Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study.

BACKGROUND: The prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF. METHODS: This retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment. RESULTS: Fifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05). CONCLUSIONS: For the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

Safety of Cidofovir Treatment for Suspected or Confirmed Adenovirus Infection in Immunocompetent Pediatric Population.

BACKGROUND: Cidofovir (CDV), a nucleoside phosphonate analogue, exhibits activity against severe cytomegalovirus and adenoviral (ADV) infection. Nevertheless, reports of elevated nephrotoxicity rates limited its use to highly vulnerable cases, mainly immunocompromised children with fulminant infection. Limited data exists regarding CDV safety in immunocompetent children. OBJECTIVE: To evaluate CDV-related toxicity, mainly nephrotoxicity, in immunocompetent children with severe ADV/cytomegalovirus infection. METHODS: We conducted a retrospective review of medical records for all immunocompetent children under 18 years of age treated with intravenous CDV from January 2005 to December 2019. RESULTS: Among the 23 patients identified, 21 were diagnosed with severe ADV infection. Median age was 15 months. Twenty-one (91%) children were admitted to the pediatric intensive care unit. Eighteen patients (78%) received standard CDV protocol (5 mg/kg CDV weekly for 2 weeks), 4 (17%) according to nephroprotective low-dose protocol and 1 patient transitioned. The median duration of CDV treatment was 14 days (range: 1-21 days). All patients received hyperhydration and probenecid with each infusion. Acute kidney injury was recorded in 1 patient (with concurrent septic shock) during CDV treatment. Two children exhibited acute kidney injury before CDV initiation, but renal function normalized during CDV treatment. One patient developed transient neutropenia (600 cells/L), apparently as a result of sepsis. No other major adverse effects were noted. Mortality rate was 3/23 (13%), unrelated to CDV toxicity. CONCLUSIONS: Our findings suggest that CDV-related nephrotoxicity rate in immunocompetent children may be lower than previously reported, perhaps lower than in the severely immunocompromised population.

Pulmonary Evaluation in Children with Post-COVID-19 Condition Respiratory Symptoms: A Prospective Cohort Study.

Background: Studies on post-COVID-19 condition (PCC) in adults have shown deterioration in pulmonary function tests (PFTs), mainly a diffusion limitation. Among the pediatric population, data are scarce. Aim: To characterize PFTs in children with PCC, including changes over time. Methods: A prospective longitudinal study of children with defined PCC and respiratory complaints who were referred to a designated multidisciplinary clinic from 11/2020 to 12/2022. Results: Altogether, 184 children with a mean age of 12.4 years (SD 4.06) were included. A mild obstructive pattern was demonstrated in 19/170 (11%) at presentation, as indicated by spirometry and/or positive exercise challenge test and/or reversibility post bronchodilators, only three had a previous diagnosis of asthma. Lung volumes and diffusion were normal in all but one patient (1/134, 0.7%). Exhaled nitric oxide levels were elevated in 32/144 (22%). A total of 33 children who had repeated PFTs had normal or near-normal PFTs on follow-up testing, including seven (21.2%) who had mild obstructive PFTs at presentation. Multivariate analysis identified older age [OR 1.36 (95% CI:1.07-1.75)], specific imaging findings (prominent bronchovascular markings (OR 43.28 (95% CI: 4.50-416.49)), and hyperinflation (OR 28.42, 95% CI: 2.18-370.84)] as significant predictors of an obstructive pattern on PFTs. Conclusions: In children with PCC and respiratory symptoms, the most common impairment was a mild obstructive pattern; most were without a history of asthma. Improvement was witnessed in long-term follow-up. In contrast to the adult population, no diffusion limitation was found. Empirical periodic inhaler therapy may be considered in children with factors associated with PFT abnormalities.

The new face of cystic fibrosis in the era of population genetic carrier screening.

BACKGROUND: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features. METHODS: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected. RESULTS: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p=  0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04). CONCLUSIONS: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF.

Periductal bile acid exposure causes cholangiocyte injury and fibrosis.

INTRODUCTION: Bile duct integrity is essential for the maintenance of the structure and function of the biliary tree. We previously showed that cholangiocyte injury in a toxic model of biliary atresia leads to increased monolayer permeability. Increased epithelial permeability was also shown in other cholangiopathies. We hypothesized that after initial cholangiocyte injury, leakage of bile acids into the duct submucosa propagates cholangiocyte damage and fibrosis. We thus aimed to determine the impact of bile acid exposure on cholangiocytes and the potential therapeutic effect of a non-toxic bile acid. MATERIALS AND METHODS: Extrahepatic bile duct explants were isolated from adult and neonatal BALB/c mice. Explants were cultured with or without glycochenodeoxycholic acid and ursodeoxycholic acid. They were then fixed and stained. RESULTS: Explants treated with glycochenodeoxycholic acid demonstrated cholangiocyte injury with monolayer disruption and partial lumen obstruction compared to control ducts. Masson's trichrome stains revealed increased collagen fibers. Myofibroblast marker α-SMA stains were significantly elevated in the periductal region. The addition of ursodeoxycholic acid resulted in decreased cholangiocyte injury and reduced fibrosis. CONCLUSIONS: Bile acid leakage into the submucosa after initial cholangiocyte injury may serve as a possible mechanism of disease propagation and progressive fibrosis in cholangiopathies.

Adenovirus can be a serious, life-threatening disease, even in previously healthy children.

AIM: Adenovirus infections are exceedingly common in childhood. However, little is known of the clinical characteristics of children admitted with severe infection to the paediatric intensive care unit (PICU). METHODS: Clinical data on children hospitalised with adenovirus infection between January 2005 and March 2020 were collected. We compared data between children hospitalised in the PICU and those who were not in a 1:2 ratio. RESULTS: During the study period, 69 children with adenovirus infection were admitted to the PICU, representing 5% of all hospitalised children with adenovirus. Thirty-four (49%) were previously healthy children. Mortality occurred in 5 patients, and all had an underlying illness. Cidofovir was used in 21 children, including 11 who were previously healthy. No side effects were attributed to the treatment. During 2005-2014, viral co-infection rates were 42% in the PICU group and 11% in the control group (p = 0.002). However, during 2015-2020, when the viral panel became widespread in our institution, the rates of co-infection were similar in the two groups (32% and 34%, p = 1.0). CONCLUSION: Our findings suggest that adenovirus may present as a serious, life-threatening disease even in previously healthy children.

Adenovirus Infection in Children with Down Syndrome.

BACKGROUND: Adenovirus infections are prevalent in children. They usually cause a mild self-limited disease. However, this infection can be associated with considerable morbidity and mortality in specific populations, especially among immunocompromised children. Children with Down syndrome are susceptible to a higher frequency and increased severity of viral infections. Little is known about the severity and clinical course of adenovirus infections in children with Down syndrome. OBJECTIVES: To characterize hospitalized children diagnosed with Down syndrome and presenting with adenovirus infection. METHODS: We performed a retrospective review of children admitted with adenovirus from January 2005 to August 2014 from a single tertiary pediatric medical center in Israel. Data were compared between patients with and without Down syndrome. RESULTS: Among the 486 hospitalized children with adenoviral infection, 11 (2.28%) were diagnosed with Down syndrome. We found that children with Down syndrome were more likely to experience a higher incidence of complications (18.2% vs. 2.4%, P = 0.008), a higher rate of admissions to the intensive care unit (36.4% vs. 2.4%, P < 0.001), and more prolonged hospitalizations (17 ± 15.9 days compared to 4.46 ± 3.16, P = 0.025). CONCLUSIONS: Children with Down syndrome who were hospitalized with adenovirus infection represent a high-risk group and warrant close monitoring. If a vaccine for adenovirus becomes available, children with Down syndrome should be considered as candidates.

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.

Secondary bacteremia following adenovirus infection.

Adenovirus is a common pediatric pathogen responsible for a wide variety of infections. Despite this, secondary bacteremia following an adenovirus infection has not been previously systematically described. Herein, we describe seven cases of secondary bacteremia following an adenovirus infection in hospitalized children during an 8-year period. Pediatricians should be informed of this serious complication.

Nosocomial respiratory syncytial virus infections in the palivizumab-prophylaxis era with implications regarding high-risk infants.

BACKGROUND: Although respiratory syncytial virus (RSV) infection continues to be a leading cause of infant hospitalization with a high transmission rate, recent data on nosocomial RSV infection are scarce. This study investigated the clinical and epidemiologic characteristics of nosocomial RSV infection in the palivizumab-prophylaxis era. METHODS: The database of a tertiary pediatric medical center was searched for all hospitalized patients with RSV-positive respiratory disease in 2008-2010. Data were compared between patients with community-associated and nosocomial disease, and the qualification of the latter group for palivizumab was evaluated. RESULTS: Of the 873 children identified, 30 (3.4%) had a nosocomial infection. This group accounted for 0.06% of all admissions during the study period. The nosocomial infection group had higher rates of preterm birth and severe underlying disease than the community-associated RSV group and a longer mean hospital stay. The nosocomial infection group also had higher rates of intensive care unit admission and mechanical ventilation. Although 73% had underlying conditions, most (80%) did not qualify for RSV immunoprophylaxis, including 7 children (23%) with immune deficiency. CONCLUSION: Nosocomial RSV infection is a significant cause of morbidity among hospitalized infants, especially those with comorbidities and lengthy hospital stay, and is associated with a complicated clinical course. In addition to strict infection-control measures, extending palivizumab prophylaxis to additional selected high-risk populations should be considered.

Compartment syndrome because of acute hemorrhagic edema of infancy: a case report and literature review.

UNLABELLED: Acute hemorrhagic edema of infancy (AHEI) is a benign, self-limiting vasculitis that usually resolves completely without any sequelae or a need for active therapy. To our knowledge, compartment syndrome because of AHEI has not been reported. Chart data for a single case were reviewed and reported in a retrospective study. A 19-month-old male presented with petechial rash and swelling of the left lower leg. AHEI was diagnosed clinically and confirmed by skin biopsy. On the basis of the clinical appearance, compartment syndrome of the foot was suspected. Measurements of compartmental pressures in the foot were well above the commonly cited ranges and a fasciotomy was performed. Following the operation, there was a marked clinical improvement in the limb perfusion. The child was discharged on the 20th day with marked clinical improvement; both active and passive leg movements were intact. We suggest that pediatric orthopedic surgeons should be familiar with this entity and its rare complication. LEVEL OF EVIDENCE: V - case report.

Hospitalization for respiratory syncytial virus bronchiolitis and disease severity in twins.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract disease and hospitalization in infants and young children. Infants of multiple births, who are often premature, might be more susceptible to developing a more severe RSV infection than singletons. OBJECTIVE: To assess the impact of multiple births on the severity of RSV infection and define risk factors for acquiring RSV infection in infants of multiple birth. METHODS: Clinical data on infants hospitalized with RSV infection between 2008 and 2010 were retrospectively collected. RESULTS: Twins comprised 7.6% (66/875) of hospitalized infants with RSV bronchiolitis during the study period. Infants in the twin group were younger (122.4 +/- 131.7 vs. 204.5 +/- 278.8 days, P = 0.014), had a lower mean gestational age (35.3 +/- 2.6 vs. 38.6 +/- 2.5 weeks, P < 0.001), and were more likely to have been born prematurely compared with singleton infants (65.6% vs. 13%, P < 0.001). On a multivariable logistic regression analysis, young age, early gestational age and male gender were the only variables identified as risk factors for pediatric intensive care unit admission (P < 0.001, P < 0.001 and P = 0.03, respectively). In contrast, the mere fact of a child being a twin was not found to be a significant risk factor for disease severity. In addition, if one twin is hospitalized due to RSV infection, the other has a 34% chance of also being hospitalized with bronchiolitis. Young age was a significant risk factor for hospitalization of the second twin (P < 0.001) CONCLUSIONS: Our findings suggest that twins hospitalized with RSV bronchiolitis do not have an increased risk for severe infection as compared to singletons. However, a twin of an infant hospitalized with RSV infection has a considerable risk of also being hospitalized with bronchiolitis, thus close monitoring is recommended.

Characterization of coaggregation of Fusobacterium nucleatum PK1594 with six Porphyromonas gingivalis strains.

Coaggregation is a key mechanism in biofilm formation. The aim of this study was to characterize the coaggregation of Fusobacterium nucleatum PK1594 with six Porphyromonas gingivalis strains in terms of kinetics and sugars inhibition. This coaggregation was quantitatively characterized by using a kinetic coaggregation assay. Sugar inhibition profiles were also quantitatively defined. Four types of interactions among these coaggregation partners were found: (1) fast coaggregation that was substantially inhibited by galactose, lactose, and fucose (strain PK1924); (2) fast coaggregation that was not inhibited by any of the sugars tested (strain 274); (3) slow coaggregation that was either substantially or partially inhibited by the sugars mentioned (strains HG405 and W50, respectively); and (4) strains that did not coaggregate with the fusobacteria (ATCC33277 and A7436). These results suggest that adhesin(s) other than the well-known galactose-mediated ones may be involved in coaggregation between F. nucleatum PK1594 and P. gingivalis strains.

Enhanced attachment of Porphyromonas gingivalis to human fibroblasts mediated by Fusobacterium nucleatum.

Fusobacterium nucleatum and Porphyromonas gingivalis are often co-isolated from endodontic infection sites. The present study tested the hypothesis that adhesin-mediated reactions might contribute to this phenomenon. F. nucleaum PK1594 and P. gingivalis PK1924 were selectively labeled with fluorochromes and allowed to adhere to human fibroblasts, either each strain alone or sequentially. The number of bacteria of each type adhering to individual fibroblasts was determined. Sugar inhibition profile of this adherence was explored. Attachment of P. gingivalis to human fibroblasts increased by nearly 10-fold when F. nucleatum was present (P < .001). Galactose, lactose, and fucose inhibited this enhanced attachment (P < .001), as well as that of F. nucleatum alone (P < .001). The results suggest that F. nucleatum might be a primary colonizer of the host tissues and serve as mediator for enhanced attachment of P. gingivalis to the host cells. This might explain in part the common co-occurrence of F. nucleatum and P. gingivalis in endodontic mixed infections.