Meningitis In Resource-limited Settings Research Articles

TB LAMP assay, a beneficial tool for the diagnosis of Tubercular meningitis in resource-limited settings.

Tubercular meningitis (TBM) is a serious public health problem in developing countries as it leads to significant mortality and residual neurological sequelae. The estimated mortality due to TBM in India is 1.5 per 100,000 population. In resource-limited settings, only the Ziehl-Neelsen (ZN) stain, which has very little sensitivity, is available. The World Health Organization recommended the Loop Mediated Isothermal Amplification (TB LAMP) assay for pulmonary tuberculosis only. We evaluated this test for tubercular meningitis as well. In a cross-sectional study of 2-year duration, we have taken 239 cerebrospinal fluid samples from suspected cases of tubercular meningitis patients. ZN staining along with Mycobacteria Growth Indicator Tube (MGIT) TB culture, Xpert MTB/RIF Ultra assay, and commercial TB LAMP assay were performed for each sample. Out of 239 samples, 40 samples (16.73%) were found TB LAMP assay positive, 48 samples (20.08%) were found Xpert ultra-assay positive, 12 samples (5.02%) were MGIT TB culture positive and acid-fast bacillus smear positive in ten samples (4.18 %). Out of 12 MGIT-positive samples, all samples (100%) were TB LAMP and Xpert ultra positive and one sample (8.33%) was ZN smear positive. In 199 negative samples from the TB LAMP assay, eight samples were positive by Xpert, none by MGIT TB culture and AFB smear. Sensitivity and specificity were found as 100% and 87.66%, respectively, for the TB LAMP assay. TB LAMP assay is a rapid, cost-effective, sensitive, and specific test for tubercular meningitis infection in resource-limited settings.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

BackgroundCryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy.MethodsWe randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks.ResultsA total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.ConclusionsOne week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509.)

Loop-Mediated Isothermal Amplification Methods for Diagnosis of Bacterial Meningitis.

The rapid, accurate, and efficient identification of an infectious disease is critical to ensure timely clinical treatment and prevention in public health settings. In 2015, meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis was responsible for 379,200 (range: 322,700–444,700) deaths. Clinical features alone cannot determine whether bacterial meningitis is present; an analysis of cerebrospinal fluid (CSF) is essential. Loop-mediated isothermal amplification (LAMP) is a nucleic acid amplification method offering an alternative to polymerase chain reaction (PCR). LAMP-based assays for detection of three leading bacteria in CSF for diagnosis of meningitis have been established. The typing assays using LAMP for detection of meningococcal serogroups A, B, C, W, X, and Y as well as H. influenzae serotypes a, b, c, d, e, and f were launched. In comparative analysis of the meningitis pathogen assays, LAMP assays did not yield false negative results, and the detection rate of LAMP assays was superior compared with PCR or conventional culture methods. LAMP assays provide accurate and rapid test results to detect major bacterial meningitis pathogens. Accumulating evidence suggests that LAMP assays have the potential to provide urgently needed diagnostics for bacterial meningitis in resource-limited settings of both developed and developing countries.

Empiric Treatment of Acute Meningitis Syndrome in a Resource-Limited Setting: Clinical Outcomes and Predictors of Survival or Death.

Bacterial meningitis is a significant cause of morbidity and mortality in the developing world. However, limited research has focused on the diagnosis and management of meningitis in resource-limited settings. We designed a prospective case series of children admitted to a large, academic referral hospital with acute meningitis syndrome. Data were collected on age, time of presentation, prior antibiotics, cerebrospinal fluid (CSF) parameters, antibiotic and steroid prescription, and clinical outcome. Data on 99 patients were collected and analyzed. Most of the patients were males, n=69 (70%), and were from a rural area, n=83 (84%). Incomplete vaccination was common, n=36 (36%) and many have evidence of malnutrition, n=25 (38%). Most patients, n=64 (72%), had received antibiotics prior to admission with a mean duration of symptoms of 4.9 days prior to admission. The CSF white blood cell (WBC) count was higher in those who had not received prior antibiotics though it was elevated in both groups. The CSF WBC count was not associated with survival; malnutrition and length of symptoms prior to admission were both associated with decreased survival. While use of antibiotics prior to obtaining CSF in patients with acute meningitis syndrome may decrease their CSF WBC count, it is not clinically significant. Many patients had a significant delay in presentation that had an effect on survival, This is a potentially modifiable risk factor despite the resourcelimited setting.

Adjunctive dexamethasone therapy in unconfirmed bacterial meningitis in resource limited settings: is it a risk worth taking?

BackgroundBacterial meningitis is associated with significant morbidity and mortality despite advances in medical care. The main objective of this study was to assess the association of adjunctive dexamethasone treatment with discharge outcome of patients treated as bacterial meningitis in low income setting.MethodsA retrospective study was conducted at four teaching hospitals across Ethiopia. Patients of age 14 years and older treated as cases of bacterial meningitis between January 1, 2011 and April 30, 2015 were included in this study. Information regarding sociodemographic data, clinical presentations, laboratory data, treatments given and status at hospital discharge were retrieved from patients’ medical records using a structured questionnaire. Predefined outcome variables at discharge were analysed using descriptive statistics. Multivariable logistic regression was used to identify factors independently associated with poor outcome.ResultsA total of 425 patients treated with the presumptive clinical diagnosis of bacterial meningitis were included in this study (lumbar puncture done in 56 %; only 19 % had CSF findings compatible with bacterial meningitis, and only 3 % had proven etiology). The overall in hospital mortality rate was 20.2 %. Impaired consciousness, aspiration pneumonia, and cranial nerve palsy at admission were independently associated with increased mortality. Adjuvant dexamethasone, which was used in 50.4 % of patients, was associated with increased in-hospital mortality (AOR = 3.38; 95 % CI 1.87–6.12, p < 0.001) and low Glasgow outcome scale (GOS) at discharge (AOR = 4.46 (95 % CI 1.98–10.08). This association between dexamethasone and unfavorable outcome was found to be more pronounced in suspected but unproven cases and in those without CSF alterations compatible with bacterial meningitis.ConclusionMost patients treated for suspected bacterial meningitis did not receive proper diagnostic workup. Adjuvant dexamethasone use in clinically suspected but unproven cases of bacterial meningitis was associated with an increased mortality and poor discharge GOS. These findings show that there are potential deleterious effects in unconfirmed cases in this setting. Physicians practising under such circumstances should thus abide with the current recommendation and defer the use of adjuvant corticosteroid in suspected cases of bacterial meningitis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0678-0) contains supplementary material, which is available to authorized users.

Epidemiology of meningitis in an HIV-infected Ugandan cohort.

There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical.

Standardized electrolyte supplementation and fluid management improves survival during amphotericin therapy for cryptococcal meningitis in resource-limited settings.

Amphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa. Human immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001-2002, and universal in 2006-2012. In 2001-2009, serum potassium (K(+)) was monitored on days 1, 7, and 14 of treatment with replacement (K(+), Mg(2+)) per clinician discretion. In 2011-2012, K(+) was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K(+), Mg(2+)) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies. With limited intravenous fluids, the 14-day survival was 49% in 2001-2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006-2010 (P = .003). In 2011-2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006-2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011-2012 with universal supplementation (P < .001). Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K(+), Mg(2+)), as part of comprehensive amphotericin-based cryptococcal therapy.

Cost-Effective Diagnostic Checklists for Meningitis in Resource-Limited Settings

Checklists can standardize patient care, reduce errors, and improve health outcomes. For meningitis in resource-limited settings, with high patient loads and limited financial resources, central nervous system diagnostic algorithms may be useful to guide diagnosis and treatment. However, the cost effectiveness of such algorithms is unknown. We used decision analysis methodology to evaluate the costs, diagnostic yield, and cost effectiveness of diagnostic strategies for adults with suspected meningitis in resource-limited settings with moderate/high HIV prevalence. We considered 3 strategies: (1) comprehensive "shotgun" approach of utilizing all routine tests; (2) "stepwise" strategy with tests performed in a specific order with additional tuberculosis (TB) diagnostics; (3) "minimalist" strategy of sequential ordering of high-yield tests only. Each strategy resulted in 1 of 4 meningitis diagnoses: bacterial (4%), cryptococcal (59%), TB (8%), or other (aseptic) meningitis (29%). In model development, we utilized prevalence data from 2 Ugandan sites and published data on test performance. We validated the strategies with data from Malawi, South Africa, and Zimbabwe. The current comprehensive testing strategy resulted in 93.3% correct meningitis diagnoses costing $32.00 per patient. A stepwise strategy had 93.8% correct diagnoses costing an average of $9.72 per patient, and a minimalist strategy had 91.1% correct diagnoses costing an average of $6.17 per patient. The incremental cost-effectiveness ratio was $133 per additional correct diagnosis for the stepwise over minimalist strategy. Through strategically choosing the order and type of testing coupled with disease prevalence rates, algorithms can deliver more care more efficiently. The algorithms presented herein are generalizable to East Africa and Southern Africa.

HIV-Associated Cryptococcal Meningitis in Resource-Limited Settings: Current Challenges and Future Developments

Cryptococcal meningitis is a severe opportunistic infection in HIV disease. Although the prevalence is declining with the expansion of antiretroviral treatment, it remains an important issue in resource-limited settings. The Cochrane Database of Systematic Reviews, PubMed, EMBASE and AJOL were searched with focus on epidemiology, mycology and pathogenesis, diagnosis and treatment, and challenges in resource-limited settings, and future developments. Challenges particularly in resource-limited settings include inadequate diagnosis due to poor laboratory facilities and low index of suspicion, and poor availability of current effective antifungal drugs. Although studies are still on going on the use of interferon-γ in cryptococcal meningitis, the tempo of research on development of preventive cryptococcal vaccine should also be increased.

HIV-Related Cryptococcal Meningitis in Resource-Limited Settings

Cryptococcal infection remains a significant problem in patients with AIDS in resource-limited settings. Even with the availability of HAART, the 6-month rate of survival after cryptococcal meningitis (CM) reported by several epidemiological studies is very low. The worldwide number of infections and deaths due to CM appears similar to those for diseases that have received greater public health attention. In sub-Saharan Africa, deaths due to CM may be more frequent than TB. However, in many developing countries the capacity to perform the complicated management of severe CM is limited and CM mortality may remain a problem in Africa, and also in areas where antiretroviral therapy is available, as late presentation with advanced disease is common and consequently IRIS is becoming an emerging problem. A focused effort to improve diagnostic capacity, expand treatment options, and identify effective measures for the prevention of cryptococcal disease is urgently required.

Management of cryptococcal meningitis in HIV-infected patients: Experience from western India

Cryptococcal meningitis is one of the acquired immunodeficiency syndrome defining infections with high mortality. Amphotericin B is the preferred drug for induction therapy. Despite advances in human immunodeficiency virus (HIV) treatment, Antiretroviral Treatment (ART) roll-out programs and availability of amphotericin B, cryptococcal meningitis remains an important cause of mortality in the African and other developing countries. We carried out a prospective observational study to determine the treatment response rate, tolerability and outcome of patients with cryptococcal meningitis in HIV treated with amphotericin B. Descriptive statistic was used to analyze the data. A total of 27 patients were diagnosed with cryptococcal meningitis during the study period. Headache (96.29%) was the single most common presenting symptom of cryptococcal meningitis in HIV-infected patients, followed by vomiting (77.77%) and fever (66.66%). Cerebrospinal fluid (CSF) routine and microscopic examination was within normal limits in six patients. CSF became sterile on the 12th day of Amphotericin B in 55.55% of the patients while 33.33% had positive CSF cultures. Patients were started with ART after achieving sterile CSF and tolerated at least 2 weeks of fluconazole consolidation treatment and were free from symptoms. Median time for antiretroviral treatment initiation was 35 (14-90) days after completion of Amphotericin B treatment. One patient developed immune reconstitution inflammatory syndrome (IRIS) after ART. We found that the recommended 2 weeks induction treatment with Amphotericin B monotherapy for HIV patients with cryptococcal meningitis in resource-limited settings may be suboptimal for at least one-third of the patients. Extending the therapy to 3 weeks is likely to result in sterilization of the CSF in a majority of these patients. This finding requires confirmation by a larger sample size in appropriately powered studies. Delaying ART initiation by at least 2 weeks after amphotericin B treatment may decrease the incidence of IRIS.

Management of cryptococcal meningitis in HIV-infected patients: Experience from western India

Introduction:Cryptococcal meningitis is one of the acquired immunodeficiency syndrome defining infections with high mortality. Amphotericin B is the preferred drug for induction therapy. Despite advances in human immunodeficiency virus (HIV) treatment, Antiretroviral Treatment (ART) roll-out programs and availability of amphotericin B, cryptococcal meningitis remains an important cause of mortality in the African and other developing countries.Materials and Methods:We carried out a prospective observational study to determine the treatment response rate, tolerability and outcome of patients with cryptococcal meningitis in HIV treated with amphotericin B. Descriptive statistic was used to analyze the data.Results:A total of 27 patients were diagnosed with cryptococcal meningitis during the study period. Headache (96.29%) was the single most common presenting symptom of cryptococcal meningitis in HIV-infected patients, followed by vomiting (77.77%) and fever (66.66%). Cerebrospinal fluid (CSF) routine and microscopic examination was within normal limits in six patients. CSF became sterile on the 12th day of Amphotericin B in 55.55% of the patients while 33.33% had positive CSF cultures. Patients were started with ART after achieving sterile CSF and tolerated at least 2 weeks of fluconazole consolidation treatment and were free from symptoms. Median time for antiretroviral treatment initiation was 35 (14–90) days after completion of Amphotericin B treatment. One patient developed immune reconstitution inflammatory syndrome (IRIS) after ART.Conclusions:We found that the recommended 2 weeks induction treatment with Amphotericin B monotherapy for HIV patients with cryptococcal meningitis in resource-limited settings may be suboptimal for at least one-third of the patients. Extending the therapy to 3 weeks is likely to result in sterilization of the CSF in a majority of these patients. This finding requires confirmation by a larger sample size in appropriately powered studies. Delaying ART initiation by at least 2 weeks after amphotericin B treatment may decrease the incidence of IRIS.

Treatment of cryptococcal meningitis in resource limited settings.

Cryptococcal meningitis most commonly occurs in advanced HIV. Although diminishing in the developed world with antiretroviral therapy (ART), it remains a major problem in resource-limited settings. ART rollout will improve long-term HIV survival if opportunistic infections are effectively treated. Considering cryptococcal meningitis in that context, this review addresses excess morbidity and mortality in developing countries, treatment in areas of limited drug availability and challenges posed by combined anticryptococcal and HIV therapy. From Early Fungicidal Activity (EFA) studies, amphotericin B-flucytosine is best induction therapy but often unavailable; high dose amphotericin B monotherapy may be feasible in some settings. Where fluconazole is the only option, higher doses are more fungicidal. Serum cryptococcal antigen testing may identify patients at highest disease risk and primary prophylaxis is effective; the clinical role of such interventions needs to be established. Timing of ART introduction remains controversial; early initiation risks Immune Reconstitution Disease (IRD) delays may increase mortality. Amphotericin B based treatment is appropriate where possible. More studies are needed to optimize fluconazole monotherapy doses. Other research priorities include management of raised intracranial pressure, appropriate ART initiation and IRD treatment. Studies should focus on developing countries where problems are greatest.

Management of cryptoccocal meningitis in resource-limited settings: A systematic review

Cryptococcal meningitis (CM) remains a serious cause of mortality and morbidity in individuals infected with the human immunodeficiency virus (HIV). The optimal treatment of CM is unknown. We conducted a systematic review to determine the best treatment for CM with an emphasis on resource-poor settings. Six studies met the inclusion criteria; none was found that compared amphotericin B with fluconazole. From the available evidence, it is not possible to determine which treatment is superior for CM.

Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings

Despite the advent and increasingly wide availability of antiretroviral therapy, cryptococcal meningitis (CM) remains a significant cause of mortality and morbidity amongst individuals with HIV infection in resource-limited settings. The ideal management of CM remains unclear. The aim of this review is to assess the evidence for deciding on which antifungal regimen to use as well as other modalities of management to utilise especially resource poor settings in order to achieve the best possible outcome and enable an individual with CM to survive their acute illness and benefit from antiretroviral therapy. To determine the most effective initial and consolidation treatment strategy for CM in HIV infected adults. The Cochrane HIV/AIDS group search strategy was used. Key words in the search included, meningitis, cryptococcus neoformans, treatment, trial, human immunodeficiency virus, acquired immunodeficiency syndrome, antifungal agents, amphotericin, flucytosine, fluconazole, azole, lumbar puncture, cerebrospinal fluid (CSF) pressure and acetazolamide. Randomised of HIV-infected adults with a first episode of CM diagnosed on CSF examination, by India ink staining, CSF culture or cryptococcal antigen testing. Data were extracted using standardised forms and analysed using Rev Man 4.2.7 software. Six studies are included in the review. Five of the studies compared antifungal treatments and one study addressed lowering intracranial pressure. This study was stopped early due to excess adverse effects. The results of the other five studies as summarised as follows.Mayanja-Kizza 1998 compared fluconazole to fluconazole with 5 flucytosine. The dose of fluconazole used 200mg initially is lower than the recommended initial dose of 400mg. No survival advantage was found with the use of 5 flucytosine in addition to fluconazole.Two studies Brouwer 2004 and van der Horst 1997 compared Amphotericin (AmB) to AmB with 5 flucytosine. Both drugs were given at currently recommended doses for 2 weeks. No survival difference was found at 14 days or at 10 weeks (only recorded in Brouwer 2004). There were significantly more patients with sterile CSF cultures at 14 days in the group that received AmB with flucytosine.Brouwer 2004 compared AmB given alone to AmB given with flucytosine and fluconazole alone or in combination. This was a small study and no differences in mortality were noted between the groups.Bicanic 2008 compared high to standard dose AmB both with flucytosine. There was no difference in mortality between the two groups or adverse events.Leenders 1997 compared standard AmB to liposomal AmB. There was no difference in death rates between the two groups. But there were significantly fewer side effects in the group treated with liposomal AmB. The main aim of this review was to determine the best treatment for cryptococcal meningitis in resource-limited settings. In these settings usually only AmB and fluconazole are available. No studies suitable for inclusion in the review were found that compared these two drugs. Therefore we are unable to recommend either treatment as superior to the other. The recommended treatment for CM is a combination of AmB and flucytosine. The optimal dosing of AmB remains unclear. Liposomal AmB is associated with less adverse events than AmB and may be useful in selected patients where resources allow.Future research into the management of cryptococcal meningitis in resource-limited settings should focus on the most effective use of medications that are available in these settings.Flucytosine in combination with AmB leads to faster and increased sterilisation of CSF compared to using AmB alone. As Flucytosine is often not available in developing countries, policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.