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Haemophagocytic lymphohistiocytosis secondary to Histoplasma infection is rare and almost always occurs in immunocompromised hosts. We report a 32-year-old immunocompetent man presenting with a nonspecific febrile illness found to have disseminated histoplasmosis and associated haemophagocytic lymphohistiocytosis. The diagnosis was confirmed on histopathological examination and PCR of liver and bone marrow biopsies. He was successfully treated with steroids, intravenous immunoglobulin and itraconazole.

Familial Haemophagocytic Lymphohistiocytosis (FHL) is an autosomal recessive disorder characterised by a hyperinflammatory state due to widespread infiltration of organs with macrophages and lymphocytes. Haemophagocytic Lymphohistiocytosis (HLH) presents with fever, hepatosplenomegaly, cytopenia, hyperferritinemia and haemophagocytosis in the reticuloendothelial tissues causing multi organ failure with fatal outcome. HLH is rare in neonates with an incidence of 1 in 50,000 to 1 in 150,000. FHL is diagnosed based on clinical criteria, biochemical abnormalities, and genetic mutation. Mutations involving the gene STXBP2 contributes to around 10% of cases of FHL and there are only a few cases of FHL5 reported from India. A six-week-old neonate presented with sepsis which was unresponsive to antibiotics. Persistent fever, bicytopenia, hepatosplenomegaly and laboratory tests made us suspect HLH, and evaluate further with whole exome sequencing. FHL5 was diagnosed based on the identification of homozygous missense mutation in exon 3 of STXBP2 gene (chr19: 7642803_7642803delA). The baby succumbed to sepsis and multi organ failure. HLH should be considered in the differential diagnosis of any sick infant who presents with prolonged fever, sepsis unresponsive to antibiotics and an unusual clinical course.

A 38-year-old male was diagnosed with aortoiliac aneurysm while evaluating for new-onset hypertension. On further workup, the cause was identified as tubercular aortoiliac aneurysm. His aneurysm had stormy course and disseminated further while ongoing antitubercular therapy with multiple episodes of aneurysmal rupture and endovascular interventions. Management of this case was complicated with several other rarer entities, such as haemophagocytosis and thrombotic microangiopathy with disseminated intravascular coagulation resistant to steroids and plasmapheresis, within a span of few weeks. Moreover, first-line antitubercular therapy had to be regularly modified in view of emerging complications. While case reports for each individual entity exists in literature, this is the first case to the best of our knowledge where such varied complications were present in a patient of tubercular mycotic aneurysm.

Familial Haemophagocytic Lymphohistiocytosis (FHL) is an autosomal recessive disorder characterised by a hyperinflammatory state due to widespread infiltration of organs with macrophages and lymphocytes. Haemophagocytic Lymphohistiocytosis (HLH) presents with fever, hepatosplenomegaly, cytopenia, hyperferritinemia and haemophagocytosis in the reticuloendothelial tissues causing multi organ failure with fatal outcome. HLH is rare in neonates with an incidence of 1 in 50,000 to 1 in 150,000. FHL is diagnosed based on clinical criteria, biochemical abnormalities, and genetic mutation. Mutations involving the gene STXBP2 contributes to around 10% of cases of FHL and there are only a few cases of FHL5 reported from India. A six-week-old neonate presented with sepsis which was unresponsive to antibiotics. Persistent fever, bicytopenia, hepatosplenomegaly and laboratory tests made us suspect HLH, and evaluate further with whole exome sequencing. FHL5 was diagnosed based on the identification of homozygous missense mutation in exon 3 of STXBP2 gene (chr19: 7642803_7642803delA). The baby succumbed to sepsis and multi organ failure. HLH should be considered in the differential diagnosis of any sick infant who presents with prolonged fever, sepsis unresponsive to antibiotics and an unusual clinical course. [ABSTRACT FROM AUTHOR]

Abstract 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.

Haemophagocytic lymphohistiocytosis is a life-threatening systemic inflammatory syndrome defined by persistent fever, cytopenia and multi-organ dysfunction. Primary haemophagocytic lymphohistiocytosis classically presents in childhood as a result of genetically abnormal perforin or inflammasome function, leading to the aberrant release of pro-inflammatory cytokines causing a hyperinflammatory state. Secondary haemophagocytic lymphohistiocytosis is an acquired phenomenon occurring at any age as a result of immune dysregulation to a specific trigger such as infection, haematological malignancy or autoimmune disease. Secondary haemophagocytic lymphohistiocytosis occurring in the pregnant woman represents a diagnostic challenge and carries a significant mortality. This has led to its first inclusion in the fourth Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the United Kingdom annual maternal report in 2017. This article presents an overview of haemophagocytic lymphohistiocytosis, reviews the literature on haemophagocytic lymphohistiocytosis in pregnancy, suggests diagnostic pathways and explores the safety and efficacy of existing and potential treatment strategies for haemophagocytic lymphohistiocytosis occurring during pregnancy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is a complex, often under‐recognised hyperinflammatory immune dysregulation syndrome arising in a diverse range of clinical scenarios and conditions. The accurate and timely diagnosis of HLH is crucial for patient survival, and usually requires a high level of clinical suspicion. The histological corollary to clinical HLH—haemophagocytosis—is neither necessary nor sufficient for the diagnosis of HLH, as it may be seen in a variety of reactive conditions and may be absent in true HLH. Nevertheless, the finding of haemophagocytosis in specific clinical situations should prompt consideration of HLH and further testing to exclude the condition. Although haemophagocytosis is traditionally described in bone marrow, identification of it in other tissues, including lymphoid, splenic, liver or neural tissue, can contribute importantly to the overall recognition of HLH. In this review we discuss the underlying pathophysiology and aetiologies of HLH, and the morphological aspects of haemophagocytosis and its associated histological findings in different tissues, and give a brief overview of diagnostic criteria and clinical evaluation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Haemophagocytic lymphohistiocytosis secondary to Histoplasma infection is rare and almost always occurs in immunocompromised hosts. We report a 32-year-old immunocompetent man presenting with a nonspecific febrile illness found to have disseminated histoplasmosis and associated haemophagocytic lymphohistiocytosis. The diagnosis was confirmed on histopathological examination and PCR of liver and bone marrow biopsies. He was successfully treated with steroids, intravenous immunoglobulin and itraconazole. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of excessive inflammation and tissue destruction owing to abnormal immune activation. We report an unusual case of haemophagocytosis associated with hepatitis A virus (HAV) infection in a 21-year-old man. This was further complicated by haemolysis secondary to G-6-PD deficiency and fungal sepsis. Our patient was treated successfully with intravenous immunoglobulin (IVIg) and supportive care. A systematic review of all reported cases of HAV associated haemophagocytosis is presented. [ABSTRACT FROM AUTHOR]

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).

Infantile disseminated BCG-osis is an uncommon complication of BCG vaccination and the presence of haemophagocytic lymphohistiocytosis (HLH) further complicates the clinical course due to its fatal outcome. Here, we describe a rare case of disseminated BCG-osis with HLH in a 3-month-old male child and the unusual morphological findings in the peripheral blood with its haematology analyser-based expression. The child presented with fever, failure to thrive, hepatosplenomegaly, erythematous skin rashes, and left axillary lymphadenopathy with history of BCG vaccination at birth. He was the first born of second-degree consanguineous marriage with no significant family history of immunodeficiency disorders. Laboratory findings included anaemia, thrombocytopenia, hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia which supported a diagnosis of HLH. The peripheral blood showed evidence of phagocytosis by neutrophils, pseudo-Chediak-Higashi-like inclusions, blue-green inclusions, and intra-cytoplasmic vacuoles with shadowy appearance and cellular debris in the background. Acid-fast bacilli were demonstrated in the peripheral blood by Ziehl-Neelsen stain. His clinical condition gradually worsened with multi organ failure and fatality. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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.

Epstein-Barr virus ( EBV) infection is ubiquitous in humans, but the majority of infections have an asymptomatic or self-limiting clinical course. Rarely, individuals may develop a pathological EBV infection with a variety of life threatening complications (including haemophagocytosis and malignancy) and others develop asymptomatic chronic EBV viraemia. Although an impaired ability to control EBV infection has long been recognised as a hallmark of severe T-cell immunodeficiency, the advent of next generation sequencing has identified a series of Primary Immunodeficiencies in which EBV-related pathology is the dominant feature. Chronic active EBV infection is defined as chronic EBV viraemia associated with systemic lymphoproliferative disease, in the absence of immunodeficiency. Descriptions of larger cohorts of patients with chronic active EBV in recent years have significantly advanced our understanding of this clinical syndrome. In this review we summarise the current understanding of the pathophysiology and natural history of these diseases and clinical syndromes, and discuss approaches to the investigation and treatment of severe or atypical EBV infection. [ABSTRACT FROM AUTHOR]

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.

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.

The use of chimeric antigen receptor T cells (CAR-T) has increased since their approval in the treatment of several relapsed/refractory B cell malignancies. The management of their specific toxicities, such as cytokine release syndrome (CRS), tends to be better understood and well-defined. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on the management of patients developing CRS following CAR-T cell therapy. A special chapter has been allocated to macrophage activation syndrome (MAS), a rare but life-threatening complication post-CAR-T. In addition to symptomatic measures and preemptive broad-spectrum antibiotics, immunomodulators such as tocilizumab and corticosteroids remain the corner stone for the treatment of CRS. Tocilizumab/corticosteroids-resistant CRS associated with haemophagocytosis markers (spleen and liver enlargement, hyperferritinaemia>10,000ng/mL, hypofibrinogenemia…) should direct the diagnosis towards an overlapping CRS/MAS. An adapted treatment will be based on high-dose IV anakinra and corticosteroids and chemotherapy with etoposide at late refractory stages. These complications and others delignate the need of close collaboration with an intensive care unit., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Paediatric haemophagocytic lymphohistiocytosis (pHLH) is a potentially life-threatening condition with significant diagnostic and therapeutic difficulties. The purpose of this study was to describe the clinical presentation, the diagnostic challenges, and the outcomes of haemophagocytic lymphohistiocytosis (HLH) in children assessed at Mukalla Hospital, Yemen. Data from 20 medical records of HLH patients admitted between January 2010 and May 2022 were retrospectively analysed. The median age at presentation was 3.5 ± 5.1 years. Male: female ratio was 1:1. The median time for referral to the hospital was 30 ± 64 days. The most common clinical manifestations were fever and pallor in 95% of cases, and splenomegaly (85%). Hepatomegaly, chest, renal and neurological manifestations were detected in 80%, 45%, 15% and 20% of cases, respectively. Bone marrow haemophagocytosis was detected in 60% of cases. Sixteen patients fulfilled the HLH diagnostic criteria, and 11 patients (55%) received the HLH 2004 protocol. Out of the 20 patients, three (15%) patients are alive. Fourteen patients died, with overall mortality of 82.35%. All mortalities were due to HLH disease with multi-organ failure. Relapse was noticed in five patients either during treatment or after full recovery. pHLH is a challenging emergency with a high mortality rate. High clinical suspicion is essential for early detection and intervention to improve the prognosis., Competing Interests: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © Sudanese Association of Pediatricians.)

Haemophagocytic lymphohistiocytosis ( HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T-cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH. The average age was 53 years (range 18-77 years) and 43 were male (63%). Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%). Patients were treated with disease-specific therapy and immunomodulatory agents. After a median follow-up of 32·2 months, 46 patients had died (69%). The median overall survival was 4 months (95% CI: 0·0-10·2 months). Patients with malignancy had a worse prognosis compared to those without (median survival 2·8 months versus 10·7 months, P = 0·007). HLH is a devastating disorder with a high mortality. Further research is needed to improve treatment and outcomes. [ABSTRACT FROM AUTHOR]

A 10 year old boy suffering from prolonged low grade fever, progressive pallor, one episode of haematemesis and melaena, was found to have hepatosplenomegaly, features of portal hypertension on abdominal ultrasound, and grade II varices in upper gastrointestinal endoscopy. During hospital stay for diagnostic workup, he developed features of hepatic failure and pancytopenia. Bone marrow aspirate revealed hemophagocytosis and plenty of Leishman-Donovan bodies. The child received Injection Sodium Stibogluconate to treat leishmaniasis and received supportive therapy for hepatic failure and pancytopenia. The child responded well to treatment. [ABSTRACT FROM AUTHOR]

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.

Extranodal NK/Tcell lymphomas (ENKTL) are rare, aggressive lymphomas. The most common primary site of involvement is the nasal cavity, nasopharynx and paranasal sinuses. The other sites of primary involvement are skin, gastrointestinal tract and testis. Advanced disease can show lymph node, bone marrow and peripheral blood involvement. We report a case of ENKTL of the jejunum, showing peripheral pancytopenia and haemophagocytosis in the bone marrow. The intestine showed multiple intestinal perforations, with evidence of infiltration by lymphoma with coexistent strongyloides infestation. The patient showed disseminated disease in the form of lymphadenopathy and had a rapidly downhill course and expired on 5th day of admission. We also discuss the problems encountered by the pathologist in diagnosing these uncommon lymphomas. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis ( HLH) has been rarely described in children treated for an anaplastic large-cell lymphoma ( ALCL). We evaluated the incidence, the clinical and histological characteristics and the prognosis of HLH associated- ALCL. The medical, biological, cytological and histological data of patients treated for ALK-positive ALCL in the paediatric department of a single institution between 1975 and 2008 were analysed and assessed for HLH according to diagnosis criteria of the Histiocyte Society. Data concerning a series of 50 consecutive children with ALCL were reviewed. HLH-associated ALCL was observed in 12% of the patients. Lung involvement was significantly more frequent in HLH-associated ALCL patients than in the group without HLH ( P = 0·004), as well as central nervous system ( CNS) and bone marrow involvement ( P = 0·001 and P = 0·007 respectively). The histological subtype in children with HLH-associated ALCL did not differ from that of the group without HLH. There was no significant difference between the two groups in 5-year EFS and OS ( P = 0·91 and P > 0·99 respectively). In conclusion, HLH is not rare in paediatric ALCL. Despite a high incidence of visceral, CNS and bone marrow involvement, HLH does not seem to exert a significant impact on outcome in children treated for ALCL. [ABSTRACT FROM AUTHOR]

Résumé: Introduction: La lymphadénite histiocytaire nécrosante (maladie de Kikuchi-Fujimoto) est une entité clinico-pathologique rare caractérisée par l’association d’une lymphadénopathie cervicale postérieure bien limitée et d’une fièvre, touchant principalement les femmes jeunes. Observation: Nous rapportons le cas d’un patient africain de 41 ans présentant une maladie de Kikuchi-Fujimoto atypique car compliquée d’un lupus cutané, d’un syndrome d’activation macrophagique et d’une méningite lymphocytaire. Une méningite tuberculeuse, initialement évoquée en raison de l’origine ethnique et de la présentation clinique, était éliminée par l’histologie ganglionnaire caractéristique de maladie de Kikuchi-Fujimoto, la négativité des prélèvements microbiologiques, l’évolution clinique et la découverte d’une intégration virale génomique d’ADN d’HHV6. Conclusion: L’association d’adénopathies cervicales, d’un syndrome d’hémophagocytose, d’une méningite lymphocytaire et d’une intégration génomique d’HHV-6 doit faire évoquer une maladie de Kikuchi. [ABSTRACT FROM AUTHOR]

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by skeletal dysplasia, exocrine pancreatic insufficiency and bone marrow failure. Various other conditions, such as hepatopathy and failure to thrive have been associated with SDS. A retrospective study was conducted to describe mutations, clinical features, and the immunological profile of 11 Belgian patients with genetically confirmed diagnosis of SDS. This study confirms the existing understanding of the classical features of SDS although the typical triad was present in only six out of nine fully studied patients. The following important observations are made in this cohort. Four out of eleven patients were misdiagnosed as having Asphyxiating Thoracic Dystrophy (Jeune syndrome) because of severe thoracic dystrophy. Another two patients presented with unexplained episodes of symptomatic hypoglycaemia. The immunological phenotype was heterogeneous although laboratory abnormalities were noticed in eight out of ten patients assessed. Three patients experienced a life threatening viral infection (respiratory syncytial virus, cytomegalovirus (CMV) and rotavirus). In one patient, CMV infection caused an episode of haemophagocytic lymphohistiocytosis. One patient has bronchiectasis at the age of 3 years due to recurrent respiratory tract infections. These findings strengthen the suspicion of an abnormal immune system in SDS. Liver anomalies, usually described as benign and transitory in SDS patients, were severe in two patients of the cohort. One patient developed hepatopulmonary syndrome. The findings in this national cohort of SDS patients could contribute to the prevention of misdiagnosis in the future and enable more rapid recognition of certain severe complications. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is a rare condition resulting from a dysregulated inflammatory response. Currently there are no guidelines on the reporting of haemophagocytosis on bone marrow biopsy (BM) and lack of evidence on correlation between haemophagocytosis with the clinical diagnostic criteria for HLH. We aimed to assess if the amount of haemophagocytosis identified in the BM correlates with HLH-2004 criteria. Secondary aims were to evaluate inter-observer variability in reporting haemophagocytosis, and to formulate recommendations for screening in bone marrow specimens. A retrospective review of bone marrow biopsies from adult patients under investigation for HLH was undertaken independently by two haematopathologists who were blinded to the original biopsy report. The average number of actively haemophagocytic cells in each slide were quantified. Cases with discordance pertaining to the degree of haemophagocytosis were reviewed by both assessors to reach a consensus. Sixty-two specimens from 59 patients were available for assessment. An underlying haematological condition was identified in 34 cases (58%). There was a significant association between the amount of haemophagocytosis identified on the aspirate samples and the number of HLH-2004 criteria met (p<0.0001). In patients where haemophagocytosis was present (n=31), there was a correlation between the amount of haemophagocytosis and ferritin (p=0.041). Based on our review, we have made recommendations for the reporting of BM haemophagocytosis. Our findings indicate that the amount of haemophagocytosis present on BM samples correlates with the number of HLH-2004 criteria. We found marked interobserver variability which we anticipate can be rectified with our recommendations for reporting., (Copyright © 2021. Published by Elsevier B.V.)

We report the case of a patient with disseminated toxoplasmosis who presented with cervical lymphadenopathies and pneumonia. Although the infection was successfully treated with co-trimoxazole, the patient developed reactive macrophage activation syndrome (rMAS). To our knowledge, this is the first reported case of rMAS triggered by toxoplasmosis in the medical literature. [ABSTRACT FROM AUTHOR]

A 5-month old infant presented with a short history of fever of unknown origin. He initially appeared well although there was a resting tachycardia during periods of normal temperature, and pancytopenia. He remained febrile in spite of antibiotic therapy and by 48 h he had developed marked hepatosplenomegaly and coagulopathy. At 72 h a bone marrow aspirate and trephine biopsy showed haemophagocytosis. By this time the infant was encephalopathic and haemodynamically unstable with multi-organ dysfunction. Treatment with high-dose methylprednisolone and cyclosporin was commenced with an initial good response. Unfortunately the patient ultimately died of infective complications of treatment and reactivation of the underlying disease process. Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the mononuclear phagocyte system characterised by proliferation of morphologically benign histiocytes resulting in hypercytokinaemia and uncontrolled activation of immune cells. The diagnosis of familial HLH should be considered in any infant with fever, splenomegaly and cytopenia of at least two cell lines. HLH may be cured by immunosuppressive therapy and eventual stem cell transplantation but rapid disease progression to multi-organ failure results in a high mortality. [ABSTRACT FROM AUTHOR]

We report a patient with the extremely rare familial multiple lipomatosis syndrome, who developed the uncommon autoimmune disease cytophagic histiocytic panniculitis, manifested as inflammation of preexisting lipomas. Despite his initial critical condition and unsuccessful treatment with steroids, he responded to cyclosporin and remains well 15 years after diagnosis. In contrast with most previous reports, our patient stays dependent on cyclosporin; repeated attempts of discontinuing or substituting treatment were quickly followed by relapse. Haemophagocytic panniculitis is considered as a T-cell disorder, but its exact pathophysiological mechanism has not been clarified. Differential diagnosis of cytophagic histiocytic panniculitis mainly includes malignant histiocytosis, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and lupus erythematosus panniculitis (lupus profundus). We discuss the main clinical features, diagnostic challenges and treatment issues of this usually benign, but at times life-threatening autoimmune condition. [ABSTRACT FROM AUTHOR]

We describe for the first time a case of macrophage activation syndrome (MAS) in a patient with a history of inflammatory myofibroblastic tumour (inflammatory pseudotumour, IPT) of the lung and thoracic spine. The patient was admitted to the intensive care unit with a history of prolonged remitting fever, hepatosplenomegaly, bilaterally enlarged thoracic lymph nodes and an acute severe inflammatory response syndrome (SIRS). Up-regulated cytokine production (e.g. IL-1ß and IL-6), increased levels of ferritin and circulating soluble interleukin-2 receptor (sIL-2R, sCD25) led to the differential diagnosis of MAS. Bone marrow aspiration, the main tool for a definite diagnosis, revealed macrophages phagocytosing haematopoietic cells. Immunosuppressive therapy with corticosteroids and cyclosporine was an effective treatment in this patient. [ABSTRACT FROM AUTHOR]

We describe an unusual presentation of Q fever with associated haemophagocytic syndrome, confirmed by bone marrow aspirate, Q fever polymerase chain reaction (PCR) and serological testing. Clinical recovery was observed after the commencement of doxycycline with normalisation of the patient's full blood count and serum biochemistry. Serial monitoring of the Q fever serology revealed the subsequent development of sustained high phase 1 IgG antibodies, suggestive of chronic Q fever. Although many infectious aetiologies have been associated with haemophagocytosis, Q fever has only rarely been described in this context. The diagnosis of Q fever is often overlooked, especially when the presentation is atypical. We describe how the use of PCR testing significantly shortened the interval to definitive diagnosis and helped elucidate the underlying cause of the patient's haematological disorder. [ABSTRACT FROM AUTHOR]

Background Cutaneous involvement has been reported in 30–40% of children with the familial form of haemophagocytic syndrome. However, few studies have focused on cutaneous manifestations in patients with reactive haemophagocytic syndrome (RHS). Objectives To describe the frequency, clinical features and prognosis of skin involvement in adult patients with RHS. Methods We conducted a retrospective study in a French university-based tertiary centre. The medical records of all adult patients with a suspected or confirmed diagnosis of RHS during a 2-year period were reviewed. Demographic, clinical, biological and histological data of patients were compared using nonparametric tests. Results The medical charts of 151 patients were reviewed, 69 of whom had a definite diagnosis of RHS (35% women; mean ± SD age 49 ± 17 years). The aetiology of RHS was mainly B-cell or T-cell lymphoma ( n = 33) or herpesvirus infection ( n = 19). Cutaneous manifestations were observed in 32 (46%) patients and were of three types: (i) specific to the underlying malignancy (Kaposi sarcoma n = 8, cutaneous lymphoma n = 4), (ii) reflecting the biological consequences of RHS (thrombopenic purpura n = 10, conjunctival jaundice n = 7), and (iii) a generalized, transient, nonpruriginous maculopapular rash ( n = 18). None presented with erythroderma, or with eczematiform, ichthyosiform, psoriasiform or bullous lesions. One patient had cytophagic histiocytic panniculitis. Histological features of maculopapular rash biopsies were usually nonspecific. The rate of in-hospital death was not significantly associated with cutaneous involvement. Conclusions A generalized, nonpruriginous, transient, maculopapular rash is frequently observed in patients with RHS. Although nonspecific, awareness of this cutaneous involvement may assist physicians in the initial diagnosis of RHS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Macrophage activation syndrome (MAS) is a rare systemic disorder which results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. Primary haemophagocytic lymphohistiocytosis (HLH) is recognized as having a genetic basis, but the secondary haemophagocytic syndrome (HS), also referred to as MAS, occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), adult onset Still''s disease and other disorders. In this second of the two part series, the clinical features and management are described. [Copyright &y& Elsevier]

Abstract: Macrophage activation syndrome (MAS) is a potentially fatal systemic disorder which results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. It is a distinct clinicopathologic entity that occurs in different haemophagocytic syndromes (HSs). Primary haemophagocytic lymphohistiocytosis (HLH) is recognized to have an immunogenetic basis, but the secondary HS (also referred to as MAS) occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, SLE, adult onset Still''s disease and other disorders. In first of the two part series, the aetiology, molecular pathogenesis and diagnostic features will be enunciated. The second part will deal with clinical features and management issues. [Copyright &y& Elsevier]

Summary: There is a clinico-pathological continuum of infection-driven sepsis syndromes, the most severe being septic shock with multi-organ failure. The organ dysfunctions are due to inflammatory cytokines from remote sources (the site of infection) and constitute the systemic inflammatory response syndrome (SIRS). The common causes are Gram-positive and Gram-negative infections; the common infection sites are (in descending frequency) lung, blood stream, intra-abdominal disease, urological sepsis and surgical wounds; the commonest organ dysfunctions are systemic shock, kidney, lung, and heart. The differential diagnosis of severe sepsis includes disseminated malignancy, atherosclerosis, and haemophagocytic syndrome. New treatments for severe sepsis are being trialled to raise the poor survival rates in intensive care. The role of the autopsy is to describe carefully the organ lesions, provide microbiological evidence of infection, and to correlate these with the clinical features and therapeutic variables. [Copyright &y& Elsevier]

Macrophage activation syndrome (MAS) is a rare and potentially lethal complication of chronic rheumatic diseases of childhood, in particular of systemic-onset juvenile idiopathic arthritis (s-JIA), resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. The onset, acute and dramatic, may mimic a flare of the underlying disease or a severe sepsis. Diagnosis is difficult and, until now, no specific criteria have been developed. Laboratory data show pancytopenia, coagulopathy, low ESR and low concentrations of serum albumin, and high levels of ferritin, liver enzymes and triglycerides. Activated macrophages are found in various organs, particularly in bone marrow. Most hypotheses on the mechanism underlying MAS are based on the data obtained in primary haemophagocytic lymphohistiocytosis (HLH), a genetic disease very similar to MAS. Prompt diagnosis is essential because prognosis is highly related to early treatment. The first approach was to use intravenous methylprednisolone pulse therapy; cyclosporin A was proposed in patients resistant to steroids. We describe nine patients affected by haemophagocytosis: seven patients developed MAS and two patients developed HLH. A child with s-JIA developed three episodes of MAS. After the third episode, as there was no improvement with pulses of methylprednisolone and cyclosporine, he was successfully given etanercept. Conclusion: Our data, together with a similar, published observation, suggest that the TNF inhibitor etanercept is potentially useful for obtaining remission in children not responding to steroids and cyclosporin A. [ABSTRACT FROM AUTHOR]

Perforin is a cytolytic protein stored in secretory granules of CTL and NK cells. It synergizes with proapoptotic serine proteases, granzymes, to deliver the lethal hit to virus-infected or transformed target cells. The mechanism of perforin action has not been described beyond its original characterization in the 1980s, and its role in human disease has remained elusive. This article addresses recent key advances in genetic, clinical and biochemical studies that have reignited the current interest in perforin biology. [ABSTRACT FROM AUTHOR]