Verifying Extra-Pulmonary Manifestation of COVID-19 in Firoozgar Hospital 2020: An Observational Study

Background: COVID-19 is a new emerging disease that causes a pandemic situation in the world. Corona virus can enter into the body via several ways and it damages other organs of the body in addition to the respiratory system. This study aimed at verifying extra-pulmonary manifestation of COVID-19. Methods: The present study was done as cross-sectional in the single center from March 1 to May 1 2020 at Firoozgar educational hospital in Tehran, Iran. 107 patients with conrmed Covid-19 pneumonia according to WHO interim guidance were recruited in this study. Extra-pulmonary manifestations of COVID-19 were recorded. SPSS, version 26 was used for all analyses. Results: The mean (SD) and median of age was 59.3 (17.4) and 62.0 respectively and 58 (54.2%) were men. Body temperature of patients who were equal or less than 60 years was signicantly higher than other patients (39.02 vs. 38.08, p=0001). The most common extra-pulmonary manifestation was GI symptoms included nausea, vomiting, abdominal pain, diarrhea, Hepatocellular LFT abnormality, Cholestatic LFT abnormality and Amylase lipase incensement (37 patients (34.6%)). Ophthalmological, cardiac, neurological and dermatological manifestations were shown in 6.5%, 6.5%, 14.9% and 14.0% of patients respectively. Conclusion: Investigating the clinical and radiological symptoms of COVID-19 showed that SARS-CoV-2 infection may also be associated with extrapulmonary symptoms. Therefore, clinicians and radiologists should be familiar with such symptoms of this disease.


Introduction
A new coronavirus causes COVID-19 infection. COVID-19 cases suffer from mild to moderate respiratory disease and they recovered with no special treatment. Older cases and people with underlying medical diseases, such as cardiovascular disease, diabetes, chronic respiratory disorder, and cancer are at higher risk for developing serious illnesses.
Respiratory symptoms have been investigated in this disease (1). Along with respiratory and other typical symptoms, like fever, cough and muscle ache, extra-pulmonary manifestations have been reported in some cases requiring special care and attention. Neurological (2), cardiac (3), gastrointestinal (GI) (4), dermatological (5) and ophthalmological (6) manifestations have been less evaluated, which should be considered more. Coronaviruses (CoVs) are able to go into the CNS via the bloodstream or neuronal retrograde pathway and cause meningitis, encephalitis, related morbidity, and risk of death. It is usually hard to diagnose viral encephalitis due to subtle or lack of symptoms; however, it is possible to detect some symptoms of the serious viral encephalitis including changed mental status and body temperament, unusual behavior or speech, unusual motor movement and focal neurological dysfunctions, like accid paralysis, paresthesia, hemiparesis, or seizures (7).
Gastrointestinal (GI) symptoms have been reported in several patients. Some COVID-19 patients with GI symptoms were found as the only manifestation of the disease with no respiratory disorders (8,9). It has been reported that from 67 COVID-19 cases with diarrhea, 13 patients had no other symptoms (10).
Although GI symptoms in COVID-19 are not speci c, they are more common in cases with approved SARS-CoV-2 infection.
Cardiovascular symptoms of COVID-19 are also challenging for physicians. Identi cation of the damage by COVID-19 to the cardiovascular system and the underlying mechanisms is crucial, because treating these cases is timely and effective with reduced mortality (3).
Recent studies have veri ed skin symptoms of COVID-19. The results of evaluating 88 COVID-19 cases, skin symptoms are erythematous rash, widespread urticaria, and chickenpox-like vesicles. Trunk skin lesions as the main area affected were not somewhat itchy (5).
The transmission of COVID-19 is done through droplets, however, other methods of transmission have been documented, for instance, transmitting via infected ocular tissue or uid (11,12). The nasolacrimal system may pave the way for viruses to travel from the upper respiratory tract to the eyes. Consequently, ocular tissue and uid are probably a likely source of coronavirus.
This study aimed at verifying extra-pulmonary manifestation of COVID-19.

Methods
The present study was done as cross-sectional in the single center from March 1 to May 1 2020 at Firoozgar educational hospital in Tehran, Iran. 107 patients with con rmed Covid-19 pneumonia according to WHO interim guidance were recruited in this study.
This study was approved by Ethics Committee of Iran University of Medical Sciences and all patients signed written informed consent. Two attending doctors separately examined patients for neurological, cardiac, GI, ophthalmological and dermatological manifestations. Lung CT involvement was categorized as mild, moderate and severs. Presence of cough, dyspnea, chest pain, anosmia and dysgeusia were recorded. Past medical history such as suffering from diabetes, hypertension (HTN), ischemic heart disease (IHD), chronic kidney disease (CKD), Immuno-compromised status, myalgia and other diseases were collected from all patients.

Statistical analysis
Continuous measurements reported as mean ± Standard deviation (SD) for normally distributed data and categorical variables were described as number of patients (percent). SPSS, version 26 was used for all analyses. Continuous variables were compared using independent sample t-test and proportions for categorical variables were compared using the χ 2 test, whereas the Fisher exact test was conducted when the data were limited.

Results
The study participants included 107 hospitalized patients with con rmed Covid-19 pneumonia. Basic characteristics of the study participants according to age groups are illustrated in Table 1. The mean (SD) and median of age was 59.3 (17.4) and 62.0 respectively and 58 (54.2%) were men. Body temperature of patients who were equal or less than 60 years was signi cantly higher than other patients (39.02 vs. 38.08, p = 0001). Of patients older than 60 years, 16 (28.6%) and 55 (98.2%) had HTN and dyspnea, respectively. Surprisingly, patients who were equal or less than 60 years, had signi cantly more underlying comorbid systemic disease than other patients (9 (17.3%) vs. 2 (3.6%), P = 0.019). Figure.1 shows comorbidities of patients on admission. Extra-pulmonary manifestations related to COVID-19 patients are shown in Table 2. The most common extra-pulmonary manifestation was GI symptoms included nausea, vomiting, abdominal pain, diarrhea, Hepatocellular LFT abnormality, Cholestatic LFT abnormality and Amylase lipase incensement (37 patients (34.6%)). Ophthalmological (7 patients (6.5%)) and cardiac (7 patients  showed dermatological symptoms such as erythema, macula, papule, morbid form rash, urticarial and patch ( Figure.2). There was no signi cant difference between the number of male and female subjects. In many studies evaluating COVID-19 cases, the numbers of men were more than women (1, 13, 14). The decreased vulnerability of women to viral infections may be associated with the protection from X chromosome and sex hormones that are crucial in innate and adaptive immunity (15). Approximately, 30% of cases affected by coronavirus were found with hypertension, diabetes and ischemic heart disease, which is also true for MERS-CoV.19 (13). Our ndings indicated that younger cases had remarkably more underlying comorbid systemic disease compared to older cases, which can be associated with underlying diseases that weaken the immune system and increase the risk of infection with coronavirus (16).
GI symptoms are more prevalent among the extrapulmonary manifestations. Nausea, vomiting, abdominal pain, diarrhea, Hepatocellular liver function test abnormalities, cholestasis, and Amylase lipase incensement have been reported in nearly 45% of cases. Some cases of COVID-19 have been observed with GI symptoms as the only manifestation of the disease with no respiratory dysfunctions (9). GI wall permeability is enhanced to foreign pathogens while infected with the virus, GI symptoms, like diarrhea, are observed because of mal-absorption of infected enterocytes (4). Cohort studies have also consistently announced GI symptoms in Covid-19 cases. Another study on 1,099 patients from 552 hospitals in China reported nausea or vomiting in 55 (5.0%) and diarrhea in 42 (3.8%) patients (17). Many cohort studies have revealed diarrhea (2.0-10.1%) and nausea and/or vomiting (1.0-10.1%) in these patients (1,18,19). Consistent with the current study, in a cohort study of 140 Covid-19 cases in Wuhan, up to 39.6% of them had GI symptoms, such as nausea (24,17.3%), diarrhea (18, 12.9%), and vomiting (7, 5.0%) (20). The receptor-binding domain on SARS-CoV-2 is capable of binding to human ACE2 with strong a nity, which is believed to help spread the virus among human population effectively (21,22). Signi cant expression of ACE2 in alveolar cells type II (AT2) in the lungs has been reported, and the receptor can be also extensively expressed in the GI tract, chie y in the small and large intestines (23). Staining of the virus nucleocapsid protein was observed in cytoplasm of gastric, duodenal, and rectal epithelium (24). Thus, it is possible to consider receptor-mediated entry into the host cells can be revealing a basis for its probable transmission way via the fecal contents.
Dermatological symptoms have been recorded in nearly 20% of 107 COVID-19 cases. Erythema has been the most common manifestation, particularly in the patients ≤ 60 years. It has been reported that patients with con rmed SARS-CoV-2 infection might develop cutaneous involvement. In another study on 88 COVID-19 patients, it was observed that erythematous rash, widespread urticaria, and chickenpox-like vesicles are the skin symptoms of the COVID-19. Trunk skin lesions as the main area affected were not somewhat itchy (5).
CoVs are capable of going into the CNS via the bloodstream or neuronal retrograde route causing meningitis and encephalitis along with morbidity and risk of mortality. It is hard to diagnose viral encephalitis due to subtle or lack of symptoms, however, symptoms in severe viral encephalitis are changed mental status and body temperament, unusual behavior or speech, abnormality in motor movement and focal neurological dysfunctions, including accid paralysis, paresthesia, hemiparesis, or seizures (7). Assessing 214 patients with COVID-19 indicated that 78 patients (36.4%) had neurological manifestations, like headache, dizziness, acute cerebrovascular diseases, and disturbed consciousness (25).
Studies on the neurological attack in COVID-19 pneumonia revealed that SARSCoV-2 was capable of attacking the CNS and nding the way throughout the systemic circulation or through the cribriform plate of the ethmoid bone. It could then damage the neuronal tissues via interaction with ACE2 receptors. COVID-19 cerebral participation through the cribriform plate can cause more complications, like hyposmia or anosmia (26,27). Some investigations have reported the likely cerebrovascular endothelial rupture leading to bleeding and irrepressible consequences (27). Due to intracerebral hemorrhage, cerebrovascular accidents have been declared as the rare COVID-19 neurological consequence (28). COVID-19-related acute hemorrhagic necrotizing encephalopathy was found in an individual with changed mental status with nasopharyngeal swab positive for SARS-CoV-2. According to imaging results, symmetric hypo attenuation in the bilateral medial thalami was detected by the head CT, as well as hemorrhagic ring-enhancing lesions in the bilateral thalami, medial temporal lobes, and sub insular areas detected by brain MRI (29). Nevertheless, more investigations should be done for the causation link.
Cardiac and ophthalmological symptoms have been reported in less than 10% of COVID-19 cases in our study. Of 107 studied patients, only 4 cases showed myocardial infarction. ACE1 is the target receptor for SARS-CoV-2 expressing remarkably in the heart. This transmembrane aminopeptidase is linked with developing hypertension, and heart function is essential in the cardiovascular system. Therefore, it is possible to consider cardiovascular injury or myocarditis a COVID-19 manifestation (30). Zheng et al. According to the American Academy of Ophthalmology report, conjunctival infection and chemosis are some extrapulmonary symptoms of the infection with SARS-CoV-2 (33). Transmitting by infected ocular tissue or uid should be more studied and is debated (11,12). Nasolacrimal system may pave the way for the viruses to travel from the upper respiratory tract to the eyes. Consequently, it is possible to consider ocular tissue and uid as likely source of SARS-CoV-2. However, in the present study, tear or secretion PCR test for detecting coronavirus was not positive.
Conclusion COVID-19 leads to viral pneumonia with some clinical symptoms. According to the clinical and radiological symptoms of COVID-19, SARS-CoV-2 infection might also be related with extrapulmonary symptoms. Consequently, clinicians and radiologists are advised to be aware of such symptoms of this disease. It is essential to perform more studies to verify the causal link between SARS-CoV-2 infection and the reported extrapulmonary symptoms of COVID-19.

Funding
The present study was supported by Iran University of Medical Sciences (grant no. IUMS16725): They had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Availability of data and material