New York cystic fibrosis consortium newborn screening quality improvement: Development and implementation of a statewide consensus recommendations for management of infants with CFTR-related metabolic syndrome.

BACKGROUND: New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium. METHODS: Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies. RESULTS: Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire. CONCLUSIONS: With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS.

The Italian external quality assessment program for Cystic Fibrosis sweat chloride test: CFTR modulators and the impact of a new sweat test report form.

Background: The advent of CFTR modulators highlighted that the sweat test (ST) for CF can be used also as an outcome measure for the basic defect of CFTR. Despite the technological advances, ST still remains operator-dependent and its execution should be strongly paired with guidelines. In 2022, due to the advent of CFTR modulators, the Italian CF Society introduced a specific ST report. The aim of the present paper is to discuss the impact of this new report in the 2022-23 round of the Italian External Quality Assessment program for ST (I-EQA-SCT). Methods: The scheme of the I-EQA-SCT is prospective, enrolment is voluntary, the payment of a fee is required and results are shared through a web-facility. Assessment covers analysis, interpretation, and reporting of results. In the 2022-23 round, 2 out of the 3 mock clinical information referred to patients who started modulators. Results: Fourteen laboratories completed the 2022-23 I-EQA-SCT round. Three of them failed in the interpretation of results from these two mock cases and/or used a wrong report not consistent with the more recent Italian Sweat Test Recommendations. Conclusions: The overall results obtained from the laboratories involved in the I-EQA-SCT program clearly showed that the laboratories' qualitative and quantitative performance improved significantly. Results emerged from this round highlighted an issue in the report form used for monitoring patients on CFTR modulator therapy thus stressing the importance of these programs in improving both the performance of lab services and ameliorating the sweat test recommendations.

Diagnosing Cystic Fibrosis in the 21st Century-A Complex and Challenging Task.

Cystic fibrosis (CF) is a chronic and potentially life-threatening condition, wherein timely diagnosis assumes paramount significance for the prompt initiation of therapeutic interventions, thereby ameliorating pulmonary function, addressing nutritional deficits, averting complications, mitigating morbidity, and ultimately enhancing the quality of life and extending longevity. This review aims to amalgamate existing knowledge to provide a comprehensive appraisal of contemporary diagnostic modalities pertinent to CF in the 21st century. Deliberations encompass discrete delineations of each diagnostic modality and the elucidation of potential diagnostic quandaries encountered in select instances, as well as the delineation of genotype-phenotype correlations germane to genetic counseling endeavors. The synthesis underscores that, notwithstanding the availability and strides in diagnostic methodologies, including genetic assays, the sweat test (ST) retains its position as the preeminent diagnostic standard for CF, serving as a robust surrogate for CFTR functionality. Prospective clinical investigations in the realm of CF should be orchestrated with the objective of discerning novel diagnostic modalities endowed with heightened specificity and sensitivity.

ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

Biochemical and genetic tools to predict the progression to Cystic Fibrosis in CRMS/CFSPID subjects: A systematic review.

OBJECTIVES: Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID). METHODS: This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed. RESULTS: Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF. CONCLUSIONS: CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up.

Diagnostic challenges in CFTR-related metabolic syndrome: Where the guidelines fall short.

Newborn screening (NBS) for cystic fibrosis (CF) has enabled earlier diagnosis and has improved nutritional and growth-related outcomes in children with CF. For those with a positive NBS for CF that do not meet the diagnostic criteria for CF, the clinical entity called CFTR-Related Metabolic Syndrome (CRMS) or CF Screen- Positive, Inconclusive Diagnosis (CFSPID) is used. Although most children with CRMS remain relatively asymptomatic, studies have shown that between 11% and 48% of these patients may eventually progress to a diagnosis of CF over time. Although the CF Foundation guidelines for CRMS management and European CF Society guidelines for CFSPID have some similarities, there are also some differences. Here, we review challenging case scenarios that highlight remaining gaps in CRMS guidelines, thus supporting the need to update and unify existing guidelines.

Sweat induction using Pilocarpine microneedle patches for sweat testing in healthy adults.

BACKGROUND: The sweat test using pilocarpine iontophoresis remains the gold standard for diagnosing cystic fibrosis, but access and reliability are limited by specialized equipment and insufficient sweat volume collected from infants and young children. These shortcomings lead to delayed diagnosis, limited point-of-care applications, and inadequate monitoring capabilities. METHODS: We created a skin patch with dissolvable microneedles (MNs) containing pilocarpine that eliminates the equipment and complexity of iontophoresis. Upon pressing the patch to skin, the MNs dissolve in skin to release pilocarpine for sweat induction. We conducted a non-randomized pilot trial among healthy adults (clinicaltrials.gov, NCT04732195) with pilocarpine and placebo MN patches on one forearm and iontophoresis on the other forearm, followed by sweat collection using Macroduct collectors. Sweat output and sweat chloride concentration were measured. Subjects were monitored for discomfort and skin erythema. RESULTS: Fifty paired sweat tests were conducted in 16 male and 34 female healthy adults. MN patches delivered similar amounts of pilocarpine into skin (1.1 ± 0.4 mg) and induced equivalent sweat output (41.2 ± 25.0 mg) compared to iontophoresis (1.2 ± 0.7 mg and 43.8 ± 32.3 mg respectively). Subjects tolerated the procedure well, with little or no pain, and only mild transient erythema. Sweat chloride concentration measurements in sweat induced by MN patches (31.2 ± 13.4 mmol/L) were higher compared to iontophoresis (24.0 ± 13.2 mmol/L). Possible physiological, methodological, and artifactual causes of this difference are discussed. CONCLUSIONS: Pilocarpine MN patches present a promising alternative to iontophoresis to enable increased access to sweat testing for in-clinic and point-of-care applications.

Risk of CFTR-related disorders and cystic fibrosis in an Italian cohort of CRMS/CFSPID subjects in preschool and school age.

The identification of cystic fibrosis screening-positive, inconclusive diagnosis (CFSPID) in infants is a controversial outcome of newborn screening for cystic fibrosis (CF). Today, despite improvements in the knowledge of CFSPID and the description of several cohorts, little data are available on cohorts with a follow-up period of more than 6 years. In this study, we report the outcomes of an Italian cohort of CFSPID individuals with CFSPID or formerly CFTR-related disorders (CFTR-RD) (CFSPID > CFTR-RD) or diagnosed with CF (CFSPID > CF). This was an observational and multicentre Italian study collecting clinical data on CFSPID born between the period January 1, 2011, and December 13, 2019. A total of 268 participants were included: 243 with persistent CFSPID, 7 with CFSPID > CFTR-RD, and 18 with CFSPID > CF. The trend of sweat chloride (SC) values, percentage of definitive diagnoses, lung function in school-aged children, and development of CF-related complications were evaluated. At the end of the observation period, almost 80% of the individuals with CFSPID did not have a conclusive diagnosis. A total of 29 children (10.8%) transitioned to a diagnosis of CF for pathological SC values (≥ 60 mmol/L) or multi-organ involvement, and 18 (6.7%) to CFTR-RD. Children who were followed up for > 6 years (median age, 7.5 years; range, 6.04-10.5) had normal lung function and were pancreatic sufficient, and the evolution in CF was only present in two cases. CONCLUSION: Most Italian preschool and school-aged children with CFSPID did not have a conclusive diagnosis, and progression to CF was unlikely in children > 6 years of age. An annual follow-up could be indicated to identify early evolution in clinical features consistent with a CFTR-RD. WHAT IS KNOWN: • Cystic Fibrosis newborn screening identifies also subjects with an inconclusive diagnosis (CFSPID). • Over time a variable percentage of CFSPIDs will be diagnosed as CF. • Little data is available on CFSPIDs with a follow-up period of more than six years. WHAT IS NEW: • 80% of Italian preschool and school-age CFSPIDs not have a conclusive diagnosis. • Italian preschool and school-age CFSPIDs have normal lung function and are pancreatic sufficient. • Annual follow-up after 6 years is recommended in CFSPID with abnormal LCI2.5 or with a CF-causing variant in trans with a VVCC.

Efficacy of treatment of equine anhidrosis with acupuncture and Chinese herbs is low but higher in treated horses compared with placebo.

OBJECTIVE: To assess the therapeutic efficacy of acupuncture in combination with Chinese herbs for treatment of horses affected with anhidrosis. ANIMALS: 44 horses affected with anhidrosis for up to 3 years' duration were enrolled. Inclusion required both compatible clinical signs and results of a quantitative intradermal terbutaline sweat test. METHODS: Study horses were randomly allocated into 2 groups. Group 1 (n = 19) was treated with daily Chinese herbs and 4 weekly acupuncture sessions. Group 2 (n = 25) was given daily hay powder as a placebo and 4 weekly sham acupuncture sessions. Horses were tested by quantitative intradermal terbutaline sweat test within 2 days after treatment completion and again 4 weeks following treatment. RESULTS: Terbutaline-induced sweat responses (mg) were not different between groups within 2 days and 4 weeks after treatment. Two days after treatment, ratios of sweat responses (compared to baseline) were higher (P < .05) in the treatment group compared to the placebo group at terbutaline concentrations of 1.0, 100, and 1,000 µg/mL. The number of horses responding to treatment was higher in the treatment group (5/19 [26%]), compared to horses in the placebo group (1/25 [4%]) for 1 of 5 terbutaline concentrations 2 days (10 µg/mL) or 4 weeks (0.1 µg/mL) after treatment. CLINICAL RELEVANCE: Ratios of sweat responses were higher in treatment horses 2 days after treatment, compared to baseline, but not 4 weeks later. The efficacy of a traditional Chinese veterinary medicine protocol for anhidrosis treatment with acupuncture and Chinese herbs was low but higher in treated horses compared with placebo.

Airway surface liquid pH in paediatric patients with cystic fibrosis / PH del líquido de la vía aérea en pacientes pediátricos con fibrosis quística

Background: Cystic fibrosis (CF) patients have more acidic airway surface liquid (ASL), which can denature antimicrobial defensins. Induced sputum is non-invasive and is as representative as bronchoalveolar lavage. Objectives: The objectives of this study were to analyse the ASL pH obtained by induced sputum and assess the relationship between clinical features in paediatric CF patients. Methods: This is a prospective observational study in CF paediatric patients. Sputum was induced in a patient by inhaling 4.5% hypertonic saline, the sputum was collected into a sterile container for pathological analysis, and the pH was measured from the liquid part (ASL) in a gas machine. Results: A total of 27 patients were included in the study: mean age (11.96 ± 3.9) years, mean sweat test (99.38 ± 17.76) ng/L, common mutation Del508F (N24, 88.8%), mean FEV1% 91.94% ± –12.6%, Staphylococcus colonization 14 (51.9%), normal chest CT 8 (29.6%), air trapping 12 (44.4%), bronchiectasis 6 (22.2%), and mean ASL pH 6.72 ± 0.06 (n = 15). A significant correlation was found between a higher sweat test and lower ASL pH (R = 0.683, p = 0.005). There were no differences between altered chest CT (p = 0.199) and positive Staphylococcus aureus (p = 0.17). Conclusion: This is the first publication that use induced sputum to obtain the ASL pH in CF patients. The ASL pH in CF patients is usually acidic and correlated with altered transmembrane function conductance. (AU)

Antecedentes: Los pacientes con fibrosis quística (FQ) tienen el líquido de la vía aérea (ASL) ácido, provocando desnaturalización de defensinas antimicrobianas. El esputo inducido es reproducible, no invasivo y la muestra es equiparable al lavado broncoalveolar. Objetivo: Evaluar el pH ASL obtenido por esputo inducido y analizar sus implicaciones clínicas, en niños FQ. Métodos: Estudio observacional prospectivo desarrollado en niños FQ. El esputo se indujo mediante inhalación de solución salina hipertónica 4,5%. Se recolectó el esputo y posterior al análisis patológico el ASL se colocó en una jeringa y se midió pH con una máquina de gases. Resultados: Se incluyeron 27 pacientes: edad (11,96 ± 3,9) años, test del sudor (99,38 ± 17,76) ng/L, variante común Del508F (N24, 88,8%), FEV1% 91,94% ± 12,6%, Staphylococcus 14 (51,9%), TAC pulmonar normal 8 (29,6%), atrapamiento 12 (44,4%), bronquiectasias 6 (22,2%), pH ASL 6,72 ± 0,06 (n = 15). Se observó correlación significativa entre niveles elevados del test del sudor y pH ASL ácido (R = 0,683, p = 0,005). No hubo correlación entre pH ASL y TAC pulmonar alterado (p = 0,199) o S. aureus positivo (p = 0,17). Conclusiones: Esta es la primera publicación que utiliza esputo inducido para medir pH del ASL en FQ. El pH ASL se correlacionó con la alteración del gen de conductancia transmembranal. (AU)

Comparison between Gibson-Cooke and Macroduct Methods in the Cystic Fibrosis Neonatal Screening Program and in Subjects Who Are Cystic Fibrosis Screen-Positive with an Inconclusive Diagnosis.

The sweat test (ST) is the current diagnostic gold standard for cystic fibrosis (CF). Many CF centres have switched from the Gibson-Cooke method to the Macroduct system-based method. We used these methods simultaneously to compare CF screening outcomes. STs using both methods were performed simultaneously between March and December 2022 at CF Centre in Florence. We included newborns who underwent newborn bloodspot screening (NBS), newborns undergoing transfusion immediately after birth, and children with CF screen-positive, inconclusive diagnosis (CFSPID). We assessed 72 subjects (median age 4.4 months; range 0-76.7): 30 (41.7%) NBS-positive, 18 (25.0%) newborns who underwent transfusion, and 24 (33.3%) children with CFSPID. No significant differences were found between valid sample numbers, by patient ages and groups (p = 0.10) and between chloride concentrations (p = 0.13), except for sweat chloride (SC) measured by the Gibson-Cooke and Macroduct methods in CFSPID group (29.0, IQR: 20.0-48.0 and 22.5, IQR: 15.5-30.8, respectively; p = 0.01). The Macroduct and Gibson-Cooke methods showed substantial agreement with the SC values, except for CFSPID, whose result may depend on the method of sweat collection. In case of invalid values with Macroduct, the test should be repeated with Gibson-Cooke method.

Late Diagnosis in the Era of Universal Newborn Screening Negatively Affects Short- and Long-Term Growth and Health Outcomes in Infants with Cystic Fibrosis.

Newborn screening for cystic fibrosis was fully implemented in the US by 2010, but delays in timeliness of evaluation for infants with positive newborn screening tests persist. Through evaluation of national patient registry data, we determined that late initiation of cystic fibrosis care is associated with poorer long-term nutritional outcomes.

Assessing accuracy of testing and diagnosis in cystic fibrosis.

INTRODUCTION: Next to evaluating for defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, diagnostic guidelines for cystic fibrosis (CF) include CFTR function tests. The primarily used sweat test and genetics generally produce straightforward CF diagnoses. However, a widened CF disease spectrum and large number of CFTR gene variants with unknown or varying clinical consequences shift reliance on CFTR functional tests to assess for CF or CFTR-related disease. Recently, CFTR functional tests are used to record efficiency of CFTR modulator drugs. AREAS COVERED: This review provides background and accuracy of the currently used CFTR functional tests, including the sweat test, nasal potential difference (NPD), and intestinal current measurements (ICM). We summarize published evidence addressing technical and biological reasons for test variability and test result in relation to CF-associated symptoms. EXPERT OPINION: The CFTR functional tests demonstrate high accuracy despite biological and technical variability. Data is scarce for ICM. Each test identifies CF from non-CF but show lower accuracy for individuals not fitting the classic CF diagnostic criteria. Adherence to standardized protocols is critical to improve test accuracy across different centers. Lastly, instead of relying on the single test results, diagnostic assessment should be based on integrating multiple functional and genetic test results.

Cystic Fibrosis: A Descriptive Analysis of Deaths in a Two-Decade Period in Brazil According to Age, Race, and Sex.

The diagnosis of cystic fibrosis has improved in the last few years due to greater access to diagnostic tools and the evolution of molecular biology; the knowledge obtained has contributed to the understanding of its death profile. In this context, an epidemiological study was developed focusing on deaths from cystic fibrosis in Brazil from 1996 to 2019. The data were collected from the Data-SUS (Unified National Health System Information Technology Department from Brazil). The epidemiological analysis included patients' age groups, racial groups, and sex. In our data, between 1996 and 2019, Σ3050 deaths were recorded, totaling a ≅330% increase in the number of deaths resulting from cystic fibrosis. This fact might be related to a better diagnosis of the disease, mainly in patients from racial groups that are not commonly associated with cystic fibrosis, such as Black individuals, Hispanic or Latino (mixed individuals/Pardos) individuals, and American Indians (Indigenous peoples from Brazil). Regarding of race, the Σ of deaths was: nine (0.3%) in the American Indian group, 12 (0.4%) in the Asian group, 99 (3.6%) in the Black or African American group, 787 (28.6%) in the Hispanic or Latino group, and 1843 (67.0%) in the White group. The White group showed the highest prevalence of deaths, and the increase in mortality was ≅150 times in this group, while, in the Hispanic or Latino group, it was ≅75 times. Regarding sex, the numbers and percentage of deaths of both male (N = 1492; 48.9%) and female (N = 1557; 51.1%) patients were seen to be relatively close. As for age groups, the >60-year-old group presented the most significant results, with an increase of ≅60 times in the registered deaths. In conclusion, in Brazil, despite the number of deaths from cystic fibrosis being prevalent in the White group, it increased in all racial groups (Hispanic or Latino, Black or African American, American Indian, or Asian individuals) and was associated with older age.

ß-adrenergic sweat test in children with inconclusive cystic fibrosis diagnosis: Do we need new reference ranges?

BACKGROUND: Investigating inconclusive cystic fibrosis (CF) diagnosis in children is difficult without advanced cystic fibrosis transmembrane conductance regulator (CFTR) function tests. This study investigated the utility of beta (ß)-adrenergic sweat test to exclude CF in participants with inconclusive diagnosis (CF suspects) in South Africa. METHODS: ß-adrenergic sweat test and sweat chloride tests (SCT) were performed simultaneously in CF suspects and adult controls (healthy, CFTR heterozygotes and CF). Cholinergic and ß-adrenergic induced sweat rate was measured by evaporimetry (transepithelial water loss [TEWL]: g H2 O/m2 /h) following intradermal injections. Next-generation sequencing of CFTR was performed in CF suspects. CF diagnosis was defined by genotype. RESULTS: Thirty-seven controls (10 healthy, 14 CF, 13 CFTR heterozygotes) and 32 CF suspects (26 children; 6 adults) were enrolled. Six were excluded from formal analyses due to ß-adrenergic sweat test failure. In adults, evaporimetry was superior to SCT for diagnosis of CF with ß-adrenergic:cholinergic ratio TEWL ≤ 0.05 achieving 100% sensitivity and specificity. Twenty-two CF suspect children (age range: 3.4-15.6 years) completed ß-adrenergic sweat testing of which none had CF confirmed by genotyping: ß-adrenergic:cholinergic ratio > 0.05 successfully excluded CF in all but one child who was CFTR heterozygous. Median peak ß-adrenergic TEWL and ß-adrenergic:cholinergic ratio in CFTR negative and CFTR heterozygous children was significantly lower than adult controls. CONCLUSION: ß-adrenergic sweat test is more accurate than SCT for excluding CF in children with inconclusive diagnosis. Established reference ranges for ß-adrenergic sweat test may not be suitable for children due to lower ß-adrenergic sweat secretion compared to adults.

Bothnian Palmoplantar Keratoderma: Further Delineation of the Associated Phenotype.

Bothnian palmoplantar keratoderma (PPKB, MIM600231) is an autosomal dominant form of diffuse non-epidermolytic PPK characterized by spontaneous yellowish-white PPK associated with a spongy appearance after water-immersion. It is due to AQP5 heterozygous mutations. We report four patients carrying a novel AQP5 heterozygous mutation (c.125T>A; p.(Ile42Asn)), and belonging to the same French family. Early palmoplantar swelling (before one year of age), pruritus and hyperhidrosis were constant. The PPK was finally characterized as transgrediens, non-progrediens, diffuse PPK with a clear delineation between normal and affected skin. The cutaneous modifications at water-immersion test, "hand-in-the-bucket sign", were significantly evident after 3 to 6 min of immersion in the children and father, respectively. AQP5 protein is expressed in eccrine sweat glands (ESG), salivary and airway submucosal glands. In PPKB, gain of function mutations seem to widen the channel diameter of ESG and increase water movement. Thus, swelling seems to be induced by hypotonicity with water entrance into cells, while hyperhidrosis is the result of an increased cytosolic calcium concentration.

ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria.

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.

Establishment of Normative Data for Autonomic Function Tests in Indian Population.

Background: Normative data for autonomic function tests (AFT) is not available for Indian population. Objective: The aim of the study was to establish normative data in AFT and its correlation with age, gender, and body mass index. Material and Methods: The study was done on 254 healthy subjects of age ≥18 years. All AFTs were done in autonomic laboratory at the Department of Neurology, Christian Medical College and Hospital, Ludhiana. Cardiovascular tests (heart rate response to deep breathing, HR changes in Valsalva maneuver and head-up tilt test (HUT)) and quantitative sudomotor axon reflex testing (QSART) were performed in all the subjects. Fifty subjects underwent thermoregulatory sweat test (TST). Results: The mean age (SD) of study participants was 43 (16.0) years (range 20-84), and 129 (50.8%) were men. The normative value range (2.5-97.5 percentile) for HR difference, E: I ratio, and Valsalva ratio (VR) was 3.5-47.0, 1.05-1.93, and 1.11-2.64, respectively, for all the subjects. HR difference and E: I ratio showed an significant inverse relation with age (r = -0.623 and r = -0.584, respectively). VR also showed an inverse relation with age (r = -0.575, P =< 0.001), and female had a lower value than male (1.63 vs 1.78, P =< 0.001). In QSART, mean (SD) sweat volume was higher in males 0.630 (0.230) compared to females 0.513 (0.132) for all sites, P < 0.001, and similar trend was noticed for sweat area in TST. Discussion and Conclusion: Normative AFT data has been established for Indian population for the first time. The values are comparable to previously published studies.

Clinical complications in children with false-negative results in cystic fibrosis newborn screening

Abstract Objective: To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS). Materials and methods: All children presented in this paper were covered by CF NBS. The group of 1.869.246 newborns was screened in the Institute of Mother and Child in Warsaw within a period of 01.01.1999 - 31.05.2019. Screening protocols evolved over time from IRT/IRTto IRT/DNA/EGA. Results: The authors identified 11 patients with false-negative NBS, in whom CF was diagnosed based on clinical symptoms or the examination of siblings with positive CF NBS. In the study group, the diagnosis was made significantly later in comparison to positive CF NBS patients ranging from 2 months to 15 years of age. CF NBS strategy does not significantly affect the sensitivity of the screening. Conclusion: In the presence of clinical symptoms, additional diagnostics must be implemented, in spite of the negative screening results. At first, the sweat test should be conducted, followed by a DNA analysis of the most common mutations in the given population. The diagnostic process requires searching for CFTR mutations not typically associated with a high chloride concentration in sweat. Repetition of sweat chloride concentration enables the diagnosis in children whose initial chloride values in sweat are borderline, and no CF-causing mutations are detected. In strong clinical indications, the extension of DNA analysis (EGA) is recommended in order to identify rare CF variants. In children with meconium ileus, genetic analysis is mandatory.

Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme.

More than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings.