An Uncommon Complication of a Common Tropical Infection in a Kidney Transplant Recipient - A Case Report.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition due to extensive and uncontrolled immune activation. There is sparse literature on HLH in kidney transplant recipients. We report a case of a 27-year -old male kidney transplant recipient who presented with dengue fever and acute allograft dysfunction. Following improvement in allograft function with supportive treatment, he was found to have worsening pancytopenia with unusually high serum ferritin levels. Bone marrow aspiration performed for pancytopenia revealed hemophagocytosis. A diagnosis of HLH secondary to dengue viral infection was made based on the modified HLH diagnostic criteria (2009). He received supportive treatment and steroids and was discharged in a stable condition with normal kidney allograft functions. To our knowledge, this is the first case report of HLH secondary to dengue viral infection in a kidney allograft recipient managed successfully with timely diagnosis and appropriate treatment.

Clinical characterization of hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors: a review of published cases.

OBJECTIVE: An association exists between immune checkpoint inhibitors and hemophagocytic lymphohistiocytosis (HLH). Therefore, the main objective of this study was to collect data on this rare but potentially life-threatening immune-related adverse reaction to identify the medications that cause it, the clinical characteristics, and effective treatments. METHODS: Literature in English and Chinese on immune checkpoint inhibitors causing HLH published from August 2014 to March 2024 was analyzed. Immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome keywords were used to find the literature on China Knowledge Network, Wanfang, PubMed and Emabase Databases. RESULTS AND DISCUSSION: Twenty-four studies were included, with a total of 27 patients (18 males and 9 females) with a mean age of 58 years (range 26-86). The mean time to the onset of symptoms was 10.3 weeks (7 days-14 months). The main clinical characteristics were fever, cytopenia, splenomegaly, methemoglobinemia, hypofibrinogenemia, and bone marrow biopsy showed phagocytosis. Twenty-two patients improved after the treatment with steroids, cytokine blocking therapy and symptomatic treatment, four patients died, and one patient was not described. CONCLUSION: HLH should be not underestimated as a potentially serious adverse effect of immune checkpoint inhibitors since appropriate treatments may save the life of patients.

Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients.

BACKGROUND: Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. METHODS: In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 µg/L) and underwent bone marrow biopsy during their ICU course. RESULTS: Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. CONCLUSIONS: Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.

Using HScore for Evaluation of Hemophagocytosis in Multisystem Inflammatory Syndrome Associated with COVID-19 in Children.

Hemophagocytic syndrome is a key point in the pathogenesis of severe forms of multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C). The factors associated with hemophagocytosis in patients with MIS-C were assessed in the present study of 94 boys and 64 girls ranging in age from 4 months to 17 years, each of whose HScore was calculated. In accordance with a previous analysis, patients with HScore ≤ 91 (n = 79) and HScore > 91 (n = 79) were compared. Patients with HScore > 91 had a higher frequency of symptoms such as cervical lymphadenopathy, dry cracked lips, bright mucous, erythema/swelling of hands and feet, peeling of fingers, edematous syndrome, hepatomegaly, splenomegaly, and hypotension/shock. They also had a higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and D-dimer levels, and a tendency to anemia, thrombocytopenia, and hypofibrinogenemia. They more often needed acetylsalicylic acid and biological treatment and were admitted to ICU in 70.9% of cases. Conclusion: The following signs of severe MIS-C were associated with HScore > 91: myocardial involvement, pericarditis, hypotension/shock, and ICU admission.

Upregulation of ATP6V0D2 benefits intracellular survival of Leishmania donovani in erythrocytes-engulfing macrophages.

Visceral leishmaniasis (VL) is the most severe type of leishmaniasis which is caused by infection of Leishmania donovani complex. In the BALB/c mouse model of VL, multinucleated giant cells (MGCs) with heavy parasite infection consist of the largest population of hemophagocytes in the spleen of L. donovani-infected mice, indicating that MGCs provide the parasites a circumstance beneficial for their survival. Although ATP6V0D2 is a demonstrated factor inducing the formation of hemophagocytic MGCs during L. donovani infection, functions of this protein in shaping the infection outcome in macrophages remain unclear. Here we evaluated the influence of upregulated ATP6V0D2 on intracellular survival of the parasites. L. donovani infection-induced hemophagocytosis of normal erythrocytes by macrophages was suppressed by RNAi-based knockdown of Atp6v0d2. The knockdown of Atp6v0d2 did not improve the survival of amastigotes within macrophages when the cells were cultured in the absence of erythrocytes. On the other hand, reduced intracellular survival of amastigotes in macrophages by the knockdown was observed when macrophages were supplemented with antibody-opsonized erythrocytes before infection. There, increase in cytosolic labile iron pool was observed in the L. donovani-infected knocked-down macrophages. It suggests that ATP6V0D2 plays roles not only in upregulation of hemophagocytosis but also in iron trafficking within L. donovani-infected macrophages. Superior access to iron in macrophages may be how the upregulated expression of the molecule brings benefit to Leishmania for their intracellular survival in the presence of erythrocytes.

[Hemophagocytic lymphohistiocytosis and macrophage activation syndrome : A multidisciplinary challenge]. / Hämophagozytische Lymphohistiozytose und Makrophagenaktivierungssyndrom : Eine multidisziplinäre Herausforderung.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is characterized by hyperferritinemia, cytopenia, disseminated intravascular coagulopathy and functional disorders of the liver and the central nervous system. The term macrophage activation syndrome is predominantly used for secondary HLH in the context of autoimmune diseases (e.g., systemic juvenile idiopathic arthritis). In addition, malignancies and genetic inborn errors of immunity can predispose to the development of HLH. Infections (e.g., Epstein-Barr virus) in turn represent possible triggers of an acute episode. Due to the unspecific manifestation of the disease, a systematic evaluation of the organ systems is recommended in the clinical and laboratory analytical clarification of hyperinflammatory syndromes. In general, the treatment should be carried out by a multidisciplinary team with expertise in rheumatology, hematological oncology, infectious diseases and intensive care medicine. The primary treatment of HLH usually consists of glucocorticoids and in cases of a rapid deterioration of the condition anakinra (interleukin 1 block) and intravenous immunoglobulins can be employed. Treatment of the underlying disease should be consequently carried out in parallel, together with antimicrobial treatment.

Liver Dysfunction in Adult Hemophagocytic Lymphohistiocytosis: A Narrative Review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition that has been increasingly recognized in adults and is characterized by a hyperinflammatory state due to immune dysregulation. Its nonspecific presentation, the lack of clinician familiarity given its rarity, and shared clinical features with sepsis and other syndromes can lead to a delay in diagnosis and a poor prognosis. Significant liver function abnormalities as the initial manifestation of HLH are uncommon and can range from mild elevation of aminotransferases to fulminant hepatic failure with high mortality rates. The authors encountered a case of adult HLH mimicking acute viral hepatitis in which a markedly elevated ferritin level led to a prompt diagnosis, early initiation of treatment, and a successful outcome. Clinicians, including gastroenterologists and hepatologists, are often called upon to evaluate patients with abnormal liver tests and may lack experience in the early diagnosis and management of liver dysfunction in the context of HLH. Thus, we expand our reporting to a narrative review of literature which explores the pathogenesis of HLH, challenges associated with its diagnosis, previous reports of liver disease associated with the syndrome, recommended treatments for the familial and adult variations including the role of liver transplantation, and the outcomes of these treatments.

Uncovering the Spectrum of Hemophagocytic Lymphohistiocytosis: A Nephrology Department's Analysis of 14 Cases.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a disease of multi-organ dysfunction due to excessive immune activation causing widespread inflammation and tissue destruction. It is a severe condition associated with high morbidity and mortality. Early identification is crucial for prompt treatment. The objective of this case series is to underscore the intricacy of managing HLH in individuals with renal dysfunction. Methods: This is a retrospective study of patients diagnosed with HLH in a nephrology department over a period of 30 years. We retrospectively reviewed the medical files by applying the Revised HLH-2004 criteria. Results: Among the 14 female patients included, the mean age was 45.2 years (range 23-78). Nine patients presented with sudden onset of fever and chills. Physical examination revealed purpura in 3 cases, hepatomegaly and splenomegaly in 6 and 5 cases respectively, and peripheral lymphadenopathy in 1 case. Hemorrhagic complications were observed in 5 cases, hypertriglyceridemia in 9 cases, and hyperferritinemia in all cases. Hypothyroidism was observed in all cases, and impaired renal function was detected in 11 of them, with 5 experiencing it as a result of lupus nephritis, and 1 case attributed to pre-eclampsia. Hemophagocytosis was confirmed through sternal puncture in 11 cases. Treatment involved etiological therapy with corticosteroids and immunosuppressants and/or anti-infectives. Intravenous immunoglobulins were administered in 6 cases, while 2 cases required coagulation factor transfusions. Unfortunately, 9 patients did not survive. Conclusion: The study highlights the need for increased awareness and prompt recognition of HLH, particularly in patients with associated renal complications.

Spectrum of Hemophagocytosis in Bone Marrow Aspirates: Experience from a Tertiary Care Hospital in North India.

Background: Hemophagocytosis refers to the engulfment of hematopoietic cells by histiocytes. It can be seen in various conditions but is usually reported in the setting of hemophagocytic lymphohistiocytosis (HLH). Optimal interpretation of hemophagocytosis in the bone marrow in relation to the underlying disease significantly contributes to correct patient management. Aim: The present study was done to identify the spectrum of conditions associated with hemophagocytosis in the bone marrow aspirates and grade the degree of hemophagocytosis. Material and Methods: This retrospective observational study included all the bone marrow aspirates showing hemophagocytosis, identified over a period of 5 years (January 2015 to January 2020). Two pathologists independently reviewed bone marrow slides. Hemophagocytosis was graded as mild, moderate, or severe by observing the number of histiocytes showing hemophagocytosis per 500 nucleated cells. Results: Eighty-eight patients showing hemophagocytosis in the bone marrow aspirate smear were included in the study. The most common cause of hemophagocytosis was infection (18%). There were 4 (5%) cases of HLH. Grade 1 (mild) hemophagocytosis was seen in 25 (29%) cases followed by Grade 2 (moderate) in 53 (60%) cases and Grade 3 (severe) in 10 (11%) cases. Fever was the most common clinical symptom present in 45 (51%) cases. Conclusion: Hemophagocytosis in bone marrow aspirates is a common and under-reported finding. It is not only seen in cases of HLH but also in infections and other conditions. Documenting hemophagocytosis, even in the absence of fulfilled HLH criteria, is vital to explain cytopenias.

The Decimating Army: Hemophagocytic Lymphohistiocytosis as the Initial Presentation of Adult-Onset Still's Disease.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often missed presentation in the hospital setting. It is a hyperinflammatory syndrome of immune activation and dysregulation characterized by fever, cytopenias, elevated serum ferritin levels, and hepatosplenomegaly. It has a multifactorial etiology occurring primarily secondary to infection, malignancy, immune checkpoint inhibitors, or autoimmune disease. HLH that occurs in autoimmune diseases such as adult-onset Still's disease and systemic lupus erythematosus is referred to as macrophage activation syndrome. However, it may rarely be a primary disorder from a genetic defect. The pathophysiology of HLH is poorly understood and often results in multiorgan dysfunction. We present an older adult male patient with several hospital stays due to his symptoms, who presented with lethargy, low-grade fever, cough, dyspnea, and recurrent pleural effusions. He had bicytopenia, elevated ferritin, and hypertriglyceridemia. The diagnosis of HLH may be delayed, especially in older adult patients with an insidious course, and requires a high index of suspicion.

Refractory pancytopenia upon initiation of asciminib in tyrosine kinase inhibitor-resistant chronic myeloid leukemia.

Asciminib, a "Specifically Targeting the ABL Myristoyl Pocket" inhibitor, is a new drug in the treatment of tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML). Hemocytopenias associated with asciminib are common adverse events documented by clinical trials. We report a case of precipitous-onset pancytopenia with the initiation of asciminib treatment in a patient with TKI-resistant CML. This case had a confounding array of laboratory findings that evidenced a drug-induced hemophagocytic component. We hope that our case stimulates further reporting of similar cases to enhance the understanding of the pathophysiology underlying asciminib-induced hemocytopenias.

Bone marrow alterations in COVID-19 infection: The root of hematological problems.

INTRODUCTION: The 2019 coronavirus disease (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus with a significant impact on the hematopoietic system and homeostasis. The effect of the virus on blood cells indicates the involvement of the bone marrow (BM) as the place of production and maturation of these cells by the virus and it reminds the necessity of investigating the effect of the virus on the bone marrow. METHOD: To investigate the effects of COVID-19 infection in BM, we reviewed literature from the Google Scholar search engine and PubMed database up to 2022 using the terms "COVID-19; SARS-CoV-2; Bone marrow; Thrombocytopenia; Hemophagocytosis; Pancytopenia and Thrombocytopenia. RESULTS: Infection with the SARS-CoV-2 virus is accompanied by alterations such as single-line cytopenia, pancytopenia, hemophagocytosis, and BM necrosis. The presence of factors such as cytokine release syndrome, the direct effect of the virus on cells through different receptors, and the side effects of current treatments such as corticosteroids are some of the important mechanisms in the occurrence of these alterations. CONCLUSION: To our knowledge, this review is the first study to comprehensively investigate BM alterations caused by SAR-CoV-2 virus infection. The available findings show that the significant impact of this viral infection on blood cells and the clinical consequences resulting from them are deeper than previously thought and it may be rooted in the changes that the virus causes in the BM of patients.

Fever of Unknown Origin, a Vascular Event, and Immunosuppression in Tick-Endemic Areas: Think About Neoehrlichiosis.

Three patients were referred to our hospital because of fever of unknown origin (FUO) and thrombosis or thrombophlebitis. All of them had been under immunosuppression (IS) with rituximab. Intensive diagnostics for FUO and blood cultures remained negative. Finally, the association of fever, immunosuppression, and a vascular event led to the suspicion of Candidatus Neoehrlichia mikurensis (CNM) infection. The diagnosis was confirmed by species-specific polymerase chain reaction (PCR) in the peripheral blood. Therapy with doxycycline or rifampicin led to the resolution of the disease. A liver biopsy was performed in one patient due to hepatomegaly and elevated liver enzymes demonstrating hemophagocytosis. To our knowledge, this is the first histopathological study of liver tissue in CNM infection. The evidence of hemophagocytosis raises the question of whether symptomatic CNM infection might be in part related to host inflammatory and immune responses.

Dengue hepatitis: Incidence, spectrum and outcome.

BACKGROUND AND AIMS: While dengue infection is common in India, there is scarce information on dengue hepatitis. The aim of this study was to analyze the incidence, spectrum and outcome of dengue hepatitis. METHODS: We retrospectively analyzed consecutive patients, who had hepatitis among those with dengue infection admitted to two tertiary care hospitals in western India from January 2016 to March 2021. Diagnosis of dengue infection was made by serology. Dengue hepatitis was diagnosed and the severity of dengue was categorized by standard criteria. RESULTS: Of 1664 patients admitted with dengue fever during the study period, 199 patients had hepatitis (i.e. incidence of dengue hepatitis was 11.9%). Of the 199 dengue hepatitis patients (age: 29 [13 - 80] years, median [range], 67% males), 100 patients (50%) had severe dengue, 73 (36%) had severe dengue hepatitis, 32 (16%) had dengue shock syndrome and eight (4%) had acute liver failure. Forty-five patients (23%) had acute lung injury and 32 (16%) had acute kidney injury. The dengue hepatitis patients were treated with standard medical care, including vital organ support, as needed-166 (83%) patients survived, while 33 patients (17%) died (cause of death: multi-organ failure: 24 patients, septic shock: nine patients). The presence of shock independently predicted mortality (odds ratio 6.4, 95% confidence interval: 1.2 - 34). Among patients with dengue hepatitis, mortality rate was higher in those with severe dengue (23%), dengue shock syndrome (47%), severe dengue hepatitis (24%) and acute liver failure (38%). CONCLUSION: In this large series of hospitalized patients with dengue infection, the incidence of dengue hepatitis was 11.9%. Among 199 dengue hepatitis, 17% died; multi-organ failure was the commonest cause for death and death rate was higher in patients with more severe disease. The presence of shock at presentation independently predicted mortality.

The Challenging Aspect of Macrophage Activation Syndrome in the Setting of Sepsis or Systemic Inflammatory Response Syndrome (SIRS).

Macrophage activation syndrome (MAS) is a rare but potentially fatal disease. It is characterized by hyperinflammation, including the proliferation and activation of immune cells (CD8 T cells and NK cells) associated with hypercytokinemia. Patients present with fever, splenomegaly, and cytopenia, associated with a hemophagocytosis picture in the bone marrow. It can progress to a multiorgan failure syndrome (MODS), mimicking sepsis or a systemic inflammatory response syndrome (SIRS). We report the case of an 8-year-old girl admitted to the pediatric intensive care unit for the management of major trauma due to a domestic accident. She presented with a protracted fever in the context of a septic shock, despite appropriate treatment. The association with bicytopenia, hyperferritinemia, hypofibrinogenemia, and hypertriglyceridemia was suggestive of MAS which was confirmed by a bone marrow puncture showing hemophagocytosis. A Bolus of corticotherapy was then added to the supportive treatment and broad-spectrum antibiotherapy, with a good outcome.

Hemophagocytic Lymphohistiocytosis syndrome (HLH) associated with acute pancreatitis: A case report.

Hemophagocytic Lymphohistiocytosis syndrome is fatal hyper-inflammatory condition due to over-activation of the immune system, being of primary and secondary types. This case report emphasizes the difficulty and challenge in and of the HLH diagnosis, and therapy should be employed promptly given the high mortality associated with HLH.