1 Introduction
2 Risk in exogenous glucocorticoid excess
First author | Year of publication | Patient cohort | Number of patients | Number of hospitalized patients | Risk for infection / hospitalization / severe outcome | Key messages/ authors’ conclusion |
---|---|---|---|---|---|---|
Glucocorticoids and the risk of infection | ||||||
Favalli et al. [26] | 2020 | Patients with chronic inflammatory arthritis | 641 with GC treatment, of which 13 had a SARS-CoV-2 infection | unknown | • Increased risk for infection, OR 2.89 (95%CI 1.26 to 6.62, p=0.01); prednisone dose <2.5mg/day OR 1.41 (95%CI 0.39 to 5.15, p=0.61); prednisone dose ≥2.5mg/day OR 4.22 (95%CI 1.74 to 10.23, p=0.001) | • Use of GCs (prednisone doses ≥2.5mg/day) increased the risk of SARS-CoV-2 infection • Use of GCs independently predict increased risk of SARS-CoV-2 infection • Use of GCs should be cautiously evaluated during the pandemic |
Fitzgerald et al. [29] | 2021 | Patients with autoimmune or inflammatory conditions | 1120 with GC treatment, 85 of whom with SARS-CoV-2 infection | unknown | • GC exposure in the past year was associated with 43% increased odds of COVID-19 in multivariable-adjusted models (OR 1.43, 95%CI 1.08 to 1.89) • Higher odds for COVID-19 in individuals with high prednisone equivalent doses: 7.5 to 60mg/day OR 1.60 (95%CI 1.05 to 2.44); >60mg/day OR 1.95 (95%CI 0.87 to 4.39) | • Exposure to GCs may increase risk of contracting COVID-19 • A potential non-linear association between total GC dose and COVID-19 risk was noted |
Soldevila-Demenech et al. [30] | 2020 | Patients with immunomediated inflammatory diseases | 527 with GC treatment, 35 with symptoms of SARS-CoV-2 infection | unknown | • Adjusted relative risk for COVID-19 symptoms in patients with GC treatment ≤10mg/day 0.94 (95%CI 0.61 to 1.43) and >10mg/day 1.76 (95%CI 0.90 to 3.45) • Adjusted relative risk for COVID-19 symptoms in women with low GC treatment ≤10mg/day 0.72 (95%CI 0.42 to 1.22) | • Treatment with low GC doses decreased the incidence of COVID-19 predominantly in women, whereas high doses seemed to produce the opposite effect |
Glucocorticoids and the risk of hospitalization | ||||||
Gianfrancesco et al. [31] | 2020 | Patients with rheumatic diseases | 189 with GC treatment and SARS-CoV-2 infection | 110 | • Higher proportion of patients receiving high doses of glucocorticoids in hospitalized patients vs non-hospitalized patients (16% vs 7% for doses ≥10mg/day, p=0.01) • GC treatment (prednisone-equivalent doses ≥10mg/day) was associated with higher odds of hospitalization (adjusted OR 2.05, 95%CI 1.06 to 3.96, p=0.03); odds for patients with prednisolone-equivalent doses 1-9mg/day: OR 1.03, 95%CI 0.64 to 1.66, p=0.91 | • GC use at a prednisone-equivalent dose ≥10mg/day was associated with a higher odds of hospitalization |
Haberman et al. [32] | 2020 | Patients with immune-mediated inflammatory diseases | 8 with GC treatment and SARS-CoV-2 infection; overall 86 patients with SARS-CoV-2 infection | 4 | • GC use was higher among patients hospitalized (4 of 14, 29%) than those that were not hospitalized (4 of 72, 6%) | • The use of oral GCs was higher among patients with immune-mediated inflammatory disease for whom hospitalization was warranted |
Haberman et al. [33] | 2020 | Patients with inflammatory arthritis | 13 with GC treatment and SARS-CoV-2 infection; overall 103 patients with SARS-CoV-2 infection | 10 | • Chronic GC treatment was more common in patients requiring hospitalization (37% hospitalized vs 4% ambulatory, p<0.001) • Risk of hospitalization in patients with oral GCs: adjusted OR 21.2 (95%CI 4.09 to 109.03, p<0.001) | • Patients with inflammatory arthritis and GC treatment are at higher risk for hospitalization after contracting SARS-CoV-2 • COVID-19 outcomes were worse in patients receiving oral GCs |
Arleo et al. [34] | 2021 | Patients with rheumatic diseases | 37 with oral GC treatment and SARS-CoV-2 infection; overall 70 patients with SARS-CoV-2 infection | 24 | • Hospitalized patients for COVID-19 used oral GC more frequently than those treated as outpatients (71% vs 36%, p<0.01) • Out of 24 patients with oral GC treatment that were hospitalized for COVID-19, 6 patients died (5 patients with >10mg/day) • All patients who died in the study cohort (6/70) used oral GCs | • Patients with rheumatic diseases and chronic GCs were hospitalized more frequently • Chronic GC use increased COVID-19 disease severity |
Hasseli et al. [35] | 2021 | Patients with inflammatory rheumatic and musculoskeletal diseases | 180 with GC treatment and SARS-CoV-2 infection | 77 | • Higher odds for hospitalization in GC treated patients (dosages >5mg/day) by multivariable logistic regression: OR 3.67, 95%CI 1.49 to 9.05, p=0.005; dosages ≤5mg/day OR 1.38, 95%CI 0.80 to 2.37, p=0.25 • Of 77 hospitalized patients, 18 needed invasive ventilation | • Current or prior treatment with GCs was a major and independent risk factor for hospitalization • Since uncontrolled rheumatic and musculoskeletal disease activity also enhances the risk of infections, the results should not encourage stopping GC therapy • GCs should be administered in the lowest possible dose |
Fredi et al. [36] | 2020 | Patients with rheumatic and musculoskeletal diseases | 43 with GC treatment and SARS-CoV-2 infection; overall 65 patients with SARS-CoV-2 infection | 31 | • Cases that required admission to hospital vs those that were not admitted to hospital showed no significant difference in background therapy and comorbidities • No differences in therapies between deceased patients and survivors | • A poor outcome from COVID-19 seems to be associated with older age and the presence of comorbidities rather than the type of rheumatic disease or background therapy |
Freites Nunez et al. [37] | 2020 | Patients with autoimmune inflammatory rheumatic diseases | 61 with GC treatment and SARS-CoV-2 infection; overall 123 patients with SARS-CoV-2 infection | 29 | • OR of hospital admission related to COVID-19 in patients with GC treatment by univariate analysis 2.01 (95%CI 0.97 to 4.13, p=0.05) • GC exposure showed no significant difference (probability of hospital admission) in the multivariable analysis (adjusted OR 1.97, 95%CI 0.77 to 5.01, p=0.15) | • No statistically significant findings for exposure to disease-modifying antirheumatic drugs were found in the final multiple regression model |
Cordtz et al. [38] | 2020 | Patients with rheumatoid arthritis | 2411 with GC therapy, of which 5 were hospitalized with COVID-19; unknown how many with (ambulatory) SARS-CoV-2 infection | 5 | • Absolute standardized risk for hospitalization at 60 days 0.16 (95%CI 0.03 to 0.33) • Adjusted HR for hospitalization 1.22 (95%CI 0.47 to 3.15) | • Patients with inflammatory rheumatic diseases had higher incidence of COVID-19 hospitalization • Treatment with GCs was not associated with hospitalization |
Glucocorticoids and the risk of severe course of disease/ COVID-19-related death | ||||||
Brenner et al. [40] | 2020 | Patients with inflammatory bowel disease | 37 with systemic GC treatment and SARS-CoV-2 infection | 26 | • Out of 37 patients with oral GC treatment, 9 patients (24%) had a severe course of disease (ICU/ventilator/death) • Adjusted OR for ICU/vent/death 6.87 (95%CI 2.30 to 20.51, p<0.001) • Adjusted OR for COVID-19-related death 11.62 (95%CI 2.09 to 64.74, p=0.005) | • GC use was a strong risk factor for adverse COVID-19 outcomes and positively associated with the outcome of death • Steroid-sparing treatments will be important managing patients with inflammatory bowel disease through this pandemic |
Strangfeld et al. [41] | 2021 | Patients with rheumatic diseases | 1273 with GC treatment and SARS-CoV-2 infection; overall 3729 patients with SARS-CoV-2 infection | unknown | • 217 of 1273 patients with GC treatment deceased • Adjusted OR for COVID-19-related death in patients with prednisolone-equivalent dose >10mg/day: OR 1.69 (95%CI 1.18 to 2.41) • Adjusted OR for COVID-19-related death in patients with prednisolone-equivalent dose ≤10mg/day: OR 1.43 (95%CI 0.98 to 2.09) | • Treatment with higher dosages of glucocorticoids (>10mg/day prednisolone-equivalent dose) was an independent factor associated with COVID-19-related death • Patients with higher disease activity have higher odds of COVID-19-related death |
Rutherford et al. [42] | 2021 | Patients with systemic vasculitis | 45 with GC treatment and SARS-CoV-2 infection | 45 | • 22 patients (49%) with GC therapy experienced a severe outcome (advanced oxygen therapy/ventilation/death) • Adjusted OR for severe outcome in patients with GC therapy: OR 3.7 (95%CI 1.1 to 14.9, p=0.047) | • GC therapy at presentation was associated with severe outcome in COVID-19 • GC exposure remained a poor prognostic indicator even after adjusting for vasculitis disease activity • Patients who are receiving GCs should be closely monitored when presenting with COVID-19 since their risk of progression to a severe state appears higher |
Pablos et al. [43] | 2020 | Hospitalized patients with rheumatic diseases | 91 with GC treatment and SARS-CoV-2 infection; overall 228 patients with SARS-CoV-2 infection | 91 | • GC therapy in hospitalized patients was associated with poorer outcome by bivariable analysis (OR 2.20, 95%CI 1.36 to 3.54, p=0.001) • No association of antirheumatic therapies and a severe COVID-19 outcome in the multivariable adjusted analysis (GC treatment: OR 1.10, 95%CI 0.60 to 2.01, p=0.76) | • Immunosuppressive therapies do not significantly greater the risk for poor outcomes |
Ye et al. [44] | 2021 | Patients with connective tissue diseases | 22 with GC treatment and SARS-CoV-2 infection; overall 48 with SARS-CoV-2 infection | 22 | • Patients on low- to medium-dose GCs (5–15mg/day prednisone) had less severe/critical conditions compared to those without GC use before diagnosis (6/22 vs 15/26, p<0.05) | • Low- to medium-dose GCs may reduce the progression of COVID-19 from mild/moderate conditions to severe/critical conditions |
3 Risk in endogenous glucocorticoid excess
First author | Year of publication | Patient cohort | Number of patients | Number of hospitalized patients | Risk for infection / hospitalization / severe outcome | Key messages |
---|---|---|---|---|---|---|
Belaya et al. [48] | 2021 | Patients with active CS | 22 with active CS, of whom 3 had confirmed SARS-CoV-2 infection | 3 | • One 71-year-old woman with newly diagnosed CS (late-night serum cortisol >1750nmol/L, LNSC 908.6nmol/L) developed dyspnea and died from hemorrhagic pneumonia 7 days later • One 38-year-old woman with a 5-year medical history of active pituitary CS (late-night serum cortisol 581.3nmol/L, 24hUFC 959.7nmol/24h) suffered from dyspnea, cough, fever and chest pain; oxygen therapy, antibiotics and symptomatic treatments lead to full recovery 24 days later • One 66- year-old woman with a 4-year medical history of mild Cushing’s disease (late-night serum cortisol 420.2 nmol/L, LNSC 10.03nmol/L) tested positive for COVID-19 in routine screening and remained asymptomatic | • Severe CS affected by COVID-19 is more likely to require emergency care despite a lack of clinical presentations and low inflammation biomarkers • It seems possible that the clinical course of COVID-19 is dependent on the severity of endogenous hypercortisolism |
Serban et al. [49] | 2020 | Patients with Cushing’s disease | 61 with confirmed Cushing’s disease (15 with active disease, 28 in remission with hypoadrenalism, 18 eucortisolemic), of whom 2 (3.2%) had confirmed SARS-CoV-2 infection | 1 | • One male patient with active CS, obesity, hypertension, dyslipidaemia; discontinued adrenostatic therapy with metyrapone one month before because of side effects; his general state improved after one week of isolation in the domestic environment • One female patient in remission, with hypoadrenalism adequately treated, 55-years, end-stage chronic kidney disease and malnutrition, died after 6 days of hospitalization | • 3.2% of Cushing’s disease patients had a confirmed SARS-CoV-2 infection, compared with 0.6% in the general population in Lombardy at that time • Chronic hypercortisolism may be associated with more serious SARS-CoV-2 infection • Active Cushing’s disease patients should be considered as a fragile population |
Yuno et al. [50] | 2020 | Patient with active Cushing’s disease | 1 with active Cushing’s disease and COVID-19 | 1 | • One female patient with active Cushing’s disease and COVID-19 pneumonia, 27-years old, need of 7 L/min oxygen supply by mask, medical treatment with steroidogenesis inhibitors and hydrocortisone (“block and replace”); COVID-19 pneumonia improved with multi-modal treatment; successful trans-sphenoidal surgery was performed one month later after a negative SARS-CoV-2 test result | • Hypercortisolism due to active Cushing’s disease may worsen a SARS-CoV-2 infection • Multi-disciplinary management is mandatory in such cases |
First author | Year of publication | Patient cohort | Number of patients | Number of hospitalized patients | Risk for infection / hospitalization / severe outcome | Key messages |
---|---|---|---|---|---|---|
Tan et al. [51] | 2020 | Patients with confirmed diagnosis of COVID-19 | 403 patients with diagnosis of COVID-19, of whom 112 patients died in the study period | 403 | • Multivariable analysis showed that a doubling of cortisol concentration was associated with a significant 42% increase in the hazard of mortality | • Patients with COVID-19 mount a marked and appropriate acute cortisol stress response • High cortisol concentrations were associated with increased mortality and a reduced median survival |
Ramezani et al. [52] | 2020 | Patients with confirmed diagnosis of COVID-19 | 30 hospitalized patients with SARS-CoV-2 infection | 30 | • Higher serum levels of cortisol were found in non-survival patients vs surviving patients (p=0.017) | • Severe COVID-19 infection outcomes are more prominent at a higher level of serum cortisol |
3.1 Considerations for patients with endogenous Cushing’s syndrome
3.2 Hypercortisolism-associated comorbidities per se might increase the risk for a severe course of disease
Comorbidity in endogenous CS | Reported risk factor in COVID-19 | ||
---|---|---|---|
Arterial hypertension [69] | 58-85 % | Zhou et al. [2] | • Hypertensive patients with CS should be considered at high risk for severe COVID-19 • Optimization of medical treatment is recommended to improve the eventual clinical course of COVID-19 |
Diabetes mellitus [70] | 20-47 % | Corona et al. [9] | • Optimization of medical treatment is recommended to improve the eventual clinical course of COVID-19 |
Hypercoagulability [63] | 54 % | Levi et al. [62] | • Strict monitoring of coagulation parameters • Treatment with low-molecular-weight heparin is recommended, especially for hospitalized, moderately to severely ill patients |
Immune impairments [45] | 21-51% | Wu et al. [116] | • Due to a poor immune response, febrile response in the early phase might be limited • Because of the increased risk of secondary infections, prolonged antiviral treatment and empirical prophylaxis with broad-spectrum antibiotics should be considered in hospitalized cases of COVID-19 and florid CS |
Obesity [117] | 32-41 % | Rottoli et al. [118] | • Patients with CS and visceral obesity should be carefully monitored in case of COVID-19, due to an increased morbidity and mortality |
Atherosclerosis/ cardiovascular diseases [68] | 27-31 % | Zou et al. [8] | • Optimization of medical treatment is recommended to improve the eventual clinical course of COVID-19 |
Myopathy [75] | 60-82 % | De Giorgio et al. [119] | • Dyspnea might be enhanced due to left ventricular cardiomyopathy and/or thoracic muscle weakness in patients with CS |
Dyslipidemia [120] | 38-71 % | Zuin et al. [121] | • Optimization of medical treatment is recommended to improve the eventual clinical course of COVID-19 |
Mental illness [122] | 50-81 % | Barcella et al. [123] | • As mental illness is associated with an unfavorable outcome in patients with COVID-19, neuropsychiatric disorders in patients with CS should be considered and adequately treated |
Obstructive sleep apnea [115] | 50 % | Strausz et al. [124] | • Consistent therapy is recommended to improve the risk profile and prevent secondary consequences such as hypertension, reduced physical performance and further systemic effects |