key: cord-0963310-xzsbkh5i
authors: Buckner, Frederick S; McCulloch, Denise J; Atluri, Vidya; Blain, Michela; McGuffin, Sarah A; Nalla, Arun K; Huang, Meei-Li; Greninger, Alex L; Jerome, Keith R; Cohen, Seth A; Neme, Santiago; Green, Margaret L; Chu, Helen Y; Kim, H Nina
title: Clinical Features and Outcomes of 105 Hospitalized patients with COVID-19 in Seattle, Washington
date: 2020-05-22
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa632
sha: bcc802d1e0f4aa8d7969da031d1bf493ece49a6a
doc_id: 963310
cord_uid: xzsbkh5i

BACKGROUND: Washington State served as the initial epicenter of the SARS-CoV-2 pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with COVID-19 may provide guidance for management. METHODS: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, WA between March 2 and March 26, 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death. RESULTS: One-hundred-five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years and half were women. Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%) and diabetes (33%) being the most prevalent. Most (63%) had symptoms for 5 days or longer prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation and the overall mortality rate was 33%. CONCLUSIONS: During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients.

Infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in late 2019 in Hubei Province, China, and has since disseminated worldwide [1, 2] . The first confirmed case in the United States was a returning traveler from Wuhan, China, who presented to medical attention on January 19, 2020, in Snohomish County, Washington [3] . In February, a cluster of COVID-19 cases was identified at a nursing home in Kirkland, Washington, resulting in the first reported death in the US on February 29 [4, 5] . Since that time, the disease has occurred widely in the greater Seattle area and cases have been reported in all 50 states [6] .

The epidemiology and clinical features of hospitalized COVID-19 patients have been described in China, South Korea, and Singapore [1, [7] [8] [9] [10] . The prominent clinical manifestations have included fever, cough, dyspnea, fatigue, myalgia, and radiographic evidence of pneumonia. Shock, acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, and deaths were reported in severe cases [1, 5, 9, 11] . Early reports indicated that the infection occurs in clusters within groups in close contact, and that severe disease was more common in the elderly, men, and those with comorbidities [9] . The epidemiologic and clinical features of COVID-19 disease in the United States are beginning to be elucidated, specifically in critically ill patients [5] . Additional information is needed to help clinicians understand the characteristics of this disease. In this case series, we examine the epidemiology, clinical features, and outcomes of 105 hospitalized patients from three university-affiliated hospitals in Seattle, Washington. The characteristics associated with severe versus non-severe clinical courses are described.

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We conducted a retrospective chart review examining the clinical characteristics of adult patients with laboratory-confirmed SARS-CoV-2 infection. Patients were included if they were admitted to one of three University of Washington (UW) affiliated hospitals in Seattle between March 2 and March 26, 2020.

The hospitals included UW Medical Center (comprised of two campuses: Montlake, a 570-bed tertiary/quaternary care facility and Northwest, a 281-bed community-based care facility) and

Harborview Medical Center (HMC), a 413-bed level one trauma center.

Demographic data, encounter dates and laboratory measurements were extracted electronically from the UW clinical data warehouse for confirmed cases. The medications, vital signs, radiology studies and clinical events were reviewed by physicians in the Division of Infectious Diseases and entered into a standardized data collection instrument using REDCap (Research Electronic Data Capture) [12] .

The primary outcome was severe COVID-19, defined as a composite endpoint of admission to an intensive care unit (ICU) or death [13] . Each death was reviewed by two physicians independently to determine whether it was related to COVID-19. Secondary outcomes included shock and acute respiratory distress syndrome (ARDS), which were also adjudicated by two physicians independently.

These outcomes were evaluated until May 8, 2020, 43 days from the date the last patient was admitted.

A c c e p t e d M a n u s c r i p t 7

Fever was defined as a recorded temperature of 38.0°C or higher. Hypoxia was defined as an oxygen saturation less than 90% on ambient air, or requirement of supplemental O2 [14] . Acute kidney injury (AKI) was defined as an increase in creatinine of 0.3 mg/dL from baseline, or 1.5 times the patient's baseline creatinine [15] . Leukopenia was defined as white blood cell count less than 4x10 9 /L , and lymphopenia was defined as a lymphocyte count less than 1.5x10 9 /L. Cardiac injury was defined as a maximum troponin value of 0.1 ng/mL or higher during hospitalization. Patients were denoted as having ARDS if the physician indicated this in their clinical notes, or, in the absence of this documentation, if the patient had new respiratory failure, bilateral lung opacities on chest imaging, and a PaO2:FIO2 ratio ≤ 300 [16] . Shock was defined as hypotension requiring vasopressors. Patients were considered to have received antibiotics during their admission if these were given for more than 48 hours. Patients were considered to have received corticosteroids during their admission if they were newly started on systemic corticosteroids.

Laboratory testing Nasopharyngeal samples were tested for SARS-CoV-2 by real-time reverse-transcriptase polymerasechain-reaction (RT-PCR) developed by the University of Washington Virology laboratory [17] . Continuous variables were displayed as median values with simple or interquartile ranges as appropriate. Categorical variables were summarized as counts of all patients or a subset of evaluated patients with percentages. All analyses were conducted using Stata 14.2 (StataCorp).

This study was approved by the University of Washington Institutional Review Board (STUDY00006181). Informed consent was waived for retrospective review of patient charts.

and March 26, 2020, with a median follow-up of 9 days (range 1-53). The demographic and clinical characteristics are shown in Table 1 . The median age was 69 (range 23-97), half were women and 71% were white. Thirty-five percent of patients lived in a skilled nursing facility or senior living. Most patients (93%) had at least one comorbidity; 55% had three or more chronic medical problems. The most common comorbidities were hypertension (59%), obesity (47%), cardiovascular disease (38%) and diabetes (33%).

The majority of patients (63%) presented with symptoms lasting more than 5 days ( Table 2 ). The most common presenting symptoms were cough (72%), dyspnea (53%), and fatigue (49%). Twentythree percent of patients reported diarrhea and 22% either nausea or vomiting. Nasal symptoms (congestion/rhinorrhea) and sore throat occurred in 14% and 7%, respectively. The initial chest x-ray was abnormal in 86% of cases. A minority of patients (39%) had a fever on admission or within the first 24 hours. Hypoxia was observed in 41% at the time of admission. Blood laboratories at admission showed leukopenia in 15% and lymphopenia in 73% of patients (Table 3) .

A c c e p t e d M a n u s c r i p t 9 Of 39 patients who had SARS-CoV-2 samples available for semi-quantitative testing, the median Ct was 26.5 (range 12. 4-35.4) with no difference between severe and non-severe cases. Fifty samples were available for viral coinfection testing. No coinfections with influenza A or B, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza viruses, rhinovirus, or bocavirus were identified. There were no co-infections with coronaviruses 229E, NL63, OC43, or HKU1.

Angiotensin converting enzyme inhibitors or angiotensin receptor blockers were used in 33% of patients (Table 4 ) while aspirin or non-steroidal anti-inflammatory drugs were used in 35%. The proportion of all patients on corticosteroids was 10% or other immunosuppressants was 11%.

During hospitalization, 42% of patients were treated with hydroxychloroquine (Table 4 ). In nearly all This is a relatively high mortality rate compared to reports from China and Singapore, where mortality rates in hospitalized patients were 1.4% [9] , 4.3% [7] , and 0% [8] . This is likely due to the more advanced age (median 69 years) of our cohort compared with these previous case series, which reported average ages of 47 [9] , 56 [7] , and 47 [8] . Additionally, the burden of comorbidities in our population was extremely high, with 93% of patients having at least one comorbidity, also higher than the previously reported rate of comorbidity of 46.4% [7] and 32% [1] .

Patients living in nursing or senior living homes comprised 35% of the patients, reflecting the increased risk of living in congregated settings. Aside from one homeless patient, the remaining 65% of patients were domiciled at private residences prior to hospitalization, indicating that the infection was already distributed throughout the community. Travel was not an important risk, indicating that infections were unlikely to be imported. Only 16% participants reported a known contact, indicating ongoing community transmission in the several weeks between the first case and this time period [19] .

With respect to comorbidities, hypertension (59%), obesity (47%), cardiovascular disease (38%), diabetes (33%), and chronic kidney disease (26%) were the most notable and tended to be more A c c e p t e d M a n u s c r i p t 11 prevalent in cases with severe clinical outcomes. It is striking that 55% of the patients had 3 or more comorbidities, underscoring the vulnerability of chronically ill individuals to COVID-19. Similar associations have been observed in influenza: diabetes and cardiovascular disease are known to increase the risk of developing complications from influenza [20], and previous work has shown an association between obesity and poor outcomes in influenza infection [21, 22] . Furthermore, the association between the presence of hypertension, cardiovascular disease, and diabetes with poor outcomes was documented among patients with Middle East respiratory syndrome (MERS) coronavirus infection [23] . Chronic lung disease including COPD (10%) and asthma (10%) were surprisingly uncommon. Only two pregnant patients were observed in this cohort and they recovered without complications. The frequency of obesity, hypertension, and diabetes associated with our hospitalized COVID-19 patients is concerning given the high prevalence of these conditions in the US population.

Of pre-admission medications, statins were the most common (42%) followed by ACE inhibitors or ARBs (33% combined). There is conflicting evidence on the effect of renin-angiotensin-aldosterone system (RAAS) inhibitors on angiotensin-converting enzyme 2 (ACE2) [24] . In animal models, ACE inhibitors and ARBs upregulate surface expressed ACE2, a binding target of SARS-CoV2 [25] , which could worsen disease. However, animal studies have shown that these medications decrease severe lung injury in some viral pneumonias [26] . Our study could not determine if these medications were a risk factor for severe disease.

For most patients, COVID-19 was not an abrupt illness leading to sudden hospitalization; the majority (63%) of patients reported symptoms for least 5 days prior to admission. Only a minority of patients (39%) had documented fever in the first 24 hours of hospitalization. Absence of fever in some patients has been previously reported [9] . The absence of fever in the majority of this largely geriatric cohort is an important finding. Clinicians evaluating older patients will need to have a high index of suspicion for COVID-19 in those who present without fever. Cough (72%), dyspnea (53%), A c c e p t e d M a n u s c r i p t 12 and fatigue (49%) were the most common symptoms reported by patients, consistent with other studies [1, 7] . Gastrointestinal complaints were noted in a minority. Hypoxia and elevated temperatures in the first 24 hours of hospitalization were more frequent in severe COVID-19 but notably, there were few presenting clinical signs or symptoms that distinguished those who would go on to severe disease.

Objective data on the patients demonstrated findings previously reported. Chest imaging was abnormal in the vast majority of patients, consistent with previous reports [7] . A majority of patients (73%) had lymphopenia, which was more commonly observed in severe COVID-19.

Transaminases were mildly elevated in 22-33% of patients, but rarely more than twice the upper limit of normal. Viral coinfection was not identified, concordant with previous published studies describing influenza coinfection only in case reports.

Few patients (3%) received corticosteroids, consistent with recent published recommendations [27] .

A subset of patients was treated with hydroxychloroquine (40%) or were enrolled in a trial with remdesivir (20%) based on preliminary data suggesting antiviral activity against SARS-CoV2 [28, 29] ; whether these provide clinical benefit remains unknown.

A large fraction (76%) of these patients required oxygen supplementation, including 18% who received mechanical ventilation. Hemodynamic shock, which occurred in 16% of patients in this group, has been reported previously [5, 9] . The frequency of acute kidney injury (30%) appears higher than the reports from China of 0.5% to 7% [1, 9] and likely attributable to the advanced age and high comorbidity burden of our cohort, although severe illness was not limited to the elderly patients in this group.

Our study has some limitations. First, as with any observational study derived from routinely collected clinical data, there is the potential for incomplete capture or misclassification of baseline characteristics, particularly for patients who did not receive primary care in our system. Next, this A c c e p t e d M a n u s c r i p t 13 study was performed early in the COVID-19 outbreak when testing was not widespread and attention was heavily focused on nursing homes. In addition, 4 of these patients remained hospitalized at the time of manuscript submission with partial follow-up. A larger clinical cohort may reveal additional features not readily apparent in our series.

In conclusion, COVID-19 has spread rapidly throughout the United States and most of the world. The early experience in Seattle indicated that patients requiring hospitalization for COVID-19 were generally of advanced age with multiple comorbidities. The high morbidity and mortality we M a n u s c r i p t 21 White blood cell count, x 10 9 /L <4 4-10 A c c e p t e d M a n u s c r i p t 24 Figure 1 

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report -56

First Case of 2019 Novel Coronavirus in the United States

COVID-19) -United States

Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State

cases-updates/cases-inus.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fcases-in-us.html#2019coronavirus-summary

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Novel Coronavirus-Infected Pneumonia in Wuhan, China

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Cryptic transmission of SARS-CoV-2 in Washington State

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Arguments in favour of remdesivir for treating SARS-CoV-2 infections

All values are noted as median (interquartile range, IQR), n of all patients (%) or a proportion of subset

We thank the clinical staff at University of Washington affiliated hospitals for their excellent and tireless care of patients with and without COVID-19. We are grateful to Kristine Lan and Ayushi Gupta for their assistance with data extraction. 

A c c e p t e d M a n u s c r i p t 15 A c c e p t e d M a n u s c r i p t 18 Values represent all patients, N (%) or a proportion of subset, n/N (%).