Role of hyperglycemia in cystic fibrosis pulmonary exacerbations.

BACKGROUND: Hyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations. METHODS: The STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables. RESULTS: Glucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL. CONCLUSIONS: Hyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations.

Systemic Corticosteroids in the Management of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

Rationale: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note that a short course of systemic corticosteroids may offer benefit without contributing to long-term adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment. Objectives: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx are associated with improved clinical outcomes compared with treatment without systemic corticosteroids. Methods: We conducted a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006 and 2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed-effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighting was used. Results: A total of 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -0.36; 95% confidence interval [CI], -1.14, 0.42; P = 0.4) or a higher odds of returning to lung function baseline (odds ratio, 0.97; 95% CI, 0.84-1.12; P = 0.7) but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio, 0.91; 95% CI, 0.85-0.96; P = 0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but, in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (hazard ratio, 0.96; 95% CI, 0.86, 1.07; P = 0.42). Conclusions: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.

A longitudinal assessment of diabetes autoantibodies in the SEARCH for diabetes in youth study.

To assess changes in diabetes autoantibodies (DAs) over time in children and young adults with diabetes and determine whether observed changes were associated with demographic characteristics, clinical parameters and diabetes complications. Participants had DAs measured at baseline (10.3 ± 7.1 months after diabetes diagnosis) and at 12, 24 months and ≥5 years after the baseline measurement. At the ≥5-year follow-up, the presence of diabetes complications was assessed. We examined the associations between change in number of positive DAs and changes in individual DA status with the participants' characteristics and clinical parameters over time. Out of 4179 participants, 62% had longitudinal DA data and 51% had complications and longitudinal DA data. In participants with ≥1 baseline positive DA (n = 1699), 83.4% remained positive after 7.3 ± 2.3 years duration of diabetes. Decrease in number of positive DAs was associated with longer diabetes duration (p = 0.003 for 1 baseline positive DA; p < 0.001 for 2 baseline positive DAs) and younger age at diagnosis (p < 0.001 for 2 baseline positive DAs). No associations were found between change in number of positive DAs in participants with ≥1 baseline positive DA (n = 1391) and HbA1c, insulin dose, acute, or chronic complications after 7.7 ± 1.9 years duration of diabetes. DA status likely remains stable in the first 7 years after diabetes diagnosis. Younger age at diabetes diagnosis and longer duration were associated with less persistence of DAs. Measuring DAs after initial presentation may aid in diabetes classification but not likely in predicting the clinical course.

Household food insecurity is associated with diabetic ketoacidosis but not severe hypoglycemia or glycemic control in youth and young adults with youth-onset type 2 diabetes.

OBJECTIVE: To examine the association between household food insecurity (HFI), glycemic control, severe hypoglycemia and diabetic ketoacidosis (DKA) among youth and young adults (YYA) with youth-onset type 2 diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional study included 395 YYA with type 2 diabetes from the SEARCH for Diabetes in Youth Study (2015-2019). HFI was reported by young adult participants or parents of minor participants via the US Household Food Security Survey Module. Glycemic control was assessed by HbA1c and analyzed as a continuous and categorical variable (optimal: <7.0%, suboptimal: ≥7.0%-9.0%, poor: >9.0%). Acute complications included self-reported severe hypoglycemia or DKA in the last 12 months. Adjusted logistic and linear regression were used for binary and continuous outcomes, respectively. RESULTS: Approximately 31% reported HFI in the past 12 months. Mean HbA1c among those with HFI was 9.2% compared to 9.5% without HFI. Of those with HFI, 56% had an HbA1c >9.0% compared to 55% without HFI. Adjusted models showed no associations between HFI and glycemic control. Of those with HFI, 14.4% reported experiencing DKA and 4.7% reported severe hypoglycemia. YYA with HFI had 3.08 times (95% CI: 1.18-8.06) the odds of experiencing DKA as those without HFI. There was no association between HFI and severe hypoglycemia. CONCLUSIONS: HFI was associated with markedly increased odds of DKA but not with glycemic control or severe hypoglycemia. Future research among YYA with type 2 diabetes should evaluate longitudinally whether alleviating HFI reduces DKA.

The role of modulators in cystic fibrosis related diabetes.

The development and introduction of modulator therapies have completely shifted the paradigm for the treatment of cystic fibrosis (CF). Highly effective modulator therapies have driven marked improvements in lung function, exacerbation rate, weight and quality of life in CF patients. However, their effect on CF related diabetes (CFRD) is not well delineated. The role of CF transmembrane conductance regulator (CFTR) in CFRD pathogenesis is inadequately understood and research aimed at deciphering the underlying mechanisms of CFRD continues to evolve. In this review, we summarize what is known regarding the effect of CFTR modulators on CFRD. Small studies using ivacaftor monotherapy in gating mutations have revealed improvement in insulin secretion, glucose tolerance and/or decrease in insulin requirement. However, lumacaftor/ivacaftor studies (primarily in delta F 508 homozygous) have not revealed significant improvement in CFRD or glucose tolerance. No studies are yet available regarding the effect of the highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) on CFRD or insulin secretion. CFTR modulators might affect development or progression of CFRD through many mechanisms including improving insulin secretion by correcting the CFTR defect directly, improving ductal function, reducing islet inflammation, and improving incretin secretion or by enhancing insulin sensitivity via reduced systemic inflammation and increased physical activity driven by improved lung function and quality of life. On the other hand, they can stimulate appetite and improve gastrointestinal function resulting in increased caloric intake and absorption, driving excessive weight gain and potentially increased insulin resistance. If the defect in insulin secretion is reversible then it is possible that initiation of CFTR modulators at a younger age might help prevent CFRD. Despite the advances in CF management, CFRD remains a challenge and knowledge continues to evolve. Future studies will drive better understanding of the role of highly effective CFTR modulators in CFRD.

Eating disorders and body image in cystic fibrosis.

Eating disorders and disturbed body image have been reported in individuals with cystic fibrosis (CF) and may contribute to poor weight gain, reduced lung function and increased mortality. CF individuals often look and feel different from their peers and bear the additional burden of body-altering side effects of treatment. As a result, the impact of disorders such as binge eating, anorexia nervosa, and bulimia nervosa may adversely affect the social, emotional, and physical development of those with CF. Multiple risk factors may contribute to the development of an eating disorder in CF. Growth failure is affected by the physical impairments of CF, including pancreatic insufficiency, high energy demands, respiratory infections, and delayed and stunted growth and puberty. Psychological factors, such as CF associated depression and anxiety, intense focus on BMI, lack of control in a chronic disease, and preoccupation with morbidity and mortality, likely further contribute. Exercise inefficiency, secondary to poor lung function, low BMI and pulmonary exacerbations, and the potential for medication manipulation are also additional risk factors. The intense scrutiny around BMI may lead to a poor relationship with food, including disordered eating habits, abnormal mealtime behaviors, and stressful caregiver-patient interactions regarding meals. This further contributes to a discrepancy between ideal CF nutritional standards and the reality of the challenges of appropriate daily energy intake for an individual with CF. It is imperative that CF providers are equipped to identify potential eating disorders and disturbed body image in their CF patients. Improved screening and monitoring practices should be developed and implemented, with multidisciplinary support from all CF care team members, including dietitians, mental health professionals, and social workers, to best support holistic care and optimize outcomes. Increased attention to these concerns may help reduce CF related morbidity and mortality.

Gynecologic health care for females with cystic fibrosis.

As females with cystic fibrosis (CF) increasingly reach their reproductive years, gynecologic issues have become an important area of clinical care and research. First, females with CF may have disease-specific gynecologic problems, including cyclic pulmonary symptoms, vaginal yeast infections, and urinary incontinence. Next, contraceptive methods are thought to be overall safe and effective, however further research is needed to confirm this and to understand the lower rates of uptake among females with CF compared to the general population. Further, females with CF have reduced fertility, although the etiology of this is unknown and under investigation. While assisted reproductive technologies may help achieve pregnancy, decision-making around parenthood remains complex. Finally, while patients and providers agree on the importance of sexual and reproductive health care, females with CF underutilize basic preventive services such as cervical cancer screening, and better approaches are needed to bridge the gap with gynecology. In this review, we discuss the current state of gynecologic care for females with CF, as well as clinical and research opportunities for improvement.

Acute hyperglycaemia in cystic fibrosis pulmonary exacerbations.

Background: Hyperglycaemia may contribute to failure to recover from pulmonary exacerbations in cystic fibrosis (CF). We aimed to evaluate the prevalence and mechanism of hyperglycaemia during and post-exacerbations. Methods: Nine paediatric CF patients, not on insulin, hospitalized for intravenous antibiotics, underwent an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) upon admission (visit 1) and an OGTT 2 weeks (visit 2) and 6 weeks to 12 months later when at stable baseline (visit 3). Insulin and glucose levels were measured before, 30, 60 and 120 min after glucose ingestion during OGTT. Hyperglycaemia on OGTT was defined according to the American Diabetes Association criteria as abnormal OGTT or consistent with diabetes. Hyperglycaemia on CGM was defined as CGM time above 140 mg/dL > 4.5%. Results: At visit 1, 8/9 patients had hyperglycaemia on both CGM and OGTT (2 diabetes and 6 abnormal OGTT). At visit 2, 5/8 had hyperglycaemia (all abnormal OGTT). At visit 3, (median (IQR) time since visit 1, 4.9 (3.8-6.3) months), 5/7 had hyperglycaemia (2 diabetes and 3 abnormal OGTT). At visits 1, 2 and 3, respectively, mean (SD) 2-hour OGTT glucose was 175.8 (42.3), 146.3 (31.9) and 176.9 (51.7) mg/dL. CGM time above 140 mg/dL at visit 1 was 25.3% (16.9). Insulin AUC decreased from visit 2 (median (IQR) 5449 (3321-8123) mcIU-min/mL) to visit 3 (3234 (2913-3680) mcIU-min/mL). Conclusion: Hyperglycaemia is prevalent during paediatric CF exacerbations; it appears to improve with exacerbation treatment but to worsen later in association with decreased insulin secretion.

The association of low-density lipoprotein cholesterol with elevated arterial stiffness in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth study.

AIM: Our aim was to explore the relationship of Low-Density Lipoprotein Cholesterol (LDL-C) with subclinical cardiovascular disease (CVD) in youth with T1D and T2D. We hypothesized the association of LDL-C with elevated arterial stiffness (AS) would be partially accounted by the co-occurrence of other CVD factors. METHOD: We included 1376 youth with T1D and 157 with T2D from the SEARCH study. CVD risk factors including LDL-C, waist to height ratio (WHtR), mean arterial pressure (MAP), HbA1c, albumin to creatinine ratio (ACR), and insulin sensitivity (IS) score were measured at both visits. At follow up, elevated carotid-femoral AS was defined as levels above 6.8 m/s. Multivariable logistic regression evaluated the odds of elevated AS as a function of the average CVD risk factors. RESULTS: At follow up, age was 18.0 ± 4.1 and 21.6 ± 3.5 years and duration of diabetes was 7.8 ± 1.9 and 7.7 ± 1.9 years in T1D and T2D, respectively. Elevated AS was found in 8.4% of T1D and 49.0% of T2D participants. Each SD increase in LDL-C was associated with 1.28 increased odds (95% CI 1.05-1.54, P = .013) of elevated AS in youth with T1D. The association was similar but not statistically significant in T2D. WHtR, IS, and MAP were associated with elevated AS in both groups. Adjustment for WHtR or IS attenuated to non-significance the relationship between LDL-C and AS in T1D. CONCLUSIONS: Obesity and insulin resistance attenuate the association of high LDL-C with AS suggesting they partially account for the adverse effects of LDL-C on cardiovascular health in youth with T1D.

Adolescent Polycystic Ovary Syndrome: An Update.

Menstrual irregularities and cutaneous signs of androgen excess are commonly encountered when caring for adolescent girls. Polycystic ovary syndrome (PCOS) is the most common cause of these symptoms in adult women, and it can be diagnosed in adolescents as well. Diagnostic criteria used to diagnose adult women are not applicable in adolescents, as some diagnostic criteria overlap with the normal physiology of a maturing reproductive system. Thus, application of adult criteria will overdiagnose adolescents with PCOS. Two recent guidelines on the diagnosis and treatment of PCOS in adolescence were created to provide clarity in the diagnosis of PCOS in adolescent girls and to guide best practices in treatment. This review summarizes the recommendations and gives practical advice on the application of these recommendations to everyday pediatric practice. [Pediatr Ann. 2019;48(8):e304-e310.].

Survival in a bad neighborhood: pancreatic islets in cystic fibrosis.

In cystic fibrosis (CF), ductal plugging and acinar loss result in rapid decline of exocrine pancreatic function. This destructive process results in remodeled islets, with only a modest reduction in insulin producing ß cells. However, ß-cell function is profoundly impaired, with decreased insulin release and abnormal glucose tolerance being present even in infants with CF. Ultimately, roughly half of CF subjects develop diabetes (termed CF-related diabetes, CFRD). Importantly, CFRD increases CF morbidity and mortality via worsening catabolism and pulmonary disease. Current accepted treatment options for CFRD are aimed at insulin replacement, thereby improving glycemia as well as preventing nutritional losses and lung decline. CFRD is a unique form of diabetes with a distinct pathophysiology that is as yet incompletely understood. Recent studies highlight emerging areas of interest. First, islet inflammation and lymphocyte infiltration are common even in young children with CF and may contribute to ß-cell failure. Second, controversy exists in the literature regarding the presence/importance of ß-cell intrinsic functions of CFTR and its direct role in modulating insulin release. Third, loss of the CF transmembrane conductance regulator (CFTR) from pancreatic ductal epithelium, the predominant site of its synthesis, results in paracrine effects that impair insulin release. Finally, the degree of ß-cell loss in CFRD does not appear sufficient to explain the deficit in insulin release. Thus, it may be possible to enhance the function of the remaining ß cells using strategies such as targeting islet inflammation or ductal CFTR deficiency to effectively treat or even prevent CFRD.

Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency.

CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. OBJECTIVE: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. RESULTS: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. CONCLUSION: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.

A novel TRPS1 gene mutation causing trichorhinophalangeal syndrome with growth hormone responsive short stature: a case report and review of the literature.

The role of growth hormone (GH) and its therapeutic supplementation in the trichorhinophalangeal syndrome type I (TRPS I) is not well delineated. TRPS I is a rare congenital syndrome, characterized by craniofacial and skeletal malformations including short stature, sparse, thin scalp hair and lateral eyebrows, pear-shaped nose, cone shaped epiphyses and hip dysplasia. It is inherited in an autosomal dominant manner and caused by haploinsufficiency of the TRPS1 gene. We report a family (Mother and 3 of her 4 children) with a novel mutation in the TRPS1 gene. The diagnosis was suspected only after meeting all family members and comparing affected and unaffected siblings since the features of this syndrome might be subtle. The eldest sibling, who had neither GH deficiency nor insensitivity, improved his growth velocity and height SDS after 2 years of treatment with exogenous GH. No change in growth velocity was observed in the untreated siblings during this same period. This report emphasizes the importance of examining all family members when suspecting a genetic syndrome. It also demonstrates the therapeutic effect of GH treatment in TRPS I despite normal GH-IGF1 axis. A review of the literature is included to address whether TRPS I is associated with: a) GH deficiency, b) GH resistance, or c) GH-responsive short stature. More studies are needed before recommending GH treatment for TRPS I but a trial should be considered on an individual basis.