Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

Pre-admission antibiotics for suspected cases of meningococcal disease.

BACKGROUND: Meningococcal disease can lead to death or disability within hours after onset. Pre-admission antibiotics aim to reduce the risk of serious disease and death by preventing delays in starting therapy before confirmation of the diagnosis. OBJECTIVES: To study the effectiveness and safety of pre-admission antibiotics versus no pre-admission antibiotics or placebo, and different pre-admission antibiotic regimens in decreasing mortality, clinical failure, and morbidity in people suspected of meningococcal disease. SEARCH METHODS: We searched CENTRAL (6 January 2017), MEDLINE (1966 to 6 January 2017), Embase (1980 to 6 January 2017), Web of Science (1985 to 6 January 2017), LILACS (1982 to 6 January 2017), and prospective trial registries to January 2017. We previously searched CAB Abstracts from 1985 to June 2015, but did not update this search in January 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing antibiotics versus placebo or no intervention, in people with suspected meningococcal infection, or different antibiotics administered before admission to hospital or confirmation of the diagnosis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data from the search results. We calculated the risk ratio (RR) and 95% confidence interval (CI) for dichotomous data. We included only one trial and so did not perform data synthesis. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We found no RCTs comparing pre-admission antibiotics versus no pre-admission antibiotics or placebo. We included one open-label, non-inferiority RCT with 510 participants, conducted during an epidemic in Niger, evaluating a single dose of intramuscular ceftriaxone versus a single dose of intramuscular long-acting (oily) chloramphenicol. Ceftriaxone was not inferior to chloramphenicol in reducing mortality (RR 1.21, 95% CI 0.57 to 2.56; N = 503; 308 confirmed meningococcal meningitis; 26 deaths; moderate-quality evidence), clinical failures (RR 0.83, 95% CI 0.32 to 2.15; N = 477; 18 clinical failures; moderate-quality evidence), or neurological sequelae (RR 1.29, 95% CI 0.63 to 2.62; N = 477; 29 with sequelae; low-quality evidence). No adverse effects of treatment were reported. Estimated treatment costs were similar. No data were available on disease burden due to sequelae. AUTHORS' CONCLUSIONS: We found no reliable evidence to support the use pre-admission antibiotics for suspected cases of non-severe meningococcal disease. Moderate-quality evidence from one RCT indicated that single intramuscular injections of ceftriaxone and long-acting chloramphenicol were equally effective, safe, and economical in reducing serious outcomes. The choice between these antibiotics should be based on affordability, availability, and patterns of antibiotic resistance.Further RCTs comparing different pre-admission antibiotics, accompanied by intensive supportive measures, are ethically justified in people with less severe illness, and are needed to provide reliable evidence in different clinical settings.

Nutritional supplements for people being treated for active tuberculosis.

BACKGROUND: Tuberculosis and malnutrition are linked in a complex relationship. Tuberculosis may cause undernutrition through increased metabolic demands and decreased intake, and nutritional deficiencies may worsen the disease, or delay recovery by depressing important immune functions. At present, there is no evidence-based nutritional guidance for adults and children being treated for tuberculosis. OBJECTIVES: To assess the effects of oral nutritional supplements in people being treated with antituberculous drug therapy for active tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2016), MEDLINE (from 1946 to 4 February 2016), EMBASE (from 1980 to 4 February 2016), LILACS (from 1982 to 4 February 2016), the metaRegister of Controlled Trials (mRCT), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the Indian Journal of Tuberculosis up to 4 February 2016, and checked the reference lists of all included studies. SELECTION CRITERIA: Randomized controlled trials that compared any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. The primary outcomes of interest were all-cause death, and cure at six and 12 months. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, and extracted data and assessed the risk of bias in the included trials. We presented the results as risk ratios (RR) for dichotomous variables, and mean differences (MD) for continuous variables, with 95% confidence intervals (CIs). Where appropriate, we pooled data from trials with similar interventions and outcomes. We assessed the quality of the evidence using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Thirty-five trials, including 8283 participants, met the inclusion criteria of this review. Macronutrient supplementationSix trials assessed the provision of free food, or high-energy supplements. Only two trials measured total dietary intake, and in both trials the intervention increased calorie consumption compared to controls.The available trials were too small to reliably prove or exclude clinically important benefits on mortality (RR 0.34, 95% CI 0.10 to 1.20; four trials, 567 participants, very low quality evidence), cure (RR 0.91, 95% CI 0.59 to 1.41; one trial, 102 participants, very low quality evidence), or treatment completion (data not pooled; two trials, 365 participants, very low quality evidence).Supplementation probably produces a modest increase in weight gain during treatment for active tuberculosis, although this was not seen consistently across all trials (data not pooled; five trials, 883 participants, moderate quality evidence). Two small studies provide some evidence that quality of life may also be improved but the trials were too small to have much confidence in the result (data not pooled; two trials, 134 participants, low quality evidence). Micronutrient supplementationSix trials assessed multi-micronutrient supplementation in doses up to 10 times the dietary reference intake, and 18 trials assessed single or dual micronutrient supplementation.Routine multi-micronutrient supplementation may have little or no effect on mortality in HIV-negative people with tuberculosis (RR 0.86, 95% CI 0.46 to 1.6; four trials, 1219 participants, low quality evidence), or HIV-positive people who are not taking antiretroviral therapy (RR 0.92, 95% CI 0.69 to 1.23; three trials, 1429 participants, moderate quality evidence). There is insufficient evidence to know if supplementation improves cure (no trials), treatment completion (RR 0.99, 95% CI 0.95 to 1.04; one trial, 302 participants, very low quality evidence), or the proportion of people who remain sputum positive during the first eight weeks (RR 0.92, 95% CI 0.63 to 1.35; two trials, 1020 participants, very low quality evidence). However, supplementation may have little or no effect on weight gain during treatment (data not pooled; five trials, 2940 participants, low quality evidence), and no studies have assessed the effect on quality of life.Plasma levels of vitamin A appear to increase following initiation of tuberculosis treatment regardless of supplementation. In contrast, supplementation probably does improve plasma levels of zinc, vitamin D, vitamin E, and selenium, but this has not been shown to have clinically important benefits. Of note, despite multiple studies of vitamin D supplementation in different doses, statistically significant benefits on sputum conversion have not been demonstrated. AUTHORS' CONCLUSIONS: There is currently insufficient research to know whether routinely providing free food, or energy supplements improves tuberculosis treatment outcomes, but it probably improves weight gain in some settings.Although blood levels of some vitamins may be low in people starting treatment for active tuberculosis, there is currently no reliable evidence that routinely supplementing above recommended daily amounts has clinical benefits.

Pre-admission antibiotics for suspected cases of meningococcal disease.

BACKGROUND: Meningococcal disease can lead to death or disability within hours after onset. Pre-admission antibiotics aim to reduce the risk of serious disease and death by preventing delays in starting therapy before confirmation of the diagnosis. OBJECTIVES: To study the effectiveness and safety of pre-admission antibiotics versus no pre-admission antibiotics or placebo, and different pre-admission antibiotic regimens in decreasing mortality, clinical failure and morbidity in people suspected of meningococcal disease. SEARCH METHODS: We updated searches of CENTRAL (2013, Issue 4), MEDLINE (1966 to April week 4, 2013), EMBASE (1980 to May 2013), Web of Science (1985 to May 2013), CAB Abstracts (1985 to May 2013), LILACS (1982 to May 2013) and prospective trials registries to May 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing antibiotics versus placebo or no intervention, in people with suspected meningococcal infection, or different antibiotics administered before admission to hospital or confirmation of the diagnosis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data from the search results. We calculated the risk ratio (RR) and 95% confidence interval (CI) for dichotomous data. We included only one trial so data synthesis was not performed. We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We found no RCTs that compared pre-admission antibiotics versus no pre-admission antibiotics or placebo. One open-label, non-inferiority RCT, conducted during an epidemic in Niger, evaluated a single dose of intramuscular ceftriaxone versus a single dose of intramuscular long-acting (oily) chloramphenicol. Ceftriaxone was not inferior to chloramphenicol in reducing mortality (RR 1.2, 95% CI 0.6 to 2.6; N = 503; 308 confirmed meningococcal meningitis; 26 deaths; moderate-quality evidence), clinical failures (RR 0.8, 95% CI 0.3 to 2.2; N = 477, 18 clinical failures; moderate-quality evidence) or neurological sequelae (RR 1.3, 95% CI 0.6 to 2.6; N = 477; 29 with sequelae; low-quality evidence). No adverse effects of treatment were reported. Estimated treatment costs were similar. No data were available on disease burden due to sequelae. AUTHORS' CONCLUSIONS: We found no reliable evidence to support or refute the use of pre-admission antibiotics for suspected cases of non-severe meningococcal disease. Evidence of moderate quality from one RCT indicated that single intramuscular injections of ceftriaxone and long-acting chloramphenicol were equally effective, safe and economical in reducing serious outcomes. The choice between these antibiotics would be based on affordability, availability and patterns of antibiotic resistance.Further RCTs comparing different pre-admission antibiotics, accompanied by intensive supportive measures, are ethically justifiable in participants with severe illness, and are needed to provide reliable evidence in different clinical settings.

Nutritional supplements for people being treated for active tuberculosis.

BACKGROUND: Tuberculosis and malnutrition are linked in a complex relationship. The infection may cause undernutrition through increased metabolic demands and decreased intake, and nutritional deficiencies may worsen the disease, or delay recovery by depressing important immune functions. At present, there are no evidence-based nutritional guidance for adults and children being treated for tuberculosis. OBJECTIVES: To assess the effects of oral nutritional supplements (food, protein/energy supplements or micronutrients) on tuberculosis treatment outcomes and recovery in people on antituberculous drug therapy for active tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, mRCT, and the Indian Journal of Tuberculosis to July 2011, and checked the reference lists of all included studies. SELECTION CRITERIA: Randomized controlled trials comparing any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data, and assessed the risk of bias. Results are presented as risk ratios (RR) for dichotomous variables, and mean differences (MD) for continuous variables, with 95% confidence intervals (CI). Where appropriate, data from trials with similar interventions and outcomes have been pooled. The quality of evidence was assessed using the GRADE methods. MAIN RESULTS: Twenty-three trials, with 6842 participants, were included. Macronutrient supplementation Five trials assessed the provision of free food, or high energy supplements, although none were shown to provide a total daily kilocalorie intake above the current daily recommended intake for the non-infected population.The available trials were too small to reliably prove or exclude clinically important benefits on mortality, cure, or treatment completion. One small trial from India did find a statistically significant benefit on treatment completion, and clearance of the bacteria from the sputum, but these findings have not been confirmed in larger trials elsewhere (VERY LOW quality evidence).The provision of free food or high-energy nutritional products probably does produce a modest increase in weight gain during treatment for active tuberculosis (MODERATE quality evidence). Two small studies provide some evidence that physical function and quality of life may also be improved but the trials were too small to have much confidence in the result (LOW quality evidence). These effects were not seen in the one trial which included only human immunodeficiency virus (HIV)-positive patients.Micronutrient supplementation Five trials assessed multi-micronutrient supplementation in doses up to ten times the dietary reference intake, and 12 trials assessed single or dual micronutrient supplementation.There is insufficient evidence to judge whether multi-micronutrients have a beneficial effect on mortality in HIV- negative patients with tuberculosis (VERY LOW quality evidence), but the available studies show that multi-micronutrients probably have little or no effect on mortality in HIV-positive patients with tuberculosis (MODERATE quality evidence). No studies have assessed the effects of multi-micronutrients on cure, or treatment completion.Multi-micronutrient supplements may have little or no effect on the proportion of tuberculosis patients remaining sputum positive during the first eight weeks (LOW quality evidence), and probably have no effect on weight gain during treatment (MODERATE quality evidence). No studies have assessed quality of life.Plasma levels of vitamin A appear to increase following initiation of tuberculosis treatment regardless of supplementation. In contrast, plasma levels of zinc, vitamin D and E, and selenium may be improved by supplementation during the early stages of tuberculosis treatment, but a consistent benefit on tuberculosis treatment outcomes or nutritional recovery has not been demonstrated. AUTHORS' CONCLUSIONS: There is insufficient research to know whether routinely providing free food or energy supplements results in better tuberculosis treatment outcomes, or improved quality of life. Further trials, particularly from food insecure settings, should have adequate sample sizes to identify, or exclude, clinically important benefits.Although blood levels of some vitamins may be low in patients starting treatment for active tuberculosis, there is currently no reliable evidence that routinely supplementing at or above recommended daily amounts has clinical benefits.

Cerebral Venous Thrombosis, Seasonal Trends, and Climatic Influence: A Region-SpecificStudy.

BACKGROUND AND PURPOSE: Studies looking at seasonal variation on cerebral venous thrombosis (CVT) are few with conflicting conclusions. In this region-specific study, we looked for climatic influence and seasonal trends on the incidence of CVT. METHODS: Imaging proven adult CVT cases treated over a period of 18 years from a specific geographical location with similar seasons and climatic conditions were studied. Metrological parameters prepared using 30 years of data was used. Quantum geographical information system (QGIS software) and SPSS v 22 were used for patient plotting and analysis. RESULTS: Total of 970 cases were studied. The incidence was significantly higher in summer 411 (42.3%) compared with autumn 317 (32.7%) and winter 242 (25.05); P = 0.038. This trend was consistent across all the 18 years in time series analysis. Mean age was 33.5 years (range 18-88 years). A significant majority 673 (69.4%) were below 40 years of age; P = 0.012. Females constituted 394 (40.6%) of cases. Postpartum CVT cases constituted 237 (30%). Interaction analysis showed younger age (<40 years) were more vulnerable for CVT in summer; P = 0.009. There was no seasonal influence on postpartum CVT. Apart for a weak positive correlation between rain fall (r = 0.18, P < 0.01); humidity and cloud cover was not influencing the incidence. CONCLUSIONS: Higher ambient temperatures were consistently associated with higher incidence of CVT. This is the largest region-specific study on CVT in the world. These results may be applicable to other regions with similar climatic conditions.

Generalised dystonia: clinical diagnosis is possible.

Neurodegeneration with brain iron accumulation type 1 (previously known as Hallervorden-Spatz syndrome) is a rare neurodegenerative disorder characterised by its typical clinical and radiological features. We present a case of an adolescent girl with rapidly progressive dystonia in whom the diagnosis of the above disorder was made prior to radiological investigation. This report has been made to highlight the diagnostic relevance of a good history and clinical examination. This is particularly important in a developing country where diagnostic radiological investigations are expensive.

Nutritional supplements for people being treated for active tuberculosis.

BACKGROUND: Tuberculosis is a serious infection affecting mainly the lungs. It may contribute to nutritional deficiencies which in turn may delay recovery by depressing immune functions. Nutritional supplements might therefore promote recovery in people being treated for tuberculosis. OBJECTIVES: To assess the provision of oral nutritional supplements to promote the recovery of people being treated with antituberculous drug therapy for active tuberculosis. SEARCH STRATEGY: We searched the Cochrane Infectious Disease Group Specialized Register (June 2008), CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE (June 2008), EMBASE (June 2008), LILACS (June 2008), mRCT (June 2008), the Indian Journal of Tuberculosis (1983 to June 2008), and checked the reference lists of all included studies. SELECTION CRITERIA: Randomized controlled trials comparing any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data, and assessed risk of bias. We calculated risk ratios (RR) for dichotomous variables and mean differences (MD) for continuous variables, with 95% confidence intervals (CI). We pooled data from trials with similar interventions and outcomes. MAIN RESULTS: Twelve trials (3393 participants) were included. Five trials had adequate allocation concealment. Interventions included a high energy supplement, high cholesterol diet, vitamin D, vitamin A, zinc, arginine, multiple micronutrient supplements, combined multiple micronutrient supplements and zinc, combined vitamin A and zinc, and combined vitamin A and selenium. The following supplements were associated with increased body weight at follow up: high energy supplements (MD 1.73 kg, 95% CI 0.81 to 2.65; 34 participants, 1 trial); multiple micronutrients plus additional zinc (MD 2.37 kg, 95% CI 2.21 to 2.53; 192 participants, 1 trial); and vitamin A plus zinc (MD 3.10 kg, 95% CI 0.74 to 5.46; 80 participants, 1 trial). There was no evidence that any supplement affected the number of deaths or number of participants with sputum test positive results at the end of treatment. AUTHORS' CONCLUSIONS: There is limited evidence that high energy supplements and some combinations of zinc with other micronutrients may help people with tuberculosis to gain weight. There is not enough evidence to assess the effect of other combinations of nutrients. A number of relevant trials are in progress, and, where appropriate, the results will be incorporated into future updates of this review.