Reactive Hemophagocytic Syndrome Research Articles

An uncommon diagnosis of a young female with fever of unknown origin (FUO): Idiopathic Hemophagocytic Lymphohistiocytosis (HLH)

Background. Hemophagocytic Lymphohistiocytosis (HLH), characterized by the uncontrolled activation of immune cells leading to a hyperinflammatory state, is seldom considered in the initial differential diagnosis of FUO. The rarity of idiopathic HLH, especially in young individuals without an identifiable trigger, emerges as an uncommon and particularly challenging diagnosis. This case report presents a compelling narrative of a young female grappling with the complexities of FUO, ultimately revealing the rare and life-threatening entity of idiopathic HLH. Case report. A 25 year old female was referred to our hospital in view of persistent high grade fever since 3 months. Patient has no other complaints. Vitals stable. General and systemic examination normal. Lab investigations showed a total leukocyte count 18000 cell/μL, hemoglobin 9.2 g/dL, and platelets 68000 cells/μL. Other blood investigations showed erythrocyte sedimentation rate (ESR) 88 mm/h, C-reactive protein 21 mg/L, ferritin 670 ng/mL, triglyceride 281 mg/dL, and fibrinogen 1.2g/L. She also had transaminitis with AST 80, ALT 92 and ALP 1442. The entire infectious diseases panel was done which came negative for all, including viral serologies and hepatitis markers. Procalcitonin level was normal and no other relevant investigations came positive. Autoimmune panel analysis also came negative. Blood cultures came negative in two different samples. Also, there is no evidence of vegetation in echocardiography. Coming to the invasive investigations, bone marrow biopsy and aspiration were done to arrive at a diagnosis and it showed hemophagocytosis. Endoscopy and colonoscopy were done, which came normal. CT thorax and abdomen also showed no significant abnormalities, ruling out the probability of missing any gross malignancies. After all this extensive work up and according to Hscore, which is used to estimate an individual’s risk of having reactive hemophagocytic syndrome, this patient was diagnosed with HLH. According to the current HLH guidelines, initial treatment for the disease consists of etoposide, corticosteroids (dexamethasone), or cyclosporine given for 8 weeks. The patient was started on the same above treatment regimen, but only with corticosteroids for a period of 8 weeks, after a consultation with the hematologist. No recurrence is seen in her 6-months of follow-up. The regimen was well tolerated by the patient. Studies also have shown that therapeutic plasma exchange also has a role in HLH treatment, which can be tried in familial and relapsing cases. Conclusion. In our case, this young female was diagnosed to have idiopathic HLH, after ruling out all the familial and secondary causes of HLH including infections, malignancy and autoimmune diseases. The patient was also started on treatment early after the bone marrow and other relevant investigations according to HScore suggested the diagnosis of HLH and the patient improved accordingly. Hence, apart from clearly knowing the etiology or clinical manifestations, HLH is associated with a high mortality rate if appropriate treatment not given. Generally, the underlying etiology determines the prognosis of the disease. But, it is not a good idea to delay the treatment in order to find the cause and type of HLH, because the exhaustive work up might lead to unacceptable delays in improvement and prognosis of the patient. The diagnostic work up and treatment should be done simultaneously in the patient, which has been done in our case and it lead to a good outcome. Though HLH is a fatal and dangerous disease and also highly challenging to make a diagnosis due its uncommon and largely variable clinical presentation, smart work up and early initiation of treatment will lead to better prognostic outcomes.

HLH Secondary to Influenza

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a pathological condition characterized by excessive inflammation and tissue damage resulting from an aberrant immune system response. HLH can be classified into two distinct categories: primary HLH and secondary HLH. Secondary hemophagocytic lymphohistiocytosis (HLH) is an acquired condition that can be precipitated by various infections, malignancies, or rheumatological disorders. Herein, we present a rare case of HLH secondary to influenza B infection. Case Presentation A 37-year-old who routinely vapes and smokes cannabis presented to the emergency department with subjective fevers, body pains, fatigue, productive cough, shortness of breath, nausea, non-bloody, non-bilious vomiting, and watery diarrhea for one week. He was tachypneic, tachycardic, and febrile (101.1 F). He had loud bibasilar crackles on auscultation. Hb 14.8, total WBC 2.2, platelets 170, AKI with serum creatinine 1.9, and transaminitis with AST/ALT/ALP 130/56/122 U/L were the patient's initial lab results. Rapid influenza, strep, and COVID-19 antigen tests were negative. He exhibits hypoxemia with pH 7.46, pCO2 32.5, pO2 52.1, HCO3 22.9, and FIO2 40%. Urinalysis showed nonsignificant. CRP was 8.3 mg/dL. Negative procalcitonin. chest x-ray and ct showed bilateral diffuse patchy airspace infiltration, suggesting infectious process with mild pleaural effusion. In the critical care unit, he received Antibiotics and inhaled therapy for acute hypoxic respiratory failure with severe ARDS. After deteriorating, he was intubated. The respiratory pathogen panel detected Influenza B. Blood cultures and remaining pneumonia workup were negative. The lab results suggested HLH (table 1). Autoimmune tests were negative. Oseltamivir was given for 5 days. Repeat chest x-rays showed stable pulmonary infiltrates in the right middle and lower lobes, but the patient decompensated clinically with increasing ventilator requirements and dyssynchrony despite heavy sedation, paralytics, and proning and was transferred to a different hospital for ECMO evaluation on day 12. Discussion Primary and secondary HLH: Secondary HLH is caused by infections, malignancies, or rheumatological illnesses, while primary HLH is hereditary. The mortality outcome of HLH is extremely dependent on early detection and treatment 1. Due to the rarity of this disease entity, difficult diagnostic criteria, and concern for alternate diagnoses, internists may be less aware of it. Further complicating the diagnosis is the fact that the first bone marrow biopsy may not always show hemophagocytosis 2. This is why it is important to be cognizant of this diagnosis and it's diagnostic criteria. Our patient was suspected of HLH based on HScore for reactive hemophagocytic syndrome and the newest updated HLH diagnostic criteria (5 of 8 criteria should be met) 6. EBV is the most common viral infection which can cause HLH. CMV, Parvo, HSV, and H1N1 are other infections. HLH-Influenza B connection is poorly documented 7 Only one case of HLH induced by influenza B in a healthy patient was found in literature. To our knowledge, Our 38-year-old patient is the second known case of secondary HLH secondary to Influenza B in a healthy patient. Influenza B seldom causes HLH. This connection in adulthood is poorly researched. Patients with influenza virus infections have significant intestinal apoptosis and reactive hemophagocytic activity in bone marrow, lungs, and liver3. Influenza variants reduce CD8+ T cell cytotoxicity and perforin expression, likely causing HLH syndrome 4. A study suggests that virus-associated hemophagocytic syndrome (VAHS) is a common consequence of severe 2009 influenza A (H1N1) infection and contributes to multiorgan failure and mortality. 9 (36%) of 25 severely ill patients with confirmed 2009 influenza A (H1N1) infection developed VAHS, and 8 (89%) died 5. Conclusion: We present this case to raise awareness among physicians regarding the potential occurrence of hemophagocytic lymphohistiocytosis (HLH) as a complication in adult patients who present with influenza B virus infection accompanied by fever and pancytopenia. The aim is to emphasize the importance of considering HLH as a differential diagnosis in order to facilitate timely identification and initiation of appropriate treatment for this condition.

665 THE UNFORSEEN MECHANISM: A CASE OF DISTRIBUTIVE SHOCK SECONDARY TO REACTIVE HAEMOPHAGOCYTIC SYNDROME LEADING TO SEVERE REVERSIBLE BIVENTRICULAR DYSFUNCTION.

Abstract Distributive shock comprises a variety of processes causing dysregulated vasodilation with consequent life-threatening end-organ dysfunction. While sepsis constitutes by far its most common aetiology, other pathological mechanisms with different therapeutic targets may lead to a similar haemodynamic picture. We hereby present the case of a 35-year-old male with no past cardiological history and a recent diagnosis of stage IVsB Hodgkin's lymphoma relapse 10 years after effective disease eradication with first-line chemotherapy. Shortly after a single cycle of second-line chemotherapy, the patient presented with high fever, acute chest pain and dyspnea associated with marked hypotension and sinus tachycardia. Laboratory tests revealed pancytopenia and raised inflammatory markers as well as evidence of acute kidney injury and hepatocellular damage. Urgent thoracic CT revealed no signs of pneumonia while echocardiography demonstrated severe biventricular dysfunction with 25% left ventricular ejection fraction and severe functional mitral regurgitation. Due to worsening tachypnea and desaturation the patient was intubated and transferred to our Intensive Cardiac Care Unit where urgent instatement of circulatory support with iv fluids, blood transfusions, adrenaline and intra-aortic balloon pump were performed and empirical broad-spectrum antibiotic therapy was started after performing blood cultures from peripheral and central veins. Concurrent right ventricular catheterisation demonstrated high-output cardiac failure (Qs Fick 7.89 Qp/m2, Qs thermodilution 8.0 Qp/m2) with mild increase in biventricular filling pressures and post-capillary pulmonary hypertension. Endomyocardial biopsy in turn revealed only mild subendocardial fibrosis and oedema thus excluding myocarditis as a potential cause for the severe biventricular dysfunction. Due to worsening of renal function with persistent anuria despite circulatory support the patient required continuous veno-venous haemofiltration. Notably, over the coming days no pathogen was isolated from any of the cultures with haemodynamic and respiratory parameters gradually improving, allowing for weaning from circulatory and respiratory support. On further examination of blood tests on admission, hypertriglyceridemia, raised ferritin levels and thrombin consumption were noted. These biochemical features, together with the history of Hodgkin's lymphoma relapse, recent chemotherapy, pancytopenia and splenomegaly, suggestive of natural killer cell dysfunction-related haemophagocytosis, pointed to reactive haemophagocytic syndrome as a potential aetiology of the severe distributive shock (> 99% probability on recently published “HS Score” for Reactive Haemophagocytic Syndrome). This hypothesis was further corroborated by the gradual albeit not complete regression of the severe biventricular dysfunction after haemodynamic support suggesting that this may have represented a byproduct of the patient's high-output state. Unfortunately, due to lymphoma progression with severe multiorgan involvement the patient was admitted shortly after discharge and deceased thereafter. This case provides an example of the diversity of potential disease mechanisms underlying distributive shock where biventricular dysfunction may represent a reversible albeit severe bystander rather than the true driving factor of its life-threatening haemodynamic compromise.

Brescia-COVID Respiratory Severity Scale (BRCSS) and Quick SOFA (qSOFA) score are most useful in showing severity in COVID-19 patients

In this study, we compare the predictive value of clinical scoring systems that are already in use in patients with Coronavirus disease 2019 (COVID-19), including the Brescia-COVID Respiratory Severity Scale (BCRSS), Quick SOFA (qSOFA), Sequential Organ Failure Assessment (SOFA), Multilobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension, and Age (MuLBSTA) and scoring system for reactive hemophagocytic syndrome (HScore), for determining the severity of the disease. Our aim in this study is to determine which scoring system is most useful in determining disease severity and to guide clinicians. We classified the patients into two groups according to the stage of the disease (severe and non-severe) and adopted interim guidance of the World Health Organization. Severe cases were divided into a group of surviving patients and a deceased group according to the prognosis. According to admission values, the BCRSS, qSOFA, SOFA, MuLBSTA, and HScore were evaluated at admission using the worst parameters available in the first 24 h. Of the 417 patients included in our study, 46 (11%) were in the severe group, while 371 (89%) were in the non-severe group. Of these 417 patients, 230 (55.2%) were men. The median (IQR) age of all patients was 44 (25) years. In multivariate logistic regression analyses, BRCSS in the highest tertile (HR 6.1, 95% CI 2.105–17.674, p = 0.001) was determined as an independent predictor of severe disease in cases of COVID-19. In multivariate analyses, qSOFA was also found to be an independent predictor of severe COVID-19 (HR 4.757, 95% CI 1.438–15.730, p = 0.011). The area under the curve (AUC) of the BRCSS, qSOFA, SOFA, MuLBSTA, and HScore was 0.977, 0.961, 0.958, 0.860, and 0.698, respectively. Calculation of the BRCSS and qSOFA at the time of hospital admission can predict critical clinical outcomes in patients with COVID-19, and their predictive value is superior to that of HScore, MuLBSTA, and SOFA. Our prediction is that early interventions for high-risk patients, with early identification of high-risk group using BRCSS and qSOFA, may improve clinical outcomes in COVID-19.

Prognostic Factors and Outcomes in Adults with Hemophagocytic Lymphohistiocytosis: A Single-Center Experience

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare disorder caused by severe immune activation and, often, life-threatening inflammation (1). It is usually associated with hematological malignancies, mostly non-Hodgkin lymphoma (2). There are no specific criteria to establish the diagnosis in adults, however the criteria of the HLH-04 are used, which include: 1) fever ≥38.5ºC, 2) splenomegaly, 3) cytopenias (hemoglobin ≤ 9 g/dl, platelets ≤ 100,000 platelets/μl or neutrophils ≤1000), 4) triglycerides ≥265 mg/dl or fibrinogen ≤150 mg/dl, 5) ferritin ≥500 mcg/L, 6) hemophagocytosis in the bone marrow, bone, spleen, lymph node or liver, 7) soluble IL-2 receptor ≥ 2400 U/ml and 8) absent or low NK cell activity, 5/8 are required to establish the diagnosis (3). The HScore is an unvalidated tool that can be useful for HLH diagnosis (4).We described the prognostic factors and outcomes of 64 adults diagnosed with HLH in a referral center in Mexico City.MethodsWe included adult patients (≥ 18 years) with HLH, diagnosed and treated at our institution from 1998 to 2016. Patients were diagnosed according to the HLH-04 diagnostic criterion, meeting 5 of 6 criteria, because we didn´t measure IL-2 receptor and the NK cell activity. HScore was and it was considered positive if ≥180 with a probability of having HLH of 70%.ResultsSixty-four patients met the HLH-04 diagnostic criteria. The median age was 35 years (range, 18-77 years); 37 (57.81%) were men. The underlying cause of HLH was lymphoma in 33 patients (51.56%), infection in 17 patients (26.56%), autoimmune disorders in 3 patients (4.68%), and idiopathic disease in 11 patients (17.18%). HLH was clinically characterized by high fever (98.43%), splenomegaly (78.12%), lymphadenopathy (74.43%) and hepatomegaly (71.87%). Laboratory abnormalities included bicytopenia (98.44%), hemoglobin <9 g/dL (46.9%), neutrophil <1.0 x 109/L (14%), thrombocytopenia (< 100 x 109/L platelets) (67%), hipertriglyceridemia (≥ 256 mg/dL) (52%), serum ferritin ≥ 500 µg/L (77.2%) and hypofibrinogenemia (≤ 150 mg/dL) (32%).Cutaneous involvement was more frequent in lymphoma-associated HLH (33.33%), when compared to non-lymphoma-associated HLH (9.68%) (p = 0.022). On the other hand, neurological symptoms were more frequent in non-lymphoma-associated HLH (25.81%) than in lymphoma-associated LHH (6.06%) (p = 0.032) table 1. Of our 64 patients, 47 had a HScore ≥ 180 (73.70%).All patients received specific treatment for the underlying cause and (54.7%) received also corticosteroids. Only (17.2%) received the HLH-04 protocol. After a median follow-up of 14 months (range, 0-216 months), 30-day mortality was 26.56%. The median overall survival (OS) of the entire cohort was 4 months; the 3-years OS of patients with lymphoma-associated HLH was 41% compared with 22.5% for patients with non-lymphoma-associated HLH (p=0.046) figure 1. On a multivariate analysis, the presence of disseminated intravascular coagulation (DIC), nosocomial infection and neurological symptoms were statistically significant predictors of inferior OS (p= 0.058, p=0.034, p=0.033, respectively) table 2.Conclusion :In this series of adults with HLH treated at a single tertiary care center, patients with DIC, nosocomial infections and neurological symptoms had a statistically significant worse survival. This study improves the understanding of HLH in our institution, helps us validate the diagnostic criteria in our populations, and contributes to the development of effective treatment strategies.Bibliography:1.-Ramos-Casals M, Brito-Zeron P. Adult haemophagocytic syndrome. Lancet. 2014;383(9927): 1503-1516.2.-Schram AM, Berliner N. How I treat hemophagocytic lymphohistio- cytosis in the adult patient. Blood. 2015;125(19):2908-2914.3.-Henter JI, Horne A. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.4.-Fardet L, Galicier L. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheum. 2014;66(9):2613-2620. DisclosuresNo relevant conflicts of interest to declare.

Bone marrow haemophagocytosis indicates severe infection with severe acute respiratory syndrome coronavirus 2.

Haemophagocytosis in the bone marrow of patients who have succumbed to coronavirus disease 19 (COVID-19) has not been widely studied. The aims of the present study were to perform morphological analyses and morphometry of haemophagocytosis in the bone marrow of patients with severe COVID-19, and to correlate the findings with the clinical course of the disease. In this single-centre study performed at the University Hospital Jena, bone marrow specimens of 15 deceased patients who had experienced a severe course of COVID-19 were sampled from the vertebral column during autopsy. Slides of the bone marrow were stained with routine stains or immunohistochemically, and further examined for haemophagocytosis by the use of light microscopy. To substantiate the morphological findings, additional slides were stained for CD163 and morphometry was performed. In all bone marrow samples, an increase in cellularity was found. Haemophagocytes with erythrophagocytosis were detected in 67% of the deceased patients. In tissues with low numbers of haemophagocytes or ill-defined haemophagocytes, an increase in iron deposits was frequently seen. Morphological findings were then correlated with several important clinical data, and the HScore (probability of having a reactive hemophagocytic syndrome) was calculated to posthumously confirm the diagnosis of secondary haemophagocytic lymphohistiocytosis. The median duration of disease and the hospitalisation time were lower in patients with haemophagocytosis (n=10) than in patients without haemophagocytosis (n=5). In addition, patients with haemophagocytes showed increased inflammatory parameters 2-5days prior to death, in contrast to patients without haemophagocytes. Haemophagocytosis is a common finding in the bone marrow of deceased individuals with severe COVID-19, and may indicate fatal severe acute respiratory syndrome coronavirus 2 infections.

Diagnostic and management of life-threatening Adult-Onset Still Disease: a French nationwide multicenter study and systematic literature review

BackgroundAdult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course and phenotype of life-threatening AOSD, including response to therapy and long-term outcome.MethodsA multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review.ResultsTwenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high (median: 29,110 ng/mL). Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effective. After ICU discharge, most patients required additional treatment. Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively.ConclusionsAOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.

Haemophagocytic syndrome in a dog with granulomatous splenitis

SummaryA golden retriever dog was evaluated for cranial abdominal organomegaly. Clinical investigation found concurrent splenomegaly, anaemia, thrombocytopenia, hypoalbuminaemia and hypocholesterolaemia. Cytological evaluation of splenic aspirate samples identified a population of...

Reactive Hemophagocytic Syndrome after Hematopoietic Stem Cell Transplantation: A Multicenter Retrospective Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)

▪Reactive hemophagocytic syndrome (HS) is a rare but serious complication that may occur after both autologous and allogeneic hematopoietic stem cells transplantation (HSCT). Our knowledge of this post-HSCT complication mainly derives from single reports or small series and only about sixty cases have been reported in the literature so far. We present here the results of a multicenter retrospective study, performed on behalfof the SFGM-TC, including adult (>16 years) HSCT recipients transplanted in France, Switzerland or Stockholm (Sweden) and diagnosed with HS after transplantation. Patient data were extracted from medical files and the recently reported HScore [Fardet et al., Arthritis Rheumatol. 2014 66(9):2613-20] was applied for confirmation of HS diagnosis. Among the thirty-two patients reported, one patient was excluded because of insufficient data for HScore calculation and four patients for an HScore less than 169. We included in the final analysis 27 patients in which the HS diagnosis was confirmed (median HScore 218, median HS probability of 97%). The median age was 45 years (range 21-68) and 10 patients were female (37%). Three patients underwent autologous HSCT for non-Hodgkin lymphoma (NHL). Twenty-four patients received allogeneic HSCT for hematological malignancies (n=23) or severe aplastic anemia (n=1) from HLA-identical siblings (n=4), HLA-matched (n=10) or HLA-mismatched (n=6) unrelated donors, haploidentical donors (n=2) or cord blood (n=2). The median time from transplantation to HS diagnosis was 66 days (range 6-326). Fever was present in almost all patients (n=25, 93%) while we observed splenomegaly in 13 (48%), hepatomegaly in 11 (41%), and lymphadenopathy in 8 (30%) patients. All patients had cytopenia in at least one hematopoietic lineage and we found pancytopenia in 14 patients (52%). All patients displayed elevated ferritin levels with 22 patients (81%) having levels higher than 7500 µg/L. Eleven patients (41%) had triglyceride levels at >4 mmol/l, while only 7 patients (26%) had fibrinogen <2.5 g/L. Aminotransferases were elevated in half of the patients (n=14). Bone marrow hemophagocytosis was observed in 15 patients (56%). Twenty patients (74%) had pharmacological immune suppression at time of HS diagnosis. Twenty-two patients (81%) had an infection at HS diagnosis, mainly viral infections [17 patients with evidence of one or more viral infection or reactivation: Epstein-Barr virus (n=14), cytomegalovirus (n=10), adenovirus (n=2), human herpesvirus 6 (n=1), metapneumovirus (n=1) and human parainfluenza virus type 3 (n=1)], but also pyogenic bacterial infections (n=6), parasitic infections (n=3, toxoplasmosis) and fungal infections (n=3: two aspergillosis and one disseminated Rhizomucor infection). Eleven patients (41%) had evidence of active cancer at time of HS diagnosis, either as primary disease progression/relapse (n=5) or as post-transplant lymphoproliferative disease (PTLD; n=6). Graft-versus-Host-Disease (GvHD) was present in 11 patients (41%) at time of HS diagnosis (grade II-IV acute GvHD in 8 patients; chronic GvHD in 3 patients) and was considered a contributing triggering factor for HS in 4 of them. The median survival after HS diagnosis was 58 days (95%CI 21-86) and the 1-year overall survival (OS) was 22% (95%CI 8%-41%) [Figure 1]. Treatments most frequently employed, either alone or in combination, were glucocorticoids (GCs, n=16), intravenous immunoglobulins (IVIG, n=7) and Etoposide (VP-16, n=7). Etiological anti-infectious or anti-cancer agents were employed alone in 7 patients. We found no significant difference in OS of patients with malignancy-associated HS or infection-triggered HS compared with HS from other causes. Similarly, we detected no impact of the use of GCs, IVIG or VP-16 on patients survival. However these results should be interpreted with caution given the limited number of patients. Three patients underwent a second allogeneic HSCT that provided long-term rescue in one patient, while offered only a short-term benefit to the others. Our study, which is to the best of our knowledge the largest series of HS following HSCT reported so far, provides a description of HS as a rare but devastating complication of HSCT associated with an extremely high mortality. [Display omitted] DisclosuresPeffault De Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Assessment of the HScore for reactive haemophagocytic syndrome in patients with rheumatic diseases

Objectives: Reactive haemophagocytic syndrome (RHS) is a hyperinflammatory disorder often occurring in the background of several disorders such as infections, malignancies, and rheumatic diseases. Recently, a score known as the HScore was developed for the diagnosis of RHS. In the original study, most of the patients had underlying haematological malignancy or infection and the best cut-off value for the HScore was 169 (sensitivity 93%; specificity 86%). In this study we aimed to analyse the performance of the HScore in rheumatic disease-related RHS.Method: The patients with rheumatic disorders evaluated in the Departments of Rheumatology and Paediatric Rheumatology at Hacettepe University, Ankara, Turkey between 2002 and 2014 were reviewed retrospectively. The first group (n = 30) consisted of patients with RHS; the control group (n = 64) included patients with active rheumatic diseases without RHS.Results: In the RHS group, 14 (46.7%) had adult-onset Still’s disease (AOSD), 10 (33.3%) systemic juvenile idiopathic arthritis (SJIA), and six (20%) systemic lupus erythematosus (SLE). The control group (n = 64) consisted of 32 (50%) AOSD, 13 (20.3%) SJIA, and 19 (29.7%) SLE patients. Applying the HScore to the RHS patients, the best cut-off value was 190.5 with a sensitivity of 96.7% and specificity of 98.4%. When we excluded the patients from the control group who had not had bone marrow aspiration (n = 23), the same cut-off (190.5) performed best (sensitivity 96.7%; specificity 97.6%). Applying the 2004 haemophagocytic lymphohistiocytosis (HLH-2004) criteria gave a sensitivity of 56.6% and a specificity of 100% in the whole study group.Conclusions: In our study, a cut-off value for the HScore different from the original study performed better. Further studies are warranted to determine optimum cut-off values in different studies.

Diversity and combinations of infectious agents in 38 adults with an infection-triggered reactive haemophagocytic syndrome: a multicenter study

Reactive haemophagocytic syndrome (HS) is a rare condition that occurs in patients with infections, haematological malignancies or autoimmune diseases. Although various microorganisms are thought to trigger HS, most of the literature data on this topic have been gathered in single-centre case series. Here, we sought to characterize infectious triggers in a large, multicentre cohort of patients with HS. Patients were included in the present study if HS was solely due to one or more infections. Detailed microbiological data were recorded. Of the 162 patients with HS in the cohort, 40 (25%) had at least one infection and 38 of the latter (including 14 women, 36.8%) were included. The median age was 46 years. Seven patients were presumed to be immunocompetent (18.4%), whereas 19 patients (50%) were infected with human immunodeficiency virus and 12 patients (31.6%) were immunocompromised for other reasons. Twenty-seven patients (71.1%) had a single infection, whereas six (15.8%) and five (13.1%) patients had, respectively, two and three concomitant infections. We observed pyogenic bacterial infections (n = 7), tuberculosis (n = 10), non-tuberculous mycobacteriosis (n = 3), viral infections (n = 17: 11 cytomegalovirus, three Epstein–Barr virus, two human herpesvirus 8, one herpes simplex virus 2), parasitic infections (n = 8: four disseminated toxoplasmosis, one leishmaniasis, three malaria), fungal infections (n = 5: four pulmonary pneumocystosis and one candidaemia). Eighteen patients (47.4%) received corticosteroids and/or etoposide. Twelve patients died (31.6%). All multiple infections and all deaths occurred in immunocompromised patients. When compared with patients suffering from malignancy-associated HS, patients with infection-triggered HS were younger and more likely to be immunocompromised, and had a better outcome.

Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features, predictive factors, and prognosis in 21 patients.

Hemophagocytic syndrome (HPS) is a potentially life-threatening complication of systemic inflammatory disorders. Adult-onset Still disease (AOSD) is one of the systemic autoimmune diseases associated with reactive hemophagocytic syndrome (RHS). This study aimed to evaluate the characteristic findings, predictive factors, and prognosis of RHS in patients with AOSD.We retrospectively evaluated 109 patients diagnosed with AOSD and reviewed their clinical data and laboratory findings, including the biopsy results of 21 AOSD patients with RHS. Moreover, data from 17 hemophagocytic lymphohistiocytosis (HLH) patients evaluated during the same period were compared with those from the RHS patients.Twenty-one patients (19.3%) developed RHS during the course of AOSD, and only 7 patients (6.4%) were confirmed by bone marrow, liver, or lymph node biopsy. AOSD patients with RHS showed significantly higher frequencies of splenomegaly, hepatomegaly, and lymphadenopathy than did those without RHS. Moreover, patients with RHS showed significantly higher relapse rates than those without RHS (61.9% vs 18.2%, P < 0.001). Possible triggering factors inducing hemophagocytosis were detected in 16 of 21 RHS patients (76.2%): disease flare in 12 patients (75%), infection in 3 patients (18.8%), and drug use in 1 patient (6.3%). AOSD patients with RHS showed higher frequencies of leukopenia, anemia, thrombocytopenia, hypoalbuminemia, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia, and elevated lactate dehydrogenase levels than did those without RHS. Multivariate logistic regression with forward selection procedure showed that low platelet count (<121,000/mm3), anemia, and hepatomegaly were independent predictors of RHS. Patients with definite RHS and those with probable RHS showed comparable results. Although RHS is a life-threatening complication of AOSD, long-term prognosis was observed to be similar in patients with and those without RHS. Compared to RHS patients, HLH patients had poor prognosis, such as higher death rates (52.9% vs 9.5%, P = 0.005).RHS can be considered when an AOSD patient shows at least 2 of the following 3 findings: low platelet count, anemia, and hepatomegaly. Diagnostic confirmation by biopsy may not be essential if typical clinical findings of RHS are present. Moreover, prognosis of RHS was better than that of HLH diagnosed by the presence of trilineage cytopenia at admission.

Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.

Because it has no unique clinical, biologic, or histologic features, reactive hemophagocytic syndrome may be difficult to distinguish from other diseases such as severe sepsis or hematologic malignancies. This study was undertaken to develop and validate a diagnostic score for reactive hemophagocytic syndrome. A multicenter retrospective cohort of 312 patients who were judged by experts to have reactive hemophagocytic syndrome (n = 162), were judged by experts to not have reactive hemophagocytic syndrome (n = 104), or in whom the diagnosis of reactive hemophagocytic syndrome was undetermined (n = 46) was used to construct and validate the reactive hemophagocytic syndrome diagnostic score, called the HScore. Ten explanatory variables were evaluated for their association with the diagnosis of hemophagocytic syndrome, and logistic regression was used to calculate the weight of each criterion included in the score. Performance of the score was assessed using developmental and validation data sets. Nine variables (3 clinical [i.e., known underlying immunosuppression, high temperature, organomegaly], 5 biologic [i.e., triglyceride, ferritin, serum glutamic oxaloacetic transaminase, and fibrinogen levels, cytopenia], and 1 cytologic [i.e., hemophagocytosis features on bone marrow aspirate]) were retained in the HScore. The possible number of points assigned to each variable ranged from 0-18 for known underlying immunosuppression to 0-64 for triglyceride level. The median HScore was 230 (interquartile range [IQR] 203-257) for patients with a positive diagnosis of reactive hemophagocytic syndrome and 125 (IQR 91-150) for patients with a negative diagnosis. The probability of having hemophagocytic syndrome ranged from <1% with an HScore of ≤90 to >99% with an HScore of ≥250. The HScore can be used to estimate an individual's risk of having reactive hemophagocytic syndrome. This scoring system is freely available online (http://saintantoine.aphp.fr/score/).

Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide.

Reactive haemophagocytic syndrome is a life-threatening disease for which factors influencing the outcome remain unclear. We sought to identify determinants of early mortality in patients with reactive haemophagocytic syndrome by conducting a non-interventional retrospective multicentre study in three tertiary care teaching hospitals over a 6-year period. The medical files of 162 patients fulfilling our diagnostic criteria of haemophagocytic syndrome were reviewed. Patients were classified according to 30-d outcome following diagnosis. Thirty-three patients (20·4%) died within 30 d. Clinical features at diagnosis associated with 30-d death in univariate analysis were older age (P = 0·004), underlying lymphoma (P = 0·04), lower platelet count (P = 0·001) and elevated aspartate aminotransferase and lactate dehydrogenase (P = 0·04 both). The use of etoposide as a first-line treatment tended to be associated with a better outcome (P = 0·079). In multivariate analyses, increasing age, decreasing platelet count, underlying lymphoma and no etoposide in the management were associated with a poorer prognosis (P = 0·03, 0·01, 0·003 and 0·04, respectively). These prognostic factors could help to identify those patients more severely affected by reactive haemophagocytic syndrome, who should benefit from aggressive supportive care, combined with specific treatment of the precipitating factor.

Reactive Hemophagocytic Syndrome in Adults: A Retrospective Analysis of 162 Patients

ObjectivesCurrent knowledge in reactive hemophagocytic syndrome mainly relies on single-center case series including a relatively small number of patients. We aimed to identify a multicenter large cohort of adult patients with reactive hemophagocytic syndrome and to describe relevant clinical and laboratory features, underlying conditions, and outcome. MethodsWe conducted a multicenter study in 3 tertiary care centers in France over a 6-year period. The medical files of 312 patients with suspected hemophagocytic syndrome were retrospectively reviewed. Patients were classified with a positive, negative, or undetermined diagnosis of hemophagocytic syndrome by experts' consensus. ResultsAmong the 312 patients fulfilling our inclusion criteria, 162 were classified with positive hemophagocytic syndrome (male, 67%; median age, 48 [35-62] years). Compared with patients without hemophagocytic syndrome, patients with hemophagocytic syndrome more frequently had an underlying immunodepression (45% vs 33%, P = .03) and exhibited higher temperature, ferritin, triglycerides, aspartate transaminase, bilirubin, lactate dehydrogenase, and C-reactive protein, and lower hemoglobin, leukocytes, platelets, and sodium levels. Only 70% of them had hemophagocytosis features on bone marrow aspiration. Hematologic malignancies, especially non-Hodgkin lymphomas, were the main trigger of hemophagocytic syndrome, accounting for 56% of cases. The early mortality rate (ie, within 1 month after diagnosis) was 20%. Patients with hematologic malignancies-associated hemophagocytic syndrome had a poorer early outcome than those with underlying infection. ConclusionsIn this large, multicenter study, hematologic malignancies are the main disease associated with hemophagocytic syndrome in adults. Early mortality is high, and outcome is influenced by the underlying disease.

Adult-Onset Still Disease

We conducted a retrospective observational study to describe a cohort and identify the prognostic factors in adult-onset Still disease (AOSD). Patients enrolled in this retrospective chart review fulfilled either Yamaguchi or Fautrel criteria. Candidate variables were analyzed with logistic unadjusted and adjusted regression models.Fifty-seven patients were seen in the internal medicine (75%) and rheumatology (25%) departments over a mean period of 8.4 years. The median time to diagnosis was 4 months. The course of AOSD was monocyclic in 17 patients, polycyclic in 25, and chronic in 15. The assessment of glycosylated ferritin (GF) in 37 patients was correlated with early diagnosis. Nine 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scans identified the lymph nodes and glands as the main sites of hypermetabolism. Complications were frequent (n = 19), including reactive hemophagocytic syndrome (n = 8). None of the 3 deaths could be attributed to AOSD. Corticosteroid dependence, as predicted by a low GF level, occurred in 23 patients (45%). A quarter of the patients received tumor necrosis factor-α blockers or anakinra with good tolerance. Fever >39.5°C was predictive of monocyclic AOSD, while arthritis and thrombocytopenia were associated with chronic and complicated AOSD, respectively. The youngest patients had the highest risks of resistance to first-line treatments.AOSD remains difficult to diagnose. Mortality is low despite frequent complications. GF and 18FDG-PET scans were of value in the diagnostic approach. The condition in highly symptomatic patients evolved to systemic AOSD, whereas more progressive patterns with arthritis predicted chronic AOSD.

Diagnosis and classification of adult Still's disease

The cornerstone of adult onset Still's disease is the triad of daily fever, arthritis and rash. This syndrome remains enigmatic and most often a disease of exclusion. There are both musculoskeletal as well as systemic features. More importantly, reactive hemophagocytic syndrome may occur in patients. In this review we attempt to place this syndrome in perspective, including data on geoepidemiology, clinical and laboratory features.

BK virus-associated hemophagocytic syndrome in a renal transplant recipient

Hemophagocytic syndrome (HPS) is a life-threatening hematological disorder in immunocompromised patients. Reactive HPS is observed in patients with systemic infection, neoplasia or auto-immune diseases. It is a rare hematological disorder after renal transplantation and must be suspected when fever and pancytopenia are seen in association with viral infections. HPS is usually associated with infection with the Cytomegalovirus and Epstein-Barr viruses. We report here a case of BK-virus-associated HPS.

An Unusual Case of Adult-Onset Still’s Disease with Hemophagocytic Syndrome, Necrotic Leukoencephalopathy and Disseminated Intravascular Coagulation

Case. A 34-year-old African-American female with a history of adult-onset Still's disease presented to an outside hospital with oligoarthritis. She experienced a generalized tonic-clonic seizure en route via ambulance, was intubated upon arrival, and transferred to the intensive care unit for treatment of suspected pneumonia and sepsis. She subsequently developed generalized cutaneous desquamation that progressed despite the cessation of antibiotics and other potential offending drugs which required transfer to our hospital's burn unit. She was suspected to have reactive hemophagocytic syndrome based on her clinical presentation of fever, rash, polyarthritis, elevated liver enzymes, coagulopathy, splenomegaly, normocytic anemia, thrombocytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis visualized in bone marrow biopsy specimen. Magnetic resonance imaging demonstrated necrotic demyelination of the deep white matter and corona radiata. The patient developed multiorgan dysfunction and DIC without any other attributable etiology. Despite aggressive broad spectrum therapy and high dose of steroids she progressively deteriorated and eventually expired. Conclusion. Previous publications have highlighted the prevalence of necrotic leukoencephalopathy in children with familial hemophagocytic syndrome. Our patient demonstrated some uncommon features complicating her HLH including DIC and necrotic leukoencephalopathy, which are very rare entities in AOSD.

Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Female Patient With Systemic Lupus Erythematosus

Hemophagocytic syndrome (HPS) is a rare but potentially fatal disease caused by the activation of benign macrophage in various organs including bone marrow and the mononuclear phagocytes system. Here we report a case of 23-year-old woman in whom HPS occurred along with lupus flare during follow-up after the diagnosis of systemic lupus erythematosus. The patient showed aggravated malar rash, discoid rash, febrile cytopenia, hyperferritinemia, and elevated liver enzymes. She underwent ultrasound-guided percutaneous gun biopsy of the liver using an 18-gauge needle. As activated macrophages with hemophagocytosis were confirmed in hepatic histology, the patient was diagnosed as having reactive HPS related to a lupus flare. Clinical symptoms and laboratory findings were improved through high-dose intravenous methylprednisolone therapy followed by oral prednisolone and cyclosporine maintenance therapy. In lupus patients with persistent high fever, cytopenia, elevated levels of serum ferritin, and liver enzymes, reactive HPS should be strongly suspected, and aggressive examinations such as liver biopsy need to be considered for early diagnosis and proper treatment.