Joseph Press

Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy

BACKGROUNDnPolyarteritis 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.nnnMETHODSnWe 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.nnnRESULTSnIn 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.nnnCONCLUSIONSnRecessive 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.).

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 &mgr;g/ml). All 24 S. pneumoniae isolates had amoxicillin MIC ≤ 2.0 &mgr;g/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.

Oral ciprofloxacin vs. intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children.

BACKGROUNDnAcute invasive diarrhea is a potentially serious condition in children. Because of the increasing resistance of enteric pathogens to commonly used oral antibiotics, intramuscular ceftriaxone has become the routine drug in the treatment of acute invasive diarrhea requiring an emergency visit in southern Israel. The inconvenience of this parenteral regimen created an increased need for oral pediatric formulations for the treatment of invasive diarrhea.nnnOBJECTIVESnTo evaluate the efficacy and safety of a suspension formulation of ciprofloxacin in the treatment of acute invasive diarrhea in infants and children.nnnPATIENTS AND METHODSnFrom July 1996 through December 1997, 201 evaluable children ages 6 months to 10 years (35% <1 year; 70% <3 years) presenting with acute invasive diarrhea at the Pediatric Emergency Room were randomized to receive either ciprofloxacin suspension (10 mg/kg twice a day + im placebo; n = 95) or im ceftriaxone (50 mg/kg/day + placebo suspension; n = 106) for 3 days in a double blind manner. Stool cultures for Shigella, Salmonella, Campylobacter spp. and diarrheagenic Escherichia coli were obtained on Days 1, 3, 4 to 5 and 21 +/- 5. Clinical response and safety were assessed on Days 1, 2, 3, 4 to 5 and 21 +/- 5.nnnRESULTSnWe isolated 127 pathogens from 121 (60%) patients: 73 (57%) Shigella; 23 (18%) Salmonella; 18 (14%) E. coli; and 13 (10%) Campylobacter. Overall bacteriologic eradication on Day 4 to 5 was 99% for Shigella, 77% for Salmonella and 77% for Campylobacter, with no difference between the 2 groups. Clinical cure or improvement was observed in 100 and 99% of the ciprofloxacin and ceftriaxone groups, respectively. Serum ciprofloxacin values determined on Day 3 of the treatment were higher in the majority of patients than were the MIC50 and MIC90 values for the Shigella and Salmonella spp. isolated. Possible drug-related adverse events occurred in 13 patients [ciprofloxacin, 8 (8%); ceftriaxone, 5 (4.7%)] and were mild and transient. Joint examination was normal during and after completion of therapy in all patients.nnnCONCLUSIONnOral ciprofloxacin was as safe and effective as intramuscular ceftriaxone for the empiric treatment of acute invasive diarrhea in ambulatory pediatric patients requiring an emergency room visit.

Bacteriologic and clinical efficacy of one day vs. three day intramuscular ceftriaxone for treatment of nonresponsive acute otitis media in children.

BACKGROUNDnOne dose of intramuscular ceftriaxone has been recently licensed in the United States for the treatment of acute otitis media. However, data regarding the bacteriologic and clinical efficacy of this regimen in the treatment of nonresponsive acute otitis media are incomplete.nnnOBJECTIVESnTo determine the bacteriologic and clinical efficacy of a 1-day 50-mg/kg vs. a 3-day 50-mg/kg/day intramuscular ceftriaxone regimen in the treatment of nonresponsive acute otitis media in children.nnnPATIENTS AND METHODSnIn an open, prospective study 109 patients ages 3 to 36 months with culture-proved, nonresponsive acute otitis media were randomized to receive 1 (n = 49) or 3 (n = 60) 50-mg/kg/day intramuscular ceftriaxone doses, respectively. Middle ear fluid was aspirated for culture by tympanocentesis on the day of enrollment (Day 1); a second tympanocentesis with middle ear fluid culture was performed on Days 4 to 5. Additional middle ear fluid cultures were obtained if clinical relapse occurred after completion of therapy. Bacteriologic failure was defined by positive cultures on Days 4 to 5. Patients were followed until Day 28 after completion of therapy. Susceptibility of the middle ear pathogens was measured by E-test.nnnRESULTSnOrganisms recovered (n = 133) were Streptococcus pneumoniae (30 and 35 isolates for the 1-day and 3-day treatment group, respectively), Haemophilus influenzae (26 and 38, respectively) and Moraxella catarrhalis (n = 4). Of the 30 S. pneumoniae isolated from the 1-day group, 27 (90%) and 6 (20%) were nonsusceptible to penicillin and ceftriaxone, respectively; 9 of 27 (33%) were fully resistant to penicillin. Thirty-four (97%) and 6 (17%) of the 35 S. pneumoniae isolated from the 3-day group were nonsusceptible to penicillin and ceftriaxone, respectively; 16 of 34 (47%) were fully resistant to penicillin. Bacterial eradication of all H. influenzae and penicillin-susceptible S. pneumoniae was achieved in both treatment groups. Bacterial eradication of 14 of 27 (52%) and 33 of 34 (97%) penicillin-nonsusceptible S. pneumoniae was achieved in the 1-day and 3-day group, respectively. Seven (50%) of the 14 patients from the 2 groups who did not achieve bacterial eradication did not improve clinically on Days 4 to 5 and required additional ceftriaxone treatment.nnnCONCLUSIONnThe 3-day intramuscular ceftriaxone regimen was significantly superior to the 1-day intramuscular ceftriaxone regimen in the treatment of nonresponsive acute otitis media caused by penicillin-resistant S. pneumoniae.

Influenza Virus Vaccination of Patients with SLE: Effects on Generation of Autoantibodies

Abstract: The sera of 24 women with SLE who received influenza vaccine were tested by ELISA for anti-DNA, anticardiolipin, anti-Sm, anti-Sm/RNP, anti-Ro and anti-La. Blood samples were withdrawn at the time of vaccination and 6 and 12 weeks after vaccination. The mean age at enrolment into the study was 46.1 years. The mean disease duration was 9.1 years. SLEDAI scores were 6.6 at vaccination, 4.9 at 6 weeks and 5.1 at week 12. The vaccine was not associated with the generation of anti-DNA. At time of vaccination a single patient had anti-Sm, four patients had anti-Sm/RNP antibodies, none of the patients had anti-La antibody and six had anti-Ro antibodies. Six weeks after vaccination four, eight, nine and three patients had autoantibodies reacting with Sm, Sm/RNP, Ro and La, respectively. Twelve weeks after vaccination none of the patients had anti-Sm, three had anti-Sm/RNP, five had anti-Ro and two had anti-La antibodies. Following vaccination six and three patients developed IgG and IgM anticardiolipin antibodies, respectively. In summary, although the influenza virus vaccine is clinically safe for patients with SLE it may trigger the generation of autoantibodies. This effect is usually short term and has no clinical significance.

Bacteriologic and clinical efficacy of trimethoprim-sulfamethoxazole for treatment of acute otitis media.

Background. Trimethoprim-sulfamethoxazole (T/S) has often been used as first and second line of treatment for acute otitis media (AOM). Because of the increasing resistance of Streptococcus pneumoniae and Haemophilus influenzae to T/S, we undertook the present study to investigate the bacteriologic and clinical efficacy of this drug in AOM. Methods. Fifty-four culture-positive evaluable patients ages 3 to 32 months with AOM were treated with T/S 4/20 mg/kg in two divided daily doses for 10 days. Middle ear fluid (MEF) was cultured at enrollment (Day 1) and on Days 4 and 5 after initiation of treatment. Additional MEF cultures were obtained if clinical relapse occurred. Clinical failure was determined when the symptoms and signs of AOM did not improve or recurred during therapy. Bacteriologic failure was defined by positive culture on Days 4 and 5, or negative on Days 4 and 5 but positive again before the end of treatment. Patients were followed until Day 28 ± 2. Results. A total of 67 organisms were isolated from MEF specimens of the 54 study patients:S. pneumoniae, 24;H. influenzae, 40; and Streptococcus pyogenes, 3. Fifteen (63%) of 24 S. pneumoniae were nonsusceptible to T/S (trimethoprim MIC, >0.5 &mgr;g/ml), of which 10 (67%) were highly resistant to T/S (trimethoprim MIC, ≥4.0 &mgr;g/ml). Twelve (30%) of 40 H. influenzae and all 3 S. pyogenes isolates were nonsusceptible to T/S (MIC ≥ 4.0 &mgr;g/ml). Bacteriologic eradication occurred in 9 of 9 (100%) and 27 of 27 (100%) T/S-susceptible S. pneumoniae and H. influenzae, respectively, vs. 4 of 15 (27%) and 6 of 12 (50%) T/S-nonsusceptible S. pneumoniae and H. influenzae, respectively (P < 0.001). The 3 patients with S. pyogenes failed bacteriologically. Nine new organisms, not initially isolated, emerged during treatment, 7 of which (77%) were resistant to T/S. Altogether bacteriologic failure (organisms not eradicated plus newly emerged) occurred in 29 (53%) of 54 patients. Clinical failures occurred in 8 (15%) of 54 patients, and in 7 of these 8 cases the clinical failures occurred in those with bacteriologic failures. Ten patients relapsed clinically after completion of treatment and in 8 of them tympanocentesis for MEF culture was performed. Six of these 8 cultures were positive, and the initial pathogen was isolated in 4 of 6 (67%). Conclusions. A high bacteriologic failure rate as well as a considerable clinical failure rate occurred among patients with AOM treated with T/S. We believe that T/S is no longer an appropriate empiric choice for the treatment of AOM in regions where high T/S resistance among respiratory pathogens is reported.

Bacteriologic efficacy of a three-day intramuscular ceftriaxone regimen in nonresponsive acute otitis media

OBJECTIVEnTo determine the bacteriologic efficacy of ceftriaxone in nonresponsive acute otitis media in children.nnnMETHODSnIn a prospective study 92 patients ages 3 to 36 months (median, 11 months) with culture-proved nonresponsive acute otitis media were studied from January, 1995, through August, 1997. The patients were treated with intramuscular ceftriaxone (50 mg/kg/l/day) for 3 days. Middle ear fluid was aspirated for culture by tympanocentesis on day of enrollment (Day 1); a second tap was performed on Days 4 to 10. Additional middle ear fluid cultures were obtained if clinical relapse occurred. Bacteriologic failure was defined by positive culture on Days 4 to 10. Patients were followed until Day 17+/-2. Susceptibility was measured by E test.nnnRESULTSnThe main drugs administered before enrollment were amoxicillin (38%), amoxicillinclavulanate (25%) and cefaclor (20%). Organisms recovered (n=105) were: Haemophilus influenzae, 54; Streptococcus pneumoniae, 47; Moraxella catarrhalis, 2; and Streptococcus pyogenes, 2. Thirty-four (72%) of the 47 S. pneumoniae isolates were intermediately resistant to penicillin (MIC 0.1 to 1.0 microg/ml), but all were susceptible to ceftriaxone (MIC < 0.5 microg/ml). Bacteriologic eradication was achieved in 100 of 105 (95%) cases: 54 of 54 (10O%) H. influenzae, 43 of 47 (92%) S. pneumoniae, 1 of 2 (50%) M. catarrhalis and 2 of 2 (100%) S. pyogenes. Bacteriologic success (with no relapse) occurred in 13 of 13 (100%) penicillin-susceptible S. pneumoniae vs. 28 of 34 (82%) S. pneumoniae intermediately resistant to penicillin (4 cases of bacteriologic failure and 2 cases of relapse).nnnCONCLUSIONnA 3-day intramuscular ceftriaxone regimen is efficacious for the treatment of nonresponsive acute otitis media. The optimal duration of treatment in cases of nonresponsive acute otitis media and whether ceftriaxone is efficacious for the treatment of nonresponsive otitis media caused by S. pneumoniae highly resistant to penicillin is yet to be determined.

Predictive value of pneumococcal nasopharyngeal cultures for the assessment of nonresponsive acute otitis media in children

Background. Nonresponsive acute otitis media (NR‐AOM) is reported in >10% of children with AOM treated with antibiotics. Drug‐resistant Streptococcus pneumoniae is currently considered the leading cause of antibiotic failures in AOM. Nasopharyngeal colonization with S. pneumoniae was found to increase significantly during episodes of AOM. Objectives. To investigate the nasopharyngeal colonization with S. pneumoniae during NR‐AOM and compare it with that found in AOM not recently treated with antibiotics (NT‐AOM); to assess the predictive value of nasopharyngeal pneumococcal cultures results for the bacteriologic assessment of NR‐AOM. Materials and methods. Patients age 3 to 48 months with NT‐AOM and NR‐AOM were prospectively studied. Simultaneous nasopharyngeal cultures for S. pneumoniae and middle ear fluid cultures were obtained at enrollment. Antibiotic susceptibility testing was performed in all S. pneumoniae isolates. Penicillin and ceftriaxone MICs for S. pneumoniae were determined by E‐test. The sensitivity, specificity and positive and negative predictive values of positive or negative nasopharyngeal cultures for the presence of S. pneumoniae in middle ear fluid were calculated. Results. We studied 362 and 217 children with NT‐AOM and NR‐AOM, respectively. Of the children with NT‐AOM and NR‐AOM, 95 and 97%, respectively, were younger than 2 years of age. S. pneumoniae was isolated in the nasopharynx of 66 and 58% of children with NT‐AOM and NR‐AOM, respectively. Penicillin‐nonsusceptible S. pneumoniae was isolated more frequently from the nasopharynx of patients with NR‐AOM than from those with NT‐AOM (84%vs. 47%;P < 0.01). Antibiotic susceptibility patterns were similar for S. pneumoniae isolates recovered from the nasopharynx and those from the middle ear fluid in both NT‐AOM and NR‐AOM. A positive nasopharyngeal culture had only little predictive value for the presence of S. pneumoniae in middle ear fluid (41 and 51% for NT‐AOM and NR‐AOM, respectively). However, the negative predictive value of nasopharyngeal cultures for recovery of S. pneumoniae in NR‐AOM was high and significantly higher in NR‐AOM than in NT‐AOM (91%vs. 78%, respectively;P = 0.009). The negative predictive value of nasopharyngeal cultures for recovery of antibiotic‐resistant S. pneumoniae was 95 and 93% in NT‐AOM and NR‐AOM, respectively. Conclusions. A significantly higher nasopharyngeal colonization rate with antibiotic‐resistant S. pneumoniae was found in patients with NR‐AOM than in those with NT‐AOM. Negative nasopharyngeal culture for antibiotic‐resistant S. pneumoniae practically rules out its presence in middle ear fluid.

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.

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.