Cause Of Secondary Hemophagocytic Lymphohistiocytosis Research Articles

A rare case of streptococcal pharyngitis in an adult male causing hemophagocytic lymphohistiocytosis

Hyperinflammatory responses due to cytokine storms involve multiple systems in hemophagocytic lymphohistiocytosis (HLH) leading to morbidities. Multiple bacterial etiologies have been suggested as a cause of secondary HLH but streptococcal infection has only been reported in pediatric cases. Streptococcus has been considered a notorious pathogen due to its ability to interfere with host immunity through the phenomenon of molecular mimicry. This case report shows the sequence of events post-streptococcal pharyngitis in a 28-year-old male, which lead to HLH and fatality to life, and how a timely intervention of steroids salvaged the patient.

Clinical Features and Outcomes of Hemophagocytic Lymphohistiocytosis Secondary to Lymphoma: Insights from a Tertiary Center in Saudi Arabia

Introduction: Lymphoma encompasses a prominent cause of secondary hemophagocytic lymphohistiocytosis (HLH), an aggressive hyperinflammatory syndrome characterized by immune dysregulation. The concurrence of lymphoma and HLH represents a challenging entity due to the ambiguity of clinical features and paucity of standardized treatment regimens. Limited data exists regarding the characteristics and outcomes of secondary HLH within the Middle East and Saudi Arabia. Moreover, the structure of the population within our region, characterized by a predominance of males and young adults, offers a unique perspective to the literature regarding secondary HLH. Herein, we evaluate the clinical features and outcomes of patients presenting with HLH secondary to lymphoma at a tertiary center in Saudi Arabia. Methods: We retrospectively reviewed the electronic medical records of patients diagnosed with lymphoma over the past ten years at our center to identify patients who developed secondary HLH. The Kaplan-Meier method was used to estimate median overall survival (OS). OS was defined as the incidence of death from any cause from the onset of HLH diagnosis until the end of follow-up. The Cox proportional hazards model was used to identify demographic, clinical, and treatment associated prognostic indicators which had a significant impact on OS. Results: A total of 1484 patients with lymphoma were identified, of which seventeen (1.1%) patients had concurrent HLH. Of the seventeen patients, the median age was 42 years (range 17-64) with 5 (29.4%) patients aged 50 and over. Interestingly, all 17 (100.0%) patients within our cohort were male. Regarding lymphoma subtypes, 10 (58.8%) patients had T and NK-cell lymphoma, 5 (29.4%) had B -cell lymphoma, and 2 (11.7%) had Hodgkin lymphoma. The median HScore was 272.0 (range 182-337) whereas the median HLH-2004 diagnostic criteria score was 6 out of 8 points (range 4-8). Hemophagocytic features in the bone marrow were present in 13 (76.5%) patients. Epstein-Barr virus infection was detected in 9 (52.9%) patients with a median quantitative PCR level of 37347.5 IU/mL (range 1960.0-402847.0). HLH therapy utilized in our patient sample included corticosteroids in 15 (88.2%) patients, etoposide in 8 (47.1%) patients, and intravenous immunoglobulin in 3 (17.6%) patients. Death occurred in 7 (41.2%) patients whilst the median OS of the cohort was 13.0 months (95% CI 0.0-27.4). Using the cox proportional hazards model, both age ≤50 years (P=0.04, hazard ratio=0.186) and etoposide administration (P=0.002, hazard ratio=0.011) were associated with significantly improved survival. Conclusions: To our knowledge, this is the first cohort study reporting the clinical features and outcomes of HLH secondary to lymphoma within our region. Our study highlights the significant disparities between our population and other countries across the globe as our cohort demonstrated a significant male predominance as well as a relatively young median age at diagnosis. Nonetheless, the survival outcomes of secondary HLH remain poor despite the advances in the diagnostication and recognition of the disease. Future efforts ought to explore both the pathophysiological mechanisms underlying lymphoma-associated HLH and the efficacy of different targeted therapeutic modalities.

Clinicomorphological spectrum of hemophagocytic syndrome in a tertiary care hospital

Introduction: The HLH-2004 trial established the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory condition. It typically develops due to inappropriate macrophage activation. Our objective was to assess the spectrum of hemophagocytic syndrome presentations by identifying hemophagocytic activity in the bone marrow, and to unravel the etiopathogenesis of this condition. Material and methods: A retrospective study was carried out in the Department of Pathology in a tertiary care hospital reporting the clinical and laboratory findings of patients who had been previously diagnozed with hemophagocytosis in the bone marrow. The parameters in the diagnostic criteria of HLH of the same patients were documented and analyzed. Results: The characteristics of the 32 patients who presented with hemophagocytosis in the bone marrow were documented. Persistent fever was the most frequent presentation. Mild to moderate anemia (69%), severe leucopenia (59%), and mild to moderate thrombocytopenia (63%) were other frequent findings. The incidence of primary HLH was found to be only 3%; 87% had hyperferritinemia, 78% had bicytopenia, 59% had hypertriglyceridemia, and 53% had splenomegaly. Infections followed by malignancies were shown to be the most frequent cause of secondary HLH, while the prognosis for malignancy-associated HLH appeared to be poor. Conclusions: Based on the findings of this study, conclusions about the clinical symptoms and etiologies of HLH may be drawn, which will assist in early identification. Hence, all subjects with a clinical suspicion of HLH should be thoroughly investigated for a possible etiology.

Treatment and mortality of hemophagocytic lymphohistiocytosis in critically ill children: A systematic review and meta-analysis.

Risk factors of mortality in critically ill children with hemophagocytic lymphohistiocytosis (HLH) are not well described. This systematic review aims to determine overall mortality of critically ill children with HLH, and describes etiologies, treatment, and pediatric intensive care unit (PICU) support employed. PubMed, Embase, Web of Science, CINAHL, and Cochrane Library from inception until February 28, 2022. Observational studies and randomized controlled trials reporting children aged 18years or below, diagnosed with HLH and admitted to the PICU. Etiologies, treatment modalities, PICU therapies, and mortality outcomes were summarized. Random-effects meta-analysis was performed. Total 36 studies (total patients = 493, mean age: 49.5months [95% confidence interval (CI): 30.9-79.5]) were included. Pooled mortality rate was 32.6% (95% CI: 23.4-42.4). The most frequent etiologies for HLH were infections (53.3%) and primary HLH (12.8%), while the remaining cases were due to other causes of secondary HLH, including autoimmune diseases, malignancy, and drug-induced and idiopathic HLH. Pooled mortality rate was higher in primary than secondary HLH (72.2%, 95% CI: 57.8-84.5 vs. 23.9%, 95% CI: 14.4-35.02; p < .01). Univariate analysis found that treatment with etoposide was associated with higher mortality, while intravenous immunoglobulins (IVIGs) were associated with lower mortality. Conversely, multivariable analysis adjusted for etiology demonstrated no association between etoposide and IVIG use, and mortality. Twenty-one studies (total patients = 278) had detailed information on PICU therapies. Mechanical ventilation (MV), continuous renal replacement therapy, and inotropes were used in 107 (38.5%), 66 (23.7%), and 51 patients (18.3%), respectively. Need for MV was associated with increased risk of mortality (mean difference = 28%, 95% CI: 9-47). Critically ill children with HLH have high mortality rates and require substantial PICU support. Collaborative work between multiple centers with standardized data collection can potentially provide more robust data.

Macrophage Activation Syndrome in Adult Onset Still’s Disease: A Life Threatening Complication

Adult onset Still’s disease (AOSD), a multi-systemic inflammatory disorder, is a rare disorder but an important differential to be considered in patients of Pyrexia of Unknown Origin, especially if patient presents with polyarthritis. Macrophage activation syndrome (MAS), a subset of Secondary Hemophagocytic Lymphohistiocytosis (HLH), considered as the most life threatening complication of AOSD, mostly develops around the onset of disease. Hence, in a previously undiagnosed case of AOSD, recognizing MAS as a presenting feature complicating underlying AOSD is essential for increased patient survival, as in our case.&#x0D; &#x0D; &#x0D; A 39 year old diabetic female presented with high grade fever with chills and multiple joint pains symmetrically involving proximal shoulder, knees and distal joints (involving MCP, PIP and DIP joints of hand) associated with swelling and early morning stiffness, relieved on activity, since past 6 months. No history of oral ulcers, rash, jaundice, weight loss, loss of appetite, foreign travel or close animal contact.&#x0D; &#x0D; On examination, Pallor was present, Blood Pressure was 120/70 mm Hg, pulse rate was 102/min and temperature was 100 F. On per abdomen, mild hepatomegaly was present and other system examination was unremarkable.&#x0D; &#x0D; Routine laboratory findings on day of presentation have been summarised (Table 1.1). Ultrasound Abdomen revealed hepatomegaly and Chest X-ray showed signs of old infective foci. Peripheral smear for Malarial parasite, Ns1Ag and dengue serology, Widal test and Montoux test were negative. Blood cultures and urine cultures were sterile. X-Ray of joints were normal. USG of B/L Knee joints showed mild joint effusion bilaterally with no internal echoes (non tappable). Trans-thoracic echo and Trans-esophageal echo were normal. CT chest, neck and abdomen showed old tubercular changes in lung. Tests for atypical bacterial infections which was normal (RK 39, Chickungunya, Brucella, Leptospirosis and Scrub typhus). Fever did not respond to Broad Spectrum Antibiotics, Antimalarials or Antitubercular therapy and patient continued to have persistent fever spikes.&#x0D; &#x0D; Autoimmune profile showed ANA and RA Factor negative but markers of inflammation were raised: CRP- 521, ESR -148, IL-6 – 84.0, Procalcitonin-6.9 and S.Ferritin &gt;2000. During the work up for Anemia, Microcytic hypochromic anemia was found with Elevated NAP SCORE-165. Incidentally, her triglycerides were found to be elevated (356) and a reduced fibrinogen. With these results, we planned for a bone marrow aspirate and biopsy which showed increased myeloid preponderance (32:1), increased histiocytes and evidence of hemophagocytosis.&#x0D; &#x0D; The 2004 diagnostic criteria of HLH was fulfilled. After ruling out almost all infectious and malignant causes of secondary HLH, we searched for a rheumatologic cause. Thus diagnosis of AOSD (after fulfilling Yamaguchi’s criteria) with MAS (a subset of 2’ HLH) was made. Patient had dramatic improvement after receiving steroids with her fever episodes and joint pains settling completely thereafter.&#x0D; &#x0D; &#x0D; Prompt recognition of life threatening complications like MAS which pose diagnostic difficulty due to overlapping features in a patient of AOSD, should be done at the earliest to improve patient prognosis and survival. Serum Ferritin levels can be considered a useful marker to assess the disease activity and to predict MAS occurrence in such patients.

&lt;i&gt;Ehrlichia chaffeensis&lt;/i&gt;&lt;i&gt;-&lt;/i&gt;associated Hemophagocytic Lymphohistiocytosis: A Case Series and Literature Review

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition characterized by abnormal, excessive immune activation resulting in severe cytopenias from an uncontrolled inflammatory response. It can be primary/ familial or secondary/sporadic. Infections, particularly viral infections are a common cause of secondary HLH. HLH due to Human monocytic ehrlichiosis (HME) is very rare, hence we are reporting our cases. Objective: To review cases of Ehrlichia-associated HLH at our institution and perform a literature review regarding this entity. Methods: We reviewed cases of Ehrlichia-associated HLH for the previous two years at our institution (Carilion Clinic). We then performed a review of the published literature on it, using Pubmed. Results: Over the past two years, five cases of Ehrlichia-associated HLH were diagnosed at our hospital. The average age of the patients was 67 years with predominantly males. All the patients were pancytopenic, and a majority had abnormal liver function tests. Diagnosis of ehrlichiosis was made by serum polymerase chain reaction (PCR) assay on blood. Patients had further testing done because of lack of clinical improvement. All patients had significantly elevated ferritin levels. Bone marrow biopsy samples of all patients showed findings of hemophagocytosis. All, but one, patients were treated with doxycycline and a combination of etoposide and dexamethasone. Three patients recovered while two died. On review of medical literature, we found a total of only 36 cases of Ehrlichia-associated HLH, including our five cases. There were 19 adults and 17 children. Both population groups showed varying degrees of pancytopenia. Splenomegaly was relatively uncommon, seen in less than one-third of the patients. Ferritin and triglyceride levels were routinely elevated. Bone marrow biopsy showing hemophagocytosis was the confirmatory test in all patients. A significant number of patients, both adults and children, required a combination of doxycycline and chemotherapy (etoposide and dexamethasone) to achieve clinical cure. Children had a better prognosis than adults, with one child and four adults succumbing to their illness. Conclusions: Ehrlichia-associated HLH is a rare but emerging disease entity. In endemic areas, a high degree of suspicion is required to diagnose ehrlichiosis and HLH resulting from it. Early diagnosis and prompt initiation of treatment for HLH is key to a favorable outcome.

Clinical characteristics and outcomes of adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH).

e19526 Background: Lymphoma is a major cause of secondary HLH, a life-threatening hyperinflammatory syndrome due to immune dysregulation. This study examines the clinical and biological characteristics, management, and outcomes of patients with lymphoma and HLH. Methods: We retrospectively reviewed 44 adult patients with combined diagnoses of lymphoma and HLH at Memorial Sloan Kettering Cancer Center between June 2012 and September 2020. Overall survival (OS) was measured from the date of HLH diagnosis to the date of death or last follow-up. We evaluated the association of demographic, clinical, laboratory, and treatment variables on survival using log-rank tests and Cox proportional hazards model. Results: Of the 44 patients, 30 (68%) had T and NK-cell lymphoma, 12 (27%) had B-cell lymphoma, and 2 (5%) had Hodgkin lymphoma. All but one patient received HLH therapy including corticosteroids (95%), etoposide (68%), and intravenous immunoglobulin (18%), which was initiated within 1 day of diagnosis in 84% of cases. Twenty-five patients (57%) received lymphoma-directed therapy with etoposide (n = 17) or without etoposide (n = 8). Five of the 15 patients who underwent targeted tumor-sequencing of 400 genes harbored a TP53 mutation and all were refractory to frontline therapy, while 7 of 10 patients without TP53 mutation demonstrated initial treatment response ( p= 0.03). The median OS (mOS) of the entire cohort was 1.4 months, with a 30-day cumulative mortality incidence of 36.4%. Most deaths were attributed to relapsed or refractory HLH (n = 25/36, 69%) and lymphoma progression (n = 6/36, 17%). Patients with T/NK-cell lymphoma-associated HLH had a mOS of 1.4 months compared to 9.2 months in B-cell lymphomas ( p= 0.09). Ten patients (23%) were diagnosed with HLH within 60 days of their initial lymphoma diagnosis and had an improved prognosis (mOS 12.8 vs 1.3 months, p= 0.006). Treatment with etoposide, either alone or as part of a lymphoma-directed regimen, was associated with significantly improved survival (HR 0.48, 95% CI 0.24-0.96) whereas lymphoma-directed therapy with or without etoposide was not (HR 0.66, 95% CI 0.34-1.29). Significant predictors of mortality included age ≥60 years, non-white race, and concurrent infection during the hospitalization. Conclusions: In this large cohort from a single U.S. institution, there was a wide range of lymphoma subtypes associated with HLH. Despite increased disease recognition and prompt initiation of standard HLH and lymphoma-directed therapies, the prognosis remains very poor. Patients treated with etoposide had improved survival, highlighting the importance of controlling hyperinflammation during initial management. Notably, TP53 mutation was associated with primary refractory HLH. Future studies will aim to elucidate the pathophysiology of lymphoma-associated HLH in order to inform novel therapeutic approaches.

Severe anaplasmosis represents a treatable cause of secondary hemophagocytic lymphohistiocytosis: Two cases and review of literature

Anaplasmosis is an emerging infection in the United States and remains under-recognized in many areas including Pennsylvania. Presenting signs and symptoms are often nonspecific, but fulminant infection can occur in vulnerable populations. We present two cases of severe anaplasmosis that progressed to secondary hemophagocytic lymphohistiocytosis (HLH). This severe immune dysregulation syndrome has an extremely high mortality, but anaplasmosis represents one of the few treatable underlying etiologies. It is imperative for physicians to recognize this complication and start empiric doxycycline, as early treatment improves mortality. We also present a case of anaplasmosis-induced HLH successfully treated with a combination of doxycycline, steroids, and anakinra (an IL-1 receptor antagonist), highlighting that this primarily immune-mediated complication is amenable to treatment with both antibiotics and immune suppression.

Etiologies and Clinical Outcomes of Patients With Secondary Hemophagocytic Lymphohistiocytosis at a Tertiary PICU.

To assess the etiologies and outcomes of patients with secondary hemophagocytic lymphohistiocytosis in the PICU. Prospective observational cohort study. A single PICU at a pediatric tertiary hospital in Hanoi, Vietnam. Pediatric patients meeting the criteria for secondary hemophagocytic lymphohistiocytosis. None. Between June 2017 and May 2018, 25 consecutive patients with a mean (SD) age of 23.3 months (21.6 mo) were included. Collected variables included etiologies of hemophagocytic lymphohistiocytosis and clinical and laboratory findings at admission. The Pediatric Index of Mortality 2 score at admission was calculated. Outcomes were death and multiple organ dysfunction. The severity of multiple organ dysfunction was assessed by the Pediatric Logistic Organ Dysfunction 2 score. The mean (SD) Pediatric Index of Mortality 2 predicted mortality rate was 5.6% (7.6%). Cytomegalovirus and Epstein-Barr virus coinfections (60%) were the most common suspected etiology of hemophagocytic lymphohistiocytosis. Other etiologies included Epstein-Barr virus sole infections (20%), cytomegalovirus sole infections (16%), and one unknown cause (4%). Multiple organ dysfunction (excluding hematologic failure) was found in 22 patients (88%) with death occurring in 14 patients (56%). The mean (SD) Pediatric Logistic Organ Dysfunction 2 predicted mortality rate among patients with multiple organ dysfunction was 11.9% (11.2%). Despite having lower Pediatric Index of Mortality 2 predicted mortality rates at admission, Epstein-Barr virus-cytomegalovirus coinfection cases with multiple organ dysfunction had slightly greater Pediatric Logistic Organ Dysfunction 2 predicted mortality rates than Epstein-Barr virus sole infection cases with multiple organ dysfunction: 12.2% (10.5%) versus 11.3% (11.0%). However, these rates were lower than cytomegalovirus sole infection cases with multiple organ dysfunction (14.4% [16.3%]). Area under the curve values for Pediatric Index of Mortality 2 and Pediatric Logistic Organ Dysfunction 2 were 0.74 (95% CI, 0.52-0.95) and 0.78 (95% CI, 0.52-1.00), respectively, suggesting that both scales were fair to good at predicting mortality. Viral infections, particularly Epstein-Barr virus-cytomegalovirus coinfections, were a common cause of secondary hemophagocytic lymphohistiocytosis. The implication of these coinfections on the clinical course of hemophagocytic lymphohistiocytosis needs to be delineated.

18F-FDG PET/CT for identifying the potential causes and extent of secondary hemophagocytic lymphohistiocytosis

We aimed to evaluate the value of 18F-FDG positron emission tomography/computed tomography (PET/CT) for identifying the possible causes of secondary hemophagocytic lymphohistiocytosis (HLH). Forty-five cases (17 female, 28 male; age, 17-79 years) with secondary HLH were included. The standard of reference for diagnosis in all patients was a combination of histology, clinical results (medical history, physical examination, and laboratory test results), and follow-up imaging for at least 12 months. All cases underwent 18F-FDG PET/CT to identify the possible trigger in HLH. Of 45 secondary HLH cases 10 (22.2%) were associated with infection, seven (15.6%) with rheumatic disease, and 28 (62.2%) with lymphoma. PET/CT images of 22 secondary HLH cases (48.9%) showed true positive results. PET/CT images demonstrated obvious tracer uptake in five of 10 secondary HLH cases with infection, one of three cases with lupus, two of two cases with rheumatoid arthritis, one of two cases with adult-onset Still disease, and 13 of 28 cases with lymphoma. PET/CT is helpful for identifying the possible trigger (infection or malignant disease) and extent of secondary HLH. However, PET/CT alone is not sufficient to make a correct differential diagnosis.

Secondary Hemophagocytic Lymphohistiocytosis (HLH) From a Brown Recluse Spider Bite

Systemic loxoscelism is a rare complication from Loxosceles reclusa (brown recluse spider) envenomation that occurs in children more often than adults. It is often difficult to diagnose and there is currently no standard treatment. Symptoms can consist of localized skin necrosis, organ dysfunction, hemolysis, systemic inflammation, and possible death. We present a case of systemic loxoscelism that presented with renal failure, hepatotoxicity, DIC, hemolytic anemia, and secondary hemophagocytic lymphohistiocytosis (HLH). Our patient is a previously healthy 10 year old male, who developed the acute onset of malaise, nausea, fever, and a right elbow rash while attending camp in Tennessee. Upon presentation to our emergency department one day after the initiation of symptoms, he was noted to have severe renal dysfunction, liver dysfunction, hemolytic anemia, and thrombocytopenia. His physical exam was significant for fever and small, non-purulent blisters with surrounding erythema in the right antecubital fossa. Further investigation revealed elevation of soluble IL-2 receptor (9204 units/ml), ferritin (>40,000 ng/ml), and triglycerides (762 mg/dl) with hypofibrinogenemia (102 mg/dl). A bone marrow aspirate had moderate hemophagocytic activity present. With continued worsening of his organ dysfunction, he was started on high dose dexamethasone therapy for HLH. After initiation of steroid therapy, his organ dysfunction resolved rapidly and he was able to come off dialysis. His liver dysfunction also resolved and his inflammatory markers normalized. Investigation of his HLH did not reveal any known disease causing mutations. The clinical course following brown recluse spider bite can be relatively benign to life threatening with severe organ dysfunction and systemic inflammation. Loxosceles venom contains pro-inflammatory proteins which stimulate the production of interleukin-8, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor all of which have been shown to be elevated in patients with HLH. Secondary HLH can be seen in patients without an underlying genetic cause of the disease and is often triggered by a concurrent medical condition. Loxosceles envenomation should be considered as a potential cause of secondary HLH.