CNS infections in HIV.

PURPOSE OF REVIEW: Central nervous system (CNS) infections associated with HIV remain significant contributors to morbidity and mortality, particularly among people living with HIV (PLWH) in resource-limited settings worldwide. In this review, we discuss several recent important scientific discoveries in the prevention, diagnosis, and management around two of the major causes of CNS opportunistic infections-tuberculous meningitis (TBM) and cryptococcal meningitis including immune reconstitution syndrome (IRIS) associated with cryptococcal meningitis. We also discuss the CNS as a possible viral reservoir, highlighting Cerebrospinal fluid viral escape. RECENT FINDINGS: CNS infections in HIV-positive people in sub-Saharan Africa contribute to 15-25% of AIDS-related deaths. Morbidity and mortality in those is associated with delays in HIV diagnosis, lack of availability for antimicrobial treatment, and risk of CNS IRIS. The CNS may serve as a reservoir for replication, though it is unclear whether this can impact peripheral immunosuppression. SUMMARY: Significant diagnostic and treatment advances for TBM and cryptococcal meningitis have yet to impact overall morbidity and mortality according to recent data. Lack of early diagnosis and treatment initiation, and also maintenance on combined antiretroviral treatment are the main drivers of the ongoing burden of CNS opportunistic infections. The CNS as a viral reservoir has major potential implications for HIV eradication strategies, and also control of CNS opportunistic infections.

Impact of the BCG vaccination policy on tuberculous meningitis in children under 6 years in metropolitan France between 2000 and 2011.

In France, Bacillus Calmette­Guérin (BCG) vaccination by multipuncture device was withdrawn in 2006. In 2007, universal mandatory BCG vaccination was replaced by vaccination of high-risk children. To evaluate the impact of these changes on tuberculous meningitis (TBM) epidemiology, data on culture-positive and culture-negative (or unknown microbiological result) TBM in ≤5 years olds were collected from 2000­2011. Ten culture-positive and 17 culture-negative TBM cases were identified, with an annual incidence rate ranging from 0.16 to 0.66 cases per 10 million inhabitants. The average annual numbers of TBM cases were 2.7 and 1.8 from 2000­2005 and 2006­2011, respectively. In Ile-de-France where all children are considered at risk, the overall incidence rates were 1.14 and 0.29 per million for the two periods. In other regions where only at-risk children are vaccinated since 2007, rates were 0.30 and 0.47, respectively. None of these differences were significant. Annual incidence rates for each one year age group cohort were comparable before and after changes. Childhood TBM remains rare in France. No increase in incidence was observed after changes in BCG vaccination strategy. Ongoing surveillance should be maintained, as a slight increase in TBM in the coming years remains possible, in the context of suboptimal vaccination coverage of high-risk children.

Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.

BACKGROUND: Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood. METHODS: We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression. RESULTS: We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25). CONCLUSIONS: Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.

Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness.

BACKGROUND: BCG vaccine has shown consistently high efficacy against childhood tuberculous meningitis and miliary tuberculosis, but variable efficacy against adult pulmonary tuberculosis and other mycobacterial diseases. We assess and compare the costs and effects of BCG as an intervention against severe childhood tuberculosis in different regions of the world. METHODS: We calculated the number of tuberculous meningitis and miliary tuberculosis cases that have been and will be prevented in all children born in 2002, by combining estimates of the annual risk of tuberculosis infection, the proportion of infections that lead to either of these diseases in unvaccinated children, the number of children vaccinated, and BCG efficacy. FINDINGS: We estimated that the 100.5 million BCG vaccinations given to infants in 2002 will have prevented 29,729 cases of tuberculous meningitis (5th-95th centiles, 24,063-36,192) in children during their first 5 years of life, or one case for every 3435 vaccinations (2771-4177), and 11,486 cases of miliary tuberculosis (7304-16,280), or one case for every 9314 vaccinations (6172-13,729). The numbers of cases prevented would be highest in South East Asia (46%), sub-Saharan Africa (27%), the western Pacific region (15%), and where the risk of tuberculosis infection and vaccine coverage are also highest. At US2-3 dollars per dose, BCG vaccination costs US206 dollars (150-272) per year of healthy life gained. INTERPRETATION: BCG vaccination is a highly cost-effective intervention against severe childhood tuberculosis; it should be retained in high-incidence countries as a strategy to supplement the chemotherapy of active tuberculosis.

The SIGLEC14 null allele is associated with Mycobacterium tuberculosis- and BCG-induced clinical and immunologic outcomes.

Humans exposed to Mycobacterium tuberculosis (Mtb) have variable susceptibility to tuberculosis (TB) and its outcomes. Siglec-5 and Siglec-14 are members of the sialic-acid binding lectin family that regulate immune responses to pathogens through inhibitory (Siglec-5) and activating (Siglec-14) domains. The SIGLEC14 coding sequence is deleted in a high proportion of individuals, placing a SIGLEC5-like gene under the expression of the SIGLEC14 promoter (the SIGLEC14 null allele) and causing expression of a Siglec-5 like protein in monocytes and macrophages. We hypothesized that the SIGLEC14 null allele was associated with Mtb replication in monocytes, T-cell responses to the BCG vaccine, and clinical susceptibility to TB. The SIGLEC14 null allele was associated with protection from TB meningitis in Vietnamese adults but not with pediatric TB in South Africa. The null allele was associated with increased IL-2 and IL-17 production following ex-vivo BCG stimulation of blood from 10 week-old South African infants vaccinated with BCG at birth. Mtb replication was increased in THP-1 cells overexpressing either Siglec-5 or Siglec-14 relative to controls. To our knowledge, this is the first study to demonstrate an association between SIGLEC expression and clinical TB, Mtb replication, or BCG-specific T-cell cytokines.

BCG vaccine: efficacy and indications for vaccination and revaccination.

OBJECTIVES: To review the protective efficacy of the first and second doses of BCG vaccine and to assess its major indications and contraindications. SOURCES OF DATA: A systematic review of the literature was made by searching PubMed and selecting studies carried out in the last 50 years. The studies were grouped according to their design (clinical trials, case-control studies, and meta-analyses) and the results were presented separately for each type of study. Other relevant topics such as BCG and HIV/AIDS, use of tuberculin skin test, issues related to vaccine scars and to the development of new vaccines were also reviewed. SUMMARY OF THE FINDINGS: BCG vaccine has been used since 1921. However, the data concerning its use are variable and inconsistent. The protective efficacy of the first dose of BCG vaccine against miliary tuberculosis or tuberculous meningitis is remarkably important. Nevertheless, results regarding pulmonary tuberculosis have been inconsistent, either showing no efficacy or a protective efficacy rate around 80%. There is some evidence that a second dose of BCG vaccine does not increase its protective efficacy. Studies have shown that BCG vaccine protects against leprosy. The development of new vaccines to replace BCG in the future has been investigated. CONCLUSIONS: Despite the hope that a new vaccine against tuberculosis will be available in the future, BCG vaccine, in spite of its deficiencies, is today and will be for many years to come an important tool in controlling the harmful effects of tuberculosis, especially in countries where this disease has moderate to high levels of incidence.

[Tuberculous meningitis in children under 5 years of age in Argentina]. / Meningitis tuberculosa en menores de cinco años en la Argentina.

Tuberculous (TB) meningitis in children under 5 years of age is a serious health problem in Argentina, with a rate of 0.39/100000 inhabitants, for 2003-2004. This rate indicates recent infections. It is an operational indicator for case finding and treatment of pulmonary adult cases, and for BCG vaccination of the newborn. The object of this study was to describe epidemic and clinical variables registered in cases of TB meningitis in children less than 5 years old in Argentina, from 1999 to 2001 and to determine the real number of TB meningitis cases in our country. Fifteen cases of TB meningitis out of 32 (46.8%) were studied through epidemic records. The average age was 14 months. Six children presented BCG scars but in only one child it was proved that he had been vaccinated at birth; 11/13 (92.3%) were at the second stage of illness, the bacteriological investigation was positive in 8/11 (72.7%) and in (46.8%) chest radiography revealed abnormal findings. The tuberculin reaction was negative in all tested cases. This study showed that the diagnosis was made at an advanced stage of disease. None of these patients was cured without sequels and a high death rate (46%) was observed. In order to control this epidemic situation, it is necessary to increase case finding and directly observed treatment of smear positive pulmonary TB cases, as well as BCG vaccination given at birth.

Protective role of BCG vaccination against tuberculous meningitis in Indian children: a reappraisal.

BACKGROUND: The protective role of BCG vaccination against tuberculous meningitis (TBM) is still controversial in India, largely due to the presence of other predisposing factors such as age, nutritional and socioeconomic status, and household contact. Very few Indian studies have focused on the interaction between BCG and these factors on the occurrence of TBM. METHODS: We did an unmatched hospital-based case-control study with prospective enrolment. Children with TBM diagnosed on the basis of predefined criteria were enrolled as cases. For each case, two children admitted on the same day and who did not have any neurological symptoms were enrolled as controls. Demographic data and information on predisposing factors for tuberculosis were collected for both cases and controls and the presence of a BCG scar was charted. Cases and controls were compared by univariate followed by multivariate analysis to obtain significant independent predictors for the occurrence of TBM. To assess the interaction between other predisposing factors and protective efficacy of BCG, a stratified analysis was also done. RESULTS: A total of 91 cases and 182 controls were enrolled over a one-year study period, of which 37 cases and 111 controls had a BCG scar. The crude odds ratio for the occurrence of TBM in the absence of a BCG scar was 2.28 (range: 1.32-3.94). The time elapsed since vaccination was significantly longer in the cases. Also, the proportion with a household contact was significantly higher in the cases, the mean age of the cases was higher than that of the controls, and the mean weight and height for age percentage were significantly lower. The cases had a significantly lower socioeconomic status. On multivariate analysis, the significant independent predictors for the occurrence of TBM were positive household contact with tuberculosis (adjusted OR 4.26; 95% CCI 2.26-8.04), absent BCG scar (adjusted OR 1.98; 95%ClI 1.09-3.57) and rural residence (adjusted OR 2.07; 95% ClI 1.02-4.17). CONCLUSION: Vaccination with BCG was found to be protective even after controlling for the effect of other variables. Stratified analysis showed that protection due to BCG failed to reach significance for those > 5 years of age, if the weight was <6 0% of that expected for age, in the presence of a household contact with tuberculosis, and in socioeconomic classes III, IV and V.

[Evaluating 82 cases of tuberculous meningitis]. / Sekseniki tüberküloz menenjitli olgunun degerlendirilmesi.

Tuberculous meningitis (TBM) is not the most common but the most serious clinical form of extrapulmonary tuberculosis. Serious complications resulting from difficulties in diagnosis and treatment of the disease makes it an important health problem. In our study, 82 patients with TBM, followed up in our clinic between January 1998-December 2002, are evaluated with their clinical and laboratory properties. 52% of our patients were females, 48% were males and their ages ranged from 15 to 70 with a mean of 32 years. The diagnosis was based on patients' history, clinical and laboratory properties, cerebrospinal fluid (CSF) findings and radiographic findings. 59% of our patients were grade II clinically, 29% were grade I, and 23% were grade III. Mostly observed complaints were headache (87%) and nausea-vomiting (63%) and fever (45%) and mostly seen physical findings were stiff neck (70%), alterations in consciousness (57%). Pleocytosis in CSF was detected in 94%, low CSF glucose level in 87%, and elevated CSF protein level in 82% of the patients. From CSF samples of 40 patients, out of total 82, Mycobacterium tuberculosis was isolated on Loewenstein-Jensen medium (49%). Nineteen patients had tuberculomas, 13 had basal meningitis, and 11 had hydrocephalus on cranial radiographic studies. 28% had miliary pattern and 26% had active infiltration and cavities on chest roentgenogram. A four-drug antituberculous regimen was administered for 88% of the patients and dexamethasone treatment was administered for 75%; 56 (68.3%) patients recovered from the illness, 14 (17%) patients had slight and 4 (4.9%) patients had serious neurological sequeales and 8 (9.8%) patients died in spite of tuberculous therapy. As a conclusion, TBM is an infectious disease with high morbidity and mortality rates. Various prognosis patterns may be observed according to the clinical grade of the patient on application. When suspected, an early diagnosis and early treatment of the disease are the most important factors which effect complication and mortality rates.

Central nervous system manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome during adalimumab therapy: a case report and review of the literature.

A 64-year-old neurologically asymptomatic woman with rheumatoid arthritis who was treated with the tumor necrosis factor (TNF)-α antagonist adalimumab developed disseminated tuberculosis (TB). After receiving anti-TB therapy and discontinuing adalimumab, she exhibited paradoxical worsening due to immune reconstitution inflammatory syndrome (IRIS) with the appearance of meningitis and brain tuberculomas. This case indicates that continuing anti-TNF therapy may be necessary to prevent IRIS in patients who develop TB, particularly disseminated TB, during the course of anti-TNF therapy. In addition, careful screening for central nervous system (CNS) TB should be performed prior to the initiation of therapy, as even neurologically asymptomatic patients can develop CNS manifestations of IRIS.

Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis.

The protective effect of BCG against tuberculosis (TB) estimated in randomized controlled trials and observational studies ranges from negative to close to a 100%. One of the many explanations offered for this is that different immunological mechanisms may be associated with protective effect against different forms and sites of disease. In this investigation, we recalculated vaccine protective effect separately for pulmonary disease and for meningeal/miliary disease in randomized controlled trials and case-control studies, tested for heterogeneity in site-specific estimates of protective effect and calculated a summary measure when appropriate. We found protective effect against pulmonary disease to be heterogeneous to a statistically significant degree, and thus we did not calculate a summary measure of protection. Protective effect against meningeal and miliary TB was higher than against pulmonary disease and, except for a single study with two cases only, appeared to be homogenous. Summary BCG protective effect against miliary or meningeal TB in randomized controlled trials was 86% (95% confidence interval [CI] 65, 95) and in case-control studies 75% (95% CI: 61, 84). The fact that protective effect appeared to be homogeneous against meningitis and miliary TB but not against pulmonary disease may result from the fact that patients with meningitis are on average younger and thus less likely to have been exposed to atypical bacteria; to a waning of the protective effect of BCG; or from the diversity of mechanisms of pathogenesis of pulmonary disease, which can originate from reinfection, reactivation or primary progression.

Risk assessment for acquiring meningitis tuberculosis among children not vaccinated with BCG: a case-control study.

This case-control study was conducted to assess the risk, among children aged 0-12 years, of developing meningitis tuberculosis (MT) associated with a lack of intradermal BCG vaccination. Cases (45) of MT admitted for treatment at the Fundacao Benjamin Guimaraes Hospital (Belo Horizonte, MG, Brazil), from 1975 to 1981, were matched for age at hospitalization, date of hospitalization and nutritional status, with two types of controls--patients with acute diarrhoea (AD) and patients with acute non-tuberculous bacterial pneumonias (BP)--admitted to the same hospital. Vaccination status was ascertained from the patients' medical records. Results showed a risk for MT, estimated by the odds ratio, between BCG non-vaccinated and BCG vaccinated patients, of 6.7 (95% Cl 2.3-19.0) comparing cases and AD controls, of 4.0 (95% Cl 1.5-11.0) comparing cases and BP controls and 5.7 (95% Cl 2.3-14.0) comparing cases with both controls. When adjustments were made for place of residence (Metropolitan Region of Belo Horizonte and other regions of Minas Gerais State), the risks decreased to 5.2 (95% Cl 1.9-14.0) and 2.9 (95% Cl 1.2-7.3) comparing cases with AD and BP controls, respectively.

Methodological considerations in case-control studies to evaluate BCG vaccine effectiveness.

Several case-control studies evaluating the effectiveness of BCG vaccine in the last decade have presented contradictory results like previous prospective studies. Methodological differences could explain some of the case-control study results. This study explores the possibility that contradictory results could be imputed to the choice of different series of controls. Three controls were compared for each case of tuberculous meningitis: neighbourhood, hospital and household. BCG effectiveness estimates were 86.8%, 92.0% and 29.5%, respectively. The data indicated an interaction between BCG vaccine status and tuberculous focus. This could have influenced the lower effectiveness estimates found when cases were compared with household controls. The paper discusses aspects related to case-control studies applied to evaluate BCG effectiveness such as: incubation period and sufficient time since vaccination to allow development of an immune response; the presence of a tuberculous focus among the groups of cases and controls and the interaction between focus and BCG vaccination; recall bias; and optimum selection of controls in case-control studies in the context of infectious diseases.

Evaluation of the effectiveness of BCG vaccination using the case-control method in Buenos Aires, Argentina.

A retrospective case-control study was conducted in Argentina to determine the protection conferred by BCG vaccination against tuberculosis in children under six years of age, in an area where coverage is about 55%. A total of 175 tuberculosis patients were included. Five controls selected from patients treated at the same hospital as those under study for reasons other than tuberculosis were matched to each case on the basis of age, socioeconomic origin, nutritional status and place of residence. Information on BCG vaccination status was collected by an independent examiner. Tuberculosis localizations were as follows: 152 pulmonary, pleural and/or miliary; 18 meningitis; 2 lymphadenitis; 2 osteoarticular; and 1 otic. The diagnosis was based on bacteriological and histopathological tests, computerized tomography, radiology, clinical examination, endoscopy, and proved source of infection. The protective effect of BCG among those who were vaccinated was 73.0% with 95% confidence limits of 82% and 62%. According to these results BCG vaccination given early in life is very effective in preventing tuberculosis.

Trends in childhood tuberculosis in Hungary 1953-1983: quantitative methods for evaluation of BCG policy.

To analyse the effectiveness of the BCG policy on childhood tuberculosis in Hungary, the following three quantitative methods have been organized and systematically applied since 1959; regression analysis with multiple comparison of the incidence trends of age groups; stepwise regression analysis to select the strongest childhood incidence decrease factor; and a log-linear model to compare the risk of disease in vaccinated and non-vaccinated children. The increasing BCG coverage of children as a specific antituberculous measure (i) has decreased the childhood incidence (23-32% per year) 3-4 times more rapidly than the adult incidence (6-16% per year) as shown by the regression analysis, (ii) has acted as the strongest incidence decrease effect among other factors and (iii) has protected the vaccinated children 2.8 times better than the non-vaccinated ones. The use of valid and exact models, from statistical inferences ensure the objective interpretation of the epidemiological events in tuberculosis.

Issues in cerebrospinal fluid management. Acid-fast bacillus smear and culture.

Meningeal tuberculosis is an uncommon disease in the United States with an annual incidence of fewer than 200 cases. This study evaluates three approaches to improving the use of the cerebrospinal (CSF) acid-fast bacillus (AFB) smear and culture procedure: (1) education alone; (2) optional screening by which physicians can select to have the AFB analysis stopped if the initial CSF findings are unremarkable; and (3) mandatory screening before the performance of all CSF AFB analyses. With education alone, the CSF AFB culture rate decreased from 20.6% of all CSF acquisitions to 15.7% (P less than 0.001); however, the effect may have been related to a decrease in all types of AFB testing. Optional screening had no impact on the AFB testing rate. Mandatory screening significantly decreased the CSF AFB rate to 6.7% (P less than 0.001), unrelated to changes in other types of AFB testing. Laboratories that employ mandatory screening should report the screening results immediately and have a mechanism whereby physicians can bypass the screen, providing CSF AFB analysis on unremarkable fluid from high-risk patients.