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1.
Arch Pathol Lab Med ; 146(4): 507-519, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1791951

ABSTRACT

CONTEXT.­: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can eventually result in end-organ damage and death. HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. The prognosis is generally poor, warranting rapid diagnosis and aggressive management. OBJECTIVE.­: To provide a comprehensive review of the pathogenesis, clinical features, diagnosis, and management of HLH. DATA SOURCES.­: Peer-reviewed literature. CONCLUSIONS.­: HLH is a condition where a complete understanding of the pathogenesis, early diagnosis, and proper management has an important role in determining patient outcome. Genetic mutations causing impairment in the function of cytotoxic T lymphocytes and natural killer cells have been identified as the root cause of familial HLH; however, the specific pathogenesis of acquired HLH is unclear. The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population. The HLH-2004 protocol still forms the basis of the diagnosis of HLH in adults, although its use in adults has not been formally validated yet. Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Child , Humans , Killer Cells, Natural , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/therapy , Macrophages
2.
BMJ Case Rep ; 15(3)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1736043

ABSTRACT

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.


Subject(s)
Arthritis, Rheumatoid , Lymphohistiocytosis, Hemophagocytic , Adult , Aged , Anticonvulsants/therapeutic use , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/drug therapy , Child , Female , Fever/complications , Humans , Lamotrigine/therapeutic use , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Middle Aged
5.
Exp Biol Med (Maywood) ; 247(4): 330-337, 2022 02.
Article in English | MEDLINE | ID: covidwho-1649719

ABSTRACT

Cytokine storm is an umbrella term that describes an inflammatory syndrome characterized by elevated levels of circulating cytokines and hyperactivation of innate and/or adaptive immune cells. One type of cytokine storm is hemophagocytic lymphohistiocytosis (HLH), which can be either primary or secondary. Severe COVID-19-associated pneumonia and acute respiratory distress syndrome (ARDS) can also lead to cytokine storm/cytokine release syndrome (CS/CRS) and, more rarely, meet criteria for the diagnosis of secondary HLH. Here, we review the immunobiology of primary and secondary HLH and examine whether COVID-19-associated CS/CRS can be discriminated from non-COVID-19 secondary HLH. Finally, we review differences in immunobiology between these different entities, which may inform both clinical diagnosis and treatment of patients.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Cytokine Release Syndrome/virology , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/therapy
6.
Turk J Pediatr ; 63(6): 1103-1107, 2021.
Article in English | MEDLINE | ID: covidwho-1622999

ABSTRACT

BACKGROUND: Based on the information obtained so far, COVID- 19 is relatively mild in children. We will present a 6-month-old male patient infected with COVID -19 in April 2020, while receiving HLH 2004 chemotherapy protocol with the diagnosis of familial (Genetic / Primary) Hemophagocytic Lymphohistiocytosis (HLH). CASE: Herein we present a case accompanied by a defective perforin gene defect in the primary HLH pathogenesis, Covid-19 infection with the presence of fever and hyperferritinemia, which was evaluated in favor of reactivation and the patient was given both the HLH-2004 chemotherapy protocol treatment and COVID -19 therapy as recommended by the guidelines. Our patient improved clinically and in terms of laboratory test results at the end of the 15 < sup > th < /sup > day of hospitalization and was discharged. CONCLUSIONS: It should be remembered that COVID-19 can be seen with different clinical manifestations in the pediatric age group, and COVID-19 tests should be recommended, especially in children with immunosuppression and fever.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Child , Fever , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , SARS-CoV-2
8.
J Infect Dev Ctries ; 15(11): 1607-1614, 2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1572707

ABSTRACT

Novel coronavirus infections 2019 (COVID-19) associated hyperinflammatory syndromes are well-defined clinical conditions and have a potential risk for severe infection. Hemophagocytic lymphohistiocytosis (HLH), a rare type of acute progressive hyperinflammatory syndrome, has been reported in a limited number of COVID-19 cases. In this article, we aimed to present a patient with HLH secondary to COVID-19 diagnosed by bone marrow biopsy, and to summarize and review HLH cases associated with COVID-19 in the literature. A 47-year-old male patient presented with complaints of fever, cough, abdominal discomfort, and nausea-vomiting. He had recovered from COVID-19 a month ago and was readmitted to the hospital due to the re-appearance of clinical symptoms after a two-week interval. The patient was diagnosed with HLH secondary to COVID-19 on sixth day of admission and fully recovered with systemic pulse steroid, intravenous immunoglobulin, and plasma exchange therapy. Analysis of literature searches revealed that 22 cases were definitely diagnosed with COVID-19-associated HLH, 16 of them were male. They had been treated with different anti-cytokine drugs, of which nine had died. The increasing number of HLH cases, which have high mortality rates, shows the importance of hyperinflammatory syndromes in COVID-19 patients. Some patients may experience hemophagocytosis in the late period of COVID-19, even while in recovery. Increased awareness and early treatment for HLH triggered by COVID-19 can be a life-saving effort for reducing mortality in severe COVID-19 cases.


Subject(s)
COVID-19/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , SARS-CoV-2 , Diagnosis, Differential , Humans , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/therapy , Male , Middle Aged , Plasma Exchange
9.
Clin Med (Lond) ; 21(6): e677-e679, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1551863

ABSTRACT

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.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Adult , COVID-19 Vaccines , Female , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , SARS-CoV-2 , Vaccination
10.
ESC Heart Fail ; 9(1): 219-223, 2022 02.
Article in English | MEDLINE | ID: covidwho-1530139

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.


Subject(s)
COVID-19 , Heart Transplantation , Lymphohistiocytosis, Hemophagocytic , Adult , Child , Cytokine Release Syndrome , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , SARS-CoV-2
11.
Clin Infect Dis ; 73(9): e3110-e3112, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1501010

ABSTRACT

The clinical manifestation of moderate to severe coronavirus disease 2019 (COVID-19) has parallels to secondary hemophagocytic lymphohistiocytosis (HLH) both clinically and based on molecular inflammatory response. We found no evidence to support the utility of risk-stratifying COVID-19 patients using risk scoring methodology designed for HLH.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Risk Factors , SARS-CoV-2
12.
BMC Infect Dis ; 21(1): 811, 2021 Aug 13.
Article in English | MEDLINE | ID: covidwho-1477276

ABSTRACT

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.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Female , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Middle Aged , Pandemics , SARS-CoV-2
13.
Am J Case Rep ; 22: e932765, 2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1468751

ABSTRACT

BACKGROUND Constant stimulation of lymphocytes and histiocytes can result in hemophagocytic lymphohistiocytosis (HLH), which can be primary or secondary (sHLH). The main causes of sHLH are infections and hematological malignancies, especially non-Hodgkin lymphoma. Despite new insights into the pathogenesis of HLH, the diagnosis and treatment of this immune disorder remain a great challenge. CASE REPORT We present a case of a young adult without comorbidities whose clinical course was nonspecific for several months and resulted in late diagnosis of HLH secondary to peripheral T cell lymphoma (PTCL). The etiological factor of recurring fever, hepatosplenomegaly, and deteriorating condition was unidentified for a long time before fatal sHLH was finally diagnosed. The patient was treated according to the HLH-2004 protocol; however, he did not achieve any response. Unfortunately, due to nonspecific symptoms, lack of lymphadenopathy for a long time, and negative positron emission tomography results, the diagnosis of PTCL was established only after the patient's death. CONCLUSIONS It should be emphasized that early diagnosis is crucial for better prognosis of patients with sHLH. Bone marrow biopsy is worth considering in patients with prolonged fever of unknown origin, hyperferritinemia, splenomegaly, and unexplained cytopenia of 2 or more lineages. Despite the existence of diagnostic and therapeutic protocols available in the literature, the prompt diagnosis and treatment of HLH remains a great challenge. More precise and specific diagnostic tools for HLH are needed.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Lymphoma, T-Cell, Peripheral , Bone Marrow , Fever , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphoma, T-Cell, Peripheral/complications , Lymphoma, T-Cell, Peripheral/diagnosis , Male , Neoplasm Recurrence, Local , Young Adult
14.
BMJ Case Rep ; 14(9)2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1416644

ABSTRACT

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.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Adult , Female , Fever , Humans , Infant , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Pandemics , Pregnancy , SARS-CoV-2
15.
BMJ Case Rep ; 14(9)2021 Sep 13.
Article in English | MEDLINE | ID: covidwho-1406643

ABSTRACT

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.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Adult , Etoposide/therapeutic use , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , SARS-CoV-2
16.
Arthritis Rheumatol ; 73(10): 1791-1799, 2021 10.
Article in English | MEDLINE | ID: covidwho-1391545

ABSTRACT

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.


Subject(s)
COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Interleukin-18/blood , Interleukin-8/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Macrophage Activation Syndrome/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Diagnosis, Differential , Female , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/complications , Male , Middle Aged , Young Adult
20.
J Hematol Oncol ; 14(1): 87, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259207

ABSTRACT

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.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Lymphohistiocytosis, Hemophagocytic/etiology , Adult , Anti-Inflammatory Agents/therapeutic use , Bone Marrow/pathology , Dexamethasone/analogs & derivatives , Dexamethasone/therapeutic use , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Male , SARS-CoV-2/isolation & purification
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