Tuberculosis: Pathogenesis Protection and Control - Preface : Chaptter-1 Gobal Burden Tuberculosis By Dixie E. Snider
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Tuberculosis: Pathogenesis Protection and Control - Preface :
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Preface
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Today, as it has been for centuries, tuber disease in the industrialized world has been
culosis remains the leading cause of death taken for granted and its persistence in
in the world from infectious disease. Ap developing countries largely ignored. Sup
proximately a third of the world’s popula port for research dwindled, and the exper
tion has been infected with Mycobacterium tise of a generation of scientists and clini
tuberculosis and is at risk for developing cians knowledgeable about tuberculosis
disease. Globally, tuberculosis accounts for was lost.
almost 3 million deaths annually and oneThe current global reemergence of tuber
fifth of all deaths of adults in developing culosis can be attributed to several factors.
countries. Tuberculosis is a reemergent The compromise of immune mechanisms in.
problem in many industrialized countries. human immunodeficiency virus (HlV)-inIn the modern world of global interdepen fected individuals that leads either to reac
dency, rapid transportation, expanding tivation of old tuberculous infections or to
trade, and changing social and cultural pat increased susceptibility to new infection is
terns, tuberculosis in any country is a a major contributor to the increasing inci
threat to people in every country. In the dence of tuberculosis. Other factors are
context of infectious diseases, there is no social dislocations, poverty, overcrowding,
place in the world from which we are re and a failure to invest in public health
mote and no one from whom we are discon infrastructures. Particularly ominous is the
nected.
emergence of multidrug-resistant tubercle
Current knowledge of evolutionary biol bacilli. In the preantibiotic era, the case
ogy and genetics makes clear that what is at fatality rate of untreated tuberculosis was
stake in the battle^ against infectious dis about 50%. With appropriate treatment,
eases is the survival not only of human and cure rates greater than 85% can now be
animaT hosts but of _the_p.athogeQs_ them achieved in both HIV-positive and immu
selves, a confrontation that cannot be taken nocompetent individuals with conventional
lighU^y^J-Iuman interventions serve as se tuberculosis, even in developing countries.
lections for genetic mutations, adaptations, However, the case fatality rates of multiand migrations that enable pathogens to drug-resistant tuberculosis in the United
survive. While societies traditionally deal States arc about 40% for immunocompetent
with epidemics and outbreaks of infectious individuals and over 80% for HIV-infected
diseases in an episodic or discontinuous individuals. Thus, tuberculosis has emerged
fashion, the evolutionary process of the as a major and devastating global threat to
pathogens is a continuous one. That ele health, and many of the tools currently
mentary truth demands vigilance rather available for rapid diagnosis, prevention,
than complacency in applying the tools we and treatment arc woefully lacking.
have and a continuing scientific effort both
The aim of this book is to provide in one
to anticipate new threats from infectious volume an overview of the current state of
pathogens and to develop new tools with knowledge about tuberculosis and a critical
which to protect the public health. In the appraisal of the exciting new molecular,
case of tuberculosis, the demise of the immunological, and epidemiological apxiii
* •
♦
%
xiv
Preface
proaches to understanding and controlling
tuberculosis. The emphasis is on research.
The authors hope to make existing knowl
edge and new avenues of research accessi
ble to a new generation of researchers and
clinicians. We hope to encourage scientists,
clinicians, and students in many disciplines
to undertake research on tuberculosis and
want to facilitate the rapid generation of
new knowledge, insights, and interven
tions.
Distinguished scientists knowledgeable
in major areas of tuberculosis research and
control have contributed critical reviews of
current understanding and their thoughts
on new approaches to each area. For most
chapters in this book, I asked world experts
to write collaboratively in order to provide
balance, multiple perspectives on key is
sues, and critical delineation of the areas of
consensus and contention. The authors
were asked to be provocative rather than
comprehensive. Our hope is that most
chapters will be read with interest by any
one concerned with tuberculosis. Our in
tention is for the book to serve both as a
challenge to scientists knowledgeable about
aspects of tuberculosis and as a useful
introduction to those with expertise in
other disciplines who may wish to apply
their knowledge and skills to the problem of
tuberculosis. We hope, too, that the book
will make accessible to scientists and stu
dents in developing countries, where the
needs are greatest, the excitement of the
new approaches to pathogenesis, resis
tance, and control.
This book is intended to honor rather
than replace some of the classic sources of
knowledge about tuberculosis. The classic
studies of A. R. Rich (The Pathogenesis of
Tuberculosis, 2nd ed., 1,028 p., Charles C
Thomas, Publisher, 1951) and G. Canetti
(The Tubercle Bacillus in the Pulmonary
Lesion of Man, 226 p., Springer, 1955) on
the pathogenesis of the human disease, of
L. Barksdale and K.-S. Kim on the charac
teristics of the genus Mycobacterium (Bac
teriological Reviews, 41:217-372, 1977), of
M. B. Lurie (Resistance to Tuberculosis:
Experimental Studies in Native and Ac
quired Defensive Mechanisms, Harvard
University Press, Cambridge, Mass., 1964)
on experimental tuberculosis, and of K.
Styblo (Epidemiology of Tuberculosis,
Royal Netherlands Tuberculosis Associa
tion Selected Papers, vol. 24, The Hague,
1991) on epidemiology remain important
reading for any student of the disease. The
comprehensive texts edited by C. Ratledge
and J. Stanford (The Biology of the Myco
bacteria, 2 vol., Academic Press, 1981) and
G. B. Kubica and L. G. Wayne (The My
cobacteria: a Sourcebook, 2 vol., Marcel
Dekker, 1984) remain a repository of much
valuable information. Yet the revolution in
molecular biology, genetics, and immunol
ogy and the advances in understanding ep
idemiology and control of the disease in
both developing and industrialized coun
tries now offer far greater opportunities
than were previously available for under
standing and developing improved inter
ventions in the disease. We hope this book
will make a useful contribution to filling
that gap in time and knowledge.
c/ja
Tuberculosis: Pathogenesis, Protection, and Control
Edited by Barry R. Bloom
© 1994 American Society for Microbiology, Washington, DC 20005
Chapter 1
Global Burden of Tuberculosis
Dixie E. Snider, Jr., Mario Raviglione, and Arata Kochi
INTRODUCTION
a
The purpose of this chapter is to review the
current epidemiology of tuberculosis (TB)
in the world. From a global perspective, the
magnitude of the TB problem is enormous.
Furthermore, unless aggressive interven
tion is undertaken soon, the worldwide
situation concerning TB will deteriorate
rapidly; during this decade, nearly 90 mil
lion new cases will occur and 30 million
people will die from TB. The disease is now
the world’s foremost cause of death from a
single infectious agent.
Although in this chapter we concentrate
on the number of new cases of and deaths
from this disease, we recognize that these
data do not fully describe the effect of the
disease on the population. For example, we
have not discussed the economic impact of
the disease: direct and indirect costs of
treatment of cases and suspected cases,
costs of contact investigations, costs of TB
screening and preventive therapy programs
(where these are used), costs of hospital
and institutional infection control pro
grams, and costs to patients in lost income.
Dixie E. Snider, Jr. • Office of the Director,
Centers for Disease Control and Prevention, Atlanta,
Georgia 30333.
Mario Raviglione and Arata
Kochi • Tuberculosis Programme, World Health
Organization, CH-1211, Geneva 27, Switzerland.
3
An increasing number of cases due to or
ganisms multiply resistant to anti-TB drugs
could escalate these costs dramatically.
Other factors we do not discuss in this E)
chapter are the frequency of early and late
complications and the impact of these com
plications on morbidity, mortality, and
costs. There are few data on the frequency
with which complications occur.
We also do not discuss the social impact q
of TB on the population: for example, loss
of employment, decreased likelihood of
marriage (especially for women), and cre
ation of orphans and one-parent house
holds. Again, few or no current data in the
literature address these issues.
Ideally, we would like to present the
exact numbers of new cases of TB and
deaths from TB that occur each year. Un
fortunately, disease surveillance in many
countries is too incomplete to provide this
information (Styblo and Bouillon, 1981).
Because of this limitation, the burden of TB
must be estimated indirectly by using sev
eral epidemiological parameters, including
the average annual risk of TB infection, the
reported incidence- of smear-positive pul
monary TB, the estimated coverage of the
population by health care services, the es
timated proportion of all cases of TB that
are smear-positive, and the estimated case
fatality rates for smear-positive and other
forms of TB.
4
Snider et al.
Tuberculosis Infection
detect thelity °f the tUberCUlin Skin test to
prfesence o( My^bac,erium tu.
the nre
'nfeCtlon can be used 1° measure
the prevalence of infection. A method for
converting the prevalence of infection into
the annual risk of infection has been deveh
oped (Styblo et al., 1969; Sutherland, 1976)
he annual risk of infection is the probabilM
any,'nd,vidual will be infected with
M- tuberculosis in 1 year. If several tuberuhn surveys of the same population have
been done at different times (using similar
techniques and testing a representative
mple of non-BCG-vaccinated subjects of
he same age), the trend in the annual risk
Tabie 1 Estimated annual risk of TB and trends in
aeve|oping countries. 1985 to 199(y'
Estimated annual (%):
Area(s)
Sub-Saharan Africa
Norlh Africa and
western Asia
Southeast Asia
South America
Central America and
Caribbean
Risk of
infection
Decrease
in risk
1.5-2.5
0.5-1.5
U2
5-6
1.0-2.0
0.5-1.5
0.5-1.5
1- 3
2- 5
1-3
** BaSCd °n da,a in Cauthen and Ten Dam (1988).
Annual Incidence of Disease and Death
Table 2 shows the distribution of the
present burden of cases and deaths. Over 8
1 cases of TB occurred in 1992 Of
11
^^0“’ 3’3 milli°n Were in the World
theTR UC wr estimatin8 the magnitude of
Health Organization’s (WHO’s) Southeast
■ons
' A,th°Ugh there are l™i>a.Asian region, 1.9 million were in the west
that
aPP:°aCh’ Stybl° has shown
ern Pacific region, 1.2 million were in subponds
nSk °f infection COTm- Saharan Africa, and 1.6 million, including
spontls, on average, to an incidence of 50
9,000 cases tn industrialized countries
HnnearMP°S“lVe CaS6S PCr 100’000 POpulawere in the remainder of the world. TB has
tion (Murray et al., 1990).
1
Cauthen and Ten Dam (1988) have used a devastating effect in the developing
the results of tuberculin skin test surveys world, where 95% of cases occur. Eighty
done m developing countries since the frein’Jh
“S CaSeS °CCUr “ persons
1950s to estimate the annual risks of infec- are in their productive years (ages 15 to 59)
‘ n ‘n d,fferent regions of the developing According to a 1989 WHO report, 1.3 mil-'
world (Table 1). The annual risk of tuber8
cases and 450,000 deaths from TB in
jeve
oplng countries occur in children un
Sah?5 "T(C“On iS Pr°bably h'8hcst in sub
Saharan Africa, followed closely by risk in der the age of 15 years (World Health
Southeast Asia.
y
n Organization, 1989).
In the prechemotherapy
Kochi (1991) has estimated that about
era, mortality
from
TB was about 50 to 60% (Murray et
atatmtlhe WOrld'S wa'ation,
m
population.
abom 1 7 b,1Ilon peop]e> js jnf
al-, 1990). Today, death rates in <■
‘ ’
developing
tuberculosis-. The great majority of the caTnio "r nO‘ 3S high beCaUse a
of WS^PUlati°n’ and thus 'heT majority treated POrt'On °f CaSeS are detected and
of infected persons, reside in developing
Nevertheless, an estimated 2.7 million
of inf
!ndustrialized countries, 80%
of infected individuals are aged 50 years or Peruns died from TB in 1992: 1.1 million in
more, whfie in developing countriS,3^
western peaSfi S'an reg'On’ 672’000
the
western Pacific region, 468,000 in the AfrithP rCg,IO,n; "nd 426’000 in the remainder of
c wor d (I able 2). TB causes over 25% of
:M7KoThtr99i)nsare,ess,han50years
Chapter 1
fB and trends in
<0 1990°
_
led annual (%):
Decrease
in risk
l
1-2
5-6
1- 3
2- 5
1-3
Table 2. Estimated global TB incidence
Area
3,263,000
1,921,000
1,182,000
683,000
584,000
197,000
199,000
8,029,000
5
and mortality in 1992
Mortality
Rate"
No. of deaths
Rate"
136
214
166
128
47
22
146
1,142,000
672,000
468,000
266,000
117,000
29,000
14,000
2,708,000
84
48
85
65
26
7
2
49
Per 100,000 population.
r8’-
Global Burden of Tuberculosis
Incidence
__________ No. of cases
Southeast Asia
Western Pacific?
Africa
Eastern Mediterranean
Americas4Eastern Europe
Industrialized countries^
All regions
•
Western Europe p.us Austria, Canada, Japan, New Zea.and, and the United States.
Death
n of the
KdverS
1992. Of
fefWorld
putheasl
fcLwest5 in subEnding
xintrics,
MBhas
gslopiiip
||ighty
Kwho
m
avoidable adult deaths in the developing
world (Murray et al., 1990).
domic until mid-1993, more than 5 million
persons worldwide have had dual HIV and
TB infection. A great majority (3.8 million)
Impact of the HIV-AIDS Epidemic
of these patients lived in sub-Saharan Af
The pandemic of human immunodefi rica (Fig. 1). HIV seroprevalence rates of
ciency virus (HIV) infection and the evi more than 40% are common among patients
dence of an association between tuberculo with TB in many African countries. The
sis and HIV infection has caused marked annual risk of progression to active TB
increases m the incidence of TB in some among individuals infected with both HIV
countries. Because of its ability to destroy and TB is 5 to 10% (Narain et al., 1992).
the immune system, HIV has emerged as
I he result of this increased risk is evident
the most significant risk factor for progres from the reported numbers of TB cases in
sion of dormant TB infection to clinical several countries. After years of declining
disease (Selwyn et al., 1989).
incidence of the disease, the number of
The Global Programme on AIDS of the reported cases of TB increased dramati
' WHO estimated that in 1992 at least 13 cally during the 1980s in many countries in
million adults and 1 million child^ThTd- sub-Saharan Africa. Within a 7-year period
been infected with HIV worldwide (World from 1985 to 1991, the annual number of
Health Organization, 1993). Nearly 85% of
cases in Zambia nearly tripled, that in
HIV infections have occurred in developing
Malawi more than doubled, and those in
countries, and the vast majority have oc Tanzania and Burundi increased by about
curred in the age group 15 to 49 years
70 and 40%, respectively. The numbers of
It is estimated that about 1,700 million
deaths from TB have also increased in
people are infected with M. tuberculosis
these countries (Narain et al., 1992).
(Kochi, 1991). The impact of HIV infection
T he situation in some countries in South
on the IB situation is greatest in those
east Asia and the western Pacific is now
populations where the prevalence of TB
similar to that in Africa several years ago.
infection in young adults (who are at great
Since almost two-thirds of the world’s TBest risk of HIV infection) is high. By using
infected population is in Asia, entry of HIV
estimates of the prevalence of TB infection
into Asian communities may result in large
in various regions, it has been estimated
increases
in HIV-associated TB in the com
that since the beginning of the HIV paning years. In Bombay, HIV seroprevalence
6
Snider et al.
A
11 000
60 000
110 000+
17 000 +
•;r
3 760 000+
5 000 +
450 000
[global TOTAL 5.1 M +
Figure 1. Estimated global distribution of adults who have been infected with HIV and TB as of mid-1993
Source of data is WHO Tuberculosis Programme.
among TB patients increased from 2% in mission to both HIV-positive and HIV
1988 to 10 to 15% in 1991 and 1992. In negative populations. Nevertheless, pre
northern Thailand, HIV seroprevalence in liminary data from the second round of the
TB patients increased from 5% in late 1989 National Tuberculin Survey in Tanzania,
to 15% in 1992, and there is evidence that where the TB control program has achieved
the incidence of TB is increasing (World an 80% cure rate of patients with newly
Health Organization, unpublished data).
diagnosed smear-positive cases during the
In many developing countries, TB has last 5 years and a 65% case detection rate,
emerged as the most common opportunistic suggest that the p£evalence of infection in
disease associated with HIV infection. school children did not change appreciably
Twenty to forty-four percent of AIDS pa from 1983-1985 to 1989-1991, despite the
tients in Africa, 18% of patients in Haiti, increase in the number of detected new
and up to 25% of patients in some Latin smear-positive cases (Narain et al., 1992).
American countries, namely Brazil, Mex Thus, a good control program may be able ,
ico, and Argentina, had clinical TB during to reduce to some extent the increased i
the course of HIV infection (Narain et al.
chance of transmission.
1992).
HIV-infected patients with TB also have
It is still unclear how the increasing num a higher incidence of noninfectious extrabers of HIV-positive patients with TB will pulmonary forms of disease and higher
affect the transmission of TB in the commu mortality rates and thus may have a lesser
nity. It is possible that the increase in the impact on transmission than non-HIV-innumber of TB cases will increase TB trans fected TB patients.
Chapter 1
rUBERCULOSIS IN INDUSTRIALIZED
COUNTRIES
United States
II
as of mid-1993.
e and HIVtheless, pre
round of the
in Tanzania,
has achieved
with newly
s during the
tection rate,
infection in
appreciably
despite the
Jtected new
t al., 1992).
may be able
e increased
B also have
tious extraand higher
ave a lesser
lon-HIV-in-
7
• Observed cases
------Expected cases
35 ■
30 -
brom 1953, when national surveillance
began, through 1984, the United States ex
20 i
perienced a significant decline in TB cases:
15
51,700 Excess Cases
from 84,304 cases in 1953 to only 22,225
cases in 1984. The average annual decline
10
in cases was about 5.3% per year. From
80 81 82 83 &4 85 86 87 8B 89 90 9'1 92
1985 to 1992, however, the number of re
Year
ported cases has increased by about 20%. Figure 2. Numbers of expected and observed cases of
Using the trend for 1980 to 1984 to calculate TBfinlhe.Un^Sta,es from 1980 through 1992- Table
' Disease Control and
the number of expected cases, the Centers is from the CDC (Centers for
Prevention, 1993).
for Disease Control and Prevention (CDC)
estimates that from 1985 through 1992,
about 51,000 excess cases have accumu
largest increases in reported TB case numlated (Fig. 2). Case rates in urban areas bers have occurred i
------------ in geographic areas and
have increased more rapidly than those in
age
groups
heavily impacted by the HIV
rural areas.
epidemic. TB prevalence among AIDS pa
Of the 26,673 TB cases reported in 1992,
tients is high. Matching of TB and AIDS
71% occurred in racial and ethnic.-minori
registries through 1990 revealed that 4.9%
ties. From 1985 to 1992, TB case numbers
of reported AIDS cases were also in the TB
declined about 10% among non-Hispanic
registry (CDC, unpublished data). CDC
whites and 23% among Native Americans.
HIV seroprevalence surveys in TB clinics
However, case numbers increased 27% have shown a high prevalence of HIV in
among blacks, 46% among Asians and Pa fection among TB patients. Pooled sero
cific Islanders, and 75% among Hispanics.
prevalence data from 13 cities that tested at
From 1985 through 1992, all age groups, least 50 serum samples per year for 1989,
except that of patients 65 years of age and 1990, and 1991 showed seroprevalence
older, experienced an increase in number
rates of 13.1% in 1989, 17.8% in 1990, and
of cases. The largest numerical and per 21.4% in 1991. Trend analysis from 1989
centage increases (+3,686; +55%) were through 1991 also showed significant up
among persons 25 to 44 years of age. How
ward trends in HIV seroprevalence among
ever, there was a 36% increase in case black, Hispanic, and white males with TB
numbers among 0- to 4-year-old patients
or suspected TB. Among females, the up
and a 34% increase among children 5 to 14
ward trend was significant only for blacks
years old.
(Onorato et al., 1993).
Of all patients with TB reported to the
The United States has also experienced
CDC in 1992, 27% were born in another
an increasing number of outbreaks of TB.
country. The numbers and percentages of Outbreaks have occurred in a variety of
foreign-born patients increased from
settings, including hospitals, correctional
4,925 and 22% in 1986 to 7,270 and 27% in
facilities, shelters for the homeless, resi
1992.
dential care facilities for patients with
In addition to the effect of immigration on
AIDS, nursing homes, and even crack
the change in the TB morbidity trend, there houses.
is evidence that the HIV epidemic is at least
The most serious problem has been the
in part contributing to this change. The
outbreaks of multidrug-resistant TB (MDR-
J
5 000 +
50 45 40 -
Global Burden of Tuberculosis
25 -
8
I
Snider et al.
TB), i.e., outbreaks due to organisms resis ing the biennium 1988 through 1989 had TB
tant to isoniazid and rifampin (and often (Raviglione et al., 1993).
other drugs as well). From 1990 through
In Australia, death rates have remained
1992, the CDC investigated outbreaks of stable at about 0.4/100,000, and notification
MDR-TB in eight hospitals and a state rates of all cases have slightly increased
correctional system. As of November 1992, from 5.6/100,000 in 1986 to 5.9/100,000 in
297 cases of MDR-TB had been identified in 1990 (Cheah, 1992a). The HIV epidemic
these outbreaks. Most but not all of the has had little impact on the TB situation in
cases occurred in persons infected with Australia. Two-thirds of the new patients
HIV. Mortality was high (about 70%), and
reported in 1991 were foreign born (Cheah
the median interval from TB diagnosis to 1992b).
death was short (4 to 16 weeks). The out
In Canada, a similar stagnation of notifi
break investigations demonstrated trans
cations and rates has been observed over
mission of infection to health care workers. the past 6 years. In 1991, 2,044 cases were
At least 17 health care and correctional
reported (rate, 7.6/100,000). Foreign-born
workers have developed active TB with patients constituted 48% of all patients in
multidrug-resistant organisms (CDC, un 1989, and native Canadians constituted
published data).
20% of patients. TB mortality rates were
Factors contributing to nos_Qcomial out- stable at around 0.5/100,000 during recent
breaks include the convergence of highly
years (WHO, unpublished data [from the
susceptible, immunocompromised patients Canadian Centre for Health Information,
and TB patients; the delayed recognition of Ottawa]).
TB (because of unconsidered diagnoses,
In Japan,_the downward trend of TB
nonclassical radiographic findings, and lab notifications continues. The average de
oratory delays); the delayed recognition of cline between 1980 and 1991 has been 3.5%
drug resistance; and the delayed initiation
per year. However, this decline is smaller
of effective anti-TB treatment. Other fac
than that seen in previous years. Further
tors contributing to nosocomial transmis more, the incidence of sputum-smear-posi
sion include delayed initiation of isolation,
tive cases has steadily increased since 1980.
inadequate ventilation for acid-fast bacillus
In general, mortality rates have regularly
(AFB) isolation, lapses in maintaining AFB decreased at about 4.6% per year since
isolation, inadequate duration of AFB iso- .......
uh uun
•
1980 (WHO, unpublished data [from the
lation, and inadequate precautions during Japan' A^t/ruberculoX
.
-------------- .3 Association, To
cough-inducing procedures.
kyo]).
T
Tuberculosis in Other Industrialized
Countries
Seven of 15 Western European countries
(Denmark, Ireland, Italy, Netherlands,
Norway, Spain, and Switzerland) have also
recently experienced increases in reported
cases (Raviglione et al., 1993). The major
factor responsible for most of these in
creases appears to be immigration from
higher-prevalence countries. However, in
Italy, 11.4% of AIDS patients reported dur
A
•
In New Zealand, case notifications have
recently increased from a nadir in 1988 of
295 cases reported. In 1991, 335 cases were
reported (rate, 9.9/100,000). Mortality rates
have decreased from 0.9 to 0.5/100,000 dur
ing the period 1980 to 1990 (WHO, unpub
lished data [from the New Zealand Depart
ment of Health, Wellington]).
In Israel, TB notifications, after being /
stable in the 1980s, recently increased to
505 in 1991 (rate, 10.2/100,000). However,
if rates for Ethiopian immigrants are ex
cluded from the data, the rate among native
Jews in 1991 was 4.6/100,000 and that
1
o
■
1,
I
1 1989 had TB
ave remained
d notification
tly increased
’.9/100,000 in
(IV epidemic
B situation in
new patients
born (Cheah,
tion of notifibserved over
4 cases were
Foreign-born
11 patients in
constituted
/ rates were
uring recent
ta [from the
Information,
rend of TB
average debeen 3.5%
is smaller
s. Furthersmear-posi1 since 1980.
/e regularly
year since
i [from the
nation, To-
ations have
■ in 1988 of
cases were
rtality rates
00,000 durIO, unpubnd Departifter being /
creased to
However,
its are cx-
ong native
and that
Chapter 1
among native non-Jews was 3.7/100,000.
Ethiopians, who generally constitute less
than 25% of all cases, constituted 50% of all
cases in 1985 and 55% of all cases in 1991,
following two waves of migration (Opera
tion Moses and Operation Shlomo) (WHO,
unpublished data [from the Israel Ministry
of Health, Jerusalem]).
In Turkey, TB notifications during the
past few years have decreased, and in 1990,
24,468 cases were reported (rate, 43.8/
100,000) (WHO, unpublished data [from the
Turkish Ministry of Health, Ankara]).
DRUG RESISTANCE
•
Global Burden of Tuberculosis
9
successfully introducing rifampin-containing short-course chemotherapy. Thus, the
incidence of acquired resistance was sub
stantially reduced, and the incidence of
primary resistance remains relatively low.
In many developing countries, particularly
in Asia, the incidence of acquired resis
tance remains high and the incidence of
primary resistance is higher than that in
industrialized countries, because national
TB control programs in the developing
countries have not been able to achieve a
high cure rate over a very long period, even
after the introduction of short-course che
motherapy.
This already serious situation may
quickly worsen as the HIV epidemic
spreads. The HIV epidemic may produce
increased levels of both acquired and pri
mary resistance not only by overtaxing the
national TB control programs as a result of
increased caseload but also by affecting
compromised immunity (Kochi et al
1993).
Acquired resistance is defined as resis
tance to at least one anti-TB drug that arises
during or after the course of treatment,
usually as a result of nonadherence to the
recommended regimen or of faulty pre
scribing. A high level of this type of resis
tance is a mark of a poorly functioning TB
control program.
Primary resistance is defined as the pres
ence of drug resistance to at least one
FUTURE TRENDS
anti-TB drug in a TB patient who has never
received prior treatment. It is caused by
Without recognition of the TB crisis con
infection with drug-resistant specimens fronting the world and prompt, effective
from another patient excreting a drug-resis action, the TB epidemic can be expected to
tant organism; many of these patients ac worsen for several reasons.
quired resistance as a result of inadequate
First, demographic forces are at work.
treatment. Thus, primary resistance is an Children born in past decades in regions
indicator of efficacy of TB control efforts in with high population growth rates are now
the past (Weyer and Klecberg, 1992).
reaching the ages at which morbidity and
An accurate picture of the drug resis mortality for TB are high. Even if the
tance problem in the world is not available, age-specific rates of new cases do not in
because only a limited number of countries crease, the changing sizes of the population
(both industrialized and developing) have a age groups will now begin to cause a large
reliable drug resistance surveillance sys increase in the number of TB deaths and
tem. However, limited available informa new cases.
tion indicates that, generally speaking,
Second, famine, war, and natural disasters
many industrialized countries that faced that create large populations of displaced,
severe MDR-TB in the late 1950s and early malnourished peopledin crowded living con
1960s successfully reduced the problem in a ditions may cause increases in TB case rates.
rather short time by improving application
Third, age-specific TB incidence rates
of the same regimen used previously and by can be expected to rise in those areas of the
I
10
Snider et al.
world where immunity of the population is
seriously challenged by HIV infection. By
mid-1993, the global cumulative number of
persons coinfected with HIV and tubercle
bacilli since the beginning of the HIV pan
demic was estimated to be over 5 million
(Fig. 1). In addition, HIV seroprevalence
among TB patients is expected to increase
further in areas like sub-Saharan Africa and
to increase at least threefold in areas like
Southeast Asia during the next decade. As
a result, while about 315,000 persons are
estimated to have developed HIV-associ
ated TB in 1990, more than 700,000 people
are expected to develop HIV-related TB in
1995. In the year 2000, the figure may reach
1.4 million. In 1990, 4.2% of all TB cases
were associated with HIV; in the year 2000,
an estimated 13.8% of all TB cases may be
associated with HIV (Dolin et al., in press).
In addition, there is the threat of the in
creasing incidence of drug-resistant strains.
This phenomenon is largely a consequence
of poorly managed and inappropriately fo
cused TB programs and is accelerated and
amplified by the HIV coinfection epidemic.
Drug-resistant strains are as contagious as
the normal TB bacillus. The cure rates of at
least 95% that can be achieved for regular
TB fall to 70% or less when isoniazid and
rifampin resistance occurs.
If the effectiveness and availability of TB
control do not improve substantially over
those existing now, more than 30 million
TB deaths and 90 million new cases are
expected to occur in the last decade of this
century. Conservative estimates indicate
that the incidence of TB can be expected to
increase to 8.8 million cases annually by
1995, 10.2 million cases annually by the
year 2000, and 11.9 million cases annually
by 2005 (Dolin et al., in press). Demo
graphic factors will account for three-quar
ters of the predicted increase in new cases.
Assuming that the availability and effec
tiveness of treatment programs remain at
the 1990 level, 3 million TB deaths can be
expected to occur annually by 1995, and 3.5
million deaths will be occurring annually by
the year 2000. Action must be taken now to
avert this global health disaster.
REFERENCES
Cauthen, G. ML, and H. G. Ten Dam. 1988. Annual
risk of tuberculosis infection. Geneva: W.H.OJTB
88:154.
Centers for Disease Control and Prevention. 1993.
Tuberculosis morbidity—United States, 1992. Mor
bid. Mortal. Weekly Rep. 42:696-704.
Cheah, D. 1992a. Tuberculosis notification rates, Aus
tralia final data for 1986 to 1990. Communicable Dis.
Intell. 16:234-236.
Cheah, D. 1992b. Tuberculosis notification rates, Aus
tralia, 1991. Communicable Dis. Intell. 16:398-400.
Dolin, P. J., M. C. Raviglione, and A. Kochi. Global
tuberculosis incidence and mortality during 19902000. Bull. W.H.O., in press.
Kochi, A. 1991. The global tuberculosis situation and
the new control strategy of the World Health Orga
nization. Tubercle 72:1-6.
Kochi, A., B. Vareldzis, and K. Styblo. 1993. Multi
drug-resistant tuberculosis and its control. Res. Mi
crobiol. 2:104-110.
Murray, C. J. L., K. Styblo, and A. Rouillon. 1990.
Tuberculosis in developing countries: burden, inter
vention and cost. Bull. Int. Union Tuberc. Lung Dis.
65:6-24.
Narain, J. P., M. C. Raviglione, and A. Kochi. 1992.
HIV-associated tuberculosis in developing coun
tries: epidemiology and strategies for prevention.
Tuberc. Lung Dis. 73:311-321.
Onorato, I., S. McCombs, M. Morgan, and E. McCray.
1993. HIV infection in patients attending tuberculo
sis clinics, United States, 1988-1992. Program Abstr. 33rd Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 1363.
Raviglione, M. C., P. Sudre, H. L. Rieder, S. Spinaci,
and A. Kochi. 1993. Secular trends of tuberculosis in
Western Europe. Bull. W.H.O. 71:297-306.
Selwyn, P. A., D. Hartel, and I. A. Lewis. 1989. A
prospective study of the risk of tuberculosis among
intravenous drug abusers with human immunodefi
ciency virus infection. N. Engl. J. Med. 320:545550.
Styblo, K., J. Meiger, and I. Sutherland. 1969. The
transmission of tubercle bacilli, its trend in a human
population. Bull. Int. Union. Tuberc. Lung Dis.
42:5-104.
Styblo, K., and A. Rouillon. 1981. Estimated global
incidence of smear-positive pulmonary tuberculosis.
Unreliability of officially reported figures on tubercu-
Chapter 1
?5, and 3.5
nnually by
<en now to
1988. Annual
: W.H.OJTB
ention. 1993.
s, 1992. Mor-
>n rates, Ausunicable Dis.
>n rates, Aus. 16:398-400.
<ochi. Global
during 1990situation and
Health Orga-
1993. Multirol. Res. Mi
tuillon. 1990.
nirden, interrc. Lung Dis.
Kochi. 1992.
loping coun• prevention.
ll E. McCray,
ig tuberculoProgram Ab■ob. Agents
r, S. Spinaci,
iberculosis in
-306.
wis. 1989. A
ilosis among
immunodefi
ed. 320:545-
1. 1969. The
d in a human
. Lung Dis.
nated global
tuberculosis,
s on tubercu-
losis. Bull. Int. Union Tuberc. Lung Dis. 56:118-126.
Sutherland, I. 1976. Recent studies in the epidemiol
ogy of tuberculosis, based on the risk of being
infected with tubercle bacilli. Adv. Tuberc. Res.
19:1-63.
Weyer, K., and H. H. Kleeberg. 1992. Primary and
acquired drug resistance in adult black patients with
tuberculosis in South Africa: results of a continuous
• Global Burden of Tuberculosis
11
national drug surveillance programme involvement.
Tuberc. Lung Dis. 73:106-112.
World Health Organization. 1989. Childhood tubercu
losis and BCG vaccine. In EPI Update Supplement.
World Health Organization, Geneva.
World Health Organization. 1993. Global Programme
on AIDS. The HIV/AIDS pandemic: 1993 overview.
WHO/EPA/CNP/EVA/93.1.
Tuberculosis: Pathogenesis, Protection, and Control
Edited by Harry R. Bloom
<D 1994 American Society for Microbiology. Washington, DC 20005
rculosis. Harlass.
ty of Disease,
g. Springfield,
Courting Danennis. Golden
^ing. St. Mar-
Chapter 3
Overview of Clinical Tuberculosis
ks of disease
a simulation
7:483-496.
. Ucko. 1964.
Rev. Respir.
Philip C. Hopewell
Evidence for
n. JAMA 241:
The clinical expression of infection with
Mycobacterium tuberculosis is quite varied
and depends on a number of identified
factors. Table 1 lists both host- and mi
crobe-related characteristics as well as the
consequences of their interactions that in
fluence the manifestations of tuberculous
infection. Among generally healthy per
sons, infection with M. tuberculosis is
highly likely to be asymptomatic. Data
from a variety of sources suggest that the
lifetime risk of developing clinically evident
tuberculosis after being infected is approx
imately 10%, with a 90% likelihood of the
infection remaining latent (Comstock,
1982). Only a positive tuberculin skin test
indicates the presence of the organism in
persons with latent infections. In specific
subpopulations, for example, in persons
with immunodeficiency states or in infants,
the proportions who develop evident tuber
culosis are much higher (Allen et al., 1992;
Comstock, 1982; Selwyn et al., 1992).
Immunization with bacillus of Calmette
and Guerin (BCG) in persons with intact
cell-mediated immunity minimizes the risk
of early disseminated tuberculosis, espe
cially in children. In addition to host fac-
iw, and W. H.
of streptomy. Tuberc. 71:
:ako: Estudio
ercolombinas
ibro. La Paz,
Discussion of
■enic PhysiolC.V. Mosby
ohn Harvard.
U. Sultan, F.
ifectiousness
ziolet irradiactiousness of
Dis. 85:5112. Hydrazine
on, Marsilid)
aseous-pneu65:402-428.
y of the dis2. Bull. bit.
almette and
ace to tuber-
nimal tuber-
"uberculosis.
yHoeber Inc.,
I
ice of tubcr195-225.
i
Philip C. Hopewell • University of California, San
Francisco, and Division of Pulmonary and Critical
Care Medicine, San Francisco General Hospital, 1001
Potrero Avenue, Room 5K1, San Francisco, Califor
nia 94110.
25
tors, there probably are factors related to
the organism itself, such as its virulence or
predilection for specific tissues, that influ
ence the outcome and features of the infec
tion; however, these features of the organ
ism have not been characterized.
The most obvious and important factor
influencing the clinical features of tubercu
losis is the site of involvement. Prior to the
beginning of the epidemic of infection with
the HIV, approximately 85% of reported
tuberculosis cases were limited to the
lungs, with the remaining 15% involving
only nonpulmonary sites or both pulmo
nary and nonpulmonary sites (Farer et al.,
1979) (Fig. 1). This proportional distribu
tion is substantially different among per
sons with HIV infection. Although there
are no national data that describe the sites
of involvement in HIV-infected persons
with tuberculosis, in one large retrospec
tive study of tuberculosis in patients with
advanced HIV infection, it was reported
that 38% had only pulmonary involvement,
30% had extrapulmonary sites, and 32%
had both pulmonary and nonpulmonary in
volvement (Small et al., 1991). The multi
plicity of sites in HIV-infected persons is
typical of what is seen in an individual
having an immune system that is limited
in its ability to contain infection with M.
tuberculosis. Included in this category are
infants, the elderly, and persons with pri-
<3
26
Hopewell
_______________
Microbial factors
Age
Immune status
Specific immunodeficiency states
Virulence of organism (?)
Predilection (tropism) for
specific tissues (?)
Malnutrition
Host-microbe interaction
Sites of involvement
Severity of disease
Genetic factors (?)
Coexisting diseases
Immunization with bacillu:
IS of Calmette and
Guerin (BCG)
°r i Sec°ndaI3,
malnutrition ng
immunodeficiency
diSeases or
i
Va one et al., 1988). Of the systemic ef^
SYSTEM,C x
rremote effects of observed
Thhc m patients with tuberculosis
’hl“
TUBERCULOSIS
varI
Tuberculosis occurring at any site may
produce symptoms and findings that are not
----- not
spectficaUy related to the organ
or
tissue
organ
or
tissue
involved but, rather, are systemic in nature
are
systemic
in
nature
or are remote from the site of di J"
Systemic manifestations oHbe disease Jncludm8 fever, malaise, and weight loss, are
ikely mediated by cytokines, especially
tumor necrosis factor alpha (TNF-a). Ex
perimental data suggest that TNF-a is an
e“ 13? ‘O 8°% (Aran8°
bv KiM ?
St al” 1981^ In a study ■
1980
sd,C0Workers (KiMawi et al.,
Cficai v 7
a feVer reSp°nSe was sPe‘
examined. 21% of patients had no
Nation f
yr PKO,nt ‘n the
of hosP'ta|-
zation for tuberculosis. Of the febrile patients, 34% were afebrile within 1 week and
64% were afebrile within 2 weeks. The
median duration of fever after beginning
treatment was 10 days, with a range of 1 to
100 —,
[Extra-
90 -
pulmonary
14 6%
=
80 -
Bone/Joint 8.5%
Other 9.3%
70 -
I
----------- Peritoneal 3.7%
—
Meningeal 4.2%
60 -
Miliary 9.8%
50 -
Genitourinary 16.0%
40 Pleural 21.5%
30 20 10 -
i;
■ ■ Pulmonary
Lymphatic 27.0%
0
ALL CASES
ALL
EXTRAPULMONARY
CASES
“S1*u,ion °f si‘“ of involvement in
newly reported cases of tuberculosis in 1978
epidemic of infection with HIV.
prior to the
9
a
Chapter 3
obe interaction
/olvement
f disease
jmic effects
al., 1990;
ystemic efquantified.
ir has been
culosis var)% (Arango
. In a study
>lawi et al.,
>e was spc•nts had no
of hospitalfebrile pa1 week and
'eeks. The
beginning
nge of 1 to
l
I
prior to the
109 days. Weight loss, weakness, and mal
aise appear to be less common but are more
difficult to quantify.
In addition to these generalized effects of
tuberculosis, there are remote manifesta
tions that arc not a result of the anatomic
site of involvement. These include hemato
logic abnormalities, hyponatremia, and psy
chological disorders. The most common
hematologic manifestations of tuberculosis
are increases in the peripheral blood leuko
cyte count and anemia, each of which oc
curs in approximately 10% of patients with
apparently localized tuberculosis (Cam
eron, 1974; Carr et al., 1964). The increase
in leukocyte counts is usually slight, but
leukemoid reactions may occur. Leukope
nia has also been reported. An increase in
the peripheral blood monocyte and eosino
phil counts also may occur with tuberculo
sis. Anemia is common when the infection
is disseminated. In some instances, anemia
or pancytopenia may result from direct
involvement of the bone marrow and thus
be a local rather than a remote effect.
Other than weight loss, the most frequent
metabolic effect of tuberculosis is hy
ponatremia, which in one series was found
to occur in 11% of patients (Chung and
Hubbard, 1969). Hyponatremia is caused
by production of an antidiuretic hormonelike substance found within affected lung
tissue (Vorken et al., 1970). The poor prog
nosis that in the prechemotherapy era was
associated with hyponatremia was proba
bly related simply to the amount of lung
involved and perhaps to adrenal involve
ment. In addition, because the syndrome of
inappropriate secretion of antidiuretic hor
mone is also associated with central ner
vous system disorders, hyponatremia may
be a feature of central nervous system
tuberculosis.
The psychological effects of tuberculosis
are very poorly defined but were commonly
recognized prior to the advent of effective
therapy. These effects include depression
and, on occasion, hypomania. The best
•
Overview of Clinical Tuberculosis
27
descriptions of the psychological alter
ations in patients with tuberculosis are
found in literary works, such as Thomas
Mann’s The Magic Mountain, rather than
in medical writings.
In many patients, tuberculosis is associ
ated with other serious disorders, including
HIV infection, alcoholism, chronic renal
failure, diabetes mcllitus, neoplastic dis
eases, and drug abuse, to name but a few.
The signs and symptoms of these diseases
and their complications can easily obscure
or modify those of tuberculosis and can
result in considerable delays in diagnosis or
in misdiagnoses for extended periods, espe
cially in patients with HIV infection
(Kramer et al., 1990). For this reason it is
important that clinicians have an under
standing of the diseases with which tuber
culosis may coexist and have a high index
of suspicion for a combination of the two
disorders.
TUBERCULIN SKIN TESTING
As noted above, a positive tuberculin
skin test is usually the only evidence of
latent tuberculous infection (Sbarbaro,
1986). Among persons with symptoms or
clinical findings of tuberculosis, the tuber
culin skin test may provide useful diagnos
tic information. However, in an individual
patient a positive test (usually defined as an
induration of >10 mm in immunocompetent
persons and >5 mm in persons with HIV
infection) does not establish a diagnosis and
a negative test does not exclude tuberculo
sis. Up to 25% of apparently immunocom
petent persons will have negative tubercu
lin skin tests at the time of diagnosis of
tuberculosis (Nash and Douglas, 1980).
Among patients with tuberculosis and HIV
infection, the frequency of positive tuber
culin reactions varies considerably depend
ing on the degree of immune compromise
(Reider et al., 1989).
28
Hopewell
i, showing extensive tuberculosis causing respiratory failure.
PULMONARY TUBERCULOSIS
causing chest pain and perhaps dyspnea
Dyspnea (difficulty in breathing) as a result
of
parenchymal lung involvement is un
Cough is the most common symptom of
usual
unless there is extensive disease. Tu
pulmonaiy tuberculosis. Early in the
berculosis may, however, cause severe res
course of the illness, the cough may be
piratory failure (Huseby and Hudson 1976nonproductive, but subsequently, as in
flammation and tissue necrosis ensue, spu Murray et al., 1978) (Fig. 2). Hemoptysis
(coughing blood) may also be a presenting
tum IS usually produced. Inflammation of
symptom
but does not necessarily indicate
the lung parenchyma adjacent to a pleural
an
active
tuberculous
process. Hemoptysis
surface may cause pleuritic pain. Spontane
may
result
from
residual
tuberculous bron
ous pneumothorax may also occur, often
chiectasis, rupture of a dilated vessel in the
Symptoms and Physical Findings
3
a
Chapter 3
• Overview of Clinical Tuberculosis
29
Figure 3. Frontal view, chest radiograph, showing right paratracheal adenopathy as a manifestation of recently
acquired tuberculous infection.
wall of an old cavity (Rasmussen’s aneu
rysm), bacterial or fungal infection (espe
cially aspergillus in the form of a fungus ball
or mycetoma) in a residual cavity, or ero
sion of calcified lesions into the lumen of an
airway (broncholithiasis).
Physical findings in pulmonary tubercu
losis are generally not particularly helpful
in defining the disease. Rales may be heard
in the area of involvement, and bronchial
breath sounds may also be heard if there is
lung consolidation. Amphoric breath
sounds may be indicative of a cavity.
■y failure.
>s dyspnea.
) as a result
tent is unlisease. Tusevere resdson, 1976;
iemoptysis
presenting
ily indicate
Iemoptysis
ilous bron3ssel in the
I
Radiographic Features of Pulmonary
Tuberculosis
In developed countries, radiographic ex
amination of the chest is usually the first
diagnostic study undertaken after history
and physical examination. Pulmonary tu
berculosis nearly always causes abnormal
ities on the chest film, although an endo
bronchial lesion may not be associated with
a radiographic finding. In primary tubercu
losis occurring as a result of recent infec
tion, the process is generally seen as a
middle or lower lung zone infiltrate, often
associated with ipsilateral hilar adenopathy
(Fig. 3). Atelectasis (partial lung collapse)
may result from compression of airways by
enlarged lymph nodes. If the primary pro
cess persists beyond the time when specific
cell-mediated immunity develops, cavita
tion may occur (so-called “progressive pri
mary” tuberculosis).
Tuberculosis that develops as a result of
30
Hopewell
an immunocompetent patient
endogenous reactivation of latent infection
usually causes abnormalities in the upper
lobes of one or both lungs. Cavitation (de
struction of lung tissue) is common in this
form of tuberculosis. The most frequent
sites of involvement are the apical and
posterior segments of the right upper lobe
and the apical-posterior segment of the left
upper lobe (Fig. 4). Healing of the tubercu
lous lesions usually results in development
of a scar with loss of lung parenchymal
volume and, often, calcification. In the im
munocompetent adult with tuberculosis, intrathoracic adenopathy is uncommon but
may occur, especially with primary infec
tion. As tuberculosis progresses, infected
reactivation tuberculosis in
material may be spread via the airways into
the lower portions of the lung or to the
other lung. Erosion of a parenchymal focus
of tuberculosis into a blood or lymph ves
sel may result in dissemination of the or
ganism and a “miliary” (evenly distributed
small nodules) pattern on the chest film
(Fig. 5).
In patients with HIV infection, the nature
of the radiographic findings depends to a
certain extent on the degree of immuno
compromise produced by the infection. Tu
berculosis that occurs relatively early in the
course of HIV infection tends to have the
typical radiographic findings described
above (Chaisson et al., 1987; Pitchenik and
Chapter 3
•
Overview of Clinical Tuberculosis
I
Figure 5. Portion of chest radiograph showing nodular lesions in a
uberculosis in
patient with disseminated tuberculosis.
Rubinson, 1985). With more advanced HIV
disease, the radiographic findings become
more “atypical”: cavitation is uncommon
and lower lung zone or diffuse infiltrates
and mtrathoracic adenopathy are frequent
nvays into
or to the
/mal focus
/mph vesof the orhstributed
3hest film
the nature
ends to a
immunoetion. Tu*rly in the
have the
iescribed
lenik and
I
I
the time of the initial evaluation. Single
early-morning specimens have a higher
yield and a lower rate of contamination
than pooled specimens. The sensitivity of
sputum examination increases with the
(hig- 6).
number of specimens, but there is no in
crease in cumulative recovery of organisms
Bacteriologic Evaluation
with more than five specimens, and the
At present, a definitive diagnosis of tu increased yield between three and five
berculosis can be established only by isola- specimens is slight (Kubica et al., 1975).
There arc several ways of obtaining spec
tion of tubercle bacilli in culture, although
imens
from patients who are not producing
nwl th|a'
sPecific M. tuberculosis
sputum.
The first and most useful is induc
. . u/?° d S°On be avai,ab'e for clinical
use. When the lung is involved, sputum is ing sputum production by the inhalation of
the initial diagnostic specimen of choice. a mist of hypertonic (3 to 5%) saline gener
Sputum specimens should be collected at ated by an ultrasonic nebulizer. This is a
benign and well-tolerated procedure, al-
31
32
Hopewell
HlvTnfccXn"'2' Vie"’ Ch'St radi°8raph- Sh°win8 diffuse inli"ra'io"
M. tuberculosis i„ a patient with
though bronchospasm may occasionally be (Burk et al., 1978; Danek and Bower, 1979;
precipitated in asthmatics. Samples of gas So et al., 1982). For larger nodular lesions,
tric contents obtained via a nasogastric needle aspiration biopsy may also provide
tube have lower yields than induced spu specimens from which M. tuberculosis can
tum, and the procedure is more compli be isolated. This technique is more suited
cated and uncomfortable for the patient. to the evaluation of lesions when there is a
However, in children and some adults, gas suspicion of malignancy.
tric contents may be the only specimen that
In some situations, a therapeutic trial of
can be obtained.
antitubcrculosis chemotherapy may be in
Usually, fiberoptic bronchoscopy is the dicated before more invasive studies are
next diagnostic step if the sputum is nega undertaken (Gordin et al., 1989). Im
tive or cannot be obtained by induction.
provement in the chest film concomitant
In general, the bronchoscopic procedure with antituberculosis treatment would be
should include bronchoalveolar lavage and sufficient reason for making a diagnosis of
transbronchial lung biopsy. The yield of tuberculosis and continuing with a full
bronchoscopy has been high both for mili course of therapy. If a response is going
ary tuberculosis and for localized disease to occur, it should be seen within 3
Chapter 3
1-!
•
Overview of Clinical Tuberculosis
Respiratory TB Other than Lung
Meninges or Central Nervous System
-e- Genitourinary System
0.8-
i
I
I
-a- Disseminated
— Lymphatic System
/
Case Rate o.eper
100,000
population 0.4-
0.2i
0
0-4
i
I
5-14
I--------- - 1
15-24
25-34
I--------- 1
1
1
35-44
45-54 55-64 65+
1
Age
Figure 7. Age-specific case rates for the most frequent forms of extraputaonaty tuberculosis.
I
in a patient with
I
Sower, 1979;
'ular lesions,
also provide
rculosis can
more suited
3n there is a
mtic trial of
■ may be in
studies are
1989). Im)ncomitant
t would be
iagnosis of
vith a full
>e is going
within 3
months of starting treatment. In the
United States, the criteria for defining a
case of tuberculosis allow for culture negatjvity if the patient in question has a
positive tuberculin skin test and responds
to multidrug chemotherapy.
EXTRAPULMONARY TUBERCULOSIS
i
i
As noted above, prior to the epidemic of
HIV infection, approximately 15% of newly
reported cases of tuberculosis involved
only extrapulmonary sites (Farer et al.,
1979). For reasons that are not understood,
as rates of pulmonary tuberculosis de
creased, rates of extrapulmonary disease
remained constant, resulting in an increas
ing proportion of cases being extrapulmo
nary. With the onset of the HIV epidemic,
however, both absolute and relative rates
of extrapulmonary involvement have in
creased.
Extrapulmonary
tuberculosis
presents
more of a diagnostic and therapeutic prob
lem than pulmonary tuberculosis. In part,
this problem relates to its being less com
mon and therefore less familiar to most
clinicians (Alvarez and McCabe, 1984Weir and Thornton, 1985). In addition, extrapulmonary tuberculosis involves rela
tively inaccessible sites, and because of the
nature
can camof the sites involved, fewer bacilli
can
cause much greater damage. The combination
---- 1 of small numbers of bacilli and
inaccessible sites makes bacteriologic con
firmation of a diagnosis more difficult, and
invasive procedures are frequently required
to establish a diagnosis.
The relative frequencies of tuberculosis
at various sites in persons without immuno
compromise are shown in Fig. 1, and dis
tribution by age is shown in Fig. 7 (Farer et
al., 1979). As can be seen, in general, the
incidence for each extrapulmonary site in
creases with increasing age, except for lym
phatic and meningeal tuberculosis, which
3.
34
Hopewell
Table 2. Recovery of A/, tuberculosis from various sites in patients with tuberculosis and HIV infection"
No. positive/no. tested (%)
Specimen
Sputum
Bronchoalveolar lavage
Transbronchial biopsy
Lymph node
Blood
Bone marrow
Cerebrospinal fluid
Urine
OtheH’
Smear
Culture
43/69 (62)
9/44 (20)
1/10 (10)
21/44 (48)
64/69 (93)
39/44 (89)
7/10 (7)
39/44 (91)
15/46 (33)
13/22 (62)
4/21 (19)
12/17 (71)
24/31 (76)
4/22 (18)
5/31 (16)
“ Data are from Small ct al. (1991).
'■ Pleural fluid or tissue, pericardial fluid or tissue, liver peritoneal fluid, abscess drainage, or bone.
are relatively more common in young chil
dren.
scriptive epidemiology of disseminated
tuberculosis. Disseminated or miliary tu
berculosis occurs because of the inade
Extrapulmonary Tuberculosis in
quacy of host defenses in containing tu
HIV-Infected Patients
berculous infection. This failure of
Presumably, the basis for the frequency containment may occur in either latent or
of extrapulmonary tuberculosis among pa recently acquired tuberculous infection.
tients with HIV infection is the failure of Because of HIV or other causes of immu
the immune response to contain M. tuber nosuppression, the organism proliferates
culosis, thereby enabling hematogenous and disseminates throughout the body.
dissemination and subsequent involvement Multiorgan involvement is probably much
of single or multiple nonpulmonary sites. more common than is recognized, because
As evidence of this sequence, tuberculosis generally, once M. tuberculosis is identified
bacillemia has been documented in HIV- in any specimen, other sites are not evalu
inlected patients on a number of occasions ated. The term “miliary” is derived from
(Handwerger et al., 1987; Kramer et al., the visual similarity of the lesions to millet
1990; Shafer et al., 1989). Because of the
seeds. Grossly, these lesions are 1- to
frequency of extrapulmonary tuberculosis
2-mm-diameter yellowish nodules that, his
among HIV-infected patients, diagnostic tologically, are granulomas. Persons with
specimens from any suspected site of dis
HIV infection may not be able to form
ease should be examined for mycobacteria.
granulomas; thus, the individual lesions
Moreover, cultures of blood and bone mar
may not be present. Instead, a diffuse uni
row may reveal M. tuberculosis in patients
form pattern of lymphocytic infiltration and
who do not have an obvious localized site
edema is seen.
of disease but who are being evaluated
Although disseminated tuberculosis near
because of fever. Table 2 lists the sites from
ly always involves the lungs, it is consid
which M. tuberculosis was recovered in a
group of patients with advanced HIV infec ered among the extrapulmonary forms of
the disease because of the multiplicity of
tion (Small et al., 1991).
organs affected. In the past, miliary tuber
culosis
occurred mainly in young children;
Disseminated Tuberculosis
currently, however, except among HIVThe epidemic of HIV infection has con infected persons, it is more common among
siderably altered the frequency and de- older persons (Farer et al., 1979). The shift
Chapter 3
' infection"
Culture
64/69 (93)
39/44 (89)
7/10 (7)
39/44 (91)
15/46 (33)
13/22 (62)
4/21 (19)
12/17 (71)
24/31 (76)
geminated
liliary tuie inadelining tuilure of
latent or
nfection.
□f immu)liferates
e body,
’ly much
because
dentified
>t evalu
ed from
to millet
e 1- to
hat, his•ns with
to form
lesions
ase uni
ion and
•is nearconsid»rms of
icily of
• tubcrn’ldren;
: Hivamong
ie shift
J
• Overview of Clinical Tuberculosis
35
in age-specific incidence presumably has
bin and alanine aminotransferase levels
been caused by the paucity of new infec
may also be increased.
tions relative to the number of endogenous
The chest film is abnormal in most but
reactivations that take place in the United
not all patients with disseminated tubercu
States. The sex incidence is nearly equal
losis. In the series reported by Grieco and
except in the HIV-infected population, Chmel (1974), only 14 (50%) of 28 patients
wherein men predominate.
had a miliary pattern on chest film, whereas
Because of the multisystem involvement
90% of 69 patients reported by Munt (1971)
m disseminated tuberculosis, the clinical had a miliary pattern. Overall, it appears
manifestations are protean. The presenting that at the time of diagnosis
.
----- , approximately
symptoms and signs are g
iaVv me
generally nonspe- o5% of patients ,have
the ciiarcharacteristic racific and are dominated by the systemic diographic findings of milU^Tuberculosfe
Sects, particularly fever, weight loss, an- Other
Other radiographic
abnormalities may
may be
be
radiographic abnormalities
orexia, and weakness (Grieco and Chmel, present 22
"
c."
rT
”
as well. These include upper lobe
1974; Munt, 1971; Prout and Bcnatar, 1980- infiltrates with
1 or without cavitation, pleu
Sahn and Neff, 1974; Slavin et al., 1980). ral effusion, and pericardial effusion. In
Other symptoms depend on the relative patients with HIV infection, the radio
severity of disease in the organs involved
graphic pattern is one of diffuse infiltration
Cough and shortness of breath are com rather than discrete nodules.
mon; headache and mental status changes f The tuberculin ...............
skin
test is positive 1CS
less5
are less frequent and are usually associated frecluently in patients with disseminated
with meningeal involvement (Munt, 1971). tuberculosis
tuberculosis than in those with other forms
Physical findings are likewise variable. Fe- of the dise
ase. The rate of positivity at the
disease.
ver, wasting, hepatomegaly, pulmonaiy time
t,me of diagnosis in apparently immunohndings, lymphadenopathy, and spleno- competent
comPetent persons ranges from approximegaly occur in descending order of fre- matc,y
to 75% (Grieco and Chmel 1974quency. The only physical finding that is Munt, 1971; Sahn and Neff, 1974; Slavin et
specific for disseminated tuberculosis is the al., 1980). As the disease is treated, tuberchoroidal tubercle, a granuloma located in culm reactivity tends to return unless there
the choroid of the retina (Massaro et al.. is systemic immunocompromise.
1964).
Autopsy series have shown the liver,
Initial screening laboratory studies are lungs, bone marrow, kidneys, adrenals, and
not particularly helpful for the diagnosis of spleen to be the organs most frequently
miliary tuberculosis. Both leukopenia and involved in miliary tuberculosis, but any
leukocytosis may be seen, but the majority organ can be the site of disease (Slavin et
of patients have normal leukocyte counts. al., 1980). Because of the multiplicity of
Anemia is common and may be normo sites involved, there arc many potential
cytic, normochronic, or microcytic and sources of material used to provide a diag
hypochromic. Coagulation disorders are nosis. Acid-fast smears of sputum arc pos
unusual, but disseminated intravascular co itive in 20 to 25% of patients, and M.
is isolated from sputum in 30
agulation has been reported in association tuberculosis
tn
—*:
•
______
With miliary tuberculosis in severely ill pa"
°f Pat'entS zx-.
(GrieCO
,
--J and Chmel,
1974; Munt, 1971; Sahn and Neff, 1974;
etT
and HUdS°n’ 19?6; Murray S1avin
1 et al., 1980). Gastric washings or
Cl al., 1978). Hyponatremia also occurs, as
induced
sputum may be positive when the
discussed above. The most frequent abnorpatient
is
not expectorating spontaneously.
mahty Of liver function is an increased
In
a
patient
with an abnormal chest film and
alkaline phosphatase concentration. Bilirunegative sputum examinations, bronchos-
4
36
Hopewell
copy should be the next step. Combinations
In non-HIV-infectcd persons with tuber
of bronchoalveolar lavage and transbronculous
lymphadenitis, systemic symptoms
cheal biopsy would be expected to have a
are
not
common unless there is concomi1hnc|hud>lebve<?thanrdPhtentiaI S‘teS
bi°PSy ‘ant '^erculosis'ekewheie:
.
- -------- The frequency
inciuae liver and bone marrow, each of
which has a high likelihood of showing oi pulmonary involvement in reported se
ries of patients with tuberculous lymphad
granulomas (70 to 80%) but only a 25 to 40%
enitis
is quite variable, ranging from ap
chance of providing bacteriologic confirma
proximately
5 to 70%. In HIV-infected
tion (Sahn and Neff, 1974). Urine is easy to
persons,
lymphadenitis
is commonly asso
obtain and may be positive in up to 25% of
ciated with multiple-organ involvement, al
patients (Sahn and Neff, 1974). Selection of
though localized lymphadenitis, as de
other potential sources of diagnostic mate
scribed above, may occur as well.
rial should be guided by specific findings.
The diagnosis of tuberculous lymphade
nopathy is established by lymph node
Lymph Node Tuberculosis
biopsy or aspiration with histologic examiPrior to the HIV
i
u
.
nation> including stains for acid-fast organ-
I
tuberculosis made r‘
■*
the cases of extrapuiminary"tu'beTculosfe in
the United States (Farer et al., 1979). Al|
iz>L
*L •
L _
•
«
•
of tuberculosis applies to lymphatic tuber
culosis, there are two main differences:
lymphatic tuberculosis is relatively more
common among children, and. it occurs
more frequently in women •
also appears
to be more common among Asians and
Pacific Islanders than among
___ blacks and
whites. Among HIV-infected
------- 1 persons, du
the
demographic features of tuberculous l^iph
1 C »-x
1«
t —
adenitis
parallel
those
of HIV infection.1"*1
I
n1
1
••«-» 1
I A —
—
I
5
L
Pleural Tuberculosis
_
Tuberculous lymphadenitis usually
y presents as painless swelling of one or more
lymph nodes. The nodes most c.
commonly
involved are those of the posterior or antenor cervical chain or those in f
the supraclavicular fossa. Frequently, the process is
bilateral, and other noncontiguous groups
oi nodes can be involved (Kent, 1967). At
least initially, the nodes arc discrete and the
overlying skin is normal. With continuing
disease, the nodes may become matted and
the overlying skin inflamed. Rupture of the
node can result in formation of a sinus tract
which may be difficult to heal. Intrathoracic
adenopathy may compress bronchi, caus
ing atelectasis and leading to lung infection
and perhaps bronchiectasis.
I
losis (Huhti et al., 1975). Caseating granu
lomas are seen in nearly all biopsy samples
from immunocompetent patients. In immunodeficiency states, granulomas may be
poorly formed or absent (Marchevsky et
y
al., inoc
1985).'
The epidemiology of pleural tuberculosis
parallels that of the overall pattern for tu
berculosis, with the disease being more
common among males and increasing in
incidence with increasing age between ages
5 and 45 (Farer et al., 1979). As noted
above,
fied by this
the epidemiologic pattern is modiJ ' ', ’ 1 occurrence of HIV infection,
although pleural involvement seems rela
tively less frequent among HIV-infected
persons.
There are two mechanisms by which the
pleural space becomes involved in tubercu
losis, and the difference in pathogenesis
results in different clinical presentations,
approaches to diagnosis, treatment, and
sequelae. Early in the course of a tubercu
lous infection, a few organisms may gain
a
o
Chapter 3
with tuber
symptoms
; concomifrequency
ported selymphadfrom apV-infected
□nly assoement, al, as deI.
ymphadeiph node
;ic examiist organI. Smears
jximately
, and M.
y 70% of
tubercuig granu’ samples
In immumay be
evsky et
irculosis
i for tuig more
asing in
3en ages
s noted
s modifection,
ns relanfected
iich the
ubercugenesis
tations,
it, and
ibercuty gain
i
• Overview of Clinical Tuberculosis
37
access to the pleural space, and in the whom tuberculous pleuritis is ultimately
presence of cell-mediated immunity, they diagnosed (Levine et al., 1970; Scharer and
can cause a hypersensitivity response McClement, 1968). In a patient who has a
(Berger and Mejia, 1973; Elinor, 1978). pleural effusion that remains undiagnosed
Commonly, this form of tuberculous pleu- after a full evaluation, including pleural
ritis goes unnoticed, and the process re biopsy, and who has a positive tuberculin
solves spontaneously. In some patients, skin test reaction, antituberculosis treat
however, tuberculous involvement of the ment should be initiated.
pleura is manifested as an acute illness with
The second variety of tuberculous in
fever and pleuritic pain. If the effusion is volvement of
____
________________
the_pleura
is a true empyema
large enough, dyspnea may occur, although (pus in the pleura). This condition is^much
the effusions generally are small and rarely less common than tuberculous pleurisy
are bilateral. In ;approximately
'
’ 30%
----- of pa- with effusion and results from a large num
tients, there is no radiographic evidence of ber of organisms spilling into the pleural
involvement of the lung parenchyma; how space, usually from rupture of a cavity or
ever, parenchymal disease is nearly always an adjacent parenchymal focus via a bronpresent, as evidenced by findings by lung chopleural fistula (Johnson et al., 1973). A
dissections (Stead et al., 1955).
tuberculous empyema is usually associated
The diagnosis of pleural tuberculosis is with evident pulmonary parenchymal dis- *
generally established by analysis of pleural ease on chest films, and air may be seen in
fluid and/or pleural biopsy. A thoracentesis the pleural space. In this situation, the fluid
(aspiration of fluid from the chest) should is generally thick and cloudy and may con
be performed, and sufficient fluid for cell tain cholesterol, causing the fluid to look
count, cytologic examination, biochemical like chyle (pseudochylous effusion). The
analysis, and microbiologic evaluation fluid is exudative and usually has a rela
should be obtained, leaving enough to allow tively high leukocyte count, with nearly all
a n<:eedlc biopsy to be performed if the fluid of the leukocytes being lymphocytes. Acid
is exudative and no diagnosis is evident. fast smears and mycobacterial cultures are
The fluid is nearly always straw colored, usually positive, making pleural biopsy un
although it may be slightly bloody. Cell necessary. This type of pleural involvement
counts are usually in the range of 100 to has a tendency to burrow through soft tis
5,000/p,l (Jay, 1985). Early in the course of sues and may drain spontaneously through
the process, polymorphonuclear leuko the chest wall. An example of this type of
cytes may predominate, but mononuclear tuberculosis is shown in Fig. 8.
cells soon become the majority. The fluid is
exudative, with a protein concentration
Genitourinary Tuberculosis
greater than 50% of the scrum protein con
centration, and the glucose level may be
As with pleural tuberculosis, the epide
normal to low.
miologic pattern of genitourinary tubercu
Because few organisms are present in the losis parallels that of tuberculosis in general
pleural space, smears of pleural fluid are except that the incidence is nearly equal in
rarely positive, and M. tuberculosis is iso men and women. The pathogenesis appears
lated by culture in only 20 to 40% of pa to be one of seeding of the kidney at the
tients with proved tuberculous pleuritis time of the initial infection and bacillcmia.
(Levine et al., 1970; Scharer and McIn patients with genitourinary tuberculo
Clement, 1968). A single blind needle bi sis, local symptoms predominate, and sys
opsy of the pleura will confirm the diagno temic symptoms are less common (Chris
sis in approximately 65 to 75% of patients in
tensen, 1974; Simon et al., 1977). Dysuria,
38
Hopewell
IF
J
■■
I
ISO I V
141? Mh
LPG £FOV
IO 0 MM
0 0 TILT
I
I
I
120 KV
IZO Mh
/
v
—
LPG SFOV
5 O MM
0 O TILT
2 0 SEC 17 17 37
Chapter 3
I
I
)
I
I
I
•
Overview of Clinical Tuberculosis
39
hematuria, and frequent urination are com
mon, and flank pain may also be noted. requires biopsy, because the differential
However the symptoms may be very sub- asaoZ.SIS r “ ‘nC1UdeS ne°Plasia as well
nf thn v°Iten there iS advanced destruction as other infectious processes
Significant effects of tuberculosis on reof the kidneys by the time a diagnosis is
nal
function are unusual, but renal failure
established (Lattimer, 1965). Genital in
may
occur, especially in patients with pre
volvement without renal tuberculosis is
existing
renal disease. Nephrolithiasis and
more common in women than in men and
recurrent
bacterial infections in seriously
may cause pelvic pain, menstrual irregular
k
"?neys aIso occur- Hypertension
ities, and infertility as presenting com
.
*
?
P
,??
ds tO nePfirectomy has also been
plaints (Simon et al., 1977). In men a
described
but
is rare.
painless or only slightly painful scrotal
mass is probably the most common pre
senting symptom of genital involvement
Skeletal Tuberculosis
b .Symptoms of Prostatitis, orchitis, or
The incidence of tuberculosis involving
19741 yT'tlSulay a’SO °ccur (Christensen,
e joints and bones increases with increas^
1974). A substantial number of patients
with any form of genitourinary tuberculosis mg age and is equally frequent among men
are asymptomatic and are detected because and women, overall making up approxi
of an evaluation for an abnormal routine mately 9% of cases of extrapulmona^y tun( J6'6'aL’ 1979)' Compared to
urinalysis. In more than 90% of patients black
WhlteS’ °ther racial t’rouPs are
with renal or genital tuberculosis, urinaly less
in fi‘ h Y
’
e.SS lkey to have skeletal involvement
ses are abnormal, with the main
in Ending Skeletal tuberculosis does not a^ea“
being pyuria and/or hematuria The finding
-----of pyuria (pus in urine) in an acid urine wi ,
among persons with HIV infecno organisms isolated from a routine urine
It is presumed that most osteoarticular
culture should prompt an evaluation for
■vatio“'T, results
endogenous reac
uberculosis. The suspicion of genitouri
tivation
of
foci
of
infection
seeded during
nary tuberculosis should be heightened by
the
initial
bacdlemia,
although
spread from
e presence of abnormalities on the chest
him In most series, approximately 40 to kuLTt h™ lymph n°des has been Postu
red '0 account for the common localizaV5/o of patients have chest radiographic
abnormalities, although in many patients, tion of spinal tuberculosis to the lower
these abnormalities may be the result of thoracic and upper lumbar vertebrae
previous not current, tuberculosis (Chris (®urke, 195°). It is also postulated that the
piedilechon for tuberculosis to localize in
tensen, 1974; Simon et al., 1977)
he metaphyses of long bones is due to the
When genitourinary tuberculosis is sus
elatively rich blood supply and the scarcity
pected, at least three first-voided early>„P?inOCy"C Ce,IS in this Pott'0" of the
morning urine specimens should be col.n
( unuy 'L* aL’ 1972)- Aftcr begmning
ected for acid-fast stains and cultures M
«6erculosis is isolated from the urine in 80 m the subchondral region on the bone, the
sis rrt iCaSCS Of 8enitourinary tuberculo- infection spreads to involve the cartilage
synovium and joint space. This produces
( hnstensen, 1974; Simon et al. 1977)
Diagnosis of isolated genital lesions ’usually• the typical findings of metaphyseal erosion
and cysts and the loss of cartilage, with
num with mediastinal involvement (B).
40
Hopewell
narrowing of the joint space. Typically, in
changes, and sclerosis may be noted before
the spine these changes involve two adja
the joint space is actually narrowed. The
cent vertebrae and the intervertebral disk.
early
changes of spinal tuberculosis may be
Paravertebral or other para-articular ab
particularly difficult to detect by standard
scesses may develop, with occasional for
films of the spine. Computed tomographic
mation of sinus tracts. Although weight
scans
and magnetic resonance imaging of
bearing joints are the most common sites
the spine are considerably more sensitive
for skeletal tuberculosis, any bone or joint
than routine films and should be obtained
may be involved (Berney et al., 1972) In
when
there is a high index of suspicion of an
most series, tuberculosis of ’the spine
infectious process.
(Pott’s disease) makes up 50 to 70% of the
Confirmation of the diagnosis is obtained
cases reported. In adults, the lower tho
by aspiration of joint fluid or periarticular
racic and upper lumbar vertebrae are most
abscesses or by biopsy of bone or syn
commonly involved, whereas in children,
ovium
with histologic and microbiologic
the upper thoracic spine is the most fre
evaluation of the material obtained. Acid
quent site of vertebral tuberculosis. The hip
fast stains of joint fluid are positive in 20 to
or knee is involved in 15 to 20% of cases
25% of those examined, and M. tuberculo
and shoulders, elbows, ankles, wrists, and
other bones or joints are also involved in 15 sis is isolated in approximately 60 to 80%
(Berney et al., 1972). Biopsies of synovium
to 20% of cases. Usually only one bone or
or bone have a higher yield and allow
joint is involved, but occasionally the pro
histologic examination as well. Evidence of
cess is multifocal (Gremin et al 1970granulomatous
inflammation even in the
McTammany et al., 1963). Evidence of ei
absence of bacteriologic proof of the diag
ther previous or current pulmonary tuber
nosis is sufficient evidence of tuberculosis
culosis is found in approximately one-half
to begin therapy unless another etiology is
of the reported patients, and other extrapul
monary sites may also be involved.
The usual presenting symptom of skeletal
tuberculosis is pain (Berney et al., 1972).
Central Nervous System Tuberculosis
Swelling of the involved joint may be
Meningitis is the most frequent form of
noted, as may limitation of motion and
central nervous system tuberculosis; soli
occasionally sinus tracts. Systemic symp
toms of infection are not common. Because tary or multiple tuberculomas occur less
of the subtle nature of the symptoms, diag commonly. The epidemiologic pattern of
nostic evaluations often are not undertaken central nervous system tuberculosis is quite
different from either pulmonary or other
until the process is advanced. Delay in
diagnosis can be especially catastrophic in forms of extrapulmonary tuberculosis in
that the peak incidence is in children in the
vertebral tuberculosis, in which compres
sion of the spinal cord may cause severe zero- to 4-year age group, but an apprecia
and irreversible neurologic sequelae, in ble number of cases occur in adults (Bar
rett-Connor, 1967; Farer et al., 1979). Cen
cluding paraplegia.
tral
nervous system disease accounts for
The first diagnostic test undertaken is
only approximately 5% of all cases of ex
usually a radiograph of the involved area,
he typical findings just described repre trapulmonary tuberculosis, and the cases
are equally divided between males and fe
sent the more severe end of the spectrum
males.
Early in the process, the only abnormality
Central nervous system involvement, es
noted may be soft tissue swelling. Subse
pecially
tuberculomas, seems to occur with
quently, subchondral osteoporosis, cystic
greater frequency among HIV-infected per
Chapter 3
3 noted before
arrowed. The
ulosis may be
t by standard
tomographic
:e imaging of
lore sensitive
I be obtained
Jspicion of an
is is obtained
periarticular
>one or synnicrobiologic
ained. Acid•itive in 20 to
1. tuberculoy 60 to 80%
of synovium
I and allow
Evidence of
iven in the
of the diagtuberculosis
r etiology is
i
I
erculosis
’nt form of
jlosis; solioccur less
pattern of
3Sis is quite
y or other
rculosis in
dren in the
i appreciadults (Bar979). Cencounts for
tses of exthe cases
;es and fcement, es)ccur with
ected per-
I
1
•
Overview of Clinical Tuberculosis
41
sons. Tuberculomas have been reported establishing a diagnosis. In the presence of
even in patients who are receiving what meningeal signs on physical examination,
should be adequate chemotherapy (Bish- lumbar puncture is usually the next step in
berg et al., 1986). The findings produced by the diagnostic sequence. If there are focal
tuberculomas may be indistinguishable on findings on examination or if there are sug
computed tomographic scan from those of gestions of increased intracranial pressure,
toxoplasmosis. For this reason, a specific a computerized tomographic scan of the
diagnosis should be sought when such le head, if it can be obtained expeditiously,
sions are noted.
should be performed before the lumbar
Meningitis presumably can result from puncture. With meningitis, the scan may be
direct meningeal seeding and proliferation normal, but it can also show diffuse edema
during a tuberculous bacillemia either at the or obstructive hydrocephalus. Tuberculo
time of initial infection or at the time of mas are generally seen as ring-enhancing
breakdown of an old pulmonary focus, or it mass lesions.
can result from breakdown of an old paraIn tuberculous meningitis, the lumbar
meningeal focus with rupture into the sub puncture usually shows increased opening
arachnoid space. The consequences of the pressure and the cerebrospinal fluid usually
subarachnoid space contamination include contains between 100 and 1,000 cells per p.1.
diffuse meningitis, a localized arteritis, en In approximately 65 to 75% of patients,
cephalitis, or myelitis. With meningitis, the lymphocytes predominate, whereas poly-process takes place primarily at the base of morphonuclear leukocytes predominate in
the brain (Auerbach, 1951). Symptoms the remainder of patients, generally early iin
therefore include those related to cranial the course of the illness. The protein connerve involvement in addition to headache, centration is elevated in nearly all patients.
decreased level of consciousness, and neck Very high (>300 mg/dl) protein concentra
stiffness. The duration of illness prior to tions have been associated with a poor
diagnosis is quite variable and relates in prognosis (Weiss and Flippin, 1961). The
part to the presence or absence of other glucose concentration in cerebrospinal fluid
sites of involvement. In most series, over is usually low but not as low as concentra
50% of patients with meningitis have ab tions that occur during pyogenic bacterial
normalities on chest film that are consist meningitis. Acid-fast organisms are seen on
ent with an old or current tuberculous pro smears of cerebrospinal fluid in only 10 to
cess, often miliary tuberculosis. At au 20% of patients, and the rate of culture
topsy, disseminated disease is found in a positivity varies from 55 to 80% (Barrettvery high percentage of patients with men Connor, 1967). A substantial number of
ingitis (Auerbach, 1951). In patients with patients will have M. tuberculosis isolated
tuberculous meningitis, sputum cultures from other sources, and in the presence of
have been positive in 40 to 50%; thus, a compatible cerebrospinal fluid findings,
substantial number of patients will have such isolation is sufficient to diagnose tu
pulmonary and systemic symptoms in addi berculous meningitis. Given the severity of
tion to those referable to the central ner tuberculous meningitis, a presumptive diag
vous system. Arteritis may be the predom nosis justifies empiric treatment if no other
inant manifestation of meningitis and can diagnosis can be established promptly.
result in a variety of focal ischemic syn
The other major central nervous system
dromes in addition to the symptoms already form of tuberculosis, the tuberculoma, pre
described.
sents a more subtle clinical picture than
Physical findings and screening labora tuberculous meningitis (Damcrgis et al.,
tory studies are not particularly helpful in 1979). The usual presentation is that of a
42
Hopewell
slowly growing focal lesion, although a few
patients have increased intracranial pres
sure and no focal findings. The cerebrospi
nal fluid is usually normal, and the diagno
sis is established by computed tomographic
or magnetic resonance scanning and subse
quent resection, biopsy, or aspiration of
any ring-enhancing lesion.
i|
I
nal ileum and the cecum, with other por
tions oi the colon and the rectum involved
less frequently (Bhansali, 1977). In the ter
minal ileum or cecum, the most common
manifestations are pain, which may be mis
diagnosed as appendicitis, and intestinal
obstruction. A palpable mass may be noted
and, together with the appearance of the
abnormality on barium enema or small
Abdominal Tuberculosis
bowel films, may easily be mistaken as a
carcinoma. Rectal lesions usually present
Tuberculosis can involve any intra-ab
dominal organ as well as the peritoneum. as anal fissures or fistulae or as perirectal
abscesses. Because of the concern with
The age distribution of abdominal tubercu
carcinoma, the diagnosis often is made at
losis shows a relatively higher incidence in
surgery.
young adults and a second peak in older
For tuberculous peritonitis, pain, often
persons. Males and females have a similar
accompanied
by abdominal swelling, is
incidence. Intra-abdominal tuberculosis
commonly
the
presenting manifestation
has not been common in HIV-infected per- (Bhansalf
sons.
’, 1977; Borhanmanesh et al.,
1972; Burack and Hollister, 1960; Singh et
Abdominal tuberculosis presumably re
al., 1968). Fever, weight loss, and anorexia
sults from seeding at the time of initial
are also common. Active pulmonaiy tuber
infection and then either direct or late pro
culosis is uncommon in patients with tuber
gression to clinical disease. Peritonitis can
culous peritonitis. Because the process fre
also be caused by rupture of tuberculous
quently coexists with other disorders,
lymph nodes within the abdomen. Intesti
especially hepatic cirrhosis with ascites,
nal tuberculosis may also result from in
the symptoms of tuberculosis may be ob
gested tubercle bacilli with direct implanta
scured. The combination of fever and abtion in the gut. Before chemotherapy, dominal tenderness in a person with ascites
tuberculous enteritis was quite common in
should always prompt an evaluation for
patients with advanced pulmonary tubercu
intra-abdominal infection, and a paracente
losis, presumably being caused by bacilli
sis should be performed. Ascitic fluid in
from the lungs that were swallowed. In a
tuberculous peritonitis is exudative (fluid
prospective study conducted between 1924
protein content greater than 50% of serum
and 1949, intestinal abnormalities compati
protein concentration) and contains be
ble with tuberculous enteritis were found
by contrast radiography in 1, 4.5 and tween 50 and 10,000 leukocytes per p,l, the
majority of them being lymphocytes, al-
berculosis, respectively (Mitchell and Bris
tol, 1954).
The clinical manifestations of abdominal
tuberculosis depend on the areas of in
volvement. In the gut itself, tuberculosis
may occur m any location from the mouth
to the anus, although lesions proximal to
the terminal ileum are unusual. The most
common sites of involvement are the termi-
I
J --3 oc
casionally predominate (Borhanmanesh et
al., 1972; Singh et al., 1968). Acid-fast
organisms are rarely seen on smears of the
fluid, and cultures are positive in only ap
proximately 50% of patients. Because of
the generally low yield from culture of the
fluid, laparoscopic biopsy is often neces
sary to confirm the diagnosis.
Microscopic evidence of liver involve
ment is common in patients with all forms
B5
Chapter 3
:h other por:um involved
')• In the terost common
may be misid intestinal
iay be noted
ance of the
a or smallistakcn as a
ally present
is perirectal
mcern with
is made at
pain, often
welling, is
anifestation
sh et al.,
0; Singh et
id anorexia
nary tuberwith tuberrocess fredisorders,
h ascites,
iay be ob-r and abith ascites
aation for
aaracentec fluid in
tive (fluid
of serum
tains be
er |il, the
cytes, alcytes oclanesh et
Acid-fast
irs of the
only apcause of
re of the
n neces-
involvetll forms
of tuberculosis, but actual hepatic tubercu
losis of functional consequence is rare. A
variety of histologic abnormalities may be
seen, but none is specific for tuberculosis
unless M. tuberculosis is isolated from he
patic tissue (Frank and Raffensperger,
1965). For this reason, all liver biopsy spec
imens should be cultured for mycobacteria.
I
[
• Overview of Clinieal Tuberculosis
43
the inflammatory response in the pericar
dium, as presumably occurs in the pleura.
On the other hand, rupture of a caseous
lymph node into the pericardium may cause
contamination with a much greater number
of organisms; a greater inflammatory re
sponse with thicker, more purulent fluid;
and a greater likelihood of either early or
late hemodynamic effects.
The most common form or stage of tu
Pericardial Tuberculosis
berculous pericarditis is characterized by
The descriptive epidemiology of pericar pericardial effusion with little pericardial
dial tuberculosis is not well defined, but in thickening or epicardial involvement. The
general the disease tends to occur among fluid itself is usually serosanguineous or
older persons, with approximately 50% of occasionally grossly bloody, is exudative,
the patients being older than 55 years and has a leukocyte count of 500/mm3 to as
(Farer et al., 1979). Nonwhites and men high as 50,000/mm3, with an average of
have a relatively higher frequency of tuber 5,000 to 7,000/mm3 (Harvey and Whitehill,
culous pericarditis. Before the use of anti 1937). The cells are predominantly mono
tuberculosis chemotherapy, tuberculous nuclear, although polymorphonuclear leu
pericarditis was found in 0.4 to 1.0% of all kocytes occasionally predominate. Tuberautopsied patients and in 73 to 8% of' autop- cle bacilli have been identified in pericardial
sied patients in whom there was other evi fluid in approximately 25 to 30% of cases
dence of tuberculosis (Schepers, 1962). A (smear and culture combined) (Rooney et
clinical diagnosis of tuberculous pericardi
- .
1970). Biopsy of the pericardium with
tis was made in C0.35% of approximately both histologic and bacteriologic evaluation
th any form of »..i
10,000 patients with
tuberculo 1S much more Iikely tQ provide a diagnosis,
sis admitted to Kings County Hospital Cen although a nonspecific histologic pattern
ter, Brooklyn, N.Y., 1
1 Januaiy and failure to recover the organisms do not
1960 and 31 December 1966 (Rooney et al"
exclude a tuberculous etiology.
1970).
With persistence of the inflammation,
The pericardium may become involved there is thickening of the pericardium and
during the initial bacillemia, with early pro progressive epicardial involvement. Granu
gression to clinically evident disease or lomas, various amounts of free or loculated
recrudescence following a quiescent pe fluid, and fibrosis may be present during
riod. Hematogenous seeding may also oc this stage, and evidence of cardiac constric
cur during the course of endogenous re tion may begin to appear. The necrosis
activation. Alternatively, there may be associated with the granulomatous inflam
direct extension of an adjacent focus of mation may involve the myocardium, with
disease into the pericardium. This focus consequent functional and electrocardio
may be in lung parenchyma, pleura, or graphic manifestations.
tracheobronchial lymph nodes. In fact, all
Although it is not well documented, it
of these mechanisms probably occur and appears that if the patient survives the
may account for some of the variability in subacute phase without treatment, chronic
the characteristics of the pericardial fluid, fibrotic pericarditis nearly always follows.
severity of the process, and prognosis Prior to the advent of antituberculous ther
(Schepers, 1962). It is likely that tuberculin apy, 88% of one series of patients who had
hypersensitivity plays a role in producing tuberculous pericarditis developed evidence
44
l;
I
Hopewell
hinChiro™ C2nstric,ion (Ha™y and Whitehill, 1937). Constriction has also been ob pericarditis requires identification of tuberserved to develop during the course of ah?301? 'n PericardiaI ^id or tissue.
antituberculous chemotherapy, although Although not conclusive, demonstration of
this development appears to be uncommon caseating granulomata in the pericardium
and consistent clinical circumstances is
in patients who have had symptoms for less
convincing
evidence of a tuberculous etiol
han 3 months. In the series reported by
ogy
Less
conclusive
but still persuasive
H^man and coworkers (Hageman et al.,
evidence
is
the
finding
of another form of
yM), 11 of 13 patients who had symptoms
tuberculosis in a patient with pericarditis of
ectomy^
6 m°nths recluired pericarditn"eti°,Ogy- Approximately 25
The fibrotic reaction noted above to 5°% of patients with tuberculous pericar
ditis have evidence of other organ involve
progresses to complete fusion of visceral
and parietal pericardium and encasement of ment, particularly pleuritis, at the time peri
the heart in a rigid scar. There are various carditis is diagnosed (Gooi and Smith, 1978Harvey and Whitehill, 1937). Still less di
amounts of calcium within the fibrotic
rect
and more circumstantial evidence of a
mass. Impairment of coronaiy circulation is
tuberculous etiology is the combination of a
common. At this point, the histologic patern is usually nonspecific; thus, confirma positive intermediate-strength tuberculin
tion of a tuberculous etiology is infrequent. s in test reaction and pericarditis of un
proven etiology.
Hie symptoms, physical findings, and
laboratory abnormalities associated with
tuberculous pericarditis may be the result
references
of either the infectious process per se or the
pericardial inflammation causing pain, effu
‘•f’
Ba‘unswanayo, K. Kerlikowske, A. R.
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P2
P'taL
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nhO?ar> <-rT fever’ the most con,mon
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I
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arditis of
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