Dwight R. Johnson

Increased Prevalence and Mortality in Undiagnosed Celiac Disease

BACKGROUND & AIMS The historical prevalence and long-term outcome of undiagnosed celiac disease (CD) are unknown. We investigated the long-term outcome of undiagnosed CD and whether the prevalence of undiagnosed CD has changed during the past 50 years. METHODS This study included 9133 healthy young adults at Warren Air Force Base (sera were collected between 1948 and 1954) and 12,768 gender-matched subjects from 2 recent cohorts from Olmsted County, Minnesota, with either similar years of birth (n = 5558) or age at sampling (n = 7210) to that of the Air Force cohort. Sera were tested for tissue transglutaminase and, if abnormal, for endomysial antibodies. Survival was measured during a follow-up period of 45 years in the Air Force cohort. The prevalence of undiagnosed CD between the Air Force cohort and recent cohorts was compared. RESULTS Of 9133 persons from the Air Force cohort, 14 (0.2%) had undiagnosed CD. In this cohort, during 45 years of follow-up, all-cause mortality was greater in persons with undiagnosed CD than among those who were seronegative (hazard ratio = 3.9; 95% confidence interval, 2.0-7.5; P < .001). Undiagnosed CD was found in 68 (0.9%) persons with similar age at sampling and 46 (0.8%) persons with similar years of birth. The rate of undiagnosed CD was 4.5-fold and 4-fold greater in the recent cohorts, respectively, than in the Air Force cohort (both P < or = .0001). CONCLUSIONS During 45 years of follow-up, undiagnosed CD was associated with a nearly 4-fold increased risk of death. The prevalence of undiagnosed CD seems to have increased dramatically in the United States during the past 50 years.

Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study.

OBJECTIVE. If pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is a unique clinical entity, we hypothesized that children meeting diagnostic criteria would have more clinical exacerbations temporally linked to bona fide group A β-hemolytic streptococcus infection than matched control subjects (chronic tic and/or obsessive-compulsive disorder with no known temporal relationship to group A β-hemolytic streptococcus infection). PATIENTS AND METHODS. Subjects included 40 matched pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections case-control pairs who were prospectively evaluated with intensive laboratory testing for group A β-hemolytic streptococcus and clinical measures for an average of 2 years. Additional testing occurred at the time of any clinical exacerbations or illness. Laboratory personnel were blinded to case or control status and clinical (exacerbation or not) condition. Clinical raters were blinded to the results of laboratory tests. RESULTS. The cases had a higher clinical exacerbation rate and a higher bona fide group A β-hemolytic streptococcus infection rate than the control group. Only 5 of 64 exacerbations were temporally associated (within 4 weeks) with a group A β-hemolytic streptococcus infection, and all occurred in cases. The number (5.0) was significantly higher than the number that would be expected by chance alone (1.6). Yet, ≥75% of the clinical exacerbations in cases had no observable temporal relationship to group A β-hemolytic streptococcus infection. CONCLUSIONS. Patients who fit published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections seem to represent a subgroup of those with chronic tic disorders and obsessive-compulsive disorder who may be vulnerable to group A β-hemolytic streptococcus infection as a precipitant of neuropsychiatric symptom exacerbations. Group A β-hemolytic streptococcus infection is not the only or even the most common antecedent event associated with exacerbations for these patients. Additional intensive studies are needed to determine whether there is clinical or scientific evidence to support separating out subgroups of tic disorder and/or obsessive-compulsive disorder patients based on specific symptom precipitants.

Invasive Group A Streptococcal Infections in North Carolina: Epidemiology, Clinical Features, and Genetic and Serotype Analysis of Causative Organisms

During 1994 and 1995, an increase in the number and severity of group A streptococcal (GAS) infections was noted in North Carolina. Ninety-six patients had GAS recovered from blood and other sterile body fluids, abscesses, and soft tissue. The overall case fatality rate was 11% but was much higher in patients with toxic shock syndrome (55%) and necrotizing fasciitis (58%). Recent invasive GAS isolates were compared with pre-1994 invasive isolates and temporally related pharyngeal isolates by M protein serotyping, pulsed field gel electrophoresis (PFGE), and polymerase chain reaction amplification of the streptococcal pyrogenic exotoxin A gene. Serotypes M1 and M3 accounted for 50% of recent invasive isolates (1994-1995) and 58% of pharyngeal isolates (1994). The latter isolates demonstrated PFGE patterns that were identical to invasive M1 and M3 strains, suggesting that pharyngeal infections may have served as a reservoir for virulent GAS clones.

Susceptibility of Group A beta-hemolytic streptococci to thirteen antibiotics: examination of 301 strains isolated in the United States between 1994 and 1997

BACKGROUND Because of continuing reports from many countries of increasing resistance of group A streptococci to macrolide antibiotics, we determined the antibiotic susceptibility of recent group A streptococcal isolates from the United States. METHODS We evaluated 301 Streptococcus pyogenes isolates (245 from patients with uncomplicated pharyngitis and 56 isolates from patients with invasive systemic infections) for susceptibility using the Etest technique. The isolates came from 24 states and the District of Columbia during the years 1994 through 1997. Thirteen antibiotics (azithromycin, ceftriaxone, cephalothin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, imipenem, levofloxacin, oxacillin, penicillin G, tetracycline and trimethoprim-sulfamethoxazole) were studied. RESULTS The MIC90 for penicillin was 0.016 microg/ml, which is not significantly different from previous reports. Of the 301 isolates only 2.6% were resistant to a macrolide antibiotic and only 4% were resistant to tetracycline. CONCLUSIONS These data indicate that antibiotic resistance among recent isolates of group A streptococci (including those from patients with severe infections) currently is not a clinically significant problem in the United States.

Antistreptolysin O and anti-deoxyribonuclease B titers : normal values for children ages 2 to 12 in the United States

Background. Measurement of antibodies to the extracellular antigens produced by group A streptococci, antistreptolysin O (ASO) and anti-deoxyribonuclease B (anti-DNase B), is often necessary to confirm a clinical diagnosis of a previous group A streptococcal infection, especially in patients suspected of having a nonsuppurative sequel to this infection. Age is among several factors that may influence antibody levels in children. Thus, in contrast to adults, what is considered a normal titer for one age group (infants) is not appropriate for another (older children). Age-related “normal” values for ASO and anti-DNase B are provided in the package inserts of commercially available kits; however, there are no recent comprehensive data to validate such values. Objective. Using sera from 1131 children (from 23 states) ages 2 to 12 years, we determined age-specific geometric mean titers (GMT) and upper limits of normal (ULN) of ASO and anti-DNase B. Methods. ASO and anti-DNase B titers were measured by conventional laboratory methods. Results. Children 7 years of age comprised the largest proportion (14%) of the study population. Approximately two-thirds of the sera were collected during winter and early spring months. For both ASO and anti-DNase B, both GMT values and ULN increased with age. The GMTs for ASO and anti-DNase B for the entire group of subjects were 89 and 112, respectively. The ULN for the entire group for ASO and anti-DNase B were 240 and 640, respectively. Conclusion. The age-specific values for GMT and ULN for this group of children from 23 states were slightly higher than previously reported. These values are likely representative of the pediatric population in the United States and should be of clinical value to physicians, epidemiologists, and clinical laboratory personnel.

Dynamic epidemiology of group A streptococcal serotypes associated with pharyngitis.

BACKGROUND Despite the past 15 years of heightened awareness of the disease-causing potential of group A streptococci, the possible epidemiological influence of rapid changes in prevalent serotypes has not been fully appreciated. METHODS We analysed throat cultures collected as part of routine medical care in a semi-closed community of nearly 500 children and adults between January, 1999, and April, 2000. beta-haemolytic streptococci from all positive cultures were characterised by serological grouping, T-agglutination pattern, and serotyping for M protein or opacity factor. FINDINGS We saw an increase in the number of symptomatic individuals with pharyngitis beginning in mid-1999. Between July 1 and Dec 31, 1999, 111 (29%) of 378 throat cultures yielded group A streptococci, 102 (92%) of which were serotype M1. Between Jan 1 and Mar 31, 2000, 126 (45%) of 277 throat cultures yielded group A streptococci. Unexpectedly, 106 (84%) of these throat isolates were serotype M6, and only 16 (13%) were M1. 20 (28%) of the 71 individuals with M1 infection subsequently acquired infection with M6. INTERPRETATION This rapid and almost complete shift in predominance of group A streptococcal serotype in this community draws attention to the dynamic epidemiology of these organisms. This change has important implications for further understanding the epidemiology of group A streptococcal infections, and for the development and use of a vaccine.

Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: A prospective longitudinal study

OBJECTIVE The objective of this blinded, prospective, longitudinal study was to determine whether new group A β hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. METHOD Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. CONCLUSIONS This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.

Streptococcal Upper Respiratory Tract Infections and Psychosocial Stress Predict Future Tic and Obsessive-Compulsive Symptom Severity in Children and Adolescents with Tourette Syndrome and Obsessive-Compulsive Disorder

BACKGROUND One goal of this prospective longitudinal study was to identify new group A beta-hemolytic streptococcal infections (GABHS) in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared with healthy control subjects. We then examined the power of GABHS infections and measures of psychosocial stress to predict future tic, obsessive-compulsive (OC), and depressive symptom severity. METHODS Consecutive ratings of tic, OC, and depressive symptom severity were obtained for 45 cases and 41 matched control subjects over a 2-year period. Clinical raters were blinded to the results of laboratory tests. Laboratory personnel were blinded to case or control status and clinical ratings. Structural equation modeling for unbalanced repeated measures was used to assess the sequence of new GABHS infections and psychosocial stress and their impact on future symptom severity. RESULTS Increases in tic and OC symptom severity did not occur after every new GABHS infection. However, the structural equation model found that these newly diagnosed infections were predictive of modest increases in future tic and OC symptom severity but did not predict future depressive symptom severity. In addition, the inclusion of new infections in the model greatly enhanced, by a factor of three, the power of psychosocial stress in predicting future tic and OC symptom severity. CONCLUSIONS Our data suggest that a minority of children with TS and early-onset OCD were sensitive to antecedent GABHS infections. These infections also enhanced the predictive power of current psychosocial stress on future tic and OC symptom severity.

The Heterogeneity of Endemic Community Pediatric Group A Streptococcal Pharyngeal Isolates and Their Relationship to Invasive Isolates

By use of molecular techniques, the genetic heterogeneity of 63 community pediatric pharyngeal group A streptococcal (GAS) isolates circulating within a 3-week period were compared with 17 contemporaneous invasive pediatric isolates. Pharyngitis isolates represented 16 pulsed-field gel electrophoresis (PFGE) patterns with 12 emm serotypes, and invasive isolates represented 10 PFGE patterns with 9 emm serotypes. One-fourth of the pharyngeal isolates (16/63) were identical to at least 1 invasive isolate; conversely, 10 (59%) of 17 invasive isolates were identical to at least 1 pharyngeal strain. sic allele analysis of emm1 strains demonstrated additional heterogeneity and overlap. More pharyngeal (71%) than invasive isolates (35%) were positive for both speA and speC (P<.02). Many pharyngitis GAS strains circulate simultaneously. Most invasive pediatric GAS strains are identical to acute pharyngitis strains; thus, childhood pharyngitis is a major reservoir for strains with invasive potential. Pharyngeal isolates were more likely to be speA and speC positive than were the invasive isolates.

Treatment of streptococcal pharyngitis with once-daily compared with twice-daily amoxicillin : A noninferiority trial

Background: Two relatively small previous studies comparing once-daily amoxicillin with conventional therapy for group A streptococcal (GAS) pharyngitis reported similar rates of bacteriologic success for each treatment group. The purpose of this study was to further evaluate once-daily amoxicillin for GAS pharyngitis in a larger study. Methods: In a single pediatric practice, from October through May for 2 consecutive years (2001–2003), we recruited children 3 to 18 years of age who had symptoms and signs suggestive of GAS pharyngitis. Patients with a positive rapid test for GAS were stratified by weight (<40 kg or ≥40 kg) and then randomly assigned to receive once-daily (750 mg or 1000 mg) or twice-daily (2 doses of 375 mg or 500 mg) amoxicillin for 10 days. We determined bacteriologic failure rates for GAS in the pharynx from subsequent swabs taken at 14 to 21 (visit 2) and 28 to 35 (visit 3) days after treatment initiation. We conducted a randomized, controlled, investigator-blinded, noninferiority trial to evaluate whether amoxicillin given once daily would have a bacteriologic failure rate no worse than that of amoxicillin given twice daily within a prespecified margin of 10%. GAS isolates were characterized to distinguish bacteriologic failures from new acquisitions. Adverse events were described and adherence was evaluated by review of returned daily logs and dosage bottles. Results: Of 2139 potential study patients during the 2-year period, we enrolled 652 patients, 326 into each treatment group. Children in the 2 groups were comparable with respect to all demographic and clinical characteristics except that children <40 kg more often presented with rash in each treatment group. At visit 2, failure rates were 20.1% (59 of 294) for the once-daily group and 15.5% (46 of 296) for the twice-daily group (difference, 4.53%; 90% confidence interval [CI], −0.6 to 9.7). At visit 3, failure rates were 2.8% (6 of 216) for the once-daily group and 7.1% (16 of 225) for the twice-daily group (difference, −4.33; 90% CI, −7.7 to −1.0). Gastrointestinal and other adverse events occurred in the once-daily treatment group with a frequency comparable to that in the twice-daily treatment group. Presumed allergic reactions occurred in 0.9% (6 of 635). More than 95% (516 of 541) of patients complied with 10 days of therapy with no significant differences between groups. Conclusions: We conclude that amoxicillin given once daily is not inferior to amoxicillin given twice daily. Gastrointestinal and other events did not occur significantly more often in the once-daily treatment group. From the data in this large, investigator-blinded, controlled study, once-daily amoxicillin appears to be a suitable regimen for treatment of GAS pharyngitis.