Lut Lynen

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

HIV Viral Load Monitoring in Resource-Limited Regions: Optional or Necessary?

Although it is a standard practice in high-income countries, determination of the human immunodeficiency virus (HIV) load is not recommended in developing countries because of the costs and technical constraints. As more and more countries establish capacity to provide second-line therapy, and as costs and technological constraints associated with viral load testing decrease, the question of whether determination of the viral load is necessary deserves attention. Viral load testing could increase in importance as a guide for clinical decisions on when to switch to second-line treatment and on how to optimize the duration of the first-line treatment regimen. In addition, the viral load is a particularly useful tool for monitoring adherence to treatment, performing sentinel surveillance, and diagnosing HIV infection in children aged <18 months. Rather than considering viral load data to be an unaffordable luxury, efforts should be made to ensure that viral load testing becomes affordable, simple, and easy to use in resource-limited settings.

Rapid diagnostic tests for neurological infections in central Africa

Infections are a leading cause of life-threatening neuropathology worldwide. In central African countries affected by endemic diseases such as human African trypanosomiasis, tuberculosis, HIV/AIDS, and schistosomiasis, delayed diagnosis and treatment often lead to avoidable death or severe sequelae. Confirmatory microbiological and parasitological tests are essential because clinical features of most neurological infections are not specific, brain imaging is seldom feasible, and treatment regimens are often prolonged or toxic. Recognition of this diagnostic bottleneck has yielded major investment in application of advances in biotechnology to clinical microbiology in the past decade. We review the neurological pathogens for which rapid diagnostic tests are most urgently needed in central Africa, detail the state of development of putative rapid diagnostic tests for each, and describe key technical and operational challenges to their development and implementation. Promising field-suitable rapid diagnostic tests exist for the diagnosis of human African trypanosomiasis and cryptococcal meningoencephalitis. For other infections-eg, syphilis and schistosomiasis-highly accurate field-validated rapid diagnostic tests are available, but their role in diagnosis of disease with neurological involvement is still unclear. For others-eg, tuberculosis-advances in research have not yet yielded validated tests for diagnosis of neurological disease.

Azithromycin and ciprofloxacin resistance in Salmonella bloodstream infections in Cambodian adults.

Background Salmonella enterica is a frequent cause of bloodstream infection (BSI) in Asia but few data are available from Cambodia. We describe Salmonella BSI isolates recovered from patients presenting at Sihanouk Hospital Centre of Hope, Phnom Penh, Cambodia (July 2007–December 2010). Methodology Blood was cultured as part of a microbiological prospective surveillance study. Identification of Salmonella isolates was performed by conventional methods and serotyping. Antibiotic susceptibilities were assessed using disk diffusion, MicroScan and E-test macromethod. Clonal relationships were assessed by Pulsed Field Gel Electrophoresis; PCR and sequencing for detection of mutations in Gyrase and Topoisomerase IV and presence of qnr genes. Principal Findings Seventy-two Salmonella isolates grew from 58 patients (mean age 34.2 years, range 8–71). Twenty isolates were identified as Salmonella Typhi, 2 as Salmonella Paratyphi A, 37 as Salmonella Choleraesuis and 13 as other non-typhoid Salmonella spp. Infection with human immunodeficiency virus (HIV) was present in 21 of 24 (87.5%) patients with S. Choleraesuis BSI. Five patients (8.7%) had at least one recurrent infection, all with S. Choleraesuis; five patients died. Overall, multi drug resistance (i.e., co-resistance to ampicillin, sulphamethoxazole-trimethoprim and chloramphenicol) was high (42/59 isolates, 71.2%). S. Typhi displayed high rates of decreased ciprofloxacin susceptibility (18/20 isolates, 90.0%), while azithromycin resistance was very common in S. Choleraesuis (17/24 isolates, 70.8%). Two S. Choleraesuis isolates were extended spectrum beta-lactamase producer. Conclusions and Significance Resistance rates in Salmonella spp. in Cambodia are alarming, in particular for azithromycin and ciprofloxacin. This warrants nationwide surveillance and revision of treatment guidelines.

Scaling up antiretroviral treatment and improving patient retention in care: lessons from Ethiopia, 2005-2013.

BackgroundAntiretroviral treatment (ART) was provided to more than nine million people by the end of 2012. Although ART programs in resource-limited settings have expanded treatment, inadequate retention in care has been a challenge. Ethiopia has been scaling up ART and improving retention (defined as continuous engagement of patients in care) in care. We aimed to analyze the ART program in Ethiopia.MethodsA mix of quantitative and qualitative methods was used. Routine ART program data was used to study ART scale up and patient retention in care. In-depth interviews and focus group discussions were conducted with program managers.ResultsThe number of people receiving ART in Ethiopia increased from less than 9,000 in 2005 to more than 439, 000 in 2013. Initially, the public health approach, health system strengthening, community mobilization and provision of care and support services allowed scaling up of ART services. While ART was being scaled up, retention was recognized to be insufficient. To improve retention, a second wave of interventions, related to programmatic, structural, socio-cultural, and patient information systems, have been implemented. Retention rate increased from 77% in 2004/5 to 92% in 2012/13.ConclusionEthiopia has been able to scale up ART and improve retention in care in spite of its limited resources. This has been possible due to interventions by the ART program, supported by health systems strengthening, community-based organizations and the communities themselves. ART programs in resource-limited settings need to put in place similar measures to scale up ART and retain patients in care.

Nontuberculous mycobacterial disease in patients with HIV in Southeast Asia.

RATIONALE Although nontuberculous mycobacteria (NTM) are widely documented as a cause of illness among HIV-infected people in the developed world, studies describing the prevalence of NTM disease among HIV-infected people in most resource-limited settings are rare. OBJECTIVES To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia. METHODS We enrolled people with HIV from three countries in Southeast Asia and collected pulmonary and extrapulmonary specimens to evaluate the prevalence of mycobacterial disease. We adapted American Thoracic Society/Infectious Disease Society of America guidelines to classify patients into NTM pulmonary disease, NTM pulmonary disease suspects, NTM disseminated disease, and no NTM categories. MEASUREMENTS AND MAIN RESULTS In Cambodia, where solid media alone was used, NTM was rare. Of 1,060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had tuberculosis and 218 (21%) had NTM. Of 218 patients with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM disease was 2% (19 of 1,060). Of 51 patients receiving antiretroviral therapy (ART), none had NTM disease compared with 19 (2%) of 1,009 not receiving ART. CONCLUSIONS Although people with HIV frequently have sputum cultures positive for NTM, few meet a strict case definition for NTM disease. Consistent with previous studies, ART was associated with lower odds of having NTM disease. Further studies of NTM in HIV-infected individuals in tuberculosis-endemic countries are needed to develop and validate case definitions.

Rational use of antiretroviral therapy in low-income and middle-income countries: optimizing regimen sequencing and switching

This editorial reviews objective is to support the development of strategies to maximize the effectiveness of first-line and second-line antiretroviral therapy (ART) regimens and optimize the training of regimen switching in lower-income and middle-income countries (LMICs). The support is required to fully utilize the survival benefit of available treatment options maintain program cost-effectiveness and enable achievement of universal access to HIV treatment and states that the comprehensive strategy must be evidence based and focused on the rational long-term use of ART at a population level.

Bloodstream Infection among Adults in Phnom Penh, Cambodia: Key Pathogens and Resistance Patterns.

Background Bloodstream infections (BSI) cause important morbidity and mortality worldwide. In Cambodia, no surveillance data on BSI are available so far. Methods From all adults presenting with SIRS at Sihanouk Hospital Centre of HOPE (July 2007–December 2010), 20 ml blood was cultured. Isolates were identified using standard microbiological techniques; antibiotic susceptibilities were assessed using disk diffusion and MicroScan®, with additional E-test, D-test and double disk test where applicable, according to CLSI guidelines. Results A total of 5714 samples from 4833 adult patients yielded 501 clinically significant organisms (8.8%) of which 445 available for further analysis. The patients’ median age was 45 years (range 15–99 y), 52.7% were women. HIV-infection and diabetes were present in 15.6% and 8.8% of patients respectively. The overall mortality was 22.5%. Key pathogens included Escherichia coli (n = 132; 29.7%), Salmonella spp. (n = 64; 14.4%), Burkholderia pseudomallei (n = 56; 12.6%) and Staphylococcus aureus (n = 53; 11.9%). Methicillin resistance was seen in 10/46 (21.7%) S. aureus; 4 of them were co-resistant to erythromycin, clindamycin, moxifloxacin and sulphamethoxazole-trimethoprim (SMX-TMP). We noted combined resistance to amoxicillin, SMX-TMP and ciprofloxacin in 81 E. coli isolates (62.3%); 62 isolates (47.7%) were confirmed as producers of extended spectrum beta-lactamase. Salmonella isolates displayed high rates of multidrug resistance (71.2%) with high rates of decreased ciprofloxacin susceptibility (90.0%) in Salmonella Typhi while carbapenem resistance was observed in 5.0% of 20 Acinetobacter sp. isolates. Conclusions BSI in Cambodian adults is mainly caused by difficult-to-treat pathogens. These data urge for microbiological capacity building, nationwide surveillance and solid interventions to contain antibiotic resistance.

Validation of primary CD4 gating as an affordable strategy for absolute CD4 counting in Cambodia

Objective:To validate primary CD4 gating in lysed whole blood for absolute CD4 counts in fresh and aged blood using an affordable compact volumetric commercial flow cytometer. Design:Comparison of CD4 counts between the FACSCount and the 2-parameter CyFlow SL Green. Methods:One hundred twenty fresh blood samples from patients likely to be infected with HIV were simultaneously run on a FACSCount at the Pasteur Institute of Cambodia and on a CyFlow SL Green at the Sihanouk Hospital Center of Hope (SHCH), Phnom Penh, Cambodia. Intra- and interrun precision was assessed using 2 blood samples. Stability of CD4 counting in blood stored up to 96 hours at room temperature was assessed using 27 blood samples. Results:CD4 counts on the CyFlow SL Green and on the FACSCount correlated well apart from a relative bias (R2 = 0.993, bias of −9.5%, 95% confidence interval [CI]: −11.8% to −7.1%, limits of agreement: −32.5% to 13.6%). Intra- and interrun variability ranged from 3% to 5% and from 5% to 6%, respectively. CD4 counts on aged blood using the CyFlow SL Green showed an interassay variability of <10%. Conclusions:Primary CD4 gating in lysed whole blood using the CyFlow SL Green is an affordable and precise method for CD4 counting. Because the fluorescence (FL) and light scatter signals have to be analyzed manually, however, intensive training of the technician and/or operator is imperative.

Remote consultations and HIV/AIDS continuing education in low-resource settings

BACKGROUND Telemedicine is a way to support physicians working in resource-poor settings, providing remote consultations and continuing medical education on HIV/AIDS care. METHODS A hybrid E-mail/web support telemedicine service was created in 2003 at the Institute of Tropical Medicine, Antwerp, Belgium, with a discussion forum hosting more than 170 healthcare professionals from 40 different countries, generally resource constrained. Interesting posts and recurring questions from this discussion forum have been elaborated as case studies or frequently asked questions, available on the website for consultation. Education and support are also provided through interactive quizzes, user-friendly guidelines, and policy documents with a particular focus on HIV/AIDS care in developing countries. RESULTS From April 2003 to March 2005, 342 questions were sent from over 17 countries in Africa, Asia, and South America. The vast majority of these questions (93%) were patient-oriented, with only 7% being general questions. Of the patient-oriented questions, 49% were related to antiretroviral therapy, and 44% were related to the diagnosis and treatment of opportunistic infections. CONCLUSIONS Telemedicine is a cheap and effective method of providing clinical support and continuing education to healthcare workers treating HIV-positive patients in resource-poor settings.