Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

After completing this article, readers should be able to: Corticosteroids are the most potent, naturally occurring anti-inflammatory agents known. Despite more than 50 years of controversy regarding their clinical use, risks, and benefits, corticosteroids still play a significant role in the management of a wide variety of diseases. They have reduced the morbidity and mortality significantly in children afflicted with leukemia, asthma, rheumatic diseases, and other inflammatory disorders. In this article, we review the mechanism of action, clinical indications, and adverse effects of corticosteroids and other commonly used immunosuppressive agents in children. We also review immunization recommendations for children receiving immunosuppressive therapy.Corticosteroids have a diverse role in the human body at the physiologic level. The actions of glucocorticoids include: 1) negative feedback modulation of corticotropin-releasing factor and adrenocorticotropic hormone; 2) regulation of blood glucose and liver glycogen levels; 3) maintenance of water-electrolyte homeostasis; 4) influence on the metabolism of protein, fat, and purine; 5) maintenance of normal cardiovascular, central nervous system (CNS), and renal functions; 6) influence on circadian rhythmicity; 7) maintenance of bone and muscle work capacity; and 8) protection of the body against moderate stress. Glucocorticoids also have pharmacologic properties that are used in the treatment of rheumatic and other inflammatory diseases.Cellular receptors for cortisol are ubiquitous in cell cytoplasm, reflecting the critical role of the hormone in maintaining cell homeostasis. The type 1 glucocorticoid receptor, known as the mineralocorticoid receptor, has high affinity for aldosterone. The type 2 glucocorticoid receptor, known as the glucocorticoid receptor, exhibits strong affinity for dexamethasone. Although the differential function of these two receptors is not understood fully, it is speculated that type 1 receptors primarily regulate basal functions such as circadian rhythmicity, whereas type 2 receptors respond to stress levels of corticosteroids.Corticosteroids suppress inflammation and have immunosuppressive effects that are mediated through inhibition of: 1) the early stages of inflammation such as edema, fibrin disposition, capillary dilatation, migration of lymphocytes into inflamed tissues, and phagocytic activity; and 2) the late stages such as proliferation of capillaries and fibroblasts and the deposition of collagen. Corticosteroids are believed to reduce the production of arachidonic acid that serves as a substrate for cyclooxygenase-2 without affecting cyclooxygenase-1.Corticosteroids inhibit macrophage and T-helper type 1 cell production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-2, IL-12, interferon-gamma, granulocyte-macrophage colony-stimulating factor, and to a lesser extent, IL-4, IL-10, and transforming growth factor-beta. Both TNF-alpha and IL-1 exert a number of inflammatory actions, including production of prostaglandin E2 and collagenase, activation of T lymphocytes, stimulation of fibroblast proliferation, and induction of hepatic synthesis of acute-phase reactants. Corticosteroids also inhibit the action of humoral regulators of inflammation, such as platelet-activating factor and macrophage migration inhibition factor. In addition, corticosteroids inhibit expression of adhesion molecules directly and indirectly through inhibitory effects on cytokines such as TNF-alpha and IL-1.Through many of the previously noted mediators, corticosteroids inhibit the cellular cascade of inflammation and immune response at any given level. They cause an increase in neutrophil and monocyte migration to the inflammatory site; macrophage antigen presentation to lymphocytes; and lymphocyte proliferation, activation, and differentiation to effector cells, particularly T-helper cells, cytotoxic lymphocytes, natural killer cells, and immature B cells.The effect of corticosteroids on neutrophils and other nonlymphoid cells such as monocytes, macrophages, eosinophils, mast cells, and dendritic cells is significant. The circulating monocytes and macrophages (including Langerhans and dendritic cells) are reduced markedly, and eosinophils significantly diminished from the blood and sites of allergic reactions. Corticosteroids inhibit neutrophil migration into inflammatory sites, although they increase circulating neutrophils by as much as two- to four-fold.Corticosteroids have a profound effect on cell migration of lymphocytes. Administration of a single dose of corticosteroid results in a marked but transient lymphopenia due to redistribution of all lymphocyte populations to other body compartments, especially to the bone marrow. T lymphocytes are affected more than are B lymphocytes, and low doses of corticosteroids have little effect on immunoglobulin levels or on antigen-stimulated antibody production. Under the influence of corticosteroids, certain activated lymphocyte subpopulations may be susceptible to lysis and apoptosis. Immature cortical thymic lymphocytes are more sensitive to corticosteroid-induced apoptosis than are mature lymphocytes.Nonimmunomodulatory effects are not related directly to the immunomodulatory effects of corticosteroids and can affect the patient adversely. Corticosteroids have a catabolic effect on protein, leading to its breakdown to form carbohydrate, which results in a negative nitrogen balance, muscle wasting, and impaired wound healing. Growth suppression that occurs in children receiving chronic steroid therapy is mediated by effects on protein, bone, and growth hormone. In addition, corticosteroids stimulate glucose synthesis, diminish its peripheral utilization, and increase glycogen deposition. This facilitates insulin resistance, impaired glucose tolerance, and occasional overt diabetes. Treatment with high or moderate doses of corticosteroids in children results in weight gain due to both fat redistribution and increased appetite. In addition, sodium and water retention occur in children receiving long-term steroid therapy. To minimize this effect, the glucocorticoid analogs used today have been modified to reduce their mineralocorticoid potency.Although corticosteroids are powerful anti-inflammatory agents, long-term systemic high-daily dose therapy is associated with substantial adverse effects (Table 1). The goal in corticosteroid therapy should be to limit the dose to the lowest possible level and the duration to the minimum necessary to achieve clinical disease control. The adverse effects of corticosteroid therapy are summarized in Table 2. Most of the adverse effects are dose-related and result from prolonged exposure to high doses of systemic corticosteroids. Short courses of corticosteroids (<2 wk), even with high doses, are associated with minimal risk of toxicity. By contrast, patients receiving high doses of steroids, such as 1 to 2 mg/kg per day of prednisone, for 3 months or more eventually suffer significant adverse effects. Withdrawal of therapy after prolonged use of large doses of corticosteroids can result in acute adrenal insufficiency.Signs and symptoms of cushingoid appearance (moon face, truncal obesity, and "buffalo" hump), obesity, and hypertension are seen commonly among children receiving prolonged moderate- to high-dose steroid therapy (1 to 2 mg/kg per day for more than 3 mo). Many skin changes are of minor clinical importance but can be disturbing to the patient, including acne, hirsutism, hyperpigmentation, skin thinning, and striae.Growth suppression is one of the most serious adverse effects associated with prolonged corticosteroid therapy in children. Young children may develop growth suppression when they have received prolonged therapy with doses equivalent to 3 mg/d of prednisone or more. The mechanism is generalized suppression of cell growth and division and inhibition of somatomedin C (insulin-like growth factor I) production. Furthermore, growth failure sometimes is related to the underlying condition.Patients receiving relatively high doses of steroids (>1 mg/kg per day or >30 mg/d) for prolonged periods may develop steroid myopathy. For patients who have juvenile dermatomyositis or polymyositis, this might be misinterpreted as exacerbation of their underlying disease. However, patients who have steroid myopathy generally experience an insidious onset of painless proximal muscle weakness and have normal serum levels of muscle enzymes. Electromyography detects minimal myopathic changes, and type IIB fiber atrophy is noted on muscle biopsy. The acute form has been reported after short-term high-dose corticosteroid therapy. Both proximal and distal muscle weakness can occur, and elevation of serum creatinine phosphokinase or aldolase levels in conjunction with rhabdomyolysis may result.Patients who have rheumatic diseases, especially systemic lupus erythematosus (SLE) and to a lesser extent juvenile rheumatoid arthritis (JRA), are at risk of developing avascular necrosis (AVN) of the bone. This risk is increased further by long-term therapy with corticosteroids (at least 4 to 6 mo of continuous use). AVN most frequently affects the femoral head, although other sites, such as the knees and shoulders, may be affected. This complication has been described with both high oral doses (2 mg/kg per day) and intravenous pulse doses (10 to 30 mg/kg per pulse). The exact mechanism is not known, although both underlying disease and high-dose steroid therapy (possibly high-dose intravenous administration) play roles.The development of osteopenia from exogenous corticosteroid use first was described in 1950. Osteoporosis is related to both the dose and duration of steroid therapy and appears to involve several mechanisms, including decreased intestinal absorption of calcium, increased renal calcium loss (that results in secondary hyperparathyroidism), the underlying disease activity (especially in children who have systemic and polyarticular onsets of JRA), and reduction of bone formation by direct inhibition of osteoblasts. Bone loss is most rapid during the first 6 to 12 months of steroid therapy, subsequently reaching a plateau. Short-term corticosteroid use generally is not associated with osteopenia. In adults, bone loss often is trabecular rather than cortical, whereas in children it is generalized, affecting both trabecular and cortical bone. In adults, large cumulative doses of corticosteroids (>10 to 30 g) result in significant bone loss, and alternate-day dosing may not be protective. Steroid-induced osteoporosis has been studied to a lesser extent in children. There are no reliable biochemical markers to predict the significance of bone loss, although bone densitometry can be used to screen high-risk children and planned for 6 to 12 months after the initiation of therapy. Several methods of preventing and treating steroid-induced osteoporosis in adult patients have been studied in controlled trials, including the use of vitamin D, calcitonin, and bisphosphonates. Although these regimens were found to be effective in reducing bone loss, none demonstrated a significant decrease in the incidence of fractures. Open trials of vitamin D and calcium in children who have rheumatic diseases receiving long-term steroids have showed benefit.Chronic corticosteroid use predisposes patients to bacterial, viral, fungal, and protozoal infections. In addition, the anti-inflammatory effect of corticosteroids can mask the signs and symptoms of infection. Furthermore, diagnostic confusion and inappropriate investigations can result if it is not recognized that corticosteroids cause neutrophilia and an elevated total white blood cell count.Due to a defect in cell-mediated immunity, patients receiving prolonged high (but not low) doses of steroids, especially when administered in divided daily doses, are prone to tuberculosis, fungi, Pneumocystis carinii pneumonia (PCP), and toxoplasmosis. A purified protein derivative skin test should be performed prior to the initiation of prolonged high-dose corticosteroid treatment. Complications of varicella infection also may occur. Except for herpesviruses, most viruses are not a major threat during corticosteroid treatment. Although humoral defense mechanisms are less impaired, high-dose steroids can be a risk for more frequent and severe pyogenic infections, particularly bacteremia, with organisms such as Staphylococcus aureus, group A Streptococcus, and Eschericia coli. This effect appears to be related to the decreased migration of polymorphonuclear leukocytes to the sites of infection and inhibition of chemotaxis. Very high doses of steroid inhibit phagocytosis and intracellular killing, thus predisposing to infections with intracellular pathogens such as Listeria monocytogenes and Salmonella, Brucella, and Legionella sp.Corticosteroids may increase the risk of peptic ulceration, especially when combined with nonsteroidal anti-inflammatory drugs, although the data supporting this association have been based on retrospective studies and meta-analyses. The data often are confounded by the simultaneous use of both drugs in patients who have more severe diseases. Corticosteroids may mask the signs and symptoms of intra-abdominal catastrophes (such as intestinal perforation), leading to delayed diagnosis and subsequent increased morbidity and mortality.The association of corticosteroid use with pancreatitis is not well established. Many of the reported cases have occurred with concomitant drug use (such as azathioprine or hydralazine) or as a result of complication (eg, vasculitis) due to an underlying disease such as SLE.The primary cardiovascular adverse effect seen in children receiving corticosteroid therapy is hypertension, probably related to sodium retention and increased antidiuretic hormone activity and plasma renin levels. Other adverse effects of corticosteroids include hyperlipidemia and accelerated coronary atherosclerosis.The frequency of posterior subcapsular cataracts in patients receiving prolonged high-dose corticosteroids is greater than that seen in idiopathic Cushing syndrome. The risk of developing cataracts is more significant when the steroid dose is 0.3 mg/kg per day (9 mg/m2 per day) or more administered for longer than 1 year. In children, prednisone doses of 20 mg/d for 4 years or more were associated with cataracts. An earlier report suggested that younger patients and children develop cataracts in a shorter time and with lower doses of corticosteroids than do older patients.CNS adverse effects include a wide range of psychiatric symptoms from changes in mood, such as emotional lability, euphoria, insomnia, and depression, to psychosis. A study in adults found mood changes to be the most common psychiatric adverse effect, developing in almost 90% of patients receiving steroid therapy. Most of the reactions occurred within the first 5 days of therapy, although delayed reactions after many weeks were observed. Psychosis is more frequent in patients who have idiopathic Cushing syndrome than in those receiving corticosteroids. A prospective study on the adverse effects of intermittent intravenous corticosteroid (30 mg/kg per dose) therapy in 213 children who had rheumatic diseases revealed behavioral changes in 10%; these abnormalities included alterations in mood, hyperactivity, sleep disturbances, and psychosis. In some cases, the CNS changes may be attributed to the underlying disorder, such as SLE. Behavioral abnormalities usually resolve when corticosteroids are withdrawn.Pseudotumor cerebri (benign intracranial hypertension) has been described rarely with corticosteroid use, often noted following rapid tapering of the corticosteroid dose. Patients typically present with persistent headaches; visual symptoms may be absent, although papilledema is evident. The diagnosis is based on increased cerebrospinal fluid pressure during lumbar puncture.Withdrawal of short-term corticosteroid therapy (days or a few weeks) is not associated with symptoms of adrenal insufficiency. However, sudden withdrawal of prolonged and high-dose therapy may result in serious, life-threatening adrenal insufficiency with possible circulatory collapse and death. Manifestations may include high fever in the absence of infection, hypotension, nausea, vomiting, diarrhea, confusion, hyponatremia, hyperkalemia, hypoglycemia, and eosinophilia. In addition to the duration and dose of corticosteroid therapy, studies in adults revealed that the risk of hypothalamic pituitary adrenal axis (HPA) suppression depends on the mode of administration; suppression is the highest with divided daily doses and lowest with alternate-day dosing. The recovery of the HPA axis following discontinuation of the steroid therapy is related inversely to the duration of the preceding steroid therapy. Children receiving prolonged steroid therapy who encounter serious infections, trauma, and surgery are at risk for HPA axis suppression and need steroid supplementation to prevent addisonian crisis.Besides corticosteroids, several other classes of immunosuppressive drugs are used routinely by pediatric rheumatologists, oncologists, nephrologists, and transplant surgeons and include cytotoxic/antiproliferative agents (eg, azathioprine, 6-mercaptopurine, chlorambucil, cyclophosphamide), calcineurin inhibitors (eg, cyclosporine, tacrolimus), and antimetabolites (eg, methotrexate, mycophenolate mofetil). All current immunosuppressive agents target T-cell activation and cytokine production, clonal expansion, or both (Table 3). These agents produce cytotoxicity through their effect on rapidly dividing cells such as the malignant cells as well as normal cells of the immune system, primarily T lymphocytes.Children receiving chronic immunosuppressive therapy should be monitored closely for serious adverse effects (Table 4). When used in chemotherapeutic doses for management of cancer, the cytotoxic agents may cause significant bone marrow and immune suppression, leading to life-threatening infections. Therefore, any febrile child who has an absolute neutrophil count of fewer than 500 cells/mm3 associated with myelosuppressive chemotherapy must be considered septic. The degree and duration of neutropenia remain the most critical factors predictive of infection. The status and type of underlying malignancy, degree of disruption of host defenses, and presence of indwelling central venous catheters are other important factors that influence the risk and type of infection encountered. It is important to note that the classic signs of infection generally are absent in affected patients.The initial evaluation of a patient who has febrile neutropenia involves a meticulous physical examination, with particular attention paid to the skin, perirectal area, and other mucous membrane sites. Blood cultures should be obtained promptly, and the patient should be started on broad-spectrum intravenous antibiotics that provide excellent coverage against gram-positive pathogens, most notably staphylococci and alpha-hemolytic streptococci, as well as gram-negative enteric organisms such as Enterobacteriaceae and Pseudomonas aeruginosa. Patients are hospitalized until they have become afebrile for at least 24 to 48 hours and blood, urine, or cerebrospinal fluid cultures are negative. If fever continues beyond 1 week despite broad-spectrum antibiotic therapy, empiric use of amphotericin B may be indicated for treatment of fungal infection, including that caused by Candida and Aspergillus sp.Children who have lymphomas and those who are maintained on steroids as part of consolidation therapy appear to be at increased risk for the development of PCP. The incidence of PCP has been reduced drastically with the routine use of trimethoprim-sulfamethoxazole prophylaxis.Early recognition of exposure to varicella in children receiving immunosuppressive therapy is critical. Physical contact with the skin lesions of herpes zoster ("shingles") can transmit infection, leading to visceral dissemination in immunocompromised patients, especially those receiving corticosteroid therapy. Prophylactic intervention with varicella-zoster immunoglobulin (VZIG) within 96 hours of exposure is recommended in immunocompromised children who have no history of varicella, regardless of serologic tests. VZIG can prevent or attenuate the disease manifestations of varicella in susceptible contacts at high risk of infection. Patients who develop chickenpox, either with or without VZIG, must be treated promptly with intravenous acyclovir. Early treatment, especially within 24 hours of the onset of rash, prevents fatalities.In addition to cancer chemotherapy, cytotoxic agents (eg, cyclophosphamide, methotrexate) also are used commonly for inflammatory rheumatic and renal disorders. For these indications, the doses typically are lower, and adverse effects, when noted, often are less profound and less common. For example, methotrexate in a low-dose regimen of 0.3 to 1.1 mg/kg per week (10 to 25 mg/m2 once weekly dosing) is used most frequently as a disease-modifying antirheumatic drug in JRA. Minor adverse effects, such as oral mucous membrane lesions, may occur. Two primary adverse effects may be bone marrow suppression and Both resolve with dose or discontinuation of has been reported in clinical and that include a blood count and liver are to immune therapy is used in a number of inflammatory diseases, including idiopathic and some cases of juvenile dermatomyositis and JRA. therapy usually is and well when administered nausea, and are and and can occur several agents (eg, TNF-alpha have been for rheumatic and inflammatory disease The particularly TNF-alpha and play a major role in the of inflammation, especially the production of that to formation and in patients who have rheumatoid and are by the and Administration for use in children. The most common adverse effects are increased risk of infection in the of skin at sites, which has occurred in of of activation in adults are that data on long-term exposure are to the of these of immunosuppressive therapy for management of diseases, malignancy, or are at increased risk of diseases, some of which can be by children also may be more susceptible to adverse effects from although serious have been reported Several factors must be considered in the immunization of children receiving chronic steroid or other immunosuppressive therapy. In either or (eg, and oral and are in of high doses of systemic corticosteroids or other immunosuppressive therapy. are not administered until the underlying is in and immunosuppressive therapy has been for at least and of in children receiving corticosteroid therapy are by the frequency and of the underlying and the of other immunosuppressive In previously children, the minimal immunosuppressive dose and duration of systemic corticosteroids are not well on by the of receiving chronic steroid therapy are considered immunocompromised if they prednisone or an equivalent at a dose of at least 2 mg/kg per day a total dose of at least 20 mg/d for children more than administered daily or on days for or more recommendations for use of in previously children receiving corticosteroids are summarized in Table children who are treated with or children receiving physiologic corticosteroid therapy without other and children who are treated with doses of systemic corticosteroids administered daily or on days can during steroid treatment. are for children receiving high doses of systemic steroids administered daily or on days for days or more until steroid therapy has been for at least 1 In addition, children who have underlying that are considered to suppress the immune system and who are receiving systemic or corticosteroids should not in (eg, type and are and are recommended routinely for children receiving immunosuppressive therapy. However, high-dose immunosuppressive therapy may inhibit an immune response to The to an immune response to usually 3 to 12 months after discontinuation of immunosuppressive therapy. Children who have received during the of immunosuppressive therapy should be after therapy is is recommended for most patients during the For children who have cancer, may be administered 3 to 4 weeks after chemotherapy is if the absolute neutrophil and lymphocyte are greater than When immunization should be that or such as or contacts of children should be to the However, oral should be in contacts of immunocompromised children it may the If and contacts should and and is no of In addition, varicella is recommended for susceptible contacts of is and severe disease is even in should with disease when for children receiving immunosuppressive therapy. are to the of the for regarding immunization in immunocompromised children, including those who have primary and secondary immune those receiving chronic corticosteroid therapy, and transplant

BACKGROUND: Following the short-term outbreak of coronavirus disease 2019 (COVID-19) in December 2022 in China, clinical data on kidney transplant recipients (KTRs) with COVID-19 are lacking. METHODS: We conducted a single-center retrospective study to describe the clinical features, complications, and mortality rates of hospitalized KTRs infected with COVID-19 between Dec. 16, 2022 and Jan. 31, 2023. The patients were followed up until Mar. 31, 2023. RESULTS: A total of 324 KTRs with COVID-19 were included. The median age was 49 years. The median time between the onset of symptoms and admission was 13 d. Molnupiravir, azvudine, and nirmatrelvir/ritonavir were administered to 67 (20.7%), 11 (3.4%), and 148 (45.7%) patients, respectively. Twenty-nine (9.0%) patients were treated with more than one antiviral agent. Forty-eight (14.8%) patients were treated with tocilizumab and 53 (16.4%) patients received baricitinib therapy. The acute kidney injury (AKI) occurred in 81 (25.0%) patients and 39 (12.0%) patients were admitted to intensive care units. Fungal infections were observed in 55 (17.0%) patients. Fifty (15.4%) patients lost their graft. The 28-d mortality rate of patients was 9.0% and 42 (13.0%) patients died by the end of follow-up. Multivariate Cox regression analysis identified that cerebrovascular disease, AKI incidence, interleukin (IL)‍-6 level of >6.8 pg/mL, daily dose of corticosteroids of >50 mg, and fungal infection were all associated with an increased risk of death for hospitalized patients. CONCLUSIONS: Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality. The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival, while higher doses of corticosteroids may increase the death risk.

COVID-19 in Kidney Transplantation: Outcomes, Immunosuppression Management, and Operational Challenges.

Cardiopulmonary Resuscitation During the Coronavirus Crisis: Important Updates for the Cardiothoracic and Vascular Anesthesia Community

MULTIPLE SCLEROSIS AFTER COVID-19: A SIGN OF THINGS TO COME?

* Abbreviations: ARDS — : acute respiratory distress syndrome COVID-19 — : coronavirus disease 2019 GI — : gastrointestinal HFNC — : high-flow nasal cannula IMV — : invasive mechanical ventilation IVIg — : intravenous immunoglobulin NIV — : noninvasive ventilation Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, disproportionally affects adults (children <5% in most reports).1 Adult critical illness is characterized by acute hypoxemia, multiorgan failure, and high mortality.2,3 Reported risk factors for severe illness include age, cardiorespiratory comorbidities, obesity, and laboratory findings (lymphopenia and elevated D-dimer).2,4 Pediatric reports describe low infection rates and infrequent PICU admission.5,6 The largest PICU report consists of 48 North American children.7 It describes treatments and outcomes but not with … Address correspondence to Sebastian Gonzalez-Dambrauskas, MD, Red Colaborativa Pediatrica de Latinoamerica and Cuidados Intensivos Pediatricos Especializados, Casa de Galicia, Montevideo, Uruguay. E-mail: sgdambrauskas{at}gmail.com

Coronavirus Disease 2019: Coronaviruses and Kidney Injury.

COVID-19 infection in patients with severe aplastic anaemia

Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized Patients With Coronavirus Disease 2019 From a Large Healthcare System

The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), as the AHR’s heterodimerization partner, and NADPH‐cytochrome P450 oxidoreductase (POR), as the key electron donor for all microsomal P450s, are important players in the adaptive and toxic responses to polycyclic and halogenated aromatic hydrocarbons. Expression of both ARNT and POR in rat liver is induced by dexamethasone (DEX), a synthetic glucocorticoid known to activate both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). To study the role of GR in ARNT and POR regulation, we treated male rats with a low DEX dose (0.5 mg/kg), shown to activate GR selectively, and a high DEX dose (50 mg/kg), shown to activate both GR and PXR, in the absence and presence of the GR antagonist RU486 (50 mg/kg). The role of PXR was assessed by comparing the responses to similar low (1 mg/kg) and high (50 mg/kg) DEX doses in wild‐type and PXR‐knockout rats. In both studies, rats were euthanized at 6 and 24 h after DEX dosing. The induction of ARNT mRNA levels by low‐dose DEX and the increase in ARNT protein levels by high‐dose DEX were prevented by RU486, whereas the induced levels of ARNT mRNA and protein did not differ between wild‐type and PXR‐knockout rats. RU486 did not inhibit the induction by DEX of POR expression at the mRNA, protein, and catalytic activity levels. The induction of POR mRNA levels by low‐ and high‐dose DEX was significantly attenuated in PXR‐knockout rats and the increase in POR protein levels and catalytic activity by high‐dose DEX was completely absent in PXR‐knockout rats. These results are consistent with important roles for GR in the DEX induction of rat hepatic ARNT and PXR in the DEX induction of rat hepatic POR.Grant Funding Source: Supported by the Canadian Institutes of Health Research

In December 2019, a novel coronavirus was identified in Wuhan City, Hubei Province, China and later the disease was named coronavirus disease 2019 (COVID-19). On March 11, 2020, the World Health Organization (WHO) officially announced that COVID-19 had reached global pandemic status. This article summarized the understanding of the etiology, pathogenesis, epidemiology, clinical characteristics, diagnosis, treatment, rehabilitation, and prevention and control measures of COVID-19 based on the available data and anti-epidemic experience in China.

Background: Corticosteroids suppress the immune system and have been proposed as a treatment for the severe form of coronavirus disease 2019 (COVID-19) due to their potential ability to inhibit the COVID-19- induced cytokine storm. We aimed to evaluate the effects of cumulative doses of corticosteroids on the recovery of COVID-19 patients. Patients and methods: In this descriptive cross-sectional study, we retrospectively evaluated patients with COVID-19 (confirmed by polymerase chain reaction [PCR]) receiving corticosteroids at Shahid Mohammadi Hospital, Bandar Abbas, Iran during June-October 2020. All patients had been admitted to the general wards and not the intensive care unit. COVID-19 was not severe in any of the patients. Beside corticosteroids, all patients had received similar standard COVID-19 treatment according to the National COVID-19 Committee protocols. In addition to the demographic features of the patients including age and gender, COVID-19 symptoms, respiratory rate (RR), lactate dehydrogenase (LDH) level, C-reactive protein (CRP) level, oxygen saturation (SpO2 ), lymphocyte percentage and count, and lung infiltration (in chest computed tomography) on admission and at the last evaluation before discharge were extracted from the patients’ medical files. Results: A total of 200 patients with confirmed COVID-19 were included in this study. The mean age of the patients was 51.65 ± 9.35 years and 117 (58.5%) were male. The administered corticosteroid was dexamethasone in 55%, methylprednisolone in 32.5%, and prednisolone in 12.5%. The mean administered cumulative corticosteroid dose was equal to 82.69 ± 59.40 mg prednisolone. All COVID-19 symptoms, including fever, cough, dyspnea, headache, body ache, and anosmia/ageusia, decreased in the patients. However, there was no significant difference between patients using &lt; 65 mg of corticosteroids and those using ≥ 65 mg of the medicine regarding the final status of symptoms. The increase in SpO2 was significantly higher in patients using &lt; 65 mg of corticosteroids (P = 0.008). Moreover, the proportion of patients with negative final CRP was significantly higher in this group (P &lt; 0.001). On the contrary, hospital length of stay was significantly shorter in patients using ≥ 65 mg of corticosteroids (P = 0.034). The two groups had no significant differences in terms of LDH levels, lymphocyte percentage and count, RR, and the final status of lung infiltration (P &gt; 0.05). Conclusions: While the cumulative dose of corticosteroids equal to &lt; 65 mg of prednisolone is associated with increased SpO2 and decreased CRP in COVID-19 patients, it leads to prolonged hospital stay compared to the ≥ 65 mg dose of corticosteroids.

Perinatal COVID-19.

Successful Use of COVID-19 Convalescent Plasma in a Patient Recently Treated for Follicular Lymphoma

Corticosteroids are currently used routinely in the management of acute severe asthma. The optimal dose and route of administration continues to be debated. Some investigators have reported a greater benefit of higher doses of corticosteroids in the management of severe asthma, while others have not. To determine whether higher doses of systemic corticosteroids (oral, intravenous or intramuscular) are more effective than lower doses in the management of patients with acute severe asthma requiring hospital admission. Randomised controlled trials were identified from the Cochrane Airways Group Asthma Register. In addition, primary authors and content experts were contacted to identify eligible studies. Bibliographies from included studies, known reviews and texts were also searched. Studies were selected for inclusion in the review if they met the following broad inclusion criteria: described as randomised controlled trials, included patients with acute severe asthma, compared different doses of corticosteroids (any route) in 2 or more treatment arms, and had a minimum period of follow up of 24 hours. Two reviewers independently assessed the studies for inclusion and disagreement was resolved by third party adjudication. Data were extracted independently by two reviewers if the authors were unable to verify the validity of information. Missing data were obtained from authors or calculated from other data presented in the paper. The data were analysed as weighted mean differences (WMD) for primary pulmonary function outcomes using a fixed effects model. For the purposes of the review, three broad categories of corticosteroid dose (equivalent dose of methylprednisolone in 24 hours) were defined in advance: low dose (< or = 80 mg), medium dose (> 80 mg and < or = 360 mg) and high dose (> 360 mg). There were thus 3 main comparison groups: low versus medium dose, medium versus high dose and low versus high dose. Nine trials were included; a total of 344 adult patients have been studied (96 with low dose, 85 with medium dose and 163 with high dose corticosteroids). Only 6 trials provided sufficient data for the meta-analysis. There were no clinically or statistically significant differences detected in % predicted FEV1 among comparison groups after 24, 48 or 72 hours. At 48 hours, the weighted mean difference was -3.3% predicted (95% confidence interval -12.4 to + 5.8) for the low vs medium dose comparison, -1. 9% predicted (95% CI -8.1 to + 4.3) for the medium vs high dose comparison and + 0.5% predicted (95% CI - 7.8 to + 8.8) for the low vs high dose comparison. There appeared to be no significant differences in side effects or rates of respiratory failure among the varying doses of corticosteroids. No differences were identified among the different doses of corticosteroids in acute asthma requiring hospital admission. Low dose corticosteroids (< or = 80 mg/day of methylprednisolone or < or = 400 mg/day of hydrocortisone) appear to be adequate in the initial management of these adult patients. Higher doses do not appear to offer a therapeutic advantage.