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Impact of the Coronavirus Disease 2019 Pandemic on Physical and Mental Health of Patients With COPD: Results From a Longitudinal Cohort Study Conducted in the United States (2020-2021)

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at higher risk for severe Coronavirus Disease 2019 (COVID-19). From the pandemic’s onset there has been concern regarding effects on health and well-being of high-risk patients. METHODS: This was an ancillary study to the Losartan Effects on Emphysema Progression (LEEP) Trial designed to collect descriptive information longitudinally about the health and wellbeing of COPD patients who were enrolled in a clinical trial were interviewed by telephone about their health status every 2 weeks and their mental health, knowledge, and behaviors every 8 weeks from June 2020 to April 2021. The were no pre-specified hypotheses. RESULTS: We enrolled 157 of the 220 participants from the parent LEEP trial. Their median age was 69 years, 55% were male, and 82% were White; median FEV 1 % predicted was 48%. Nine confirmed COVID-19 infections were reported, two resulting in hospitalization. Rates of elevated anxiety or depressive symptoms were 8% and 19% respectively in June 2020 and remained relatively stable during follow-up. By April 2021, 85% of participants said they were “very likely” to receive a vaccine; 91% were vaccinated (≥1 dose) by the end of December 2021. CONCLUSION: Our select cohort of moderate to severe COPD patients who were well integrated into a health care network coped well with the COVID-19 pandemic. Few participants were diagnosed with COVID-19, levels of depression and anxiety were stable, most adopted accepted risk reduction behaviors and did not become socially isolated; most were vaccinated by the end of 2021. we examined during year on the of a well-characterized of with moderate to severe with evidence of emphysema on CT enrolled in a clinical trial18. We found similar rates of both hospitalization and of moderate to severe depression and anxiety compared to rates prior to the pandemic, but hospitalizations for COPD exacerbations were reduced in the pandemic. Our results indicate that our cohort of moderate-severe, symptomatic COPD stayed strongly connected to healthcare systems and coped well during the pandemic. It should be noted that as participants in a clinical trial, these patients were a select group with strong ties to health care providers and high levels of health literacy, which limits the generalizability of our results. We observed 9 COVID-19 infections in almost 100 person years but only 2 of the 9 participants were hospitalized for COVID-19, which was much lower than the rate of 62% reported for COPD patients diagnosed with COVID-19 infections in the National COVID Cohort Collaborative 25 . None of the 9 died from COVID-19. We also observed lower rates of hospitalization for COPD exacerbations in our cohort than those observed in the clinical trial during the first two years study (2017-2019), which is consistent with reductions reported in a systematic review of hospitalization for COPD exacerbations 26 . We speculate that the rapid adoption of COVID-19 risk reduction behaviors led to fewer respiratory viral infections which often trigger severe COPD exacerbations 27 . Because of the few COVID-19 cases observed in our study we were unable to conduct planned analyses about potential factors affecting risk or severity of COVID-19 in patients with COPD. reduction in severe COPD exacerbations. These results emphasize the need to examine the impact of the COVID-19 pandemic on vulnerable populations across multiple domains of health.


INTRODUCTION
The Coronavirus Disease 2019 (COVID-19) pandemic has had a devastating impact on health worldwide, resulting in excess morbidity and mortality, especially among individuals with co-morbidities 1 . Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for more severe COVID-19 infection, including an elevated risk of ICU admission, mechanical ventilation, and death from COVID-19 2,3 . Additionally, there is concern that social restrictions and heightened awareness of health risks may lead to increased rates of depression or anxiety, both of which are associated with poor medication adherence 4 morbidity and mortality in people with COPD 5,6,7,8,9,10 . There are conflicting reports about the effects of the pandemic on those with chronic respiratory disease, in particular COPD. While some studies report negative consequences from social restrictions and lockdown 11,12,13,14 , others describe a remarkable resilience in these high-risk populations 15,16 .
Quantitative information on the effects of the pandemic on COPD patients is required to determine the needs of this vulnerable population now and to prepare for public health emergencies in the future. In this study, we examined the impact of the COVID-19 pandemic on patients with moderate to severe COPD living in the United States from June 2020 to April 2021.
Specifically, we examined their physical and mental health, their knowledge and beliefs about COVID-19, and their risk-reduction behaviors to better understand how patients were impacted by and coped with the pandemic during its first year.

Participants
This study was conducted as an ancillary study to the Losartan Effects on Emphysema Progression (LEEP) trial (NCT02696564), a randomized clinical trial designed to evaluate the effect of losartan on the progression of the emphysema based on high-resolution computed tomography (HRCT) 17,18 . LEEP was conducted by the American Lung Association Airways Clinical Research Centers (ACRC) in collaboration with the Pulmonary Trials Cooperative.
Ongoing and completed participants were invited to participate between May 2020 and November 2020. LEEP eligibility criteria included post-bronchodilator (BD) forced expiratory volume in one second (FEV1) 20-80% predicted, forced vital capacity (FVC) ratio ≤ 0.70, age 40 years or older, a history of 10 pack-years or greater of cigarette smoking, and a HRCT scan with between 5 and 35% of voxels with density < -950 Hounsfield Units (HU). Twenty-one of the 26 ACRC sites participated in the ancillary study. All sites participating in the ancillary study received local institutional review board approval before contacting participants and all ancillary study participants provided informed consent.
At the genesis of this ancillary study in March 2020, the objective was to evaluate whether current treatment with losartan versus placebo affected COVID-19 infection rates in the participants under active follow-up in the LEEP trial. Secondary objectives were to evaluate overall infection rates and to describe effects of the pandemic on physical and mental health status, and social support networks in the entire group and perform exploratory analysis for potential risk modifiers in well-characterized COPD patients. Given the few cases of COVID-19 observed, our primary and some of our secondary objectives were not achievable. A protocol for the study is posted as a supplement (Supplement).

Data collection
Study interviews were conducted by trained study staff at each study by phone every 2 weeks to query participants about COVID-19 exposures, symptoms, testing, and healthcare utilization since the last interview. At the first interview and every 8 weeks thereafter, participants were also asked about their knowledge of and attitudes towards COVID-19 and administered the following 5 validated questionnaires (Supplementary Table 1

Statistical analysis
Descriptive analyses were used to summarize participant characteristics at enrollment and during follow-up. Data from all interviews were evaluated to determine the incidence of COVID-19 infections and hospitalizations during the follow up period. Data from the standard and COVID-19 specific questionnaires were evaluated over 6 approximately two-month periods beginning in May 2020 and with the last period ending in May 2021. If two sets of standard or COVID-19 specific questionnaires were available for a participant in one two-month period, the first one was selected for inclusion in the analysis.
Differences in prevalence of characteristics among time periods were evaluated with logistic regression models with covariates for sex and race using generalized estimating equations and adjusting for repeated measurements 24 ; an autoregressive covariance structure was used. The first period, June 2020, was the reference period and P-values reported for period differences are from contrasts of subsequent periods with June 2020. Rates of hospitalization from data collected in the ancillary study were compared to the rates in the LEEP cohort from May 2017 to March 1st, 2020. Data were analyzed with SAS version 9.4 and Stata/IC 15.1 for comparison of rates.

Characteristics of the Study Population
Of the 220 patients enrolled in the parent LEEP study, 185 were contacted about the COVID-19 ancillary study, 157 of whom enrolled (Figure 1). Contacted participants who elected not to enroll cited "time" as the main reason for not participating. Most participant, 104 (66%) study had completed the LEEP trial, overall 50% had been randomly assigned to losartan ( Table 1). The median age of ancillary study participants was 66 years; most were White (82%) and male (56%) ( Table 1). The median post-BD FEV1 percent predicted at trial enrollment was 48% predicted, with over 75% of participants having CAT scores greater than 10 at enrollment, indicating that this was a cohort of severe, symptomatic COPD patients ( Table 2). Most participants (73%) enrolled between May 2020 and July 2020 with 73 to 138 participants being interviewed in each 8-week period (Supplemental Figure 1). The median length of follow-up was 38 weeks and the median number of interviews completed per participant was 19

Impact of COVID-19 on Physical Health
Between May 2020 and May 2021, 9 participants reported a diagnosis of COVID-19 that was confirmed by a positive test, one of whom was asymptomatic. Two reported being hospitalized for COVID-19 infection, including one before enrolling in the ancillary study  Table 2). These scores remained stable throughout follow-up Figure 3).

DISCUSSION
In this study, we examined the impact of the COVID-19 pandemic during the first year on the physical and mental health of a well-characterized cohort of patients with moderate to severe COPD with evidence of emphysema on CT enrolled in a clinical trial18. We found similar rates of both hospitalization and of moderate to severe depression and anxiety compared to rates prior to the pandemic, but hospitalizations for COPD exacerbations were reduced in the pandemic. Our results indicate that our cohort of moderate-severe, symptomatic COPD stayed strongly connected to healthcare systems and coped well during the pandemic. It should be noted that as participants in a clinical trial, these patients were a select group with strong ties to health care providers and high levels of health literacy, which limits the generalizability of our results.
We observed 9 COVID-19 infections in almost 100 person years but only 2 of the 9 participants were hospitalized for COVID-19, which was much lower than the rate of 62% reported for COPD patients diagnosed with COVID-19 infections in the National COVID Cohort Collaborative 25 . None of the 9 died from COVID-19. We also observed lower rates of hospitalization for COPD exacerbations in our cohort than those observed in the clinical trial during the first two years study (2017-2019), which is consistent with reductions reported in a systematic review of hospitalization for COPD exacerbations 26 . We speculate that the rapid adoption of COVID-19 risk reduction behaviors led to fewer respiratory viral infections which often trigger severe COPD exacerbations 27 . Because of the few COVID-19 cases observed in our study we were unable to conduct planned analyses about potential factors affecting risk or severity of COVID-19 in patients with COPD.
While risk reduction behaviors were protective from COVID infection, there was concern that these behaviors could cut patients off from their support systems. In turn, this deprivation of support systems could lead to increased stress, anxiety, feelings of isolation or depression, all of which have been shown to be associated with higher risk of exacerbation risk and other poor outcomes in COPD patients 5,6,10 . The rates of depression observed in our study (19%) which was similar to the prevalence of elevated depression scores in a less severe group of 2022 COPD patients in 2016 enrolled in a cohort study conducted by our group using the same depression screening questionnaire 28,29 . The observed rates are also similar to rates of 15% and 19% respectively 30 . Therefore, while a rate of close to 20% may be alarming, the rates of depression in people with moderate to severe COPD are higher than those of the general population 31 . The observed prevalence of moderate to severe symptoms of anxiety of 8% was similar to what we reported in the aforementioned cohort of COPD patients study in 2016, which was 13% using the same instrument 29 . Some studies that asked participants about changes in mental health specifically due to the pandemic reported increased anxiety 13,14 . Our study and others 15,16,32 that used validated measures of anxiety, such as the GAD-7, which do not reference COVID-19, and reported no increase in anxiety.
Our participants reported high levels of social support and low levels of isolation which likely contributed to the relatively low rates of depression and anxiety. Anecdotally, many participants reported that they enjoyed the study interviews and looked forward to them, and it is possible that being in the study may have affected the very rates of depression and anxiety that we were trying to measure. Taken together, these findings suggest that for this select group of COPD patients who were already coping with physical limitation, the impact of pandemic restrictions on the prevalence of depression and anxiety may be less than in healthier, more active groups.
A major strength of our study is that we leveraged an ongoing clinical trial to collect longitudinal information about the impact of the pandemic on a well-characterized cohort of participants with moderate to severe COPD who were socioeconomically diverse and from different regions of United States. However, generalizability of our findings is limited to a select group of patients with significant morbidity that are well connected to the health care and not representative of COPD patients at large. Additionally, we did not have pre-pandemic measurements of depression and anxiety from the same population and therefore rely on rates from other studies for comparison. Finally, it should be noted that risk avoidance behaviors were self-reported, but it would be extremely difficult to objectively assess compliance of behaviors such as mask wearing and hand hygiene for a large, geographically diverse population.

Figure 5: Risk-reduction behaviors by period
Legend for Figure 5: The percentage of participants practicing behavior is on the Y-axis for each period on X=axis.

Figure 6: Beliefs and concerns by period
Legend for Figure 6: The percentage of participants who responded "very likely" to the question about receiving a COVID-19 vaccine if available, and "quite a lot" or "very much" to questions about COVID-19 affecting their COPD or affecting their access to medical care. The total number of participants with response in each period is displayed above the X-axis.