Haemophagocytic lymphohistiocytosis following a COVID-19 infection: case report.

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.

An Unusual Case of Hemophagocytic Lymphohistiocytosis Associated with Mycobacterium chimaera or Large-Cell Neuroendocrine Carcinoma.

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.

Lamotrigine-associated haemophagocytic lymphohistiocytosis (HLH) confounded with underlying rheumatoid arthritis.

Haemophagocytic lymphohistiocytosis (HLH) is one of the rare haematological syndromes more commonly reported in infants/children than adults. This disease is known for its aggressive dysregulated immune response affecting the host rapidly, causing multiorgan dysfunction and thus carries a high mortality. The disease still remains cryptic in this current decade despite all the developments in the ever-evolving field of haematology. Due to its rare occurrence and being more frequent in infants and the paediatric population, the literature lacks enough data to standardise therapies. Such events in adults and the elderly are invariably related to an underlying insult such as infections, other autoimmune or rheumatological diseases or drugs. We describe an interesting case of a middle-aged Caucasian woman who presented with fever, pancytopenia and hepatitis, who was eventually diagnosed with HLH just in time to receive the life-saving specific treatment as per available guidelines.

Severe Pediatric COVID-19 Pneumonia Treated With Adjuvant Anakinra.

BACKGROUND AND OBJECTIVES: To compare previous hemophagocytic lymphohistiocytosis criteria with adult coronavirus disease 2019 (COVID-19)-associated hyperinflammatory syndrome (cHIS) criteria for the diagnosis of hyperinflammation in pediatric patients with COVID-19. The secondary objective was to assess treatment response to intravenous (IV) anakinra in these patients. METHODS: This case series included children admitted to the PICU for COVID-19 pneumonia with hyperinflammation and treated with IV anakinra between July 2020 to April 2021. Hyperinflammatory criteria were determined for each patient. Clinical course, chest imaging, and inflammatory marker trends were assessed pre- and post-anakinra treatment. RESULTS: All patients had a cHIS criteria score of ≥5. Two patients met 2004-hemophagocytic lymphohistiocytosis criteria. Only the patient that required extracorporeal membrane oxygenation met the H-Score cut-off value. All but one patient had a decrease in their inflammatory markers and improvement in clinical status with early initiation of adjunctive IV anakinra. CONCLUSIONS: In this case series, adult cHIS criteria were successfully used to identify pediatric COVID-19 patients with hyperinflammation. Ferritin levels decreased after the early initiation of IV anakinra.

Hemophagocytic lymphohistiocytosis after SARS-CoV-2 vaccination.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has led to the approval of novel vaccines with different mechanisms of action. Until now, more than 4.7 billion persons have been vaccinated around the world, and adverse effects not observed in pre-authorization trials are being reported at low frequency. METHODS: We report a case of severe hemophagocytic lymphohistiocytosis (HLH) after SARS-CoV-2 immunization and performed a literature search for all reported cases of COVID-19 vaccine-associated HLH. RESULTS: A 24-year-old female developed HLH after immunization with the mRNA COVID-19 vaccine Comirnaty. Diagnosis was made according to HLH-2004 criteria; the HScore was 259 (> 99% HLH probability) with maximum ferritin of 138.244 µg/L. The patient was initially treated with intravenous immunoglobulins (IVIGs) and dexamethasone without response. The addition of the human interleukin 1 receptor antagonist Anakinra resulted in full recovery within 6 weeks after vaccination. A literature search revealed 15 additional cases of HLH after SARS-CoV-2 vaccination, the majority after immunization with Comirnaty (n = 7) or the viral vector vaccine Vaxzevria (n = 6). Treatment modalities included corticosteroids (n = 13), Anakinra (n = 5), IVIGs (n = 5), and etoposide (n = 2). Eight patients underwent combination treatment. Three of 16 patients died. CONCLUSION: COVID-19 vaccines may occasionally trigger HLH, and Anakinra may be an efficacious treatment option for this condition.

Haemophagocytic lymphohistiocytosis (HLH)-associated stress cardiomyopathy secondary to autoimmune conditions successfully treated with anakinra.

We describe two young cases of reactive haemophagocytic lymphohistiocytosis (HLH) with the resultant stress cardiomyopathy in the setting of underlying autoimmune diseases, systemic lupus erythematosus (SLE) and Still's disease. The initial presentation was similar in both cases with fever, hyperinflammatory response, hypotension (vasoplegia), bicytopenia and hyperferritinemia. Despite standard of care and multiple broad-spectrum antibiotics, both cases remained pyrexic and were ultimately admitted to the intensive therapy unit to treat cardiogenic shock. Echocardiogram of both cases showed low ejection fraction, the cause for which was not found until the final diagnosis of HLH was made. Both cases made a complete clinical and cardiac recovery following the initiation of high-dose glucocorticoids and anakinra.

Lessons of the month 3: Haemophagocytic lymphohistiocytosis following COVID-19 vaccination (ChAdOx1 nCoV-19).

A 36-year-old woman presented to hospital 9 days after receiving her first dose of the ChAdOx1 nCoV-19 vaccine with fever, myalgia and a sore throat. She was previously fit and well with no prior vaccine reactions.There was no clinical response to initial treatment with intravenous (IV) antibiotics. Microbiology tests including for COVID-19 were negative. At day 5, she developed pleuritic pain and a pericardial rub. Echocardiography and subsequent cardiac magnetic resonance imaging showed evidence of constrictive pericarditis. Computed tomography revealed gross hepatomegaly and moderate splenomegaly. Blood tests showed raised inflammatory markers, deranged clotting, low platelets and a marked hyperferritinaemia.A presumptive diagnosis of a multi-system inflammatory disorder secondary to recent COVID-19 vaccination was made and high-dose IV methylprednisolone initiated. Following a high 'H score' of 70%-80% a diagnosis of secondary haemophagocytic lymphohistiocytosis (HLH) was made. She was treated with IV immunoglobulin with subsequent clinical response.HLH is a rare syndrome of acute and rapidly progressive systemic inflammation characterised by cytopenias, excessive cytokine production and hyperferritinaemia. The adult form has multiple triggers, including recent vaccination. This case prompts awareness among clinicians of HLH as a rare complication of COVID-19 vaccination but should not discourage individuals from vaccination.

Hemophagocytic syndrome secondary to SARS-Cov-2 infection: a case report.

BACKGROUND: Hemophagocytic syndrome (HPS) is a severe hyperinflammatory disease, whose diagnosis is based on the HLH-2004 criteria. In secondary forms of HLH (sHLH), the primary goal is treating the triggering factors such as COVID-19 (Coronavirus disease 2019). The link between the cytokine storm related to COVID-19 and development of sHLH has already been reported since the onset of pandemic, but little is known about clinical manifestations of HLH which develop after the patient's recovery from mild symptomatic or asymptomatic Sars-CoV-2 infection. CASE PRESENTATION: We describe the case of a woman diagnosed with sHLH related to previous Sars-CoV-2 infection and successfully treated with steroids, colchicine, etoposide and ruxolitinib. CONCLUSIONS: Our report suggests that HLH-like syndrome might be secondary to Sars-CoV-2 infection, even if the patient utterly recovered from the mildly symptomatic viral infection. In addition, we underline the treatment with low dose ruxolitinib plus etoposide as a potential choice for Sars-CoV-2 infection related HLH.

Haemophagocytic lymphohistiocytosis in pregnancy: a pertinent case during the COVID-19 pandemic.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, often fatal disease, and presents a diagnostic challenge in the pregnant patient. This challenge is particularly relevant during the current COVID-19 pandemic. We present a case of HLH in a pregnant woman presenting with fever predating the COVID-19 pandemic. A 33-year-old, gravida 2, para 1 at 27 weeks' gestation presented with fever, transaminitis, thrombocytopenia and elevated ferritin. After treatment according to the HLH-94 protocol, caesarean delivery and weeks of intensive care, the patient recovered fully. With prompt diagnosis and a multispecialty team at our tertiary care facility, she and her baby overcame a dire prognosis. HLH should be considered in pregnant patients presenting with a febrile illness. Particularly in cases of severe COVID-19, secondary HLH must be considered as an associated diagnosis.

Haemophagocytic lymphohistiocytosis in an adult with postacute COVID-19 syndrome.

Haemophagocytic lymphohistiocytosis (HLH) causing multiorgan failure has been reported as an acute clinical presentation of COVID-19. However, the literature surrounding HLH in the context of a postacute COVID-19 syndrome is limited. This report presents a case of a life-threatening HLH occurring 6 weeks after a pauci-symptomatic COVID-19 infection in a previously healthy adult. A bone marrow aspirate confirmed the HLH and the patient was successfully treated with dexamethasone and etoposide. To our knowledge, this is the first case of HLH occurring as a postacute COVID-19 syndrome following a pauci-symptomatic initial infection.

Continuous intravenous anakinra for treating severe secondary haemophagocytic lymphohistiocytosis/macrophage activation syndrome in critically ill children.

The cytokine storm of secondary haemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) can cause life-threatening multiorgan failure. Interleukin-1 (IL-1) receptor blockade with anakinra can be effective in the management of sHLH/MAS. Subcutaneous (SC) dosing regimens are widely described; however, intravenous (IV) dosing is advantageous where time-critical intervention is vital and where SC oedema and/or hypoperfusion limits absorption. We review three critically ill children (aged 9, 11 and 17) with sHLH and rapidly progressive multiorgan dysfunction, successfully treated with continuous IV anakinra infusion. This case series significantly enhances the incipient knowledge regarding the safety and efficacy of IV anakinra for life-threatening sHLH.

Hemophagocytic lymphohistiocytosis after COVID-19 vaccination.

Cases of thrombotic thrombocytopenia induced by coronavirus disease 2019 (COVID-19) vaccines have been reported recently. Herein, we describe the first case of another critical disorder, hemophagocytic lymphohistiocytosis (HLH), in a healthy individual after COVID-19 vaccination. A 43-year-old Chinese farmer developed malaise, vomiting, and persistent high fever (up to 39.7 °C) shortly after receiving the first dose of the inactivated SARS-CoV-2 vaccine. The initial evaluation showed pancytopenia (neutrophil count, 0.70 × 109/L; hemoglobin, 113 g/L; platelet, 27 × 109/L), elevated triglyceride (2.43 mmol/L), and decreased fibrinogen (1.41 g/L). Further tests showed high serum ferritin levels (8140.4 µg/L), low NK cell cytotoxicity (50.13%-60.83%), and positive tests for Epstein-Barr virus (EBV) DNA. Hemophagocytosis was observed in the bone marrow. Therefore, HLH was confirmed, and dexamethasone acetate (10 mg/day) was immediately prescribed without etoposide. Signs and abnormal laboratory results resolved gradually, and the patient was discharged. HLH is a life-threatening hyperinflammatory syndrome caused by aberrantly activated macrophages and cytotoxic T cells, which may rapidly progress to terminal multiple organ failure. In this case, HLH was induced by the COVID-19 vaccination immuno-stimulation on a chronic EBV infection background. This report indicates that it is crucial to exclude the presence of active EBV infection or other common viruses before COVID-19 vaccination.

Complicated case of COVID-19 disease with overlapping features of thrombotic thrombocytopenic purpura and haemophagocytic lymphohistiocytosis.

Haemophagocytic lymphohistiocytosis has been reported as an uncommon complication of severe COVID-19 disease while thrombotic thrombocytopenic purpura has been rarely reported. Here, we are reporting a 21-year-old man who developed a combination of these complications during the hospital stay in the post-COVID-19 recovery period. He presented with fever and bilateral COVID-19-related pneumonia requiring invasive ventilation. His hospital course was complicated by the development of pneumothorax, ventilator-associated pneumonia, thrombotic thrombocytopenic purpura and haemophagocytic lymphohistiocytosis. He received remdesivir, IVIG, steroid, fresh frozen plasma and supportive care but had a fatal outcome.

SARS-CoV-2 Triggering Severe Acute Respiratory Distress Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-Old Child With Down Syndrome.

Down syndrome (DS) predisposes to severe immunologic reaction secondary to infectious triggers. Here, we report a pediatric DS patient with coronavirus disease 2019 (COVID-19) who developed a hyperinflammatory syndrome, severe acute respiratory distress syndrome, and secondary hemophagocytic lymphohistiocytosis requiring pediatric intensive care unit admission and treatment with steroids, intravenous immunoglobulin, and remdesivir. Investigations into genetic susceptibilities for COVID-19 and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated complications warrant systematic clinical and scientific studies. We report a pediatric Down syndrome patient with coronavirus disease 2019 (COVID-19) who developed secondary hemophagocytic lymphohistiocytosis requiring treatment with steroids, intravenous immunoglobulin, and remdesivir. Investigations into genetic susceptibilities for COVID-19-associated complications warrant systematic clinical and scientific studies.

Hemophagocytic lymphohistiocytosis in COVID-19: Case reports of a stepwise approach.

RATIONALE: The immunologic syndrome induced by severe acute coronavirus disease 2019 (COVID-19) is yet not fully understood. Typical patterns of clinical and laboratory features match secondary hemophagocytic lymphohistiocytosis (sHLH). However, the optimal approach to COVID-19 patients testing positive for sHLH is still unclear. PATIENT CONCERNS: Three patients with COVID-19 are reviewed. All showed hyperinflammation and cytokine storm, necessitating intensive care treatment including mechanical ventilation. DIAGNOSIS: Secondary hemophagocytic lymphohistiocytosis due to severe COVID-19; diagnosed via HScore. INTERVENTIONS: A treatment regimen of methylprednisolone, pentaglobin, and anakinra was developed and administered. OUTCOMES: One patient survived the ICU stay. Two other patients, in whom sHLH was diagnosed too late, deceased. LESSONS: A routine screening of COVID-19 patients for secondary HLH by using the HScore is feasible; especially those patients deteriorating clinically with no sufficient response to shock management might be at particular high risk. A stepwise therapeutic approach comprising corticosteroids, immunoglobulins and anakinra, accompanied by immunoadsorption, may dampen cytokine storm effects, and potentially reduce mortality.

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.