key: cord-0704708-2hnhn7jx authors: Shaha, M.; Islam, M. A.; Huq, F.; Roy, B.; Kabir, A.; Salimullah, M.; Mahtab, M. A.; Akbar, S. M. F. title: Clinical manifestations of hospitalized COVID-19 patients in Bangladesh: a 14-day observational study date: 2021-04-29 journal: nan DOI: 10.1101/2021.04.27.21256018 sha: afedbb277560821a90dd1d975f50b2a0f511fd3d doc_id: 704708 cord_uid: 2hnhn7jx Objectives: Severe acute respiratory coronavirus-2 (SARS-CoV-2) is currently a significant public health concern and causing a pandemic in the world. Despite of immense attention to the coronavirus disease-2019 (COVID-19), very little attention has been given to the kinetics of disease progression in infected patients. Therefore, in this study, we present a 14-day clinical observation of hospital-admitted COVID-19 patients. Methods: After recording the demography of 42 COVID-19 patients on day 1, we observed the clinical progression for 14 days by investigating the hematological and biochemical responses of patients blood and serum, respectively. Results: Approximately 62% of the hospital-admitted COVID-19 patients presented cough, followed by fever (approximately 52%). The top comorbidities of these patients were hypertension (30%) and diabetes mellitus (19%). The average blood hemoglobin level was slightly low among the patients in early days of infection and went up to the normal level on the latter days. A substantial increase in the level of ALT/SGPT (up to 106 units/L; SEM: 12.64) and AST/SGOT (up to 64.35 units/L; SEM: 5.013) in COVID-19 patients was observed, which may suggest that infection with CoV-2019 is associated with the functionality of other organs of COVID-19 patients. Conclusion: This 14-day observational study may help clinicians to decide the choice of treatment of COVID-19 patients. Coronaviruses have been causing significant disease outbreaks globally over the past two decades. In 2002, severe acute respiratory syndrome (SARS) emerged in East Asia (Cherry 2004) , and later on, the Middle East respiratory syndrome ( However, the clinical manifestations of how the infection progresses to the severe disease and/or subsequently recovers are yet to be understood. Here in this study, we present the . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 kinetics of clinical manifestations of the hospital-admitted COVID-19 patients for 14 days and patients' comorbidity with the COVID-19 disease. The study was conducted between April and May 2020 at Combined Military Hospital, Dhaka, Bangladesh. Forty-two patients were included in this study who tested COVID-19 positive and were admitted to the hospital. The mean age of these patients was 40.02 years, with a standard error of the mean (SEM) of 1.911. Of these patients, female (mean age: 32.13; SEM: 5.313) and male (mean age: 41.88; SEM: 1.91) patients were approximately 19% and 81%, respectively. The demographic of these patients were collected on the day of hospital admission. The enrolled patients were in observation for 14 days (unless otherwise stated), and their blood samples were collected each day at the same time during the course of observation. For hematological analyses, blood samples of the COVID-19 patients were collected in tubes containing anticoagulant EDTA. For performing serum biochemistry, blood samples were collected without anticoagulant and was centrifuged at 500 g for 10 min to separate serum (Eppendorf 5702, Hamburg, Germany). The separated serum was then stored at -20 until use. This study was approved by the institutional ethics committee (approval number: FGH/2020/01) of Farabi General Hospital, Dhaka, Bangladesh. A complete blood count (CBC) using the COVID-19 patients' blood samples was performed using the commercial kit (Promega corporation, Fitchburg, WI, USA) using ADVIA 2120 Hematology System (Siemens Diagnostics, Erlangen, Germany) according to the . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 manufacturer's instructions. Blood oxygen was measured using a pulse oximeter (Thermo Fisher Scientific, Waltham, MA, USA) as per the protocol given by the supplier. Biochemical analyses of serum components such as Albumin, Bilirubin, creatinine, chloride, sodium, and potassium were performed using standard routine techniques. Serum AST and ALT levels were determined by the standard colorimetric method of Reitman and Frankel. Enzyme activities were determined at 37 o C. Serum biochemistry was performed using a standard autoanalyzer (ABX-Diagnostics, Tokyo, Japan). Body temperature, respiratory rate, blood pressure, and heart rate of the COVID-19 patients were measured as routine procedures in the lab. Chest X-ray reports were kindly provided by the imaging unit of the hospital on day 1. GCS score was determined as per the standard protocol (Teasdale and Jennett 1974) . All statistical analysis was performed using GraphPad Prism v9. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101/2021.04.27.21256018 doi: medRxiv preprint 6 Of the 42 hospital-admitted COVID-19 patients, approximately 62% were affected by cough, followed by fever (~52%), breathing difficulty (~24%), myalgia (~22%), loose motion (~17%), and others ( Figure 1A ). Of these patients, approximately 19% got pneumonia, and only about 2% were asymptomatic. These results indicate that in addition to fever and cough, COVID-19-infected patients presented a wide range of other clinical symptoms. Chronic conditions were reported as common comorbidities among the COVID19 patients. Data revealed that nearly 30% of the included patients were affected with hypertension. Diabetes Mellitus was the second comorbid condition, as reported by approximately 19%. Ischemic Heart Disease (5%), Non-alcoholic Steatohepatitis (6%), Hypothyroidism (<5%) were the other common comorbid condition among the patients (Figure 1B) . At that time of COVID-19 pandemic, the patients were treated with Fevipiravir plus SoC (~19%), Hydroxychloroqine plus azithromycin plus SoC (~38.1%), and Hydroxychloroqine plus doxycycline plus SoC (54.8%). Approximately 14.3% of the patients was given a combination of Fevipiravir and Hydroxychloroqine plus doxycycline plus SoC therapy at that time. Only 1 (2.4%) patient needed oxygen during the course of observation. As the COVID-19 patients present a wide range of clinical symptoms and comorbidities related to both respiratory and heart organs, we determined the respiratory rate as well as the heart rate of these patients from day 1 to day 14. We observed a higher mean respiratory rate (25.07 breaths/min; SEM: 0.6652; normal range 12-16 breaths/min) among the COVID-19 patients on day 1. The respiratory rate of these patients fluctuated slightly during the course . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101/2021.04.27.21256018 doi: medRxiv preprint 7 of observation but remained higher than the normal range, as shown in Figure 2 . However, the heart rate of these patients was in the normal range during the course of observation. We also measured the body temperature of the COVID-19 patients in the course of observation. Analysis of data revealed that the mean body temperature of the patients gradually decreased from the hospital's 1st day ( After observing a differential level of respiratory rate and body temperature of the COVID-19 patients in different days of hospital stay, we hypothesized that the level of blood components would vary in patients in the course of the disease. Therefore, we considered four observation periods (day 1, 3, 7, and 14) for each patient in this course of COVID-19 infection. We collected blood samples from these patients on respective days and measured the level of blood hemoglobin (Hb), red blood cell (RBC), white blood cell (WBC), platelet, neutrophil, and blood oxygen (SPO2). On day 1, we observed a downregulated Hb level (approximately 11.5 g/dL; SEM: 0.4008) among the female COVID-19 patients, where the normal range of Hb level is 12.1-15.1 g/dL. The Hb level among them was then found to be gradually increased to the normal level by day 3 with a slight decrease to approximately 12.1 (SEM: 0.621) on day 7. In regard to the male COVID-19 patients, the Hb level goes down to approximately 13.6 g/dL (SEM: 0.3602) from 14.0 g/dL on day 7 and then went up to the normal level (13.8-17.2 g/dL) again on day 14 (Figure 3-A,B) . This result suggests that blood Hb level is slightly downregulated among male and female COVID-19 patients in the early days of disease progression. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101/2021.04.27.21256018 doi: medRxiv preprint 8 We observed an increased level of RBC from day 1 to day 7 in both male (normal range is 4.5-5.9×10 12 /L) and female (normal range is 4.1-5.1×10 12 /L) COVID-19 patients compared to the normal range as shown in Figure 3 -C,D. However, after 7 days of disease symptoms, RBC level went down to the normal range. Infection with CoV-2019 may not alter the level of SPO2, neutrophil, blood platelet, and WBC. However, the level of blood platelet and WBC were observed gradually upregulated within the normal range from day 3 to day 14 (data not shown). As the level of some of the blood components was differentially influenced by COVID-19, we tried to analyze the effect of this disease on the level of serum components in the hospitaladmitted patients during the course of the disease. Therefore, we measured the level of serum albumin, bilirubin, creatinine, sodium, potassium, and chloride from the prepared serum samples of the COVID-19 patients. We observed the average serum chloride level is downregulated to approximately 95 mEq/L (SEM: 0.7997) below the normal range (96-106 mEq/L) on day 14. However, infection with CoV-2019 does not significantly affect the level of serum albumin, bilirubin, creatinine, sodium, and potassium (supplementary Figure S1 ). After observing the effect of COVID-19 on blood and serum components of the CoV-2019infected patients, we hypothesized that COVID-19 influences the functionality of other organs of COVID-19 patients. Therefore, we analyzed the level of ALT/SGPT, AST/SGOT, and GCS scores in these patients during the course of the disease. ALT/SGPT is an enzyme, . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101/2021.04.27.21256018 doi: medRxiv preprint 9 which is synthesized mainly by the liver, whereas the AST/SGOT is synthesized by multiple organs, including the liver, heart, etc. On day 1, approximately 19% of the patients developed pneumonia. Also, the overall respiratory rate of the patients was higher than the normal range on day 1, which is consistent with other studies with COVID-19 patients (Zhou et al. 2020) . The increase in respiratory rate was observed heightened during the course of disease till day 14. Though the patients were not tested for chest X-ray in the subsequent days, the gradual increase in the respiratory rates may suggest that the disease was still influencing the patient's lung over time. Our findings noted hypertension and diabetes were the most common comorbid condition is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. (Ng et al. 2021; Sanyaolu et al. 2020 ) and meta-analysis reported hypertension and diabetes as the common comorbid conditions among people infected by the virus. The COVID-19 patients were observed to have a reduced Hb level than the normal range on day 1, which is aligned with a study conducted with COVID-19 ICU patients (Lippi and Mattiuzzi 2020) . This is a unique feature of CoV-2019 infection, which may indicate that the virus is acquiring the iron from the patient's body for their survival and replication, though more research is needed to confirm this. Hb is essential to transfer oxygen from the lung to the tissues through the blood. Interestingly, though there is a lower Hb level in the patients' blood, the level of oxygen was not altered enough. ALT/SGPT level of the patients was found enormously heightened after 7 days of disease progression than the normal range and sustained upregulated till day-14. Serum ALT is a potential marker of liver functionality (Gowda et al. 2009 ). The normal range of this enzyme is 7-56 units per liter of serum. On day 14 of our observation, we found that the level of ALT went significantly up by more than twice (108 units/L) than the normal range. Likewise, the . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. Heightened AST level further denotes a risk of heart failure. Therefore, these results suggest that infection with CoV-2019 poses threat to not only the respiratory tract organ, but also to the liver as well as the heart. In this study, we found one patient who sadly died of COVID-19 on day 4 after hospital admission. That patient was in 56-60 age range who had the comorbidity of hypertension and presented symptoms of fever and breathing difficulties from day 1 of hospital admission. The respiratory rate was consistently high (average of 42.4 breaths/min) and slightly low blood pressure (110/70 on day 3 and 80/50 on day 4). The GCS rate was regular (GCS 15) in the first two days of observation. However, on day 3 and 4, GCS rate went much lower to 12 and 11, respectively. Notably, the patient had already developed pneumonia on day 1 of hospital admission. This study presents a novel 14-day clinical observation of COVID-19 patients and is significant for three main reasons. Firstly, we present the potential comorbidities and wide ranges of symptoms shown by the COVID-19 patients. Secondly, the COVID-19 patients were essentially in our observation for approximately 14 days, and the clinical manifestations during the observations were analyzed. Thirdly and most importantly, the association of COVID-19 with subsequent liver and heart functionalities was identified by assessing the level of ALT and AST. We believe that the data of this study will help clinicians to decide . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 1 3 the appropriate management of COVID-19 patients and take necessary actions to prevent the failure of other organs of the affected patients. Data is decribed throughout the manuscript. None declared. None. All authors of this manuscript show highest gratitude to the participants of this study. Supplementary Figure S1 : A 14-day observation of the level of serum components chloride (A), sodium (B), potassium (C), creatinine (D), albumin (E), and bilirubin (F) synthesized in COVID-19 patients. The graph was prepared using GraphPad Prism v9 software package. The represented data denotes Mean±SEM. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 The represented data denotes Mean±SEM. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 29, 2021. ; https://doi.org/10.1101/2021.04.27.21256018 doi: medRxiv preprint 2 1 Figure 2 : A 14-day observation of respiratory rate (A) and heart rate (B) of the COVID-19 patients. The graph was prepared using GraphPad Prism v9 software package. The represented data denotes Mean±SEM. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The graph was prepared using GraphPad Prism v9 software package. The represented data denotes Mean±SEM . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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