Sean Wasserman

Yellow fever cases in Asia: primed for an epidemic

There is currently an emerging outbreak of yellow fever in Angola. Cases in infected travellers have been reported in a number of other African countries, as well as in China, representing the first ever documented cases of yellow fever in Asia. There is a large Chinese workforce in Angola, many of whom may be unvaccinated, increasing the risk of ongoing importation of yellow fever into Asia via busy commercial airline routes. Large parts of the region are hyperendemic for the related Flavivirus dengue and are widely infested by Aedes aegypti, the primary mosquito vector of urban yellow fever transmission. The combination of sustained introduction of viraemic travellers, an ecology conducive to local transmission, and an unimmunized population raises the possibility of a yellow fever epidemic in Asia. This represents a major global health threat, particularly in the context of a depleted emergency vaccine stockpile and untested surveillance systems in the region. In this review, the potential for a yellow fever outbreak in Asia is discussed with reference to the ecological and historical forces that have shaped global yellow fever epidemiology. The limitations of surveillance and vector control in the region are highlighted, and priorities for outbreak preparedness and response are suggested.

AIDS-Related Endemic Mycoses in Western Cape, South Africa, and Clinical Mimics: A Cross-Sectional Study of Adults With Advanced HIV and Recent-Onset, Widespread Skin Lesions

Abstract Background Skin lesions are common in advanced HIV infection and are sometimes caused by serious diseases like systemic mycoses (SM). AIDS-related SM endemic to Western Cape, South Africa, include emergomycosis (formerly disseminated emmonsiosis), histoplasmosis, and sporotrichosis. We previously reported that 95% of patients with AIDS-related emergomycosis had skin lesions, although these were frequently overlooked or misdiagnosed clinically. Prospective studies are needed to characterize skin lesions of SM in South Africa and to help distinguish these from common HIV-related dermatoses. Methods We prospectively enrolled HIV-infected adult patients living in Western Cape, South Africa, with CD4 counts ≤100 cells/μL and widespread skin lesions present ≤6 months that were deemed clinically compatible with SM. We obtained skin biopsies for histopathology and fungal culture and collected epidemiological and clinical data. Results Of 34 patients enrolled and in whom a diagnosis could be made, 25 had proven SM: 14 had emergomycosis, and 3 each had histoplasmosis and sporotrichosis; for 5 additional patients, the fungal species could not be identified. Antiretroviral therapy (ART) had been initiated in the preceding 4 weeks for 11/25 (44%) patients with SM (vs no patients without SM). Plaques and scale crust occurred more frequently in patients with SM (96% vs 25%, P = .0002; and 67% vs 13%, P = .01, respectively). Conclusions Recent ART initiation and presence of plaques or scale crust should make clinicians consider SM in patients with advanced HIV infection in this geographic area. Clinical overlap between SM and other dermatoses makes early skin biopsy critical for timely diagnosis and treatment.

Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index

ABSTRACT Introduction: Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid’s prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent. Areas covered: This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis. The focus is on the pharmacokinetic-pharmacodynamic determinants of linezolid’s efficacy and toxicity in tuberculosis, and how this relates to defining an optimal dose. Mechanisms of linezolid toxicity and resistance, and the potential role of therapeutic drug monitoring are also covered. Expert commentary: Prospective pharmacokinetic-pharmacodynamic studies are required to define optimal therapeutic targets and to inform improved linezolid dosing strategies for drug-resistant tuberculosis.

Thrombolysis for acute ischemic stroke in South Africa

Background Stroke is an important cause of death and disability in sub-Saharan Africa. Thrombolysis with recombinant tissue plasminogen activator (tPA) is the only effective therapy for acute ischaemic stroke. Essential requirements for stroke thrombolysis include availability of CT scanning and arrival at hospital within 4.5 hours of symptom onset. However, in developing countries where the prerequisites are met at certain centres, the efficacy and safety of thrombolysis have not been firmly established. Aims We aimed to evaluate the early outcomes and safety of stroke thrombolysis in a South African setting. Method We conducted a prospective observational study of all stroke patients receiving tPA for thrombolysis over the period January 2000 to February 2011. The primary outcome measure was the proportion of patients achieving significant early neurological recovery defined as an improvement of four or more points on the NIHSS score at discharge. The safety endpoint was the rate of symptomatic intracranial haemorrhage (SICH) and death. Results Forty-two patients received thrombolysis over the study period. Sixty-seven percent achieved significant neurological improvement. The majority of patients (53.8%) were discharged home, and by the time of discharge 17 (40.5%) were functionally independent. SICH occurred in 2 (4.8%) patients with an overall mortality rate of 7.1%. Conclusions Our findings indicate that the use of thrombolysis in routine clinical practice in a South African setting has similar safety and early efficacy outcomes to developed and other developing countries.

Recent controversies about MDR and XDR-TB: Global implementation of the WHO shorter MDR-TB regimen and bedaquiline for all with MDR-TB?

Tuberculosis (TB) is now the biggest infectious disease killer worldwide. Although the estimated incidence of TB has marginally declined over several years, it is out of control in some regions including in Africa. The advent of multidrug‐resistant TB (MDR‐TB) and extensively drug‐resistant TB (XDR‐TB) threatens to further destabilize control in several regions of the world. Drug‐resistant TB constitutes a significant threat because it underpins almost 25% of global TB mortality, is associated with high morbidity, is a threat to healthcare workers and is unsustainably costly to treat. The advent of highly resistant TB with emerging bacillary resistance to newer drugs has raised further concern. Encouragingly, in addition to preventative strategies, several interventions have recently been introduced to curb the drug‐resistant TB epidemic, including newer molecular diagnostic tools, new (bedaquiline and delamanid) and repurposed (linezolid and clofazimine) drugs and shorter and individualized treatment regimens. However, there are several controversies that surround the use of new drugs and regimens, including whether, how and to what extent they should be used, and who specifically should be treated so that outcomes are optimally improved without amplifying the burden of drug resistance, and other potential drawbacks, thus sustaining effectiveness of the new drugs. The equipoise surrounding these controversies is discussed and some recommendations are provided.

The diagnosis, management and prevention of HIV-associated tuberculosis

Tuberculosis (TB) and its strong association with HIV infection are the most important causes of the high rates of infectious morbidity and mortality in South African adults. The interaction between HIV and TB leads to more frequent smear-negative and extrapulmonary disease, resulting in atypical clinical presentations and altered performance characteristics of diagnostic tests. New and emerging diagnostics are being used to support earlier initiation of therapy and detection of drug resistance, although these have inherent limitations and empirical therapy is often still required. The management of HIV-associated TB is complicated by rapid clinical progression of disease, immune reconstitution inflammatory syndrome, drug-drug interactions and shared toxicities. A strong evidence base now provides guidance on the timing of initiation of antiretroviral therapy, the use of corticosteroids in TB and the use of isoniazid preventive therapy. This article provides a clinically oriented overview of the diagnosis, management and prevention of HIV-associated TB, with a focus on recent evidence in the field.

Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: protocol for a systematic review

BackgroundReports from Africa have suggested that pneumocystis pneumonia (PCP) is a less important cause of morbidity than in the developed world. However, more recent studies have shown high seroprevalence rates of P. jirovecii in healthy individuals with HIV as well as high rates of clinical disease in African children. This suggests that PCP may be more common in Africa than was previously recognised. Understanding the contribution of PCP to disease in HIV-infected individuals in sub-Saharan Africa (SSA) has important implications for diagnosis, management and resource allocation. We therefore propose to conduct a systematic review and meta-analysis in order to investigate the burden of PCP in this population.Methods and designWe plan to search electronic databases and reference lists of relevant articles published from 1995 to May 2013 using broad terms for pneumocystis, HIV/AIDS and sub-Saharan Africa. Studies will be included if they provide clear diagnostic criteria for PCP and well-defined study populations or mortality data (denominator). A novel quality score assessment tool has been developed to ensure fidelity to inclusion criteria, minimise risk of selection bias between reviewers and to assess quality of outcome ascertainment. This will be applied to eligible full-text articles. We will extract data using a standardised form and perform descriptive and quantitative analysis to assess PCP prevalence, mortality and case fatality, as well as the quality of included studies. This review protocol has been published in the PROSPERO International Prospective Register of systematic reviews, registration number CRD42013005530.DiscussionOur planned review will contribute to the diagnosis and management of community-acquired pneumonia in HIV-infected individuals in SSA by systematically assessing the burden of PCP in this population. We also describe a novel quality assessment tool that may be applied to other prevalence reviews.

Early outcomes of thrombolysis for acute ischaemic stroke in a South African tertiary care centre

BACKGROUND Stroke is an important cause of death and disability in sub-Saharan Africa. Recombinant tissue plasminogen activator (tPA) thrombolysis is effective in treating acute ischaemic stroke, but may not be a viable option in developing countries. METHODS We assessed the short-term outcomes and safety of tPA for the treatment of stroke at Groote Schuur Hospital from the year 2000. Patients with a clinical diagnosis of acute stroke with onset of stroke symptoms within 4.5 hours of receiving thrombolysis were included. Exclusion criteria were based on the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial protocol (upper age limit was 75 years). Primary outcomes were the proportion of patients achieving significant early neurological recovery defined as an improvement of 4 or more points on the National Institutes of Health stroke scale (NIHSS) score and functional independence defined as a modified Rankin score of 2 or less at discharge. The primary safety measures were the rates of symptomatic intracranial haemorrhage (SICH) and death. RESULTS From January 2000 to February 2011 42 patients were thrombolysed, with a mean time to tPA infusion of 160 minutes (standard deviation (SD) 50; range 60 - 270). By discharge the median NIHSS score fell from 14 (interquartile range (IQR) 10.5 - 17) to 7.5 (IQR 1 - 15); 28 (66.7%) achieved significant neurological improvement, and 17 (40.5%) were functionally independent. Two patients (4.8%) suffered SICH and there were 3 (7.1%) deaths. CONCLUSION Thrombolysis in routine clinical practice in a South African setting has similar safety and early efficacy outcomes to controlled trials and open-label studies in developing and developed countries.

Diagnosis of bacterial infection

Accurate diagnosis of bacterial infection is crucial to avoid unnecessary antibiotic use and to focus appropriate therapy. Bacterial infection is the combination of the presence of bacteria and inflammation or systemic dysfunction; therefore, more than one diagnostic modality is usually required for confirmation. History and examination to determine if a patient fits a clinical case definition is sometimes adequate to confirm or exclude a diagnosis. The second stage is bedside tests – some are used widely, such as urine dipstick tests, but others, such as skin scrapings of petechial rashes, are underutilised. The third stage is laboratory tests – indirect non-culture-based tests, including C-reactive protein and procalcitonin tests, when negative, can be used to prevent the unnecessary use of antibiotics. Direct non-culture-based tests detect antigens or specific antibodies, e.g. group A streptococcal antigen testing can be employed to reduce antibiotic use. Culture-based tests are often considered the reference standard in modern microbiology. Because of slow turnaround times, these tests are frequently used to focus or stop antibiotic therapy after empiric initiation. Nucleic acid amplification tests raise the possibility of detecting organisms with high sensitivity, specificity and reduced turnaround time, and novel diagnostic modalities relying on nanotechnology and mass spectrometry may dramatically alter the practice of microbiology in future.

Paradoxical worsening of Emergomyces africanus infection in an HIV-infected male on itraconazole and antiretroviral therapy

1 Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 2 Department of Dermatology, University of Cape Town, Cape Town, Western Cape, South Africa, 3 Department of Anatomical Pathology, National Health Laboratory Service Groote Schuur Hospital Branch, Cape Town, Western Cape, South Africa, 4 Division of Infectious Diseases & HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 5 Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 6 National Institute for Communicable Diseases-Centre for Healthcare-Associated Infections, Antimicrobial Resistance and Mycoses, National Health Laboratory Service, Sandringham, Gauteng, South Africa, 7 Sexually Transmitted Infectious Unit, Institute of Tropical Medicine, Antwerp, Belgium, 8 Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, 9 Global Health Institute, University of Antwerp, Antwerp, Belgium