Estimating the Seroincidence of Scrub Typhus using Antibody Dynamics after Infection.

Scrub typhus, a vector-borne bacterial infection, is an important but neglected disease globally. Accurately characterizing the burden is challenging because of nonspecific symptoms and limited diagnostics. Prior seroepidemiology studies have struggled to find consensus cutoffs that permit comparisons of estimates across contexts and time. In this study, we present a novel approach that does not require a cutoff and instead uses information about antibody kinetics after infection to estimate seroincidence. We use data from three cohorts of scrub typhus patients in Chiang Rai, Thailand, and Vellore, India, to characterize antibody kinetics after infection and two population serosurveys in the Kathmandu Valley, Nepal, and Tamil Nadu, India, to estimate seroincidence. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi-derived recombinant 56-kDa antigen using commercial enzyme-linked immunosorbent assay kits. We used Bayesian hierarchical models to characterize antibody responses after scrub typhus infection and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. Median responses persisted above an optical density (OD) of 1.8 for 23.6 months for IgG and an OD of 1 for 4.5 months for IgM. Among 18- to 29-year-olds, the seroincidence was 10 per 1,000 person-years (95% CI, 5-19) in Tamil Nadu, India, and 14 per 1,000 person-years (95% CI: 10-20) in the Kathmandu Valley, Nepal. When seroincidence was calculated with antibody decay ignored, the disease burden was underestimated by more than 50%. The approach can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to efficiently generate scrub typhus seroincidence estimates.

Missing a case of nitrous oxide toxicity.

Nitrous oxide is a highly lipid-soluble molecule, which can produce euphoria and calming effects through noncompetitive antagonism of the N-methyl-D-aspartate (NMDA) glutamate receptor and agonism of the y-aminobutyric acid (GABA) A receptor. It can also produce toxicities likely through inactivation of methylcobalamin (vitamin B12) with subsequent neurological, psychiatric, and other sequelae that may be mistaken for other clinical entities. We present a classic presentation of nitrous oxide toxicity, which was missed and urgently referred to infectious diseases with concerns for an infectious neuromyelitis. Knowing the constellation of symptoms and findings and maintaining a high index of suspicion are key to diagnosing nitrous oxide toxicity, which can otherwise easily be missed. Cessation of use, B12 supplementation, and supportive measures such as occupational and physical therapy are helpful for maximizing long-term beneficial outcomes.

Opioid Use and Chronic Infections: The Value of Addressing the Syndemic in Correctional Settings Via Telemedicine Guidance and Broader Use of Long-Acting Medications.

In the United States, we are experiencing linked epidemics (a syndemic) of substance use disorders (SUDs) and infections associated with drug use, including unsafe injecting and unsafe sex in exchange for drugs or money. Current drug laws, together with risk-taking behavior among persons with SUDs, contribute to disproportionately high prevalences of these conditions in correctional settings. Detection and treatment of diseases with a high impact on public health are best addressed in the settings where such conditions are most prevalent (ie, jails and prisons for SUDs and chronic infections). The effectiveness, safety, cost of care. and public health impact of these conditions can be improved by means of broader screening and expanded access to specialty consultations through telemedicine/telehealth, along with broader use of long-acting medications for the treatment of human immunodeficiency virus and SUDs. Expanding telemedicine/telehealth, first for specialties which do not require advanced technology (eg, infectious diseases, addictions), can eventually lead to further advancements in correctional healthcare.

Use of Buprenorphine-Naloxone in the Treatment of Tianeptine Use Disorder.

: Tianeptine is an atypical antidepressant which exerts an opioid-like effect on the µ-opioid receptor. There is well documented intentional misuse and addiction to tianeptine in Europe, and this is increasingly being seen in the United States. We presented a case of buprenorphine/naloxone successfully being used to aid in cessation and subsequent abstinence from tianeptine after years of use. An additional consideration with tianeptine use is the potential for the development or re-emergence of depression and anxiety on cessation. Chronic daily use of tianeptine may represent tianeptine use disorder, which can have a clinical course consistent with opioid use disorder, including the development of impaired control, functional impairment, tolerance, and withdrawal. It is appropriate to consider medications for opioid use disorder for the management of tianeptine use disorder.

Kinetics of IgM and IgG antibodies after scrub typhus infection and the clinical implications.

OBJECTIVES: The serological detection of IgM antibodies is the most widely used test to diagnose scrub typhus infection. However, the kinetics of IgM and IgG antibodies post-infection remain elusive, which could contribute to false positivity. The objective of this study was to document the nature of the evolution of these antibody titres after infection. METHODS: Adult patients previously confirmed to have scrub typhus by IgM ELISA, positive PCR, or both, were included in this cross-sectional study. The levels of IgM and IgG antibodies in serum samples were tested using an ELISA and the distribution curve was plotted. RESULTS: Two hundred and three patients were included in this study. Post-infection serum sampling was done between 1 month and 46 months after documented infection. IgM levels declined gradually but remained elevated above the diagnostic cut-off for up to 12 months post-infection. However, IgG levels continued to rise reaching a peak at 10 months, followed by a gradual decline over several months. In the majority of cases, the IgG levels remained above the cut-off threshold for more than 36 months. CONCLUSIONS: Clinicians need to be cautious in using a single serum sample for the detection of IgM to diagnose scrub typhus, as it remains elevated for up to 12 months after the infection, whereas the serum IgG level could be used as an indicator of past infection.

Addiction consultation services - Linking hospitalized patients to outpatient addiction treatment.

BACKGROUND: Approximately 15% of hospitalized patients have an active substance use disorder (SUD). Starting treatment for SUD, including medications, during acute hospitalizations can engage patients in addiction care. In July 2015, the Boston Medical Center Addiction Consult Service (ACS), began providing inpatient diagnostic, management, and discharge linkage consultations. We describe this implementation. METHODS: The ACS staff recorded SUDs diagnoses and medication recommendations and tracked follow-up data for affiliated outpatient office-based addiction clinics and methadone maintenance programs. We assessed the number of consults, SUDs diagnoses, medications recommended and initiated, and outpatient addiction clinic follow-up. RESULTS: Over 26weeks, the BMC ACS completed 337 consults: 78% had an opioid use disorder (UD), 37% an alcohol UD, 28% a cocaine UD, 9% a benzodiazepine UD, 3% a cannabinoid (including K2) UD, and <1% a methamphetamine UD. Methadone was initiated in 70 inpatients and buprenorphine in 40 inpatients. Naltrexone was recommended 45 times (for opioid UD, alcohol UD, or both). Of the patients initiated on methadone, 76% linked to methadone clinic, with 54%, 39%, and 29% still retained at 30, 90, and 180days, respectively. For buprenorphine, 49% linked to clinic, with 39%, 27%, and 18% retained at 30, 90, and 180days, respectively. For naltrexone, 26% linked to clinic, all with alcohol UD alone. CONCLUSIONS: A new inpatient addiction consultation service diagnosed and treated hospitalized patients with substance use disorders and linked them to outpatient addiction treatment care. Initiating addiction medications, particularly opioid agonists, was feasible in the inpatient setting. Optimal linkage and retention of hospitalized patients to post-discharge addiction care warrants further innovation and program development.

Prevalence and risk factors for scrub typhus in South India.

OBJECTIVE: To determine the prevalence and risk factors of scrub typhus in Tamil Nadu, South India. METHODS: We performed a clustered seroprevalence study of the areas around Vellore. All participants completed a risk factor survey, with seropositive and seronegative participants acting as cases and controls, respectively, in a risk factor analysis. After univariate analysis, variables found to be significant underwent multivariate analysis. RESULTS: Of 721 people participating in this study, 31.8% tested seropositive. By univariate analysis, after accounting for clustering, having a house that was clustered with other houses, having a fewer rooms in a house, having fewer people living in a household, defecating outside, female sex, age >60 years, shorter height, lower weight, smaller body mass index and smaller mid-upper arm circumference were found to be significantly associated with seropositivity. After multivariate regression modelling, living in a house clustered with other houses, female sex and age >60 years were significantly associated with scrub typhus exposure. CONCLUSIONS: Overall, scrub typhus is much more common than previously thought. Previously described individual environmental and habitual risk factors seem to have less importance in South India, perhaps because of the overall scrub typhus-conducive nature of the environment in this region.

Epidemiology & risk factors of scrub typhus in south India.

BACKGROUND & OBJECTIVES: Scrub typhus is a major public health threat in South and Southeastern Asian countries including India. Understanding local patterns of disease and factors that place individuals at risk is pivotal to future preventive measures against scrub typhus. The primary aim of this study was to identify specific epidemiological and geographical factors associated with an increased risk of developing scrub typhus in this region. METHODS: We mapped 709 patients from Tamil Nadu, Andhra Pradesh and Telangana who were admitted to the Christian Medical College (CMC) Hospital, Vellore, Tamil Nadu, India, for the period 2006-2011, assessed seasonality using monthly counts of scrub typhus cases, and conducted a case-control study among a subset of patients residing in Vellore. RESULTS: The geographic distribution of cases at CMC Hospital clusters around the Tamil Nadu-Andhra Pradesh border. However, distinct hotspots clearly exist distal to this area, near Madurai and the coast in Tamil Nadu, and in the Northeast of Andhra Pradesh. Seasonally, the highest numbers of cases were observed in the cooler months of the year, i.e. September to January. In the case-control analysis, cases were more likely to be agricultural laborers (OR 1.79, 95% CI 1.01 - 3.15), not wear a shirt at home (OR 4.23, 95% CI 1.12 - 16.3), live in houses adjacent to bushes or shrubs (OR 1.95, 95% CI 1.08 - 3.53), and live in a single room home (OR 1.75, 95% CI 1.02 - 3.01). On binary logistic regression, the first three of these variables were statistically significant. INTERPRETATION & CONCLUSIONS: With the growing number of cases detected in India, scrub typhus is fast emerging as a public health threat and further research to protect the population from this deadly infection is essential. Health education campaigns focusing on the agricultural workers of Southern India, especially during the cooler months of the year, can serve as an important public health measure to control infection.

Molecular epidemiology and genetic diversity of Orientia tsutsugamushi from patients with scrub typhus in 3 regions of India.

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus-endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010-August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development.

Diagnosis of scrub typhus.

Scrub typhus is an acute febrile illness that, if untreated, can result in considerable morbidity and mortality. One of the primary reasons for delays in the treatment of this potentially fatal infection is the difficulty in diagnosing the condition. Diagnosis is often complicated because of the combination of non-specific symptoms that overlap with other infections commonly found in endemic areas and the poor available diagnostics. In the majority of the endemic settings, diagnosis still relies on the Weil-Felix test, which is neither sensitive nor specific. Other methods of testing have become available, but at this time, these remain insufficient to provide the rapid point-of-care diagnostics that would be necessary to significantly change the management of this infection by providers in endemic areas. This article reviews the currently available diagnostic tools for scrub typhus and their utility in the clinical setting.

Clinical profile and improving mortality trend of scrub typhus in South India.

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.

Scrub typhus in South India: clinical and laboratory manifestations, genetic variability, and outcome.

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.

Differential diagnosis of scrub typhus meningitis from bacterial meningitis using clinical and laboratory features.

BACKGROUND: Central nervous system (CNS) involvement in the form of meningitis or meningoencephalitis is common in scrub typhus. As specific laboratory methods remain inadequate or inaccessible in developing countries, prompt diagnosis is often difficult. AIM: To identify the clinical and laboratory parameters that may help in differentiating scrub typhus meningitis from bacterial meningitis. SETTING AND DESIGN: This is a cross-sectional analysis of adult patients admitted with scrub typhus and bacterial meningitis to a tertiary care teaching institute in South India. MATERIALS AND METHODS: A comparison of clinical and laboratory features of 25 patients admitted with meningitis to a university teaching hospital during a 15-month period was made. These patients had meningitis diagnosed based on abnormal cerebrospinal fluid (CSF) analysis with either positive IgM scrub typhus ELISA serology (n =16) or with CSF culture isolating bacteria known to cause bacterial meningitis (n =9). The clinical and laboratory features of the patients with scrub typhus meningitis and bacterial meningitis were compared. RESULTS: The mean age was similar in the scrub typhus and bacterial meningitis groups (44.0 ± 18.5 years vs. 46.3 ± 23.0 years). Features at admission predictive of a diagnosis of scrub typhus meningitis were duration of fever at presentation >5 days (8.4 ± 3.5 days vs. 3.3 ± 4.2 days, P < 0.001), CSF white cell count of a lesser magnitude (83.2 ± 83.0 cells/cumm vs. 690.2 + 753.8 cells/cumm, P < 0.001), CSF lymphocyte proportion >50% (83.9 ± 12.5% vs. 24.8 ± 17.5% P < 0.001), and alanine aminotransferase (ALT) elevation more than 60 IU (112.5 ± 80.6 IU vs. 35 ± 21.4 IU, P =0.02). CONCLUSION: This study suggests that clinical features, including the duration of fever and laboratory parameters such as CSF pleocytosis, CSF lymphocyte proportion >50%, and ALT values are helpful in differentiating scrub typhus from bacterial meningitis.

Investigating and managing pyrexia of unknown origin in adults.

Few clinical problems generate such a wide differential diagnosis as pyrexia (fever) of unknown origin. The initial definition proposed by Petersdorf and Beeson in 1961,¹ later revised, is "a fever of 38.3°C (101°F) or more lasting for at least three weeks for which no cause can be identified after three days of investigation in hospital or after three or more outpatient visits." ²â»4Essentially the term refers to a prolonged febrile illness without an obvious cause despite reasonable evaluation and diagnostic testing. A fever that is not self limiting for which no cause can be found can become a source of frustration for both patient and doctor. There is little consensus on how such patients should be investigated, although recent prospective studies have evaluated diagnostic protocols to suggest approaches to investigation. ³56 We discuss evidence from epidemiological and diagnostic studies and suggest an approach to investigating and managing pyrexia of unknown origin. Immunocompromised individuals, those with HIV infection, and patients admitted to hospital for other reasons with persistent or unexplained fever represent distinct subgroups in which the likely causes, diagnosis, and treatment of pyrexia usually differ from those in patients who are not immunocompromised. We do not discuss these subgroups in this review other than to provide definitions of pyrexia of unknown origin in different groups of patients (see box 1).