ABSTRACT
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. SARS-CoV-2 infection can induce secondary HLH, as described in previous case reports, but diagnosis and treatment are challenging. Case Study: We described an older male patient diagnosed with HLH related to previous SARS-CoV-2 infection. Fever was the only clinical manifestation initially but deterioration in clinical condition and laboratory parameters was observed during hospitalization. He responded poorly to classical therapy but was successfully treated with ruxolitinib. Conclusion: Clinicians should be aware of the possibility of HLH secondary to mild SARS-CoV-2 infection and take timely therapeutic measures to inhibit an inflammatory factor storm. Ruxolitinib is a potential choice for COVID-19 related HLH.
ABSTRACT
A 66-year-old male with end-stage liver disease (ESLD) secondary to non-alcoholic fatty liver disease (NAFLD), complicated by hepatocellular carcinoma (HCC), underwent deceased donor liver transplantation from a Coronavirus disease 2019 (COVID-19) positive donor. He presented a month later with fever, diarrhea and pancytopenia which led to hospitalization. The hospital course was notable for respiratory failure, attributed to invasive aspergillosis, as well as a diffuse rash. A bone marrow biopsy revealed hypocellular marrow without specific findings. In the following days, laboratory parameters raised concern for secondary hemophagocytic lymphohistiocytosis (HLH). Clinical concern also grew for solid organ transplant graft-versus-host-disease (SOT-GVHD) based on repeat marrow biopsy with elevated donor-derived CD3+ T cells on chimerism. After, a multidisciplinary discussion, the patient was started on ruxolitinib, in addition to high dose steroids, to address both SOT-GVHD and secondary HLH. Patient developed symptoms concerning for hemorrhagic stroke and was transitioned to comfort care. Although GVHD has been studied extensively in hematopoietic stem cell transplant (HSCT) patients, it is a rare entity in SOT with a lack of guidelines for management. Additionally, whether COVID-19 may play a role in development of SOT-GVDH has not been explored.Copyright © 2023 The Authors
ABSTRACT
Severe acute liver injury (ALI) is mostly triggered by viral infections and hepatotoxic drugs;however, it can also be seen in systemic diseases. Hemophagocytic lymphohistiocytosis (HLH) is a rare, immune-mediated syndrome that presents as a life-threatening inflammatory disorder affecting multiple organs. Secondary causes occur mainly in the set of malignancy, infection, and autoimmune disease, and are seldom triggered by vaccination. Although liver involvement is common, presentation as severe ALI is rare. We describe a case of a 65-year-old male with history of low-risk chronic lymphocytic leukemia and rheumatoid arthritis treated with prednisolone who presented with persistent fever and jaundice 1 week after COVID-19 vaccination. The diagnosis was challenging given the predominant liver impairment, characterized by hyperbilirubinemia, transaminases over 1,000 U/L, and prolonged INR, which prompted an extensive investigation and exclusion of autoimmune, toxic, and viral causes of hepatitis. Laboratory workup revealed bicytopenia, hyperferritinemia, which together with organ failure and evidence of hemophagocytosis in bone marrow suggested the diagnosis of HLH. After excluding infectious etiologies, flare of rheumatological disease, and the progression of hematological disease, HLH was diagnosed. He was successfully treated with etoposide and corticosteroids, with dramatic improvement of liver tests. After exclusion of other causes of secondary HLH, the recent vaccination for COVID-19 was the likely trigger. We report a case of double rarity of HLH, as it presented with severe liver dysfunction which was probably triggered by vaccination. In this case, the predominant liver involvement urged extensive investigation of liver disease, so a high index of suspicion was required to make an early diagnosis. Clinicians should consider HLH in patients with unexplained signs and symptoms of systemic inflammatory response and multiorgan involvement, including severe liver involvement as the first presentation. © 2023 S. Karger AG. All rights reserved.
ABSTRACT
Alemtuzumab is a humanized monoclonal antibody indicated for treatment of highly active relapsing-remitting multiple sclerosis (HA-RRMS). It binds to CD52 antigen and produces a rapid and prolonged lymphocyte depletion followed by a different pattern of T and B cell repopulation. Among others, its adverse events are autoimmune diseases.In this article, we present a patient with HA-RRMS, who was subsequently treated with alemtuzumab and afterwards developed hemophagocytic lymphohistiocytosis (HLH). Albeit rarely, HLH can be triggered by alemtuzumab treatment.HLH can favourably respond to prompt immunosuppressant therapy.Multidisciplinary approach by a team consisting of a neurology, hematology and rheumatology specialist is needed to treat this potentially lethal condition.
Subject(s)
Lymphohistiocytosis, Hemophagocytic , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Humans , Alemtuzumab/adverse effects , Multiple Sclerosis/chemically induced , Lymphohistiocytosis, Hemophagocytic/chemically induced , Antibodies, Monoclonal, Humanized/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapyABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by a pathologic immune response in the setting of infection, malignancy, acute illness, or any immunological stimulus. Infection is the most common etiology of HLH. HLH involves aberrant activation of lymphocytes and macrophages with resultant hypercytokinemia due to an inappropriately stimulated and ineffective immune response. Here, we present the case of a previously healthy 19-year-old male presenting with hiccups and scleral icterus, who was found to have HLH due to a severe Epstein-Barr virus infection. Despite a morphologically normal bone marrow biopsy, the patient met the diagnostic criteria for HLH, including a low natural killer cell count and elevated soluble interleukin-2 receptor. Notably, ferritin was severely elevated at 85,810 ng/mL. The patient was treated with an induction course of dexamethasone intravenously for eight weeks. Since HLH can progress into multi-organ failure, timely diagnosis and prompt initiation of treatment are critical. Novel disease-modifying therapies and further clinical trials are warranted to treat this potentially fatal immunological disease with multisystem ramifications.
ABSTRACT
Hemophagocytic lymphohistiocytosis may occur in patients with genetic predisposition and in sporadic cases due to malignancy or infection. We describe a 49-year old man with hemorrhagic fever, type 1 respiratory insufficiency and acute kidney injury. Diagnostic work up showed a hyperinflammatory syndrome, hypertriglyceridemia, hemophagocytosis, very high ferritin and significantly elevated sCD25. The findings were compatible with hemophagocytic lymphohistiocytosis based on the HLH-2004 criteria. Serological testing indentified Puumala virus as the causal pathogen. The patient was successfully treated with pulse corticosteroids, intravenous immunoglobins and supportive therapy.
ABSTRACT
X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency associated with recurrent hemophagocytic lymphohistiocytosis (HLH) episodes. The clinical phenotypes of XIAP deficiency vary, ranging from splenomegaly to life-threatening inflammation. We report a case of XIAP deficiency with unusual late-onset HLH presentation likely triggered by a drug allergy. A previously healthy adolescent boy presented to the hospital with fever and rash seven days after starting antibiotics for a neck abscess. Laboratory evaluation demonstrated cytopenias, elevated liver enzymes, and increased inflammatory markers. Initially, antibiotics were discontinued due to concern for drug rash. He continued to deteriorate clinically and became hypotensive. Additional testing revealed decreased NK cell function, as well as elevated ferritin, triglycerides, and soluble IL-2 receptor. SLAM-Associated Protein (SAP) and XIAP evaluation by flow cytometry demonstrated decreased XIAP expression. Subsequently, genetic testing revealed a known pathogenic mutation in BIRC4 (c.421_422del), confirming the diagnosis of XIAP deficiency.Copyright © 2023
ABSTRACT
The hyperinflammatory immune response in severe COVID-19 infection shares features with secondary hemophagocytic lymphohistiocytosis (sHLH) in the form of fever, cytopenia, elevated inflammatory markers, and high mortality. There are contrasting opinions regarding utility of HLH 2004 or HScore in the diagnosis of severe COVID-19-related hyperinflammatory syndrome (COVID-HIS). This was a retrospective study of 47 patients of severe COVID-19 infection, suspected to have COVID-HIS and 22 patients of sHLH to other illnesses, to evaluate the diagnostic utility and limitations of HLH 2004 and/or HScore in context to COVID-HIS and to also evaluate the utility of Temple criteria for predicting severity and outcome in COVID-HIS. Clinical findings, hematological, and biochemical parameters along with the predictor of mortality were compared between two groups. Only 6.4% (3/47) of cases fulfilled ≥5/8 HLH 2004 criteria and only 40.52% (19/47) of patients showed HScore >169 in COVID-HIS group. 65.9% (31/47) satisfied the Temple criteria in COVID-HIS as compared with 40.9% (9/22) in the non-COVID group (p = 0.04). Serum ferritin (p = 0.02), lactate dehydrogenase (p = 0.02), direct bilirubin (p = 0.02), and C-reactive protein (p = 0.03) were associated with mortality in COVID-HIS. Both HScore and HLH-2004 criteria perform poorly for identifying COVID-HIS. Presence of bone marrow hemophagocytosis may help to identify about one-third of COVID-HIS missed by the Temple Criteria.
Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , COVID-19/complications , Retrospective Studies , Syndrome , C-Reactive ProteinABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of excessive immune system activation. We report a case of HLH in a 20-year-old primigravid woman who presented with postpartum fevers. She was successfully treated with dexamethasone and anakinra, a deviation from the HLH-94 protocol, to preserve her ability to breastfeed.
ABSTRACT
We reported a case of secondary hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening condition, which was suspected to have been triggered by a severe case of coronavirus disease 2019 (COVID-19). A 50-year-old man with a past medical history of ulcerative colitis with recent pancolitis status post colectomy and ileostomy two weeks before presentation presented to the emergency department with one week of subjective fevers, weakness, watery diarrhea, and decreased oral intake. A CT scan showed fluid in the rectum and post-surgical changes from his recent colectomy along with diffuse reticulonodular opacities of the lungs. His COVID-19 reverse transcriptase-polymerase chain reaction (RT-PCR) test was positive. Over the subsequent days, the patient's condition worsened as he developed worsening acute hypoxic respiratory failure with diffuse lymphadenopathy, splenomegaly, worsening cytopenias, and increased ferritin of >100,000 ng/ml on hospital day six. Hematology oncology was consulted and he was started on empiric steroid therapy followed by etoposide. However, his condition continued to worsen, and eventually, the patient passed away on hospital day eight.
ABSTRACT
During the treatment of a patient on hemodialysis with severe coronavirus disease 2019 (COVID-19), the patient was weaned from extracorporeal membrane oxygenation, which was used to treat severe COVID-19 pneumonia. However, the patient's condition worsened after the peak infection phase of COVID-19 because of acute respiratory distress syndrome with suspected hemophagocytic lymphohistiocytosis (HLH). After a bone marrow biopsy confirmed the diagnosis, methylprednisolone pulse therapy, followed by combination therapy (including oral prednisolone and cyclosporine) was immediately administered, and the patient survived. Because HLH can occur a month or more after the onset of COVID-19, even if the viral load is reduced to the point of being undetectable by reverse transcriptase-polymerase chain reaction, it can be considered to correspond to the "post-acute COVID-19 syndrome," which has recently been proposed. Early intervention is necessary, because HLH can be fatal. Therefore, it is important to know that HLH can occur at any stage of COVID-19 and to pay attention to the patient's progress over time, including checking the HScore.
ABSTRACT
Familial hemophagocytic lymphohistiocytosis is a rare and potentially life-threatening genetic condition characterized by unsuppressed immune activation and hypercytokinemia. Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is a central nervous system inflammatory disorder characterized by punctate and curvilinear gadolinium-enhancing lesions in the brainstem, cerebellum, and spinal cord, which responds well to corticosteroid treatment. Hemophagocytic lymphohistiocytosis has been known to mimic CLIPPERS on neuroimaging, and patients previously diagnosed with CLIPPERS may carry familial hemophagocytic lymphohistiocytosis-related gene mutations that serve as predisposing factors. In this article, we describe a case initially diagnosed with CLIPPERS based on characteristic magnetic resonance imaging features and clinical course, who was later diagnosed with hemophagocytic lymphohistiocytosis based on a heterozygous familial hemophagocytic lymphohistiocytosis-associated PRF1 gene mutation.
ABSTRACT
The case of a 57-year-old male patient with jaundice, high-grade fever, and upper abdominal pain who was recovering from a mild coronavirus disease-19 (COVID-19) infection is reported. Laboratory analysis showed liver injury with high levels of AST and ALT, as well as an elevated serum ferritin level. The patient underwent a bone marrow biopsy which showed features of hemophagocytic lymphohistiocytosis (HLH), a systemic syndrome caused by immune activation. The patient was successfully treated with etoposide and dexamethasone and kept on maintenance therapy with cyclosporine, with resolution of the HLH. The discussion highlights that COVID-19 infection may cause liver injury, and in severe cases, patients may develop HLH as a cause for liver injury. The incidence of HLH in adults with severe COVID-19 infection is estimated to be lower than 5%. The association between HLH and COVID-19 infection has been studied due to immunological hyperactivation. Signs such as persistent high fever, hepatosplenomegaly, and progressive pancytopenia should raise suspicion for the diagnosis of overlapping HLH. A specific approach using steroids and etoposide, followed by maintenance therapy with cyclosporine, is proposed in the HLH-94 protocol as the mainstay of treatment. It is suggested that HLH should be suspected in patients with laboratory signs of liver injury following COVID-19 infection, especially in patients with high-grade fever and a history of rheumatic conditions.
Subject(s)
COVID-19 , Cyclosporins , Lymphohistiocytosis, Hemophagocytic , Male , Adult , Humans , Middle Aged , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , COVID-19/complications , Etoposide/therapeutic use , Bone Marrow , FeverABSTRACT
Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 and is associated with pronounced hematopathologic findings. Peripheral blood features are heterogeneous and very often include neutrophilia, lymphopenia, myeloid left shift, abnormally segmented neutrophils, atypical lymphocytes/plasmacytoid lymphocytes, and atypical monocytes. Bone marrow biopsies and aspirates are often notable for histiocytosis and hemophagocytosis, whereas secondary lymphoid organs may exhibit lymphocyte depletion, pronounced plasmacytoid infiltrates, and hemophagocytosis. These changes are reflective of profound innate and adaptive immune dysregulation, and ongoing research efforts continue to identify clinically applicable biomarkers of disease severity and outcome.
Subject(s)
COVID-19 , Lymphopenia , Humans , SARS-CoV-2 , Lymphopenia/diagnosisABSTRACT
India is an endemic country for dengue. The incidence of hemophagocytic lymphohistiocytosis (HLH) with dengue in children has been well-reported. However, central nervous system (CNS) HLH associated with dengue has not been described in the literature yet. We hereby report a novel case of CNS HLH triggered by dengue infection. An eight-month-old, well-grown male infant with uneventful antenatal, perinatal, and neonatal history was admitted with a history of febrile illness associated with cough, cold, vomiting, and loose motions and one episode of hematochezia and hepatosplenomegaly on examination. Investigations revealed bi-cytopenia, hyper-ferritinemia, deranged coagulation profile, liver function test, and hypo-fibrinogenemia. Dengue non-structural protein 1 ( NS1) antigen was positive. The child was given dexamethasone and continued supportive care with a diagnosis of dengue shock syndrome. The child showed an overall transient improvement, however, he had rebound fever followed by right focal convulsion on Day 9 of steroids. MRI brain revealed areas of diffusion-restricted embolic infarcts with diffuse leptomeningeal enhancement and mild cerebral edema, and CSF showed a total leukocyte count of 80 cells with 75% lymphocytic picture, histiocytes with hemophagocytosis, confirmatory of CNS HLH. Intrathecal methotrexate, hydrocortisone, and intravenous (IV) etoposide were started. However, the child succumbed to his illness. CNS involvement in dengue-triggered HLH needs to be suspected despite subtle neurological signs and aggressively managed following a multi-departmental approach to ensure the best clinical and neuro-developmental outcomes.
ABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a rare and very dangerous condition characterized by abnormal activation of the immune system, causing hemophagocytosis, inflammation, and potentially widespread organ damage. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity, is most commonly seen in children. Secondary HLH is commonly associated with infections, malignancies, and rheumatologic disorders. Most current information on diagnosis and treatment is based on pediatric populations. HLH is a disease that should be diagnosed and treated promptly, otherwise it is fatal. Treatment is directed at treating the triggering disorder, along with symptomatic treatment with dexamethasone and etoposide. We present a 56-year-old patient who was admitted with worsening weakness, exertional dyspnea, dry and nonproductive cough, and a 5-pound weight loss associated with loss of appetite. This is among the rare disorders that are not commonly encountered in day-to-day practice. Our differential diagnoses were broad, including infection, such as visceral leishmaniasis, atypical/tuberculous mycobacteria, histoplasmosis, Ehrlichia, Bartonella, Brucella, Adenovirus, disseminated herpes simplex virus (HSV), hematological-like Langerhans cell histiocytosis, or multicentric Castleman disease; drug reaction, such as drug rash with eosinophilia and systemic symptoms (DRESS); and metabolic disorder, including Wolman's disease (infantile lysosomal acid lipase deficiency) or Gaucher's disease. Based on our investigations as described in our case report, it was narrowed down to hemophagocytic lymphohistiocytosis and COVID-19. Two COVID-19 tests were negative. His lab abnormalities and diagnostic testing revealed hemophagocytic lymphohistiocytosis. He was empirically started on antibiotics and dexamethasone, to be continued for 2 weeks then tapered if the patient showed continued improvement. Dexamethasone was tapered over 8 weeks. He improved on just one of the Food and Drug Administration (FDA)-approved medications, proving that treatment should be tailored to the patient. In addition, in this case study, we included the background, etiology, pathogenesis, diagnosis, management, and prognosis of HLH.
Subject(s)
COVID-19 , Carcinoma, Neuroendocrine , Lymphohistiocytosis, Hemophagocytic , United States , Male , Child , Humans , Middle Aged , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , COVID-19/complications , Dexamethasone/therapeutic useABSTRACT
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.
ABSTRACT
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with multiple inflammatory symptoms involving several organ systems, including hematologic manifestations. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome caused by excessive inflammation in the absence of immune regulation. We present the case of a patient with HLH secondary to dysregulated inflammatory response following COVID-19; we also describe the diagnostic and management challenges associated with the condition.
ABSTRACT
Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.
Subject(s)
COVID-19 , Hemorrhagic Fever Virus, Crimean-Congo , Hemorrhagic Fever, Crimean , Lymphohistiocytosis, Hemophagocytic , Adult , Humans , Child , Hemorrhagic Fever, Crimean/drug therapy , Hemorrhagic Fever, Crimean/epidemiology , Hemorrhagic Fever, Crimean/pathology , Turkey/epidemiology , Pandemics , COVID-19/epidemiology , Cytokines , Disease Progression , Chemokines , Interferons , Lymphohistiocytosis, Hemophagocytic/epidemiologyABSTRACT
The aim: to highlight the importance of considering hemophagocytic lymphohistiocytosis in patients with jaundice of unclear origin and systemic inflammatory manifestations after coronavirus infection. Key points. A 64-y.o. patient was admitted to the hospital with jaundice, pruritus, fatigue, weight loss. The complaints occurred 2 weeks after discharge from the hospital for treatment of patients with coronavirus infection. Laboratory tests revealed signs of hepatic insufficiency, markers of cholestasis and inflammation persisted in time. Upon instrumental examination no signs of hepatosplenomegaly, biliary tree changes, intra- and extrahepatic obstruction were found. S. aureus was identified in blood cultures, CT scan of the facial skull bones showcased the focus of infection in the area of the roots of teeth 2.4 and 2.5. Therefore, antibiotics were prescribed. Subsequently, the patient's condition was complicated by the development of two episodes of acute respiratory distress syndrome, which occurred during the withdrawal of glucocorticosteroid therapy. Liver biopsy was performed, morphological study revealed signs of "vanishing bile duct” syndrome, excessive activation of macrophages and hemosiderosis of sinusoidal cells. Identified lesions can be found in hemophagocytic lymphohistiocytosis (HLH), a life-threatening complication of coronavirus infection. Glucocorticosteroids therapy, transfusions of human immunoglobulin, albumin, and parenteral nutrition have led to patient's condition improvement. Conclusion. COVID-19 provokes the development of secondary HLH 10 times more often than other respiratory viral infections. The possibility of hemophagocytic syndrome development should be considered, including cases of overlap syndrome with sepsis, in patients with unresolved jaundice, hyperferritinemia after coronavirus infection. Routinely used scales and criteria for diagnosis of HLH (H-score, HLH 2004) in such cases lacks sensitivity, therefore, careful analysis of clinical picture and exclusion of other causes of jaundice are required. © 2022 Russian Journal of Gastroenterology, Hepatology, Coloproctology