Approach towards surveillance-based diagnosis of acute respiratory illness in India: Expert recommendations.

BACKGROUND: Emerging infectious diseases, often zoonotic, demand a collaborative "One-Health" surveillance approach due to human activities. The need for standardized diagnostic and surveillance algorithms is emphasized to address the difficulty in clinical differentiation and curb antimicrobial resistance. OBJECTIVE: The present recommendations are comprehensive diagnostic and surveillance algorithm for ARIs, developed by the Indian Council of Medical Research (ICMR), which aims to enhance early detection and treatment with improved surveillance. This algorithm shall be serving as a blueprint for respiratory infections landscape in the country and early detection of surge of respiratory infections in the country. CONTENT: The ICMR has risen up to the threat of emerging and re-emerging infections. Here, we seek to recommend a structured approach for diagnosing respiratory illnesses. The recommendations emphasize the significance of prioritizing respiratory pathogens based on factors such as the frequency of occurrence (seasonal or geographical), disease severity, ease of diagnosis and public health importance. The proposed surveillance-based diagnostic algorithm for ARI relies on a combination of gold-standard conventional methods, innovative serological and molecular techniques, as well as radiological approaches, which collectively contribute to the detection of various causative agents. The diagnostic part of the integrated algorithm can be dealt at the local microbiology laboratory of the healthcare facility with the few positive and negative specimens shipped to linked viral disease research laboratories (VRDLs) and other ICMR designated laboratories for genome characterisation, cluster identification and identification of novel agents.

Coagulation Abnormalities in Severe Scrub Typhus and Their Association with Complications.

AIM: To describe coagulation abnormalities and their association with complications in patients with severe scrub typhus. MATERIALS AND METHODS: A cohort study was conducted among all patients of severe scrub typhus [immunoglobulin M (IgM) positive] who reported to this facility from 1st August 2019 to 31st July 2020 and met our inclusion criteria. We estimated the incidence of severe thrombocytopenia (<50,000/µL) and overt disseminated intravascular coagulation (DIC) (DIC score of ≥5). We determined the association [risk (RR) ratios] of these abnormalities with complications of scrub typhus, namely-septic shock, multiple organ dysfunction syndrome (MODS), and septic shock with MODS. RESULTS: In total, 71 patients were studied with a mean age of 50 ± 15.5 years, of which 45 (63.4%) were females. On presentation, fever 70 (98.5%), myalgias 22 (31.0%), loose stools 13(18.3%), cough, vomiting, headache 11 (15.5%), altered sensorium 10(14.1%), and pain abdomen 9 (12.7%) were main symptoms. On examination, hypotension 31 (43.7%), eschar 25 (35.2%), icterus 17 (23.9%), and rash 16 (22.5%) were noted. The d-dimer (>0.5 µg/mL) levels were increased in all (100%) patients. Thrombocytopenia (91.5%) was the commonest hematological abnormality and 31 (43.6%) of them had severe thrombocytopenia, 25 (35.2%) patients had low fibrinogen levels (<200 mg/dL) and prothrombin time (PT >16.7 seconds) was prolonged in 20 (28.1%). A total of 42 (59.1%) patients developed MODS, 33 (46.4%) developed septic shock, 24 (33.8 %) had MODS with septic shock, 17 (23.9%) developed overt DIC, and eight (11.2%) died. Severe thrombocytopenia (p = -0.028) and overt DIC (p = 0.045) were significantly associated with septic shock development. CONCLUSION: In the patients admitted with severe scrub typhus; thrombocytopenia was the commonest hematological abnormality. The development of septic shock was significantly associated with severe thrombocytopenia and overt DIC.

Assessing clinical and molecular outcomes of prophylactic thermal pulsation therapy on ocular surface health following refractive surgery.

Purpose: To study ocular surface signs, symptoms, and tear film composition following prophylactic thermal pulsation therapy (TPT) prior to refractive surgery, and to compare these outcomes with those who underwent TPT after refractive surgery. Methods: Patients with mild-to-moderate evaporative dry eye disease (DED) and/or meibomian gland dysfunction (MGD) undergoing refractive surgery were included. Group 1 patients received TPT (LipiFlow) prior to laser-assisted in situ keratomileusis (LASIK; n = 32, 64 eyes), and Group 2 patients received TPT three months after LASIK (n = 27, 52 eyes). Ocular Surface Disease Index (OSDI) score, Schirmer's test (ST1, ST2), Tear Breakup Time (TBUT), meibography, and tear fluid were obtained preoperatively and at three months postoperatively in Groups 1 and 2. Additional postoperative evaluation was performed three months after TPT in Group 2. Tear soluble factor profile was measured by multiplex enzyme-linked immunosorbent assay (ELISA) using flow cytometry. Results: Postoperative OSDI score was significantly lower and TBUT was significantly higher when compared with matched preoperative values of Group 1 participants. On the other hand, the postoperative OSDI score was significantly higher and TBUT significantly lower when compared with matched preoperative values of Group 2 participants. TPT significantly reduced the postoperative elevation in OSDI and significantly reduced the postoperative reduction in TBUT in Group 2 participants. Tear Matrix metalloproteinase-9/ Tissue inhibitor matrix metalloproteinase 1 (MMP-9/TIMP1) ratio was significantly higher, postoperatively, when compared with matched preoperative levels in Group 2. However, MMP9/TIMP1 ratio remained unaltered in Group 1 participants. Conclusion: TPT prior to refractive surgery improved postsurgical ocular surface signs and symptoms and reduced tear inflammatory factors, thereby suggesting the plausibility of reduced post-refractive surgery DED in patients.

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.).

Altered Ocular Surface Health Status and Tear Film Immune Profile Due to Prolonged Daily Mask Wear in Health Care Workers.

Prolonged daily face mask wearing over several months might affect health of the ocular surface and is reported to be associated with complaints of discomfort and dry-eye-like symptoms. We studied the ocular surface clinical parameters, tear soluble factors and immune cell proportions in ophthalmologists practicing within similar environmental conditions (n = 17) at two time points: pre-face-mask period (Pre-FM; end of 2019) and post-face-mask-wearing period (Post-FM; during 2020 COVID-19 pandemic), with continuous (~8 h/day) mask wear. A significant increase in ocular surface disease index (OSDI) scores without changes in tear breakup time (TBUT), Schirmer's test 1 (ST1) and objective scatter index (OSI) was observed Post-FM. Tear soluble factors (increased-IL-1ß, IL-33, IFNß, NGF, BDNF, LIF and TSLP; decreased-IL-12, IL-13, HGF and VEGF-A) and mucins (MUC5AC) were significantly altered Post-FM. Ex vivo, human donor and corneoscleral explant cultures under elevated CO2 stress revealed that the molecular profile, particularly mucin expression, was similar to the Post-FM tear molecular profile, suggesting hypercapnia is a potential contributor to ocular surface discomfort. Among the immune cell subsets determined from ocular surface wash samples, significantly higher proportions of leukocytes and natural killer T cells were observed in Post-FM compared to Pre-FM. Therefore, it is important to note that the clinical parameters, tear film quality, tear molecular factors and immune cells profile observed in prolonged mask-wear-associated ocular surface discomfort were distinct from dry eye disease or other common ocular surface conditions. These observations are important for differential diagnosis as well as selection of appropriate ocular surface treatment in such subjects.

Is Hyperuricemia a Marker of Severity of Disease in Scrub Typhus?

AIMS: To study association of hyperuricemia with severity of scrub typhus. METHODS: We studied clinical features, laboratory profile, in hospital course and outcome of 92 patients of scrub typhus and association of hyperuricemia with severity of disease. RESULTS: Of total 92 patients in study group, 66 (71.7%) were females and 26(28.3%) were males. Fever (100%), cough (37%), headache (33%), vomiting (31%), altered sensorium (23%), diarrhea (18%), abdominal pain (16%), myalgia (14%), and seizures (3%) were common clinical features. Eschar was present in 23%. Of total 92 patients 34 (37%) patients had hyperuricemia (HU) and 58 patients had normal serum uric acid levels. The patients of scrub typhus with HU had significantly higher presentation with altered sensorium (35.3%). In HU group, mean TLC, mean serum urea and serum creatinine were higher and mean serum albumin and mean HDL cholesterol were lower than patients of scrub typhus without hyperuricemia. These differences between two groups were statistically significant. Neurological dysfunction, severe sepsis, serum creatinine >3.5mg/dL and involvement of at least single organ was significantly higher in HU group. Total 4 patients (4.3%) died and all had HU. CONCLUSION: Hyperuricemia in patients of scrub typhus was associated with severe scrub typhus. The serum uric acid levels should be done in early course of all patients suffering from scrub typhus. The patients showing hyperuricemia should be monitored closely for early recognition of complications and management aggressively.

Heerfordt-Waldenström Syndrome.

Heerfordt's-Waldenström syndrome is a very rare presentation of neurosarcoidosis characterized by parotid gland enlargement, facial palsy, anterior uveitis and fever. World over only few cases of this syndrome have been reported. We present such a case of Heerfordt-Waldenström syndrome.

Rare Interaction of Warfarin and Digoxin in a Case of Digoxin Toxicity.

Warfarin is known to interact with many drugs and can lead to serious consequences. We report a case of 52 years old female patient from Himachal Pradesh. During hospital stay patient developed coagulopathy in form of INR above 10 and bradycardia with ventricular rate on ECG with digoxin level of 3.76 ng/ml. In this way digoxin toxicity was confirmed and it was considered as cause of coagulopathy after ruling out interactions of warfarin.

Predictors of Severity in Scrub Typhus.

AIMS: To study predictors of severity in patients of scrub typhus admitted in a tertiary care hospital. MATERIAL AND METHODS: Total 92 patients of scrub typhus were included in the study. The diagnosis was established by presence of IgM antibodies by Indirect Immunofluorescence Assay (IFA) test which is currently the reference standard for the diagnosis of scrub typhus. The clinical and laboratory profile, course in hospital, and outcome were documented. Factors associated with severe disease were analyzed. OBSERVATIONS: Fever (100%), cough (37%), headache (33%), vomiting (31%), altered sensorium (23%), diarrhea (18%), abdominal pain (16%), myalgia (14%), and seizures (3%) were common clinical features. An eschar was present in 23% of patients. Common laboratory findings included elevated transaminases (61%), thrombocytopenia (39%), and leukocytosis (30%). Severe sepsis was present in 33% patients. Septic shock was present in 4% patients. Presence of one or more organ failure was seen in 34% of patients. The overall case-fatality rate was 4%. Factors significantly associated with organ failure (severe disease) were leucocytosis (p < 0.001), hyperbilirubinemia (p < 0.001), high SGOT levels (p 0.030), hypoalbuminemia (p < 0.001), high urea levels (p < 0.001), and high creatinine levels (p 0.012). Among the criteria used to classify severity of scrub typhus, presence of one or more organ failure was significantly associated with mortality (p 0.004). CONCLUSION: Scrub typhus can manifest with potentially life-threatening complications such as meningoencephalitis, septic shock, ARDS, acute liver failure, acute kidney injury, severe thrombocytopenia. Leukocytosis, hyperbilirubinemia, transaminitis, hypoalbuminemia, and uremia were associated with organ failure and were significantly associated with morbidity and mortality.

Are We Neglecting Nontuberculous Mycobacteria Just as Laboratory Contaminants? Time to Reevaluate Things.

OBJECTIVES: Nontuberculous mycobacteria (NTM) incidences are on the rise worldwide, including the tuberculosis endemic areas. They should be identified rapidly to the species level and should be carefully differentiated as contamination, colonization, or disease. This study was aimed at determining the prevalence and clinicoepidemiological profile of mycobacteriosis cases. MATERIALS AND METHODS: Cultures were made on liquid and solid media. NTM were identified by polymerase chain reaction (PCR) restriction analysis (PRA) and gene sequencing. Data was analyzed using Epi-info 7. RESULTS: Out of the 1042 processed specimens, 16% were positive for M. tuberculosis complex and 1.2% for clinically significant NTM. M. intracellulare was the commonest species isolated. NTM were treated mainly on outdoor basis (92%), involving more extrapulmonary system (62%) and higher age-group of 41-60 years (69%). No significant factor was seen to be associated clinically, radiologically, and biochemically with the NTM infections. CONCLUSIONS: Our study highlights the importance of early diagnosis and differentiation among Mycobacterium tuberculosis and NTM so that these NTM are not underestimated in routine diagnostic procedures merely as environmental or laboratory contaminants.

The Evolving Pattern and Outcome of Stroke at Moderate Altitude.

BACKGROUND: The people residing in hills of this Sub-Himalayan region traditionally have a distinct lifestyle involving high level of physical activity. However, increased urbanization in the last two decades has led to changes in lifestyle of people. The present study was an endeavor to document changes in the pattern of stroke in people residing at moderate altitude. AIM: This study was aimed to study the evolving trends in clinical profile, risk factors, and outcome at 3 months in hospitalized patients of stroke in a Tertiary Care Hospital situated at moderate altitude. SETTING AND DESIGN: This prospective, observational study was carried out in a Tertiary Care Hospital, situated at 2000 m mean sea level, from July 2014 to June 2015 in Sub-Himalayan region of India. METHODS: The clinical features and risk factors profile of 235 patients of stroke consecutively admitted in hospital were analyzed, and findings were expressed in percentage. The profile was compared with a study conducted at this institute 15 years back. The outcome of patients at 3 months in terms of modified Rankin Scale >3 (mRS) and Barthel Index <60 (BI) was also studied. RESULTS: The occurrence of stroke as a cause of hospitalization was decreasing. Ischemic stroke was noted in 74%, and 26% had hemorrhagic stroke (HS). There was male predominance (58%), but affliction of females with stroke increased from 34% to 42%. The altered sensorium (P = 0.00) and neurological weakness (P = 0.024) were significantly associated with poor outcome in stroke. The occurrence of hypertension, diabetes mellitus, and coronary artery disease increased but smoking decreased among indoor patients of stroke in the last 15 years. Poor outcome of 203 patients at 3 months follow-up in terms of mRS >3 was 79 (IS-47, HS-32) but in term of BI, 63 (IS-32, HS-31) had poor outcome. Overall HS had poorer outcome. Age >70 years, female sex, altered sensorium, hypertension, and diabetes mellitus, were observed as poor prognostic factors, but the association was significant with advanced age, headache, and altered sensorium. CONCLUSION: The occurrence of stroke decreased among hospitalized patients. Hypertension, diabetes mellitus, and coronary artery disease increased but smoking decreased among patients of stroke.

Neuropsychiatric Manifestations of Scrub Typhus.

Scrub typhus is caused by Orientia tsutsugamushi characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen and central nervous system. It was thought to have been eradicated from India. Recently it is being reported from many areas of India. The clinical picture and severity of the symptoms varies widely. The neurological manifestations of scrub typhus are not uncommon but are diverse. Meningoencephalitis is classical manifestation of scrub typhus but cerebellitis, cranial nerve palsies, plexopathy, transverse myelitis, neuroleptic malignant syndrome and Guillan-Barré syndrome are other manifestations reported in literature. The availability of literature on the neurological manifestations of scrub typhus is limited to case reports mainly. This article reviews various neurological manifestations of scrub typhus reported in literature.

Neurological manifestations of scrub typhus in adults.

In order to study the neurological manifestations in adult patients suffering from scrub typhus, 323 patients aged over 18 years, admitted with a positive diagnosis, were screened for neurological dysfunction; 37 patients with symptoms and/or signs suggestive of neurological dysfunction were included in the study. Of these, 31 (84%) patients had altered sensorium, four (11%) had cerebellitis, one (2%) patient had acute transverse myelitis and one (2%) had bilateral papilloedema without focal neurological deficit. Of the 31 patients with altered sensorium, 15 (40%) had meningoencephalitis, three (8%) had seizures, two (5%) had cerebral haemorrhages, one (2%) had a presentation likened to neuroleptic malignant syndrome (NMS) and one (2%) had a 6th nerve palsy with inflammation of the right cavernous sinus. Cerebrospinal fluid (CSF) analysis was abnormal in 23 patients (raised lymphocytes in 68%, raised protein in 80%). All patients improved with anti-rickettsial therapy.

Pattern of Clinical Presentation, Laboratory Findings and Mortality Risk Among Patients of Scrub Typhus in Western Himalayas.

OBJECTIVE: To study the pattern of the clinical presentation, laboratory findings and mortality risk among patients infected by scrub typhus in Western Himalayan region of India. METHODS: We studied all serologically confirmed cases of scrub typhus admitted to our hospital from July 2010 through December 2011. Presence of IgM antibodies to scrub typhus antigens by ELISA was considered as serological confirmation of the diagnosis. We observed the symptoms, signs, laboratory findings, risk factors for death from the time of admission till discharge/death. We performed bivariate and logistic regression analysis to look for independent risk factors for death. RESULTS: Total 253 patients were studied. All patients came from rural areas. More than 2/3rd were women and below 50 years of age each. High grade fever (90%), chills and rigors (68%), conjunctival suffusion (50%), body aches (43%), headache (41%), myalgias (37%), abdominal pain (21%), lymphadenopathy (17%), splenomegaly (17%), cough (16%), altered sensorium (16%), vomiting (15%), hepatomegaly (13%) were main presenting features. Eschar was present in 112 (44%) patients. Transaminitis (49%); and abnormal renal functions (31%) were predominant biochemical abnormalities. All patients were empirically treated with doxycycline/azithromycin. Thirteen (5%) patients died. CONCLUSIONS: In our region, rural women below 50 years of age presenting with high grade fever with or without eschar should be strongly suspected to be having scrub typhus. Renal dysfunction and altered sensorium are significant mortality risk factors (p < 0.05) and need to be identified at early stage to improve the treatment outcomes.

Scrub Typhus Presenting as Acute Cerebellitis.

Scrub typhus is known to present with varied presentation including involvement of central nervous system. We present a case who presented with fever and features of isolated cerebellitis. Serum showed IgM antibodies to scrub typhus by ELISA. Patient showed rapid response to doxycycline and dexamethasone.

Neurobrucellosis: an often forgotten cause of chronic meningitis.

We report a 26-year-old man of neurobrucellosis who presented with intermittent fever and headache for 2 years, sensori-neural hearing loss with cerebellar ataxia. He responded well to a combination of antimicrobials with significant clinical improvement.

Scrub typhus with visual hallucinations.

The occurrence of psychiatric symptoms in scrub typhus is not commonly reported in literature. We present a case of scrub typhus with visual hallucinations.

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.