StatPearls

Book. 2020 01

Authors:

Abstract
Spinal muscular atrophy (SMA) denotes a collection of inherited clinical syndromes causing degeneration of anterior horn cells in the spinal cord with associated destruction of alpha motor cells and presents clinically with characteristic proximal muscle weakness and atrophy.[1] Homozygous deletion at 5q13 (the coding region for the survival motor neuron (SMN1) gene) is responsible for 95% of cases of SMA, and after cystic fibrosis is the second most common cause of autosomal recessive inherited related mortality with an estimated incidence of 1 in 6000 to 11000.[2][3] Homozygous deletion at 5q13 is also referred to as classical proximal SMA and will be the focus of this article with differentials and other causes of SMA discussed below. SMA is heterogeneous in presentation and ranges from death within weeks of birth to mild proximal weakness developing during adulthood. Earlier presentations are typically associated with poorer function and prognosis: classification of SMA subtypes are determined by the age of onset as well as clinical severity and life expectancy.[4]  SMA was first described in the 1890s, first by Guido Werdnig in describing intermediate and severe SMA in 2 brothers and then 7 cases by Johan Hoffmann; type I SMA is sometimes eponymously referred to as Werdnig-Hoffmann disease. Similarly, milder forms of SMA (type III) detailed by Kugelberg and Welander is sometimes eponymously referred to as Kugelberg-Welander disease.[5]

PMID: 32809522

Rethinking bedtime resistance in children with autism: is restless legs syndrome to blame?

J Clin Sleep Med. 2020 Aug 17;:

Authors: Kanney ML, Durmer JS, Trotti LM, Leu R

Abstract
STUDY OBJECTIVES: In this study we investigated the clinical correlates of restless legs syndrome in children with autism and report on our experiences with response to treatment.
METHODS: A retrospective chart review of children seen in our sleep center from 2016-2019 was performed to identify children with autism and chronic insomnia. Patients underwent clinical assessments for restless legs symptomatology. Overnight polysomnogram, serum ferritin testing, and response to clinical treatment data were collected.
RESULTS: A total of 103 children with autism and chronic insomnia were identified (age range 2 - 19 years). Of these, 41 children (39%) were diagnosed with restless legs syndrome. The diagnosis of restless legs syndrome was associated with significantly lower serum ferritin levels (mean 29 ±18.62 ng/mL versus non-RLS 56.7 ± 17.59, P<0.001) and higher PLMS on PSG (8.12 ± 6.6 versus non-RLS 0.06 ±0.17). The presence of leg kicking, body rocking, or any symptoms involving the legs, highly correlated with the diagnosis of RLS. Positive treatment response was noted in nearly all treated patients, including those treated with oral iron supplementation alone (25 children, 23 responders), gabapentin alone (12 children, all responders), and combination therapy (3 children, all responders).
CONCLUSIONS: Our findings suggest restless legs syndrome may represent an underrecognized cause of insomnia in children with autism. Initial assessment should include a thorough query of behaviors related to nocturnal motor complaints, because restless legs syndrome may be a treatable cause of sleep disruption.

PMID: 32804073 [PubMed - as supplied by publisher]

Ceftaroline versus Vancomycin for the Treatment of Acute Pulmonary Exacerbations in Pediatric Patients with Cystic Fibrosis.

Pediatr Pulmonol. 2020 Aug 17;:

Authors: Branstetter J, Searcy H, Benner K, Yarbrough A, Crowder C, Troxler B

Abstract
INTRODUCTION: Respiratory infection with methicillin-resistant Staphylococcus aureus (MRSA) is an increasing complication in cystic fibrosis (CF) that results in accelerated lung function decline and mortality. Vancomycin is considered a first-line intravenous treatment agent for MRSA associated acute pulmonary exacerbations (APEs); however, rates of vancomycin intolerance and resistance have been observed. These factors have led to the exploration of additional treatment options for treating MRSA associated APEs.
METHODS: This is a retrospective chart review conducted at a CF center including patients 0 to 21 years of age with CF admitted for an APE and treated with either vancomycin or ceftaroline between January 2016 and August 2018. The primary endpoint was to determine ceftaroline efficacy compared to vancomycin in the treatment of MRSA associated APEs.
RESULTS: There were 180 patients included in the study with 90 patients in each antibiotic group. Admission to discharge forced expiratory volume in 1 second (FEV1 ) improved in the ceftaroline (66.5% vs 81.1%; p < 0.001) and vancomycin (65.5% vs 77.3%; p < 0.001) treatment groups. No difference existed in mean change in FEV1 (14.1 vs 13.5%; p=0.25) or readmissions (15 vs. 22; p=0.27) between ceftaroline and vancomycin groups, respectively.
DISCUSSION: In this retrospective study, no difference existed between ceftaroline and vancomycin with regard to observed improvement in lung function from admission to discharge. Additionally, no difference was observed in mean FEV1 or readmission rate between the two groups. Ceftaroline may represent an effective and safe intravenous antimicrobial option for targeting MRSA in pediatric CF patients with APEs. This article is protected by copyright. All rights reserved.

PMID: 32803907 [PubMed - as supplied by publisher]

The Gut Microbiota and Respiratory Diseases: New Evidence.

J Immunol Res. 2020;2020:2340670

Authors: Chunxi L, Haiyue L, Yanxia L, Jianbing P, Jin S

Abstract
Human body surfaces, such as the skin, intestines, and respiratory and urogenital tracts, are colonized by a large number of microorganisms, including bacteria, fungi, and viruses, with the gut being the most densely and extensively colonized organ. The microbiome plays an essential role in immune system development and tissue homeostasis. Gut microbiota dysbiosis not only modulates the immune responses of the gastrointestinal (GI) tract but also impacts the immunity of distal organs, such as the lung, further affecting lung health and respiratory diseases. Here, we review the recent evidence of the correlations and underlying mechanisms of the relationship between the gut microbiota and common respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), lung cancer, and respiratory infection, and probiotic development as a therapeutic intervention for these diseases.

PMID: 32802893 [PubMed - as supplied by publisher]

Haemophilus influenzae persists in biofilm communities in a smoke-exposed ferret model of COPD.

ERJ Open Res. 2020 Jul;6(3):

Authors: Hunt BC, Stanford D, Xu X, Li J, Gaggar A, Rowe SM, Raju SV, Swords WE

Abstract
Rationale: Non-typeable Haemophilus influenzae (NTHi) is a common inhabitant of the human nasopharynx and upper airways that can cause opportunistic infections of the airway mucosa including bronchopulmonary infections in patients with chronic obstructive pulmonary disease (COPD). It is clear that opportunistic infections contribute significantly to inflammatory exacerbations of COPD; however, there remains much to be learned regarding specific host and microbial determinants of persistence and/or clearance in this context.
Methods: In this study, we used a recently described ferret model for COPD, in which animals undergo chronic long-term exposure to cigarette smoke, to define host-pathogen interactions during COPD-related NTHi infections.
Results: NTHi bacteria colonised the lungs of smoke-exposed animals to a greater extent than controls, and elicited acute host inflammation and neutrophilic influx and activation, along with a significant increase in airway resistance and a decrease in inspiratory capacity consistent with inflammatory exacerbation; notably, these findings were not observed in air-exposed control animals. NTHi bacteria persisted within multicellular biofilm communities within the airway lumen, as evidenced by immunofluorescent detection of bacterial aggregates encased within a sialylated matrix as is typical of NTHi biofilms and differential bacterial gene expression consistent with the biofilm mode of growth.
Conclusions: Based on these results, we conclude that acute infection with NTHi initiates inflammatory exacerbation of COPD disease. The data also support the widely held hypothesis that NTHi bacteria persist within multicellular biofilm communities in the lungs of patients with COPD.

PMID: 32802827 [PubMed - as supplied by publisher]

Effect of hypertonic saline on mucociliary clearance and clinical outcomes in chronic bronchitis.

ERJ Open Res. 2020 Jul;6(3):

Authors: Bennett WD, Henderson AG, Ceppe A, Zeman KL, Wu J, Gladman C, Fuller F, Gazda S, Button B, Boucher RC, Donaldson SH

Abstract
Background: Mucus dehydration and impaired mucus clearance are common features of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). In CF, inhaled hypertonic saline (HS) improves lung function and produces sustained increases in mucociliary clearance (MCC). We hypothesised that administration of HS (7% NaCl) twice daily for 2 weeks would improve clinical outcomes and produce sustained increases in MCC in COPD subjects with a chronic bronchitis (CB) phenotype.
Methods: Twenty-two CB subjects completed a double-blinded, crossover study comparing inhaled HS to a hypotonic control solution (0.12% saline) administered via nebuliser twice daily for 2 weeks. Treatment order was randomised. During each treatment period, symptoms and spirometry were measured. MCC was measured at baseline, shortly after initial study agent administration, and approximately 12 h after the final dose.
Results: HS was safe and well tolerated but overall produced no significant improvements in spirometry or patient-reported outcomes. CB subjects had slower baseline MCC than healthy subjects. The MCC rates over 60 min (Ave60Clr) in CB subjects following 2 weeks of HS were not different from 0.12% saline but were slower than baseline (Ave60Clr was 9.1±6.3% at baseline versus 5.3±6.9% after HS; p<0.05). Subgroup analyses determined that subjects with residual baseline central lung clearance (14 subjects) had improved spirometry and symptoms following treatment with HS, but not 0.12% saline, treatment.
Conclusions: Inhaled HS appeared to be safe in a general CB population. A specific phenotypic subgroup may benefit from HS but requires additional study.

PMID: 32802823 [PubMed - as supplied by publisher]

Inhibition of Alk signaling promotes the induction of human salivary gland-derived organoids.

Dis Model Mech. 2020 Aug 14;:

Authors: Yoshimoto S, Yoshizumi J, Anzai H, Morishita K, Okamura K, Hiraki A, Hashimoto S

Abstract
Hyposalivation and xerostomia are the cause of several conditions of morbidities such as dental caries, painful mucositis, oral fungal infections, sialadenitis and dysphagia. For these reasons, preservation of normal saliva secretion is critical for the maintenance of functionally normal oral homeostasis and finally for keeping good health. Several strategies for restoring salivary gland hypofunction have been reported from different points of view based on such salivary gland-derived epithelial stem/progenitor cells and tissue engineering approaches to induce organoids mimicking in vivo salivary glands. In this study, we clarified that inhibition of Activin receptor-like kinase (Alk) signaling was essential for the induction of human salivary gland-derived organoids and showed their usefulness as an inflammatory disease model. In the inflammatory conditions like sialadenitis, in general, pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) are upregulated but their function is still unclear. In our established human salivary gland-derived organoid culture system, we successfully induced an organoid swelling revealing the function of saliva secretion by the stimulation of carbachol, a non-selective cholinergic agonist, and forskolin, an activator of cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, we found that this organoid swelling was inhibited by TNF-α. From these results, we could clarify the inhibitory function of TNF-α on the saliva secretion in vitro Thus, our established human salivary gland-derived organoids would be able to be useful for the in vitro analyses of the morphological and functional changes of salivary gland dysfunctions in several research fields such as pathobiology, inflammation and regenerative medicine.

PMID: 32801121 [PubMed - as supplied by publisher]

Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment.

J Cyst Fibros. 2020 Aug 13;:

Authors: VanDevanter DR, Heltshe SL, Sanders DB, West NE, Skalland M, Flume PA, Goss CH, STOP-OB Study

Abstract
INTRODUCTION: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822.
METHODS: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression.
RESULTS: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to -11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was -26 [-29, -23]. Odds of -26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041).
CONCLUSIONS: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.

PMID: 32800708 [PubMed - as supplied by publisher]

Decreased survival in cystic fibrosis patients with a positive screen for depression.

J Cyst Fibros. 2020 Aug 12;:

Authors: Schechter MS, Ostrenga JS, Fink AK, Barker DH, Sawicki GS, Quittner AL

Abstract
BACKGROUND: The International Depression Epidemiological Study (TIDES) found elevated rates of screen positivity for depression and anxiety among individuals with cystic fibrosis (CF). Depression is associated with worse adherence and health-related quality of life in CF. We investigated the relationship with mortality.
METHODS: Subjects were untransplanted participants in TIDES 12+ years of age receiving care at one of 45 collaborating US CF care centers who completed the Hospital Anxiety and Depression Scale and/or Center for Epidemiologic Studies Depression Scale during a stable visit between 2006 and 2010. Clinical characteristics and mortality data were obtained from the CF Foundation Patient Registry. The association of a positive screen with 5-year survival was evaluated using Cox Proportional Hazards modeling.
RESULTS: Of 1005 eligible patients, 25% screened positive for depression and 34% screened positive for anxiety. Patients who screened positive for depression were more likely to be older, have a residual function mutation, public insurance, and more pulmonary exacerbations in the screening year. There were 96 deaths. The unadjusted 5-year Hazard Ratio (HR) for death among those with depression was 2.0; 95% CI (1.3, 3.0)]. When adjusted for predetermined potential confounders the HR for the entire population was 1.4; 95% CI (0.9, 2.2). The adjusted HR was higher in adults [1.6; 95% CI (1.0, 2.4)] and those screening in the severe range [2.0; 95% CI (1.2, 3.4)]. Anxiety was not associated with mortality.
CONCLUSIONS: A positive depression screen is associated with increased mortality among adults with CF. Research into the etiology of this relationship is needed.

PMID: 32800486 [PubMed - as supplied by publisher]

Concerns regarding the safety of azithromycin in pregnancy - relevance for women with cystic fibrosis.

J Cyst Fibros. 2020 Aug 12;:

Authors: Taylor-Cousar JL, Jain R, Kazmerski TM, Aitken ML, West NE, Wilson A, Middleton PG, Nash EF

Abstract
Chronic oral azithromycin therapy improves clinical outcomes in people with cystic fibrosis (CF), and is recommended for treatment of CF lung disease. Azithromycin is categorized as pregnancy class B. The data for risk of congenital malformations associated with use of azithromycin during pregnancy ranges from no risk to a small increased risk. As with other chronic medications used to treat CF, potential risk to the infant of use of azithromycin during pregnancy must be weighed against the potential risk to the mother of treatment discontinuation. Women with CF considering pregnancy while on chronic azithromycin should be counseled regarding potential risks and benefits.

PMID: 32800485 [PubMed - as supplied by publisher]

Encephalopathy in cystic fibrosis.

Paediatr Respir Rev. 2020 Apr 09;:

Authors: Thornton T, Pillai A

Abstract
Cystic fibrosis liver disease (CFLD) affects a large proportion of cystic fibrosis (CF) patients; however encephalopathy is a rare complication. While classical hepatic encephalopathy can be a feature of end-stage liver disease, "hyperammonemic encephalopathy" can be precipitated in previously stable CFLD by various triggers including systemic corticosteroids. We describe one such case and review the relevant literature.

PMID: 32800451 [PubMed - as supplied by publisher]

Novel lung tropic AAV capsids for therapeutic gene delivery.

Hum Gene Ther. 2020 Aug 16;:

Authors: Carneiro A, Lee HC, Lin L, van Haasteren J, Schaffer D

Abstract
Efforts to identify mutations that underlie inherited genetic diseases combined with strides in the development of gene therapy vectors over the last three decades have culminated in the approval of several adeno-associated virus (AAV)-based gene therapies. Genetic diseases that manifest in the lung such as cystic fibrosis and surfactant deficiencies, however, have so far proven to be elusive targets. Early clinical trials in CF using AAV serotype 2 (AAV2) achieved safety but not efficacy endpoints, but importantly these studies provided critical information on barriers that need to be surmounted to translate AAV lung gene therapy towards clinical success. Bolstered with an improved understanding of AAV biology and more clinically relevant lung models, next generation molecular biology and bioinformatics approaches have given rise to novel AAV capsid variants that offer improvements in transduction efficiency, immunological profile, and the ability to circumvent physical barriers in the lung such as mucus. This review discusses the principal limiting barriers to clinical success in lung gene therapy and focuses on novel engineered AAV capsid variants that have been developed to overcome those challenges.

PMID: 32799685 [PubMed - as supplied by publisher]

Treating cystic fibrosis with mRNA and CRISPR.

Hum Gene Ther. 2020 Aug 16;:

Authors: Sanchez ADS, Paunovska K, Cristian A, Dahlman J

Abstract
Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed. Over the past several years, an increasing number of clinical trials with siRNA- and ASO-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by non-viral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells. Here, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for non-viral mRNA or CRISPR-based drugs to treat CF successfully in patients.

PMID: 32799680 [PubMed - as supplied by publisher]

Experience of Ceftazidime/avibactam in a UK tertiary cardiopulmonary specialist center.

Expert Rev Anti Infect Ther. 2020 Aug 15;:

Authors: Nwankwo L, Butt Z, Schelenz S

Abstract
OBJECTIVES: Antimicrobial resistance is a major threat to public health. New drugs such as Ceftazidime/avibactam have been developed for the treatment of Multi-Drug resistant (MDR) pathogens. Susceptibility can be variable and inappropriate use can add a financial strain on the National Health Service (NHS). There is a pressing need to ensure these new and invaluable antimicrobials are preserved and used effectively.
METHODS: We undertook a retrospective observational study to assess the use of Ceftazidime/avibactam and evaluated prescribing against applied standards.
RESULTS: Between August 2017 and January 2019, 28 patients received 31 courses of Ceftazidime/avibactam. Prescribing according to the approved indications was observed for 68% of prescriptions (p<0.0001). Duration of therapy was often prolonged but improved with Antimicrobial stewardship interventions. We observed 56% susceptibility (15/27 isolates) of MDR organisms (Pseudomonas, Klebsiella, Burkholderia, Enterobacter aerogenes, Achromobacter). We also report first in vivo experience to treat pulmonary disease caused by Non-tuberculous mycobacteria (NTM). Ceftazidime/avibactam was well tolerated, with no evidence of development of resistance at six months follow-up.
CONCLUSIONS: Our study showed that Antimicrobial stewardship interventions led to a more appropriate use of Ceftazidime/avibactam (as measured by duration of therapy), preserving it as a treatment option for MDR infections.

PMID: 32799594 [PubMed - as supplied by publisher]

Isolation of CFTR and TMEM16A inhibitors from Neorautanenia mitis (A. Rich) Verdcourt: Potential lead compounds for treatment of secretory diarrhea.

Phytochemistry. 2020 Aug 13;179:112464

Authors: Dawurung CJ, Noitem R, Rattanajak R, Bunyong R, Richardson C, Willis AC, Kamchonwongpaisan S, Yimnual C, Muanprasat C, Pyne SG

Abstract
A phytochemical study on the root extracts of Neorautanenia mitis, a Nigerian medicinal plant used in the management of diarrhea, led to the isolation of one new and 19 known natural products. These compounds and crude extracts were evaluated for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- channel and calcium-activated Cl- channel (TMEM16A) inhibitory activities in T84 and Calu-3 cells, respectively. Four compounds namely dolineon, neodulin, pachyrrhizine, and neotenone inhibited cAMP-induced Cl- secretion across T84 cell monolayers with IC50 values of ~0.81 μM, ~2.42 μM, ~2.87 μM, and ~4.66 μM, respectively. Dolineon having the highest inhibitory activity also inhibited a Ca + activated Cl- channel (TMEM16A) with an IC50 value of ~4.38 μM. The in vitro antidiarrheal activity of dolineon was evaluated on cholera toxin (CT) induced chloride secretion in T84 cells, where it inhibited CT-induced chloride secretion by >70% at 100 μM. Dolineon also inhibited CT-induced fluid secretion by ~70% in an in vivo mouse closed loop model at a dose of 16.9 μg/loop. The cytotoxicity of the extracts and compounds was evaluated on KB, Vero and BHK21 cells, dolineon showed low cytotoxicity of >29.6 μM and 57.30 + 6.77 μM against Vero and BHK21 cells, respectively. Our study revealed that several compounds isolated from N. mitis showed antidiarrheal activity. The most active compound dolineon can potentially serve as a lead compound towards the development of CFTR and TMEM16A inhibitors as future therapeutics for secretory diarrhea.

PMID: 32798746 [PubMed - as supplied by publisher]

Attitudes of pain and opioids prescription practices in U.S. cystic fibrosis centers.

J Cyst Fibros. 2020 Aug 11;:

Authors: Yaoli Y, Trina H, Zubin M, Anita L, Catherine D, Andrew T B

Abstract
BACKGROUND: The high incidence and prevalence of chronic pain in patients with cystic fibrosis (CF) is well documented. However, there is limited data on chronic pain management in this population.
METHODS: We designed a questionnaire examining care team members' views on the prevalence and characteristics of pain, pain management, and opioid use. The questionnaire was distributed to accredited programs throughout the US via a CF Foundation (CFF) email list-serve.
RESULTS: Responses came from 52 adult core or affiliated centers (Adult Responders - AR), 36 pediatric core or affiliated centers (Pediatric Responders - PR), and 9 were from combined programs. AR perceive more patients having chronic pain compared to PR. Furthermore, 40% of the AR said that > 50% of those with chronic pain also have comorbid depression or anxiety. 61% of PR ranked sinus/headache symptoms as the most common while AR ranked chest wall as the most frequent site (58%). While most centers (83%) report that pain management in patients with CF is a very important or important issue, 50% of AR feel uncomfortable or only slightly comfortable in prescribing opioids. 44% report that CF providers are currently responsible for this task.
CONCLUSIONS: Chronic pain is common in adult patients with CF and management presents a formidable challenge to providers. The development of guidelines and/or collaboration with pain specialists will likely benefit both patients and providers.

PMID: 32798122 [PubMed - as supplied by publisher]

Management of superior mesenteric venous thrombus in cystic fibrosis related liver disease.

Paediatr Respir Rev. 2020 Apr 21;:

Authors: Scott JA, Barry PJ, Jones AM, Athwal VS

Abstract
Abdominal pain is a common feature in patients with cystic fibrosis (CF) and CF related liver disease (CFLD). Superior mesenteric venous (SMV) thrombosis is an uncommon but important cause of abdominal pain. Management strategies are complicated by an underlying prothrombotic state and increased risk of bleeding from complications of CF and CFLD. This review addresses clinical presentation, detection and management options of an acute SMV thrombus in the context of CF.

PMID: 32798114 [PubMed - as supplied by publisher]

Quantity not sufficient rates and delays in sweat testing in US infants with cystic fibrosis.

Pediatr Pulmonol. 2020 Aug 14;:

Authors: McColley SA, Elbert A, Wu R, Ren CL, Sontag MK, LeGrys VA

Abstract
BACKGROUND: Diagnostic sweat testing is required for infants with positive newborn screening (NBS) tests for cystic fibrosis (CF). Infants have "quantity not sufficient" (QNS) sweat volumes more often than older children. A comprehensive study of QNS sweat volumes in infants has not previously been reported.
METHODS: We surveyed US CF Centers to obtain QNS rates in all infants who had sweat testing at < 14 days and < 3 months of age. We then calculated QNS rates reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60 days of life. We compared QNS sweat tests rates in preterm (< 37 weeks gestational age) versus term infants. We assessed age at sweat test and proportion of infants who did not have a sweat test reported by 60 days of age.
RESULTS: Thirty-nine of 144 (27%) of CF Centers reported a mean QNS rate of 10.5 % (range, 0-100) in infants < 14 days old. CFFPR data showed highest QNS rates in the youngest infants and in those born < 37 weeks gestation. The median age at sweat testing decreased over time, but > 22% of infants did not have a sweat test reported by 60 days.
CONCLUSION: Higher QNS rates are seen in the youngest infants with CF, but > 80% of infants < 2 weeks of age have adequate sweat volumes. Sweat testing should not be delayed in infants with a positive CF NBS test. This article is protected by copyright. All rights reserved.

PMID: 32797669 [PubMed - as supplied by publisher]

Choline in cystic fibrosis: relations to pancreas insufficiency, enterohepatic cycle, PEMT and intestinal microbiota.

Eur J Nutr. 2020 Aug 14;:

Authors: Bernhard W

Abstract
BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive disorder with life-threatening organ manifestations. 87% of CF patients develop exocrine pancreas insufficiency, frequently starting in utero and requiring lifelong pancreatic enzyme substitution. 99% develop progressive lung disease, and 20-60% CF-related liver disease, from mild steatosis to cirrhosis. Characteristically, pancreas, liver and lung are linked by choline metabolism, a critical nutrient in CF. Choline is a tightly regulated tissue component in the form of phosphatidylcholine (Ptd'Cho) and sphingomyelin (SPH) in all membranes and many secretions, particularly of liver (bile, lipoproteins) and lung (surfactant, lipoproteins). Via its downstream metabolites, betaine, dimethylglycine and sarcosine, choline is the major one-carbon donor for methionine regeneration from homocysteine. Methionine is primarily used for essential methylation processes via S-adenosyl-methionine.
CLINICAL IMPACT: CF patients with exocrine pancreas insufficiency frequently develop choline deficiency, due to loss of bile Ptd'Cho via feces. ~ 50% (11-12 g) of hepatic Ptd'Cho is daily secreted into the duodenum. Its re-uptake requires cleavage to lyso-Ptd'Cho by pancreatic and small intestinal phospholipases requiring alkaline environment. Impaired CFTR-dependent bicarbonate secretion, however, results in low duodenal pH, impaired phospholipase activity, fecal Ptd'Cho loss and choline deficiency. Low plasma choline causes decreased availability for parenchymal Ptd'Cho metabolism, impacting on organ functions. Choline deficiency results in hepatic choline/Ptd'Cho accretion from lung tissue via high density lipoproteins, explaining the link between choline deficiency and lung function. Hepatic Ptd'Cho synthesis from phosphatidylethanolamine by phosphatidylethanolamine-N-methyltransferase (PEMT) partly compensates for choline deficiency, but frequent single nucleotide polymorphisms enhance choline requirement. Additionally, small intestinal bacterial overgrowth (SIBO) frequently causes intraluminal choline degradation in CF patients prior to its absorption. As adequate choline supplementation was clinically effective and adult as well as pediatric CF patients suffer from choline deficiency, choline supplementation in CF patients of all ages should be evaluated.

PMID: 32797252 [PubMed - as supplied by publisher]

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Clin Infect Dis. 2020 Aug 14;71(4):905-913

Authors: Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ, Andrejak C, Böttger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL

Abstract
Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

PMID: 32797222 [PubMed - as supplied by publisher]