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.

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.

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.

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.

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.

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.

UNASSIGNED: To report a case of intravascular lymphoma (IVL) in a Caucasian patient who presented with anasarca as his sole clinical sign.
UNASSIGNED: 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.
UNASSIGNED: Closer review of the bone marrow aspirate demonstrated haemophagocytic histiocytosis, while core, renal and duodenal biopsies showed a B-cell IVL.
UNASSIGNED: The differential diagnosis of anasarca, a relatively common clinical sign, should include IVL although the diagnosis may still be challenging.
UNASSIGNED: 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.

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).

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.