dmcanzi@watserv1.waterloo.edu (David Canzi) (09/28/90)
Center for Disease Control Reports
Morbidity and Mortality Weekly Report
Thursday September 6, 1990
International Notes
Tuberculin Reactions in Apparently Healthy HIV-Seropositive and
HIV-Seronegative Women -- Uganda
Persons latently infected with Mycobacterium tuberculosis are at
substantially increased risk for developing clinically apparent tuberculosis
(TB) if they become infected with human immunodeficiency virus (HIV) (1,2).
Although skin testing with purified protein derivative (PPD) by the Mantoux
method is a standard method of screening for tuberculous infection, this
method may be hampered by nonreactivity to skin tests of persons who become
immunosuppressed because of progressive HIV infection. In Uganda, a continuing
study of HIV infection in postpartum women, conducted by the Ministry of
Health in collaboration with Case Western Reserve University, provided an
opportunity to study the tuberculin reactivity of apparently healthy women of
known HIV serologic status. This report presents data from the Uganda study.
In 1988-89, approximately 95% of 2000 pregnant women presenting to Mulago
Hospital in Kampala for uncomplicated delivery volunteered to participate in a
prospective study of HIV infection. Serum specimens obtained from these
participants were tested for HIV antibody by enzyme-linked immunosorbent assay
(ELISA) using Recombigen-HIV EIA Kits* (Cambridge BioScience, Worcester,
Massachusetts). All seropositive women and a random sample of seronegative
women were then enrolled in the study.
During the postpartum period, women were tuberculin tested by the Mantoux
technique using Old Tuberculin (OT) 1:2000 (equivalent to 5 tuberculin units
(TU) of PPD) with Tuberculin "GT"* (Behringwerke AG, Marburg, Federal Republic
of Germany) (this preparation is used by the Tuberculosis Control Program of
Uganda). All tuberculin tests were applied and read by the same trained
technician who did not know the HIV status of participants. All reactions were
measured at 48 hours with a millimeter rule and recorded as the mean of two
perpendicularly intersecting diameters of induration. Results were available
for analysis for 94 women (33 HIV-seronegative and 61 HIV-seropositive), all
of whom appeared healthy and had no signs or symptoms attributable to HIV
infection or opportunistic infection.
Of the 33 HIV-seronegative women, 27 (82%) had tuberculin skin test
reaction sizes greater than or equal to 3 mm (the diameter the Ministry of
Health selected as a cutpoint), and the median reaction size for this group
was 10.6 mm (Figure 1). Of the 61 HIV-seropositive women, 29 (48%) had
reactions greater than or equal to 3 mm, and the median reaction size was 7.5
mm (p less than 0.05 for frequency of reactions greater than or equal to 3 mm,
chi-square test; p less than 0.01 for difference in medians, Mann-Whitney U
test) (Figure 1).
All but one patient were examined for a BCG (Bacillus of Calmette and
Guerin) vaccination scar. Of 32 HIV-seronegative women, 18 (56%) had a BCG
scar; of the 61 HIV-seropositive women, 28 (46%) had a BCG scar. For both HIV-
seronegative and HIV-seropositive women, tuberculin nonreactivity was more
likely among those without a BCG scar. Among the HIV-seronegative women, two
(11%) of 18 with a BCG scar had no detectable tuberculin reaction, compared
with four (29%) of 14 without a BCG scar (p=0.17, Fisher's exact test). Among
the HIV-seropositive women, seven (25%) of 28 with a BCG scar had no reaction
to tuberculin, compared with 25 (76%) of 33 without a BCG scar (p=0.05,
Fisher's exact test). However, for HIV-seropositive women with and without BCG
scars, the relative risk for tuberculin nonreactivity was similar (2.3 and
2.6, respectively).
Reported by: A Okwera, MD, PP Eriki, MD, Ministry of Health, Kampala, Uganda.
LA Guay, MD, P Ball, TM Daniel, MD, Case Western Reserve Univ, Cleveland,
Ohio. Div of Tuberculosis Control, Center for Prevention Svcs; Div of
HIV/AIDS, Center for Infectious Diseases, CDC.
Editorial Note: The interaction between HIV and the tubercle bacillus has
dramatically affected the incidence of TB throughout the world. The recent
interruption in the decline of TB cases in the United States is attributed in
large part to the occurrence of TB among persons also infected with HIV (3).
In some countries in central Africa, where more than half the adult population
is infected with the tubercle bacillus, the HIV epidemic has been associated
with sharp increases in TB morbidity (4). Based on the frequency of HIV and
tuberculous coinfection in Uganda, an estimated excess of 250,000 TB cases
could occur in that country during the next 5 years (5). An important
intervention to control HIV-associated TB is the administration of isoniazid
preventive therapy to coinfected persons. However, the occurrence of HIV-
induced anergy to tuberculin hampers both the diagnosis of tuberculous
infection and the identification of coinfected persons.
The number of women tested in the Uganda study was relatively small, and
data to evaluate comparability between HIV-seropositive and HIV-seronegative
women regarding other characteristics (e.g., age) were not available. However,
the findings suggest that HIV infection can depress tuberculin reactions
before signs and symptoms develop. Because additional diagnostic studies
(e.g., CD4 cell counts, anergy test panels, beta-2-microglobulin, p-24 antigen
levels, or other measures of the stage of HIV disease) were not done in these
women, the investigators could not determine whether nonreactivity to
tuberculin was associated with more advanced HIV disease.
However, a recent study in Florida of patients who were reported as having
both TB and acquired immunodeficiency syndrome (AIDS) indicated that the
probability of tuberculin anergy was inversely related to the interval between
diagnosis of TB and diagnosis of AIDS (6). Tuberculin skin testing in
asymptomatic HIV-seropositive and HIV-seronegative intravenous-drug users in
Switzerland and in prisoners in Italy also detected lower rates of PPD
reactivity among those with HIV infection (7,8). In Italy, the mean CD4 count
for those with HIV infection was 569/mm3, and the CD4:CD8 ratio was 0.6:1.0;
both of these values were lower than normal. Thus, the reliability of
tuberculin skin tests in screening for TB and tuberculous infection may be
lower in HIV-infected persons, especially those with low CD4 counts.
An important finding in Uganda is that the prior administration of BCG
appears to maintain tuberculin reactivity at higher levels than in persons
with "natural" mycobacterial infection. Therefore, prior BCG vaccination
complicates the interpretation of skin test results and decisions about
preventive therapy (9).
The Adivsory Committee for Elimination of Tuberculosis and the American
Thoracic Society recommend that tuberculin reactions greater than or equal to
5 mm be considered positive in HIV-seropositive persons (regardless of BCG
vaccination status) and that such persons be considered for isoniazid
prophylaxis (2). Based on the data from Uganda and the other sources cited
above, persons with HIV infection and tuberculin skin test reaction sizes less
than 5 mm who have evidence of immunosuppression (e.g., CD4 count less than
400/mm3 and/or anergy to other delayed-type hypersensitivity skin test
antigens) may also need to be considered for isoniazid preventive therapy;
such consideration should also be based on individual clinical and
epidemiologic assessments of the likelihood of M. tuberculosis infection.
The problem of HIV-related tuberculin anergy among persons in the United
States requires further evaluation, and a more sensitive and specific method
for diagnosing tuberculous infection among immunosuppressed persons is needed.
Studies of the usefulness of CD4 counts or other laboratory parameters in
predicting anergy and of the optimal method of determining anergy (e.g.,
single antigen or anergy panel) are particularly important. CDC will be
developing more specific recommendations on anergy testing and the
administration of preventive therapy for immunosuppressed persons.
References
1. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of
tuberculosis among intravenous drug users with human immunodeficiency virus
infection. N Engl J Med 1989; 320:545-50.
2. CDC. Tuberculosis and human immunodeficiency virus infection:
recommendations of the Advisory Committee for the Elimination of Tuberculosis
(ACET). MMWR 1989;38:236-8, 243-50.
3. Rieder HL, Cauthen GM, Kelly GD, Bloch AB, Snider DE. Tuberculosis in the
United States. JAMA 1989;262:385-9.
4. Styblo K. The global aspects of tuberculosis and HIV infection. Bull Int
Union Tuberc Lung Dis 1990;65:28-32.
5. Goodgame RW. AIDS in Uganda--clinical and social features. N Engl J Med
1990;323:383-9.
6. Rieder HL, Cauthen GM, Bloch AB, et al. Tuberculosis and acquired
immunodeficiency syndrome--Florida. Arch Intern Med 1989;149:1268-73.
7. Robert CF, Hirschel B, Rochat T, Deglon JJ. Tuberculin skin reactivity in
HIV-seropositive intravenous drug addicts (Letter). N Engl J Med
1989;321:1268.
8. Canessa PA, Fasano L, Lavecchia MA, Torraca A, Schiattone ML. Tuberculin
skin test in asymptomatic HIV seropositive carriers (Letter). Chest
1989;96:1215-6.
9. Snider DE. Bacille Calmette-Guerin vaccinations and tuberculin skin tests.
JAMA 1985;253: 3438-9.
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*Use of trade names is for identification only and does not imply endorsement
by the Public Health Service or the U.S. Department of Health and Human
Services.
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Volume 3, Number 32 September 25, 1990
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David Canzi "Interesting, the Soviets get alt.*, but UW doesn't."