key: cord-1002558-a1y01vdv
authors: Alshukry, A.; Ali, H.; Ali, Y.; Al Taweel, T.; Abu-farha, M.; AbuBaker, J.; Devarajan, S.; Dashti, A. A.; Bandar, A.; Taleb, H.; Al Bader, A.; Aly, N. Y.; Al-Ozairi, E.; Al-Mulla, F.; Bu Abbas, M.
title: Clinical characteristics of Coronavirus Disease 2019 (COVID-19) patients in Kuwait
date: 2020-06-16
journal: nan
DOI: 10.1101/2020.06.14.20131045
sha: 575dc2431667e408e3b88d30847a04f91d0eaff5
doc_id: 1002558
cord_uid: a1y01vdv

Abstract Background: In early December 2019, the first clusters of Coronavirus Disease 2019 (COVID-19) were identified in Wuhan, China and attributed to a novel coronavirus, now known as Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV2). Kuwait reported its first cases of COVID-19 on February 24th 2020 and since then the number of cases has been increasing rapidly. Methods and Findings: This is a retrospective single-center study of consecutive 417 COVID-19 patients admitted to Jaber Al-Ahmad hospital between 24/2/2020 and 24/5/2020. The mean age of cohort was 45.35 years (S.D. 17.16) and 62.8% of cases were males. Patients were divided into four groups; Asymptomatic group, symptomatic group with mild form of the disease, ICU survivors and ICU death. In total, 39.3% of patients were asymptomatic, 41% were symptomatic with mild symptoms, 5.3% were admitted to ICU and recovered and 14.4% died. Mean age of ICU patients was 53.61 years (S.D. 13.43). Comorbidities were more prevalent in ICU death group when compared to other groups (p<0.05) including Diabetes (40%), Hypertension (46.7%), Asthma (20.3%) and cardiovascular disease (21.7%). Blood biochemistry analysis showed that ICU death group had a characteristic abnormal pattern of certain markers upon admission in the ICU. Including significantly high WBC and neutrophil counts (P<0.05) and prolonged Prothrombin Time (PT) and activated partial thromboplastin time (APTT) (P<0.05). D-dimer, C-reactive protein and Procalcitonin (PCT) showed significantly high levels in ICU admissions and in ICU death group in particular (P<0.05). Kidney injury complications were reported in 65% of ICU death group (P<0.05) which also showed significantly elevated urea levels (P<0.05). We also reported rapid deteriorating kidney function (eGFR) in ICU death cases during ICU stay until the outcome was reached. Conclusions: In this single-center study of 417 COVID19 patients in Kuwait. The disease showed varying degree of severity ranging from asymptomatic status to death. Our comprehensive laboratory analysis revealed distinct abnormal patterns of markers that are associated with poor prognosis. Our dynamic profiling of eGFR in COVID-19 ICU patients highlight potential role of renal markers in forecasting disease outcome and perhaps identify patients at risk of poor outcome.

In early December 2019, the first clusters of Coronavirus Disease 2019 were identified in Wuhan, China 1 . Initially, these cases were reported as pneumonia of unknown cause. Still, they later were attributed to a novel coronavirus, now known as Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV2), an enveloped single-strand RNA β-coronavirus with a 30 thousand bases genome 2 . On March 11 th , 2020 the World Health Organization (WHO) confirmed COVID-19 as a pandemic. Since then, the disease has been spreading hastily affecting more than 5 million people and resulting in more than 350 thousand deaths, which emphasize the threat it poses on global health 3 .

Clinical manifestations of COVID-19 showed a high degree of variability including asymptomatic carriers, Acute Respiratory Distress Syndrome (ARD), and pneumonia with variable severity 4, 5 .

Most of the identified patients experience mild symptoms, including fever, cough, dyspnea, myalgia, and fatigue. In contrast, patients in severe cases develop ARDS and severe cardiac and renal complications, which can potentially lead to death 2,6 . Additionally, a worse prognosis has been associated with older age, being male, and having pre-existing chronic conditions such as hypertension, cardiovascular disease, and diabetes. At the same time, pediatric cases showed a milder clinical course 7 .

Countries worldwide have been affected differently by the COVID-19 pandemic ranging from high infection and high mortality rates in countries like the USA, France, and Spain to low infection and mortality rates in countries like New Zeeland for example 3, 8 . Multiple theories have been suggested to explain the current infection and death rate, including tight measures, better health . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint care system as well as genetic factors amongst others. One particular hypothesis focused on genetic variants within the Angiotensin Converting Enzyme 2 (ACE2) gene 9, 10 . Multiple studies have suggested that variants within the ACE2 gene can influence the viral entry into the host cell 11, 12 . In a recent study, we have shown that one variant within the ACE2 gene (N720D) was responsible for reduced infection rates in Middle Eastern countries compared to Europeans 9 .

Such findings highlight the importance of investigating various populations worldwide to gain more insight into this disease. This study is focused on presenting a cohort from Kuwait, a small country located on the northern tip of the Persian Gulf, with a population of nearly 4.5 million.

Kuwait reported its first cases of COVID-19 on February 24 th in passengers coming from Iran.

Since then, the reported cases were increasing exponentially, reaching over 35,000 cases at the time of writing this report and more than 280 registered deaths 3, 13 . While the search for effective treatment and vaccine for COVID-19 continues, health care systems, including Kuwait, are trying to strengthen their frontline clinical services to cope with the pandemic.

Here, we describe the demographics, baseline comorbidities, clinical characteristics, and outcomes of COVID-19 patients' cohort in Kuwait. We further investigate the dynamics of certain laboratory parameters in intensive care unit (ICU) admissions in relation to clinical outcomes.

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This is a retrospective study reviewed and approved by the standing committee for coordination of health and medical research in the ministry of health in Kuwait (IRB 2020/1404). The medical records of the confirmed COVID-19 cases admitted to Jaber Al-Ahmad Hospital in Kuwait between 24/2/2020 and 24/5/2020 were included in the study. COVID-19 diagnosis was established based on a positive result of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasal and/or nasal and pharyngeal swabs, in accordance with (WHO) interim guidance 14 . Cases were divided into three groups; asymptomatic, mild/moderate and Intensive care unit (ICU) group.

All cases admitted to Jaber Al-Ahmad Hospital between 24/2/2020 and 24/5/2020 were included in the study. A total of 417 COVID-19 confirmed cases were included in the study. Cases medical records were accessed and analyzed by the research team at Dasman Diabetes Institute, Kuwait University and Jaber Al Ahmad Hospital. Epidemiological, clinical, laboratory, radiological characteristics, in addition to treatment plans and outcomes, were accessed and obtained from the medical records.

Recorded information included demographic data, medical history including underlying comorbidities, travel history, contact tracing data, clinical chemistry and hematology laboratory findings, chest radiological images, treatments, complications, intensive care unit (ICU) admission, durations and dynamics of hospital stay and outcomes. Signs, symptoms and . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint laboratory findings were recorded on the day of hospital admission (ward and ICU). ARDS was determined in accordance with Berlin definition 15 . Acute kidney injury was determined in accordance with Kidney Disease: Improved global outcomes definition 16 . Cardiac injury was concluded based on blood cardiac markers, electrocardiography and/or echocardiography 6 .

The period in which cases were enrolled in this study, a 100% hospitalization policy was implemented in Jaber Al Ahmad hospital, by the ministry of health. Any patient with a positive RT-PCR test was admitted, isolated, and put under clinical surveillance, including asymptomatic cases. Patients with mild to moderate COVID-19 symptoms who were hemodynamically stable and without any signs of respiratory distress were admitted to the ward after RT-PCR confirmation for isolation and clinical surveillance and re-evaluation. Patients in this sub-group were transferred to the (ICU) only if they developed signs of respiratory distress and desaturation of oxygen levels -confirmed by pulse oximetry and arterial blood gases -and/or signs of hemodynamic instability requiring close monitoring and intensive re-establishment of homeostasis. Patients with severe to critical COVID-19 symptoms were directly admitted to the ICU should they meet any of the following criteria of severity: Hypoxemic respiratory failure that required respiratory support such as cases that developed ARDS, hemodynamic instability due to cardiogenic or septic shock and clinical/radiological/laboratory evidence of heart failure, acute cardiac injury and acute kidney injury secondary to COVID-19 manifestations. For ICU dynamic analysis, we divided subjects into two groups; ICU survivors and ICU death. Clinical analysis of blood samples was done for all subjects on daily bases. The daily values of selected laboratory parameters were averaged and plotted until an outcome was achieved.

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The variables analyzed in the study were divided into categorical and continuous variables. The categorical variables were described as frequencies and percentages, while continuous variables were presented as medians and interquartile range (IQR) values and means and standard deviations. Means between groups were compared using One-way analysis of variance (ANOVA).

Categorical variables were analyzed by using the chi-square test, and wherever the data were limited, Fisher Exact test was used. Differences between groups means and medians are considered significant when a p value is < 0.05. All statistical analyses were performed using . 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)

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In our study, 417 hospitalized COVID-19 cases with a positive viral PCR test were enrolled. The cohort had a median age of 47 years (IQR 32-60 years), and 63% of the cohort were males. The age structure of the cohort showed that the majority of patients belonged to the 21-40 years age group, and notably, only 0.3% belonged to the 81-90 years age group ( Figure 1 and Table 1 ). The cohort consisted of 39.3% asymptomatic patients, 41% symptomatic (mild to moderate), 5.3% admitted to the ICU, and recovered, while 14.4% admitted to ICU and died (Table. 2).

The majority of admissions to ICU belonged to the age group (41-50 years, 29.5%), while 24.8% belonged to the 51-60 years and 24% to the 61-70 years age group ( Figure. 1 and Table. 1). No ICU admissions were recorded for the youngest age group (0-20 years).

Out of 417 cases, we recorded 60 death cases, the majority of such cases belonged to the age group (51-60 years), which represented 33.3% of all death cases reported with a case fatality rate of 24.1% ( Figure. 1 and Table. 1). However, case-fatality rate was highest in the 71-80 years age group as it was 35.3% (Table.1). COVID-19 patients were divided into four groups. The first group was composed of asymptomatic patients. These patients have positive viral PCR but did not show any symptoms and were kept in hospital isolation until a negative viral PCR was achieved with an average hospital admission length of 20.69 ± 8.57 days (Table. 2). The asymptomatic group made up 39.3 % of the cohort, with an average age of 41.97 ± 19.21 years. Symptomatic cases made up 41% of the cohort. This group consisted of cases that exhibited mild/moderate symptoms but did not require ICU . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint admission. 55% of these patients experienced fever, 52% of them presented with a dry cough, 29 .8% of them reported sore throat, and 21.6% described symptoms of myalgia (Table. 2). Cases admitted to ICU were divided into two groups based on outcome; the ICU survivors groupcomposed of 22 cases (5.3% of the cohort) and the ICU death group -composed of 60 cases counting for 14.4% of the cohort (Table. 2). The pattern of symptoms in the ICU survivors' group was similar to the symptomatic group except for the shortness of breath, which was present in 59.1% of cases (Table. 2). Shortness of breath was more prevalent in the ICU death group (81.7%).

Furthermore, this group had more comorbidities than other groups -including diabetes, hypertension, asthma, cardiovascular disease, chronic renal disease, and malignancies (Table. 2).

Clinical data analysis indicated significant differences between COVID-19 patients' groups. The asymptomatic group generally showed normal laboratory findings with minimal borderline abnormalities (Table. 3). Numerous markers showed significant differences between the symptomatic/mild group and patients admitted to ICU, including complete blood count (CBC) ( Table. 3). Inflammatory markers, including Procalcitonin (PCT) and C-Reactive Protein (CRP) showed progressive increasing patterns from symptomatic group to ICU death group. Markers of blood clotting, including Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) showed prolonged timings in the ICU death group.

Markers related to renal function showed significant abnormalities in the ICU death group, including declined eGFR and increased urea (Table. 3), which coincide with reported kidney injury complications in 65% of cases in this particular group (Table.4 ). Markers associated with heart . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint injury including Troponin and Lactate Dehydrogenase (LDH) showed significant increase in subjects admitted to ICU and in particular the ICU death group (Table. 3), which coincided with reported heart failure in 86% of cases in this specific group and cardiac injury in 44.1% of them (Table.4 ). D-dimer was within normal range in the asymptomatic and symptomatic groups but was significantly elevated in ICU groups and the ICU death group (Table. 3).

81.8% of cases in the ICU survivor group developed ARDS compared to 100% of cases in the ICU death group (Table. 3). Chest radiographs of patients in the ICU survivor and death groups showed diffuse bilateral airspace opacification with patches of consolidation ( Figure. 2). High-Resolution CT chest in ICU death case showed multifocal large patchy areas of ground glass opacification mixed with dense consolidations (Figure. 2). Intubation was required for 55% of the cases in ICU survivor group and in 94.4% in the ICU death group (Table. 3). Treatment-wise, antibiotics, like Amoxicillin, Augmentin, Rocephine and Piperacllin/tazobactam, were the most commonly administered medication as 31.6% of symptomatic, 95% of ICU survivors and 94.4% of ICU death group received them. Antiviral drugs, such as Oseltamivir and Lopinavir, were given to 90% of cases in ICU survivor group and 70.4% of ICU death cases. Antimalarial drug Hydroxychloroquine were given to 60% of ICU survivor group and 68.5% of ICU death group (Table.4 ).

We tracked the levels of 6 blood markers associated with infection, inflammation, and kidney function in ICU patients to study disease progression and outcome. The ICU death group showed elevated levels of White Blood Cells (WBC) after the second day of disease onset onward. In contrast, ICU survivor group had an average below 10x10 9 cells/L ( Figure.3A) . A similar pattern . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint was observed in the Neutrophil count ( Figure.3B) . ICU death cases also showed lymphocytopenia when compared to ICU survivors ( Figure 3C ). Inflammatory markers, namely CRP and PCT, showed a significant increase during ICU stay until outcome in the ICU death group ( Figure.3D and E). Renal function declined progressively in the ICU death group during stay until outcome ( Figure 3F ).

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To our knowledge, this report is one of the first detailed reports of COVID-19 clinical characteristics in Kuwait and the region. Kuwait reported its first cases from travelers arriving from Iran on the 24 th of February 2020 followed by further cases arriving from Europe before cases from community transmission started to accumulate 13 . We have recruited our cohort between 1/4/2020 and 10/4/2020 during which the hospitalization rate was 100% for all SARS-CoV-2 positive cases. Capturing all the cases during a specific period and from one place allows more comprehensive clinical insights, especially in relation to the inclusion of asymptomatic cases, which were isolated in the hospital with full medical surveillance.

The most prevalent symptoms in our cohort were fever which was present in 34.3% of the cohort, dry cough (32.6%) and shortness of breath (18.2%), with the latter being more prevalent in ICU admissions (Table. 2). Prevalence's of symptoms varied between studies, for instance fever was reported in 43.8% of patients on admission in a multi-centers study in China 17 . While in another study conducted in the city of Wuhan a fever prevalence of 98.6% was reported 6 . These variable findings are influenced by the diagnostic criteria utilized and effectiveness of surveillance strategies. It is more of a question of which lead to admission; a symptom or random surveillance testings based in viral PCR which shall result in capturing asymptomatic individuals.

The age structure of the cohort provided a good representation of the population in Kuwait ( Figure.1 19, 20 . Capturing asymptomatic individuals is challenging as these cases do not raise any . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint flags for medical attention; therefore, they can intensify infection 21 . In Kuwait, extensive viral PCR testing was conducted for every passenger entering the country during the period of recruitment in addition to active contact tracing being put in action.

The Case fatality rate (CFR) calculated for the cohort was 14.4%, which could represent an overestimation due to the proportion of ongoing cases, especially at the early stage of the outbreak, as is the case in our study 22 . The highest case fatality rate was recorded in the 70-80 years age group (35.3%), which is close to what has been reported in New York City 23 .

ARDS was one of the main causes for ICU admissions as it was reported in all death cases and 81.8% of ICU survivors. Patients admitted to the ICU were older in comparison to other groups.

Our results also indicated that the ICU death group had higher prevalence of comorbidities and were pronominally males (Table. 2). Several studies have shown significant association between poorer outcome with being a male. That was the case in 2003 during the SARS-Cove outbreak and now with COVID-19 24 . While the reasons underlining this observation are not fully understood, the levels of ACE2 in males were suggested as a possible explanation 24 . Death outcome also correlated with higher prevalence of comorbidities, as seen in the ICU death group with hypertension being the most prevalent comorbidity followed by diabetes. Similar findings were also reported in New York 23 and Wuhan 6 .

Direct comparison between groups revealed than ICU admissions and particularly the ICU group indicated significantly lower levels of hemoglobin (HB) ( Table. 3). This observation has been reported previously in patients with other kinds of pneumonia and was associated with higher mortality rates 25 . ICU death group also showed prolonged Prothrombin Time (PT) and Activated . 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 June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint partial thromboplastin time (APPT) when compared to other groups (Table. 3), which indicate abnormalities in coagulation. Such abnormal coagulation parameters were reported by previous studies and showed an association with poor prognosis 26 . Recent recommendations advise that such prolonged APPT should not halt the use of anticoagulation therapies to prevent or treat venous thrombosis in COVID-19 patients 27 . D-dimer levels were also significantly elevated in the ICU death group (Table. 3). Previous studies indicated that patients who required intubation and have higher levels of D-dimer would have a higher risk of developing pulmonary embolism 28 , which highlights the need for a protocol to identify and treat such cases with anticoagulants.

For ICU admissions, a dynamic analysis of a set of markers was performed throughout the stay in ICU until an outcome was reached (recovery or death). In the ICU death group, the WBC and neutrophil counts continued to increase until day 10, where the averages dropped but remained above the upper normal limit, which with the decreasing lymphocytes indicate active ongoing infection. PCT levels continued to increase in the ICU death group until an outcome was concluded which could be caused by bacterial coinfection and has been associated with severe disease outcome 29 . CRP also followed a similar increasing pattern, which could indicate a severe inflammatory cascade possibly associated with ARDS (Table.4 ) and eventually leading to death 30 .

Kidney injury was more prevalent in the ICU death group when compared to ICU survivor and symptomatic groups (65% vs. 4.5% and 0.6% respectively). This matched the reported progressive impairment of kidney function in ICU death group as suggested by the declining eGFR low total protein and albumin and increased urea ( Figure.3, Table3, 4) . ACE2 may play an important role in the involvement of kidney in COVID-19 and notably in severe cases as it is highly expressed in the tubular epithelial cells in the kidneys 31 . When SARS-CoV2 infect the renal . 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 June 16, 2020. Moreover, 46.7% of death cases had a history of hypertension which could negatively impact the deteriorating kidney function 34 . The burden of kidney injury on COVID-19 prognosis should not be underestimated as our results indicated that kidney injury is a negative prognostic factor for survival. Therefore, therapeutic and preventive protocols need to be developed and adapted to control the burden of kidney injury and reduce morbidity and mortality. . 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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In here, we provide a detailed clinical analysis of a cohort of 417 consecutively recruited COVID-19 patients from a single hospital in Kuwait. In total, 39.3% of patients were asymptomatic, 41%

were symptomatic with mild symptoms, 5.3% were admitted to ICU and recovered and 14.4% died. Notably kidney damage was the most prevalent complication reported in death cases which is supported by renal markers laboratory findings. Our dynamic profiling of eGFR in COVID-19 ICU patients highlight potential role of renal markers in forecasting disease outcome and perhaps identify patients at risk of poor outcome.

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The copyright holder for this preprint this version posted June 16, 2020. . https://doi.org/10.1101/2020.06.14.20131045 doi: medRxiv preprint Figure 1 . Categorical age structures. Each age group percentage is calculated by dividing the count by the total in each category. Majority of cohort belonged to the age group (21-40 years) while highest numbers of death cases were recorded in the age groups (51-60 years). is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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