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.).

SMART-lipid nanoparticles enabled mRNA vaccine elicits cross-reactive humoral responses against the omicron sub-variants.

The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has necessitated the development of broad cross-reactive vaccines. Recent findings suggest that enhanced antigen presentation could lead to cross-reactive humoral responses against the emerging variants. Toward enhancing the antigen presentation to dendritic cells (DCs), we developed a novel shikimoylated mannose receptor targeting lipid nanoparticle (SMART-LNP) system that could effectively deliver mRNAs into DCs. To improve the translation of mRNA, we developed spike domain-based trimeric S1 (TS1) mRNA with optimized codon sequence, base modification, and engineered 5' and 3' UTRs. In a mouse model, SMART-LNP-TS1 vaccine could elicit robust broad cross-reactive IgGs against Omicron sub-variants, and induced interferon-γ-producing T cells against SARS-CoV-2 virus compared with non-targeted LNP-TS1 vaccine. Further, T cells analysis revealed that SMART-LNP-TS1 vaccine induced long-lived memory T cell subsets, T helper 1 (Th1)-dominant and cytotoxic T cells immune responses against the SARS-CoV-2 virus. Importantly, SMART-LNP-TS1 vaccine produced strong Th1-predominant humoral and cellular immune responses. Overall, SMART-LNPs can be explored for precise antigenic mRNA delivery and robust immune responses. This platform technology can be explored further as a next-generation delivery system for mRNA-based immune therapies.

Canonical notch activation in patients with scrub typhus: association with organ dysfunction and poor outcome.

PURPOSE: The mechanisms that control inflammation in scrub typhus are not fully elucidated. The Notch pathways are important regulators of inflammation and infection, but have not been investigated in scrub typhus. METHODS: Plasma levels of the canonical Notch ligand Delta-like protein 1 (DLL1) were measured by enzyme immunoassay and RNA expression of the Notch receptors (NOTCH1, NOTCH2 and NOTCH4) in whole blood was analyzed by real-time PCR in patients with scrub typhus (n = 129), in patients with similar febrile illness without O. tsutsugamushi infection (n = 31) and in healthy controls (n = 31); all from the same area of South India. RESULTS: Our main results were: (i) plasma DLL1 was markedly increased in scrub typhus patients at hospital admission with a significant decrease during recovery. (ii) RNA expression of NOTCH4 was decreased at admission in whole blood. (iii) A similar pattern for DLL1 and NOTCH4 was seen in febrile disease controls. (iv) Admission DLL1 in plasma was associated with disease severity and short-term survival. (vi) Regulation of Notch pathways in O. tsutsugamushi-infected monocytes as evaluated by public repository data revealed enhanced canonical Notch activation with upregulation of DLL1 and downregulation of NOTCH4. CONCLUSION: Our findings suggest that scrub typhus patients are characterized by enhanced canonical Notch activation. Elevated plasma levels of DLL1 were associated with organ dysfunction and poor outcomes in these patients.

Distinct patterns of postoperative fever in paediatric neurosurgery patients.

PURPOSE: Postoperative fever is a common problem following neurosurgery but data on the causes among paediatric patients is sparse. In this report, we determined the incidence, causes, and outcomes of postoperative fever in paediatric neurosurgical patients (< 18 years), and contrasted the findings with an adult cohort published recently from our unit. METHODS: We recruited 61 patients who underwent 73 surgeries for non-traumatic neurosurgical indications over 12 months. A standard protocol was followed for the evaluation and management of postoperative fever. We prospectively collected data pertaining to operative details, daily maximal temperature, clinical features, and use of surgical drains, urinary catheters, and other adjuncts. Elevated body temperature of > 99.9 °F or 37.7 °C for > 48 h or associated with clinical deterioration or localising features was considered as "fever"; elevated temperature not meeting these criteria was classified as transient elevation in temperature (TET). RESULTS: Twenty-six patients (35.6%) had postoperative fever, more frequent than in adult patients. TET occurred in 12 patients (16.4%). The most common causes of fever were aseptic meningitis (34.6%), followed by urinary tract infections (15.4%), pyogenic meningitis, COVID-19, and wound infections. Postoperative fever was associated with significantly longer duration of hospital admission and was the commonest cause of readmission. CONCLUSION: In contrast to adults, early temperature elevations in paediatric patients may portend infectious and serious non-infectious causes of fever, including delayed presentation with aseptic meningitis, a novel association among paediatric patients. Investigation guided by clinical assessment and conservative antibiotic policy in keeping with the institutional microbiological profile provides the most appropriate strategy in managing paediatric postoperative fever.

Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.

BACKGROUND: Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. METHODS: We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. RESULTS: Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. CONCLUSIONS: Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.

The patient-reported outcome measurement in heart failure clinic trial: Rationale and methods of the PRO-HF trial.

BACKGROUND: Among patients with heart failure (HF), patient-reported health status provides information beyond standard clinician assessment. Although HF management guidelines recommend collecting patient-reported health status as part of routine care, there is minimal data on the impact of this intervention. STUDY DESIGN: The Patient-Reported Outcomes in Heart Failure Clinic (PRO-HF) trial is a pragmatic, randomized, implementation-effectiveness trial testing the hypothesis that routine health status assessment via the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) leads to an improvement in patient-reported health status among patients treated in a tertiary health system HF clinic. PRO-HF has completed randomization of 1,248 participants to routine KCCQ-12 assessment or usual care. Patients randomized to the KCCQ-12 arm complete KCCQ-12 assessments before each HF clinic visit with the results shared with their treating clinician. Clinicians received education regarding the interpretation and potential utility of the KCCQ-12. The primary endpoint is the change in KCCQ-12 over 1 year. Secondary outcomes are HF therapy patterns and health care utilization, including clinic visits, testing, hospitalizations, and emergency department visits. As a sub-study, PRO-HF will also evaluate the impact of routine KCCQ-12 assessment on patient experience and the accuracy of clinician-assessed health status. In addition, clinicians completed semi-structured interviews to capture their perceptions on the trial's implementation of routine KCCQ-12 assessment in clinical practice. CONCLUSIONS: PRO-HF is a pragmatic, randomized trial based in a real-world HF clinic to determine the feasibility of routinely assessing patient-reported health status and the impact of this intervention on health status, care delivery, patient experience, and the accuracy of clinician health status assessment.

Persistent bacteremia predicts poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections receiving appropriate therapy.

PURPOSE: Identifying persistent bacteremia early in patients with neutropenia may improve outcome. This study evaluated the role of follow-up blood cultures (FUBC) positivity in predicting outcomes among patients with neutropenia and carbapenem-resistant gram-negative bloodstream infections (CRGNBSI). METHODS: This retrospective cohort study conducted between December 2017 and April 2022 included patients more than 15 years old with neutropenia and CRGNBSI, who survived for ≥ 48 h, receiving appropriate antibiotic therapy and had FUBCs. Patients with polymicrobial bacteremia within 30 days were excluded. The primary outcome was 30 day mortality. Persistent bacteremia, septic shock, recovery from neutropenia, prolonged or profound neutropenia, requirement of intensive care and dialysis, and initiation of appropriate empirical therapy were also studied. RESULTS: In our study cohort of 155 patients, the 30 day mortality rate was 47.7%. Persistent bacteremia was common in our patient cohort (43.8%). Carbapenem resistant isolates identified in the study were K.pneumoniae (80%), E.coli (12.26%), P.aeruginosa (5.16%), A.baumanii (1.94%) and E.cloacae (0.65%). The median time for sending a FUBC was 2 days (IQR, 1-3 days). Patients with persistent bacteremia had higher mortality than those without (56.76% versus 32.1%; p < 0.001). Appropriate initial empirical therapy was given to 70.9%. Recovery from neutropenia occurred in 57.4% while 25.8% had prolonged or profound neutropenia. Sixty-nine percent (107/155) had septic shock and needed intensive care; 12.2% of patients required dialysis. Non-recovery from neutropenia (aHR, 4.28; 95% CI 2.53-7.23), presence of septic shock (aHR, 4.42; 95%CI 1.47-13.28), requirement of intensive care (aHR,3.12;95%CI 1.23-7.93), and persistent bacteremia (aHR,1.74; 95%CI 1.05-2.89) significantly predicted poor outcomes in multivariable analysis. CONCLUSION: FUBC showing persistent bacteremia predicted poor outcomes among neutropenic patients with carbapenem-resistant gram-negative bloodstream infections (CRGNBSI) and should be routinely reported.

A Standardized Protocol for the Safe Retrieval of Infectious Postmortem Human Brain for Studying Whole-Brain Pathology.

ABSTRACT: We describe a safe and standardized perfusion protocol for studying brain pathology in high-risk autopsies using a custom-designed low-cost infection containment chamber and high-resolution histology. The output quality was studied using the histological data from the whole cerebellum and brain stem processed using a high-resolution cryohistology pipeline at 0.5 µm per pixel, in-plane resolution with serial sections at 20-µm thickness. To understand the pathophysiology of highly infectious diseases, it is necessary to have a safe and cost-effective method of performing high-risk autopsies and a standardized perfusion protocol for preparing high-quality tissues. Using the low-cost infection containment chamber, we detail the cranial autopsy protocol and ex situ perfusion-fixation of 4 highly infectious adult human brains. The digitized high-resolution histology images of the Nissl-stained series reveal that most of the sections were free of processing artifacts, such as fixation damage, freezing artifacts, and osmotic shock, at the macrocellular and microcellular level. The quality of our protocol was also tested with the highly sensitive immunohistochemistry staining for specific protein markers. Our protocol provides a safe and effective method in high-risk autopsies that allows for the evaluation of pathogen-host interaction, the underlying pathophysiology, and the extent of the infection across the whole brain at microscopic resolutions.

Role of Neutrophil Gelatinase-associated Lipocalin (NGAL) and Other Clinical Parameters as Predictors of Bacterial Sepsis in Patients Presenting to the Emergency Department with Fever.

Background: Bacterial sepsis is associated with significant morbidity and mortality. However, to date, there is no single test that predicts sepsis with reproducible results. We proposed that using a combination of clinical and laboratory parameters and a novel biomarker, plasma neutrophil gelatinase-associated lipocalin (NGAL) may aid in early diagnosis. Method: A prospective cohort study was conducted at a tertiary care center in South India (June 2017 to April 2018) on patients with acute febrile episodes fulfilling the Systemic Inflammatory Response Syndrome (SIRS) criteria. Plasma NGAL and standard clinical and laboratory parameters were collected at the admission. Bacterial sepsis was diagnosed based on blood culture positivity or clinical diagnosis. Clinically relevant plasma NGAL cut-off values were identified using the receive operating characteristic (ROC) curve. Clinically relevant clinical parameters along with plasma NGAL's risk ratios estimated from the multivariable Poisson regression model were rounded and used as weights to create a new scoring tool. Results: Of 100 patients enrolled, 37 had bacterial sepsis. The optimal plasma NGAL cut-off value to predict sepsis was 570 ng/mL [area under the curve (AUC): 0.69]. The NGAL sepsis screening tool consists of the following clinical parameter: diabetes mellitus, the presence of rigors, quick sequential organ failure assessment (qSOFA) >2, a clear focus of infection, and the plasma NGAL >570 ng/mL. A score of <3 ruled out bacterial sepsis and a score >7 were highly suggestive of bacterial sepsis with an interval likelihood ratio (LR) of 7.77. Conclusion: The NGAL sepsis screening tool with a score >7 can be used in the emergency department (ED) to identify bacterial sepsis. How to cite this article: Paul A, Newbigging NS, Lenin A, Gowri M, Varghese JS, Nell AJ, et al. Role of Neutrophil Gelatinase-associated Lipocalin (NGAL) and Other Clinical Parameters as Predictors of Bacterial Sepsis in Patients Presenting to the Emergency Department with Fever. Indian J Crit Care Med 2023;27(3):176-182.

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

Efficacy of Crushed Delayed-Release Posaconazole Tablets in Rhino-Orbito-Cerebral Mucormycosis.

A significant proportion of patients with Rhino-orbito-cerebral mucormycosis (ROCM) develop oroantral fistulas. Due to the unclear efficacy of crushed delayed-release posaconazole tablets (DRPT) via nasogastric tube in this group of patients, clinicians often use inferior alternatives like posaconazole suspension. In this prospective study, we report good plasma concentrations (median, 2,639 ng/mL; interquartile range [IQR], 1,690 to 3,575 ng/mL; and range, 1,004 to 4,835ng/mL) and complete cure and survival at 3 and 6 months in 19 such patients.

The role and diagnostic accuracy of serology for COVID-19.

BACKGROUND: The role and performance of various serological tests for the diagnosis of COVID-19 are unclear. This study aimed to evaluate the performance of seven commercially available serological assays for SARS-CoV-2 antibodies by testing COVID-19 cases and controls. METHODS: Adult patients with fever for > 5 days, admitted to a tertiary-care teaching hospital in South India, were enrolled prospectively between June and December 2020. SARS-CoV-2 RT-PCR confirmed patients were classified as cases, and patients with febrile illness with laboratory-confirmed alternative diagnosis and healthy participants were controls. All participants were tested with SCoV-2 Detect™ IgM ELISA kit and SCoV-2 Detect™ IgG ELISA kit (InBios International, Seattle, USA) (Inbios), SARS-CoV-2 Total and SARS-CoV-2 IgG (Siemens Healthcare Diagnostics Inc., Tarrytown, USA) (Siemens), Roche Elecsys® Anti-SARS-CoV-2 (Roche Diagnostics, Rotkreuz, Switzerland) (Roche), Abbott SARS-CoV-2 IgG (Abbott Diagnostics, IL, USA) (Abbott), and Liaison® SARS-CoV-2 S1/S2 IgG (DiaSorinS.p.A., Saluggia, Italy) (Liaison). The sensitivities, specificities, positive predictive values (PPV), negative predictive values (NPV), and accuracies were compared. RESULTS: There were 303 participants: 153 cases and 150 controls. ELISA detecting anti-S protein antibody was more sensitive (88.9% for IgG and 86.3% for IgM) than the CLIAs (82.4% for total antibodies and 76.5-85.6% for IgG). Among CLIAs, Roche IgG was most sensitive (85.6%) followed by Abbott (83%) and Liaison (83%). Abbot had the best PPV (88.8%) and was more specific (89.3%) than Liaison (82%) and Roche (82%). Siemens IgG was less sensitive (76.5%) than Siemens Total (82.4%). The specificity of all the serological assays was modest (75-90%). Antibody test positivity increased with the duration of illness reaching 90% after 10 days of illness. When cases were compared against pre-pandemic controls, the IgG gave excellent specificity (98-100%). For seroprevalence studies, InBios IgG had the best accuracy (90.8%) with 88.9% sensitivity and 97.6% specificity. CONCLUSION: The serological assays are important adjuncts for the diagnosis of COVID-19 in patients with persistent symptoms, especially in the second week of illness. The value of serological diagnostic tests is limited in the first week of illness and they provide additional value in seroprevalence studies. The diagnostic accuracy of the ELISA and CLIA platforms were comparable.

Rhinofacial conidiobolomycosis: Clinical and microbiological characterisation and shift in the management of a rare disease.

BACKGROUND: Conidiobolomycosis is a rare tropical rhinofacial fungal infection which has not been well characterised. The available evidence in its management is sparse due to lack of clinical studies and the limited data on antifungal susceptibility patterns. OBJECTIVE: To analyse the clinical manifestations, antifungal treatment and outcomes of patients with conidiobolomycosis and to determine antifungal susceptibility profiles of the isolates. PATIENTS/METHODS: Retrospective analysis of data of all patients with a diagnosis of conidiobolomycosis confirmed by histopathology and culture at a tertiary care hospital from 2012 to 2019 was done. RESULTS: There were 22 patients, 21 males and one female, with a mean age of 37.1 years. Most common presenting symptom was nasal obstruction, found in 20 (90.90%) patients. Patients who presented within 12 months had a better cure rate (85%) compared to those who presented late (67%). Among the 19 patients who had a follow-up, good outcome was seen in 15 of the 17 (88.24%) patients who were on itraconazole or potassium iodide containing regimen. Of the six patients who received additional trimethoprim-sulphamethoxazole (co-trimoxazole), 67% showed good outcome with two patients showing complete cure and two patients still on treatment with significant improvement. High minimum inhibitory concentration (MIC) values were noted for azoles and amphotericin B, whereas co-trimoxazole showed lowest MIC ranges. CONCLUSION: Itraconazole and potassium iodide are reasonable first-line options for the treatment of conidiobolomycosis. Good clinical response to KI and comparatively lower MIC of co-trimoxazole are promising. Further studies are required for developing clinical breakpoints that can predict therapeutic outcomes.

Adapting management strategies for sellar-suprasellar lesions during the COVID-19 pandemic: a pragmatic approach from the frontline.

PURPOSE: During the ongoing COVID-19 pandemic, endonasal surgeries for sellar-suprasellar lesions were discouraged due to the risk of transmission of the disease. We reviewed the changes in our management protocol for these lesions as our disease understanding and preparedness evolved. MATERIALS AND METHODS: This was a retrospective observational study including patients with sellar-suprasellar and clival lesions presenting to us between March and October 2020. Management protocols were divided into three phases based on the prevalence of the disease and the number of mandatory preoperative COVID-19 tests being conducted. The surgical approach used was analyzed in relation to the preferred approach during pre-COVID times, and surgical outcomes and complications were noted. RESULTS: A total of 31 cases were operated during this period. During Phase I (low prevalence; no preoperative COVID testing) endonasal surgeries were largely abandoned in favor of transcranial approaches. In Phase II (medium prevalence; one preoperative COVID test) we gradually resumed endonasal surgeries for 'emergent' and 'essential' cases, and subsequently in Phase III (high prevalence; two preoperative COVID tests), we had no hesitation in performing 'elective' endonasal surgeries with additional barriers for prevention of aerosol transmission. No patient developed COVID-19 infection postoperatively. Eight HCWs in our department acquired the disease during this period, none of whom were directly involved in the surgeries for the above cohort of patients. CONCLUSIONS: With a strict preoperative COVID testing protocol, adherence to proper drilling techniques and using additional barriers to prevent droplet and aerosol spread, endonasal surgeries for sellar-suprasellar lesions are safe during this COVID-19 pandemic.

Prospective study to assess the treatment modalities and fever defervescence in patients with scrub typhus from a tertiary care centre in South India.

BACKGROUND AND OBJECTIVES: Fever defervescence in scrub typhus, a zoonotic bacterial infection is used as a surrogate marker of disease resolution. Failure of fever defervescence prompts clinicians to suspect alternate diagnoses and treatment. In this observational study, various treatment regimens were correlated with clinical outcomes. METHODS: All adult patients with a diagnosed scrub typhus were included; various antibiotic regimens used and clinical outcomes were studied. Data was analyzed using SPSS software for windows 16, with a 2-sided P-value of 0.05 or less was considered statistically significant. RESULTS: In 177 hospitalized patients with scrub typhus, combination therapy (doxycycline and azithromycin) was used in 74 subjects with doxycycline and azithromycin used in 46 and 57 subjects, respectively. Incidence of delayed defervescence was seen in 31.6%, Combination therapy being preferred in sicker patients (SOFA score 8.82). Presence of respiratory dysfunction was associated with a delay in fever defervescence [risk ratio 2.50(1.18-5.3)]. Patients receiving doxycycline did better in terms of oxygen requirement and the presence of hypotension. The overall case fatality rate was 5.6%. The severity of illness rather than the choice of antibiotics predicted the outcome in scrub typhus. INTERPRETATION & CONCLUSION: Combination therapy with doxycycline and azithromycin is the most common regimen used. Incidence of delayed defervescence (31.6%) is increasing despite therapy and the involvement of respiratory dysfunction is an independent predictor of delayed fever defervescence.

Scrub Typhus and Other Rickettsial Infections.

Scrub typhus and other rickettsial infections contribute to 25 - 50% of acute undifferentiated febrile illnesses in endemic regions. Delayed recognition and therapy increase the morbidity and mortality. The constellation of fever with eschar or rash and multisystem involvement should facilitate the diagnosis and initiation of appropriate therapy. The pathological hallmark of rickettsial infections is endothelial infection and inflammation causing vasculitis. Endothelial inflammation results in microvascular dysfunction and increased vascular permeability. Immune and endothelial activation may worsen microvascular dysfunction, predisposing to multi-organ failure. Serology is the mainstay of diagnosis, although false negatives occur early in the disease. Point-of-care rapid diagnostic tests and molecular techniques, such as quantitative polymerase chain reaction (qPCR), can hasten diagnostic processes. Intravenous doxycycline with a loading dose is the most widely used antibiotic in critically ill patients, with azithromycin as a suitable alternative. Early appropriate treatment and organ support can decrease the duration of illness and be life-saving. How to cite this article: Gunasekaran K, Bal D, Varghese GM, et al. Scrub Typhus and Other Rickettsial Infections. Indian J Crit Care Med 2021;25(Suppl 2):S138-S143.

Scrub typhus: a reemerging infection.

PURPOSE OF REVIEW: Scrub typhus, caused by Orientia tsutsugamushi, is a widely neglected disease which is gaining global momentum because of its resurgence patterns. The disease is now being reported in newer regions as well as areas previously endemic areas. In this review, we aim to comprehensively review the data available to assist physicians in making an accurate diagnosis and appropriate management of the disease. RECENT FINDINGS: Several diagnostic tests have been developed for confirming scrub typhus. However, there is lack of clarity on which tests are most appropriate in a given clinical scenario. A recent study has demonstrated that in early disease (<7 days) when serological tests remain negative, the quantitative polymerase chain reaction is the most sensitive test. Among the serological tests, both IgM enzyme-linked immunosorbent assay as well as rapid diagnostic tests revealed excellent sensitivities and specificities. SUMMARY: With the reemergence of scrub typhus, a high degree of clinical suspicion is required to appropriately diagnose this disease which presents as an acute febrile illness. It can progress to develop various complications leading to multi-organ dysfunction syndrome. Mild illness responds well to antibiotic treatment with doxycycline and azithromycin. Further studies are required to determine the most optimal therapy in severe scrub typhus infections and superiority of one drug over the other.

Clinical management of COVID-19.

The novel coronavirus disease 2019 (COVID-19) with its early origin from Wuhan city in China has evolved into a global pandemic. Maximal precautionary measures and resources have been put forward by most nations in war footing to mitigate transmission and decrease fatality rates. This article was aimed to review the evidence on clinical management and to deal with the identification of high-risk groups, warning signs, appropriate investigations, proper sample collection for confirmation, general and specific treatment measures, strategies as well as infection control in the healthcare settings. Advanced age, cardiovascular disease, diabetes, hypertension and cancer have been found to be the risk factors for severe disease. Fever lasting for >five days with tachypnoea, tachycardia or hypotension are indications for urgent attention and hospitalization in a patient with suspected COVID-19. At present, reverse transcription-polymerase chain reaction (RT-PCR) from the upper respiratory tract samples is the diagnostic test of choice. While many drugs have shown in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there are insufficient clinical data to promote or dissuade their usage. Among the currently available drugs, hydroxychloroquine and lopinavir/ritonavir may be considered for patients with severe COVID-19 infection, awaiting further clinical trials. Stringent droplet and contact precautions will protect healthcare workers against most clinical exposures to COVID-19.