Infection-associated HLH
HLH associated with infection was originally described in patients under iatrogenic immunosuppression. Infections are commonly implicated triggers of genetic HLH; therefore, the identification of an infection does not discriminate between genetic and acquired forms.
A number of infectious organisms have been associated with HLH (see Table 2). Viral infections of the herpesvirus family are frequently reported, particularly cytomegalovirus and EBV infections, with EBV regarded as the pathogen that most commonly triggers infection-associated HLH (see further discussion below). Herpes simplex virus infections are associated with up to 30% of neonatal HLH in Japan. Human herpesvirus 8–associated HLH has been described in 13 patients, mostly occurring in the setting of Kaposi sarcoma or multicentric Castleman disease.
Other viruses reported in association with HLH include hepatitis viruses, adenovirus, measles, mumps, rubella, dengue, hantavirus, parvovirus B19, and enterovirus. Influenza-associated HLH has also been reported.
HLH may also be the first manifestation of a human immunodeficiency virus (HIV) infection. Around 10% to 20% of bone marrow biopsy specimens in patients with HIV before initiation of highly active antiretroviral therapy showed hemophagocytosis; however, it is not known whether these patients fulfilled other criteria for HLH. The fact that viral infections may interfere with the function of cytotoxic T cells represents a possible mechanism of infection-associated HLH.
The incidence of bacterial-associated HLH varies between studies. Bacterial organisms include Staphylococcus aureus, as well as various Gram-negative and atypical bacteria such as Campylobacter spp, Fusobacterium spp, Mycoplasma spp, Chlamydia spp, Legionella spp, Salmonella typhi, Rickettsia spp, Brucella spp, Ehrlichia spp, and Borrelia burgdorferi. As many as 36 cases of HLH have been published in association with tuberculosis.
Among parasitic infections that trigger HLH, malaria (Plasmodium falciparum and Plasmodium vivax), toxoplasmosis, babesiosis, and strongyloidiasis have also been described in HLH. Fungal infections include Candida, Cryptococcus,Pneumocystis, Histoplasma,Aspergillus, and Fusarium species. These are more frequent in patients with immunosuppression due to HIV infection, lymphoma, and chronic steroid use, as well as in transplant recipients.Leishmania is a frequent nonviral agent reported in children. The mechanism by which these various infectious organisms cause HLH is poorly understood, with the exception of EBV-associated HLH.
EBV-associated HLH
EBV has been identified as the triggering virus in 74% of children in whom infectious agents were identified. EBV-associated HLH is most often seen in East Asian countries. In Japan, the estimated incidence is at least 25 cases per year in the pediatric population, with a peak incidence occurring between 1 and 2 years and with a slightly higher frequency in girls. This higher geographic prevalence points to possible genetic factors involved in the pathogenesis of EBV-associated HLH. It may also be related to the higher prevalence of EBV and EBV-infected T cells in Asians or to better detection and diagnosis of HLH in Asian hospitals.
Most patients with EBV-associated HLH present with a prolonged atypical infectious mononucleosis–like course, although some will develop an abrupt, rapidly fatal disease. Although EBV-associated HLH appears to be more common in the setting of reactivation, its occurrence in some immunocompetent children or young adults with classic mononucleosis suggests also an association with primary EBV infections.
In primary EBV infection, EBV infects and replicates primarily in CD21+ B cells. Occasionally, T cells are also infected. However, unlike in chronic persistent EBV infection, in which infected NK cells and CD4+ T cells are more frequent, in EBV-associated HLH, infected CD8+ T cells predominate. The infection of the cytotoxic CD8+ T cells by EBV is believed to impair the proper function of these T cells, thus setting up the basic mechanism of a cytotoxic pathway defect characteristic of HLH.
Clonality studies have shown that a significant number of patients with EBV-associated HLH have a clonal proliferation of T cells, particularly patients with recurrent disease. The clonal expansion is also indicated by the presence of homogeneous viral terminal repetitive sequences in both EBV-associated HLH and EBV-positive T-cell lymphoma. These findings shared by both T-cell lymphomas and EBV-associated HLH are intriguing given the strong association between the 2 diseases.
EBV infection is also the commonly implicated trigger in genetic HLH. In particular, the pathogenesis of EBV-associated HLH is similar to that of XLP, and EBV infection can easily tip a compensated XLP immune system into HLH by further compromising an impaired pathway. In XLP, mutations in the SAP/SH2D1A gene lead to abnormal levels of SAP protein. Normally, the SAP protein acts as a negative regulator of the SLAM/ERK signal pathway for T-cell activation to secrete cytokines such as IFN-γ and TNF-α. EBV affects infected T cells by inhibiting SAP/SH2D1A gene expression through the action of EBV latent membrane protein 1 (LMP1), thus resulting in an enhanced cytokine secretion. When coupled with an underlying mutation of SAP, EBV infection of XLP T cells would further abrogate negative regulation of cytokine production. In addition to the role of LMP1, EBV also causes immortalization of infected T cells by blocking apoptotic signaling through TNF-α/TNF receptor 1 in the infected B and T cells via the activation of the nuclear factor–κB signal pathway. Thus, the persistent effect of EBV predisposes these patients to have recurrent episodes of HLH.
Malignancy-associated HLH
Malignant neoplasms are commonly seen in association with HLH in both children and adults. It may be the presenting clinical picture of an underlying malignancy, or it may develop during the treatment for a malignancy. An incidence of 20% has been reported in the pediatric population. A concomitant triggering infection is common and contributes to mask the underlying malignancy.
Hematologic malignant neoplasms account for the majority of cases, although solid tumors such as prostate, lung, and hepatocellular carcinoma have also been described. Mediastinal neoplasms such as germ cell tumor and thymomas are known associations. Among the hematologic neoplasms, peripheral NK/T-cell lymphomas, anaplastic large-cell lymphoma, and acute lymphocytic leukemias are often implicated. Hodgkin lymphoma, multiple myeloma, and acute erythroid leukemia have also been reported. HLH is rarely seen in patients with non-Hodgkin B-cell lymphomas.
Given the current understanding of the pathogenesis of other types of HLH, a possible mechanism of malignancy-associated HLH may be the impairment of the cytotoxic pathway by the neoplasm through neoplastic changes in the cytotoxic cell itself or through malignancy-associated immune dysregulation. The strong association with NK/T-cell lymphomas and other EBV-related malignant neoplasms points to a possible common mechanism shared by cases of nonmalignant EBV-associated HLH.
Macrophage Activation Syndrome
MAS is the name of HLH that arises as a complication of autoimmune diseases. The estimated prevalence ranges from 7% to 13% of children with soJIA or Still disease. Other autoimmune diseases have also been reported in association with HLH, including Kawasaki disease, systemic lupus erythematosus, and seronegative spondyloarthropathies in adults.
MAS was first described in association with a pediatric rheumatic disease in 1985, although first descriptions may have been as early as the mid-1970s. Although these patients may exhibit many of the clinical features of HLH, severe coagulopathy and cardiac impairment have been reported as common manifestations.
As mentioned previously, because of the overlap of clinical and laboratory findings between HLH and the rheumatologic process, modified diagnostic criteria for HLH must be applied in the case of MAS, based on a change from baseline laboratory values. For example, soJIA is often associated with anemia, hyperferritinemia, and leukocytosis, even in the absence of MAS, requiring a high index of suspicion to make a diagnosis of MAS. Patients with soJIA-associated MAS typically have lower levels of ferritin than in bona fide HLH, albeit still elevated above normal. However, patients may be afebrile and cytopenias may be less severe, at least initially.
The mechanism of MAS is presumably the impaired function of NK/T cells, similar to the other types of HLH. Patients with MAS have been shown to exhibit decreased expression of perforin or the SAP gene, mimicking the defects associated with familial HLH and XLP, respectively.