key: cord-0700233-77mqazg1
authors: Yoke, Leah H; Lee, Juhye M; Krantz, Elizabeth M; Morris, Jessica; Marquis, Sara; Bhattacharyya, Pooja; So, Lisa; Riedo, Francis X; Simmons, Jason; Khaki, Ali Raza; Cheng, Guang-Shing; Greninger, Alexander L; Pergam, Steven A; Waghmare, Alpana; Ogimi, Chikara; Liu, Catherine
title: Clinical and Virologic Characteristics and Outcomes of Coronavirus Disease 2019 at a Cancer Center
date: 2021-04-16
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab193
sha: c3403c2bfcce8f1b578e5cd3b771adeb1ce9c1ae
doc_id: 700233
cord_uid: 77mqazg1

BACKGROUND: High morbidity and mortality have been observed in cancer patients with COVID-19 infection; however, there are limited data on antimicrobial use, co-infections, and viral shedding. METHODS: We conducted a retrospective cohort study of adult patients at the Seattle Cancer Care Alliance diagnosed with COVID-19 infection between 2/28/2020 and 6/15/2020 to characterize antimicrobial use, coinfections, viral shedding and outcomes within 30 days after diagnosis. Cycle threshold values were used as a proxy for viral load. We determined viral clearance, defined as two consecutive negative PCR results using SARS-CoV-2 RT-PCR results through 7/30/2020. RESULTS: Seventy-one patients were included with a median age of 61 years; 59% had a solid tumor. Only 3 patients had documented respiratory bacterial co-infection. Empiric antibiotics for pneumonia were prescribed more frequently early in the study period (2/29/20-3/28/20;12/34) compared to the later period (3/29/20-6/15/20; 2/36) (P = .002). The median number of days from symptom onset to viral clearance was 37 days with viral load rapidly declining in the first 7-10 days after symptom onset. Within 30 days of diagnosis, 29 (41%) patients were hospitalized and 12 (17%) died. Each additional comorbidity was associated with 45% lower odds of days alive and out of hospital in the month following diagnosis in adjusted models. CONCLUSIONS: Patients at a cancer center, particularly those with multiple comorbidities, are at increased risk of poor outcomes from COVID-19 disease. Prolonged viral shedding is frequently observed among cancer patients and its implications on transmission and treatment strategies warrant further study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic leading to significant morbidity and mortality worldwide [1] [2] [3] [4] . Earlier reports of coronavirus disease 2019 demonstrate that cancer patients have worse outcomes compared to those without cancer [5] [6] [7] [8] . Several large cohort studies demonstrated that older age, male sex, and underlying comorbidities are risk factors for severe disease and mortality in cancer patients [9] [10] [11] [12] . However, important questions with regard to clinical and virologic characteristics of COVID-19 among cancer patients remain.

Limited data exist regarding symptom duration, viral shedding, and viral load trajectories among cancer patients [13, 14] , leading to questions about the optimal approach to discontinuation of transmission-based precautions in this population. Additionally, coinfections and antibiotic use in immunocompromised populations are not well-described.

Studies in other populations found high rates of empiric antibiotic use but relatively low rates of bacterial co-infections, raising concerns that the COVID-19 pandemic may further fuel antimicrobial resistance [15] [16] [17] . The above information is important to inform infection prevention strategies and clinical management in this vulnerable population. We aimed to characterize clinical and virologic features of COVID-19 infection among patients at a cancer center in Seattle, Washington, including viral shedding, antibiotic use and respiratory coinfections.

We conducted a retrospective cohort study of patients at Seattle Cancer Care Alliance (SCCA) who had laboratory-confirmed SARS-CoV-2 infection between February 28, 2020 and June 15, 2020. The SCCA comprises a large ambulatory cancer center with inpatients cared for in a 20-bed inpatient hospital and at the affiliated teaching hospital of the University of Washington (UW). Some patients were admitted to other centers in the region. Patients eligible for inclusion were  18 years old with a diagnosis of cancer or hematologic disorder;

A c c e p t e d M a n u s c r i p t 4 to characterize the full spectrum of disease, symptomatic and asymptomatic individuals were included. Laboratory testing for SARS-CoV-2 PCR evolved over the course of the pandemic and initially focused on symptomatic patients only. In late March to early April, testing expanded to include asymptomatic individuals on admission, pre-procedure as well as weekly testing of hematopoietic cell transplant (HCT) and cellular therapy patients.

Frequency of PCR testing following a positive result varied according to the discretion of the treating physician, but often occurred weekly until two consecutive negative results were observed. From March 23, 2020 to April 21, 2020, symptomatic outpatients with SARS-CoV-2 infection received daily nurse monitoring phone calls until symptom resolution to evaluate need for higher levels of care.

The study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board with a waiver of informed consent.

Nasopharyngeal swabs were tested for SARS-CoV-2 RNA using a UW virology laboratorydeveloped real-time reverse-transcription polymerase chain reaction (RT-PCR) ( 

The date of the first positive SARS-CoV-2 RT-PCR test served as day of COVID-19 diagnosis. COVID-19 exposures were based on documentation in the medical record.

Household contact was defined as known exposure to a suspected or laboratory-confirmed COVID-19 case residing in the same household. Community contact was defined as known exposure to a person with suspected or laboratory-confirmed COVID-19 outside of the household in the community. A long-term care facility (LTCF) exposure was noted if the patient resided within a LTCF for the entire two weeks prior to COVID-19 diagnosis. A healthcare-associated exposure was defined if patient was hospitalized for the entire two weeks prior to diagnosis or had known exposure to a laboratory-confirmed COVID-19 case in a healthcare facility. A travel-related exposure was defined based on a history of domestic or international travel in the two weeks prior to diagnosis. Lower respiratory tract infection (LRTI) was defined as new abnormal respiratory exam, radiographic findings, or new oxygen requirement in conjunction with a provider's diagnosis of LRTI. A co-infection was defined as detection of pathogen by diagnostic tests including respiratory bacterial cultures (e.g., sputum, endotracheal aspirate, bronchoalveolar lavage) and a laboratory-developed multiplex respiratory viral panel PCR that can detect 12 respiratory viruses [19] . To examine how antibiotic use varied throughout the study period, we divided patients equally into an early (2/29/20-3/28/20) and late (3/29/20-6/15/20) period. Viral shedding was defined as detection of viral RNA [20, 21] .

We evaluated the following outcomes present at or within 30 days after COVID-19 diagnosis:

all-cause mortality, LRTI, hospitalization, and intensive care unit (ICU) admission.

Additionally, we evaluated a composite outcome of number of days alive and out of hospital in the 30 days after COVID-19 diagnosis, which was computed for each patient by subtracting the number of days spent in the hospital from the total number of days each A c c e p t e d M a n u s c r i p t 6 patient was alive, in the 30-day period [19] . For the purpose of this outcome, hospital admission date, but not discharge date was considered a day spent in the hospital.

Among patients with at least two PCR tests performed, the duration of viral shedding, or time from symptom onset to viral clearance, was estimated using cumulative incidence methodology. Viral clearance was defined by two consecutive negative tests; date of viral clearance was defined as the date of the first of these two negative tests. Deaths occurring before two consecutive negatives were treated as a competing risk. Patients without two consecutive negatives and who did not die within two weeks of their last PCR test were censored at two weeks after the last test. Median and interquartile (IQR) range for duration of shedding were then estimated from the cumulative incidence curve. To test for associations between baseline variables and our composite outcome, we used generalized estimating equations (GEE) with the binomial distribution and logit link, treating the number of days alive and out of the hospital as the number of successes out of 30 days. GEE accommodates overdispersion that arises from the correlation among days in the same patient. Model estimates are presented as odds ratios (OR) with 95% confidence intervals (CI). We prespecified the following candidate explanatory variables: age (continuous), sex, race (non-white vs. white), obesity (body mass index ≥ 30 vs. <30), smoking (past/current vs never), number of comorbidities (continuous), primary disease (hematological malignancy vs solid tumor/other), statin use at the time of COVID-19 diagnosis, steroid use in the two weeks before COVID-19 diagnosis, and chemotherapy in the 30 days before COVID-19 diagnosis. For each candidate explanatory variable, we reported unadjusted ORs from univariable models and adjusted ORs from multivariable models that were adjusted for the following pre-specified variables: age, sex, and number of comorbidities 

We identified 71 patients for inclusion during the study period. Baseline characteristics are summarized in Table 1 . Median age was 61 years (range 22-98 years) with 32 (45%) male patients and 9 (13%) Hispanic. Thirty-five (49%) had ≥ 2 identified comorbidities with hypertension, chronic kidney disease, and coronary artery disease as the most common.

Forty-two (59%) patients had a solid tumor malignancy, with breast cancer being the most prevalent diagnosis. No patients in the cohort were recipients of HCT or cellular therapy.

Nineteen (27%) patients received chemotherapy in the 30 days prior to COVID-19 diagnosis.

Eleven (15%) patients received systemic steroids in the two weeks prior to COVID-19 diagnosis.

The most commonly reported known exposures included household contact (27%) and LTCF residence (24%). There were no known healthcare-associated exposures (Supplemental Figure 1) .

Sixty-five (92%) patients had symptoms which prompted testing, with cough (68%), fever/chills (58%), and shortness of breath (37%) reported most often (Supplemental Figure   2 ). Among 64 patients with known symptom onset, the median number of days from symptom onset to laboratory confirmed COVID-19 diagnosis was 4 days (range 0-26 days).

Among 23 (32%) symptomatic outpatients who underwent daily telephone monitoring until symptom resolution, median number of days from symptom onset until resolution was 17 days (range 3-55 days); two were subsequently admitted to the hospital.

Of the 13 patients who received therapy for COVID-19, the most commonly used treatments either alone or in combination with another agent were hydroxychloroquine, given in nine patients while six received remdesivir. One patient received prednisone. 

Of 50 patients with ≥2 RT-PCR tests, the median duration between consecutive tests was 7 days (IQR: 3-15 days). The percentage of these patients with positive follow-up RT-PCR tests results was 83% at week 2, 56% at week 4, and 27% at 6 weeks following symptom onset (Figure 2A) . The cumulative incidence of viral clearance from days of symptom onset is shown in Figure 2B ; the median number of days from symptom onset to viral clearance was 37 days (IQR: 23-48). Individual patient patterns in PCR positivity are shown in Supplemental Figure 3 . The median initial Ct value was 24.9 (range 13.2-40.1).

Trajectories of Ct values generally showed a rapid decline in viral load in the first 7 to 10 days following symptom onset, followed by more prolonged low level viral shedding ( Figure   2C ).

A c c e p t e d M a n u s c r i p t 9

Twenty-nine (41%) patients were hospitalized; nine (13%) required ICU level care (Supplemental Table 1 ). LRTI was diagnosed in 27 (39%) patients. The most common abnormal findings on chest imaging were multifocal or patchy opacities (18/27, 67%), 

In this study, we observed high rates of hospitalization, and significant morbidity and mortality in patients with COVID-19 who were seen at a cancer center. Empiric antibiotic use for pneumonia was common early in the study period despite few documented bacterial coinfections. Although we saw a rapid decline in viral load in the first 7-10 days following symptom onset, RT-PCR results remained positive at low viral loads in a substantial proportion of patients over a month following symptom onset.

A c c e p t e d M a n u s c r i p t 10 Among baseline factors associated with the composite outcome of days alive and out of the hospital in univariable models, only number of comorbidities remained significant in multivariable models. This is consistent with other studies suggesting the importance of underlying comorbidities on outcomes among cancer patients [4, 7, 9, 22] . A trend was observed between systemic steroid use in the two weeks before COVID-19 diagnosis and worse clinical outcomes, an intriguing finding as clinical trials of steroid administration demonstrated a therapeutic benefit among those mechanically ventilated or requiring supplemental oxygen but a trend towards harm among those not requiring oxygen [23, 24] .

Steroid exposure is a known risk factor for LRTI or death for other respiratory viruses in a dose-dependent fashion in immunocompromised hosts [25, 26] . This suggests the complex effect of steroids for SARS-CoV-2, potentially deleterious during the early viral replication phase with benefit later targeting an excessive host immune response.

Early reports from China as well as from New York City suggest healthcare acquisition is an important source of exposure among cancer patients [7, 27] and a nosocomial outbreak of SARS-CoV-2 infection has been described in a hematology unit [28]. While we did not observe any cases of healthcare associated infection, more than half of cases appeared to acquire SARS-CoV-2 from LTCF or household exposures. Notably, patients with LTCF exposure had high rates of LRTI and mortality, most likely reflecting a population of older individuals with multiple comorbidities, and who are at high-risk for severe disease and death [29, 30] . These observations indicate the importance of targeting vaccine distribution and other prevention efforts to congregate settings and to household members and caregivers in order to reduce risk of transmission to vulnerable populations.

Our cohort exhibited a longer median duration of viral shedding of 37 days when compared to findings from a recent meta-analysis which reported a mean duration of viral shedding of A c c e p t e d M a n u s c r i p t 11 illness or older age in our cohort which have been associated with delayed viral clearance [28] . Although prolonged viral shedding was observed in our cohort, viral loads declined rapidly in the first 7-10 days from symptom onset, similar to findings reported in the general population and in patients with renal transplantation [20, [31] [32] . While we were unable to directly assess for the presence of replication-competent virus through culture, studies suggest an inverse relationship between Ct value and quantity of viable virus, with low likelihood of infectivity with high Ct value [33] .

Notably, our study had no HCT recipients and a smaller proportion of patients with hematologic malignancies when compared to solid tumors which may reflect more stringent efforts among the most highly immunosuppressed patients to limit exposures. Prolonged and persistent shedding of infectious virus among patients with hematologic malignancy and HCT recipients has been described in a few cases. In a report of a patient with chronic lymphocytic leukemia and acquired hypogammaglobulinemia, shedding of infectious virus was observed up to 70 days after diagnosis [34] . In another report, a patient with mantle cell lymphoma and treatment associated B-cell deficiency shed replication competent virus for at least 119 days [35] . In a study that included 18 recipients of HCT or CAR T cell therapy and 2 patients with lymphoma, 3 patients had viable virus cultured beyond 20 days; one patient had viable virus detected at 61 days [36] . The Centers for Disease Control and Prevention currently recommends either a time/ symptom-based or test-based approach to guide discontinuation of isolation precautions among severely immunosuppressed patients [37] .

Further study is needed to characterize viral shedding dynamics among cancer patients and in particular those who are at increased risk for prolonged shedding of infectious virus.

Though several studies have noted significant use of empiric antibiotics despite low prevalence of co-infections, immunocompromised patients were not specifically identified in these studies [15, 16, 38] . In our cohort of patients at a cancer center, empiric antibiotic use for pneumonia within 30 days of diagnosis was common, despite few documented bacterial coinfections. Empiric antibiotic use decreased over the study period in the absence of We acknowledge several limitations to our study including its retrospective study design in a single geographic region with less ethnic diversity. Less than one-third of our cohort had hematologic malignancies and there were no HCT recipients; it is unknown whether our findings, in particular, the data regarding viral shedding are generalizable to these highly immunosuppressed populations. The frequency of PCR testing used to measure duration of viral shedding in this observational study was not standardized and varied by physician discretion; this may have impacted the precision of our estimates of shedding duration.

However, in most cases, testing occurred at least every 1-2 weeks after initial positive result.

As Ct values were only available in a subset of patients with variable timing of diagnosis relative to symptom onset, we were unable to assess for any association between initial Ct value and mortality as described in other studies [40] . Limited use of diagnostic studies early in the pandemic such as bronchoscopy may have underestimated the true incidence of bacterial or fungal co-infections.

In conclusion, patients at a cancer center, in particular those with multiple comorbidities, are at increased risk for poor outcomes associated with COVID-19. Opportunities exist to target There was a significant decrease in empiric antibiotic use for pneumonia in day 0-2 from the early to late calendar period (p=0.002, Fisher's exact test). For empiric antibiotic use for pneumonia in day 3-30, the decrease from early to late time period was not significant (p=0.42). 

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The authors would like to thank the physicians, advanced practice providers, nurses, and staff at the SCCA and University of Washington Medical Center for their tremendous dedication, and care of these patients.

A c c e p t e d M a n u s c r i p t 6 

A c c e p t e d M a n u s c r i p t 23 Any immune checkpoint inhibitors received 5 

Immunoglobulin in 4 weeks before COVID-19 diagnosis, n(%) 6 

No steroids 58 (84%) < 1mg/kg 6 (9%) ≥ 1mg/kg 5 (7%) 1 Percentages that total less than 100% indicate baseline characteristics with missing data. Missing data comprised less than 5% of the 71 patients. 2 Includes cirrhosis, solid organ transplant, hyperlipidemia, anemia, steroid-induced hyperglycemia, hypothyroidism, recurrent pancreatitis, recurrent small bowel obstruction, selective IgA immunodeficiency, common variable immune deficiency, congenital hypogammaglobulinemia, atrial fibrillation, prosthetic aortic valve, sickle cell disease, thalassemia, bicuspid aortic valve, chronic left hip Propionibacterium infection, polymyalgia rheumatica, s/p nephrectomy for benign oncocytoma, pulmonary embolism, spinal stenosis s/p spinal fusion complicated by vertebral osteomyelitis, seizure disorder secondary to meningioma, aortic stenosis, Hashimoto thyroiditis. 3 Includes sickle cell disease (n=1), other hematologic disorder (n=3), inherited immunodeficiency (n=1), autoimmune disorder (n=1), and other unspecified (n=4). 4 Among 70 patients with medication status known. Calcineurin inhibitor status was among all 71 patients and indicates any receipt in the 2 weeks before COVID-19 diagnosis. 5 Includes ipilimumab (n=2) and nivolumab (n=2). 6 Among 69 patients with known immunoglobulin status in 4 weeks before COVID-19 diagnosis.A c c e p t e d M a n u s c r i p t