Helen van der Plas

Corticosteroid Therapy, Vitamin D Status, and Inflammatory Cytokine Profile in the HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome

Vitamin D deficiency is common in human immunodeficiency virus–tuberculosis coinfected patients in Cape Town. Those who develop tuberculosis-immune reconstitution inflammatory syndrome have a further reduction in circulating 25-hydroxyvitamin D levels 2 weeks into combined antiretroviral therapy with a concomitant increase in inflammatory cytokines and chemokines.

Mycobacterial Antigen Driven Activation of CD14++CD16- Monocytes Is a Predictor of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.

The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons

BACKGROUND The presence of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid (CSF) is used as a marker of HIV-associated primary central nervous system lymphoma (PCNSL). In our setting, EBV DNA is frequently detected in the CSF of HIV-infected patients with miscellaneous neurological diseases and thus its presence is a poor predictor of PCNSL. OBJECTIVES To determine whether quantification of EBV DNA in CSF improves its diagnostic specificity for PCNSL. STUDY DESIGN EBV viral loads were determined on CSF samples from 55 HIV-infected patients with CNS disease. RESULTS Twenty of the 55 patients had detectable EBV DNA in their CSF (median viral load 6120copies/ml, range 336-1,034,000copies/ml). PCNSL was confirmed in 2 patients. Their CSF EBV loads were 1,034,000 and 15,460copies/ml, respectively. Using a cut-off of 10,000copies/ml improved the specificity and positive predictive value (PPV) compared to a qualitative result for the diagnosis of PCNSL (96% vs. 66% and 50% vs. 10%, respectively). CONCLUSION EBV DNA is commonly detected in CSF of HIV-infected patients. Quantitative PCR improves the diagnostic specificity, however, the PPV remains too low for it to be used as an isolated marker for PCNSL.

HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

Silent casualties from the measles outbreak in South Africa

South Africa, home to the worlds largest population of people living with HIV (5.7 million), experienced a measles outbreak that started in late 2009. There was a stepped increase in cases of measles, with the highest incidence reported in March 2010. By September 2010, more than 17 000 new measles cases had been reported to the National Institute of Communicable Diseases since January 2009. A mass vaccination campaign from mid-April to early May 2010 resulted in a significant decline in new measles cases.

Complications of antiretroviral therapy initiation in hospitalised patients with HIV-associated tuberculosis.

Background HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries. Methods Prospective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded. Results Between May 2009 and November 2010, 112 patients (60% female), with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mm3 (IQR 31–106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%. Conclusions High rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1st three months following ART initiation.

High prevalence of comorbidity and need for up-referral among inpatients at a district-level hospital with specialist tuberculosis services in South Africa - the need for specialist support

OBJECTIVES. To define the patient population at Cape Towns district-level hospital offering specialist tuberculosis (TB) services, concerning the noted increase in complex, sick HIV-TB co-infected patients requiring increased levels of care. METHODS. A cross-sectional study of all hospitalised adult patients in Brooklyn Chest Hospital (a district-level hospital offering specialist TB services) from 27 - 30 October 2008. Outcome measures were: Type of TB and drug sensitivity, HIV co-infection, comorbidity, Karnofsky performance score, and frequency and reason for referral to other health care facilities. RESULTS. More than two-thirds of patients in the acute wards were HIV-co-infected, of whom 98% had significant comorbidities and 60% had a Karnofsky performance score ≤30. Twenty-eight per cent of patients did not have a confirmed diagnosis of TB. In contrast, long-stay patients with multi-drug-resistant (MDR), pre-extensively (pre-XDR) and extensively drug-resistant (XDR) TB had a lower prevalence of HIV co-infection, but manifested high rates of comorbidity. Overall, one-fifth of patients required up-referral to higher levels of care. CONCLUSIONS. District-level hospitals such as Brooklyn Chest Hospital that offer specialist TB services share the increasing burden of complex, sick, largely HIV-co-infected TB patients with their secondary and tertiary level counterparts. To support these hospitals effectively, outreach, skills transfer through training, and improved radiology resources are required to optimise patient care.

Optimizing Tuberculosis Diagnosis in Human Immunodeficiency Virus–Infected Inpatients Meeting the Criteria of Seriously Ill in the World Health Organization Algorithm

Background The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill human immunodeficiency virus (HIV)-infected patients lacks a firm evidence base. We aimed to develop a clinical prediction rule for the diagnosis of tuberculosis and to determine the diagnostic utility of the Xpert MTB/RIF assay in seriously ill HIV-infected patients. Methods We conducted a prospective study among HIV-infected inpatients with any cough duration and WHO-defined danger signs. Culture-positive tuberculosis from any site was the reference standard. A priori selected variables were assessed for univariate associations with tuberculosis. The most predictive variables were assessed in a multivariate logistic regression model and used to establish a clinical prediction rule for diagnosing tuberculosis. Results We enrolled 484 participants. The median age was 36 years, 65.5% were female, the median CD4 count was 89 cells/µL, and 35.3% were on antiretroviral therapy. Tuberculosis was diagnosed in 52.7% of participants. The c-statistic of our clinical prediction rule (variables: cough ≥14 days, unable to walk unaided, temperature >39°C, chest radiograph assessment, hemoglobin, and white cell count) was 0.811 (95% confidence interval, .802-.819). The classic tuberculosis symptoms (fever, night sweats, weight loss) added no discriminatory value in diagnosing tuberculosis. Xpert MTB/RIF assay sensitivity was 86.3% and specificity was 96.1%. Conclusions Our clinical prediction rule had good diagnostic utility for tuberculosis among seriously ill HIV-infected inpatients. Xpert MTB/RIF assay, incorporated into the updated 2016 WHO algorithm, had high sensitivity and specificity in this population. Our findings could facilitate improved diagnosis of tuberculosis among seriously ill HIV-infected inpatients in resource-constrained settings.

Hepatitis E virus infection: An underdiagnosed infection in transplant patients in Southern Africa?

• Hepatitis E virus infection (HEV) is the most common cause of acute viral hepatitis worldwide.

The role of the Infectious Diseases unit at Groote Schuur Hospital in addressing South Africa’s greatest burden of disease

BACKGROUND The greatest burden of disease in South Africa (SA) comes from infectious diseases (ID), with human immunodeficiency virus (HIV) and tuberculosis (TB) dominating the health landscape. However, other infections including community-acquired and imported infections and the rise in hospital-acquired infections pose a considerable threat to public health. METHODS AND OBJECTIVES We used a prospective cross-sectional study to examine the profile of patients referred to the Infectious Diseases Unit at Groote Schuur Hospital (GSH) between 2008 and 2011. RESULTS A total of 2 142 patient consultations were performed, the majority at the request of secondary hospital level medical teams; 80% of patients were HIV-infected (with a median CD4 count of 128/mm3). Approximately half of antiretroviral-naïve, HIV-infected patients started antiretroviral therapy in hospital. TB, predominantly extrapulmonary, was the most common diagnosis. Imported infections, notably severe falciparum malaria, accounted for a large number of the 81 different diagnoses in HIV-seronegative patients. Over half of all patients had co-morbidity complicating their clinical presentation. In-hospital mortality was 5.8%, with overwhelming sepsis the cause in 40% of deaths, largely due to hospital-acquired infection, particularly in the HIV-infected cohort. CONCLUSION The overwhelming burden of ID in SA is revealed in this experience at GSH, a tertiary level referral hospital serving the Cape metropolitan area. The needs of the population warrant a reappraisal of human resource capacity and training in ID in SA.