key: cord-0934126-pq0xasz0 authors: Almazeedi, S.; Al Youha, S.; Jamal, M. H.; Al-Haddad, M.; Al-Muhaini, A.; Al-Ghimlas, F.; Al-Sabah, S. title: Clinical Characteristics, Risk Factors and Outcomes Among the First Consecutive 1,096 Patients Diagnosed with COVID-19: The Kuwait Experience date: 2020-05-15 journal: nan DOI: 10.1101/2020.05.09.20096495 sha: 71bf4e394d82dee568dd363f4e53cb6bc058226d doc_id: 934126 cord_uid: pq0xasz0 Background In Kuwait, prior to the first case of COVID-19 being reported in the country, mass screening of incoming travelers from countries with known outbreaks was performed and resulted in the first identified cases in the country. All COVID-19 cases at the time and subsequently after, were transferred to a single center, Jaber Al-Ahmad Al-Sabah Hospital, where the patients received standardized investigations and treatments. The objective of this study was to characterize the demographics, clinical manifestations and outcomes in this unique patient population. Methods This retrospective cohort study was conducted between 24th February 2020 and 20th April 2020. All consecutive patients in the entire State of Kuwait diagnosed with COVID-19 according to WHO guidelines and admitted to Jaber Al-Ahmad Al-Sabah Hospital were recruited. Patients received standardized investigations and treatments. Multivariable analysis was used to determine the associations between risk factors and outcomes. Findings Of 1096 patients, the median age was 41 years and 81% of patients were male. Most patients were asymptomatic on admission (49.5%), 69.4% had no signs of infection and 94.6% were afebrile. Only 3.6% of patients required an ICU admission and 1.7% were dead at the study cutoff date. On multivariate analysis, the risk factors found to be significantly associated with admission to intensive care were age above 50 years old, a qSOFA score above 0, smoking, elevated CRP and elevated procalcitonin levels. Asthma, smoking and elevated procalcitonin levels correlated significantly with mortality in our cohort. Interpretation To our knowledge, this is the first large retrospective cohort study observing the characteristics of the initial consecutive COVID-19 patients of an entire country. Further, large proportion of asymptomatic patients provides novel insights into the clinical features of patients with milder disease. Jaber Al-Ahmad Al-Sabah hospital is a 1240 bed tertiary hospital based in South Surra, Kuwait. All patients admitted to Jaber Al-Ahmad Al-Sabah hospital in Kuwait, with a diagnosis of COVID-19, based on the World Health Organization (WHO) interim guidance 4 and have been confirmed by laboratory testing using PCR testing, between February 24 th 2020 and the study's cutoff date of April 20 th 2020 were included in the study. Patients who had equivocal testing results or were suspected cases were excluded from the study. Ethical approval for this study was obtained from the Kuwait Ministry of Health Ethical Review Board. Data regarding patients' demographics and initial clinical presentation (signs, symptoms, laboratory and radiographic findings) was collected for the study from Jaber Al-Ahmad Al-Sabah hospital's electronic medical record system. Radiologic findings were extracted from the radiologists' reports on the electronic medical record system. A custom data collection form was created using the SurveyCTO (Dobility, Inc) platform. To minimize data entry errors, appropriate constraints were placed on most of the data entry fields. All data then underwent a secondary quality check and was reviewed by a physician and a statistician. Any discrepancies were resolved by a third physician to ensure accuracy of the data that was entered. Study participants' signs, symptoms, vital signs, laboratory investigations and radiologic findings were all recorded on admission. 'On admission', 'at the time of diagnosis' and 'on presentation' are used interchangeably to describe the variables that were collected initially for patients on the first day they were admitted to hospital. All the chest x-rays that were ordered on admission for patients were reviewed by a consultant radiologist and formally reported. The normal reference ranges for vital signs are provided in (Appendix 1). Fever was defined as an oral temperature of 38.0°C and above. The disease severity of Covid-19 on admission was quantified using the quick sequential organ failure assessment score (qSOFA) score for sepsis 5 . Patients' BMIs 6 were categorized according the WHO 6 criteria. The diagnostic criteria that were used for the adverse events that were collected are listed in (Appendix 2). The treatment protocols of patients with COVID-19 pneumonia at our center followed the official Kuwait Ministry of Health COVID-19 management guidelines, the latest version of which can be found in (Appendix 4). All patients diagnosed with COVID-19 stayed in the hospital until they had resolution of symptoms; defined as being afebrile for more than 72 hours and having oxygen saturations equal to or above 94%, Discharge occurred after two consecutive negative PCR tests for COVID-19, more than 24 hours apart. All diagnostic tests were performed in Jaber Al-Ahmad Al-Sabah hospital in Kuwait. testing was performed via real-time reverse-transcriptase-polymerase chain-reaction (RT-PCR) assay of specimens obtained via nasopharyngeal swabs. Entered data were checked for accuracy, then for normality, using Kolmogorov-Smirnov & Shapiro-Wilk tests, and proved to be not normally distributed. Qualitative variables were expressed as numbers and percentages while quantitative variables were expressed as medians and interquartile ranges (IQR). Vital signs were categorized as 'normal' if their value was within the normal reference range, as reported in Appendix 1., and 'abnormal' if their value was below or above the normal range. Laboratory values were categorized as 'below', 'within' and 'above' the reference ranges described in Appendix 3. Clinical outcomes were subcategorized by age: below 18, between 18 and 64 and above 65 years old. For the possible confounding effects of the variables, multiple logistic regression were used for the final analysis to predict factors which may be associated with COVID-19 outcomes; namely, mortality and admission to the intensive care unit (ICU). All the explanatory variables included in the logistic models were categorized into two levels (0 for no and 1 for yes). In multivariate analysis, the associations between exposure and outcomes were expressed in terms of odds ratio (OR), together with 95% confidence intervals (95% CI). A 5% level is chosen as a level of significance in all statistical significance tests used. All statistical analysis was performed using IBM SPSS® version 22 for Windows. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint A research grant was awarded by the Kuwait Foundation for the Advancement of Science to aid in data collection, and purchasing statistical software and database packages for the paper. A total of 1096 patients were included in the study. Most patients were of Indian origin (48·1%), followed by Kuwaitis (27·1%) and Egyptians (6·6%). Of note, 506/527 (96·0%) of the Indian nationals were male. The mean BMI of our sample was 26·6 (SD, 8·3), after excluding children below the age of 12. 41·5% of those were classed as overweight, with a BMI between 25-29·9. Most of the patients were non-smokers 1052/1096 (96·0%). Many patients had a history of recent travel (within the past 30 days), 287/1096 (26·2%); mainly from the United Kingdom (8·7%) and Iran (7·4%). The most common mode of COVID-19 transmission in our patient population was contact with a known positive case of COVID-19 (48·3%). Almost half of the patients were asymptomatic at the time of diagnosis, and around 70% had no signs of infection. For the patients who presented with symptoms, the vast majority had either cough (29%), chills (26·8%) or sore throat (11·7%). Table 2 provides a summary of the symptoms present at the time of diagnosis. The vital signs taken on presentation were within normal limits for most patients, with 1039 (94·6%) having no fever initially (Table 2) . Although most patients did not have any co-morbidities (69·4%), hypertension and diabetes mellitus were present in 177/1096 (16·1%) and 155/1096 (14·1%) of the patients respectively (Table 2) . Of note there were 3 (0·3%) patients who were pregnant. Most patients had a qSOFA score of 0 on admission (63%) and only a small number of patients required vasopressors or intubation on admission (0·6% and 0·9% respectively) ( Table 2) . Table 3 summarizes the laboratory findings on admission, with most patients having results within the normal laboratory reference range. Of note, 89% of the patients had a normal white blood count. Only 14·6% had a lymphocyte percentage below the reference range and 30·7% had a monocyte percentage that is above the reference range on the white blood count differential. One third of the patients were hyperglycemic on admission, and the predominant electrolyte imbalances were hyponatremia (28·7%) and hypocalcemia (20·6%). With regards to the inflammatory markers, 36·6% of patients had elevated C-reactive protein (CRP) initially and 60% had a D-dimer level lower than the normal range. More than half (53·4%) of the patients had low prothrombin time (PT) and most patients had a normal coagulation profile. In terms of liver enzymes, the aspartate transaminase (AST), was the most elevated above the normal reference range value for our sample (14·4% of patients). Most patients had albumin and total protein levels below the normal reference range (18·2% and 18·7%, respectively). As depicted in Table 4 , only one third of patients had a chest x-ray that was reported as being 'normal' by the radiologist on admission (33%). The most reported findings by the radiologists were prominent broncho-vascular markings (43·3%), unilateral local patchy shadowing or opacification (16·6%) or diffuse opacification (8·2%) ( Table 4 ). Only 71 patients had a computed tomography (CT) of the chest, of which 54 (76·1%) were reported as normal by the radiologist. The most reported finding on CT chest was ground glass opacity (15·4%) Based on the previously described treatment protocols at our center, a total of 27·9% of patients did not receive any medications or treatments and were admitted to hospital for institutional quarantine purposes. Most patients (68·2%) were labeled as having received 'other treatments', and this mostly included supportive medications such as paracetamol and vitamin supplements ( Table 5 ). The most common non-supportive medications that were prescribed, were antibiotics (27·9%), followed by antivirals (13·8%) and hydroxychloroquine (7·1%). For therapeutic interventions, admission to the intensive care unit (3·6%), oxygen therapy (3·2%) and mechanical ventilation (2·8%) were the most frequently administered. Most patients (90·1%) had no adverse events during hospital admission. Pneumonia was the most common complication associated with COVID-19 (7·1%), followed by acute respiratory distress syndrome (7·1%) ( Table 5) . At the study's cutoff date, most of the patients in our cohort were eventually discharged from the hospital (88·2%), and only 19 (1·7%) patients succumbed to the disease. The median length of stay (LOS) for the patients was 18 days (interquartile range, 13-24 days), with patients aged above 65 years having the longest median LOS of 24 days (interquartile range, 18-31 days). A breakdown by age of the most frequent adverse events and clinical outcomes is outlined in Table 6 . On multivariate analysis, the risk factors significantly associated with an admission to the intensive care unit were found to be age above 50 (Table 7) . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. To our knowledge, this is one of the first large retrospective cohort studies to summarize demographic, clinical characteristics and outcomes of consecutive COVID-19 patients in a single country. Our study sample had several distinguishing features, such as; a large proportion of asymptomatic hospitalized COVID-19 patients (49·5%), the majority of patients had definitive outcomes at the study's cutoff date (90·0%) and all the patients in our sample were admitted at a single center for treatment and/or quarantine purposes where they all received standardized investigations and treatment protocols, irrespective of disease severity (Appendix 4.). In this study sample, we found an association between several risk factors and admission to the intensive care unit: namely, age above 50 years old, smoking, elevated qSOFA score, elevated C-reactive protein and procalcitonin levels. Also, the following risk factors were identified as having a correlation with mortality in our sample: asthma, smoking and elevated procalcitonin levels. The median age for our sample was lower (41 years old), compared to the two other large retrospective cohort studies from China 1 (47 years old) and New York City 2 (63 years old ). This is likely a result of our sample encompassing a large cohort of patients who were asymptomatic and were only identified as being COVID-19 positive due to the mass screening efforts of the Kuwaiti government for incoming travelers. This may also account for the large proportion of patients with a history of recent travel in our cohort (21·7%). Only 19% of our study's patients were female, which is lower but in keeping with findings by Guan et al. 1 and Richardson et al. 2 , who also reported a lower admission rate for women compared to men (41·9% and 39·7%, respectively). A contributing factor to the lower proportion of women in our study sample, may be the high rates of COVID-19 detected in manual laborer of Indian ethnicity, who tend to be both male and younger. An outbreak in two main epicenters, Al-Jileeb and Mahboula areas in Kuwait, both of which house high concentrations of Indian male manual laborers may also account for the large proportion of young, male, Indian patients in our study sample (48·1%) 7 . Also, South Asian ethnicity and lower socio-economic state have been hypothesized to be associated with higher rates of COVID-19 and poorer outcomes, based on epidemiological observations 8 . The mean BMI for our sample was 26·6 kg/m 2 , with 41·5% of patients in the overweight category, which is reflective of the normal weight demographics in Kuwait 9 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. As reported by other studies 10 , hypertension (16·1%) and diabetes mellitus (14·1%) were the most common co-morbidities in our cohort. For symptomatic patients, the most common symptom was cough (49·5%), which is in keeping with several other retrospective cohort studies 1-3,11,12 . Interestingly, almost half of our sample were asymptomatic on initial presentation (49·5%) and had no signs of infection on clinical examination (69·4%). This may explain why only 5·4% of our patient population had a temperature of 38°C or above, which is in stark contrast to the other retrospective cohort studies in COVID-19 patients which reported much higher rates (Richardson et al, 30·7%, Guan et al., 59·2%, Wu et al. 38·3% above 39°C, Zhou et al. 94% above 37·3°C), as almost all their patients were symptomatic. As a result, we believe our study sample provides a more accurate portrayal of the clinical manifestations of COVID-19 in a general population. Our findings also raise the question of whether fever is an effective screening tool for COVID-19. Most of the laboratory findings were within the normal reference range in our study, probably secondary to the mild disease present in most of the cases. Interestingly, a large proportion of patients had sodium and calcium levels below the reference range on admission (28·7% and 20·6%, respectively). Hong et al. 13 recently reported similar findings, where 50% of COVID-19 patients they examined had hyponatremia and hypokalemia and they suggested there was a correlation with the degree of renal injury in those patients. Similarly, Sun et al. 14 found high rates of hypocalcemia (74·7%) in their COVID-19 patient population, on admission. Elevated C-reactive protein levels were present in a large percentage of patients (36·6%), as noted by other studies [15] [16] [17] . Further studies are needed to determine whether CRP can be used a surrogate for monitoring disease severity and resolution. Additionally, prothrombin levels below the reference range were present in over half our study population (53·4%). The implications of this findings are unclear but we hypothesize it may be related the procoagulant state that is thought to occur in COVID-19 patients 18 . As almost all our patients had a chest x-ray on admission, we determined that 76·3% patients either had a normal chestray or benign findings such as prominent broncho-vascular markings, as reported by a radiologist. Conversely, Wong et a. reported that in a cohort of 64 patients they studied, only 31% of COVID-19 had normal initial chest x-ray 19 . Of our patients with abnormal chest x-ray findings, 16·6% had unilateral local patchy shadowing or opacification, as the most common pathological finding. Most of our patient cohort did not experience any adverse events (90·1%). As other studies have shown, pneumonia and ARDS were the most common complication of COVID-19 11 . As a result, the most prescribed medications were antibiotics (13·8%). Of note, 27·9% of patients received no All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint medications and 68·2% received 'other' treatments. 'Other treatments' consisted of supportive medications such as paracetamol and ibuprofen and vitamin supplements, such as vitamin C and D, as well as prophylactic anticoagulation, as outlined in Kuwait's Ministry of Health COVID-19 protocols (Appendix 4). The median length of hospital stay was 18 days (IQR 13-24) for our study sample. This was longer that the median length of stay observed in similar studies 1,2 . In addition, the length of stay was longer in older patients, above 65 years of age in our sample (24 days, IQR 18-31). This may reflect the stringent discharge criteria at our center (2 consecutive nasopharyngeal swabs, 24 hours apart after symptom resolution). Despite the prolonged median length of hospital stay for most of our patients, 88·2% were discharged alive at the study cutoff date, 90·1% of patients had no reported adverse events during their admission, 3·6% required an ICU admission and only 1·7% died. This may reflect the young age of our study population and the fact that our cohort included a large portion of asymptomatic patients. Our mortality rates and admission rates are similar to Guan et al. 1 (mortality, 1·4% and ICU admission, 5%), but much lower than the other large retrospective cohort studies (Wu Multivariate analysis, demonstrated an association between mortality and being a smoker, having asthma and elevated procalcitonin levels. There was also an association between ICU admission and age above 50 years old, a qSOFA above 0, smoking, elevated CRP levels and elevated procalcitonin levels. Interestingly, being a smoker and elevated procalcitonin levels were the only factors found to be correlated with both mortality and ICU admission. Both factors have also been associated with unfavorable outcomes by other recent studies 20,21 . Similarly, several studies have found a correlation between older age 2,11,22 and elevated CRP levels [15] [16] [17] and poor outcomes. High qSOFA and SOFA score was found to be correlated with death by Zhou et al 3 . Our findings did not find an association between qSOFA score and death, but we did find a correlation with ICU admission. This may be due to the small number of deaths in our sample. Although an association between asthma and poor outcomes has been suggested by some authors 23,24 , we did not find any other studies that have reported this. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Most of the limitations in our study are due to its retrospective nature, such as potential loss of data due to omissions. In addition, for asymptomatic patients, we did not follow their hospital course and they may have developed symptoms later during their admission. However, based on unpublished reports, we have observed that most patients who were asymptomatic on admission, remained asymptomatic 7 . Also, as the number of COVID-19 cases escalated, the guidelines for its treatments and discharge/diagnostic criteria slightly evolved over time, which may have implications on our results. At the end of the study, some patients remained hospitalized (10%) and their clinical course is still unclear. This study is, to our knowledge, the first comprehensive study to provide data on the initial 1097 consecutive COVID-19 cases of an entire country, all admitted to a single center, undergoing the same investigations and treatment protocols. We believe it gives a different perspective on the nature and clinical course of this novel disease, compared to other large retrospective cohort studies, as it includes patients with a wide spectrum of disease severity. Future studies, directed at further characterizing risk factors for disease severity and outcomes, particularly predictive scoring systems, are needed. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Diagnosis is made in patients with either dark urine or an acute neuromuscular illness with an elevation of serum creatine kinase x 5 upper limit 31 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint Appendix 3. White blood count ( (which was not certified by peer review) 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 May 15, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. • Fever • Cough (usually dry) • Anorexia • Sore throat • Approximately 90% of patients present with more than one symptom, and 15% of patients present with fever, cough, and dyspnea 10 • Patients may present with nausea or diarrhea 1 to 2 days prior to onset of fever and breathing difficulties 11-12 . • Sudden loss of taste and smell may present as an early symptom 13 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint If inflammatory markers (e.g. CRP) are used to monitor disease activity, it should not be repeated sooner than 3 days. Daily repeat of inflammatory markers rarely affects patient management. • Elevated troponin (> 2 times upper limit of normal) without hemodynamic compromise, can repeat troponin in 24 hours. Up-trending troponin with hemodynamic compromise or other concerning cardiovascular symptoms signs should prompt consideration of obtaining an urgent cardiology consultation. Management principles of Uncomplicated Illness + all other patients: • Adhere to infection prevention measures. • Vitamin C 1000 mg Tablet Daily 25 . • Zinc Acétate Lozenges one every 6-8 hours [26] [27] . • In patients with serum Vitamin D deficiency, supplement with Vitamin D 10,000 IU daily 28 . • If the patient meets criteria for high risk (see appendix), consult Infectious Diseases. • All patients should receive standard prophylactic anticoagulation with LMWH in the absence of any contraindications 29 (Contraindications include active bleeding or platelet count less than 25,000; monitoring advised in severe renal impairment; abnormal PT or APTT is not a contraindication. If LMWH contraindicated due to renal failure (Creatine Clearance < 30mL/min), Unfractionated Heparin 5000 units SC q12 can be used as an alternative. fondaparinux is preferred in those with heparin-induced thrombocytopenia. • In All patients requiring assistant ventilation, placement in airborne isolation is preferred. • All patients admitted to ICU, placement in airborne isolation is preferred. • Airborne precaution is required for all patients undergoing aerosol generating medical procedures, including nebulizer treatment. In one study, COVID19 viral particles remained viable in aerosols for 3 hours following nebulization 30 . • If inhaler medications are needed, use MDI + spacer device. In patients < 50 yo with no comorbidities and mild pneumonia - 6. Consult ID to consider treatment with Lopinavir-ritonavir 43 . Imperative to start treatment early. In one study late initiation of Lopinavir/ritonavir did not improve mortality rate 44 (LPV/r is considered a second line agent) * . 7. Obtain CRP baseline and serially follow. 8. Obtain ECG daily, if using QTc prolonging agent. 9. Review above antibiotic regimen in 72 hours. If started, usual course is 5 days. May discontinue if concern for bacterial pneumonia low (confirmation of COVID-19, classic presentation, PCT <0.2). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint *We adopt both the Infectious Diseases Society of America (IDSA) 35 and the American Thoracic Society (ATS) 36 regarding COVID19 treatment chloroquine/hydroxychloroquine (HCQ), hydroxychloroquine with azithromycin, lopinavir/ritonavir, tocilizumab, corticosteroids for acute respiratory distress syndrome (ARDS). To date, there is no sufficient evidence to recommend any specific treatment. We suggest treatment on case-by-case basis using best clinical judgement. It is also important to note the French Trial (Gautret P et al. PMID 32205204) : -For asymptomatic/mildly symptomatic please follow MOH discharge guidance. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint -The following criteria should be used for patients with moderate-severe disease: 1. Days since testing positive ≥ 14 days, and 2. Resolution of respiratory symptoms ≥ 7 days (not requiring supplemental oxygen; or pulmonary status at baseline), and 3. Afebrile ≥ 72 hours without anti-pyretics, and 4. Improving/Regression of abnormalities on imaging, and 5. A Negative real time PCR result collected from nasopharyngeal swabs.Testing suggested to be done on Day 12 and 13 of admission to complete the 14 days of hospitalization. 6. Discharged patients to be home quarantined imperatively for 14 days (wear a mask at home; maintain social distancing with family members, particularly elderly; resides in a single room with restroom and with good ventilation, and avoid sharing same utensils and cups). 7. Agree to maintain health monitoring with follow up visit in COVID19 Clinic (Jaber Hospital) in 2 weeks. 8. For more information, please follow public health guidance for home quarantine. Monitoring for Hydroxychloroquine (HCQ) and renal dose adjustment: • The estimated half-life is 40 days • Monitor for hemolytic anemia with CBC every 2 days. Post-marketing studies suggest the risk of hemolysis is very low. It is reasonable to start hydroxychloroquine in most patients while awaiting G6PD testing. • Alternative therapy if hydroxychloroquine is unavailable or if the patient has contraindications or adverse effects. • Adverse events: Hepatotoxicity, pancreatitis, diabetes, QT prolongation, lipid elevations, and fat redistribution • Major substrate and inhibitor of Cytochrome P450, and can cause severe drug-drug interactions. Thorough evaluation of a patient's mediation profile and clinical pharmacy consultation should be initiated before starting therapy. • Pregnancy: Lopinavir-ritonavir is safe to use during pregnancy. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint Angiotensin/RAS Blocking Agents (ACEi/ARBs) [45] [46] [47] Do not discontinue these therapies for COVID-19 disease. Multiple professional societies in cardiology and have reviewed the current data and conclude that the evidence suggesting discontinuation of ACEi/ARB therapy to decrease risk for more severe COVID-19 is not well supported at this time. No activity for SARS-CoV-2. Single study of combination therapy with hydroxychloroquine does not convincingly suggest added benefit to azithromycin combination therapy, given the study was recently retracted and concern for antibiotic overuse. Do not discontinue these therapies for COVID-19 disease. Paracetamol is the preferred fever reducer for use in COVID-19. Although there has been theoretical concern raised for these agents worsening outcomes, no data currently exist to support this. FDA is not aware of scientific evidence connecting the use of NSAIDs, like ibuprofen, with worsening COVID-19 symptoms. The agency is investigating this issue further and will communicate publicly when more information is available. There is significant interest and controversy surrounding the role of corticosteroids for the management of severe pneumonia due to coronaviruses. The potential benefit of these agents to blunt the inflammatory cascade seen in severe disease needs to be carefully weighed against the concerns for secondary infections, adverse events, and other complications of corticosteroid therapy. The data for corticosteroids are inconsistent, confusing, and inconclusive. While target patients where corticosteroids will improve outcomes may exist (e.g., those with cytokine-related lung injury who may develop rapidly progressive pneumonia), that population remains ill-defined. Clinicians need to carefully weigh the risks and benefits of corticosteroids on the individual patient level. This need for a risk benefit assessment in individual patients and careful consideration of dose is exemplified in the COVID-19 Diagnosis and Treatment Guide from the National Health Commission of the People's Republic of China where the authors state "Based on respiratory distress and chest imaging, may consider glucocorticoid that is equivalent to methylprednisolone 1-2 mg/kg/day for 3-5 days or less. Note that large-dose glucocorticoid suppresses immune system and could delay clearance of SARS-CoV-2." A recent consensus statement from the Chinese Thoracic Society recommends a lower dose, ≤0.5-1 mg/kg/day methylprednisolone for ≤ 7 days in select patients, after careful consideration of risks and benefits. Tocilizumab 53-55 IL-6 inhibitor; IV formulation. Preliminary clinical experience from China in COVID-19 reported benefit, however neutropenia can be long-lasting so risk of secondary infection is possible and unquantified. 6 . List of Appendices: • Appendix 1: Flow sheet for stratifying risk factors to initiate infectious diseases referral • Appendix 2: High risk features • Appendix 3: Brief Overview of Agents • Appendix 4: Cardiac Monitoring for patients on Hydroxychloroquine. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. -Given the growing evidence of myocarditis and arrhythmias with COVID, HCQ should be used with caution in this group of patients. -Obtain baseline EKG All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 May 15, 2020. . https://doi.org/10.1101/2020.05.09.20096495 doi: medRxiv preprint Open Forum Infectious Diseases, ofaa105 Ghanem Alhojailan Clinical syndromes associated with 2019-nCoV infection: -If on telemetry, check QTc and see if that corresponds to EKG QTc -If yes, use telemetry for further QTc monitoring. Otherwise Get EKG#2 and daily EKG as noted below. -Discontinue all other QT prolonging agents -Do not start Hydroxychloroquine if baseline QTc > 500 msec (or QTc > 550 msec in wide QRS patients) or discuss with cardiology if benefit vs risk is deemed high -Be cautious if Baseline QTc > 470 msec QTc/ Acquire EKG#2 -preferably >2 hours after the 2nd dose of 400 mg Hydroxychloroquine • If QTc increases by less <50 msec; and if absolute QTc < 500 msec (<550 in wide QRS) -use lower dose • If QTc increases by >50 msec; or if absolute QTc > 500 msec (>550 in wide QRS) -use lower dose and recheck EKG daily for 2 days Any evidence of Torsades on Tele --D/c Hydroxychloroquine regardless of QT interval. • Note -* Wide QRS defined as QRS > 120 msec Interim guidance: 25 • Mild pneumonia. Patient with pneumonia (Infiltrate on imaging + clinical symptoms consistent with pneumonia) and no signs of severe pneumonia (PSI > 130 or SIRS ≥ 2).• Severe pneumonia. Fever or suspected respiratory infection, plus one of respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% on room air.• Sepsis. Life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection, with organ dysfunction. Signs of organ dysfunction including altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia.• Septic shock. Persistent hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥65 mmHg and serum lactate level >2 mmol/L. • Age ≥ 60 years and older • Male gender • Those with comorbidities (10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6% for hypertension, and 5.6% for cancer) Plus smokers. • Immunocompromised hosts (T-cell depleted medications; Corticosteroid equivalent to prednisone >15 mg per day for more than 2 months). All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.