Safety of reducing antibiotic use in children with febrile neutropenia: A systematic review.

Febrile neutropenia is the most frequent complication in children treated with chemotherapy. Nevertheless, neutropenic children are a very heterogeneous group and invasive bacterial infections concern a minority of patients. Reducing antibiotics would bring many benefits. Yet, we can only explore this strategy if the safety of children is preserved. The main aims of this review were to study the safety and effectiveness of reducing antibiotic use in children with febrile neutropenia in terms of duration, route of administration (oral versus intravenous) and narrowing of antimicrobial spectrum. Cochrane Library, Pubmed and Embase were searched for relevant articles until February 2020. We have included all articles describing controlled trials written in French or in English. The risk of bias was assessed with ROB-2 (Cochrane Handbook for Systematic Reviews of Interventions Version 6.0. 2019, Chap. 8) or ROBINS-1 (Cochrane Handbook for Systematic Reviews of Interventions Version 6.0. 2019, Chap. 25). On 2351 articles, the systematic research retained 13 studies. Nine were used for a meta-analysis comparing oral versus intravenous treatment. We found no pediatric studies concerning de-escalation of empiric broad-spectrum antibiotics. No publication biases were found and almost all of the selected studies were at low risk or with some concern for bias. In comparing oral versus intravenous treatment and early cessation versus continuing antibiotics when no infection is proven, we found no difference in terms of safety (mortality and admission in intensive care unit) and efficacy (need of readmission/antibiotic modification/recurrence of fever). It seems safe and effective to provide oral treatment in low-risk febrile neutropenia and to stop antibiotics when no bacterial infection is proven. Spectrum reduction remains an important topic in pediatric research.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2055245.

Boosting Teenagers With Acellular Pertussis Vaccines Containing Recombinant or Chemically Inactivated Pertussis Toxin: A Randomized Clinical Trial.

BACKGROUND: Protection induced by acellular pertussis (aP) vaccines is partial and short-lived, especially in teenagers, calling for novel immunization strategies. METHODS: We conducted an investigator-driven proof-of-concept randomized controlled trial in aP-primed adolescents in Geneva to assess the immunogenicity and reactogenicity of a novel recombinant aP (r-aP) vaccine including recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) coadministered with tetanus-diphtheria toxoids (Td), compared to a licensed tetanus-diphtheria-aP vaccine containing chemically detoxified PT (cd/Tdap). The primary immunological endpoints were day 28/365 geometric mean concentrations (GMCs) of total and neutralizing anti-PT antibodies. Memory B cells were assessed. RESULTS: Sixty-two aP-primed adolescents were randomized and vaccinated with r-aP + Td or cd/Tdap. Reactogenicity, adverse events, and baseline GMCs were similar between the groups. Day 28 PT-neutralizing GMCs were low after cd/Tdap (73.91 [95% confidence interval {CI}, 49.88-109.52] IU/mL) and approximately 2-fold higher after r-aP + Td (127.68 [95% CI, 96.73-168.53] IU/mL; P = .0162). Anti-PT GMCs were also low after cd/Tdap (52.43 [95% CI, 36.41-75.50] IU/mL) and 2-fold higher after r-aP + Td (113.74 [95% CI, 88.31-146.50] IU/mL; P = .0006). Day 28 anti-FHA GMCs were similar in both groups. Day 365 anti-PT (but not PT-neutralizing) GMCs remained higher in r-aP + Td vaccinees. PT-specific memory B cells increased significantly after r-aP + Td but not cd/Tdap boosting. CONCLUSIONS: Boosting aP-primed adolescents with r-aP induced higher anti-PT and PT-neutralizing responses than cd/Tdap and increased PT-specific memory B cells. Despite this superior immunogenicity, r-aP may have to be given repeatedly, earlier, and/or with novel adjuvants to exert an optimal influence in aP-primed subjects. CLINICAL TRIALS REGISTRATION: NCT02946190.

Burden of severe RSV disease among immunocompromised children and adults: a 10 year retrospective study.

BACKGROUND: Respiratory syncytial virus (RSV) is associated with significant mortality rates amongst hematopoietic stem cell transplant (HSCT) recipients, with less known about other immunocompromised patients. METHODS: Ten-year retrospective cohort study of immunocompromised patients presenting with RSV disease documented at University Hospitals of Lausanne and Geneva. Severe RSV-related outcomes referred to RSV documented respiratory conditions requiring hospital admission, presenting as lower respiratory tract infection (LRTI) or pneumonia. We used multivariable logistic regression to assess clinical and laboratory correlates of severe RSV disease. RESULTS: From 239 RSV-positive immunocompromised in and out-patients 175 were adults and 64 children of whom 111 (47.8%) presented with LRTI, which resulted in a 38% (89/239) admission rate to hospital. While immunocompromised children were more likely to be admitted to hospital compared to adults (75% vs 62.9%, p = 0.090), inpatients admitted to the intensive care unit (17/19) or those who died (11/11) were mainly adults. From multivariable analyses, adults with solid tumors (OR 5.2; 95% CI: 1.4-20.9 P = 0.015) or those requiring chronic immunosuppressive treatments mainly for rheumatologic conditions (OR 4.1; 95% CI: 1.1-16.0; P = 0.034) were significantly more likely to be admitted to hospital compared to hematopoietic stem cell (HSCT) recipients. Bacterial co-infection was significantly and consistently associated with viral LRTI and pneumonia. CONCLUSIONS: From our findings, RSV-related disease results in a significant burden among adults requiring chronic immunosuppressive treatments for rheumatological conditions and those with solid tumors. As such, systematic screening for respiratory viruses, should be extended to other immunocompromised populations than HSCT recipients.

Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both.

BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.

SARS-CoV-2 Infection in Children Less Than Forty Days Hospitalized in Belgium Between 2020 and 2022.

Our study aimed to assess the severity of severe acute respiratory syndrome coronavirus 2 infection in hospitalized infants under 40 days old, across 21 Belgian hospitals between 2020 and 2022. Of the 365 infants studied, 14.2% needed respiratory support. The median hospital stay was 3 days (interquartile range, 2-4), and there were no deaths. Infection severity was similar during the Omicron and Alpha/Delta periods.

Bacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler.

Post-operative bacterial infections are a leading cause of mortality and morbidity after ongoing liver transplantation. Bacteria causing these infections in the hospital setting can exhibit high degrees of resistance to multiple types of antibiotics, which leads to major therapeutic hurdles. Alternate ways of treating these antibiotic-resistant infections are thus urgently needed. Phage therapy is one of them and consists in using selected bacteriophage viruses - viruses who specifically prey on bacteria, naturally found in various environmental samples - as bactericidal agents in replacement or in combination with antibiotics. The use of phage therapy raises various research questions to further characterize what determines therapeutic success or failure. In this work, we report the story of a toddler who suffered from extensively drug-resistant Pseudomonas aeruginosa sepsis after liver transplantation. He was treated by a bacteriophage-antibiotic intravenous combination therapy for 86 days. This salvage therapy was well tolerated, without antibody-mediated phage neutralization. It was associated with objective clinical and microbiological improvement, eventually allowing for liver retransplantation and complete resolution of all infections. Clear in vitro phage-antibiotic synergies were observed. The occurrence of bacterial phage resistance did not result in therapeutic failure, possibly due to phage-induced virulence tradeoffs, which we investigated in different experimental models.

SARS-CoV-2 Transmission in Belgian French-Speaking Primary Schools: An Epidemiological Pilot Study.

Schools have been a point of attention during the pandemic, and their closure one of the mitigating measures taken. A better understanding of the dynamics of the transmission of SARS-CoV-2 in elementary education is essential to advise decisionmakers. We conducted an uncontrolled non-interventional prospective study in Belgian French-speaking schools to describe the role of attending asymptomatic children and school staff in the spread of COVID-19 and to estimate the transmission to others. Each participant from selected schools was tested for SARS-CoV-2 using a polymerase chain reaction (PCR) analysis on saliva sample, on a weekly basis, during six consecutive visits. In accordance with recommendations in force at the time, symptomatic individuals were excluded from school, but per the study protocol, being that participants were blinded to PCR results, asymptomatic participants were maintained at school. Among 11 selected schools, 932 pupils and 242 school staff were included between January and May 2021. Overall, 6449 saliva samples were collected, of which 44 came back positive. Most positive samples came from isolated cases. We observed that asymptomatic positive children remaining at school did not lead to increasing numbers of cases or clusters. However, we conducted our study during a period of low prevalence in Belgium. It would be interesting to conduct the same analysis during a high prevalence period.

A Case of In Situ Phage Therapy against Staphylococcus aureus in a Bone Allograft Polymicrobial Biofilm Infection: Outcomes and Phage-Antibiotic Interactions.

Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing's sarcoma resection surgery. Chronic infection by Clostridium hathewayi, Proteus mirabilis and Finegoldia magna was worsened by methicillin-susceptible Staphylococcus aureus exhibiting an inducible Macrolides-Lincosamides-Streptogramin B resistance phenotype (iMLSB). After failure of conventional conservative treatment, combination of in situ anti-S. aureus PT with surgical debridement and intravenous antibiotic therapy led to marked clinical and microbiological improvement, yet failed to prevent a recurrence of infection on the midterm. This eventually led to surgical graft replacement. Multiple factors can explain this midterm failure, among which incomplete coverage of the polymicrobial infection by PT. Indeed, no phage therapy against C. hathewayi, P. mirabilis or F. magna could be administered. Phage-antibiotic interactions were investigated using OmniLog® technology. Our results suggest that phage-antibiotic interactions should not be considered "unconditionally synergistic", and should be assessed on a case-by-case basis. Specific pharmacodynamics of phages and antibiotics might explain these differences. More than two years after final graft replacement, the patient remains cured of her sarcoma and no further infections occurred.

A 7-Year-Old Child With Headaches and Prolonged Fever Associated With Oral and Nail Lesions.

A 7-year-old child of Turkish origin presented with headache and vomiting in the context of prolonged fever of unknown source. At examination, oral candidiasis and chronic onychomycosis were noted. A Candida meningoencephalitis was diagnosed and intravenous Amphotericin B liposomal was given during 6 months relayed by oral Fluconazole after regression of CNS lesions was observed on MRI. A complete immune evaluation was performed, and genetic analysis detected homozygous CARD9 mutation. CARD9 deficiency have been associated with invasive candidiasis in otherwise healthy patients. Culture of the cerebrospinal fluid grew for multisensitive Candida albicans. Brain magnetic resonance (MRI) showed the presence of focal lesions in the left caudate nucleus and in the right cerebellar hemisphere. Medullar MRI showed diffuse meningeal nodular lesions. Treatment with intravenous amphotericin B liposomal was given during 6 months relayed by oral fluconazole after regression of CNS lesions was observed on MRI. A complete immune evaluation was performed and genetic analysis detected a homozygous CARD9 mutation. CARD9 deficiency have been associated with invasive candidiasis in otherwise healthy patients.