A variant of KSHV-associated inflammatory cytokine syndrome in elderly men of Mediterranean descent.

The spectrum of HHV-8-associated disorders includes Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease, and the recently described KSHV inflammatory cytokine syndrome (KICS), a life-threatening disorder complicating HIV infection. There have been no reports in the literature concerning non-immunosuppressed individuals affected with KICS. We report here a KICS-like illness occurring in two elderly Greek men without HIV infection or other recognizable cause of immunosuppression.

Clinical Presentation and Management of Multisystem Inflammatory Syndrome in Children With COVID-19: A Systematic Review.

Multisystem inflammatory syndrome in children (MIS-C) is a relatively new syndrome associated with coronavirus disease 2019 (COVID-19) that is characterized by a severe clinical course compared to pediatric COVID-19. This review aimed to compile the available evidence on the clinical presentation and management of MIS-C in children with COVID-19. During this systematic review, a comprehensive search was performed in the following databases: PubMed, Embase, Medline, Google Scholar, Cochrane, and Scopus, using predetermined search terms, such as Medical Subject Headings (MeSH) and keywords to find relevant studies on the MIS-C. Relevant data were extracted, and the quality of the studies was evaluated using suitable methods. The collected findings were synthesized and discussed in the study. The World Health Organization's (WHO) definition of MIS-C was the most favored due to its precision and inclusiveness. MIS-C primarily affected children aged 6-12 years, with male predominance. MIS-C involves a range of systems, including gastrointestinal, cardiovascular, hematologic, mucocutaneous, and respiratory. Radiographic findings revealed cardiovascular abnormalities, solid visceral organ involvement, and bowel abnormalities, reflecting a systemic inflammatory process. Laboratory investigations unveiled elevated inflammatory markers, neutrophil activation, release of extracellular traps in vessels, elevated procalcitonin, hyponatremia, hypoalbuminemia, low hemoglobin, and thrombocytopenia. The inflammatory markers and autoantibody profiles are essential in differentiating MIS-C from COVID-19. The preferred treatment primarily involves immunomodulatory therapies like intravenous immunoglobulin (IVIG), glucocorticoids, and interleukin-6 or 1RA inhibitors or a combination of those. In severe cases, extracorporeal membrane oxygenation (ECMO) and mechanical ventilation are necessary, leading to reduced mortality and quick recovery. This review found that the average hospital stay was seven days, and most discharged children fully recovered within seven days. MIS-C is a life-threatening post-COVID-19 condition and involves multiple systems due to systemic inflammation, with elevated inflammation markers. Recognition of multisystem involvement is crucial, and prompt identification and multidisciplinary treatment are vital for optimal outcomes.

Spectre of COVID-19 infection confounding myocarditis related to cytomegalovirus mononucleosis syndrome and hyperinflammatory syndrome.

Viral infections have multiple mechanisms of affecting internal and external organs by direct invasion or by molecular mimicry. They have also been described as triggers for inflammatory processes like hyperinflammatory syndrome (HIS), Adult-onset Stills Disease (AOSD), and myocarditis [1]. Here we report an interesting case of a young adult with recent infection with SARS-CoV-2 (COVID-19) who presented with myocarditis requiring circulatory support in the cardiac care unit. During the admission, he was found to have concurrent cytomegalovirus (CMV) mononucleosis syndrome and presentation consistent with HIS resembling AOSD. This patient had multiple etiologies that could have caused myocarditis: CMV infection, COVID-19 infection, and HIS. As noted, viral infections have been proposed as potential triggers for the onset of HIS and AOSD with unknown mechanisms. We aim to add to the literature regarding CMV infection in an immunocompetent host causing myocarditis and HIS with features of AOSD with recent history of COVID-19 infection.

Hyperinflammatory syndrome in a paediatric patient with a recent diagnosis of HIV/AIDS infection: hemophagocytic lymphohistiocytosis or immune reconstitution syndrome?

INTRODUCTION: Haemophagocytic lymphohistiocytosis is a rare and life-threatening condition caused by uncontrolled immune activation leading to excessive inflammation and tissue destruction. It could either be due to a primary genetic defect or be triggered by secondary causes such as infections, autoimmune diseases, rheumatological diseases or post-transplant immunosuppression. We here report the case of a 4-year-old child with a recent AIDS diagnosis who developed a severe systemic inflammation. CASE REPORT: We here report the case of a 4-year-old child with a recent AIDS diagnosis who was admitted to the ER with acute respiratory failure due to Pneumocystis jiroveci infection and Aspergillosis; the following microbiological assessment also showed a CMV, HSV, EBV and HHV-7 coinfection. On the 51st day after she'd started antiretroviral therapy, 39th after she'd followed a course of Bactrim and Caspofungin for PJI and Ambisome for pulmonary Aspergillosis, she started presenting fever, unresponsive to broad-spectrum antibiotic therapy. She also presented worsening of her clinical conditions, with evidence at the laboratory assessments of progressive raise in inflammatory indexes, coagulopathy, trilinear cytopenia and hyperferritinemia. To perform the differential diagnosis between IRIS and HLH, HLA-DR on T cells was studied, turning out negative for IRIS. Therefore, in the suspicion of HLH, a bone marrow aspirate and biopsy were performed with evidence of trilinear cytopenia, prevalence of T-cells and macrophages with signs of phagocytosis. She was started on high-dose steroids and Anakinra for a total of 29 days, resulting in prompt apyrexia and progressive improvement of her clinical conditions and laboratory results. CONCLUSION: To the best of our knowledge there is poor literature available about the differential diagnosis of HLH and IRIS, therefore medical management in the concurrence of these two conditions needs to be further investigated, especially in a setting where immunological testing is not quickly available. The clinical differences between these pathologies are blurred and the bone marrow biopsy within marker for IRIS helped us to distinguish these two entities.

Human Adenovirus Infection Causing Hyperinflammatory Syndrome Mimicking Multisystem Inflammatory Syndrome in Children (MIS-C): A Case Report.

Transmission of human adenovirus (HAdV) infection and the associated clinical disease can be sporadic or epidemic and manifestations may range from mild infection to severe disease. HAdV has been seen to behave as a proinflammatory virus that can trigger the release of high levels of inflammatory cytokines and chemokines in children. Here, we report an unusual case of an infant with HAdV infection who presented with respiratory illness, with a protracted course, complicated with hyperinflammation and multi-system involvement with clinical characteristics mimicking multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease. The patient was an 11-month-old male infant with a background of infantile epilepsy, epileptic encephalopathy, hemimegaloencephaly, and global developmental delay, diagnosed as Ohtahara syndrome. He was admitted with a three-day history of cough, cold, fever, and respiratory distress. Management was initiated with a heated humidified high-flow nasal cannula and given ceftriaxone and hypertonic saline nebulization. Additionally, he developed loose motion on the fifth day of admission. The reverse transcriptase polymerase chain reaction (RT-PCR) of the nasopharyngeal swab was positive for HAdV. Due to persistent fever, elevated inflammatory markers, multisystem involvement (diarrhea, coagulopathy), an absence of a clear microbial etiology, and an epidemiologic link to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, MIS-C was diagnosed. The first dose of intravenous immunoglobulins (IVIG) was administered over the course of 48 hours and the baby required a second dose of IVIG as the fever failed to settle after the first dose. Within 24 hours of the second IVIG dose, defervescence occurred. His platelet count started to rise, and the baby developed thrombocytosis in the third week of illness. Echocardiography was suggestive of dilatation of mild left main coronary artery. He was weaned off oxygen support by day 14 and discharged on day 17. To our knowledge, this is the first reported case of HAdV infection with hyperinflammatory syndrome and vasculitis akin to MIS-C and Kawasaki disease.

Severe COVID-19-associated hyperinflammatory syndrome versus classic hemophagocytic lymphohistiocytosis: similarities, differences, and the way forward.

The hyperinflammatory immune response in severe COVID-19 infection shares features with secondary hemophagocytic lymphohistiocytosis (sHLH) in the form of fever, cytopenia, elevated inflammatory markers, and high mortality. There are contrasting opinions regarding utility of HLH 2004 or HScore in the diagnosis of severe COVID-19-related hyperinflammatory syndrome (COVID-HIS). This was a retrospective study of 47 patients of severe COVID-19 infection, suspected to have COVID-HIS and 22 patients of sHLH to other illnesses, to evaluate the diagnostic utility and limitations of HLH 2004 and/or HScore in context to COVID-HIS and to also evaluate the utility of Temple criteria for predicting severity and outcome in COVID-HIS. Clinical findings, hematological, and biochemical parameters along with the predictor of mortality were compared between two groups. Only 6.4% (3/47) of cases fulfilled ≥5/8 HLH 2004 criteria and only 40.52% (19/47) of patients showed HScore >169 in COVID-HIS group. 65.9% (31/47) satisfied the Temple criteria in COVID-HIS as compared with 40.9% (9/22) in the non-COVID group (p = 0.04). Serum ferritin (p = 0.02), lactate dehydrogenase (p = 0.02), direct bilirubin (p = 0.02), and C-reactive protein (p = 0.03) were associated with mortality in COVID-HIS. Both HScore and HLH-2004 criteria perform poorly for identifying COVID-HIS. Presence of bone marrow hemophagocytosis may help to identify about one-third of COVID-HIS missed by the Temple Criteria.

Methylprednisolone pulses as an initial treatment in hyperinflammatory syndrome after COVID-19 in children: evaluation of laboratory data, serial echocardiography and outcome: a case series.

BACKGROUND: Hyper-inflammatory syndrome in children and young adult occur 2-6 weeks after COVID-19 infection or closed contact with COVID-19 persons. In this study, the laboratory data and echocardiography and abdominal ultrasonography assessments were evaluated before and after Methylprednisolone pulse as an initial treatment of hyper-inflammatory syndrome. Therefore, the aim of this study is to assessment the clinical manifestations and laboratory data and outcome after methylprednisolone pulse as an initial treatment. METHOD: In this retrospective study, the demographic status, clinical features, laboratory data, echocardiography, abdominal ultrasound, treatment and outcome of 31 pediatric patients under 16 years old, with inflammatory process after COVID-19 were evaluated. The clinical assessments, laboratory data, sonography and echocardiography were evaluated before and after methylprednisolone pulse. The patients were divided in two age group < and ≥ 7 years old and the clinical manifestations were compared with each other. The Mann-Whitney U test was used to assess the difference in quantitative variables between two groups. To compare pre- and post- treatment values, Wilcoxol test was used. To assess the correlation between qualitative variables chi-square test was used. The level of significant was considered 0.05. These patients with fever and hyper-inflammation features admitted to the referral pediatric rheumatology ward in Children Medical Center of Tehran University of medical sciences, from April 2020 to May 2021 were assessed. RESULT: The mean age ± SD were (5.94 ± 3) and 51.6% (16) patients were male and 48.4% (15) patients were female. The most documented of previous COVID infection were antibody positive in about 27 (87%) patients. Moreover, 1 (3.8%) was PCR positive, 2 (7.7%) were positive in both PCR and serology and 3(11.5%) had closed contact with COVID-19 patients. About 9(29%) of patients were admitted in Intensive Care Unit (ICU). There were significant correlation between days of delay in starting treatment and ICU admission (P-value = 0.02). The mortality rate was negative in patients and no re-hospitalization was documented. There were significant differences (P-value < 0.05) between lymphocytes, platelet, Erythrocyte Sedimentation rate, C-reactive protein, Aspartate transaminase, Alanine transaminase and ferritin before and after treatment. Skin rashes and cardiac involvement totally as carditis (myocarditis, vulvulitis and pericarditis) (33.3%) and coronary involvements (53.3%) were the most prominent initial presentation in patients. There were near significant correlation (P-value = 0.066) between ferritin level and carditis before treatment. Cervical lymphadenopathy was seen significantly more in ≥ 7 years old (P-value = 0.01). CONCLUSION: Multisystem inflammatory system in children as a hyperinflammatory syndrome could be treated with first step methylprednisolone pulse with decreasing inflammation in laboratory data and cardiac involvements and good outcome. Furthermore, the ferritin level may be one of the predictor of severe hyper-inflammatory syndrome leading to aggressive and urgent treatment with methylprednisolone pulse.

Hyperinflammatory syndrome resembling haemophagocytic lymphohistiocytosis following axicabtagene ciloleucel and brexucabtagene autoleucel.

Haemophagocytic lymphohistiocytosis-like toxicity following chimeric antigen receptor T cells (CAR-HLH) is being increasingly recognized, while published data are limited and criteria for recognition are elusive. We describe three patients who developed CAR-HLH after infusion of brexucabtagene autoleucel (n = 2) or axicabtagene ciloleucel (n = 1). All three patients presented following cytokine release syndrome, with fever, recurrent or worsening cytopenias, hyperferritinaemia, elevated soluble interleukin (IL)-2 receptor, hypofibrinogenaemia, hypertriglyceridaemia, elevated liver transaminases, and decreasing C-reactive protein and IL-6. Clinical improvement following treatment with anakinra (n = 2) and ruxolitinib (n = 1) was observed. Our report offers an opportunity for prompt recognition and initiation of potentially life-saving treatment for CAR-HLH.

Two cases of multisystem inflammatory syndrome in adults: experience at a single centre in Sydney.

We report two cases of middle-aged men who presented with clinical features that satisfied the diagnostic criteria for multisystem inflammatory syndrome in adults (MIS-A). Both patients were treated for toxic shock syndrome and MIS-A and have recovered. The purpose of this article is to communicate our experience and challenges of assessing and treating this condition and to raise awareness of the condition.

New Insights on Effects of Glucocorticoids in Patients With SARS-CoV-2 Infection.

OBJECTIVE: Since January 2020, the highly contagious novel coronavirus SARS-CoV-2 has caused a global pandemic. Severe COVID-19 leads to a massive release of proinflammatory mediators, leading to diffuse damage to the lung parenchyma, and the development of acute respiratory distress syndrome. Treatment with the highly potent glucocorticoid (GC) dexamethasone was found to be effective in reducing mortality in severely affected patients. METHODS: To review the effects of glucocorticoids in the context of COVID-19 we performed a literature search in the PubMed database using the terms COVID-19 and glucocorticoid treatment. We identified 1429 article publications related to COVID-19 and glucocorticoid published from 1.1.2020 to the present including 238 review articles and 36 Randomized Controlled Trials. From these studies, we retrieved 13 Randomized Controlled Trials and 86 review articles that were relevant to our review topics. We focused on the recent literature dealing with glucocorticoid metabolism in critically ill patients and investigating the effects of glucocorticoid therapy on the immune system in COVID-19 patients with severe lung injury. RESULTS: In our review, we have discussed the regulation of the hypothalamic-pituitary-adrenal axis in patients with critical illness, selection of a specific GC for critical illness-related GC insufficiency, and recent studies that investigated hypothalamic-pituitary-adrenal dysfunction in patients with COVID-19. We have also addressed the specific activation of the immune system with chronic endogenous glucocorticoid excess, as seen in patients with Cushing syndrome, and, finally, we have discussed immune activation due to coronavirus infection and the possible mechanisms leading to improved outcomes in patients with COVID-19 treated with GCs. CONCLUSION: For clinical endocrinologists prescribing GCs for their patients, a precise understanding of both the molecular- and cellular-level mechanisms of endogenous and exogenous GCs is imperative, including timing of administration, dosage, duration of treatment, and specific formulations of GCs.

A Case of Delayed COVID-19-Related Macrophage Activation Syndrome.

Although coronavirus disease 2019 (COVID-19) is primarily a respiratory illness, clinical experiences have shown that almost no system is exempted. The severity of the disease can also range from mild presentation with complaints such as headache, aches and pains, taste and sense of smell disturbances to a more severe presentation with acute respiratory distress syndrome (ARDS) that necessitate admission to intensive care units. In such severe presentation, hypercytokinemia, typically found in cytokine storm syndrome (CSS), particularly macrophage activation syndrome (MAS) is often present. CSS can result from diverse, heterogeneous conditions of different clinical phenotypes, such as infections, hematological, rheumatological or iatrogenic conditions leading to systemic hyperinflammation. Some clinical and laboratory findings may give clues to such a highly lethal syndrome and allow early diagnosis and introduction of effective therapy. In this case we describe a COVID-19 pneumonia patient who was discharged home following improvement in his respiratory symptoms to present few days later with a fatal form of CSS, presenting with ARDS, fulminant hepatic failure and coagulopathy.

Hemophagocytic Lymphohistiocytosis Secondary to Immune Checkpoint Inhibitor Therapy.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal systemic inflammatory syndrome. HLH has been reported as a rare immune-related adverse event (irAE) in patients receiving immunotherapy with nivolumab, ipilimumab, and/or pembrolizumab. The data are limited to case reports and case series. The objective of this research is to compile data on this rare but potentially life-threatening adverse event of immune checkpoint inhibitors (ICIs) and identify the common agents that cause this irAE, clinical spectrum, and successful management strategies to assist the treating oncologists. A review was done using PubMed database. Eligible articles included case reports and case series published from January 1, 2015, through February 1, 2021. Reports published in languages other than English were excluded. Data were compiled into a detailed supplementary table and simple descriptive analysis was used to interpret data. A total of 22 cases were included, which constituted 14 individual case reports and two case series. The immunotherapy prescribed consisted of antibodies against and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1) in all 22 patients. Out of them, immunotherapy consisting of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibodies was prescribed in nine patients. Fever was the most common symptom at the presentation (90.9%). The most common laboratory findings were anemia (90.9%), thrombocytopenia (90.9%), and elevated ferritin (90.9%). All the patients received steroids (100%). HLH responded to treatment in 19 patients. Three patients died. Three patients were rechallenged with immunotherapy, with no recurrence of HLH. HLH in the setting of ICI therapy is life-threatening, but potentially treatable with early detection. However, diagnosis is often delayed due to difficulty in differentiating the presenting symptoms and laboratory findings from complications of cancer and other therapies. Majority have shown an adequate response to standard HLH treatment; however, some required a longer course of corticosteroids. HLH is not always associated with other irAE. Rechallenging with immunotherapy was successful in some patients after completing treatment for HLH.

Hemophagocytic Lymphohistiocytosis Following BNT162b2 mRNA COVID-19 Vaccination.

Although serious adverse events have remained uncommon, cases of myocarditis induced by messenger RNA (mRNA) COVID-19 vaccines have been reported. Here, we presented a rare but potentially fatal disorder, hemophagocytic lymphohistiocytosis, in a 14-year-old previously healthy adolescent after BNT162b2 mRNA vaccination. The initial evaluation showed splenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia. Further examination revealed positive blood EBV DNA, and other infectious pathogen surveys were all negative. Hemophagocytosis was observed in the bone marrow aspiration and biopsy. HLH was confirmed and intravenous immunoglobulin (IVIG) and methylprednisolone pulse therapy were given. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) was set up for cardiopulmonary support for 3 days due to profound hypotension. The patient was kept on oral prednisolone treatment for 28 days with the following gradual tapering. The hemogram and inflammatory biomarkers gradually returned to normal, and the patient was discharged. The fulminant presentation of HLH in our case could be the net result of both acute immunostimulation after COVID-19 vaccination and EBV infection. Our case suggests that the immune activation after COVID-19 vaccination is likely to interfere with the adequate immune response to certain infectious pathogens, resulting in a hyperinflammatory syndrome.

The Treatment of COVID-19 Purgatory Syndrome With Tocilizumab and Steroids.

Hyperinflammation is a key component of severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. It is imperative to distinguish severe COVID-19 from hyperinflammatory syndromes such as multisystem inflammatory syndrome (MIS) and hemophagocytic lymphohistiocytosis. There is a subset of post-COVID-19 patients who present with some symptoms characteristic of MIS in adults (MIS-A) yet do not meet all the criteria for a diagnosis. We describe the unique case of a patient with this kind of presentation who clinically improved following tocilizumab and corticosteroid usage.

Hemophagocytic lymphohistiocytosis: An unusual presentation of disseminated tuberculosis: A case report and literature review.

Background: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome associated with cytokine storm. Here, we present a patient with acquired HLH associated with Mycobacterial tuberculosis infection. Case presentation: We report a 66-year-old hypertensive and diabetic male patient who presented with four days history of fever and abdominal pain. Denied history of cough and weight loss. Laboratory investigation showed: elevated ferritin, C-reactive protein, and triglyceride. Bone marrow examination showed > 50% hemophagocytosis (RBCs and platelets ingested by macrophages), positive acid-fast bacillus for Mycobacterium tuberculosis bacilli, and no evidence of malignancy. Complete blood count showed anemia and thrombocytopenia. The patient fulfilled six out of eight clinical criterions of the acquired Hemophagocytic lymphohistiocytosis (HLH). The patient was managed with anti-tuberculous medications with adjuvant steroid. On the subsequent days, the patient showed significant clinical improvement and discharged home. However, the patient passed away a week after home discharge. Conclusion: The present case highlights on the importance of early diagnosis and treatment of acquired HLH associated with tuberculous infection to improve the clinical outcome of the patient.

Multisystem Inflammatory Syndrome in Adults or Hemophagocytic Lymphohistiocytosis: A Clinical Conundrum in Fully Vaccinated Adults With Breakthrough COVID-19 Infections.

Hyperinflammatory syndrome with breakthrough coronavirus disease 2019 (COVID-19) infection in a fully vaccinated patient is not a common finding. To the best of our knowledge, this is the first such case of a patient who received the Spikevax/Moderna (elasomeran mRNA-1273) vaccine. The patient exhibited clinical characteristics consistent with both multisystem inflammatory syndrome in adults (MIS-A) and hemophagocytic lymphohistiocytosis (HLH), thus posing a diagnostic challenge. Multi-inflammatory syndrome in COVID-19 patients is frequently seen in the pediatric population, but it is a rare entity in adults especially after receiving COVID-19 vaccination. The pathophysiology of MIS-A is not completely understood yet, but it is believed that this likely occurs due to antibody-mediated immune dysregulation. There is a possibility of enhanced serologic response in patients like ours who are vaccinated and have breakthrough COVID-19 infection, thus paving the way for overwhelming antibody-mediated immune activation. There is a significant overlap between symptoms of MIS-A and other hyperinflammatory syndromes such as HLH; hence, a high degree of clinical suspicion and thorough diagnostic workup is required to explore all differentials. Our case raises concerns regarding the lack of clear algorithms and guidelines to diagnose and manage MIS-A in adults post-COVID-19 vaccination.

CXCL10/IP10 as a Biomarker Linking Multisystem Inflammatory Syndrome and Left Ventricular Dysfunction in Children with SARS-CoV-2.

BACKGROUND: To investigate the diagnostic accuracy of CXCL10/IP10 for left ventricular (LV) dysfunction in multisystemic inflammatory syndrome (MIS-C). METHODS: This cross-sectional, longitudinal study included 36 patients with MIS-C. Patients were classified as follows: (1) patients presenting with Kawasaki-like features (group I = 11); (2) patients presenting with LV systolic dysfunction (group II = 9); and (3) other presentations (group III = 3). CXCL10/IP10 levels were measured upon admission and on days 3 and 7 of treatment. RESULTS: Twenty patients were male and 16 were female. The median age of patients at diagnosis was 7.5 (1.5-17) years. All patients had a fever lasting for a median of 4 (2-7) days. Ten patients had LV systolic dysfunction. The duration of hospitalization was longer in group II. Lymphocyte and platelet counts were lower, whereas NT-pro-BNP, troponin-I, D-dimer, and CXCL10/IP10 levels were higher in group II. Baseline levels of CXCL10/IP10 were weakly negatively correlated with ejection fraction (r = -0.387, p = 0.022). Receiver operator characteristic curve analysis yielded a cutoff value of CXCL10/IP10 to discriminate patients with LV dysfunction was 1839 pg/mL with sensitivity 88% and specificity 68% (Area under curve (AUC) = 0.827, 95% CI 0.682-0.972, p = 0.003). CONCLUSION: Having a good correlation with cardiac function, CXCL10/IP10 is a potential biomarker to predict LV dysfunction in MIS-C patients.