Severe COVID-19-associated hyperinflammatory syndrome versus classic hemophagocytic lymphohistiocytosis: similarities, differences, and the way forward.

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.

Severe Covid-19 Associated Hemophagocytic Lymphohistiocytosis : A Comparative Study with Hemophagocytic Lymphohistiocytosis Secondary to Causes Other Than Covid-19

Introduction: Severe COVID-19 infection in a subset of patients is associated with hyperinflammation similar to hemophagocytic lymphohistiocytosis (HLH) however it may not fulfill the required diagnostic criteria (HLH 2004 criteria or H score). We compared clinical, laboratory parameters, bone marrow findings and disease outcome of severe COVID-19 infection related HLH with HLH secondary to causes other than severe COVID-19 to describe features specific to severe COVID-19 associated HLH and limitations of currently available diagnostic criteria of HLH in context to severe COVID -19 infection induced hyperinflammation. Method(s): We analyzed 69 patients diagnosed as HLH of which 47 had severe COVID-19 and 22 had HLH secondary to causes other than COVID-19. Clinical, hematological and biochemical parameters were compared using Mann-Whitney U test. Bone marrow examination (BME) was done in all for presence of hemophagocytosis. Immunohistochemical staining for CD68 and CD163 were done for identification of histiocytes. Occurrence of COVID-19 related HLH was taken as the dependent variable to determine predictors of COVID-19 HLH. Result(s): Organomegaly was seen in only 4.3% (2/47) cases with COVID-19 related HLH as compared to 54.5% (12/22) with non-COVID HLH (p< 0.001). Amongst the quantitative variables, a significant difference in COVID-19 related and non-COVID-19 related HLH was found in the following parameters: Age (p< 0.001), Triglyceride (p=0.009), Fibrinogen (p< 0.001), Ferritin (p< 0.001), Hemoglobin (p< 0.001), Total leukocyte count (p=0.003), Absolute neutrophil count (p< 0.001), Neutrophil lymphocyte ratio (p< 0.001) and H score (p< 0.001). BME of all patients showed presence of hemophagocytes. Only 6.4% (3/47) cases with COVID related HLH had 5/8 HLH 2004 criteria as compared to 63.6% (14/22) cases with non-COVID related HLH (p< 0.001). H-Score >=169 was also significantly less common in COVID HLH as compared to non-COVID HLH (40.42% vs 86.36%, p=0.001). Conclusion(s): Organomegaly, cytopenias, hypofibrinogenemia and hypertriglyceridemia which are part of HLH diagnostic criteria are rare in severe COVID-19 making it difficult to diagnose. Demonstration of hemophagocytes in bone marrow should be recommended in suspicious cases for initiation of early immunosuppressive therapy. (Figure Presented).

A rare case of intravascular diffuse large B-cell lymphoma with secondary hemophagocytic lymphohistiocytosis

Introduction Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and potential life-threatening syndrome characterized by excessive immune activation and cytokine release. In adults, infections, inflammatory diseases and more rarely hematological malignancies can trigger the onset of HLH. We describe a rare case of intravascular diffuse large B cell lymphoma (DLBCL) associated with HLH. Case presentation A 53-year-old woman, presenting with high fever since 3 weeks and asthenia, was admitted to the hospital. She had a negative medical and travel history. On physical examination, generalized edema and hypotension were noted. An extensive bacterial and viral work-up (including COVID-19) was negative. During admission, the patient developed progressive anasarca and an episode of epileptic convulsions. Laboratory results showed increasing cytopenia, major hyperferritinemia, hypofibrinogenemia and hypertriglyceridemia. A bone marrow examination showed prominent hemophagocytosis. Cerebrospinal fluid examination showed the presence of aberrant monocytes, indicating CNS involvement. Genetic analysis to detect hemophagocytosis-associated mutations was negative. PET-CT revealed increased FDG uptake in both adrenal glands, hypophysis, bone marrow and spleen. Biopsy of the adrenal gland was not contributive. Brain MRI showed two cerebral masses radiologically suggestive for meningioma, confirmed by histology. The patient was refractory to high-dose corticotherapy and treatment was adapted to the HLH-94 protocol. A blind skin biopsy showed the presence of a population of pathological B-lymphocytes with aberrant immunophenotype (CD20+/Pax5+/Bcl6+/Bcl2+/cMYC-) in and around the small blood vessels leading to the diagnosis of intravascular DLBCL. Treatment was adjusted to lymphoma-specific immune-chemotherapy upon which a gradual clinical improvement was noted. After four cycles R-CHOP, three cycles of high dose methotrexate and high dose Endoxan for stem cell mobilisation, treatment was intensified with two cycles R-DHAP because of laboratory signs of persistent hemophagocytosis. Thereafter, the patient received an autologous stem cell transplantation (auto-HCT) after BEAM chemotherapy. End of treatment PET-CT and skin biopsy documented complete remission of the lymphoma. Because of slow hematological recovery, repeated bone marrow examinations were done and showed hypoplasia and persistent hemophagocytosis. Dexamethasone in combination with eltrombopag led to a gradual hematological response. At 20 months after auto-HCT, the patients stay in complete remission of the DLBCL and are independent of corticotherapy, with acceptable hematological parameters and no clinical signs of HLH. Discussion In the absence of infection, HLH is a diagnostic challenge frequently leading to delayed identification of the primary trigger, if any. A characteristic image on PET-CT with increased uptake in adrenal glands and hypophysisis led us to perform a blind skin biopsy to diagnose intravascular DLBCL, a rare subtype of lymphoma. Our case also shows that 1) HLH is very difficult to manage without dealing with the primary trigger and 2) HLH can persist for prolonged periods of time after successful treatment of the primary cause and may require specific therapy for sufficient control.

Role of copper levels in patients with myelodysplastic syndromes

Background: Patients with inadequate amounts of copper often present with cytopenias and exhibit dysplasia on bone marrow, mimicking myelodysplastic syndrome (MDS) and pose diagnostic difficulties. Method(s): This cross-sectional observational study was performed from January 2020 to June 2021. Patients diagnosed with MDS were included in the study and serum copper levels were measured by the Inductively Coupled Plasma Mass Spectrometry (ICPMS) method. Copper supplementation with intravenous copper chloride 2.5mg daily for the first two weeks, followed by oral 3mg copper sulfate thrice daily for the next three months, was given for copper-deficient patients. Response assessment was performed with repeat hemogram and serum copper levels. Result(s): A total of 57 patients were diagnosed with MDS, of these, 33 (57.89%) were males and 24 (42.10%) were females. The mean age was 54.3+/-14.6 years (13-81). The distribution of patients in different types of MDS was MDS-SLD in 15, MDS-MLD in 18, MDS-EB1 in 7, MDS-EB2 in 8, and MDS-U in 9 patients. Anemia was seen in (87.71%) of patients, with mean hemoglobin 7.6+/-2.1g/dL (4.6-14.5g/dL). Neutropenia was seen in 31 (54.38%) with a mean absolute neutrophil count(ANC) of 2073+/-2139/muL (211-10,952/muL). Thirty seven (64.91%) patients had thrombocytopenia with a mean platelet count of 1,05,298+/-1,21,769/muL (9,000-6,74,000/muL). The mean serum copper levels were 146.69+/-42.36mug/dL (54.2-254.0mug/dL). Only three (5.26%) patients out of 57 were found to have copper deficiency. All three patients with low copper levels were found to have anemia, thrombocytopenia, and mildly raised serum erythropoietin levels. All three patients had dyserythropoiesis on bone marrow examination, and only one patient each had cytoplasmic vacuolations in erythroid precursors and dysmegakaryopoiesis. Among the three patients with copper deficiency, two patients had significant improvement in cytopenias after copper supplementation, and one had lost follow-up due to COVID-19. Conclusion(s): This study is the first from India to evaluate the role of copper in patients presenting with predominantly hematological manifestations. For patients presenting with cytopenias or marrow dysplasia resembling MDS, copper deficiency should be considered in the differential diagnosis. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest. Copyright © 2022

LATE ONSET PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS in AN INDIAN ADOLESCENT BOY during A PEAK of POST COVID-19 MULTISYSTEM INFLAMMATORY SYNDROME

Background: Familial Hemophagocytic lymphohistiocytosis (fHLH) categorized as FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), and FHL5 (STXBP2) encoding for Perforin, Munc13-4, Syntaxin11, and Syntaxin binding protein 2, respectively. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. Objectives: To delineate clinical and laboratory features of late onset familial Hemophagocytic Lymphohistiocytosis. Methods: A 12-years-old well nourished sick looking boy, born to a non-consanguineous parents with normal birth, development and immunization history with uneventful past presented to us with 6 days history of high fever, cough, breathing difficulty and severe headache. He had occasional vomiting, abdominal pain, polyarthragia & chest pain from last 10 days. Mother also had given history of throat pain, backache & some non-specifc papular rashes over face before the onset of fever. His vitals were normal. Examination revealed faint diffuse fxed erythematous rash all over the body, pallor, icterus and hepatos-plenomegaly. Musculoskeletal examination was unremarkable. Lab evaluation revealed HB 8.9gm%, TLC 4700/cumm with neutrophils 40% and lymphocytes 56% with 8-9% activated lympocytes. Further evaluation showed low ESR 6mm/hr, fbrinogen 97mg% and albumin 2.2 gm% with elevated CRP 40mg/L, ferritin 2000ng/ml, LDH 658IU/L, SGPT 110IU/L, SGOT 221 IU/L, total bilirubin 6mg%, D-dimer 4355 ng:EFU/ml and Triglycerides 441mg%. His blood, urine, CSF and bone marrow cultures were sterile for endemic bacterial and viral infections in our area. His EBV PCR, CoVID RT PCR and CoVID antibody (Total & IgG) test were negative. His immunoglobulin leves were normal. HRCT Chest showed bilateral mild-moderate plural effusions, mild interstitial thickening in both the lower lobes, few fbrotic opacities & old areas of consolidation bilaterally. 2D echo showed mild pericardial effusion. Bone marrow examination showed Hypercellular marrow with iron depletion and occasional hemophagocytosis with CD8 T lymphocytes proliferation (55.2%) and double positive CD4 & CD8 (1.2%). He was initially commenced on supportive therapy, oxygen & intravenous antibiotics. In view of most probable non-infectious, non-malignant hemophagocytic lymphohistiocytosis, he was fnally given intravenous immunoglobulin (2gm/kg) and intravenous pulse methylprednisolone (30mg/kg). He responded well to above regimen within 3 days. He was discharged with tapering steroids over few weeks. Clinical exome by NGS revealed Homozygous Mutation in STXBP2 gene Intron 14, c.1280-1G>C (3' Splice Site) His parents has been counselled for hematopoietic stem cell transplantation and their decision is still pending. Results: We compared our patietnt with a reference to the largest Indian series of pediatric HLH1. Conclusion: Primary HLH type 5 can present frst time during childhood and adolescence. Any child presenting with unexplained HLH features should undergo genetic analysis irrespective of person's past and family history.

Concurrent Presentation of Acute Myeloid Leukemiawith COVID 19: A Diagnostic Challenge

Introduction: COVID-19 disease caused due to infection with thenovel coronavirus (SARS CoV-2) is causing havoc worldwide eversince its first appearance in Wuhan, China in December 2019.Although the awareness regarding the disease has increased manifoldsince its inception in December 2019, the treatment of patients withalready suppressed immune status owing to hematological malignancies and other comorbidities is a challenge. Patients withleukemias and COVID-19 show a higher fatality rate of 37%.Thetime-lapse between disease presentation and diagnosis is alsoincreased due to COVID-19 as many symptoms are overshadoweddue to the typical presentation of COVID-19.Aims &Objectives: The aim is to diagnose the patients with leukemias at the very onset of disease during this pandemic as theoutcome is very poor so that the management and follow-up of thepatients begin at the earliest.Materials &Methods: We are presenting case series of four patientsof COVID-19 with coexistent AML. The diagnosis was establishedwith the correlation of flow cytometry, bone marrow examination,and radiology.Interestingly all the patients diagnosed with AML were not havingany clinical abnormality before the COVID-19 infection so we feelthat this is a de-novo presentation of AML with COVID-19 and canonly speculate about the coronavirus per se causing the hematologicalmalignancy. However, more data is required to confirm this association, particularly the role of IL-6 and its direct effect in the causationof hematological malignancy.Result: One of the patients was in the intensive care unit for a weekhowever patient's condition deteriorated and he could not survive.Rest of them are under follow-up.Conclusions: Concurrent presentation of AML and COVID-19 ischallenging from a diagnostic and management point of view. Therehave been few case reports in patients with leukemia getting infectedwith COVID-19 but to the best of our knowledge, these are possiblythe first few cases of AML occurring in concurrence with COVID-19infection detected incidentally without any prior history of any significant disease. These cases highlight the association ofhematological malignancies with the current pandemic and also difficulty in their management.

Hemophagocytic histiocytosis in severe SARS-CoV-2 infection: A bone marrow study.

INTRODUCTION: The clinical and laboratory features of severe COVID-19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes. METHODS: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID-19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME). RESULTS: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H-score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D-dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high-dose pulsed corticosteroid therapy. CONCLUSION: The immune response associated with severe COVID-19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID-19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early.