Anaemia in patients with HIV-associated TB: relative contributions of anaemia of chronic disease and iron deficiency.

BACKGROUND: Anaemia commonly complicates both human immunodeficiency virus (HIV) infection and tuberculosis (TB), contributing substantially to morbidity and mortality. The mechanisms underlying anaemia and corresponding treatments in co-infected patients are poorly defined. OBJECTIVE: To determine the relative contributions of anaemia of chronic disease (ACD) and iron deficiency to anaemia in patients with HIV-associated TB. DESIGN: Consecutively recruited hospitalised (n = 102) and matched ambulatory patients (n = 51) with microbiologically confirmed HIV-associated TB in Cape Town, South Africa, were included. Haemoglobin levels, iron status markers, hepcidin and pro-inflammatory cytokines in blood were measured. We determined the prevalence of ACD and iron-deficiency anaemia (IDA) using seven different published definitions of IDA. RESULTS: More than 80% of enrolled HIV-associated TB patients were anaemic, and anaemia was more severe among in-patients. Over 95% of anaemic HIV-associated TB patients had ACD, whereas the proportion with IDA using a range of seven different definitions was low overall (median <3%, range 0-32.6) in both patient groups. The proportion with IDA and hepcidin concentration â©¿ 20.0 ng/ml (predictive of responsiveness to oral iron supplementation) was also very low (median <3%, range 0-15.1). CONCLUSIONS: ACD was the predominant cause underlying anaemia in HIV-associated TB patients, and IDA was very uncommon in this setting. The majority of anaemic HIV-associated TB patients were unlikely to benefit from oral iron supplementation.

What is the role for Xpert® MTB/RIF in high-resource settings? Experience from a central London hospital.

The role of Xpert(®) MTB/RIF for tuberculosis (TB) diagnosis remains to be clearly delineated in high-resource settings. At a London hospital, we evaluated a policy of selective assay use, with testing restricted to defined sub-groups of patients. Management was directly influenced in 30% of patients studied, including 'ruling-in' a TB diagnosis (leading to initiation of treatment for TB or for potential multidrug-resistant TB); negative assay results also helped support decisions for cessation of empirical anti-tuberculosis treatment or the safe initiation of other treatments such as immunosuppressant drugs. The benefits and pitfalls of this assay's use within high-resource settings are discussed.

Impact of human immunodeficiency virus and CD4 count on tuberculosis diagnosis: analysis of city-wide data from Cape Town, South Africa.

BACKGROUND: The impact of human immunodeficiency virus (HIV) infection and CD4 count on the diagnosis of tuberculosis (TB) at population level is incompletely defined. OBJECTIVE: To determine how HIV infection and CD4 count affect disease site, sputum smear status and overall rate of laboratory confirmation (sputum smear microscopy or culture) of TB cases under routine programme conditions. DESIGN: Retrospective analysis of the 2009 electronic TB register for Cape Town, South Africa. RESULTS: Of 29,478 TB cases notified in 2009, HIV status was known for 25,744 (87.3%) cases, of whom 13,237 (51.4%) were HIV-positive. Of these, 61.2% had CD4 cell counts of <200 cells/µl and 82.7% had counts of <350 cells/µl. Laboratory confirmation of TB (by smear or culture) was obtained less frequently in HIV-infected than non-HIV-infected adult cases (53.9% vs. 74.3%, P< 0.001). HIV infection was associated with a higher proportion of sputum smear-negative and extra-pulmonary TB and lower grades of sputum smear positivity even among those with CD4 counts of ≥ 500 cells/µl. However, the relationship between the proportion of smear-positive cases and CD4 count was non-linear. CONCLUSION: Much TB is not laboratory-confirmed in this setting despite good laboratory services. HIV-associated TB is more difficult to diagnose even at high CD4 cell counts of >500 cells/µl, suggesting early impact after HIV seroconversion.

Diagnostic and prognostic value of serum C-reactive protein for screening for HIV-associated tuberculosis.

BACKGROUND: Rapid means of ruling in or ruling out tuberculosis (TB) would permit more efficient management of patients starting antiretroviral treatment (ART). OBJECTIVE: To assess the diagnostic and prognostic utility of C-reactive protein (CRP) among patients being screened for TB before ART in a South African ART clinic. DESIGN: Patients were microbiologically screened for TB regardless of symptoms; serum CRP was measured, and mortality at 3 months was assessed. RESULTS: Among 496 patients (median CD4 count 171 cells/l), culture-positive TB was diagnosed in 81 (16.3%). CRP concentrations were much higher among TB cases (median 57.8 mg/l, IQR 20.0202.7) than in those without TB (6.4 mg/l, IQR 2.121.8, P < 0.001). Very low (<1.5 mg/l) CRP concentrations excluded TB (100% negative predictive value), whereas very high concentrations (>400 mg/l) were strongly predictive of TB (100% positive predictive value). However, these thresholds encompassed only 14.3% and 2.0%, respectively, of all patients screened and identified only 12.3% of TB cases. CRP concentrations ≥50 mg/l were associated with poor prognostic characteristics, higher mycobacterial load, disseminated disease and greater mortality risk. CONCLUSION: CRP concentrations identified groups of patients with very high or very low TB risk, but only in an unacceptably small minority of patients screened. However, in those with confirmed TB, CRP concentrations had useful prognostic value.

Diagnostic yield of tuberculosis using sputum induction in HIV-positive patients before antiretroviral therapy.

Adults (n = 602) enrolling in a South African antiretroviral treatment clinic underwent culture-based screening for tuberculosis (TB), regardless of symptoms. For those unable to spontaneously expectorate a 'spot' sample (n = 124), sputum induction with nebulised hypertonic saline was used to obtain a first sample and also to rapidly obtain a second sample from all patients. Collection of both samples typically took 10-15 min. The prevalence of culture-positive TB was 15.6% (95%CI 12.8-18.8). Spontaneously expectorated spot samples yielded 79.8% of all culture-positive TB diagnoses. The incremental yield from those needing an induced first sample was 5.3% and the yield from induced second samples was 14.9%.

Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it?

The human immunodeficiency virus (HIV) associated tuberculosis (TB) epidemic remains an enormous challenge to TB control in countries with a high prevalence of HIV. In their 1999 article entitled 'Will DOTS do it?', De Cock and Chaisson questioned whether the World Health Organization's DOTS Strategy could control this epidemic. Data over the past 10 years have clearly shown that DOTS is insufficient as a single TB control intervention in such settings because it does not address the fundamental epidemiological interactions between TB and HIV. Immunodeficiency is a principal driver of this epidemic, and the solution must therefore include immune recovery using antiretroviral therapy (ART). Thus, in the era of global ART scale-up, we now ask the question, 'Will ART do it?' ART reduces the risk of TB by 67% (95%CI 61-73), halves TB recurrence rates, reduces mortality risk by 64-95% in cohorts and prolongs survival in patients with HIV-associated drug-resistant TB. However, the cumulative lifetime risk of TB in HIV-infected individuals is a function of time spent at various CD4-defined levels of risk, both before and during ART. Current initiation of ART at low CD4 cell counts (by which time much HIV-associated TB has already occurred) and low effective coverage greatly undermine the potential impact of ART at a population level. Thus, while ART has proven a critical intervention for case management of HIV-associated TB, much of its preventive potential for TB control is currently being squandered. Much earlier ART initiation with high coverage is required if ART is to substantially influence the incidence of TB.

Potential utility of empirical tuberculosis treatment for HIV-infected patients with advanced immunodeficiency in high TB-HIV burden settings.

The human immunodeficiency virus (HIV) and HIV-associated tuberculosis (TB-HIV) epidemics remain uncontrolled in many resource-limited regions, especially in sub-Saharan Africa. The scale of these epidemics requires the consideration of innovative bold interventions and 'out-of-the-box' thinking. To this end, a symposium entitled 'Controversies in HIV' was held at the 40th Union World Conference on Lung Health in Cancun, Mexico, in December 2009. The first topic debated, entitled 'Annual HIV testing and immediate start of antiretroviral therapy for all HIV-infected persons', received much attention at international conferences and in the literature in 2009. The second topic forms the subject of this article. The rationale for the use of empirical TB treatment is premised on the hypothesis that in settings worst affected by the TB-HIV epidemic, a subset of HIV-infected patients have such a high risk of undiagnosed TB and of associated mortality that their prognosis may be improved by immediate initiation of empirical TB treatment used in conjunction with antiretroviral therapy. In addition to morbidity and mortality reduction, additional benefits may include prevention of nosocomial TB transmission and TB preventive effect. Potential adverse consequences, however, may include failure to consider other non-TB diagnoses, drug co-toxicity, compromised treatment adherence, and logistical and resource challenges. There may also be general reluctance among national TB programmes to endorse such a strategy. Following fruitful debate, the conclusion that this strategy should be carefully evaluated in randomised controlled trials was strongly supported. This paper provides an in-depth consideration of this proposed intervention.

Tuberculosis research update.

Tuberculosis (TB) remains a major challenge to global public health in the 21st century. In 2007, there were an estimated 9.27 million new cases and 1.3 million deaths among HIV-negative patients with TB. The HIV-associated TB epidemic, drug-resistant disease, the need for better diagnostic assays and the limited efficacy of Bacille Calmette-Guerin vaccination are four important obstacles to further progress in global TB control. In this brief review, we provide a focused update on these four key areas of TB research.

Changing prevalence of tuberculosis infection with increasing age in high-burden townships in South Africa.

SETTING: Crowded townships of Cape Town, South Africa, where human immunodeficiency virus (HIV) prevalence and tuberculosis (TB) notification rates are among the highest in the world. OBJECTIVES: To determine age-specific prevalence rates of latent tuberculosis infection (LTBI) among HIV-negative individuals, and the annual risk and force of infection during childhood and adolescence. DESIGN: A cross-sectional survey using a standardised tuberculin skin test (TST) in HIV-negative individuals aged 5-40 years. A TST diameter of > or =10 mm was defined as indicative of LTBI. RESULTS: Among 1061 individuals, only 4.7% had low-grade TST responses of 1-9 mm. However, the proportions of individuals with TST > or =10 mm increased from 28.0% in the 5-10 year age stratum to 88.0% in the 31-35 year age stratum. The mean annual risk of infection was 3.9% up to 5 years of age. The estimated force of infection (the rate of acquisition of LTBI among the residual pool of non-infected individuals) increased throughout childhood to a maximum of 7.9% per year at age 15 years. CONCLUSIONS: Extremely high rates of infection in childhood and adolescence result in very high LTBI prevalence rates in young adults who are most at risk of acquiring HIV infection. This may be an important factor fuelling the high rates of HIV-associated TB in southern Africa.

Chest radiograph reading and recording system: evaluation for tuberculosis screening in patients with advanced HIV.

SETTING: An antiretroviral treatment (ART) service in Gugulethu township, Cape Town, South Africa. OBJECTIVE: To assess the inter-observer agreement when using the chest radiographic reading and reporting system (CRRS) to detect radiographic abnormalities in patients with advanced human immunodeficiency virus (HIV) associated immunodeficiency being actively screened for tuberculosis (TB). Second, to assess the associated performance characteristics of radiology as a routine screening test for detection of culture-confirmed pulmonary TB. DESIGN: Radiographs from a study in which patients were actively screened for TB just before starting ART were independently reported by two CRRS-certified readers blinded to clinical status. RESULTS: Good kappa statistic agreements between observers were found when reporting any radiological abnormality consistent with TB among all patients (n = 203, kappa = 0.63, 95%CI 0.52-0.73) and among those with culture-confirmed TB (n = 53, kappa = 0.61, 95%CI 0.40-0.83). However, in comparison with sputum culture, the sensitivity (0.68, 95%CI 0.54-0.79) and specificity (0.53, 95%CI 0.45-0.61) of radiology in this patient group were low. CONCLUSION: This study provides evidence of the good inter-observer agreement using the CRRS standardised reporting methodology when used among patients with advanced HIV-associated immunodeficiency and a high prevalence of culture-proven pulmonary TB. The utility of radiology as a screening test for TB in this patient group, however, remains limited.

Providing HIV care for co-infected tuberculosis patients: a perspective from sub-Saharan Africa.

Human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) and tuberculosis (TB) are overlapping epidemics that cause an immense burden of disease in sub-Saharan Africa. This region is home to the majority of the world's co-infected patents, who have higher TB case fatality and recurrence rates than patients with TB alone. A World Health Organization interim policy has been developed to reduce the joint burden of TB-HIV disease, an important component of which is provision of HIV care to co-infected patients. This review focuses on HIV testing of TB patients and, for those who are HIV-positive, the administration of adjunctive cotrimoxazole preventive treatment (CPT) and antiretroviral treatment (ART). HIV testing has moved from a voluntary, client-initiated intervention to one that is provider-initiated and a routine part of the diagnostic work-up. The efficacy and safety of CPT in HIV-infected patients is now well established, and this is an essential part of the package of HIV care. ART scale-up in Africa can substantially improve outcomes in co-infected patients. However, the clinical and programmatic challenges of combining ART with anti-tuberculosis treatment need to be resolved to realise the full potential of this benefit. These include the optimal time to start ART, how best to combine rifampicin-containing regimens with first-line and second-line ART regimens, management of immune reconstitution disease, the role of isoniazid preventive treatment with ART after TB treatment completion, and where and how to provide combined treatment to best suit the patient. Clinical and operational studies in the next few years should help to resolve some of these issues.

Immune reconstitution disease associated with parasitic infections following antiretroviral treatment.

HIV-associated immune reconstitution disease (IRD) is the clinical presentation or deterioration of opportunistic infections that results from enhancement of pathogen-specific immune responses among patients responding to antiretroviral treatment (ART). The vast majority of reported cases of IRD have been associated with mycobacterial, chronic viral and invasive fungal infections; such cases result from dysregulated augmentation of cell-mediated type 1 cytokine-secreting host immune responses. However, the spectrum of infections now recognized as associated with IRD is expanding and includes a number of parasitic infections, which may be mediated by different immunopathological mechanisms. These include leishmaniasis (visceral, cutaneous, mucosal and post kala azar dermal leishmaniasis), schistosomiasis and strongyloidiasis. Since the major burden of HIV lies in resource-limited countries where access to ART is now rapidly expanding, increased awareness and knowledge of these phenomena is important. Here we review the clinical spectrum and pathogenesis of IRD associated with parasitic infections.

New world mucosal and cutaneous leishmaniasis: an emerging health problem among British travellers.

BACKGROUND: Mucosal leishmaniasis (ML) is an important complication of new world cutaneous leishmaniasis (CL) caused by species of the Leishmania Viannia subgenus. Previous reports of ML among travellers to Latin America are few. AIMS: To determine the annual number of cases of CL due to L. Viannia species diagnosed at this institution and to correlate this with changing patterns of travel. Secondly, to document the clinical presentation, diagnosis, treatment and outcome of ML at this institution. DESIGN: Retrospective observational study. METHODS: Data were collected from a clinical database, laboratory records, patient case notes and an international passenger survey. RESULTS: Between 1995 and 2003, the annual number of cases of CL (total 79) steadily increased from 4 per year to 18 per year; the estimated number of travellers from the UK to Latin America increased 3.5-fold. Six cases of ML were diagnosed among British travellers in 1995 (1), 1997 (1) and 2002 (4). These infections were acquired in Bolivia (3), Colombia (2) and Belize (1). Nasopharyngeal symptoms developed 0-15 months after returning to the UK. Four patients had concurrent CL at diagnosis. Diagnosis of ML was delayed up to 6 months from the onset of symptoms. Mucosal biopsies from all 6 patients were PCR-positive for L. (Viannia) DNA; microscopy and culture were less sensitive. ML relapsed in one patient following treatment. DISCUSSION: Increasing travel to Latin America from the UK was associated with an increasing number of diagnoses of L. Viannia CL. ML is likely to emerge as a more frequently imported infection among such travellers. Familiarity with these diseases is important for prompt diagnosis and optimal management.

AIDS in Africa: the impact of coinfections on the pathogenesis of HIV-1 infection.

The intimate relationship between the HIV-1 life-cycle and the activation state of cells supporting viral replication results in a dynamic interaction between coinfections and HIV-1 replication in dually infected people. The immunologic impact of recurrent coinfections has the potential to increase viral replication, viral genotypic heterogeneity and CD4 T lymphocyte loss, leading to accelerated decline in immune function, reduced survival and increased HIV-1 transmission risk. These effects may play a particularly significant role in the HIV-1 epidemic in sub-Saharan Africa. The mechanisms underlying these effects on virus-host dynamics are reviewed and data describing the impact of tuberculosis, malaria, schistosomiasis and genital ulceration on HIV-1 infection are presented.

Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person

Two months after starting highly active antiretroviral treatment (HAART), an individual with human immunodeficiency virus type 1 (HIV-1) infection and profound CD4+ T lymphocytopenia developed several erythematous plaques on his face, which were due to borderline tuberculoid leprosy with reversal reaction. The temporal association between the development of these lesions and changes in blood CD4+ lymphocyte count and plasma HIV-1 load observed during HAART strongly suggests that the presentation of leprosy resulted from immune reconstitution.