COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; revisiting the Western New York approach as the pandemic evolves.

Multisystem inflammatory syndrome of children (MIS-C) continues to be a highly concerning diagnosis in those recently infected with SARS-CoV-2. The diagnosis of MIS-C cases will likely become even more challenging as vaccine uptake and natural immunity in previously infected persons leads to lower circulating rates of SARS-CoV-2 infection and will make cases sporadic. Febrile children presenting with cardiac dysfunction, symptoms overlapping Kawasaki disease or significant gastrointestinal complaints warrant a thorough screen in emergency departments, urgent care centers, and outpatient pediatric or family medicine practices. An increased index of suspicion and discussion regarding higher level of care (transferring to pediatric tertiary care centers or to intensive care) continues to be recommended. Herein we outline a broad approach with a multidisciplinary team for those meeting the case definition and believe such an approach is crucial for successful outcomes.

Case report: A case of severe retropharyngeal edema after COVID-19 successfully treated with intravenous immunoglobulin.

Multisystem inflammatory syndrome in children (MIS-C) has been widely reported, mainly in Western countries. The clinical features of MIS-C and Kawasaki disease are similar. The latter is common in Asian countries, including Japan. Meanwhile, the incidence of MIS-C seems to be low in Japan. Retropharyngeal edema is relatively common in older patients with Kawasaki disease and has been reported in a few patients with MIS-C. We describe a case of severe retropharyngeal edema after coronavirus disease 2019 (COVID-19) that improved quickly with high-dose of intravenous immunoglobulin treatment. Onset of retropharyngeal edema was 3 weeks after COVID-19. The patient received appropriate intravenous antibiotics for 5 days, but his symptoms worsened. Therefore, we suspected that his retropharyngeal edema was caused by suspected MIS-C even though he did not have the typical clinical symptoms of suspected MIS-C such as gastrointestinal symptoms and shock. Retropharyngeal edema was refractory to antibiotic therapy but lessened quickly with high-dose immunoglobulin therapy, without other typical clinical manifestations of MIS-C, suggesting that early immunoglobulin therapy might prevent the progression of MIS-C.

Case Report: High-dose steroid and IVIG successful treatment in a case of COVID-19-associated autoimmune encephalitis: a literature review.

Autoimmune encephalitis is a rare but critical complication of COVID-19. The management of COVID-19-associated autoimmune encephalitis includes the use of steroids, intravenous immunoglobulin (IVIG), plasmapheresis, and monoclonal antibody therapy. This study presented a patient with critical COVID-19 autoimmune encephalitis who rapidly recovered after the initiation of corticosteroids and IVIG therapy. This study reviewed the current literature on the pathophysiological mechanisms, diagnosis, and management of COVID-19-associated autoimmune encephalitis.

Hemolytic anemia following intravenous immunoglobulins in children with PIMS-TS: Two case reports.

This is the first case report on two children presenting with immediate and severe hemolytic anemia following the administration of high-dose intravenous immunoglobulins (IVIGs) in the context of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Hemolytic anemia was described as a significant decrease in hemoglobin and an increase in lactate dehydrogenase after the second administration of high-dose IVIGs was performed. Both patients were found to have AB blood group. One of our patients showed massive pallor, weakness, and inability to walk in association with hemolysis. However, in both cases, the anemia was self-limiting and transfusion of red blood cells was not required: both patients recovered without persistent impact. Nonetheless, we aim to draw attention to this widely unknown adverse effect of IVIG, especially in the context of PIMS-TS. We suggest determining the patient's blood group prior to high-dose IVIG infusion and replacing the second IVIG through high-dose steroids or anticytokine therapy. Using IVIGs containing lower titers of specifically anti-A or anti-B antibodies to avoid isoagglutinin-caused hemolytic anemia is desirable; however, the information is not routinely available.

Multisystem Inflammatory Syndrome therapies in children (MISTIC): A randomized trial.

Background: Multisystem Inflammatory Syndrome in Children (MIS-C), which occurs 2-6 weeks after initial exposure to SARS-CoV-2, was first identified in early 2020 when patients presented with fever and significant inflammation, often requiring management in the intensive care unit. To date, there has been no clinical trial to determine the most effective treatment. This study compares anti-inflammatory treatments that were selected based on current treatments for Kawasaki disease, a coronary artery vasculitis that shares many clinical features with MIS-C. Methods: This randomized, comparative effectiveness trial of children with MIS-C uses the small N Sequential Multiple Assignment Randomized Trial (snSMART) design for rare diseases to compare multiple therapies within an individual. Study participants were treated first with intravenous immunoglobulin (IVIG), and if needed, subjects were then randomized to one of three additional treatments (steroids, anakinra, or infliximab). Participants were re-randomized to remaining treatments if they did not demonstrate clinical improvement. Conclusion: This trial continues to enroll eligible participants to determine the most effective therapies in addition to IVIG and best order in which to use them to treat MIS-C. Trial Registration: NCT04898231.

HTLV-1-associated demyelinating neuropathy: A case report and review of the literature.

A 78-year-old man developed paresthesias in the extremities. He was referred to our hospital because of positive anti-human T-cell leukemia virus type 1 (HTLV-1) antibodies in the serum and the presence of abnormal lymphocytes. He was diagnosed as chronic-type adult T-cell leukemia/lymphoma. Neurological examination revealed sensory impairment in the distal parts of the extremities with loss of deep tendon reflexes. Nerve conduction study showed motor and sensory demyelinating polyneuropathy, indicating a diagnosis of HTLV-1-associated demyelinating neuropathy. Corticosteroid therapy followed by intravenous immunoglobulin therapy improved his symptoms. Since demyelinating neuropathy associated with HTLV-1 infection is not well recognized, we here report its characteristics and clinical course through our case report and literature review.

Efficacy and safety of treatments in newly diagnosed adult primary immune thrombocytopenia: A systematic review and network meta-analysis.

Background: Immune thrombocytopenia is an autoimmune disease characterised by decreased platelet count. In recent years, novel therapeutic regimens have been investigated in randomised controlled trials (RCTs). We aimed to compare the efficacy and safety of different treatments in newly diagnosed adult primary immune thrombocytopenia. Methods: We did a systematic review and network meta-analysis of RCTs involving treatments for newly diagnosed primary immune thrombocytopenia. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched up to April 31, 2022. The primary outcomes were 6-month sustained response and early response. Secondary outcome was grade 3 or higher adverse events. This study is registered with PROSPERO (CRD42022296179). Findings: Eighteen RCTs (n = 1944) were included in this study. Pairwise meta-analysis showed that the percentage of patients achieving early response was higher in the dexamethasone-containing doublet group than in the dexamethasone group (79.7% vs 68.7%, odds ratio [OR] 1.82, 95% CI 1.10-3.02). The difference was more profound for sustained response (60.5% vs 37.4%, OR 2.57, 95% CI 1.95-3.40). Network meta-analysis showed that dexamethasone plus recombinant human thrombopoietin ranked first for early response, followed by dexamethasone plus oseltamivir or tacrolimus. Rituximab plus prednisolone achieved highest sustained response, followed by dexamethasone plus all-trans retinoic acid or rituximab. Rituximab plus dexamethasone showed 15.3% of grade 3 or higher adverse events, followed by prednis(ol)one (4.8%) and all-trans retinoic acid plus dexamethasone (4.7%). Interpretation: Our findings suggested that compared with monotherapy dexamethasone or prednis(ol)one, the combined regimens had better early and sustained responses. rhTPO plus dexamethasone ranked top in early response, while rituximab plus corticosteroids obtained the best sustained response, but with more adverse events. Adding oseltamivir, all-trans retinoic acid or tacrolimus to dexamethasone reached equally encouraging sustained response, without compromising safety profile. Although this network meta-analysis compared all the therapeutic regimens up to date, more head-to-head RCTs with larger sample size are warranted to make direct comparison among these strategies. Funding: National Natural Science Foundation of China, Major Research Plan of National Natural Science Foundation of China, Shandong Provincial Natural Science Foundation and Young Taishan Scholar Foundation of Shandong Province.

Potential intravenous immunoglobulin-induced optic disc edema.

Purpose: To report a case of recurrent and bilateral optic disc edema following intravenous immunoglobulin (IVIG) administration. Observations: A 46 year-old woman received IVIG on 3 separate occasions over 7 years for Non-Hodgkin's Lymphoma (NHL) and each time developed headaches and transient visual disturbance, and was subsequently found to have bilateral optic disc swelling. Lumbar puncture confirmed raised cerebrospinal fluid (CSF) opening pressure and there was resolution following treatment with oral acetazolamide (Diamox). Conclusions and importance: To our knowledge there is no literature on papilledema following administration of IVIG. This case is pertinent for physicians treating patients with IVIG who develop headache, transient visual disturbance and optic disc edema.

Differential Treatment Effects for Renal Transplant Recipients With DSA-Positive or DSA-Negative Antibody-Mediated Rejection.

BACKGROUND: Antibody-mediated rejection (ABMR) is the main cause of renal allograft loss. The most common treatment strategy is based on plasmapheresis plus the subsequent administration of intravenous immunoglobulin (IVIG). Unfortunately, no approved long-term therapy is available for ABMR. The current study was designed to analyze the effect of various ABMR treatment approaches on allograft survival and to compare treatment effects in the presence or absence of donor-specific antibodies (DSAs). METHODS: This single-center study retrospectively analyzed 102 renal allograft recipients who had biopsy-proven ABMR after transplant. DSA was detectable in 61 of the 102 patients. Initial standard treatment of ABMR consisted of plasmapheresis (PS) or immunoadsorption (IA), followed by a single course of IVIG. In case of nonresponse or recurrence, additional immunosuppressive medications, such as rituximab, bortezomib, thymoglobulin, or eculizumab, were administered. In a second step, persistent ABMR was treated with increased maintenance immunosuppression, long-term therapy with IVIG (more than 1 year), or both. RESULTS: Overall graft survival among transplant patients with ABMR was <50% after 3 years of follow-up. Compared to the use of PS/IA and IVIG alone, the use of additional immunosuppressive medications had no beneficial effect on allograft survival (p = 0.83). Remarkably, allografts survival rates were comparable between patients treated with the combination of PS/IA and IVIG and those treated with a single administration of IVIG (p = 0.18). Renal transplant patients with ABMR but without DSAs benefited more from increased maintenance immunosuppression than did DSA-positive patients with ABMR (p = 0.01). Recipients with DSA-positive ABMR exhibited significantly better allograft survival after long-term application of IVIG for more than 1 year than did recipients with DSA-negative ABMR (p = 0.02). CONCLUSIONS: The results of our single-center cohort study involving kidney transplant recipients with ABMR suggest that long-term application of IVIG is more favorable for DSA-positive recipients, whereas intensification of maintenance immunosuppression is more effective for recipients with DSA-negative ABMR.

A young child with pediatric multisystem inflammatory syndrome successfully treated with high-dose immunoglobulin therapy.

Pediatric multisystem inflammatory syndrome (MIS-C) is a disease that presents mainly in older children after coronavirus disease 2019 (COVID-19) and is associated with Kawasaki-like symptoms and multiple-organ failure. The number of cases of MIS-C has increased since April 2020, with reports mainly from Europe and the United States. The reason is unclear, but few cases of MIS-C have been reported in Asian countries, including Japan. No treatment has been established for MIS-C. In this study, we report the case of a young boy treated with IVIg for MIS-C by measuring the cytokine profile over time. A 4-year-old boy presented with Kawasaki disease-like symptoms 28 days after a positive result from polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), meeting the World Health Organization criteria for MIS-C diagnosis. Blood tests showed lower levels of C-reactive protein and ferritin, and no decrease in lymphocyte count (<1000/µL) or more increase in fibrinogen than those reported in Japan for MIS-C in school-aged children and older. Neopterin, interleukin (IL)-6, IL-18, soluble tumor necrosis factor receptor (sTNF-R)I and sTNF-RII were all high at disease onset, but neopterin, IL-6, and sTNF-RII rapidly decreased with fever resolution after the second dose of IVIg, while IL-18 and sTNF-RI decreased bimodally. As far as we can determine, this case represents the youngest identified in Japan. The key point of difference between MIS-C and Kawasaki disease is older age in MIS-C, but attention is also needed in infants.

SARS-CoV-2/COVID-19 associated pediatric acute-onset neuropsychiatric syndrome a case report of female twin adolescents.

"Pediatric acute-onset neuropsychiatric syndrome", or PANS, is a rare syndrome characterized by an acute onset of obsessive-compulsive disorder (OCD), and/or severely restricted food intake accompanied by a variety of neuropsychiatric symptoms. To our knowledge, this is the first case report of twin adolescents with COVID-19-associated PANS. Dizygotic twin sisters in late teens, with abrupt and acute onset of severely restrictive food intake, weight loss, OCD, anxiety with intermittent auditory and visual hallucinations, depression, attention deficit, and sleep disturbances, simultaneously accompanied by milder neurologic symptoms such as hand tremor, tinnitus, dizziness, headache, and weakness of proximal muscles, were applied to child and adolescent psychiatry clinic. The only relevant agent underlying those neuropsychiatric and somatic complaints was COVID-19, and it was validated with laboratory testing, such as positive IgG titers of SARS-CoV-2 and negative biomarkers for other possible bacterial or viral agents. Generalized epileptic anomaly and a vermian/folial atrophy in the cerebellum were detected in further evaluations. Treatment options consisted of psychotropic agents, antibiotics, antiepileptic, and intravenous immunoglobulin transfusion finely treated the neuropsychiatric symptoms. Clinicians should consider SARS-CoV-2 as a potential agent, when a child presents with abrupt onset, dramatic neuropsychiatric symptoms also consisting of PANS, even in asymptomatic patients or with mild respiratory symptoms.

MOG antibody associated disease (MOGAD) presenting with extensive brain stem encephalitis: A case report.

Background: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a relatively new entity of demyelinating diseases, clinically presenting with optic neuritis, transverse myelitis, or encephalic symptoms. Typical radiological features include demyelinating cerebral and spinal lesions, cortical involvement, leptomeningeal enhancement, or tumefactive lesions. Here we present a rare case of a young patient with extensive brain stem lesion on the MRI while exhibiting nystagmus, singultus and somnolence. Case presentation: A 30-year-old male patient presented initially with fever and impaired consciousness, but furthermore developed nystagmus, singultus and tetraparesis during the following week. Repeated MRI examinations revealed extensive brain stem edema with notable bilateral affection of the cerebellar peduncles and the pons. Antiviral and antibiotic treatment was changed to intravenous corticosteroids and immunoglobulins as soon as the diagnosis of MOGAD was established by testing serum and cerebrospinal fluid positive for MOG specific antibodies. MRI alterations vanished completely over time with a delayed, nearly complete clinical recovery of our patient. Conclusion: Brain stem affection in MOGAD is rare. However, in patients presenting with an unclear brain stem encephalitis the possibility of MOGAD should be considered and tested using MOG antibodies. In case of a positive testing treatment with steroids and immunoglobulins seems recommendable.

Invasive Pulmonary Aspergillosis and Tuberculosis Complicated by Hemophagocytic Lymphohistiocytosis - Sequelae of COVID-19 in a Liver Transplant Recipient.

Liver transplant recipients are at an increased risk of opportunistic infections due to the use of immunosuppression. Coronavirus disease of 2019 (COVID-19) increases the risk of these infections further due to associated immune dysfunction and the use of high-dose steroids. We present a case of a liver transplant recipient who developed disseminated tuberculosis and invasive pulmonary aspergillosis complicated by acquired hemophagocytic lymphohistiocytosis after recovering from severe COVID-19.

Acute Graft Versus Host Disease Following Liver Transplantation: Case Report With Review of Current Literature.

Graft verus host disease (GVHD) following Liver transplantation is rare life threatening complication with very high mortality rate around 85%. Due to increased recognition of this condition management approach is rapidly evolving due to newer diagnostic methods and drugs. Etiology, risk factors, pathogenesis, preventive strategies, management approach and newer drugs are discussed. We present our experience of 2 cases from a large cohort of 1052 Liver transplant operations over a decade.

Clinical aspects and presumed etiology of multisystem inflammatory syndrome in children (MIS-C): A review.

The COVID-19 outbreak sparked by SARS-CoV-2, begat significant rates of malady worldwide, where children with an abnormal post-COVID ailment called the Multisystem Inflammatory Syndrome (MIS-C), were reported by April 2020. Here we have reviewed the clinical characteristics of the pediatric patients and the prognosis currently being utilized. A vivid comparison of MIS-C with other clinical conditions has been done. We have addressed the probable etiology and fundamental machinery of the inflammatory reactions, which drive organ failure. The involvement of androgen receptors portrays the likelihood of asymptomatic illness in children below adolescence, contributing to the concept of antibody-dependent enhancement.

Successful Treatment of Pembrolizumab-Induced Severe Capillary Leak Syndrome and Lymphatic Capillary Dysfunction.

Although capillary leak syndrome has a high mortality rate, its trigger, diagnosis, and treatment remain a challenge to clinicians because of the poor understanding of its mechanism and lack of treatment guidelines. With the extended use of immune checkpoint inhibitors in modern oncology, immune checkpoint inhibitor-associated immune-related adverse events have also expanded. We present a case of pembrolizumab-induced capillary leak syndrome and lymphatic capillary dysfunction in which the patient had an excellent clinical response to a tailored treatment strategy.

Corrigendum: MIS-C Treatment: Is IVIG Always Necessary?

[This corrects the article DOI: 10.3389/fped.2021.753123.].

MIS-C Treatment: Is IVIG Always Necessary?

Background: MIS-C is a potentially severe inflammatory syndrome associated with SARS-CoV-2 exposure. Intravenous immunoglobulin (IVIG) is considered the first-tier therapy, but it implies infusion of large fluid volumes that may worsen cardiac function. Patients and Methods: Since April 2020, we have developed a treatment protocol that avoids the infusion of IVIG as first-line therapy in the early phase of MIS-C. In this study, we retrospectively analyzed a cohort of consecutive patients treated according to this protocol between 01/04/2020 and 01/04/2021. Results: In the last year, 31 patients have been treated according to the protocol: 25 with high-dose pulse MP (10 mg/kg) and 6 with 2 mg/kg. 67.7% of the patients responded to the initial treatment, while the others needed a step-up, either with Anakinra (25.8%) or with MP dose increase (6.5%). IVIG was administered in four patients. Overall, only one patient (3.2%) needed ICU admission and inotropic support; one patient developed a small coronary artery aneurysm. Conclusions: Timely start of MP therapy and careful fluid management might improve the outcomes of MIS-C patients.

Early Immunosuppression and Rapid Recovery of Cardiogenic Shock in Multisystem Inflammatory Syndrome From Convalescent COVID-19.

A previously healthy 39-year-old man presented in cardiogenic shock with evidence of multisystem inflammatory syndrome of adults 2 months after a mild case of coronavirus disease 2019. He was treated with intravenous immunoglobulin and pulse-dose corticosteroids with rapid resolution of his symptoms and normalization of biventricular function. (Level of Difficulty: Intermediate.).