Machine learning to understand risks for severe COVID-19 outcomes: a retrospective cohort study of immune-mediated inflammatory diseases, immunomodulatory medications, and comorbidities in a large US health-care system.

BACKGROUND: In the context of immune-mediated inflammatory diseases (IMIDs), COVID-19 outcomes are incompletely understood and vary considerably depending on the patient population studied. We aimed to analyse severe COVID-19 outcomes and to investigate the effects of the pandemic time period and the risks associated with individual IMIDs, classes of immunomodulatory medications (IMMs), chronic comorbidities, and COVID-19 vaccination status. METHODS: In this retrospective cohort study, clinical data were derived from the electronic health records of an integrated health-care system serving patients in 51 hospitals and 1085 clinics across seven US states (Providence St Joseph Health). Data were observed for patients (no age restriction) with one or more IMID and for unmatched controls without IMIDs. COVID-19 was identified with a positive nucleic acid amplification test result for SARS-CoV-2. Two timeframes were analysed: March 1, 2020-Dec 25, 2021 (pre-omicron period), and Dec 26, 2021-Aug 30, 2022 (omicron-predominant period). Primary outcomes were hospitalisation, mechanical ventilation, and mortality in patients with COVID-19. Factors, including IMID diagnoses, comorbidities, long-term use of IMMs, and COVID-19 vaccination status, were analysed with multivariable logistic regression (LR) and extreme gradient boosting (XGB). FINDINGS: Of 2 167 656 patients tested for SARS-CoV-2, 290 855 (13·4%) had confirmed COVID-19: 15 397 (5·3%) patients with IMIDs and 275 458 (94·7%) without IMIDs. In the pre-omicron period, 169 993 (11·2%) of 1 517 295 people who were tested for COVID-19 tested positive, of whom 23 330 (13·7%) were hospitalised, 1072 (0·6%) received mechanical ventilation, and 5294 (3·1%) died. Compared with controls, patients with IMIDs and COVID-19 had higher rates of hospitalisation (1176 [14·6%] vs 22 154 [13·7%]; p=0·024) and mortality (314 [3·9%] vs 4980 [3·1%]; p<0·0001). In the omicron-predominant period, 120 862 (18·6%) of 650 361 patients tested positive for COVID-19, of whom 14 504 (12·0%) were hospitalised, 567 (0·5%) received mechanical ventilation, and 2001 (1·7%) died. Compared with controls, patients with IMIDs and COVID-19 (7327 [17·3%] of 42 249) had higher rates of hospitalisation (13 422 [11·8%] vs 1082 [14·8%]; p<0·0001) and mortality (1814 [1·6%] vs 187 [2·6%]; p<0·0001). Age was a risk factor for worse outcomes (adjusted odds ratio [OR] from 2·1 [95% CI 2·0-2·1]; p<0·0001 to 3·0 [2·9-3·0]; p<0·0001), whereas COVID-19 vaccination (from 0·082 [0·080-0·085]; p<0·0001 to 0·52 [0·50-0·53]; p<0·0001) and booster vaccination (from 2·1 [2·0-2·2]; p<0·0001 to 3·0 [2·9-3·0]; p<0·0001) status were associated with better outcomes. Seven chronic comorbidities were significant risk factors during both time periods for all three outcomes: atrial fibrillation, coronary artery disease, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, chronic liver disease, and cancer. Two IMIDs, asthma (adjusted OR from 0·33 [0·32-0·34]; p<0·0001 to 0·49 [0·48-0·51]; p<0·0001) and psoriasis (from 0·52 [0·48-0·56] to 0·80 [0·74-0·87]; p<0·0001), were associated with a reduced risk of severe outcomes. IMID diagnoses did not appear to be significant risk factors themselves, but results were limited by small sample size, and vasculitis had high feature importance in LR. IMMs did not appear to be significant, but less frequently used IMMs were limited by sample size. XGB outperformed LR, with the area under the receiver operating characteristic curve for models across different time periods and outcomes ranging from 0·77 to 0·92. INTERPRETATION: Our results suggest that age, chronic comorbidities, and not being fully vaccinated might be greater risk factors for severe COVID-19 outcomes in patients with IMIDs than the use of IMMs or the IMIDs themselves. Overall, there is a need to take age and comorbidities into consideration when developing COVID-19 guidelines for patients with IMIDs. Further research is needed for specific IMIDs (including IMID severity at the time of SARS-CoV-2 infection) and IMMs (considering dosage and timing before a patient's first COVID-19 infection). FUNDING: Pfizer, Novartis, Janssen, and the National Institutes of Health.

Risk factors for severe COVID-19 outcomes: a study of immune-mediated inflammatory diseases, immunomodulatory medications, and comorbidities in a large US healthcare system.

Background: COVID-19 outcomes, in the context of immune-mediated inflammatory diseases (IMIDs), are incompletely understood. Reported outcomes vary considerably depending on the patient population studied. It is essential to analyse data for a large population, while considering the effects of the pandemic time period, comorbidities, long term use of immunomodulatory medications (IMMs), and vaccination status. Methods: In this retrospective case-control study, patients of all ages with IMIDs were identified from a large U.S. healthcare system. COVID-19 infections were identified based on SARS-CoV-2 NAAT test results. Controls without IMIDs were selected from the same database. Severe outcomes were hospitalisation, mechanical ventilation (MV), and death. We analysed data from 1 March 2020 to 30 August 2022, looking separately at both pre-Omicron and Omicron predominant periods. Factors including IMID diagnoses, comorbidities, long term use of IMMs, and vaccination and booster status were analysed using multivariable logistic regression (LR) and extreme gradient boosting (XGB). Findings: Out of 2 167 656 patients tested for SARS-CoV-2, there were 290 855 with confirmed COVID-19 infection: 15 397 patients with IMIDs and 275 458 controls (patients without IMIDs). Age and most chronic comorbidities were risk factors for worse outcomes, whereas vaccination and boosters were protective. Patients with IMIDs had higher rates of hospitalisation and mortality compared with controls. However, in multivariable analyses, few IMIDs were rarely risk factors for worse outcomes. Further, asthma, psoriasis and spondyloarthritis were associated with reduced risk. Most IMMs had no significant association, but less frequently used IMM drugs were limited by sample size. XGB outperformed LR, with the AUROCs for models across different time periods and outcomes ranging from 0·77 to 0·92. Interpretation: For patients with IMIDs, as for controls, age and comorbidities were risk factors for worse COVID-19 outcomes, whereas vaccinations were protective. Most IMIDs and immunomodulatory therapies were not associated with more severe outcomes. Interestingly, asthma, psoriasis and spondyloarthritis were associated with less severe COVID-19 outcomes than those expected for the population overall. These results can help inform clinical, policy and research decisions. Funding: Pfizer, Novartis, Janssen, NIH.

Post-COVID-19 Pulmonary Fibrosis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions worldwide with a high mortality rate due to a lack of definitive treatment. Despite having a wide range of clinical features, acute respiratory distress syndrome (ARDS) has emerged as the primary cause of mortality in these patients. Risk factors and comorbidities like advanced age with limited lung function, pre-existing diabetes, hypertension, cardiovascular diseases, and obesity have increased the risk for severe COVID-19 infection. Rise in inflammatory markers like transforming growth factor ß (TGF-ß), interleukin-6 (IL-6), and expression of matrix metalloproteinase 1 and 7 (MMP-1, MMP-7), along with collagen deposition at the site of lung injury, results in extensive lung scarring and fibrosis. Anti-fibrotic drugs, such as Pirfenidone and Nintedanib, have emerged as potential treatment options for post-COVID-19 pulmonary fibrosis. A lung transplant might be the only life-saving treatment. Despite the current advances in the management of COVID-19, there is still a considerable knowledge gap in the management of long-term sequelae in such patients, especially concerning pulmonary fibrosis. Follow up on the current clinical trials and research to test the efficacy of various anti-inflammatory drugs is needed to prevent long-term sequelae early mortality in these patients.

Angiotensin-Converting Enzyme (ACE) Inhibitors May Moderate COVID-19 Hyperinflammatory Response: An Observational Study with Deep Immunophenotyping.

Background: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARB), the most commonly prescribed antihypertensive medications, counter renin-angiotensin-aldosterone system (RAAS) activation via induction of angiotensin-converting enzyme 2 (ACE2) expression. Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells, the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation. Methods: We conducted retrospective analyses using both unmatched and propensity score (PS)-matched cohorts on electronic health records (EHRs) to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation (IMV) and 30-day mortality among hospitalized COVID-19 patients. Additionally, we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort. Results: The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use. In fact, the use of ACEi showed decreased risk for mortality. Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications. From the analysis of gene expression profiles, we observed a noticeable up-regulation in the expression of 1L1R2 (an anti-inflammatory receptor) and RETN (an immunosuppressive marker) genes in monocytes among prior users of ACE inhibitors. Conclusion: Overall, the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.

Use of Epoprostenol in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary Hypertension (PH) is defined as a disorder in which the mean Pulmonary Arterial Pressure (mPAP) is greater than 20 mmHg at rest. Pulmonary Arterial Hypertension (PAH) is considered when mPAP is > 20 mmHg and pulmonary vascular resistance (PVR) is ⩾ 3 WU. PAH is a chronic progressive disease resulting in right heart failure and premature death. It is postulated to be due to an inactivating mutation of a gene named bone morphogenetic protein receptor type 2 (BMPR2), whose predominant function is halting vascular proliferation. It has a lamentable prognosis if not rapidly diagnosed and adequately treated. Treatment of PAH has evolved in the past few decades since many related pathways and potential therapeutic targets have been explored. Parenteral prostanoids are the most effective therapeutic options for PAH. Epoprostenol is a synthetic analog of prostacyclin and a potent vasodilator that was Food and Drug Administration (FDA)-approved in December 1995 for intravenous use to treat PAH. It has also been used to treat different PAH subtypes, including connective tissue-related PAH like lupus and systemic sclerosis, congenital heart disease, and drug-induced PAH. It is effective in reducing mortality rates and improving survival rates. Although the use of Epoprostenol for PAH is challenging, it has been one of the most successful therapies used. In this manuscript, we review the pathophysiology of PAH and the risk stratification tool. We also discuss the mechanism of action of PAH-targeted therapies while focusing on the role of epoprostenol that has been investigated in many clinical trials. Finally, we discuss two ongoing clinical trials which highlight some potential therapeutic options.