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Meconium ileus and pancreatic sufficiency with D1152H mutation: A case report and review of the literature [Case Report]

Lang, Emma; Kiernan, Bridget; Muise, Eleanor D; Giusti, Robert
Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR) mutations and pancreatic insufficiency (PI). D1152H is a class IV mutation that corresponds with a milder CF phenotype and pancreatic sufficiency (PS). We present the case of an infant with G542X/D1152H mutations and MI who required surgical intervention with small bowel resection. The sweat testing was normal, and this child presently remains PS, however at age 5 continues to experience short gut syndrome and failure to thrive. Eight cases were identified in the CF Registry and seven cases in the literature describing patients with D1152H and echogenic bowel (EB) or MI. Our case highlights the importance of CFTR gene sequencing in infants with EB or MI and sweat testing not suggestive of CF. It is our practice to perform full CFTR gene sequencing for infants who present with MI, recognizing protocols for newborn screening across the United States vary. Increased awareness of D1152H association with PS may also well inform both prenatal and postnatal genetic counseling.
PMID: 37423798
ISSN: 1873-5010
CID: 5537332

The clinical impact of the Covid-19 pandemic first wave on patients with cystic fibrosis in New York

Simonson, Joseph L; Esposito, Christine; Frantzen, Theresa; Henthorne, Katherine; Espinal, Aileen; Romano, Serena; Ramdeo, Ramona; Trentacoste, Jessica; Tsang, Donna; LaVecchia, Geralyn; Abdullah, Robert; Berdella, Maria; Bonitz, Lynn; Condos, Rany; Constantinescu, Andrei; DeCelie-Germana, Joan K; DiMango, Emily; Draine, Myah; Gimeli, Tara; Giusti, Robert; Guzman, Jessenia; Hammouda, Soumia; Keating, Claire; Kier, Catherine; Lennox, Alison T; Liriano, Carmen; Messer, Zachary; Plachta, Amy; Sadeghi, Hossein; Schwind, Elinor; Stables-Carney, Teresa; Walker, Patricia; Wang, Janice
BACKGROUND:People with cystic fibrosis (pwCF) may be at risk of complications from COVID-19 but the impact of COVID-19 on pwCF remains unknown. METHODS:We conducted a multicenter retrospective cohort study to assess the impact of the COVID-19 pandemic first wave on pwCF in the New York metropolitan area (NY) from March 1, 2020 to August 31, 2020. Objectives were to determine (1) the prevalence of COVID-19 by PCR and IgG antibody testing, (2) the clinical characteristics of COVID-19, (3) delay in routine outpatient care, and (4) the effect on anxiety and depression in pwCF. RESULTS:There were 26 COVID-19 cases diagnosed by PCR or antibody testing among the study cohort of 810 pwCF. The prevalence of COVID-19 by PCR (1.6%) and IgG antibody (12.2%) testing was low. 58% of cases were asymptomatic and 82% were managed at home. 8% were hospitalized and 1 person died. 89% of pwCF experienced delay in care. The prevalence of anxiety increased from 43% baseline to 58% during the pandemic (P<0.01). In post-hoc analysis, the proportion of patients with diabetes (38% versus 16%, P<0.01) and pancreatic insufficiency (96% versus 66%, P<0.01) were higher while CFTR modulator use was lower (46% versus 65%, P = 0.05) in pwCF who tested positive for COVID-19. CONCLUSIONS:The prevalence of COVID-19 among pwCF in NY during the pandemic first wave was low and most cases were managed at home. CFTR modulators may be protective. PwCF experienced delay in routine care and increased anxiety.
PMCID:8858720
PMID: 35256307
ISSN: 1873-5010
CID: 5190822

80 New York Cystic Fibrosis Newborn Screening Consortium quality improvement: Focus on parent and pediatrician education and development of a statewide standard of care for CF-related metabolic syndrome infants

Choudhary, S; Giusti, R; Goetz, D; Kaslovsky, R; Berdella, M; Sadeghi, H; DeCelie-Germana, J; Welter, J; Kier, C; Fortner, C; Voter, K; Kay, D; Hammouda, S
Background: The New York State (NYS) Cystic Fibrosis Newborn Screening Consortium (NYSCFNBS) has cooperated in advocating for continued monitoring of outcomes and improvement in CF newborn screening (NBS) through quality improvement (QI) since 2002. The10 CF Foundation-accredited CF centers have a close working relationship with the NYS Department of Health (DOH) Wadsworth Screening Lab. This cooperative approach has resulted in several interventions to improve the screening program in NYS. In 2002, NYS initiated an IRT, 39 CF mutation screening algorithm. On December 1, 2017, infants with 1 CF mutation identified began to undergo full CFTR gene sequencing; those infants with 2 CF mutations are referred to CF centers. Subsequently, the state replaced the 39 mutation panel with a 338 mutation panel, followed by the sequencing step when 1 CF mutation is detected. The new screening algorithm increases infants classified as CF-related metabolic syndrome (CRMS) in the United States, or CF screen positive inconclusive diagnosis (CFSPID) in Europe. CRMS is used to describe these infants with a sweat chloride value < 30 mmol/L and 2 CFTR mutations, or an intermediate sweat chloride value (30-59 mmol/L) and 1 or no CF-causing mutations. Between 10% and 20% of CRMS/CFSPID individuals can develop clinical features suggestive of CF. This project is an extension of a 2-year CFNBS QI project, which was developed due to the COVID-19 pandemic. NYS was the epicenter of the pandemicin the spring of2020. Due to statewide lockdown, all CF centers were closed for 2 months, and sweat testing for infants with an abnormal CFNBS was not available. Parents of CRMS/CFSPID infants were lost to follow-up because of anxiety about returning to the CF center during the pandemic. This QI project aims to educate the parents and primary care physicians (PCP) to increase awareness and monitor these infants over several years and standardizing care across the 10 NYSCFcare centers.
Method(s): Since the initiation of the sequencing algorithm in December 2017, 250 CRMS/CFSPID infants had been diagnosed. Aparental questionnaire was developed to assess their willingness to be contacted by the CF team to return for a CF clinic visit and repeat swe at test. Parentalagreement to permit the CF team to contact the PCP to educate them concerning CRMS/CFSPID was requested. The questionnaire and QI project were shared with the CF Foundation Clinical Research Community Engagement specialist to facilitate parental feedback from the CF community voice team. Monthly Zoom meetings were held with all 10 NYS CF teams to implement the QI effort.
Result(s): Each CF center is in the process of contacting CRMS/CFSPID patients and their pediatricians and assessing their previous evaluation, including genetic counseling, their knowledge of CRMS/ CFSPID, and willingness to follow up at the CF center again. This data is being collected and analyzed currently.
Conclusion(s): Despite CRMS/ CFSPID guidelines published in 2009 [1], there is controversy regarding management and follow-up of these infants, as well as on the education of busy PCP on this topic. The NYS NBS program offers a unique opportunity to assess infants with CRMS/CFSPID due to the full genetic sequencing available in these infants, and the NYSCFNBS QI data on the follow-up of these infants will help in the understanding and monitoring of this condition.
Copyright
EMBASE:2014917920
ISSN: 1873-5010
CID: 5104002

Pulmonary Manifestations of Renal Disorders in Children

Malaga-Dieguez, Laura; Trachtman, Howard; Giusti, Robert
The causes of kidney disease in pediatric patients are evenly divided between congenital abnormalities of the kidney and urinary tract and acquired disorders. Nearly 10% to 15% of adults in the United States have chronic kidney disease (CKD); there are no comparable data in children. Regardless of patient age, CKD is a systemic problem that affects every organ system, including the lung. We review the tests used to diagnose and evaluate kidney disease and the main clinical syndromes that are likely to be encountered to aid the pulmonology consultant who is asked to evaluate patients with kidney disease.
PMID: 33228933
ISSN: 1557-8240
CID: 4680392

Airway manifestations of sarcoidosis in adolescents

Obsekov, Vladislav; Chen, Linda; Pirzada, Melodi; Giusti, Robert; Kazachkov, Mikhail
Endobronchial sarcoid lesions have previously been described and visualized upon bronchoscopy in adult patients with pulmonary sarcoid involvement. Endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS-TBNA) has come into favor as the preferred method of diagnosis, but it remains a novel technique in pediatric pulmonology. We describe the first two known cases of visualized endobronchial sarcoid lesions in the pediatric population with pathological confirmation of sarcoidosis with endobronchial and EBUS-TBNA biopsies.
PMID: 32741147
ISSN: 1099-0496
CID: 4559952

Design and implementation of a custom sequencing panel for CF newborn screening in New York State [Meeting Abstract]

Kay, D; Stevens, C; Sicko, R; Berdella, M; Boyer, J; DeCelie-Germana, J; Dozor, A; Fortner, C N; Giusti, R; Goetz, D M; Guida, L; Hughes, E; Kaslovsky, R; Kier, C; Krein, L; Langfelder-Schwind, E; Saavedra-Matiz, C; Sadeghi, H; Seguin, J M; Soultan, Z N; Ting, A; Torkington-Wood, H; Welter, J; Caggana, M
Background: CF newborn screening (NBS) has high false-positive rates, leading to unnecessary referral of unaffected infants, burdening families. In 2017, a three-tier IRT-DNA-SEQ algorithm was implemented by the NYS NBS program. Referring only infants with two variants resulted in an 83.1% reduction in referrals and a nearly 7-fold increase in positive predictive value (3.7% to 25.2%).
Method(s): A new CFTR algorithm was implemented in 2019. A custom ArcherDx VariantPlex panel utilizing multiplex target enrichment and next-generation sequencing (NGS) technology combines second- and third-tier testing onto a single platform. A panel of 338 CFTR variants are reported for all specimens with high IRT (top 5%). Third-tier full gene sequencing and deletion/duplication (del/dup) analysis is only unblinded in infants with one panel variant or ultra-high IRT.
Result(s): The custom assay's second-tier panel includes all CF-causing sequence variants in CFTR2, including 23 recommended for population- based carrier screening, p.R117H with intron 8 polyT, and additional pathogenic/likely pathogenic variants. Third-tier analysis requires no additional laboratory work. Rather, the full CFTR gene coding sequence and other relevant regions are simply unmasked. Third-tier analysis detects variants not catalogued in CFTR2, and algorithms are used to impute large del/dup that are typically not detectable by sequencing. Approximately 18% of alleles in confirmed cases are detected by sequencing, verifying the diverse NYS CFTR mutation spectrum. However, as expected, a 3-fold increase in the ratio of CF screen positive, inconclusive diagnosis/CFTR-related metabolic syndrome to CF cases is detected. Nearly all of these cases had at least one variant of varying clinical consequence or of uncertain significance and are asymptomatic.
Conclusion(s): The new CFTR assay has higher throughput (96-well format) and is customizable, allowing the Program to add/remove variants from the panel bioinformatically, without assay redesign. Results and outcomes thus far are similar using the two sequencing platforms. Comprehensive genetic analysis allows release of infants without two clinically relevant variants as screen negative, with a recommendation for genetic counseling for carriers
EMBASE:633656024
ISSN: 1099-0496
CID: 4782862

Outcomes in infants identified by IRT-DNASEQ newborn screening algorithm in New York State [Meeting Abstract]

Kay, D; Berdella, M; Boyer, J; DeCelie-Germana, J; Dozor, A; Fortner, C N; Giusti, R; Goetz, D M; Guida, L; Kaslovsky, R; Kier, C; Krein, Lea H; Langfelder-Schwind, E; Laterza, Ozarowski A; Maldonado, V; Martin, L; Saavedra-Matiz, C; Sadeghi, H; Seguin, J M; Soultan, Z N; Ting, A; Torkington-Wood, H; Welter, J; Stevens, C; Caggana, M
CF newborn screening (NBS) began in New York state (NYS) using an immunoreactive trypsinogen (IRT)-DNA algorithm in 2002. On 12/1/2017, NYS became the second in the US to implement enhanced NBS including CFTR sequencing (IRT-DNA-SEQ), with a primary goal of minimizing unnecessary referral of unaffected infants. Infants with high IRT (top 5%) were first screened for 39 CFTR variants using the Luminex xTAG CF39v2 panel. Those with one variant or ultra-high IRT (top 0.1%) were sequenced using MiSeqDx CF Clinical Sequencing Assay (Illumina) with confirmation by Sanger and supplemental testing for specific deletions. Infants with two potentially clinically significant variants were referred to accredited specialty care centers for diagnostic testing. The primary care provider and birth hospital were issued reports for all screen-negative infants, with a recommendation of genetic counseling for carriers. During the first year, >100 different reportable CFTR variants were identified, and 127 infants with two variants were referred. Using the previous IRT-DNA algorithm, 445 carriers and 177 infants with no variants would also have been referred, corresponding to an 83% reduction in referrals with the IRT-DNA-SEQ algorithm. Thirty-one infants have been confirmed to have CF. The median age at earliest consult among CF cases was 12 days (range 0-62), with >=93% seen within 30 days of life. Eighty-six infants with two variants and intermediate/low sweat chloride levels were classified as CFSPID/CRMS and are followed; 83/86 carried 1-2 variants of varying clinical consequence or uncertain significance, compared to only 2/31 CF cases. Such variants with low or variable penetrance complicate diagnosis and prompt long-term follow-up to monitor for symptoms related to CFTR dysfunction or "conversion" to CF. Furthermore, the ratio of CFSPID/CRMS to CF cases increased from 0.9:1 to 2.8:1 overall, and differed by center, ranging from 0.8:1 to 15:0. Sequencing increases lab workload, turnaround times and cost, but is balanced by reduction in follow-up by NBS staff and care centers, and an overall reduction in healthcare costs by elimination of diagnostic evaluation for most infants with false-positive screens. Identification of asymptomatic infants with two CFTR variants and intermediate/negative sweat chloride values poses new clinical and practical challenges for care teams and families
EMBASE:629387710
ISSN: 1099-0496
CID: 4120252

Serum perfluoroalkyl substances and lung function in adolescents exposed to the World Trade Center disaster

Gaylord, Abigail; Berger, Kenneth I; Naidu, Mrudula; Attina, Teresa M; Gilbert, Joseph; Koshy, Tony T; Han, Xiaoxia; Marmor, Michael; Shao, Yongzhao; Giusti, Robert; Goldring, Roberta M; Kannan, Kurunthachalam; Trasande, Leonardo
The effects of childhood exposure to perfluoroalkyl substances (PFASs) on lung function remain mostly unknown. Previous research indicates that children living or going to school near the World Trade Center (WTC) disaster were exposed to high levels of PFASs, among other toxic chemicals. To explore the effects of PFAS exposure on lung function, we measured serum PFASs in a cohort of children from the WTC Health Registry and a matched control group. Perfluorooctanesulfonate had the highest median concentrations in both groups (WTCHR = 3.72 ng/mL, Comparison = 2.75 ng/mL), while the lowest median concentrations were seen for perfluoroundecanoic acid (WTCHR = 0.12 ng/mL, Comparison = 0.01 ng/mL). Lung function outcomes were measured by spirometry, plethysmography, and oscillometry. Asthma diagnosis and serum eosinophil count were also recorded. We examined the relationships of each PFAS with lung function parameters and eosinophil count using linear regressions. Odds ratios for asthma were obtained for each PFAS using logistic regression. The effect of total PFASs on these outcomes was also assessed. All regression models were adjusted for sex, race/ethnicity, age, body mass index (BMI) and tobacco smoke exposure. We found that serum PFASs were not statistically associated with the measured lung function parameters, asthma diagnosis, or eosinophil count in this cohort (p < 0.05). These findings highlight the need for more longitudinal studies to explore the long-term effects of childhood PFAS exposure on lung function past adolescence and early adulthood.
PMID: 30822559
ISSN: 1096-0953
CID: 3698762

NEW YORK STATE CYSTIC FIBROSIS NEWBORN SCREENING: A STATEWIDE QUALITY IMPROVEMENT PROJECT TO ASSESS THE IMPACT OF NEXTGEN SEQUENCING [Meeting Abstract]

Chen, L. M.; Goetz, D. M.; Hammouda, S.; Giusti, R.
ISI:000484544000313
ISSN: 8755-6863
CID: 4448592

OUTCOMES IN INFANTS IDENTIFIED BY IRT-DNA-SEQ NEWBORN SCREENING ALGORITHM IN NEW YORK STATE [Meeting Abstract]

Kay, D.; Berdella, M.; Boyer, J.; DeCelie-Germana, J.; Dozor, A.; Fortner, C. N.; Giusti, R.; Goetz, D. M.; Guida, L.; Kaslovsky, R.; Kier, C.; Lea, Krein H.; Langfelder-Schwind, E.; Ozarowski, Laterza A.; Maldonado, V; Martin, L.; Saavedra-Matiz, C.; Sadeghi, H.; Seguin, J. M.; Soultan, Z. N.; Ting, A.; Torkington-Wood, H.; Welter, J.; Stevens, C.; Caggana, M.
ISI:000484544000306
ISSN: 8755-6863
CID: 4448582