Long COVID syndrome: An unfolding enigma.

Post-acute sequelae of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19), called as long COVID syndrome, is a major global public health issue after recovery from COVID-19. The disease occurs in symptomatic patients irrespective of illness severity. The symptoms continue after four wk of recovery from acute illness and persist beyond three months. Risk factors for long COVID include older age, female gender, multiple co-morbidities including diabetes mellitus, prior chronic respiratory illnesses, hospitalized patients with severe disease, especially receiving assisted ventilation, high viral load, reactivation of Epstein Barr (EB) virus and human herpes virus 6 (HH6), circulating auto antibodies against various organs and type I interferon. The prevalence varies from 10 to 20 per cent, and most data have been reported from high-income countries. Any system can get involved in long COVID. The symptoms include fatigue, cognition impairment, cough and dyspnoea, anosmia, hair loss and diarrhoea, among others. While there are no laboratory tests for confirmation of diagnosis, reduced complement C7 complexes at six months, and a two-gene biomarker including FYN and SARS-CoV-2 antisense ribonucleic acid (RNA) are emerging as potentially useful biomarkers for long COVID. There should be no alternative disease to explain various symptoms. Vaccination against SARS-CoV-2 and early use of oral antiviral nirmatrelvir within the first five days in patients with acute mild disease having various risk factors for progression to severe disease help in preventing long COVID. Several clinical trials are underway for the treatment of long COVID and the results of these are eagerly awaited. Physical and mental rehabilitation at home, at community level or in the hospital setting as appropriate is essential in patients with long COVID.

Efficacy of low-dose lung radiotherapy in the management of COVID-19 patients: a randomised, open-label study.

OBJECTIVE: Evaluate role of low-dose radiotherapy (LDRT) in COVID-19 pneumonia. METHODS: Sixty-five patients 40 years or older tested positive for COVID-19 reverse transcriptase-polymerase chain reaction with mild to moderate acute respiratory distress syndrome (ARDS), were randomised 1:1, from 4 June 2021, to either best standard of care (control arm) according to the Indian Council of Medical Research guidelines or a single dose of LDRT (LDRT-0.5Gy) to both lungs along with best standard of care (experimental arm). The primary outcome was either progression to severe disease (PaO2/FiO2 ratio <100 mmHg) within 28 days of randomisation or all-cause mortality at 28 days. If the primary outcome could have been prevented, it was considered "favourable"; if not, it was considered "unfavourable." RESULTS: Thirty-three patients were allocated to experimental arm, 32 to control arm. An intention to treat analysis was performed. Unfavourable outcome was seen in 5 (15.2%) patients in experimental arm, vs , 12 (37.5%) patients in control arm, odds of an unfavourable outcome in experimental arm were 0.3, 95% CI 0.09-0.97; two-sided p = 0.04. Four and five patients died in experimental and control arm, respectively. No radiation-induced toxicity was observed. CONCLUSION: LDRT reduced the number of patients with unfavourable outcome at 28 days. ADVANCES IN KNOWLEDGE: One of the few randomised studies showing reduced unfavourable outcome in mild to moderate ARDS COVID-19 patients receiving LDRT.CTRI/2021/06/034001, Clinical Trials Registry - India (ICMR-NIMS).

Molecular diversity of Mycobacterium tuberculosis isolates in Treatment-experienced Patients from Andhra Pradesh, India.

INTRODUCTION: To get a comprehensive idea about the transmission and epidemiology of TB globally and locally, the use of molecular typing methods has become imperative not only for understanding genetic diversity but also the population structure of Mycobacterium tuberculosis complex (MTBC). We aimed to investigate the drug resistance pattern and genetic diversity of MTBC among previously treated patients with sputum smear-positive pulmonary tuberculosis in a South Indian population. METHODOLOGY: 104 patients with sputum smear positivity and who had previously undergone treatment were selected. Drug susceptibility testing, Spoligotyping, MIRU-VNTR, and SNP typing were performed. RESULTS: Mono-resistance to isoniazid 16 (15.38%) was the highest among all drugs. Out of 104 isolates, 24 (23%) isolates were classified as MDR strains. The distributions of most common lineages were: EAI3-Ind-20 (19.23%), EAI5-13 (12.50%), Beijing-12 (11.54%), CAS1-Delhi- 9 (8.65%), and 7 (6.73%) each of T-H37rv, Unknown and Orphan types. MIRU-VNTR-based analysis revealed that there are two major groups: CAS1-Delhi and Beijing groups. Out of 104 isolates, 82 belonged to well-defined lineages and 6 clusters, and the remaining 22 were singletons. SNP analysis showed no mutations associated with five sets of genes in 33 strains. CONCLUSIONS: The occurrence of 11.54% Beijing strains in South India is an important finding. High frequency of Isoniazid mono resistance noticed. Spoligotyping along with MIRU-VNTR and SNP typing is the best approach to the identification of strain lineages. No mutation with Antigen85C gene represents, can be used for vaccine candidates.

Mutation Analysis of SARS-CoV-2 Variants Isolated from Symptomatic Cases from Andhra Pradesh, India.

There has been a continuous evolution in the SARS-CoV-2 genome; therefore, it is necessary to monitor the shifts in the SARS-CoV-2 variants. This study aimed to detect various SARS-CoV-2 variants circulating in the state of Andhra Pradesh, India. The study attempted to sequence the complete S-gene of SARS-CoV-2 of 104 clinical samples using Sanger's method to analyze and compare the mutations with the global prevalence. The method standardized in this study was able to amplify the complete length of the S-gene (3822 bp). The resulting nucleotide and amino acid mutations were analyzed and compared with the local and global SARS-CoV-2 databases using Nextclade and GISAID tools. The Delta variant was the most common variant reported in the present study, followed by the Omicron variant. A variant name was not assigned to thirteen samples using the Nextclade tool. There were sixty-nine types of amino acid substitutions reported (excluding private mutations) throughout the spike gene. The T95I mutation was observed predominantly in Delta variants (15/38), followed by Kappa (3/8) and Omicron (1/31). Nearly all Alpha and Omicron lineages had the N501Y substitution; Q493R was observed only in the Omicron lineage; and other mutations (L445, F486, and S494) were not observed in the present study. Most of these mutations found in the Omicron variant are located near the furin cleavage site, which may play a role in the virulence, pathogenicity, and transmission of the virus. Phylogenetic analysis showed that the 104 complete CDS of SARS-CoV-2 belonged to different phylogenetic clades like 20A, 20B, 20I (Alpha), 21A (Delta), 21B (Kappa), 21I (Delta), 21J (Delta), and 21L (Omicron).

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.).

Arterial and venous thrombosis in a patient with Covid-19: A unique presentation.

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection not only affects the respiratory system but also induces coagulation abnormalities and thrombosis. We report a middle-aged woman who presented during the Covid-19 pandemic with sudden-onset acute left upper limb ischaemia of short duration, with no history of dry cough, breathlessness or fever, and tested positive on TrueNAT for SARS-CoV-2. Later, she developed deep venous thrombosis of the right lower limb during isolation in the hospital.

A study on the effect of mobile phone use on sleep.

Background & objectives: Several studies have been conducted globally to assess the impact of usage of mobile phones on quality and duration of sleep as also on day time sleepiness. The objective of the present study was to assess the effect of mobile phone usage on the quality and composition of sleep in a sample from Indian population. Methods: The study was conducted at two tertiary care hospitals in north India from July 2014 to September 2019. A total of 566 participants were recruited in this study from both the centres. Sleep quality was assessed with the help of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Subsequently, actigraphy was done in 96 participants and polysomnography in 95 participants. Results: Of the 566 participants, 128 (22.61%) had PSQI ≥5, reflecting poor sleep quality. A higher use of mobile phone was significantly associated with a poor sleep quality as a component of PSQI questionnaire (P=0.01) and higher overall PSQI score (P=0.01). The latency from sleep onset to N2 and N3 sleep stages was significantly shorter in participants having a higher mobile phone usage as compared to those with a lower usage [Median (range): 13.5 min (1.5-109) vs. 6.5 min (0-89); P=0.02] and [Median (range): 49 min (8.5-220.5) vs. 28.75 min (0-141); P=0.03], respectively. Interpretation & conclusions: This study focused on the maladaptive changes brought on by mobile phone usage on sleep. More studies with larger sample sizes need to be done that may serve to confirm the hypothesis generating findings of our study.

Pulmonary drug delivery and retention: A computational study to identify plausible parameters based on a coupled airway-mucus flow model.

Pulmonary drug delivery systems rely on inhalation of drug-laden aerosols produced from aerosol generators such as inhalers, nebulizers etc. On deposition, the drug molecules diffuse in the mucus layer and are also subjected to mucociliary advection which transports the drugs away from the initial deposition site. The availability of the drug at a particular region of the lung is, thus, determined by a balance between these two phenomena. A mathematical analysis of drug deposition and retention in the lungs is developed through a coupled mathematical model of aerosol transport in air as well as drug molecule transport in the mucus layer. The mathematical model is solved computationally to identify suitable conditions for the transport of drug-laden aerosols to the deep lungs. This study identifies the conditions conducive for delivering drugs to the deep lungs which is crucial for achieving systemic drug delivery. The effect of different parameters on drug retention is also characterized for various regions of the lungs, which is important in determining the availability of the inhaled drugs at a target location. Our analysis confirms that drug delivery efficacy remains highest for aerosols in the size range of 1-5 µm. Moreover, it is observed that amount of drugs deposited in the deep lung increases by a factor of 2 when the breathing time period is doubled, with respect to normal breathing, suggesting breath control as a means to increase the efficacy of drug delivery to the deep lung. A higher efficacy also reduces the drug load required to be inhaled to produce the same health effects and hence, can help in minimizing the side effects of a drug.

Molecular Characterization and Identification of Potential Inhibitors for 'E' Protein of Dengue Virus.

Dengue is an arthropod-borne acute febrile illness caused by Dengue Virus (DENV), a member of Flaviviridae. Severity of the infection ranges from mild self-limiting illness to severe life-threatening hemorrhagic fever (DHF) and dengue shock syndrome (DSS). To date, there is no specific antiviral therapy established to treat the infection. The current study reports the epidemiology of DENV infections and potential inhibitors of DENV 'E' protein. Among the various serotypes, DENV-2 serotype was observed more frequently, followed by DENV-4, DENV-1, and DENV-3. New variants of existing genotypes were observed in DENV-1, 2, and 4 serotypes. Predominantly, the severe form of dengue was attributable to DENV-2 infections, and the incidence was more common in males and pediatric populations. Both the incidence and the disease severity were more common among the residents of non-urban environments. Due to the predominantly self-limiting nature of primary dengue infection and folk medicine practices of non-urban populations, we observed a greater number of secondary dengue cases than primary dengue cases. Hemorrhagic manifestations were more in secondary dengue in particularly in the pediatric group. Through different computational methods, ligands RGBLD1, RGBLD2, RGBLD3, and RGBLD4 are proposed as potential inhibitors in silico against DENV-1, -2, -3, and -4 serotypes.

Spatial analysis of chronic obstructive pulmonary disease and its risk factors in an urban area of Trivandrum, Kerala, India.

Background: Chronic obstructive pulmonary disease (COPD) is the second leading cause of death in India. The objective of this study was to map COPD cases and its risk factors and to determine the association between them using geographic information system (GIS) in a semi-urban area of Trivandrum, South India. Materials and Methods: This community-based cross-sectional, descriptive study (n = 494) was conducted in a subcenter area of a primary health center. Location was mapped and COPD population screener questionnaire was administered to all the study subjects enrolled by census method. Lifetime firewood exposure (person-hours) and tobacco smoking were enquired and distance from road was mapped using portable differential global positioning system. The association with COPD was assessed by kriging and hotspot analysis using ArcGIS software. Results: The prevalence of COPD (6.5%) was comparable to national prevalence estimates. Spatial maps showed COPD case clustering in areas with higher firewood exposure, greater smoking exposure, and in households with closer proximity to local roads. A particular high-risk cluster was obtained which had a significant association with all the risk factors. Conclusion: GIS technology is useful in identification of spatial clustering of COPD cases and its environmental risk factors, making it an important tool for targeted interventions for COPD.

Diagnostic yield of CBNAAT in the diagnosis of extrapulmonary tuberculosis: A prospective observational study.

Background: Extrapulmonary Tuberculosis (EPTB) accounts for 15%-53% of all TB cases. In recent years, cartridge-based nucleic acid amplification test (CBNAAT) has emerged as an important diagnostic tool since the diagnostic yield is higher. We conducted this study to evaluate the diagnostic yield of CBNAAT in EPTB. Methods: One hundred and four patients with EPTB were included in the study. Samples were subjected to CBNAAT, AFB smear, culture for Mycobacterium tuberculosis and histopathology examination (HPE). Yield of each was estimated as compared to a composite reference standard (CRS). Results: The most common EPTB was lymph node TB (48.1%). CBNAAT was positive in 30.76% of EPTB cases. The highest yield was for bone and joint TB (35.7%), followed by lymph node TB (34%) and abdominal TB (33.3%). Taking CRS as the gold standard, sensitivity of CBNAAT was 32.3%, that of AFB culture was 33.3% and that of HPE was 87.2%. Conclusion: When taken as a single diagnostic tool, HPE had highest sensitivity in diagnosing EPTB when compared to CBNAAT and AFB culture. Use of CBNAAT alone for diagnosis of EPTB may result in missing the diagnosis. A combined modality incorporating CBNAAT, histopathology and AFB culture is the best approach for diagnosis of EPTB.

Extrapulmonary tuberculosis.

Introduction: Tuberculosis (TB) is a major cause of morbidity and mortality globally. Extrapulmonary TB (EPTB) constitutes about 15%-20% of all TB patients, but accounts for 50% among HIV-coinfected. Confirmation of microbial diagnosis of EPTB is usually challenging.Areas covered: Availability of newer imaging modalities like 18FDG-PET-CT and PET-MRI has facilitated precise anatomical localization of the lesions and mapping the extent of EPTB. The use of image- and endoscopy-guided invasive diagnostic methods has made procurement of tissue/body fluids for diagnostic testing possible. With the advent of universal drug-susceptibility testing, a rapid diagnosis of drug-resistance is now possible in EPTB. Drug-susceptible EPTB usually responds well to first-line anti-TB treatment; TB meningitis, bone and joint TB and lymph node TB requires longer durations of treatment.Expert opinion: Adjunctive use of corticosteroids in the initial period is recommended in the central nervous system and pericardial TB. Surgical intervention is helpful to obtain tissue samples for diagnosis. Adjunctive surgical treatment along with medical treatment is useful in treating complications like hydrocephalus, Pott's spine. Follow-up of EPTB patients is crucial as treatment period is usually prolonged, requires recognition of development of immune reconstitution and inflammatory syndrome (IRIS), monitoring of adverse events, serious adverse events like anti-TB drug-induced hepatotoxicity, organ-related complications, and treatment adherence.

Serum procalcitonin as a biomarker of bloodstream infection & focal bacterial infection in febrile patients.

Background & objectives: Bacteraemia is a serious form of infection in patients presenting with fever, thus, there is a necessity for a biomarker for rapid diagnosis of bacteraemia in such patients to make better therapeutic decisions. This study was conducted to measure the serum procalcitonin (PCT) levels at the time of initial presentation as a biomarker for identifying bacteraemia and as a predictor of mortality in patients admitted with acute fever. Methods: Four hundred and eighty patients, who presented with acute fever requiring admission to a tertiary care teaching hospital in south India, were prospectively studied. All patients were evaluated with a detailed history, physical examination, laboratory and imaging studies. Baseline serum PCT was measured for each patient within six hours of admission. Results: Among patients with single infectious cause (n=275), significantly higher median serum PCT levels were evident in bacteraemia compared to leptospirosis (P=0.002), dengue (P <0.001), scrub typhus (P <0.001) and evident focus of infection without bacteraemia (P=0.036). By receiver-operator characteristic curve analysis, at a cut-off value of >3.2 ng/ml, the sensitivity and specificity of serum PCT levels in predicting bacteraemia were 81.1 and 63.3 per cent, respectively. As per the worst-case scenario analysis, 91 (18.9%) patients had a poor outcome and these had significantly higher median serum PCT levels compared to survivors (n=389) [9.46 (2.03-44.4) vs. 1.23 (0.34-7.645); P <0.001]. At a cut-off value of >3.74 ng/ml, serum PCT levels at initial presentation predicted in-hospital mortality with a sensitivity and specificity of 67 and 67.5 per cent, respectively. Interpretation & conclusions: Our observations suggest that serum PCT level may be a useful biomarker for identifying bacteraemia as well as predicting mortality in patients with acute fever requiring admission to hospital.

Cleistanthus collinus Poisoning.

How to cite this article: Mohan A, Harikrishna J. Cleistanthus collinus Poisoning. Indian J Crit Care Med 2019;23(Suppl 4):S256-S259.

Co-circulation of four dengue serotypes at South Eastern Andhra Pradesh, India: A prospective study.

Background: Dengue is one of the most important mosquito-borne viral diseases in the world. The emergence and spread of four dengue viruses (DENVs) (serotypes) represent a global pandemic. The four distinct serotypes are, namely, DENV-1, DENV-2, DENV-3 and DENV-4. Very few dengue serotyping studies have been reported from Andhra Pradesh. In this context, the present study focuses on the circulating serotypes of dengue in South-Eastern Andhra Pradesh. Methodology: Study was done at Sri Venkateswara Institute of Medical Sciences, a teaching hospital in Tirupati, Andhra Pradesh. Acute phase dengue serum samples were collected and tested for NS1 antigen and anti-human IgM antibodies by enzyme-linked immunosorbent assay (ELISA). NS1-positive samples were further serotyped by reverse transcriptase real-time polymerase chain reaction (rRT-PCR). Results: A total of 398 serum samples were received from clinically suspected dengue fever cases. Of these, 150 (37.7%) samples were positive for NS1 and/or IgM ELISA. The 96 NS1 antigen-positive samples were further processed for serotyping, of which 36 were negative by rRT-PCR. DENV-2 (41%) was the predominant serotype, followed by DENV-4 (37%), DENV-3 (12%) and DENV-1 (10%) in descending order. Conclusion: This study reports the all four dengue serotypes' co-circulation. This is the first report from South Eastern Andhra Pradesh. Amongst four, DENV-2 was predominant followed by DENV-4. The information of predominant serotypes can guide in forecasting dengue outbreaks and improving control measures of vectors thus may be helpful in the prevention of outbreaks.

Impact of nicotine replacement therapy as an adjunct to anti-tuberculosis treatment and behaviour change counselling in newly diagnosed pulmonary tuberculosis patients: an open-label, randomised controlled trial.

We evaluated the impact of intensive smoking cessation activities as an adjunct to anti-tuberculosis treatment on patient-related treatment outcomes. In this open-label, randomised controlled trial, self-reporting smokers with pulmonary tuberculosis who initiated standard anti-tuberculosis treatment were randomised to either nicotine replacement therapy and behaviour change counselling (n = 400) or counselling alone (n = 400) provided at baseline and two follow-up visits. The primary outcomes were change in TBscore at 24-weeks and culture conversion at 8-weeks. Biochemical smoking quit rates defined as serum cotinine levels <10 ng/mL and/or exhaled carbon monoxide levels <6 ppm (47·8% vs 32·4%, p-value =< 0·001) and self-reported quit rates (69.3% vs 38·7%, p-value =< 0·001) were significantly higher in the intervention arm at 24-weeks. Though the TBscores at 24 weeks (95% CI) were lower in the intervention arm [2·07 (1·98, 2·17) versus 2.12 (2·02, 2·21)], the difference was not clinically meaningful. Patients in the control arm required treatment extension more often than intervention arm (6·4% vs 2·6%, p-value = 0·02). Combining nicotine replacement therapy with behaviour change counselling resulted in significantly higher quit rates and lower cotinine levels, however, impact on patient-related (TBscore) or microbiological outcomes (culture conversion) were not seen.

Impact of Severity of Illness on the Function of the Hypothalamo-pituitary-gonadal Axis in Postmenopausal Women with Acute Severe Illness: Implications for Predicting Disease Outcome.

BACKGROUND: While elevated levels of estradiol were predictive of mortality in critically ill surgical and trauma patients, their ability to predict outcome in nonsurgical patients has not been studied. We aimed to study the determinants of gonadotropin levels in acutely ill postmenopausal women with nonsurgical disease and the impact of changes in the gonadal axis on the outcome of these patients. METHODS: Thirty-five postmenopausal women admitted to medical intensive care with acute severe illness and having a Simplified Acute Physiology Score (SAPS II score) ≥30 (in-hospital mortality rate ≥ 10%) were recruited. On the 5th day of hospitalization, fasting samples were collected at 8.00 am and tested for luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, free triiodothyronine, free thyroxine, thyrotropin, cortisol, prolactin, dehydroepiandrosterone, androstenedione, and sex hormone-binding globulin. Multiple linear regression analysis was performed to identify independent determinants if any of LH and FSH. Receiver operating characteristic (ROC) curves were drawn for different cutoffs of LH, FSH, and estradiol to diagnose mortality and prolonged hospitalization. RESULTS: There was an independent negative association between the FSH and the SAPS II score (beta = -0.435; P = 0.014), but not with any of the other tested parameters (estradiol, prolactin, or cortisol). Among components of the SAPS II score, the total leukocyte count (TLC) was negatively associated with serum FSH (beta coefficient = -0.635, P = 0.013). None of these parameters were determinants of LH. On ROC analysis, neither estradiol nor gonadotropins were diagnostic for in-hospital mortality. However, among survivors, low estradiol was diagnostic for prolonged hospital stay (area under the curve = 0.785; P = 0.015). CONCLUSION: FSH, but not LH, is negatively associated with the severity of illness, particularly to its inflammatory component (TLC). Low estradiol in survivors was a predictor of prolonged hospital stay.