduction of the
expanded programme on immunization.
There are no reasons to modify this current policy,
but its effectiveness should of course be studied forthwith.
Every effort should be made
to identify the local factors that apparently may modify the outcome of BCG vaccination.
Due attention should continue to be paid to the quality of the vaccine, its handling,
techniques of application, training of personnel, coverage of population, evaluation and
monitoring the programme as suggested in the ninth report of the WHO Expert Committee.
6.
THE NATIONAL TUBERCULOSIS PROGRAMME
The national tuberculosis programme is a methodical approach within the country health
programme designed to reduce progressively the tuberculosis problem in the community by
working through the network of existing general health service institutions forming the
primary health care system.
The essential components of the programme are case-finding
with effective treatment of the cases found and immunization of the vulnerable population.
This concept, which is current WHO policy on tuberculosis control was formulated
in the ninth report in 1974.
Organization of the national tuberculosis programme
The main recommendations in the 1974 report were:
1. The programme should be permanent, organized on a country-wide basis (serving the
rural equally with the urban areas), be a well-balanced component of the country health
programme, integrated into the community health structure, meet the public demand and be
accessible, available and convenient for the consumer rather than for those providing the
services’
2. The plan of action should clearly enumerate the main events and the activities
required to achieve them in their logical sequence.
There should be a systematic planning
of operational steps for implementation, monitoring and evaluation of the tuberculosis
programme which should be based on demographical information, the system of administration
and communications, the structure and coverage of the health services and the availability
of manpower and resources at the central, intermediate and peripheral levels.
3. Diagnosis and treatment should be carried out by suitably trained staff operating
from a network of permanent health services including outpatient departments of hospitals,
health centres, dispensaries and health posts.
These should be located so that all
persons have reasonable access to a health-unit of some sort.
WHO/TB/82.133
page 14
4. For implementation of the programme there should be a single strong directing
authority at the central level under the Ministry of Health which should be responsible
for policy making, planning coordination, training, direction and evaluation.
Managerial
teams, specially trained in the technical and operational aspects of the programme should
play a key role and be responsible for the implementation of the programme; they should
spend much of their time in the field supervising the activities and on-the-job training
of the field workers, particularly at the peripheral level.
Their other activities
should include the organization of the distribution of equipment and supplies, and the
technical evaluation of the programme components based on simple, effective and meaningful
recording and reporting systems which should provide information for future planning.
5. Adequate training for all categories of health personnel emphasizing the
community aspects of tuberculosis.
Members of the managerial teams should, in principle,
be trained as a group at a national centre and particular importance should be paid to
management technology, not necessarily limited to tuberculosis.
Basic information on
national tuberculosis programmes should be added to the curricula of medical, para-medical
and nursing schools.
Current situation of tuberculosis control progranunes
In many developing countries there is little integration of the tuberculosis programme
with the general health services in the capital city or very large towns.
At this level
there is often a considerable degree of specialization in the form of tuberculosis
specialists, tuberculosis clinics, a tuberculosis laboratory and beds for cases of tuber
culosis.
At the intermediate level specialized clinics may exist, sometimes in the form
of general chest clinics, and at the periphery in the primary health centres and sub
centres, tuberculosis patients are normally managed and treated in the general health services.
The process of integration is proceeding with varied success, but many countries are
having major problems in the organization of their programmes.
This is particularly true
when attempts are made to integrate an already existing specialized tuberculosis service
into the general health services, for such a move is usually resisted by all categories
The specialized tuberculosis staff having limited confidence in the
of health personnel.
ability of the general service staff to master the techniques properly and the latter
showing a degree of reluctance to undertake it because of the extra work involved.
Key
Sometimes the planning of the programme is inadequate at the central level,
personnel trained abroad may fail to implement the programme on their return with the
result that there is little or no central planning and a lack of support from the Ministry
of Health; directions from the centre are vague and ill defined resulting in confusion and
minimal activity at the lower levels.
However, frequently there is a degree of policymaking, planning and programming at the centre but this is often negated by a general
weakness of the infrastructure due to the scarcity and frequent turnover of staff at all
levels, an inadequate number of health units which may be poorly distributed and thus
Irregularity of the supply of drugs
inaccessible to large sections of the population,
and equipment is common and almost invariably there is a shortage of funds resulting in a
serious restriction of transport and travelling which is so necessary for the essential
work of supervision and evaluation.
Often the failure at the intermediate level is due to the absence or ineffectiveness
of managerial teams under the overall supervision of the general duty medical officer.
It is necessary for them to be better trained as multipurpose teams in the detailed planning
and managerial aspects of the programme and to have more support from the centre particularly
in the provision of transport and allowances to enable them to travel and undertake the
supervision and evaluation which is crucial to success.
WHO/TB/82.133
page 15
The improvement of the managerial teams should in turn lead to improvement at the
peripheral level where often the rural health staff are untrained or improperly trained,
infrequently if ever supervised and often show lack of interest and enthusiasm.
Technological skills can readily be acquired by health workers in the general health
service but due to lack of training, poor communication with the intermediate level,
shortage of chemicals, equipment and drugs and breakdown of vehicles, their motivation
is frequently blunted.
The ready availability of drugs and supplies is essential but
frequently fails to be achieved for many and sometimes complex reasons and its
rectification presents a managerial and planning challenge.
In many developed countries tuberculosis control activities are based on an
independent sub-system in the health service, in others specialized tuberculosis units
continue to provide specific activities but administratively they are incorporated in
general health services and in a few others the activities are fully integrated into the
general health services.
The reason for the retention of the specialized services in
these countries is the belief in them that specialized experience is necessary for the
treatment of tuberculosis.
Further, owing to the decline of the disease there is a
generally decreasing interest in it.
Tuberculosis, however, still presents a problem
in the majority of developed countries and there is a need for comprehensive surveillance
surveys to follow the trends in notifications, the types and severity of the disease, the
management of patients and to observe the extent that clinical practice keeps abreast with
modern developments (e.g. in chemotherapy).
The organization of laboratory services in the programme
In the great majority of developing countries there is normally a central laboratory,
situated in the capital city, which undertakes smear and culture examinations and sometimes
sensitivity testing also.
In the development of the laboratory service at the central
level the first step is to upgrade the quality of work at the central laboratory so that
it can efficiently undertake smear examination by fluorescence microscopy and culture
examinations.
Sensitivity testing should only be introduced when sufficient skill and
equipment is available and should be restricted to the central laboratory.
At present
there is difficulty in producing a high class culture service and, in those laboratories
where it is done, sensitivity testing.
The central laboratory should also play
. an important part in the planning of the
national programme, have representation on and close participation with the central
management team, undertake training of technicians, be responsible for equipment
specifications and for quality control of bacteriological work throughout the country.
It should be a c
- ‘
centre
for epidemiological studies and should undertake research primarily
aimed at solvingZ practical
.
’
.problems within
i- the
-"-J country.
As the service develops, it is visualized that there will be an increase in the
number of multipurpose intermediate laboratories capable of doing cultures as a
specialized section within a larger general laboratory.
The first priority in the bacteriological facilities for a developing country is the
provision of a country-wide service for the examination of direct smears of sputum.
At present facilities for the examination of sputum smears are usually available in the
general laboratories at intermediate level; if they are not, they should be made so.
There are certain advantages in locating microscopes in the more peripheral areas because
sputum smears can then be examined on the spot and the necessity of transporting sputum
in containers, or fixed smears for examination, to the hospital is avoided.
The
disadvantages lie in the regular maintenance of microscopes, the training and supervision
of the microscopists and the maintenance of a regular supply of staining reagents and
slides.
The balance of advantages between these two approaches is uncertain but it is
unwise to assume that the same solution applies with equal force to all countries or to
all regions in any one country.
WHO/TB/82.133
page 16
It is evident that
nature.
worker, motivated to
central p'"'-*--laboratory
. service
- — <and the Mmistry of Health.
It is of the greatest importance to
ensure a regular supply of slides.
stains and facilities for maintenance of equipment.
particularly the microscopes.
n. ‘-p-£bb«"y
xr
Training is important but should not c----wholly on teaching the technical
performance of certain tests (for instance concentrate
how to examine
---- j a sputum smear).
Of equal
importance is to teach peripheral microscopists the
proper
use
and
maintenance
of the
microscope, including minor repairs,
An additional requirement will be for one or more
workshops capable of microscope repairs
i which may be part of a department carrying out a
wide range of repairs of laboratory equipment.
Exner^
• C°ntr°1 18 most important and should be the function of the c - - ' ' ■
Experience in developed countries suggests that the most efficient way is central
fo/thelaboratory.
’central '
boratory to send out to participating laboratories prepared specimens or smears with
ntral laboratory.
This however requires skilled and dedicated personnel
A small
and^^sam deVel°Pln8 countri^ have a monitoring system whereby all known positive smears
centra
r^ular^
"
inte™adiate -d peripheral laboratories are v wed
satisfactory
stretch the reso. r
ftT1S ' Satisfact
°ry method provided it does not unduly
tretcn the resources of the central laboratory and that
‘
7
appropriate action is taken
routinely to notify the results to the participating laboratories,
However, the best and
most practical method of undertaking this work will have
to depend on local circumstances.
Evaluation of the programme
Evaluation of the programme differs considerably from
country to country but in the
vast majority it cannot be said to be satisfactory.
T
In a few countries evaluation is
carried out by managerial teams or other supervisory staff but only
j on a limited scale
because of shortage of staff and transport facilities,
Sometimes the programme is
evaluated through routine statistical returns received from the periphery indicating
...7 inaicatln8J the
number of cases.treated in various areas.
C
*,
Occasionally national and regional seminars are
organized at which the programme is discussed.
Although the need for evaluation of the
programme is recognized, its implementation suffers due
f inancial resources and poor communication between the i < to shortage of trained staff and
financial
centre and periphery.
oatient^rn^
eValuatinS national programmes is by nationwide surveys of cohorts of
loeic^ > r’
which can provide much useful information on the epidemiomelhod of d
they WiU indiCate the types °f tuberculosis being treated the
methods of diagnosis employed, the drug sensitivity pattern, the types of treatment given
Tuberculosis registers
. ----- .
In developing countries, the "notification” of cases of
tuberculosis on ia national basis frequently depends on a system of registration in
tuberculosis registers of- cases of tuberculosis coming under treatment.
These registers
are often maintained at an intermediate level and perform a most important function in
tuberculosis control,
The aim should be for them to be.simple and provide essential
information, ]"
‘
including
age and sex of the patient,. the site of the disease, the method of
diagnosis^(bacteriological , radiographic, histological,
, clinical) and the exact address
so that the patient cani be contacted readily.
7”
They
should also provide a cross reference
to the individual case cards detailing the treatment of the patients and the management of
their families,
Apart from providing information for the national statistics the
registers provide an essential guide in the surveillance of the anti-tuberculosis activities
within each area, m relation to.the site of the disease, the method of diagnosis, the
initial treatment and the areas in which the patients live.
WHO/TB/82.133
page 17
Economics
A tuberculosis programme requires special resources, even if integrated in the general
health services.. As tuberculosis is a disease against which a highly efficient technology
exists the position is favourable in competing for resources with other health demands.
However, because comparison between the importance of different diseases in the community
is very often based on subjective considerations, the decisions on allocation of resources
will also remain highly subjective.
A balance has to be found in the antituberculosis programme between curative (casefinding/treatment) and preventive (BCG vaccination) services.
Chemotherapy is essential for the control of the disease and consideration has to be
given to the relative cost of drug regimens.
Cheaper regimens with lower individual
efficiency under programme conditions may prove expensive in the long run.
Thus, they may
result in a large number of unsuccessfully treated patients who may still be infective to
others and who are in need of retreatment with more expensive drugs probably for considerable
periods in hospital.
However, there is no objective final formula which will take into
account the large number of factors involved.
The economics of tuberculosis control in relation to integration will behave
differently according to the degree of integration of health services.
The balance is
between the trade-off between technical knowledge (presumed to be higher in a specialized
system) and the advantages in lower cost and continuous care afforded by the integrated
system.
'To become efficient, integration requires a basic infrastructure into which
to integrate and this is frequently non-existent or too weak, and must be strengthen-. '
before it can become economically advantageous.
7.
PRINCIPAL REASONS FOR FAILURES IN THE NATIONAL TUBERCULOSIS CONTROL PROGRAMME
The failure of a national tuberculosis programme
programme can
can be
be broadly
broadly defined
defined as a failure
achieve a decrease in the tuberculosis problem in the country over a number of years.
This
can be said to have occurred in the majority of developing countries.
In a few, mainly
those with considerable financial resources, there has been a decrease in the problem.
In
the economically favoured developed countries there has been a marked success in the control
of the diseases over the period of the last half century, which has been achieved because
of the full availability of technical and financial resources and in spite of mistakes,
sometimes serious, which have been made.
■“
The
present document attempts to summarize
the main reasons for the failure of national programmes in the developed countries.
The fundamental reasons for failure are the lack of financial resources and manpower.
Failures, directly or indirectly resulting from these can be broadly identified under the
following headings:
7.1
Planning of the programme
a) A lack of planning or ineffective planning of a (country-wide programme is usually
due to a lack of interest of control key staff which results
the------absence^2of strong
-- --in -managerial teams at the Ministry level, with a wide and comprehensive membership, to carry
the plans into effect.
b) A deficiency or absence of epidemiological data in the country on which to
base a plan.
c) A failure of planning and coordination at the intermediate level, often due to the
non-involvement of the district medical officer and the absence of .a managerial team.
d) Because of the absence of support, supervision and proper instruction the peripheral
staff are left to carry on as best they can.
WHO/TB/82.133
page 18
e) The.absence of managerial teams, or the failure to provide facilities for travel
when they exist, leads to a lack of technical guidance, supervision and training at all
levels.
7.2
Staff
a) Doctors, specially trained to organize control programmes frequently have an
undue clinical bias and find it more satisfying to treat patients than to organize a
countrywide programme.
b) rStaff
— responsible for organizing the programme may lack the full support of the
Ministry of Health
--- when
--- it_ comes to the implications of launching or maintaining the
programme.
c) There is a disinclination by the central organizing staff to devolve responsibility
because of their limited confidence in the ability of the general service‘ staff to master
the techniques properly.
d) The.general 'health
- - service staff are most reluctant, without extra help, to
increase their work-load by being involved in other more chronic conditions, requiring
extra time
and expertise.
time.and
They have many priorities, particularly acute conditions
demanding immediate attention (e.g. trauma, pneumonia, malaria. acute surgical emergencies,
etc.)
e)
The staff at the periphery are poorly trained and lack adequate supervision.
f) /"
All.grades of general health service staff are subject to frequent postings.
often with little notice.
g) There is a $great. .lack
. of- organized
.
- training
- ■
schemes for all grades of staff and
of on-the-spot training, particularly for staff at the periphery.
7.3
Transport
a) There is a general lack of vehicles and often those that are available are
immobilized because of lack of spare parts and/or breakdowns.
T.
There is almost universal
lack of proper maintenance for vehicles particularly at the intermediate and peripheral
levels.
b) rBecause of the escalating price of oil, the use of vehicles has to be severely
restricted.
c) There is often insufficient planning in the optimal use
use of
of transport enabling a
variety of functions to be undertaken in one journey rather than
several
------separate journeys.
d) - - cycles and motor bicycles in place
The use of- pedal
of cars is frequently impossible
in the rough conditions
----- of
-- rural
--- 1 areas.
e)
•’
’
In the
absence of vehicles, funds required for travelling (e.g. by public
transport) and living expenses for supervisory staff are frequently totally inadequate.
7.4
Supply of drugs, vaccines and equipment
a) Because of difficulties in the transport system, and often because of po.
poor
organization, supplies of drugs, chemicals, vaccines and equipment are allowed to
-j run out
without being replaced for considerable periods.
This results in frustration of the
medical and paramedical staff and disenchantment of the population with the health services.
b)
Often "time-expired” drugs and vaccines are being used.
WHO/TB/82.133
page 19
c) Occasionally anti-tuberculosis drugs, and sometimes diagnostic procedures are
charged for.
7.5
Distribution of health facilities
Peripheral health facilities are often insufficient in number, and those that do
exist are inaccessible or situated long distances from large sections of the population.
7.6
Referral services
a) The use of supportive referral services between the various levels is greatly
hampered, particularly at the peripheral level, by lack of transport and adequate road
communications.
b) There is often confusion and misunderstanding by patients being referred by
private practitioners, and mission hospitals to government institutions and vice versa.
7.7
Bacteriological services
a) There is a lack of well qualified and motivated staff to plan the expansion of the
bacteriological service, and to create a liaison with the clinical services which is
crucial.
b) The regular supply of chemicals to laboratories and the maintenance of equipment,
particularly microscopes, is frequently defective.
c) 1More supervision of laboratories at the intermediate and peripheral levels,
including; an effective monitoring service, is required.
7.8.
Case-finding
a)
There is a general lack of sustained attempts at case-finding.
b) The identification and appropriate examination of chronic respiratory symptomatics
attending out-patient departments is not attaining its full potential, due principally
to the lack of motivation and training of the staff, particularly at the peripheral level.
c)
Very few active case—finding measures are being pursued in the community.
d) •
•
The examination
of household contacts, of at least the smear-positive index cases.
as a routine is frequently not done.
7.9
Treatment
There is a universal problem of maintaining patients on chemotherapy for a year:
a)
'
"
‘
*
Default
and■ irregularity
in the self-administration of the drugs is outstandingly
the most important reason for failure of treatment.
The identification and tracing of
defaulters is hampered sometimes by the absence of an organized
organized method
method ot
of approach
approach but
but more
often by the scarcity of staff and transport to enable defaulting patients to be contacted,
* the rural- areas.
particularly in
T
b)
‘
.
The non-availability
of drugs at the distribution points often causes irregularity
in the administration of chemotherapy.
c) Inadequate instructions to the patient on the administration of drugs may lead
to incorrect dosages being self-administered.
d) The transfer of patients during their treatment from one area to another can lead
to interruption and possibly cessation of treatment unless standard procedure for such
transfers is laid down.
WHO/TB/82.133
page 20
frequeLlIOunaiX°fft^ drUSS
interruPtio^ of chemotherapy and staff are
frequent rr u
V
^cessity for it to be dealt with urgently in order to avoid
q
t irregularities m the administration of drugs.
7.10
Evaluation and surveillance
a) Because of the absence <or of the failure of managerial teams to function
properly there is inadequate routine
--- 2 supervision and surveillance at all levels.
b)
‘
This
results in the irregular and insufficient collection of statistics necessary
to evaluate
te the programme.
J
c) Periodic country-wide surveys of cohorts of patients coming under treatment to
evaluate the ]programme,
’
including the results of chemotherapy, are undertaken in only a
very few countries.
d) There is a need for more countries to maintain adequate registers
of all patients
coming under treatment.
e) The countries require to undertake estimates of BCG
coverage through vaccination
returns and scar surveys.
8.
RESEARCH
It is relatively easy to specify the broad areas in which research in tuberculosis is
important, but more difficult to qualify the specific activities which should be pursued.
These have been set out m detail in a recent report on research on tuberculosis by a
Committee of the British Medical Council20.
Taken as
Taken
as a world problem the priority for
research must be to help the developing countries improve the performance of their national
tuberculosis programmes and thereby reduce the incidence of the disease.
There is little doubt that the main problem in the
national programmes of developing
the national
countries lies in the organization of the programme.
The
for more
The first
first priority
priority is
is for
operations research to find simpler and more acceptable methods of administration and
organization (including methods of decentralization and integration).
Of equal priority
is to conduct research into methods
—j 1to improve training, including motivation of all
grades of staff in case-finding and case-holding,
These may seem mundane and unimpressive
research projects, but they are of crucial importance to the improvement of the national
health programmes.
Pot>entif1 control technology already exists for tuberculosis and the
implementation of this has led to a remarkable reduction in the incidence of the disease
in developed countries.
]'
However, in order to simplify the organization of the tuberculosis
control programme in developing
further
i
’ into
’
• - countries
- -----•’ research
methods of control is needed,
Thus, there is a need for a simple test, possibly serological, which can L
be used clinically
and epidemiologically, for diagnosing active tuberculosis in a quantitative and
_..J qualitative
munn^’ partlcularly for diagnosing tuberculosis in children and extra-pulmonary xuims
forms oi
of
the disease.
Better methods of case-finding both active and passive (including research
into methods of motivating staff, particularly at the periphery) require investigation in
different countries and different situations,
In the field of chemotherapy, it is most
important to find s imple and effective methods of preventing default (e.g. use of community
leaders) and there remains a need for research
---- into new drugs and regimens for further
shortening the length of chemotherapy and to assess the efficacy of short-course regimen
s
in programme conditions.
For preventive measures, there is a requirement for a more
effective and possibly oral vaccine.
In the epidemiological field there is a need for a more specific tuberculin test or other
methodological approach so t'
that the impact of the control measures (case-finding/treatment
and/or vaccination) can be measured simply and accurately.
WHO/TB/82.133
page 21
Important other areas for research are the development of simple methods of
surveillance, monitoring methods of therapy and notification by surveys, and assessing
the impact that quality control schemes (e.g. of smears) have at the peripheral level.
Of a more fundamental nature, but in a rapidly expanding field, is research in the
immunological aspects of tuberculosis, particularly in identifying reasons for breakdown
of inactive disease.
Childhood tuberculosis has been particularly neglected and there
is a need for more attention to be paid to research in this field.
9.
LIST OF WORKING AND BACKGROUND PAPERS
V. K. Agadzi
Critical review of the application of tuberculosis control technology in
primary health care
WHO/IUAT/JSG/WP/81.4
P. Cavalie
Solutions to some problems facing integrated tuberculosis control
programmes in developing countries
WHO/IUAT/JSG/BP/81.5
P. Chaulet
Applicability of short-course chemotherapy to the national tuberculosis
control programmes of the developing countries
WHO/IUAT/JSG/WP/81.7
G. Dahlstrom
Identification of problems requiring further research if they are to be
solved
WHO/IUAT/JSG/WP/81.25
S. Endo
Comments on current tuberculosis control policy
WHO/IUAT/JSG/WP/81.4
A. F. Farah
Tuberculosis control and primary health care services
WHO/IUAT/JSG/WP/81.13
L. S. Farer
The problem of high prevalence groups in low prevalence countries
WHO/IUAT/JSG/WP/81.10
L. S. Farer
The role of preventive treatment (chemoprophylaxis) in tuberculosis control
WHO/IUAT/JSG/WP/81.19
J. Grosser
Changes and advances in current technology for the bacteriological
diagnosis of tuberculosis
WHO/IUAT/JSG/WP/81.2
F. Luelmo
Critical review of the application of tuberculosis control technology in
primary health care
WHO/IUAT/JSG/BP/81.3
P. Mercenier
Operational problems encountered in the implementation of tuberculosis
control programmes and need for health services research to solve them
WHO/IUAT/JSG/WP/81.23
D. A. Mitchison
Organization of tuberculosis laboratory services in developing countries
WHO/IUAT/JSG/WP/81.3
WHO/TB/82.133
page 22
D. R. Nagpaul
WTiy integrated tuberculosis programmes have not succeeded as per
expectations in many developing countries - a collection of observations
WHO/IUAT/JSG/BP/81.4
S. J. Nkinda
Critical review of the application of tuberculosis control technology in
primary health care
WHO/IUAT/JSG/WP/81.11
W. P. Ott
Critical review of the application of tuberculosis control technology in
primary health care
WHO/IUAT/JSG/WP/81.12
K. S. Sanjivi
Can tuberculosis be eradicated through primary health care?
WHO/IUAT/JSG/BP/81.2
T. Shimao
A review of case-finding methods and problems of delay in case-finding
WHO/IUAT/JSG/WP/81.9
H. Stott
Centralization and decentralization of case-finding activities for
pulmonary tuberculosis at district level in Kenya
WHO/IUAT/JSG/WP/81.8
K. Styblo
The present epidemiological situation of tuberculosis in developing countries
WHO/IUAT/JSG/WP/81.1
K. Styblo
Epidemiology of tuberculosis in children
WHO/IUAT/JSG/WP/81.20
TRI Unit
WHO, Geneva
TRI Unit
WHO, Geneva
H. Th. Waaler
The role of BCG vaccination in tuberculosis control programmes
WHO/IUAT/JSG/WP/81.15
Tuberculosis control - a world summary
WHO/IUAT/JSG/BP/81.9
Tuberculosis and economics
WHO/IUAT/JSG/WP/81.21
10.
OTHER REFERENCES
1.
World Health Organization Expert Committee on Tuberculosis Ninth report, Wld Hlth Org.
techn. Rep. Ser., 552: 1-40 (1974).
----------- ’
2.
Report of the International Conference on Primary Health Care, Wld Hlth Org. "Health for
all" series. No. 1 (1978).
3.
Styblo, K. Recent advances in epidemiological research in tuberculosis, Adv. Tuberc.
Res. 20:
1-63 (1980)
4.
Smith, P. G. & Revill, W. D. L. The prevalence of persistent coughs in a rural
community in Lango District of Uganda,, Tubercle,, 58: 157 (1977).
5.
Blanc, M. Note d’information sur 1’enquete concernant la lepre et la tuberculose en
Haute Volta, Act. Lepr., 68: 15-24 (1977)
WHO/TB/82.133
page 23
6.
Ministry of Health of the Government of Burma,
Burma in 1972, Tubercle, 55: 313 (1974).
7.
Toman, K. Tuberculosis control activities in Indonesia.
001 (1976).
Assignment Report, INO MED
8.
Fox, W.
Short course chemotherapy for tuberculosis.
Medicine. Ed. D. C. Flenley, Churchill Livingstone:
Recent Advances in Respiratory
182-203 (1980).
9.
Fox. W. Whither short-course chemotherapy?
(1980).
10.
World Health Organization.
Ser., 651: 1-21 (1980).
Vaccination against tuberculosis, Wld Hlth Org, techn. Rep.
11.
World Health Organization.
652, 1-17 (1980).
BCG vaccination policies, Wld Hlth Org. techn. Rep. Ser.
12.
Research in tuberculosis.
/A report of- a Committee set up by the British Medical
Research Council to study future prospects.
Bull. Un. Int. Tuberc., 55: 86-99
(1980).
11.
ACKNOWLEDGMENT
Tuberculosis baseline survey in
Brit. J. Dis. Chest,
75:
331 (in press)
The authors would
to express their gratitude and thanks to all who contributed to
wouxa like
iiKe co
the preparation of this document with working and background papers written for the Study
Group on Tuberculosis control (see the List of working and background papers).
They are alsc
grateful to all the others who contributed with letters or personal discussion: H. Acan
(Turkey) W G. L. Allan (Hong Kong), K. Amoli (Iran), R. H. Andrews (United Kingdom),
fFeder
“‘T (Italy) ’ A‘ Bulla (^nia), P. Chasles (France), E. Freerksen
( ederal Republic of Germany), H. H. van Geuns (Netherlands), S. Grzybowski (Canada),
M
D- ISeman (USA)’ S- ISlam (WH° Kenya)> T' Iwasaki (JaPa”) A- G. Khomer
zt a- >
; “ ln <Czach°sl°''akia), A. Laszlo (Canada), W. McDermott (USA), M. L. Mehrotra
(India), Z. S.
S Moulding (USA), F. R. Ogasarawa (USA), C. R. Pacheco (Mexico), H. W. Perera
J I Sha*?
Hr;Aiel^man (USA)’ J- R°8OWski (p°land), A. Saenz (Uruguay), H. Saleh (Iran),
sill!b/rbaru (ySA)’.Ex1"Sayed Salem (Egypt), Nadda Sriyabhaya (Thailand), W. W. Stead (USA),
L. Sula (Czechoslovakia), J. A. Tao (USA), L. Trnka (Czechoslovakia), P. M. Udani (India),
C. G. Uragoda (Sri Lanka) and I. Vadasz (Hungary).
WHO/TB/82.133
page 24
TABLE 1
Newly registered tuberculosis fcases by WHO Regions
1965 - 1970 - 1975 - 1979
~ All forms -
Reporting countries
Year and WHO Region
Newly
registered cases
Number
Population in thousands
Africa
Americas
Eastern Mediterranean
Europe
South-East Asia
Western Pacific
33
40
12
23
1
12
141 283
366 087
89 045
388 056
11 164
196 642
157 822
183 544
76 469
311 802
13 112
509 258
Total
126
1 192 277
1 252 007
Africa
Americas
Eastern Mediterranean
Europe
South-East Asia
Western Pacific
36
38
15
24
2
22
222 672
499 124
138 584
430 737
48 259
213 693
196 316
202 834
108 648
358 885
45 439
404 564
Total
137
1 553 069
1 316 686
Africa
Americas
Eastern Mediterranean
Europe
South-East Asia
Western Pacific
30
42
17
25
5
21
170 658
553 074
201 956
493 526
821 629
195 305
68 044
178 140
184 601
208 089
551 669
279 867
Total
140
2 436 148
1 470 410
Africa
Americas
Eastern Mediterranean
Europe
South-East Asia
Western Pacific
17
41
11
20
3
16
150 253
597 233
139 335
399 181
875 097
157 920
54 064
164 466
149 891
141 312
559 395
100 390
Total
108
2 319 019
1 169 518
1965
1970
1975
1979
WHO/TB/82.133
page 25
TABLE 2
Deaths from tuberculosis in the world
1965 - 1970 - 1975 - 1979
-all forms -
Reporting countries
Year
No. of countries
Population - in thousands
(Zof world population)
Officially reported
deaths
1965
116
1 223 808
(36.6Z)
178 213
1970
134
1 488 900
(40.5Z)
156 880
1975
112
1 426 245
(35.5Z)
121 634
1979
61
1 001 894
(23.1Z)
53 545
•o
TABLE 3
Cb
00
(D
The effectiveness in controlled studies of some standard and short-course regimens and their cost
Regimen
Duration of regimen and potential efficacy (Z)
Duration of regimen and cost (US$) to UNICEF*
1 year
1 year
9 months
8 months
6 months
1 STH/TH
95
8
1 SPH/PH
95
73
2 2
1 STH/S-H
/ 2»2
90
14
95
2 SHR/HR
9 months
8 months
6 months
18
100
95
2 SHRZ/HR
191
130
99
140
2 SHRZ/TH
100
90
60
59
2 SHRZ/S-H
2 2Z2
100
90
82
74
1 SHRZ/TH
90
80
33
31
1 SHRZ/S_H Z
2 2 2
4 S_H Z_/SOH Z
3 3 3 2 2 2
1 HR/H R
2 2
1 HR/H R,
11
SnH Z
3 3 3
98
90
57
48
99
95
37
29
100
81
95
46
95
75
52
44
S = streptomycin; P = PAS; H = isoniazid; R = rifampicin; Z = pyrazinamide; TH = thioacetazone
The number preceding a set of letters is the number of months of the intensive
phase; the continuation regimen follows
the stroke (/).
For intermittent regimens the number of doses per week is shown by the suffixed numbers.
*The cost of the drugs is based on current prices to UNICEF and includes a 30Z handling and freight charge.
The cost of the regimens is calculated for an adult weighing less than 50 kg and is expressed to the nearest dollar.
s
o
NJ W
Ch \
00
NJ
GJ
WH0/TB/82.133
page 27
TABLE 4
The varying cost of drug regimens
Cost in U.S. dollars
Length of
treatment
Latin
America
1979
1STH/H
12
13
isth/s2h2
12
2SHRZ/RH
Therapeutic
regimen
Algeria
1980
UNICEF*
1981
U.K.
1978
U.K.**
1980
7.5
8
10
27
30
12
17
20
64
6
183
167
161
273
393
2SHRZ/TH
6
8
91
92
70
71
59
60
103
104
159
161
2SHRZ/S2H2Z2
6
119
91
74
129
203
The UNICEF and U.K. prices have been calculated for an adult weighing less than
50 kg and expressed to the nearest dollar.
■k
The UNICEF prices include 30Z handling and freight costs,
pyrazinamide is that quoted to WHO by the manufacturers
The price of
** The conversion from sterling to dollars has been based on an average exchange
rate during 1980 of US$ 2.3 to £1 (Bank of England quote).
DISTR. : LIMITED
WORLD HEALTH ORGANIZATION
DISTR. : LIMITEE
WHO/TB/83.141 Rev.2
ENGLISH ONLY
ORGANISATION MONDIALE DE LA SANTE
TREATMENT OF TUBERCULOSIS:
CASE HOLDING UNTIL CURE
Professor Pierre Chaulet^
(1)
Clinique de Pneumo-phtisiologie Matiben, Centre Hospitalier et Universitaire d’Alger Quest,
Beni-Messous, Algiers, Algeria
This document is not issued to the general public, and
all rights are reserved by the World Health Organization
(WHO). The document may not be reviewed, abstracted,
quoted, reproduced or translated, in part or in whole,
without the prior written permission of WHO. No part
of this document may be stored in a retrieval system or
transmitted in any form or by any means - electronic,
mechanical or other without the prior v',itfen permission
of WHO.
Ce document n'est pas destine a fetre distribue au grand public
et tous les droits y afferents sont ieserv^s par ('Organisation
mondiale de la Sant£ (OMS). II ne peut etre comment^, r^sum6,
cite, reproduit ou traduit, partiellement ou en totality sans
une autorisation pr^alable dcrite de I'OMS. Aucune partie
ne doit 6tre chargee dans un systdme de recherche documentaire ou diffusee sous quelque forme ou par quelque moyen
que ce soit • ^lectronique, m^canique, ou autre • sans une auto
risation prealable ecrite de I'OMS.
The views expressed in documents by named authors are
solely the responsibility of those authors.
Les opinions exprimees dens les documents par des auteurs
citds nommement n'engagent que lesdits auteurs.
WHO/TB/83.141 Rev.2
page 3
A.
INTRODUCTION
For the national tuberculosis programme, the final objective of treatment is not only to
deliver adequate chemotherapy to every newly discovered infectious case but also to take all
possible measures to ensure proper drug dosage, regularity of drug intake and adequate
duration of treatment, to achieve the patient’s cure. In order to achieve this goal,
technical guidelines must be available that have correct and locally adapted answers to the
following eight questions:
a)
b)
c)
d)
e)
f)
g)
h)
Who are the patients that should be admitted to treatment?
Which is the place of treatment?
Which therapeutic regimen to apply?
How to organize a regular supply and distribution of drugs?
How to ensure treatment compliance of individual patients?
How to arrange for treatment follow-up?
How to organize the supervision of all treatment activities?
How to evaluate the results of treatment within a national tuberculosis programme?
In addition, there are two problems that can arise and which need specific but transitory
decisions to be taken:
J)
How to implement a modern policy of tuberculosis treatment in a situation of
organizational anarchy? Or how to modify a current practice of inappropriate treatment?
In a well organized and standardized tuberculosis programme, how to introduce new
regimens of chemotherapy that are different in composition and duration from the ones in
use?
B.
TREATMENT GROUPS
1.
The two main groups with absolute priority for treatment are:
i)
sputum smear positive, pulmonary tuberculosis cases (actual sources of infection)
smear negative but culture positive, pulmonary tuberculosis cases (potential sources
of infection).
These two groups are responsible for the transmission of the infection and the
perpetuation of the disease in the community; they represent from 70 to 80% of tuberculosis
cases, all forms, Without treatment, half of the smear positive cases would die within two
to three years.
2.
The subsidiary treatment groups that should be treated according to the means available
are:
a)
The few acute tuberculosis cases without bacteriological confirmation (febrile acute
miliary disease and tuberculous meningitis)
b)
Smear (and culture) negative pulmonary tuberculosis, which can only be diagnosed
through X-ray examination.
In children with pulmonary lesions, whether isolated or associated with mediastinal
or pleural lesions, frequently the sputum examination by microscopy is negative.
Childhood tuberculosis is mainly found among the contacts of an active source of
infection.
Among the adults, on the contrary, these cases should be precisely defined under two
situations:
If culture facilities are not available, smear negative pulmonary tuberculosis,
defined as those cases that had two series (from four to six specimens each) of
negative smears, are treated only if there is highly suggestive evidence of
progressive tuberculosis on chest X-ray.
WHO/TB/83.141 Rev.2
page 4
If cultures are performed, treatment is justified only when there are signs of
radiological deterioration for 2-4 weeks before culture results are available.
(C)
C.
Cases of extrapulmonary tuberculosis, identified on the basis of clinical signs
(tuberculous lymphadenitis, tuberculous pleurisy or ascitis) or radiological signs
(osteo-articular or urogenital tuberculosis) and a positive reaction to tuberculin,
with or without bacteriological or histopathological confirmation (according to the
type of laboratories which are available).
PLACE OF TREATMENT
It has been established beyond any doubt that success in the treatment of tuberculosis
depends neither on duration of hospitalization nor on rest and special diet but that it is
function of quality and duration of chemotherapy. Domiciliary/ambulatory chemotherapy,
regularly delivered, not only gives equally good results as chemotherapy delivered in
hospitals or sanatoria but also is sociologically more acceptable to patients because it does
not disrupt their normal life. Finally, isolation of a patient in a hospital bed does not
necessarily reduce the risk of contagion to the contacts, since transmission of infection
within the household takes place mostly before the diagnosis. Home is the ideal place for
treatment, even if it is in a slum or favelas, or is a nomadic tent, because this is most
acceptable to the patient, since it interferes less with his work and his family life.
It is simpler and more practical to organize domiciliary treatment than hospitalization
for a long period and for all the patients, and it is far less expensive so that with the
amount of money needed to treat one patient in a hospital, six to ten patients can be treated
domiciliarily.
1.
The most important problem is to organize health services able to deliver permanently
adequate chemotherapy. This can be achieved through:
(a)
either the organization of delivery of chemotherapy in the patient’s home,
(b)
or the organization of services for the administration of chemotherapy to patients
at the basic health units, dispensaries or health centres. These health units must
be easily accessible to the patients, clean, open for service daily, and able to
deal with patients with sympathy and consideration. They must deliver;
either fully supervised treatment (daily or intermittent), the drugs being
taken by the patient under the direct supervision of health personnel
or treatment which is partly supervised (during the first phase) and partly
self~administered by the patient (during the second phase of treatment).
Self-administration of the drugs depends upon the active participation of the
patient in his own cure. His participation should be supported by a member of
his family, by a community health worker and by the attention given by all
health personnel to regularity of treatment.
2.
A secondary problem is often put forward by doctors: the need to have enough beds for all
patients who have to be hospitalized for the daily administration of drugs and the
application of injections.
The usual medical indications for hospitalization are; severe haemoptysis; serious
deterioration of the patient’s general condition; pyopneumothorax secondary to the
rupture of a pulmonary cavity through the pleura; complications of diseases associated
with tuberculosis (for example, acquired immunodeficiency syndrome, and worsening of
diabetes, of cardiac, hepatic or renal insufficiency); tuberculosis of the hip or spine
leaving the patient unable to walk.
Some relative indications are linked to the qualification of the health staff at
peripheral level. This personnel often prefers to refer to the hospitals:
WHO/TB/83.141 Rev. 2
page 5
cases of failure of domiciliary chemotherapy (real or supposed)
relapse cases in whom a decision of a retreatment regimen should be taken
cases with manifestations of drug toxicity requiring chemotherapy adjustments.
When there are no beds, or the existing beds are not easily accessible to patients, there
is no reason to establish them. Judicious use should be made of the available beds in a
planned manner under clear guidelines of the national tuberculosis programme. When
hospitalization of tuberculous patients is clearly indicated, there is no reason why beds
in the nearest general hospital should not be used: the old ideas on isolation of
tuberculous patients should be abandoned because appropriate chemotherapy ensures that
even the most infectious patients are rapidly rendered non-contagious. There is no point
in sending all patients to a specialized hospital (when one exists): such a hospital is
generally situated much further from the patients’ homes than the general hospital, and
its communication with the basic health units is more difficult or non-existent. In
summary, there is no good reason why general hospital beds cannot be used for
tuberculosis when indications are specified by the national control programme and if the
number of patients is small.
Certain physicians bring up the question of insufficient health personnel at the
periphery, and the inadequate qualification of such personnel, to justify hospitalization
of all patients - particularly those from the poorest and most distant rural areas - for
the initial phase of treatment. However, even when patients would accept this, it can
only be a partial and temporary solution. It could not be applied in all parts of the
country, due to the lack of hospitals and although it allows supervision of treatment to
be made for one or two months, it does not solve the problem for the total duration of
treatment. In such a situation, the efforts of the physicians would be better employed
in training primary health care personnel at the periphery, rather than in persuading
patients to stay in hospital for two months, far from their families.
It is not necessarily true that supervision of chemotherapy is always better organized at
hospital than in domiciliary treatment. Patients, as a general rule, do not need to be
hospitalized. In the long term it is more efficient to organize treatment supervision on
an ambulatory basis, ensuring that the responsibility for the regular drug intake is
assumed by the patient, the family and the health personnel right from the beginning of
treatment.
D.
CHEMOTHERAPY
Chemotherapy quickly reduces the number of bacilli present in the lesions and thus very
quickly reduces the infectiousness of a patient. Because of the slow rate of multiplication
of bacilli, chemotherapy must be followed for many months in order to achieve their total
destruction and to prevent relapse.
1.
Basic principles of good chemotherapy
The following are the main principles of good chemotherapy:
a)
The patient must receive an effective drug regimen, i.e. one which has been shown in
a controlled trial to be effective, is acceptable by the patient, and does not
interfere with his family and social life.
b)
The patient must know and accept to consume the exact dosages of each drug as
prescribed. If he feels that he has a problem, he should not modify or stop
treatment on his own, but must discuss it with the doctor or nurse at the health
service.
c)
Treatment must be uninterrupted, and the drugs must be taken very regularly, every
day or three times or twice per week as the case may be. The patient should be
Informed that interruptions can cause failure of treatment.
WHO/TB/83.141 Rev.2
page 6
d)
Treatment must be taken for the full prescribed duration, one year, eight or six
months as the case may be, even if the symptoms disappear within a few weeks.
In addition to the above technical principles of good chemotherapy, there are several
operational ones which must also be observed in national tuberculosis programmes:
2.
a)
Only the standard drug regimens with proven efficacy must be prescribed. There is
no place for tailoring the drug regimen to the needs of a particular patient or for
haphazard modifications to regimens made on the spot by the personnel and not in
line with the technical recommendations. This does not mean that other regimens
might not be good on an individual basis but uncontrolled multiplication of regimens
hinders a planned procurement and distribution of drugs. Standardization of
regimens is the first requisite to permanent availability of drugs in a programme.
b)
Prescribed regimens must be supplied free of charge to every patient, to ensure that
treatment is not interrupted because of the inability of the patient to pay for the
drugs. T*----- said
* ’ •that
’
’ do not value things that are given to them
It is sometimes
people
free. This is not a good
„ ’ argument,
« —• A large volume of evidence exists which shows
that the inability for the individual patient or for the community to buy even
inexpensive drugs is one of the main reasons for the interruption of treatment in
developing countries.
c)
Patients’ convenience, and not that of staff in the health unit, is what matters
most in ensuring good chemotherapy. Thus treatment organization must make sure that
the chemotherapy is made available near to the patient's home; that he is
contacted/visited at home whenever he does not appear in the health unit to collect
the drugs; that his treatment is readily transferred to another convenient health
centre when he moves home; that he is precisely informed about the new place where
he should call or the name of the person whom he should contact to continue his
chemotherapy.
d)
Health education of the patient and his family should not be limited in time, and
independent from treatment activities. It must be systematic, repeated and
integrated with other activities. Welcoming, clean and accessible health clinics
together with punctual, conscientious and kind health staff are very powerful
factors of health education. They will ensure the patient’s full and wholehearted
cooperation in bringing his treatment to a successful end.
Essential Antituberculosis Drugs
Six essential antituberculosis drugs (Table 1) are sufficient for organizing a
chemotherapy programme in any given situation:
isoniazid and rifampicin, which are the two major bactericidal drugs
streptomycin and pyrazinamide which have a complementary bactericidal action
thioacetazone and ethambutol which (like PAS, in previous times) are companion drugs
to the major drugs and serve to avoid emergence of drug resistance.
a)
Isoniazid (H); is the most potent bactericidal drug. It is given by mouth. It is
usually supplied in tablets of 100 mg and 300 mg. The therapeutic daily dose is 4—6
mg/kg body weight, both for adults and children. The total daily dose should never
be more than 300 mg. This low daily amount is sufficient in both slow and rapid
isoniazid~acetylators on condition that it is taken in one single dose. It is not
only unnecessary but also impracticable under programme conditions to measure the
serum concentration of isoniazid in order to adjust for individual treatment.
In twice weekly intermittent regimens the dosage should be.increased to 12 to 15
mg/kg body weight (dosage should never exceed 15 mg/kg) in both adults and children.
WHO/TB/83.141 Rev.2
page 7
Table 1
Essential antituberculosis drugs (1) and their pharmaceutical presentations
Name
Pharmaceutical presentation
Isoniazid (H)
Tablet
Rifampicin (R)
100, 300 mg
150, 300 mg
Tablet or capsule
Pyrazinamlde (Z)
Streptomycin (S)
Dosage
500 mg
Tablet
Powder for injection (sulfate)
Ethambutol (E)
1 g
100, 400, 500 mg
Tablet (chlorhydrate)
Combinations
Thioacetazone + (TH)
Isoniazid
Tablet
Rifampicin + (RH)
Isoniazid
Tablet
Rifampicin + (RHZ)
Isoniazid+
Pyrazinamlde
Tablet
and
T 50 + H 150 mg,
T 150 + H 300 mg
and
R 150 + H 100 mg
R 300 + H 150 mg
At least four different
dosage combinations
are available (2)
(1)
The Use of Essential Drugs, WHO Technical Report Series N.722, 1985.
(2)
For daily administration;
R 120 + H 50 + Z 300 mg
R 120 + H 80 + Z 250 mg
R 150 + H 75 + Z 400 mg
For intermittent administration, three times a week;
R 100 + H 125 + Z 375 mg
WH0/TB/83.141 Rev.2
page 10
In daily treatment the usual dosage is 20-25 mg/kg body weight during the initial
two months, and thereafter 15 mg/kg body weight. The daily dose should never exceed
1.2 g. In intermittent treatment the dosage should be adjusted to 40 mg/kg body
weight for each day of treatment, without exceeding 2 g.
Intermittent treatment with ethambutol should be reserved for retreatment schemes in
association with rifampicin. The association of ethambutol with isoniazid is less
efficient in intermittent treatment than in daily regimens: this is why intermittent
treatment with ethambutol and isoniazid is not recommended.
Ethambutol is generally better tolerated than thioacetazone but much more
expensive. The main side effects are optic neuritis, diminution of visual acuity,
confusion in colour vision and finally blindness. Toxicity can be detected in
adults and all complications avoided by early withdrawal. Ethambutol should not be
prescribed to children because it is difficult to detect in them the early signs of
ocular toxicity. The dosage of ethambutol should be reduced in patients with renal
failure.
f)
Thioacetazone (T); is given by mouth. It is a bacteriostatic drug which is always
associated with isoniazid in a fixed combination (TH), supplied in two different
tablets:
one tablet containing 300 mg isoniazid and 150 mg thioacetazone, which
. represents the effective daily dose for adults
one tablet containing 100 mg isoniazid and 50 mg thioacetazone, which
facilitates the adjustment of the daily dose to the patient’s body weight,
particularly in children.
The daily dosage is 2.5 mg/kg body weight in both adults and children.
Thioacetazone should never be used in intermittent regimens.
It is well tolerated in a large number of developing countries, as has been shown in
many international cooperative controlled trials. The main side effects are
hypersensitivity, skin rash and digestive problems. A very severe toxic reaction
that may exceptionally be seen during the initial weeks of treatment is the
Stevens-Johnson syndrome or exfoliative dermatitis. This reaction may be more
common in some countries than in others. Thioacetazone is safe enough, however, to
be used as a companion drug in many countries.
The combination isoniazid-thioacetazone is an effective combination with the
advantage of being very cheap.
The doses of the six essential antituberculosis drugs for daily and intermittent regimens
are presented in Table 2.
WHO/TB/83.141 Rev.2
page 11
Table 2
ESSENTIAL DRUGS AGAINST TUBERCULOSIS
Recommended dosages
Intermittent
Daily
Drug
Abbreviation
mg/kg
maximum
mg
mg/kg
maximum
mg
Isoniazid
H
5*
300
15
750
Rifampicin
R
10
600
10
600
Pyrazinamide
Z
30
2000
2500
50
(3 times a week)
70
3500
(2 times a week)
Streptomycin
S
15
1000**
15-20
1000
Ethambutol
E
25***
1200
40
2000
Thioacetazone
T
2.5
150
* 10 in children
** 750 patients of over 50 years of age
*** 15 after two months
WHO/TB/83.141 Rev. 2
page 12
Table 3
SUITABLE REGIMENS OF CHEMOTHERAPY FOR TUBERCULOSIS
IN NATIONAL CONTROL PROGRAMMES (1987)
Duration
in
months
Regimens(l)
Failures/
relapses
Z
WHO drug cost^)
dollars
ratio
(1987)
(4)
12
2 STH/TH
1 SH/SH2
2 SEH/EH
5-10
5-10
5-10
7.2
9.0
13.2
1.0
KT
1.8
8
2 SRHZ/TH
2 SRHZ/H
2 SRHZ/SHZ2
0-3
0-3
0-4
31.1
30.0
43.7
4.3
4.1
6.0
6
2 SRHZ/RH
2 ERHZ/RH
0-2
0-2
69.4
67.6
9.6
9.4
2 RHZ/RH
2 RHZ/RH3
2 RHZ/RH2
0-2
0-2
0-2
66.1
43.3
37.5
2A
6.0
5.2
Key:
(1)
The drugs utilized in these regimens are conventionally represented by the following
letters: H = isoniazid, R ■ rifampicin, S ■ streptomycin, Z = pyrazinamide,
T » thioacetazone, E = ethambutol.
The number preceding the first letter indicates the duration in months of the
initial intensive phase; the number which follows the last letter represents the
number of weekly doses in the continuation phase if the regimen is intermittent.
(2)
The prices are average prices for adults, calculated on the basis of prices paid by
WHO to producers in 1987. They are not the actual price of the drugs on the shelf
of the pharmacy of the health unit. It is necessary to add the cost of
transportation and distribution which represents an increase of 50 to 100Z over the
WHO price.
(3)
The ratio or relative cost of regimens is based on their cost relation to the less
expensive regimen, to which a value 1 was assigned.
WHO/TB/83.141 Rev.2
page 13
3.
Standard drug regimens
The essential drugs available today allow us to compose highly efficient chemotherapy
regimens: the potential efficacy of these drug regimens, when regularly followed, is
virtually 100X, as demonstrated in different controlled clinical and comparative field
trials in many countries (see Table 3).
These regimens share the following characteristics:
they have two phases: an initial Intensive phase, usually of eight weeks, with three
or four essential drugs and a subsequent continuation phase with generally two drugs
given daily or intermittently, three or two times a week.
they are well tolerated
they are of low toxicity.
These drug regimens differ in two main respects: their duration (12 months for the
longest and six months for the shortest regimen) and their price.
In the tuberculosis programme of a country, two alternative regimens could be adopted;
one, a daily drug regimen, fully supervised during the initial intensive phase, if
possible, and then self-administered in the continuation phase; the other initially daily
in the intensive phase and subsequently intermittently, both phases fully supervised.
These two regimens can guarantee efficient chemotherapy of all newly diagnosed patients,
wherever they live (urban or rural), whatever their way of life (sedentary or nomadic),
■ their medical problems (other diseases) or behavioural problems (psychopaths or drug
addicts).
The categories of standard drug regimens based on different durations, but all highly
efficient, are as follows:
3.1 Twelve-month drug regimens
The 12-month drug regimens have been widely used in the world after the Sth Report of the
WHO Expert Committee on Tuberculosis, published in 1964.
All these regimens have a potential efficacy of more than 90Z and over 95Z if
streptomycin is given daily for at least the first eight weeks. The risk of major
toxicity which implies the discontinuation of at least one drug is variable but it is not
higher than 4%.
These regimens are still used in many developing countries because of their low cost.
Their effectiveness under programme conditions is always inferior to their potential
efficacy, which entails the need for retreatment of a large proportion of patients, 20
per cent or more.
3.1.1 2STH/TH
The regimen associating 12 months of daily isoniazid and thioacetazone, with an initial
supplement of daily streptomycin (from four to eight weeks), is the least expensive
regimen. The association of three drugs in the initial intensive phase quickly reduces
the number of bacilli and makes it useless to continue up to 18 months.
Moreover, this association considerably reduces relapses from pre-treatment drug
resistance, whether primary resistance to streptomycin and/or to isoniazid, or a natural
resistance to thioacetazone, which is common in West Africa, where strains of
Mycobacterium africanum are prevalent.
When streptomycin cannot be given to all patients, due to financial constraints, the use
of this regimen should be restricted to sputum positive cases.
WHO/TB/83.141 Rev.2
page 14
3.1.2
2SEH/EH (and 2SThH/ThH)
In some countries, isoniazid and ethambutol are associated for one year in a daily
regimen (ethambutol thus replacing thioacetazone). This regimen SEH/EH is comparable in
efficacy to the former one; it is better tolerated but always more expensive.
In other countries, thioamides (Th - ethionamide or prothionamide) are utilized instead
of thioacetazone. Wherever applied, this regimen seems efficient, but there are no
controlled trials that r
- the efficacy of _this
‘„2. regimen to STH/TH‘ moreover, optimal
compare
daily dosages of thioamide
in---------association—
with
-- —
... 300 mg of isoniazid are not yet clearly
determined. Usually 500 mg of thioamides are prescribed as the daily dose, but some
studies suggest that lower doses could be equally effective.
Tolerance to thioamides is variable in different countries, and the association of
isoniazid and thioamide is always more expensive than the combination isoniazid and
thioacetazone.
3.1.3
1STH/SH? or 1SH/SH2
This 12-month alternative drug regimen has the advantage of being aa fully
fully supervised
supervised one
one
and the disadvantage of having 124 to 136 Intramuscular injections of streptomycin, which
may not be welcome. After an initial intensive phase of daily chemotherapy, the
continuation phase comprises fully supervised twice weekly isoniazid (at higher doses,
12-15 mg/kg) and streptomycin.
It is also possible to give a fully intermittent regimen (SH2) for one year with
comparable efficiency. Intermittent drug regimens with thioacetazone and isoniazid or
isoniazid and ethambutol have lower efficacy and should not be used.
3.2
Nine~month regimens
The nine month regimens — 2RHE/RH or 2 RHS/RH - have been widely used in developed
countries since 1976. They are based on a daily administration of isoniazid and
rifampicin during nine months, with the addition of a third drug - ethambutol or
streptomycin — during the first two months. Now they are being gradually abandoned
because, having the same efficacy, they are longer and more expensive than the 6-month
regimens which contain pyrazinamide in the first phase.
3.3 Eight-month regimens
In the eight-month regimens, rifampicin is given only during the first two months.
Therefore they are less expensive than 6-month regimens in which rifampicin is present
throughout the full course. To compensate for the lack of rifampicin in the second phase
a total duration of eight months is required with these regimens.
3.3.1 2SRHZ/TH or 2 SRHZ/H
This drug regimen combines in the initial intensive phase of two months (eight weeks)
four essential drugs: isoniazid, rifampicin, pyrazinamide and streptomycin, daily; in the
continuation phase of six months, isoniazid and thioacetazone (or isoniazid alone) are
given daily. The regimen is well tolerated and has over 98Z efficacy. The risk of
toxicity is very low, even during the initial four-drug intensive phase. The regimen
2SRHZ/H should be used only in countries where the initial mycobacterial resistance to
isoniazid is low.
The use of four drugs in the initial intensive phase makes it possible to achieve 90Z
culture negative results in two months; therefore drug consumption under strict
supervision is imperative during this phase, whether in hospital, in the health centre or
at home. The six-month continuation phase of thioacetazone and isoniazid (or isoniazid
alone) is self-administered daily.
WHO/TB/83.141 Rev.2
page 15
The advantages of these regimens are shortening of duration of treatment and supervision,
high efficacy, low toxicity and a fairly large possibility of applicability, even in
rural areas of developing countries, because of their relatively low cost.
3.3.2
2SRHZ/SHZ2
If there is a need for a fully supervised eight-month regimen it is possible to give
isoniazid, streptomycin and pyrazinamide, twice a week, during the second phase, The
total duration of this regimen should be eight months, since its discontinuation after
the sixth month reduces the efficacy.
3.4
Six-month regimens
These are the shortest regimens that can be applied in tuberculosis programmes, They are
also the most effective regimens; their potential efficacy is more than 98Z. The
combination of isoniazid, rifampicin and pyrazinamide has the highest bactericidal and
sterilizing activity against tubercle bacilli.
3.4.1
2RHZ/RH
This regimen is based on the association of daily isoniazid and rifampicin for six
months, with the supplement of daily pyrazinamide during the first two months, The use
of tablets combining the three drugs of the first phase and the two drugs of the second
phase makes compliance easier to the patient, and reduces the risks of toxicity and
failure due to errors in the dosage.
This regimen is effective in the treatment of pulmonary and extrapulmonary tuberculosis,
in children and in adults.
If fully supervised treatment is desirable, isoniazid and rifampicin can be given either
three times or two times a week during the continuation phase - regimens 2RHZ/RH3 and
2RHZ/RH2 -.
3.4.2 2SRHZ/RH or 2ERHZ/RH
In countries with high prevalence of initial mycobacterial drug resistance it is
desirable to add a fourth drug - ethambutol or streptomycin - in the first phase of
treatment of smear-positive pulmonary tuberculosis. Ethambutol is a good fourth drug
choice because primary resistance to it is still quite rare. However, streptomycin is
generally preferred because the need for the injection offers the best opportunity to the
health personnel to fully supervise the first phase of intake of oral drugs.
In these two regimens, isoniazid and rifampicin can be administered intermittently, three
or two times a week during the continuation phase, The regimens can also be administered
intermittently throughout, three times a week.
4.
Choice of standard drug regimens
One of the most important decisions is the choice of drug regimens to be applied in a
national programme.
Many factors should be taken into consideration when taking a decision:
a.
wrong prescribing habits (for example, intermittent monotherapy with daily isoniazid
and streptomycin twice weekly, systematic addition of tonics and pyridoxin, too long
treatments, fanciful associations) or drug consumption habits within the country
(complete disregard for pyrazinamide, but widespread use of thioamides; free sale of
antituberculosis drugs by chemists, even without prescription)
WHO/TB/83.141 Rev.2
page 16
b.
the insufficient competence in tuberculosis control of those in charge of training
health personnel (medical and nursing students). The inadequate knowledge of the
teachers often poses considerable obstacles to a modern policy of chemotherapy, as
it contributes to perpetuating schemes which are archaic or scientifically unfounded
c.
the direct or indirect influence of drug manufacturers.
This list of constraints is not exhaustive, but it shows possible causes of failure if
obstacles are not
--- removed
--- — beforej a good chemotherapy programme is to start.
4.1 Criteria of decision
Three objective criteria should be applied in decision-making:
a.
the money which is available for antituberculosis drugs at national level
b.
the number of patients to treat, 1taking
’ *
into consideration the number of cases that
can realistically be diagnosed and kept under treatment
forr an appropriate period.
-------- —
c.
the--------state of development
health
servicesp present coverage of the population and
v wa. of
ucaxuii
ocivAuea,
level of training of health personnel who have to deliver and supervise chemotherapy
at the peripheral level.
The amount of money spent on antituberculosis drugs in the country is not only the drugs
budget of the public health services; one should also find out the consumption of such
drugs in the private and social security systems and compare the information with
national pharmaceutical production figures (when drugs are manufactured locally) and the
quantities imported. The analysis of the amount spent for each of the essential or
subsidiary drugs consumed in the country makes it possible to identify erroneous or
excessive prescribing, to detect whether financial resources under public services that
were meant for the purchase of antituberculosis drugs are being diverted to other
purposes, and to determine how the available money could be spent in a wiser and more
useful way. Obviously, the cost of antituberculosis drugs on the world market is an
important criterion for planning a more rational policy for the purchase of drugs.
In this respect, the list of prices paid by WHO for essential drugs is a valuable
indication to estimate the basic price of the drugs (price FOB, excluding transport to
destination and distribution within the country) (Table 4),
WHO/TB/83.141 Rev.J?
page 17
Table 4
WHO PRICELIST OF ESSENTIAL ANTITUBERCULOSIS DRUGS (1987)
Form/dosage
Drug
WHO cost
(US dollars) Quantity
Isoniazid
tablets
100 mg
300 mg
2.74
4.93
1000
1000
Rifampicin
tablets 150 mg
300 mg
(or
capsules)
4.05
8.15
100
100
100 + 50 mg
300 + 150 mg
4.83
10.60
1000
1000
Isoniazid+
rifampicin
tablets 100 + 150 mg
150 + 300 mg
(or
capsules)
N.A.
16.00
100
100
Pyrazinamide
tablets
500 mg
35.13
1000
Streptomycin
vials
1 g
5 g
6.00
25.00
100
100
Ethambutol
tablets
400 mg
9.10
1000
tablets
Isoniazid+
thioacetazone
Note: - The FOB (free on board) price of purchases ordered through WHO may be calculated by
adding 3% to the price indicated above.
- The GIF (cost, insurance, freight) price is the FOB price plus the cost of transport
with insurance to the purchasing country.
- To obtain the price of the drug ready for delivery to the patients, the cost of
distribution within the country should be added to the GIF price.
WHO/TB/83.141 Rev. 2
page 18
The number of patients to be treated should be calculated as realistically as possible.
If the health services cover the overall population and if the diagnostic facilities are
also widely extended, the annual infection rate may be used as a direct criterion (50 to
60 new smear positive pulmonary tuberculosis cases per 100 000 population per year for
each 1% of the risk of infection).
However, this relationship should be adjusted if the means for case-finding and diagnosis
only allow identification of a fraction of all cases. /As an indication,r the reported
incidence of cases diagnosed under routine conditions may be noted; if the number of
cases diagnosed is really low (in relation to the estimated annual risk of infection),
the principal task is to increase the coverage of the case-finding activities in order to
arrive at diagnosing two thirds of the infectious cases present in the community. If
two-thirds of infectious cases are identified every year, it is necessary to estimate how
many comply regularly with the drug intake, how many are cured and how many need a
retreatment course.
The participation of the health services in respect of treatment of tuberculosis should
be evaluated according to two indicators:
the proportion of basic health units which participate in the delivery of
tuberculosis treatment;
and, in particular, the number of auxiliary health personnel who are able to
dispense the drugs distributed, to supervise the intake of drugs by the patients and
to administer intramuscular injections.
In spite of the differences between regions, or between urban and rural areas within any
country, it is also possible (and simpler) to use a single significant overall indicator:
government health expenditure per year and per inhabitant, which is an exact indication
of the public services’ possibilities of maintaining an efficient health network and of
paying its personnel^).
In these basically unequal conditions of resources it is impossible to define a unique
chemotherapy policy for all the countries and each country should decide on its own
strategy.
4.2
A model for de cis i on
Bearing in mind the following three criteria for decision:
- the cost of different regimens, according to their duration of twelve, eight or six
months
~ the number of patients to be treated
- the budget for health per year and per inhabitant
it is possible to choose a strategy for chemotherapy, using a model for decision. This
model might be useful in those countries where health expenditure per year is less than
20 dollars per inhabitant (Table 5).
When the per capita expenditure is around one dollar, the 12—month regimens have to be
chosen, regardless of the epidemiological situation.
(1) According to the annual report of the World Bank in 1983, these expenses are:
one dollar per year in countries with a low Income (2210 million inhabitants) ten dollars
per year in countries with intermediate Income (1128 million inhabitants) 240 dollars per
year for industrialized countries (1100 million inhabitants).
WHO/TB/83.141 Rev.2
page 19
When the expenditure per capita is between two and four dollars, 12-month regimens must
be used if the risk of infection is higher than 2%. But if the risk of infection is 2%
or less, an eight-month regimen can be chosen.
When the per capita expenditure is between five and 10 dollars, the 12-month regimens an
applicable where the risk of infection is superior to 4%; the eight-month regimen if the
risk of infection is lower than 4%, the six-month regimen if the risk of infection is
lower than 2%.
When the per capita expenditure for health is between 11 and 20 dollars, six-month, or
eight-month regimens can be chosen, according to the epidemiological situation.
When the per capita expenditure is superior to 20 dollars, six-month regimens should be
generalized and there is no reason why longer regimens should be adopted.
The model presented in Table 5 may help to decide on the national policy for
chemotherapy. The current world trend is to adopt 6- or 8-month^regimens because they
are more effective against both sensitive and initially resistant bacilli than the
12-month regimens. The reduction in treatment failures and relapses implies a reduction
in the use of retreatment drugs. Although the cost of short-course regimens is higher
than that of the drugs for one-year treatment, the over-all cost for the patients, the
families and the health services is lower if the duration of treatment and cure rates are
taken into account. It should also be considered that in most developing countries the
price of drugs for an 8-month regimen is less than the cost of four standard thorax
radiographies or hospitalization for one week.
Table 5
A SIMPLIFIED MODEL OF DECISION-MAKING FOR CHOOSING
A STANDARD CHEMOTHERAPY REGIMEN IN A NATIONAL PROGRAMME
OF TUBERCULOSIS CONTROL ACCORDING TO DRUG COST AND DURATION
Governmental health expenditure
per annual per capita (dollars US)
Annual risk
of infection (%)
1
Key:
2-4
5-10
11-19
20 and more
up to 1%
does not
exist
8
6
6
6
1-2%
12
8
6
6
6
2-4%
12
12
8
6
6
4-6%
12
12
12
8
does not
exist
The numbers inside the table represent the duration in months of standard
chemotherapy regimens.
The duration is connected with the WHO prices in 1987 (Table 3).
12-month-regimens (2 STH/TH or 1 SH/SH2) cost 10 dollars as an average.
8^-month-regimens (2SRHZ/TH or H) cost 30 dollars.
fr-month regimens (2 SRHZ/RH or RH2) cost 40-70 dollars.
WHO/TB/83.141 Rev.2
page 20
E.
PERMANENT AVAILABILITY AND REGULAR DISTRIBUTION OF DRUGS
Three basic conditions should be met in order to ensure success of the chosen
chemotherapy policy:
drugs must always be available in sufficient quantity
drugs must be distributed free of charge
distribution of drugs to the patient must be controlled to ensure his regular supply.
1.
Permanent availability of drugs
Once the decision to use standard chemotherapy has been taken and all personnel has been
informed, sufficient quantities of the drugs must be made available at all levels,
especially
at the most
health units. TheThefinancial
financialresources
resources
necessaryto to
.
. peripheral
.
necessary
purchase these drugs should be included in the regular budget of the health services in
order to ensure regular supply. Relying on extrabudgetary sources for the purchase of
antituberculosis drugs could result in non-integration of these drugs in the national
list of essential drugs; interruption in supply if extrabudgetary aid is no longer
received; outside assistance agencies (of governments or non-governmental organizations)
imposing a regimen that is inappropriate or too costly for the national means; national
health authorities’ losing interest in a health action programme because others have
taken responsibility.
The quantity of drugs can easily be calculated on the basis of the selected regimens and
the number of cases to be treated, Purchase orders for one full year should be
established with anticipation at all levels; peripheral, intermediate and central, The
national global purchase order for antituberculosis drugs should be controlled at the
central level.
Whenever possible, it is advisable that the drug purchasing system be centralized, This
procedure is economical and helps in obtaining better prices. Purchasing procedures vary
according to country; private dealing markets or tender procedure. Whatever the
procedure, it is essential to use the generic names of drugs and not the rommerria 1 ones;
to specify the exact dosage, composition and form of the active product content
(sometimes it is useful to mention the colour and the different form of tablets
containing the same product or the same association but at a different dosage); to
foresee the necessary quantity for the needs of one year plus a security stock of 20-25Z
of supplementary provision of drugs over the requirements of one year. Centralized
purchasing has another advantage; it offers the opportunity for quality control of drugs
at the central level, using methods which are independent of those which are (or should
be) applied by the manufacturers. Such quality control methods are essential in order to
obtain constant guarantee of the quality and uniformity of the drugs purchased by the
health services.
Central pharmacy services should be equipped in such a way that storage of drugs (to
avoid deterioration) and their manipulation for transport are constantly guaranteed. A
transport service using trucks, trains or even planes should be organized in order to
ensure the flow of drugs from the central pharmacy to regional warehouses and from there
to the rural hospitals and the periphery. The personnel of these services should be
trained to control purchasing and product flow, to preserve the products from
deterioration and to control and respect the expiry dates.
Each pharmacy hospital should hold a stock of drugs sufficient for three to six months
(this varies according to country or the regions within the country) and distribution to
the peripheral health units for all the essential drugs should be done each month or week
(according to local conditions) so that all health units should regularly receive a
sufficient quantity of tuberculosis drugs in proportion with the number of cases treated.
The distribution of drugs to patients should be foreseen by the central services.
Antituberculosis drugs should never be handed loose or in a paper bag to the patient:
rain or the patient’s perspiration could accidentally dissolve the drugs and render them
useless. A special container (in glass, aluminium or plastic) or small plastic sachets
that are easy to press shut should be supplied to all peripheral health units with the
packages of drugs (boxes of 100, 1000 or 10 000 tablets).
WHO/TB/83.141 Rev.2
page 21
2.
Free-of-charge distribution of antituberculosis drugs
As already discussed, the free supply of antituberculosis drugs is one of the operational
principles of the chemotherapy programme. Ibis principle is easily applicable when free
supply of essential drugs is ensured within the framework of a primary health care
policy. It is sufficient to include in the list of essential drugs the names of the
antituberculosis drugs constituting the chosen standard chemotherapy regimen.
In countries where the health system is supported by a social insurance system, it would
be advisable to organize a national central purchase of drugs, rather than ask the
patients to buy and be refunded later, which could lead to corrosion of the family budget
and encourage patients to buy only part of the prescribed drugs. In countries where
there is neither free-of-charge supply of essential drugs nor a social insurance system,
health services should organize the free distribution of antituberculosis drugs
themselves.
3.
Regular and controlled administration of drugs to the patients
All the previously mentioned measures are indispensable but the true key to success of a
chemotherapy programme is the regular and controlled administration of drugs to the
patients.
During the first phase of treatment, generally eight weeks, it is essential that the
daily dose be taken by the patient under the supervision of health personnel.
Drug intake can be either intermittent, fully supervised, or daily, self-administered, in
the continuation phase (4, 6 or 10 months). If it is daily, self-administered, the
patient must collect the drug supply at regular intervals, once a week, or every 2 or 4
weeks, which has to be clearly established from the start of treatment. Drugs should be
given in closed boxes or plastic envelopes to protect them from humidity. Each box or
envelope should carry a label indicating the patient’s name and the exact number of
tablets needed until the following collection day.
F.
HOW TO ENSURE THE PATIENTS* COMPLIANCE
Once the drug distribution has been efficiently organized, the health units should ensure
that the correct drugs and doses are prescribed to the patients and that the patients
follow closely the given Indications. Measures intended to ensure the patients’
compliance should be written with the same detail as the chemotherapy regimens in the
national guides on treatment of tuberculosis. The following measures should be
considered:
The first contact between the patient (and a member of his family) and the doctor/health
officer and nurse in charge of the supervision of treatment, is often a crucial event on
which the success of treatment and the future of the patient depend. This contact should
be standardized and should include a personal conversation with the patient in a language
understood by him. This conversation makes it possible;
to inform the patient about his disease, about its infectiousness and its
curability; and about the choice of regimen which is available within the national
programme
to obtain the various addresses of the patient: his present home address, the
address of his family (spouse and children), of his parents, relations and friends,
and that of his place of work. Having these addresses makes it possible to locate
him at a later date in case of absence during treatment
to establish a list of contacts living in the same house, or same room
to enrol him in the tuberculosis register of the health unit, to establish his
individual record and to supply him with a treatment card where the date of the next
appointment is clearly indicated.
WHO/TB/83.141 Rev.2
page 22
During the first visit a clinical form must be filled in before treatment: weight of the
patient information on previous antituberculosis treatment, pre-existing pathologies
(allergies, liver and digestive problems, psychological problems, renal function),
associated pathology (diabetes, pneumoconiosis), pregnancy, and regular intake of other
drugs that might interact with the antituberculosis treatment (antiepileptics, adrenal
hormones, oral contraceptives, etc.). Sugar and proteins in the urine may be
Investigated when possible. These investigations may help to prevent toxic reactions and
to adapt the chemotherapy regimen to the social and medical situation of the patient.
During the initial intensive phase, all the drugs should be given to the patient every
day (or three times weekly) and he should swallow them at once (with a glass of water),
under the supervision of a nurse or community health agent. This intensive phase can
take place as already discussed, at home, at the health unit, or sometimes in hospital,
in any place where injection of streptomycin can be applied.
It is essential that all drugs are «administered
’ ’ '
L Jday to the patient and that the
each
health personnel check the drug tolerance and register■ any complaints or toxicity
reactions. Strict supervision in this phase allows corrective measures to be made in
good time and helps to convince the patient of the seriousness of the treatment.
During the continuation phase, the drugs may be distributed regularly to patients in two
different ways:
For patients living within 5 km of the dispensary or health unit where the drugs are
distributed, or in specific situations where complete supervision
is
.
5 necessary.
intermittent chemotherapy regimens are often selected. The
T.._ patients come for their
drugs twice or three times weekly and take them under strict
-- - supervision, until the
end of treatment.
In all other cases: rural patients or those living more than 5 km from the
dispensary and patients who are responsible and who have received a good health
education, are handed the drugs at fixed dates, for periods of one to four weeks
maximum, for a daily, self-administered treatment.
Drugs
urugs could
couia exceptionally be given for longer periods to patients who make seasonal
changes of residence, who work far from their region of origin, or who are nomads, In
all these cases, daily, self-administered chemotherapy regimens are prescribed. Simple
measures of health education should be taken in order to encourage the patient to take
his drugs regularly; the patient and a member of his family (spouse, relation, elder
brother or sister) should be informed as to the number of tablets to be swallowed each
morning; the number of tablets for a given period should be counted in front of him; he
should be given a container (glass, aluminium or plastic) with a screw lid, in which to
protect his drugs from damp; the date of his next appointment should be given to him and
marked on his treatment card. The same procedure should be followed at each appointment
until the end of his treatment.
In case the patient is absent from the expected appointment, iimmediate
Jl-L- action (defaulter
action) should be started: home visit, convocation, visit to relatives, friends, or place
of work, in order to encourage the patient to continue his treatment, This action should
be started within one week after the day of absence, othe;
otherwise the neglected patient will
soon be forgotten and lost sight of before the end of the treatment period. The health
personnel is more responsible for the patients’ compliance than the patients themselves.
Every visit the patient pays to the health unit in relation to his tuberculosis treatment
should be registered on the treatment card, The patient may also carry a copy of his
card.
The treatment card provides the exact information on the patients’ compliance with drug
intake in the supervised treatment, and with drug collection in the self-administered
treatment. The control of these cards is essential to monitor the organization of
domiciliary treatment.
WHO/TB/83.141 Rev.2
page 23
To evaluate patient compliance other control measures have been proposed, such as
unannounced visits to count the number of tablets the patient still holds, and the urine
test to detect drug metabolites. These procedures are very useful in controlled clinical
trials but they are expensive and are not easy to implement in national control
programmes. They may also create the feeling in the patient that he is a mistrusted
individual.
G.
TECHNICAL MEASURES FOR THE FOLLOW-UP OF TREATMENT
When selecting the chemotherapy regimens to be applied under the national programme and
the methods to ensure compliance, it is important to prepare technical instructions on the
measures to be taken in order to monitor the efficacy of the treatment, to interrupt or
change a treatment, and to detect and correct any undesirable effects.
1.
Control of the efficacy of treatment
In cases of pulmonary tuberculosis, bacteriological examination of sputa (by microscopy
at least, and by culture where possible) at appropriate intervals is far more important
than periodical X-ray examination. Bacteriological examination of sputa during treatment
is carried out at the microscopy (and, if possible, culture) laboratory which is nearest
to the health unit where the patient collects his drugs. The sputum samples are
collected at the patient’s home or in the health unit and are sent the same day, whenever
possible (and at the latest five days after collection), to the laboratory. Once or
twice monthly bacteriological examination of sputa is optional during the first two
months of treatment; if it can be done, it makes it possible to show the patient and the
health personnel that the treatment is being correctly followed and that it is effective,
by pointing out the progressive decrease and then the disappearance of bacilli from the
samples.
In 12-month regimens, it is recommended to repeat sputum examinations at the sixth and
ninth month and, in particular, at the end of treatment, at the eleventh and twelfth
months. In six-month and eight-month regimens, it is recommended to carry out the
bacteriological examinations of sputa one month prior to the end of treatment, and at the
end of treatment (at the fifth and sixth months, or at the seventh and eighth months).
Each time, two sputum samples should be collected, if necessary the same day. If the
patient is unable to produce a sample (which is frequent), he should be asked to produce
the result of strongly clearing his throat after prolonged coughing. When a good
chemotherapy regimen is regularly administered to and correctly taken by the patient, no
bacilli are generally found in the sputum beyond the third month of treatment.
In cases of extrapulmonary tuberculosis, clinical examination (and possibly also X-ray
examination) of the affected organ, after two and six months, and at the end of
treatment, makes it possible to monitor the disappearance of symptoms or the appearance
of scars and inactive sequelae. In cases of urinary tuberculosis, bacteriological
examination of the urine should be carried out during treatment and at the end of
treatment, at the same Intervals as bacteriological examination of sputum in pulmonary
tuberculosis.
2.
Criteria to decide on the termination^ resumption or change of chemotherapy
In cases of pulmonary tuberculosis, the bacteriological examinations carried out during
and at the end of treatment are sufficient to allow a decision to be made.
a.
If the examinations of the last two months of a regular treatment are negative, the
patient should be considered cured, whatever the extent of radiological pulmonary
sequelae. Treatment should be stopped. The cured patient is informed that he
should consult if the respiratory symptoms recur, but systematic medical supervision
after treatment is absolutely unnecessary.
WHO/TB/83.141 Rev.2
page 24
b.
If one of the two examinations carried out in the last two months of treatment is
^°8icaliexaminatiuns
negative, the patient can be considered cured.
If
r X Rie SupPlementary bacteriological examinations is positive, treatment failure
is probable and a new treatment should be prescribed.
Treatment failure occurs when, during the regular course of treatment,
> the
bacteriological examinations of isputum
—*■—--’ ■ positive,
• •
persist
or they become again positive
after a transient period of negativity, Relapse is the emergence of positive results in
the bacteriological examinations any time after the completion of a regular successful
period of treatment.
In pulmonary tuberculosis the failures ;and’ relapses
_1_
together should not be higher than 5
per cent with the 6-month and 8-month regimens,
‘ZJ
» or
or 10
10 per cent with the 12-month regimens
if all patients are correctly treated.
In cases of extrapulmonary tuberculosis.
signs of active disease.
3.
The problem of retreatment
3.1 Most often this problem concerns patients who have taken their drugs irregularly or
-Interrupted treatment prematurely. Ihe risk of failure or relapse is high when more than
r:r?a\CenT
prescribed doses of a determined regimen are not taken by the
pa, T
In thaae cases the same Chemotherapeutic regimen which was prescribed
originally should be started again, under close supervision and strict monthly
bacterioiogica! control. An effort should be made to identify the social, economic
psychological, educational or organizational factors which induced the irregularity or
defaulting to study whether any corrective measure can be undertaken.
3.2 Failure during regular chemotherapy is very rare,
Initial resistance to isoniazid
or streptomycin is the most likely cause of failure in .a patient who complies with the
prescribed chemotherapy regimen. Other causes can be a
^ndSotherdmedl°Sa8et’
‘he Pharmacolo8^ interaction between ^tuberculosis d^gs
d
W
ta whlch the Patient might be taking.
If no other causes can be
s^itiv^; testn«h^lZKSUaPtlOn ? that the bacilli are resistant.
If feasible a
rnn, i , i
should be done. As a general rule, the patient should be prescribed
a
completely different regimen including:
during the first three months, three drugs to which the bacilli were shown to be
susceptible
susceptible,, or which the patient has not received before for more than three months,
thereafter, two drugs daily or twice a week,
for a continuation period of nine
months.
The most effective retreatment
---regimens are those in which rifampicin, ethambutol and
pyrazinamide are associated in the first phase (3 —
REZ/RE
.'-J or 3 REZ/RE2).
af^r a?
c*ultt4 course of chemotherapy
cnemotnerapy is rare in compliant patients. They
regular
are 5-10 times less frequent after short-course chemotherapy than after the 12-month
regimens.
If relapse occurs after a 6-month regimen, the isolated bacilli
are generally susceptible
to the drugs. T._
The same regimen as previously prescribed should be given again, under
close supervision.
WHO/TB/83.141 Rev.2
page 25
3.4 Repeated relapses after several, complete or incomplete, courses of chemotherapy may
be caused by Irregularities in drug Intaking, medical errors
errors In the prescribed regimens,
or deficiencies in the organization of domiciliary treatment.
The number of chronic ” patients (those who have excreted tubercle bacilli for more than
one year) is large when supervision and control of tuberculosis treatment is not well
organized.
Many of these cases have received all or almost all the known antituberculosis drugs.
Therefore a sensitivity test is essential to select a rational therapy.
4.
Detection and correction of side effects
Technical guides should clearly state all possible side effects that can occur during
treatment with the standard regimen so that health personnel should be properly informed
of the corrective measures to be applied.
Preventive measures should make it possible to identify "risk” groups of patients: those
who are underweight, who have a history of renal or hepatic insufficiency or of allergy,
and those with proteinury. <•Such
• patients
•
....be closely supervised, or should undergo
should
complementary biological examinations whenever possible, with a view to adapting or
adjusting the standard treatment, if necessary.
a
--------- J
“ — —
U. 0 •
Corrective measures would depend upon the nature and seriousness of the secondary effects
observed. Some side effects, such as digestive problems, are minor and do not justify
stopping the treatment,
--- • Others are more serious and call for temporary or final
withdrawal of one of the drugs; these normally need hospitalization and referral of the .
patient to a medical consultant to identify the drug responsible for the problem and to
decide on the continuation of treatment. Lastly, problems which may arise due to the
combination of anti tuberculosis drugs and other drugs which the patient may be taking
(oral contraceptives, corticosteroids, oral antidiabetics, cardiac glycosides) should be
considered: health personnel should be able to consult the national technical guidelines
in order to find instructions for any specific situation.
H.
SUPERVISION OF TREATMENT ACTIVITIES UNDER PROGRAMME CONDITIONS
1.
Supervision of treatment delivered at the health unit itself is easy; it is sufficient to
check that each patient whose treatment card is marked has in fact taken the number and
doses of drugs prescribed on each day of his daily or intermittent treatment.
2.
Supervision of drug distribution to patients collecting their drugs for
self-administration is also easy. In a health unit having more than 10 patients to
supervise, it may be preferable to decide on one or two days each week for the
distribution of antituberculosis drugs; each patient’s prescription can thus be prepared
in advance, which facilitates supervision. Each time the patient collects his drugs, the
quantity and the date should be noted on his treatment card and on his personal file
which is kept in the health unit. Supervision consists of a weekly check on the
treatment cards or on the individual files of patients under treatment.
3.
It is more difficult to supervise the actual taking of drugs for self-administration in
the patient’s home. The essential measure is to motivate the patient or a member of the
family to take the responsibility for treatment as a result of the explanations given at
the beginning of treatment and renewed in each successive contact with the patient and
his family. Urine tests on samples of patients may be used to evaluate compliance in the
programme.
4.
Any weaknesses in the distribution system should be identified and corrected; absence on
the part of the patient at an appointment should result in defaulter action. Treatment
supervision and defaulter action are facilitated by decentralization and by integration
of tuberculosis treatment within the routine activities of the basic health services in
WHO/TB/83.141 Rev.2
page 26
the most peripheral health units, as close as possible to the patient’s home. With
increasing decentralization, there
th
are fewer and fewer patients who are irregular in
their treatment or who default.
t. With strong supervision of treatment activities, there
are fewer errors, and omissions by the health staff, and less waste of drugs.
I.
EVALUATION OF A TREATMENT PROGRAMME
Intermediate and central level evaluation of a treatment programme has two principal
aspects:
evaluation of a treatment programme during the application
evaluation of the results of thje treatment programme.
1.
The basic documents for this evaluation are the register of notified tuberculosis cases
(register of notifications in which all the tuberculosis cases of an area or district are
registered chronologically) and the individual records of the patients in the health
units.
The information to be collected for each patient is: the name, surname, sex, age,
address, health unitj the initial diagnosis (pulmonary or extrapulmonary tuberculosis),
the initial bacteriological status, background or previous diagnosis and treatment of
tuberculosis; prescribed chemotherapy and the starting date of treatment.
The register can be completed at a later date for each patient, with the results of
-follow-up and of the bacteriological examinations carried out until the end of treatment,
and an indication of the patient's condition at the end of treatment or 12 months after
the start (cure, death). In a last column there should be space for any special roTnmpnts
(such as transfer of the patient to another health service, or early interruption of
treatment).
The patient’s personal file should include all medical and social data collected before
or during treatment. It should be possible to find the exact quantity of drugs received
by the patient, the frequency and duration of omissions or interruptions in treatment,
and the results of follow-up.
2.
Evaluation of a treatment programme during application
The simplest method is to send to the intermediate c~
; _1 1
or central
level"each month a copy or
reproduction of the pages of the register, with the information concerning the» cases
reported during the last month. This monthly list permits the control of the number of
cases admitted to treatment, their classification by diagnostic methods, age and sex,
1 is thus possible to follow monthly, at intermediate or central
regimens prescribed. It
level, the field application of the treatment
- ----- - programme.
3.
Evaluation of the results of a treatment progra
e
The basic method consists of assessing the status of cohorts of patients one year after
t
1'- start of treatment,
•
22
the
and- of- measuring
according
to the initial diagnosis (site of the
disease and bacteriological status) the number of deaths, cures, transfers, chronic cases
and defaulters.
Evaluation of results can be permanent (routine) or periodical (or centralized) and
retrospective or prospective.
Permanent evaluation may be carried out retrospectively in all health areas where the
register of reported cases i_
is kept up-to-date, or, which is a harder and slower method,
by analysis of patients’ individual files.
The simplest method is the study of the status
r*--*’ ~ one year after the start of treatment of a
cohort of sputum positive pulmonary tuberculosis patients
. ---- who
—) were admitted over a given
period.
WHO/TB/83.141 Rev.2
page 27
In a more advanced stage it is possible to organize periodically, every five to seven
years, prospective studies on treatment programme
results
in a national representative
-- —
sample. For this purpose, aa he,
* • unit
- - s sample
health
representative of all the count
country
health units should be selected <and 800 to 1600 registered pulmonary tuberculosis
J cases
are followed up for a given period.
Clinical, bacteriological and radiological examinations concerning these patients at the
start and at the end of treatment, should be assembled at central level. Pre-treatment
sputum samples should also be collected and fexamined
*
by microscopy, culture and
sensitivity test at the central reference laboratory,
, • Continuous Information on
evolution of patients during treatment should be reported to central level.
This national survey is more expensive and difficult to organize than the previous one;
but it is more objective and precise, It gives valuable data to assess the results of
the programme and eventually to introduce corrective modifications: changes in the
organization of treatment or changes in the chemotherapy regimens.
J.
HOW TO IMPLEMENT PROGRESSIVELY A STANDARDIZED CHEMOTHERAPY PROGRAMME IN A SITUATION OF
AN ARC HY
---------------- —----------------
In many countries, the chemotherapy programme selected by the health authorities is not
doctors’ re fuse^t^©^^^
^k^°Wn
th®ihe^th^Personnel, or because the prescribing
In such a situation chronic
bacterfal resistance increases and doctors call more
more and more
more for expensive drugs
drugs
that the community cannot provide.
1.
How to recognize such a situation?
An evaluation survey in a few treatment centres having archives or registers will quickly
identify this situation:
more negative patients than positive patients are admitted to treatment
among the smear positive pulmonary tuberculosis patients admitted to treatment.
there are more "old" than "new" patients
there are imore .patients
’ *
who default before the end of their treatment than patients
who complete their treatment
the applied therapeutic regimens are not standardized.
2.
How to correct this situation at national level?
Firstly, a national informative seminar should assemble all those responsible for the
^h°Sf1in char8e of medical training at the University and the doctors most
involved. A collective evaluation of the situation should be carried out by a group of a
few persons in responsible positions (including at least one administrator from the
health services, one clinician and one bacteriologist) and this should be followed by a
communication of the most relevant information on modern chemotherapy of tuberculosis.
At the end of the seminar, the general directives of the new programme should be agreed
upon, and the most urgent corrective measures decided immediately. In a second step, the
new technical directives are described in detail and circulated among all health
personnel. The means for evaluation are set up through new organizational methods
detailed in the technical directives. A supervisory team (or teams) visits the various
health teams in each province in order to check on the application of the technical
directives, to explain them whenever necessary, and to Identify problems. During a third
step, evaluation of the new policy of standardized chemotherapy can be carried out, 18 to
24 months after its application, either on the national level or in the more active
WHO/TB/83.141 Rev.2
page 28
health units. Further seminars are then set up: either a second national seminar
grouping all those who participated in the first seminar, or regional seminars with a
view to disseminating the information as widely as possible or to more easily overcoming
local resistance caused by the persistence of old habits. Regular evaluation seminars,
held at all levels, make it possible to involve in evaluation tasks an ever-increasing
number of health personnel, and to extend the measures of standardization and
simplification of chemotherapy to the whole country.
3.
How to correct a deficient situation at health cent re level?
If it has been decided to implement, e.g. an
a)
b)
8-month standard regimen:
all the new cases registered after the issue of the new directives should be treated
according to the new regimen.
all the old cases admitted to treatment for the last two years, or still under
treatment, should be analysed individually and a decision taken for each of them.
For all old pulmonary cases, two sputum smears are requested:
all those who have been treated for 12 months or more and have had two negative
sputum smears are considered cured and their treatment is stopped
those who have been treated for less than 12 months and who have smear negative
sputum should follow the old standard regimen up to completion of the twelfth month.
those who have smear positive sputum should be carefully assessed and the drugs they
have taken identified. In general, they should follow the new standard regimen (and
not a retreatment regimen) as they have in fact never had a treatment which was
adequate in both quality and duration.
For extrapulmonary tuberculosis, clinical and possibly also radiological examination
should be performed:
those who have been treated for 12 months or more should be considered cured and
treatment stopped
those treated for less than 12 months should be treated with the old standard
regimen until they have completed 12 months.
Once the standardization of the chemotherapy regimens has been enforced, it is necessary
to ensure, through the described methods of management and supervision, that the
directives are in fact respected; it is also necessary to point out to the health
personnel concerned, using evaluation methods, that the efficiency of the services has
actually improved (less work, less drug wastage, more cures, less defaulting).
K.
HOW TO INTRODUCE NEW CHEMOTHERAPY REGIMENS
In those countries where standard chemotherapy regimens are being applied already but
where they are inappropriate (i.e. 18-month regimens), or in cases where it is Intended to
introduce new standard regimens which differ in composition or duration, the movement towards
change should involve an improvement in the entire treatment programme, in both technical and
organizational aspects. The change is made progressively and implies the following:
1)
A national survey should be conducted to evaluate the existing regimen, if possible on a
national representative sample.
2)
If, in the new regimen, there are drugs which have never been utilized on a large scale
in the country, a survey should be organized, preferably in several regions, in order to
test the acceptability and toxicity of the new regimens. This survey should cover small
groups of 20-30 strictly supervised patients in each place. If the new regimens contain
only well known drugs, it is possible to omit this survey.
*
WHO/TB/83.141 Rev.2
page 29
3)
Under the responsibility of a competent clinician, a controlled study should be organize
to compare the old and the new regimens in two groups of patients chosen at random.
These groups should be sufficiently large for the results to have a statistical
significance.
4)
A national seminar should be held to present the status of chemotherapy of tuberculosis
throughout the world and the results of the acceptability survey and the controlled sLf.d
to all personnel concerned in the application of the new regimens. This seminar would
bring about general agreement as to the adjustment of technical chemotherapy directives.
5)
The newly chosen regimens should be applied under routine conditions on a limited scale.
The validity of the new technical directives should be tested.
6)
The new regimens applied to the first 50 to 100 patients in each district should be
evaluated one year after the end of treatment.
7)
The evaluation of the results of the new regimens should be presented during a second
national seminar. Adoption of the new technical directives should be discussed and a
date should be set for the start of the new programme.
WHO/TB/83.141 Rev.2
page 30
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Medicine, 1980. Ed.: DC Finley
Fox, W.
Whither short course chemotherapy?
Recent Advances in Respiratory
Br. J. Dis. Chest 1981, 75; 331-357
Fox, W. Short course chemotherapy for pulmonary tuberculosis and some problems of its
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Chaulet, P., Ait Khaled, W., Amrane, R. T
1982. Rev. Fr. Mai. Resp. 1983, 11: 76-110
Chaulet, P.
26-36
Pos®s Par
La chimiothgrapie de la tuberculose en 1983.
Chaulet, P. Strategies de lutte antituberculeuse. in:
Poumon-pleure mediastin, 6019 A 31, 11-1984.
Girling, D.J.
123-147.
tuberculose dans le monde en
Bull. Un. Int. Tuberc., 1983, 58;
Encycl. Med. Chir (Paris, France).
Effets secondaires des medicaments antituberculeux.
New Ethicals, 1982,
Ross, J.D.,Horne N.W. Modern Drug Treatment in Tuberculosis. 66th Edition, The Chest,
-Heart and Stroke Association, Tavistock Square, London, 1983.
Rouillon, A., Perdrizet, S., Parrot, R. La transmission du bacille tuberculeux; 1’effet
des
antibiotiques. Rev. Fr. Mai. Resp. 1976, £; 241-272
BCG Vaccination1
Am. Rev. Resp. Dis.,
Koch Centennial Memorial
125 (3)Part 2:70-72,1982
FABIO LUELMO
At (he beginning of (his century, sev
eral biologicals were used in attempts
to prevent tuberculosis by developing a
degree of resistance similar to that ob
served in previously infected persons.
Calmette and Guerin observed changes
;n the characteristics of colonies in cul
tures contaminated with oxbile and used
their findings to obtain an attenuated
strain of Mycobacterium bovis (BCG).
After 231 passages through media con
taining glycerin and oxbile, this BCG
strain was unable to produce progres
sive lesions in experimental animals
such as guinea pigs, rabbits, monkeys,
and calves.
On May 21, 1921, Dr. Weil Halle in
Paris for the first time administered a
vaccine to a child al high risk of acquir
ing tuberculosis. The child experienced
no untoward reaction. Based on this
and other clinical observations, the use
of BCG vaccination quickly spread
across Europe.
The vaccine was initially adminis
tered by mouth. Later, it was given by
subcutaneous injection, which pro
duced excessive local tissue destruc
tion. Finally, it was given by the intra
dermal route.
The publications of Petroff in the
United States and the disaster in Lu
beck, Germany in 1930 generated more
than 10 years of discussions on the
safety of BCG and the possibility of
virulent mutations of the strain. The
episode in Lubeck, Germany, in which
72 children died, was due to a labora
tory error, the contamination of the
vaccine with a virulent strain (Kiel),
which at the moment was thought to be
fully attenuated. This strain produces a
particular coloration in cultures, which
allowed its identification as the cause
of disease and deaths. However, by
1945, this method for preventing tuber
culosis was well-established, based
largely on clinical observations, indi
vidual experience, and a few uncon
trolled studies on the relative risks in
vaccinated and unvaccinated persons.
As described by Guld (1), the studies of
Heimbeck, in nurses in Oslo, and of
school girls in Hyge, confirmed that
70
vaccination conferred good protection
against tuberculosis.
The principal controlled studies of
the efficacy of BCG are reproduced in
table 1 (2). The results show wide vari
ation in protection, from 0 to 80%.
Several hypotheses have been proposed
to explain these differences. The most
probable factors influencing the results
arc the quality of the vaccine, and par
tial protection due to infection with
nontuberculous (“atypical”) mycobac
teria. In the Aronson trial (9), a vac
cine produced in poor culture medium
resulted in diminished tuberculin con
version rates (16 versus 46%) and de
creased protection during a 5-year
period (53 versus 80% in the total populalion). Some of (he st rains produced
by the Tice Laboratory around 1950
showed low activity in animal experi
ments, which is compatible with low
immunogenicity.
The route of administration of BCG
vaccine is also important. Only intra
dermal injection with a syringe and
needle permits adequate measurement
of an individual dose. A multipuncture
technique was used in Georgia (4), Ala
bama (3), and Illinois (1).
The discovery of a high prevalence
of low-grade tuberculin sensitivity in
humid tropical and subtropical areas,
interpreted as cross reactions due to the
sensitization to nontuberculous myco
bacteria, and the animal experiments
showing that these infections confer
partial protection against Mycobacteri
um tuberculosis (3) led to the hypothe
sis that atypical infection diminishes or
masks the effect of BCG by providing
partial immunity. Although there is
general agreement that this effect is im
portant, it alone cannot completely ex
plain the lack of protection found in
some studies.
A new study was started in Chingleput, South India in 1968 in an attempt
to avoid the methodologic errors that
might have affected previous trials (4).
Two doses of two different strains of
BCG were compared with a placebo.
The area was known to have a high
prevalence of nontuberculous myco-
bacterial infection, and purified pro
tein derivative (PPD)-B was used in ad
dition to PPD-S to distinguish infections
due to these mycobacteria. Subjects of
all ages were included, with a total
study population near 250,000 persons.
This was the first trial in which the vac
cines used were freeze-dried and stored.
In previous studies, the BCG strains
were lost or might have undergone
changes caused by permanent transfers
in culture media.
The findings of this trial, which was
sponsored by (he World Health Orga
nization (WHO), the Indian Council of
Medical Research, and the U.S. Public
Health Service, were disappointing:
(/) The vaccinated and unvaccinated
groups previously classified as not in
fected had similar incidences of dis
ease; no protective effect of BCG was
apparent. (2) The unvaccinated group
had a very low incidence of active
tuberculosis after infection, whereas
the previously infected population pro
duced large numbers of bacillary cases,
maintaining a high annual risk of
tuberculosis.
The tri^l tried to compensate for the
lack of bacteriologic data in previous
trials and the possibility of interference
from tuberculosis control programs.
Therefore, the study was oriented to
ward bacteriologically proved pulmo
nary tuberculosis in adults, and the
area selected was almost completely
lacking in resources for diagnosis, es
pecially for primary tuberculosis in
children. No data are available from
the study to evaluate protection in chil
dren, which is the current target group
for world vaccination. The results,
then, cannot be extrapolated to current
vaccination practices.
Very little disease was observed in
the period immediately after infection.
It is not clear whether this was due to
lack of diagnostic facilities, or to real
differences between the epidemiologic
model observed in India in previous
1 From the Pan American Health Organiza
tion, Washington, D.C.
TABLE 1
RESULTS OF 8 CONTROLLED TRIALS OF OCG VACCINATION AGAINST TUBERCULOSIS*
Population group and reference
North American Indians,
8 tribes (9)
Period ol
intake and
age range
1935-38
0-20 yr
Chicago infants, high-risk areas
(3)
Georgia, schoolchildren (14)
1937-48
under 3 months
Criterion ol eligibility
for vaccination
Source o( vaccine
Duration ol
lollowup
(years)
Vaccination
grouo
NO. Of
subjecta
Catos of
lubofcuiosts
-efficacy
No.
Rate!
Protec
tive
(%)
Negative to 0 005 mg
PPD Seibert (250 TU)
Henry Philippa Institute.
Philadelphia
9-11
Unvaccinaled
BCG
1,457
1.551
238
64
1.563
320
BOl
(No initial tuberculin testing)
Tico Laboratory, Chicago}
12-23
Unvaccinaled
BCG
1.665
1,716
65
17
2231
75
11
17
571
1947
6-17 yr
Under 5 mm to 0.002 mg
RT 18 (100 TUJ
Tice Laboratory, Chicago}
20
Unvaccinated
BCG
2.341
2.498
3
5
Illinois, school lor I ho monlally
rolardcd (11)
1947-48
Adolosconts and
young adults
Nogalivo to 1/1000 and
1/100 OT
Tico Laboratory, Chicago}
12
Unvaccinulod
BCG
404
531
8
12
Puerto Rico, general population
(10)
1949- 51
1-18 yr
Under 6 mm to 0.0002 mg
RT 19-20-21 (10 TU)
State Department of Health.
New York
5V.-71*
(Mean: 6.3)
Unvaccinated
BCG
27,338
50.634
73
93
43
30
31
1950
5 yr and over
Under 5 mm to 0.0001 mg
RT 19-20-21
Tico Laboratory, Chicago}
14
Unvaccinaled
BCG
17.854
16.913
32
26
13
11
14l
Great Britain, urban populations
(12)
1950- 52
14-15V« yr
Under 5 mm to 0.1 ml 1/100
Old Tuberculin (100 TU)
Statens Seruminstitut,
Copenhagen
15
Unvaccinaled
BCG
12.699
13.598
240
56
128
28
78
South India, rural population
(15)
1950-55
All ages
Under 5 mm to 5 TU
RT 19-20-21
BCG Laboratory, Madras
9-14
(Mean: 12.3)
Unvaccinated
BCG
5.808
5.069
46
28
89
61
31
Grargia 4 Alabama, general
population (13)
None
Norm
* fl«pro0uc»d Irom ten Dam. er el. (2).
1 Annual lato per 100.000 population, uaualiy allowing lor loaaet from oDaervation.
I Tl>o pioloclivo ollicacy against Ooulh bom tubvrculoaaa was 07 % lor a ixmkxI ot IS-70 yuais.
4 This lalxxaiary lias p'uuuuxl a itumlxir <jl sliains at Uiltoiunl Innus and it is not known wliuthur Ilia slruuih ubud mi IIiuso luur Inals wuru tliv miim> or not.
I Assuming a moan opaervanon period ol 17.5 yr.
..
< Not eigmlicant.
(rials and dial of wcslcrn counirics.
The relation between incidence of dis
ease in previously infected and in re
cently infected persons was 1:16, where
as it was 1:1 in the British study (12).
The sex dislribniion was also greatly
changed, with 3 male cases to 1 female
case. Comparing the age distribution
of the cases in the total population with
the distribution in South American
TABLE 2
BCG VACCINATION COVERAGE PER 100
POPULATION
(PROVISIONAL DATA). REGION OF THE AMERICAS, 1980’
Country
Esl. pop.
under 1
year of age
Argentina
Bahamas
Barbados
Bolivia
Brazil
Canada
Chile
Colombia
Costa Rica
Cuba
Dominica
Dominican Rep.
Ecuador
El Salvador
Grenada
Guatemala
Guyana
Haiti
Honduras
Jamaica
Mexico
Nicaragua
Panama
Paraguay
Peru
Saint Lucia
St. Vincent and the Grenadines
•Suriname
Trinidad and Tobago
U.S.A.
Uruguay
Venezuela
674,000
5,400
4,200
103,380
3,582,640
372,000
243,000
765,000
72,000
136,900
2,600
184,650
327,950
188,,033
2,700
246,994
23,000
216,013
164,543
58,500
2,848,000
114,685
53,853
105,461
690,000
4,000
3,300
14,500
26,300
3,276,000
53,386
506,441
BCG
64
71
49
58
99
40
79
99
17
74
56
43
60
22
26
40
33
68
31
48
96
66
Dilinltion ol abbreviations: — « No routine vaccination under 1 yr old;... « Data unavailable.
• Source; PAHO/WHO, Expanded Program ot Immunization, 1981.
counirics having similar risks of infec
tion (nearly 3% per yr), (he absence in
India of incidence peaks in young chil
dren and in young adults is striking.
Only the former may be due to lack of
diagnosis. In contrast, incidence in
creases logarithmically with age to more
than 1,000 cases per 100,000 persons.
These observations could be explained
by a long delay in tuberculous break
down after primary infection (in which
case any effect of BCG would be ob
served much later, as in the study of
Frimodt-Mdllcr in South India [6]) or
by repealed infections (in which case
the vaccine would not show any protec
tion).
Two meetings on this subject were
recently convened by WHO. Partici
pants of the first one, in New Delhi (5),
recognized that there were no major
methodologic errors that could have
produced the observed results. They
recommended a series of research pro
posals designed to produce results that
could explain the findings. Participants
of the second meeting, in Geneva (6),
analyzed the results and their relevance
to current vaccination policies. They
recommended maintaining the current
BCG policy in countries with a high
risk of infection with tuberculosis: ad
minister BCG vaccine as early in life as
possible.
The main reason for this recommen
dation was that BCG has shown a pro
tective effect in all studies in young
children (7), and the study in India did
not produce any contradictory evi
dence. In several European countries
where BCG vaccination was suspended
72
because of the low risk of infection,
childhood lubcrculosis has recently re
appeared within the expected frequency.
The objective of using BCG in con
trol programs is to prevent childhood
tuberculosis, especially the more seri
ous forms such as meningitis. It has
been recognized for several years that,
even if BCG has a protection of 80% in
vaccinated persons and a high coverage
is achieved, the effect on the chain of
transmission of infection is very low
(8). The decisions on vaccination poli
cy should be based on the risk of infec
tion (and disease in children, as shown
in India), as well as economic and soci
ologic considerations, such as accep
tance of local reactions (9).
The present WHO policy in coun
tries with a high risk of infection is
BCG vaccination of newborns when
feasible, or of children less than I year
of age simultaneously with other vac
cines, as recommended by the WHO
Expanded Program on Immunization
(table 2). Revaccination is usually ad
ministered in the first year of primary
school. Freeze-dried products arc pre
ferred, and the most commonly used
strains are Pasteur 1173P2, Copen
hagen 1331, Glaxo, Tokyo 172, and
Moreau (Brazil, Cuba). In routine con
trol vaccination programs, direct vacci
nation without previous tuberculin test
is preferred for its operational advan
tages.
Vaccination does not have increased
risk in previously infected persons, and
the need for tuberculin testing and
reading is avoided, thus improving the
coverage and reducing the cost. Vacci
nation induces skin sensitivity to the
tuberculin test, of a somewhat lower
degree than natural infection and wan
ing faster than induced protection.
Therefore, the tuberculin test loses its
FASIO LUELMO
value (except for very strong reactions)
in vaccinated individuals, and cannot
be used as an indicator for revaccination.
A comprehensive analysis of vaccin
ation practices and undesirable reac
tions has been compiled by Lotte and
Wasz-Hockert for the International
Union Against Tuberculosis (10). Seri
ous general reactions, including
deaths, arc very rare in world litera
ture, and BCG is one of the safest vac
cines. Most local and regional undesir
able reactions are of little consequence
and slowly evolve the resolution and
cure, usually without treatment. Over
sized ulcers or scars are generally caused
by too deep injections, less frequently
by excessive dose. In just 25 years
(from 1949 to 1974), 187 countries vac
cinated almost 1.4 billion persons with
BCG. This effort and investment justi
fies the expenditures in BCG research.
Al present, BCG research is focused
on two topics: protection of children
who are contacts of bacillary patients,
in attempts to obtain results in short
periods of time, and the immunologic
mechanisms of disease and protection.
Information obtained from the latter
may prove useful not only in tubercu
losis, but also in leprosy. The vaccines
being tried arc mixtures of BCG with
killed leprosy bacilli, and the immuno
logic mechanism might be similar in
both diseases.
Analysis of other areas of the world
with epidemiologic characteristics simi
lar to those of South India (prevalence
of nontuberculous mycobacteria, lowvirulence variants of M. tuberculosis,
and an epidemiologic model different
from the classic one) is also a priority
for developing regional and national
policies on BCG vaccination.
Bibliography
1. Child J. I'lic early evidence in favour of a
proleciive effecl of BCG in man. WHO/TRI/
ScG/79.5
2. ten Dam HG, et al. Present knowledge of im
munization against tuberculosis. Bull WHO
1976; 54:255-69.
3. Palmer CE, Edwards LB. Sensitivity to my
cobacterial PPD antigens with some laboratory
evidence of its significance. Tuberkuloza 1966;
IK: 193-200.
4. Tuberculosis Prevention Trial. Trial of BCG
vaccines in South India as tuberculosis preven
tion: First Report, Bull WHO 1979; 57:667-82.
5. WHO. Vaccination against Tuberculosis,
Wl lO/Technical Report Scries 651, 1980.
6. WHO. BCG vaccination policies. WHO/
Technical Report Series 652, 1980.
7. ten Dam HG, Hitze K. BCG vaccination on
the newborn and young infants. WHO/TRl/ScG/
79.12, 1979.
8. Styblo K. Recent advances in epidemiologi
cal research in tuberculosis. Adv Tuberc Res
1980; 20:1-63.
9. Rouillon A, Waaler H. BCG vaccination and
epidemiological situation. Adv Tuberc Res 1976;
19:64-126.
10. Lotte A, et al. BCG complications: esti
mates of the risks among vaccines and statistical
analysis of their main characteristics. Adv
Tuberc Res (in press).
11. Bettag OL, el al. Dis Chest 1964; 45:503.
12. Baily GVJ, Toman K. Notes on the epide
miology of tuberculosis in the area of the Tuber
culosis Prevention Trial in India. WHO/TRU/
ScG/79.9.
13. British Medical Research Council. Bull
WHO 1972; 46:381.
14. Comstock GW, Palmer CE. Am Rev Respir
Dis 1966; 93:171.
15. Comstock GW, Webster RG. Am Rev
Respir Dis 1969; 100:839.
16. Frimodt-Mpller J, et al. Indian J Tuberc
1968; 15:40.
17. Palmer CE, el al. Am Rev Tuberc 1958;
77:877.
18. Rosenthal SR, et al. Pediatrics 1961; 28:622.
19. Stein SC, Aronson JD. Am Rev Tuberc
1953; 68:695.
EPI NEWSLETTER, VOL.V111,NUM.6, PP 2-3
DECEMBER 1986.
Efficacy of Infant BCG Immunization
BCG immunization is widely practiced within the
Expanded Program on Immunization (EPI). However,
information on the efficacy of BCG in preventing child
hood tuberculosis is scarce, and the policy has been chal
lenged by the results of a large-scale controlled trial in
South India. Recent studies, which have been designed to
avoid the pitfalls of earlier trials, now confirm that BCG
immunization of newborns and young children provides a
significant level of protection against tuberculosis in
childhood, especially against tuberculous meningitis
where the protective effect may be as high as 95%. WHO
continues to recommend BCG immunization for all new
borns or young children in high-risk countries or areas.
hospitals. For each case, seven neighborhood controls and
one hospital control were matched for age, sex, area and
socioeconomic status. Fifty-two percent of cases had pre
viously been immunized, compared with 90% of controls.
The estimated protective effect was 90% or 87%, depending
on whether the neighborhood or hospital controls were
considered. Of the 73 hospital cases, 37 had died from
meningitis, 19 had serious, and 4 mild neurological seque
lae, 2 died later, and the remaining 11 appeared healthy.
Therefore, as regards tuberculous meningitis alone, over
400 deaths and over 200 cases of serious sequelae have been
prevented so far in the population in which the cases
occurred.
In accordance with the recommendations of a WHO
Study Group, the Organization initiated a program of
evaluating BCG immunization of newborns and young
children in developing countries using two techniques.
The first is the case-control study, in which the immuniza
tion coverage is determined in patients and in matching
controls so that the relative risk of the unimmunized child
contracting tuberculosis can be estimated. The.second is
the contact study, in which the relative risk is determined
from the incidence of tuberculosis in actively followed-up
child contacts of newly detected patients with infectious
tuberculosis.
A contact study carried out in Bangkok, Thailand in
1981-1984, included 1,507 child contacts, up to 5 years of
age, of newly detected smear-positive cases of pulmonary
tuberculosis. Of the 218 children diagnosed as having
tuberculosis (mostly by X-ray), 158 were from the group of
1,253 who had been immunized and 60 from the group of
253 who were unimmunized. Detailed analysis showed a
protective effect of 53% against all forms of the disease,
indicating that in the study population 185 cases were
probably prevented by the immunization. The protective
effect was over 60% against multiple lesions and extrapulmonary tuberculosis, but lower for other forms.
Both techniques use stratification to deal with the prob
lem of comparability, an issue which has frequently
evoked justifiable criticism of studies other than con
trolled trials. In case-control studies the controls are
matched with the cases for characteristics which could
influence the incidence or the immunization coverage,
such as sex, age, and socioeconomic status. In contact
studies these characteristics are recorded, and stratified
analysis is applied if both the incidence and the coverage
are found to vary from stratum to stratum.
Another contact study was carried out in Lome, Togo in
1983-1985 in 1,421 child contacts up to 6 years of age,
among whom 175 were found to suffer from tuberculosis:
62 cases among the 875 immunized, and 113 among the 546
non-immunized. The protective effect was over 80% for the
more extensive and serious types of tuberculosis, and less
than 50% for milder forms. The protective effect appeared
to be reduced in children under 1 year and over 4 years of
age.
Since both techniques make it possible to include many
cases at low cost and in a short period of time, they are far
more efficient than controlled trials, provided that the
BCG immunization coverage is not extremely high or low.
The techniques can be used to advantage where an
immunization program is already established in a coun
try, and therefore controlled trials might not be justified
ethically. Five such studies have been completed with
support from WHO.
WHO-supported studies
In a case-control study in Sao Paulo, Brazil, 73 cases of
tuberculous meningitis were traced that occurred in 19811983 in children up to 4 years of age admitted to two
2
In Rangoon, Burma, a hospital-based case-control
study was carried out in children up to 5 years of age in
1982-1985 comprising 311 cases, each with 5 controls
matched for age, sex and township. The immunization
coverage was 52% among the cases and 64% among the
controls. The protective effect was 39%, with 95% confi
dence limits of 22% and 52%. Protection was only 20%
among 89 cases clasified as primary complex, and appar
ently there was no protection against abdominal and bone
tuberculosis. Protection was about 50% for tuberculous
pneumonia, lymphadenitis and meningitis, and 80% for
disseminated tuberculosis. Protection decreased with
increasing age.
A similar study carried out in Buenos Aires, Argentina,
comprised 175 cases up to 5 years of age and 875 controls
matched for age, sex, socioeconomic status and district.
4J
Immunization coverage among the cases was 29% and
among the controls 59%. Stratified analysis shows an over
all protective effect of 74% (with 95% confidence limits of
82% and 62%). In this study, protection apparently
increased with age from around 50% in children under 1, to
more than 80% in children of 3 years of age and over.
Other retrospective studies
A few retrospective studies have been reported in indus
trialized countries that refer to the efficacy of BCG
immunization in newborns. The incidence of tuberculosis
among unimmunized children was found to be four times
higher than that of immunized children in a study carried
out in Manchester, United Kingdom, where BCG immun
ization was offered to newborns. A study from 1956 to 1979
in Israel showed that BCG immunization at birth had an
overall protective effect of 38% in children 0-12 years, of
24% for pulmonary and 64% for extra-pulmonary disease.
In Japan in 1979, 30 cases of tuberculous meningitis were
reported in children aged 0-4 years. Only 3 of the children
had been immunized, whereas the estimated coverage in
this group was 69%. The data are compatible with a pro
tective effect against meningitis of about 95%. In Sweden,
BCG immunization of the newborn was discontinued in
1975. The incidence of the disease in children born in
1969-1974 was compared with the incidence in children
born in 1975-1980. For pulmonary, miliary and meningeal
tuberculosis there were 5 and 23 cases in the respective
periods and for lymphadenopathy 1 and 13 cases. Fur
thermore, 78 cases of mycobacteriosis (mainly with M.
avium-intracellulare) occurred after BCG immunization
was discontinued, whereas only 1 such case had been
observed in the previous period.
Conclusion
Although the results appear much less ambiguous than
those of the controlled trials, estimates of protection still
vary widely. Such variations, however, occur within stu
dies as well as between them. The estimated immunization
efficacy may have been reduced in several ways. Probably
protection against the more serious forms is likely to have
been estimated accurately, as serious forms of tuberculosis
stand out and are easier to diagnose than mild ones. In
milder forms, evidence limited to hilar lymphadenopathy
on X-ray may merely be indicative of recent infection. If
these are counted as positive cases, “mild cases’’ will be
over-estimated and will distort the data so that the protec
tive effect of immunization appears to be lower.
A cause of diminished protection may lie in re-infection.
Young children almost always contract infection through
intrafamilial transmission, associated with an increased
risk of disease, probably because the infectious load is
larger or infection occurs repeatedly. In the latter case
BCG may not show protection since the first infection will
have induced immunity, whether or not BCG immuniza
tion was carried out.
Finally, the reduced protection observed in the youngest
children may be explained by the possibility thdt the index
case already existed (undetected) when the child was born
so that infection may have occurred before BCG had
induced immunity.
Although the foregoing factors may explain, to some
extent, the variations in protection, a more important
issue is probably the quality of the immunizations.
Although it is not possible to tell whether a particular
vaccine is more effective than another, there seems to be
ample room for technical improvement in vaccine admin
istration. Tuberculin testing carried out in the contact
studies revealed that even those who received BCG vaccine
often showed little or no skin reaction, suggesting that
immunization had induced very little lasting sensitivity.
Notwithstanding the fact that the response in the newborn
is known to be reduced, it appears that the dose of vaccine
administered is sometimes too small.
In view of the importanceof intra-familial transmission
of childhood tuberculosis, WHO recommends that in
high-risk countries and areas, immunization of infants
should continue to be carried out, within the EPI, as early
in life as possible. Although the response to BCG may be
reduced at this age, studies have shown that there is signif
icant protection provided in childhood by BCG immuni
zation against all forms of tuberculosis, but especially for
the more serious forms, such as tuberculous meningitis.
Source: Weekly Epidemiological Record 61 (28):216-218, 11
July 1986.
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