SARS-CoV-2 re-infection: development of an epidemiological definition from India.

The current investigation was conducted with the objective to develop an epidemiological case definition of possible severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) re-infection and assess its magnitude in India. The epidemiological case definition for SARS-CoV-2 re-infection was developed from literature review of data on viral kinetics. For achieving second objective, the individuals who satisfied the developed case definition for SARS-CoV-2 re-infection were contacted telephonically. Taking available evidence into consideration, re-infection with SARS-CoV-2 in our study was defined as any individual who tested positive for SARS-CoV-2 on two separate occasions by either molecular tests or rapid antigen test at an interval of at least 102 days with one negative molecular test in between. In this archive based, telephonic survey, 58 out of 1300 individuals (4.5%) fulfilled the above-mentioned definition; 38 individuals could be contacted with healthcare workers (HCWs) accounting for 31.6% of the cases. A large proportion of participants was asymptomatic and had higher Ct value during the first episode. While SARS-CoV-2 re-infection is still a rare phenomenon, there is a need for epidemiological definition of re-infection for establishing surveillance systems and this study contributes to such a goal.Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) re-infection is an emerging concern and there is a need to define it. Therefore, working epidemiological case definition for re-infection was developed and its magnitude was explored via archive-based, telephonic survey. Re-infection with SARS-CoV-2 was defined as two positive tests at an interval of at least 102 days with one interim negative test. Thirty-eight of the 58 eligible patients could be contacted with 12 (31.6%) being HCWs. Majority of the participants were asymptomatic and had higher Ct value during their first episode. To conclude, a working epidemiological case definition of SARS-CoV-2 re-infection is important to strengthen surveillance. The present investigation contributes to this goal and records reinfection in 4.5% of SARS-CoV-2 infected individuals in India.

Use of convalescent plasma for COVID-19 in India: A review & practical guidelines.

Convalescent plasma (CP) therapy is one of the promising therapies being tried for COVID-19 patients. This passive immunity mode involves separating preformed antibodies against SARS-CoV-2 from a recently recovered COVID-19 patient and infusing it into a patient with active disease or an exposed individual for prophylaxis. Its advantages include ease of production, rapid deployment, specificity against the target infectious agent, and scalability. In the current pandemic, it has been used on a large scale across the globe and also in India. However, unequivocal proof of efficacy and effectiveness in COVID-19 is still not available. Various CP therapy parameters such as donor selection, antibody quantification, timing of use, and dosing need to be considered before its use. The current review attempts to summarize the available evidence and provide recommendations for setting up CP protocols in clinical and research settings.

Guidance for building a dedicated health facility to contain the spread of the 2019 novel coronavirus outbreak.

Preparedness for the ongoing coronavirus disease 2019 (COVID-19) and its spread in India calls for setting up of adequately equipped and dedicated health facilities to manage sick patients while protecting healthcare workers and the environment. In the wake of other emerging dangerous pathogens in recent times, such as Ebola, Nipah and Zika, it is important that such facilities are kept ready during the inter-epidemic period for training of health professionals and for managing cases of multi-drug resistant and difficult-to-treat pathogens. While endemic potential of such critically ill patients is not yet known, the health system should have surge capacity for such critical care units and preferably each tertiary government hospital should have at least one such facility. This article describes elements of design of such unit (e.g., space, infection control, waste disposal, safety of healthcare workers, partners to be involved in design and plan) which can be adapted to the context of either a new construction or makeshift construction on top of an existing structure. In view of a potential epidemic of COVID-19, specific requirements to handle it are also given.

The 2019 novel coronavirus disease (COVID-19) pandemic: A review of the current evidence.

A novel coronavirus (nCoV) spillover event, with its epicenter in Wuhan, People's Republic of China, has emerged as a public health emergency of international concern. This began as an outbreak in December 2019, and till February 28, 2020, there have been 83,704 confirmed cases of novel coronavirus disease 2019 (COVID-19) globally, with 2,859 deaths, resulting in an overall case fatality rate of 3.41 per cent (95% confidence interval 3.29-3.54%). By this time (February 28, 2020) 58 countries or territories and one international conveyance (Diamond Princess Cruise Ship) were affected. As a part of the global response to manage and contain the pandemic, major emphasis was placed on generating research intelligence to guide evidence-based responses to contain the virus, which was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), owing to its genetic similarities with the SARS virus. This review summarizes the emerging evidence which can help guide the public health response, particularly in India. Key areas have been identified in which research needs to be conducted to generate critical intelligence for advising prevention and control efforts. The emergence of SARS-CoV-2 has once again exposed the weaknesses of global health systems preparedness, ability to respond to an infectious threat, the rapidity of transmission of infections across international borders and the ineffectiveness of knee-jerk policy responses to emerging/re-emerging infectious disease threats. The review concludes with the key learning points from the ongoing efforts to prevent and contain COVID-19 and identifies the need to invest in health systems, community-led response mechanisms and the need for preparedness and global health security.

Prudent public health intervention strategies to control the coronavirus disease 2019 transmission in India: A mathematical model-based approach.

Background & objectives: Coronavirus disease 2019 (COVID-19) has raised urgent questions about containment and mitigation, particularly in countries where the virus has not yet established human-to-human transmission. The objectives of this study were to find out if it was possible to prevent, or delay, the local outbreaks of COVID-19 through restrictions on travel from abroad and if the virus has already established in-country transmission, to what extent would its impact be mitigated through quarantine of symptomatic patients? Methods: These questions were addressed in the context of India, using simple mathematical models of infectious disease transmission. While there remained important uncertainties in the natural history of COVID-19, using hypothetical epidemic curves, some key findings were illustrated that appeared insensitive to model assumptions, as well as highlighting critical data gaps. Results: It was assumed that symptomatic quarantine would identify and quarantine 50 per cent of symptomatic individuals within three days of developing symptoms. In an optimistic scenario of the basic reproduction number (R0) being 1.5, and asymptomatic infections lacking any infectiousness, such measures would reduce the cumulative incidence by 62 per cent. In the pessimistic scenario of R0=4, and asymptomatic infections being half as infectious as symptomatic, this projected impact falls to two per cent. Interpretation & conclusions: Port-of-entry-based entry screening of travellers with suggestive clinical features and from COVID-19-affected countries, would achieve modest delays in the introduction of the virus into the community. Acting alone, however, such measures would be insufficient to delay the outbreak by weeks or longer. Once the virus establishes transmission within the community, quarantine of symptomatics may have a meaningful impact on disease burden. Model projections are subject to substantial uncertainty and can be further refined as more is understood about the natural history of infection of this novel virus. As a public health measure, health system and community preparedness would be critical to control any impending spread of COVID-19 in the country.

Epidemiology of heart failure in rural Chhattisgarh, India.

Background Cardiovascular diseases, including heart failure (HF), are leading causes of death and disability in India. However, most studies in India only include urban populations or rural regions with improved access and may not represent the poorest patients or regions. We studied the epidemiology of HF patients admitted to a secondary care hospital in rural Chhattisgarh, India. Methods We did a retrospective chart review of patients hospitalized with HF in 2018 to obtain their demographic data and risk factors for developing HF. We reviewed echocardio-grams to assign patients to their most probable HF category. Results We studied 88 HF patients with a mean age of 42 years including 55 (62.5%) women. The most common categories of HF were cardiomyopathy (36.8%), rheumatic heart disease (RHD; 25.3%) and right heart failure (RHF; 18.4%). Prior tuberculosis was more prevalent in patients with RHF compared with other types of HF (43.8% v. 13.9%). Conclusions HF patients in this study from rural central India were young and predominantly women. Cardiomyopathy, RHD and RHF due to past tuberculosis were common causes of HF in this population. Further studies are needed to expand upon these single centre findings to better understand the risk factors and outcomes of HF among the rural poor.

Association of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19: A Meta-analysis.

Importance: COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. Objective: To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. Data Sources: From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. Study Selection: Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. Data Extraction and Synthesis: A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. Main Outcomes and Measures: Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. Results: Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. Conclusions and Relevance: This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.

Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma.

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact. Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics. Design, Setting, and Participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants). Exposure: Receipt of CCP. Main Outcomes and Measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI. Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs. Conclusions and Relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Convalescent plasma, political narrative, and public health ethics in the Covid-19 pandemic.

Convalescent plasma therapy emerged as an early experimental therapy for the treatment of Covid-19. However, despite limited data regarding its safety and efficacy, the therapy was extensively publicised by multiple politicians as a cure. We analyse the impact of this political narrative around medical therapeutics on the pandemic using the coherentist model of public health ethics. The clinical benefits of the therapy are evaluated in terms of reduction in mortality and disease progression as compared to the potential transfusion-related adverse events. Political advocacy of therapeutics might hamper the autonomy and decision-making of individuals and institutions. Marketing and monetisation of convalescent plasma might cause inequitable distribution and unregulated use. It also creates an economic burden on the government and healthcare which should be justified by the additional cost/effectiveness ratio of the therapy. This article exemplifies the inadvertent effects and ethical challenges following political narratives about medical therapeutics and the importance of involving ethics in designing policies concerning public healthcare.

Measuring Knowledge of Community Health Workers at the Last Mile in Liberia: Feasibility and Results of Clinical Vignette Assessments.

INTRODUCTION: Community health workers (CHWs) can provide lifesaving treatment for children in remote areas, but high-quality care is essential for effective delivery. Measuring the quality of community-based care in remote areas is logistically challenging. Clinical vignettes have been validated in facility settings as a proxy for competency. We assessed feasibility and effectiveness of clinical vignettes to measure CHW knowledge of integrated community case management (iCCM) in Liberia's national CHW program. METHODS: We developed 3 vignettes to measure knowledge of iCCM illnesses (malaria, diarrhea, and pneumonia) in 4 main areas: assessment, diagnosis, treatment, and caregiver instructions. Trained nurse supervisors administered the vignettes to CHWs in 3 counties in rural Liberia as part of routine program supervision between January and May 2019, collected data on CHW knowledge using a standardized checklist tool, and provided feedback and coaching to CHWs in real time after vignette administration. Proportions of vignettes correctly managed, including illness classification, treatment, and referral where necessary, were calculated. We assessed feasibility, defined as the ability of clinical supervisors to administer the vignettes integrated into their routine activities once per year for each CHW, and effectiveness, defined as the ability of the vignettes to measure the primary outcomes of CHW knowledge of diagnosis and treatment including referrals. RESULTS: We were able to integrate this assessment into routine supervision, facilitate real-time coaching, and collect data on iCCM knowledge among 155 CHWs through delivery of 465 vignettes. Diagnosis including severity was correct in 65%-82% of vignettes. CHWs correctly identified danger signs in 44%-50% of vignettes, correctly proposed referral to the facility in 63% of vignettes including danger signs, and chose correct lifesaving treatment in 23%-65% of vignettes. Both diagnosis and lifesaving treatment rates were highest for malaria and lowest for severe pneumonia. CONCLUSION: Administration of vignettes to assess knowledge of correct iCCM case management was feasible and effective in producing results in this setting. Proportions of correct diagnosis and lifesaving treatment varied, with high proportions for uncomplicated disease, but lower for more severe cases, with accurate recognition of danger signs posing a challenge. Future work includes validation of vignettes for use with CHWs through direct observation, strengthening supportive supervision, and program interventions to address identified knowledge gaps.

Factors associated with mortality among moderate and severe patients with COVID-19 in India: a secondary analysis of a randomised controlled trial.

OBJECTIVE: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma. DESIGN: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease. SETTING: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020. PARTICIPANTS: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed. PRIMARY OUTCOME MEASURE: Factors associated with all-cause mortality at 28 days after enrolment. RESULTS: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death. CONCLUSION: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death. TRIAL REGISTRATION NUMBER: CTRI/2020/04/024775.

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).

OBJECTIVE: To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India. DESIGN: Open label, parallel arm, phase II, multicentre, randomised controlled trial. SETTING: 39 public and private hospitals across India. PARTICIPANTS: 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm). INTERVENTIONS: Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study. MAIN OUTCOME MEASURE: Composite of progression to severe disease (PaO2/FiO2 <100 mm Hg) or all cause mortality at 28 days post-enrolment. RESULTS: Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval -0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54). CONCLUSION: Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19. TRIAL REGISTRATION: Clinical Trial Registry of India CTRI/2020/04/024775.

A 54-year-old Woman with Myelofibrosis and Massive Hemothorax Due to Primary Extramedullary Hematopoiesis of the Pleura.

Extramedullary hematopoiesis, which represents ectopic blood cell production, is usually an incidental finding accompanying hematologic pathology. The liver and spleen are the most common sites of extramedullary hematopoiesis, but thoracic involvement is likewise observed. Pleural effusions in the setting of intrathoracic extramedullary hematopoiesis have been attributed to mechanical interactions between the pleural surface and neighboring paravertebral masses consisting of hematopoietic tissue. Rupture of these highly vascularized lesions into the adjacent pleural space has been the putative mechanism in cases complicated by hemothorax. Histologically proven instances of islets of extramedullary hematopoiesis occurring on the pleural surface itself are exceedingly rare. Our case of a patient with myelofibrosis and massive pleural effusion is only the third such example described in the literature and the second to result in a confirmed hemothorax requiring surgery. As expected, technetium-99m sulfur (Tc-99m sulfur) colloid scanning accurately localized sites of extramedullary hematopoiesis in our patient, and there was a salutary response to radiation therapy.

New demodulation method for efficient phase-rotation-based beamforming.

In this paper, we present a new demodulation method to reduce hardware complexity in phase-rotation-based beamforming. Due to its low sensitivity to phase delay errors, quadrature demodulation, which consists of mixing and lowpass filtering, is commonly used in ultrasound machines. However, because it requires two lowpass filters for each channel to remove harmonics after mixing, the direct use of quadrature demodulation is computationally expensive. To alleviate the high computational requirement in quadrature demodulation, we have developed a two-stage demodulation technique in which dynamic receive focusing is performed on the mixed signal instead of the complex baseband signal. Harmonics then are suppressed by using only two lowpass filters. When the number of channels is 32, the proposed two-stage demodulation reduces the necessary number of multiplications and additions for phase-rotation beamforming by 82.7% and 88.2%, respectively, compared to using quadrature demodulation. We have found from simulation and phantom studies that the proposed method does not incur any significant degradation in image quality in terms of axial and lateral resolution. These preliminary results indicate that the proposed two-stage demodulation method could contribute to significantly reducing the hardware complexity in phase-rotation-based beamforming while providing comparable image quality.

Babesiosis-associated immune thrombocytopenia.

Thrombocytopenia is a common feature of babesiosis. The mechanism for thrombocytopenia in babesiosis remains elusive. We report a case of babesiosis with severe new onset immune thrombocytopenia (ITP). In addition to antibiotics treatment for babesiosis, ITP therapy was administered. ITP in the present case was most likely triggered by the babesia infection. The severity of ITP in this case was not proportional to the severity of parasitemia. The neoantigen triggering the autoimmune response in babesiosis requires further characterization.

New demodulation filter in digital phase rotation beamforming.

In this paper, we present a new quadrature demodulation filter to reduce hardware complexity in digital phase rotation beamforming. Due to its low sensitivity to phase delay errors, digital quadrature demodulation is commonly used in ultrasound machines. However, since it requires two lowpass filters for each channel to remove harmonics, the direct use of conventional finite impulse response (FIR) filters in ultrasound machines is computationally expensive and burdensome. In our new method, an efficient multi-stage uniform coefficient (MSUC) filter is utilized to remove harmonic components in phase rotation beamforming. In comparison with the directly implemented FIR (DI-FIR) and the previously-proposed signed-power-of-two FIR (SPOT-FIR) lowpass filters, the proposed MSUC filter reduces the necessary hardware resources by 93.9% and 83.9%, respectively. In simulation, the MSUC filter shows a negligible degradation in image quality. The proposed method resulted in comparable spatial and contrast resolution to the DI-FIR approach in the phantom study. These preliminary results indicate that the proposed quadrature demodulation filtering method could significantly reduce the hardware complexity in phase rotation beamforming while maintaining comparable image quality.