Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Primary glioblastomas and anaplastic astrocytoma in a glioma family.

A 72-year-old man presented with a short duration of symptoms relating to a right fronto-parietal glioblastoma and a family history of children with brain tumours. Analysis of the patient's family tree revealed that out of seven children, he had a living son with anaplastic astrocytoma, a daughter who had died with a glioblastoma, and a son who had died with a histologically undiagnosed intrinsic brain tumour. One niece was also thought to have died from a brain tumour. All of the other affected family members had onset in their third or fourth decades. Tissue was only available from two of the affected individuals, precluding familial genetic analysis at this stage. There is no clinical evidence to support a diagnosis of a multiple cancer or neurocutaneous syndrome in this family. In view of what is known about the genetics of familial glioma, it is interesting to note the clinical evidence of both 'primary' glioblastoma and anaplastic astrocytoma in the same kindred.     

Intraperitoneal hemorrhage in essential hypertension

Our case represents the eleventh example of intra-abdominal hemorrhage due to the rupture of a splanchnic artery. Most of the cases occur in the right or the left gastric artery. One occurred in the gastroduodenal and one in the left gastroepiploic artery. Only four cases of the superior mesenteric artery have been noted, including the present case. The association with severe hypertension is rather striking as it occurred in seven of the eleven cases. Six cases showed definite marked arteriosclerosis of the rupture vessel. We feel that hypertension, severe gastrointestinal vascular sclerosis, separately or in combination, are decided factors in the precipitation of rupture of the vessel, comparable to cerebral hemorrhage in hypertension. The infrequency of this accident is probably in part due to the infrequent findings of vascular sclerosis in the intestinal arteries. The clinical symptoms are severe abdominal pain associated with varying degrees of shock. All the patients operated on recovered completely.     

Deep Granuloma Annulare (Pseudorheumatoid Nodule) in Children: Clinicopathologic Study of 35 Cases

Deep granuloma annulare (DGA) is one of several lesions of skin and superficial soft tissues whose histologic character is a palisading granuloma with a small central focus of necrosis or necrobiosis. Unlike the other palisading necrobiotic lesions, DGA has a predilection for children in the first 5 to 6 years of life. A painless subcutaneous nodule(s) in the lower anterior tibial region or foot and the scalp, typically in the occiput, was the most common presenting feature in this study of 35 cases. Additional or recurrent lesions were reported in approximately 70% of cases with clinical follow-up. All lesions showed the presence of necrobiosis; however, one of the characteristic features was the multinodular character of the predominantly mononuclear cellular aggregates. The presence of vascular spaces at the periphery of the nodular profiles served as a clue to the diagnosis of DGA. The palisading arrangement of the mononuclear cells was evident only in those foci with central necrobiosis. A histiocytic disorder or fibrohistiocytic process was a common consideration in the differential diagnosis, especially in those cases with less apparent foci of necrosis. Palisading histiocytes with prominent eosinophilic cytoplasm and some nuclear atypism were problematic with regard to possible epithelioid sarcoma. Our study failed to identify any underlying or predisposing factors in the development of DGA. Despite the fact that DGA is a well-documented lesion in children, it occurs sufficiently infrequently that it is often not considered clinically when it presents as a subcutaneous mass or masses in a child. Its recognition by the pathologist is especially important as the occurrence of additional lesions in a high proportion of children can be anticipated without undue concern. Received June 16, 1997; accepted October 28, 1997.     

Ca2+ mobilization in physiologically stimulated single T cells gradually increases with peptide concentration (analog signaling)

We have investigated Ca²⁺ mobilization in single T cells stimulated with their physiological ligand, i.e. antigenic peptide bound to major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC). Fibroblasts expressing I-E^d class II molecules were pulsed with a peptide derived from the λ2³¹⁵ immunoglobulin light chain. Onto such antigen-pulsed fibroblasts were sedimented cloned Th1 cells loaded with Fura-2. Changes in cytosolic Ca²⁺ concentration in single T cells were continually monitored by use of an imaging system based on fluorometry. Ca²⁺ mobilization was both peptide-specific and MHC-restricted. Within seconds of the initial APC-T cell contact, a Ca²⁺ spike could be observed. The Ca²⁺ response gradually declined over a 25-min period, during which oscillations were noted. Various parameters characterizing the magnitude of the Ca²⁺ response (latency, increase rate, max and mean Ca²⁺ increase, frequency and period of oscillations) all correlated with the amount of peptide used for pulsing the fibroblasts. Thus, Ca²⁺ mobilization in single T cells appears not to be an all or none phenomenon. Rather, activation is incremental (analog signaling), the degree of Ca²⁺ mobilization probably being related to the number of stimulatory peptide-MHC complexes on the surface of the APC. The extent of calcium mobilization and lymphokine production (interleukin (IL)-2, IL-3, interferon-γ) correlated, at least at the population level.     

Changes in zinc level in the serum, whole blood and erythrocytes in disorders of thyroid function

The zinc level in serum and whole blood was determined in a series of 121 patients, 20 suffering from overt hyperthyroidism, 34 with manifest hypothyroidism and a control group of 67 euthyroid subjects. The zinc content per deciliter of erythrocytes was calculated from the haematocrit. The hyperthyroid group revealed a highly significantly elevated serum zinc level (p less than 0.01), but a most significantly reduced zinc content in whole blood (p less than 0.001) in comparison with the euthyroid group. On the other hand, the reverse changes were observed in the hypothyroid group, i.e. a most significantly reduced serum zinc content (p less than 0.001) and a highly significantly increased zinc content in whole blood (p less than 0.01). These results suggest that the determination of zinc levels both in serum and in whole blood may be a useful additional parameter of peripheral thyroid hormone effect.     

Tick-borne Borrelia-meningitis in children. An outbreak in the Kalmar area during the summer of 1984

Nine children, aged 5 to 11 years, with subacute or chronic meningitis were studied. Symptoms started during the summer season in all patients and in eight of the patients the disease began with a localized erythematous lesion (ECM), mostly in the face. In one patient only there was a history of an insect bite at the site of the erythema. The neurological abnormalities included aseptic meningitis, peripheral facial nerve palsy (5/9) and oculomotor nerve palsy (1/9). Most children complained of headache, fatigue, loss of appetite and had a low grade fever. High antibody titers to Borrelia spirochetes in serum and/or cerebrospinal fluid (CSF) were demonstrated by ELISA in eight of the nine patients and by indirect immunofluorescence assay (IFA) in three patients. All patients had a dramatic improvement in their general condition and became afebrile within three days of institution of i.v. penicillin G treatment (i.v. cefuroxime in one patient).