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While severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection primarily causes inflammation in the respiratory system, there is growing evidence of extrapulmonary tissue damage mediated by the host innate immune system in children and adults. A cytokine storm can manifest as a viral‐induced haemophagocytic lymphohistiocytosis (HLH). Here, we present a previously healthy 8‐year‐old boy with newly diagnosed cardiac injury and COVID‐19‐related HLH syndrome with haemophagocytosis in bone marrow biopsy. After remission of inflammation, the patient underwent a heart transplant due to persistent cardiac failure. The histology of the explanted heart showed only a focal subtle subendocardial inflammation. Three days after transplant, he developed progressive acute respiratory distress syndrome (ARDS) with the rise of inflammatory markers. He unfortunately died after 20 days because of disseminated intravascular coagulation (DIC). For the first time, we described a child with COVID‐19‐related HLH and severe cardiac failure, which had a poor prognosis despite a heart transplant.

The 2019 novel coronavirus (2019-nCoV) originated in Wuhan City of China. In India, first confirmed case of coronavirus disease (COVID-19) was reported on January 30, 2020 and India is presently hit by second wave of COVID-19. The aim of the present study was to evaluate bone marrow findings of COVID-19 by minimally invasive autopsies to aid in understanding pathophysiology of the disease. This prospective study was conducted at tertiary care centre of Western Rajasthan. After obtaining approval from Institute's ethics committee and consent from next of kins, minimally invasive autopsies were conducted in 37 COVID-19 deceased patients within an hour after the death. The tissue specimens were processed with standard biosafety measures. Electronic medical records were reviewed retrospectively and patients' clinical details and results of laboratory investigations were noted. In this prospective study, bone marrow biopsies were collected from 37 COVID-19 minimally invasive autopsies. Mean age of these cases was 61.8 years and male: female ratio was 2.36. Comorbidities were observed in 25 (67.5%) of all cases. Histopathological analysis revealed hypercellular, normocellular and hypocellular marrow in 5, 25 and 5 cases respectively (two biopsies were inadequate). There was marked interstitial prominence of histiocytes in 24 (68.5%) cases. Out of these, evidence of haemophagocytosis was observed in 14 (40%) cases, marked increase of haemosiderin laden macrophages in 20 (57.1%) cases. There was prominence of plasma cells in 28 (80%) cases. The present study attempted to fill the gap of dearth of literature from our country in COVID-19 autopsy studies by highlighting bone marrow findings. The data support the evidence of development of secondary haemophagocytic lymphocytosis in COVID-19 cases.

The difficulties and challenges of applying the HLH-2004 diagnostic criteria to early identification and diagnosis of haemophagocytic lymphohistiocytosis have been fully addressed in previous studies. However, the distribution of the diagnostic time lag of haemophagocytic lymphohistiocytosis and related patient characteristics remain unclear. This study investigated the time lags between symptom onset and diagnosis and between hospital admission and diagnosis among pediatric patients with haemophagocytic lymphohistiocytosis, and identified factors that associated with a shorter or longer diagnostic time lag. The cohort of patients with haemophagocytic lymphohistiocytosis was drawn from a tertiary children's hospital and consisted of 122 pediatric patients. The distributions of symptom-to-diagnosis and admission-to-diagnosis time lags were assessed. Clinical characteristics within 48 h of admission and the fulfillment of HLH-2004 diagnostic criteria were compared among admission-to-diagnosis time lag categories. Logistic regression analyses were conducted to identify factors associated with an admission-to-diagnosis time lag >3 days. The median interval from first symptom onset to HLH diagnosis was 12 days (range 4–71 days) and the median interval from hospital admission to HLH diagnosis was 2 days (range 0–23 days). The following factors were negatively associated with admission-to-diagnosis > 3 days: Epstein–Barr virus infection; admission through pediatric intensive care unit; diagnosis established without NK-cell activity and soluble CD25 tests; the performance of all readily available diagnostic tests for HLH (within 48 and 72 h); concurrent fever, splenomegaly, and cytopenias within 48 h; hemophagocytosis, hypertriglyceridemia and/or hypofibrinogenemia within 48 h; and elevated ferritin, total bilirubin, alanine aminotransferase, and prothrombin time within 48 h. Our findings suggest that performance of adequate diagnostic tests for HLH is essential for early diagnosis of HLH. Once suspected, immediate and adequate diagnostic tests for HLH should be arranged for PICU patients. Improvements in diagnostic procedures and monitoring plans are needed to promote early diagnosis of HLH.

Background . Haemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome if not recognised and managed early. It involves an uncontrolled pathological activation of the immune system, and it is either genetic or acquired. It presents with clinical and laboratory features of severe inflammation. Early initiation of effective therapy may reduce mortality from 95% to 35%. Objective. To raise awareness of HLH among healthcare professionals, particularly intensivists. Methods. We report nine cases of secondary HLH seen at tertiary hospitals in Bloemfontein, South Africa. Results. All patients presented with fever, hypertriglyceridaemia, hyperferritinaemia, transaminitis and cytopenia. Haemophagocytosis was noted on bone marrow biopsy in 66.7% ( n =6/9) of the patients. More than one-third (44.4%; n =4/9) of the cases were triggered by a lymphoma, 44% ( n =4/9) were associated with infection and 11% ( n =1/9) were associated HIV. Finally, 11.1% ( n =1) of the patients were triggered by an underlying autoimmune disease. More than half (55.6%; n =5/9) of the cases had a fatal outcome. Conclusion. A high index of suspicion may promote the accurate diagnosis of HLH in patients presenting with fever, transaminitis and unexplained cytopenia.

Macrophage activation syndrome (MAS) is a severe and potentially fatal life-threatening condition associated with excessive activation and expansion of T cells with macrophages and a high expression of cytokines, resulting in an uncontrolled inflammatory response, with high levels of macrophage colony-stimulating factor and causing multiorgan damage. This syndrome is classified into primary (genetic/familial) or secondary forms to several etiologies, such as infections, neoplasias mainly hemopathies or autoimmune diseases. It is characterised clinically by unremitting high fever, pancytopaenia, hepatosplenomegaly, hepatic dysfunction, encephalopathy, coagulation abnormalities and sharply increased levels of ferritin. The pathognomonic feature of the syndrome is seen on bone marrow examination, which frequently, though not always, reveals numerous morphologically benign macrophages exhibiting haemophagocytic activity. Because MAS can follow a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are essential. However, it is difficult to distinguish underlying disease flare, infectious complications or medication side effects from MAS. Although, the pathogenesis of MAS is unclear, the hallmark of the syndrome is an uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to massive hypersecretion of pro-inflammatory cytokines. Mutations in cytolytic pathway genes are increasingly being recognised in children who develop MAS in his secondary form. We present here a case of Macrophage activation syndrome associated with Griscelli syndrome type 2 in a 3-years-old boy who had been referred due to severe sepsis with non-remitting high fever, generalized lymphoadenopathy and hepato-splenomegaly. Laboratory data revealed pancytopenia with high concentrations of triglycerides, ferritin and lactic dehydrogenase while the bone marrow revealed numerous morphologically benign macrophages with haemophagocytic activity that comforting the diagnosis of a SAM according to Ravelli and HLH-2004 criteria. Griscelli syndrome (GS) was evoked on; consanguineous family, recurrent infection, very light silvery-gray color of the hair and eyebrows, Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. The molecular biology showed mutation in RAB27A gene confirming the diagnosis of a Griscelli syndrome type 2. The first-line therapy was based on the parenteral administration of high doses of corticosteroids, associated with immunosuppressive drugs, cyclosporine A and etoposide waiting for bone marrow transplantation (BMT).

The authors describe a rare case of a 27-year old previously healthy male presenting with high grade fever, pancytopenia, hepatosplenomegaly, high levels of ferritin and triglyceride, suggesting a diagnosis of hemophagocytic lymphohistiocytosis (HLH) syndrome. Other investigations showed a positive Leishmania infantum serology and high Epstein-Barr virus (EBV) viremia. The diagnosis of a visceral leishmaniasis was confirmed by bone morrow biopsy, which showed Leishman-Donovan bodies and evidence of HLH. The patient received liposomal amphotericin B and he had a complete resolution of his symptoms and clearance of EBV viremia. This case of HLH associated with visceral leishmaniasis and EBV co-infection raises the question about the significance of EBV in patients with HLH. The treatment of actual etiological agent can lead to complete cure while using current recommend chemotherapy for HLH-related EBV in a patient with hidden infection may have deleterious effects.

Objectives To report a case of intravascular lymphoma (IVL) in a Caucasian patient who presented with anasarca as his sole clinical sign. Material and Methods A man presented with anasarca-type oedema and fatigue. After excluding heart failure, hepatic cirrhosis, nephrotic syndrome, hypothyroidism, AL-amyloidosis and adverse drug reaction which can all cause oedema, we turned our attention to capillary permeability disorders. Results Closer review of the bone marrow aspirate demonstrated haemophagocytic histiocytosis, while core, renal and duodenal biopsies showed a B-cell IVL. Conclusion The differential diagnosis of anasarca, a relatively common clinical sign, should include IVL although the diagnosis may still be challenging. LEARNING POINTS Anasarca-type oedema is an unusual initial presentation of intravascular lymphoma (IVL) and is normally attributed to capillary permeability disorders. Two clinical forms of IVL have been recognized: a Western form and an Asian variant which is characterized by haemophagocytosis. Patients of Caucasian origin who have the clinical features of the Asian variant of IVL make the diagnosis of this condition even more challenging.

Introduction: Macrophage activation syndrome (MAS) is a pathological systemic inflammatory reaction that is often fatal and underdiagnosed. There may be multiple organ failure that could be triggered in association with rheumatic, neoplastic or infectious diseases and/or drugs. It has been reported more in children than adults, probably as it is often associated with genetic abnormalities not described yet undescribed, genetic abnormalities. In most cases the genetic defect is not recognized in adults, or has a different etiology. The signs and symptoms of macrophage activation syndrome have been defined. Not suspecting its presence may lead to not making the diagnosis and thus, an increase in mortality. Diagnosis is a challenge, treatment has to be started early and be aggressive to reduce the high mortality rate. Objectives: To describe four adult patients with five MAS episodes related to different under-lying diseases, with the aim of making it familiar to the reader, to look for the syndrome and make a diagnosis. Materials and methods: Patients evaluated in outpatients and while in the hospital. Results: We present the characteristics of MAS, with the diagnostic approach and the ther-apeutic possibilities and their outcomes. Conclusions: MAS is not looked for in the adult and could be fatal. It requires identification and early treatment to reduce the risk of mortality. It still needs to be studied to define the genetic defect, or other causes that may be responsible for the development of the syndrome. Introducción: El síndrome de activación macrofágica (SAM) es una reacción patológica inflamatoria sistémica, frecuentemente fatal y comúnmente no diagnosticada, que se acompaña de una falla multiorgánica y puede desencadenarse asociada a enfermedades reumáticas, neoplásicas, infecciosas o a drogas. Más descrita en niños que en adultos, probablemente en muchas ocasiones se relaciona con alteraciones genéticas aún no descritas. Sus síntomas y signos han sido definidos. El no sospecharlo conlleva a no diagnosticarlo y como consecuencia a un incremento importante del riesgo de mortalidad en el paciente; es por esto que el diagnóstico es un reto y el tratamiento debe de ser temprano y agresivo. Objetivos: Describir 4 pacientes adultos con 5 episodios de SAM relacionado con diferentes enfermedades reumáticas, con el interés de familiarizar al lector con la búsqueda del síndrome y de realizar su diagnóstico. Materiales y métodos: Estudio descriptivo de pacientes adultos evaluados en la consulta y hospitalizados. Resultado: Presentamos las características de los pacientes con SAM, el enfoque diagnóstico, las posibilidades terapéuticas y la evolución. Conclusiones: El SAM es una enfermedad no buscada en el adulto que puede ser fatal, requiere ser identificada y tratada tempranamente para disminuir el riesgo de mortalidad. Aún requiere ser estudiada para definir defectos genéticos u otras etiologías que puedan ser responsables de este síndrome.

Haemophagocytic lymphohistiocytosis (HLH) is a devastating syndrome due to uninhibited immune activation. Disseminated histoplasmosis is a rare cause of HLH. There have been few case reports and series demonstrating a relation between the two disease entities in immunosuppressed hosts. HLH secondary to disseminated histoplasmosis is even rarer in an immunocompetant host. We report a rare case of HLH triggered by disseminated histoplasmosis in an immunocompetant patient.

Ramesh Bhat.Y, K Shruthi, MS Padma, SR Vamsi, G Sherin, K Annamma Infection associated haemophagocytic syndrome (HPS) is rare and could be potentially fatal. Reactive HPS has been reported with various infections including tuberculosis. Tuberculosis associated HPS is more common in adults than in children. Severe pancytopenia due to HPS complicating tuberculosis and while on therapy has been rarely described. Success of therapy depends on early initiation of treatment. We describe herein a 13-years old girl who developed severe pancytopenia while on anti-tuberculous treatment. Her bone marrow aspirate showed trilineage dyspoiesis, histiocytes with phagocytosed debris and haemophagocytosis confirming a reactive haemophagocytic syndrome. She recovered completely with supportive treatment., Enfeksiyon ilişkili hemofagositik sendrom (HPS) nadirdir ve potansiyel olarak ölümcül olabilir. Reaktif HPS, tüberküloz dâhil olmak üzere çeşitli enfeksiyonlarla birlikte bildirilmiştir. Tüberküloz ilişkili HPS erişkinlerde çocuklara göre daha sık görülür. Tüberküloz tedavisi ile birlikte HPS ilişkili şiddetli pansitopeni nadiren bildirilmiştir. Tedavi başarısı tedavinin erken başlamasına bağlıdır. Bu makalede anti-tüberküloz tedavisi sırasında ciddi pansitopeni gelişen 13 yaşında bir kız çocuğu sunulmaktadır. Kemik iliği aspirasyonunda trilineage dispoyez, debris fagosite etmiş histiyositler ve reaktif HPS’yi gösteren hemofagositoz vardı. Hasta destek tedavisi ile tamamen iyileşti

A hemofagocitose reativa ou síndrome de ativação macrofágica (SAM) é uma complicação das doenças inflamatórias sistêmicas, causada por expansão de células T e macrófagos, com produção maciça de citocinas pró-inflamatórias, ocorrendo mais freqüentemente na artrite idiopática juvenil sistêmica e raramente no lúpus eritematoso sistêmico juvenil (LESJ). OBJETIVO: Relatar um caso de LESJ que evoluiu com SAM precipitada por infecção e infarto esplênico, com desfecho fatal. RELATO DE CASO: Uma menina de 7 anos, com diagnóstico de LESJ desde os 5 anos, evoluiu com artrite em atividade, alopecia intensa, citopenias, cefaléia, infecções respiratórias recorrentes e elevação intermitente de transaminases. Os anticorpos anti-DNA e anticardiolipina IgG e IgM foram identificados e a biópsia renal evidenciou glomerulonefrite lúpica de classe III. A paciente foi tratada com pulso de metilprednisolona, prednisona, azatioprina e hidroxicloroquina. Após dois anos, na vigência de pneumonia apresentou abdome agudo e convulsões, evoluindo para o choque hemorrágico fatal após esplenectomia, que evidenciou infarto esplênico e infiltração maciça por macrófagos hemofagocíticos CD163+. CONCLUSÃO: A revisão do desfecho sugere a SAM precipitada por infecção e sobreposta a atividade inflamatória do lúpus com febre persistente, citopenias, disfunção hepática, hepatomegalia e esplenomegalia, como efeitos do excesso de produção de citocinas. Os anticorpos anticardiolipina podem ter tido papel precipitante na coagulopatia, que resultou infarto esplênico e choque hemorrágico.Reactive haemophagocytosis or macrophage activation syndrome (MAS) is a complication of systemic inflammatory disorders, caused by expansion of T cells and haemophagocytic macrophages, with cytokine overproduction. It has been described most often in systemic juvenile idiopathic arthritis and rarely in juvenile systemic lupus erythematosus (JSLE). OBJECTIVE: To report a JSLE case who developed MAS in association with spleen infarct triggered by infection, with fatal outcome. CASE REPORT: A 7-year old-girl diagnosed with lupus since age 5-y developed several episodes of arthritis flare, cytopenias, severe alopecia, headaches and recurrent episodes of respiratory infections with intermittently increased serum transaminases. Anti-DNA and anti-cardiolipin IgG and IgM were identified and Class III lupus glomerulonephritis was diagnosed by renal biopsy. The patient was treated with methylprednisolone pulses, prednisone, azatioprine and hydroxychloroquine. Last admitted due to pneumonia, she evolved into abdominal crisis and seizures, undergoing splenectomy and evolving into haemorragic shock with fatal outcome. A spleen infarct was found and anti-CD163 antibodies staining disclosed intense haemophagocytic macrophage infiltration. CONCLUSION: This outcome suggests infection-triggered MAS overlapping lupus flare with persistent fever, cytopenia, liver dysfunction, hepatomegaly and splenomegaly as cytokine excess driven effect. Anti-cardiolipin antibodies may also had a coagulopathy precipiting role.

Allergy, asthma & clinical immunology 8(1), 6 (2012). doi:10.1186/1710-1492-8-6, Published by BioMed Central Ltd., London

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T19:02:58Z No. of bitstreams: 1 S0482-50042008000400010.pdf: 162538 bytes, checksum: 0b42e0b4efe82968927bc28a643ef04b (MD5) Made available in DSpace on 2013-08-22T19:02:58Z (GMT). No. of bitstreams: 1 S0482-50042008000400010.pdf: 162538 bytes, checksum: 0b42e0b4efe82968927bc28a643ef04b (MD5) Previous issue date: 2008-08-01 Made available in DSpace on 2013-09-30T18:23:46Z (GMT). No. of bitstreams: 2 S0482-50042008000400010.pdf: 162538 bytes, checksum: 0b42e0b4efe82968927bc28a643ef04b (MD5) S0482-50042008000400010.pdf.txt: 19419 bytes, checksum: e92ef42951dff2efacee0963abcb343c (MD5) Previous issue date: 2008-08-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T13:37:13Z No. of bitstreams: 2 S0482-50042008000400010.pdf: 162538 bytes, checksum: 0b42e0b4efe82968927bc28a643ef04b (MD5) S0482-50042008000400010.pdf.txt: 19419 bytes, checksum: e92ef42951dff2efacee0963abcb343c (MD5) Made available in DSpace on 2014-05-20T13:37:13Z (GMT). No. of bitstreams: 2 S0482-50042008000400010.pdf: 162538 bytes, checksum: 0b42e0b4efe82968927bc28a643ef04b (MD5) S0482-50042008000400010.pdf.txt: 19419 bytes, checksum: e92ef42951dff2efacee0963abcb343c (MD5) Previous issue date: 2008-08-01 A hemofagocitose reativa ou síndrome de ativação macrofágica (SAM) é uma complicação das doenças inflamatórias sistêmicas, causada por expansão de células T e macrófagos, com produção maciça de citocinas pró-inflamatórias, ocorrendo mais freqüentemente na artrite idiopática juvenil sistêmica e raramente no lúpus eritematoso sistêmico juvenil (LESJ). OBJETIVO: Relatar um caso de LESJ que evoluiu com SAM precipitada por infecção e infarto esplênico, com desfecho fatal. RELATO DE CASO: Uma menina de 7 anos, com diagnóstico de LESJ desde os 5 anos, evoluiu com artrite em atividade, alopecia intensa, citopenias, cefaléia, infecções respiratórias recorrentes e elevação intermitente de transaminases. Os anticorpos anti-DNA e anticardiolipina IgG e IgM foram identificados e a biópsia renal evidenciou glomerulonefrite lúpica de classe III. A paciente foi tratada com pulso de metilprednisolona, prednisona, azatioprina e hidroxicloroquina. Após dois anos, na vigência de pneumonia apresentou abdome agudo e convulsões, evoluindo para o choque hemorrágico fatal após esplenectomia, que evidenciou infarto esplênico e infiltração maciça por macrófagos hemofagocíticos CD163+. CONCLUSÃO: A revisão do desfecho sugere a SAM precipitada por infecção e sobreposta a atividade inflamatória do lúpus com febre persistente, citopenias, disfunção hepática, hepatomegalia e esplenomegalia, como efeitos do excesso de produção de citocinas. Os anticorpos anticardiolipina podem ter tido papel precipitante na coagulopatia, que resultou infarto esplênico e choque hemorrágico. Reactive haemophagocytosis or macrophage activation syndrome (MAS) is a complication of systemic inflammatory disorders, caused by expansion of T cells and haemophagocytic macrophages, with cytokine overproduction. It has been described most often in systemic juvenile idiopathic arthritis and rarely in juvenile systemic lupus erythematosus (JSLE). OBJECTIVE: To report a JSLE case who developed MAS in association with spleen infarct triggered by infection, with fatal outcome. CASE REPORT: A 7-year old-girl diagnosed with lupus since age 5-y developed several episodes of arthritis flare, cytopenias, severe alopecia, headaches and recurrent episodes of respiratory infections with intermittently increased serum transaminases. Anti-DNA and anti-cardiolipin IgG and IgM were identified and Class III lupus glomerulonephritis was diagnosed by renal biopsy. The patient was treated with methylprednisolone pulses, prednisone, azatioprine and hydroxychloroquine. Last admitted due to pneumonia, she evolved into abdominal crisis and seizures, undergoing splenectomy and evolving into haemorragic shock with fatal outcome. A spleen infarct was found and anti-CD163 antibodies staining disclosed intense haemophagocytic macrophage infiltration. CONCLUSION: This outcome suggests infection-triggered MAS overlapping lupus flare with persistent fever, cytopenia, liver dysfunction, hepatomegaly and splenomegaly as cytokine excess driven effect. Anti-cardiolipin antibodies may also had a coagulopathy precipiting role. Unesp Faculdade de Medicina de Botucatu Departamento de Pediatria Unesp Faculdade de Medicina de Botucatu Departamento de Patologia Unesp Faculdade de Medicina de Botucatu Departamento de Pediatria Unesp Faculdade de Medicina de Botucatu Departamento de Patologia

El síndrome hemofagocítico se caracteriza por proliferación histiocítica con fagocitosis de células hemáticas que ocasionan citopenia. Ha sido relacionado antes con diversas infecciones, principalmente por virus. Informamos de tres pacientes con síndrome hemofagocítico secundario a dengue hemorrágico, confirmado por exámenes específicos de laboratorio, quienes fueron internados en el Hospital Universitario Ramón González Valencia de Bucaramanga, Colombia, durante los últimos dos años. Los tres pacientes fueron escolares que presentaron dengue hemorrágico y manifestaron dolor abdominal intenso, fiebre prolongada, hipotensión y hepatomegalia dolorosa; los exámenes paraclínicos mostraron plaquetopenia, anemia y leucopenia; en la ecografía abdominal se observó colecistitis acalculosa y en todos los aspirados de medula ósea se encontraron histiocitos fagocitando células hemáticas de la serie eritroide, mieloide o plaquetaria. Se definió y clasificó el síndrome hemofagocítico, según la Sociedad Internacional de Histiocitosis, en tres grandes clases, recalcando que los casos informados corresponden a histiocitosis clase II y, más específicamente, al síndrome hemofagocítico secundario. Se mencionan las diversas asociaciones de este síndrome con infecciones, principalmente virales, y otras enfermedades no infecciosas; se hace diferenciacion entre síndrome hemofagocítico familiar o primario y el secundario. Finalmente, se enfatiza que los tres pacientes con este síndrome asociado con dengue hemorrágico tuvieron una evolución atípica durante el curso de su enfermedad; la fiebre prolongada y el dolor abdominal persistente fueron los síntomas más importantes. Los autores recomiendan realizar un aspirado de médula ósea como parte de los estudios para el diagnóstico diferencial de casos atípicos de dengue, especialmente con fiebre prolongada, buscando la posibilidad de un síndrome hemofagocítico secundario.