Cystic fibrosis (CF), also known as mucoviscidosis, is the most common autosomal recessive genetic disease in the Caucasian population, with an estimated frequency of 1:2000-3000 live births. CF results from the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene localized in the long arm of chromosome 7. The product of CFTR gene expression is CFTR protein, an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that regulates the transport of chloride ions (Cl-) across the apical cell membrane. Primary manifestations of CF include chronic lung and pancreas function impairment secondary to the production of thick, sticky mucus resulting from dehydrated secretions. It is well known that CF can cause both anterior and posterior ocular abnormalities. Conjunctival and corneal xerosis and dry eye disease symptoms are the most characteristic manifestations in the anterior segment. In contrast, the most typical anatomical and functional changes relating to the posterior segment of the eye include defects in the retinal nerve fiber layer (RNFL), vascular abnormalities, and visual disturbances, such as reduced contrast sensitivity and abnormal dark adaptation. However, the complete background of ophthalmic manifestations in the course of CF has yet to be discovered. This review summarizes the current knowledge regarding ocular changes in cystic fibrosis.

OBJECTIVE: 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.

Asthma is one of the main non-communicable chronic diseases and affects a huge portion of the population. It is a multifactorial disease, classified into several phenotypes, being the allergic the most frequent. The pathophysiological mechanism of asthma involves a Th2-type immune response, with high concentrations of allergen-specific immunoglobulin E, eosinophilia, hyperreactivity and airway remodeling. These mechanisms are orchestrated by intracellular signaling from effector cells, such as lymphocytes and eosinophils. Ion channels play a fundamental role in maintaining the inflammatory response on asthma. In particular, transient receptor potential (TRP), stock-operated Ca2+ channels (SOCs), Ca2+-activated K+ channels (IKCa and BKCa), calcium-activated chloride channel (TMEM16A), cystic fibrosis transmembrane conductance regulator (CFTR), piezo-type mechanosensitive ion channel component 1 (PIEZO1) and purinergic P2X receptor (P2X). The recognition of the participation of these channels in the pathological process of asthma is important, as they become pharmacological targets for the discovery of new drugs and/or pharmacological tools that effectively help the pharmacotherapeutic follow-up of this disease, as well as the more specific mechanisms involved in worsening asthma.

Since the onset of the coronavirus disease, COVID-19 pandemic, concern arose for those who might be at higher risk of a worse COVID-19 prognosis, such as those with cystic fibrosis (CF). In this context, we evaluated the features of hospitalized patients with CF due to severe acute respiratory infection (SARI) in Brazil and we also performed a systematic review including all the studies published from the beginning of the first case of COVID-19 (17 November 2019) to the date of this search (23 May 2022) which included, concomitantly, patients with CF and COVID-19 in the worldwide population. In our Brazilian data, we evaluated the period from December 2019 to March 2022, and we included 33 demographical and clinical patients\' features. We classified the patients into groups: (G1) SARI due to another viral infection than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (23; 5.4%), (G2) SARI due to an unknown etiological agent (286; 67.1%), and (G3) SARI due to SARS-CoV-2 infection (117; 27.5%). The individuals in G3 tended to be older, especially over 50 years old, and presented a higher prevalence of dyspnea, peripheral capillary oxygen saturation (SpO2) <95%, and cardiopathy. The highest prevalence for intensive care unit (ICU) treatment (52; 44.4%) and invasive mechanical ventilation (29; 24.8%) was for patients in G3. Almost half of the patients in G3 died (51; 43.6%); in contrast, none in G1 died. However, we observed 43 (15.0%) deaths in G2. In addition, 12 (4.2%) and one (0.9%) death not associated with SARI occurred, respectively, in the G2 and G3. The patients who died due to SARS-CoV-2 infection had a higher frequency of SpO2 <95% (46; 90.2%), ICU treatment (34; 66.7%), and invasive mechanical ventilation (27; 52.9%) when compared to those who recovered. The systematic review comprised a total of 31 papers published as observational studies. These studies comprised 661,386 patients in total, including children, adults, and elderly age groups. However, only 19,150 (2.9%) patients were diagnosed with CF and, from these patients, 2523 (0.4%) were diagnosed with both CF and COVID-19. It was observed that the most common outcome was the need for hospitalization (n = 322 patients with CF), and the need for oxygen support (n = 139 patients with CF). One hundred patients with CF needed intensive care units, fifty patients needed non-invasive mechanical ventilation support, and only three patients were described as receiving invasive mechanical ventilation support. Deaths were described in 38 patients with CF. Importantly, lung-transplanted patients with CF represented an increased risk of death in one publication; in accordance, another study described that lung transplantation and moderate to severe lung disease were independent risk factors for severe outcomes after SARS-CoV-2 infection. In contrast with the literature, in conclusion, Brazilian patients in G3 presented a severe phenotype, even though most of the other studies did not observe worse outcomes in patients with CF and COVID-19.

Cystic Fibrosis (CF) is associated with gut dysbiosis, local and systemic inflammation, and impaired immune function. Gut microbiota dysbiosis results from changes in the complex gut milieu in response to CF transmembrane conductance regulator (CFTR) dysfunction, pancreatic malabsorption, diet, medications, and environmental influences. In several diseases, alteration of the gut microbiota influences local and systemic inflammation and disease outcomes. We conducted a systematic review of the gut microbiota in CF and explored factors influencing dysbiosis.
An electronic search of three databases was conducted in January 2019, and re-run in June 2021. Human, animal, and in vitro studies were included. The primary outcome was differences in the gut microbiota between people with CF (pwCF) and healthy controls. Secondary outcomes included the relationship between the gut microbiota and other factors, including diet, medication, inflammation, and pulmonary function in pwCF.
Thirty-eight studies were identified. The literature confirmed the presence of CF-related gut dysbiosis, characterized by reduced diversity and several taxonomic changes. There was a relative increase of bacteria associated with a pro-inflammatory response coupled with a reduction of those considered anti-inflammatory. However, studies linking gut dysbiosis to systemic and lung inflammation were limited. Causes of gut dysbiosis were multifactorial, and findings were variable. Data on the impact of CFTR modulators on the gut microbiota were limited.
CF-related gut dysbiosis is evident in pwCF. Whether this influences local and systemic disease and is amenable to interventions with diet and drugs, such as CFTR modulators, requires further investigation.

Constipation is one of the most frequent abnormalities of the gastrointestinal system that affects the patient\'s quality of life. Constipation is more common in women and affects them more frequently as they get older. Many constipated patients take over-the-counter drugs for treatment, but some do not respond to these medicines and need newer, more expensive drugs. Still, many patients are not completely satisfied with these medicines. Unlike other areas, constipation research is not given much importance.
This review discusses targets such as ClC-2, CFTR, opioid receptors, and 5HT-4 receptors, which are important in constipation therapy. The recent focus is also on the gut microbiome with the help of various randomized controlled trials. Pharmacological advances have also added novel targets such as IBAT, PAR-2, and intestinal NHE-3 for constipation treatment.
This review summarises the research on these targets collected from various databases. ClC-2 and CFTR are involved in intestinal chloride secretion followed by sodium or water, which increases stool passage. Non-cancer pain treatment with opioids targeting opiate receptors is considered in 40-90% of patients, which causes constipation as a side effect. On activation, 5HT-4 receptors increase gastrointestinal motility. IBAT is responsible for transporting bile acid into the liver. Bile acid will reach the colon by inhibiting IBAT, stimulating colonic motility, and providing a laxative effect. Activation of the ghrelin receptor results in prokinetic activity in both animals and humans. Intestinal NHE-3 mediates the absorption of Na+ and the secretion of hydrogen into the intestine. Many reports show that PAR-2 is involved in the pathogenesis of gastrointestinal diseases. The gut microbiota influences the peristaltic action of the intestine.
Drugs working on these targets positively impact the treatment of constipation, as do the drugs that are currently in clinical trials acting on these targets. The results from the ongoing clinical trials will also provide some valuable information regarding whether these medications will meet the patients\' needs in the future.

BACKGROUND: Patients with asthma who have neutrophilic bronchitis may have an underlying cause leading to increased susceptibility to airway infections.
METHODS: Retrospective review of patients with asthma who had a previous history of recurrent exacerbations that had been associated with airway or sinus infections referred to a tertiary asthma center between 2005 and 2020. Demographics, clinical features, and airway inflammation type determined by sputum cytometry were compared between CFTR carriers and non-carriers. Multiple linear regression was used to identify clinical predictors of CFTR carrier status. Response to nebulized hypertonic saline was assessed by comparing the number of infective exacerbations before and after its initiation.
RESULTS: 75 patients underwent CFTR mutation testing. Of these, 13 (17%) were CFTR carriers. The most common mutation was [Formula: see text]F508. CFTR carriers were older (adjusted odds ratio 1.06 (CI 95% 1.01, 1.13)) and had more frequent flares requiring hospitalization (4.19 (1.34, 24.74)). Neutrophilic airway inflammation was the most common inflammatory subtype in CFTR carriers, though 8/13 also had eosinophilic bronchitis. Nebulized hypertonic saline was well tolerated by most and reduced the frequency of infective exacerbations.
CONCLUSIONS: The prevalence of CFTR heterozygosity in this cohort with recurrent neutrophilic bronchitis is higher than in the general population. Respiratory disease in CFTR carriers is associated with older age and may cause significant morbidity. Airway neutrophilia is the most common inflammatory subtype, but > 50% had eosinophilic bronchitis requiring treatment. Hypertonic saline appears to be well tolerated and effective in reducing the number of infective exacerbations.

UNASSIGNED: Meconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting. MI can lead to bowel perforation, a twisting of the bowel, or inflammation and infection of the abdominal cavity.
UNASSIGNED: To find the incidence and prevalence of meconium ileus in cystic fibrosis patients and to report on the most common gene mutation of MI in CF patients.
UNASSIGNED: Retrospective review of the medical documentations of all MI patients during the period of 1989-2018.
UNASSIGNED: A total of 40 CF confirmed patients were presented with MI. Twenty-nine patients (71%) are alive and 11 patients (29%) died or lost to follow-up. The following CFTR mutations were found: Eight patients (20%) with c.2988+1G>A; Intron 18. Seven patients (17.5%) with c.1418delG; Exon 11. Five patients (12.5%) with c.579+1G>T; Intron 5. Four patients (10%) with c.1911delG; Exon 14. Four patients (10%) with c.1521_1523delCTT; Exon 11. Four patients (10%) with c.416A>T; Exon 13. Three patients (7.5%) with c.2421A>G; Exon 14. Two patients (5%) with c.3908A>C; Exon 21. One patient (2.5%) with c.3889dupT; Exon 24. One patient (2.5%) with c.1657C>T; Exon 12. One patient (2.5%) with c.2547C>A; Exon 14a. Eighteen patients (45%) were presented with vomiting, 38 patients (95%) had postnatal radiological findings, 7 patients (17.5%) had electrolytes imbalance. Five patients (12.5%) had cholestasis and 4 patients (10%) developed chronic liver disease. Thirty-five patients (79.5%) underwent surgical repair and 9 patients (20.5%) were treated medically. Mean age of operation was 2.25 (2) days. Of 9 patients, 6 (66.6%) were treated with gastrograffin enema, 2 patients (22.2%) with oral N-acetylcysteine and 1 patient (11.1%) with saline rectal wash. Thirteen patients (31.5%) required TPN. Five patients had recurrent operation.
UNASSIGNED: CF and meconium ileus are commonly present in CF patients in Saudi Arabia. Prognosis is similar to other CFs without MI, if treated early. Thirty percent of our CF/MI patients have intronic mutations.

Cystic fibrosis-related liver disease (CFLD) is the leading cause of death in cystic fibrosis (CF), after pulmonary disease. To improve identification and management of this condition requires an understanding of the underlying disease mechanism.
This review summarises the current understanding of CFLD epidemiology, pathology, diagnosis and management.
Relevant reports on cystic fibrosis liver disease were identified using a literature search and summarised.
CFLD is a heterogeneous condition with several different co-existent pathologies, including environmental and genetic factors. Incidence of clinically significant CFLD continues at a linear rate into early adulthood and has been described in up to 25% of CF patients. Diagnosis strategies lack precision and patient risk stratification needs to look beyond Childs-Pugh scoring. Efficacious therapies are lacking and, at present, newer modulator therapies lack data in CFLD and carry an increased risk of hepatotoxicity. Outcomes of liver transplant are comparable to non-CF transplant indications.
The incidence of CFLD increases with age and hence is increasingly important to adult patients with CF. Effective therapies are lacking. For progress to be made a better understanding of pathogenesis and disease detection are required.

Undetected cystic fibrosis transmembrane regulator (CFTR) mutations may predispose individuals to develop CRS independent of formal CF diagnosis. The objective of this study was to determine the prevalence of CFTR mutations among individuals with CRS.
A systematic search following PRISMA guidelines was performed. A meta-analysis was performed to calculate pooled estimates for the prevalence of any CFTR mutation and for the DF508 mutation.
The systematic search included all studies identifying adults diagnosed with CRS, with no limitation to region or publication date. Studies had to identify a sample of patients previously diagnosed with CRS but not with CF and reporting testing for the prevalence of CF or the CFTR gene mutation.
Prevalence of CFTR mutations among the general CRS population, with subgroup analysis of individuals with the dF508 mutation.
The 6 included studies represented five countries: the United States, the UK, France, Poland and Finland. The pooled prevalence of CFTR mutations of any kind in CRS subjects without CF was 5.65% (RE 95% CI 2.99 - 10.41). The overall prevalence for the dF508 mutation was 4.22% (RE 95% CI 1.71 - 10.07). These estimates were significantly higher than the baseline estimated prevalence of CFTR carrier status of 3%-4% in the general population. However, the clinical relevance of the presence of CFTR mutations in CRS patients who have not been diagnosed with CF is currently unclear. Future studies should include sweat chloride testing as a measure of CFTR function.