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
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
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.
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.
Rieder HL, Cauthen GM, Kelly GD, Bloch AB, Snider DE.
Tuberculosis in the United States. JAMA 1989;262:385-9.
Styblo K. The global aspects of tuberculosis and HIV
infection. Bull Int Union Tuberc Lung Dis 1990;65:28-32.
Goodgame RW. AIDS in Uganda--clinical and social features. N
Engl J Med 1990;323:383-9.
Rieder HL, Cauthen GM, Bloch AB, et al. Tuberculosis and
acquired immunodeficiency syndrome--Florida. Arch Intern Med
1989;149:1268-73.
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.
Canessa PA, Fasano L, Lavecchia MA, Torraca A, Schiattone ML.
Tuberculin skin test in asymptomatic HIV seropositive carriers
(Letter). Chest 1989;96:1215-6.
Snider DE. Bacille Calmette-Guerin vaccinations and tuberculin
skin tests. JAMA 1985;253: 3438-9.
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