The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. An individual patient data meta-analysis.

OBJECTIVE: Recent studies have shown that a dosage of 8 g/d of oral valacyclovir reduces substantially the vertical transmission rate of cytomegalovirus in women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy. This individual patient data meta-analysis aimed to assess the effectiveness and safety of valacyclovir treatment in the secondary prevention of congenital cytomegalovirus infection. DATA SOURCES: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, the US registry of clinical trials (www. CLINICALTRIALS: gov), and gray literature sources were searched from inception to March 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and quasi-randomized studies administering 8 g/d of oral valacyclovir in pregnant women with primary cytomegalovirus infection acquired periconceptionally or during the first trimester of pregnancy were included. METHODS: All corresponding authors of the eligible studies were contacted. Cochrane's Risk of Bias 2 and Risk Of Bias In Non-randomised Studies - of Interventions tools were used for the risk of bias assessment. The result of amniocentesis was the primary outcome of interest. A 1-stage individual patient data meta-analysis was performed, using a generalized linear mixed model, clustered by the different trials. A subgroup analysis was performed, assessing separately the effect of valacyclovir in the periconceptional period and first trimester of pregnancy. RESULTS: Overall, 3 studies were included in the analysis (n=527 women). Valacyclovir reduced the vertical transmission rate of cytomegalovirus (adjusted odds ratio, 0.34; 95% confidence interval, 0.18-0.61). This reduction was apparent for both periconceptional period (adjusted odds ratio, 0.34; 95% confidence interval, 0.12-0.96) and first-trimester (adjusted odds ratio, 0.35; 95% confidence interval, 0.16-0.76) infections. Moreover, valacyclovir reduced the rate of neonatal infection (adjusted odds ratio, 0.30; 95% confidence interval, 0.19-0.47), in both periconceptional period (adjusted odds ratio, 0.30; 95% confidence interval, 0.14-0.61) and first-trimester (adjusted odds ratio, 0.30; 95% confidence interval, 0.17-0.54) infections. Furthermore, valacyclovir reduced the rate of termination of pregnancy because of cytomegalovirus-associated severe fetal findings (adjusted odds ratio, 0.23; 95% confidence interval, 0.22-0.24). The gestational age at the initiation of treatment has a positive correlation with all outcomes. The overall prevalence of severe side effects was 2.1%. CONCLUSION: A dosage of 8 g/d of oral valacyclovir reduced the vertical transmission rates of cytomegalovirus following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy, with a low incidence of side effects.

Revised Protocol for Secondary Prevention of Congenital Cytomegalovirus Infection With Valaciclovir Following Infection in Early Pregnancy.

BACKGROUND: A previous randomized placebo-controlled study found valaciclovir to be effective in reducing the rate of vertical cytomegalovirus transmission from mother to fetus. The better results in women infected in the first trimester compared to the periconception period were attributed to the timing of treatment. The aim of the present study was to evaluate valaciclovir efficacy in this setting using a revised protocol. METHODS: All pregnant women treated with valaciclovir in 2020-2022 who met the same criteria as in the original study were identified retrospectively from the database of the same medical center. Treatment, however, was initiated earlier: up to 9 weeks or 8 weeks from the presumed time of infection in women infected in the periconception period or the first trimester, respectively. The primary endpoint was rate of vertical cytomegalovirus transmission. Results were compared with the placebo arm in the previous study. RESULTS: Among 178 women who completed valaciclovir treatment, amniocentesis was positive for cytomegalovirus in 14 women (7.9%), significantly (P < .001) lower compared with 14 of 47 (30%) in the placebo arm in the previous study. The proportion of positive amniocentesis in the valaciclovir was significantly lower than the placebo arm both among women infected in the first trimester (14/119 vs 11/23; odds ratio [OR] = 0.15; 95% confidence interval [CI]: .05-.45, P < .001), as well as among those infected in the periconception period (0/59 vs 3/24, OR = 0; 95% CI 0-.97, P = .02). CONCLUSIONS: This study provides further evidence of the efficacy of valaciclovir in preventing vertical transmission of cytomegalovirus after primary maternal infection. Efficacy is improved with earlier treatment.

Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Cytomegalovirus is a common congenital infection, with high morbidity after an early primary maternal infection. No effective means exist to prevent viral transmission to the fetus. We aimed to investigate whether valaciclovir can prevent vertical transmission of cytomegalovirus to the fetus in pregnant women with a primary infection acquired early in pregnancy. METHODS: This prospective, randomised, double-blind, placebo-controlled trial was done at the Infectious Feto-Maternal Clinic of Rabin Medical Center (Petach Tikvah, Israel). Pregnant women aged 18 years or older, with serological evidence of a primary cytomegalovirus infection acquired either periconceptionally or during the first trimester of pregnancy, were randomly assigned to oral valaciclovir (8 g per day, twice daily) or placebo from enrolment until amniocentesis at 21 or 22 gestational weeks. Randomisation was done separately for participants infected periconceptionally or during the first trimester and was done in blocks of four. Patients and researchers were masked to participant allocation throughout the entire study period. The primary endpoint was the rate of vertical transmission of cytomegalovirus. Statistical analyses were done according to per-protocol principles. The study was registered at ClinicalTrials.gov, NCT02351102. FINDINGS: Between Nov 15, 2015, and Oct 8, 2018, we enrolled and randomly assigned 100 patients to receive valaciclovir or placebo. Ten patients were excluded, five from each study group; therefore, the final analysis included 45 patients (all singletons) in the valaciclovir group and 45 patients (43 singletons and two sets of twins) in the placebo group. In the valaciclovir group, including both first trimester and periconceptional infections, five (11%) of 45 amniocenteses were positive for cytomegalovirus, compared with 14 (30%) of 47 amniocenteses in the placebo group (p=0·027; odds ratio 0·29, 95% CI 0·09-0·90 for vertical cytomegalovirus transmission). Among participants with a primary cytomegalovirus infection during the first trimester, a positive amniocentesis for cytomegalovirus was significantly less likely in the valaciclovir group (two [11%] of 19 amniocenteses) compared with the placebo group (11 [48%] of 23 amniocenteses; p=0·020. No clinically significant adverse events were reported. INTERPRETATION: Valaciclovir is effective in reducing the rate of fetal cytomegalovirus infection after maternal primary infection acquired early in pregnancy. Early treatment of pregnant women with primary infection might prevent termination of pregnancies or delivery of infants with congenital cytomegalovirus. FUNDING: None.

Treatment of congenital cytomegalovirus beyond the neonatal period: an observational study.

Recently, valganciclovir treatment of symptomatic congenital cytomegalovirus (cCMV) disease, commenced during the neonatal period (≤ 4 weeks), was found to improve hearing and developmental outcome. However, many children (symptomatic or asymptomatic at birth) present only after 4 weeks of age. The purpose of this observational retrospective study was to describe the outcome and safety of valganciclovir therapy in infants with cCMV who started treatment > 4 weeks of life. Of the 91children who started antiviral treatment > 4 weeks of age, 66/298 (22.2%) were symptomatic at birth; 25/217 (11.5%) were asymptomatic at birth. Treatment was initiated on average at 14 weeks of age (range 5-77 weeks) and at 53.3 weeks (range 12-156 weeks), respectively. Of the 45 affected ears in the symptomatic group, 30 (66.7%) improved and only 2 (4.4%) deteriorated, with most of the improved ears (27/30, 90%) returning to normal. In the asymptomatic group, late-onset treatment was initiated and out of the 42 deteriorated ears, 38 (90.5%) improved after at least 1 year of follow-up. Hematological adverse events, i.e., neutropenia, were noted in a minority of cases (4.4%).Conclusion: Our study demonstrates the benefits and safety aspects of treating symptomatic and asymptomatic children with cCMV even beyond the recommended neonatal period.What is Known:• Valganciclovir treatment of symptomatic congenital cytomegalovirus (cCMV) disease, commenced during the neonatal period, is beneficial in improving hearing and developmental outcome.• However, data of treatment started beyond the neonatal period is lacking.What is New:• Our study demonstrates the benefits of treating symptomatic children with cCMV as well as asymptomatic children that develop late-onset hearing loss even beyond the recommended neonatal period.• This was true for symptomatic children who presented > 4 weeks as well as to those were asymptomatic at birth but experienced late hearing deterioration.

Musculoskeletal Manifestations as Presenting Symptoms of Inflammatory Bowel Disease in Children and Adolescents.

A comparison of 23 children with inflammatory bowel disease presenting with musculoskeletal symptoms and 46 children with arthritis of other causes yielded significantly higher rates in the inflammatory bowel disease group of sacroiliitis, arthralgia, additive and recurrent arthritis, microcytic anemia, elevated inflammatory markers, and hypoalbuminemia. Clinical awareness of these findings could expedite diagnosis and treatment.

Long-Term Follow-Up of Infants After a Brief Resolved Unexplained Event-Related Hospitalization.

OBJECTIVE: A brief resolved unexplained event (BRUE) in infancy is a common reason for visiting the emergency department. However, little is known about the long-term outcomes of such an event. This study evaluates future mortality, morbidity, and/or developmental outcome after a BRUE. METHODS: A single-center retrospective study performed in 2009 to 2013 included 87 hospitalized infants (<1 year old) fitting the American Academy of Pediatrics' criteria of a lower-risk BRUE, with 2 exceptions: no time limit to duration of episode and no age limit of ≥60 days. Hospitalized infants were followed up for up to 5 years via a telephone questionnaire to assess mortality rates, developmental delay, neurological/cardiovascular morbidity, and future hospitalizations. RESULTS: Most infants (94%) who experienced a BRUE were hospitalized before 6 months of age. No cases of mortality occurred. In terms of developmental outcome, 1 child (1.15%) was diagnosed as having a global developmental delay and 12 (13.7%) with a language delay, similar to prevalence rates by age in the United States. Three children (3.4%) were diagnosed as having an autism spectrum disorder, with higher prevalence rates than the global average. Simple febrile and nonfebrile seizures were seen at a rate similar to the general population. None of the children developed cardiovascular disease. Rehospitalization occurred in 22% of cases: 90% for common acute pediatric causes and 10% for recurrent choking events secondary to gastroesophageal reflux disease. CONCLUSIONS: Low-risk hospitalized infants younger than 1 year who experienced a BRUE seem to generally have an excellent prognosis.

Valganciclovir Is Beneficial in Children with Congenital Cytomegalovirus and Isolated Hearing Loss.

OBJECTIVE: To evaluate the efficacy of antiviral treatment for infants with congenital cytomegalovirus (cCMV) with isolated sensorineural hearing loss (SNHL). STUDY DESIGN: Data were reviewed retrospectively for infants with isolated SNHL who received prolonged antiviral treatment between 2005 and 2017. Hearing status was evaluated for infants who had been followed for >1 year. RESULTS: Among 329 infants treated for cCMV, 59 (18%) were born with isolated SNHL. Hearing impairment was unilateral in 38 (64.4%) infants and bilateral in 21 (35.6%). Of the 80 affected ears at baseline, 55 (68.8%) improved, and only 2 (2.5%) deteriorated. Most of the improved ears (53/55 = 96.3%) returned to normal hearing with no deterioration observed in the ears that were unaffected at baseline. On best ear evaluation, of 21 infants who had bilateral hearing loss, 16 (76.1%) improved (93.7% regaining normal functional hearing); none deteriorated. CONCLUSION: Infants born with isolated SNHL due to cCMV were found to benefit from prolonged antiviral treatment. These children (and ears) showed significant improvement in hearing status and no deterioration of unaffected ears at baseline. Our data serve as observational evidence of the benefits of antiviral treatment in these children. Avoiding treatment of these children due to the lack of prospective data is debatable.

Mycobacterium marinum: a rare cause of chronic lymphocutaneous syndrome.

We investigated the prevalence of Mycobacterium marinum lymphadenitis and describe 4 children with the disease. The database of the microbiology laboratory of a tertiary pediatric medical center was searched for all cases of nontuberculous mycobacterial lymphadenitis from 1996 to 2016. M. marinum lymphadenitis was defined as isolation of the pathogen from a lymph node or from a skin lesion with an enlarged regional lymph node. M. marinum was isolated from lymph nodes in 2 of 167 patients with nontuberculous mycobacterial lymphadenitis and from skin lesions in 2 children with skin lesions and regional reactive lymphadenitis, yielding a 2.4% prevalence of M. marinum lymphadenitis. All 4 affected children were younger than 7 years and had been referred for evaluation of enlarged lymph nodes. Preauricular/submandibular and inguinal lymph nodes (n = 2 each) were involved. Three patients had skin traumas and visited the same natural spring. The diagnosis was delayed because a history of aquatic exposure was initially missed. Two children were managed with anti-mycobacterial antibiotics and 2 by observation only. All showed good resolution. CONCLUSION: A detailed history, specifically regarding exposure to spring water sources, in cases of lymphocutaneous syndrome can point to the diagnosis of M. marinum infection. What is Known: • M. marinum can cause chronic nodular or ulcerative skin infections. • Lymphadenitis due to M. marinum has rarely been reported. What is New: • M. marinum infection can present as isolated chronic lymphadenitis; it accounts for about 2.4% of all cases of nontuberculous mycobacterial lymphadenitis and it tends to occur in noncervicofacial regions relative to infections of other nontuberculous mycobacterial species. • Careful history taking including water source exposure, especially in association with skin trauma, can point to the correct diagnosis in children with chronic lymphadenitis.

Symptomatic congenital cytomegalovirus disease following non-primary maternal infection: a retrospective cohort study.

BACKGROUND: Scarce data exist about screening, diagnosis and prognosis of non-primary Cytomegalovirus (CMV) during pregnancy. We aimed to examine antenatal diagnosis of maternal non-primary CMV infection and to identify risk factors for congenial CMV disease. METHODS: Retrospective cohort of 107 neonates with congenital symptomatic CMV infection, following either primary (n = 95) or non-primary (n = 12) maternal CMV infection. We compared the groups for the manifestations and severity of congenial CMV disease, as well as for possible factors associated with the risk of developing CMV related infant morbidity. RESULTS: Disease severity is not similar in affected newborns, with a higher incidence of abnormal brain sonographic findings, following primary versus non-primary maternal CMV infection (76.8% vs. 8.3%, p < .001). Symptomatic congenital CMV disease following a non-primary infection is more frequent if gestational hypertensive disorders and/or gestational diabetes mellitus have ensued during pregnancy (33.3% vs. 9.9%, p <0.038), as well as if any medications were taken throughout gestation (50% vs. 16.8%, p <0.016). CMV-IgM demonstrates a low detection rate for non-primary maternal infection during pregnancy compared to primary infection (25% vs. 75.8%, p = 0.0008). CONCLUSION: Non-primary maternal CMV infection has an impact on the neonate. Although not readily diagnosed during pregnancy, knowledge of risk factors may aid in raising clinical suspicion.

Children after renal transplantation hospitalized for fever: Is empirical antibiotic treatment always justified?

Infections are a major cause of morbidity and mortality after renal transplantation. However, data focusing on children are scarce. The objective of this study was to investigate the frequency and predictors of bacterial infection in pediatric renal transplant recipients in a specific setting of hospitalization due to fever. Clinical and laboratory data were retrospectively collected for all pediatric renal transplant recipients hospitalized for fever in a national renal transplantation center from 2004 to 2012. One hundred and sixty-eight hospital admissions for fever of 52 children were analyzed. A bacterial etiology was diagnosed in 85 admissions (50.6%); 49 cases (57.6%) were documented microbiologically and 36 (42.4%) clinically. Risk factors and markers of bacterial infection included older age, presence of a central venous catheter, sonographic findings, and elevated inflammatory indices. C-reactive protein level was a more sensitive marker than white blood cell count and absolute neutrophil count. In patients without identified risk factors, no bacterial infections were diagnosed. Pediatric renal transplant recipients hospitalized for fever are at high risk of bacterial infections and usually require empirical antibiotic treatment at admission. However, there is a minority of low-risk patients in whom clinicians may consider withholding antibiotic treatment with close follow-up.

Real-life comparison of three general paediatric wards showed similar outcomes for children with bronchiolitis despite different treatment regimens.

AIM: This study evaluated the effectiveness of three different treatments for bronchiolitis in a tertiary paediatric facility. METHODS: Patients with bronchiolitis who were younger than two years of age and were randomly allocated to three general wards at Schneider Children's Medical Center, Israel, after admission were included. Different treatment protocols in the wards were retrospectively compared. RESULTS: The study comprised 286 children. The clinical and laboratory parameters on admission were similar between the wards. In Ward C where nebulised hypertonic saline was infrequently administered (6.7%), the mean number of days with oxygen saturation under 92% and the meanlength of hospital stay (1.8 and 3.8 days) were significantly lower than Ward A (2.8 and 5.3 days) and Ward B, (2.9 and 4.7 days) where nebulised hypertonic saline was given more frequently (38.7%-74.7%). Multivariate analysis indicated that low saturation on admission, leukocytosis and use of nebulised hypertonic saline or adrenalin were independent predictors of a longer period of desaturation and hospital stay. CONCLUSION: Different treatment protocols for bronchiolitis were used in three paediatric wards in this real-life study. No treatment regimen proved superior. Inhalations of hypertonic saline or adrenaline were associated with a longer hospital stay.

Clinical Implications for Children Born With Congenital Cytomegalovirus Infection Following a Negative Amniocentesis.

BACKGROUND: Recently, congenital cytomegalovirus (cCMV) infection was reported irrespective of a negative amniotic fluid prenatal analysis for cytomegalovirus (CMV). The question of whether this phenomenon represents low sensitivity of the test or late development of fetal infection (after amniocentesis) was discussed, but not answered. However, if late transmission is the rule, then infants born with cCMV after negative amniocentesis would be expected to carry better prognosis than those who tested positive. METHODS: Data of all infants with cCMV infection, followed in 2 pediatric centers from 2006 to 2015, were reviewed. Infant outcome after birth of symptomatic vs asymptomatic disease was compared with infants born after a negative amniocentesis (study group) and those with a positive amniocentesis (control group). RESULTS: Amniocentesis was performed in 301 pregnancies of our cohort of infants with cCMV and was negative for CMV in 47 (15.6%). There were fewer symptomatic cCMV neonates in the study group than in the control group (4.3% vs 25%; P < .001). Hearing impairment at birth was also less frequent in the study group (2.2% vs 17.4%; P = .012). None of the children in the study group had neurologic sequelae at long-term follow up, compared with 13 (14.1%) in the control group (P < .001). CONCLUSIONS: Although negative amniocentesis does not exclude cCMV, infants with cCMV born after a negative amniocentesis seldom present with mild clinical symptoms or cerebral ultrasound features at birth. These children also have a very good long-term outcome. Our findings support the theory of a late development of fetal infection, after the time of the amniocentesis.

Pseudomonas aeruginosa identified as a key pathogen in hospitalised children with aspiration pneumonia and a high aspiration risk.

AIM: Data on the causative pathogens and optimal empirical therapy of aspiration pneumonia in children are limited. This study sought to describe the bacteriology of aspiration pneumonia in hospitalised children with a high aspiration risk. METHODS: Respiratory tract specimens were prospectively collected using the induced sputum technique from children with a high aspiration risk who were hospitalised for aspiration pneumonia in a tertiary paediatric medical centre from 2009 to 2014. Clinical, microbiological and treatment data were recorded and analysed for each admission. RESULTS: The cohort comprised 50 children with 235 hospital admissions. Of the 183 respiratory tract cultures performed, 110 were positive for bacteria, with 169 isolates, mostly Gram-negative. The most common Gram-negative pathogen was Pseudomonas aeruginosa. If patients had Pseudomonas aeruginosa isolation, the risk of them having the pathogen again was 81%. The multivariate analysis showed that the use of antibiotic prophylaxis and number of hospitalisations were significantly associated with Pseudomonas aeruginosa isolation. CONCLUSION: Gram-negative bacilli, especially Pseudomonas aeruginosa, were the major causative agents of paediatric aspiration pneumonia in our study. Empiric antipseudomonas treatment should be considered, particularly in patients who are receiving antibiotic prophylaxis, have experienced recurrent hospitalisations or with previous respiratory cultures that showed Pseudomonas aeruginosa isolation.

Using the Rochester criteria to evaluate infantile fever is more effective in males than females.

AIM: The reliability of low-risk and high-risk criteria in evaluating febrile infants aged up to 60 days has been well documented. The aim of this study was to evaluate gender differences in the reliability of these criteria in order to exclude serious bacterial infection (SBI) in febrile infants. METHODS: This study used the Rochester risk criteria, the study group was divided into low- or high-risk status for SBI, and the data were stratified by gender. SBI was defined as a urinary tract infection, bacteraemia, meningitis or bacterial enteritis. RESULTS: We enrolled 1896 infants (58.3% males), and SBIs were found in 10.6% of the males and 8% of the females (p = 0.21). The sensitivity of the risk criteria was 91.5% for the males and 73.4% (p < 0.05) for the females, and the positive likelihood ratio was 2.64 in the males versus 2.14 in the females (p < 0.001). A multivariable analysis showed that high-risk male patients were more than two times more likely to develop a bacterial infection than high-risk females. CONCLUSION: The Rochester risk criteria had a significantly higher sensitivity and positive likelihood ratio in males. Our findings suggest that clinicians should take gender into account when evaluating febrile infants.

Antenatal risk factors for symptomatic congenital CMV disease following primary maternal CMV infection.

OBJECTIVES: This study aimed to evaluate antenatal risk factors associated with symptomatic congenital cytomegalovirus (CMV) disease, following in utero vertical infection. METHODS: This study included a retrospective cohort of 155 neonates with congenital CMV infection, following primary maternal CMV infection during pregnancy, and were divided to symptomatic (n=95) and asymptomatic (n=60) newborns. RESULTS: Young maternal age (29.1±5.12 vs. 31.6±5.36 years, P=0.005), high risk occupation for viral exposure (20.0% vs. 11.7%, P=0.04), CMV IgG seroconversion at diagnosis (83.1% vs. 63.3%, P=0.005) and abnormal fetal MRI (11.6% vs. 0%, P=0.003) were found to be prognostic risk factors associated with symptomatic CMV disease of the newborn. Maternal febrile illness at diagnosis, IgG avidity, US findings and the timing of maternal infection were not associated with the occurrence of neonatal symptoms. CONCLUSIONS: Knowledge of the reported risk factors may assist in counseling parents with intra uterine CMV infection.

Lenticulostriated vasculopathy is a high-risk marker for hearing loss in congenital cytomegalovirus infections.

AIM: This study investigated the relationship between lenticulostriated vasculopathy (LSV) and hearing loss in 141 infants with congenital cytomegalovirus (cCMV) infection. METHODS: We included all infants with cCMV infection who were followed in our clinic for more than a year with only LSV signs of brain involvement on initial brain ultrasound. Group one comprised 13 infants with no hearing impairment at birth who were not treated with gan/valganciclovir during 2006-2009. Group two was 51 infants with LSV and no hearing impairment who had been treated since mid-2009. Group three was 25 infants born with LSV and hearing loss, who had been treated from birth. Group four was 52 control infants born during the same period with asymptomatic cCMV. Hearing tests were performed during the neonatal period and every four to six months until four years of age. RESULTS: Hearing deterioration was more extensive in group one (85%) than in group two (0%, p < 0.001) and the asymptomatic group (10%, p < 0.001) and occurred more often in group four (10%) than in group two (0%, p = 0.008). CONCLUSION: Lenticulostriated vasculopathy was common in infants with cCMV infection and may serve as a sign of central nervous system involvement and further hearing deterioration. Antiviral treatment may be prudent in such infants.

Changes in acute mastoiditis in a single pediatric tertiary medical center: our experience during 2008-2009 compared with data for 1983-2007.

OBJECTIVE: The objective of this study was to assess clinical reports and bacteriological changes over a 25-y period in children with acute mastoiditis. METHODS: The medical files of all children with a discharge diagnosis of mastoiditis, hospitalized in a tertiary pediatric medical center over a 2-y period (2008-2009), were reviewed and compared to previously published data from the same center for the y 1983-1985, 1993-1995, and 2003-2007. RESULTS: One hundred and thirty-four children (143 episodes) with acute mastoiditis were identified during 2008-2009; 81% had fever, 95% auricular displacement, and 80% post-auricular swelling. Forty-nine children were diagnosed with acute otitis media and had been treated with antibiotics prior to hospitalization. However, 22% showed no clinical symptoms preceding ear protrusion. Cultures grew Streptococcus pneumoniae in 32%, Streptococcus pyogenes in 20%, Pseudomonas aeruginosa in 13%, and Haemophilus influenzae in 10% of cases. From 1990 to 2005, the incidence of S. pyogenes isolation increased from approximately 5% to 20%. During this period, the number of cases increased from 8-20 to 67 per y. CONCLUSIONS: S. pyogenes has emerged as a significant pathogen. We found that acute mastoiditis may appear without preceding symptoms in approximately 22% of cases.

Fever survey highlights significant variations in how infants aged ≤60 days are evaluated and underline the need for guidelines.

AIM: To assess the common practices for evaluating and treating febrile infants aged ≤60 days in a nationwide survey. METHODS: Questionnaires were administrated to inpatient paediatric departments in all 25 hospitals in Israel. RESULTS: Of the 25 centres surveyed (100% response rate), only 36% had written protocols concerning the approach to young febrile infants. The existence of a written protocol was significantly associated with the level of medical centre (tertiary versus primary and secondary, p = 0.041) and with the number of local paediatric infectious disease specialists (p = 0.034). In 13 (52%) hospitals, a normal white blood cell count was defined as 5000-15 000 cells/mL and 20 (80%) centres use C-reactive protein. Hospitalisation was mandatory in most (96%) centres for all neonates aged ≤28 days. Low-risk infants aged 29-60 days were hospitalised in 68.4% of the primary and secondary hospitals, compared with 33.3% tertiary centres. Ampicillin and gentamicin was the routine empiric antibiotic treatment for febrile infant in 92% of centres. CONCLUSION: Significant differences exist among centres in the evaluation of febrile infants aged ≤60 days exist. These differences reflect the lack of, and highlight the need for, national or international guidelines for the evaluation of fever in this age group.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy syndrome is associated with activation of GM-CSF and burst-like expression of IL-8 in peripheral blood.

INTRODUCTION: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy (PFAPA) is an autoinflammatory syndrome characterized by periodic fever with aphthous stomatitis, cervical lymphadenopathy, myalgia, and abdominal pain. Peripheral blood concentrations of selected cytokines of PFAPA patients during and between febrile episodes were analyzed in a search for PFAPA-specific molecular signature. METHODS: 23 children with PFAPA (age 6.07 ± 2.94 years, range 5-9 years) and three control children with severe oropharyngeal infections (age 6.2 ± 7.95 years, range 1-17 years) participated in the study. Peripheral blood concentrations of IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, GM-CSF, TNF-α were measured using Luminex technology. RESULTS: PFAPA febrile episodes were characterized by detection of GM-CSF - 134.07 ± 315.5 pg/mL; significant (P < 0.001), compared to baseline and controls, elevation of concentrations of IL-8 (3193.7 ± 2508 pg/mL vs. 100.36 ± 119. pg/mL vs. 2.04 ± 4.08 pg/mL, respectively), IL-6 (1355.38 ± 2026.53 pg/mL vs. 28.8 ± 44.2 pg/mL and 27.13 ± 26.42 pg/mL, respectively). IL-1ß was detected only in febrile and afebrile PFAPA patients (922.8 ± 1639 pg/mL vs. 10.98 ± 19.4 pg/ml, P < 0.002, respectively), but not in controls. Peripheral blood concentration of TNFα did not differ significantly between study groups. IL-2, IL-4, IL-5, and IL-10 were negligible in all study subjects. DISCUSSION: PFAPA febrile episodes are characterized by activation of GM-CSF and IL-8 with Th1 skewing. We propose a molecular mechanism governing this phenomenon.