Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

A longitudinal PRINTO study on growth and puberty in juvenile systemic lupus erythematosus.

OBJECTIVE: To obtain longitudinal data on growth/puberty in a large-scale, multi-national prospective cohort of juvenile systemic lupus erythematosus (SLE). METHODS: Data from 331/557 (59.4%) patients ≤18 years old with juvenile SLE in active phase, with anthropometric data available at four follow-up visits, were studied. RESULTS: There was a significant reduction in parent-adjusted height z score with time in females and males (p<0.0001), with a significant gender difference (p<0.0001) and with male height being most affected. Median body mass index z score peaked at 6 months and was still significantly above baseline after 26 months (p<0.01), with no gender difference. Standardised height reduction was inversely related to age at onset. Females with onset age <12 years had a median parent-adjusted height z score of -0.87 with no catch-up growth. At the end of the study, growth failure was seen in 14.7% of the females and 24.5% of the males. Height deflection (less than -0.25/year) was found in 20.7% of the females and 45.5% of the males. Delayed pubertal onset was seen in 15.3% and 24% of the females and males, respectively, and delayed/absent menarche was seen in 21.9%, while 36.1% of the females and 44% of the males had some degree of delayed pubertal development. Growth failure baseline determinants were previous growth failure (OR: 56.6), age at first visit ≤13.4 years (OR: 4.2) and cumulative steroid dose >426 mg/kg (OR: 3.6). CONCLUSIONS: The children at risk of having a negative effect on height and pubertal development are prepubertal and peripubertal children treated with >400 mg/kg cumulative dose of corticosteroids.

Multiple hymenoptera stings in children: clinical and laboratory manifestations.

Multiple hymenoptera stings are a cause of rhabdomyolysis, elevated liver enzymes, clotting abnormalities, kidney injury, and even death. However, the progression of the clinical and laboratory findings has been described mainly in sporadic case reports. We report the clinical and laboratory manifestations of multiple hymenoptera stings in six children who were hospitalized and referred for a nephrology evaluation and follow-up over a 12-year period. One patient succumbed 13 h after the stinging accident. In the five surviving patients, we found somewhat similar pattern of clinical and laboratory course: rhabdomyolysis with elevated liver enzymes are the earliest manifestations, followed by kidney injury and anemia. An asymptomatic phase of several days between the stinging accident and severe kidney injury can occur. There was a strong seasonal association, with all six events occurring in August or September. In children with multiple hymenoptera stings, a somewhat predictable clinical and laboratory course is expected and an initial laboratory evaluation is needed, and even in asymptomatic children, a repeated laboratory evaluation is highly recommended.

Referral criteria from community clinics to pediatric emergency departments.

Referral of patients to a pediatric emergency department (PED) should be medically justified and the need for referral well communicated. The objectives of this paper were (1) to create a list of criteria for referral from the community to the PED, (2) to describe how community physicians categorize their need for referral, and (3) to determine agreement between the physician's referral letter and the selected criteria. We present a descriptive study of referrals to the PED of Soroka University Medical Center, Beer-Sheva, Israel, during February to April 2003. A list of 22 criteria for referral was created, using the Delphi method for reaching consensus. One or more criteria could be selected from this list for each referral, by the referring community physicians and, independently, based on the physicians' referral letters, by two consultants, and compared. There were 140 referrals included in the study. A total of 262 criteria for referral were selected by the referring community physicians. The criteria most frequently selected were: "Need for same-day consultation/laboratory/imaging result not available in the community" (32.1%), "Suspected life- or organ-threatening infection" (16.4%), and "Need for hospitalization" (15.7%). Rates of agreement regarding criteria for referral between the referring physicians and the two consultants, and a senior community pediatrician and a senior PED pediatrician, were 57.9 and 48.6%, respectively. We conclude that the standard referral letter does not convey in full the level of need for referral to the PED. A list of criteria for referral could augment efficient utilization of emergency department services and improve communication between community physicians and the PED.

Unrealistic concerns about fever in children: the influence of cultural-ethnic and sociodemographic factors.

BACKGROUND: Parental fear and misconceptions about fever are widespread in western society. Ethnicity and sociodemographic factors have been suggested as contributing factors. OBJECTIVES: To test the hypothesis that undue parental concern about fever is less in traditional than in western cultural-ethnic groups. METHODS: Bedouin (traditional society) and Jewish (western society) parents of children aged 0-5 years with fever were interviewed in a pediatric emergency unit. Interviews were conducted in the parents' most fluent language (Arabic or Hebrew). A quantitative variable (a 9 item "fever phobia" scale) was constructed. RESULTS: The parents of 101 Jewish and 100 Bedouin children were interviewed. More Bedouin parents were unemployed, had less formal education and had more and younger children than the Jewish parents. Parents in both groups expressed erroneous beliefs and practices about fever; quantitative but not qualitative differences in fever phobia variables were documented. Compared with their Jewish counterparts, more Bedouin parents believed that fever may cause brain damage and death, administered antipyretic medications for temperature < or = 38 degrees C and at excessive doses, and consulted a physician within 24 hours even when the child had no signs of illness other than fever (all Pvalues <0.001). The mean fever phobia score was higher in the Bedouin than in the Jewish group (P< 0.001). By multivariate analysis, only the cultural-ethnic origin correlated with fever phobia. CONCLUSIONS: A higher degree of fever phobia was found among parents belonging to the traditional Bedouin group as compared to western society parents.

Increased proportion of CD3+CD4-CD8- double-negative T cells in peripheral blood of children with Behcet's disease.

INTRODUCTION: Behcet's disease (BD) is a multi-system inflammatory disorder of poorly understood pathogenesis, which is characterized by oral aphtosis, genital ulcers and uveitis. OBJECTIVE: To assess the role of CD3+CD4-CD8- double negative (DN) T cells in pathogenesis of Behcet's disease. PATIENTS: Ten BD patients (age 12.2+/-2.2 years, 7 in remission, 3 in exacerbation state) treated at the Pediatric Rheumatology unit of Soroka University Medical Center and 3 age-matched controls participated in the study. METHODS: Peripheral blood lymphocytes of study subjects were isolated and stained with fluorescein-labeled anti-CD45, CD3, CD4, CD8 antibodies and analyzed by FACS assay. RESULTS: Proportion of CD4-CD8- DN T cells was significantly increased in BD patients (n=10) as compared to healthy controls (6.2+/-3.4% vs. 3.2+/-1.1% of total CD3+ cells, p<0.05), this cell group was additionally enhanced in BD exacerbation, compared to patients in remission (10+/-4.1% vs. 4.7+/-1.2%, p<0.05, respectively). DN T cells were significantly increased in BD patients in remission, compared to healthy controls (4.7+1.2% vs. 3.2+1.1% of total CD3+ cells, p<0.05, respectively). CONCLUSIONS: Behcet's disease is characterized by increased proportion of CD3+CD4-CD8- double negative T cells in peripheral blood. Further studies, that include additional immunophenotyping and analysis of gene expression, aimed at characterization of these cells are currently underway.

Influenza vaccination of patients with systemic lupus erythematosus: safety and immunogenecity issues.

The influenza vaccine is highly efficacious in the general population; however there have been concerns about the safety, and immunogenecity of the vaccine in patients with SLE. Several studies have suggested that the immune response of patients with SLE to influenza vaccine is significantly lower than the general population, mainly in patients with age > or =50 years and those treated with prednisone. The vaccine is safe for patients with SLE and it does not affect the clinical manifestations of SLE including renal features, disease activity, or the requirement for steroids or cytotoxic drugs. However, the vaccine may trigger the generation of autoantibodies which is usually short term and is not associated with clinical significance.

Blood culture contamination in pediatric patients: young children and young doctors.

OBJECTIVE: The objective of this study was to assess the role played by the patient's age and physician's experience in determining the contamination rate of pediatric blood cultures. METHODS: The proportion of true-positive (isolation of a pathogen) and false-positive (isolation of a contaminant) results among blood cultures obtained by in-training physicians and experienced pediatricians from young children (aged 1-35 months) and older children (>or=36 months of age) and the value of a positive blood culture to predict a true-positive result were retrospectively determined. RESULTS: The odds of a positive blood culture to predict isolation of a true-pathogen was 0.366 only when the sample was obtained by an inexperienced physician and 0.523 when it was drawn by an experienced physician (P < 0.001), 0.419 when it was obtained from a young child and 0.429 when it was drawn from an older child (P = 0.781). The predictive value of a positive result for isolating a pathogen was significant higher when an experienced physician drew the blood culture regardless of the patient's age. CONCLUSIONS: Patient's young age and lack of experience of the physician who draws the specimen increase the risk of blood culture contamination. These results strengthen the need to improve the technical skills of young physicians.

Determinants of antipyretic misuse in children up to 5 years of age: a cross-sectional study.

BACKGROUND: Fever in children is a common and usually benign symptom. It is known that antipyretic treatment is ineffective in the prevention of simple febrile seizures. Caregivers' administration of antipyretic medications to children has been reported, but data concerning the formulations used, actual doses administered, and effects of ethnicity and socioeconomic status on administration practices are incomplete. OBJECTIVE: The aim of this study was to identify the factors affecting antipyretic administration (higher-than-recommended doses in particular) by caregivers to their febrile children in 2 differing cultural-ethnic backgrounds. METHODS: This cross-sectional survey study, conducted from January to March 2002, was part of a larger, ongoing survey study of the differences in care givers' knowledge, beliefs, and attitudes concerning children's fever in the 2 major cultural-ethnic groups in the Negev District in Israel: Jews and Bedouin Moslems. It was conducted at the Pediatric Emergency Department (PED), Soroka Medical Center, Beer-Sheva, Israel. A structured questionnaire was administered to Jewish and Bedouin Moslem parents or usual caregivers of young (age, 0-60 months) children attending the PED due to fever. Each child's weight was obtained from the PED medical record. After completion of the interview, the reported antipyretic dose per kilogram of body weight was calculated. Less-than-recommended dose was defined as <9 mg/kg for acetaminophen and <4.5 mg/kg for ibuprofen. Higher-than-recommended dose was defined as >16.5 mg/kg for acetaminophen and >11 mg/kg for ibuprofen. RESULTS: The caregivers of a total of 201 children (mean [SD] age, 20 [17] months; mean [SD] weight, 10.4 [4.0] kg) were included in the study. The study included 101 Jewish and 100 Bedouin Moslem caregivers. The proportion of people surveyed who were parents was 98%; grandmothers, 2%. Differences existed between the 2 cultural-ethnic groups in the source of knowledge regarding antipyretic use in children (a significantly larger proportion of Jewish caregivers received their knowledge concerning antipyretic use from package inserts compared with Bedouin caregivers [25.7% vs 6.0%; P < 0.001], and a significantly lower proportion of Jewish caregivers used "other" sources [15.8% vs 39.0%; P < 0.001]). Most (65.2%) caregivers indicated that they administered antipyretics for no or minimal elevations in body temperature (<-38 degrees C); 52.7% administered individual acetaminophen doses within 10% of the recommended dose, 34.8 % administered a higher-than-recommended dose, and 21.4% repeated the dose at intervals of

Adherence to therapeutic guidelines for acute otitis media in children younger than 2 years.

OBJECTIVES: to analyze adherence to therapeutic guidelines for AOM. METHODS: Descriptive retrospective study of community primary care providers in southern Israel. Study population (n = 590) included all children aged 0-48 months diagnosed with AOM in PED during the year 2000 who had a referral letter from a community physician and an AOM diagnosis confirmed by tympanocentesis. AOM antibiotic treatment was considered appropriate when in accord with CDC and local therapeutic guidelines. RESULTS: Referral letter data allowing characterization of AOM by category were available in 471 (79.8%) children, 320 (68%) with simple AOM and 151(32%) with complicated AOM. AOM diagnosis made by the primary care physician was in accord with PED diagnosis in 365/590 (62%) patients. Three hundred and fifty-five (60.2%) patients did not receive antibiotics in the community. Of 365 (62%) children diagnosed with AOM in the community, 235 (64.4%) were treated with antibiotics prior to arrival to PED. Amoxicillin was prescribed to 109 (46.4%), cefuroxime axetil to 48 (20.4%), amoxicillin/clavulanate to 31 (13.2%) and i.m. ceftriaxone to 20 (8.5%) of the patients. Eighty-three (25.9%) patients with simple AOM were treated with antibiotics in the community and only 46 (55.4%) received amoxicillin according to the therapeutic guidelines. Eighty-one (53.6%) patients with complicated AOM were treated with antibiotics in the community and only 41 (50.6%) of them received antibiotics according to AOM therapeutic guidelines. More antibiotics were prescribed in the community to patients with complicated AOM than to patients with simple AOM (81/151, 53.6% versus 83/320, 25.9%, respectively, p < 0.001). Adherence to therapeutic guidelines was similar between the simple and the complicated AOM groups (46/83, 55.4% versus 41/81, 50.6%, respectively, p = 0.5). CONCLUSION: We found partial adherence to AOM therapeutic guidelines among primary care providers in the community in Southern Israel.

Genetic factors in neuromuscular pain.

Recent evidence suggests that fibromyalgia, a chronic widespread pain condition and related syndromes (chronic fatigue syndrome, irritable bowel syndrome, etc.) may share heritable pathophysiologic features. We review the recent literature on genetic and familial factors found to participate in the pathogenesis of these syndromes, specifically fibromyalgia, including evidence suggesting that serotonin- and dopamine-related genes may play a role in the pathogenesis of these illnesses. The importance of environmental factors triggering these conditions in predisposed individuals is also discussed.

Prevalence of post-traumatic stress disorder in fibromyalgia patients: overlapping syndromes or post-traumatic fibromyalgia syndrome?

OBJECTIVES: The primary aim of this study was to assess the frequency of post-traumatic stress disorder (PTSD) in patients with the fibromyalgia syndrome (FMS). The influence of gender on measures of PTSD in fibromyalgia (FM) patients also was examined. METHODS: Seventy-seven consecutive patients (40 women and 37 men) who fulfilled the criteria for FM were asked to complete questionnaires measuring the prevalence and severity of symptoms of PTSD, anxiety, and depression. The subjects were divided in 2 groups based on the presence or absence of PTSD symptoms. RESULTS: In this study, 57% of the FM sample had clinically significant levels of PTSD symptoms. The FM patients with PTSD reported significantly greater levels of avoidance, hyperarousal, reexperiencing, anxiety, and depression than did the patients without clinically significant levels of PTSD symptoms. The prevalence of PTSD among the FM patients in this study was significantly higher than in the general population. Women with FM and PTSD reported a greater number of past traumatic events than did their male counterparts. CONCLUSIONS: The results represent the first comprehensive study applying structured clinical assessment of trauma exposure and PTSD to a group of FM patients. This study shows a significant overlap between FM and PTSD, according to the currently accepted diagnostic criteria for each.

Cytology of middle ear fluid during acute otitis media.

BACKGROUND: Limited information is available on the cellular characteristics of the middle ear fluid (MEF) during acute otitis media (AOM). OBJECTIVES: To determine the white blood cell (WBC) composition of the MEF in AOM before and during antibiotic therapy. MATERIALS AND METHODS: Total WBC and differential counts were determined in the MEF of 96 infants and children (ages 2 weeks to 3 years) with AOM who were receiving antibiotics. WBC counts were reported as number of WBC/mg MEF (mean +/- sd). RESULTS: One hundred forty-five MEF samples were obtained by tympanocentesis at enrollment (Day 1), and 36 samples were collected on Days 4 to 5 after initiation of antibiotic therapy. Sixty-one percent of the patients were <1 year of age, and 38% were receiving antibiotic therapy at enrollment. Twenty-eight MEF samples were paired (same ear, Day 1 and Days 4 to 5). One hundred twelve pathogens were isolated from 95 of 145 (66%) culture-positive samples obtained on Day 1: 67 Haemophilus influenzae, 40 Streptococcus pneumoniae and 5 others. MEF WBC counts were lower on Day 1 in patients who had received previous antibiotic therapy than in those who had not (432.4+/- 412.8 vs. 590.5 +/- 436.8, P = 0.03). WBC counts were higher on Day 1 in culture-positive than in culture-negative samples (603.9 +/- 504.9 vs.421.4 +/- 373.4, P = 0.02). WBC counts were higher on Day 1 in MEF samples positive for S. pneumoniae than in those positive for H. influenzae (799.2 +/- 641.5 vs.506.4 +/- 401.9, P = 0.04). There were no differences in the number of neutrophil WBC present in the samples obtained on Day 1 vs. Days 4 to 5 or between samples positive vs.samples negative for bacterial pathogens. CONCLUSIONS: WBC counts were higher in the MEF of patients with culture-positive AOM than in those with culture-negative AOM and in those with AOM caused by S. pneumoniae.

Dynamics of pneumococcal nasopharyngeal carriage in children with nonresponsive acute otitis media treated with two regimens of intramuscular ceftriaxone.

BACKGROUND: A 3-day intramuscular ceftriaxone regimen was superior to a 1-day regimen in the treatment of nonresponsive acute otitis media caused by resistant Streptococcus pneumoniae. However, the effect of various regimens of intramuscular cefriaxone on the nasopharyngeal carriage of S. pneumoniae and especially that of resistant strains during and after therapy has not been thoughtfully studied. OBJECTIVES: To compare the effect of one dose and three dose intramuscular ceftriaxone regimens on the nasopharyngeal carriage of S. pneumoniae in patients with nonresponsive acute otitis media treated with these two regimens and to document the dynamics of nasopharyngeal colonization with S. pneumoniae during and after completion of these two therapeutic regimens. PATIENTS AND METHODS: In a prospective study performed during January, 1998, through September, 1999, 170 evaluable patients ages 3 to 36 months with nonresponsive acute otitis media were randomized to receive the 1 (n = 83)- or 3 (n = 87)-day intramuscular ceftriaxone regimen (50 mg/kg/day), respectively. Nasopharyngeal cultures for S. pneumoniae were obtained on Days 1, 4 to 5, 11 to 14 and 28 to 30. Susceptibility of S. pneumoniae to penicillin and ceftriaxone was determined by E-test. RESULTS: On Day 1 nasopharyngeal S. pneumoniae carriage was found in 108 (64%) patients, 54 in each treatment group. Forty-seven of 54 (87%) and 9 of 54 (17%) S. pneumoniae isolates from the one dose group were nonsusceptible to penicillin and ceftriaxone, respectively; the respective values in the three dose group were 49 of 54 (91%) and 8 of 54 (15%). On Days 4 and 5 negative nasopharyngeal cultures were achieved in 43 of 83 (52%) and 70 of 87 (80%) cases from the one dose and three dose group, respectively (P < 0.001). Eradication of penicillin-nonsusceptible S. pneumoniae was achieved on Day 4 to 5 in 18 of 49 (37%) and 39 of 49 (80%) organisms isolated from the one dose and three dose groups, respectively (P < 0.001). Nasopharyngeal S. pneumoniae carriage among evaluable patients on Days 11 to 14 and Days 28 to 30 was 43 of 69 (62%) and 31 of 45 (69%) for the one dose group and 42 of 73 (58%) and 31 of 50 (62%) for the three dose group, respectively (P not significant). A decrease was observed during the study period in the proportion of highly penicillin-resistant S. pneumoniae isolated in the three dose group compared with the one dose group (30, 24, 17 and 13% vs. 30, 27, 19 and 26% at Days 1, 4 to 5, 11 to 14 and 28 to 30, respectively; P = 0.05). CONCLUSIONS: A marked reduction in the carriage of penicillin-nonsusceptible S. pneumoniae (including highly penicillin-resistant organisms) was achieved on Days 4 to 5 of therapy with both ceftriaxone regimens. The 3-day intramuscular ceftriaxone regimen was significantly superior to the 1-day regimen in the reduction of carriage during the treatment period. The reduction of overall S. pneumoniae nasopharyngeal carriage by both ceftriaxone regimens was a short-lived phenomenon followed by rapid recolonization of the nasopharynx.

Recurrent acute otitis media occurring within one month from completion of antibiotic therapy: relationship to the original pathogen.

OBJECTIVES: (1) To determine the relationship between acute otitis media (AOM) pathogens isolated in cases of early clinical recurrence of AOM (occurring within 1 month from completion of therapy) to the original pathogens causing the initial AOM episode; and (2) To determine whether shorter time intervals between completion of antibiotic therapy and clinical recurrences of AOM are associated with higher rates of true bacteriologic relapse. PATIENTS AND METHODS: From 1995 through 2000, 1077 infants and young children ages 3 to 36 months with AOM were enrolled in double tympanocentesis (performed on Day 1 in all patients and Days 4 to 6 in those initially culture-positive) studies. Of these, 834 (77%) completed successfully the antibiotic treatment [pathogen eradication on Days 4 to 6 of therapy or no pathogen on middle ear fluid (MEF) culture on Day 1 and clinical improvement at end of therapy]. Patients were followed for 3 to 4 weeks after completion of therapy, and additional MEF cultures were obtained if clinical recurrence occurred. True bacteriologic relapse was defined as the presence of a pathogen identical with that isolated before therapy by serotype and pulsed field gel electrophoresis for and by pulsed field gel electrophoresis for Streptococcus pneumoniae and beta-lactamase production for Haemophilus influenzae. RESULTS: MEF cultures were performed in 108 consecutive patients with early recurrent AOM. One hundred pathogens were isolated at recurrence in 88 of 108 (81%) patients: 54 H. influenzae; 45 S. pneumoniae; and 1 Moraxella catarrhalis. Most recurrent AOM episodes developed during the first 2 weeks of follow-up; 39 (36%), 38 (35%), 21 (19%) and 10 (9%) recurrent AOM episodes occurred on Days 1 to 7, 8 to 14, 15 to 21 and 22 to 28 after completion of therapy, respectively. In most patients these episodes were caused by a new pathogen. True bacteriologic relapses were found in 30 (28%) of 108 patients whose MEF cultures were positive for 35 pathogens: 13 of 108 (12%) S. pneumoniae; 12 of 108 (11%) H. influenzae; and 5 of 108 (5%) both. When timing of recurrent AOM after completion of therapy was analyzed, true bacteriologic relapses were found in 16 of 39 (41%), 10 of 38 (26%), 3 of 21 (14%) and 1 of 10 (10%) of all episodes on Days 1 to 7, 8 to 14, 15 to 21 and 22 to 28 after completion of therapy, respectively (P = 0.01). The respective rates for were 11 of 17 (65%), 3 of 10 (30%), 3 of 13 (23%) and 1 of 5 (20%) (P = 0.02). For H. influenzae the respective rates were 8 of 19 (42%), 9 of 23 (39%), 0 of 8 (0%) and 0 of 4 (0%) (P = 0.02). CONCLUSIONS: Most recurrent AOM episodes occurring within 1 month from completion of antibiotic therapy are in fact new infections. Most of the true bacteriologic AOM relapses occur within 14 days after completion of therapy, but even during this time interval most of the recurrences are caused by new pathogens. H. influenzae is very unlikely to cause true bacteriologic AOM relapses 14 days or later after completion of therapy.

Bacteriologic and clinical efficacy of high dose amoxicillin for therapy of acute otitis media in children.

BACKGROUND: High dose (70 to 90 mg/kg/day) amoxicillin is recommended as first line therapy of acute otitis media (AOM) in geographic areas where drug-resistant Streptococcus pneumoniae is prevalent. Information on the bacteriologic efficacy of high dose amoxicillin treatment for AOM is limited. OBJECTIVES: To evaluate the bacteriologic and clinical efficacy of high dose amoxicillin as first line therapy in AOM. METHODS: In a prospective study 50 culture-positive patients ages 3 to 22 months (median, 9 months; 77% <1 year) were treated with high dose amoxicillin (80 mg/kg/day three times a day for 10 days) No antibiotics were administered 72 h before enrollment. Twenty-four (48%) patients presented with their first episode of AOM. Middle ear fluid was cultured by tympanocentesis at enrollment and on Days 4 to 6 of therapy. Additional middle ear fluid cultures were obtained if clinical relapse occurred. Bacteriologic failure was defined by positive cultures on Days 4 to 6 and clinical failure by no change or worsening of AOM signs and symptoms and requirement for additional antibiotics during therapy and/or at end of therapy. Patients were followed until Day 28 +/- 2. Susceptibility to penicillin and amoxicillin was measured by E-test. RESULTS: Sixty-five organisms were recovered at enrollment: Haemophilus influenzae (38), Streptococcus pneumoniae (24), Streptococcus pyogenes (2) and Moraxella catarrhalis (1). Eighteen (75%) S. pneumoniae were nonsusceptible to penicillin (MIC > 0.1 microg/ml). All 24 S. pneumoniae isolates had amoxicillin MIC < or = 2.0 microg/ml. Thirteen (34%) of the 38 H. influenzae were beta-lactamase producers. Eradication was achieved in 41 (82%) patients for 54 of 65 (83%) pathogens: 22 of 24 (92%) S. pneumoniae, 21 of 25 (84%) beta-lactamase-negative H. influenzae, 8 of 13 (62%) beta-lactamase-positive H. influenzae, 2 of 2 S. pyogenes and 1 of 1 M. catarrhalis. Seven organisms not initially present were isolated on Days 4 to 6 in 5 patients: 3 beta-lactamase-positive H. influenzae; 1 beta-lactamase-negative H. influenzae; 2 S. pneumoniae; and 1 M. catarrhalis. In total 14 of 50 (28%) patients failed bacteriologically on Days 4 to 6 (persistence + new infection), of whom 9 (64%) had beta-lactamase-positive H. influenzae. Three (33%) of the 9 patients with bacteriologic failure (2 beta-lactamase-positive H. influenzae, 1 S. pneumoniae) failed also clinically on Days 4 to 6. CONCLUSIONS: The predominant pathogens isolated from children with AOM failing high dose amoxicillin therapy were beta-lactamase-producing organisms. Because its overall clinical efficacy is good, high dose amoxicillin is still an appropriate choice as first line empiric therapy for AOM, followed by a beta-lactamase-stable drug in the event of failure.

Can acute otitis media caused by Haemophilus influenzae be distinguished from that caused by Streptococcus pneumoniae?

BACKGROUND: Previous limited data suggest that acute otitis media (AOM) caused by Streptococcus pneumoniae can present as a more severe disease than that caused by Haemophilus influenzae or Moraxella catarrhalis, as expressed by both tympanic membrane and systemic findings. OBJECTIVES: To evaluate the severity of disease and impact of various pathogens, age, disease history and previous antibiotic therapy in children with AOM by using a comprehensive clinical/otologic score. PATIENTS AND METHODS: The study group consisted of 372 children ages 3 to 36 months with AOM seen at the pediatric emergency room during 1996 through 2001. All patients had tympanocentesis and middle ear fluid culture performed at enrollment. Clinical status was determined by a clinical/otologic score evaluating severity (0 = absent to 3 = severe) of tympanic membrane findings (redness and bulging) and patient's fever, irritability and ear tugging. Maximal severity score was 15. RESULTS: There were 138 (37%) H. influenzae, 76 (21%) S. pneumoniae, 64 (17%) mixed infections (H. influenzae + S. pneumoniae) and 94 (25%) culture-negative cases. The overall clinical/otologic score was higher in culture-positive than in culture-negative patients (9.27 +/- 2.75 vs.8.38 +/- 3.08, P = 0.01). When analyzed by age groups, this difference was significant only for the youngest age group (3 to 6 months, P = 0.05). The severity scores for AOM caused by H. influenzae and S. pneumoniae were significantly higher than in the culture-negative AOM when tympanic membrane redness and bulging were analyzed separately. No differences were recorded in clinical/otologic scores between different pathogens (9.49 +/- 2.86, 9.03 +/- 2.72 and 9.09 +/- 2.54 for H. influenzae, S. pneumoniae and H. influenzae + S. pneumoniae, respectively). The mean clinical/otologic score was higher in culture-positive than in culture-negative patients without relationship to previous antibiotic treatment or number of previous AOM episodes. CONCLUSIONS: (1) The clinical/otologic score of culture-positive young infants was higher than that of culture-negative infants; (2) the severity of tympanic membrane redness and bulging were the most indicative factors discriminating between a bacterial and nonbacterial etiology of AOM; and (3) the use of a clinical/otologic score could not discriminate among various bacterial etiologies of AOM.

Bacteriologic and clinical efficacy of oral gatifloxacin for the treatment of recurrent/nonresponsive acute otitis media: an open label, noncomparative, double tympanocentesis study.

BACKGROUND: Gatifloxacin is an 8-methoxyfluoroquinolone with good activity against respiratory pathogens. OBJECTIVES: To document the bacteriologic and clinical efficacy of gatifloxacin in recurrent/nonresponsive acute otitis media (AOM). METHODS: One hundred sixty patients 6 to 48 months of age with recurrent/nonresponsive AOM received gatifloxacin suspension (10 mg/kg once daily for 10 days). Recurrent AOM was defined as > or =3 AOM episodes during the previous 6 months or > or =4 AOM episodes during the previous 12 months. Nonresponsive AOM was defined as AOM occurring < or =14 days after completing antibiotic treatment or not improving after > or =48 h of therapy. Middle ear fluid (MEF) obtained by tympanocentesis pretreatment (Day 1) and 3 to 5 days after initiation of treatment (Days 4 to 6) was cultured. Additional MEF cultures were obtained if clinical failure or recurrence of AOM occurred. Bacteriologic failure was defined by culture-positive MEF during treatment. Patients were followed until Days 22 to 28. Susceptibility was determined by broth microdilution. RESULTS: One hundred twenty-eight (80%) patients completed treatment, and 32 discontinued the study prematurely (adverse events, 17; lost to follow-up, 10; consent withdrawal, 3; and laboratory abnormalities, 2). From 89 patients (median age, 1 year; median number of prior AOM episodes, 4; range, 0 to 12), 121 pathogens were recovered: Haemophilus influenzae, 74 (61%); Streptococcus pneumoniae, 36 (30%); Moraxella catarrhalis, 9 (7%); and Streptococcus pyogenes, 2 (2%). The 36 S. pneumoniae isolates were susceptible to gatifloxacin (MIC50 0.25 microg/ml); 26 of 36 (72%) were penicillin-nonsusceptible (15 fully resistant). All 74 H. influenzae isolates were susceptible to gatifloxacin (MIC < or = 0.03 mg/ml). Fourteen of 74 (19%) and 9 of 9 (100%) H. influenzae and M. catarrhalis isolates, respectively, produced beta-lactamase. Bacteriologic eradication was achieved for 118 of 121 (98%) pathogens: 74 of 74 H. influenzae; 34 of 36 (94%) S. pneumoniae; 9 of 9 M. catarrhalis; and 1 of 2 S. pyogenes. Clinical improvement/cure at end of treatment was seen in 103 of 114 (90%) clinically evaluable patients. Clinical recurrence of AOM after completion of therapy occurred in 31 patients. Of the 27 recurrent AOM cases in which tympanocentesis was performed, there were 16 (59%) new infections, 4 (15%) culture-negative results and only 7 (26%) true bacteriologic relapses. Adverse events were recorded in 21 of 160 (13%) patients: vomiting, 16; diarrhea, 3; maculopapular rash, 2. No articular adverse events were recorded. CONCLUSION: Gatifloxacin is efficacious and safe for the treatment of recurrent/nonresponsive AOM.

Pain sensitivity in prematurely born adolescents.

BACKGROUND: Several studies reported that preterm infants were found to be hypersensitive to pain. However, longitudinal and quantitative assessments of subsequent pain thresholds in adolescence are scarce. OBJECTIVE: To assess the tenderness threshold in adolescents born prematurely compared with matched children born at full term. DESIGN: Case-control study. SETTING: Children in the community recruited from the files of the neonatal intensive care unit. PARTICIPANTS: Sixty adolescents (aged 12-18 years) born prematurely and 60 adolescents born at full term. MAIN OUTCOME MEASURES: Tenderness thresholds were assessed by tender-point count and by dolorimeter. RESULTS: The preterm-born children had significantly more tender points (6.0 +/- 5.2 vs 3.3 +/- 3.3; P =.001) and lower tender thresholds (4.2 +/- 1.5 vs 4.8 +/- 1.6 kg; P =.04), measured by a dolorimeter, than children born at full term. In both groups, girls had significantly more tender points and lower tender thresholds. Despite their increased tenderness, most of the preterm children did not report pain or other related symptoms. CONCLUSIONS: The fact that preterm-born children and adolescents display higher somatic pain sensitivity may be of relevance to physicians taking care of these children, since they may be prone to developing pain syndromes in the future. Further follow-up studies are needed to confirm this hypothesis.

Fibromyalgia in systemic lupus erythematosus: prevalence and clinical implications.

Fibromyalgia (FM) is common in SLE patients, and is the source of many of the symptoms and much of the disability in these patients. The association of FM and SLE may pose diagnostic dilemmas. Fibromyalgia does not correlate with SLE disease activity, but the clinical features of FM in these patients may contribute to a misinterpretation of lupus activity. The recognition of the association between SLE and FM is relevant to every physician who treats lupus patients.