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BACKGROUND: Improvements in the early diagnosis of dengue are urgently needed, especially in resource-limited settings where the distinction between dengue and other febrile illnesses is crucial for patient management.METHODS: In this prospective, observational study (IDAMS), we included patients aged 5 years and older with undifferentiated fever at presentation from 26 outpatient facilities in eight countries (Bangladesh, Brazil, Cambodia, El Salvador, Indonesia, Malaysia, Venezuela, and Viet Nam). We used multivariable logistic regression to investigate the association between clinical symptoms and laboratory tests with dengue versus other febrile illnesses between day 2 and day 5 after onset of fever (ie, illness days). We built a set of candidate regression models including clinical and laboratory variables to reflect the need of a comprehensive versus parsimonious approach. We assessed performance of these models via standard measures of diagnostic values.FINDINGS: Between Oct 18, 2011, and Aug 4, 2016, we recruited 7428 patients, of whom 2694 (36%) were diagnosed with laboratory-confirmed dengue and 2495 (34%) with (non-dengue) other febrile illnesses and met inclusion criteria, and were included in the analysis. 2703 (52%) of 5189 included patients were younger than 15 years, 2486 (48%) were aged 15 years or older, 2179 (42%) were female and 3010 (58%) were male. Platelet count, white blood cell count, and the change in these variables from the previous day of illness had a strong association with dengue. Cough and rhinitis had strong associations with other febrile illnesses, whereas bleeding, anorexia, and skin flush were generally associated with dengue. Model performance increased between day 2 and 5 of illness. The comprehensive model (18 clinical and laboratory predictors) had sensitivities of 0·80 to 0·87 and specificities of 0·80 to 0·91, whereas the parsimonious model (eight clinical and laboratory predictors) had sensitivities of 0·80 to 0·88 and specificities of 0·81 to 0·89. A model that includes laboratory markers that are easy to measure (eg, platelet count or white blood cell count) outperformed the models based on clinical variables only.INTERPRETATION: Our results confirm the important role of platelet and white blood cell counts in diagnosing dengue, and the importance of serial measurements over subsequent days. We successfully quantified the performance of clinical and laboratory markers covering the early period of dengue. Resulting algorithms performed better than published schemes for distinction of dengue from other febrile illnesses, and take into account the dynamic changes over time. Our results provide crucial information needed for the update of guidelines, including the Integrated Management of Childhood Illness handbook.FUNDING: EU's Seventh Framework Programme.TRANSLATIONS: For the Bangla, Bahasa Indonesia, Portuguese, Khmer, Spanish and Vietnamese translations of the abstract see Supplementary Materials section.

Additional file 1. Factors associated with knowledge, attitude and practice of HCPs.

BACKGROUND: Diagnosis of tuberculosis should be improved in children infected with HIV to reduce mortality. We developed prediction scores to guide antituberculosis treatment decision in HIV-infected children with suspected tuberculosis. METHODS: HIV-infected children with suspected tuberculosis enrolled in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS 12229 PAANTHER 01 Study), underwent clinical assessment, chest radiography, Quantiferon Gold In-Tube (QFT), abdominal ultrasonography, and sample collection for microbiology, including Xpert MTB/RIF (Xpert). We developed 4 tuberculosis diagnostic models using logistic regression: (1) all predictors included, (2) QFT excluded, (3) ultrasonography excluded, and (4) QFT and ultrasonography excluded. We internally validated the models using resampling. We built a score on the basis of the model with the best area under the receiver operating characteristic curve and parsimony. RESULTS: A total of 438 children were enrolled in the study; 251 (57.3%) had tuberculosis, including 55 (12.6%) with culture- or Xpert-confirmed tuberculosis. The final 4 models included Xpert, fever lasting >2 weeks, unremitting cough, hemoptysis and weight loss in the past 4 weeks, contact with a patient with smear-positive tuberculosis, tachycardia, miliary tuberculosis, alveolar opacities, and lymph nodes on the chest radiograph, together with abdominal lymph nodes on the ultrasound and QFT results. The areas under the receiver operating characteristic curves were 0.866, 0.861, 0.850, and 0.846, for models 1, 2, 3, and 4, respectively. The score developed on model 2 had a sensitivity of 88.6% and a specificity of 61.2% for a tuberculosis diagnosis. CONCLUSIONS: Our score had a good diagnostic performance. Used in an algorithm, it should enable prompt treatment decision in children with suspected tuberculosis and a high mortality risk, thus contributing to significant public health benefits.

International audience; BACKGROUND:Tuberculosis is a major cause of morbidity and mortality in HIV-infected children, but is difficult to diagnose. We studied mortality and its determinants in antiretroviral treatment (ART)-naive HIV-infected children presenting with suspected tuberculosis.METHODS:In this observational cohort study, HIV-infected children aged 13 years or younger with suspected tuberculosis were followed up for 6 months as part of the ANRS 12229 PAANTHER 01 cohort in eight hospitals in four countries (Burkina Faso, Cambodia, Cameroon, and Vietnam). Children started ART and antituberculosis treatment at the clinician's discretion and were retrospectively classified into one of three groups by tuberculosis documentation: confirmed by culture or Xpert MTB/RIF, unconfirmed, and unlikely. We assessed mortality and associated factors using Kaplan-Meier methods and Cox proportional hazard models. The ANRS 12229 PAANTHER 01 study is registered at ClinicalTrials.gov, number NCT01331811.FINDINGS:266 (61%) of 438 children enrolled in the study between April 27, 2011, and May 31, 2014, were ART-naive and included in the analysis (40 had confirmed tuberculosis, 119 unconfirmed tuberculosis, and 107 unlikely tuberculosis). 112·5 person-years of follow-up were available. 154 children (58%) started antituberculosis treatment and 212 (80%) started ART. 50 children (19%) died. Mortality by 6 months was higher in children with confirmed tuberculosis (14 deaths; 2 month survival probability 65·0% [95% CI 50·2-79·8]) compared with unconfirmed tuberculosis (19 deaths; 83·5% [76·8-90·3]) and unlikely tuberculosis (17 deaths; 83·5% [76·3-90·7]; log-rank p=0·0141) and was lower in children with confirmed or unconfirmed tuberculosis who started antituberculosis treatment (p

To the Editor: Guidelines for the diagnosis and management of Mycobacterium bovis BCG disease in HIV-infected children are lacking. BCG strains are intrinsically resistant to pyrazinamide and in some cases have low-level resistance to isoniazid (6). However, data on acquired drug resistance in M. bovis BCG are limited. We describe a case of BCG disease caused by a rifampin-resistant strain of M. bovis BCG in an HIV-infected infant in Vietnam. The daughter of a known HIV-infected woman, who did not fully adhere to antiretroviral therapy (ART) during pregnancy, received the M. bovis intradermal BCG (Pasteur strain) vaccine at birth. HIV infection was diagnosed in the infant by PCR when she was 8 weeks of age. At 9 months of age, she was admitted to the Pediatric Infectious Diseases Department of the Pham Ngoc Thach Hospital (Ho Chi Minh City, Vietnam) because of a voluminous ipsilateral axillary mass at the site of the vaccination, fever, weight loss, and hepatosplenomegaly. The percentage of CD4+ T cells was 27% (1,620 cells/mm3). Regional BCG disease was clinically diagnosed without microbiological investigation, and a broad antimycobacterial therapy targeting M. tuberculosis complex species was started with 5 mg/kg isoniazid, 10 mg/kg rifampin, and 25 mg/kg pyrazinamide. After 6 weeks of antimycobacterial therapy, ART was initiated with lamivudine, stavudine, and abacavir. After 6 months of antimycobacterial treatment, the infant was hospitalized again for recurrent inflammation and fistulization of the axillary lymph nodes associated with fever. Fluid from the axillary mass was collected by fine-needle aspiration for bacteriologic investigations. Direct microscopic examination showed acid-fast bacilli, and the mycobacterial infection was confirmed by culture. By using conventional biochemical methods, the mycobacterial isolate was assigned to the M. bovis species. Pyrazinamide was discontinued, and antimycobacterial therapy was continued for 4 supplementary months with rifampin (15 mg/kg) and isoniazid (10 mg/kg). After 2 months, drug susceptibility testing results confirmed pyrazinamide intrinsic resistance and isoniazid and ethambutol susceptibility and showed rifampin resistance. The late inflammatory reaction after introduction of ART was evocative of immune reconstitution inflammatory syndrome. Nevertheless, drug resistance may have contributed. Despite the rifampin resistance, the patient showed clinical improvement, and the rifampin/isoniazid treatment was continued for 2 more months. The child’s BCG disease was cured on completion of 10 months of antituberculous treatment. Retrospective molecular investigations using the GenoType MTBC Kit (Hain Lifescience, Nehren, Germany) enabled identification of the isolate stored at −80°C as M. bovis BCG strain. A mutation in the rpoB gene (codon 531, Ser531Tyr) associated with rifampin resistance was detected by using the GenoType MTBDRplus Kit (Hain Lifescience) and partial sequencing of the rpoB gene (5,7). No mutation in the katG and inhA genes, frequently associated with isoniazid resistance, was detected. To our knowledge, this case is the second report of rifampin-resistant M. bovis BCG disease in HIV-infected children. The first report involved a child in South Africa who was vaccinated with the Danish BCG strain (4); this strain shows low-level resistance to isoniazid and therefore has a high risk of evolving to multidrug resistance in instances of suboptimal isoniazid levels. The M. bovis BCG Pasteur strain (American Type Culture Collection 35734) used for vaccination in Vietnam is isoniazid and rifampin susceptible and pyrazinamide resistant (9). Despite appropriate antimycobacterial treatment, the relatively low doses of isoniazid (5 mg/kg), poor adherence, or inadequate absorption of drugs because of HIV-related gastrointestinal disease may have resulted in subtherapeutic in vivo drug concentrations and thus in selection of a drug-resistant M. bovis BCG strain. This case should alert clinicians of the possible emergence of rifampin resistant M. bovis BCG strains. Because disseminated BCG disease in HIV-infected children presents a high risk for illness and/or death, these patients should receive optimal tuberculosis treatment (2) based on 4-drug (rifampin, isoniazid, ethambutol, and pyrazinamide) regimen doses for at least 9 months until M. tuberculosis is ruled out (3). Untreated local BCG immune reconstitution inflammatory syndrome may not necessarily progress to dissemination; therefore, treatment would not appear necessary (8). Some studies suggest that the survival of HIV-infected children with BCG disease could be attributed to early initiation of ART in combination with other treatments (1,3). In the South Africa case, the child died, and the authors suggested that this outcome was related to the severity of the clinical features, the severe HIV-related immune suppression, and the absence of ART (4). In the case in Vietnam, despite the emergence of drug resistance, the early initiation of ART in a child with a localized disease, the persistent efficacy of isoniazid, and the spontaneous fistulization of the abscess probably contributed to the good outcome for the infant. In conclusion, this case highlights the challenges in management of BCG disease in children. It also emphasizes the possible risk for emergence of acquired drug resistance in M. bovis BCG strains, complicating the medical management of such cases.