Definition and History
Farquhar and Claireux first described this disease in siblings in 1952.143 Although many case reports using several eponyms ensued, Henter and Elinder provided a logical organization of the diverse clinical presentations.144 HLH is an aggressive and potentially fatal syndrome that results from inappropriate prolonged activation of lymphocytes and macrophages. The name describes the characteristic (but not diagnostic) pathologic finding of macrophages engulfing all types of blood cells in marrow, lymph nodes, spleen, or liver biopsies (Fig. 72–4). HLH is also known as autosomal recessive familial hemophagocytic lymphohistiocytosis, familial erythrophagocytic lymphohistiocytosis, viral-associated hemophagocytic syndrome, and infection-associated hemophagocytosis. “Primary” HLH has been used to describe young children with HLH with known gene mutations or a family history of HLH. Older children with HLH, or children without identifiable mutations, are sometimes described as having “secondary” or “acquired” HLH with the assumption that the condition is caused by infection or other stimulus and not a result of genetic predisposition. The same mutations may be present in both situations, and there is no rapid and definitive gene-testing strategy to identify the two groups. In general, presentation and outcome are the same for primary and acquired HLH. Thus this distinction is not clinically useful in the acute setting as they both must be diagnosed promptly and treated aggressively.
The incidence of HLH in Sweden was estimated at 1.2 children per 1 million children per year, or 1 in 50,000 livebirths with equal sex distribution.144 At the Baylor College of Medicine, HLH was diagnosed in 1 of 3000 inpatient admissions in a 2-year study.145
Defects in the function of natural killer (NK) cells and cytotoxic T cells have been found in HLH patients. This results in the inappropriate activation of T cells and macrophages, which produce proinflammatory cytokines, including interferon-, tumor necrosis factor-, IL-6, IL-10, IL-12, and soluble IL-2 receptor- (sCD25).146,147 Hypercytokinemia generated by activated T cells and macrophages results in multiorgan dysfunction that can rapidly lead to death.
Perforin was identified as a candidate HLH gene by gene mapping and was confirmed by poor expression of perforin in NK cells and cytotoxic T lymphocytes of HLH patients.148 Some HLH characteristics were reproducible in PRF1 knockout mice.149 Perforin is secreted from NK cells and cytotoxic T cells upon activation by target cells and introduces pores in the target cell membrane, allowing granzyme to enter and trigger apoptosis.150
Other Defects Causing HLH
Mutations in other genes encoding proteins involved in NK and cytotoxic T-cell–mediated killing of target cells have also been discovered in patients with HLH, including granzyme B, MUNC13–4, and syntaxin 11.151 Mutations in the gene that encodes rab27a (protein that controls secretion of lytic granules) have been identified in patients with Griscelli syndrome.152
Immune Deficiencies Associated with HLH
Patients with other immune deficiencies associated with lysosomal trafficking defects (e.g., Chédiak-Higashi syndrome, Hermansky-Pudlak syndrome type II) also have a high frequency of HLH.151 HLH, often associated with infection by the Epstein-Barr virus, is the commonest fatal complication of X-linked lymphoproliferative disease.153
Clinical Features – Signs and symptoms
Initial signs and symptoms of HLH mimic more common problems (e.g., fever of unknown origin or sepsis).154 Confounding diagnoses such as infection, autoimmune disease, hepatitis, multisystem organ failure, encephalitis, and malignancy do not exclude a diagnosis of HLH. Important clues are an acutely ill patient with unexplained fever, rash, or neurologic symptoms. A medical history of immune deficiency should bring HLH to mind. Family history of consanguinity, recurrent spontaneous abortions, or HLH in siblings (or symptoms suggesting undiagnosed HLH) should prompt full evaluation for HLH.
Prominent early clinical signs in one study included fever (91%), hepatomegaly (90%), splenomegaly (84%), neurologic signs (47%), rash (43%), and lymphadenopathy (42%).155 Another study found 75 percent of patients with HLH to have CNS symptoms that may mimic encephalitis.156 Patients with HLH develop liver failure with markedly elevated bilirubin, pancytopenia, coagulopathy, renal failure heralded by hyponatremia, and pulmonary failure similar to acute respiratory distress syndrome with interstitial infiltrates on chest radiography
The cumulative experiences from the first prospective international treatment protocol sponsored by the Histiocyte Society, HLH-94, as well as other observations and studies, have led to the Histiocyte Society treatment protocol HLH-2004, which includes diagnostic guidelines (Table 72–5).156 Mutations in PRF1 (encodes perforin),157 UNC13D (encodes MUNC13–4),158 or syntaxin 11 genes159 are diagnostic. Gene mutation studies may be helpful in the acute setting if polymerase chain reaction methodology is readily available. In the absence of a known gene mutation, a diagnosis of HLH can be made with at least five of eight criteria (Table 72–5).
|*Five of these eight clinical or laboratory findings are sufficient to make the diagnosis of HLH. It is important to obtain serial measurements of ferritin as well as the complete blood count, coagulation, and liver function tests when evaluating a patient.|
Hemophagocytosis is sometimes misunderstood as pathognomonic and necessary for the diagnosis of HLH, but biopsies fail to demonstrate hemophagocytosis in approximately one-third of patients.160 HLH changes over time such that the cytokine stimulation resulting in hemophagocytosis may be modest early in the disease, or the marrow may progress to become aplastic with few macrophages available to engage in hemophagocytosis. Repeat marrow aspirates and biopsies, as well as lymph node or liver biopsies, may be helpful. Finding hemophagocytosis is highly suggestive of HLH, but is neither necessary nor sufficient to make the diagnosis. HLH. Cerebrospinal fluid should be tested in patients with signs of CNS abnormalities; pleocytosis and hyperproteinemia support HLH with CNS involvement. The clonal proliferation of lymphocytes in lymph nodes may be confused with a lymphomatous infiltrate.161
Although no one diagnostic criterion is sufficient to make the diagnosis of HLH, a highly elevated serum ferritin along with four other criteria is strongly indicative. A ferritin concentration of more than 500 mcg/L was included because a survey found that most children with infectious diseases had levels less than that level and those with rheumatologic diagnoses only rarely had higher levels. Ferritin concentrations greater than 500 mcg/L were 100 percent sensitive for HLH in a retrospective review of ferritin concentrations of more than 500 mcg/L over a 2-year period.145 However, at this level there is considerable overlap with other disorders. Ferritin concentrations more than 10,000 mcg/L were 90 percent sensitive and 96 percent specific for HLH with very minimal overlap with sepsis, infections, and liver failure.
The following tests should be done on a previously healthy patient who presents with persistent fevers, hepatosplenomegaly, and cytopenia of at least two cell lines: serum ferritin, aspartate aminotransferase/alanine aminotransferase, lactate dehydrogenase, bilirubin, coagulation studies, fibrinogen, triglycerides. A marrow biopsy and aspirate is needed as well as a lumbar puncture for spinal fluid examination. NK-cell function, perforin expression of T cells and NK cells, and sCD25 concentrations should be measured if four or more of the HLH diagnostic criteria are met.162 Following daily serum ferritin levels is useful because rapidly rising ferritin is a strong indicator of HLH. It may be necessary to repeat the marrow biopsy or biopsy an enlarged liver or lymph nodes, if the first marrow biopsy fails to show hemophagocytosis and clinical suspicion of HLH is high. Other conditions should be evaluated and treated as sepsis, viral infection, autoimmune disease, and malignancy do not exclude a concurrent diagnosis of HLH.
Patients with fever of unknown origin, moderate infections, sepsis, multiorgan dysfunction, hepatitis, anemia and thrombocytopenia, and autoimmune phenomena such as Kawasaki disease, lupus erythematosus, or rheumatoid arthritis may present with features that overlap the diagnostic criteria for HLH. One must consider HLH if no clear diagnosis is established for the above mentioned entities and the patient is deteriorating. Identification of an underlying immune deficiency such as X-linked lymphoproliferative disease (Chap. 84), Griscelli syndrome (Chap. 65), or Chédiak-Higashi syndrome (Chap. 66) should increase the suspicion of HLH. Epstein-Barr virus, cytomegalovirus, and other herpes virus infections are the most frequent viral infections associated with HLH. A wide variety of bacterial fungal and protozoal infections may also lead to HLH.
Treatment cure & Therapy of Hemophagocytic Lymphohistocytosis
Before treatment with immune-modulating therapy fewer than 10 percent of patients with HLH survived.155 After case reports and case series described patients successfully treated with strategies that included aggressive immune suppression, podophyllotoxin derivatives, or a combination of immune suppression with etoposide, a prospective treatment protocol was developed that included induction therapy with dexamethasone and etoposide, followed by continuous treatment with cyclosporine and pulses of dexamethasone and etoposide.156,163–165 Patients with CNS symptoms or cerebrospinal fluid lymphocytosis or pleocytosis also received intrathecal methotrexate. Patients with resistant disease, recurrent disease, or familial HLH had hematopoietic stem cell transplant. The overall estimated 3-year survival on the HLH-94 protocol is 55 percent.165 Some physicians prefer to start treatment with dexamethasone and cyclosporine before adding etoposide. If the patient deteriorates etoposide treatment is necessary.
A second protocol containing minor modifications from the first included starting cyclosporine at the onset of induction therapy, adding glucocorticoids to intrathecal therapy in patients with CNS disease, adding etoposide to conditioning in patients who undergo stem cell transplantation, and considering depletion of T cells in patients who receive stem cells from unrelated donors.166 This protocol should be used for patients who fit the diagnostic criteria for HLH, with the exception of patients with systemic juvenile rheumatoid arthritis or systemic lupus erythematosus with macrophage activation syndrome (see “Macrophage Activation Syndrome” below). Treatment may be modified for patients with HIV-associated HLH and patients with iatrogenic immune suppression. The protocol outlines specific treatment modifications for marrow toxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity. One must be especially careful of cyclosporine levels greater than 200 ng/mL if a patient is hypertensive or has renal or hepatic failure.167 In such patients, seizures and encephalopathy, accompanied by the imaging findings of the posterior reversible encephalopathy syndrome (PRES) can occur. Patients may require multiple transfusions of red cells, platelets, and fresh frozen plasma. Prophylaxis against Pneumocystiscarinii infection with sulfamethoxazole and against fungi with fluconazole is necessary. Newly diagnosed HLH patients should have HLA typing done and a donor search initiated in case allogeneic hematopoietic stem cell transplantation is required for therapy.
Antithymocyte globulin (ATG) has been used as a primary treatment of 38 cases of familial HLH.168 It was intended that all of these patients undergo stem cell transplantation, which ultimately cured 16 of 19 cases. ATG was ineffective for patients who had been previously treated with etoposide, dexamethasone, and cyclosporine and who had relapsed while on therapy.
Stem cell transplantation for Treatment cure & Therapy of Hemophagocytic Lymphohistocytosis
Stem cell transplantation is needed for all patients with familial HLH or with gene defects, CNS disease, or who relapse either on or off HLH therapy. Survival ranges from 45 to 60 percent in several series, which included use of matched-related and matched-unrelated donor stem cell transplantation with conventional or reduced-intensity conditioning