HIV-1 co-infection in children hospitalised with tuberculosis in South Africa.

SETTING: Hospitals associated with the Department of Paediatrics at the University of the Witwatersrand, Johannesburg, South Africa. OBJECTIVES: To define the prevalence of human immunodeficiency virus (HIV) co-infection and differences in clinical presentation between HIV-infected and non-infected hospitalised children with tuberculosis. DESIGN: Children were prospectively enrolled between August 1996 and January 1997. RESULTS: Of 161 children enrolled, 42% were HIV-infected, including 67/137 with pulmonary tuberculosis (PTB) and 1/24 with extra-pulmonary disease (EPTB). Positive microscopy or bacteriology did not differ by HIV status for children with either PTB or EPTB. Although age did not differ between HIV-infected and non-infected children with PTB, non-HIV-infected children with EPTB were significantly older than those with PTB only (median age 32 months vs 14.5 months, P = 0.004). Chronic weight loss, malnutrition and the absence of BCG scarring were more common in HIV-infected children with PTB. HIV-infected children were also more likely to show cavitation (P = 0.001) and miliary TB (P = 0.01) on chest X-ray. Reactivity to tuberculin (> or = 5 mm and > or = 10 mm in HIV-infected and non-infected children, respectively) was significantly lower in HIV-infected children, as were CD4+ lymphocyte levels. The mortality rate during the study was 13.4% in HIV-infected children compared with 1.5% in non-HIV-infected children (P = 0.03). CONCLUSIONS: There is a high prevalence of HIV co-infection in children with TB. Progressive PTB and death are more common in HIV-infected children. Tuberculin skin testing is of limited use in screening for TB in HIV-infected children even when using a cut-point of > or = 5 mm.

Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus pneumoniae in Malawian children after treatment for malaria with sulfadoxine/pyrimethamine.

Treatment of malaria with sulfadoxine/pyrimethamine and of presumed bacterial infections with trimethoprim/sulfamethoxazole (cotrimoxazole) was assessed to see if either increases the carriage of cotrimoxazole-resistant Streptococcus pneumoniae in Malawian children. Children <5 years old treated with sulfadoxine/pyrimethamine, cotrimoxazole, or no antimicrobial agent were enrolled in a prospective observational study. Nasopharyngeal swabs were taken before treatment and 1 and 4 weeks later. Pneumococci were tested for antibiotic susceptibility by broth microdilution. In sulfadoxine/pyrimethamine-treated children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci increased from 38.1% at the initial visit to 44.1% at the 4-week follow-up visit (P=.048). For cotrimoxazole-treated children, the proportion colonized with cotrimoxazole-nonsusceptible pneumococci increased from 41.5% at the initial visit to 52% at the 1-week follow-up visit (P=.0017) and returned to 41.7% at the 4-week follow-up. Expanding use of sulfadoxine/pyrimethamine to treat chloroquine-resistant malaria may have implications for national pneumonia programs in developing countries where cotrimoxazole is widely used.

Prevalence of nasopharyngeal antibiotic-resistant pneumococcal carriage in children attending private paediatric practices in Johannesburg.

OBJECTIVES: To determine the nasopharyngeal carriage rate, serogroups/types, and antibiotic resistance of Streptococcus pneumoniae in children attending paediatric practices in the private sector in Johannesburg and to relate patterns of resistance to antimicrobial exposure and other demographic characteristics in individual children. DESIGN: A total of 303 children aged from 1 month to 5 years were recruited from eight private paediatric practices in northern Johannesburg. Nasopharyngeal samples were taken and parent interviews were conducted. RESULTS: Pneumococci were isolated from 121 children (40%). The most common serotypes were 6B, 19F, 6A, 23F, 14, and 19A. Carriage was significantly associated with prior hospital admission (odds ratio 1.89) and day care attendance (odds ratio 2.31) and was negatively associated with antibiotic use within the previous 30 days. Antibiotic resistance was found in 84 isolates (69.4%); 45 (37.2%) were multiply resistant. One-third of the pneumococci showed intermediate level resistance to penicillin and 12.4% were highly resistant. There was a high level erythromycin resistance in 38% of the isolates. A total of 94/214 children (42%) had recently used antibiotics and were four times more likely to carry antibiotic-resistant pneumococci (P < 0.05). CONCLUSION: Pneumococcal resistance was significant in this group of children with easy access to paediatric services and antibiotic use. The implication of such high resistance for the treatment of pneumococcal diseases is that high-dose amoxicillin is the preferred empirical oral therapy for treatment of otitis media. Ceftriaxone or cefotaxime should be used in combination with vancomycin for the treatment of meningitis until a cephalosporin-resistant pneumococcal cause is excluded. Intravenous penicillin or ampicillin will successfully treat pneumococcal pneumonia in this population. Antimicrobial resistance among pneumococci colonising children in the private sector has increased dramatically in recent years.

Correlation between CD4+ lymphocyte counts, concurrent antigen skin test and tuberculin skin test reactivity in human immunodeficiency virus type 1-infected and -uninfected children with tuberculosis.

BACKGROUND: HIV-infected children are at high risk of developing tuberculosis after infection by Mycobacterium tuberculosis. Emphasis is placed on tuberculin skin testing (TST) for diagnosing tuberculosis in children; however, its value in HIV-infected children is controversial. OBJECTIVES: To determine whether concurrent antigen testing and/or CD4+ lymphocyte counts help in the interpretation of the TST in children with tuberculosis. METHODS: Children eligible for the study were diagnosed as having tuberculosis on clinical criteria. CD4+ lymphocyte counts and delayed-type hypersensitivity (DTH) test, using the CMI Multitest were performed when tuberculosis was diagnosed. RESULTS: One hundred thirty children were enrolled. Tuberculin reactivity was lower in HIV-infected children at all cutoff levels than in HIV-uninfected children (P < 0.0001). The positive predictive value of normal CD4+ lymphocyte counts in predicting tuberculin reactions of > or =5 mm (in HIV-1-infected) and > or =10 mm (in HIV-uninfected patients) were 50 and 80.3%, respectively (P < 0.0001). An intact DTH reaction to the CMI Multitest in predicting reactions of > or =5 mm and > or =10 mm to tuberculin in HIV-infected and -uninfected children were 55 and 76%, respectively (P < 0.001). Kwashiorkor was responsible for 53.3% of false-negative TST in HIV-uninfected children with normal CD4+ lymphocyte counts. CONCLUSION: TST is of limited value as an adjunct in diagnosing tuberculosis in HIV-infected children. CD4+ lymphocyte counts and concurrent DTH testing are not useful for predicting tuberculin reactivity in HIV-infected patients with tuberculosis.

Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.

The safety, immunogenicity, and impact on carriage of a nonvalent pneumococcal vaccine given at ages 6, 10, and 14 weeks were examined in a double-blind, randomized, placebo-controlled trial in 500 infants in Soweto, South Africa. No serious local or systemic side effects were recorded. Significant antibody responses to all pneumococcal serotypes were observed 4 weeks after the third dose. Haemophilus influenzae type b polyribosylribitol phosphate (geometric mean titer, 11.62 microg/mL) and diphtheria (1.39 IU/mL) antibodies were significantly higher in children receiving pneumococcal conjugate, compared with placebo recipients (4.58 microgram/mL and 0.98 IU/mL, respectively). Nasopharyngeal carriage of vaccine serotypes decreased in vaccinees at age 9 months (18% vs. 36%), whereas carriage of nonvaccine serotypes increased (36% vs. 25%). Carriage of penicillin-resistant pneumococci (21% vs. 41%) and cotrimoxazole-resistant pneumococci (23% vs. 35%) were significantly reduced 9 months after vaccination, compared with controls.

Use of Dorset egg medium for maintenance and transport of Neisseria meningitidis and Haemophilus influenzae type b.

Studies of bacterial meningitis are hampered by the inability to maintain the viability of etiological agents during transport to reference laboratories. The long-term survival rate of 20 isolates of Neisseria meningitidis and Haemophilus influenzae type b (Hib) on Dorset egg medium, supplemented Columbia agar base medium, chocolate agar, and Amies medium was compared with that on 70% GC agar (chocolate) transport medium. N. meningitidis isolates were also inoculated onto 5% horse blood agar, and Hib was inoculated onto Haemophilus test medium. All of the N. meningitidis isolates remained viable on Dorset egg medium for 21 days; viability on the other media was poor after only 7 days. Recovery rates of Hib isolates were similar on Dorset egg and Haemophilus test media (100% after 21 days) and significantly better than on the other media. Dorset egg medium is inexpensive and easy to make and may be invaluable for studies of bacterial meningitis in developing countries.

Tuberculin reactivity in a pediatric population with high BCG vaccination coverage.

SETTING: The tuberculin skin test (TST) is often included in diagnostic algorithms for tuberculosis (TB) in children. TST interpretation, however, may be complicated by prior Bacillus Calmette-Guerin (BCG) vaccination. We assessed the prevalence of and risk factors for positive TST reactions in children 3 to 60 months of age in Botswana, a country with high TB rates and BCG coverage of over 90%. METHODS: A multi-stage cluster survey was conducted in one rural and three urban districts. Data collected included demographic characteristics, nutritional indices, vaccination status, and prior TB exposure. Mantoux TSTs were administered and induration measured at 48-72 hours. RESULTS: Of 821 children identified, 783 had TSTs placed and read. Of the 759 children with vaccination cards, 755 (99.5%) had received BCG vaccine. Seventy-nine per cent of children had 0 mm induration, 7% had > or =10 mm induration ('positive' TST), and 2% had > or =15 mm. A positive TST was associated with reported contact with any person with active TB (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.02-3.6), or a mother (OR 5.1; 95% CI 2.1-12.4) or aunt (OR 5.3; 95% CI 2.0-14.0) with active TB. TSTs > or =5 mm (but not > or =10 mm) were associated with presence of a BCG scar. Positive reactions were not associated with age, time since BCG vaccination, clinical signs or symptoms of TB, nutritional status, crowding, or recent measles or polio immunization. CONCLUSION: The TST remains useful in identifying children with tuberculous infection in this setting of high TB prevalence and extensive BCG coverage.

Nasopharyngeal carriage and antimicrobial resistance in isolates of Streptococcus pneumoniae and Haemophilus influenzae type b in children under 5 years of age in Botswana.

OBJECTIVES: A prospective survey was conducted to determine the prevalence of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae type b in children under 5 years of age in Botswana and to determine the antibiotic resistance patterns of these organisms to commonly used antimicrobial agents. METHODS: Children 2 months to 5 years of age (n = 249) were recruited from outpatient clinics in Gaborone and Francistown, and 29 were sampled from the pediatric wards at Princess Marina (Gaborone) and Nyangabgwe (Francistown) Hospitals. Nasopharyngeal specimens were collected and the carriage and antibiotic resistance of S. pneumoniae and H. influenzae type b were determined. Analyses of risk factors associated with carriage and resistance were performed. RESULTS: Streptococcus pneumoniae was isolated from 69% of the outpatient children in Gaborone and 85% of the children in Francistown; the carriage rate in hospitalized children was 36% and 33% in Gaborone and Francistown, respectively. Approximately half of the isolates at both sites were resistant to at least one antibiotic, the most common being cotrimoxazole and penicillin. Resistance to three or more antibiotics (multiple resistance) was found in less than 10% of the isolates. Most penicillin resistance at both sites was at the intermediate level; however, almost 20% of the isolates demonstrated high-level resistance to cotrimoxazole. The most prevalent serogroups or serotypes of antibiotic-resistant isolates were 14, 19F, 19A, 6A, 6B, and 4. No risk factors for antibiotic resistance were identified. Haemophilus influenzae type b was isolated from 8% of the children in Gaborone and from 3% of the children in Francistown. Almost a third of the isolates were resistant to ampicillin. CONCLUSIONS: The high levels of antibiotic resistance in pneumococci isolated from children in Botswana suggest that the clinical management of meningitis and otitis media with a b-lactam antibiotic may fail in a significant proportion of cases and that empiric first-line use of cefotaxime or ceftriaxone for meningitis and higher dose amoxicillin (90 mg/kg/day) for otitis media is recommended. The levels of penicillin resistance in this study would not impact on the management of pneumonia with amoxicillin.

Long-term survival of Streptococcus pneumoniae at room temperature on Dorset egg medium.

Forty-five isolates of Streptococcus pneumoniae were inoculated on Dorset egg and supplemented Columbia agar base media, incubated overnight at 37 degrees C, and then kept at room temperature (RT; 21 degrees C) or 4 degrees C. Long-term viability was best at RT for both media, with all isolates remaining viable on Dorset egg medium for 44 days; viability was 90 and 57% on Columbia agar base medium after 7 and 30 days. We recommend the use of Dorset egg medium for the maintenance of pneumococci at RT.

Survey of physician use of radiography and sputum smear microscopy for tuberculosis diagnosis and follow-up in Botswana.

SETTING: National survey of physician knowledge, attitudes, and practices for tuberculosis (TB) diagnosis and monitoring in Botswana. OBJECTIVE: To assess adherence to national guidelines for TB diagnosis and monitoring. DESIGN: Questionnaires were mailed to all physicians registered with the Ministry of Health. RESULTS: The response rate was 69%. Diagnostic and follow-up practices differed substantially from national recommendations. Senior District Medical Officers (SDMOs) were the most likely to adhere to guidelines on use of sputum examination for diagnosis (87%) and follow-up (50%); private practitioners were the least likely to follow the same guidelines (53% and 10%, respectively). SDMOs were also less likely to use radiographs for diagnosis (27%); the greatest use was seen in government hospital-based physicians (86%). While most SDMOs had received an introduction to the TB programme and had access to the programme manual and recent information on TB, the majority of other practising physicians in the country did not. CONCLUSION: Recommended diagnostic procedures for TB were not being followed by a substantial percentage of physicians. Efforts are being made to inform hospital-based physicians and private practitioners about TB programme policies. Adherence to programme recommendations is vital to strengthen TB control efforts.

Changing practices in mycobacteriology: a follow-up survey of state and territorial public health laboratories.

The resurgence of tuberculosis, which includes an increase in the isolation of multidrug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for more rapid laboratory testing for identification of the etiological agent of the disease. In December 1991, state and territorial public health laboratories were surveyed to determine the methods that they were using for testing and reporting of M. tuberculosis. A follow-up survey was conducted in June 1994 to measure changes in the testing and reporting practices that had occurred as a result of efforts focused on the disease and on laboratory improvement. Completed questionnaires were received from 51 of 55 laboratories. Comparative data indicate that the proportion of laboratories reporting testing results within the number of days recommended by the Centers for Disease Control and Prevention has increased. Starting from the time at which the laboratory receives the specimen, the proportion of laboratories reporting the results of microscopic smear examination within the recommended 24 h has increased from 52.1 to 77.6%; the proportion reporting isolation and identification within 21 days has increased from 22.1 to 72.9%; and the proportion reporting results of isolation, identification, and drug susceptibility testing within 28 days has increased from 16.7 to 48.9%. Use of the recommended rapid testing methods has also increased: the proportion of laboratories using fluorescence staining for acid-fast microscopy has increased from 71.4 to 85.7%, the proportion using BACTEC for primary culture has increased from 27.1 to 79.6%, the proportion using rapid methods for M. tuberculosis identification has increased from 74.5 to 100.0%, and the proportion using BACTEC for primary drug susceptibility testing has increased from 26.2 to 73.3%. By implementing the recommended methods for M. tuberculosis testing and reporting, state and territorial public health laboratories are now able to transmit results to physicians more rapidly.

U.S. hospital mycobacteriology laboratories: status and comparison with state public health department laboratories.

In response to the resurgence of tuberculosis, the Centers for Disease Control and Prevention recommended the use of certain mycobacteriology laboratory methods to improve the accuracy of diagnosis and/or minimize times to complete specimen processing. A study to determine the extent to which these recommended methods were being used in hospital laboratories was needed. In 1992, a survey was mailed to infection control and laboratory personnel at 1,076 hospitals with > or = 100 beds to determine the mycobacterial laboratory services being performed, the methods being used, the number of specimens being processed, and the times to completion during 1991. In 1995, a 20% sample of hospital laboratories that responded to the initial questionnaire was resurveyed. Responses to the 1992 survey were received from personnel at 756 (70%) hospitals representing 750 laboratories. Among laboratories performing the services, the use of recommended methods was as follows: fluorochrome stain for acid-fast bacillus microscopy (47%); radiometric methods for primary culture (29%); rapid (radiometric methods, use of nucleic acid probes, high-performance liquid chromatography, or gas-liquid chromatography) methods for identification of Mycobacterium tuberculosis (59%); and radiometric methods for drug susceptibility testing (55%). Reported times to complete specimen processing were shortest for laboratories that used recommended methods and longest for hospitals that referred specimens to outside laboratories. Only 46% of surveyed laboratories performed at least the minimal number of mycobacterial cultures (20/week) deemed necessary to maintain competence. Among 145 laboratories that performed the services and were resurveyed in 1995, use of recommended techniques increased from 44 to 73% for acid-fast bacillus microscopy, from 27 to 37% for primary culture, from 59 to 88% for M. tuberculosis identification, and from 55 to 75% for drug susceptibility testing. These changes were associated with reductions in reported specimen turnaround times. Use of the methods recommended by the Centers for Disease Control and Prevention increased at the resurveyed hospital mycobacteriology laboratories between 1991 and 1995. However, continued efforts are needed to increase the use of recommended methods at moderate- and high-volume laboratories, encourage referral of specimens from low-volume laboratories, and transmit results rapidly from all laboratories.

The changing face of tuberculosis.

Tuberculosis (TB) remains an important public health problem worldwide, resulting in a estimated 8 to 10 million new cases and 2 to 3 million deaths each year. Between 1953 and 1985, the number of TB cases in the US declined by an average of 6% per year. However, since 1985, TB has been increasing in the US. Approximately 64,000 additional cases of the disease have been reported beyond the number expected had the rate of decline observed from 1980 to 1984 continued from 1985 through 1993. Increases in the number of TB cases have been significant in racial and ethnic minorities, in persons born outside the US, and in children less than 15 years of age. Infection with the human immunodeficiency virus (HIV) has also been recognized as a major risk factor for the development of active TB in persons with latent Mycobacterium tuberculosis infection. The unusual radiographic findings and the increased likelihood of extrapulmonary TB in HIV-infected persons make diagnosis of the disease problematic. Lastly, concomitant with the resurgence of TB has been the emergence of drug resistance. All of these factors make successful control of TB in the US difficult.

Delayed-type hypersensitivity anergy in human immunodeficiency virus-infected persons screened for infection with Mycobacterium tuberculosis.

A total of 479 human immunodeficiency virus (HIV)-infected persons at an HIV clinic in Florida and a tuberculosis clinic in New Jersey were skin-tested with tuberculin, tetanus toxoid, mumps antigen, and Candida antigen in a study of the prevalence of delayed-type hypersensitivity (DTH) anergy and the usefulness of two-step tuberculin testing in this population. Of the patients tested, 12% had a positive (> or = 5-mm) response to tuberculin; 57%, 45%, and 35% had a positive (> or = 3-mm) response to Candida antigen, tetanus toxoid, and mumps antigen, respectively; and 31% were anergic (< 3 mm of induration in response to each antigen). In a multivariate logistic regression model, anergy was significantly associated with a history of Kaposi's sarcoma, Pneumocystis carinii pneumonia, or oral candidiasis and with White race. Anergy was four times and 15 times as likely for persons with CD4+ T-lymphocyte counts of 200-400/mm3 and < 200/mm3, respectively, as for persons with > 499 CD4+ T lymphocytes/mm3. Of 103 patients who were tuberculin-tested a second time after their initial test result was negative, seven had > or = 5 mm of induration in response to the second test; only one of these patients was anergic at the initial screening. The findings of this study indicate that DTH antigens should be used in conjunction with tuberculin testing and that two-step tuberculin testing is not an alternative to anergy testing but may be useful for the detection of infection with Mycobacterium tuberculosis in nonanergic HIV-infected patients.

Current practices in mycobacteriology: results of a survey of state public health laboratories.

Fifty-six state and territorial public health laboratories were surveyed to determine whether currently available rapid methods for the identification and drug susceptibility testing of Mycobacterium tuberculosis were being performed. Forty (71%) laboratories use fluorochrome rather than conventional basic fuchsin stains for screening clinical specimens for acid-fast bacilli. Of the 55 laboratories that routinely culture for mycobacteria, 16 (29%) use the more rapid radiometric methods. Species identification of isolates is done by biochemical tests in 13 (23%) laboratories; 40 (72%) use nucleic acid probes, high-performance liquid chromatography, or the BACTEC p-nitro-alpha-acetylamino-beta-hydroxypropiophenone (NAP) test (rapid tests); 3 laboratories do not perform species identification. Drug susceptibility testing is performed with solid media by 36 of 45 (80%) laboratories, while the more rapid radiometric methods are used by 9 (20%) laboratories. Compared with the laboratories that use conventional methods, laboratories that use rapid methods report results more quickly: for species identification, 43 days (conventional) versus 22 days (rapid); for drug susceptibility testing, 44 days (conventional) versus 31 days (rapid) from specimen processing. Rapid technologies for microscopy and species identification are being used by many, but not all, state and territorial public health laboratories; however, most laboratories do not use the more rapid radiometric methods for routine culture or drug susceptibility testing of mycobacteria. Implementation of such rapid technologies can shorten turnaround times for the laboratory diagnosis of tuberculosis and recognition of drug resistance.