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1114 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1115

Perforin Expression TABLE 71–4. Clinical Criteria for Diagnosis of
Perforin was identified as a candidate HLH gene by gene mapping and Hemophagocytic Lymphohistiocytosis
was confirmed by poor expression of perforin in NK cells and cytotoxic
T lymphocytes of HLH patients. 223,224 Some HLH characteristics were Hemophagocytic lymphohistiocytosis (HLH) diagnosis is estab-
reproducible in PRF1 knockout mice. Perforin is secreted from NK lished with at least five of the following:
225
cells and cytotoxic T cells upon activation by target cells and introduces • Fever
pores in the target cell membrane, allowing granzyme to enter and trig- • Splenomegaly
ger apoptosis. 226 • Cytopenias in at least two cell lines:

Other Defects Causing Hemophagocytic Lymphohistiocytosis • Hemoglobin <90 g/L
9
Mutations in other genes encoding proteins involved in NK and cyto- Platelets <100 × 10 /L
9
toxic T-cell–mediated killing of target cells also have been discovered in Neutrophils <1 × 10 /L
patients with HLH, including UNC13D (encodes MUNC13-4), STX11 • Hypertriglyceridemia and/or hypofibrinogenemia:
(encodes syntaxin 11), and UNC18B (encodes STXBP2). Mutations Fasting triglycerides >3 mmol/L (>265 mg/dL)
227
in the gene that encodes RAB27a (protein that controls secretion
of lytic granules) have also been identified in patients with Griscelli Fibrinogen <1.5 g/L
syndrome. 228 • Hemophagocytosis in marrow or spleen or lymph nodes
• Low or absent activity of natural killer cells (specialized laboratory
Immune Deficiencies Associated with Hemophagocytic test)
Lymphohistiocytosis • Ferritin >500 mcg/L (>2000 mcg/L may be more specific)
Patients with other immune deficiencies associated with lysosomal • Soluble cD25 (soluble interleukin-2 receptor) >2400 U/mL
trafficking defects (e.g., Chédiak-Higashi syndrome, Hermansky- or
Pudlak syndrome type II) also have a high frequency of HLH. HLH, • HLH-associated gene mutations
229
often associated with infection by the Epstein-Barr virus, is the most
common fatal complication of X-linked lymphoproliferative disease
(XLP1/SH2D1A and XLP2/XIAP). 230
cytometry degranulation assays that measure membrane CD107a are
also effective for identifying patients with lymphocytes with impaired
CLINICAL FEATURES cytotoxic function. 236
Hemophagocytosis is sometimes misunderstood as pathogno-
Initial signs and symptoms of HLH mimic more common problems monic and necessary for the diagnosis of HLH, but biopsies fail to
(e.g., fever of unknown origin or sepsis). Confounding diagnoses demonstrate hemophagocytosis in approximately one-third of patients
231
such as infection, autoimmune disease, hepatitis, multisystem organ (Fig. 71-4). HLH changes over time such that the cytokine stimula-
237
failure, encephalitis, and malignancy do not exclude a diagnosis of HLH. tion resulting in hemophagocytosis may be modest early in the disease,
Important clues include an acutely ill patient with unexplained fever, or the marrow may progress to become aplastic with few macrophages
rash, or neurologic symptoms. A medical history of immune deficiency available to engage in hemophagocytosis. Repeat marrow aspirates
should bring HLH to mind. Family history of consanguinity, recurrent and biopsies, as well as lymph node or liver biopsies, may be helpful.
spontaneous abortions, or HLH in siblings (or symptoms suggesting Finding hemophagocytosis is highly suggestive of HLH, but is neither
undiagnosed HLH) may be suggestive of a risk for HLH. necessary nor sufficient to make the diagnosis. Cerebrospinal fluid
Prominent early clinical signs in one study included fever (91 per- should be tested in patients with signs of CNS abnormalities; pleocyto-
cent), hepatomegaly (90 percent), splenomegaly (84 percent), neuro- sis, hyperproteinemia and hemophagocytosis support HLH with CNS
logic signs (47 percent), rash (43 percent), and lymphadenopathy (42 involvement.
percent). Another study found 75 percent of patients with HLH to
232
have CNS symptoms that may mimic encephalitis. Patients with HLH
233
develop liver failure with markedly elevated conjugated bilirubin, pan-
cytopenia, coagulopathy, renal failure heralded by hyponatremia, and
pulmonary failure similar to acute respiratory distress syndrome with
interstitial infiltrates on chest radiography. 231

Diagnostic Criteria
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 Soci-
ety treatment protocol HLH-2004, which includes diagnostic guidelines
(Table 71–4). The HLH criteria are derived from retrospective anal-
234
ysis of patients treated on HLH-94 and describe patients with extreme
pathologic inflammation and associated defects in cytotoxic immune
function.
Biallelic mutations in HLH-associated (or monoallelic in case of
X-linked genes) are diagnostic for HLH, but generally not helpful for Figure 71–4. Hemophagocytosis by macrophages. Marrow aspirate
acute management although genetic results are becoming available treated with Wright-Giemsa stain illustrating prominent hemophagocy-
more quickly. More rapid flow cytometry studies can identify absence tosis of multiple cell types by macrophages (arrows) in the marrow of a
of protein expression of PRF1, SAP (XLP1), or XIAP (XLP2). Flow patient with hemophagocytic lymphohistiocytosis.
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