Page 1318 - Hematology_ Basic Principles and Practice ( PDFDrive )

1164 Part VII Hematologic Malignancies

hinder tumor formation in these patients. As mentioned earlier, polyneuropathy), pulmonary infiltrates, paranasal sinus abnormalities,
lymphomas may also be accompanied by reactive/paracrine HE. and extravascular eosinophil infiltrates on tissue biopsies. When four
A number of different immunologic and other reactive conditions out of these six criteria apply, the diagnosis CSS can be established.
can cause reactive HE (HE R ). These include infectious diseases (e.g., Based on the considerable clinical overlap with classical HES variants,
helminth infections, HIV, and certain fungal infections), allergic CSS is also regarded as a special HES variant, defined by an ANCA+
disorders (e.g., asthma, food allergy, atopic dermatitis, and drug vasculitis. The prognosis of patients with CSS depends on a number
reactions), chronic inflammatory reactions, and autoimmune pro- of clinical variables, including lung involvement, duration of disease,
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cesses (see Table 71.2). Treatment of the underlying disease is and response to therapy. Treatment of patients with CSS is based on
usually followed by resolution of HE R , thereby confirming the etiol- the individual situation in each case and the presence or absence of
ogy of HE. In most reactive conditions, HE is triggered by cytokines prognostic factors. A combination of high-dose corticosteroids and
derived from activated immune cells, such as T cells or mast cells. In cyclophosphamide remains a standard for treatment. More recently,
some of these patients, an underlying disease is not detectable, but antibody-based drugs, such as rituximab or mepolizumab, have been
clonal T lymphocytes and/or lymphocytes with an aberrant surface proposed as therapeutic alternatives and should be considered in cases
immunophenotype are present. In such cases, HE-related organ resistant to cyclophosphamide.
damage may also be seen, which leads to the diagnosis of the lym- EMS is a flu-like condition defined by recurrent episodes of
phoid variant of HES (HES L ). 15 myalgia and persistent eosinophilia. In many patients, neurological
symptoms and skin abnormalities are found. In addition, patients
Specific Syndromes and Conditions Associated may suffer from fever, weight loss, edema, and severe fatigue. The
etiology of EMS remains uncertain. A clue to pathogenesis was the
With HE detection or a relationship between EMS and exposure to contami-
nated L-tryptophan or rapeseed oil (toxic oil syndrome). EMS is an
Several specific conditions and syndromes defined by HE and organ incurable disease, but fatal cases are rare. As in Gleich syndrome and
damage may fulfill the criteria of a HES, but based on traditional CSS, the clinical overlap with HES is obvious, and many experts
views and their unique etiologies, these syndromes are still regarded believe that EMS could be regarded as a special subvariant of HES.
as distinct entities that should be discriminated from the classical Eosinophilic fasciitis (EF) is a scleroderma-like syndrome with
HES variants. In the future, however, most or all of these syndromes HE, polyclonal hypergammaglobulinemia, and signs of systemic
may be regarded as a special form of HES. These syndromes include, inflammation. The etiology of EF remains unknown, but most
among others, episodic angioedema and eosinophilia (Gleich syn- authors regard EF as an immunologic hyperreactivity disorder mani-
drome), CSS, eosinophilia myalgia syndrome (EMS), OS, and festing in the skin. Painful swelling of the skin with progressive
hyper-IgE syndrome (see Table 71.4A). induration and thickening of the skin and soft tissues of the limbs
Gleich syndrome is characterized by recurrent angioedema and trunk are typical clinical findings. Corticosteroids are usually
associated with eosinophilia (HE), elevated serum cytokine (IL-5) prescribed and have been shown to be efficacious in EF patients. In
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levels, and increased (polyclonal) IgM production. The episodes of a subset of patients, spontaneous improvement is found. Again, based
angioedema and eosinophilia typically occur at monthly intervals and on clinical findings and HE, it is difficult to differentiate between EF
often resolve spontaneously without therapy. Patients with Gleich and skin involvement in HES R .
syndrome may suffer from fever and increasing body weight. The OS is a rare, autosomal recessive form of severe combined immu-
clinical course is usually benign without involvement of internal nodeficiency (SCID) associated with leukocytosis, HE, elevated IgE
organs, thereby contrasting the typical HES variants. In a subset levels, and a high mortality rate. Recognition in early childhood is
of patients, the symptoms and HE persist. These patients usually required in order to initiate life-saving therapy. OS is caused by
respond to low-dose corticosteroids. So far, little is known about the hypomorphic missense-mutations in the recombination-activating
pathogenesis of Gleich syndrome. Several lines of evidence suggest genes RAG1 and RAG2 (see Table 71.4A). Unlike patients with
that multiple cell types are involved, including neutrophils, mast typical SCID, patients with OS have well-populated lymphatic
cells, eosinophils, and T lymphocytes. Whereas most of these cells organs and usually suffer from diarrhea, hepatosplenomegaly, lymph-
are considered to be cytokine-mobilized cells, T cells are often found adenopathy, and weight loss. In addition, severe erythroderma,
to be clonal in these patients. In fact, in many patients with Gleich increased IgE levels, and eosinophilia are found in most cases. HE
syndrome, T-cell phenotyping reveals an abnormal phenotype of and inflammation observed in these patients may result from the
+
CD4 lymphocytes, with decreased or absent CD3 expression (see activity of clonally expanded T cells, which are predominantly of the
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Table 71.4A). In addition, in several of these patients a clonal Th2 type. Overall, the disease presents very similar to a graft-versus-
T-cell receptor rearrangement has been found. Therefore, Gleich host reaction, which is due to patients producing T cells with limited
syndrome has also been considered as a special (cycling) subvariant recombination ability (mutant RAG genes) and a specific affinity for
of HES L . self-antigens, making them autoreactive T lymphocytes. Other
CSS, also known as eosinophilic granulomatosis with polyangiitis SCID-related mutations may also lead to an OS-like disease, includ-
(EGPA), is defined by a disseminated necrotizing vasculitis that is ing certain mutations in the IL-7 receptor (IL-7R) gene. The treatment
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accompanied by asthma and (tissue) eosinophilia (HE). CSS is a of choice in OS is allogeneic HSCT. For patients who cannot be
small-vessel vasculitis characterized by the formation of extravascu- transplanted or need a bridging therapy prior to allogeneic HSCT,
lar granulomas and the production of antineutrophil cytoplasmic cyclosporine A (CSA) may be considered.
antibodies (ANCA). Both, tissue HE and the ANCAs produced in Hyper-IgE syndromes (HIES) are a group of rare hereditary
these cases are considered to play an active role in the pathogenesis immunodeficiency syndromes characterized by elevated IgE levels,
of CSS. However, the exact etiology of CSS remains unknown. More severe recurrent infections, and HE. In many cases, skin eczema and
recent data suggest that CSS/EGPA may be a Th2-mediated disease. facial anomalies are found. So far, little is known about the patho-
Clinically, CSS develops in three distinct phases: the initial (early) genesis of the HIES. The disease can manifest as an autosomal domi-
phase is characterized by asthma and rhinosinusitis, the eosinophilic nant or autosomal recessive variant. Several different genes may be
phase is defined by HE R and HE-related organ involvement, and affected. In the autosomal dominant variant, STAT3 mutations are
the late (“vasculitic”) phase is defined by clinical manifestations most commonly described. Since STAT3 acts as a key transcription
originating from the small-vessel vasculitis (see Table 71.4A). CSS factor downstream of multiple cytokine receptors regulating diverse
is a systemic disease that may affect a number of different organ immunologic responses, impaired STAT3 function is likely to cause
systems, including the lungs, skin, kidneys, nerves, and heart. Criteria immunodeficiency. In the autosomal recessive HIES variants, muta-
for CSS have been proposed by various expert groups. According to tions in DOCK8 and, less commonly, in the phosphoglucomutase 3
the American College of Rheumatology, the following criteria define (PGM3) gene, have been reported (see Table 71.4A). The natural
CSS: asthma, eosinophilia (>10%), neuropathy (mononeuropathy or course of HIES patients is variable, but overall the long-term