Preetam Arthur

Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study

BACKGROUND Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. METHODS In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100,000 per μL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (≤7500 and >7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01376167. FINDINGS Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and 54·5% [38-71], p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% [21-59], p=0·0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration. INTERPRETATION Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3. FUNDING GlaxoSmithKline, Medicines for Malaria Venture.

Performance of BinaxNOW G6PD Deficiency Point-of-Care Diagnostic in P. vivax-Infected Subjects

Accurate diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is required to avoid the risk of acute hemolysis associated with 8-aminoquinoline treatment. The performance of the BinaxNOW G6PD test compared with the quantitative spectrophotometric analysis of G6PD activity was assessed in 356 Plasmodium vivax-infected subjects in Brazil, Peru, Thailand, and India. In the quantitative assay, the median G6PD activity was 8.81 U/g hemoglobin (range = 0.05–20.19), with 11 (3%) subjects identified as deficient. Sensitivity of the BinaxNOW G6PD to detect deficient subjects was 54.5% (6 of 11), and specificity was 100% (345 of 345). Room temperatures inadvertently falling outside the range required to perform the rapid test (18–25°C) together with subtlety of color change and insufficient training could partially explain the low sensitivity found. Ensuring safe use of 8-aminoquinolines depends on additional development of simple, highly sensitive G6PD deficiency diagnostic tests suitable for routine use in malaria-endemic areas.

Role of Gender in the Associations of Microalbuminuria with Inflammatory Markers in Hypertensive Subjects: A Cross-Sectional Study

Background: Though the association between microalbuminuria (MA) and inflammatory markers has been studied, the possible gender differences in these associations have not yet been analyzed. Our study aims to analyze the role of gender in the associations of MA and inflammatory markers. Methods: 1,060 hypertensive patients were assessed for MA (albumin-creatinine ratio), plasma levels of HsCRP (high-sensitivity C-reactive protein), IL-18, and sCD40L (soluble CD40 ligand). Patients with diabetes mellitus, metabolic syndrome and overt nephropathy were excluded. Results: Mean age was 46 ± 9.6 years, with 560 males and 500 females. The prevalence of MA was 35.6% (n = 378). MA was associated with HsCRP (OR: 2.13, CI: 1.155–3.168, p = 0.001) and sCD40L (OR: 2.35, CI: 1.014–3.912, p = 0.013) in the premenopausal females, whereas in males (OR: 1.83, CI: 1.037–3.920, p = 0.023) and postmenopausal females (OR: 2.31, CI: 1.688–3.274, p = 0.031) MA was associated only with HsCRP and not with sCD40L or IL-18. Conclusions: Association between MA and HsCRP is consistent in all hypertensive patients. However, MA is associated with sCD40L only in premenopausal females and not in males and postmenopausal females.

Hypertensive retinal changes, a screening tool to predict microalbuminuria in hypertensive patients: a cross-sectional study

BACKGROUND Studies have shown that hypertensive retinal changes (HRC) have a moderate accuracy in predicting microalbuminuria (MA) in elderly hypertensive patients (age >65 years). This study is an effort to identify a similar relationship in hypertensive patients aged <65 years. METHODS Eight hundred and seventy consecutive hypertensive patients (males, 460; females, 410) aged 18-65 years were assessed for their demographic characteristics and other laboratory variables. Patients with diabetes mellitus, metabolic syndrome and overt nephropathy were excluded. Optic fundi were assessed for HRC after pupillary dilatation, which were photographed. MA (albumin-creatinine ratio) was measured as an average of two non-consecutive overnight spot urine samples. RESULTS Mean age was 45 +/- 13.4 years. Prevalence of MA and HRC was 36.7 and 38%, respectively. MA showed a strong association with HRC (P < 0.0001). Logistic regression identified the association between MA, duration of hypertension (HTN) (P = 0.016), smoking (P = 0.012) and elevated high-sensitivity C-reactive protein (HsCRP) (P = 0.032). HRC were associated with duration of HTN (P = 0.021) and smoking (P < 0.0001). Tests of accuracy for HRC as a predictor of MA showed sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio of a positive test and likelihood ratio of a negative test of 78%, 86%, 76%, 87%, 5.2 and 0.26, respectively. Area under the receiver operating characteristic curve was 81%. Similarly, the individual grades of HRC had a moderate predictive accuracy. Higher grades had higher predictive accuracy. Inter- and intra-observer correlation in interpreting HRC was acceptable. CONCLUSIONS HRC of any grade have moderate accuracy in predicting MA and hence can be used as a cost-effective screening tool to predict MA especially in a resource-poor setting.

False positive immunoassay for acetyl choline receptor antibody (AChR Ab) in patients exposed to polyvalent antisnake venom

Acute flaccid paralysis is a neuromuscular emergency characterized by rapidly worsening weakness that evolves quickly to cause diaphragmatic failure. The challenge for the treating physician is to stabilize the patient, generate the differential diagnosis and determine the management; all in quick time. Neurotoxic snake bites have inadequate signs of inflammation and are easily missed. Myasthenic crisis, on the other hand, could be the first sign of myasthenia gravis in up to 20% of patients. Both present with acute respiratory failure and inadequate history. Two of our patients presented with similar clinical picture, and received polyvalent anti-snake venom obtained from hyperimmunised horses (Equus caballus). Both tested positive for anti-acetyl choline receptor antibody. After recovery, both patients narrated a history suggestive of neurotoxic envenomation. We later discovered that patients, who are exposed to polyvalent anti-snake venom (Equus caballus) prior to radioimmunoassay, demonstrate high titers of Anti-AChR Ab in their serum erroneously.

Hypoxia as an independent predictor of adverse outcomes in pulmonary embolism

Background The purpose of this study was to investigate the correlation between the computed tomography pulmonary artery obstruction index and parameters of functional lung impairment in acute pulmonary embolism, and establish the value of these parameters in prognosticating right ventricular dysfunction and 30-day mortality. Methods This study included 322 consecutive patients (mean age 45.6 ± 13.2 years, 46.9% male) with acute pulmonary embolism, free of other cardiopulmonary disease, who underwent computed tomography pulmonary angiography. Correlations of arterial CO2, O2, and alveolar-arterial oxygen gradient with the computed tomography pulmonary artery obstruction index, measured using the Qanadli score, were analyzed. Logistic regression was used to identify independent predictors of right ventricular dysfunction and 30-day mortality. Results Of the 322 patients, 196 (60.9%) had right ventricular dysfunction, and 58 (18.0%) died within 30 days. The pulmonary artery obstruction index had a significant correlation with partial pressures of arterial O2 (r = −0.887, p < 0.001) and CO2 (r = −0.618, p = 0.019) and alveolar-arterial oxygen gradient (r = +0.874, p < 0.001). Arterial O2 pressure had a good predictive accuracy and discriminative power for both right ventricular dysfunction (sensitivity 80.6%, specificity 85.1%, area under the curve 0.91) and 30-day mortality (sensitivity 77.8%, specificity 82.0%, area under the curve 0.89). Conclusions In patients with acute pulmonary embolism, free of other cardiopulmonary disease, parameters of functional impairment have a strong correlation with computed tomography pulmonary artery obstruction index. Hypoxia is an independent predictor of both right ventricular dysfunction and 30-day mortality in these patients.

Melioidosis presenting as septicaemia and facial nerve palsy.

A 43-year-old farmer presented with acute onset pneumonia, septicaemia and peripheral facial nerve palsy (left side). Burkholderia pseudomallei was isolated from the blood culture of the patient. The patient was successfully treated with intravenous meropenem and oral cotrimoxazole for 2 weeks followed by maintenance therapy with cotrimoxazole. The case is reported to increase awareness among the clinicians and microbiologists regarding melioidosis.

Allergic bronchopulmonary aspergillosis mimicking lung cancer in a nonasthmatic male patient

Presentation of Aspergillus infections of the lung is varied. Allergic bronchopulmonary aspergillosis (ABPA) is one such presentation in which there is hypersensitivity reaction to Aspergillus antigens. It occurs commonly in asthmatics and patients with cystic fibrosis. We report a case of ABPA in a 55-year-old male initially evaluated for left lung cancer who had never been diagnosed with asthma.

Tuberculous pseudoaneurysm of the ascending aorta.

Increase in the incidence of drug resistance and association with HIV has led to a resurgence of tuberculosis. However, tubercular arteritis continues to remain a rare entity with a prelidection for the thoracic aorta. We report a tubercular ascending aortic pseudoaneurysm in a patient already on treatment for disseminated tuberculosis who underwent successful surgical repair and also review literature pertaining to this entity.