Medical Progress

Hemophagocytic Lymphohistiocytosis: Advances in Pathophysiology, Diagnosis, and Treatment

Hemophagocytic lymphohistiocytosis (HLH) is a rare but often fatal hyperinflammatory syndrome caused by an inborn or acquired error of immunity. In adults, the underlying immunodeficiency generally arises alongside severe infections, malignancies, autoimmune diseases, and immunosuppressive treatment. To analyze risk factors and outcome in adults, we conducted a multicenter retrospective study. A total of 62 adult (age ≥18 years) patients met at least one of the following inclusion criteria: (1) ≥5 of 8 HLH-2004 criteria, (2) HScore ≥ 200 plus 4 HLH-2004 criteria, or (3) mutation compatible with an HLH diagnosis. Most patients (65%) were male, and the median age at diagnosis was 53.5 years (range, 19-81 years). All patients were assigned to 4 etiologic subgroups based on their most likely HLH trigger. The survival probability of the 4 etiologic subgroups differed significantly (P = .004, log-rank test), with patients with an underlying malignancy having the worst clinical outcome (1-year survival probability of 21%). The parameters older age, malignant trigger, elevated serum levels of aspartate transferase, creatinine, international normalized ratio, lactate dehydrogenase, sCD25, and a low albumin level and platelet count at treatment initiation were significantly (P < .1) associated with worse overall survival in the univariate Cox regression model. In multivariate analysis, sCD25 remained the only significant prognostic factor (P = .005). Our results suggest that sCD25 could be a useful marker for the prognosis of patients with HLH that might help to stratify therapeutic interventions.

We report a case of hemophagocytic syndrome (HPS) secondary to brucellosis, in which typhoidal cells were found in bone marrow, suggesting typhoidal cells present not only in Salmonella typhi infections but also in other bacterial infections. Typhoidal cells in bone marrow can be used to quickly identify the presence of bacterial infection pending the results of bone marrow and/or blood cultures.

In immunocompromised hosts, it may be more difficult to recognize infection as typical signs and symptoms are not present. Therefore routine monitoring for de novo infection or reactivation of a latent infection is extremely important. In this chapter, we will review strategies for monitoring cytomegalovirus, Epstein–Barr virus, hepatitis B virus, BK virus, adenovirus, and human herpesvirus 6 in immunocompromised hosts, focusing on solid organ transplant and hematopoietic cell transplant recipients. We will also review monitoring strategies for increased risk organ transplant donors and recipients.

Lymphoma-associated hemophagocytic syndrome is a life-threatening disease with poor prognosis and may present as ischemic stroke. We report a case of a 56-year-old female with recurrent multi-territory infarcts caused by diffuse large B-cell lymphoma with secondary hemophagocytic lymphohistiocytosis. She had been diagnosed with ischemic stroke and hemophagocytic syndrome probably secondary to Epstein-Barr virus infection 3 months previously and treated with Dexamethasone and Aspirin. High resolution vessel wall magnetic resonance imaging showed vessel wall thickening at some intracranial vessels suggesting vasculitis. Abdominal computed tomography scan revealed splenomegaly, multiple bilateral small nodules of the lung, multiple liver lesions, multiple bilateral renal masses, gastric wall thickening and multiple nodules in the omentum. Cerebrospinal fluid cytology showed increased cerebrospinal-fluid protein level. Hemophagocytosis was showed on bone marrow aspirate cytology. Gastric tissue biopsy revealed large B cell lymphoma. Chemotherapy was not given because the patient had severe pneumonia and sepsis. The patient died 28 days after the definitive diagnosis was confirmed. Ischemic stroke in our patient with diffuse large B-cell lymphoma may be due to vasculitis or intravascular large B-cell lymphoma.

Familial hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disease caused by genetic defects in the granule-mediated cytotoxic pathway. Success of hematopoietic cell transplantation, the only cure, is correlated with the extent of disease control before transplantation. Unfortunately, disease refractoriness and toxicities to standard chemotherapy-based regimens are fatal in a fraction of patients. Novel targeted immunotherapies, such as IFN-γ blocking antibodies or ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, are promising but only partially effective at controlling disease.

We asked whether combinations of cytokine-targeted therapies, using antibodies or JAK inhibitor, work synergistically to counteract HLH.

Genetically predisposed mice were infected and treated with distinct combinations of immunotherapies. Disease outcome was monitored and compared to monotherapies.

We showed that inhibiting IL-6 or IL-18 signaling in combination with IFN-γ blockade or ruxolitinib did not increase disease control compared to anti–IFN-γ antibodies or ruxolitinib monotherapies. In contrast, clinically relevant doses of ruxolitinib combined with low doses of anti–IFN-γ blocking antibodies corrected cytopenias, prevented overt neutrophilia, limited cytokinemia, and resolved HLH immunopathology and symptomatology.

Our findings demonstrate that IFN-γ blockade and ruxolitinib act synergistically to suppress HLH progression. This supports the use of combined cytokine-targeted therapies as a bridge to hematopoietic cell transplantation in severe familial hemophagocytic lymphohistiocytosis.

To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes.

We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes.

Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term.

Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.