Richard Waddell

High Rates of Clinical and Subclinical Tuberculosis among HIV-Infected Ambulatory Subjects in Tanzania

BACKGROUND We sought to determine the prevalence of active tuberculosis among ambulatory HIV-infected persons in Tanzania with CD4 cell counts of > or =200 cells/mm3 and a bacille Calmette-Guerin vaccination scar. METHODS Subjects who volunteered for a tuberculosis booster vaccine trial were screened for active tuberculosis by obtainment of a history, physical examination, chest radiography, sputum culture and acid fast bacillus (AFB) stain, and blood culture. All subjects underwent a tuberculin skin test (TST) and lymphocyte proliferation assays (LPAs) for detection of responses to mycobacterial antigens. RESULTS Active tuberculosis was identified at baseline in 14 (15%) of the first 93 subjects who were enrolled: 10 (71%) had clinical tuberculosis (symptoms or chest radiograph findings), and 4 (29%) had subclinical tuberculosis (positive sputum AFB stain or culture results but no symptoms or chest radiograph findings). An additional 6 subjects with subclinical tuberculosis were identified subsequently. The 10 subjects with subclinical tuberculosis included 3 with positive sputum AFB stains results and 7 who were only identified by a positive sputum culture result. Compared with subjects who did not have tuberculosis, the 10 subjects with subclinical tuberculosis were more likely to have peripheral lymphadenopathy, positive TST results, and elevated LPA responses to early secreted antigenic target-6 (ESAT). Eight of 10 patients had received isoniazid because of a positive TST result before active tuberculosis was recognized. CONCLUSIONS Clinical and subclinical tuberculosis are common among ambulatory HIV-infected persons, and some cases can only be identified by sputum culture. World Health Organization guidelines for screening for latent tuberculosis before treatment do not recommend sputum culture and, therefore, may fail to identify a substantial number of HIV-infected persons with subclinical, active tuberculosis.

A Case–Control Study of Smoking and Bladder Cancer Risk: Emergent Patterns Over Time

BACKGROUND Cigarette smoking is a well-established risk factor for bladder cancer. The effects of smoking duration, intensity (cigarettes per day), and total exposure (pack-years); smoking cessation; exposure to environmental tobacco smoke; and changes in the composition of tobacco and cigarette design over time on risk of bladder cancer are unclear. METHODS We examined bladder cancer risk in relation to smoking practices based on interview data from a large, population-based case-control study conducted in Maine, New Hampshire, and Vermont from 2001 to 2004 (N = 1170 urothelial carcinoma case patients and 1413 control subjects). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. To examine changes in smoking-induced bladder cancer risk over time, we compared odds ratios from New Hampshire residents in this study (305 case patients and 335 control subjects) with those from two case-control studies conducted in New Hampshire in 1994-1998 and in 1998-2001 (843 case patients and 1183 control subjects). RESULTS Regular and current cigarette smokers had higher risks of bladder cancer than never-smokers (for regular smokers, OR = 3.0, 95% CI = 2.4 to 3.6; for current smokers, OR = 5.2, 95% CI = 4.0 to 6.6). In New Hampshire, there was a statistically significant increasing trend in smoking-related bladder cancer risk over three consecutive periods (1994-1998, 1998-2001, and 2002-2004) among former smokers (OR = 1.4, 95% CI = 1.0 to 2.0; OR = 2.0, 95% CI = 1.4 to 2.9; and OR = 2.6, 95% CI = 1.7 to 4.0, respectively) and current smokers (OR = 2.9, 95% CI = 2.0 to 4.2; OR = 4.2, 95% CI = 2.8 to 6.3; OR = 5.5, 95% CI = 3.5 to 8.9, respectively) (P for homogeneity of trends over time periods = .04). We also observed that within categories of intensity, odds ratios increased approximately linearly with increasing pack-years smoked, but the slope of the increasing trend declined with increasing intensity. CONCLUSIONS Smoking-related risks of bladder cancer appear to have increased in New Hampshire since the mid-1990s. Based on our modeling of pack-years and intensity, smoking fewer cigarettes over a long time appears more harmful than smoking more cigarettes over a shorter time, for equal total pack-years of cigarettes smoked.

The international epidemiology of disseminated Mycobacterium avium complex infection in AIDS

Objective:To determine rates of disseminated Mycobacterium avium complex (MAC) infection among AIDS patients in developed and developing countries, and to determine whether different rates reflect differences in exposure or immunity, or both. Design:Prospective cohort study. Setting:University hospitals and outpatient AIDS programs. Methods:HIV-infected subjects with CD4 counts < 200×106/l were interviewed and had CD4 lymphocyte counts, blood cultures for mycobacteria (baseline and at 6 months), and skin tests with purified protein derivative (PPD) and M. avium sensitin. Results:Among 566 study patients rates of disseminated MAC were 10.5–21.6% in New Hampshire, Boston and Finland compared to 2.4–2.6% in Trinidad and Kenya (P < 0.001). PPD skin test reactions ≥ 5 mm were present in 20% of patients from Kenya compared to 1% at other sites (P < 0.001). Among patients from the United States and Finland, multiple logistic regression indicated that occupational exposure to soil and water was associated with a decreased risk of disseminated MAC, whereas the following were associated with an increased risk of disseminated MAC: low CD4 count, swimming in an indoor pool, history of bronchoscopy, regular consumption of raw or partially cooked fish/shellfish and treatment with granulocyte colony-stimulating factor. Conclusions:Rates of disseminated MAC in AIDS are higher in developed than developing countries and are due to both differences in exposure and differences in immunity. These data provide a rationale for prevention of MAC through both active immunization and reduction in exposure to the organism.

Safety and Immunogenicity of a Five-Dose Series of Inactivated Mycobacterium vaccae Vaccination for the Prevention of HIV-Associated Tuberculosis

Five doses of inactivated Mycobacterium vaccae vaccine were administered intradermally to 22 human immunodeficiency virus (HIV)-infected patients (11 bacille Calmette-Guérin [BCG]-positive and 11 BCG-negative) in Zambia whose CD4 lymphocyte counts were >/=200 cells/mm(3). HIV viral load and lymphocyte proliferation responses were compared for vaccine recipients and 22 HIV-infected control patients (11 BCG-positive and 11 BCG-negative). Immunization was safe and well tolerated in all patients, and induration at the vaccine site decreased from dose 1 to dose 5. A transient decrease in HIV viral load was observed in BCG-positive vaccine recipients after dose 3 but not after subsequent doses. Median lymphocyte stimulation indices to M. vaccae were 6.0 in vaccine recipients and 2.3 in control patients (P<.001). Stimulation indices were >/=3.0 in 19 vaccine recipients (86%) and 7 control patients (32%; P=.001). A 5-dose series of vaccination with inactivated M. vaccae is safe in HIV-infected patients and induces lymphocyte proliferation responses to the vaccine antigen. M. vaccae vaccine is a candidate for the prevention of tuberculosis in HIV infection.

Bacteremia due to Mycobacterium tuberculosis or M. bovis, Bacille Calmette-Guérin (BCG) among HIV- positive children and adults in Zambia.

BackgroundAmong adults with advanced HIV infection in developing countries, bacteremia due to Mycobacterium tuberculosis (MTB) is common and bacteremia due to M. bovis (bacille Calmette–Guérin; BCG) is rare. Comparable data are not available for children with HIV. ObjectiveTo compare the prevalence of bacteremia due to M. tuberculosis or M. bovis BCG in hospitalized children and adults with HIV infection in a developing country with a high prevalence of tuberculosis and HIV and > 95% BCG immunization coverage. DesignDescriptive cross-sectional study. MethodsProspectively hospitalized patients in Lusaka, Zambia who were suspected to have HIV infection underwent phlebotomy for HIV ELISA, HIV viral load, and lysis-centrifugation blood culture for mycobacteria. Histories were obtained and patients were examined for BCG scars. Mycobacterial isolates were identified using DNA probes for MTB complex (MTBC), multiplex PCR and IS 6110 typing. ResultsThe median age of 387 HIV-positive children was 15 months; 98% were BCG immunized. The median age of 344 HIV-positive adults was 32 years; 44% were BCG immunized. Blood cultures were positive for mycobacteria in six children (2%) and 38 adults(11%) (P < 0.001). The six pediatric isolates included five MTBC (40% clustered) and one BCG. The 38 adult isolates included 36 MTBC (16% clustered) and two M. avium complex. ConclusionBacteremia due to MTB is less common among children than adults with advanced HIV infection in Zambia. Bacteremia due to M. bovis BCG is rare even among children with recent BCG immunization and symptomatic HIV infection.

High rates of disseminated infection due to non-tuberculous mycobacteria among AIDS patients in Finland.

OBJECTIVE to determine the rate of disseminated infection due to non-tuberculous mycobacteria (NTM) among Finnish AIDS patients, and to analyse the epidemiology of these infections. METHODS in a prospective cohort study HIV-infected patients with CD4 counts < 200 x 10(6)/l were interviewed, and had mycobacterial blood cultures performed at baseline and at 6 months, then subsequently for clinical indications; autopsies were performed on patients who died. The cohort was followed at least for 24 months or to death. Water samples were collected from the homes of patients and from the environment and cultured for organisms of the Myobacterium avium complex (MAC). Environmental and clinical isolates were compared using pulsed field gel electrophoresis (PFGE). RESULTS NTM infection occurred in 22 (43%) of 51, 19 isolates were Mycobacterium avium, two M. genavense and one M. intracellulare. Multivariate analysis identified urban residence (P=0.04) and eating raw fish (P=0.04) as independent risk factors. Molecular analysis revealed two clusters of related isolates (three M. avium, two M. genavense) among urban residents. CONCLUSION AIDS patients in Finland have high rates of disseminated infection due to NTM. Clusters of identical organisms and association with urban residence suggests that these are newly acquired infections in advanced AIDS.

Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality.

BACKGROUND Disseminated tuberculosis (TB) is a major cause of death in patients with the acquired immune-deficiency syndrome (AIDS), but its pathogenesis and clinical features have not been defined prospectively. METHODS Human immunodeficiency virus (HIV) infected adults with a CD4 count ≥ 200 cells/μl and bacille Calmette-Guérin scar underwent immunologic evaluation and subsequent follow-up. RESULTS Among 20 subjects who developed disseminated TB, baseline tuberculin skin tests were ≥15 mm in 14 (70%) and lymphocyte proliferative responses to Mycobacterium tuberculosis were positive in 14 (70%). At the time of diagnosis, fever ≥2 weeks plus ≥5 kg weight loss was reported in 16 (80%) patients, abnormal chest X-rays in 7/17 (41%), and positive sputum cultures in 10 (50%); median CD4 count was 30 cells/μl (range 1-122). By insertion sequence (IS) 6110 analysis, 14 (70%) blood isolates were clustered and 3/8 (37%) concurrent sputum isolates represented a different strain (polyclonal disease). Empiric TB treatment was given to eight (40%) patients; 11 (55%) died within a month. CONCLUSIONS Disseminated TB in HIV occurs with cellular immune responses indicating prior mycobacterial infection, and IS6110 analysis suggests an often lethal combination of reactivation and newly acquired infection. Control will require effective prevention of both remotely and recently acquired infection, and wider use of empiric therapy in patients with advanced AIDS and prolonged fever.

Sputum microscopy for the diagnosis of HIV-associated pulmonary tuberculosis in Tanzania.

BackgroundIn many resource poor settings only sputum microscopy is employed for the diagnosis of HIV-associated pulmonary tuberculosis; sputum culture may not be available.MethodsWe determined the diagnostic accuracy of sputum microscopy for active case finding of HIV-associated pulmonary tuberculosis using TB culture as the reference standard.Results2216 potential subjects screened for a TB vaccine trial submitted 9454 expectorated sputum specimens: 212 (2.2%) were sputum culture positive for Mycobacterium tuberculosis (MTB), 31 (0.3%) for non-tuberculous mycobacteria, and 79 (0.8%) were contaminated. The overall sensitivity of sputum microscopy was 61.8% (131/212) and specificity 99.7% (9108/9132). Sputum microscopy sensitivity varied from 22.6% in specimens with < 20 colony forming units (CFU)/specimen to 94.2% in patients with > 100 CFU/specimen plus confluent growth. The incremental diagnostic value for sputum microscopy was 92.1%, 1.8% and 7.1% for the first, second and third specimens, respectively. The positive predictive value and negative predictive values for sputum microscopy were 84.5% and 99.1%, respectively. The likelihood ratio (LR) of a positive sputum microscopy was 235.1 (95% CI 155.8 – 354.8), while the LR of a negative test was 0.38 (95CI 0.32 – 0.45). The 212 positive sputum cultures for MTB represented 103 patients; sputum microscopy was positive for 57 (55.3%) of 103 patients.ConclusionSputum microscopy on 3 expectorated sputum specimens will only detect 55% of culture positive HIV-infected patients in active screening for pulmonary tuberculosis. Sensitivity is higher in patients with greater numbers of CFUs in the sputum. Culture is required for active case finding of HIV- associated pulmonary tuberculosis.

Basis for treatment of tuberculosis among HIV-infected patients in Tanzania: the role of chest x-ray and sputum culture

BackgroundActive tuberculosis (TB) is common among HIV-infected persons living in tuberculosis endemic countries, and screening for tuberculosis (TB) is recommended routinely. We sought to determine the role of chest x-ray and sputum culture in the decision to treat for presumptive TB using active case finding in a large cohort of HIV-infected patients.MethodsAmbulatory HIV-positive subjects with CD4 counts ≥ 200/mm3 entering a Phase III TB vaccine study in Tanzania were screened for TB with a physical examination, standard interview, CD4 count, chest x-ray (CXR), blood culture for TB, and three sputum samples for acid fast bacillus (AFB) smear and culture.ResultsAmong 1176 subjects 136 (12%) were treated for presumptive TB. These patients were more frequently male than those without treatment (34% vs. 25%, respectively; p = 0.049) and had lower median CD4 counts (319/μL vs. 425/μL, respectively; p < .0001). Among the 136 patients treated for TB, 38 (28%) had microbiologic confirmation, including 13 (10%) who had a normal CXR and no symptoms. There were 58 (43%) treated patients in whom the only positive finding was an abnormal CXR. Blood cultures were negative in all patients.ConclusionMany ambulatory HIV-infected patients with CD4 counts ≥ 200/mm3 are treated for presumptive TB. Our data suggest that optimal detection requires comprehensive evaluation, including CXR and sputum culture on both symptomatic and asymptomatic subjects.

The risks and benefits of childhood bacille Calmette-Guerin immunization among adults with AIDS

Objective:To define the risks of disseminated bacille Calmette-Guérin (BCG) or disseminated Mycobacterium tuberculosis in adults with AIDS who were immunized with BCG in childhood. Design:HIV-infected patients with CD4 < 200 × 106/l were enrolled from five study sites (New Hampshire, Boston, Finland, Trinidad and Kenya). Prior BCG immunization was determined and blood cultures for mycobacteria were obtained at study entry and at 6 months. Acid-fast bacilli were identified as Mycobacterium tuberculosis complex (MTBC) using DNA probes. MTBC isolates were then typed by both IS6110 restriction fragment length polymorphism and polymerase chain reaction/restriction enzyme analysis. Setting:Most patients in New Hampshire and Finland were outpatients; most patients in Trinidad were inpatients with terminal illness; and most patients in Kenya were outpatients, although 44 were inpatients with terminal illness. Participants:A total of 566 patients were enrolled, including 155 with childhood BCG immunization; 318 patients had a single study visit and culture, and 248 patients had two study visits and cultures. Main outcome measures:Isolation and identification of mycobacteria from blood cultures. Results:Blood cultures were positive for MTBC in 21 patients; none were positive for M. bovis BCG, and 21 were M. tuberculosis-positive. In Trinidad, seven (87%) out of eight isolates of M. tuberculosis were indistinguishable by IS6110 typing; BCG immunization was associated with a decreased risk of bacteremic infection with M. tuberculosis (P = 0.05). Conclusions:The risk of disseminated BCG among adult AIDS patients with childhood BCG immunization is very low. Childhood BCG immunization is associated with protection against bacteremia with M. tuberculosis among adults with advanced AIDS in Trinidad.