Helicobacter cinaedi bacteremia presenting as macules in an afebrile patient with X-linked agammaglobulinemia.

We describe a 54-year-old man with X-linked agammaglobulinemia (XLA) and Helicobacter cinaedi bacteremia, who presented with tender, hyper-pigmented skin macules without increased local warmth or fever. We propose that this presentation may be a characteristic early sign of bacteremia caused by H. cinaedi and related organisms in otherwise healthy immunocompromised patients. This case demonstrates the importance of a high index of suspicion for H. cinaedi bacteremia in immunocompromised patients with unexplained skin lesions.

Enteroviral infections in primary immunodeficiency (PID): a survey of morbidity and mortality.

We have explored the natural history of enteroviral infection in patients with primary antibody deficiency by surveying both published and unpublished case reports before the new anti-enteroviral drug, pleconaril, was available. Many different enteroviruses were involved, Echovirus 11 being the most common. The central nervous system was nearly always involved, with evidence of systemic involvement of muscle and/or liver and/or joints in about 40% of patients. Neurological symptoms and signs varied with minor or no changes in the cerebro-spinal fluid. There was high morbidity and mortality; a third of polio cases (usually vaccine related), and nearly half of non-polio infected patients died; about 40% of survivors of the initial illness had long-term neurological symptoms. Prophylactic immunoglobulin therapy did not prevent infection but these patients were on lower doses as compared to current recommendations. Our data provides a useful background for assessing the efficacy of new anti-viral treatment in this condition.

Cytokine and chemokine dysregulation in hyper-IgE syndrome.

Hyper-IgE syndrome is characterized by severe recurrent staphylococcal infections, eczema, bone abnormalities, and markedly elevated levels of immunoglobulin E (IgE). The genetic basis is not known and the central immunologic defect is largely undefined. Reduced neutrophil chemotaxis is often described, and variable T cell defects have been demonstrated in some patients. It has been hypothesized that hyper-IgE is associated with a Th1/Th2 imbalance. We wished to characterize cytokine and chemokine imbalances that might reflect the underlying disease process or reflect ongoing pathologic processes. Nine patients with hyper-IgE syndrome and six controls were studied. Radioimmunoassays, flow cytometry, and gene array analyses were performed to characterize cytokine and chemokine production. Hyper-IgE patients express more IL-12, while ENA-78, MCP-3, and eotaxin are markedly underexpressed. Underexpression of a set of chemokines could explain a number of features of hyper-IgE syndrome and may offer a new paradigm for the understanding of this disorder.

Successful treatment of enterovirus infection with the use of pleconaril in 2 infants with severe combined immunodeficiency.

Two patients with severe combined immunodeficiency and enterovirus infections were successfully treated with pleconaril. There were no adverse affects.

Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM(197) among infants with sickle cell disease. Pneumococcal Conjugate Vaccine Study Group.

OBJECTIVES: To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM(197) (7-valent conjugate pneumococcal vaccine [7VPnC]) among infants with sickle cell disease (SCD) and a comparison group of infants without SCD (non-SCD). DESIGN: Two cohorts of infants were enrolled and received open-label doses of 7VPnC vaccine; infants enrolled before 2 months of age received 7VPnC vaccine at 2, 4, and 6 months of age followed by 23-valent pneumococcal polysaccharide vaccine (PS-23) at 24 months of age for those infants with SCD (schedule A), and infants enrolled between 2 and 12 months of age received 7VPnC at 12 months of age followed by PS-23 at 24 months of age for infants with SCD (schedule B). Safety data were collected for 3 days after each dose of vaccine. Antibody concentrations were measured to each of the 7VPnC serotypes by enzyme-linked immunosorbent assay before each vaccine dose and 1 month after the last 7VPnC dose and the PS-23 vaccine dose. RESULTS: Forty-five infants (34 SCD and 11 non-SCD) were vaccinated according to schedule A and 16 infants (13 SCD and 3 non-SCD) according to schedule B. The 7VPnC vaccine was highly immunogenic for all serotypes among infants with and without SCD who received 3 doses of vaccine according to schedule A: depending on serotype, 89% to 100% achieved antibody concentrations above.15 microg/mL and 56% to 100% achieved antibody concentrations above 1.0 microg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above.15 microg/mL in 53% to 92% by serotype and above 1.0 microg/mL in 31% to 71% by serotype. A single dose of PS-23 resulted in dramatic increases in the antibody concentrations to all serotypes regardless of 1- or 3-dose priming. There was no difference in the reactogenicity of the 7VPnC vaccine between those with and without SCD. There were no serious reactions to the 7VPnC or PS-23 vaccines, even among those with high antibody concentrations before immunization. CONCLUSIONS: Infants with SCD respond to 7VPnC vaccine with antibody concentrations that are at least as high as infants without SCD. Infants immunized with 7VPnC vaccine at 2, 4, and 6 months of age developed antibody concentrations in the same range as those achieved among infants without SCD enrolled in a large trial that demonstrated vaccine efficacy against invasive disease. Significant rises were seen in antibody concentrations to all 7VPnC serotypes after the PS-23 booster in children receiving schedule A or B.

Lymphoid malignancy as a presenting sign of ataxia-telangiectasia.

Ataxia-telangiectasia (AT) is an uncommon genetic disorder characterized by cerebellar ataxia, oculocutaneous telangiectasias, progressive immunodeficiency, and a predisposition to lymphoid malignancy. The genetic defect in AT predisposes not only to malignancy but also to severe toxicity from anti-neoplastic therapies. It is important to consider the diagnosis of AT in any child with a lymphoid malignancy at a younger than expected age, or who has a pre-existing ataxia, to anticipate unusually severe toxicities from the antineoplastic therapy, to avoid confusing the development of ataxia with toxicity from therapy, and to provide appropriate genetic counseling. We describe two children at a young age with a lymphoid malignancy diagnosed before the diagnosis of AT. One patient had severe toxicity from his chemotherapy, requiring truncation of the planned course of treatment. The other child was able to tolerate his entire planned course of therapy, but ataxia that was initially interpreted as toxicity from chemotherapy rather than as a sign of his AT developed. Lymphoid malignancy may be the presenting sign of AT. Making this diagnosis may influence therapy of the malignancy. The neurologic manifestations of the disease can be misinterpreted as toxicities of the chemotherapy, and diagnosis of AT allows appropriate genetic counseling for the family.

Serum opsonic activity in infants with sickle-cell disease immunized with pneumococcal polysaccharide protein conjugate vaccine. The Pneumococcal Conjugate Vaccine Study Group.

Pneumococcal infections are an important cause of morbidity and mortality in children with sickle-cell disease (SCD). Pneumococcal conjugate vaccines (PCVs) are immunogenic in healthy infants <2 years of age but have not been evaluated in young children with SCD. Infants with SCD were immunized with a 7-valent PCV (Wyeth-Lederle Vaccines & Pediatrics) at 2, 4, and 6 months of age. A booster dose of 23-valent pneumococcal polysaccharide vaccine (PPV; Pnu-Immune) was administered at 24 months of age. Antipneumococcal type 6B and 14 serum opsonic activity was measured to assess the biologic function of the antibody. Following the administration of three doses of PCV, opsonic activity against serotype 6B increased from 4. 8% at 2 months to 33.5% at 7 months, with a subsequent decline to 8.1% at 12 months and 7.5% at 24 months and with an increase to 30.7% at 25 months after administration of a booster dose of PPV. Similar trends were seen with serotype 14 (opsonic activities were 9.4% at 2 months, 24.9% at 7 months, 16.5% at 12 months, and 12.6% at 24 months, and the opsonic activity was 27.3% 1 month after the administration of PPV). Serum opsonic activity correlated with antibody levels for both serotypes. PCV induces serum opsonic activity in infants with SCD. Antipneumococcal serum opsonic activity correlates with antibody levels.

Chronic granulomatous disease. Report on a national registry of 368 patients.

A registry of United States residents with chronic granulomatous disease (CGD) was established in 1993 in order to estimate the minimum incidence of this uncommon primary immunodeficiency disease and characterize its epidemiologic and clinical features. To date, 368 patients have been registered; 259 have the X-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms, and in 28 the mode of inheritance is unknown. The minimum estimate of birth rate is between 1/200,000 and 1/250,000 live births for the period 1980-1989. Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause), followed by suppurative adenitis (53% of patients; Staphylococcus most prevalent cause), subcutaneous abscess (42% of patients; Staphylococcus most prevalent cause), liver abscess (27% of patients; Staphylococcus most prevalent cause), osteomyelitis (25% of patients; Serratia most prevalent cause), and sepsis (18% of patients; Salmonella most prevalent cause). Fifteen percent of patients had gastric outlet obstruction, 10% urinary tract obstruction, and 17% colitis/enteritis. Ten percent of X-linked recessive kindreds and 3% of autosomal recessive kindreds had family members with lupus. Eighteen percent of patients either were deceased when registered or died after being registered. The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients). Patients with the X-linked recessive form of the disease appear to have a more serious clinical phenotype than patients with the autosomal recessive forms of the disease, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age versus 7.81 years of age, respectively), have a significantly higher prevalence of perirectal abscess (17% versus 7%), suppurative adenitis (59% versus 32%), bacteremia/fungemia (21% versus 10%), gastric obstruction (19% versus 5%), and urinary tract obstruction (11% versus 3%), and a higher mortality (21.2% versus 8.6%).

Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia.

OBJECTIVES: To determine whether patients with ataxia-telangiectasia exhibit oropharyngeal dysphagia with concomitant aspiration and to examine the relationships among swallowing function, age, and nutritional status. STUDY DESIGN: Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had feeding/swallowing and nutritional evaluations. Fifty-one patients, in whom there were concerns about swallowing safety, were examined with a standardized videofluoroscopic swallow study. RESULTS: Fourteen of the 51 patients (27%) with histories suggestive of dysphagia demonstrated aspiration. Of these, silent aspiration (aspiration without a cough) occurred in 10 (71%) patients. Aspirators were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P =.002). Advancing age was the strongest factor associated with aspiration during continuous drinking (P =.01). In patients with ataxia-telangiectasia, weight and weight/height were abnormally low at all ages and most compromised in older patients. Patients who aspirated had significantly lower mean weight (P <.002) and weight/height z scores (P <.001) than did patients who did not aspirate. CONCLUSIONS: Oropharyngeal dysphagia is common and appears to be progressive in patients with ataxia-telangiectasia. Older patients also have a higher incidence of poorer nutritional status. The relationship between dysphagia and nutritional status deserves further investigation.

Bilateral consecutive central corneal perforations associated with hypogammaglobulinemia.

OBJECTIVE: To describe the presentation and the clinical course of a patient with consecutive central sterile corneal perforations associated with common variable immunodeficiency. DESIGN: Case report. METHODS: Multiple corneal cultures and scrapings were performed in an effort to identify an infectious cause and all were negative. Corneal biopsy did not demonstrate any evidence of micro-organisms. An extended investigation failed to uncover a collagen vascular cause or atopy. RESULTS: Progressive sterile stromal thinning with intact epithelium in the left eye proceeded to perforation despite topical treatment, and cyanoacrylate gluing was performed. However, a secondary Haemophilus influenza endophthalmitis developed, and the eye was eventually lost. The fellow eye proceeded along the same clinical course with sterile stromal thinning. A lamellar patch graft was performed when the central ulceration progressed to a descemetocele. The eye remained quiet with 20/25 vision for 2 years, until the patient died from complications of a liver transplant. CONCLUSIONS: Devastating central sterile corneal thinning leading to perforation may occur in patients with hypogammaglobulinemia.

Oligo-/monoclonal gammopathy and hypergammaglobulinemia in ataxia-telangiectasia. A study of 90 patients.

We investigated the presence of hypergammaglobulinemia and oligo-/monoclonal gammopathy in 90 patients (from 80 families) with ataxia-telangiectasia ranging in age from 2 to 29 years. Of the 90 patients, 38.8% displayed hypergammaglobulinemia. An isolated increase in IgM was the most common finding (23.3%) followed by a simultaneous increase in IgM and IgG (8.8%), an isolated increase in IgA (3.3%), an elevated level of IgG (2.2%) and a concomitant increase in IgM and IgA (1.1%), respectively. Seven of the patients (8.1%) had oligo-/monoclonal gammopathy. The gammopathies included all major immunoglobulin isotypes. Chemotherapeutic intervention in 2 cases precipitated the emergence of new clones within a matter of weeks. Further investigation of oligo-/monoclonal gammopathies in these patients may lead to a clearer understanding of the clinical course and provide further insight into the underlying mechanisms of B-cell abnormalities in ataxia-telangiectasia.

Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fcgamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and FcgammaRIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an FcgammaRIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an FcgammaRIIa genotype (P = 0.04). Patients with variant forms of both MBL and FcgammaRIIa had the highest risk of developing an AID (P = 0.003).

Consequences of the delayed diagnosis of ataxia-telangiectasia.

OBJECTIVES: Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. DESIGN: The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. RESULTS: In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. CONCLUSIONS: The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.

Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in common variable immunodeficiency.

The clinical presentations of adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are widely variable and include clinical and immunologic findings compatible with common variable immunodeficiency. The screening of 44 patients with common variable immunodeficiency failed to identify any individuals with deficiencies of these enzymes.

Thymoma and cellular immune deficiency in an adolescent.

Thymoma has been associated with both humoral immunodeficiency and cellular immunodeficiency, but the latter association has never been described in the pediatric age group. We report a 15-year-old female with thymoma, recalcitrant oropharyngeal candidiasis, recurrent generalized cutaneous herpes simplex virus type 2 infection, recurrent pneumonia and myasthenia gravis. Pathology of the thymic lesion showed a 10x5x6 cm extensively hyalinized mass with residual regions of spindle cell predominant and lymphocyte-rich thymoma. There was no evidence of humoral immunodeficiency but there was clinical and laboratory evidence of cellular immunodeficiency with cutaneous anergy and absence of T cell proliferation to Candida antigen. Six weeks after the thymoma was resected, she was no longer anergic and Candida proliferation was normal, although she continued to experience infections. This is the first reported pediatric patient with an association of cellular immunodeficiency with thymoma.

Molecular analysis of the third component of canine complement (C3) and identification of the mutation responsible for hereditary canine C3 deficiency.

Genetically determined deficiency of the third component of complement (C3) in the dog is characterized by a predisposition to recurrent bacterial infections and to type 1 membranoproliferative glomerulonephritis. The current studies were undertaken to characterize the cDNA for wild-type canine C3 and identify the molecular basis for hereditary canine C3 deficiency. Amplification, cloning, and sequence analysis indicated that canine C3 is highly conserved in comparison with human, mouse, and guinea pig C3. Southern blot analysis failed to show any gross deletions or rearrangements of DNA from C3-deficient animals. Northern blot analysis indicated that the livers of these animals contain markedly reduced quantities of a normal length C3 mRNA. The full-length 5.1-kb canine C3 cDNA was amplified in overlapping PCR fragments. Sequence analysis of these fragments has shown a deletion of a cytosine at position 2136 (codon 712), leading to a frameshift that generates a stop codon 11 amino acids downstream. The deletion has been confirmed in genomic DNA, and its inheritance has been demonstrated by allele-specific oligonucleotide hybridization.