ECMO for the immunocompromised pediatric patient: Our experience

Objectives: To present a series of immunosuppressed patients (oncohematological disease, congenital immunosuppression, hematopoietic stem cell (HSCT), and solid organ transplant) assisted on ECMO. Method(s): Descriptive, retrospective study (2011-2020) of a cohort of 9 immunosuppressed patients, supported on ECMO. Medical records were reviewed and demographic, clinical, and analytical variables were collected. Result(s): In our series of 9 patients, 5 were male, the median age was 8 years [RIC 3-11 years]. Considering the underlying disease, 6 were oncologic, 1 liver transplant and 2 with congenital immunodeficiency after HSCT. 4 were under active chemotherapy (median 6 days after the last cycle [RIC 5-188]). 6 were admitted due to acute respiratory failure, 3 due to hemodynamic instability (3/9), (one septic shock). The median PEEP was 12 [RIC 9-15] and FiO2 100% (81-100%). 78% (6) required vasoactive drugs (median inotropic score 35 [RIC 0-75]. 40%. 5 had severe neutropenia and/or plateletopenia in the 24 hours prior to ECMO, and alterations in acid-base balance (median pH 7. 1 [RIC 6.9-7.15]. 5 were on multiorgan failure. TPrimary ECMO transport was performed in 4 patients (44%). Cannulation was peripheral in 80% (57% cervical, 43% femoral) and central in 20%;70% VA-ECMO. Median time of assistance was 15 days [RIC 3.5-31.5] in cardiac ECMO (4), and 29 days [RIC 13.5-42] and in pulmonary ECMO (n=5). The median total time of admission was 45 days [RIC 27-59]. 9 had an infection, 2 COVID after HSCT, and 8 bleeding complications, but only one required surgical revision. Renal replacement therapy was used in 5 (median 9 days [RIC 5-34.5]). Other therapies used were polymyxin hemadsorption(2), intratracheal surfactant(2), plasma exchange(1), infusion of mesenchymal cells(1) and specific memory T lymphocytes(2). 4 patients died, 5 survived decannulation, 2 died later, with an overall survival rate to hospital discharge of 33% (3/9). Conclusion(s): Despite having a worse prognosis, ECMO can increase survival in immunosuppressed patients, in situations that are challenging and require a multidisciplinary approach.

The impact of pre-existing chronic heart failure on the intensive care treatment and outcome of old intensive care patients suffering from COVID-19

Background: Patients suffering from COVID-19 with pre-existing chronic heart failure (CHF) are considered to have a significant risk regarding morbidity and mortality. Similarly, older patients on the intensive care unit (ICU) constitute another vulnerable subgroup. This study investigated the association between pre-existing CHF and clinical practice in critically ill older ICU patients with COVID-19. Method(s): Patients with severe COVID-19 and who were >=70 years old were recruited from this prospective multicenter international study. Patients' treatment, follow-up, and pre-existing heart failure data were collected during ICU stay. Univariate and multivariate logistic regression analyses examined the association between pre-existing heart failure and the primary endpoint of 30-day mortality. Result(s): The study included 3,917 patients, with 407 patients (17%) evidencing pre-existing CHF. These patients were older (77+/-5 versus 76+/-5, p<0.001) and more frail (Clinical Frailty Scale 4+/-2 versus 3+/-2, p<0.0001). The other comorbidities were also significantly more common in CHF patients. Before hospital admission, CHF patients suffered fewer days from symptoms (5 days (3-8) versus 7 days (4-10), p<0.001), but there was no difference in the days in the hospital before ICU admission (2 days (1-5) versus 2 (1-5) days, p=0.21). At ICU admission, disease severity assessed by SOFA scores was significantly higher in CHF patients (7+/-3 versus 5+/-3). During ICU-stay, intubation, mechanical ventilation, and tracheostomy occurred significantly more often in patients without CHF (63% versus 69%, p=0.017;and 13% versus 18%, p=0.002, respectively). In contrast, there was no difference regarding non-invasive ventilation (28% versus 27%, p=0.20), and the need for vasoactive drugs (66% versus 64, p=0.30). Regarding the limitation of life-sustaining therapy, therapy was significantly more often withheld (32% versus 25%, p=0.001) but not withdrawn (18% versus 17%, p=0.21) in CHF patients. Length of ICU stay was significantly shorter in CHF patients (166 (72-336) hours versus 260 hours (120-528), p<0.001). CHF patients had significantly higher ICU-(52% versus 46%, p=0.007), 30-day mortality (60% vs. 48%, p<0.001;OR 1.87, 95% CI 1.5- 2.3) and 3-month mortality (69% vs. 56%, p<0.001). In the univariate regression analysis, having pre-existing CHF was significantly associated with 30-day mortality (OR 1.89, 95% CI 1.5-2.3;p<0.001), but after adjusting for confounders (SOFA, age, gender, frailty), heart failure was not independently associated any more (aOR 1.2, 95% CI 0.5-1.5;p=0.137). Conclusion(s): In critically ill old COVID-19 patients, pre-existing chronic heart failure is associated with significantly increased short-and long-term mortality, but heart failure is not independently associated with increased 30-day mortality when adjusted for confounders.

Incidence and Risk Factors of Acute Kidney Injury in Patients with Severe Covid-19 Infection in Tertiary Care Hospital in Thailand

Introduction: Acute kidney injury (AKI) in COVID-19 infection is common, especially in severe diseases, and is associated with worsening outcomes. Data from many countries demonstrate differences in the incidence and risk factors of AKI. However, there is limited data available for AKI among severe COVID-19 patients in Thailand. This study aims to investigate the incidence and identify AKI risk factors in patients with severe COVID-19 infection at tertiary care hospitals. Method(s): In this retrospective cohort study, we analyzed data of patients admitted to the intensive care unit with PCR-confirmed diagnoses of COVID-19 infection from electronic medical records at Thammasat University Hospital. All patients who were admitted between 1st January 2021 and 30th June 2022 were included. Result(s): Of the 215 severe COVID-19-infected patients included, 134 (62.33%) experienced AKI injury. 81 (60.45%), 19 (14.18%), and 34 (25.37%) patients had AKI KDIGO stage 1, 2, and 3, respectively. From the univariate logistic regression analysis, the risk factors of AKI in COVID-19 patients were female, older age, preexisting hypertension, dyslipidemia, coronary artery disease, chronic kidney disease (CKD), higher APACHE II score, low serum albumin, high serum potassium, low serum bicarbonate, presence of proteinuria from dipstick and used of vasoactive drugs. Multivariate analysis showed that pre-existing CKD [odds ratio (OR) 13.95, 95%CI 2.24-86.88;p = 0.005], presence of proteinuria (OR 7.33, 95%CI 1.5-35.78;p=0.014) and APACHE-II score (OR 1.78, 95%CI 1.02-1.36;p=0.024) were independently associated with developing AKI. Multivariate analysis showed that AKI was associated with 30-day mortality with an OR of 4.34;95%CI 1.63-11.51 (p=0.003). Among AKI-patient survivors, 27 patients (20.15%) fully recovered their renal function, 22 patients (16.42%) were not recovering, and 11 patients (8.21%) required kidney replacement therapy during admission. The most common dialysis indication was volume overload. Conclusion(s): AKI in severe COVID-19 patients was common. Pre-existing CKD, presence of proteinuria, and higher APACHE II score were independently associated with AKI. Only one-fifth of AKI survivors had full renal recovery. Thus, the COVID-19 patients with these risk factors should be closely monitored and treated cautiously in order to prevent AKI development. No conflict of interestCopyright © 2023

Association of Liver Abnormalities with Disease Severity in Covid-19

Introduction and Objectives: Identifying independent risk factors for adverse outcomes in patients infected with severe acute respiratory syndrome coronavirus 2 can support prognostication, resource utilization, and treatment. The presenting symptoms of this virus are variable and the evolution and clinical significance of abnormal liver chemistries on outcomes in patients with coronavirus disease 2019 (COVID-19) is not well characterized. This study aimed to evaluate if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels could predict disease severity in patients with COVID-19. Material(s) and Method(s): a retrospective, observational and cross-sectional study was carried out with data from the medical records of patients who had positive SARS-CoV2 nasal swabs, were over 18 years of age and were admitted consecutively and under free demand at a Brazilian academic hospital from April 1 to May 31, 2021. The characteristics of liver abnormalities and outcomes of patients with COVID-19 were compared. Result(s): altogether, 222 patients were enrolled, three patients with cirrhosis and 82% with abnormal liver chemistries during hospitalization. Of these, 20% showed transaminases >5 times the upper limit of normal (ULN). The most prevalent liver abnormality was AST. The increase in transaminases was directly proportional to the higher rates of intensive care unit admission, longer hospital stays, higher rates of vasoactive drug use and greater pulmonary involvement in its severe forms. We found that elevations of transaminases >5 times the ULN, at any time during hospitalization were associated with increased mortality. Conclusion(s): coronavirus 2 hepatitis may lead to poor outcomes in patients who are hospitalized for the disease. Therefore, monitoring liver chemistries, especially AST is necessary for hospitalized patients with COVID-19.Copyright © 2023

Cardiac Management in Pediatric COVID-19 Disease

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can involve children of all ages, although less frequently and with a milder presentation than adults. Cardiovascular abnormalities (myocardial injury, acute myocarditis, cardiomyopathy, heart failure, arrhythmias, pericarditis, cardiogenic shock, pulmonary embolism, myocardial infarction) may accompany, especially with the multisystem inflammatory syndrome in children and adolescents (MIS-C). Severe disease is managed in the hospital setting. Supportive care is the mainstay of therapy. Antiviral therapy, immune-mediated therapies, empiric antibiotics, and therapy for influenza infection are used in selective patients. Cardiac management focuses on maintaining hemodynamic stability and providing adequate systemic perfusion. Children presenting with shock should be resurrected according to standard protocols. Vasoactive agents such as epinephrine or norepinephrine and, if possible, milrinone is used in fluid-refractory shock. Children with Kawasaki disease (KD) features should receive standard therapies for KD, including intravenous immune globulin (IVIG), aspirin, and glucocorticoids. Patients with severe LV dysfunction, intravenous diuretics and inotropic agents, such as milrinone, dopamine, and dobutamine are suggested. Continuous cardiac monitoring is essential. In cases of the fulminant disease, mechanical hemodynamic support may be necessary. For moderate or severe manifestations (shock, left ventricular systolic dysfunction, elevated troponin or brain natriuretic peptide, arrhythmia, coronary artery aneurysm, or presentations requiring PICU care), therapy with combined IVIG plus a glucocorticoid is suggested. Patients may be at risk for venous thromboembolism due to COVID- 19 associated hypercoagulability. Patients with MIS-C and those with severe LV dysfunction or CA aneurysms are at increased risk. It is suggested that all patients with MIS-C receive low-dose aspirin, and severe cases requiring PICU care receive prophylactic-dose anticoagulant therapy. Patients with current or prior VTE, severe LV dysfunction, large or giant CA aneurysms, markedly elevated D-dimer should receive therapeutic anticoagulation (low molecular weight heparin) plus aspirin. Most children with cardiac involvement have recovery of function by hospital discharge. The overall mortality rate for MIS-C is approximately 1 to 2 percent. Cardiology follow-up after discharge is recommended.

IMPACT of COVID-19 PANDEMIC on HEALTHCARE RESOURCE USE and CLINICAL OUTCOMES in A COHORT of PATIENTS with SYSTEMIC AUTOIMMUNE DISEASES-AN INTERIM ANALYSIS from the PERMAS PROJECT

Background: Management of the health emergency caused by COVID-19 pandemic majorly disrupted the delivery of healthcare services to patients with chronic conditions like Systemic Autoimmune Diseases (SAD), both because resources were mainly channeled towards the care of infected patients, but also because patients tended to avoid seeking medical care for fear of becoming infected. PER-MAS is a 2-year project aimed at assessing the clinical, psychopathological, and socio-economic impact of COVID-19 in a cohort of patients with SAD. Objectives: To assess the impact of COVID-19 pandemic on drug withdrawal, disease fares and hospitalizations for disease exacerbation in a cohort of patients with SAD through an interim analysis of data from the PER-MAS project. Methods: A sample of 214 consecutive patients was recruited in a reference center for rare and complex autoimmune diseases from April 2021 to January 2022. Inclusion criteria were definite diagnosis of SAD (Connective Tissue Disease (CTD), Inflammatory Arthritis (IA) or Vasculitis), regular follow-up and at least 2 years of disease. Patients were asked to fill out an extensive self-administered questionnaire on disease activity and healthcare resource use during the pandemic (March 2020-moment of assessment). Pre-pandemic (March 2019-February 2020) and early pandemic (March 2020-February 2021) clinical data were recorded through retrospective chart review and patient interview. Results: At enrolment, 119 patients were affected by CTDs (55.6%), 71 by IA (33.18%), 24 by vasculitis (11.21%), with mean age 50.44± 12.97, and mean disease duration 11.17 ± 8.94. 30.37% took steroids, 39.7% hydroxy-chloroquine, 61.68% DMARDs, and 9.3% vasoactive drugs. Overall, disease course was similar in pre-pandemic and early pandemic phase: in the first period, rheumatologic condition was stable in 57.35% of patients, persistently active in 27.3% and 35.61% had ≥ 1 episode of disease exacerbation (mean 0.665±1.15, range 0-6);in the second period, 60.56% of patients was stable, 24.88% persistently active, and 39.44% had ≥1 exacerbation (mean 0.49 ±0.77, range 0-4). Mean number of visits (2.56±2.57 and 2.61±2.79), hos-pitalizations (0.168±0.698 and 0.14±0.473, p=0.6), number of patients with outpatient visits=0 (7.47 vs 7%), and number of patients with ≥ 1 hospital admission (10.28 vs 11.6%) were also similar, while the number of patients with hospital admissions for disease exacerbation was significantly higher in the second period (6.1 vs 11.21%, p=0.001). 170 patients completed the survey: from March 2020 to enrolment, 18.2% suspended ≥1 anti-rheumatic drug (6.25% of them for fear of contracting COVID-19 disease, 15.6% for difficulty in obtaining medications), 20% self-managed ≥ 1 disease exacerbation, and 40% had ≥ 1 telemedicine consult. From March to July 2020, 41.76% had their visit rescheduled (35.23% for hospital access restrictions, 5.3% for travel restrictions, 1.17% for fear). Conversely, only 14.7% of patients had their visit rescheduled (8.23% for hospital access restrictions, 4.7% for other reasons) from July 2020 to enrolment. Conclusion: In the early pandemic phase, overall disease course was similar to the pre-pandemic phase, but we observed an increase in the number of patients with ≥ 1 hospitalization for disease. Moreover, despite our efforts, patients reported a non-negligible rate of drug discontinuation for non-medical indication and difficulty to get access to rheumatologic consultation, highlighting the need of alternative organizational models in case of future pandemics.

Mysterious cause of hypotension in MIS-C

Case Report Multisystem inflammatory syndrome (MIS-C) involves severe multi-organ inflammatory injury 2-6 weeks after COVID-19 infection. Seventy to 85% of patients have cardiovascular involvement, including diminished left ventricular ejection fraction (EF), coronary aneurysm, arrhythmias, valvular dysfunction, and pericardial effusion. Here we present a patient who arrived to the pediatric emergency department (ED) with MIS-C and suspected cardiogenic shock, though without the echocardiogram abnormalities commonly associated with MIS-C. A 7 year old African American male presented for a third time to our ED over the course of 4 days of febrile illness and was found to have MIS-C. During this time, he had no chest pain, palpitations, shortness of breath, or abnormal cardiopulmonary exam. At the first 2 ED visits, he was generally well appearing and after treating fever, had vital signs normal for his age. At his third visit, his vital signs were notable for borderline hypotension 86/48 (threshold 83/39 for his height of 1.25 meters). Troponins, chest X-ray, and EKG were normal. Bedside ultrasound was normal, with EF 55-60% so the hypotension was presumed to be secondary to hypovolemia and sepsis. However, despite 40 mL/kg of fluid boluses and maintenance fluid x1.5, his blood pressure continued to downtrend to a nadir of 79/39. He soon developed an S3 gallop and facial edema indicating fluid overload. His proBNP 4986 pg/mL also resulted at this time, suggesting cardiac injury was present. A formal cardiology echocardiogram confirmed the bedside ultrasound findings, noting normal ventricular size and motion, trivial pericardial effusion, and normal coronary artery size. However, it also detected diastolic dysfunction evident in mildly elevated E/e' of 10.86 of lateral mitral annulus, and 12.7 at medial mitral annulus. Three hours after starting solumedrol for treatment of MIS-C, his blood pressure improved to 110/52. The patient had no further episodes of hypotension, though it is unclear if steroids had resolved this by alleviating the underlying inflammation or as a secondary effect. We present a case of MIS-C that led to diastolic heart failure detected by mild hypotension, elevated proBNP, and subtle findings on formal echocardiogram. Although less common than systolic dysfunction in MIS-C, early recognition of diastolic heart failure is important for effective fluid management and initiation of vasoactive agents in criticallly 'ill patients. Diastolic heart failure with preserved systolic function has been seen on echo of MIS-C patients, and is hypothesized to be the subacute period after recovery of systolic function. However, we did not find clinical symptoms of systolic heart failure prior to the patient's development of diastolic heart failure. It is therefore essential to recognize that a patient with MIS-C may present with diastolic heart failure without preceding symptoms or echo findings of other cardiac anomalies.

Encephalopathy and life-threatening gastrointestinal hemorrhage in a child with mis-c

INTRODUCTION: Multisystem Inflammatory Syndrome in Children (MIS-C) is a recently described phenomenon associated with Coronavirus Disease 2019 (COVID-19). Children typically present with fever and laboratory evidence of systemic inflammation. Additional signs and symptoms can vary widely, leading to diagnostic and management challenges. Given the range of clinical manifestations in children with MIS-C, it is important to report unique cases that represent uncommon but life-threatening complications associated with the disease and its management. DESCRIPTION: A previously healthy 11 year old male was admitted to the pediatric ICU and diagnosed with MIS-C based on clinical appearance, laboratory pattern, and SARS-CoV-2 antibody profile. The patient presented with shock and neurologic symptoms including encephalopathy and dysarthria. The shock was relatively mild and consistent with the hemodynamic profile commonly seen with MIS-C. Brain MRI, obtained to rule out thromboembolic injury, demonstrated cytotoxic edema of the corpus callosum, an imaging finding similar in nature to several previous reports of MRI abnormalities in children with MIS-C. Following administration of intravenous immunoglobulin and pulse dose steroids, the patient convalesced and was discharged home. Medications prescribed at discharge included a steroid taper, aspirin, and proton pump inhibitor. Four days later, he was readmitted with shock and life threatening gastrointestinal hemorrhage. The patient required large scale resuscitation with vasoactive agents and over twice his own circulatory volume in blood products delivered by a rapid infusion system. After extensive evaluation of potential bleeding sources, angiography revealed active bleeding from two arterial vessels supplying the duodenum. The patient demonstrated no further bleeding following successful coil embolization of the two arteries. DISCUSSION: We hypothesize that the vasculitic nature of MIS-C combined with anti-inflammatory and anti-thrombotic therapy placed the patient at risk of hemorrhage. This case highlights unique radiologic features of MIS-C as well as potential complications of treatment and the disease process itself. To our knowledge, this is the first report of a child with life-threatening GI hemorrhage in the setting of MIS-C.

Long-term cardiac outcome in patients with multisystem inflammatory syndrome in children (MIS-C)

Introduction: Multisystem Inflammatory Syndrome in children (MISC) was initially described during the first phase of COVID-19 pandemic as a severe clinical condition with systemic inflammation and multi-organ involvement. Many patients show features of Kawasaki Disease. Cardiac involvement, from myocarditis to coronary abnormalities, is a key feature of the syndrome, but there are still little data concerning the long-term outcome in these patients. Objectives: The aim of our study was to evaluate long-term cardiac outcome in patients diagnosed with MIS-C during the first phase of COVID-19 pandemic in Italy. Methods: We previously published the results of the Italian multicenter survey of MIS-C, launched by the Rheumatology Study Group of Italian Pediatric Society during the first wave of COVID-19 pandemic. For each patient who received MIS-C diagnosis, we collected demographic, clinical, laboratory data, imaging findings, and treatment information in an online anonymized database (RedCAP). Data collection included all the admission period and all follow/up visits. For the purpose of this study, we analyzed all patients with at least 3months of follow/up mainly focusing on heart involvement. Results: Fifty-three patients who received MIS-C diagnosis between February 1st and May 31st 2020 were included in our study. The median age at diagnosis was 7 years (IQR 4,5-11). Forty-one patients showed cardiac involvement during the course of the disease. Treatment with IVIG was reported in 66% of patients at diagnosis and glucocorticoids in 56,6%. Four patients received treatment with IL-1 receptor antagonist (anakinra) and one with hydroxychloroquine. Use of vasoactive agents was reported in 20,8% of patients. No case of death was reported in our population. Data on cardiac outcome were available for 33 patients after a median time of follow-up of 6 months (IQR 7.2- 4.08). Twenty-eight out of 33 patients presented a cardiac involvement during hospitalization for MIS-C: 17 had myocarditis, 5 had pericarditis, 3 coronary artery abnormalities, 8 heart failure, 9 valvular insufficiency, 11 shock or hypotension. For each patient cardiac outcome was assessed by heart ultrasonography. At the end of our follow-up period only four patients still had heart abnormalities: all of them presented mild valvular insufficiency and 2 patients still had ultrasonographic signs of hypokinesia. None of them was on medication. Conclusion: MIS-C is an emerging inflammatory condition that spreads among the pediatric population in parallel to SARS-CoV2 pandemic. The disease is frequently complicated by cardiological involvement but, differently to Kawasaki disease, myocarditis and shock are the most common complications. As we reported in our previous study, short-term outcome is usually good in children with MIS- C and heart involvement. With this study we also provide a long-term cardiac follow-up and we showed that only a minority of patients with previous cardiac involvement presented minor heart abnormalities. Furthermore, no patients developed new heart disease during follow-up.

Multisystem inflammatory syndrome in children: results of a multicenter Italian survey during SARS-COV2 pandemic

Introduction: Multisystem Inflammatory Syndrome in children (MISC) was initially described during the first phase of COVID-19 pandemic as a severe clinical condition with systemic inflammation and multi-organ involvement. We previously published the results of the Italian multicenter survey of MIS-C, launched by the Rheumatology Study Group of Italian Pediatric Society We suggested that SARS-Cov- 2 might determine two types of inflammatory diseases in children: the classic KD, that could be triggered by the coronavirus, and the multisystem inflammatory syndrome, which has some specific clinical peculiarities. Objectives: The aim of our study was to analyze clinical features, laboratory findings and treatment strategies in patients diagnosed with MIS-C in Italy during SARS-CoV2 pandemic and evaluate if different outcomes may be related to different disease phenotype in order to establish specific prognostic criteria. Methods: This is an observational, retrospective, multicenter study. We enrolled the children hospitalized between September 1st 2020 and April 30th, 2021 with clinical diagnosis of multi-inflammatory syndrome (MIS-C). For each patient who received MISC diagnosis, we collected demographic, clinical, laboratory data, imaging findings, and treatment information in an online anonymized database (REDCap). We focused on the following main outcomes: the presence of heart abnormalities at dischargement, ICU admission, need of respiratory support or vasoactive agents and number of IVIG cycle administered analyzing a possible relationship with different disease phenotype. Results: 186 children were included in the study. The median age at presentation was 8 years (4-11), 103 (55%) patients were male and 83 (45%) female. 23 (12%) patients had pre-existing comorbidities. 130 (70%) patients presented a positive IgG serology for SARS-CoV-2 and 51% of patients reported a close contact. Markers of systemic inflammation at onset was elevated in all patients: CRP 143,2 mg/dl (111,0- 156,3), ESR 51,5 mm/h (51,0 -54,5), neutrophils 8200/mmc (6490-9011), D-dimer 2175 ng/ml (1076 - 2814). 16 (8%) children needed oxygen supplementation at baseline. 129 patients showed cardiac involvement characterized by myocarditis (23%), valve dysfunction (20%), hypotension (19%) and heart failure (15%). MAS was a complication in 11(6%) patients. ICU admission was required in 40 patients (22%). In our study, a majority of patients were treated with glucocorticoids (77%) and intravenous immunoglobulin (91%), of which 9% receveid two doses of IGEV. At dischargement heart ultrasonography showed valvular insufficiency (19%) and coronary abnormalities (8%). Conclusion: MIS-C has an extensive clinical spectrum that led to serious and life-threating illness. Systemic inflammation and specific organ involvement of cardiac and gastrointestinal involvement are the hallmarks. Good outcomes depends on prompt recognition and timely treatment, based on the combined use of glucocorticoids, high-dose immunoglobulins and anti-cytokine therapy.