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1.
Clin Exp Rheumatol ; 39(5): 1119-1125, 2021.
Article in English | MEDLINE | ID: covidwho-2207207

ABSTRACT

OBJECTIVES: The results of the RECOVERY trial identified dexamethasone as the first pharmacological therapy that reduces mortality in patients with COVID-19. The aim of this paper is to conduct a systematic literature review on safety and efficacy of pulse glucocorticoid therapy for Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV), Middle East Respiratory Syndrome (MERS)-CoV or SARS-CoV-2 infections and describe a case-series of COVID-19 patients treated with off-label pulse doses of methylprednisolone. METHODS: We performed a systematic literature review on safety and efficacy of pulse therapy for betacoronaviridae infections as described in the protocol registered on PROSPERO (CRD42020190183). All consecutive patients admitted to Arcispedale Santa Maria Nuova di Reggio Emilia or Guastalla Hospital with COVID-19 between March 1st and April 30th, 2020 and treated with methylprednisolone 1 gram/day for at least three days were included in the case series. A retrospective review of available computed tomography (CT) scan and chest x-ray was performed independently by two radiologists blinded to clinical data, and discordances were resolved by consensus. RESULTS: Twenty papers were included for SARS, but only two were comparative and were included in the primary endpoint analysis. Likewise, eleven papers were included for COVID-19, four of which were comparative and were considered for the primary outcome analysis. Included studies for both SARS and COVID-19 are mostly retrospective and highly heterogeneous, with lethality ranging from 0% to 100% and ICU admission rate ranging from 9% to 100%. Fourteen patients were included in our case series, 7 males and 7 females. CONCLUSIONS: No randomised controlled trial is available yet for corticosteroids pulse-therapy defined as at least ≥500mg/day methylprednisolone in patients with emerging coronavirus pneumonia. Lethality among our cohort is high (4/14), but this finding should be interpreted with caution due to the fact that in our setting pulse-steroids were used in patients not eligible for other treatments because of comorbidities or as rescue therapy. The incidence of steroid-related adverse events seems low in our cohort. The quality of the evidence on glucocorticoid pulse-therapy in SARS, MERS and COVID-19 is poor. Randomised controlled trials are greatly needed.


Subject(s)
COVID-19 , Coronaviridae , Female , Glucocorticoids/adverse effects , Humans , Male , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
2.
Medicine (Baltimore) ; 100(19): e25865, 2021 May 14.
Article in English | MEDLINE | ID: covidwho-2191002

ABSTRACT

RATIONALE: Coronavirus disease 2019 (COVID-19) has spread worldwide. It involves multiple organs of infected individuals and encompasses diverse clinical manifestations. We report a case of acute optic neuritis (ON) associated with myelin oligodendrocyte glycoprotein (MOG) antibody possibly induced by COVID-19. PATIENT CONCERNS: A 47-year-old man presented to our clinic with left eye pain and vision loss. Magnetic resonance imaging of the orbit revealed the bilateral high intensity of the optic nerve sheaths. He tested positive for COVID-19 by polymerase chain reaction (PCR) testing on the day of admission but he had no signs of respiratory illness. Laboratory testing revealed that MOG immunoglobulin G (MOG IgG) was positive, but other antibodies including aquaporin-4 were negative. DIAGNOSIS: The patient was diagnosed with MOG antibody-positive acute ON possibly induced by COVID-19. INTERVENTIONS: Steroid pulse therapy consisting of methylprednisolone 1 g/day for a total of 3 days, followed by an oral prednisolone taper was performed. OUTCOMES: His left eye pain was immediately relieved, and his decimal vision improved from 0.03 to 0.1 on the day of discharge. Outpatient follow-up 2 weeks later revealed left a decimal vision of 1.2, and a complete resolution of the left eye pain. LESSONS: Our case indicated that COVID-19 might trigger an autoimmune response that leads to MOG antibody-associated ON, similar to other pathogens that were reported in the past. The treatment response to steroid pulse therapy was preferable following a typical course of MOG antibody-positive ON.


Subject(s)
COVID-19/complications , Myelin-Oligodendrocyte Glycoprotein/immunology , Optic Neuritis/etiology , Optic Neuritis/immunology , Autoantibodies , Glucocorticoids/therapeutic use , Humans , Male , Methylprednisolone/therapeutic use , Middle Aged , Optic Neuritis/drug therapy , SARS-CoV-2
3.
Ther Drug Monit ; 42(3): 360-368, 2020 06.
Article in English | MEDLINE | ID: covidwho-2152206

ABSTRACT

BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.


Subject(s)
Antiviral Agents/adverse effects , Coronavirus Infections/drug therapy , Drug Monitoring , Immunosuppressive Agents/adverse effects , Pneumonia, Viral/drug therapy , Transplant Recipients , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized , Antiviral Agents/therapeutic use , Betacoronavirus , COVID-19 , Drug Interactions , Glucocorticoids , Humans , Hydroxychloroquine , Immunosuppressive Agents/therapeutic use , Pandemics , Protease Inhibitors , SARS-CoV-2
4.
Pharmacol Res ; 185: 106511, 2022 11.
Article in English | MEDLINE | ID: covidwho-2132084

ABSTRACT

Coronavirus Disease 19 (COVID-19) is associated with high morbidity and mortality rates globally, representing the greatest health and economic challenge today. Several drugs are currently approved for the treatment of COVID-19. Among these, glucocorticoids (GCs) have received particular attention due to their anti-inflammatory and immunosuppressive effects. In fact, GC are widely used in current clinical practice to treat inflammatory, allergic and autoimmune diseases. Major mechanisms of GC action include inhibition of innate and adaptive immune activity. In particular, an important role is played by the inhibition of pro-inflammatory cytokines and chemokines, and the induction of proteins with anti-inflammatory activity. Overall, as indicated by various national and international regulatory agencies, GCs are recommended for the treatment of COVID-19 in patients requiring oxygen therapy, with or without mechanical ventilation. Regarding the use of GCs for the COVID-19 treatment of non-hospitalized patients at an early stage of the disease, many controversial studies have been reported and regulatory agencies have not recommended their use. The decision to start GC therapy should be based not only on the severity of COVID-19 disease, but also on careful considerations of the benefit/risk profile in individual patients, including monitoring of adverse events. In this review we summarize the effects of GCs on the major cellular and molecular components of the inflammatory/immune system, the benefits and the adverse common reactions in the treatment of inflammatory/autoimmune diseases, as well as in the management of COVID-19.


Subject(s)
Autoimmune Diseases , COVID-19 , Humans , COVID-19/drug therapy , Glucocorticoids/therapeutic use , Glucocorticoids/pharmacology , Anti-Inflammatory Agents/adverse effects , Autoimmune Diseases/drug therapy
5.
Infect Dis Clin North Am ; 36(1): 1-14, 2022 03.
Article in English | MEDLINE | ID: covidwho-2130977

ABSTRACT

Although COVID-19 has impacted many children, severe disease is rare and most recover with supportive care. Manifestations are diverse and often nonrespiratory. Adolescents/children with medical comorbidities are at risk for severe respiratory compromise. The most serious manifestation in previously healthy children is a delayed multisystem inflammatory syndrome with cardiac compromise in severe cases. Anti-SARS-CoV-2 monoclonal antibodies are available for adolescents at risk of progression and not hospitalized. Therapeutic options for severe respiratory disease with hypoxia include remdesivir and glucocorticoids. Therapies for multisystem inflammatory syndrome in children include intravenous immunoglobulin and glucocorticoids. Refractory cases may benefit from additional immunomodulators.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adolescent , Alanine/analogs & derivatives , Alanine/therapeutic use , COVID-19/complications , COVID-19/epidemiology , COVID-19/therapy , Child , Glucocorticoids/therapeutic use , Hospitalization , Humans , Immunoglobulins, Intravenous/therapeutic use , Systemic Inflammatory Response Syndrome
6.
Ann Intern Med ; 173(11): 870-878, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-2110823

ABSTRACT

BACKGROUND: Low-dose glucocorticoids are frequently used for the management of rheumatoid arthritis (RA) and other chronic conditions, but the safety of long-term use remains uncertain. OBJECTIVE: To quantify the risk for hospitalized infection with long-term use of low-dose glucocorticoids in patients with RA receiving stable disease-modifying antirheumatic drug (DMARD) therapy. DESIGN: Retrospective cohort study. SETTING: Medicare claims data and Optum's deidentified Clinformatics Data Mart database from 2006 to 2015. PATIENTS: Adults with RA receiving a stable DMARD regimen for more than 6 months. MEASUREMENTS: Associations between glucocorticoid dose (none, ≤5 mg/d, >5 to 10 mg/d, and >10 mg/d) and hospitalized infection were evaluated using inverse probability-weighted analyses, with 1-year cumulative incidence predicted from weighted models. RESULTS: 247 297 observations were identified among 172 041 patients in Medicare and 58 279 observations among 44 118 patients in Optum. After 6 months of stable DMARD use, 47.1% of Medicare patients and 39.5% of Optum patients were receiving glucocorticoids. The 1-year cumulative incidence of hospitalized infection in Medicare patients not receiving glucocorticoids was 8.6% versus 11.0% (95% CI, 10.6% to 11.5%) for glucocorticoid dose of 5 mg or less per day, 14.4% (CI, 13.8% to 15.1%) for greater than 5 to 10 mg/d, and 17.7% (CI, 16.5% to 19.1%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). The 1-year cumulative incidence of hospitalized infection in Optum patients not receiving glucocorticoids was 4.0% versus 5.2% (CI, 4.7% to 5.8%) for glucocorticoid dose of 5 mg or less per day, 8.1% (CI, 7.0% to 9.3%) for greater than 5 to 10 mg/d, and 10.6% (CI, 8.5% to 13.2%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). LIMITATION: Potential for residual confounding and misclassification of glucocorticoid dose. CONCLUSION: In patients with RA receiving stable DMARD therapy, glucocorticoids were associated with a dose-dependent increase in the risk for serious infection, with small but significant risks even at doses of 5 mg or less per day. Clinicians should balance the benefits of low-dose glucocorticoids with this potential risk. PRIMARY FUNDING SOURCE: National Institute of Arthritis and Musculoskeletal and Skin Diseases.


Subject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Glucocorticoids/adverse effects , Infections/chemically induced , Aged , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/therapeutic use , Female , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Hospitalization/statistics & numerical data , Humans , Male , Retrospective Studies , Risk Factors
7.
JAMA Netw Open ; 5(11): e2241622, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2117818

ABSTRACT

Importance: Minimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C). Objectives: To evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C. Design, Setting, and Participants: This retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months. Exposures: Glucocorticoid treatment. Main Outcomes and Measures: Main outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness. Results: Among 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91). Conclusions and Relevance: In this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.


Subject(s)
Hyperglycemia , Pneumonia, Viral , Child , Humans , Male , Female , Pneumonia, Viral/epidemiology , Pandemics , Patient Discharge , Glucocorticoids/therapeutic use , Retrospective Studies , Stroke Volume , Aftercare , Ventricular Function, Left , Weight Gain
8.
Lancet ; 398(10303): 843-855, 2021 09 04.
Article in English | MEDLINE | ID: covidwho-2106189

ABSTRACT

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.


Subject(s)
Budesonide/administration & dosage , COVID-19/drug therapy , Glucocorticoids/administration & dosage , Administration, Inhalation , Aged , Bayes Theorem , COVID-19/mortality , Female , Hospitalization , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , SARS-CoV-2 , Treatment Outcome
9.
Am J Case Rep ; 23: e937739, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2100411

ABSTRACT

BACKGROUND We present the report of the first case, to the best of our knowledge, of central retinal vein occlusion (CRVO) that occurred 3 days after anticoagulation discontinuation in a patient with a history of pulmonary embolism in the course of COVID-19. CASE REPORT A previously healthy 38-year-old man was hospitalized in April 2021 with severe COVID-19 pneumonia, complicated by segmental and subsegmental pulmonary embolism. The patient was treated with a concurrent combination of remdesivir, dexamethasone, therapeutic enoxaparin, ceftriaxone, passive oxygen therapy, and convalescent plasma therapy, which led to pulmonary improvement. The treatment with therapeutic enoxaparin (80 mg/0.8 mL twice a day) was continued for 1 month after discharge, followed by 15 mg of rivaroxaban twice a day for 3 weeks and 20 mg of rivaroxaban once a day for 11 weeks. Within 3 days after rivaroxaban discontinuation, the patient experienced a decrease in visual acuity in his right eye, to the level of 5/25. Nonischemic CRVO with cystoid macular edema was diagnosed and an intravitreal injection of ranibizumab was performed. Common identifiable factors contributing to CRVO were excluded, and the treatment with prophylactic enoxaparin was initiated. Two weeks later, macular edema decreased significantly and visual acuity improved to 20/20. The treatment with enoxaparin was discontinued. CONCLUSIONS Rebound hypercoagulability after discontinuation of rivaroxaban therapy can manifest as CRVO in a young patient with a history of COVID-19 pulmonary embolism. It was successfully treated with an intravitreal injection of ranibizumab.


Subject(s)
COVID-19 , Macular Edema , Pulmonary Embolism , Retinal Vein Occlusion , Male , Humans , Adult , Retinal Vein Occlusion/complications , Retinal Vein Occlusion/drug therapy , Retinal Vein Occlusion/diagnosis , Rivaroxaban/therapeutic use , Ranibizumab/therapeutic use , Enoxaparin/therapeutic use , Glucocorticoids/therapeutic use , Macular Edema/drug therapy , Macular Edema/etiology , Intravitreal Injections , Pulmonary Embolism/drug therapy , Pulmonary Embolism/complications , Tomography, Optical Coherence , Angiogenesis Inhibitors/therapeutic use , Treatment Outcome
10.
Endocr Pract ; 28(11): 1166-1177, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2086180

ABSTRACT

OBJECTIVE: Optimal glucocorticoid-induced hyperglycemia (GCIH) management is unclear. The COVID-19 pandemic has made this issue more prominent because dexamethasone became the standard of care in patients needing respiratory support. This systematic review aimed to describe the management of GCIH and summarize available management strategies for dexamethasone-associated hyperglycemia in patients with COVID-19. METHODS: A systematic review was conducted using the PubMed/MEDLINE, Cochrane Library, Embase, and Web of Science databases with results from 2011 through January 2022. Keywords included synonyms for "steroid-induced diabetes" or "steroid-induced hyperglycemia." Randomized controlled trials (RCTs) were included for review of GCIH management. All studies focusing on dexamethasone-associated hyperglycemia in COVID-19 were included regardless of study quality. RESULTS: Initial search for non-COVID GCIH identified 1230 references. After screening and review, 33 articles were included in the non-COVID section of this systematic review. Initial search for COVID-19-related management of dexamethasone-associated hyperglycemia in COVID-19 identified 63 references, whereas 7 of these were included in the COVID-19 section. RCTs of management strategies were scarce, did not use standard definitions for hyperglycemia, evaluated a variety of treatment strategies with varying primary end points, and were generally not found to be effective except for Neutral Protamine Hagedorn insulin added to basal-bolus regimens. CONCLUSION: Few RCTs are available evaluating GCIH management. Further studies are needed to support the formulation of clinical guidelines for GCIH especially given the widespread use of dexamethasone during the COVID-19 pandemic.


Subject(s)
COVID-19 , Hyperglycemia , Humans , Glucocorticoids/adverse effects , COVID-19/drug therapy , Hyperglycemia/chemically induced , Hyperglycemia/therapy , Dexamethasone/adverse effects , Steroids/adverse effects
11.
Endocrinol Metab Clin North Am ; 51(4): 741-753, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2076066

ABSTRACT

Patients with adrenal insufficiency, despite standard glucocorticoid replacement therapy, continue to experience and report impaired self-perceived health status and quality of life. In this review, we will describe quality of life in this patient population, and summarize the determinants of quality of life, based on previous survey-based studies and clinical trials. In addition, some new emerging data during the still ongoing coronavirus disease pandemic are also reviewed in the present article.


Subject(s)
Adrenal Insufficiency , Glucocorticoids , Adrenal Insufficiency/drug therapy , Hormone Replacement Therapy , Humans , Hydrocortisone/therapeutic use , Quality of Life
12.
Int J Mol Sci ; 23(20)2022 Oct 11.
Article in English | MEDLINE | ID: covidwho-2071503

ABSTRACT

Treatments for COVID-19 infections have improved dramatically since the beginning of the pandemic, and glucocorticoids have been a key tool in improving mortality rates. The UK's National Institute for Health and Care Excellence guidance is for treatment to be targeted only at those requiring oxygen supplementation, however, and the interactions between glucocorticoids and COVID-19 are not completely understood. In this work, a multi-omic analysis of 98 inpatient-recruited participants was performed by quantitative metabolomics (using targeted liquid chromatography-mass spectrometry) and data-independent acquisition proteomics. Both 'omics datasets were analysed for statistically significant features and pathways differentiating participants whose treatment regimens did or did not include glucocorticoids. Metabolomic differences in glucocorticoid-treated patients included the modulation of cortisol and bile acid concentrations in serum, but no alleviation of serum dyslipidemia or increased amino acid concentrations (including tyrosine and arginine) in the glucocorticoid-treated cohort relative to the untreated cohort. Proteomic pathway analysis indicated neutrophil and platelet degranulation as influenced by glucocorticoid treatment. These results are in keeping with the key role of platelet-associated pathways and neutrophils in COVID-19 pathogenesis and provide opportunity for further understanding of glucocorticoid action. The findings also, however, highlight that glucocorticoids are not fully effective across the wide range of 'omics dysregulation caused by COVID-19 infections.


Subject(s)
COVID-19 , Glucocorticoids , Humans , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Proteomics/methods , COVID-19/drug therapy , Hydrocortisone , Metabolomics/methods , Amino Acids/metabolism , Tyrosine , Arginine , Bile Acids and Salts
13.
Crit Care ; 26(1): 308, 2022 10 08.
Article in English | MEDLINE | ID: covidwho-2064835

ABSTRACT

The 40-year-old experience with glucocorticosteroids (GCs) in the context of severe infections is complex and troublesome. Recently, however, a clear indication for GCs in severe COVID-19 has been established. This may constitute a harbinger of a wider use of GCs in critical illnesses. A fundamental prerequisite of such an action is a better understanding of the heterogeneity of critical illness and GCs operationalization within the precision medicine approach. In this perspective, we formulate ten major questions regarding the use of GCs in critical illness. Answering them will likely facilitate a new era of effective and personalized GCs use in modern critical care.


Subject(s)
COVID-19 , Glucocorticoids , Adult , COVID-19/drug therapy , Critical Care , Critical Illness/therapy , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans
14.
Cornea ; 40(11): 1502-1504, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-2063050

ABSTRACT

ABSTRACT: The coronavirus disease 2019 global pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several ophthalmic manifestations have been reported to be associated with SARS-CoV-2 infection, including conjunctivitis, acute sixth nerve palsy, and multiple cranial neuropathies. We present a unique case of unilateral phlyctenular keratoconjunctivitis in a 5-year-old boy in the setting of SARS-CoV-2 infection.


Subject(s)
COVID-19/diagnosis , Conjunctivitis, Viral/diagnosis , Eye Infections, Viral/diagnosis , Keratoconjunctivitis/diagnosis , SARS-CoV-2/pathogenicity , Administration, Oral , Anti-Bacterial Agents/administration & dosage , Ascorbic Acid/administration & dosage , Azithromycin/administration & dosage , COVID-19/drug therapy , COVID-19/virology , COVID-19 Nucleic Acid Testing , Child, Preschool , Conjunctivitis, Viral/drug therapy , Conjunctivitis, Viral/virology , Drug Therapy, Combination , Eye Infections, Viral/drug therapy , Eye Infections, Viral/virology , Fluorometholone/therapeutic use , Glucocorticoids/therapeutic use , Humans , Keratoconjunctivitis/drug therapy , Keratoconjunctivitis/virology , Male , Ophthalmic Solutions , Slit Lamp Microscopy , Tomography, Optical Coherence , Visual Acuity/physiology
15.
Endocr Pract ; 28(10): 1100-1106, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2061131

ABSTRACT

OBJECTIVE: Since January 2020, the highly contagious novel coronavirus SARS-CoV-2 has caused a global pandemic. Severe COVID-19 leads to a massive release of proinflammatory mediators, leading to diffuse damage to the lung parenchyma, and the development of acute respiratory distress syndrome. Treatment with the highly potent glucocorticoid (GC) dexamethasone was found to be effective in reducing mortality in severely affected patients. METHODS: To review the effects of glucocorticoids in the context of COVID-19 we performed a literature search in the PubMed database using the terms COVID-19 and glucocorticoid treatment. We identified 1429 article publications related to COVID-19 and glucocorticoid published from 1.1.2020 to the present including 238 review articles and 36 Randomized Controlled Trials. From these studies, we retrieved 13 Randomized Controlled Trials and 86 review articles that were relevant to our review topics. We focused on the recent literature dealing with glucocorticoid metabolism in critically ill patients and investigating the effects of glucocorticoid therapy on the immune system in COVID-19 patients with severe lung injury. RESULTS: In our review, we have discussed the regulation of the hypothalamic-pituitary-adrenal axis in patients with critical illness, selection of a specific GC for critical illness-related GC insufficiency, and recent studies that investigated hypothalamic-pituitary-adrenal dysfunction in patients with COVID-19. We have also addressed the specific activation of the immune system with chronic endogenous glucocorticoid excess, as seen in patients with Cushing syndrome, and, finally, we have discussed immune activation due to coronavirus infection and the possible mechanisms leading to improved outcomes in patients with COVID-19 treated with GCs. CONCLUSION: For clinical endocrinologists prescribing GCs for their patients, a precise understanding of both the molecular- and cellular-level mechanisms of endogenous and exogenous GCs is imperative, including timing of administration, dosage, duration of treatment, and specific formulations of GCs.


Subject(s)
COVID-19 , Glucocorticoids , COVID-19/drug therapy , Critical Illness , Dexamethasone/therapeutic use , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , SARS-CoV-2
16.
N Engl J Med ; 387(13): 1173-1184, 2022 09 29.
Article in English | MEDLINE | ID: covidwho-2050642

ABSTRACT

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).


Subject(s)
Bronchodilator Agents , Pulmonary Disease, Chronic Obstructive , Adrenergic beta-2 Receptor Agonists/therapeutic use , Anti-Bacterial Agents/therapeutic use , Bronchodilator Agents/therapeutic use , Forced Expiratory Volume , Glucocorticoids/therapeutic use , Glycopyrrolate , Humans , Lung , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/physiopathology , Tobacco/adverse effects , Treatment Outcome
17.
Cells ; 11(19)2022 Sep 21.
Article in English | MEDLINE | ID: covidwho-2043597

ABSTRACT

Endogenous glucocorticoids and their synthetic analogues, such as dexamethasone, stimulate receptor-mediated signal transduction mechanisms on target cells. Some of these mechanisms result in beneficial outcomes whereas others are deleterious in the settings of pathogen infections and immunological disorders. Here, we review recent studies by several groups, including our group, showing that glucocorticoids can directly interact with protein components on SARS-CoV-2, the causative agent of COVID-19. We postulate an antiviral defence mechanism by which endogenous glucocorticoids (e.g., cortisol produced in response to SARS-CoV-2 infection) can bind to multiple sites on SARS-CoV-2 surface protein, Spike, inducing conformational alterations in Spike subunit 1 (S1) that inhibit SARS-CoV-2 interaction with the host SARS-CoV-2 receptor, ACE2. We suggest that glucocorticoids-mediated inhibition of S1 interaction with ACE2 may, consequently, affect SARS-CoV-2 infectivity. Further, glucocorticoids interactions with Spike could protect against a broad spectrum of coronaviruses and their variants that utilize Spike for infection of the host. These notions may be useful for the design of new antivirals for coronavirus diseases.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , COVID-19/drug therapy , Dexamethasone , Glucocorticoids/pharmacology , Humans , Hydrocortisone , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
18.
Medicine (Baltimore) ; 101(38): e30634, 2022 Sep 23.
Article in English | MEDLINE | ID: covidwho-2042657

ABSTRACT

RATIONALE: In December 2019, a new epidemic of coronavirus disease 2019 (COVID-19) appeared in Wuhan, Hubei Province, and spread rapidly to other parts of China and worldwide. Although established methods exist for the diagnosis and treatment of COVID-19 infection, the management of dermatomyositis (DM) patients with COVID-19 is unknown. PATIENT CONCERNS: In this article, we describe case reports of 2 patients with DM. The first case was a 67-year-old patient with DM and infected with COVID-19 who was admitted to Leishenshan Hospital for a 1-month history of fever, cough, and expectoration. The second case was a 51-year-old male patient who was admitted to Leishenshan Hospital due to fever with cough, expectoration and shortness of breath for 1 month. DIAGNOSES: The first patient was diagnosed with COVID-19 secondary to DM based on repeated SARS-CoV-2 real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) test, detailed medical history and chest computed tomography; The second patient was diagnosed with interstitial lung disease associated with anti-MDA5 DM based on the results of antirheumatic and anti-inflammatory therapy and the above 3 methods. INTERVENTIONS AND OUTCOMES: The first patient received supportive and empirical treatment, including antiviral treatment, anti-inflammatory treatment, oxygen therapy and prophylactic anticoagulation therapy. The symptoms and laboratory results got improved after the treatments. He was discharged with thrice negative PCR tests for the SARS-CoV-2 virus. The second patient received a comprehensive treatment, including glucocorticoid and plasma exchange; his symptoms were relieved and improved. LESSONS: These cases suggest that repeated new pathogenic test results for the coronavirus and a detailed diagnosis of the medical history are important means to distinguish these diseases. Increased attention to the individual characteristics of different cases may allow for more effective diagnosis and treatment.


Subject(s)
COVID-19 , Dermatomyositis , Aged , Anti-Inflammatory Agents , Anticoagulants , Antiviral Agents/therapeutic use , China/epidemiology , Cough/drug therapy , DNA-Directed RNA Polymerases , Dermatomyositis/drug therapy , Dermatomyositis/therapy , Fever/epidemiology , Glucocorticoids/therapeutic use , Humans , Male , Middle Aged , Oxygen , Pandemics , SARS-CoV-2
19.
Clin Transl Sci ; 15(11): 2758-2771, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2037940

ABSTRACT

Alternative polyadenylation (APA) is a common genetic regulatory mechanism that generates distinct 3' ends for RNA transcripts. Changes in APA have been associated with multiple biological processes and disease phenotypes. However, the role of hormones and their drug analogs in APA remains largely unknown. In this study, we investigated transcriptome-wide the impact of glucocorticoids on APA in 30 human B-lymphoblastoid cell lines. We found that glucocorticoids could regulate APA for a subset of genes, possibly by changing the expression of 142 RNA-binding proteins, some with known APA-regulating properties. Interestingly, genes with glucocorticoid-mediated APA were enriched in viral translation-related pathways, while genes with glucocorticoid-mediated expression were enriched in interferon and interleukin pathways, suggesting that glucocorticoid-mediated APA might result in functional consequences distinct from gene expression. For example, glucocorticoids, a pharmacotherapy for severe COVID-19, were found to change the APA but not the expression of LY6E, an important antiviral inhibitor in coronavirus diseases. Glucocorticoid-mediated APA was also cell-type-specific, suggesting an action of glucocorticoids that may be unique to immune regulation. We also observed evidence for genotype-dependent glucocorticoid-mediated APA (referred to as pharmacogenomic-alterative polyadenylation quantitative trait loci), providing potential functional mechanisms for a series of common genetic variants that had previously been associated with immune disorders, but without a clear mechanism. In summary, this study reports a series of observations regarding the impact of glucocorticoids on APA, raising the possibility that this mechanism might have implications for both disease pathophysiology and drug therapy.


Subject(s)
COVID-19 , Polyadenylation , Humans , Polyadenylation/genetics , Transcriptome , Glucocorticoids/pharmacology , RNA-Binding Proteins
20.
Rom J Morphol Embryol ; 63(1): 39-48, 2022.
Article in English | MEDLINE | ID: covidwho-2026773

ABSTRACT

Cortisol is a key element in acute stress including a severe infection. However, in coronavirus-associated disease, 20% of subjects experience hypocortisolemia due to direct or immune damage of pituitary and adrenal glands. One extreme form of adrenal insufficiency is found in 2∕3 of cases with viral and post-viral adrenal infarction (AI) (with∕without adrenal hemorrhage) that is mostly associated with a severe coronavirus disease 2019 (COVID-19) infection; it requires prompt glucocorticoid intervention. Some reports are incidental findings at computed tomography (CT)∕magnetic resonance imaging (MRI) scans for non-adrenal complications like pulmonary spreading and others are seen on post-mortem analysis. This is a review of PubMed-accessible, English papers focusing on AI in addition to the infection, between March 1, 2020 and November 1, 2021. Exclusion criteria were acute adrenal insufficiency without the histopathological (HP) and∕or imaging report of adrenal enlargement, necrosis, etc., respective adrenal failure due to pituitary causes, or non-COVID-19-related adrenal events. We identified a total of 84 patients (different levels of statistical evidence), as follows: a retrospective study on 51 individuals, two post-mortem studies comprising nine, respectively 12 patients, a case series of five subjects, seven single-case reports. HP aspects include necrosis associated with ischemia, cortical lipid degeneration (+/- focal adrenalitis), and infarcts at the level of adrenal cortex, blood clot into vessels, acute fibrinoid necrosis in arterioles and capsules, as well as subendothelial vacuolization. Collateral potential contributors to adrenal damage are thrombotic events, coagulation anomalies, antiphospholipid syndrome, endothelial dysfunction, severe COVID-19 infection with multiorgan failure, etc. Clinical picture is variable from acute primary adrenal insufficiency to asymptomatic or mild evolution, even a retrospective diagnostic; it may be a part of long COVID-19 syndrome; glucocorticoid therapy for non-adrenal considerations might mask cortisol deficient status due to AI∕hemorrhage. Despite its rarity, the COVID-19-associated AI/hemorrhage represents a challenging new chapter, a condition that is essential to be recognized due to its gravity since prompt intervention with glucocorticoid replacement is lifesaving.


Subject(s)
Adrenal Insufficiency , COVID-19 , Thrombosis , Adrenal Glands , Adrenal Insufficiency/complications , COVID-19/complications , Glucocorticoids , Hemorrhage/complications , Humans , Hydrocortisone , Infarction/complications , Necrosis/complications , Retrospective Studies , Thrombosis/complications
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