Should Comorbidities Be Considered in the Decision to Discharge COVID-19 Patients From Hospital? A Case Series

An outbreak of COVID-19 started in December 2019 in the city of Wuhan and is now rapidly spreading across the world. We report two cases of confirmed COVID-19 with pre-existing comorbidities who were discharged from the hospital with a good clinical condition and in concordance with interim discharge protocols. However, they were readmitted and died on the discharge day. Here we discuss the importance of patient demographics in clinical management vs. the resolution of the pulmonary disease alone and raise a question about the impact of comorbidities on discharge protocols.

Disease waves of SARS-CoV-2 in Iran closely mirror global pandemic trends (preprint)

SARS-CoV-2 genome surveillance projects provide a good measure of transmission and monitor the circulating SARS-CoV-2 variants at regional and global scales. Iran is one of the most affected countries still involved with the virus circulating in at least five significant disease waves, as of September 2021. Complete genome sequencing of 50 viral isolates in an early phase of outbreak in Iran, shed light on the origins and circulating lineages at that time. As part of a genomic surveillance program, we provided an additional 319 complete genomes from October 2020 onwards. The current study is the report of complete SARS-CoV-2 genome sequences of Iran in the March 2020-May 2021 time interval. We aimed to characterize the genetic diversity of SARS-CoV-2 in Iran over one year. Overall, 35 different lineages and 8 clades were detected. Temporal dynamics of the prominent SARS-CoV-2 clades/lineages circulating in Iran is comparable to the global perspective and introduces the 19A clade (B.4) dominating the first disease wave, followed by 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7) clades, dominating second, third and fourth disease waves, respectively. We observed a mixture of circulating 20A (B.1.36), 20B (B.1.1.413), 20I (B.1.1.7) clades in winter 2021, paralleled in a diminishing manner for 20A/20B and a growing rise for 20I, eventually prompting the 4th outbreak peak. Furthermore, our study provides evidence on the entry of the Delta variant in April 2021, leading to the 5th disease wave in summer 2021. Three lineages are highlighted as hallmarks of SARS-CoV-2 outbreak in Iran; B4, dominating early periods of the epidemic, B.1.1.413 (specific B.1.1 lineage carrying a combination of [D138Y-S477N-D614G] spike mutations) in October 2020-February 2021, and the co-occurrence of [I100T-L699I] spike mutations in half of B.1.1.7 sequences mediating the fourth peak. Continuous monthly monitoring of SARS-CoV-2 genome mutations led to the detection of 1577 distinct nucleotide mutations, in which the top recurrent mutations were D614G, P323L, R203K/G204R, 3037C>T, and 241C>T; the renowned combination of mutations in G and GH clades. The most frequent spike mutation is D614G followed by 13 other frequent mutations based on the prominent circulating lineages; B.1.1.7 (H69_V70del, Y144del, N501Y, A570D, P681H, T716I, S982A, D1118H, I100T, and L699I), B.1.1.413 (D138Y, S477N) and B.1.36 (I210del). In brief, mutation surveillance in this study provided a real-time comprehensive picture of the SARS-CoV-2 mutation profile in Iran, which is beneficial for evaluating the magnitude of the epidemic and assessment of vaccine and therapeutic efficiency in this population.

SARS-COV-2 Seroprevalence among Health Care Workers in Private and Public Hospitals in Tehran, Iran (preprint)

BackgroundEstimating the prevalence of SARS-COV-2 antibody seropositivity among health care workers (HCWs) is crucial. In this study the seroprevalence of anti-SARS-COV-2 antibodies among HCWs of five hospitals of Tehran-Iran with high COVID-9 patient’s referrals was assessed.MethodsHCWs from public and private hospitals were included and were asked questions on their demographic characteristics, medical history, hospital role and usage of personal protective equipment (PPE). Seroprevalence was estimated on the basis of ELISA test results (IgG and IgM antibodies in blood samples) and adjusted for test performance.ResultsAmong the 2065 participants, 88.4% and 11.6% HCWs were recruited from the public and private hospitals, respectively. The overall test-performance adjusted seroprevalence estimate among HCWs was 22.6 (95% CI 20.2-25.1) and it was higher in private hospitals (37.0%; 95% CI 28.6-46.2) than public hospitals (20.7%; 95% CI 18.2-23.3). PPE usage was significantly higher among HCWs of public versus private hospitals (66.5% vs. 20.0%). Test-adjusted seroprevalence estimates were highest among assistant nurses and nurses, and lowest among janitor/superintendent categories. ConclusionsSeroprevalence of SARS-COV-2 among HCWs depends on hospital type, hospital department, and hospital role. The PPE usage was especially suboptimal among HCWs in private hospitals. Continued effort in access to adequate PPE is warranted.

COVID-19 Antibody Seroprevalence Among General Population and High-Risk Occupational Groups in Eighteen Cities of Iran (preprint)

Background: As the COVID-19 pandemic unfolded, rapid case increase was observed in multiple cities in Iran. However, in the absence of seroprevalence surveys, the true infection rate remains unknown. In this population-based study we assessed the seroprevalence of SARS-CoV-2 antibodies in eighteen cities of Iran.Methods: We randomly selected and invited study participants from the general population (N = 3,547) and occupations with high risk of COVID-19 exposure, defined as high-risk population (e.g., supermarket employees) (N = 5,391), in eighteen cities of Iran. SARS-CoV-2 ELISA kits were used to detect antibody against COVID-19. Crude, population weight adjusted, and test performance adjusted seroprevalence rates were estimated.Findings: The population weight adjusted and test performance adjusted prevalence rates of antibody seropositivity in general population were 13·1% (95% CI 11·6-14·8%) and 18·5% (95% CI 16·1-21·3%), respectively. The population-weighted seroprevalence estimate implies that 3,290,633 (95% CI 2,907185-3,709,167) individuals, from the eighteen included cities in this study, were infected by end of April 2020.The overall prevalence rate was higher among individuals aged ≥ 60 years (32·0%, 95% CI 23·9-40·8%) and with comorbidity condition (23·7%, 95% CI 18·5-28·8%). The estimated seroprevalence of SARS-CoV-2 antibodies varied greatly by city and the highest population test-adjusted prevalence rates were in Rasht 78·1% (95% CI 58·3-98·3%) and Qom (66·5%, 95% CI 39·9-95·4%) cities. The test-adjusted prevalence did not differ between low and high-risk populations and was about 20.0%.Interpretations: The findings of this study imply that prevalence of seropositivity is likely much higher than the reported prevalence rates based on confirmed COVID-19 cases in Iran. Despite the high seroprevalence rates in a few cities, the low overall prevalence estimates indicate that a large proportion of population is still susceptible to the virus. The similar seroprevalence estimates between low and high-risk occupations might be an indicator of inadequate or low adherence to infection control measures among general population.Funding Statement: Iranian Ministry of Health and Medical Education COVID-19 Grant (number 99-1-97-47964).Declaration of Interests: None to disclose.Ethics Approval Statement: Ethics approval for this study was granted by Vice-Chancellor in Research Affairs-Tehran University of Medical Sciences (IR. TUMS.VCR.REC.1399.308)

Two independent introductions of SARS-CoV-2 into the Iranian outbreak (preprint)

The SARS-CoV-2 virus has been rapidly spreading globally since December 2019, triggering a pandemic, soon after its emergence, with now more than one million deaths around the world. While Iran was among the first countries confronted with rapid spread of virus in February, no real-time SARS-CoV-2 whole-genome tracking is performed in the country. To address this issue, we provided 50 whole-genome sequences of viral isolates ascertained from different geographical locations in Iran during March-July 2020. The corresponding analysis on origins, transmission dynamics and genetic diversity, represented at least two introductions of the virus into the country, constructing two major clusters defined as B.4 and B.1*. The first entry of the virus occurred around 26 December 2019, as suggested by the time to the most recent common ancestor, followed by a rapid community transmission, led to dominancy of B.4 lineage in early epidemic till the end of June. Gradually, reduction in dominancy of B.4 occurred possibly as a result of other entries of the virus, followed by surge of B.1.* lineages, as of mid-May. Remarkably, variation tracking of the virus indicated the increase in frequency of D614G mutation, along with B.1* lineages, which showed continuity till October 2020. According to possible role of D614G in increased infectivity and transmission of the virus, and considering the current high prevalence of the disease, dominancy of this lineage may push the country into a critical health situation. Therefore, current data warns for considering stronger prohibition strategies preventing the incidence of larger crisis in future.

SARS-CoV-2 infection suppresses ACE2 function and antiviral immune response in the upper respiratory tract of infected patients (preprint)

There is an urgent need to elucidate the molecular mechanisms underlying the transmissibility and pathogenesis of SARS-CoV-2. ACE2 is a host ectopeptidase with well-described anti-inflammatory and tissue protective functions and the receptor for the virus. Understanding SARS-CoV-2-ACE2 interaction and the expression of antiviral host genes in early infection phase is crucial for fighting the pandemic. We tested the significance of soluble ACE2 enzymatic activity longitudinally in positive nasopharyngeal swabs at two time points after symptom consultation, along with gene expression profiles of ACE2, its proteases, ADAM17 and TMPRRS2, and interferon-stimulated genes (ISGs), DDX58, CXCL10 and IL-6. Soluble ACE2 activity decreased during infection course, in parallel to ACE2 gene expression. On the contrary, SARS-CoV-2 infection induced expression of the ISG genes in positive SARS-CoV-2 samples at baseline compared to negative control subjects, although this increase wanes with time. These changes positively correlated with viral load. Our results demonstrate the existence of mechanisms by which SARS-CoV-2 suppress ACE2 expression and function casting doubt on the IFN-induced upregulation of the receptor. Moreover, we show that initial intracellular viral sensing and subsequent ISG induction is also rapidly downregulated. Overall, our results offer new insights into ACE2 dynamics and inflammatory response in the human upper respiratory tract that may contribute to understand the early antiviral host response to SARS-CoV-2 infection.

Natural deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape (preprint)

Zoonotic pandemics follow the spillover of animal viruses into highly susceptible human populations. Often, pandemics wane, becoming endemic pathogens. Sustained circulation requires evasion of protective immunity elicited by previous infections. The emergence of SARS-CoV-2 has initiated a global pandemic. Since coronaviruses have a lower substitution rate than other RNA viruses this gave hope that spike glycoprotein is an antigenically stable vaccine target. However, we describe an evolutionary pattern of recurrent deletions at four antigenic sites in the spike glycoprotein. Deletions abolish binding of a reported neutralizing antibody. Circulating SARS-CoV-2 variants are continually exploring genetic and antigenic space via deletion in individual patients and at global scales. In viruses where substitutions are relatively infrequent, deletions represent a mechanism to drive rapid evolution, potentially promoting antigenic drift.

Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results (preprint)

BACKGROUND WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs. METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-{beta}1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry. RESULTS In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration. CONCLUSIONS These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151, NCT04315948)

CovidCTNet: An Open-Source Deep Learning Approach to Identify Covid-19 Using CT Image (preprint)

Coronavirus disease 2019 (Covid-19) is highly contagious with limited treatment options. Early and accurate diagnosis of Covid-19 is crucial in reducing the spread of the disease and its accompanied mortality. Currently, detection by reverse transcriptase polymerase chain reaction (RT-PCR) is the gold standard of outpatient and inpatient detection of Covid-19. RT-PCR is a rapid method, however, its accuracy in detection is only ~70-75%. Another approved strategy is computed tomography (CT) imaging. CT imaging has a much higher sensitivity of ~80-98%, but similar accuracy of 70%. To enhance the accuracy of CT imaging detection, we developed an open-source set of algorithms called CovidCTNet that successfully differentiates Covid-19 from community-acquired pneumonia (CAP) and other lung diseases. CovidCTNet increases the accuracy of CT imaging detection to 90% compared to radiologists (70%). The model is designed to work with heterogeneous and small sample sizes independent of the CT imaging hardware. In order to facilitate the detection of Covid-19 globally and assist radiologists and physicians in the screening process, we are releasing all algorithms and parametric details in an open-source format. Open-source sharing of our CovidCTNet enables developers to rapidly improve and optimize services, while preserving user privacy and data ownership.

The Utility of rRT-PCR in Diagnosis and Assessment of Case-fatality rates of COVID-19 In the Iranian Population. Positive Test Results are a Marker for Illness Severity (preprint)

The utility of PCR-based testing in characterizing patients with COVID-19 and the severity of their disease remains unknown. We performed an observational study among patients presenting to hospitals in Iran who were tested for 2019-nCoV viral RNA by rRT-PCR between the fourth week of February 2020 to the fourth week of March 2020. Frequency of symptoms, comorbidities, intubation, and mortality rates were compared between COVID-19 positive vs. negative patients. 96103 patients were tested from 879 hospitals. 18754 (19.5%) tested positive for COVID-19. Positive testing was more frequent in those 50 years or older. The prevalence of cough (54.5% vs. 49.7%), fever (49.5% vs. 44.7%), and respiratory distress (43.0% vs. 39.0%) but not hypoxia (46.9% vs. 56.7%) was higher in COVID-19 positive vs. negative patients (p<0.001 for all). More patients had cardiovascular diseases (10.6% vs. 9.5%, p<0.001) and type 2 diabetes mellitus (10.8% vs. 8.7%, p<0.001) among COVID-19 positive vs. negative patients. There were fewer patients with cancer (1.1%, vs. 1.4%, p<0.001), asthma (1.9% vs. 2.5%, p<0.001), or pregnant (0.4% vs. 0.6%, =0.001) in COVID-19 positive vs. negative groups. COVID-19 positive vs. negative patients required more intubation (7.7% vs. 5.2%, p<0.001) and had higher mortality (14.6% vs. 6.3%, p<0.001). Odds ratios for death of positive vs negative patients range from 2.01 to 3.10 across all age groups. In conclusion, COVID-19 test-positive vs. test-negative patients had more severe symptoms and comorbidities, required higher intubation, and had higher mortality. rRT-PCR positive result provided diagnosis and a marker of disease severity in Iranians.