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.

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.

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.

Sustained plasma TNF-alpha and HIV-1 load despite resolution of other parameters of immune activation during treatment of tuberculosis in Africans.

OBJECTIVE: To determine the impact of treatment of tuberculosis on plasma HIV-1 load in African subjects and to correlate viral load with response to treatment and changes in immune activation. DESIGN: Clinical and microbiological responses, immune activation parameters and plasma HIV-1 load were determined in 20 patients with pulmonary tuberculosis and HIV-1 coinfection in Ghana, West Africa during the first 3 months of anti-tuberculosis treatment. METHODS: Plasma HIV-1 load and markers of immune activation were determined by commercially available assays. Human leukocyte antigen (HLA)-DR incorporation into the HIV-1 envelope was measured by using an immunomagnetic capture technique. RESULTS: Treatment of tuberculosis resulted in significant improvements in weight and haemoglobin, a high sputum smear conversion rate and marked reductions in mean plasma tumour necrosis factor (TNF) receptor-1, interleukin-6 and C-reactive protein. Furthermore, incorporation of host HLA-DR into the HIV-1 envelope decreased; this also suggested a reduction in immune activation of the cells supporting viral replication. However, of importance with regard to AIDS pathogenesis, neither mean plasma TNF-alpha nor HIV-1 load decreased significantly. CONCLUSIONS: The failure of HIV-1 plasma load to decline significantly during the initial months of anti-tuberculosis treatment is associated with high, sustained systemic levels of TNF-alpha. The dissociation between the sustained levels of plasma TNF-alpha and the major reductions in other, diverse immune activation parameters may represent dysregulation of cytokine production in these African patients.

The effect of treatment of schistosomiasis on blood plasma HIV-1 RNA concentration in coinfected individuals.

OBJECTIVE: To determine whether drug treatment of Schistosomiasis mansoni infection leads to a reduction in plasma HIV-1 RNA concentration in coinfected individuals. METHODS: Stool and plasma samples were obtained prospectively from a cohort of HIV-infected persons (n = 30) in Kisumu, Kenya, before and after treatment of schistosomiasis with praziquantel (mean follow-up, 5.6 months; range 1-15 months). Schistosomal circulating cathodic antigen (CCA) concentrations in plasma were determined by ELISA and fecal egg counts were determined by microscopy. HIV-1 RNA concentrations were measured in pre- and post-treatment plasma samples obtained from the patients whose stool samples remained free of schistosomal eggs for the great majority of the follow-up period. RESULTS: Comparison of pretreatment and follow-up samples revealed that mean +/- SD fecal egg burden was reduced by 96.7% (481.5+/-803.5 versus 16.1+/-24.4 eggs/g feces) and mean plasma CCA concentration decreased by 90.1% (3.22+/-3.26 versus 0.32+/-0.38 microg/ml). In contrast, mean plasma HIV-1 load increased from 3.60+/-0.90 to 3.93+/-0.95 log10 RNA copies/ml (P< 0.001). Although no correlation was found between changes in HIV-1 load and changes in schistosomal burden, there was a significant correlation between changes in plasma HIV load and the time interval between pretreatment and follow-up samples (r = 0.41; P = 0.027). CONCLUSIONS: Treatment of schistosomiasis was not associated with a reduction in plasma HIV-1 load. This study does not, however, exclude the possibility of an adverse effect of helminthic infections on HIV-1 pathogenesis.

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.

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.

Pulmonary tuberculosis: diagnostic delay in Ghanaian adults.

SETTING: Department of Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana, West Africa. OBJECTIVE: To determine the factors affecting the delay from the onset of symptoms of pulmonary tuberculosis until the initiation of treatment. DESIGN: A retrospective questionnaire survey of 100 adults with newly diagnosed smear-positive pulmonary tuberculosis. RESULTS: The median total delay in diagnosis was 4 months (mean = 7.7), and total delay exceeded 6 months in 44% of patients. Total delay was strongly associated with rural residence (P = 0.001). The median doctor delay from the first consultation until diagnosis was double the median patient delay in initial presentation (8 weeks versus 4 weeks). Doctor delay was significantly increased in females, rural patients, and among those needing hospital admission. Increased doctor delay was strongly correlated with rates of failure to perform sputum microscopy (r = 0.99), low rates of diagnosis, and was seen particularly among private practitioners and rural government institutions. CONCLUSION: Delays in the diagnosis of pulmonary tuberculosis are prolonged in Kumasi, Ghana, with a frequently lengthy doctor delay. The new National Tuberculosis Programme is decentralising the diagnosis and management of tuberculosis, with the introduction of widely available sputum microscopy and rigorous training of health personnel. This should help to reduce doctor delay and thereby improve tuberculosis control.

Resolution of the acute-phase response in West African patients receiving treatment for pulmonary tuberculosis.

SETTING: The Komfo Anokye Teaching Hospital, Kumasi, Ghana, West Africa. OBJECTIVE: To evaluate simple and commonly used parameters of the acute-phase response as correlates of successful resolution of smear-positive pulmonary tuberculosis (PTB) during drug treatment. DESIGN: Serum C-reactive protein (CRP) concentration, erythrocyte sedimentation rate (ESR), body weight, and blood haemoglobin were measured in human immunodeficiency virus (HIV) negative Ghanaian patients with PTB (n = 15) and in age- and sex-matched healthy controls (n = 15). These parameters were subsequently measured in patients after 1, 2 and 3 months of antituberculosis treatment. Serum concentrations of soluble interleukin-2-receptor-alpha (sCD25) were also measured as a comparative index of resolution of the systemic inflammatory process. RESULTS: Anti-tuberculosis treatment resulted in sputum smear conversion in all 15 patients. After one month of treatment, reductions in serum CRP concentration (>20%) and increases in haemoglobin concentration (>0.4 g/dl) occurred in the majority of patients and correlated with steep reductions in serum levels of sCD25. In contrast, weight loss and elevated ESR were slower to resolve, and were insensitive early markers of response to treatment. CONCLUSION: A fall in serum CRP and a rise in blood haemoglobin are correlates of the initial response to drug treatment of PTB. These parameters may assist in the evaluation of empiric trials of treatment in microbiologically unconfirmed cases of suspected PTB.

Case reports: acute hookworm infection: an unusual cause of profuse watery diarrhoea in returned travellers.

We describe 3 returned travellers who developed profuse watery diarrhoea associated with marked blood eosinophilia. Delayed appearance of ova in stool samples caused difficulty in establishing diagnoses of acute hookworm infection. Low activity of ivermectin against hookworm resulted in failure of empiric treatment with this agent prior to parasitological diagnosis.

New World cutaneous leishmaniasis in returned travellers: treatment failures using intravenous sodium stibogluconate.

Treatment outcome was determined among a cohort of travellers who returned to the UK between February 2000 and February 2001 with New World cutaneous leishmaniasis caused by species of the Leishmania (Viannia) subgenus. Among 18 patients who completed treatment with 20 mg/kg/d of i.v. sodium stibogluconate (NaSb) for 20 d, early relapse of disease occurred in 2 patients with regional dissemination in 1 and mucocutaneous involvement in the other. Drug susceptibility testing in vitro of the clinical isolate from 1 of these patients confirmed tolerance to high concentrations of NaSb.

Lack of induction of interleukin-2-receptor-alpha in patients with tuberculosis and human immunodeficiency virus co-infection: implications for pathogenesis.

Since expression of both interleukin-2 (IL-2) and IL-2-receptor-alpha (IL-2R-alpha) by lymphocytes is inhibited by human immunodeficiency virus (HIV) in vitro, we hypothesized that HIV-co-infection among persons with tuberculosis (TB) might impair T-lymphocyte responses to TB via this mechanism. We measured soluble IL-2R-alpha (sIL-2R-alpha), a surrogate marker of T-lymphocyte activation and proliferation, and soluble tumour necrosis factor receptor I (sTNF-RI) in sera from West African patients categorized into 4 groups: those with TB alone (TB+ HIV-, n = 55), CD4-matched groups with TB and HIV co-infection (TB+ HIV+, n = 50) or HIV infection alone (TB- HIV+, n = 35), and patients with neither disease (TB- HIV-, n = 35). The median level of sIL-2R-alpha was markedly greater in the TB+ HIV- group (1580 U/mL) compared to the TB- HIV- (670 U/mL; P < 0.001) and TB- HIV+ (880 U/mL; P < 0.01) groups. More importantly, the median concentration of sIL-2R-alpha was much lower in the TB+ HIV+ group (855 U/mL) compared to the TB+ HIV- group (1580 U/mL; P < 0.01) despite similar levels of sTNF-RI. These results suggest that T-lymphocyte activation in TB patients is impaired by HIV co-infection and, furthermore, this suppressive effect was independent of numerical depletion of CD4 lymphocytes. Impairment to IL-2-signalling might contribute to the profound impact that HIV has had on both the incidence and the clinicopathological manifestations of TB.

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.

Pulmonary tuberculosis: radiological features in west Africans coinfected with HIV.

A retrospective study was performed to document and compare the radiological appearances of newly diagnosed pulmonary tuberculosis (PTB) in groups of West African patients with (n = 86) and without (n = 106) human immunodeficiency virus (HIV) coinfection. Analysis of chest radiographs showed that the HIV-positive group had less consolidation (mean 3.1 zones vs 3.7 zones; p < 0.05), less apical involvement (64.0% vs 85.5%; p < 0.001), less bronchopulmonary spread (27.9% vs 58.5%; p < 0.001), less volume loss (53.5% vs 76.4%; p < 0.001) and less pleural thickening (46.5% vs 61.3%; p < 0.05) compared with the HIV-negative group. However, HIV-positive patients more commonly had pleural effusions (17.4% vs 6.6%; p < 0.05) and lymphadenopathy (9.3% vs 1.9%; p < 0.05). Previous studies on this subject from sub-Saharan Africa have focused either on selected patient groups likely to have more advanced immunosuppression or on smear-positive cases only, or where there has been only limited radiological documentation. This study suggests that the highly significant differences that exist may not be as frequent as previously shown. The lower frequencies of bronchopulmonary pattern of consolidation and pleural thickening in HIV-positive subjects have not previously been documented. The possible reasons for the altered radiographic appearance of PTB in HIV positive subjects are discussed.

Pulmonary tuberculosis in adults: factors associated with mortality at a Ghanaian teaching hospital.

Tuberculosis (TB) is a leading cause of global mortality. The aim of this study was to compare factors associated with poor outcome (death) and good outcome (cure) of adult patients receiving treatment for pulmonary TB (PTB) at the Komfo Anokye Teaching Hospital, Kumasi, Ghana. The case notes and chest radiographs of 80 such patients who died were retrospectively reviewed and compared to 80 patients who were cured during the same period. Patients who died were 3.4 times more likely to be HIV-positive (p < 0.001). Mortality was also associated with increased age (p < 0.001), residence in a rural area (p < 0.05) sputum smear-negative disease (p < 0.01), and more prolonged symptom duration prior to initial diagnosis (p < 0.05). Furthermore, patients who died were 2.1 times more likely to have a history of previous TB treatment (p < 0.01), 2.0 times more likely to have previously defaulted from treatment ((p < 0.05), and 2.9 times more likely to have > or = 5 chest radiographic zones affected by disease (p < 0.001). In conclusion, although mortality among patients with PTB is strongly associated with HIV infection in this community, other factors identified reflect late diagnosis, poor treatment compliance and inadequate resources for diagnosis and treatment of TB in rural areas. Improved rates of diagnosis, enhancement of treatment compliance and decentralization of TB services to the district level may therefore help to reduce mortality from TB.

Life-threatening cutaneous reactions to thiacetazone-containing antituberculosis treatment in Kumasi, Ghana.

Antituberculosis treatment containing thiacetazone is associated with a high incidence of life-threatening cutaneous drug reactions in patients infected with the human immunodeficiency virus (HIV). In order to develop a local policy concerning the use of this drug, a study was undertaken to determine the incidence of such reactions in a total of 1063 Ghanaian adult patients treated for pulmonary tuberculosis (PTB) with thiacetazone-containing regimens. The incidence was retrospectively determined in 3 different treatment groups, comparing: (A) unselected use of thiacetazone; (B) exclusion of thiacetazone from all patients with positive HIV serology; (C) selective exclusion of thiacetazone from patients with clinical criteria suggesting HIV infection plus education of health workers and patients. Of the 408 patients in group A receiving thiacetazone, 9 (2.2%) developed life-threatening cutaneous reactions and 7 of these were HIV-positive. Overall, 6.8% of HIV-positive patients compared to 0.65% of HIV-negative patients developed severe reactions (P < 0.01; relative risk = 10.5). Six of the 9 patients with reactions died. All 379 patients in group B were screened for HIV antibodies and positive cases (23%) received a regimen in which thiacetazone was substituted by ethambutol. In contrast to Group A, only one HIV-negative patient (0.26%) developed a severe cutaneous reaction (P = 0.02). Among 276 patients in group C, thiacetazone was substituted with ethambutol only in those with clinical evidence of HIV infection (8%) and staff and patients were educated about early recognition of the side-effect. With this policy, these were no admissions with severe cutaneous reactions compared to 2.2% of those in group A (P = 0.01). In conclusion, a policy of selective use of thiacetazone in the treatment of PTB based on clinical criteria combined with patient and staff education was found to be a practical and cost-effective strategy combating severe cutaneous reactions to thiacetazone.

Pulmonary tuberculosis in Kumasi, Ghana: presentation, drug resistance, molecular epidemiology and outcome of treatment.

To assist implementation of tuberculosis (TB) control measures, knowledge of the disease characteristics in a community is essential. This study in Kumasi, Ghana, correlates the clinical presentation, microbiology, molecular epidemiology and clinical outcome of thirty consecutively diagnosed patients with new smear-positive pulmonary TB. Several important factors that potentially promote disease transmission in the community were identified: patients had prolonged duration of productive cough prior to diagnosis (mean=4.1 months; SD=2.1); the disease was typically advanced at presentation and Ziehl-Neelson sputum smears indicated a high bacterial load (80% graded > AFB++); home accommodation was overcrowded with a mean of 3.3 other persons sleeping in the same room as the patients at night. IS6110 restriction fragment length polymorphism (RFLP) fingerprinting of 25 isolated (23 Mycobacterium tuberculosis and 2 Mycobacterium africanum) from epidemiologically unrelated cases identified 3 identical strains and 3 clusters containing 2, 4 and 8 isolates of > or =80% similarity, suggesting high rates of disease transmission. A high prevalence of primary resistance to isoniazid was found (6 out 26; 23%) but resistance to rifampicin, pyrazinamide, ethambutol, streptomycin and ciprofloxacin was not detected. Smear coversion at 2 months and final outcome of treatment with short courses chemotherapy were independent of isoniazid resistance, but the rate of treatment default was unacceptably high (37%). High rates of disease transmission, primary isoniazid resistance and treatment default all indicate poor TB control. The use of rifampicin-containing short-course chemotherapy in this community must be accompanied by adequate resources and infrastructure to ensure very stringent treatment supervision to improve case-holding and reduce the risk of multi-drug resistance.

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.

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.