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.

Rheumatic fever in a developed country - is it still relevant? A retrospective, 25 years follow-up.

BACKGROUND: Our aims were to clinically and epidemiologically characterize rheumatic fever (RF) in the current era in Israel. Although there has been a steady decline in the incidence of RF in the western world, evidence of disease resurgence in developed countries continues to be published. The paucity of recent epidemiological data prompted our study. METHODS: Medical files were retrospectively reviewed for all children with RF in our tertiary pediatric university-affiliated hospital from 1993 to 2017. Main outcome measures were patients and disease related characteristics, incidence trends, risk factors, disease course, relapse rates and secondary prophylaxis. RESULTS: The cohort included 307 children. Sixty-four percent presented with arthritis, interestingly including hips and small joints of hands and feet at presentation, 52% presented with carditis. Severe carditis developed in 31 patients (19.5%), of whom 21 (13.2% of all carditis patients) acquired heart failure, 5 required intensive care monitoring, with one recent death. The percentage of patients with acute carditis of the overall RF patients remained relatively stable. Thirty-two patients (10% of patients with RF) relapsed, including 11 with a cardiac relapse (3.6% of all cardiac patients). The recurrence rate of RF continued to rise up to 9 years from the initial episode. One of 147 patients (< 0.7%) with a non-cardiac initial presentation had carditis at relapse. CONCLUSION: RF and rheumatic heart disease remain an important cause of morbidity and mortality including developed countries, with relapse rate continuing after 9 years of prophylaxis. Presentation of small joints as well as hips, although uncommon, should not exclude the diagnosis.

Comparative Study of Parenteral Penicillin G vs. Amoxicillin-Clavulanate for the Treatment of Dentoalveolar Abscess in Hospitalized Children.

Objectives: To compare the clinical efficacy and the safety profiles of parenteral penicillin G vs. amoxicillin-clavulanate for the treatment of dentoalveolar abscess (DA) in hospitalized pediatric patients. Methods: A retrospective cohort study that was conducted at the Schneider Children's Medical Center in Israel. Results: Seventy-one patients that were included, 25 received parenteral penicillin G and 46 amoxicillin-clavulanate. There were no significant differences in the baseline clinical features except for higher rate of females in the amoxicillin-clavulanate group. Patients that were treated with penicillin G had shorter duration of fever, swelling and total length-of-stay (4.16 vs. 5 days in the penicillin G vs. amoxicillin-clavulanate groups, respectively, p = 0.007) and lower need for surgical intervention. Side effect were minor in both groups. In multivariate analysis, antimicrobial regimen was the only significant factor related with the total length-of-stay (p < 0.001). Conclusions: In pediatric patients hospitalized for DA, parenteral penicillin G was associated with better outcome compared with amoxicillin-clavulanate.

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.

Efficacy and Safety of a Weight-based Dosing Regimen of Valganciclovir for Cytomegalovirus Prophylaxis in Pediatric Solid-organ Transplant Recipients.

BACKGROUND: Valganciclovir has been widely used for cytomegalovirus (CMV) prophylaxis in solid-organ transplant recipients. However, the optimal dosing protocol and target exposure in children are still unclear. Specific data as to the efficacy and safety of low-dose/low-exposure regimens are lacking and urgently needed. METHODS: During 2010 to 2015, the clinical efficacy and safety of a weight-based regimen of valganciclovir of 17 mg/kg/day, with a stratified dose reduction for impaired creatinine clearance, given as a CMV prophylaxis for 3 to 6 months, was retrospectively evaluated among pediatric kidney and liver transplant recipients, 12 months posttransplantation. Incidence of CMV infection was assessed by periodic measurements of viral load; adverse events were evaluated. RESULTS: Eighty-three children who had undergone 86 transplantations and were treated with 17 mg/kg of valganciclovir were included. Median age was 9.77 years (range, 0.6 to 18.9). Twelve (14%) developed CMV infection: 1 during prophylaxis and 11 during follow-up. These events comprised 6 cases of asymptomatic viremia and 6 cases of a clinically significant disease without occurrences of tissue-invasive disease. Treatment-related adverse effects occurred in 7 patients (8%), mostly hematological, resulting in premature drug cessation. CONCLUSIONS: Our results support the use of 17 mg/kg of valganciclovir for CMV prophylaxis in liver and kidney transplanted children as it showed satisfactory long-term efficacy and a good safety profile.

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.

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.

Hematologic Adverse Events Associated With Prolonged Valganciclovir Treatment in Congenital Cytomegalovirus Infection.

BACKGROUND: Valganciclovir (2/d) therapy for 6 months in neonates with symptomatic congenital cytomegalovirus (cCMV) infection improves hearing and neurodevelopmental outcome. The only reported adverse event was neutropenia. Since 2009, our protocol for symptomatic cCMV infection was a 1-year treatment of 2/d for the first 3 months followed by 9 months of 1/d. METHODS: A retrospective study. Infants with cCMV treated with valganciclovir for 1 year were recruited. Data of drug-related hematologic adverse events were collected. RESULTS: One hundred sixty infants were eligible; 46 (28.8%) had experienced at least 1 episode of neutropenia (58 episodes), the majority (39/46, 84.8%) during the first 3 months of treatment and 7 (15.2%) during the last 9 months of treatment. Grades 3 and 4 neutropenia occurred in 9 (5.6%) children, almost exclusively during the first 3 months of treatment. Anemia (hemoglobin <9 g/dL) was recorded in 12 (7.5%) children during the first 3 months of 2/d treatment. Four children presented with hemoglobin levels <7 g/dL and needed a blood transfusion. One child was diagnosed with transient pure red cell aplasia. No long-term adverse events were recorded. CONCLUSIONS: Although prolonged valganciclovir treatment for cCMV is safe, a close monitoring of the white blood cell count and hemoglobin levels is warranted. Much lower rates of grades 3 and 4 neutropenia were observed than previously reported, probably owing to our unique treatment protocol. Nevertheless, drug-induced anemia should be of primary concern. The optimal protocol assessing clinical outcome, concurrently with potential side effects, has not yet been determined.

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.

Protracted febrile myalgia syndrome treated with pulse of corticosteroids.

OBJECTIVE: This study describes our 5-year experience treating protracted febrile myalgia syndrome (PFMS) with pulsed doses of corticosteroids. METHODS: Eight patients with PFMS who received pulse corticosteroid therapy were identified from the electronic database of a tertiary pediatric medical center (2011-2016). Their clinical and laboratory data were collected. Differences in continuous variables between hospital admission and discharge were analyzed using Wilcoxon's matched pairs test. RESULTS: There were 6 female and 2 male patients of median age 10.45 years (range 6.2-17.1) Six patients were found to be homozygous for the M694V mutation. In 4 patients, PFMS was the first-ever manifestation of familial Mediterranean fever. Pulse corticosteroid therapy was administered at a dose of 10mg/kg for 3 days. Pain was alleviated (visual analog scale score, 0) within hours of initiation of therapy, although pain flare-ups lasting for minutes to hours were still observed during hospitalization. At discharge, all patients were prescribed continuous oral corticosteroids (1-2mg/kg) with gradual tapering down over 6 weeks. CONCLUSION: Pulse corticosteroid therapy is effective in alleviating PFMS pain; however, it does not completely abort a PFMS episode.

Congenital Cytomegalovirus Infection After a Multiple Birth Pregnancy.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is an important cause of hearing loss and neurodevelopment delay. While data on vertical transmission and neonatal outcome after singleton pregnancy with cCMV are well established, only scarce reports have addressed cCMV in multiple birth pregnancies. Furthermore, no studies have yet compared the outcome after birth and long-term follow-up of children with cCMV born after a singleton versus multiple pregnancies. METHODS: Infant outcome after birth of symptomatic versus asymptomatic infection was compared for infants born with cCMV after multiple (study group) and singleton (control group) pregnancies in a 1:2 ratio. RESULTS: Of 508 infants diagnosed with cCMV, 25 (4.9%) were born after a multiple pregnancy. Children in the study and control groups did not differ in terms of specific prenatal CMV investigations including amniocentesis and brain magnetic resonance imaging studies. However, prematurity rates were significantly higher in the study compared with control group (52% vs. 4%, P < 0.001). There was a higher rate of symptomatic cCMV infection in the study group than in the controls (48% vs. 14%, P < 0.001). Hearing impairment at birth was also more frequent in the study group (32% vs. 8%, P = 0.016). A long-term follow-up demonstrated that children in the study group had higher rates of neurologic sequelae (hearing impairment or neurodevelopmental delay) compared with children in the control group (20% vs. 4%, P = 0.016). CONCLUSIONS: Infants with cCMV born after multiple birth pregnancies are born earlier and have a higher risk of symptomatic disease at birth and worse long-term neurologic outcome than those born after a singleton pregnancy. This important group of children warrants meticulous prenatal and postnatal care.

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.

Acute hemorrhagic edema of infancy: the experience of a large tertiary pediatric center in Israel.

BACKGROUND: Acute hemorrhagic edema of infancy (AHEI) is a rare leukocytoclastic vasculitis of the small vessels occurring at a young age and considered as a benign self-limited disease. Due to its low prevalence, there are limited data on the presentation and complications of this disease. METHODS: All computerized files of children who were hospitalized at a tertiary pediatric center due to AHEI over a 10 year period were reviewed. Clinical, laboratory and histopathological data were collected. RESULTS: Twenty-six patients were included in our study, accounting for 0.7 cases per 1000 admissions of children aged 2 years or less. Mean age was 12.9 months. More than two thirds of the children had preceding symptoms compatible with a viral infection. Upon admission, all patients presented with typical findings of a rash and edema. Edema was most profound over the lower extremities (73%). Concomitant viral or bacterial infections were found in six children. Skin biopsy was performed in six patients revealing leukocytoclastic vasculitis. Thirteen children (50%) had systemic involvement including joint involvement (n=9), gastrointestinal hemorrhage (n=4), microscopic hematuria (n=1) and compartment syndrome of the limb (n=1). The latter was diagnosed in a patient with familial Mediterranean fever. CONCLUSIONS: Our largest data series highlighted what is known regarding clinical and histological findings in children with AHEI. However, contrary to what was previously reported, we found a higher rate of systemic involvement. Although AHEI is a rare entity, pediatricians should be familiar with its presentation, management and our reported complications.

Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Pediatric Solid-organ Transplant Recipients: A Prospective Pharmacokinetic Study.

BACKGROUND: Valganciclovir is extensively used for prophylaxis and treatment of cytomegalovirus (CMV) infection in solid-organ transplant recipients. However, pharmacokinetic data in children are scarce, and the pediatric dosing regimen is uncertain. This study sought to prospectively evaluate the pharmacokinetic profile, the clinical efficacy and safety of oral valganciclovir in pediatric transplant recipients and compare different dosing regimens. METHODS: The cohort included solid-organ transplant recipients treated with valganciclovir for CMV prophylaxis in 2014-2015 at a tertiary pediatric medical center. All received a weight-based once-daily oral dose of 17 mg/kg. Ganciclovir concentrations were measured and the area under the curve (AUC0-24) was calculated. RESULTS: Thirteen children of median age 7.3 years (interquartile range, 2.2-11.6) were included. Median ganciclovir AUC0-24 was 21.0 mcg·h/mL (interquartile range, 17.1-39.8); 10 patients (77%) attained AUC0-24 <40 mcg·h/mL. Exposure to ganciclovir was about 2-fold lower in young children (<9 years old; P = 0.01) and children with low body surface area (BSA; <0.7 m; P = 0.006) than in their counterparts. Significantly lower doses were recommended with our weight-based protocol than with the manufacturer-recommended BSA- and glomerular filtration rate-based protocol (P = 0.002), reaching a 3-fold difference in infants. No evidence of CMV viremia or disease was observed while prophylaxis was given. CONCLUSIONS: The weight-based regimen of 17 mg/kg/dose oral valganciclovir results in relatively low ganciclovir exposure, especially in young children with low BSA, yet showed satisfactory clinical efficacy for CMV prophylaxis. The manufacturer's dosing recommendation appears to result in supratherapeutic ganciclovir concentrations. Further studies are needed to establish target AUCs and valganciclovir dosing for CMV prophylaxis in pediatric transplant recipients.

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.