HPS associated with viral infections
Epstein-Barr virus (EBV) is the most commonly reported trigger of HPS [
24]. The epidemiology of EBV-related HPS is not well known, although a higher incidence has been observed in Asian countries, where it has been theorised there may be a more pathogenic viral strain that is genetically similar to the strains observed in nasopharyngeal carcinoma cell lines [
25]. Two forms of EBV-related HPS have been described: the first occurring during primary infection and the second during a reactivation process [
26]. During primary infection, EBV typically infects and replicates in B cells, whereas EBV-specific cytotoxic T cells are required to produce memory cells. In rare cases, EBV may infect T and NK cells and induce persistent EBV infection, which may lead to chronic active EBV infection, lymphoproliferative disorders and fulminant EBV-related HPS [
27‐
29]. Serological testing can help determine whether EBV-associated HPS has occurred in the setting of acute infection or is the result of a reactivation process. In addition, the real-time polymerase chain reaction (PCR) detection and quantification of EBV nucleic acid is an important laboratory means of adequately reflecting viral replication and assessing EBV load in patients with EBV-related HPS [
30]. The quantitative analysis of cell-free EBV genome copy numbers after four months of treatment can assess therapeutic responses and is prognostically significant [
31].
The clonal expansion of EBV-infected T lymphocytes has been demonstrated in EBV-related HPS [
32] and EBV-positive T cell lymphoma [
33] on the basis of the presence of homogeneous viral terminal repeat sequences. The clonality of infected T lymphocytes is further suggested by the finding of monoclonal rearrangements of the T cell receptor-alpha gene in EBV-related HPS [
34]. The distinction between the monoclonal proliferation of T lymphocytes seen in EBV-related HPS and EBV-positive T cell lymphomas may describe the extremes of a spectrum of disordered T lymphocyte proliferation following EBV infection. The inflammatory cytokine over-production seen in patients with EBV-related HPS tends to be much more pronounced than that observed in patients with other forms of HPS [
35]. Of all of the infections associated with HPS, EBV infection has the worst prognosis in the presence of underlying hereditary disorders, diffuse intravascular coagulation, neutropenia, or central nervous system involvement [
36].
Treatment strategies vary significantly depending on the clinical features of the infection: mild cases of EBV-related HPS are treated conservatively as spontaneous regression has been reported, and antiviral therapy with acyclovir, ganciclovir or cidofovir has led to disappointing results [
37]. In the case of severe EBV-related HPS, the introduction of immuno-chemotherapy and, if necessary, allogenic stem cell transplantation has radically changed the history and prognosis of the disease: in such cases, the optimal treatment strategy can be centred on immunosuppressive medications that inhibit overactive T and NK cell responses (i.e. corticosteroids, cyclosporine A, intravenous immunoglobulin, anti-thymocyte globulins, etoposide, rituximab, and plasma or blood exchange transfusions) [
38,
39]. Hematopoietic stem cell transplantation is the last treatment resort for refractory forms of EBV-related HPS, and in the case of EBV infection occurring in genetic forms of HPS [
40].
The most frequent herpes viruses associated with HPS other than EBV are cytomegalovirus (CMV) and human herpes virus 8 (HHV8).
CMV up-regulates tumour necrosis factor gene expression and has been associated with HPS in otherwise healthy patients, patients with inflammatory bowel disease, rheumatological diseases and cancer, and transplant recipients [
41]. HPS was observed in seven of a series of 171 patients undergoing hematopoietic stem cell transplantation, and was triggered by CMV in three cases [
42]. Younger age may be associated with a worse prognosis [
43]. A recent study has shown that the use of specific anti-CMV therapy, such as CMV immunoglobulin, foscarnet or ganciclovir, may be therapeutic [
44].
HHV8 has been associated with HPS in 13 patients: most of these cases occurred in patients with a lymphoproliferative disorder [
45] or immunocompromised patients [
46], and rarely in immunocompetent hosts [
47]. Treatment based on etoposide, ganciclovir, foscarnet or rituximab has led o successful results [
48].
HPS can be associated with human immunodeficiency virus (HIV) infection, alone or with a wide variety of underlying disorders. It is likely that this condition is underestimated as HIV infection and HPS have many clinical and laboratory similarities. About 10% of bone marrow biopsies taken from HIV patients before the start of highly active antiretroviral therapy show active signs of hemophagocytosis [
49]. HIV-related HPS can be observed in cases of acute or late HIV infection, and in conjunction with immune reconstitution inflammatory syndrome, opportunistic infections, or malignancies [
50]. HPS may even be the initial presentation of HIV infection [
51], and it has been suggested that HIV itself may play a direct role in triggering the syndrome [
52]. Other common viral triggers of HPS in HIV patients are EBV, CMV and HHV8, and EBV-related HPS seems to be more frequent in HIV-infected children [
53].
Influenza-related HPS has been rarely reported in immunocompromised and otherwise healthy children [
54‐
57]. One fatal case of HPS was observed among 32 children hospitalised with seasonal influenza in a prospective pediatric study [
58], but reactive HPS has also been associated with avian and swine (non-pandemic) influenza [
59,
60]. In particular, patients with severe H5N1 (avian) influenza infection have symptoms and laboratory findings that are similar to those observed in patients with HPS, mainly encephalitis, organ dysfunction with hemophagocytosis, bone marrow failure, and pro-inflammatory cytokine over-production [
61]. Clinical studies have found that mutations in some viral genes (NS1, PB2, HA and NA) are significantly related to cytokine release, and it has been demonstrated that recombinant hemagglutinin (H5) from H5N1 virus can suppress perforin expression and reduce the cytotoxicity of T cells, including their ability to kill H5-bearing cells [
62]. Some authors have suggested treatment with a shorter course of etoposide and dexamethasone [
63].
HPS has been reported in 28 cases of parvovirus B19 infection, most of whom had hereditary spherocytosis as the underlying disease: fewer than half were children [
64‐
68]. Of these patients, 16 did not receive any treatment and 22 survived, thus suggesting that the prognosis of parvovirus-associated HPS is better than that of the other viral-mediated forms of HPS.
Fulminant viral hepatitis may mimic and even cause HPS, with hepatitis A virus being more frequently associated with HPS than the other hepatotrope viruses. Fifteen cases (including children) have been described, mainly in Asia: three of these patients also had a concurrent rheumatological disease (systemic juvenile idiopathic arthritis or Still’s disease) and two also had hepatitis C. Their treatment consisted of corticosteroids, variously combined with intravenous immunoglobulin, but four patients received no specific treatment and 11 of the 15 experienced a favourable outcome [
69‐
71].
Enterovirus-related HPS has been described in 12 pediatric cases: five occurred in infants aged <1 year, and the oldest patient was 18 years old. An underlying disease was found in four patients who experienced a fatal outcome (lymphoid neoplasms, lymphoblastic leukemia and juvenile idiopathic arthritis). Ten patients received intravenous immunoglobulin (six in combination with corticosteroids), but only seven patients survived [
72].
Other viruses associated with HPS include adenovirus, paramyxovirus (leading to measles and mumps), rubella virus, human parainfluenza viruses, Flavivirus (leading to dengue fever) and hantavirus (leading to hemorrhagic fever and severe acute respiratory syndrome), all of which have been treated with varying courses of corticosteroids and intravenous immunoglobulin.
HPS associated with bacterial infections
Reactive HPS has frequently been associated with intracellular pathogens. The pathophysiology of HPS associated with non-viral agents may be related to the production of high levels of activating cytokines by host lymphocytes and monocytes. Although the pathophysiological response of the host immune system to the infectious agent is not fully understood, it is hypothesised that functional deficiencies in NK and cytoxic T cells may occur during the illness [
73].
HPS can be associated with disseminated
Mycobacterium tuberculosis infection. Thirty-six cases (including infants and children) have so far been reported, approximately half of which were accompanied by comorbidities: eight patients had end-stage renal disease and were receiving hemodialysis or had undergone renal transplantation, four had a history of a malignancy, two had AIDS, and one had sarcoidosis. Fever was the most frequent clinical feature upon presentation, combined with visceromegaly and pancytopenia, and all of the patients underwent bone marrow aspirations that confirmed hemophagocytosis. Evidence of extra-pulmonary tuberculosis was found in 83% of cases. The concluding remarks of the report stated that tuberculosis-related HPS has a poor prognosis, with a mortality rate of approximately 50%, although anti-tuberculous and immunomodulatory therapy (consisting of high-dose corticosteroids, intravenous immunoglobulin, anti-thymocyte globulin, cyclosporine A, epipodophyllotoxin or plasma exchange) may lead to a better outcome [
74]. Early diagnostic confirmation and the timely administration of anti-tuberculous medication seem to be crucial in these patients. One reported case of HPS occurred after childhood vaccination with the bacillus Calmette-Guérin [
75].
HPS has also been described in association with brucellosis, with
Brucella melitensis being the most frequently isolated organism [
76]. Leptospirosis can cause life-threatening HPS as a result of an insufficient or misdirected immunological response to
Leptospira itself: antibiotic treatment alone is not sufficient in such cases, and treatment with corticosteroids, intravenous immunoglobulin or etoposide is required [
77]. Rickettsial diseases, transmitted to humans by arthropod bites and usually controlled at an intracellular level by nitric oxide synthesis, hydrogen peroxide production, and tryptophan degradation have also been related to HPS: overall, 15 cases of rickettsial disease confirmed serologically and complicated by HPS have been published in the period 1990–2010, with only 3 cases occurring in patients less than 15 years and a prognosis influenced by the specific
Rickettsia species, patient’s immunologic equipment, and delay in antibiotic therapy or corticosteroid therapy [
78]. In 2009, sepsis caused by multidrug-resistant
Acinetobacter baumannii following urinary tract infection was reported for the first time in a previously healthy 3-year-old child, who recovered after multiple doses of granulocyte colony stimulating factor and red blood cell/platelet transfusions without any cytotoxic treatment or immunotherapy [
79].
HPS associated with parasitic and fungal infections
HPS can be associated with
Leishmania donovani and
Leishmania infantum infections, but leishmaniasis may also mimic the syndrome, as it is characteristically associated with organomegaly and pancytopenia. This is particularly important in non-endemic areas, where visceral leishmaniasis is unlikely to be included in the differential diagnosis, and repeated bone marrow smears are often required to identify
Leishmania species by means of PCR with species-specific probes [
80]. Specific anti-leishmania treatment with amphotericin B is usually sufficient to control HPS. Unfortunately, sporadic cases of undiagnosed leishmaniasis have been treated as HPS with fatal consequences [
81].
Malaria (caused by
Plasmodium falciparum and
Plasmodium vivax), toxoplasmosis, babesiosis, and strongyloidiasis have been rarely identified in association with HPS: a history of travel from endemic countries may help to identify these triggering agents [
82].
Yeast (
Candida spp.,
Cryptococcus spp. and
Pneumocystis spp.) and moulds (
Histoplasma spp.,
Aspergillus spp. and
Fusarium spp.) have been associated with the occurrence of HPS, most commonly during HIV infection, neoplastic diseases, protracted corticosteroid administration, and transplantation [
83‐
85].
Disseminated
Penicillium marneffei infection is common among HIV-infected patients in many regions in Southeast Asia: the first case of HPS associated with penicilliosis in a Thai HIV-infected child was reported in 2001, with complete recovery after antifungal and intravenous immunoglobulin therapy [
86].