Search

Patients and methods A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate ( AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. Results The median age at the beginning of the study was 10 years ( IQR 7-12). The median clotting factor concentrate ( CFC) usage was 662 IU kg−1 year−1 ( IQ range: 280-1437). The median AJBR was 10 ( IQ range: 5-17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses ( P < 0.001); The median change in WFH clinical score and Pettersson radiological score over the 5 years was 0.4/year for each, while the FISH deteriorated at a rate of 0.2/year with poor correlation of these changes with CFC dose. WFH and FISH scores were significantly worse in those with an AJBR of >3 per year ( P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year ( P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. Conclusion Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia. [ABSTRACT FROM AUTHOR]

AIM: Hypoglycemia in fasting subjects with diabetes during Ramadan is a problem that demands attention. We aimed to assess the efficacy and cost-effectiveness of pioglitazone on subjects fasting during the Ramadan period and to determine its role in improving the glycemic control and reducing hypoglycemic episodes when used as an adjunctive form of therapy for subjects with type 2 diabetes mellitus. METHODOLOGY: This multicenter, double-blind randomized controlled trial included 86 fasting Muslim subjects with type 2 diabetes mellitus. The study was initiated 74 days prior to Ramadan to optimize glycemic control. The subjects were randomized to 30 mg of pioglitazone once daily and placebo in addition to the existing oral hypoglycemic agents (OHAs) and the doses of other OHAs were titrated according to their glycemic status at each visit. Primary outcomes included were glycemic control, as assessed by serum fructosamine, and number of hypoglycemic episodes per week during Ramadan. Secondary outcome evaluated the cost-effectiveness in using pioglitazone as an adjuvant form of therapy to conventional OHAs. RESULTS: Pioglitazone was tolerated well by subjects in this study. Glycemic control was better during early Ramadan (Fructosamine: 320.80 versus 360.94 µM/l, P=0.02), mid-Ramadan (fructosamine: 315.92 versus 374.79 µM/l, P=0.003), and 2 weeks post-Ramadan, (which reflects the glycemic control in the last week of Ramadan) (320.45 versus 375.12 µM/l, P=0.01) in patients in the pioglitazone arm versus those on placebo. There was no significant difference in the number of hypoglycemic events between the two groups (P=0.21). The common adverse effects in the pioglitazone arm were a mean weight gain of 3.02 kg (P=0.001) and ankle edema in 16 subjects (P=0.0002). Direct cost per month per subject in the pioglitazone group was INR 780.62 (US $17.36) vs INR 1232.50 (US $27.41) in the placebo group (P=0.02). CONCLUSION: Pioglitazone is safe and efficacious in lowering blood glucose in fasting subjects during Ramadan in combination with other OHAs. There is no reduction in the number of hypoglycemic events when compared with conventional therapy without pioglitazone. There is a significant cost benefit when pioglitazone is added to other OHAs in this study. [ABSTRACT FROM AUTHOR]

Background & objectives: Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin's lymphomas (NHLs), with universally poor outcome. This study was undertaken to provide data on demographics and outcomes of patients with PTCL who underwent treatment in a single tertiary care centre in southern India. Methods: Retrospective study was done on all patients (age ≥18 yr) diagnosed with PTCL from January 2007 to December 2012. The diagnosis of PTCL was made according to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Results: A total of 244 adult patients were diagnosed with PTCL (non-cutaneous). The most common subtype was PTCL-not otherwise specified (35.7%), followed by anaplastic large cell lymphoma (ALCL), ALK negative (21.3%), natural killer/T cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), ALCL, ALK positive, hepatosplenic T cell lymphoma (HSTCL) and adult T cell leukaemia/lymphoma followed in frequency with 13.1, 11.5, 8.6, 8.2 and 1.6 per cent cases, respectively. The three-year Kaplan-Meier overall survival (OS) and event-free survival (EFS) for the patients who received chemotherapy (n=122) were 33.8±5.0 and 29.3±4.7 per cent, respectively. Various prognostic indices developed for T cell lymphomas were found to be useful. Interpretation & conclusions: Except for ALCL, ALK positive, all other PTCLs showed poor long-term outcome with CHOP-based chemotherapy. Novel therapies are needed to improve the outcome. [ABSTRACT FROM AUTHOR]

The use of thiotepa-treosulfan-fludarabine conditioning regimen and peripheral blood stem cell grafts is associated with improved outcomes of hematopoietic stem cell transplantation (HCT) in patients with high-risk thalassemia major. However, there remains a need to identify predictors of poor outcomes in this cohort to further optimize outcomes. The Endothelial Activation and Stress Index (EASIX) is a biomarker shown to predict survival in various settings, including graft-versus-host disease, veno-occlusive disease, and nonrelapse mortality following allogeneic HCT. In this retrospective analysis, we evaluated the role of EASIX-PreTx (measured before conditioning therapy) as a biomarker in predicting day +100 transplantation-related mortality (TRM+100) in 281 patients with thalassemia major who underwent HCT with a uniform conditioning regimen using thiotepa-treosulfan-fludarabine at our center between January 2012 and December 2019. The median patient age was 9 years (range, 1 to 25 years), and 109 (38.8%) were females. According to the Pesaro classification (with Vellore modification), 3 patients (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. Stem cell donors were matched sibling (n = 218; 77.6%), matched related nonsibling (n = 23; 8.2%), or matched unrelated (n = 40; 14.2%). Five patients (1.8%) received a bone marrow graft, and the others received a peripheral blood stem cell graft. Thirty-eight patients (13.5%) had TRM+100. EASIX-PreTx was available for 184 patients (65.5%). The median EASIX-PreTx was significantly higher in patients with TRM+100 compared with those without TRM+100 (1.09 versus .75; P = .008). An EASIX-PreTx cutoff of .85 had 70.4% sensitivity and 62% specificity for predicting TRM+100. The TRM+100 for patients with EASIX-PreTx >.85 was significantly higher than those with EASIX <.85 (24.4% versus 7.5%; P = .003). In a uniform subgroup of class III patients undergoing allogeneic HCT (n = 156), EASIX-PreTx was an independent predictor of TRM+100., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Severe myelosuppression in patients with acute lymphoblastic leukemia (ALL) undergoing 6-MP-based maintenance therapy is attributed to TPMT gene polymorphisms, which is rare in Asian populations. This study aims to evaluate the role of selected polymorphisms in NUDT15, ITPA , and MRP4 genes in addition to TPMT in predicting 6-MP intolerance during ALL maintenance therapy., Patients and Methods: We screened for the presence of NUDT15*3 (c.415 C>T, rs116855232); MRP4 c.2269 C>T (rs3765534), ITPA c.94 C>A (rs1127354) polymorphisms in addition to TPMT *2 (rs1800462), *3A (*3B and *3C; rs1800460 and rs1142345) in ALL patients with documented severe neutropenia (cohort-1; n=42). These polymorphisms were then screened in a prospective cohort of ALL patients (cohort-2; n=133) and compared with 6-MP dose reduction, early/late myelotoxicity., Results: Nineteen (45%) patients in cohort-1 and 18 (14%) in cohort-2 had NUDT15 c.415 C>T variant while 4 (3%) patients in cohort-2 had TPMT*3C variant. Five (12%) in cohort-1 and 30 (24%) in cohort-2 had ITPA c.94 C>A variant while 9 (22%) and 15 (12%) had MRP4 c.2269 C>T variant in cohorts-1 and 2, respectively. All in cohort-1 and 36 (27%) in cohort-2 had severe myelotoxicity. Twenty-eight patients (66.6%) in cohort-1 and 40 (30%) patients in cohort-2 had significant 6-MP dose reduction. NUDT15 c.415 C>T variant explained severe myelotoxicity in 63% and 33% in cohort 1 and 2. TPMT *3C and ITPA c.94 C>A variants also explained myelotoxicity in cohort-2 (Median ANC: 376 vs 1014 mm 3 ; p=0.04 and 776 vs 1023 mm 3 ; p=0.04 respectively). NUDT15 c.415 C>T polymorphism explained significant myelotoxicity (507 vs 1298 mm 3 ; p<0.0001) in the multivariate analysis as well (β=-0.314, p<0.0001)., Conclusion: NUDT15 c.415 C>T (15*3), TPMT*3C, as well as ITPA c.94 C>A and MRP4 c.2269 C>T polymorphisms explain hematotoxicities. Preemptive genotype-based ( NUDT15*3, TPMT, ITPA c.94 C>A) 6-MP dosing could improve the outcome after maintenance therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Pai et al.)

Aim: To present a new protocol to optimise ultrasound (US) assessment of haemophilic arthropathy., Materials and Methods: Ultrasound of haemophilic arthropathy joints was performed using three different ultrasound protocols, namely, the Toronto-Vellore Comprehensive Ultrasound (TVC-US) protocol, the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), and the newly developed Universal Simplified Ultrasound (US-US) protocol. Synovial hypertrophy, haemosiderin deposition, effusion, erosion, and cartilage loss were evaluated in 20 joints. The reliability and diagnostic efficiency of these protocols was compared using magnetic resonance imaging (MRI)., Results: The correlation between the TVC-US and US-US protocols for synovial hypertrophy was excellent: kappa significance (KS) was 1, but was substantial (KS=0.65) with the HEAD-US protocol. For effusion, both the TVC-US and the HEAD-US protocols had substantial correlation with the US-US protocol (KS=0.7 and 0.6 respectively). The correlation for erosion and cartilage loss was excellent between the TVC-US and the US-US with MRI (KS=1), but poor (KS=0) with the HEAD-US protocol. The US-US protocol also had good interobserver agreement (KS=1)., Conclusion: The accuracy of the US-US protocol is comparable to the TVC-US protocol and MRI and is superior to the HEAD-US protocol in the assessment of haemophilic arthropathy., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

OBJECTIVE. The purpose of this article is to assess the reliability of interpretation of ultrasound findings according to data blinding in maturing hemophilic joints and to determine the diagnostic accuracy of ultrasound compared with MRI for assessing joint components. SUBJECTS AND METHODS. Ankles (n = 34) or knees (n = 25) of boys with hemophilia or von Willebrand disease (median age, 13 years; range, 5-17 years) were imaged by ultrasound, MRI, and radiography in two centers (Toronto, Canada, and Vellore, India). Ultrasound scans were performed by two operators (one blinded and one unblinded to MRI data) and were reviewed by four reviewers who were unblinded to corresponding MRI findings according to a proposed 0- to 14-item scale that matches 14 of 17 items of the corresponding MRI scale. MRI examinations were independently reviewed by two readers. RESULTS. When data were acquired by radiologists, ultrasound was highly reliable for assessing soft-tissue changes (intraclass correlation coefficient [ICC], 0.98 for ankles and 0.97 for knees) and substantially to highly reliable for assessing osteochondral changes (ICC, 0.61 for ankles and 0.89 for knees). Ultrasound was highly sensitive (> 92%) for assessing synovial hypertrophy and hemosiderin in both ankles and knees but had borderline sensitivity for detecting small amounts of fluid in ankles (70%) in contrast to knees (93%) and variable sensitivity for evaluating osteochondral abnormalities (sensitivity range, 86-100% for ankles and 12-100% for knees). CONCLUSION. If it is performed by experienced radiologists using a standardized protocol, ultrasound is highly reliable for assessing soft-tissue abnormalities of ankles and knees and substantially to highly reliable for assessing osteochondral changes in these joints.

Background: Scrub typhus, a bacterial zoonosis caused by Orientia tsutsugamushi, may cause multiorgan dysfunction syndrome (MODS) and is associated with significant mortality. This study was undertaken to document the clinical and laboratory manifestations and complications and to study time trends and factors associated with mortality in patients with scrub typhus infection., Methods: This retrospective study, done at a university teaching hospital, included 623 patients admitted between 2005 and 2010 with scrub typhus. The diagnosis was established by a positive IgM ELISA and/or pathognomonic eschar with PCR confirmation where feasible. The clinical and laboratory profile, course in hospital, and outcome were documented. Factors associated with mortality were analyzed using multivariate logistic regression analysis., Results: The most common presenting symptoms were fever (100%), nausea/vomiting (54%), shortness of breath (49%), headache (46%), cough (38%), and altered sensorium (26%). An eschar was present in 43.5% of patients. Common laboratory findings included elevated transaminases (87%), thrombocytopenia (79%), and leukocytosis (46%). MODS was seen in 34% of patients. The overall case-fatality rate was 9.0%. Features of acute lung injury were observed in 33.7%, and 29.5% required ventilatory support. On multivariate analysis, shock requiring vasoactive agents (relative risk (RR) 10.5, 95% confidence interval (CI) 4.2-25.7, p<0.001), central nervous system (CNS) dysfunction (RR 5.1, 95% CI 2.4-10.7, p<0.001), and renal failure (RR 3.6, 95% CI 1.7-7.5, p=0.001) were independent predictors of mortality. Over 4 years, a decreasing trend was observed in the mortality rate., Conclusions: Scrub typhus can manifest with potentially life-threatening complications such as lung injury, shock, and meningoencephalitis. MODS occurred in a third of our patients. The overall case-fatality rate was 9%, with shock, renal failure, and CNS associated with a higher mortality., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study sought to document the clinical and laboratory manifestations, genetic variability, and outcomes of scrub typhus, an often severe infection caused by Orientia tsutsugamushi, in South India., Methods: Patients admitted to a large teaching hospital with IgM ELISA-confirmed scrub typhus were evaluated. Clinical examination with a thorough search for an eschar, laboratory testing, chest X-ray, and outcome were documented and analyzed. Additionally, a 410-bp region of the 56-kDa type-specific antigen gene of O. tsutsugamushi was sequenced and compared with isolates from other regions of Asia., Results: Most of the 154 patients evaluated presented with fever and non-specific symptoms. An eschar was found in 86 (55%) patients. Mild hepatic involvement was seen in most, with other organ involvement including respiratory, cardiovascular, and renal. Multi-organ dysfunction was noted in 59 (38.3%), and the fatality rate was 7.8%. Hypotension requiring vasoactive agents was found to be an independent predictor of mortality (p<0.001). The phylogeny of 26 samples showed 17 (65%) clustering with the Kato-like group and eight (31%) with the Karp-like group., Conclusions: The presentation of scrub typhus can be variable, often non-specific, but with potentially severe multi-organ dysfunction. Prompt recognition is key to specific treatment and good outcomes. Further study of the circulating strains is essential for the development of a successful vaccine and sensitive point-of-care testing., (Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: Scrub typhus is a zoonotic illness endemic in the Asia-Pacific region. Early diagnosis and appropriate management contribute significantly to preventing adverse outcomes including mortality. Serology is widely used for diagnosing scrub typhus. Recent reports suggest that polymerase chain reaction (PCR) could be a rapid and reliable alternative. This study assessed the utility of these tests for scrub typhus diagnosis., Materials and Methods: Nested PCR to detect the 56 kDa antigen gene of O. tsutsugamushi was performed on blood clots from 87 individuals with clinically suspected scrub typhus. Weil-Felix test and scrub typhus IgM ELISA were performed on serum samples from the same patients. As a gold standard reference test was not available, latent class analysis (LCA) was used to assess the performance of the three tests., Results: The LCA analysis showed the sensitivity of Weil-Felix test, IgM ELISA and PCR to be 59%, 100% and 58% respectively. The specificity of ELISA was only 73%, whereas those of the Weil-Felix test and PCR were 94% and 100% respectively., Conclusion: Nested PCR using blood clots while specific, lacked sensitivity as compared to IgM ELISA. In resource-poor settings Weil-Felix test still remains valuable despite its moderate sensitivity.

Objectives: To derive a clinical algorithm for diagnosis of scrub typhus among patients hospitalized with febrile illness and to determine predictors of bad prognosis., Methods: Patients hospitalized with febrile illness of 5-30 days duration were evaluated for common aetiologies. Sera were tested for antibodies (IgM and IgG) to Orientia tsutsugamushi using ELISA kit., Results: Among 207 patients, 50 had elevated levels of IgM antibodies. The data of these patients were compared with that of 16 controls having febrile illnesses in whom rickettsial infection was ruled out. Transaminase elevation (>twice normal) was present in 90% and was significantly (P=0.004) more common in those with scrub typhus. If a combination of elevated transaminases, thrombocytopenia and leukocytosis is used, the specificity and positive predictive value are about 80%. Case fatality rate was 14%. Univariate analysis showed that hyperbilirubinemia (>1.5mg%) has a RR of 9 (95% CI=1.48-58.5) and elevated creatinine level (>1.4 mg%) had a RR of 43.99 (95% CI=3.65-530.5) for death. Elevated creatinine level was found to be an independent predictor of mortality (P=0.02)., Conclusion: In developing countries with limited diagnostic facilities, it is prudent to recommend empiric therapy in patients with undifferentiated febrile illness having evidence of multiple system involvement especially if there is transaminase elevation. Elevated creatinine may predict bad outcome.

Severe haemophilia (factor [F]VIII/FIX activity < 0.01 IU mL(-1)) is characterized by repeated haemarthroses resulting in severe arthropathy in adulthood. In 1958, Professor Nilsson in Sweden introduced prophylactic infusions with clotting factor concentrates at regular intervals in order to maintain clotting factor levels above 0.01 IU mL(-1) and to prevent bleeding. Since then, evidence of the long-term beneficial effects of prophylactic treatment for severe haemophilia has been increasing and it has become the recommended treatment strategy for children with severe haemophilia by both the World Health Organization and the US National Hemophilia Foundation Medical and Scientific Advisory Committee. However, the implementation of this recommendation has been hampered by issues of cost and venous access. The high costs of prophylaxis have largely prevented its use in major parts of the world. The question therefore is whether the current models of replacement of clotting factor concentrates, while certainly being effective, are also optimal. Can the data on outcome at different levels of factor replacement be used to assess their cost-effectiveness?