HIGHLIGHTS

• Persons with substance use disorders, especially those using drugs that impair the cardiovascular and respiratory systems, may be particularly vulnerable to the adverse respiratory effects of COVID-19.

• This double-cohort study of 11,124 adults diagnosed as having COVID-19 found that—after propensity score matching on demographic characteristics and presence of diabetes and obesity—substance use disorders were associated with increased hospitalization, ventilator use, and mortality.

• The reduction of risks, particularly mortality—after additional matching on hypertension, chronic obstructive pulmonary disease, ischemic heart disease, and cerebrovascular diseases—suggests that observed risks may be mediated, at least in part, by drug-related respiratory and cardiovascular diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to rapidly spread worldwide. As health care systems across the globe battle this pandemic, identifying patients at high risk of contracting COVID-19 and associated complications has become critically important. Persons with a substance use disorder are likely to be at increased risk of contracting SARS-CoV-2 because of their higher rates of homelessness, having overcrowded living conditions or being incarcerated, and having poor access to health care (1). In addition, given the virus’s impact on the respiratory, cardiovascular, and immune systems—which can be impaired by opioids, tobacco, and abuse of other substances—persons with substance use disorders are at increased risk of COVID-19 complications, including acute respiratory distress syndrome (ARDS), renal failure, and death (1, 2).

Persons with substance use disorders, especially those using alcohol and drugs such as opioids, benzodiazepines, and methamphetamines, which damage the lungs and impair the respiratory system, may be particularly vulnerable to the adverse respiratory effects of COVID-19 (1, 2). Likewise, substance use disorders have long been linked with immunosuppression. There is ample evidence that opioids, alcohol, methamphetamines, smoking, and vaping all have strong immunosuppressive effects, resulting in greater susceptibility to infection, more severe and longer lasting illnesses, and lower levels of protective antibodies in the blood (3, 4). In addition, some substance use disorders, such as tobacco (smoking), cocaine, and alcohol use disorders, are associated with adverse cardiovascular effects, including hypertension, ischemia, venous thromboembolism, and brain hemorrhage (5, 6).

Given the range of pathways through which substance use disorders can adversely affect COVID-19 progression, understanding the impact of substance use disorders on such patients holds relevance to clinicians and public health planners as they seek clinical and policy approaches to this epidemic. The primary goal of this study was to examine the impact of substance use disorders on the risk of hospitalization, complications, and mortality among adult patients diagnosed as having COVID-19.

Methods

Data for this study were obtained from the TriNetX Research Network platform, a global federated network of electronic medical record (EMR) data from 35 health care organizations representing hospitals, primary care clinics, and specialty treatment providers. The platform was designed to facilitate research related to COVID-19. Health care organizations contributing EMR data to the TriNetX platform are typically large academic health centers and their affiliates. TriNetX provides access to continuously updated, deidentified aggregate EMR data, including demographic characteristics, diagnoses, procedures, medications, laboratory values, and genomics. At the time of this study, the network included data from approximately 54 million patients from 35 health systems across the United States. The TriNetX platform is described in detail elsewhere (7). The analyses of these data were conducted from June 17 through July 31, 2020. This study was reviewed and approved by the University of Texas Medical Branch Institutional Review Board.

We queried the TriNetx Research Network to select the adult patients (age ≥18) diagnosed as having a COVID-19 infection between February 20 and June 30, 2020. Patients were identified as COVID-19 positive if they had a billable code for COVID-19 (ICD-10 codes: B34.2, B97.29, J12.81, U07.1, U07.2) or a positive SARS-CoV-2 laboratory test result (Logical Observation Identifiers Names and Codes [LOINC]: 94500–6, 94315–9, 94309–2, 94533–7, 94534–5, 94559–2). Patients were excluded if they did not have at least one health care visit in the 12 months before COVID-19 diagnosis. We excluded patients with diagnosis codes indicating other specified viral infection (ICD-9: 079.89) or suspected exposure to other biologic agents (ICD-10: Z03.818) during the same time frame.

A diagnosis of substance use disorder in the 12 months prior to COVID-19 diagnosis was determined by using algorithms on the basis of ICD-10–Clinical Modification (CM) codes, defined in the Centers for Medicare & Medicaid Services chronic conditions disease warehouse (8). We examined demographic characteristics (age, sex, race, ethnicity) and the following comorbid conditions that have been linked to adverse outcomes in COVID-19 patients: diabetes (ICD-10-CM: E08–E13), hypertension (I10), chronic obstructive pulmonary disease (COPD) (J44), ischemic heart disease (I20–I25), obesity (E65–E68), and cerebrovascular disease (I60–I69).

Mortality and hospitalization were assessed directly from the EMR data. Mechanical ventilation was defined by using the following CPT codes: 39.65, 31500, 5A1935Z, 5A1945Z, 5A1955Z, 1015098, 0BH17EZ, 0BH13EZ, 0BH18EZ, and 1022227. All three outcomes were assessed at a follow-up time of 21 days from the date of COVID-19 diagnosis.

Descriptive statistics were presented as frequencies with percentages for categorical variables and as mean±SDs for continuous measures. Baseline characteristics were compared by using Pearson chi-square tests for categorical variables and independent-samples t tests for continuous variables. To account for differences in baseline characteristics between the groups, two propensity score (PS) matching models were developed by using logistic regression to derive well-matched groups for comparative outcomes analysis. Within the TriNetX cohort of COVID-19 patients (N=54,589), we identified two matched cohorts: the first cohort matched on demographic characteristics, obesity, and diabetes (N=5,562) and the second cohort matched on demographic characteristics, diabetes, obesity, hypertension, COPD, ischemic heart disease, and cerebrovascular disease (N=5,450). Given that many commonly abused substances increase the risk for chronic respiratory and cardiovascular diseases (1, 2, 5, 6), we determined that four of the comorbid conditions under study (hypertension, COPD, ischemic heart disease, and cerebrovascular disease) were possible mechanistic pathways between substance use disorder and adverse COVID-19 outcomes. We therefore excluded these four conditions from the primary PS-matched models. All statistical analyses were conducted with the TriNetX platform, which utilizes a combination of JAVA, R, and Python programming languages.

Results

Table 1 presents demographic and clinical characteristics in the PS-matched substance use disorder and non–substance use disorder COVID-19 cohorts. A total of 54,529 patients who were positive for COVID-19 were identified in the U.S. TriNetx database. Of those, 5,562 (10.2%) had a substance use disorder (see supplement). Males; Blacks; Hispanics; and persons with diabetes, hypertension, COPD, ischemic heart disease, obesity, or cerebrovascular disease were overrepresented in the subgroup of individuals with substance use disorder. Both PS-matched cohorts achieved strong balance on all matched variables.

TABLE 1. Characteristics and outcomes in propensity score–matched COVID-19 cohorts of individuals with and without a substance use disorder

Three outcomes—hospitalization, ventilator use, and mortality—within 21 days of COVID-19 diagnosis were examined in the substance use disorder versus non–substance use disorder cohorts. In the unmatched analysis (see supplement), substance use disorder was associated with an increased risk of hospitalization (32.5% versus 17.4%, odds ratio [OR]=2.29, 95% confidence interval [CI]=2.16–2.44), ventilator use (6.0% versus 3.1%, OR=2.02, 95% CI=1.79–2.28) and mortality (4.9% versus 2.8%, OR=1.81, 95% CI=1.58–2.07). In the PS-matched cohort that was matched on demographic characteristics, diabetes, and obesity, substance use disorder was associated with an increased risk of hospitalization (32.5% versus 20.7%, OR=1.84, 95% CI=1.69–2.01), ventilator use (6.0% versus 4.2%, OR=1.45, 95% CI=1.22–1.72), and mortality (4.9% versus 3.8%, OR=1.30, 95% CI=1.08–1.56). The final PS-matched cohort included four additional comorbid conditions—hypertension, COPD, ischemic heart disease, and cerebrovascular disease—that were potentially mechanistic pathways between substance use disorder and adverse outcomes. This model showed that substance use disorder was still associated with an increased risk of hospitalization (30.9% versus 22.6%, OR=1.53, 95% CI=1.40–1.65) and ventilator use (5. 4% versus 4.3%, OR=1.28, 95% CI=1.07–1.52) but not with mortality (4.7% versus 4.7%, OR=1.00, 95% CI=0.84–1.20).

Discussion

In this double-cohort study of 11,124 adults diagnosed as having COVID-19, we found that after PS matching on demographic characteristics, diabetes, and obesity, having a substance use disorder was associated with increased hospitalization, ventilator use, and mortality. When hypertension, COPD, ischemic heart disease, and cerebrovascular disease—possible mediators between substance use disorder and COVID-19 adverse outcomes—were added to the matching algorithm, the increased risks for hospitalization and ventilator use persisted, but the mortality risk was attenuated. Overall, our findings are consistent with a broad literature that has reported adverse effects of substance use disorder on the respiratory, cardiovascular, and immune systems (1–3, 9). The attenuation of risks, particularly mortality, in the final model—after matching on respiratory and cardiovascular diseases—suggests that the increased risks experienced by patients with a substance use disorder may be driven, at least in part, by drug-related respiratory and cardiovascular disease (1–3, 9–13).

Hypertension, COPD, ischemic heart disease, and cerebrovascular disease all represent important mechanistic pathways between substance use disorder and COVID-19 adverse outcomes. For example, smoking and vaping tobacco or cannabis damage lung tissue, cause inflammation, diminish lungs’ capacity to respond to infection, and increase angiotensin-converting enzyme 2 receptor density, all of which can exacerbate respiratory disease caused by SARS-CoV-2 (1, 2, 11). Likewise, prolonged alcohol use is linked to impaired mucociliary clearance and lung function, and methamphetamine use is linked to noncardiac pulmonary edema, ARDS, alveolar hemorrhage, pneumonia, and pneumoconiosis (10, 11). In addition, cocaine, methamphetamines, alcohol, tobacco, and opioids are reported to have adverse effects on the cardiovascular system, including hypertension, ischemia, venous thromboembolism, and brain hemorrhage (5, 12, 14).

Substance use disorders can also increase the risk of adverse COVID-19 outcomes through immunosuppression (3). For example, opioids exert various suppressive effects on both the innate and adaptive immune systems, especially among those who have long used substances (≥90 days in a year). Largely by binding to the mu receptor and modulating various downstream cellular signaling pathways, opioids impair the recruitment and function of virtually all immune cells, such as macrophages, NK cells, granulocytes, and B and T lymphocytes (3). Methamphetamines are also reported to increase immune dysregulation, particularly in the lungs (15). Similarly, chronic alcohol use interferes with all aspects of the adaptive immune response, including both cell-mediated and immune responses, which increase the susceptibility of persons with alcohol use disorder to viral and bacterial infections.

The results of our study may have been influenced by several limitations. First, the diseases and medical conditions examined in this study were based on ICD-10-CM codes. Such codes are not always accurate or complete. Second, the TriNetX platform does not represent the general U.S. population, but rather only people who receive clinical care within the 35 health care organizations in the network. Third, reliance on EHR data precluded assessment of a number of potential confounding factors, such as region, and markers of adverse socioeconomic disadvantages, such as neighborhood density, occupational exposure hazards, access to care, access to timely COVID-19 testing, and quality of care for preexisting chronic conditions not related to COVID-19. Despite these limitations, this study had a number of strengths, including a large sample from 35 health systems covering all major regions of the United States and a rigorous analysis based on PS matching.

Conclusions

Our findings suggest that among patients with COVID-19, those with a comorbid substance use disorder have an increased risk of adverse outcomes. The attenuation of the risk for mortality in the final model may reflect an important mediating role of drug-related respiratory and cardiovascular disease. More longitudinal research is needed to further understand the relationship between short- and long-term use of various commonly abused substances, the interactions of the substances with medications related to COVID-19, and the pathways for COVID-19 complications. Continued research on this important topic will inform clinicians, health system leaders, and policy makers on delivery of care for the growing number of Americans living with substance use disorders who are at high risk for COVID-19 and other infections.

Summary

This study investigated the association between substance use disorders (SUDs) and adverse COVID-19 outcomes. A double-cohort study design, employing propensity score matching to control for confounding variables, analyzed data from 11,124 adults diagnosed with COVID-19.

Methodology

Data originated from the TriNetX Research Network, a federated electronic medical record (EMR) database. Inclusion criteria involved adult COVID-19 patients (diagnosed between February 20 and June 30, 2020) with at least one healthcare visit in the preceding year. Exclusion criteria included diagnoses of other viral infections or exposures. SUD diagnoses were determined using ICD-10-CM codes. Two propensity score matching models were constructed: the first adjusted for demographic factors, diabetes, and obesity; the second added hypertension, COPD, ischemic heart disease, and cerebrovascular disease. Outcomes assessed were hospitalization, ventilator use, and mortality within 21 days of diagnosis.

Results

The unmatched analysis revealed a significant association between SUD and increased risks of hospitalization, ventilator use, and mortality. After propensity score matching on demographic factors, diabetes, and obesity, SUD remained associated with elevated risks of hospitalization, ventilator use, and mortality, although the effect sizes were reduced. Further adjustment for cardiovascular and respiratory comorbidities attenuated the mortality risk, suggesting mediation by these pre-existing conditions.

Discussion

Findings align with existing literature on the adverse effects of SUDs on respiratory, cardiovascular, and immune systems. The attenuation of mortality risk in the final model indicates that pre-existing respiratory and cardiovascular diseases, often linked to substance abuse, may partially mediate the increased COVID-19 risk observed in individuals with SUDs. Specific mechanisms are discussed in relation to organ damage caused by various substances.

Limitations and Conclusions

Limitations include reliance on ICD-10-CM codes and the non-representativeness of the TriNetX database. Strengths involve the large sample size and rigorous analytical methods. The study concludes that SUD is associated with increased risk of adverse COVID-19 outcomes, with a possible mediating role of drug-related respiratory and cardiovascular diseases. Further research is suggested to elucidate the complex interplay between substance use, COVID-19, and treatment outcomes.

Summary

This study investigated the association between substance use disorders (SUDs) and adverse outcomes in adults diagnosed with COVID-19. A large dataset from the TriNetX Research Network was analyzed using propensity score matching to control for confounding factors.

Methods

The study used data from the TriNetX Research Network, encompassing electronic medical records from 35 healthcare organizations. Researchers identified adult COVID-19 patients (February 20 – June 30, 2020) and categorized them based on SUD diagnosis within the preceding 12 months. Propensity score matching was employed to create two matched cohorts: one matched on demographics, diabetes, and obesity; the other also including hypertension, COPD, ischemic heart disease, and cerebrovascular disease. Outcomes assessed were hospitalization, ventilator use, and mortality within 21 days of COVID-19 diagnosis.

Results

In the initial propensity score-matched cohort, SUD was associated with increased hospitalization, ventilator use, and mortality. After including additional comorbidities known to be affected by substance use (hypertension, COPD, ischemic heart disease, and cerebrovascular disease), the association with increased hospitalization and ventilator use remained significant. However, the increased mortality risk was no longer significant.

Discussion

The findings suggest that pre-existing respiratory and cardiovascular conditions, often linked to SUD, contribute significantly to the increased risk of adverse COVID-19 outcomes. The attenuation of the mortality risk after accounting for these conditions indicates a mediating role of these comorbidities. The study acknowledges limitations such as reliance on ICD-10-CM codes and the non-representativeness of the TriNetX sample.

Conclusions

This study highlights the increased risk of adverse COVID-19 outcomes in individuals with SUD. The findings underscore the importance of considering the impact of drug-related respiratory and cardiovascular diseases when assessing the risk profile of COVID-19 patients. Further research is needed to refine understanding of the complex interactions between substance use, COVID-19, and its complications.

Summary

This study investigated how substance use disorders affect COVID-19 outcomes. People with substance use disorders, particularly those using drugs affecting the heart and lungs, are more vulnerable to COVID-19's respiratory problems.

Study Findings

A large study of over 11,000 adults with COVID-19 showed that substance use disorders were linked to higher rates of hospitalization, need for ventilators, and death. After considering other health issues like diabetes and high blood pressure, the increased risk of hospitalization and ventilator use remained, but the increased risk of death lessened. This suggests that the higher death rate among those with substance use disorders might be partly due to pre-existing lung and heart problems caused by drug use.

Study Methods

Researchers used data from a network of electronic health records across the U.S. They compared adults with COVID-19 who had substance use disorders to those who didn't, carefully accounting for other health factors that could influence the results. They used statistical methods to create comparable groups for a fair comparison.

Discussion

The study's results confirm previous research showing that substance use disorders negatively impact respiratory, cardiovascular, and immune systems. The reduced risk of death after accounting for other health problems shows that pre-existing conditions from substance use likely play a significant role in severe COVID-19 outcomes. Specific examples are given of how various substances damage the lungs and heart.

Limitations and Conclusions

The study acknowledges limitations like relying on medical codes which might not be entirely accurate and the fact that the data doesn't represent the whole U.S. population. Despite this, the large sample size and careful analysis methods make the findings valuable. The study concludes that people with substance use disorders face higher risks from COVID-19 and further research is needed to fully understand the complex relationship between substance use and COVID-19 complications.

Summary

People who have problems with drug or alcohol use may get sicker from COVID-19. This is because some drugs hurt the lungs and heart.

Study Results

A big study looked at over 11,000 adults with COVID-19. It showed that people with substance use disorders were more likely to need to go to the hospital, need a breathing machine, and even die. However, when scientists considered other health problems these people often had (like high blood pressure or lung disease), the extra risk of death went down. This suggests that those other health problems made the COVID-19 worse.

What the Study Means

The study shows that people with substance use disorders need extra help if they get COVID-19. Things like smoking and using drugs can make your lungs and heart weaker and make you more likely to have a hard time breathing or need extra help in the hospital. More research is needed to learn how to help these people the best.