Acute human immunodeficiency virus syndrome presenting with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) has been described in patients with advanced stages of human immunodeficiency virus (HIV) infection, but rarely occurs during the seroconversion stage of acute HIV infection. We report a case of acute HIV syndrome that presented with virus-associated HLH. The patient recovered spontaneously without any immunomodulating therapy. This case suggests that acute HIV infection should be included in the differential diagnosis of HLH and indicates that HLH associated with acute HIV infection can have a favorable outcome.     

Accuracy of the criteria for hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis, also known as a hemophagocytic syndrome, is a life-threatening condition that can develop in critically ill patients with malignancies, severe infections, during chemotherapy, and may be associated with currently known or unknown genetic abnormalities; however, this list of potential causes can be extensive. The purpose of this study is to draw attention to the accuracy of its diagnostic criteria, association with a variety of clinical conditions, pathophysiological mechanisms, and outcomes of the diseases. From the medical records in our hospital, we retrospectively extracted 13 cases with hemophagocytosis over a 10-year period. Subsequently, we thoroughly analyzed medical records for the criteria used, the time required for making a diagnosis, adequacy of the criteria, management, and outcomes. We found that not all criteria were used for diagnosis, and the most sensitive and specific tests (genetic study, ferritin, and soluble IL-2r levels) were sometimes bypassed. Late diagnosis delayed management of some patients. Only a few treatment options were used for patient care. The hemophagocytic syndrome is a very rare and fatal entity requiring highly sensitive and specific diagnostic criteria for prompt diagnosis, targeted management, and thorough follow-up. Every patient admitted to the hospital with life-threatening conditions should be suspected and tested for the hemophagocytic syndrome as early as possible. The criteria for hemophagocytic lymphohistiocytosis should be revised, with the most sensitive and specific ones being done in all cases. Subsequently, each patient should be tested for the presence of genetic abnormalities that correlate with the syndrome.     

Pathology updates and diagnostic approaches to hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a complex, often under-recognized hyperinflammatory immune dysregulation syndrome arising in a diverse range of clinical scenarios and conditions. The accurate and timely diagnosis of HLH is crucial for patient survival, and usually requires a high level of clinical suspicion. The histologic corollary to clinical HLH – hemophagocytosis – is neither necessary or sufficient for the diagnosis of HLH, as it may be seen in a variety of reactive conditions, or may be absent in true HLH. Nevertheless, the finding of hemophagocytosis in specific clinical situations should prompt the consideration of HLH and further testing to exclude the condition. While traditionally described in bone marrow, identification of hemophagocytosis in other tissues, including lymphoid, splenic, liver, or neural tissue, can be an important asset to the overall recognition of HLH. In this review, we discuss the underlying pathophysiology and etiologies of, morphologic aspects hemophagocytosis and its associated histologic findings in different tissues and give a brief overview of diagnostic criteria and clinical evaluation.     

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Los Angeles County

Data on Epstein–Barr virus‐related hemophagocytic lymphohistiocytosis (EBV‐HLH) in adults in the United States remain very limited. A cluster of four cases of EBV‐HLH was observed in a 4‐month period at a tertiary center in Los Angeles County (LA County) and the clinical and molecular characteristics identified in these cases are being described. EBV typing, immunophenotypic and molecular genetic studies were performed. Diagnostic criteria that may be used to identify EBV as a cause of HLH in adults are also being suggested. Finally, the crude incidence rate for HLH in LA County was determined and was compared to the worldwide crude incidence rate for HLH. The cases each occurred in young male adult residents of California and were associated with evidence of EBV reactivation and ferritin levels of >20,000 µg/L. A higher rate of cases of EBV‐HLH in 2010 was found at UCLA Medical Center than for 2007–2009 (4.9/10,000 hospital discharges vs. 0.14/10,000 hospital discharges, respectively; P = 0.0017). The cases were associated with EBV type 1, and the insertion of the codon CTC (leucine) was found in numerous of the EBNA‐2 gene sequences. The annual incidence of secondary, non‐familial HLH was estimated to be 0.9 cases per million persons >15 years of age in LA County. Although EBV‐HLH is a rare disease, the incidence in adults in Western countries may be underestimated. J. Med. Virol. 84:777–785, 2012. © 2012 Wiley Periodicals, Inc.     

Viral etiology,clinical and laboratory features of adult hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (SHLH) is a potentially fatal hyperinflammatory syndrome with a heterogeneous etiology and has nonspecific clinical and laboratory findings. The diagnosis and treatment of adult SHLH is challenging because the etiology of the disease is difficult to identify, and the majority of reported cases are pediatric patients. The aim of this study was to describe the etiology, clinical characteristics, and outcomes of adult SHLH. Fifty‐four adult patients who fulfilled the criteria of SHLH were enrolled in the study. Viral etiology, blood biomarkers, and clinical manifestations of SHLH were analyzed in these patients. Twenty‐four SHLH patients had viraemia, whereas 30 SHLH patients were secondary to other diseases. Epstein‐Barr virus (EBV) was the most common virus that associated SHLH among all viruses studied. Severe SHLH patients with EBV‐viraemia presented significantly high levels of ferritin, lactate dehydrogenase, aspartate transaminase (AST), and alanine transaminase (ALT). Positively relationships existed between EBV DNA titers and levels of AST and ALT (P < 0.05). The prognosis of SHLH patients with EBV viraemia was worse than that of non‐EBV SHLH and non‐viral SHLH. Our data reveal that EBV is the major pathogen in virus‐associated SHLH, and EBV load influence disease development in SHLH patients with EBV infection that prognosis is worse than other viruses associated SHLH. J. Med. Virol. 88:541–549, 2016. © 2015 Wiley Periodicals, Inc.

     

Severe hemophagocytic lymphohistiocytosis in adults-experience from an intensive care unit from North India

Background:

Hemophagocytic lymphohistiocytosis (HLH) has been reported to complicate fulminant tropical infections but data on severe HLH with multi-organ dysfunction (MODS) are scant.

Materials and Methods:

Retrospective review of medical electronic records of our intensive care unit (ICU) over a 2-year period.

Results:

We describe 10 adult patients with HLH and MODS. Patients had short symptom duration prior to presentation and had rapid deterioration during their hospitalization course. Fever, organomegaly, neurologic abnormalities, hepatic abnormalities, and cutaneous signs were very common. No patient had diagnosed HLH at ICU admission (median 4 criteria [Inter Quartile Range 2-4.25]). All patients required mechanical ventilation and 80% required vasopressors. Infection-associated HLH (IAHS) was the most common etiology (80%). Seventy percent (7/10) of patients were treated with steroids and 20% received intravenous immunoglobulin. Etoposide and/or cyclosporine were administered in 20% (2/10). Nosocomial infections occurred in 40% and the ICU mortality was 70%.

Conclusions:

Severe HLH with MODS has a very high mortality. Data on adult cohorts with IAHS in the tropics with defined treatment protocols are urgently needed.     

Evaluation of apoptosis in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis

Epstein-Barr virus (EBV) is known to be a causative agent of hemophagocytic lymphohistiocytosis (HLH). To investigate association of apoptosis in the pathogenesis of EBV-associated HLH, the serum EBV loads, and serum concentrations of soluble tumor necrosis factor receptor 1 (sTNF-R1), soluble Fas ligand, and cytochrome c were examined in 15 patients with EBV-associated HLH and 24 patients with infectious mononucleosis (IM). Levels of sTNF-R1 are known to reflect the biological activity of TNF-alpha and cytochrome c is a specific marker of apoptosis. EBV loads, and concentrations of sTNF-R1 and cytochrome c were significantly higher in patients with EBV-associated HLH than in patients with IM. On the other hand, there were no statistically significant differences in the concentrations of soluble Fas ligand. In patients with EBV-associated HLH, EBV loads, concentrations of sTNF-R1, and cytochrome c were correlated with each other. These results suggest that apoptosis, which is dependent on the EBV load and could be mediated by TNF-alpha, plays a major role in the pathophysiology of EBV-associated HLH.     

High frequency of QPY allele and linkage disequilibrium of granzyme-B in Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis

Mediation of Epstein-Barr virus (EBV)-specific cytotoxicity in T lymphocyte via the perforin/granzyme pathway has been demonstrated; therefore, a study involving cytolytic molecules was essential for the clarification of hemophagocytic lymphohistiocytosis (HLH) pathogenesis. This investigation, which analysed the frequency of three allelic mutations of granzyme-B (55Q/R, 95P/A and 247Y/H) in patients with EBV-HLH and infectious mononucleosis, identified the high prevalence of the QPY haplotype in EBV-HLH patients in comparison with healthy controls. A > G polymorphism was also detected in intron 5; furthermore, nearly complete linkage disequilibrium was observed among these polymorphisms. The recessive role of the QPY haplotype of granzyme-B might be responsible for the pathogenesis of EBV-HLH. Cytotoxicity and DNA fragmentation of cytotoxic T lymphocytes did not differ among patients characterized by the QPY/QPY, RAH/RAH and QPY/RAH genotypes. This finding suggested that DNA fragmentation in target cells is mediated not only by granzyme-B but also by other molecules, including other granzymes or Fas.     

Risk for complications in patients with hemophagocytic lymphohistiocytosis who undergo hematopoietic stem cell transplantation: myeloablative versus reduced-intensity conditioning regimens

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with primary hemophagocytic lymphohistiocytosis (HLH) and for patients with secondary HLH who fail to respond to therapy. Advances in HSCT and supportive care measures have resulted in improved patient outcomes and decreased treatment-related mortality. Despite the overall improvement in outcome, HLH patients who undergo HSCT using myeloablative conditioning regimens are still at significant risk for complications. The HLH-94 study conducted by the Histiocyte Society reported a 30% TRM with increased pulmonary and hepatic complications. Recently, the use of reduced-intensity conditioning (RIC) regimens has shown favorable outcomes when compared to conventional HSCT and lower rate of acute complications. In this review we compare the potential complications of myeloablative and RIC regimens for HSCT in HLH patients.     

Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal-recessive disease that affects young children. It presents as a severe hyperinflammatory syndrome with activated macrophages and T lymphocytes. Mutations in the perforin 1 gene (PRF1) were found in FHL-2 in 15-50% of all cases. Defective granule exocytosis caused by mutations in the hMunc13-4 gene (UNC13D) has been described in FHL-3. FHL-4 patients have mutations in STX11, a t-SNARE involved in intracellular trafficking. We analyzed a large group of 63 unrelated patients with FHL of different geographic origins (Turkey:32; Germany:23; others:8) for mutations in STX11, PRF1, and UNC13D. We identified mutations in 38 samples (20 in PRF1, 12 in UNC13D, and six in STX11). Of 32 patients from Turkey, 14 had mutations in PRF1, six had mutations in UNC13D, and six had mutations in STX11. The mutation Trp374X in PRF1 was found in 12 patients from Turkey and was associated with a very early onset of the disease below the age of 3 months in all cases. In contrast, three of 23 and four of 23 patients from Germany, and three of eight and two of eight from other origins showed mutations in PRF1 and UNC13D, respectively, but none in STX11. Thus, FHL-2, FHL-3, and FHL-4 account for 80% of the HLH cases of Turkish origin, and for 30% of German patients. Furthermore, we identified mutations in RAB27A in three patients with FHL-related Griscelli syndrome type 2. In functional studies using a mammalian two-hybrid system we found that missense mutations Ala87Pro in Rab27a and Leu403Pro in hMunc13-4 each prevented the formation of a stable hMunc13-4/Rab27a complex in vitro. Our findings demonstrate extensive genetic and allelic heterogeneity in FHL and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D.     

Stuck with pancytopenia in dengue fever: Evoke for hemophagocytic syndrome

The hemophagocytic syndrome is an atypical and rare manifestation of dengue fever (DF). We describe a 15-year-old girl developing DF associated hemophagocytic syndrome who responded with supportive treatment.     

Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people

Although mutations of perforin, MUNC13-4 and syntaxin 11 genes have been found in children with familial hemophagocytic lymphohistiocytosis (FHL), the incidence of each genetic subtype varies in different ethnic groups. We evaluated mutations of syntaxin 11 and SNAP23 genes in 30 Japanese FHL patients. The patients had no mutations and 10% had one polymorphism (146G>A) of syntaxin 11, while no mutation of SNAP23 was observed. Our results indicate that aberrations in the SNARE system may not cause FHL in Japanese families.     

Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D,STX11, STXBP2, SH2D1A,and XIAP

Hemophagocytic lymphohistiocytosis (HLH) is a rare life‐threatening hyperinflammatory disease. This study aimed to investigate the frequencies and distributions of inherited variants in PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP genes in Chinese patients with HLH. A total of 265 patients diagnosed with HLH from January, 2010 to December, 2016 were recruited and analyzed for the 6 genes. Genetic variants were observed in 87 (32.83%) patients. 36 (13.58%) exhibited variants in UNC13D, 18 (6.79%) exhibited PRF1 variants, 10 (3.77%) had variants in XIAP, 9 (3.40%) exhibited variants in STXBP2, 6 (2.26%) carried variants in SH2D1A, 1 (0.38%) had STX11 variant, and 7 (2.64%) exhibited digenic variants. Monoallelic variants were the most common, which accounted for 49.43% of all cases with variants. All variants were confirmed to be germline‐derived. The present study describes a distinct variant spectrum in Chinese patients with HLH, whereby UNC13D is the most frequently mutated gene with missense variants that are the most common molecular defects. The variant profile of Chinese HLH patients is quite different from that of Western cohorts but similar to that of Korean patients, yet showing its own uniqueness. This racial difference shows the role of genetic background in the occurrence of HLH.     

Down-regulation of CD5 expression on activated CD8 T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type 2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8⁺ T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8⁺ T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum pro-inflammatory cytokines in five patients with FHL2. All patients showed significantly increased subpopulations of activated CD8⁺ T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vβ repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8⁺ T cells may serve as a useful marker of dysregulated T cell activation and proliferation in FHL2.     

Hemophagocytic lymphohistiocytosis and primary immune deficiency disorders

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled immune activation and is traditionally associated with inherited gene defects or acquired causes. In addition to abnormalities in cytotoxic granules and lysosomes, various primary immune deficiency disorders (PID) have been identified among patients suffering from HLH. Our purpose was twofold: to better characterize and detail the association between PID and HLH.