Page 2489 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 152 Hematologic Manifestations of Childhood Illness 2221

high-dose corticosteroid therapy followed by cyclosporin A (CsA) if 700,000/µL. Thrombocytosis may serve as a marker of possible
there is not a rapid response. Intravenous methylprednisolone with atypical Kawasaki disease in infants younger than 1 year of age. In a
doses from 2 to 30 mg/kg/day has been the most common cortico- study of more than 25,000 infants with unexplained fever, 8.8% with
steroid reported in the literature and is usually effective in controlling a platelet count greater than 800,000/µL were found to have Kawa-
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hyperinflammation. The corticosteroid of choice used in the treat- saki disease, as opposed to 0.4% of those with a platelet count less
125
ment of HLH is dexamethasone, but its use has not been reported than 800,000/µL. Thrombocytosis is preceded by elevated throm-
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in MAS. CsA has been very effective in inducing remission either bopoietin levels. However, 2% of patients may have thrombocyto-
when used as initial treatment or in cases of corticosteroid failure. 101,103 penia caused by a consumptive coagulopathy. Platelets demonstrate
In addition to immunosuppression, there should be withdrawal of hyperaggregation on exposure to adenosine diphosphate, epineph-
any suspected triggering medications and treatment of infection. rine, and collagen in vitro. These abnormalities may persist for as
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Intravenous immunoglobulin (IVIg) therapy has usually been inef- long as 9 months after diagnosis. During the first month, levels of
fective, although it has been reported to induce a full recovery in one factor VIII, fibrinogen, thromboxane B 2, and thromboglobulin are
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case of a child who failed high-dose corticosteroids. For unrespon- increased. AT III and fibrinolysis activity are decreased. The PT,
sive patients, treatment with etoposide or other HLH salvage therapy aPTT, and thrombin time usually are normal. 128
may be necessary. Etanercept and infliximab have also been reported Prevention and treatment of existing coronary aneurysms consti-
to induce clinical responses in patients with MAS. 114–116 These drugs tute the primary therapeutic goals. Aspirin suppresses platelet
are recombinant soluble TNF-α receptor fusion proteins that bind aggregation but does not affect aneurysm formation. Combining
to TNF-α, blocking its effect. Although use of these agents to reduce aspirin with high-dose IVIg infusions reduces aneurysm formation,
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the elevated levels of TNF-α found in this disorder is attractive, these decreases fever, and normalizes laboratory signs of inflammation.
agents should be used with caution because there are case reports of The use of corticosteroids is controversial, with conflicting data
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MAS developing after the initiation of etanercept. Anakinra, a regarding increased aneurysm formation after steroid use. 130–132
recombinant IL-1 receptor antagonist, has shown promising results However, in a randomized, double-blind, placebo-controlled trial, a
in treatment of sJIA as well as MAS. 117,118 single pulsed dose of intravenous methylprednisolone, in addition to
conventional therapy, did not improve coronary artery outcomes. 133,134
In subgroup analysis of children with persistent fever, coronary out-
Kawasaki Syndrome comes were better in the corticosteroid group. If children at highest
risk of primary treatment failure could be identified initially, cortico-
Kawasaki syndrome is an acute multisystem disorder characterized by steroid use might be of benefit in this group. Infliximab has been
an abrupt onset of fever unresponsive to antibiotics; bilateral con- used in the treatment of IVIg-resistant patients, with limited
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junctival injection; reddening of the lips, tongue, or oral mucosa; success. Guidelines for the diagnosis, treatment, and long-term
reddening, induration, or peeling of the skin on the hands or feet; management of patients with Kawasaki syndrome have been
polymorphous truncal rash; and cervical lymphadenopathy. This published. 133,136,137
disorder occurs most commonly in children younger than 2 years of
age and has many features of a severe vasculitis. The most serious
complication is development of coronary artery aneurysms, which Henoch-Schönlein Purpura
occurs in 20% of children and is responsible for the 3% mortality
rate; death often is caused by coronary artery thrombosis or rupture. Henoch-Schönlein purpura (HSP) (anaphylactoid purpura) is a sys-
The etiology of Kawasaki disease is unknown. The immunologic and temic vasculitis characterized by unique purpuric skin lesions, tran-
clinical characteristics of this disorder are similar to those of diseases sient arthralgias or arthritis (especially affecting the knees and ankles),
associated with superantigen production, of which toxic shock syn- colicky abdominal pain, and nephritis. Recognition of HSP is impor-
drome is a classic example. 119 tant, not so much for its hematologic abnormalities (which are rare)
Children with Kawasaki syndrome may have a mild, normochro- as for the unusual nonthrombocytopenic purpuric lesions, which are
mic, normocytic anemia with reticulocytopenia. Rarely, a severe frequently confused with the hemorrhagic rash of ITP. This vasculitis
Coombs-positive, antibody-mediated hemolytic anemia has been occurs most commonly in children 3 to 7 years old, often 1 to 3
reported after administration of IVIg. Leukocytosis is almost univer- weeks after an upper respiratory tract illness. The presenting sign in
sal, with mean neutrophil counts of 21,000/µL. Ninety-five percent 50% of children is a characteristic rash, which may begin as urticaria.
of patients have neutrophilia, with a left shift persisting up to 3 weeks. As these eruptions fade, they are replaced by brownish-red maculo-
The finding of vacuoles and toxic granulation in neutrophils is a papular lesions and petechiae. The petechiae coalesce, forming areas
helpful adjunct in the diagnosis of Kawasaki disease. Activated neu- of raised or “palpable” purpura on the buttocks, legs, and extensor
trophils and monocytes may play a role in aneurysm development surfaces of the arms, with a symmetric distribution. The rash may
through the production of elastase. Granulocyte colony-stimulating fade but can recur for months, especially with increased activity.
factor levels have been correlated with coronary artery dilation during Children younger than 3 years of age often have painful soft tissue
the acute phase of Kawasaki syndrome. 120 swellings of the scalp and face (especially periorbital areas) and on
Studies of cellular immunity show normal total T-cell numbers the dorsa of the hands and feet. Infantile acute hemorrhagic edema
but decreased suppressor T cells, causing relatively elevated T helper– is an acute vasculitis affecting infants and children younger than 2
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cell levels during the first 4 weeks of disease. The change of T-cell years of age, which may be a benign form of HSP.
subsets plus B-lymphocyte stimulation may contribute to the exag- Sixty-seven percent of patients experience colicky abdominal
gerated production of all major Ig classes during the first 8 weeks of pain, often associated with vomiting, hematemesis, or melena from
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the disease. An unusual infiltration of IgA-producing plasma cells submucosal hemorrhage and edema of the small bowel wall. With
within vascular tissue in Kawasaki syndrome, with an oligoclonal IgA severe edema, the bowel wall may become a leading point for
123
response, suggests that the immune stimulation is antigen driven. intussusceptions. 138
Circulating immune complexes and high C3 (but not C4) levels are Renal involvement occurs in 30% to 50% of patients, especially
found during weeks 1 and 3. During the acute phase, increased levels boys and older children, and may present after initial systemic
of the cytokines IL-1, IL-6, IL-8, IFN-γ, and TNF are noted in the symptoms. Hematuria, either microscopic or gross, may occur with
circulation, as well as of IL-1, IL-2, IFN-γ, and TNF in blood vessels proteinuria during the first 3 weeks of the illness but rarely after 6
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and skin biopsies. Declining serum IL-6 levels appear to correlate months. With progressive involvement, hypertension, impaired renal
with clinical response after treatment with IVIg. 124 function, and renal failure can occur in up to 15% of children, with
Impressive thrombocytosis occurs in 85% of patients by the an associated mortality rate of 3%. In occasional patients, an acute
second week, peaking during the third. Platelet counts of up to scrotum that mimics testicular torsion may develop; however, surgical
2 million/µL are not uncommon, and the mean platelet count is exploration may not be necessary if appropriate clinical and