High-dose Dexamethasone Research Articles

COVID-19 patients are characterized by increased levels of immune cell membrane-bound and soluble CD48

Abstract COVID-19 is a respiratory-centered systemic disorder caused by the severe acute respiratory syndrome (SARS-CoV-2) virus. The disease can progress into a severe form causing acute lung injury (ALI), mainly diffuse alveolar damage (DAD) with thromboinflammation, immunopathology, and cytokine storm. CD48 is an activating/co-activating receptor expressed on most hematopoietic cells, existing as both membrane-bound (mCD48) and soluble (sCD48) forms. Its high-affinity ligand is 2B4 (CD244). We previously found the mCD48 and sCD48 levels are dysregulated in asthma patients regardless of their atopic status. Therefore, we reasoned that CD48 could be dysregulated in COVID-19 ALI too. CD48 expression was evaluated in tissue sections collected at autopsies of lethal COVID-19 at the first wave (patients not being exposed to high dose dexamethasone), and on peripheral blood leukocytes and in sera of COVID-19 patients by gene expression profiling (autoimmune panel pf HTG), IHC, flow-cytometry and ELISA. Lung tissue of COVID-19 patients showed significantly increased CD48 mRNA expression and infiltration of CD48+ lymphocytes in comparison to other inflammatory conditions (influenza-virus and pneumococcal pneumonia, and non-COVID-19 DAD). In the peripheral blood mCD48 was significantly increased on all the evaluated cells and, additionally, sCD48 levels were significantly higher in COVID-19 patients independent of disease severity. Positive correlation was found between mCD48 levels on monocytes and sCD48 release. Since both mCD48 and sCD48 are significantly increased in COVID-19, a specific a role for CD48 in COVID-19 can be assumed, suggesting it as a potential target for therapy. Supported by Israel Science Foundation Grant no. 3933/19 the Aimwell Charitable Trust (UK), Emalie Gutterman Memorial Endowed Fund for COPD related research (USA)

Comparative Efficacy of High Dose Dexamethasone vs Low Dose Methylprednisoslone Therapy in Covid Pneumonia

Background: Around one and half years ago in the December of 2019 a flu like disease emerged in the city Wuhan located in China. This was termed by WHO as a global pandemic due to its rapid widespread. Aim: To compare the efficacy of high dose dexamethasone (8 mgx tds) vs low dose methylprednisoslone (100 mgx bd) therapy for two weeks, in resolution of acute inflammatory markers in patients with covid pneumonia. Study Design: Quasi experimental study. Methodology: Patients (n=72) with an age range of 18-70 years with Covid 19 PCR positive having Covid associated pneumonia were enrolled. Group 1 containing 36 patients receiving high dose dexamethasone (8 mgx TDS) and group 2 with 36 participants receiving low dose methylprednisolone (100 mgx BD). Inflammatory markers (CRP, ESR and Ferritin) were recorded on Day 1 (T1) on day 7 (T2) and day 14 (T3). Patients who required ventillatory support and those who died was also recorded.All this information was recorded on Performa. Data was analyzed using SPSS version 26. Results: Mean age of the patients was 50.11±11.7 years. When we compared the inflammatory markers among group 1 and group 2 at T1, T2 and T3 no statistically significant difference was obtained. Conclusion: It was concluded that high dose dexamethasone and low dose methylprednisoslone therapy for two weeks were equally effective in resolution of acute inflammatory markers in patients with covid pneumonia. Keywords: Covid, Pneumonia, High Dose Steroids and Inflammatory Markers.

Comparison of Fentanyl plus different doses of dexamethasone with Fentanyl alone on postoperative pain, nausea, and vomiting after lower extremity orthopedic surgery.

Intravenous patient controlled analgesia (PCA) with opioids to provide perioperative analgesia is commonly used after orthopedic surgery, but have side-effects. Addition of adjutant drugs results in reducing the side-effects and the dosage of opioids. The aim of current study was to evaluation the analgesic efficacy of combination of fentanyl and dexamethasone (8 and 16 mg) in compared with fentanyl alone in patients undergoing orthopedic surgery of the lower extremity. In a double-blind clinical trial, 102 patients were randomly allocated to receive PCA, which included: F+S group (fentanyl 1 mcg/ml + isotonic saline), F+8mD group (fentanyl 1 mcg/ml + dexamethasone 8 mg/ml), and F+16mD group (fentanyl 1 mcg/ml + dexamethasone 16 mg/ml). Anesthesia technique and rescue analgesia regimen were standardized. Postoperatively, pain was assessed based on visual analog scale (VAS). In addition, we evaluated the postoperative nausea and vomiting (POVN) in different groups. In over the post-operative period, the mean VAS-score was significantly lower in the F+16mD group than the F+S and the F+8mD groups (p<0.001 and p<0.01, respectively). In addition, the incidence of PONV significantly was lower in the F+18mD group than the F+S group (p<0.05). We conclude that the addition of preoperative intravenous high dose of dexamethasone (16 mg) to fentanyl was effective in reducing postoperative pain and PONV after orthopedic surgery of the lower extremity.

P163 The cytokine horror: Kawasaki disease shock syndrome complicated with macrophage activation syndrome

Abstract Background/Aims Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown aetiology, affecting medium-sized vessels. It often occurs in children less than 5 years old. During the acute phase of the disease, less than 5% of children develop hypotension and shock. This severe form is called Kawasaki Disease Shock Syndrome (KDSS). Macrophage activation syndrome (MAS) is a heterogenous syndrome complex encompassing a broad spectrum of clinical features. MAS associated with KDSS is an extremely rare life threatening entity that warrants a high index of clinical suspicion, prompt and proper management. Methods We present our experience in the dilemmas and challenges faced in the diagnosis and management of KDSS complicated with MAS in a poor resource setting. It is our first experience of encountering MAS in KDSS. Results A 9-month-old baby with fever and a maculopapular rash involving palms and soles for 5 days duration was transferred from a peripheral hospital. A preliminary diagnosis of acute Kawasaki disease was made with the classical features that included the rash, cracked lips, pedal oedema, BCG scar inflammation, perianal excoriation and irritability. The fever did not settle following standard therapy that included three doses of intravenous immunoglobulins 2g/kg, aspirin and low dose dexamethasone. The child quickly began to decompensate. She developed cold clammy skin with hypotension on the 8th day of the illness. There was evidence of hepatosplenomegaly with transaminitis. 2D Echo revealed normal coronary vasculature without any dilatations or strictures. However, there was evidence of myocarditis supported by diffuse T inversions in the anterolateral leads and a highly positive troponin titre. Investigations revealed aa leucocytosis (22,100/dl), an abrupt drop in platelet count (350,000/dl to 80,000/dl), red blood cells, haemoglobin (11g/dl to 8g/dl) and erythrocyte sedimentation rate 95mm/hr to 50mm/hr. Hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia supported the diagnosis of MAS. Blood culture was sterile. Initial bone marrow biopsy was inconclusive. High dose dexamethasone 10mg/m2/day and cyclosporine 2mg/kg/day was initiated. The circulatory collapse was managed with fluid boluses and a low dose adrenaline infusion. Subsequently there was dramatic clinical improvement and her cell counts and transaminases normalised on day 15. Conclusion We emphasise the importance of early recognition of refractory MAS in pediatric populations with rheumatic diseases and we suggest early initiation of cyclosporin as a rapid and effective treatment option in the poor resource settings where the ideal management with anakinra is beyond the realms of possibility. Disclosure L. Rajagopala: None. J. Jagoda: None. M.L. Gunatilaka: None.

Effects of Dexamethasone on Trophoblastic, IDO, and Macrophage Cells in Domestic Pregnant Rabbits (Oryctolagus cuniculus)

The healthy pregnancy requires a healthy fetal-maternal placental development that depends not only on invasion of fetal trophoblast but also on the presence of immune cells, such as macrophages. Dexamethasone (DEX) is used to treat several diseases, but exceed exposure to exogenous DEX may impair placental and fetal development and subsequent fetal loss. The current study investigates the effects of high dose of DEX (HD) (1.125 mg) and low dose of DEX (LD) (0.562 mg) on trophoblastic (T), IDO, andCD68 macrophage (M) cells in domestic pregnant rabbits (Oryctolagus cuniculus). Forty-eight pregnant does were caged in the animal house and divided into six groups, eight for each. These groups are treated as follows: groups A and B (as an experimental groups) were daily injected by (1ml) from day 5 to 9 of gestation (dG) with HD and LD, respectively; whereas group C was injected by (1 ml) of sodium chloride (0.9%) (as a control group). Then, all the groups (A, B and C) were dissected at 10 and 28 dG.

Impacts of Dexamethazone on Progesterone, Calcitonin, and Progesterone Receptors in Domestic Pregnant Rabbit (Oryctolagus cuniculus)

Dexamethasone (DEX) is used to treat several diseases and medical conditions in both animals and humans. But the administration of synthetic glucocorticoids, including dexamethasone, as a treatment, brings about endocrine misbalance. Such a disequilibrium underlies pregnancy complications. The current study investigates effects of High Dose of DEX (HD) (1.125 mg) and Low Dose of DEX (LD) (0.562 mg) on Progesterone (P), Progesterone Receptors (PR) and Calcitonin (C) in domestic pregnant does (Oryctolagus cuniculus). Sixty pregnant does were caged in the animal house and divided into six groups; A, B, C, D, E and F (n=10). These groups are treated as follows: Groups A and B (as an experimental groups) were daily injected by (1ml) from day 5 to 9 of gestation (dG) with HD and LD, respectively; whereas group C was injected by (1 ml) of sodium chloride (0.9%) (as a control group). Then, all the groups (A, B and C) were dissected at 10 and 28 dG.

Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondrial metabolism in immune thrombocytopenia.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells and natural inhibitors of adaptive immunity. Intracellular metabolic changes in MDSCs exert a direct immunological influence on their suppressive activity. Our previous study demonstrated that high-dose dexamethasone (HD-DXM) corrected the functional impairment of MDSCs in immune thrombocytopenia (ITP); however, the MDSC population was not restored in nonresponders, and the mechanism remained unclear. In this study, altered mitochondrial physiology and reduced mitochondrial gene transcription were detected in MDSCs from HD-DXM nonresponders, accompanied by decreased levels of carnitine palmitoyltransferase-1 (CPT-1), a rate-limiting enzyme in fatty acid oxidation (FAO). Blockade of FAO with a CPT-1 inhibitor abolished the immunosuppressive function of MDSCs in HD-DXM responders. We also report that MDSCs from ITP patients had lower expression of the glucocorticoid receptor (GR), which can translocate into mitochondria to regulate the transcription of mitochondrial DNA (mtDNA) as well as the level of oxidative phosphorylation. It was confirmed that the expression of CPT-1 and mtDNA-encoded genes was downregulated in GR-siRNA-treated murine MDSCs. Finally, by establishing murine models of active and passive ITP via adoptive transfer of DXM-modulated MDSCs, we confirmed that GR-silenced MDSCs failed to alleviate thrombocytopenia in mice with ITP. In conclusion, our study indicated that impaired aerobic metabolism in MDSCs participates in the pathogenesis of glucocorticoid resistance in ITP and that intact control of MDSC metabolism by GR contributes to the homeostatic regulation of immunosuppressive cell function.

P 92 Limbic encephalitis with Contactin-associated protein like-2 (CASPR2) -antibodies: acute psychosis with late onset and abnormal EEG

Introduction: Contactin-associated protein like-2 (CASPR2)- autoantibodies are associated with distinctive syndromes 1 , such as agrypnia excitata, psychosis, neuromytonia and limbic encephalitis. All of them are highly responsive to immunotherapy. The target of these directly pathogenetic autoantibodies are surface-exposed domains of CASPR2 2 . Due to the fact of multiple variations of clinical presentations, it may be challenging to distinguish particular an autoimmune encephalitis associated with anti-neuronal autoantibodies, from primary psychiatric disorders such as psychosis. First medical treatment should be immediate immunotherapy, such as steroids, intravenous antibodies or plasma exchange given fast diagnosis of encephalitis is made. In our case the EEG showed focal slow waves with the clinical presentation of an acute psychosis which leaded to an admission to the neurology ward and further investigations. Patient and methods: A 75-years-old man was hospitalized on a psychiatric ward for psychotic symptoms characterized by psychomotor agitation, thought disorganization, persecutory delusions and auditory hallucinations with commanding voices and global insomnia. Cerebral Imaging with cMRI and cCT scan showed no acute abnormalities. EEG showed focal intermittent slow delta-theta wave activity (4-6 Hz) on the left temporal lobe, reactive to visual stimuli and provided focal cerebral dysfunction and pathology. CSF did not reveal any evidence of infection, but CASPR2- autoantibodies (1:10.000) were indentified and the diagnosis of limbic encephalitis with CASPR2-antibodies was made. Treatment with high dose dexamethasone and intravenous immunoglobulin (IVIG) was made and the clinical conditions improved. Conclusion: Fast and first medical treatment of autoimmune encephalitis should be initiated in early stages. To avoid an unnecessary delay in diagnosis and treatment, EEG, cMRI and expanded CSF examination should be performed as soon as possible to prevent severe disability in patients with limbic encephalitis with CASPR2-antibodies.

Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study.

BackgroundDuring treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases.ObjectiveThis study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes.MethodsThis prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors.ResultsPatient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed.ConclusionsThis first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions.International Registered Report Identifier (IRRID)DERR1-10.2196/33517

SARS-CoV-2 Associated Respiratory Failure in a Preterm Infant and the Outcome after Remdesivir Treatment.

Severe coronavirus disease 2019 (COVID-19) occurs in approximately 10% of neonates infected with severe acute respiratory syndrome coronavirus 2. Guidelines for optimal management of severe COVID-19 in neonates do not exist. In this report, we describe a late-preterm neonate with severe COVID-19, requiring invasive mechanical ventilation who recovered following treatment with remdesivir and high dose dexamethasone.

Dexamethasone Pulse Therapy in Pemphigus Vulgaris Associated Myocardial Infarction in Resource-Limited Settings

Pemphigus vulgaris is an autoimmune blistering disorder where biologics are the cornerstone of therapy. In resource-limited settings, a dermatologist should rely on systemic steroids. Dexamethasone pulse therapy is a cheap and established treatment of pemphigus where a supra-pharmacological dose of dexamethasone is used. High dose of dexamethasone is supposed to have atherogenic potential which could promote a hypercoagulable state. Here, we report a case of a 30-year-old woman in the resource-limited setting of Nepal, who was under monthly dexamethasone pulse therapy for pemphigus vulgaris, who had an acute episode of ST-segment elevated myocardial infarction. In such setting, although steroids are the cornerstone of therapy in various disorders, physicians should be equally cautious in using a high dose of steroids which might lead to fatal complications. This could probably be the first case report of steroid-induced acute myocardial infarction during treatment of pemphigus worldwide.

Cloverleaf plasma cell nuclei in multiple myeloma

A 65-year-old man was diagnosed with multiple myeloma (IgG-Lambda) and was treated with high-dose dexamethasone as induction therapy followed by thalidomide-based regimens. About 18 months after the initial diagnosis, the patient presented a first relapse which was treated with the LCD protocol (Lenalidomide, Cyclophosphamide, Dexamethasone).

Challenging Management of Severe Differentiation Syndrome in Pediatric Acute Promyelocytic Leukemia Treated with ATRA/ATO.

The ATRA/ATO combination treatment of acute promyelocytic leukemia (APL) represents a paradigm of successful targeted and chemotherapy-free treatment in oncology. This therapeutic strategy is aimed at sparing patients from chemotherapy toxicity, while maintaining an excellent survival with a low risk of relapse. Main induction treatment-related complications are differentiation syndrome (DS) and hyperleukocytosis, which is related to DS and its severity. In the period December 2019 – December 2020, 8 children with newly diagnosed APL underwent induction therapy with ATRA/ATO in our center. In patients with WBC≥10x109/L two doses of Gemtuzumab Ozogamicin (GO) were added. In case of severe DS or hyperleukocytosis the differentiating agents were discontinued, high dose dexamethasone (DXM) and/or hydroxyurea (HU) were recommended. Five patients presented WBC&lt;10x109/L ; all developed hyperleukocytosis and three also had DS and were initially treated with HU and DXM; due to unsatisfactory control of the symptoms GO was added in two of them.. One of the three patients with presenting WBC≥10x109/L, developed pseudotumor cerebri and another one DS. The supportive treatment was effective in all cases. Our experience shows that patients, treated with ATRA/ATO only, may develop marked hyperleukocytosis and severe DS, which may be unresponsive to discontinuation of differentiating agents and administration of HU and DXM and may benefit from the use of GO. Adequate intensive support therapy is crucial to rescue patients with severe DS.

Regulatory T-lymphocyte subsets in children with chronic immune thrombocytopenia after high-dose of dexamethasone

BackgroundImmune thrombocytopenia (ITP) is an acquired autoimmune disease. This study’s objective was to estimate the variations in the population of CD4+CD25+High FoxP3+ cells (CD4+ regulatory T-lymphocytes; Tregs) in previously untreated children with chronic ITP managed in Assiut University Hospitals, as well as to evaluate the efficacy of high-dose dexamethasone (HD-DXM) in these patients.MethodsIn this study, we investigated the frequencies of T-lymphocyte subsets in 27 untreated children with chronic ITP.ResultsPrior to treatment, the percentages of CD4+CD25High cells and Tregs were significantly lower in the chronic ITP group compared to the control group (p = 0.018 and p < 0.0001, respectively). After treatment with HD-DXM, Tregs and platelets were significantly increased in these patients (p < 0.0001 for both).ConclusionsOur results suggest that Tregs are deficient in children with chronic ITP and that HD-DXM immunosuppressive therapy can restore the levels of these cells.ImpactCD4+CD25High cells and Tregs were significantly lower in children chronic ITP compared to healthy control.HD-DXM treatment led to significantly increased Tregs and platelets in these patients.Our results suggest that Tregs are deficient in children with chronic ITP and that HD-DXM immunosuppressive therapy can restore the levels of these cells.

Mineralocorticoid receptor status in the human brain after dexamethasone treatment: a single case study.

BackgroundSynthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation but likely also result in lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms.ObjectiveIn this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone.Main outcome measuresThe efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin-embedded hippocampal tissue from the patient and two controls. In hippocampal tissue from the patient and eight controls, mRNA of MR/GR target genes was measured.ResultsIn vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient.ConclusionsDexamethasone may induce MR nuclear translocation in the human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients.

Preventive effect of total flavonoids of Trollius altaicus on a chronic obstructive pulmonary disease rat model based on the TLR4/NF-κB pathway.

BackgroundChronic obstructive pulmonary disease (COPD) is diagnosed based on the clinical symptoms, risk factors, and pulmonary function tests. Exposure to cigarette smoke (CS), microbial infection stimulates monocytes and macrophages to rapidly synthesise and release inflammatory factors. A previous study of Trollius altaicus (TAF) revealed that it had significant anti-inflammatory and anti-oxidation effects on a pneumonia disease. Based on recent studies of the inflammatory pathway of toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB), we will explore the influence of TAF on COPD.MethodsWistar rats were randomly divided into blank control group, Model Group, low-dose TAF + model group, middle-dose TAF + model group, high-dose TAF + model group, positive control + model group. Except for the blank control group, COPD inflammation models were established in all groups by CS poisoning and LPS. Prior to the daily poisoning, 125 mg/kg, 250 mg/kg, and 500 mg/kg of TAF were administered by gavage in the low-, middle-, and high-dose groups, respectively, and dexamethasone solution (1 mg/kg, once daily) was administered continuously in the positive control group on the last 5 days of modelling. General signs, lung function indices, lung imaging results, complete blood count, lung histopathological changes, inflammatory factors in the alveolar lavage fluid, relative expressions of TLR4, IκB kinase α (IKKα), p65, as well as IL-1β proteins and their mRNA relative expressions were measured and compared between each group.ResultsCompared with the blank control group, TAF effectively reduced pulmonary parenchymal oedema (wet-to-dry ratio) and respiratory secretions. It also significantly delayed lung function injury. Lung X-ray imaging and haematoxylin and eosin staining. Blood routine examination results showed that TAF effectively inhibited the increase of white blood cell, lymphocyte, and eosinophil counts, decreased the release of inflammatory cytokines [IL-1β, IL-6, IL-8, TNF-α, and transforming growth factor-1β (TGF-1β)] and promoted the release of IL-10. It also inhibited the relative expressions of TLR4, IKKα, p65, IL-1β proteins, as well as IL-1 receptor-associated kinase (IRAK-1), IKKɑ, p65, and IL-1β mRNA.ConclusionsEarly intervention of TAF can reduce the occurrence of COPD, reduce the development of inflammation via TLR/NF-κB pathway, and provide reference for further study of the medicinal value of TAF.

Cushing’s Disease of Unknown Etiology: A Clinical Case Report

Cushing’s disease (CD) remains a diagnostic and therapeutic challenge. Different subtypes may be recognized that will offer insight in this complex situation. We describe an atypical case that we assume is a common variation albeit with no previous formal description. A young female patient presented with minimal clinical features of CD, but increased adrenocorticotropic hormone (ACTH) and cortisol levels, with maintained circadian rhythm that was not suppressed either after the rapid dexamethasone or the prolonged low-dose dexamethasone tests, but suppressed with the prolonged high-dose dexamethasone test and presented a flat ACTH and cortisol response after the corticotropin-releasing hormone (CRH) test. A diffuse enlarged pituitary gland with thickened pituitary stalk was present and a mixed corticotroph adenoma was removed. CD persisted despite now normal pituitary morphology, except for pituitary stalk widening. Plasma levels of CRH were low and no abnormalities were found in the coding region or flanking introns of glucocorticoid receptor (GCR) gene ( NR3C1 ). Somatostatin receptors were not present in the octreoscan, and treatment with cabergoline or somatostatin analogs was ineffective. Morbidity and mortality are increased in CD even in patients successfully treated and in remission. Despite early success in over 80% of the patients, in the long term CD recurs in almost 50% of the patients. Defining subtypes of CD may help elucidate mechanisms of the disease. We propose a new variant that we assume is common. Furthermore adaptation to chronic hypercortisolism is present. J Endocrinol Metab. 2022;12(1):40-48 doi: https://doi.org/10.14740/jem784

COVID-19 and Cushing's disease in a patient with ACTH-secreting pituitary carcinoma.

SummaryThe pandemic caused by severe acute respiratory syndrome coronavirus 2 is of an unprecedented magnitude and has made it challenging to properly treat patients with urgent or rare endocrine disorders. Little is known about the risk of coronavirus disease 2019 (COVID-19) in patients with rare endocrine malignancies, such as pituitary carcinoma. We describe the case of a 43-year-old patient with adrenocorticotrophic hormone-secreting pituitary carcinoma who developed a severe COVID-19 infection. He had stabilized Cushing’s disease after multiple lines of treatment and was currently receiving maintenance immunotherapy with nivolumab (240 mg every 2 weeks) and steroidogenesis inhibition with ketoconazole (800 mg daily). On admission, he was urgently intubated for respiratory exhaustion. Supplementation of corticosteroid requirements consisted of high-dose dexamethasone, in analogy with the RECOVERY trial, followed by the reintroduction of ketoconazole under the coverage of a hydrocortisone stress regimen, which was continued at a dose depending on the current level of stress. He had a prolonged and complicated stay at the intensive care unit but was eventually discharged and able to continue his rehabilitation. The case points out that multiple risk factors for severe COVID-19 are present in patients with Cushing’s syndrome. ‘Block-replacement’ therapy with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred in this patient population.Learning pointsComorbidities for severe coronavirus disease 2019 (COVID-19) are frequently present in patients with Cushing’s syndrome.‘Block-replacement’ with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred to reduce the need for biochemical monitoring and avoid adrenal insufficiency.The optimal corticosteroid dose/choice for COVID-19 is unclear, especially in patients with endogenous glucocorticoid excess.First-line surgery vs initial disease control with steroidogenesis inhibitors for Cushing’s disease should be discussed depending on the current healthcare situation.

PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18–60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%–60%) and the plasma concentrations increased (170%–400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

A study on high-dose dexamethasone versus prednisolone as frontline therapy in newly diagnosed immune thrombocytopenia in children

Objectives: Treatment for children with newly diagnosed immune thrombocytopenia (ITP) includes corticosteroids, out of which prednisolone is commonly used. High-dose dexamethasone (HD-DXM) treatment for children with newly diagnosed ITP can produce better outcomes than prednisone, as stated by many studies. A few articles compare HD-DXM and prednisolone as frontline therapies in newly diagnosed adult ITP but data on pediatric ITP comparing these two drugs are scarce. Material and Methods: It was a randomized, prospective, and cohort study. After enrolment, checking the inclusion and exclusion criteria, each child was randomly distributed into two groups; one cohort was treated with HD-DXM in the dose of 40 mg/m2 (maximum daily dose 40 mg) for 4 days once every 28 days for three cycles; and one with prednisolone in the dose of 2 mg/kg/day (maximum 60 mg/day) for 2 weeks, with quick tapering. A total of 42 children were enrolled, 21 in each cohort. Results: The overall response (OR) was 42.9% with HD-DXM therapy. The OR and median time to response were similar in both HD-DXM and prednisolone cohorts. There was also no significant difference in incidences of adverse effects between the two cohorts. Conclusion: Thus, this study confirms that HD-DXM is a safe, effective, and non-inferior option compared to prednisolone as frontline therapy in newly diagnosed ITP in children.