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Clostridioides difficile infection (CDI) is generally treated with vancomycin, metronidazole or fidaxomicin, although fecal microbiota transplantation (FMT) represents a promising therapeutic option for antibiotic-resistant recurrent C. difficile infections (rCDIs) in adults. In pediatric cystic fibrosis (CF) patients, CDIs are generally asymptomatic and respond to treatment. Here, we present the case of an 8-year-old female, initially diagnosed as "CFTR-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis" (CMRS/CFSPID), who then progressed to CF at 12 months. In the absence of CF-related symptoms, she presented multiple and disabling episodes of bloody diarrhoea with positive tests for C. difficile antigen and A/B toxin. After conventional treatments failed and several CDI relapses, FMT was proposed. Donor screening and GM donor–receiver matching identified her mother as a donor. Metataxonomy and targeted metabolomics provided, through a pre- and post-FMT time course, gut microbiota (GM) profiling to assess GM engraftment. At first, the GM map revealed severe dysbiosis, with a prevalence of Bacteroidetes and Proteobacteria (i.e., Klebsiella spp., Escherichia coli), a reduction in Firmicutes, a GM nearly entirely composed of Enterococcaceae (i.e., Enterococcus) and an almost complete depletion of Verrucomicrobia and Actinobacteria, mostly represented by Veillonella dispar. Post FMT, an increment in Bifidobacterium spp. and Collinsella spp. with a decrease in V. dispar restored intestinal eubiosis. Consistently, four weeks after FMT treatment, the child's gut symptoms cleared, without CDI recurrence. [ABSTRACT FROM AUTHOR]

Clostridioides difficile infection (CDI) is generally treated with vancomycin, metronidazole or fidaxomicin, although fecal microbiota transplantation (FMT) represents a promising therapeutic option for antibiotic-resistant recurrent C. difficile infections (rCDIs) in adults. In pediatric cystic fibrosis (CF) patients, CDIs are generally asymptomatic and respond to treatment. Here, we present the case of an 8-year-old female, initially diagnosed as “CFTR-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis” (CMRS/CFSPID), who then progressed to CF at 12 months. In the absence of CF-related symptoms, she presented multiple and disabling episodes of bloody diarrhoea with positive tests for C. difficile antigen and A/B toxin. After conventional treatments failed and several CDI relapses, FMT was proposed. Donor screening and GM donor–receiver matching identified her mother as a donor. Metataxonomy and targeted metabolomics provided, through a pre- and post-FMT time course, gut microbiota (GM) profiling to assess GM engraftment. At first, the GM map revealed severe dysbiosis, with a prevalence of Bacteroidetes and Proteobacteria (i.e., Klebsiella spp., Escherichia coli), a reduction in Firmicutes, a GM nearly entirely composed of Enterococcaceae (i.e., Enterococcus) and an almost complete depletion of Verrucomicrobia and Actinobacteria, mostly represented by Veillonella dispar. Post FMT, an increment in Bifidobacterium spp. and Collinsella spp. with a decrease in V. dispar restored intestinal eubiosis. Consistently, four weeks after FMT treatment, the child’s gut symptoms cleared, without CDI recurrence.

Background: New York State implemented CFTR gene sequencing into the Cystic Fibrosis newborn screening (CF NBS) algorithm on 12/1/2017 to reduce false positive screens. With addition of sequencing, infants with 2 CFTR variants but low or intermediate sweat chloride levels classified as CFTR-related metabolic syndrome/CF screen-positive, inconclusive diagnosis (CRMS/CFSPID) are identified at a higher frequency, posing challenges to clinicians and families., Methods: Data from 375 screen-positive newborns between 12/1/2017 and 11/30/2020 were analyzed. We summarized 1-3 years of clinical follow-up for babies with CRMS/CFSPID following implementation of the IRT-DNA-SEQ algorithm., Results: Among 375 newborns referred, 223 (59.5 %) were classified as CRMS/CFSPID. Overall, 195/223 (87.4 %) had a CF-causing/pathogenic/likely pathogenic CFTR variant and a variant of varying clinical consequence (VCC) or uncertain significance (VUS). The most common VCC or VUS was 5T-12TG [n = 90/223 (40 %)]. All initial and repeat sweat chloride test (SCT) values for this cohort were <60 mmol/L after 1-3 years follow-up. Ninety-nine infants had ≥1 repeat SCT. Forty-two (18.8 %) had ≥1 SCT in the intermediate range (30-59 mmol/L) and 181 (81.2 %) were <30 mmol/L. Twenty-nine infants had sweat chloride increasing ≥5 mmol/L per year (29.3 % of infants with repeat testing). Fecal elastase was reported for 114/223 infants; none were abnormal. There were no conversions to CF during the 3-year follow-up period, however 2 infants have subsequently converted with diagnostic SCTs., Conclusions: The New York experience may help inform updates to clinical guidelines, which are needed to optimize care, management, counseling, and long-term follow-up of infants and children with CRMS/CFSPID., Competing Interests: Declaration of competing interest None., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

During the past quarter century, the diagnosis and treatment of cystic fibrosis (CF) have been transformed by molecular sciences that initiated a new era with discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The knowledge gained from that breakthrough has had dramatic clinical impact. Although once a diagnostic dilemma with long delays, preventable deaths, and irreversible pathology, CF can now be routinely diagnosed shortly after birth through newborn screening programs. This strategy of pre-symptomatic identification has eliminated the common diagnostic "odyssey" that was a failure of the healthcare delivery system causing psychologically traumatic experiences for parents. Therapeutic advances of many kinds have culminated in CFTR modulator treatment that can reduce the effects of or even correct the molecular defect in the chloride channel —the basic cause of CF. This astonishing advance has transformed CF care as described fully herein. Despite this impressive progress, there are challenges and controversies in the delivery of care. Issues include how best to achieve high sensitivity newborn screening with acceptable specificity; what course of action is appropriate for children who are identified through the unavoidable incidental findings of screening tests (CFSPID/CRMS cases and heterozygote carriers); how best to ensure genetic counseling; when to initiate the very expensive but life-saving CFTR modulator drugs; how to identify new CFTR modulator drugs for patients with non-responsive CFTR variants; how to adjust other therapeutic modalities; and how to best partner with primary care clinicians. Progress always brings new challenges, and this has been evident worldwide for CF. Consequently, this article summarizes the major advances of recent years along with controversies and describes their implications with an international perspective. [ABSTRACT FROM AUTHOR]