Secondary Hemophagocytic Syndrome
Authors: Mattos Vinicius R. P. , Silveira Michelle P. , Ferreira Flávia M. , Campelo Dirceu H. C. , Vargas Juliano Cordova , Souza Clarissa L.M. , Hamerschlak Nelson , Santos Fabio P S , Silveira Paulo A. A. 
Published: October 2019

Introduction: Hemophagocytic lymphohistiocytosis (HLH) corresponds to a wide array of potentially fatal hyper-inflammatory diseases involving pathologic immune activation and engulfment of hematopoietic cells by activated macrophages. These disorders have common clinical and laboratorial features, such as severe cytopenias, fever, hepatosplenomegaly and hyperferritinemia, leading to a dismal prognosis when treatment is delayed. Secondary hemophagocytic syndromes may develop as a result of strong immunological activation of the mononuclear phagocyte system by underlying conditions, such as infection, autoimmune diseases, malignancies and metabolic disorders. Mortality rates are high, even with proper treatments, and can reach up to 50%, usually within the first two months of the diagnosis. Diagnosis of this condition is difficult and requires a high degree of suspicion, since the diagnostic criteria are non-specific. Up to 30% of patients with confirmed hemophagocytic syndrome do not show this morphologic aspect in bone marrow examination. We report the data of our institution, regarding the clinical aspects, treatment and outcome of patients with confirmed hemophagocytosis in bone marrow aspiration analysis.

Objective: To determine clinical aspects underlying the development of secondary hemophagocytosis and the outcome of patients with this condition.

Methods: We retrospectively reviewed all bone marrow aspirations conducted from January, 2012 until December, 2013, regardless of diagnosis. A total of 1682 examinations were performed during this period and reevaluated by three specialists. We found 45 patients with cytological evidence of hemophagocytosis. The medical charts of these patients were reviewed and the following data was retrieved: age, gender, presence of fever and hepatosplenomegaly, underlying disease, past medical history, known underlying immunosuppression, treatment and outcome. Laboratory data was evaluated in the day of the bone marrow aspiration or in the two preceding or following days and included: hemoglobin, leucocytes and platelets counts; ferritin; triglycerides; fibrinogen, lactate dehydrogenase. Diagnosis criteria were defined accordingly to the guidelines of the Hemophagocytic Lymphohistiocytosis Study Group, published in 2004, excluding the soluble CD25 and NK cell activity assays that were unavailable.

Results: Median age was 52 years old (range <1 year-72 years) and 58% were male. Twenty-six (57%) had a diagnosis of neoplasia (21 hematological and 5 solid organ malignancies), and 3 patients had recently underwent bone marrow transplantation. Eighteen patients (40%) were receiving immunosuppressive therapy. Evidence of ongoing infection was identified in 34 cases (75.5%), and in 61.8% the agent was identified. Viral infections were commonly associated (26%), and in our case series, cytomegalovirus was the most implicated agent (5 cases). Other virus found were Parvovirus B19, H1N1, Parainfluenza, Herpes-Virus 6 and Epstein-Barr Virus. Bacterial and fungal infections were each responsible for 28,8% of the cases, and in 13 cases (38,2%) the agent was not identified. Among the patients who had complete laboratory evaluation (27 patients), we found that only 37% presented with all diagnostic criteria. Mortality rate was 35.5%, and median survival was 23 months (95% CI 22-60), with most deaths taking place in the first two months. None of the patients received specific treatment, being treated exclusively for the underlying conditions.

Conclusion: Secondary hemophagocytic syndrome is a rare yet severe condition, usually associated with a high mortality rate. In most cases, the diagnosis is not suspected and proper treatment not applied. Diagnosis criteria lack specificity and are more useful to the diagnosis of familial forms of HLH. The most common underlying conditions appear to be malignancies, infections and transplant-related immunosuppression. Treatment of the underlying conditions alone still retains large failure rates, and efforts must be made to achieve early diagnosis and employment of therapy.

Disclosures

No relevant conflicts of interest to declare.