Cleveland Moore

Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations

BACKGROUND A deficient antibody response to polysaccharide antigens is determined by measuring the response to the 23-valent pneumococcal polysaccharide vaccine. However, the diagnosis of this specific antibody deficiency is hampered by the lack of sufficient data and standardized testing of the response to pneumococcal polysaccharides. METHODS All patients evaluated in our allergy/immunology clinic for recurrent respiratory infections between 1995 and 1997 without immunoglobulin, IgG subclass, or other known primary or secondary immunodeficiency were included in this analysis. IgG antipneumococcal serotypes 1, 3, 4, 6B, 9V, 14, 18C, 19F, and 23F were determined by a modified ELISA protocol. An adequate IgG antibody response to an individual serotype was arbitrarily defined as a postimmunization antibody titer of 1.3 microg/ml or greater or at least four times the baseline value. RESULTS A total of 113 patients fulfilling the criteria for inclusion in this analysis were divided into five age groups. The geometric means for preimmunization and postimmunization pneumococcal antibody titers for all serotypes increased with age. For post-immunization antibody concentrations, there was a sharp increase in the specific antibody concentrations in adults in comparison with all pediatric age groups ranging in age from 7 months to 16 years. Similarly, the number of serotypes to which there was an adequate response also increased with age. CONCLUSION We conclude that the definition of what constitutes an adequate response to pneumococcal immunization needs further definition. It is clear, however, that age has an important influence on the intensity of the response to most pneumococcal polysaccharides. Correlation studies between antibody concentrations in different IgG subclasses, functional studies, and protection studies against mucosal and invasive pneumococcal infections are in progress, and these should contribute to a refined definition of a normal response. The availability of a standardized method for the measurement of IgG antibodies against relevant pneumococcal serotypes is an important step toward this goal.

Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine.

OBJECTIVE To determine whether children with recurrent respiratory infections who failed to respond to the conventional polysaccharide vaccine would respond to a pneumococcal conjugate vaccine. METHODS Children referred to our clinic for recurrent respiratory infections who had no known primary or secondary immunodeficiencies were immunized with a 23-valent pneumococcal polysaccharide vaccine. IgG antibodies to pneumococcal serotypes 1, 3, 4, 6B, 9V, 14, 18C, 19F and 23F were determined by enzyme-linked immunosorbent assay before and 4 to 6 weeks after immunization. An adequate IgG antibody response to an individual serotype was arbitrarily defined as a postimmunization antibody titer > or =1.3 microg/ml or at least 4 times the preimmunization value. Immunization with an experimental CRM197-heptavalent pneumococcal conjugate vaccine was offered to patients without an adequate response to 4 or more vaccine serotypes (nonresponders). Post-conjugate immunization antibody concentrations were measured 4 to 6 weeks later. RESULTS In nonresponder patients (n = 17) geometric mean post-conjugate immunization (C) serum antibody concentrations (microg/ml) compared with post-polysaccharide (PS) concentrations were: (serotype, C vs. PS) 4, 1.11 vs. 0.30 (P = 0.000227); 6B, 0.46 vs. 0.20 (P = 0.017267); 9V, 0.82 vs. 0.29 (P = 0.002163); 14, 1.88 vs. 0.27 (P = 0.000615); 18C, 0.98 vs. 0.32 (P = 0.021962); 19F, 1.24 vs. 0.34 (P = 0.002844); and 23F, 0.87 vs. 0.16 (P = 0.000194). In responder patients (n = 67), after 1 dose of the polysaccharide vaccine, geometric mean antibody concentrations were: 4, 1.05; 6B, 0.96; 9V, 1.55; 14, 1.65; 18C, 1.62; 19F, 1.30; and 23F, 1.02. CONCLUSIONS Our results show that a pneumococcal conjugate vaccine is capable of inducing an IgG response in patients with recurrent infections who had failed to mount an adequate response to the polysaccharide vaccine. Conjugate vaccines may be of value in the management of children with recurrent pneumococcal respiratory infections.

Low-dose methotrexate therapy for childhood sarcoidosis

OBJECTIVE To evaluate the effectiveness of low oral doses of methotrexate as a steroid-sparing agent in children with sarcoidosis. STUDY DESIGN An open-label, noncontrolled trial. Methotrexate was administered orally at a single weekly dose of 10 to 15 mg/m2. Duration of therapy was open ended, but patients received treatment for a minimum of 6 months to be considered as having completed the study. RESULTS Seven children with biopsy-proven sarcoidosis completed the study. The mean dose of prednisone was successfully tapered from 49 mg/day (1.3 mg/kg) to 18 mg/day (0.5 mg/kg) after 3 months of methotrexate therapy and to 9.9 (0.2 mg/kg) and 7.3 mg/day (0.1 mg/kg) after 6 months and at the end of the follow-up period, respectively. Other clinical and laboratory parameters improved significantly after methotrexate therapy was started. There was significant clinical improvement, as confirmed by the reduction of the clinical severity score from 8 +/- 1.1 to 0.8 +/- 0.5 point after 3 months of methotrexate therapy, and to 0.7 and 0.5 +/- 0.3 point after 6 months and at the end of the follow-up, respectively. Laboratory measurements revealed marked improvement, as reflected by a significant reduction in the erythrocyte sedimentation rate and an increase of hemoglobin values. The mean serum angiotensin-converting enzyme activity dropped significantly. No adverse side effects were noted with methotrexate therapy. CONCLUSION Our study demonstrated that low-dose oral methotrexate therapy was effective and safe and had steroid-sparing properties in seven children with sarcoidosis.

Antibody deficiency syndromes

Antibodies have a crucial role in protecting against infections, and antibody deficiencies are the commonest primary and secondary immunodeficiencies. Antibody deficiencies may be the only abnormality present in a patient, or they may be present and aggravate the symptoms of various other conditions. Because the presence of an antibody deficiency is difficult to predict from clinical presentation, physicians should perform an evaluation of antibody-mediated immunity, even knowing that, in many cases, the results are normal. When immunizations are included as a part of the evaluation, many patients experience a benefit from enhanced immunity against common pathogens. Some alternative practical approaches to the evaluation of patients with recurrent infections are outlined in Figure 8. Referral to a clinical immunologist can be based on the presence of recurrent infections, a positive family history without prior evaluation by a pediatrician, or abnormal immunologic findings that require an advanced evaluation. In any case, a close collaboration between pediatrician and immunologist likely will result in an accurate diagnosis and better treatment of patients with antibody-deficiency syndromes and their families.

Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital.

BACKGROUND Advances in immunologic techniques in recent years have led to increased recognition of primary immunodeficiency disorders, with IgA deficiency the most common phenotype reported by most registries. There have also been reports of increased associated incidence of autoimmunity, allergy, and other diseases. OBJECTIVES We wished to determine the percentage of different primary immunodeficiency disorders seen in a pediatric tertiary hospital and to determine the association of primary immunodeficiency disorders with other diseases that are not part of classic immunodeficiency disorders. METHODS We performed a retrospective review of the patients referred to our allergy/immunology clinic for immunologic evaluation of recurrent infections during an 8-year period. We also reviewed pathology reports with postmortem diagnosis of immunodeficiencies not identified while patients were alive. RESULTS Of the 91 patients with primary immunodeficiency disorders evaluated, the majority had predominantly antibody deficiencies (67%). The most common phenotype was specific antibody deficiency with normal immunoglobulins (23.1%), defined as inability to mount an adequate response to pneumococcal polysaccharides followed by IgG2 subclass deficiency (17.6%). These two phenotypes were diagnosed mostly in the last 2 years of the survey. Associated diseases, found in 40% of patients, were mostly allergic conditions followed by syndromic/chromosomal disorders. CONCLUSION The study reveals that specific antibody deficiency with normal immunoglobulins followed by IgG2 subclass deficiency was the most frequently diagnosed primary immunodeficiency disorder in our patient population. It also indicates that immunodeficiency disorders should be considered in patients with other abnormalities like allergic and syndromic/chromosomal disorders that present with recurrent infections.

Post‐immunization pneumococcal antibody titers and IgG subclasses

IgG antibodies against pneumococcal polysaccharides are found predominantly within IgG subclass 2. We wished to evaluate retrospectively IgG subclasses and post‐immunization pneumococcal antibody titers in children with recurrent respiratory infections. We examined total immunoglobulin levels and IgG subclasses, as well as pneumococcal antibody titers against serotypes 3, 7F, 9N, and 14 present 4–6 weeks after pneumococcal immunization in 56 children 2–18 years old. Titers >200 ng Ab N/ml to any of the 4 serotypes tested were arbitrarily considered protective. Four patients did not have protective antibody levels against any of the 4 serotypes tested following vaccination. Of those, 3 had normal IgG subclass levels and 1 had an IgG2 subclass deficiency. Of 3 additional patients with IgG2 deficiency, 2 had protective antibody levels to only 1 serotype and 1 had protective antibody levels to 2 serotypes. Furthermore, in 2 patients with undetectable IgG2 at the time of immunization, the response was only transient. We conclude that patients with IgG2 deficiency may not develop protective antibody levels to all pneumococcal serotypes and that some may have deficient memory for IgG anti‐pneumococcal polysaccharide antibodies. Pediatr Pulmonol. 1996; 22:167–173.

Preimmunization and postimmunization pneumococcal antibody titers in children with recurrent infections

BACKGROUND Patients with recurrent infections and normal IgG levels may have an abnormal response to pneumococcal polysaccharides. The ability to develop antibodies against different pneumococcal polysaccharides develops gradually in the first years of life, but the sequence of development and the influence of preexisting antibody titers has not been defined. METHODS Preimmunization and postimmunization IgG antibody titers against pneumococcal serotypes 3, 7F, 9N, and 14 were evaluated in a population of 100 1- to 18-year-old children referred to a pediatric allergy-immunology clinic because of recurrent respiratory infections. None of the patients had a known immunodeficiency syndrome; all had normal total IgG levels. Postimmunization antibody levels were obtained 4 to 6 weeks after immunization. Patients less than/=5 years of age who failed to develop antibody levels above 200 ng Ab N/mL against any serotype and older patients who failed to develop these levels against a second serotype in addition to serotype 3 were considered for IgG replacement therapy. RESULTS Prior to immunization, 50% of 51 patients did not have protective antibody levels against any of the serotypes tested. Immunization induced a high response to serotype 3 in all age groups, but responses to serotypes 7F and 14 increased with age. Five of 78 patients (6.4%) failed to develop protective antibody levels against any serotype tested. Three of these patients had clinical criteria that justified the use of IgG replacement therapy; all improved. Three patients were re-immunized 1 to 2 years after the first immunization and all developed protective levels of antibodies against serotype 3 after the second immunization. CONCLUSION We conclude that, although measurement of antibody levels against pneumococcal serotype 3 allows a good differentiation of patients who are able to develop anti-polysaccharide antibodies from those who are not, further studies of the development of specific antibodies against other vaccine serotypes in normal populations of different ages are needed to define a normal response to pneumococcal polysaccharides.

New concepts in the immunology of sickle cell disease.

OBJECTIVE Our objective is to review the role of adhesion molecules, cytokines, and inflammation in the abnormal adherence of sickle red blood cells to vascular endothelia in the pathogenesis of vascular complication in patients with sickle cell anemia. DATA SOURCES The MEDLINE database was used to review the hematologic, immunologic, and allergy literature in English with respect to the adhesion molecules involved in sickle hematopoiesis and vascular complications. STUDY SELECTION Studies selected for review were those that identified the adhesion molecules involved in reticulocyte-endothelial adhesion and the influence that cytokines, infections, and atopy have upon the expression of these molecules. RESULTS In sickle cell disease, a constant low level of inflammation caused by abnormal adhesion of sickle erythrocytes to endothelial cells in the microvasculature produces low-level tissue ischemia. Allergic and infectious inflammations are likely to lead to increased sickle erythrocyte trapping in the microvascular endothelia which progresses to vessel obstruction, end organ ischemic damage, and dysfunction. CONCLUSION The identification of underlying immune defects that predispose patients to infections and inflammation needs to be emphasized. Anti-inflammatory medications, anti-adhesion molecule monoclonal antibodies, and adhesion molecule binding-site analogs may have a future in the treatment of the acute vascular complications of sickle cell disease.

Care of Asthma: Allergy Clinic Versus Emergency Room

BACKGROUND Demographic and socioeconomic factors have an impact upon the morbidity and mortality rates of asthma in inner-city pediatric populations. Many pediatric patients with asthma use the emergency room as their primary care physician, while a smaller number of children with asthma use the allergy-immunology clinic. OBJECTIVE We examined the demographic and socioeconomic characteristics of asthmatic patients using the emergency room as their primary care physician and of those attending the allergy-immunology clinic in the same inner-city hospital. We compared the morbidity and cost of care of asthmatic patients who received their medical care in the emergency room to that of those who received their care in the allergy-immunology clinic. METHODS Fifty consecutive emergency room patients and 25 clinic patients were studied using an identical questionnaire. RESULTS There was no difference between the two groups in the total number of individuals per household, children per family, monthly income, type or size of dwelling, financial problems purchasing medications, health insurance type, distance to the medical center, or education of the caretaker. Severity of asthma was not different in the two groups before the start of the study. The only significant demographic difference was in age: 10.6 years for the clinic group and 7.8 years for the emergency room group (P < .002). Clinically, in the year preceding the interview, the clinic group had significantly less nocturnal cough (P < .025), sleep interruption (P < .001), weekly asthma (P < .05), and emergency room visits (P < .09). The allergy clinic group had an approximate average savings of

Topical Sodium Cromoglycate in the Treatment of Moderate-to-Severe Atopic Dermatitis

137 per patient per year. Hospital admissions and emergency room costs were increased by a small group of three allergy clinic patients, decreasing the difference in the cost of care between the two groups. CONCLUSION The data showed that patients who attended the emergency room and those who attended the allergy-immunology clinic were not demographically or socioeconomically different. The decreased morbidity of asthma and cost of care for the allergy clinic patients, as opposed to the emergency room patients, are likely due to the care given in the allergy-immunology clinic.