Frank T. Saulsbury

Clinical update: Henoch-Schönlein purpura

Henoch-Schönlein purpura (HSP) is an acute smallvessel leucocytoclastic vasculitis. HSP is the most common vasculitis in children, with an incidence of about 10 cases per 100 000 a year. In most series, boys are aff ected more often than girls. Although it can occur at any age, HSP is overwhelmingly a disease of childhood. The mean age of patients is 6 years; 75% of patients are under 8 years of age and 90% are less than 10 years of age. The clinical features of HSP may be atypical at the extremes of age. The severity tends to be milder in infants under 2 years of age and worse in adults. Most patients present from autumn to spring, and HSP often follows a respiratory infection. A wide variety of pathogens, drugs, and other environmental exposures have been associated with HSP. Of all pathogens linked to HSP, group A β-haemolytic streptococcus has been the most studied. Positive throat cultures have been reported in 10–30% of patients, and titres to anti-streptolysin O are raised in 20–50% of patients. Thus a substantial minority of patients have concomitant or recent streptococcal infection, but most cases have no direct link to streptococcal infection. Although the cause is unknown, it is clear that IgA has a pivotal role in the pathogenesis of HSP. There are two subclasses of IgA, IgA1 and IgA2, but only IgA1 is involved in HSP. The clinical manifestations of HSP are a consequence of widespread vasculitis resulting from IgA1 deposition in vessel walls and the renal mesangium. The reasons for the exclusive involvement of IgA1 in HSP remain unclear. However, IgA1, unlike IgA2, contains a hinge region with multiple O–linked glycosylation sites. Two studies showed diminished glycosylation of the hinge region of IgA1 in patients with HSP. IgA1 molecules with diminished hinge-region glycosylation are prone to aggregate into macromolecular complexes. These complexes activate the alternative pathway of complement, and then deposit in the renal mesangium. The clinical features of HSP have been amply documented in reports spanning 200 years. The major clinical features of HSP are shown in the table and other infrequent complications are shown in the panel. Cutaneous purpura is the essential element in the diagnosis of HSP. The characteristic rash consists of palpable purpuric lesions 2–10 mm in diameter. Pinpoint petechiae and coalescent echymoses may be scattered among these lesions. The purpura is concentrated on the buttocks and lower extremities, but it is not restricted to those areas. Arthritis is the second most common feature of HSP, occurring in roughly 75% of patients and most often aff ecting the knees and ankles. The joints of the upper extremities are involved in a few patients. HSP arthritis is typically painful and often inhibits walking. It is important to remember that arthritis may precede the onset of the purpura by up to a week in 15–25% of patients. Gastrointestinal involvement occurs in 50–75% of patients. Colicky abdominal pain, vomiting, and gastro intestinal bleeding are the dominant features. Gastrointestinal bleeding is usually occult, but 30% of patients have grossly bloody or melanotic stools. Intussusception has been reported in 1–5% of patients. The intussusceptions associated with HSP are ileoileal in most patients. Thus abdominal ultrasonography or computed tomography are the preferred diagnostic modalities if intus susception is suspected in a patient with HSP. Gastrointestinal signs and symptoms may precede the onset of purpura by up to 2 weeks in 10–20% of patients. Gastrointestinal symptoms before the onset of the rash may simulate several infl ammatory or surgical diseases of the bowel. The correct diagnosis becomes evident with the appear ance of the typical rash. Renal involvement occurs in 40–50% of patients. Microscopic haematuria is the most common fi nding,

Successful Treatment of Aspergillus Brain Abscess with Itraconazole and Interferon-γ in a Patient with Chronic Granulomatous Disease

This report describes the successful treatment of Aspergillus brain abscess in a boy with chronic granulomatous disease.

Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) in a child with normal serum IgD, but increased serum IgA concentration

This report describes a boy with hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). The serum IgD level was normal, but the serum IgA concentration was markedly elevated. In addition, he had a history of orchitis on two occasions, a previously unreported manifestation of HIDS. This report expands the clinical and laboratory features associated with HIDS and serves to emphasize that a normal serum IgD level does not exclude the diagnosis of HIDS.

Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with αβ-T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis proteins have been implicated, including caspase-10 (ALPS II). We investigated the role of variants of caspase-10 in ALPS. Of 32 unrelated probands with ALPS who did not have Fas defects, two were heterozygous for the caspase-10 missense mutation I406L. Like the previously reported ALPS II-associated mutation L285F, I406L impaired apoptosis when transfected alone and dominantly inhibited apoptosis mediated by wild type caspase-10 in a co-transfection assay. Other variants in caspase-10, V410I and Y446C, were found in 3.4 and 1.6% of chromosomes in Caucasians, and in 0.5 and <0.5% of African Americans, respectively. In contrast to L285F and I406L, these variants had no dominant negative effect in co-transfection assays into the H9 lymphocytic cell line. We found healthy individuals homozygous for V410I, challenging the earlier suggestion that homozygosity for V410I alone causes ALPS. Moreover, an association analysis suggested protection from severe disease by caspase-10 V410I in 63 families with ALPS Ia due to dominant Fas mutations (P<0.05). Thus, different genetic variations in caspase-10 can produce contrasting phenotypic effects.

Comparison of High-Dose and Low-Dose Aspirin Plus Intravenous Immunoglobulin in the Treatment of Kawasaki Syndrome

The efficacy of intravenous immunoglobulin (IVIG) in the treatment of Kawasaki syndrome (KS) has been unequivocally established, but questions remain concerning the proper dose of adjunctive aspirin therapy in the treatment of KS. The medical records of 72 children with KS were reviewed. All patients were treated with IVIG; 21 received 400 mg/kg/dose on 4 consecutive days and 51 received 2 g/kg as a single infusion. Seventy patients also received aspirin. Twenty-four of the 70 patients were started on high-dose aspirin (80-100 mg/kg/day) at the time of diagnosis. High-dose aspirin was given for a mean (± SE) duration of 6.1 ± 0.9 days, then switched to low-dose aspirin (3-5 mg/kg/day). Forty-six of the 70 patients were started on low-dose aspirin at the time of diagnosis and remained on low-dose aspirin for the duration of treatment. Coronary artery abnormalities were present at the time of diagnosis in 12 of 72 patients (17%), including 6 of 6 of patients (100%) with atypical KS and 6 of 66 patients (9%) with typical KS. None of the remaining 60 patients developed coronary artery abnormalities after treatment with IVIG and aspirin. The mean duration of fever after initiation of therapy was 44 ± 6 hours in patients treated with IVIG 400 mg/kg/dose on 4 consecutive days and 35 ± 5 hours in patients treated with 2 g/kg as a single infusion (p=0.3). The mean duration of fever after the initiation of therapy was 47 ± 8 hours in patients treated with high-dose aspirin compared to 34 ± 5 hours in patients treated with low-dose aspirin (p=0.13). These preliminary results indicate there is no benefit to high-dose aspirin compared to low-dose aspirin in the treatment of children with KS.

Resolution of Organ-Specific Complications of Human Immunodeficiency Virus Infection in Children with Use of Highly Active Antiretroviral Therapy

Opportunistic infections are a major source of morbidity and mortality in children and adults infected with human immunodeficiency virus (HIV). In addition, organ-specific complications of HIV infection, such as cardiomyopathy, nephropathy, encephalopathy, and others, contribute substantially to the morbidity and mortality associated with HIV infection. Highly active antiretroviral therapy (HAART) has produced a dramatic decline in the incidence of opportunistic infections among patients with HIV infection. Nevertheless, there is very little information concerning the value of HAART for organ-specific complications of HIV infection. In this report, we describe 3 children with HIV infection in whom the dominant clinical manifestations were cardiomyopathy, red cell aplasia, and nephropathy. HAART produced a decrease in the HIV ribonucleic acid level, an increase in the CD4 cell count, and resolution of the organ-specific complications in all patients. These cases add to our knowledge concerning the benefits of HAART for children with HIV infection.

Incomplete and Atypical Kawasaki Disease in a Young Infant: Severe, Recalcitrant Disease Responsive to Infliximab

This report describes a 7-week-old infant with incomplete and atypical Kawasaki disease, an acute vasculitis that predominantly affects infants and children. The patient was refractory to 2 doses of intravenous immunoglobulin and to high-dose intravenous methylprednisolone. He became afebrile only after 2 doses of infliximab. His prolonged, recalcitrant course was complicated by the development of peripheral gangrene and giant coronary artery aneurysms. Infants with incomplete and atypical Kawasaki disease are prone to intravenous immunoglobulin treatment failure and are at risk for the development of coronary artery aneurysms. In such patients, we suggest that consideration be given to early aggressive therapy with corticosteroids or infliximab added to intravenous immunoglobulin.

Incomplete Penetrance of the NOD2 E383K Substitution Among Members of a Pediatric Granulomatous Arthritis Pedigree

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patients family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patients mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 Blau mutations.

HENOCH-SCHONLEIN PURPURA IN A CHILD WITH HYPERIMMUNOGLOBULINEMIA D AND PERIODIC FEVER SYNDROME

Abstract:u2002 This report describes a 3‐year‐old girl with a long history of periodic fever who presented with Henoch‐Schönlein purpura. She was diagnosed with hyperimmunoglobulinemia D and periodic fever syndrome by means of mutation analysis of the mevalonate kinase gene. The serum IgA concentration was markedly elevated, but the serum IgD concentration was normal. This report emphasizes that Henoch‐Schönlein purpura may be an important clinical feature of hyperimmunoglobulinemia D and periodic fever syndrome. In addition, this syndrome should be considered in patients with Henoch‐Schönlein purpura in whom there is a history of recurrent fevers, even when the serum IgD concentration is normal.

Lyme Arthritis in 20 Children Residing in a Non-Endemic Area

In non-endemic areas of the country, Lyme disease may not be considered in children who present with arthritis. This report details the clinical features of Lyme arthritis in 20 children residing in central Virginia. All patients presented with transient, often recurrent oligoarthritis of large joints, particularly the knee. Most patients were referred with a presumptive diagnosis of juvenile rheumatoid arthritis (JRA). This report reiterates the clinical presentation of Lyme arthritis in children and reminds physicians to consider the diagnosis of Lyme arthritis in children who present with acute arthritis even if they reside in a non-endemic area of the country. In addition, it differentiates the clinical presentation of Lyme arthritis from JRA.