Background 
Dengue poses a substantial economic and disease burden in Southeast Asia (SEA). Quantifying this burden is critical to set policy priorities and disease-control strategies.


Methods and Findings 
We estimated the economic and disease burden of dengue in 12 countries in SEA: Bhutan, Brunei, Cambodia, East-Timor, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Viet Nam. We obtained reported cases from multiple sources—surveillance data, World Health Organization (WHO), and published studies—and adjusted for underreporting using expansion factors from previous literature. We obtained unit costs per episode through a systematic literature review, and completed missing data using linear regressions. We excluded costs such as prevention and vector control, and long-term sequelae of dengue. Over the decade of 2001–2010, we obtained an annual average of 2.9 million (m) dengue episodes and 5,906 deaths. The annual economic burden (with 95% certainty levels) was US$950m (US$610m–US$1,384m) or about US$1.65 (US$1.06–US$2.41) per capita. The annual number of disability-adjusted life years (DALYs), based on the original 1994 definition, was 214,000 (120,000–299,000), which is equivalent to 372 (210–520) DALYs per million inhabitants.


Conclusion 
Dengue poses a substantial economic and disease burden in SEA with a DALY burden per million inhabitants in the region. This burden is higher than that of 17 other conditions, including Japanese encephalitis, upper respiratory infections, and hepatitis B.

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Economic and Disease Burden of Dengue in Southeast Asia

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.

https://err.ersjournals.com/content/errev/28/151/180100.full.pdf

Fibrosing interstitial lung diseases: knowns and unknowns.

Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.

https://ard.bmj.com/content/annrheumdis/early/2019/04/26/annrheumdis-2018-214816.full.pdf

Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study

Scleroderma refers to an autoimmune connective tissue fibrosing disease, including three different subsets: localized scleroderma, limited cutaneous systemic sclerosis, and diffuse cutaneous systemic sclerosis with divergent patterns of organ involvement, autoantibody profiles, management, and prognostic implications. Although systemic sclerosis is considered the disease prototype that causes cutaneous sclerosis, there are many other conditions that can mimic and be confused with SSc. They can be classified into immune-mediated/inflammatory, immune-mediated/inflammatory with abnormal deposit (mucinoses), genetic, drug-induced and toxic, metabolic, panniculitis/vascular, and (para)neoplastic disorders according to clinico-pathological and pathogenetic correlations. This article reviews the clinical presentation with emphasis on cutaneous disease, etiopathogenesis, diagnosis, and treatment options available for the different forms of scleroderma firstly and for scleroderma-like disorders, including scleromyxedema, scleredema, nephrogenic systemic fibrosis, eosinophilic fasciitis, chronic graft-versus-host disease, porphyria cutanea tarda, diabetic stiff-hand syndrome (diabetic cheiroartropathy), and other minor forms. This latter group of conditions, termed also scleroderma mimics, sclerodermiform diseases, or pseudosclerodermas, shares the common thread of skin thickening but presents with distinct cutaneous manifestations, skin histology, and systemic implications or disease associations, differentiating each entity from the others and from scleroderma. The lack of Raynaud's phenomenon, capillaroscopic abnormalities, or scleroderma-specific autoantibodies is also important diagnostic clues. As cutaneous involvement is the earliest, most frequent and characteristic manifestation of scleroderma and sclerodermoid disorders, dermatologists are often the first-line doctors who must be able to promptly recognize skin symptoms to provide the affected patient a correct diagnosis and appropriate management.

Cutaneous Manifestations of Scleroderma and Scleroderma-Like Disorders: a Comprehensive Review

Dengue virus belongs to the virus family Flaviviridae. Dengue hemorrhagic disease caused by dengue virus is a public health problem worldwide. The viral non structural 2B and 3 (NS2B-NS3) protease complex is crucial for virus replication and hence, it is considered to be a good anti-viral target. Leaf extracts from Carica papaya is generally prescribed for patients with dengue fever, but there are no scientific evidences for its anti-dengue activity; hence we intended to investigate the anti-viral activity of compounds present in the leaves of Carica papaya against dengue 2 virus (DENV-2). We analysed the anti-dengue activities of the extracts from Carica papaya by using bioinformatics tools. Interestingly, we find the flavonoid quercetin with highest binding energy against NS2B-NS3 protease which is evident by the formation of six hydrogen bonds with the amino acid residues at the binding site of the receptor. Our results suggest that the flavonoids from Carica papaya have significant anti-dengue activities.

Abbreviations
ADME - Absorption, distribution, metabolism and excretion, BBB - Blood brain barrier, CYP - Cytochrome P450, DENV - – Dengue virus, DHF - Dengue hemorrhagic fever, DSS - Dengue shock syndrome, GCMS - – Gas chromatography- Mass spectrometry, MOLCAD - Molecular Computer Aided Design, NS - Non structural, PDB - Protein data bank, PMF - Potential Mean Force.

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Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly.

Objectives SSc is characterized by fibrotic changes in the skin and lung, and the mainstay of treatment has been CYC. B cell involvement suggests that rituximab (RTX) may also be of therapeutic benefit. The aim of the study was to compare the efficacy and safety of RTX compared with CYC in retarding the progression of interstitial lung disease and skin manifestations of primary SSc. Methods We randomly assigned 60 patients of dcSSc, age 18-60 years with skin and lung involvement, to monthly pulses of CYC 500 mg/m2 or RTX 1000 mg × 2 doses at 0, 15 days. Primary outcomes were forced vital capacity (FVC) percent predicted at 6 months. Secondary outcomes were: absolute change in litres (FVC-l) at 6 months; modified Rodnan skin scores at 6 months, 6-min walk test, Medsgers score and new onset or worsening of existing pulmonary hypertension by echocardiographic criteria. Results The FVC [%mean (s.d.)] in the RTX group improved from 61.30 (11.28) to 67.52 (13.59), while in the CYC group it declined from 59.25 (12.96) to 58.06 (11.23) at 6 months (P = 0.003). The change of FVC was 1.51 (0.45) l to 1.65 (0.47) l in the RTX group, compared with 1.42 (0.49) to 1.42 (0.46) l in the CYC group. The mRSS changed from 21.77 (9.86) to 12.10 (10.14) in the RTX group and 23.83 (9.28) to 18.33 (7.69) in the CYC group after 6 months. Serious adverse events were more common in the CYC group. Conclusion RTX is a safe and effective alternative to CYC in the primary therapy of skin and lung manifestations of scleroderma. Trial registration Clinical Trials Registry - India, www.ctri.nic.in, CTRI/2017/07/009152.

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Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial

Objectives To assess the effect of rituximab (RTX) on the lung function parameters in SSc interstitial lung disease (SSc-ILD) patients. Methods PubMed and Embase were searched to identify studies on SSc-ILD treated with RTX, confined to a predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies on changes in forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) from baseline to 6 and 12 months of follow-up. Results A total of 20 studies (2 randomized controlled trials, 6 prospective studies, 5 retrospective studies and 7 conference abstracts) were included (n = 575). RTX improved FVC from baseline by 4.49% (95% CI 0.25, 8.73) at 6 months and by 7.03% (95% CI 4.37, 9.7) at 12 months. Similarly, RTX improved DLCO by 3.47% (95% CI 0.99, 5.96) at 6 months and 4.08% (95% CI 1.51, 6.65) at 12 months. In the two studies comparing RTX with other immunosuppressants, improvement of FVC by 6 months in the RTX group was 1.03% (95% CI 0.11, 1.94) greater than controls. At the 12 month follow-up, RTX treatment was similar to controls in terms of both FVC and DLCO. Patients treated with RTX had a lower chance of developing infections compared with controls [odds ratio 0.256 (95% CI 0.104, 0.626), I2 = 0%, P = 0.47). Conclusions Treatment with RTX in SSc-ILD was associated with a significant improvement of both FVC and DLCO during the first year of treatment. RTX use was associated with lower infectious adverse events.

Rituximab in the treatment of systemic sclerosis–related interstitial lung disease: a systematic review and meta-analysis

Background Leptospirosis has a mortality rate of 5-20%. Poor prognostic factors are older age; oliguria; elevated potassium, creatinine and/or bilirubin levels; and altered mental status. We conducted this retrospective study to analyse the predictors of mortality among Indian patients with leptospirosis. Methods Clinical, biochemical, demographic and treatment related data (time between onset of symptoms and commencement of leptospira specific antibiotics) of 101 leptospirosis patients were reviewed. Predictors identified by univariate analysis were analysed by multivariable Cox regression for survival analysis. Results Prominent clinical features were: fever (101/101, 100%), jaundice (62, 62.4%), vomiting (42, 41.6%), oliguria (35, 34.7%), cough (18, 17.8%) and dyspnoea (10, 10.0%). Common complications were acute kidney injury (22, 21.8%), cardiovascular collapse (13, 12.9%), haemorrhages (10, 10.0%), meningitis (7, 6.9%), acute respiratory distress syndrome and pancreatitis (5, 5.0% each). Seventeen patients died (16.8%). Univariate predictors of mortality were older age, delayed antibiotic therapy, higher bilirubin, aspartate aminotransferase, alkaline phosphatase, leucocyte count and aspartate/alanine aminotransferase ratio (AAR). Only AAR (HR 1.208, 95% CI 1.051-1.388) and number of days the patient was symptomatic before access to specific antibiotic therapy (HR 1.304, 95% CI 1.081-1.574) remained significant predictors after Cox regression. Conclusions Multivariate analysis showed high AAR and delayed antibiotic therapy might be associated with fatality.

Predictors of mortality in leptospirosis: an observational study from two hospitals in Kolkata, eastern India

Dengue, a mosquito-borne disease caused by a flavivirus, is recognized in over 120 countries with 3.6 billion people living in areas at risk. Neurological manifestations are infrequently reported as clinical consequences of dengue infection. Though severe dengue may be associated with meningoencephalitis, meningitis is a rare initial presentation of otherwise uncomplicated dengue fever. We report two adult patients who presented with fever, headache, and nuchal rigidity without the typical symptoms of dengue infection. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis in one and slight neutrophilic pleocytosis in the other with a normal glucose value and negative bacterial cultures. Dengue was suspected because thrombocytopenia was symptomatic in one patient and documented during the hospital course, and was confirmed by demonstration of IgM antibody in the cerebrospinal fluid samples specific for dengue in both cases. Our report demonstrates that meningitis with or without encephalitis can be the first manifestation of dengue infection. In endemic areas, dengue infection should be considered as a probable etiological agent of meningitis. Regular monitoring of platelet count can be an invaluable diagnostic screening tool. In appropriate clinical settings detection of anti-dengue IgM both in serum and in CSF may lead to correct diagnosis.

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Two cases of dengue meningitis: a rare first presentation.

Background Cardiac tamponade is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Aims/Objectives To describe incidence, risk factors and treatment of cardiac tamponade in a large cohort of Indian patients with SLE. Methods This retrospective study was conducted at the Department of Rheumatology, IPGMER, Kolkata, India from May 2014 to December 2016 on admitted patients with SLE. Lupus-related serositis was diagnosed after excluding other causes, such as infection, malignancy or heart failure. Results Of 409 patients with SLE, pericarditis was diagnosed in 25.4% (104/409) and cardiac tamponade in 5.9% (24/409). Tamponade was the presenting feature of SLE in 50% (12/24). Tamponade occurred in 77.8% (14/18) of large effusions and in 11.63% (10/86) of small-to-moderate effusions. The commonest autoantibody in serum and pericardial fluid was anti-nucleosme antibody. Large pericardial effusion (>20 mm) (Odd's ratio (OR): 93.2, 95% confidence interval (CI): 11.1-782.5, P < 0.001) predicted tamponade. In the subset of patients with small-to-moderate sized pericardial effusion, tamponade was associated with pleuritis (OR: 44.5, 95% CI: 1.6-1243, P = 0.025), anti-nucleosome antibody (OR: 42.9, 95% CI: 1.6-1176, P = 0.026) and size of pericardial effusion (OR: 1.36, 95% CI: 1.04-1.76, P = 0.025). Repeated pericardiocentesis was required in 3 patients and one needed surgical intervention. Immunosuppressives used were: prednisolone with monthly intravenous cyclophosphamide (in 33.33%) and intravenous methylprednisolone with monthly cyclophosphamide (in 50%). Conclusions Pleuritis, anti-nucleosome antibody and size of pericardial effusion predicted development of tamponade. High dose immunosuppression (methylprednisolone and IV cyclophosphamide) alleviated need for surgery in majority.

Rudra Prosad Goswami

Papers

Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial

Rituximab in the treatment of systemic sclerosis–related interstitial lung disease: a systematic review and meta-analysis

Predictors of mortality in leptospirosis: an observational study from two hospitals in Kolkata, eastern India

Two cases of dengue meningitis: a rare first presentation.

Cardiac tamponade in systemic lupus erythematosus.