Potential Adverse Effects of Dexamethasone Therapy on COVID-19 Patients: Review and Recommendations.

Key Summary Points

It is necessary to apply dexamethasone as a therapy in critical COVID-19 patients, but its adverse side effects cannot be ignored. Through a variety of molecular pathways, dexamethasone can interfere with normal organ functions and cause numerous clinical manifestations, intensifying the risk and severity of sequelae of COVID-19 disease, such as osteonecrosis of the femoral head, hypertension and diabetes. Regular follow-up and evaluation of physical conditions in accordance with the time line are crucial for COVID-19 patients who have received dexamethasone treatment.

Introduction

After emerging in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the world and led to high morbidity and mortality. Globally, as of 18 April 2021, there have been 140 million confirmed cases, including 3 million deaths, reported to the World Health Organization (WHO) [ 1 ]. The clinical spectrum of COVID-19 appears to be wide, ranging from asymptomatic infection to critical illness. The common symptoms of infection are fever (94%), cough (79%), fatigue (23%), loose stools (16%), anosmia and dysgeusia (70–84%) [ 2 , 3 ]. Sepsis (59%) is the most frequently observed complication, followed by respiratory failure (54%), acute cardiac injury (23%) and septic shock (20%) [ 4 ]. Cytokine storm, clots, disseminated intravascular coagulation and thrombocytopenia have also been reported [ 5 , 6 ]. Notably, advanced age and several comorbidities including impaired renal function and thrombosis are reportedly associated with a worse disease course and increased mortality rate [ 7 – 9 ]. Hence, there is an urgent need to develop effective therapies to prevent the progression of disease. An array of drugs and therapeutic agents used to be considered as having potential efficacy against SARS-CoV-2, encompassing antiviral agents (remdesivir, chloroquine or hydroxychloroquine, azithromycin and lopinavir), blood-derived products (convalescent plasma and immunoglobulin products), anticoagulants (heparin and low-molecular-weight heparin) and immunomodulators (corticosteroids, interferons, interleukin-1 [IL-1] inhibitors, IL-6 inhibitors and kinase inhibitors) [ 10 – 14 ]. Disappointingly, on 15 October 2020, the interim results from the Solidarity trial coordinated by WHO indicated that remdesivir, hydroxychloroquine, lopinavir and interferon regimens appeared to have little or no effect on hospitalized COVID-19 patients [ 15 ], while dexamethasone, declared as the world’s first treatment to significantly reduce the risk of death [ 16 ], is still the only therapeutic agent shown to be effective for patients with severe disease [ 17 ].

As a broad-spectrum immunosuppressor, the potency and duration of action of dexamethasone are greater and longer than those of cortisone. Its immunosuppressive effect is exerted through a variety of ways. In B cells, glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling while promoting significant upregulation of the genes encoding the immunomodulatory cytokine IL-10 [ 18 ]. Similarly, dexamethasone exposure causes defects in cell division for both CD4 and CD8 T cells and dampens T cell receptor signaling and cytokine expression [ 19 , 20 ]. Moreover, in dendritic cells, dexamethasone could inhibit antigen presentation by increasing expression and activity of Na + /Ca 2+ exchanger [ 21 ]. In parallel, the anti-inflammatory actions of glucocorticoids occur by decreasing the gene transcription of pro-inflammatory cytokines (IL-1, TNF and IL-6), chemokines and adhesion molecules [ 22 ]. Studies have demonstrated that SARS-CoV-2-induced uncontrolled cytokine storm [ 23 ], severe acute respiratory distress syndrome (ARDS) and multiorgan failure, which are the main causes of COVID-19-related mortality, can be attenuated by the use of dexamethasone [ 24 ].

At the beginning of the pandemic, the use of corticosteroids was considered controversial, although Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial provided evidence that dexamethasone 6 mg once daily for 10 days reduced mortality in COVID-19 patients receiving oxygen therapy [ 16 ]. Some investigators noted that early corticosteroid use might lead to increased virus replication and thus higher viral loads [ 25 ]. Meanwhile, there is an analysis suggesting that the initiation of treatment in the second week of symptom onset, when the immunopathological phenomenon dominates, may be beneficial [ 16 ]. However, many researchers pointed out that, in practice, the symptom onset is usually impossible to ascertain, and the signs of severity often appear late. In a study that assessed the association between the dexamethasone initiation time and mortality benefits, Sulaiman et al. (2021) found survival benefits with the early initiation in critically ill COVID-19 patients [ 26 ]. The WHO panel concluded that it is preferable that critical COVID-19 patients receive corticosteroids (even if within 7 days of symptom onset) but non-critical patients do not (even if after 7 days of symptoms onset) [ 27 ]. Although described as ‘low-dose dexamethasone therapy,’ the dose of 6 mg per day is five to six times higher than that for therapeutic glucocorticoid replacement [ 28 – 31 ]. At this dose, patients suffer side effects such as skin thinning, weight gain, osteoporosis, hypertension and diabetes [ 20 ]. Hyperglycemia, gastrointestinal hemorrhage and psychosis were also considered related to dexamethasone treatment in the RECOVERY trial [ 16 ]. Recently, Weng and colleagues claimed that patients with gastrointestinal sequelae at 90 days were treated more often with corticosteroids and proton pump inhibitors than were patients without such sequelae [ 32 ]. Hence, many researchers are cautious about its extensive use for critically ill patients. Based on results of previous studies in SARS patients, avascular necrosis and osteoporosis were more likely to occur among patients with higher-dose steroid therapy. For example, in a retrospective study of 539 patients with steroid treatment following SARS, the incidence of steroid-induced osteonecrosis of the femoral head (ONFH) was 24% [ 33 ]. Notably, all the meta-analyses found patients on corticosteroid treatment were more likely to have secondary infections such as bacterial infection, invasive fungal infection or exacerbation of pre-existing conditions [ 34 ]. Due to the immunosuppressive effect, a strong association exists between corticosteroid use and respiratory infectious disease (e.g., active tuberculosis and pulmonary aspergillosis) [ 35 , 36 ]. Similarly, Strongyloides hyperinfection/dissemination in low- and middle-income countries induced by dexamethasone treatment cannot be ignored [ 37 ]. Moreover, short-term or protracted dexamethasone therapy might contribute to other potential side effects, such as neuromuscular weakness, psychiatric symptoms and even iatrogenic Cushing syndrome [ 38 – 40 ].

Although dexamethasone is recommended in critical patients infected by COVID-19, it is essential for us to develop deeper insights into the potential damage of dexamethasone in view of the large number of patients. Therefore, we searched PubMed, Scopus, the Web of Science and Google Scholar up to April 2021 for papers on the effects of dexamethasone therapy on different organs and summarized current understanding of the mechanisms of complications and sequelae induced by dexamethasone in this review. This will assist medical professionals in managing COVID-19 patients treated with dexamethasone and directing post-acute and long-term follow-up. Additionally, we hope this will provide a valuable basis for future studies. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Musculoskeletal System

Long-term or excessive use of glucocorticoids is the most common non-traumatic cause of ONFH [ 41 , 42 ] and secondary osteoporosis [ 43 , 44 ] in patients (Fig. 1 ). Owing to the use of glucocorticoids during the SARS epidemic in 2003, some patients had varying degrees of ONFH [ 33 ], and the risk of ONFH showed an aggravating trend with the increase of cumulative doses and treatment durations of steroids in SARS patients [ 45 ]. In 2014, Guo et al. found that more male SARS patients (51/129, 40%) were diagnosed with ONFH compared to female patients (79/410, 19%) [ 33 ]. Recently, a large-scale global statistical analysis revealed that while males and females are at equivalent risk of SARS-CoV-2 infection, male sex is associated with a higher risk for the development of severe disease as measured by intensive therapy unit admission [ 46 ], which indicated that male patients are more likely to receive dexamethasone treatment and suffer from ONFH. Therefore, to further explore the risk of ONFH in COVID-19 patients, we sum up the mechanisms of dexamethasone-induced ONFH. Its pathogenesis is mainly related to the differentiation of mesenchymal stem cells (MSCs) and osteoblast apoptosis. MSCs have the potential to differentiate into cells of mesodermal lineage, such as adipocytes, osteocytes and chondrocytes [ 47 ]. Yin et al. proved that dexamethasone can directly induce MSCs to differentiate into adipocytes [ 48 ]. On the one hand, adipogenesis of MSCs leads to excessive accumulation of marrow fat and increased intraosseous pressure, thus inducing venous stasis, arterial obstruction and eventually ischemic osteonecrosis [ 48 , 49 ]. On the other hand, dexamethasone inhibits osteogenesis of stem cells, reducing the ability to reshape bone and repair necrotic bone and accounting for the onset of osteonecrosis [ 48 , 50 ]. In addition, previous studies have demonstrated that dexamethasone could induce apoptosis of MSCs in a time- and concentration-dependent manner, which is probably the mechanism of pathogenesis of steroid-induced ONFH [ 51 , 52 ]. Excessive use of dexamethasone can promote the apoptosis of osteoblasts through multiple signaling mechanisms. First, forkhead box transcription factor O1 (FOXO1) targets genes involved in apoptosis, autophagy and cell cycle arrest [ 53 ]. Dexamethasone could upregulate FOXO1 expression, inhibit the viability of osteoblasts and promote apoptosis [ 54 ]. Second, the phosphatidylinositol 3-kinase/protein kinase 3 (PI3K/AKT) signaling pathway controls many cellular functions by participating in the signal transduction pertaining to proliferation, survival and motility [ 55 ]. Dexamethasone can inhibit the activation of the PI3K/AKT pathway in osteoblasts by suppressing the expression of p-PI3K and p-AKT, thereby inducing osteoblast apoptosis [ 56 ]. Third, after dexamethasone treatment, the expression of glycogen synthase kinase 3β (GSK3β) in osteoblasts is significantly upregulated, which can induce mitochondrial apoptotic and lead to ONFH [ 56 , 57 ]. Zhu et al. claimed that miR-124 accumulation following circHIPK3 downregulation appears to be the primary mechanism of dexamethasone-induced cytotoxicity and programmed necrosis in human osteoblasts [ 58 ]. Therefore, to prevent dexamethasone-induced ONFH, corticosteroids should be applied only to patients in critical cases at low-to-moderate doses and short courses. In the 1st year after prescription of corticosteroids, patients with suspected ONFH should receive periodic magnetic resonance imaging examination during follow-up to diagnose and treat the disease in the early stage [ 59 ].

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [ 60 ]. As mentioned before, glucocorticoids cause apoptosis of osteoblasts and a depletion of the osteoblastic cell population, accounting for the reduction in bone formation and trabecular width [ 61 ]. On the flip side, following dexamethasone treatment, the decline in levels of the antiresorptive molecule osteoprotegerin and the increase in levels of the osteoclastogenesis-inducing molecule, the receptor activator of nuclear factor-κB ligand, promote bone resorption by osteoclasts [ 62 ]. Taken together, these changes lead to glucocorticoid-induced osteoporosis, mainly via reduced bone formation. More recently, there have been several discoveries of key proteins that have further increased our understanding of the molecular mechanism. Dexamethasone-induced osteoporosis can be caused by suppression of the canonical Wnt signal. Secreted frizzled-related proteins (SFRPs) could compete with membrane-bound frizzled proteins for Wnt binding [ 63 ], and dickkopf-1 (Dkk-1) also mediates the inhibition of Wnt signal [ 64 ]. Then, several studies have reported dexamethasone increases the expression of Dkk-1 and SFRP1 and represses Wnt/β-catenin signaling in human osteoblasts to reduce mineral density and trabecular bone volume [ 64 – 67 ]. Additionally, dexamethasone can downregulate the expression of matrix marker biglycan [ 68 ], and the lack of biglycan contributes to the reduction in trabecular bone volume, mineral deposition rate and bone formation rate [ 69 ].

Skeletal muscle atrophy occurs also as a side effect of dexamethasone treatment [ 70 , 71 ], leading to severe muscle weakness, inactivity and reduced quality of life for the patients [ 72 ]. In general, muscle atrophy results from the imbalance between protein synthesis and degradation. Qin et al. observed that the upregulation of myostatin gene expression caused by dexamethasone was associated with the myostatin gene promoter and glucocorticoid responsive element along the promoter [ 73 ], and the increased myostatin led to the changes in ultrastructure of skeletal muscle, including the inhibition of myoblast proliferation and induction of muscle atrophy [ 74 , 75 ]. Moreover, dexamethasone induces depletion of myosin heavy chain protein and the upregulation of muscle RING-finger protein-1 [ 70 , 76 ], which affects muscle integrity by increasing protein breakdown of an important component of the sarcomere and results in muscle atrophy [ 67 ]. Concomitantly, it has been reported that dexamethasone could induce mitochondrial dysfunction, bringing about ATP deprivation and subsequently AMP-activated protein kinase activation, which further activates the FOXO3/Atrogenes and ultimately leads to protein degradation as well as muscle atrophy [ 77 ].

Cardiovascular System

As a common cardiovascular disease, hypertension is also the most frequent comorbidity (51%) in COVID-19 patients, followed by diabetes (19%) and atrial fibrillation (11%) [ 78 ]. At the same time, patients with severe COVID-19 infection commonly have a history of hypertension. Wu et al. (2020) reported that compared with COVID-19 patients without ARDS, patients who developed ARDS had a higher proportion of comorbidities such as hypertension (14% and 27%, respectively) and diabetes (5% and 19%, respectively) [ 79 ]. In Italy, almost 75% of patients who have died from COVID-19 had hypertension [ 80 ]. It is worth noting that dexamethasone, the first drug shown to reduce deaths from the coronavirus disease [ 81 ], can induce hypertension in clinical studies (Table 1 ) and animal experiments (Table 2 ) through a variety of mechanisms [ 82 , 83 ]. On the one hand, dexamethasone enhances vasoconstriction. A recent study has found that dexamethasone increased synthesis of catecholamines by inducing the transcription of the rate-limiting enzyme tyrosine hydroxylase, and excessive catecholamine levels induce direct vasoconstriction [ 84 ]. Increasing calcium influx in vascular smooth muscle is also a way in which dexamethasone causes hypertension [ 85 ]. On the other hand, dexamethasone-induced hypertension is associated with reduction of vasodilating mediators such as prostacyclin, nitric oxide (NO) and hydrogen sulfide (H 2 S). There have been reports indicating that dexamethasone can inhibit the biosynthesis of prostaglandins via the inhibition of phospholipase A2 activity [ 86 – 88 ]. Schafer et al. claimed dexamethasone could reduce NO production by means of several mechanisms including induction of oxidative stress as well as downregulation of cationic amino acid transporter-1 and endothelial NO synthase [ 89 ]. H 2 S has been proposed as a candidate for endothelium-derived hyperpolarizing factor, involved in inducing vasodilation. H 2 S biosynthesis could be inhibited by dexamethasone via the impairment of cystathionine-β-synthase and cystathionine-γ-lyase expression [ 90 ]. The vascular endothelial glucocorticoid receptor (GR) plays a critical role in mediating blood pressure response to steroids [ 91 ]. Although there is no report confirming the use of dexamethasone in the treatment of COVID-19 leads to hypertension, we still suggest follow-up, evaluation and close monitoring of blood pressure after recovery from SARS-CoV-2 infection, especially for the hypertensive patients who received dexamethasone treatment. Table 1 Organ systems of human affected by dexamethasone treatment: symptoms and sequelae Organ system affected Symptom/sequelae Subjects’ characteristic Dosage Disease incidence Onset time Precaution/therapy Monitoring indicator or method References Musculoskeletal system Necrosis of the femoral head Multiple myeloma patients 16.7 mg/kg × 56 days (median) 7% 11.1 months (median) Bisphosphonates, vitamin E, anticoagulants and vasodilators MRI [ 42 , 59 ] Skeletal muscle atrophy Hemiplegic patients 24 mg/day × 4 days - Within 10 days 1. Physical exercises 2. Vitamin D and calcium supplementation 1. Urine creatine levels 2. Muscle biopsy 3. Ultrasonography [ 71 , 198 , 199 ] Cardiovascular system Hypertension Infants with a birth weight of 714–1920 g (median 1087 g) and CLD 0.6 mg/kg/day × 3 days + 0.3 mg/kg/day × 3 days + taper the dose over a 3-week period 41% Within 2 weeks Exercise training 1. Blood pressure 2. Electrocardiogram [ 82 , 83 , 200 , 201 ] Pediatric ALL patients 6 mg/m 2 /day × 5 days 6% 4 days Ventricular hypertrophy PI with a birth weight of 500–2054 g (median 815 g) 0.4–0.6 mg/kg/day × 3 weeks 94% 2–3 days 1. Curcumin 2. Statins 1. Echocardiogram 2. MiR‐30a, MiR‐181b, VEGF‐B [ 92 , 100 , 101 , 202 – 204 ] PI with CLD 0.5 mg/kg/day (taper in a standardized fashion over a total 42-day course) 57% Within 6 weeks PI with BPD 0.5 mg/kg/day (taper at successive 3-day intervals during the next 5 to 6 weeks) - Within 1 week Digestive system Bowel perforation PI with a birth weight of 501–1000 g 0.15 mg/kg/day × 3 days + 0.10 mg/kg/day × 3 days + 0.05 mg/kg/day × 2 days + 0.02 mg/kg/day × 2 days 13% Within 2 weeks 1. Oral PGE2 analogs 2. Breast feeding CT [ 124 , 205 , 206 ] Renal system Renal calcification PI with a birth weight of 440–990 g and CLD 3.8 mg/kg 83% 26 days - Sonography [ 130 , 131 ] Nervous system Persistent nerve injury Patients undergoing surgical procedures distal to the tibial meta-diaphyseal junction 3–4 mg 65% 2 weeks - Sensory neurological examination [ 149 ] Endocrine system Adrenal insufficiency Early B-cell lineage acute lymphoblastic leukemia patients 0.2 mg/kg/day × 28 days 100% 29 days Taper doses of glucocorticoids Adrenal stimulation testing [ 156 ] Diabetes Subjects are relatives of non-insulin-dependent diabetic patients 4 mg/day × 5 days 20% 4–5 days 1. Exercise, diet therapy and oral hypoglycemic drugs (blood glucose level < 200 mg/dl) 2. Insulin therapy (blood glucose level ≥ 200 mg/dl) 1. Plasma glucose and insulin concentrations 2. OGTT 3. IVGTT 4. Hemoglobin A1c tests [ 171 , 172 , 207 ] Non-diabetic patients with newly diagnosed gastrointestinal cancer 10–12 mg/day × 1 day + 7–8 mg/day × 2 days (+ 7-8 mg/day × 1 day) (administer every 2–4 weeks in at least three cycles) 22% 3 months MRI magnetic resonance imaging, CLD chronic lung disease, ALL acute lymphoblastic leukemia, PI preterm infants, BPD bronchopulmonary dysplasia, MiR microRNA, VEGF vascular endothelial growth factor, PGE2 prostaglandin E2, CT computed tomography, OGTT oral glucose tolerance test, IVGTT intravenous glucose tolerance test Table 2 Organ systems of animal models affected by dexamethasone treatment: symptoms and sequelae Organ system affected Symptom/sequela Species Dosage Onset time Pathogenic mechanism References Musculoskeletal system Osteoporosis Female mice (BALB/c) 1 mg/kg/day × 3 weeks 3 weeks Osteocalcin decrease and leptin increase [ 62 ] Female rats (Sprague-Dawley) 0.6 mg/kg/3 days × 12 weeks 12 weeks Biglycan, LRP5, OPG and RUNX2 downregulation; Col1α1 upregulation [ 68 ] Skeletal muscle atrophy Female mice (Kun-Ming) 20 mg/kg/day × 8 days 8 days Myostatin promoter activity upregulation [ 73 ] Male mice (C57BL/J) 5 mg/kg/day × 18 days 6 days Activation of AMPK/FOXO3/agtrogenes signaling [ 77 ] Cardiovascular system Hypertension Male rats (Fisher 344) 0.03, 0.3 or 3 mg/kg/day × 10 days 8, 6 or 5 days Increased transcription of TH [ 84 ] Male rabbits (New Zealand) 1000 mg/kg Within 6 weeks Increased transmembrane Ca 2+ in VSM [ 85 ] Neonatal rats (Wistar) 0.5 mg/kg + 0.3 mg/kg + 0.1 mg/kg 3 months - [ 127 ] Male rats (Wistar) 1.5 mg/kg/day × 8 days 2 days Impaired expression of CBS and CSE [ 90 ] Cardiac hypertrophy Female neonatal rats (Wistar) 0.5 mg/kg + 0.3 mg/kg + 0.1 mg/kg 45 weeks Increased promoter methylation in the CcnD2 gene [ 94 , 96 ] Neonatal rats (Wistar) 0.5 mg/kg + 0.3 mg/kg + 0.1 mg/kg Within 15 months - [ 127 ] Arrhythmias Male rats (Wistar) 2 mg/kg/day × 7 days 1 week Increased ROS generation [ 103 ] Diastolic dysfunction Male rats (Wistar) 35 mg/kg/day × 15 days 15 days Impaired calcium handling and calcineurin signaling pathway activation [ 102 ] Ocular system Glaucoma Mice (C57BL/6) 0.1% × (~ 20 μl) × 3 times/day × 20 weeks 20 weeks Myocilin, actin and ECM proteins increase [ 110 ] Digestive system Gastric ulceration Male rats (Wister) 1 mg/kg 26 h Inhibit prostaglandin synthetase and peroxidase [ 121 ] Renal system Chronic progressive glomerulonephritis Neonatal rats (Wistar) 0.5 mg/kg + 0.3 mg/kg + 0.1 mg/kg Within 15 months - [ 127 ] Glomerulosclerosis 32 weeks Accumulation of inflammatory factors [ 128 ] Renal fibrosis Reduction of nephron 8 and 24 weeks 4 weeks Suppression of mitotic activity [ 129 ] Nervous system Anxiety Male albino mice 10 mg/kg 0.5 h Dysregulation of the HPA axis [ 136 ] Male rats (Sprague-Dawley) 5 mg/kg/day × 7 days 1 week Excessive CREB phosphorylation and BDNF upregulation [ 138 ] Depressive behavior Male mice (C57BL/6 J) 4 mg/kg/day × 21 days 20 days GR mRNA decrease [ 137 ] Male mice (ICR) 60 mg/kg/day × 21 days 22 days GR protein expression reduction [ 143 ] Cerebral edema Male rats in SE (Sprague-Dawley) 2 mg/kg 2 days - [ 150 ] Rats with acidosis (Sprague-Dawley) 3 mg/kg 4 h AQP-1–mediated pathways [ 151 ] Endocrine system Adrenocortical atrophy Female rats (Wistar) 0.15 mg/kg/day × 7 days Within 1 week Inhibition of ACTH synthesis and secretion [ 160 ] Hyperglycemia Mice (C57BL/6 J) 1 mg/kg/2 days × 2 months Within 2 months GR/KLF9/PGC1α signaling pathway [ 181 ] Diabetes Rats (Wistar) 5 mg/kg/day × 24 days Within 5 days Insulin resistance [ 182 ] Female rats Zucker ( fa / fa ) 0.2–0.4 mg/kg × 24 days Promptly LRP-5 low-density lipoprotein5, OPG osteoprotegerin, RUNX2 runt-related transcription factor 2, AMPK AMP-activated protein kinase, FOXO3 forkhead box O 3, TH tyrosine hydroxylase, VSM vascular smooth muscle, CBS cystathionine-β-synthase, CSE cystathionine-γ-lyase, CcnD2 gene cyclinD2 gene, ROS reactive oxygen species, ECM extracellular matrix, HPA hypothalamic-pituitary-adrenal, CREB anti-cAMP responsive element binding protein, BDNF brain-derived neurotrophic factor, GR glucocorticoid receptor, SE status epilepticus, AQP-1 aquaporin-1, ACTH adreno-cortico-tropic-hormone, KLF9 Krüppel-like factor 9, PGC1α peroxisome proliferator-activated receptor γ coactivator 1 α

A clinical trial suggested retardation of heart growth among dexamethasone-treated infants compared with control infants [ 92 ]. Cardiomyocytes can only divide within a limited time after birth, and once the proliferation of cardiomyocytes is inhibited during this period, it will have a negative repercussion on the total number of cardiomyocytes later in life [ 93 ]. The use of dexamethasone in newborn rats increased promoter methylation in the cardiomyocytes CcnD2 gene, which causes the decrease of D2 protein and inhibition of cardiomyocyte proliferation [ 94 , 95 ]. Eventually, neonatal dexamethasone treatment in rat pups leads to a permanent decrease in heart weight, as well as reduced number, hypertrophy and early degeneration of cardiomyocytes during adult life [ 93 , 96 ]. Since most COVID-19-positive newborns are mildly affected with cases of severe disease being very rare [ 97 ] and dexamethasone is mainly shown to be effective against the novel coronavirus for severe patients, we believe that dexamethasone is not suitable for the overwhelming majority of neonates. During the treatment of 66 babies with SARS-CoV-2 infection in a UK survey, only 2 (3%) were treated with corticosteroids [ 97 ]. Meanwhile, we recently indicated that SARS-CoV-2 infection poses a great threat to pregnant women and fetuses [ 98 ], and according to the above survey, of total 66 neonates, 16 (25%) were premature babies [ 97 ]. Bensley et al. claimed that cardiomyocyte proliferation can be inhibited by premature birth, which may adversely affect heart growth, cardiac function, functional reserve and repair ability throughout postnatal life [ 99 ]. Therefore, dexamethasone treatment may bring about more serious damage to the heart in preterm infants [ 100 , 101 ].

Recent evidence suggests that dexamethasone treatment in adults could result in hypertension, pathologic cardiac remodeling, cardiac hypertrophy associated with maladaptive remodeling and ultimate ventricular dysfunction [ 102 , 103 ]. Cardiac hypertrophy, considered an adaptive response, allows heart to withstand glucocorticoid-induced hypertension [ 102 ]. Roy et al. (2009) and De et al. (2011) reported that excess of dexamethasone treatment could induce cardiac hypertrophy, myocardial fibrosis, hypoxia and ventricular dysfunction via angiotensin II signaling pathway [ 104 , 105 ]. Pathologic heart remodeling occurs at the same time as the enhanced collagen synthesis, which leads to interstitial fibrosis [ 104 ]. Fibrosis is directly responsible for reduced blood flow to the heart and increase in cell apoptosis [ 102 ]. Additionally, myocardial fibrosis increases the stiffness of the myocytes, causing systolic or diastolic disorders [ 106 ]. However, Macedo et al. demonstrated that a short-term therapeutic regimen of dexamethasone will not decrease ventricular contractility [ 103 ]. In terms of the effect of dexamethasone on heart rate, cardiac fibrosis impairs the electrical conduction and subsequent generation of reentry circuits [ 107 , 108 ]. By increasing sympathetic modulation, but reducing the parasympathetic one, dexamethasone induces autonomic imbalance, which may make the dexamethasone-treated animals more susceptible to develop harmful forms of ventricular arrhythmias through increasing reactive oxygen species generation [ 103 ].

Ocular System

Several ophthalmic complications, such as glaucoma and cataracts, have been demonstrated to be probably linked with the use of corticosteroids. Most patients (88%) with steroid-induced glaucoma experienced an increase in intraocular pressure (IOP), a major associated risk factor leading to glaucoma [ 109 ]. Similarly, the murine model of dexamethasone-induced glaucoma exhibited an elevation of IOP, structural and functional loss of retinal ganglion cells and axonal degeneration [ 110 ] (Table 2 ). This is mainly because dexamethasone treatment can increase the deposition of myocilin, actin and extracellular matrix proteins, which are relevant to the induction of endoplasmic reticulum stress. It may cause dysfunction of the trabecular meshwork, resulting in the elevated resistance to aqueous humor outflow and subsequent IOP [ 111 – 113 ].

The impact of corticosteroids on the incidence of cataracts remains a source of much controversy and considerable debate [ 114 ]. Posterior subcapsular cataract (PSC) has been reported in a few adults and children treated with beclomethasone dipropionate or dexamethasone aerosol, but the risk seems to be much lower than when taking these corticosteroids systemically [ 115 ]. Moreover, patients taking inhaled corticosteroids were observed to have a risk that appeared negligible, even if high doses were used [ 116 ]. Contrarily, another review claimed that exposure to inhaled corticosteroids increased the prevalence of PSC about twofold [ 117 ]. There is even a third view, which argues that no firm link exists between them [ 118 ]. Further research is necessary to help elucidate the association between dexamethasone treatment and the incidence of PSC.

Digestive System

Compared with SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2-induced adverse effects on the gastrointestinal tract are of particular concern [ 119 ]. Patients with COVID-19 were prone to develop gastrointestinal symptoms such as nausea and diarrhea, which still bothered 44% of COVID-19 survivors at 90 days after discharge from hospital [ 32 ], even lasting ≥ 6 months [ 120 ].

Even worse, it has been reported that dexamethasone makes the gastric mucosa susceptible to ulceration, but the mechanism of the ulcerogenic action remains controversial. Specifically, an earlier study indicated that dexamethasone diminishes gastroprotection and damages the mucosa by inhibiting the activity of prostaglandin synthetase and peroxidase, respectively [ 121 ]. However, Filaretova et al. held that long-lasting maintenance of blood glucose level accompanied by the signs of catabolic effects may be the reason for pathologic ulcerogenic caused by dexamethasone treatment [ 122 ].

By thinning the circumferential smooth muscle and making the bowel wall more vulnerable, dexamethasone could increase the risk of bowel perforation [ 123 ]. Stark et al. claimed that early treatment with dexamethasone has no effect on mortality or chronic lung disease but is associated with spontaneous gastrointestinal perforation and decreased growth in preterm infants [ 124 ]. In addition, dexamethasone inhibits small intestinal growth via both increased degradation and decreased synthesis of protein [ 125 ]. When dexamethasone was given to growing rats, there was a significant decrease in the weights of the stomach, small intestine and colon [ 126 ].

Renal System

Neonatal dexamethasone treatment might increase the risk of renal damage in adulthood. The number of glomeruli and kidney weight were lower in neonatal rats with dexamethasone administration, and the kidneys showed signs of chronic progressive glomerulonephritis with glomerulosclerosis and extensive renal fibrosis, presumably because of an early inflammatory trigger that elicits a persistent pro-fibrotic process [ 127 – 129 ]. On the other hand, in clinical studies, dexamethasone could contribute to renal calcification formation by increasing urinary calcium excretion [ 130 ], with nephrocalcinosis occurring in 15 (83%) of 18 infants [ 131 ] (Table 1 ).

Nervous System

A survey of 402 adults surviving COVID-19 revealed that 42% of them suffered from anxiety, 40% from insomnia, 31% from depression, 28% from post-traumatic stress disorder and 20% from obsessive-compulsive symptoms, while females and younger patients suffered from higher levels of depression and sleep disturbances [ 132 ]. These psychiatric consequences can result from one or several combined factors. Due to the neurotropic properties with neuroinvasive activity [ 133 ], SARS-CoV-2 could induce neuronal injuries via directly infecting the central nervous system. Besides, cytokine storm involved in the immune response to coronaviruses may cause neuroinflammation, which indirectly leads to psychopathologic sequelae [ 134 ]. Simultaneously, the psychological impact of patients’ fear of severe illness with a very high risk of death, uncertainty about future, stigma, traumatic memories of severe illness and social isolation in an intensive care unit setting cannot be ignored [ 132 , 135 ].

Similarly, dexamethasone treatment can be associated with neuropsychiatric diseases and neurotoxicity. Peripheral administration of dexamethasone induces biphasic effects on anxiety-related behaviors: anxiolytic effects at low and anxiogenic effects at high doses [ 136 ]. According to a report from the US Food and Drug Administration, about 4% of 50,000 dexamethasone users had developed severe anxiety as an adverse effect of therapy [ 137 ]. A finding has indicated that hyperphosphorylation of cAMP-responsive element-binding protein and reduced expression of brain-derived neurotrophic factor in the cerebral cortex might be involved in high levels of anxiety-like behavior in dexamethasone-treated rats [ 138 ]. Besides, dexamethasone-treated mice demonstrated a host of depression-like behaviors, such as increased time of immobility in the forced swim test and a reduced preference for saccharin consumption. The following mechanisms are considered: first, dexamethasone treatment can cause insufficient cell energy supply through glucose inhibition [ 139 ], thereby affecting the regulation of glutamate release and reuptake. Calcium-dependent proteases, triggered by increased glutamate-mediated transmission, could cause degeneration of cytoskeletal proteins and lipases, possibly generating free radicals [ 140 ], which leads to neuronal damage and depression [ 141 ]. The second possible explanation is the hyperfunction of the hypothalamic-pituitary-adrenal axis (HPAA) caused by dexamethasone treatment, which is mainly attributed to the decreased GR mRNA [ 137 ] and protein [ 142 , 143 ] expressions and consequent impairment of GR-mediated negative feedback [ 144 ]. The raised level of cortisol in the blood will exacerbate depression by impairing brain functions, such as neuronal survival, neuronal excitability, neurogenesis and memory acquisition [ 144 ]. Notably, Skupio et al. have found that the co-chaperone FK506 binding protein 51 and serum-and glucocorticoid-inducible-kinase-1 proteins increased in the prefrontal cortex, hippocampus and striatum of mice treated with dexamethasone [ 137 ], which could regulate GR sensitivity [ 145 ], mediate glucocorticoid effects on neuronal function and contribute to major depressive disorder [ 146 ].

It is worth mentioning that peripheral nerve block is often used for postoperative analgesia; however, the pain relief lasts only a few hours [ 147 ]. As dexamethasone could prolong the analgesic duration by inducing vasoconstriction, it has been used in peripheral nerve block as an adjuvant [ 148 ]. By contrast, a recent study reported a twofold increased risk of persistent neurologic symptoms when perineural dexamethasone was applied after foot and ankle surgery [ 149 ] (Table 1 ). Besides, dexamethasone is widely used in clinics for alleviating cerebral edema. However, Duffy et al. (2014) found that after status epilepticus induced by lithium-pilocarpine, regional administration of dexamethasone (2 mg/kg) led to increased transverse magnetization relaxation time at 2 days and reduced hippocampal volumes at 3 weeks, representing aggravated cerebral edema and brain injury, respectively [ 150 ]. Another study observed that under acidotic conditions, dexamethasone also worsened the cerebral edema, which could be attenuated by selective blockage of aquaporin-1 channels with HgCl 2 [ 151 ]. Therefore, although recent studies demonstrated dexamethasone could slow Huntington’s disease progression [ 152 ] and showed protective effects against Parkinson [ 153 ] and Alzheimer’s disease-related cognitive impairments in mice [ 154 ], there is an urgent need to continue to monitor the potential influence of dexamethasone administration on mental state and damage to nerves when it is used in COVID-19 patients.

Endocrine System

A range of mechanisms that contributes to endocrine disorders has been reported in association with the use of dexamethasone, one of the most unpredictable of which is the inhibition of the HPAA. Dexamethasone mainly binds to GRs in the pituitary, where it inhibits the expression of proopiomelanocortin as well as secretion of adreno-cortico-tropic-hormone (ACTH) and subsequent adrenocortical cortisol [ 155 , 156 ]. Simultaneously, compared with other preparations with shorter half-lives, dexamethasone, as the most effective ACTH suppressant with a longer half-life, can lead to more serious HPAA inhibition [ 157 , 158 ]. For example, in cancer patients receiving chemotherapy, adrenal response suppression and adrenal insufficiency have been reported after dexamethasone use [ 156 , 159 ] (Table 1 ). Additionally, low-dose dexamethasone administered chronically could give rise to partial adrenocortical atrophy in rats [ 160 ]. There is evidence that the suppressive effects of dexamethasone at the hypothalamic-pituitary level are not only confined to ACTH, but the serum levels of thyroid-stimulating hormone (TSH) and prolactin (PRL) could be reduced by directly restraining the anterior pituitary [ 161 ]. Dexamethasone also attenuates the stimulation of the release of TSH and PRL by thyroid-releasing hormone [ 161 ]. Concurrently, there is a decrease in serum-3, 3′, 5-triiodothyronine (T3) and thyroxine (T4) serum levels with dexamethasone treatment, which is probably the consequence of the inhibitory effect of dexamethasone on TSH secretion by the pituitary, and a direct inhibitory effect on thyroid release of T3 and T4 cannot be neglected [ 161 ]. Therefore, more detailed studies are needed to better determine the mechanism involved in these effects.

Changes in growth hormone (GH), insulin-like growth factor (IGF), melatonin and parathyroid hormone levels are associated with dexamethasone-induced endocrine disorders. Jux et al. demonstrated that GH- or IGF-1-stimulated growth plate chondrocyte growth is dose-dependently blunted by dexamethasone [ 162 ]. Melatonin is considered an output signal mediated by the circadian system. Dexamethasone could diminish melatonin synthesis by reducing the expression of the key enzymes such as tryptophan hydroxylase, arylalkylamine N-acetyltransferase and hydroxyindole- O -methyltransferase [ 163 ]. In parallel, previous studies have found that dexamethasone can increase parathyroid hormone synthesis, which may be an important pathogenic role in persisting hyperparathyroidism [ 164 , 165 ].

It is well known that in skeletal muscle and adipocytes, insulin stimulates the translocation of glucose transporter (GLUT) 4 from intracellular vesicles to the cell membrane for glucose uptake [ 166 ]. As soon as insulin binds to its receptor, the receptor undergoes tyrosine phosphorylation and recruits insulin receptor substrates (IRSs) for tyrosine phosphorylation. Once phosphorylated, IRSs bind to and activate PI3K, acting as a molecular switch to phosphorylate downstream protein kinase B (PKB) [ 167 ]. Akt substrate of 160 kDa (also called AS160 or TBC1D4), which is phosphorylated by activated PKB, plays a crucial role in regulating GLUT4 transport [ 168 ]. In addition, PKB could inhibit glycogen synthase (GS) activity by mediating glycogen synthase kinase 3 (GSK-3) phosphorylation [ 169 , 170 ].

Dexamethasone, as an exogenous glucocorticoid, can significantly influence the glucose metabolism in the human body [ 171 , 172 ]. (1) In adipocytes, dexamethasone treatment affects the normal absorption of glucose by reducing the expression level of GLUT1 protein. Meanwhile, dexamethasone therapy decreases PKB expression and insulin-stimulated phosphorylation and downregulates GS expression in adipocytes [ 166 ]. In muscle, treatment with dexamethasone can not only reduce insulin-mediated PI3K and PKB activation but also increase the phosphorylation sites of GS [ 173 , 174 ]. Besides, under dexamethasone treatment, the insulin-stimulated GLUT4 translocation to the cell surface decreases without altering the GLUT4 protein in total lysates in muscle and adipose tissue [ 175 , 176 ]. All of these may lead to a decrease in insulin-stimulated glucose uptake, which causes insulin resistance (IR). (2) Moreover, it has been reported that elevated plasma free fatty acids (FFAs) could induce IR [ 177 ], and dexamethasone increases FFA content by interfering with fatty acid metabolism [ 166 ]. Studies have found that long-term incubation of soleus muscle strips with FFAs impaired insulin-stimulated PKB and reduced glucose uptake and glycogen synthesis [ 178 ]. Another possible mechanism involves peroxisome proliferator-activated receptor (PPAR) [ 179 ], a transcription factor activated by FFA, and Bernal-Mizrachi et al. have proven that human hepatocytes treated with dexamethasone induced PPARA gene expression and identified hepatic activation of PPAR-α as a mechanism underlying dexamethasone-induced IR [ 180 ]. Therefore, the increase in circulating FFA caused by dexamethasone use may make an important contribution to muscle IR [ 166 ]. (3) Furthermore, our previous work suggests that dexamethasone induces the expression of Krüppel-like factor 9 (KLF9) in the liver, which plays a critical role in the regulation of hepatic glucose metabolism. KLF9 may regulate IR via KLF9/PGC1α/TRB-3 signaling pathway and promote hepatic gluconeogenesis and hyperglycemia. Conversely, the lack of KLF9 alleviated hyperglycemia induced by dexamethasone treatment [ 181 ]. Then, due to the impaired function of insulin-stimulated glucose uptake in peripheral tissues and/or the weakened effect of insulin to suppress the liver from producing endogenous glucose, dexamethasone-induced IR can result in hyperglycemia and diabetes [ 182 ], the current common side effects in acute care settings such as emergency rooms and urgent care centers [ 180 , 183 ]. (4) In addition, Guo et al. found that dexamethasone could induce apoptosis of pancreatic β cells through activation of GSK-3β [ 184 ].

Diabetes has seriously affected the prognosis of patients with COVID-19, and according to data from Wuhan, compared with non-diabetic patients, diabetic patients have more complications and shorter overall survival time [ 185 ]. Possible explanations for this phenomenon are as follows: (1) generally, infectious diseases are more common and/or severe in diabetic patients since the hyperglycemic environment can lead to immune dysfunction, vascular disease, neuropathy and decrease in antibacterial activity of the digestive tract [ 186 ]. (2) Acute hyperglycemia has been shown to upregulate the expression of angiotensin-converting enzyme (ACE) 2 while chronic hyperglycemia reduces ACE2 expression [ 187 ]. Recently, Wijnant et al. demonstrated increased expression of ACE2 protein in the bronchi and alveoli of diabetic patients may affect the infectivity and clinical outcome of COVID-19 [ 188 ]. (3) In the case of uncontrolled hyperglycemia, the abnormally increased glycosylation of glycosylated ACE2 and the viral spike protein may promote the virus binding and inflammation [ 189 ]. (4) The fourth underlying mechanism that may explain the link between COVID-19 and diabetes involves dipeptidyl peptidase-4 (DPP-4/CD26) [ 190 ], acting as a potential receptor for SARS-CoV-2 [ 191 ]. Compared with nondiabetic subjects, DPP4 expression is enhanced on blood T lymphocytes from type 2 diabetic patients [ 192 ]. Interestingly, in 2019, Kulcsar et al. found the diabetic DPP4 H/M mice, which could express human DPP4 in the nonciliated epithelial cells and alveolar type 2 cells, exhibited more severe clinical symptoms characterized by a prolonged period of weight loss and clinical disease with a delay in the initiation of inflammation in the lung and slower inflammatory resolution after infection with MERS-CoV [ 193 ]. In addition, researchers discovered that COVID-19 may also cause hyperglycemia. The potential pathways are as follows: (1) ACE2 is expressed at high levels in pancreatic islet cells [ 194 ], and in 2003 SARS produced a transient impairment of pancreatic islet cell function. Similarly, SARS-CoV-2 may also impair β-cell insulin secretion, causing hyperglycemia, or exacerbate pre-existing diabetes [ 195 ]. (2) COVID-19 infection is accompanied by increases of many cytokines, which can induce or exacerbate IR [ 196 ].

In summary, dexamethasone has a remarkable effect on glucose homeostasis in the body, accounting for hyperglycemia and diabetes, which are risk factors for COVID-19 and adversely affect prognosis. Simultaneously, COVID-19 infection can contribute to hyperglycemia. Based on the above evidence, we make the following recommendations. (1) Blood sugar changes of COVID-19 patients treated with dexamethasone should be strictly monitored. After stopping dexamethasone therapy, IR will fall. Therefore, it is necessary to adjust insulin dose to avoid hypoglycemia. (2) More and more type 2 diabetes patients may have an increased risk for pronounced inflammatory responses, including cytokine storms, so screening for excessive inflammation is essential to improve the prognosis. (3) Regular follow-up is crucial for preventing new-onset diabetes, which may be caused by the virus and dexamethasone, and hemoglobin A1c (HbA1c), a glycosylated hemoglobin formed by the specific binding of glucose to the N-terminal valine of the hemoglobin β chain, is recommended as an annual assessment indicator for this process [ 197 ].

Conclusion

In conclusion, the impacts of COVID-19 are not just confined to the lungs, but lead to the involvement of almost all the organs of the body, including heart, brain, kidney and intestines. While dexamethasone can reduce the mortality in treating critically ill patients with COVID-19, consequences for various organ systems have also been reported. Through a variety of molecular pathways, dexamethasone can interfere with normal organ functions and cause numerous clinical manifestations, which may further intensify the risk and severity of sequelae of COVID-19 infection, such as ONFH, hypertension and diabetes. Hence, we suggest close monitoring of blood pressure, HbA1c and other necessary parameters when managing COVID-19 patients treated with dexamethasone and taking timely measures. Furthermore, regular follow-up and evaluation of physical conditions according to the monitoring indicators provided in this article are crucial for patients after recovery from SARS-CoV-2 infection. Fig. 1 Organ systems affected by dexamethasone and the side effects or sequelae

Acknowledgements

Funding

This work was supported by the Natural Science Foundation of Shandong Province (grant no. ZR2020QC100) and Innovation and Entrepreneurship Training Program for College Students of Jining Medical University (grant no. cx2019033). The Rapid Service Fee was funded by the Natural Science Foundation of Shandong Province (grant no. ZR2020QC100) and Innovation and Entrepreneurship Training Program for College Students of Jining Medical University (grant no. cx2019033).

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

Author Contributions

Chen F conceived the idea, analyzed the data, and drafted the manuscript; Hao L, Zhu S and Yang X contributed towards the conception, wrote part of the article; Shi W, Zheng K, Wang T and Chen H proofread the manuscript and contributed to editing; all authors provided critical review and approved the final manuscript before submission.

Disclosures

Fei Chen, Lanting Hao, Shiheng Zhu, Xinyuan Yang, Wenhao Shi, Kai Zheng, Tenger Wang and Huiran Chen have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References

1. World Health Organization. WHO Coronavirus Disease (COVID19) Dashboard 2021. https://covid19.who.int/ . Accessed 20 Apr 2021.

2. Ianiro G Porcari S Settanni CR Letter: prevalence and patterns of gastrointestinal symptoms in a large Western cohort of patients with COVID-19 Aliment Pharmacol Ther 2020 52 902 903 32852826 10.1111/apt.15946 PMC7436583

3. Lou JJ Movassaghi M Gordy D Neuropathology of COVID-19 (neuro-COVID): clinicopathological update Free Neuropathol 2021 2 2 33554218 10.17879/freeneuropathology-2021-2993 PMC7861505

4. Zhou F Yu T Du R Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Lancet 2020 395 1054 1062 32171076 10.1016/S0140-6736(20)30566-3 PMC7270627

5. Ombrello MJ Schulert GS COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome? Transl Res 2021 10.1016/j.trsl.2021.03.002 33684592 PMC7934701

6. Sahu KK Cerny J A review on how to do hematology consults during COVID-19 pandemic Blood Rev 2021 47 100777 33199084 10.1016/j.blre.2020.100777 PMC7648889

7. Di Gennaro F Vittozzi P Gualano G Active pulmonary tuberculosis in elderly patients: A 2016–2019 retrospective analysis from an Italian referral hospital Antibiotics 2020 9 489 10.3390/antibiotics9080489 PMC7459440 32784552

8. Di Castelnuovo A Bonaccio M Costanzo S Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study Nutr Metab Cardiovasc Dis 2020 30 1899 1913 32912793 10.1016/j.numecd.2020.07.031 PMC7833278

9. Di Gennaro F Marotta C Storto M SARS-CoV-2 transmission and outcome in neuro-rehabilitation patients hospitalized at neuroscience hospital in Italy Mediterr J Hematol Infect Dis 2020 12 e2020063 32952974 10.4084/MJHID.2020.063 PMC7485473

10. Di Castelnuovo A Costanzo S Antinori A Heparin in COVID-19 patients is associated with reduced in-hospital mortality: the multicenter Italian CORIST Study Thromb Haemost 2021 10.1055/a-1347-6070 33412596

11. Wang Y Zhang D Du G Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial Lancet 2020 395 1569 1578 32423584 10.1016/S0140-6736(20)31022-9 PMC7190303

12. Rosenberg ES Dufort EM Udo T Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State JAMA 2020 323 2493 2502 32392282 10.1001/jama.2020.8630 PMC7215635

13. Alghamdi AN Abdel-Moneim AS Convalescent plasma: a potential life-saving therapy for Coronavirus Disease 2019 (COVID-19) Front Public Health 2020 8 437 32903641 10.3389/fpubh.2020.00437 PMC7438749

14. Ingraham NE Lotfi-Emran S Thielen BK Immunomodulation in COVID-19 Lancet Respir Med 2020 8 544 546 32380023 10.1016/S2213-2600(20)30226-5 PMC7198187

15. Consortium WHOST, Pan H, Peto R, et al. Repurposed antiviral drugs for Covid-19—Interim WHO solidarity trial results. N Engl J Med. 2021;384:497–511. 10.1056/NEJMoa2023184 PMC7727327 33264556

16. Group RC Horby P Lim WS Dexamethasone in hospitalized patients with Covid-19 N Engl J Med 2021 384 693 704 32678530 10.1056/NEJMoa2021436 PMC7383595

17. Xinhua. Trial finds therapeutics including remdesivir have 'little or no' effect on COVID-19 patients: WHO. 2020. http://www.xinhuanet.com/english/2020-10/17/c_139446018.htm . Accessed 20 Jan 2021.

18. Franco LM Gadkari M Howe KN Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses J Exp Med 2019 216 384 406 30674564 10.1084/jem.20180595 PMC6363437

19. Giles AJ Hutchinson MND Sonnemann HM Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy J Immunother Cancer 2018 6 51 29891009 10.1186/s40425-018-0371-5 PMC5996496

20. Cain DW Cidlowski JA After 62 years of regulating immunity, dexamethasone meets COVID-19 Nat Rev Immunol 2020 20 587 588 32778829 10.1038/s41577-020-00421-x PMC7416654

21. Heise N Shumilina E Nurbaeva MK Effect of dexamethasone on Na+/Ca2+ exchanger in dendritic cells Am J Physiol Cell Physiol 2011 300 C1306 C1313 21307349 10.1152/ajpcell.00396.2010

22. Rhen T Cidlowski JA Antiinflammatory action of glucocorticoids–new mechanisms for old drugs N Engl J Med 2005 353 1711 1723 16236742 10.1056/NEJMra050541

23. Huang C Wang Y Li X Clinical features of patients infected with 2019 novel coronavirus in Wuhan China Lancet 2020 395 497 506 31986264 10.1016/S0140-6736(20)30183-5 PMC7159299

24. Abdin SM Elgendy SM Alyammahi SK Alhamad DW Omar HA Tackling the cytokine storm in COVID-19, challenges and hopes Life Sci 2020 257 118054 32663575 10.1016/j.lfs.2020.118054 PMC7832727

25. Prentice RE Al-Ani A Christensen B Managing COVID-19 in patients with inflammatory bowel disease: navigating unprecedented challenges Intern Med J 2021 51 284 287 33631857 10.1111/imj.15190 PMC8013000

26. Sulaiman KA, Alhubaishi A, Juhani OA, et al. Early versus late use of dexamethasone in critically ill patients with covid-19: a multicenter, prospective cohort study. Research Square. 2021. 10.21203/rs.3.rs-349677/v1.

27. World Health Organization. Therapeutics and COVID-19: living guideline, 31 March 2021. No. WHO/2019-nCoV/therapeutics/2021.1. 2021. https://apps.who.int/iris/bitstream/handle/10665/340374/WHO-2019-nCoV-therapeutics-2021.1-eng.pdf?sequence=1 . Accessed 30 Apr 2021.

28. Tang C Wang Y Lv H Guan Z Gu J Caution against corticosteroid-based COVID-19 treatment Lancet 2020 395 1759 1760 32464115 10.1016/S0140-6736(20)30749-2 PMC7247780

29. Shang L Zhao J Hu Y Du R Cao B On the use of corticosteroids for 2019-nCoV pneumonia Lancet 2020 395 683 684 32122468 10.1016/S0140-6736(20)30361-5 PMC7159292

30. Russell CD Millar JE Baillie JK Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Lancet 2020 395 473 475 32043983 10.1016/S0140-6736(20)30317-2 PMC7134694

31. Rayman G Lumb AN Kennon B Dexamethasone therapy in COVID-19 patients: implications and guidance for the management of blood glucose in people with and without diabetes Diabetic Med 2021 38 e14378 32740972 10.1111/dme.14378 PMC7436853

32. Weng J Li Y Li J Gastrointestinal sequelae 90 days after discharge for COVID-19 Lancet Gastroenterol Hepatol 2021 6 344 346 33711290 10.1016/S2468-1253(21)00076-5 PMC7943402

33. Guo KJ Zhao FC Guo Y Li FL Zhu L Zheng W The influence of age, gender and treatment with steroids on the incidence of osteonecrosis of the femoral head during the management of severe acute respiratory syndrome: a retrospective study Bone Jt J. 2014 96-B 259 262 10.1302/0301-620X.96B2.31935 24493194

34. Ni YN Chen G Sun J Liang BM Liang ZA The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis Crit Care 2019 23 99 30917856 10.1186/s13054-019-2395-8 PMC6437920

35. Dixit D Kuete NT Bene P Khan I Oprea-Ilies G Flenaugh E invasive pulmonary aspergillosis with hydropneumothorax in a patient taking high-dose glucocorticoids Am J Case Rep. 2020 21 e928499 33361740 10.12659/AJCR.928499 PMC7774990

36. Gopalaswamy R Subbian S Corticosteroids for COVID-19 therapy: potential implications on tuberculosis Int J Mol Sci 2021 22 3773 33917321 10.3390/ijms22073773 PMC8038708

37. Olivera MJ Dexamethasone and COVID-19: strategies in low- and middle-income countries to Tackle steroid-related strongyloides hyperinfection Am J Trop Med Hyg 2021 10.4269/ajtmh.20-1085 33720844 PMC8103443

38. Mishra GP Mulani J Corticosteroids for COVID-19: the search for an optimum duration of therapy Lancet Respir Med 2021 9 e8 33248469 10.1016/S2213-2600(20)30530-0 PMC7836750

39. Dutta D Shivaprasad KS Ghosh S Mukhopadhyay S Chowdhury S Iatrogenic Cushing's syndrome following short-term intranasal steroid use J Clin Res Pediatr Endocrinol 2012 4 157 159 22985615 10.4274/Jcrpe.726 PMC3459166

40. Hughes JM Hichens M Booze GW Thorner MO Cushing's syndrome from the therapeutic use of intramuscular dexamethasone acetate Arch Intern Med 1986 146 1848 1849 3753129

41. Kerachian MA Seguin C Harvey EJ Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action J Steroid Biochem Mol Biol 2009 114 121 128 19429441 10.1016/j.jsbmb.2009.02.007 PMC7126235

42. Wu X Geng C Sun W Tan M Incidence and risk factors of osteonecrosis of femoral head in multiple myeloma patients undergoing dexamethasone-based regimens Biomed Res Int 2020 2020 7126982 32509867 10.1155/2020/7126982 PMC7246411

43. den Uyl D Bultink IE Lems WF Advances in glucocorticoid-induced osteoporosis Curr Rheumatol Rep 2011 13 233 240 21365209 10.1007/s11926-011-0173-y PMC3092927

44. Weinstein RS Clinical practice. Glucocorticoid-induced bone disease N Engl J Med 2011 365 62 70 21732837 10.1056/NEJMcp1012926

45. Zhao R Wang H Wang X Feng F Steroid therapy and the risk of osteonecrosis in SARS patients: a dose-response meta-analysis Osteoporos Int 2017 28 1027 1034 27844132 10.1007/s00198-016-3824-z PMC7079838

46. Peckham H de Gruijter NM Raine C Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission Nat Commun 2020 11 6317 33298944 10.1038/s41467-020-19741-6 PMC7726563

47. Uccelli A Moretta L Pistoia V Mesenchymal stem cells in health and disease Nat Rev Immunol 2008 8 726 736 19172693 10.1038/nri2395

48. Yin L Li YB Wang YS Dexamethasone-induced adipogenesis in primary marrow stromal cell cultures: mechanism of steroid-induced osteonecrosis Chin Med J 2006 119 581 588 16620700

49. Atsumi T Kuroki Y Role of impairment of blood supply of the femoral head in the pathogenesis of idiopathic osteonecrosis Clin Orthop Relat Res 1992 277 22 30 1372850

50. Ma L Feng X Wang K Song Y Luo R Yang C Dexamethasone promotes mesenchymal stem cell apoptosis and inhibits osteogenesis by disrupting mitochondrial dynamics FEBS Open Bio 2019 10 211 220 31788976 10.1002/2211-5463.12771 PMC6996403

51. Oshina H Sotome S Yoshii T Effects of continuous dexamethasone treatment on differentiation capabilities of bone marrow-derived mesenchymal cells Bone 2007 41 575 583 17690025 10.1016/j.bone.2007.06.022

52. Fan Q Zhan X Li X Zhao J Chen Y Vanadate inhibits dexamethasone-induced apoptosis of rat bone marrow-derived mesenchymal stem cells Ann Clin Lab Sci 2015 45 173 180 25887871

53. Wang S Xia P Huang G FoxO1-mediated autophagy is required for NK cell development and innate immunity Nat Commun 2016 7 11023 27010363 10.1038/ncomms11023 PMC4820827

54. Xing L Zhang X Feng H Silencing FOXO1 attenuates dexamethasone-induced apoptosis in osteoblastic MC3T3-E1 cells Biochem Biophys Res Commun 2019 513 1019 1026 31010677 10.1016/j.bbrc.2019.04.112

55. Guntur AR Rosen CJ The skeleton: a multi-functional complex organ: new insights into osteoblasts and their role in bone formation: the central role of PI3Kinase J Endocrinol 2011 211 123 130 21673026 10.1530/JOE-11-0175 PMC3348869

56. Deng S Dai G Chen S Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/GSK3beta signaling pathway Biomed Pharmacother 2019 110 602 608 30537677 10.1016/j.biopha.2018.11.103

57. Nie Z Chen S Peng H Glucocorticoid induces osteonecrosis of the femoral head in rats through GSK3beta-mediated osteoblast apoptosis Biochem Biophys Res Commun 2019 511 693 699 30827503 10.1016/j.bbrc.2019.02.118

58. Zhu CY Yao C Zhu LQ She C Zhou XZ Dexamethasone-induced cytotoxicity in human osteoblasts is associated with circular RNA HIPK3 downregulation Biochem Biophys Res Commun 2019 516 645 652 31242973 10.1016/j.bbrc.2019.06.073

59. Zhang B Zhang S Corticosteroid-induced osteonecrosis in COVID-19: a call for caution J Bone Miner Res 2020 35 1828 1829 32697000 10.1002/jbmr.4136 PMC7404412

60. Peck WA Burkhardt P Christiansen C Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis Am J Med 1993 94 646 650 8506892 10.1016/0002-9343(93)90218-e

61. Weinstein RS Jilka RL Parfitt AM Manolagas SC Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone J Clin Investig 1998 102 274 282 9664068 10.1172/JCI2799 PMC508885

62. McLaughlin F Mackintosh J Hayes BP Glucocorticoid-induced osteopenia in the mouse as assessed by histomorphometry, microcomputed tomography, and biochemical markers Bone 2002 30 924 930 12052464 10.1016/s8756-3282(02)00737-8

63. Wang S Krinks M Lin K Luyten FP Moos M Jr Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8 Cell 1997 88 757 766 9118219 10.1016/s0092-8674(00)81922-4

64. Ohnaka K Tanabe M Kawate H Nawata H Takayanagi R Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts Biochem Biophys Res Commun 2005 329 177 181 15721290 10.1016/j.bbrc.2005.01.117

65. Wang FS Lin CL Chen YJ Secreted frizzled-related protein 1 modulates glucocorticoid attenuation of osteogenic activities and bone mass Endocrinology 2005 146 2415 2423 15677765 10.1210/en.2004-1050

66. Ohnaka K Taniguchi H Kawate H Nawata H Takayanagi R Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis Biochem Biophys Res Commun 2004 318 259 264 15110782 10.1016/j.bbrc.2004.04.025

67. Krishnan V Bryant HU Macdougald OA Regulation of bone mass by Wnt signaling J Clin Investig 2006 116 1202 1209 16670761 10.1172/JCI28551 PMC1451219

68. Ren H Liang D Jiang X Variance of spinal osteoporosis induced by dexamethasone and methylprednisolone and its associated mechanism Steroids 2015 102 65 75 26216207 10.1016/j.steroids.2015.07.006

69. Xu T Bianco P Fisher LW Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice Nat Genet 1998 20 78 82 9731537 10.1038/1746

70. Clarke BA Drujan D Willis MS The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle Cell Metab 2007 6 376 385 17983583 10.1016/j.cmet.2007.09.009

71. Moukas M Vassiliou MP Amygdalou A Mandragos C Takis F Behrakis PK Muscular mass assessed by ultrasonography after administration of low-dose corticosteroids and muscle relaxants in critically ill hemiplegic patients Clin Nutr 2002 21 297 302 12135589 10.1054/clnu.2001.0532

72. Aguilar-Agon KW Capel AJ Fleming JW Player DJ Martin NRW Lewis MP Mechanical loading of tissue engineered skeletal muscle prevents dexamethasone induced myotube atrophy J Muscle Res Cell Motil 2020 10.1007/s10974-020-09589-0 32955689 PMC8332579

73. Qin J Du R Yang YQ Dexamethasone-induced skeletal muscle atrophy was associated with upregulation of myostatin promoter activity Res Vet Sci 2013 94 84 89 22939086 10.1016/j.rvsc.2012.07.018

74. Thomas M Langley B Berry C Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation J Biol Chem 2000 275 40235 40243 10976104 10.1074/jbc.M004356200

75. Zimmers TA Davies MV Koniaris LG Induction of cachexia in mice by systemically administered myostatin Science 2002 296 1486 1488 12029139 10.1126/science.1069525

76. Chromiak JA Vandenburgh HH Glucocorticoid-induced skeletal muscle atrophy in vitro is attenuated by mechanical stimulation Am J Physiol 1992 262 C1471 C1477 1616011 10.1152/ajpcell.1992.262.6.C1471

77. Liu J Peng Y Wang X Mitochondrial dysfunction launches dexamethasone-induced skeletal muscle atrophy via AMPK/FOXO3 signaling Mol Pharm 2016 13 73 84 26592738 10.1021/acs.molpharmaceut.5b00516

78. Rodilla E Saura A Jimenez I Association of hypertension with all-cause mortality among hospitalized patients with COVID-19 J Clin Med 2020 9 3136 10.3390/jcm9103136 PMC7650567 32998337

79. Wu C Chen X Cai Y Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China JAMA Intern Med 2020 180 934 943 32167524 10.1001/jamainternmed.2020.0994 PMC7070509

80. Kreutz R Algharably EAE Azizi M Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19 Cardiovasc Res 2020 116 1688 1699 32293003 10.1093/cvr/cvaa097 PMC7184480

81. Ledford H Steroid is first drug shown to prevent deaths from Covid-19 Nature 2020 582 469 32546811 10.1038/d41586-020-01824-5

82. Warris LT van den Akker EL Bierings MB Acute activation of metabolic syndrome components in pediatric acute lymphoblastic leukemia patients treated with dexamethasone PLoS ONE 2016 11 e0158225 27362350 10.1371/journal.pone.0158225 PMC4928792

83. Smets K Vanhaesebrouck P Dexamethasone associated systemic hypertension in low birth weight babies with chronic lung disease Eur J Pediatr 1996 155 573 575 8831080 10.1007/BF01957907

84. Soto-Pina AE Franklin C Rani CS Gottlieb H Hinojosa-Laborde C Strong R A novel model of dexamethasone-induced hypertension: use in investigating the role of tyrosine hydroxylase J Pharmacol Exp Ther 2016 358 528 536 27405316 10.1124/jpet.116.234005

85. Kornel L Prancan AV Kanamarlapudi N Hynes J Kuzianik E Study on the mechanisms of glucocorticoid-induced hypertension: glucocorticoids increase transmembrane Ca2+ influx in vascular smooth muscle in vivo Endocr Res 1995 21 203 210 7588382 10.3109/07435809509030436

86. Flower RJ Blackwell GJ Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation Nature 1979 278 456 459 450050 10.1038/278456a0

87. Hirata F Schiffmann E Venkatasubramanian K Salomon D Axelrod J A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids Proc Natl Acad Sci USA 1980 77 2533 2536 6930649 10.1073/pnas.77.5.2533 PMC349435

88. Russo-Marie F Duval D Dexamethasone-induced inhibition of prostaglandin production dose not result from a direct action on phospholipase activities but is mediated through a steroid-inducible factor Biochem Biophys Acta 1982 712 177 185 6810945 10.1016/0005-2760(82)90100-x

89. Schafer SC Wallerath T Closs EI Dexamethasone suppresses eNOS and CAT-1 and induces oxidative stress in mouse resistance arterioles Am J Physiol Heart Circ Physiol 2005 288 H436 H444 15598872 10.1152/ajpheart.00587.2004

90. d'Emmanuele di Villa Bianca R, Mitidieri E, Donnarumma E, et al. Hydrogen sulfide is involved in dexamethasone-induced hypertension in rat. Nitric Oxide Biol Chem. 2015;46:80–6. 10.1016/j.niox.2014.11.013 25461303

91. Goodwin JE Zhang J Gonzalez D Albinsson S Geller DS Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension J Hypertens 2011 29 1347 1356 21659825 10.1097/HJH.0b013e328347da54 PMC3439131

92. Werner JC Sicard RE Hansen TW Solomon E Cowett RM Oh W Hypertrophic cardiomyopathy associated with dexamethasone therapy for bronchopulmonary dysplasia J Pediatr 1992 120 286 291 1735831 10.1016/s0022-3476(05)80446-9

93. de Vries WB, Bal MP, Homoet-van der Kraak P, et al. Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment. Basic Res Cardiol. 2006;101:36–42. 10.1007/s00395-005-0557-0 16283594

94. Gay MS Li Y Xiong F Lin T Zhang L Dexamethasone treatment of newborn rats decreases cardiomyocyte endowment in the developing heart through epigenetic modifications PLoS ONE 2015 10 e0125033 25923220 10.1371/journal.pone.0125033 PMC4414482

95. Gay MS Dasgupta C Li Y Kanna A Zhang L Dexamethasone induces cardiomyocyte terminal differentiation via epigenetic repression of Cyclin D2 Gene J Pharmacol Exp Ther 2016 358 190 198 27302109 10.1124/jpet.116.234104 PMC4959091

96. de Vries WB van der Leij FR Bakker JM Alterations in adult rat heart after neonatal dexamethasone therapy Pediatr Res 2002 52 900 906 12438668 10.1203/00006450-200212000-00015

97. Gale C Quigley MA Placzek A Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance Lancet Child Adolesc Health 2021 5 113 121 33181124 10.1016/S2352-4642(20)30342-4 PMC7818530

98. Jing Y Run-Qian L Hao-Ran W Potential influence of COVID-19/ACE2 on the female reproductive system Mol Hum Reprod 2020 26 367 373 32365180 10.1093/molehr/gaaa030 PMC7239105

99. Bensley JG Moore L De Matteo R Harding R Black MJ Impact of preterm birth on the developing myocardium of the neonate Pediatr Res 2018 83 880 888 29278645 10.1038/pr.2017.324

100. Skelton R Gill AB Parsons JM Cardiac effects of short course dexamethasone in preterm infants Arch Dis Child Fetal Neonatal Ed 1998 78 F133 F137 9577285 10.1136/fn.78.2.f133 PMC1720762

101. Israel BA Sherman FS Guthrie RD Hypertrophic cardiomyopathy associated with dexamethasone therapy for chronic lung disease in preterm infants Am J Perinatol 1993 10 307 310 8397569 10.1055/s-2007-994747

102. de Salvi GF de Moraes WM Bozi LH Dexamethasone-induced cardiac deterioration is associated with both calcium handling abnormalities and calcineurin signaling pathway activation Mol Cell Biochem 2017 424 87 98 27761848 10.1007/s11010-016-2846-3

103. Macedo FN Souza DS Araujo J NOX-dependent reactive oxygen species production underlies arrhythmias susceptibility in dexamethasone-treated rats Free Radical Biol Med 2020 152 1 7 32147395 10.1016/j.freeradbiomed.2020.03.005

104. Roy SG De P Mukherjee D Excess of glucocorticoid induces cardiac dysfunction via activating angiotensin II pathway Cell Physiol Biochem 2009 24 1 10 19590187 10.1159/000227803

105. De P Roy SG Kar D Bandyopadhyay A Excess of glucocorticoid induces myocardial remodeling and alteration of calcium signaling in cardiomyocytes J Endocrinol 2011 209 105 114 21282255 10.1530/JOE-10-0431

106. Weber KT Brilla CG Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system Circulation 1991 83 1849 1865 1828192 10.1161/01.cir.83.6.1849

107. van den Borne SW Diez J Blankesteijn WM Verjans J Hofstra L Narula J Myocardial remodeling after infarction: the role of myofibroblasts Nat Rev Cardiol 2010 7 30 37 19949426 10.1038/nrcardio.2009.199

108. Landstrom AP Dobrev D Wehrens XHT Calcium signaling and cardiac arrhythmias Circ Res 2017 120 1969 1993 28596175 10.1161/CIRCRESAHA.117.310083 PMC5607780

109. Rahayu NK Emily A Clinical profile of steroid-induced glaucoma in Bali Mandara Eye Hospital year 2019 Intisari Sains Med 2021 12 6 8

110. Zode GS Sharma AB Lin X Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma J Clin Investig 2014 124 1956 1965 24691439 10.1172/JCI69774 PMC4001532

111. Wordinger RJ Clark AF Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma Prog Retin Eye Res 1999 18 629 667 10438153 10.1016/s1350-9462(98)00035-4

112. Johnson D Gottanka J Flugel C Hoffmann F Futa R Lutjen-Drecoll E Ultrastructural changes in the trabecular meshwork of human eyes treated with corticosteroids Arch Ophthalmol 1997 115 375 383 9076211 10.1001/archopht.1997.01100150377011

113. Marciniak SJ Ron D Endoplasmic reticulum stress signaling in disease Physiol Rev 2006 86 1133 1149 17015486 10.1152/physrev.00015.2006

114. Langarizadeh MA Ranjbar Tavakoli M Abiri A Ghasempour A Rezaei M Ameri A A review on function and side effects of systemic corticosteroids used in high-grade COVID-19 to prevent cytokine storms EXCLI J 2021 20 339 365 33746666 10.17179/excli2020-3196 PMC7975631

115. Barnes PJ Pedersen S Efficacy and safety of inhaled corticosteroids in asthma. Report of a workshop held in Eze, France, October 1992 Am Rev Respir Dis 1993 148 S1 26 8214958 10.1164/ajrccm/148.4_Pt_2.S1

116. Hanania NA Chapman KR Kesten S Adverse effects of inhaled corticosteroids Am J Med 1995 98 196 208 7847437 10.1016/S0002-9343(99)80404-5

117. Cumming RG Mitchell P Leeder SR Use of inhaled corticosteroids and the risk of cataracts N Engl J Med 1997 337 8 14 9203425 10.1056/NEJM199707033370102

118. Dahl R Systemic side effects of inhaled corticosteroids in patients with asthma Respir Med 2006 100 1307 1317 16412623 10.1016/j.rmed.2005.11.020

119. Renu K Prasanna PL Valsala GA Coronaviruses pathogenesis, comorbidities and multi-organ damage—a review Life Sci 2020 255 117839 32450165 10.1016/j.lfs.2020.117839 PMC7243768

120. Huang C Huang L Wang Y 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study Lancet 2021 397 220 232 33428867 10.1016/S0140-6736(20)32656-8 PMC7833295

121. Bandyopadhyay U Biswas K Bandyopadhyay D Ganguly CK Banerjee RK Dexamethasone makes the gastric mucosa susceptible to ulceration by inhibiting prostaglandin synthetase and peroxidase–two important gastroprotective enzymes Mol Cell Biochem 1999 202 31 36 10705992 10.1023/a:1007018212822

122. Filaretova L Podvigina T Bagaeva T Morozova O Dual action of glucocorticoid hormones on the gastric mucosa: how the gastroprotective action can be transformed to the ulcerogenic one Inflammopharmacology 2009 17 15 22 19139829 10.1007/s10787-008-8046-3

123. Gordon PV Price WA Stiles AD Dexamethasone administration to newborn mice alters mucosal and muscular morphology in the ileum and modulates IGF-I localization Pediatr Res 2001 49 93 100 11134498 10.1203/00006450-200101000-00020

124. Stark AR Carlo WA Tyson JE Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network N Engl J Med 2001 344 95 101 11150359 10.1056/NEJM200101113440203

125. Burrin DG Wester TJ Davis TA Fiorotto ML Chang X Dexamethasone inhibits small intestinal growth via increased protein catabolism in neonatal pigs Am J Physiol 1999 276 E269 E277 9950786 10.1152/ajpendo.1999.276.2.E269

126. Read LC Tomas FM Howarth GS Insulin-like growth factor-I and its N-terminal modified analogues induce marked gut growth in dexamethasone-treated rats J Endocrinol 1992 133 421 431 1613443 10.1677/joe.0.1330421

127. Kamphuis PJ de Vries WB Bakker JM Reduced life expectancy in rats after neonatal dexamethasone treatment Pediatr Res 2007 61 72 76 17211144 10.1203/01.pdr.0000249980.95264.dd

128. Liu Y van Goor H Havinga R Neonatal dexamethasone administration causes progressive renal damage due to induction of an early inflammatory response Am J Physiol Renal Physiol 2008 294 F768 F776 18234956 10.1152/ajprenal.00163.2007

129. de Vries WB van den Borne P Goldschmeding R Neonatal dexamethasone treatment in the rat leads to kidney damage in adulthood Pediatr Res 2010 67 72 76 19745785 10.1203/PDR.0b013e3181bf570d

130. Kamitsuka MD Williams MA Nyberg DA Fox KA Lee DL Hickok D Renal calcification: a complication of dexamethasone therapy in preterm infants with bronchopulmonary dysplasia J Perinatol 1995 15 359 363 8576746

131. Cranefield DJ Odd DE Harding JE Teele RL High incidence of nephrocalcinosis in extremely preterm infants treated with dexamethasone Pediatr Radiol 2004 34 138 142 14624322 10.1007/s00247-003-1090-7

132. Mazza MG De Lorenzo R Conte C Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors Brain Behav Immun 2020 89 594 600 32738287 10.1016/j.bbi.2020.07.037 PMC7390748

133. Flores G. SARS-COV-2 (COVID-19) has neurotropic and neuroinvasive properties. Int J Clin Pract. 2021;75:e13708. 10.1111/ijcp.13708 32935417

134. Netland J Meyerholz DK Moore S Cassell M Perlman S Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2 J Virol 2008 82 7264 7275 18495771 10.1128/JVI.00737-08 PMC2493326

135. Brooks SK Webster RK Smith LE The psychological impact of quarantine and how to reduce it: rapid review of the evidence Lancet 2020 395 912 920 32112714 10.1016/S0140-6736(20)30460-8 PMC7158942

136. Vafaei AA Rashidy-Pour A Taherian AA Peripheral injection of dexamethasone modulates anxiety related behaviors in mice: an interaction with opioidergic neurons Pak J Pharm Sci 2008 21 285 289 18614426

137. Skupio U Tertil M Sikora M Golda S Wawrzczak-Bargiela A Przewlocki R Behavioral and molecular alterations in mice resulting from chronic treatment with dexamethasone: relevance to depression Neuroscience 2015 286 141 150 25433240 10.1016/j.neuroscience.2014.11.035

138. Park DI Kim HG Jung WR Shin MK Kim KL Mecamylamine attenuates dexamethasone-induced anxiety-like behavior in association with brain derived neurotrophic factor upregulation in rat brains Neuropharmacology 2011 61 276 282 21530554 10.1016/j.neuropharm.2011.04.013

139. Sapolsky RM The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death Biol Psychiat 2000 48 755 765 11063972 10.1016/s0006-3223(00)00971-9

140. McIntosh LJ Sapolsky RM Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture Exp Neurol 1996 141 201 206 8812153 10.1006/exnr.1996.0154

141. Haynes LE Barber D Mitchell IJ Chronic antidepressant medication attenuates dexamethasone-induced neuronal death and sublethal neuronal damage in the hippocampus and striatum Brain Res 2004 1026 157 167 15488477 10.1016/j.brainres.2004.05.117

142. Unemura K Kume T Kondo M Maeda Y Izumi Y Akaike A Glucocorticoids decrease astrocyte numbers by reducing glucocorticoid receptor expression in vitro and in vivo J Pharmacol Sci 2012 119 30 39 22641130 10.1254/jphs.12047fp

143. Ruksee N Tongjaroenbuangam W Mahanam T Govitrapong P Melatonin pretreatment prevented the effect of dexamethasone negative alterations on behavior and hippocampal neurogenesis in the mouse brain J Steroid Biochem Mol Biol 2014 143 72 80 24589478 10.1016/j.jsbmb.2014.02.011

144. Anacker C Zunszain PA Carvalho LA Pariante CM The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 2011 36 415 425 20399565 10.1016/j.psyneuen.2010.03.007 PMC3513407

145. Binder EB The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders Psychoneuroendocrinology 2009 34 Suppl 1 S186 S195 19560279 10.1016/j.psyneuen.2009.05.021

146. Dattilo V Amato R Perrotti N Gennarelli M The emerging role of SGK1 (serum- and glucocorticoid-regulated kinase 1) in major depressive disorder: hypothesis and mechanisms Front Genet 2020 11 826 32849818 10.3389/fgene.2020.00826 PMC7419621

147. Choi S Rodseth R McCartney CJ Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials Br J Anaesth 2014 112 427 439 24413428 10.1093/bja/aet417

148. Vieira PA Pulai I Tsao GC Manikantan P Keller B Connelly NR Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade Eur J Anaesthesiol 2010 27 285 288 20009936 10.1097/EJA.0b013e3283350c38

149. Gagne OJ Cheema A Abuhantash M Effect of dexamethasone in peripheral nerve blocks on recovery of nerve function Foot Ankle Int 2021 42 23 30 32964737 10.1177/1071100720952075

150. Duffy BA Chun KP Ma D Lythgoe MF Scott RC Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus Neurobiol Dis 2014 63 229 236 24333865 10.1016/j.nbd.2013.12.001 PMC3905166

151. Tran ND Kim S Vincent HK Aquaporin-1-mediated cerebral edema following traumatic brain injury: effects of acidosis and corticosteroid administration J Neurosurg 2010 112 1095 1104 19731985 10.3171/2009.8.JNS081704

152. Maheshwari M Bhutani S Das A Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease Hum Mol Genet 2014 23 2737 2751 24381308 10.1093/hmg/ddt667

153. Joshi N Singh S Updates on immunity and inflammation in Parkinson disease pathology J Neurosci Res 2018 96 379 390 29072332 10.1002/jnr.24185

154. Hui Z Zhijun Y Yushan Y The combination of acyclovir and dexamethasone protects against Alzheimer's disease-related cognitive impairments in mice Psychopharmacology 2020 237 1851 1860 32221697 10.1007/s00213-020-05503-1

155. Zobel AW Nickel T Sonntag A Uhr M Holsboer F Ising M Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. A prospective study J Psychiatric Res. 2001 35 83 94 10.1016/s0022-3956(01)00013-9 11377437

156. Felner EI Thompson MT Ratliff AF White PC Dickson BA Time course of recovery of adrenal function in children treated for leukemia J Pediatr 2000 137 21 24 10891816 10.1067/mpd.2000.107385

157. Paragliola RM Papi G Pontecorvi A Corsello SM Treatment with synthetic glucocorticoids and the hypothalamus-pituitary-adrenal axis Int J Mol Sci 2017 18 2201 10.3390/ijms18102201 PMC5666882 29053578

158. Helfer EL Rose LI Corticosteroids and adrenal suppression. Characterising and avoiding the problem Drugs 1989 38 838 845 2689140 10.2165/00003495-198938050-00008

159. Han HS Shim YK Kim JE A pilot study of adrenal suppression after dexamethasone therapy as an antiemetic in cancer patients Support Care Cancer 2012 20 1565 1572 21850416 10.1007/s00520-011-1248-z

160. Lesniewska B Nowak KW Malendowicz LK Dexamethasone-induced adrenal cortex atrophy and recovery of the gland from partial, steroid-induced atrophy Exp Clin Endocrinol 1992 100 133 139 1339031 10.1055/s-0029-1211193

161. Sowers JR Carlson HE Brautbar N Hershman JM Effect of dexamethasone on prolactin and TSH responses to TRH and metoclopramide in man J Clin Endocrinol Metab 1977 44 237 241 402375 10.1210/jcem-44-2-237

162. Jux C Leiber K Hugel U Dexamethasone impairs growth hormone (GH)-stimulated growth by suppression of local insulin-like growth factor (IGF)-I production and expression of GH- and IGF-I-receptor in cultured rat chondrocytes Endocrinology 1998 139 3296 3305 9645706 10.1210/endo.139.7.6099

163. Meneses-Santos D Buonfiglio DDC Peliciari-Garcia RA Chronic treatment with dexamethasone alters clock gene expression and melatonin synthesis in rat pineal gland at night Nat Sci Sleep 2018 10 203 215 30046256 10.2147/NSS.S158602 PMC6054274

164. Sugimoto T Brown AJ Ritter C Morrissey J Slatopolsky E Martin KJ Combined effects of dexamethasone and 1,25-dihydroxyvitamin D3 on parathyroid hormone secretion in cultured bovine parathyroid cells Endocrinology 1989 125 638 641 2546741 10.1210/endo-125-2-638

165. Peraldi MN Rondeau E Jousset V Dexamethasone increases preproparathyroid hormone messenger RNA in human hyperplastic parathyroid cells in vitro Eur J Clin Invest 1990 20 392 397 2121498 10.1111/j.1365-2362.1990.tb01875.x

166. Buren J Lai YC Lundgren M Eriksson JW Jensen J Insulin action and signalling in fat and muscle from dexamethasone-treated rats Arch Biochem Biophys 2008 474 91 101 18328801 10.1016/j.abb.2008.02.034

167. Shepherd PR Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues Acta Physiol Scand 2005 183 3 12 15654916 10.1111/j.1365-201X.2004.01382.x

168. Ramm G Larance M Guilhaus M James DE A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160 J Biol Chem 2006 281 29174 29180 16880201 10.1074/jbc.M603274200

169. McManus EJ Sakamoto K Armit LJ Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis EMBO J 2005 24 1571 1583 15791206 10.1038/sj.emboj.7600633 PMC1142569

170. Cohen P Dissection of the protein phosphorylation cascades involved in insulin and growth factor action Biochem Soc Trans 1993 21 Pt 3 555 567 8224471 10.1042/bst0210555

171. Henriksen JE Alford F Ward GM Beck-Nielsen H Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients Diabetologia 1997 40 1439 1448 9447952 10.1007/s001250050847

172. Jeong Y Han HS Lee HD A pilot study evaluating steroid-induced diabetes after antiemetic dexamethasone therapy in chemotherapy-treated cancer patients Cancer Res Treat 2016 48 1429 1437 26987397 10.4143/crt.2015.464 PMC5080830

173. Saad MJ Folli F Kahn JA Kahn CR Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats J Clin Investig 1993 92 2065 2072 7691892 10.1172/JCI116803 PMC288376

174. Ruzzin J Wagman AS Jensen J Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor Diabetologia 2005 48 2119 2130 16078016 10.1007/s00125-005-1886-0

175. Sakoda H Ogihara T Anai M Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction Diabetes 2000 49 1700 1708 11016454 10.2337/diabetes.49.10.1700

176. Weinstein SP, Wilson CM, Pritsker A, Cushman SW. Dexamethasone inhibits insulin-stimulated recruitment of GLUT4 to the cell surface in rat skeletal muscle. Metab Clin Exp. 1998;47:3–6. 10.1016/s0026-0495(98)90184-6 9440469

177. Chalkley SM Hettiarachchi M Chisholm DJ Kraegen EW Long-term high-fat feeding leads to severe insulin resistance but not diabetes in Wistar rats Am J Physiol Endocrinol Metab 2002 282 E1231 E1238 12006352 10.1152/ajpendo.00173.2001

178. Thompson AL Lim-Fraser MY Kraegen EW Cooney GJ Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro Am J Physiol Endocrinol Metab 2000 279 E577 E584 10950825 10.1152/ajpendo.2000.279.3.E577

179. Berger J Moller DE The mechanisms of action of PPARs Annu Rev Med 2002 53 409 435 11818483 10.1146/annurev.med.53.082901.104018

180. Bernal-Mizrachi C Weng S Feng C Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice Nat Med 2003 9 1069 1075 12847522 10.1038/nm898

181. Cui A Fan H Zhang Y Dexamethasone-induced Kruppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia J Clin Investig 2019 129 2266 2278 31033478 10.1172/JCI66062 PMC6546458

182. Ogawa A Johnson JH Ohneda M Roles of insulin resistance and beta-cell dysfunction in dexamethasone-induced diabetes J Clin Investig 1992 90 497 504 1644920 10.1172/JCI115886 PMC443126

183. Villar J Ferrando C Martinez D Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial Lancet Respir Med 2020 8 267 276 32043986 10.1016/S2213-2600(19)30417-5

184. Guo B Zhang W Xu S Lou J Wang S Men X GSK-3beta mediates dexamethasone-induced pancreatic beta cell apoptosis Life Sci 2016 144 1 7 26606859 10.1016/j.lfs.2015.11.017 PMC4703461

185. Shang J Wang Q Zhang H The relationship between diabetes mellitus and COVID-19 prognosis: a retrospective cohort Study in Wuhan, China Am J Med 2021 134 e6 e14 32653423 10.1016/j.amjmed.2020.05.033 PMC7350644

186. Casqueiro J Casqueiro J Alves C Infections in patients with diabetes mellitus: a review of pathogenesis Indian J Endocrinol Metab 2012 16 Suppl 1 S27 36 22701840 10.4103/2230-8210.94253 PMC3354930

187. Bornstein SR Rubino F Khunti K Practical recommendations for the management of diabetes in patients with COVID-19 Lancet Diabetes Endocrinol 2020 8 546 550 32334646 10.1016/S2213-8587(20)30152-2 PMC7180013

188. Wijnant SRA Jacobs M Van Eeckhoutte HP Expression of ACE2, the SARS-CoV-2 receptor, in lung tissue of patients with Type 2 diabetes Diabetes 2020 69 2691 2699 33024003 10.2337/db20-0669

189. Brufsky A Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic J Med Virol 2020 92 770 775 32293710 10.1002/jmv.25887 PMC7262330

190. Iacobellis G COVID-19 and diabetes: can DPP4 inhibition play a role? Diab Res Clin Pract 2020 162 108125 10.1016/j.diabres.2020.108125 PMC7271223 32224164

191. Vankadari N Wilce JA Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26 Emerg Microbes Infect 2020 9 601 604 32178593 10.1080/22221751.2020.1739565 PMC7103712

192. Lee SA Kim YR Yang EJ CD26/DPP4 levels in peripheral blood and T cells in patients with type 2 diabetes mellitus J Clin Endocrinol Metab 2013 98 2553 2561 23539735 10.1210/jc.2012-4288

193. Kulcsar KA Coleman CM Beck SE Frieman MB Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection JCI Insight. 2019 4 1774 10.1172/jci.insight.131774 PMC6824443 31550243

194. Yang JK Lin SS Ji XJ Guo LM Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes Acta Diabetol 2010 47 193 199 19333547 10.1007/s00592-009-0109-4 PMC7088164

195. Maddaloni E Buzzetti R Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics Diab Metab Res Rev 2020 36 e33213321 10.1002/dmrr.3321 PMC7228318 32233018

196. Ceriello A De Nigris V Prattichizzo F Why is hyperglycaemia worsening COVID-19 and its prognosis? Diabetes Obes Metab 2020 22 1951 1952 32463166 10.1111/dom.14098 PMC7283840

197. Little RR Roberts WL A review of variant hemoglobins interfering with hemoglobin A1c measurement J Diabetes Sci Technol 2009 3 446 451 20144281 10.1177/193229680900300307 PMC2769887

198. Cielen N Maes K Gayan-Ramirez G Musculoskeletal disorders in chronic obstructive pulmonary disease BioMed Res Int 2014 2014 965764 24783225 10.1155/2014/965764 PMC3982416

199. Dekhuijzen PN Decramer M Steroid-induced myopathy and its significance to respiratory disease: a known disease rediscovered Eur Respir J 1992 5 997 1003 1426209

200. Herrera NA Jesus I Shinohara AL Dionisio TJ Santos CF Amaral SL Exercise training attenuates dexamethasone-induced hypertension by improving autonomic balance to the heart, sympathetic vascular modulation and skeletal muscle microcirculation J Hypertens 2016 34 1967 1976 27434101 10.1097/HJH.0000000000001032

201. Bird K Chan G Lu H Assessment of hypertension using clinical electrocardiogram features: a first-ever review Front Med 2020 7 583331 10.3389/fmed.2020.583331 PMC7746856 33344473

202. Habibi E Esmaeeli H A review of the effects of curcumin on histone acetyltransferase activity in the prevention of cardiac hypertrophy J Babol Univ Med Sci. 2017 19 27 35

203. Liao JK Statin therapy for cardiac hypertrophy and heart failure J Investig Med 2004 52 248 253 15521546 10.1136/jim-52-04-33 PMC2662037

204. Zhu L Li C Liu Q Xu W Zhou X Molecular biomarkers in cardiac hypertrophy J Cell Mol Med 2019 23 1671 1677 30648807 10.1111/jcmm.14129 PMC6378174

205. Ng PC Brownlee KG Dear PR Gastroduodenal perforation in preterm babies treated with dexamethasone for bronchopulmonary dysplasia Arch Dis Child 1991 66 1164 1166 1750771 10.1136/adc.66.10_spec_no.1164 PMC1590277

206. Lee NK Kim S Hong SB CT diagnosis of non-traumatic gastrointestinal perforation: an emphasis on the causes Jpn J Radiol 2020 38 101 111 31848888 10.1007/s11604-019-00910-7

207. Tamez-Perez HE Quintanilla-Flores DL Rodriguez-Gutierrez R Gonzalez-Gonzalez JG Tamez-Pena AL Steroid hyperglycemia: prevalence, early detection and therapeutic recommendations: a narrative review World J Diabetes 2015 6 1073 1081 26240704 10.4239/wjd.v6.i8.1073 PMC4515447