Clinical Manifestation of Patients Who Died Due to COVID-19; A Retrospective Study from Qom-Iran

1Gastroenterology and Hepatology Diseases Research Center, Qom University of Medical Sciences, Qom, Iran 2Gastrointestinal and Liver Diseases Research Center (GILDRC), Iran University of Medical Sciences, Tehran, Iran 3Clinical Research Development Center, Qom University of Medical Sciences, Qom, Iran 4Department of Internal Medicine, Qom University of Medical Sciences, Qom, Iran 5Department of Anesthesiology and clinical care, Qom University of Medical Sciences, Qom, Iran 6Health Information and Technology, Tehran University of Medical Sciences, Tehran, Iran


Introduction
A new RNA virus from the betacoronavirus family named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first recognized in Wuhan, China, in December 2019. Since then, the virus has contaminated all parts of the world and become an endemic health problem. 1 In the Middle East, the outbreak of coronavirus disease 2019 (COVID- 19) was reported in Qom, Iran, in February 2020, for the first time. The virus was rapidly detected in the mass population in this city as well as other cities. The city of Qom is located in the center of Iran with many industrial and religious centers and many daily visitors, resulting in many travels. The main route of transmission is person-to-person transmission in society and family settings; however, other routes of transmission need to be considered. Despite the fact that the virus mainly affects the respiratory system, other vital organ can also be affected seriously. [2][3][4] Therefore, we can assume a wide spectrum of presentations in this situation. In fact, the common clinical presentations of COVID-19 are cough, dyspnea, fatigue, fever, chest pain, and myalgia. Moreover, alteration of complete blood count differential, and abnormal radiographic finding in chest CT scans are also reported. [5][6][7][8] The mortality rate of COVID-19 is reported between 2% and 16% based on age. 9 Furthermore, the rate of mortality may increase 2-10 folds among patients admitted to the intensive care unit (ICU) with preexisting morbidities such as cardiovascular diseases and diabetes. 10 In this regard, Chen et al reported that mortality in ICU admitted patients reached 4.3%. Accordingly, the main risk factors of mortality are advanced age, shortness of breath or dyspnea, low hemoglobin level, and having underlying comorbidities. 11 Li et al reported that the mortality rates for patients with hypertension, cerebrovascular diseases, and diabetes were two-, three-, and two-folds higher, respectively, in patients admitted to the ICU. 12 The clinical characteristics of expired patients in our region has not been reported. In this study, we summarized the clinical features of expired cases with COVID-19 from Qom. The purpose of this study is to identify critically ill COVID-19 patients of early and to reduce their mortality.

Patients
In this retrospective study, we reviewed medical files of 50 secondary non-surviving patients with COVID-19 who were hospitalized in March 2020. The patients were admitted to Shahid Beheshti general hospital, which is the referral hospital for COVID-19 patients. All of them were laboratory diagnosed with COVID-19 based on the WHO guideline (detection of virus RNA was considered as confirmed positive result). Due to rapidity and the emergency situation, the data for all patients could be not completed; so, we selected the patients who had almost all the related data.

Data Collection
All data were obtained from the electronic file of each patient. Moreover, a checklist including demographic, clinical presentation, clinical assessment, and laboratories data was completed. In case of any lack of data, a member of the team contacted the first-degree relative of the patient. In the next step, data was entered into the computerized database. Afterward, two experienced clinicians reviewed the data.

Laboratory Data
All activities, including sample collection and transfer, as well as lab safety issues were performed in compliance with the WHO guidelines for COVID-19 (WHO laboratory testing strategy recommendations for COVID-19: Interim guidance 2020).
Ethylene diamine tetra acetic acid (EDTA)-containing tubes were used for complete blood count (CBC) and differential blood counts using an automated blood cell counter (Sysmex K1000, Hamburg, Germany). For RNA extraction, a nasopharyngeal swab into viral transport media was used according to the manufacturer's instructions. Subsequently, a one-step real-time polymerase chain reaction (PCR) was performed by an assigned diagnostic laboratory, which was confirmed by the Ministry of Health based on universal protocols. All patients underwent a standard chest CT scan. Afterward, the results of the imaging were acquired via electronic reports for each patient.
Statistical Analysis Means (SD) and medians (IQR) were presented for normal and non-normal continuous variables, respectively. Normal distribution was checked using Shapiro-Wilk test and also normal probability plot (Q-Q plot). Categorical variables were expressed as number (%). All statistical analyses were performed using SPSS, version 20.0.

Discussion
This study presents one of the preliminary results regarding COVID-19 mortality in the city of Qom. This   city is known as the first site of COVID-19 detection in the Middle East. In this study, we observed that older age, male gender, and preexisting co-morbidities (particularly cardiovascular disease) are the most common risk factors. Almost all patient probably died secondary to respiratory failure and ARDS. Generally, COVID-19 has characteristics similar to SARS-CoV-2. 13 In the present study, the main  complications were respiratory failure and ARDS followed by the kidney injuries. In fact, COVID-19 can cause multi-organ damage. [14][15][16] In previous reports, cardiovascular damage was considered at the top of the list of organ damage among COVID-19 patients. 6,7,17 In the present study, the patients had not been evaluated regularly for cardiac events. Therefore, we cannot propose similar results in our patients. In fact, considering the common pre-existing cardiovascular problems as well as hypertension and diabetes among the patients, we suggest that cardiovascular events may be common factors that worsen the clinical situation of patients. A previous study indicated the association between cardiac events during pulmonary infection and following it. 18,19 This mostly occurs in viral infections such as influenza. 20,21 Notably, new cardiac events resulting from aggravation of preexisting cardiac problems were reported among patients with SARS. 22 The mechanism of organ injuries in COVID-19 is not elucidated yet. It is proposed that the virus can directly attack organs or it can accelerate the inflammatory mechanisms. Furthermore, cytokine storm remains as the main hypothesis in this regard. 22,6 Moreover, in older age, the defense mechanism is not intact. There is also cytokine dysregulation causing defects in viral protection. 23 Also, it has been observed that older age increases the odds of mortality. The reports from China and the United States suggest that age above 65 years significantly increases the risk of mortality. Explanations for this result may include the points that were mentioned above. 24,25 Recent studies have indicated associations with CBC differential including lymphocyte and neutrophil levels as well as hemoglobin value. [26][27][28] In fact, many studies show an association of lymphopenia with poor outcomes. Indeed, neutrophilia may be associated with acute cardiac events and sepsis development that can increase the odd of mortality. Also, studies regarding Hb value are more interesting because a decline in Hb level has been shown to be associated with poor outcome and mortality in previous reports. 29 However, in the present study, our patients did not have low Hb values, which may be related to rapid progression of the disease and also the fact that we considered the Hb concentration on admission. Altogether, we suggest the assessment of CBC with differential on admission and during the follow-up period of patients. This simple test can help the physicians to predict the patients' prognosis. Besides these findings, we must mention the elevated levels of CRP and LDH that are indicators of organ injuries and worsen the situation. Mardani et al indicated that values of LDH and CRP along with neutrophilia are associated with the presence of COVID-19. 30 Li et al also emphasized the important role of LDH in prognosis of patients. 31 Along with these laboratory data, we also need to rely on the results of CT scans as well the quick SOFA score. The presence of consolidation in CT assessment and qSOFA score more than 2 were also associated with increased odds of mortality in previous reports. 25 In conclusion, the presence of underlying diseases along with older age by themselves may worsen the outcome of patients. COVID-19 is a complex disease that cause multiorgan injuries. Therefore, simple alteration in laboratory value including Hb level, neutrophilia, and lymphopenia at the onset and during surveillance may provide a clue for poor prognosis.

Authors' Contribution
MS, AH and SFG conceived and designed the analysis. SA, SJ, AJ, RA, MA, and ER collected the data. SJ and SA performed the analysis. MS wrote the paper.

Conflict of Interest Disclosures
There is no conflict of Interest.

Ethical Statement
The study protocol was approved by the ethics committee of Qom University of Medical Sciences (ID: IR.QUMS.rec.1398.154). This work was supported by Shahid Beheshti hospital, Qom University of Medical Sciences and Firoozgar hospital, Iran University of Medical Sciences. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.