Trends over time in the risk of adverse outcomes among patients with SARS-CoV-2 infection

Abstract Background We aimed to describe trends in adverse outcomes among patients who tested positive for SARS-CoV-2 between February and September 2020 within a national healthcare system. Methods We identified enrollees in the national U.S. Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 2/28/2020 and 9/30/2020 (n=55,952), with follow-up extending to 11/19/2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation and death. Results Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%) vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%) and remdesivir (1.7% to 45.4%) among hospitalized patients. Conclusions The risk of adverse outcomes in SARS-CoV-2-positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.


Introduction
Infection with SARS-CoV-2 results in a broad spectrum of clinical severity ranging from asymptomatic infection to life-threatening illness. 1 2 Among individuals who test positive for SARS-CoV-2, there is substantial variation across different populations in rates of hospital admission (from 8% to 80.7%), [3][4][5] mechanical ventilation (from 2.3% of the Chinese population to 93.2% of critically ill admitted to New York area hospitals [5][6][7][8][9][10][11][12], and mortality (from 2.8% of unselected patients in the US to 10.2-67% of hospitalized and high-risk patients). 3 5 11 13-17 To date, only a few studies have described trends in these measures over time within populations. [18][19][20][21][22] Since the first case of SARS-CoV-2 was diagnosed in the US on January 19, 2020, there have been marked changes in the availability and approach to testing, in mitigation strategies both in the community and within health systems, in how symptomatic patients are managed medically, in the distribution of viral variants and most recently in the availability of vaccination. Some studies described improved outcomes among infected patients after the initial months of the pandemic. Improvements in mortality were reported for patients treated in an 8-hospital health system in Houston, Texas between mid-March and mid-July, in a 3-hospital system in New York between March and August, 2020, in a single hospital in Milano, Italy between late February and mid-May, 2020 and in the Hospital Clinic of Barcelona from March to September, 2020. 18 20 22 23 Improvements in in-hospital mortality were described between March and August in patients hospitalized in US medical centers using administrative data, without any adjustment for baseline characteristics or disease severity. 21 Also, improvements in outcomes were described among patients admitted to the ICU in England, Wales and Northern Ireland between February and May, 2020 and among patients admitted to the ICU in England from March through June, 2020. 19 24 To our knowledge, no prior studies have described temporal trends in the risk of severe complications of COVID-19 in a national US health care system extending beyond the first wave of A c c e p t e d M a n u s c r i p t 6 the pandemic i.e. after June 2020. The Department of Veterans Affairs (VA) healthcare system supports the largest, integrated, comprehensive national healthcare system in the US, providing a unique view of national trends in outcomes among those infected with SARS-CoV-2. We used national data from the VA to measure trends in hospitalization, ICU admission, mechanical ventilation, dialysis, medication use and death among individuals who tested positive for SARS-CoV-2 between February 28 and September 30, 2020, with follow-up extending through November 19, 2020.

Data source and study population
The VA provides care for more than six million Veterans annually and uses a single, national comprehensive electronic healthcare information network. We used data from the VA's Corporate Data Warehouse (CDW), a relational database of VA enrollees' electronic health records (EHR), developed by the VA Informatics and Computing Infrastructure (VINCI) to support research and clinical operations, including datasets and analytic variables specifically related to SARS-CoV-2 developed by VINCI as part of the "COVID-19 Shared Data Resource." 25 This study was approved by the Institutional Review Board of the Veterans Affairs Puget Sound Healthcare System, which granted a waiver of informed consent. Patients or the public were not involved in the design, conduct, reporting, or dissemination of our research.

Study Population
We identified all VA enrollees (n=559,616) with available results of testing for SARS-CoV-2 using approved polymerase chain reaction (PCR) tests from 02/28/2020 (the date of the first SARS-CoV-2 test in the VA system) to 9/30/2020, including 55,952 (10.0%) who tested positive at least once. The A c c e p t e d M a n u s c r i p t 7 index date was the earliest date of a documented positive test or, in rare instances, if the patient was already hospitalized prior to testing positive, the date of hospitalization.

Adverse outcomes
We ascertained the following four outcomes within 30 days of the index date: 1) hospitalization, 2) ICU admission, 3) mechanical ventilation, and 4) all-cause mortality. Deaths that occurred both within and outside the VA are comprehensively captured in CDW through a variety of sources including VA inpatient files, VA Beneficiary Identification and Records Locator System (BIRLS), Social Security Administration (SSA) death files, and the Department of Defense. 26 However, episodes of mechanical ventilation, ICU admission and hospitalization that occurred outside the VA are captured only if these were paid for by the VA and thus do not include episodes of care covered by Medicare, Medicaid, the Department of Defense or private health insurance. Patients were followed through 11/19/2020 allowing for a minimum follow-up time of 50 days from the most recent index date (09/30/21), which was adequate for outcomes to be electronically recorded in CDW.

Baseline characteristics
Baseline sociodemographic characteristics associated with adverse SARS-CoV-2 outcomes, 5 included age, sex, race, ethnicity, body mass index (BMI), urban vs. rural residence (based on zip codes), and geographic location (divided into 10 US Federal Regions 27 ) ( Table 2).
Comorbid conditions were based on ICD-10 codes recorded in VA electronic health records during the 2-year period before the index date. 25 We used the Deyo modification 28 of the Charlson Comorbidity Index (CCI) 29 to estimate overall burden of comorbidity ( Table 2). We also extracted the following individual comorbid condition which were associated with adverse outcomes among SARS-CoV-2 infected Veterans 5 : diabetes, chronic kidney disease, congestive heart failure, hypertension, obstructive sleep apnea, and obesity hypoventilation syndrome.
A c c e p t e d M a n u s c r i p t 8 We identified symptoms potentially associated with SARS-CoV-2 documented on or within 30 days prior to the index date based on a combination of natural language processing to capture relevant documentation in the EHR and searching for relevant ICD-10 codes, 25 occurring on or within 30 days prior to the index date. In our multivariable models, we used only two symptoms (dyspnea and fever), previously found to be associated with adverse SARS0-CoV-2-related outcomes in Veterans. 5 We extracted 5 routine laboratory blood tests (albumin, aspartate aminotransferase, creatinine, white blood cell count, neutrophil-to-lymphocyte ratio), which we recently showed to be associated with adverse outcomes in SARS-CoV-2 5 . For each test, we extracted the value closest to the index date, on or within 10 days before the index date, or if absent, within 5 days after the index date (93% of tests were performed within 2 days of the index date).

Pharmacotherapy, Noninvasive Ventilation and Dialysis
We identified inpatient and outpatient medications prescribed for SARS-CoV-2 and filled on or within 60 days after the index date, using VA electronic pharmacy records. We also report use of non-invasive ventilation (continuous (CPAP) or bilevel (BiPAP) positive airway pressure) and dialysis during the same time frame. Use of high-flow oxygen supplementation could not be reliably captured.

Statistical Analysis
We divided the observation period into monthly intervals. Using the Kaplan-Meier method, we calculated for the persons infected each month the 30-day cumulative incidence of hospitalization, ICU admission, mechanical ventilation, and mortality from the index date. Patients were censored at the time of death or after 30 days of follow-up. We used Cox proportional hazards regression, stratified by VA medical center, to compare the risk of each outcome among patients infected during each subsequent month relative to the earliest time period after adjusting for the following baseline A c c e p t e d M a n u s c r i p t 9 characteristics, which we found in a prior study to be associated with adverse outcomes among SARS-CoV-2-infected VA enrollees 5 : age, sex, race, ethnicity, BMI, geographical region, CCI, diabetes, chronic kidney disease, congestive heart failure, hypertension, obstructive sleep apnea, obesity hypoventilation, fever, and dyspnea. In analyses limited to hospitalized patients, we additionally adjusted for the 5 laboratory tests listed above 5 . The aim of these adjustments was to attempt to account for changes over time in baseline characteristics of SARS-CoV-2-positive patients that could have resulted in changes in the risk of adverse outcomes.
A non-parametric Wilcoxon-type test was used to test for trend over time across ordered groups.
Interrupted time series (ITS) analysis of trends methods with adjustment for an auto-correlation lag of one month and robust variance estimators were used to test the difference in 30-day outcome rate slope before and after July 1, 2020 30 . We used July 1, 2020 as the transition point because it marked the end of the "first-wave" and beginning of the "second-wave" of the pandemic in the USA 31 .

Trends in baseline characteristics of patients with SARS-CoV-2 infection
Among 55,952 individuals who tested positive for SARS-CoV-2 during the study period, the majority were male (89.3%), mean age was 60.0 years, 58.2% were White, 31.0% were Black, 12.3% were Hispanic, 12.4% had a CCI≥5, 25.4% had documentation of fever and 11% had documentation of dyspnea ( Table 1).
The number of patients testing positive each month ranged from 2504 in the earliest time period The proportion of patients with severe comorbidity burden (CCI≥5) decreased over time (from 18.1% to 11%) as did the proportion with documented fever (from 57.7% to 20%) or dyspnea (from 26.6% to 8.9%). Among patients who were hospitalized, there were no clear temporal trends the proportion who had abnormalities in the five laboratory tests examined.

Trends in pharmacotherapy, dialysis and non-invasive ventilation in patients with SARS-CoV-2 infection
The proportion of hospitalized patients prescribed hydroxychloroquine on or after the index date decreased from 56.6% in February/March to 2.4% in May 2020 and ranged from 0-0.6% thereafter (Table 2, Figure 1a). The proportion of hospitalized patients prescribed azithromycin decreased from 48.3% in February/March to 16.6% in September and use of vasopressors decreased from 20.6% to 8.7%. Tocilizumab prescription rates in hospitalized patients ranged from a peak of 8.7% in April to 0.8% in September 2020. In contrast, remdesivir prescriptions increased from 1.7% to 45.4% of hospitalized patients from February/March to September. Dexamethasone prescriptions were low during the first three months (<4% for hospitalized patients) but from May to September increased from 3% to 53.1% among hospitalized patients and prescription of corticosteroids other than dexamethasone also increased during the same time from 7.8% to 29%. Prescription of anticoagulants among hospitalized patients did not change appreciably over time. The percentage of hospitalized patients who received dialysis decreased from 11.6% in the earliest time period to 3.8% A c c e p t e d M a n u s c r i p t 11 in August and use of non-invasive ventilation increased from a low of 8.4% in February/March to a high of 12.5% in August.
Analogous decreases in prescription of hydroxychloroquine, azithromycin and vasopressors and increases in prescription of remdesivir, dexamethasone and other corticosteroids were observed when presented as a proportion of all infected patients (rather than the hospitalized subgroup) -   comorbid conditions, symptoms and baseline laboratory characteristics, risk for all adverse outcomes decreased most markedly during the early months of the pandemic until July with stabilization after July (Figure 2) (p<0.05 for ITS test for difference in 30-day outcome rate slope before and after July 1 for all outcomes except for mortality among mechanically ventilated patients) ( Table 3  While it is possible that temporal trends in the frequency of adverse outcomes might reflect geographic variations as the pandemic moved across the country, multivariable models were stratified by VA facility and our results were robust to adjustment for geographic region. If criteria for hospitalization, ICU admission and mechanical ventilation of SARS-CoV-2-infected patients relaxed over time, this may have resulted in some of the decreases in adverse outcomes that we observed. Our findings raise the question of whether marked improvements in outcomes among patients infected with SARS-CoV-2 during the first wave of the pandemic might reflect improvements in clinical management. 32 We did observe very substantial increases in the use of potentially effective pharmacotherapy (e.g. remdesivir and dexamethasone) and decreases in the use of ineffective (e.g. azithromycin) or potentially harmful (e.g. hydroxychloroquine) therapy toward the end of the first wave of the pandemic, although inflection points in the use of each of these agents did not exactly parallel those for adverse outcomes. The VA national Pharmacy Benefits Management (PBM) group issued numerous guidelines and criteria-for-use documents related to COVID-19 pharmacotherapies, while the VA national Antimicrobial Stewardship Task Force as well as antimicrobial stewardship programs at the facility and network level provided ongoing support and oversight of off-label use of agents such as hydroxychloroquine and azithromycin. Other shifts in clinical practice that occurred within the first months of the pandemic could not be captured reliably in the data sources available to us. Such shifts include high flow nasal canula [HFNC], pronation and noninvasive positive-pressure ventilation (NIPPV) which were increasingly used to avoid or delay intubation and may have resulted in improved outcomes. 33 A c c e p t e d M a n u s c r i p t 14 Another possible explanation for declining rates of adverse outcomes is that the severity of disease caused by SARS-CoV-2 infection may have declined. This might occur, for example, through reduction in inoculum related to physical distancing or wearing facemasks, which became more common. 34 Also, as an RNA virus, SARS-CoV-2 undergoes rapid mutation, which could impact its pathogenicity. 35 36 A SARS-CoV-2 variant carrying the spike protein amino acid change D614G became progressively more common after March 2020 throughout the world, including the United States, and was the dominant variant by July 2020 37 . This strain has enhanced replication and transmissibility compared to the wild-type strain but it is unclear if it has greater pathogenicity. [37][38][39] However, after the end of our study period, many viral variants have been described, such as the actually be associated with higher mortality. 40 41 The transmissibility and pathogenicity of new variants will need to be closely monitored.
Limitations: While our Veteran cohort is racially diverse and nationally distributed, it includes relatively few women. We did not capture episodes of hospitalization, ICU admission or mechanical ventilation of VA patients in non-VA facilities (unless they were paid for by the VA), but there is no evidence that such non-VA care increased substantially over the course of our study. Also, this would not explain the temporal trends in adverse outcomes among hospitalized patients reported here. The study was supported in part by the Department of Veterans Affairs, CSR&D grant COVID19-8900-11 to GNI.

Declaration of Personal Interests:
None of the authors has any conflicts of interest to disclose.