Preventive Therapy for Tuberculosis (TB) in HIV-infected Persons

Item

Title
Preventive Therapy for
Tuberculosis (TB)
in
HIV-infected Persons
extracted text
A.

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Preventive Therapy for
Tuberculosis (TB)
in
HIV-infected Persons
Boonmee Sathapatayavongs, MD, FRCP (UK)
Ramathibodi Hospital, Mahidol University

Prevention of Nosocomial
Transmission of TB
Boonmee Sathapatayavongs, MD, FRCP (UK)
Ramathibodi Hospital, Mahidol University

Risk of Developing TB in HIVinfected Persons with (+)
Tuberculin Skin Test*
5-8% per year or > 30% in lifetime

* TST with 5-TU PPD by the Mantoux method, (+) = > 5 mm. induration

Mechanisms of Developing TBI
■

Reactivation of latent infection

■ Rapid progression of primary infection
■ Reinfection

is
I!

Types of Preventive Intervention
for TB Control

■
■
■
■

Case-finding and treatment
Preventive chemotherapy
Use of BCG
Environmental control

Preventive Therapy of TB |
= Treatment of symptomless M. tuberculosis
infections to prevent the development of
active disease

Efficacy in non-HIV =

25-92% reduction
of TB*

* Adv Tuberc Res 1969 ; 17 : 28-106.

Efficacy of Preventive Rx in HIV-person (RCT)
TB cases/100P-Y
Study Site
(no.)

Regimen

Treatment

Placebo

RR

Haiti (118)*

12H

2.2

7.5

3.4(1.1-10.6)

PPD (+)

12 H

1.7

10.0

5.8(1.2-28.7)

PPD (-)

12 H

3.2

5.7

1.8 (0.4-9.2)

Zambia (647)**

6H

2.1

5.3

(differences decrease with time after Rx stopped)
Lancet 1993;342:268,
Wadhawan et al, 9th IC on AIDS. Berlin 1993

Efficacy of Preventive Rx in HIV-person (RCT)
TB cases/100P-Y
Study Site

Regimen

Treatment

Placebo

RR

Anergic

6H
3HR
3HRZ
6H

1.08
1.32
1.73
2.53

3.41
3.41
3.41
3.06

0.33 (0.14-0.77)
0.40 (0.18-0.86)
0.51 (0.24-1.08)
0.83 (0.34-2.04)

Kenya (684) **
PPD (+)
PPD (-)

6H
6H
6H

4.29

3.86
8.03
2.73

0.92 (0.49-1.71)
0.60 (0.23-1.60)
1.23 (0.55-2.6)

Uganda (2736)*

PPD (+)

5.59
3.28

* N Engl J Med 1997,337:801

** AIDS 1997;11:875.

/

Efficacy of Preventive Rx in HIV person
(Observational study)
<♦ 52 PPD (+) IDU in New York*, regimen 12H

compliant vs. noncompliant = 0 v.s. 9.7/100 P.Y

❖

121 PPD (+) in Madrid, Spain**, regimen 9-12H
treated v.s. non-treated = 1.6

‘ JAMA 1992;268:504

v.s.

9.4/100 P.Y

** Anch Intern Med 1997;157:1729

In summary :
❖ INH prophylaxis is effective, at least short term, among PPD (+)
HIV-person. 12-month course is preferable. In PPD (-) or
anergic HIV-person, no effectiveness has been shown.
❖ Other multi-drug regimens of shorter duration (3HR, 3HRZ) are
as effective as INH alone but more adverse effects in PPD (+)
group.

❖ The higher the proportion of TB cases from reactivation the
greater is the potential effectiveness of preventive Rx. If cases
result from reinfection, the effectiveness of preventive Rx is
likely to be short-lived.

From “study” to “practice”
Main concern : The possible emergence
of drug resistance with
increased use of INH

monotherapy and
inadequate system for

active TB exclusion.

Consideration before implementing
preventive Rx program
Feasibility
❖ Sustainability
<♦ Cost effectiveness
❖ Methods of delivery
Monitoring for exclusion of active TB

❖ Safety
Compliance

Upper room UVGI
❖ UV-C shert wavelength (~ 254 nm)
❖ Proper installation provide lethal dose to
bacteria in upper air but safe at lower intensity in
lower air (< 0.1 watt/cm2)
Need ceiling height of > 8 ft. to ensure safety

❖ Relative humidity > 60% reduces efficacy
❖ Efficacy depends on air mixing in the room
❖ UV-C : no reports of oncogenesis, may produce
burn, conjunctivitis.

Transmission of M.tuberculosis
♦ Air borne transmission
♦ Infectious particles : droplet nuclei 1-5 p,
o small enough to remain air borne for
long time and distribute widely
o produced from coughing, singing,
speaking, aerosolization of abscess
material
° AFB smear (+) source

Isolation rooms
♦ Single room
♦ Negative pressure
♦ 6-12 air exchange per hour
♦ Exhaust air to outside or recirculated by
using HERA filters

♦ Upper room UV Gl as adjunct measure

High Efficiency Particle Air

(HERA) Filter
❖ Remove 99.93% of air-borne
particles > 0.3 ji
❖ Problem of “flow limitation”

WHO recommendation on TB
preventive Rx in HIV-infected persons*
INH (6-12 months duration) shoud be considered for
HIV-infected people with positive PPD (> 5mm),

when active TB has been excluded.
( However, the emphasis of TB control program still remains
at curative Rx of cases of TB to interrupt the transmission )

*Wkly Epidemiol Rec 1993;68:361.

Principles of Control of TB Transmission
Source

Environmental

Recipient

Control

Control

Control

• Early Dx. & Rx of

case

• Air dilution
(Ventilation)

• Personal protective

resp. device

• Proper case

• Air filtration

• HCW surviellance

isolation

(HEPA)

inc. PPD status

• Face mask to trap

coughing material

• HCW education &
• UV germicidal
irradiation (UVGI)
training

Vol. 43 / No. RR-13

MMWR

1

Guidelines for Preventing
the Transmission of
Mycobacterium tuberculosis in
Health-Care Facilities, 1994
Executive Summary
This document updates and replaces all previously published guidelines for the pre­
vention of Mycobacterium tuberculosis transmission in health-care facilities. The
purpose of this revision is to emphasize the importance of a) the hierarchy of control
measures, including administrative and engineering controls and personal respiratory
protection; b) the use of risk assessments for developing a written tuberculosis (TB)
control plan; c) early identification and management of persons who have TB; d) TB
screening programs for health-care workers (HCWs); e) HCW training and education;
and f) the evaluation of TB infection-control programs.

Transmission of M. tuberculosis is a recognized risk to patients and HCWs in health­
care facilities. Transmission is most likely to occur from patients who have un­
recognized pulmonary or laryngeal TB, are not on effective anti-TB therapy, and have
not been placed in TB isolation. Several recent TB outbreaks in health-care facilities,
including outbreaks of multidrug-resistant TB, have heightened concern about noso­
comial transmission. Patients who have multidrug-resistant TB can remain infectious
for prolonged periods, which increases the risk for nosocomial and/or occupational
transmission of M. tuberculosis. Increases in the incidence of TB have been observed
in some geographic areas; these increases are related partially to the high risk for TB
among immunosuppressed persons, particularly those infected with human immu­
nodeficiency virus (HIV). Transmission of M. tuberculosis to HIV-infected persons is of
particular concern because these persons are at high risk for developing active TB if
they become infected with the bacteria. Thus, health-care facilities should be particu­
larly alert to the need for preventing transmission of M. tuberculosis in settings in
which HIV-infected persons work or receive care.
Supervisory responsibility for the TB infection-control program should be assigned tc
a designated person or group of persons who should be given the authority to imple
ment and enforce TB infection-control policies. An effective TB infection-contro
program requires early identification, isolation, and treatment of persons who have
active TB. The primary emphasis of TB infection-control plans in health-care facilities
should be achieving these three goals by the application of a hierarchy of contro
measures, including a) the use of administrative measures to reduce the risk for expo
sure to persons who have infectious TB, b) the use of engineering controls to preven
the spread and reduce the concentration of infectious droplet nuclei, and c) the use o
personal respiratory protective equipment in areas where there is still a risk for expo
sure to M. tuberculosis (e.g., TB isolation rooms). Implementation of a TB infection
control program requires risk assessment and development of a TB infection-contro
plan; early identification, treatment, and isolation of infectious TB patients; effectiv*

2

MMWR

Vo'

October 28, 1994

engineering controls; an appropriate respiratory protection program; HCW TB train­
ing^ education, counseling, and screening; and evaluation of the program's effective­

ness.

r

Although completely eliminating the risk for transmission of M. tuberculosis in all
health-care facilities may not be possible at the present time, adherence to these
guidelines should reduce the risk to persons in these settings. Recently, nosocomial
TB outbreaks have demonstrated the substantial morbidity and mortality among pa­
tients and HCWs that have been associated with incomplete implementation of CDC s
Gu delines for Preventing the Transmission of Tuberculosis in Health-Care Facilities,
with Special Focus on HIV-Related Issues published in 1990.* Follow-up investigations
at some of these hospitals have documented that complete implementation of meas­
ures similar or identical to those in the 1990 TB Guidelines significantly reduced or
eliminated nosocomial transmission of M. tuberculosis to patients and/or HCWs.

%

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Vol. 17 No. 1

Infection Control and Hospital Epidemiology

11

Probable Role of Ultraviolet Irradiation in
Preventing Transmission of Tuberculosis:
A Case Study
William W. Stead, MD; Carole Yeung, RN, CIC; Carolyn Hartnett, BSN, COHN

The problem of transmission of tuberculosis
(TB) in healthcare facilities is a serious one, all the
more so when compounded by organisms that are
drug resistant. The purpose of this report is to
describe our experience with prolonged hospital care
of a patient with advanced multidrug-resistant cavi­
tary pulmonary TB in a hospital with complete preexposufe tuberculin skin-test data.
CASE PRESENTATION

The patient, a 59-year-old white man with anky­
losing spondylitis, was admitted to our hospital on
January 2, 1992, with a diagnosis of cavitary pul­
monary TB. In June 1990. he had been treated in
another state with isoniazid (INH) and rifampin for 11
months with apparent recovery, despite irregular
compliance. However, in the fall of 1991, he again
developed a productive cough, for which the same
drugs were given. When he failed to improve, he
moved to Arkansas to be near a sister.
At the time of admission, the patient com­
plained of a persistent productive cough and weight
loss. The chest radiograph showed bilateral involve­
ment with a thick-walled cavity in the right upper lobe
measuring 60 x 110 mm. Sputum smears were 4+
positive for acid-fast bacilli (AFB).
Chemotherapy was instituted with rifampin,
isoniazid (Rifamate), and pyrazinamide. By January
21. the patient had shown little improvement, the
cough persisted, and the sputum smears remained
strongly positive for AFB. A laboratory in the state
from which he had come reported the organism to
be Mycobacterium tuberculosis, resistant to rifampin
and isoniazid but susceptible to ethambutol and
streptomycin.
At this point, the drug regimen was changed to
ethambutol (25 mg/kg/day), pyrazinamide (25 to 30
mg/kg/day) and streptomycin (1 gm/day). However,

the 4+ positive sputum smears suggested a very large
bacterial load that probably could not be controlled
without resection of the thick-walled cavity.1 After 10
days of this chemotherapy regimen, the right upper
lobe was resected.
The operating room was one used for cardiac
surgery and was particularly well ventilated (48 air
changes per hour), supplemented by sterilization of
upper air by ultraviolet germicidal irradiation
(UVGD- The operating surgeon described the opera­
tion as the most difficult in his long career. A small
empyema sac was entered inadvertently, and there
was an audible escape of air and pus under pressure.
The lobectomy succeeded in converting the
sputum smears to negative, with only one culture
showing a few colonies of M tuberculosis. Following
surgery, the patient was admitted to the surgical
intensive care unit, which had ventilation of 22 air
changes per hour supplemented by UVGI. The use of
surgical masks was optional. Fiberoptic bron­
choscopy was necessary on nine occasions to remove
copious bronchial secretions. The patient's pulmonary
reserve never was adequate to permit extubation, and
he died on the 84th day. Pathologic examination of
the right upper lobe confirmed the presence of a
thick-walled cavity with abundant tubercle bacilli and
a bronchopleural fistula with a localized empyema.
HOSPITAL CONTROL MEASURES FOR
TB IN 1992

Since 1974, the hospital had been under con­
tract with the Arkansas Department of Health for care
of TB patients, providing recommended measures to
contain TB and annual reporting of relevant data.
Isolation rooms were provided with ventilation of 15
air changes per hour, supplemented by sterilization of
the upper air by UVGI. Ventilation air (20% outside.
80% recirculated) was all HEPA filtered before enter-

From the Tuberculosis Control Program (Dr. Stead). Arkansas Department of Health. University of Arkansas College of
Medicine, and the Baptist Medical Center (Ms. Yeung and Ms. Hartnett). Little Rock. Arkansas.
Address repnnt requests to William W. Stead. MD. Director. Tuberculosis Program. Arkansas Department of Health. Mail Slot
45. 4815 W Markham St. Little Rock. AR 72205-3867.
95-OA-062. Stead IYIY. Yeung C, Hartnett C. Probable role of ultraviolet irradiation in preventing transmission of tuberculosis:
a case study. Infect Control Hosp Epidemiol 1996:17:11-13.

12

Infection Control and Hospital Epidemiology

ing the room. Exhaust was to the outside, away from
air intakes. The use of masks was not required.
In 1992, 15 other patients with TB were admit­
ted. Of approximately 600 new employees that year,
36 (6%) were purified protein derivative (PPD) posi­
tive. Of 3,500 continuing employees, approximately
350 (10%) were known to be PPD positive. Of the
remaining 3,150 PPD-negative employees, 15 (0.7%),
none involved with our patient, showed PPD conver­
sion during the year and were treated prophylactically with isoniazid. No employee developed TB. The
case rate for Arkansas that year was 10.7 per 100,000.

RESULTS OF EPIDEMIOLOGIC
INVESTIGATION
A total of 159 employees were identified as hav­
ing contact with our patient over the 84-day period,
most with daily contact during the first 30 days when
sputum smears were consistently positive. Fifteen
(9.4%) of the 159 were known already to be PPD pos­
itive (reaction 10 mm) and were followed clinically,
in accordance with our long-standing policy.2 Seven
employees had relocated before postexposure testing
and could not be located.
Of the 137 PPD-negative employees, 136 have
remained nonreactive. One 35-year-old man showed a
reaction of 15 mm on annual testing at another hospi­
tal, where he worked full time as a radiology techni­
cian. His exposure to our patient was by taking
portable chest radiographs for 2 weeks following
surgery, when the patient's bacteriology was negative.
None of the 152 employees we could follow has devel­
oped TB in almost 4 years. We have heard nothing
from the seven employees whom we could not trace.

DISCUSSION
TB generally is not a highly infectious disease.
Israel studied five consecutive classes of nursing stu­
dents at Philadelphia General Hospital in the 1930s.3
He found that 366 (57%) of 637 were PPD positive on
enrollment. After entry, 133 (48%) of 277 nonreactors
converted to positive within 4 months, and 100%
before graduation. Clinical TB developed in 34
(12.3%) of these. At the other extreme, Ehrenkranz
and Kicklighter reported 21 (35%) of 60 PPD-negative
employees converted to positive on the ward where a
patient with unsuspected tuberculous pneumonia
spent only 57 hours.’ Two (10%) of the converters
developed TB even before they could be given pro­
phylactic therapy.
Catanzaro reported PPD conversion of 10 (77%)
of 13 PPD-negative staff during fiberoptic bron­
choscopy of a patient not suspected to have TB.5 He
calculated that, to do this, the patient had to excrete

January 1996

249 infectious units per hour to achieve a concentra­
tion of one infectious unit per 69 cu ft of air.
In another episode, a similar exposure of hospi­
tal personnel occurred with PPD conversion of 36
(63%) of 60 PPD negatives. 5 (8.5%) of whom devel­
oped TB before preventive therapy could be given.6
Templeton et al found that five of five PPD-negative
employees became infected during autopsy on a man
with undiagnosed miliary TB.7 Two of the five (40%)
developed positive sputum cultures for M tuberculosis
with a restriction fragment-length polymorphism
(RFLP) fingerprint identical to that of organisms iso­
lated from autopsy material. Calculation indicated one
infectious unit per 3.5 ft3 of room air.
Based on these experiences, one might expect
a patient remaining in hospital with positive sputum
smears for a month to infect 10% to 30% of those caring
for him or her. Of those, clinical TB would develop in
at least 10% to 20%. if they were not given effective
preventive chemotherapy.2'7 However, we found only
one converter not likely related to this case, and no
one has developed TB.
For a brief time in the 1960s, it was believed
that INH-resistant tubercle bacilli were much less vir­
ulent for humans than INH-susceptible ones. The
experience of the last few years has shown the error
of this notion.89 We have no doubt the bacilli in this
case would have spread infection had they not been
killed in the air or removed by ventilation.
EXPERIENCE WITH UPPER AIR
STERILIZATION

In the 1960s. Riley et al showed that UVGI of
wavelength 254 nm was highly effective in killing
tubercle bacilli suspended in air.10 Drs. Riley and
Nardell have reviewed the theory and experience
with UVGI in two landmark papers.1112 Riley et al
showed that UVGI can provide the equivalent of 17
air changes per hour.13
A decade of experience at the Milwaukee County
Hospital in the 1960s to 1970s has been described
briefly elsewhere.14 We relied solely on UVGI to pro­
tect personnel of a 40-bed TB ward in a building of
1920s vintage with no mechanical ventilation.
Retesting of all medical and nursing students after
they had spent 6-week tours on the TB ward revealed
no PPD conversions. In newer parts of the hospital,
which had neither UVGI nor known TB patients, there
always were several PPD conversions each year, pre­
sumably from patients with unrecognized TB.
New guidelines for protection of healthcare
workers from TB have been issued by the Centers for
Disease Control and Prevention.15 They are discussed
and critiqued in a recent paper by Menzies.16 who

1

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Vol. 17 No. 1

Supplementing Ventilation With UVGI

questions the almost exclusive emphasis on ventilation
and respirators to control spread of TB in hospitals.
Perhaps one factor in the National Institute for
Occupational Safety and Health’s almost complete
reliance on ventilation and respirators to protect hos­
pital personnel is their vast experience with removing
dust from air where the number of particles is in mil­
lions of particles per cu ft. A safe concentration of
dust in the pottery industry (35% silica) is 10 million
particles per cu ft.17 This is at least seven orders of
magnitude greater concentration than ever would
occur with infectious particles of TB.
Ventilation can maintain such a safe level of
dust, but it is a very different matter to clear the air
of infectious particles of TB when inhalation of a sin­
gle particle can cause infection. Indeed, Kantor et al
demonstrated transmission ofTB during an autopsy,
despite a measured ventilation of 11 air changes per
hour.18 While air replacement is the only way to clear
dust or fumes from the air, infectious particles of TB
are readily killed with UVGI.19-20
It seems apparent that there is much yet to be
learned about the best and most cost-effective way to
protect healthcare workers from TB. We suggest that
the experience reported here constitutes an urgent
call for intensive study of upper air disinfection with
germicidal UV irradiation in this effort.
REFERENCES

1. Iseman MD. Treatment of multidrug-resistant tuberculosis. N
Engl J Med 1993;329:784-791.
2. Stead WW. Management of healthcare workers after inadver­
tent exposure to tuberculosis. A guide for use of preventive
therapy. Ann Intern Med 1995:122:906-912.
3. Israel HL. Hetherington HW. Ord JG. A study of tuberculosis
among students of nursing. JAMA 1941; 117:840-844.
4. Ehrenkranz NJ. Kicklighter J L Tuberculosis outbreak in a gen­
eral hospital: evidence for airborne spread of infection. Ann
Intern Med 1972;77:377-382.

13

5. Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis
1982;125:559-562.
6. Hutton MD, Stead WW. Cauthen GM. Block AB, Ewing WM.
Nosocomial transmission of tuberculosis associated with a
draining tuberculous abscess. J Infect Dis 1990;161:286-295.
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922-924.
8. Jarvis WR. Nosocomial transmission of multidrug-resistant
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9. Dooley SW, Villarino ME. lawrence M, et al. Nosocomial trans­
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patients. JAMA 1992;267:2632-2635.
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15. Centers for Disease Control and Prevention. Guidelines for
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16. Menzies D. Fanning A Yuan L Fitzgerald M. Current con­
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/

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