cases generally use regimens directed at the specific features of each type of complication. epstein–barr virus-related hemophagocytic lymphohistiocytosis main article: hemophagocytic lymphohistiocytosis main article: macrophage activation syndrome hemophagocytic lymphohistiocytosis (hlh) is a rare disorder characterized by a systemic inflammatory or, in extreme cases, overwhelming cytokine storm condition. it is due to the pathological proliferation and activation of benign histiocytes, macrophages, and lymphocytes along with the excessive release of proinflammatory cytokines by these cells. hlh has two distinct types. primary hlh (also termed genetic or familial hlh) is caused by loss of function (i.e. inactivating) mutations in genes that cytotoxic t and/or nk cells use to kill targeted cells such as those infected with ebv. these include mutations in the unc13d, stx11, rab27a, stxbp2, and lyst genes that encode elements needed for these cells to discharge toxic proteins into targeted cells; mutations in the pfp gene that encodes one of these toxic protein, perforin 1; and mutations in the sh2d1a, birc4, itk1, cd27, and magt1 genes that encode proteins required for the development, survival, and/or other cell-killing functions of ctyotoxic t and/or nk cells. secondary hlh is associated with and thought to be promoted by malignant and non-malignant diseases that, like primary hlh, also weaken the immune system's ability to attack ebv-infected cells. malignant disorders associated with secondary hlh include t-cell lymphoma, b-cell lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, and the myelodysplastic syndrome. non-malignant disorders associated with secondary hlh include: autoimmune disorders such as juvenile idiopathic arthritis, juvenile kawasaki disease, systemic lupus erythematosus, the juvenile onset and adult onset forms of still's disease, and rheumatoid arthritis; immunodeficiency disorders such as severe combined immunodeficiency, digeorge syndrome, wiskott–aldrich syndrome, ataxia telangiectasia, and dyskeratosis congenita); and infections caused by ebv, cytomegalovirus, hiv/aids, bacteria, protozoa, and fungi. secondary hlh may also result from iatrogenic causes such as bone marrow or other organ transplantation; chemotherapy; or therapy with immunosuppressing agents; about 33% of all hlh cases, ~75% of asian hlh cases, and nearly 100% of hlh cases caused by mutations in sh2d1a (see x-linked lymphoproliferatgive disease type 1) are associated with, and thought triggered or promoted by, ebv infection. these cases are termed ebv-positive hemophagocytic lympphohistiocytosis (ebv+ hlh). in ebv+ hlh, the virus may be found in b cells but mainly infects nk and t cells, including cytotoxic t cells. the virus induces defects in the ability of cytotoxic t cells to kill other ebv-infected cells and causes them to overproduce pro-inflammatory cytokines. these cytokines stimulate histiocyte and macrophage development, activation, proliferation, and cytokine production. the excessive release of these cytokines (e.g. tumor necrosis factor-α, interferon-γ, interleukin 1 beta, interleukin 18, and cxcl9) causes a systemic and often overwhelming inflammatory condition. primary hlh is most often seen in asians <4 years of age while secondary hlh is most often seen in older children and adults of various races. typically, the disorder presents with fever, decreased numbers of circulating white blood cells and/or platelets, enlarged liver and/or spleen, clinical evidence of hepatitis, and/or central nervous system disturbances such as irritability, decreased levels of consciousness, seizures, meningitis (i.e. neck stiffness, photophobia, and headache), impaired cranial nerve function, hemiplegia, ataxia (i.e. poor coordination of complex muscle movements), and reduced muscle tone. laboratory studies show abnormal liver function tests, reduced levels of blood fibrinogen, impaired blood clotting, and high levels of blood ferritin, triglycerides, soluble interleukin-2 receptor, and, in ebv+ hlh cases, circulating ebv. in the latter cases, histological examination of lymphatic, bone marrow, liver, neuronal, and other involved tissues show infiltrations of small ebv+ t cells, scattered small bystander ebv+ b cells, reactive histiocytes, reactive macrophages, and, in ~70% of cases, hemophagocytosis, i.e. ingestion of erythrocytes, leukocytes, platelets, and/or their precursor cells by histiocytes and macrophages. (evidence of hemophagocytosis is not critical for the diagnosis of hlh.) the ebv in infected lymphocytes is in its lytic cycle rather than any latent phase. criteria consistent with the diagnosis of hlh, as developed by the histiocytic society (2004), include finding five of the eight following signs or symptoms: fever ≥38.5 °c; splenomegaly; low blood levels of any two of the following, hemoglobin (<10 mg/l), platelets (<100,000/μl), or neutrophils <1,000/μl; either one or both of the following, blood fasting triglyceride levels >265 mg/dl or fibrinogen levels <150 mg/dl; hemophagocytosis in lymphoid tissue; low or absent nk cell activity as tested in vitro on blood cell isolates; elevated blood levels of ferritin; and elevated blood levels or the soluble il-2 receptor. the finding of ebv in t cells of blood or involved tissues is required to diagnose the ebv-associatec disease. prior to 1994, the treatments used for hlh were generally unsuccessful with average response rates to therapeutic interventions of ~10% and median survival times of ~12 month. in 1994, the histiocytic society established a drug regimen of dexamethasone + etoposide that increased the response rate to 70%. this regimen is currently recommended, particularly for primary hlh in young children, as induction therapy for ebv+ hlh except in patients with the macrophage activation syndrome where pulse methylprednisolone is the preferred treatment. response rates are somewhat higher in young children than adults and in primary rather than secondary disease. following inductive therapy, allogenic hematopoietic stem cell transplantation preceded by a reduced intensity conditioning regimen has been employed selectively, particularly in cases with primary hlh, with early results reporting some success. the management of ebv+ hlh has been less successful than that for other causes of secondary hlh. novel approaches to hlh particularly in cases of refractory or recurrent disease include the use of antithymocyte globulin, the dep regimen (i.e. liposomal doxorubicin, etoposide, methylprednisolone), an anti-interferon gamma monoclonal antibody, and, particularly in patients with ebv+-hlh, rituximab. chronic active epstein–barr virus infection main article: chronic active ebv infection chronic active epstein–barr virus infection (caebv) (also termed chronic active ebv infection of t and nk cells, systemic form) is a rare lpd of children and, less often, adults. caebv presents as severe, persistent form of infectious mononucleosis (im) or a severe lpd disorder that follows months to years after a symptomatic (i.e. im) or asymptomatic ebv infection. characteristic findings that are also diagnostic criteria for the disorder are: 1) symptoms similar to those in infectious mononucleosis but persist for >3 months; 2) high blood levels of ebv dna (i.e. >25 viral copies per mg of total dna); 3) histologic evidence of organ disease; 4) presence of ebv rna (e.g. an eber) in an affected organ or tissue; and 5) occurrence of these findings in individuals who do not have a known immunodeficiency, malignancy, or autoimmune disorder. other symptoms of caebv include persistent or intermittent fever, enlargement of lymph nodes, spleen, and/or liver, severe mosquito bite allergy, rashes, herpes virus-like skin blistering, diarrhea, and uveitis. the disorder may take a protracted course without progression over several years or a fulminant course with life-threatening complications such as hemophagocytosis (i.e. ingestion of blodd cells by histiocytes), myocarditis, liver failure, interstitial pneumonia, or rupture of the intestines. caebv can progress to a malignant type of ebv+ t-cell lpd such as aggressive nk cell leukemia, nk/t cell leukemia, or peripheral t cell lymphoma. the disorder may involve ebv+ t, nk, or, rarely, b cells. in ebv+ t and nk cell-associated disease, the tissues affected by caebv usually exhibit an histology that is not suggestive of a malignancy: lymph nodes have areas of hyperplasia, focal necrosis, and small granulomas; spleen shows atrophy of white pulp with congested red pulp; liver contains infiltrations of small lymphocytes around portal vasculature and sinuses; and lung and heart have findings typical of interstitial pneumonitis and viral myocarditis, respectively. erythrophagocytosis (i.e. ingestion of red blood cells by histiocytes) often occurs in the bone marrow, spleen, and/or liver. the principal ebv+ cells in these tissues are t cells in ~59%, both t- and nk cells in ~40%, and b cells in ~2% of cases. the involved lymphoid tissues in ebv+ b cell cases contain proliferating immunoblasts (i.e. activated b cells), plasma cells, and reed-sternberg-lide cells. the ebv+ cells in caeb express primarily lmp1, lmp2, and ebna1 viral proteins and eber micrornas, suggesting that the virus is in its latency ii phase. the mechanism underlying the development of caebv is unclear. however, patients with caebv have a hyper-inflammatory condition with elevated blood levels of the same cytokines (i.e. il-1β, il-10, and ifnγ) seen in hemophagocytic lymphohystiocytosis. furthermore, the disease has a strong racial preferences for eastern asians. these associations suggest that there are strong genetic predispositions involved in the disease's development and that this development is driven by t- and/or nk cell production of inflammatory cytokines. initially, caebv may assume a relatively indolent course with exacerbations and recoveries. however, the disease almost invariably develops lethal complications such as single or multiple organ failures. current recommendations based on studies in japan suggest that patients diagnosed with caebv be treated early in their disease with an intensive three-step sequential regimen: 1) immunotherapy (prednisolone, cyclosporine a, and etoposide; 2) cytoreduction (vincristine, cyclophosphamide, pirarubicin, and prednisolone or, alternatively, prednisolone and cyclosporine a); and 3) reconstruction: allogeneic hematopoietic stem cell transplant preceded by reduced intensity drug conditioning (i.e. etoposide and cytosine arabinoside followed by fludarabine, melphalan, anti-thymocyte globulin, methylprednisolone, and etoposide). patients receiving this regimen obtained unusually high three-year event-free and overall survival rates of >87%. further studies are required to determine how long these event-free and overall survival rates endure. severe mosquito bite allergy main article: mosquito bite allergies severe mosquito bite allergy (smba) is a rare disorder which occurs mainly in young east asians (median age 6.7 years). in most cases, it is a manifestation of caebv infection of the ebv+ nk cell type: ~33% of all individuals with caebv develop this allergy. smba has also been reported to occur in rare cases of ebv positive hodgkin disease, hydroa vacciniforme, aggressive nk‐cell leukemia (also termed aggressive nk-cell leukemia/lymphoma), and extranodal nk/t-cell lymphoma, nasal type, as well as in ebv negative lpd such as chronic lymphocytic leukemia and mantle cell lymphoma. ebv+ smba is a hypersensitivity reaction. in caev, the best studied or the predispositions to the disorder, smba is characterized by the development of skin redness, swelling, ulcers, necrosis and/or scarring at the site of a mosquito bite. this is often accompanied by fever and malaise; enlarged lymph nodes, liver, and/or spleen; liver dysfunction; hematuria; and proteinuria. affected individuals have increased blood levels of immunoglobulin e (which plays an essential role in the development of type i hypersensitivity reactions of the skin and other tissues) and ebv+ nk cells. in severer cases, the disorder is complicated by hemophagocytosis, nk/t-cell lymphoma, or aggressive nk cell leukemia. diagnostically, the skin lesions show infiltrating nk cells in the epidermis and subcutaneous tissue with a small fraction of these cells being ebv+ with the virus in its latency ii phase. a very high density of ebv+ nk cells in these lesions suggests the disorder has progressed to nk/t cell lymphoma or nk cell leukemia. while the disorder's etiology is unclear, it is thought that the mosquito salivary gland allergenic proteins trigger reactivation of ebv in latently infected nk cells. upon reactivation, ebv genes such as lmp1 express products that induce immortalization, proliferation, and in some cases malignancy of the ebv reactivated nk cells. the best treatment for smba remains unclear. mild and clearly uncomplicated cases can be treated conservatively focusing on obtaining relief of symptoms such as skin irritation, fever, and malaise. however, cases with evidence of significant complications of caefv such as the development of hemophagocytosis, nk/t cell lymphoma, or aggressive nk cell lymphoma, support the use of the chemotherapeutic regimens directed at these complications. cases of ebv+ smba associated with clear evidence of concurrent aggressive caebv have been treated with relative success by the three-step regimen used to treat caebv. rare cases of smba have been reported to occur in individuals who have no apparent predisposing disease but later develop caebv. such cases require careful evaluation and follow-up for development of a predisposing disorder. hydroa vacciniforme-like lymphoproliferative disease main article: hydroa vacciniforme hydroa vacciniforme is a rare photodermatitis reaction in which sunlight causes itchy skin papules and vesicles that develop crusts and eventually become scarred tissue. the lesions occur primarily on the sun-exposed skin of the face and back of the hand. it is an ebv+ disorder in which most cases develop in