Scrub Typhus Meningitis in South India — A Retrospective Study

Background

Scrub typhus is prevalent in India although definite statistics are not available. There has been only one study on scrub typhus meningitis 20 years ago. Most reports of meningitis/meningoencephalitis in scrub typhus are case reports

Methods

A retrospective study done in Pondicherry to extract cases of scrub typhus admitted to hospital between February 2011 and January 2012. Diagnosis was by a combination of any one of the following in a patient with an acute febrile illness- a positive scrub IgM ELISA, Weil-Felix test, and an eschar. Lumbar puncture was performed in patients with headache, nuchal rigidity, altered sensorium or cranial nerve deficits.

Results

Sixty five cases of scrub typhus were found, and 17 (17/65) had meningitis. There were 33 males and 32 females. Thirteen had an eschar. Median cerebrospinal fluid (CSF) cell count, lymphocyte percentage, CSF protein, CSF glucose/blood glucose, CSF ADA were 54 cells/µL, 98%, 88 mg/dL, 0.622 and 3.5 U/mL respectively. Computed tomography was normal in patients with altered sensorium and cranial nerve deficits. Patients with meningitis had lesser respiratory symptoms and signs and higher urea levels. All patients had received doxycycline except one who additionally received chloramphenicol.

Conclusion

Meningitis in scrub typhus is mild with quick and complete recovery. Clinical features and CSF findings can mimic tuberculous meningitis, except for ADA levels. In the Indian context where both scrub typhus and tuberculosis are endemic, ADA and scrub IgM may be helpful in identifying patients with scrub meningitis and in avoiding prolonged empirical antituberculous therapy in cases of lymphocytic meningitis.     

Cytokine Network in Scrub Typhus: High Levels of Interleukin-8 Are Associated with Disease Severity and Mortality

Background

Scrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10–20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome.

Methodology/Principal Findings

We examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = 31) and infectious disease controls (n = 31), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., interleukin-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1β) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with interleukin-8.

Conclusions/Significance

Our findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome.     

Time Series Analyses of Hand,Foot and Mouth Disease Integrating Weather Variables

Background

The past decade witnessed an increment in the incidence of hand foot mouth disease (HFMD) in the Pacific Asian region; specifically, in Guangzhou China. This emphasized the requirement of an early warning system designed to allow the medical community to better prepare for outbreaks and thus minimize the number of fatalities.

Methods

Samples from 1,556 inpatients (hospitalized) and 11,004 outpatients (non-admitted) diagnosed with HFMD were collected in this study from January 2009 to October 2013. Seasonal Autoregressive Integrated Moving Average (SARIMA) model was applied to establish high predictive model for inpatients and outpatient as well as three viral serotypes (EV71, Pan-EV and CA16). To integrate climate variables in the data analyses, data from eight climate variables were simultaneously obtained during this period. Significant climate variable identified by correlation analyses was executed to improve time series modeling as external repressors.

Results

Among inpatients with HFMD, 248 (15.9%) were affected by EV71, 137 (8.8%) were affected by Pan-EV+, and 436 (28.0%) were affected by CA16. Optimal Univariate SARIMA model was identified: (2,0,3)(1,0,0)₅₂ for inpatients, (0,1,0)(0,0,2)₅₂ for outpatients as well as three serotypes (EV71, (1,0,1)(0,0,1)₅₂; CA16, (1,0,1)(0,0,0)₅₂; Pan-EV, (1,0,1)(0,0,0)₅₂). Using climate as our independent variable, precipitation (PP) was first identified to be associated with inpatients (r = 0.211, P = 0.001), CA16-serotype (r = 0.171, P = 0.007) and outpatients (r = 0.214, P = 0.01) in partial correlation analyses, and was then shown a significant lag in cross-autocorrelation analyses. However, inclusion of PP [lag -3 week] as external repressor showed a moderate impact on the predictive performance of the SARIMA model described here-in.

Conclusion

Climate patterns and HFMD incidences have been shown to be strongly correlated. The SARIMA model developed here can be a helpful tool in developing an early warning system for HFMD.     

Contrasting spatial distribution and risk factors for past infection with scrub typhus and murine typhus in Vientiane City, Lao PDR

Background

The aetiological diagnostic of fevers in Laos remains difficult due to limited laboratory diagnostic facilities. However, it has recently become apparent that both scrub and murine typhus are common causes of previous undiagnosed fever. Epidemiological data suggests that scrub typhus would be more common in rural areas and murine typhus in urban areas, but there is very little recent information on factors involved in scrub and murine typhus transmission, especially where they are sympatric - as is the case in Vientiane, the capital of the Lao PDR.

Methodology and Principal Findings

We therefore determined the frequency of IgG seropositivity against scrub typhus (Orientia tsutsugamushi) and murine typhus (Rickettsia typhi), as indices of prior exposure to these pathogens, in randomly selected adults in urban and peri-urban Vientiane City (n = 2,002, ≥35 years). Anti-scrub and murine typhus IgG were detected by ELISA assays using filter paper elutes. We validated the accuracy of ELISA of these elutes against ELISA using serum samples. The overall prevalence of scrub and murine typhus IgG antibodies was 20.3% and 20.6%, respectively. Scrub typhus seropositivity was significantly higher among adults living in the periphery (28.4%) than in the central zone (13.1%) of Vientiane. In contrast, seroprevalence of murine typhus IgG antibodies was significantly higher in the central zone (30.8%) as compared to the periphery (14.4%). In multivariate analysis, adults with a longer residence in Vientiane were at significant greater risk of past infection with murine typhus and at lower risk for scrub typhus. Those with no education, living on low incomes, living on plots of land with poor sanitary conditions, living in large households, and farmers were at higher risk of scrub typhus and those living in neighborhoods with high building density and close to markets were at greater risk for murine typhus and at lower risk of scrub typhus past infection.

Conclusions

This study underscores the intense circulation of both scrub and murine typhus in Vientiane city and underlines difference in spatial distribution and risk factors involved in the transmission of these diseases.     

Scrub Typhus Is an Under-recognized Cause of Acute Febrile Illness with Acute Kidney Injury in India

Background

Infection-related acute kidney injury (AKI) is an important preventable cause of morbidity and mortality in the tropical region. The prevalence and outcome of kidney involvement, especially AKI, in scrub typhus is not known. We investigated all patients with undiagnosed fever and multisystem involvement for scrub typhus and present the pattern of renal involvement seen.

Methods

From September 2011 to November 2012, blood samples of all the patients with unexplained acute febrile illness and/or varying organ involvement were evaluated for evidence of scrub typhus. A confirmed case of scrub typhus was defined as one with detectable Orientia tsutsugamushi deoxyribonucleic acid (DNA) in patient''s blood sample by nested polymerase chain reaction (PCR) targeting the gene encoding 56-kDa antigen and without any alternative etiological diagnosis. Renal involvement was defined by demonstration of abnormal urinalysis and/or reduced glomerular filtration rate. AKI was defined as per Kidney Disease: Improving Global Outcomes (KDIGO) definition.

Results

Out of 201 patients tested during this period, 49 were positive by nested PCR for scrub typhus. Mean age of study population was 34.1±14.4 (range 11–65) years. Majority were males and a seasonal trend was evident with most cases following the rainy season. Overall, renal abnormalities were seen in 82% patients, 53% of patients had AKI (stage 1, 2 and 3 in 10%, 8% and 35%, respectively). The urinalysis was abnormal in 61%, with dipstick positive albuminuria (55%) and microscopic hematuria (16%) being most common. Acute respiratory distress syndrome (ARDS) and shock were seen in 57% and 16% of patients, respectively. Hyperbilirubinemia was associated with AKI (p = 0.013). A total of 8 patients (including three with dialysis dependent AKI) expired whereas rest all made uneventful recovery. Jaundice, oliguria, ARDS and AKI were associated with mortality. However, after multivariate analysis, only oliguric AKI remained a significant predictor of mortality (p = 0.002).

Conclusions

Scrub typhus was diagnosed in 24% of patients presenting with unexplained febrile illness according to a strict case definition not previously used in this region. Renal abnormalities were seen in almost 82% of all patients with evidence of AKI in 53%. Our finding is contrary to current perception that scrub typhus rarely causes renal dysfunction. We suggest that all patients with unexplained febrile illness be investigated for scrub typhus and AKI looked for in scrub typhus patients.     

Urbanization of Scrub Typhus Disease in South Korea

Background

Scrub typhus is an endemic disease in Asia. It has been a rural disease, but indigenous urban cases have been observed in Seoul, South Korea. Urban scrub typhus may have a significant impact because of the large population.

Methods

Indigenous urban scrub typhus was epidemiologically identified in Seoul, the largest metropolitan city in South Korea, using national notifiable disease data from 2010 to 2013. For detailed analysis of clinical features, patients from one hospital that reported the majority of cases were selected and compared to a historic control group. Chigger mites were prospectively collected in the city using a direct chigger mite-collecting trap, and identified using both phenotypic and 18S rDNA sequencing analyses. Their infection with Orientia tsutsugamushi was confirmed by sequencing the 56-kDa antigen gene.

Results

Eighty-eight cases of urban scrub typhus were determined in Seoul. The possible sites of infection were mountainous areas (56.8%), city parks (20.5%), the vicinity of one’s own residence (17.0%), and riversides (5.7%). Eighty-seven chigger mites were collected in Gwanak mountain, one of the suspected infection sites in southern Seoul, and seventy-six (87.4%) of them were identified as Helenicula miyagawai and eight (9.2%) as Leptotrombidium scutellare. Pooled DNA extracted from H. miyagawai mites yielded O. tsutsugamushi Boryong strain. Twenty-six patients from one hospital showed low APACHE II score (3.4 ± 2.7), low complication rate (3.8%), and no hypokalemia.

Conclusions

We identified the presence of indigenous urban scrub typhus in Seoul, and a subgroup of them had mild clinical features. The chigger mite H. miyagawai infected with O. tsutsugamushi within the city was found. In endemic area, urban scrub typhus needs to be considered as one of the differential febrile diseases and a target for prevention.     

Human Spotted Fever Group Rickettsioses Are Underappreciated in Southern Taiwan,Particularly for the Species Closely-Related to Rickettsia felis

Background

Despite increased identification of spotted fever group rickettsioses (SFGR) in animals and arthropods, human SFGR are poorly characterized in Taiwan.

Methods

Patients with suspected Q fever, scrub typhus, murine typhus, leptospirosis, and dengue fever from April 2004 to December 2009 were retrospectively investigated for SFGR antibodies (Abs). Sera were screened for Rickettsia rickettsii Abs by indirect immunofluorescence antibody assay (IFA), and those with positive results were further examined for Abs against R. rickettsii, R. typhi, R. felis, R. conorii, and R. japonica using micro-immunofluorescence (MIF) tests. Polymerase chain reaction (PCR) for detection of SFGR DNA was applied in those indicated acute infections. Case geographic distribution was made by the geographic information system software.

Results

A total of 413 cases with paired serum, including 90 cases of Q fever, 47 cases of scrub typhus, 12 cases of murine typhus, 6 cases of leptospirosis, 3 cases of dengue fever, and 255 cases of unknown febrile diseases were investigated. Using IFA tests, a total of 49 cases with 47 (11.4%) and 4 (1.0%) cases had sera potentially positive for R. rickettsii IgG and IgM, respectively. In the 49 cases screened from IFA, MIF tests revealed that there were 5 cases of acute infections (3 possible R. felis and 2 undetermined SFGR) and 13 cases of past infections (3 possible R. felis and 10 undetermined SFGR). None of the 5 cases of acute infection had detectable SFGR DNA in the blood specimen by PCR. Possible acute infection of R. felis was identified in both one case of Q fever and scrub typhus. The geographic distribution of SFGR cases is similar with that of scrub typhus.

Conclusions

Human SFGR exist and are neglected diseases in southern Taiwan, particularly for the species closely-related to R. felis.     

Diagnostic accuracy of a loop-mediated isothermal PCR assay for detection of Orientia tsutsugamushi during acute Scrub Typhus infection

Background

There is an urgent need to develop rapid and accurate point-of-care (POC) technologies for acute scrub typhus diagnosis in low-resource, primary health care settings to guide clinical therapy.

Methodology/Principal Findings

In this study we present the clinical evaluation of loop-mediated isothermal PCR assay (LAMP) in the context of a prospective fever study, including 161 patients from scrub typhus-endemic Chiang Rai, northern Thailand.A robust reference comparator set comprising following ‘scrub typhus infection criteria’ (STIC) was used: a) positive cell culture isolate and/or b) an admission IgM titer ≥1∶12,800 using the ‘gold standard’ indirect immunofluorescence assay (IFA) and/or c) a 4-fold rising IFA IgM titer and/or d) a positive result in at least two out of three PCR assays.Compared to the STIC criteria, all PCR assays (including LAMP) demonstrated high specificity ranging from 96–99%, with sensitivities varying from 40% to 56%, similar to the antibody based rapid test, which had a sensitivity of 47% and a specificity of 95%.

Conclusions/Significance

The diagnostic accuracy of the LAMP assay was similar to realtime and nested conventional PCR assays, but superior to the antibody-based rapid test in the early disease course. The combination of DNA- and antibody-based detection methods increased sensitivity with minimal reduction of specificity, and expanded the timeframe of adequate diagnostic coverage throughout the acute phase of scrub typhus.     

Phenotypic characterization of peripheral T cells and their dynamics in scrub typhus patients

Background

Scrub typhus, caused by Orientia tsutsugamushi infection, is one of the main causes of febrile illness in the Asia-Pacific region. Although cell-mediated immunity plays an important role in protection, little is known about the phenotypic changes and dynamics of leukocytes in scrub typhus patients.

Methodology/Principal Findings

To reveal the underlying mechanisms of immunological pathogenesis, we extensively analyzed peripheral blood leukocytes, especially T cells, during acute and convalescent phases of infection in human patients and compared with healthy volunteers. We observed neutrophilia and CD4⁺ T lymphopenia in the acute phase of infection, followed by proliferation of CD8⁺ T cells during the convalescent phase. Massive T cell apoptosis was detected in the acute phase and preferential increase of CD8⁺ T cells with activated phenotypes was observed in both acute and convalescent phases, which might be associated or correlated with elevated serum IL-7 and IL-15. Interestingly, peripheral Treg cells were significantly down-regulated throughout the disease course.

Conclusions/Significance

The remarkable decrease of CD4⁺ T cells, including Treg cells, during the acute phase of infection may contribute to the loss of immunological memory that are often observed in vaccine studies and recurrent human infection.     

A Systematic Review of Mortality from Untreated Scrub Typhus (Orientia tsutsugamushi)

Background

Scrub typhus, a bacterial infection caused by Orientia tsutsugamushi, is increasingly recognized as an important cause of fever in Asia, with an estimated one million infections occurring each year. Limited access to health care and the disease’s non-specific symptoms mean that many patients are undiagnosed and untreated, but the mortality from untreated scrub typhus is unknown. This review systematically summarizes the literature on the untreated mortality from scrub typhus and disease outcomes.

Methodology/Principal Findings

A literature search was performed to identify patient series containing untreated patients. Patients were included if they were symptomatic and had a clinical or laboratory diagnosis of scrub typhus and excluded if they were treated with antibiotics. The primary outcome was mortality from untreated scrub typhus and secondary outcomes were total days of fever, clinical symptoms, and laboratory results. A total of 76 studies containing 89 patient series and 19,644 patients were included in the final analysis. The median mortality of all patient series was 6.0% with a wide range (min-max) of 0–70%. Many studies used clinical diagnosis alone and had incomplete data on secondary outcomes. Mortality varied by location and increased with age and in patients with myocarditis, delirium, pneumonitis, or signs of hemorrhage, but not according to sex or the presence of an eschar or meningitis. Duration of fever was shown to be long (median 14.4 days Range (9–19)).

Conclusions

Results show that the untreated mortality from scrub typhus appears lower than previously reported estimates. More data are required to clarify mortality according to location and host factors, clinical syndromes including myocarditis and central nervous system disease, and in vulnerable mother-child populations. Increased surveillance and improved access to diagnostic tests are required to accurately estimate the untreated mortality of scrub typhus. This information would facilitate reliable quantification of DALYs and guide empirical treatment strategies.     

The Association between Health System Development and the Burden of Cardiovascular Disease: An Analysis of WHO Country Profiles

Background

Several risk factors for cardiovascular disease (CVD) have been identified in recent decades. However, the association between the health system and the burden of CVD has not yet been sufficiently researched. The objective of this study was to analyse the association between health system development and the burden of CVD, in particular CVD-related disability-adjusted life–years (DALYs).

Methods

Univariate and multivariate generalized linear mixed models were applied to country-level data collected by the World Bank and World Health Organization. Response variables were the age-standardized CVD mortality and age-standardized CVD DALY rates.

Results

The amount of available health system resources, indicated by total health expenditures per capita, physician density, nurse density, dentistry density, pharmaceutical density and the density of hospital beds, was associated with reduced CVD DALY rates and CVD mortality. However, in the multivariate models, the density of nurses and midwives was positively associated with CVD. High out-of-pocket costs were associated with increased CVD mortality in both univariate and multivariate analyses.

Conclusion

A highly developed health system with a low level of out-of-pocket costs seems to be the most appropriate to reduce the burden of CVD. Furthermore, an efficient balance between human health resources and health technologies is essential.     

Comparing Cutaneous Research Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases with 2010 Global Burden of Disease Results

Importance

Disease burden data helps guide research prioritization.

Objective

To determine the extent to which grants issued by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reflect disease burden, measured by disability-adjusted life years (DALYs) from Global Burden of Disease (GBD) 2010 project.

Design

Two investigators independently assessed 15 skin conditions studied by GBD 2010 in the NIAMS database for grants issued in 2013. The 15 skin diseases were matched to their respective DALYs from GBD 2010.

Setting

The United States NIAMS database and GBD 2010 skin condition disability data.

Main Outcome(s) and Measure(s)

Relationship of NIAMS grant database topic funding with percent total GBD 2010 DALY and DALY rank for 15 skin conditions.

Results

During fiscal year 2013, 1,443 NIAMS grants were issued at a total value of $424 million. Of these grants, 17.7% covered skin topics. Of the total skin disease funding, 82% (91 grants) were categorized as “general cutaneous research.” Psoriasis, leprosy, and “other skin and subcutaneous diseases” (ie; immunobullous disorders, vitiligo, and hidradenitis suppurativa) were over-represented when funding was compared with disability. Conversely, cellulitis, decubitus ulcer, urticaria, acne vulgaris, viral skin diseases, fungal skin diseases, scabies, and melanoma were under-represented. Conditions for which disability and funding appeared well-matched were dermatitis, squamous and basal cell carcinoma, pruritus, bacterial skin diseases, and alopecia areata.

Conclusions and Relevance

Degree of representation in NIAMS is partly correlated with DALY metrics. Grant funding was well-matched with disability metrics for five of the 15 studied skin diseases, while two skin diseases were over-represented and seven were under-represented. Global burden estimates provide increasingly transparent and important information for investigating and prioritizing national research funding allocations.     

Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease

Background

Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR.

Objective

To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation.

Materials and Methods

Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10–59 ml/min/1.73 m²) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores.

Results

Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784–0.892).

Conclusion

A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs.     

A Hybrid Model for Predicting the Prevalence of Schistosomiasis in Humans of Qianjiang City,China

Backgrounds/Objective

Schistosomiasis is still a major public health problem in China, despite the fact that the government has implemented a series of strategies to prevent and control the spread of the parasitic disease. Advanced warning and reliable forecasting can help policymakers to adjust and implement strategies more effectively, which will lead to the control and elimination of schistosomiasis. Our aim is to explore the application of a hybrid forecasting model to track the trends of the prevalence of schistosomiasis in humans, which provides a methodological basis for predicting and detecting schistosomiasis infection in endemic areas.

Methods

A hybrid approach combining the autoregressive integrated moving average (ARIMA) model and the nonlinear autoregressive neural network (NARNN) model to forecast the prevalence of schistosomiasis in the future four years. Forecasting performance was compared between the hybrid ARIMA-NARNN model, and the single ARIMA or the single NARNN model.

Results

The modelling mean square error (MSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) of the ARIMA-NARNN model was 0.1869×10⁻⁴, 0.0029, 0.0419 with a corresponding testing error of 0.9375×10⁻⁴, 0.0081, 0.9064, respectively. These error values generated with the hybrid model were all lower than those obtained from the single ARIMA or NARNN model. The forecasting values were 0.75%, 0.80%, 0.76% and 0.77% in the future four years, which demonstrated a no-downward trend.

Conclusion

The hybrid model has high quality prediction accuracy in the prevalence of schistosomiasis, which provides a methodological basis for future schistosomiasis monitoring and control strategies in the study area. It is worth attempting to utilize the hybrid detection scheme in other schistosomiasis-endemic areas including other infectious diseases.     

Modelling the Impact and Cost-Effectiveness of Biomarker Tests as Compared with Pathogen-Specific Diagnostics in the Management of Undifferentiated Fever in Remote Tropical Settings

Background

Malaria accounts for a small fraction of febrile cases in increasingly large areas of the malaria endemic world. Point-of-care tests to improve the management of non-malarial fevers appropriate for primary care are few, consisting of either diagnostic tests for specific pathogens or testing for biomarkers of host response that indicate whether antibiotics might be required. The impact and cost-effectiveness of these approaches are relatively unexplored and methods to do so are not well-developed.

Methods

We model the ability of dengue and scrub typhus rapid tests to inform antibiotic treatment, as compared with testing for elevated C-Reactive Protein (CRP), a biomarker of host-inflammation. Using data on causes of fever in rural Laos, we estimate the proportion of outpatients that would be correctly classified as requiring an antibiotic and the likely cost-effectiveness of the approaches.

Results

Use of either pathogen-specific test slightly increased the proportion of patients correctly classified as requiring antibiotics. CRP testing was consistently superior to the pathogen-specific tests, despite heterogeneity in causes of fever. All testing strategies are likely to result in higher average costs, but only the scrub typhus and CRP tests are likely to be cost-effective when considering direct health benefits, with median cost per disability adjusted life year averted of approximately $48 USD and $94 USD, respectively.

Conclusions

Testing for viral infections is unlikely to be cost-effective when considering only direct health benefits to patients. Testing for prevalent bacterial pathogens can be cost-effective, having the benefit of informing not only whether treatment is required, but also as to the most appropriate antibiotic; this advantage, however, varies widely in response to heterogeneity in causes of fever. Testing for biomarkers of host inflammation is likely to be consistently cost-effective despite high heterogeneity, and can also offer substantial reductions in over-use of antimicrobials in viral infections.     

A comparative study of leptospirosis and dengue in Thai children

Background

Leptospirosis is an emerging zoonosis that is often under-recognized in children and commonly confused with dengue in tropical settings. An enhanced ability to distinguish leptospirosis from dengue in children would guide clinicians and public health personnel in the appropriate use of limited healthcare resources.

Methodology/Principal Findings

We conducted a prospective, hospital-based, study of children with acute febrile illnesses and dengue in Thailand. Among the children without dengue, we identified those with leptospirosis using anti-leptospira IgM and microscopic agglutination titers in paired acute and convalescent blood samples. We then performed a case-control comparison of symptoms, signs, and clinical laboratory values between children with leptospirosis and dengue.In a semi-rural region of Thailand, leptospirosis accounted for 19% of the non-dengue acute febrile illnesses among children presenting during the rainy season. None of the children with leptospirosis were correctly diagnosed at the time of hospital discharge, and one third (33%) were erroneously diagnosed as dengue or scrub typhus. A predictive model to distinguish pediatric leptospirosis from dengue was generated using three variables: the absolute neutrophil count, plasma albumin, and aspartate aminotransferase levels in the first 72 hours of illness.

Conclusions/Significance

Unrecognized leptospirosis can be a significant cause of “dengue-like” febrile illness in children. Increased awareness of pediatric leptospirosis, and an enhanced ability to discriminate between leptospirosis and dengue early in illness, will help guide the appropriate use of healthcare resources in often resource-limited settings.     

Empirical Mode Decomposition and k-Nearest Embedding Vectors for Timely Analyses of Antibiotic Resistance Trends

Background

Antibiotic resistance is a major worldwide public health concern. In clinical settings, timely antibiotic resistance information is key for care providers as it allows appropriate targeted treatment or improved empirical treatment when the specific results of the patient are not yet available.

Objective

To improve antibiotic resistance trend analysis algorithms by building a novel, fully data-driven forecasting method from the combination of trend extraction and machine learning models for enhanced biosurveillance systems.

Methods

We investigate a robust model for extraction and forecasting of antibiotic resistance trends using a decade of microbiology data. Our method consists of breaking down the resistance time series into independent oscillatory components via the empirical mode decomposition technique. The resulting waveforms describing intrinsic resistance trends serve as the input for the forecasting algorithm. The algorithm applies the delay coordinate embedding theorem together with the k-nearest neighbor framework to project mappings from past events into the future dimension and estimate the resistance levels.

Results

The algorithms that decompose the resistance time series and filter out high frequency components showed statistically significant performance improvements in comparison with a benchmark random walk model. We present further qualitative use-cases of antibiotic resistance trend extraction, where empirical mode decomposition was applied to highlight the specificities of the resistance trends.

Conclusion

The decomposition of the raw signal was found not only to yield valuable insight into the resistance evolution, but also to produce novel models of resistance forecasters with boosted prediction performance, which could be utilized as a complementary method in the analysis of antibiotic resistance trends.