Page 851 - Hematology_ Basic Principles and Practice ( PDFDrive )

734 Part VI Non-Malignant Leukocytes

hepatitis with periportal lymphocytic infiltration in the majority of mia, elevated soluble CD163, elevated soluble CD25 (sCD25; also
patients. Neonates with HLH may present with hydrops fetalis and called “soluble IL-2 receptor”), and hyperferritinemia. Specialized
liver failure. Most patients have evidence of disseminated intravascu- immunologic testing may reveal low or absent NK cell or cytotoxic T
lar coagulation (DIC) and are at high risk for acute bleeding. Fur- lymphocyte function (although this is not always seen), low levels of
thermore, patients with HLH caused by degranulation defects may perforin or other disease-associated proteins (e.g., SAP or XIAP), and
have intrinsic platelet dysfunction. decreased degranulation (observed with mutations affecting granule
trafficking). Additionally, pathologic examination of BM biopsy, liver
biopsy, CSF, spleen or lymph node, or even occasionally peripheral
Bone Marrow Failure blood may reveal hemophagocytosis and infiltration with CD163
+
macrophages and activated T cells (Fig. 52.9). Examination of CSF
Anemia and thrombocytopenia occur in more than 80% of patients reveals pleocytosis, elevated protein, and elevated neopterin levels
at the time of presentation with HLH. The cellularity of BM aspirates with CNS involvement. Brain MRI often reveals polymorphic white
varies from normocellular to hypocellular or hypercellular. The preva- or grey matter abnormalities in such cases.
lence of hemophagocytosis in association with HLH diagnosis ranges Elevations in sCD25 are a particularly useful and notable labora-
from 25% to 100%. Although hemophagocytosis in BM is associated tory feature of HLH. In the authors’ experience, this marker is
with HLH, the morphologic phenomenon may also be induced dynamically associated with “active” HLH, and patients with active
by more common events, including blood transfusions, infection, HLH rarely, if ever, have normal levels of sCD25. Of note, the
autoimmune disease, and other forms of BM failure or causes of red interpretation of soluble IL-2 receptor levels must be undertaken with
blood cell destruction. Despite the nomenclature of HLH, diagnosis care because normal levels change with age and the method of analy-
of HLH should never be made or excluded solely on the presence or sis. Despite a few small reports of increased soluble IL-2 receptor
+
absence of hemophagocytosis. Infiltration of BM or liver by CD163 levels in sepsis, significant elevations of this marker are rarely observed
macrophages, along with global clinical evaluation, may distinguish outside the context of HLH. However, the clinical utility of sCD25
HLH from other causes of hemophagocytosis. is often compromised by delays because most institutions must send
patient samples to referral laboratories. Because of its ready avail-
ability in most hospitals, the serum ferritin level can serve as an
Skin Manifestations important adjunct to the decision-making process. The HLH diag-
nostic guidelines define a cutoff at greater than 500 µg/L, which may
Patients may have a variety of skin manifestations, including general- be observed in sepsis or other hyperinflammatory conditions. Ferritin
ized maculopapular erythematous rashes, generalized erythroderma, levels in HLH are usually dramatically higher, with some series
edema, panniculitis, inflamed papular lesions, petechiae, and purpura. finding mean levels near 45,000 µg/L. A recent review of elevated
The incidence of skin manifestations ranges from 6% to 65% in ferritin values at a large pediatric academic tertiary care hospital
published series with highly pleomorphic presentations. Some demonstrated that a ferritin level greater than 10,000 was 90% sensi-
patients may present with features suggestive of Kawasaki disease, tive and 96% specific for HLH.
including erythematous rashes, conjunctivitis, red lips, and enlarged
cervical lymph nodes. Rashes may correlate with lymphocyte infiltra-
tion on skin biopsy, and hemophagocytosis may also be found. Differential Diagnosis of Hemophagocytic
Lymphohistiocytosis

Pulmonary Dysfunction Because HLH presents as an inflammatory syndrome, the differential
diagnosis of this disorder is a broad one. Infection must be considered
Patients may develop pulmonary dysfunction that leads to urgent as either a mimic of HLH or as an underlying trigger of the disorder.
admission to the intensive care unit. In a review of the radiographic The list of infections reported as associated with HLH is extensive.
abnormalities in 25 patients, 17 had acute respiratory failure with If the patient presents with acute multiorgan failure, then sepsis is
alveolar or interstitial opacities, with fatal outcomes in 88% of generally considered first before a diagnosis of HLH is considered.
those cases. Viral infections, including EBV, CMV, dengue, and severe influenza,
should always be considered and treated. Protozoan infections,
including malaria, toxoplasmosis, and leishmaniasis, may be a con-
Brain, Ophthalmic, and Neuromuscular Symptoms sideration in endemic areas. Visceral leishmaniasis, in particular, may
be clinically indistinguishable from primary HLH. In addition to
More than one-third of patients present with neurologic symptoms, infectious disorders, rheumatologic disorders, including systemic
including seizures, meningismus, decreased level of consciousness, onset juvenile idiopathic arthritis (soJIA) and Kawasaki syndrome,
cranial nerve palsy, psychomotor retardation, ataxia, irritability, or should be considered. Finally, as either a mimic or trigger, malignancy
hypotonia. The cerebrospinal fluid (CSF) is abnormal in more than should be considered, particularly lymphoma and leukemia.
50% of HLH patients with findings of pleocytosis, elevated protein,
or hemophagocytosis. MRI findings are highly variable and include
discrete lesions, leptomeningeal enhancement, or global edema, and Diagnosis
images correlate with neurologic symptoms. Retinal hemorrhages,
swelling of the optic nerve, and infiltration of the choroid have been Because of the severe nature of this disorder and the existence of
reported in infants with HLH. Diffuse peripheral neuropathy with disease-altering therapies, it is crucial to identify patients early in their
pain and weakness secondary to myelin destruction by macrophages course. The Histiocyte Society established diagnostic criteria for the
may also occur. HLH-2004 trial, which is widely used for patients not treated in this
trial, using both clinical and laboratory findings (see Table 52.4).
Laboratory verification of a known genetic defect confirms the
Laboratory Manifestations diagnosis independent of the presence or absence of any clinical signs
or symptoms. However, genetic diagnosis is not usually available in
Laboratory manifestations are a critical component of diagnosing a timely fashion for patients with acute clinical presentations. In the
HLH. Biochemical abnormalities noted on clinical laboratory assess- absence of a genetic diagnosis, five of the eight clinical criteria must
ment include anemia, thrombocytopenia, neutropenia, elevated liver be met to make a diagnosis. It is important to note that NK cell
transaminases, hyperbilirubinemia, hypofibrinogenemia, coagulation dysfunction is only present in about 50% of patients with HLH.
abnormalities, hypoalbuminemia, hyponatremia, hypertriglyceride- Additionally, hemophagocytosis may not be present early in the HLH