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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 7-15

COVID-19 versus H1N1: pandemic to pandemic − a comparative analysis of clinical presentation, lab parameters, disease severity and outcome


Department of Medicine, Government Medical College, Kota, Rajasthan, India

Date of Submission07-Jul-2020
Date of Decision12-Aug-2020
Date of Acceptance09-Sep-2020
Date of Web Publication15-Feb-2021

Correspondence Address:
Dr. Drishya Pillai
Department of Medicine, Government Medical College, Room 219, PG Hostel-2, New Medical College Hospital, Kota, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jacp.jacp_46_20

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  Abstract 


Background: Since December 2019, we have been facing the coronavirus disease 2019 (COVID-19) pandemic. January 30, 2020 marked India’s first case. A similar entity H1N1 was responsible for the last pandemic our civilization saw. Comparing the clinical and radiological characteristics, severity and prognosis of the two is the objective. Methods :Cross-sectional, observational, and comparative study of patients diagnosed with COVID-19 (April–May 2020) and H1N1 (January 2017–December 2019). Results :We observed raised male to female (M:F) ratio in both, average age higher in H1N1, moderate to severe symptoms with worse clinical status in H1N1, and COVID more often being associated with mild symptoms. Thrombocytopenia, lymphocytosis, and raised lactate dehydrogenase (LDH) were seen in both the diseases but were worse in H1N1; multiorgan involvement was seen in H1N1 (P < 0.001). COVID-19 patients who did report complications were refractory to routine critical care management. Radiographic abnormality was present in both. Poor prognosis was noted in elderly, especially those with comorbidities. This association was less evident in COVID-19. Discussion: Though Severe Acute Respiratory Syndrome- Corona Virus 2 has a milder course, sudden deterioration can be fatal. Serial monitoring of history and vitals is the key. Swine flu patients with a comparatively aggressive course need to be managed accordingly, but Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation Score-II, and similar scoring can help in triage and predicting prognosis. Clinical and laboratory findings are similar − swine flu has more complications but increased risk of cardiac involvement is seen in COVID. Chest X-ray proves sufficient for imaging, reducing the requirement of computed tomography (CT) scans. Studies involving larger sample size and interventional trials are need of the hour.

Keywords: Acute respiratory distress syndrome, comparative study, coronavirus disease 2019 (COVID-19), H1N1, pandemic, Sequential Organ Failure Assessment, viral infection


How to cite this article:
Saluja M, Pillai D. COVID-19 versus H1N1: pandemic to pandemic − a comparative analysis of clinical presentation, lab parameters, disease severity and outcome. J Assoc Chest Physicians 2021;9:7-15

How to cite this URL:
Saluja M, Pillai D. COVID-19 versus H1N1: pandemic to pandemic − a comparative analysis of clinical presentation, lab parameters, disease severity and outcome. J Assoc Chest Physicians [serial online] 2021 [cited 2021 Apr 20];9:7-15. Available from: https://www.jacpjournal.org/text.asp?2021/9/1/7/309476




  Introduction Top


Since December 2019, the entire globe has been in throes of a novel viral infection, caused by Severe Acute Respiratory Syndrome- Corona Virus 2 as named by International Committee on Taxonomy of Viruses. The disease, coronavirus disease 2019 (COVID-19), is continuing to wreak havoc across all nations alike. As we move to the 27th week of this pandemic, more than 11 million of the population has been affected with more than 0.5 million deaths (∼4.5% mortality).[1]

With over 2.3 lakh cases and 18,655 deaths due to the contagion, India is experiencing a morality rate of 7.9% (higher than the global average).[2]

The last major pandemic we faced was in 2009–2010 when H1N1 influenza virus affected more than 190 countries.[3] India then reported 20,604 cases and 1763 deaths (8.5% mortality).[4]

It is important to distinguish between the two diseases, both involving the respiratory system and capable of causing great damage to health and economy alike. Higher contact transmission as noted in the current scenario of COVID-19 makes it all the more necessary to evaluate the similarities and differences from the previous epidemic for a better planning and execution of control methods.

In this study, we compare patients with the two diseases, albeit set in different time periods − H1N1 (2017–2019) and COVID-19 (April–May 2020).


  Materials and methods Top


Study design

All hospitalized patients, with laboratory confirmed COVID-19 and H1N1, were included in the study. We obtained the medical records and compiled data of COVID-19 patients admitted in the isolation wards of New Medical College Hospital, Kota and associated hospitals from April 5, 2020 to June 2, 2020. The data cutoff for the study was June 5, 2020. Patients still admitted in the isolation wards were omitted from the study to remove any possible bias in outcome. The data of H1N1 patients were collected from the hospital record room dating from January 2017 to December 2019.

Both the diseases were diagnosed on the basis of the World Health Organization interim guidance. A confirmed case (for both H1N1 and COVID-19) was defined as a positive result by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swab specimens.[5] For H1N1 cases, only pharyngeal swab was taken. Only laboratory confirmed cases were included in the analysis.

Inclusion and exclusion criteria

All COVID-19 confirmed patients who gave their consent (taken orally to reduce risk of transmission) were included in the study. Patients excluded: children <10 years of age, patients still admitted in isolation wards, and/ or those who refused to give consent.

Consent was waived for H1N1 patients, as the data to be studied was retrospective and observational.

Study definitions

We assessed complete blood count, blood chemical analysis, coagulation testing, liver and renal function tests, serum electrolytes, lactate dehydrogenase, and creatine kinase. electrocardiogram (ECG), arterial blood gas analysis (ABG), and chest imaging were done as well. Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation Score-II (APACHE II) were calculated for every patient. Fever was denoted at an axillary temperature of 37.5°C or higher. Lymphocytopenia and lymphocytosis were defined as a lymphocyte count of less than 1500 cells and more than 4000 cells per cubic millimeter, respectively.

Thrombocytopenia is defined as a platelet count of less than 150,000 per cubic millimeter. Onset to confirm diagnosis was defined as the time taken to confirm the disease by RT-PCR since the symptoms were seen first. Onset to acute respiratory distress syndrome (ARDS)/mechanical ventilator (MV) was defined as the duration between admission to MV supplementation or development of ARDS. Primary composite end point was defined when patient died. Additional definitions − including ARDS, pneumonia, acute kidney failure, acute heart failure, and rhabdomyolysis − are as provided in the Guan et al.[6]

Statistical analysis

Continuous variables were expressed as means with standard deviation or medians and interquartile ranges or simple ranges, as appropriate. Categorical variables were summarized as counts and percentages. For missing data, no imputation was made. We used GraphPad Prism, version 8.4.2, for statistical analysis as well as to plot the map. Two subanalyses were done, first included all patients of both groups and second only the symptomatic COVID-19 patients were compared to H1N1 patients. Unpaired student t-test with unequal variances and chi-square tests were used in both analyses.


  Results Top


Demography

Past few years have seen a relative decline in H1N1 cases around the globe. Spikes observed during winter months have become commonplace. Availability of specific antiviral medicine, vaccine, and herd immunity may have contributed to the same.

In our setting, we had 213 patients of H1N1 over a span of 3 years (2017–2019). COVID-19, being a novel strain, quickly spread through the community, resulting in 406 patients in a meagre 2 months. These figures are after applying the exclusion criteria. [Figure 1] shows the progression of H1N1 cases in India through the decade. Keeping in mind the increasing total population, the proportion is reducing except two spikes.
Figure 1 H1N1 from 2010 to 2019 in India. H1N1, influenza A virus subtype H1N1

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Patient characteristics and epidemiology

Patients affected with H1N1 were older than those in COVID-19, with the average age approximating 42 and 36 years, respectively (P=0.0054). The percentage of patients in each age group is shown in [Figure 2]. It is evident that a relatively young and middle-aged population is affected in COVID, while H1N1 affects more of the extremes of age. Males were affected more in both the diseases with a prevalence of >50%, but no significant difference in M:F ratio was noted on comparison (P=0.09). At the time of admission and through the hospital stay, the condition of H1N1 patients was worse, as assessed by the higher SOFA and APACHE II score, as was the association with other comorbid conditions, commonly hypertension, chronic kidney diseases, and hepatic diseases (P<0.001). Pregnancy was also associated with both the diseases but more with H1N1 (P<0.001). Association of diabetes and cardiovascular diseases was similar in both (P>0.05).
Figure 2 Age distribution of the disease. Abscissa: age in years; ordinate: % of patients. COVID-19, coronavirus disease 2019; H1N1, influenza A virus subtype H1N1

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Leukocytosis, leukopenia, lymphocytosis, and thrombocytopenia were the noted complications. Though a marked presence was observed in both the diseases, H1N1 again had more patients with abnormal hemogram than that of COVID-19 [Table 1].
Table 1 Characteristics comparison of H1N1 and COVID-19

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A similar trend was seen in organ dysfunction − be it renal, hepatic, or respiratory failure, or the number of patients requiring mechanical ventilation. Secondary infections, as evidenced by sudden spike in the total leucocyte count and a positive sputum culture, were also commonplace with swine flu patients. The unique fact was that despite better baseline condition, lesser comorbidities, and less frequency of complications, the average onset to ARDS/MV was similar in both the viral diseases amounting to 3 days. This sudden worsening in apparently stable COVID-19 patients is unpredictable and posed a therapeutic challenge.

Clinical features and laboratory examinations

Every analysis was done twice in this study to remove the bias that was present due to asymptomatic COVID-19 patients diagnosed as a result of aggressive screening and contact tracing. We compared all positive patients, 406 COVID-19 with 213 H1N1 patients, followed by symptomatic COVID-19 and H1N1 patients (162 vs 213). The separate analyses did not show substantial differences, except for the P values and in two variables, which will be enumerated later. The following results will focus on the comparison of symptomatic patients.

Patients presented with classical symptoms of respiratory infections, such as cough, fever, sputum production, and dyspnea, in both H1N1 and COVID-19, but a statistically higher incidence was seen in former (P<0.0001). Productive cough was more often a feature of H1N1; dry cough predominated in the setting of COVID-19. Symptoms such as myalgia, fatigue, olfactory, and cutaneous involvement were significantly more in COVID-19. In our sample size, gastrointestinal and CNS involvement was similar in both [Table 2].
Table 2 Comparing clinical presentations of H1N1 influenza and SARS-CoV2 (COVID-19)

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On examining the hemogram, H1N1 patients showed increased range in total leukocyte count with more patients having abnormal values, including leukocytopenia as well as leuocytosis. COVID-19 patients were inclined to have leukocytopenia, if at all abnormal. The frequency of deranged leukocyte count was higher in H1N1. Though mean total leucocyte count (TLC) was significantly higher in H1N1 (P=0.00005), both the groups were within normal limit. The average lymphocyte count suggested lymphocytopenia in H1N1 (significantly lower than COVID-19, P=0.000128). Platelet count showed a different aspect, frequency of thrombocytopenia being higher in COVID-19, and the mean platelet count being lower than that seen in swine flu, but again both being within normal limits (P=0.002) [Table 3].
Table 3 Laboratory examinations: H1N1 versus COVID-19

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Biochemistry showed significant variation between the two, H1N1 showing multiple anomalies suggestive of multiorgan involvement; be it lower mean albumin (P<0.00001), higher average transaminases [P=0.00003 for serum glutamate oxaloacetic transaminase (SGOT), 0.0001 for serum glutamate pyruvate transaminase (SGPT)], deranged renal function (mild but more than the counterpart), and raised lactate dehydrogenase (P=0.0003). The characteristic feature of COVID-19 was cardiac involvement as evidenced by the increased number of patients with raised creatine kinase-MB (CK-MB) as well as a higher mean CK-MB (P=0.009). This is further supported by the increased number of ECG abnormalities present in COVID-19 patients (P<0.00001).

Imaging

Chest X-ray was done serially to monitor the pulmonary involvement as well as the effect of treatment in both diseases. Despite asymptomatic patients constituting more than two thirds of the total sample size in COVID-19 group, >85% patients had abnormal X-ray at presentation and 21 of the remaining patients (with normal X-ray) developing some aberration during their hospital stay. Bilateral pneumonia involving lower and middle zones with peripheral and basal predominance was the commonest finding. Ground glass opacity and consolidations were seen; pleural effusion in a minor percentage of patients and nodules were a rare finding [Figure 3], [Figure 4].
Figure 3 B/L lung involvement with peripheral and basal predominance

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Figure 4 B/L extensive lung involvement in COVID19

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High resolution computed tomography (HRCT) was done in some patients, which highlighted the segmental involvement, depicted intersegmental thickening, crazy paving, halo sign, and ground glass opacities better than the X-ray images but had no significant diagnostic or prognostic benefit. Most of the findings as identified in chest computed tomography (CT) images were multiple lesions of bilateral lungs, often localized in the periphery and with more than two lobes involvement. Patients had patchy ground glass opacities, and/or consolidation. Complications such as pleural thickening, hydrothorax, pericardial effusion, and enlarged mediastinal lymph nodes were detected but only in rare cases. The imaging suggestive of a severe disease in almost all CT scans could be due to the selection bias whereby only severe cases were being subjected to added radiation (HRCT) [Figure 5],[Figure 6].
Figure 5 Sagittal sections of HRCT chest (COVID-19) showing ground glass opacities, peripheral predominance, postero-basal consolidation and prominent broncho-vascular markings

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Figure 6 Axial sections of HRCT chest (COVID-19) showing ground glass opacities, peripheral predominance, postero-basal consolidation and prominent broncho-vascular markings

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In swine flu patients, though all symptomatic, X-ray showed abnormality in 89.32% patients. Basal predominant bilateral lower zone haziness was mostly seen. Effusion was seen in only two patients and nodules in none. HRCT imaging was not done frequently in H1N1 patients. The findings were similar to those seen in COVID-19, including ground glass opacities, patchy consolidation, and interlobular septal thickening, albeit with minor differences such as less number of lobes involved and basal predominance instead of peripheral.

We were unable to compare CT findings of the two diseases with a statistical analysis owing to the minimal number of scans in H1N1 patients.

Complications

Most commonly encountered complications were secondary infections, hepatic, renal and respiratory failure, septic shock, ARDS, and requirement of mechanical ventilation. All of these were present in both but significantly more in H1N1 with more people reaching the primary composite end point. As it was discussed earlier, the clinical status at admission was worse in H1N1, mirrored in their higher SOFA and APACHE II scores and so was the disease progression with more people requiring artificial support and expiring despite ICU care.

The SOFA and APACHE II scores in COVID-19 patients with complications were lower than that in H1N1, ascertaining the possibility of severe disease in even mildly symptomatic population with none/minimal comorbidities. This makes the aspect of predicting prognosis a challenge in COVID-19.

Eight of 406 (all eight being symptomatic at presentation) died due to COVID-19, wheras 63 of 213 patients affected by H1N1 expired highlighting the drastic variation in the mortality rate of the two diseases.

Management and prognosis

Although isolation was maintained in both the diseases, contact tracing, quarantine, and raised awareness were the cornerstones of COVID-19 management. Since H1N1 has been around for a decade now, active tracing and screening were not included in the diagnostic protocol, and only symptomatic patients who visited to the OPD were investigated based on history, clinical examination, chest imaging, and RT-PCR.

During this pandemic, however, two thirds of COVID-19 patients admitted in the isolation wards were asymptomatic, diagnosed on the basis of contact/travel history or as a part of screening a hotspot region.

Asymptomatic COVID-19 patients were managed with azithromycin, hydroxychloroquine, continuation of past medical treatment, if any, while ensuring serial monitoring of vitals and ECG. Two negative RT-PCR reports were essential for discharge initially, but the protocols changed to cater to the growing number of symptomatic patients, allowing for 14 days isolation (at home/government facilitated COVID-19 care center) managed with oral medication and self-temperature charting. This rule was imposed after the data cutoff of the study was over.

We saw more use of antivirals (e.g., oseltamivir, lopinavir, ritonavir, remdesivir), antimalarial (e.g, hydroxychloroquine), and antibiotics (e.g, azithromycin) in COVID-19. Aggressive isolation of the affected member as well as the family with serial testing helped in identifying asymptomatic and presymptomatic patients during the pandemic. This approach may be one of the causes of less mortality observed in the region. Critical patients were routinely managed by multispecialty team of a physician, an anesthetist and a cardiologist (as and when required).

Oseltamivir and supportive therapy including oxygen inhalation, extracorporeal membrane oxygenation (ECMO), antipyretics, antihistamine, and antibiotics constituted the treatment protocol for H1N1.

Both infections caused ARDS and respiratory support in accordance with therapeutic strategies for ARDS was instituted.[7] In the current study, the severity of respiratory failure was not equal between COVID-19 and H1N1 patients. The PaO2/FIO2 levels in COVID-19 patients were higher than in H1N1 patients. Respiratory support in latter via noninvasive and invasive methods produced higher failure rates. The ECMO to rescue lung injury in severe ARDS trial[8] gave information about the probability of a mortality benefit for patients with acute respiratory failure,[9] in terms of reporting the success of the application of ECMO in ARDS due to influenza.[10] ECMO may also have potential in treating patients with COVID-19. Rapid growth of cases and lack of medical resources have limited standardized respiratory during this pandemic.

The disease course and outcome varied greatly. COVID-19 is more contagious than H1N1 as evident by almost the double number of patients in a small time span. This could be due to the novel strain, lack of immunity in population, lack of any effective medicine/vaccine along with low mortality that increased the prevalence. At the same time, in H1N1 patients observed during the 3 years, very few family members/close contacts of the affected patients were infected. Again, better immunity and vaccination could be associated with this finding. But in those individuals who were H1N1 positive, the disease outcome was not impressive. Increased multiple organ failure, definite ARDS, requirement for ventilation, and poor response to all lifesaving measures were noted.

COVID-19 patients rarely went to such severe stages, only 18 out of 406 developing ARDS and only eight deaths paint a slightly better picture. The catch, however, is absence of any indication whatsoever of impending critical illness in these patients. A sudden deterioration in clinical status in a seemingly well patient was not uncommon in the ongoing pandemic. A perfectly uneventful past medical history, risk free age group, and less severe symptom were no bar to a dreaded outcome.


  Discussion Top


This pandemic saw middle-aged patients, predominantly males, being affected. The average age was lower than that of the H1N1 group with a statistical significance. Though male predominance was common to both, our study observed that symptomatic patients of COVID-19 had significantly higher proportion of male gender. The protective effect of estrogen, increased vulnerability due to androgen, has been postulated by some studies, whereas increased contact and social exposure in males have been proposed by some.[11] Differences in regulation at a molecular levels have also been suggested.[12],[13]

The characteristic symptoms of respiratory infection were seen in both, more so in swine flu patients. At the same time, constitutional symptoms such as fever, myalgia, and fatigue and atypical symptoms involving olfactory and cutaneous manifestations were seen in COVID-19 patients.[14],[15],[16]

As mentioned before, active screening and raised awareness on all media platforms resulted in asymptomatic patients being diagnosed during this pandemic, something which is not observed in the H1N1 strata in our study.

The clinical and laboratory parameters were found to be along a similar line, H1N1 being on higher side of the severity scale. Leukopenia, lymphocytopenia, thrombocytopenia, raised transaminases, lactate dehydrogenase, and imaging anomalies were associated with both, [13],[15] but the frequency and the average value of all the above were significantly more deranged in H1N1 influenza. The exception highlighted was cardiac dysfunction − it was more commonly associated with COVID-19. The possibility of viral myocarditis was supported by deranged CK-MB and ECG changes (present prior to any drug administration). A pressing need for cardiac imaging is evident for further evaluation.[17],[18],[19]

A major difference was seen in critically ill patients. The frequency of complications and deaths were definitely more in H1N1 but the course was predictable with higher sequential organ failure scores even at admission. Increased requirement of vasopressors, ventilator support in case of development of ARDS was also commonly seen in H1N1. What made even the small number of ARDS and deaths in COVID-19 daunting was the unpredictability and the poor response to standard protocol. A higher PaO2/FiO2 level in the setting of ARDS and poor response to customary management have made the situation worse. Though risk factors such as extremes of age, comorbidities, and pregnancy have been stated for both, the association is less commonly observed with COVID-19.

Prospective studies with a larger study sample are the need of the hour to understand the new disease better. At the same time, constant evaluation of older epidemics and pandemics and comparison with today’s setting are also important to prevent repeating the mistakes and to use the lessons learnt.

Limitations

The study was marred by multiple drawbacks. First and foremost, the difference in time period, COVID-19 being in a stage of pandemic, with the patients taken from initial 2 months. For H1N1, the sample size constitutes the load of 3 years. This has produced multiple biases, but since the aim was to compare only the basic characteristics and lab parameters, it did not produce significant defect in the outcome.

Second, the complaints and history given by the patients are subject to recall bias. This may have led to underreporting in both the diseases. Third, the pandemic is still in its initial phases, especially in India, and so this study and its results may not be a precise representation of the disease in its entirety. Lack of resources, time, and infrastructure has contributed to underdiagnosis of various probable complications of COVID-19. The condition of patients with H1N1 was more severe than those of the COVID-19 cohort, causing a statistical disequilibrium.


  Conclusion Top


Despite being taken from different time periods, both viral diseases showed certain parallels as well as marked differences. Increased prevalence in male population and abnormalities found on chest X-rays were some of the similarities. At the same time, poor baseline clinical status, multiorgan involvement, increased complications, requirement of life support, and finally mortality were startlingly high in H1N1, whereas constitutional symptoms, cardiac complications, and ARDS less responsive to standard management were associated with COVID-19. Tang X et al. [20] showed a higher reproductive number in COVID-19 (2.2 vs 1.3); the value is subjective to change keeping in mind the dynamic state of the pandemic. A specific treatment of the ongoing pandemic is still awaited but antivirals, anticoagulants, and antibiotics along with supportive management have helped to control the disease a bit. Vaccine development is quintessential as are social distancing norms at this critical hour to fully curtail the infection. Research with better logistics and a larger sample size from multiple centers are needed for the same.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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World Health Organization. WHO coronavirus disease (COVID-19) dashboard. Available from: https://covid19.who.int/?gclid=Cj0KCQjw0YD4BRD2ARIsAHwmKVmjNVSF_OPK4Qk9nEB45qsK7UP2l-SQA9HMGpV-t9GZ-Vi7qQiLo0oaAvRUEALw_wcB. [Access on July 2, 2020].  Back to cited text no. 1
    
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Government of India. India fights corona COVID-19. COVID-19 dashboard. Available from: https://www.mygov.in/covid-19. [Access on July 2, 2020].  Back to cited text no. 2
    
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National Center for Disease Control. Seasonal Influenza (H1N1) − State/UT- wise, Year-wise number of cases and deaths from2010 to 2015. Directorate General of Health Services, Ministry of Family Welfare, Government of India. Available from: https://ncdc.gov.in/index4.php?lang=1&level=0&linkid=119&lid=276. [Access on July 1, 2020].  Back to cited text no. 4
    
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World Health Organization. Coronavirus disease (COVID-19) technical guidance: laboratory testing for 2019-nCoV in humans.  Back to cited text no. 5
    
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Guan W, Ni Z, Hu Y, Liang W, Ou C, He J et al. Clinical characteristics of coronavirus disease2019 in China. N Engl J Med 2020;382:1708-20.  Back to cited text no. 6
    
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Official American Thoracic Society/ European Society of Intensive Care Medicine/Society of Critical Care Medicine. Clinical Practice Guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195:1253-63.  Back to cited text no. 7
    
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Pam Harrison. Medscape Internal Medicine. Androgens May Explain Male Vulnerability to COVID-19. https://www.medscape.com/viewarticle/930128. [Access on May 07, 2020].  Back to cited text no. 11
    
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The Covid ‘gender’ conundrum: Men are more vulnerable to coronavirus due to high levels of ‘gateway’ molecule. The Economic Times. Panache. May 11, 2020. https://economictimes.indiatimes.com/magazines/panache/the-covid-gender-conundrum-men-are-more-vulnerable-to-coronavirus-due-to-high-levels-of-gateway-molecule/articleshow/75674117.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst.  Back to cited text no. 12
    
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Basu-Ray I, Almaddah NK, Adeboye A, Soos MP. Cardiac Manifestations Of Coronavirus (COVID-19): StatPearls; 2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556152/  Back to cited text no. 17
    
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Aghagoli G, Gallo Marin B, Soliman LB, Sellke FW. Cardiac involvement in COVID‐19 patients: Risk factors, predictors, and complications: A review. J Card Surg 2020;35:1302-5. doi: 10.1111/jocs.14538. Epub 2020 Apr 19. PMID: 32306491; PMCID: PMC7264604.  Back to cited text no. 18
    
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Szekely Y, Lichter Y, Taieb P, Banai A, Hochstadt A, Merdler I et al. Spectrum of cardiac manifestations in coronavirus disease2019 (COVID-19): A systematic echocardiographic study. Circulation 2020;142:342-53. doi:10.1161/CIRCULATIONAHA.120.047971. Epub 2020 May 29. PMID: 32469253; PMCID: PMC7382541.  Back to cited text no. 19
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

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