A novel exercise testing algorithm to diagnose mitochondrial myopathy.

INTRODUCTION: Oxygen uptake efficiency slope (OUES) is a noninvasive cardiopulmonary exercise testing (CPET) measurement based on oxygen uptake (V˙O2 ) and minute ventilation (V˙E) and is a marker of the efficiency of oxygen utilization by the body. However, it has not been studied in mitochondrial disorders. We explored noninvasive CPET parameters, including OUES, as a way to reliably diagnose mitochondrial myopathy. METHODS: We performed cycle ergometer maximal exercise testing on definite and suspected mitochondrial myopathy subjects (MM-D and MM-S) and their age- and sex-matched controls. OUES was corrected for body surface area (OUES/BSA) to eliminate the effect of body size. RESULTS: A total of 40 participants, including 20 MM-D (n = 13; 6 males; aged 14-64 years) and 7 MM-S (5 males, aged 11-30 years) subjects and 20 controls, completed the study. MM-D subjects showed lower aerobic fitness than controls. OUES/BSA was lower in MM-D subjects, suggesting inefficient oxygen utilization. Area under the curve (AUC) and 95% confidence interval (CI) for OUES/BSA (AUC, 0.91; 95% CI, 0.80-1.00), peak V˙O2 percent predicted (AUC, 0.95; 95% CI, 0.86-1.00), and V˙O2 /work slope (AUC, 0.94; 95% CI, 0.85-1.00) showed excellent ability to diagnose mitochondrial myopathy in MM-D subjects. We applied a diagnostic approach based on the parameters just noted to MM-S subjects and their controls and were able to support or disprove the diagnosis of mitochondrial myopathy. DISCUSSION: We proposed and applied an approach based on the aformentioned three CPET parameters to diagnose mitochondrial myopathy reliably and found it to be clinically useful.

Utility and efficiency of methacholine challenge testing in evaluating pediatric asthma: unraveling the diagnostic conundrum.

OBJECTIVE: Interpretation of methacholine challenge testing (MCT) results depends on the patient's pretest probability of asthma as well as the provocative concentration (PC20); however, ordering providers rarely understand the complexity associated with its interpretation. This study investigated the clinical utility and efficiency of MCT at a tertiary center in evaluating pediatric asthma. METHODS: Retrospective chart review was done for all MCT done at a tertiary center over a six year period (2011-2017). Demographics, referring provider, referral diagnosis, current symptoms with and without exercise, and baseline spirometry were collected. Pretest probability of asthma was assigned by author (RB) who was blinded to MCT results and PC20. Post-test probability of asthma was assigned based on pretest probability, MCT result (+/-), and PC20. Three assigned asthma probability categories were "unlikely" "likely", and "very likely". RESULTS: Of 172 subjects (91 Females, age range 5-21 years), 64.9% of MCT results (n = 111)) were negative and 35.1% (n = 60)) were positive. One was inconclusive. Those who tested positive were shorter, lighter, younger and had lower forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio than those who tested negative (p < 0.05). Subjects with exercise symptoms only were less likely to test positive (OR 0.2, CI 0.1-0.5). In a majority of subjects (91.8%; 157/171), MCT increased the certainty of presence or absence of asthma. CONCLUSIONS: In our subject population, MCT could be useful in evaluating pediatric asthma if subject's pretest probability of asthma and PC20 was taken into account. It was not as useful for subjects with exercise symptoms only.

Longitudinal assessment of exercise capacity and quality of life outcome measures in cystic fibrosis: A year-long prospective pilot study.

BACKGROUND: Multiple outcomes measures including exercise capacity and quality of life are necessary to get complete and accurate picture of cystic fibrosis (CF) progression. In this pilot study, we investigated these measures in CF longitudinally for a year to determine (a) minimal clinically important difference (MCID) for 6-minute walk distance (6MWD) and CF Health-Related Quality of Life Questionnaire (CFQ-R) domains and (b) how 6MWD, CFQ-R, and spirometry change during times of exacerbation and baseline health and their relationship among each other. METHODS: Subjects with moderate and severe CF (baseline FEV1 less than 70% predicted) at Akron Children's Hospital CF centre were followed for a full year longitudinally. All three tests (6MWT, CFQ-R, and spirometry) were done during each outpatient visit and weekly during inpatient admission. MCID was estimated for these parameters using distribution-based methods. Finally, data were examined visually using longitudinal graphs for each subject. RESULTS: Twelve CF subjects (eight [67%] males and age range 13-46 years) were followed for a full year resulting in at least four encounters per subject. 6MWD (m) and CFQ-R respiratory had an MCID of 33 m and 7.3, respectively. MCIDs for FEV1 (percentage predicted) and CFQ-R physical were 7.1 and 11.4, respectively. The longitudinal evaluation of multiple outcome measures during periods of disease exacerbation and baseline health showed that these parameters did not appear to change in accordance with each other. CONCLUSION: In this pilot study, MCIDs for 6MWD and CFQ-R domains were calculated for the first time to facilitate their use as additional outcome measures in CF. The disparity among multiple outcome measures highlights that these measures together may provide a more complete picture in CF than any single measure alone.

A 9-month-old with wheezing and acute hypoxic respiratory failure.

Foreign body aspiration remains a diagnostic challenge, especially in an infant. While acute onset wheezing is highly suggestive of an aspiration, wheezing carries a broad differential diagnosis resulting in frequent misdiagnoses. Many cases present with a range of nonspecific findings and normal imaging, stressing the importance of a high index of suspicion.

Exercise-Induced Dyspnea in Children and Adolescents: Differential Diagnosis.

Exercise-induced dyspnea in children and adolescents can occur for many reasons. Although asthma is the common cause, failure to prevent exercise-induced asthma by pretreatment with a bronchodilator, such as albuterol, indicates that other etiologies should be considered. Other causes of exercise-induced dyspnea include exercise-induced vocal cord dysfunction, exercise-induced laryngomalacia, exercise-induced hyperventilation, chest wall restrictive abnormalities, cardiac causes, and normal physiologic limitation. When exercise-induced dyspnea is not from asthma, cardiopulmonary exercise testing with reproduction of the patient's dyspnea is the means to identify the other causes. Cardiopulmonary exercise testing monitors oxygen use, carbon-dioxide production, end-tidal pCO2 (partial pressure of carbon dioxide), and electrocardiogram. Additional components to testing are measurement of blood pH and pCO2 when symptoms are reproduced, and selective flexible laryngoscopy when upper airway obstruction is observed to specifically identify vocal cord dysfunction or laryngomalacia. This approach is a highly effective means to identify exercise-induced dyspnea that is not caused by asthma. [Pediatr Ann. 2019;48(3):e121-e127.].

Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea.

STUDY OBJECTIVES: Current evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects. METHODS: Twenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures. RESULTS: Baseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta-cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose. CONCLUSIONS: These findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present.

Efficient Use of Simple Exercise-Induced Bronchoconstriction Challenge Testing in Pediatric Exercise-Induced Dyspnea.

BACKGROUND: A simple exercise test to evaluate for exercise-induced bronchoconstriction (EIB) is routinely ordered in pediatric patients with exercise-induced dyspnea. However, the utility of this test in establishing the cause of exercise-induced dyspnea is not thoroughly examined in the pediatric population. We sought to assess the efficiency of a simple EIB challenge test in finding the cause of exercise-induced dyspnea in pediatric patients referred to our tertiary center in the last 5 y. METHODS: We performed a retrospective chart review for all of these exercise tests done at Akron Children's Hospital from March 2011 to March 2016. Patients with chronic conditions (eg, cystic fibrosis, cardiac abnormality) were excluded. Demographics, clinical diagnosis of asthma, a presumptive diagnosis of exercise-induced asthma or EIB by the referring provider, symptoms with and without exercise, albuterol use, spirometry, and simple EIB challenge test results were collected. The chi-square test of independence was utilized in the examination of potential dependent relationships between categorical variables. A P value < .05 was considered to be statistically significant. RESULTS: Out of 164 enrolled subjects (57 males; age 6-20 y), only 19% showed evidence of EIB. There were no significant associations between EIB status (ie, EIB-positive or EIB-negative) based on exercise testing and gender, typical symptoms of EIB, diagnosis of exercise-induced asthma or EIB, and albuterol use (P > .05). However, a subject without asthma was 2.8 times more likely to have negative exercise test for EIB (odds ratio 2.8, 95% CI 1.3-6.5); in addition, approximately 85% of tests in subjects without asthma were negative. CONCLUSION: In a majority of subjects without asthma, a simple EIB challenge testing failed to uncover the cause of exercise-induced dyspnea and thus was inefficient. In these subjects, cardiopulmonary exercise testing may be more useful and cost-effective to explore other causes of dyspnea including EIB.

Calculated versus Measured MVV-Surrogate Marker of Ventilatory Capacity in Pediatric CPET.

INTRODUCTION: Maximum voluntary ventilation (MVV), a surrogate marker of maximum ventilatory capacity, allows for measuring ventilatory reserve during cardiopulmonary exercise testing (CPET), which is necessary to assess ventilatory limitation. MVV can be measured directly during a patient maneuver or indirectly by calculating from forced expiratory volume in 1 s (FEV1 × 40). We investigated for a potential difference between calculated MVV and measured MVV in pediatric subjects, and which better represents maximum ventilatory capacity during CPET. METHODS: Data were collected retrospectively from CPET conducted in pediatric subjects for exercise-induced dyspnea from January 2014 to June 2015 at Akron Children's Hospital. Subjects with neuromuscular weakness, morbid obesity, and suboptimal effort during the testing were excluded from the study. RESULTS: Thirty-five subjects (mean ± SD, age = 13.8 ± 2.7 yr, range = 7-18 yr) fulfilled the criteria. Measured MVV was significantly lower than calculated MVV (89.9 ± 26.4 vs 122.4 ± 34.5 L·min; P < 0.01). The ventilatory reserve based on measured MVV was also significantly lower than ventilatory reserve based on calculated MVV (12.4% ± 19.6% vs 36.1% ± 13.2%; P < 0.01). Calculated MVV (as well as ventilatory reserve based on calculated MVV) was significantly correlated with ventilatory parameters. By contrast, no significant correlations were found between measured MVV (or ventilatory reserve based on measured MVV) and ventilatory parameters except for peak ventilation (peak V˙E). CONCLUSIONS: The measured MVV was significantly lower than the calculated MVV in our pediatric subjects. The calculated MVV was a better surrogate of maximum ventilatory capacity as shown by significant correlation to other ventilatory parameters during CPET.

Cough and fever in an immigrant adolescent with abnormal chest X-ray.

Tuberculosis (TB) remains a leading cause of death from infectious disease worldwide with 80,000 pediatric deaths annually. Disease caused by Mycobacterium tuberculosis (Mtb) is usually asymptomatic in pediatric patients and resolves after completion of standard therapy with isoniazid (INH). Rare reports document children greater than 10 years of age in endemic regions developing adult type cavitary disease, an infectious pulmonary tuberculosis lesion. This is a notable case of post-infectious pulmonary TB disease with adult type cavitation in an immigrant adolescent, which developed even after completing standard therapy with INH. With increasing immigration of refugees from endemic regions into the United States, the Center for Disease Control implemented standardized testing and treatment of TB. However even with identification of disease, many immigrants may not seek treatment or complete therapy given lack of health insurance, and poor access to health care. This case of a 14 year old adolescent with post primary cavitary TB highlights the importance of directly observed therapy (DOT) and medication compliance. Perhaps as noteworthy, this case also emphasizes the need for pediatricians to recognize the impact on public health and the potential for spread of active TB within schools and the community especially in pulmonary cavitary lesion.

Body Fat Composition: A Predictive Factor for Sleep Related Breathing Disorder in Obese Children.

INTRODUCTION: The association between body fat composition as measured by dual energy x-ray absorptiometry (DEXA) scanning and pediatric sleep related breathing disorder (SRBD) is not well established. We investigated the relationship between body mass index (BMI) and DEXA parameters and their association with SRBD in obese children. PATIENTS AND METHODS: Overnight polysomnography was performed on obese/overweight children (10-17 years) with habitual snoring. Total body fat mass (g), trunk fat mass (g), total body % fat, and trunk % fat were determined by DEXA. RESULTS: Forty-one subjects were studied. Logarithm (Log) total arousal index correlated with BMI (p < 0.01, r = 0.473), total body fat mass (p < 0.05, r = 0.331), and trunk fat mass (p < 0.05, r = 0.319). Log desaturation index correlated with BMI (p < 0.05, r = 0.313), total body fat mass (p < 0.05, r = 0.375), and trunk fat mass (p < 0.05, r = 0.391), whereas obstructive apnea hypopnea index (OAHI) did not. In males 10-12 years, there was a significant correlation between Log total arousal index and obesity parameters, but not for males aged 13-17 years. BMI correlated with DEXA parameters in all subjects: total body fat mass (p < 0.001, r = 0.850); total body % fat (p < 0.01, r = 0.425); trunk fat mass (p < 0.001, r = 0.792) and trunk % fat (p < 0.05, r = 0.318) and in 10-12 year old males. This relationship was not significant in males aged 13-17 years. CONCLUSIONS: Total body fat mass and trunk fat mass as well as BMI correlated with total arousal index and desaturation index. BMI correlated with DEXA parameters in 10-12 year old males but not in 13-17 year old males. The value of using DEXA scanning to study the relationship between obesity and SRBD may depend on age and pubertal stage.

Effect of residential proximity to major roadways on cystic fibrosis exacerbations.

Ambient air pollution has been attributed with an increase in exacerbation frequencies among the cystic fibrosis (CF) population. This study correlates exacerbation frequency with proximity to roadways and two criteria air pollutants. Clinical data was extracted from the Cystic Fibrosis Foundation National Patient Registry and Electronic Medical Records at Children's Hospital Los Angeles (CHLA). Average annual air pollutant levels were obtained from selected US Environmental Protection Agency's monitoring stations. Geographic proximity to monitoring stations and roadways were analyzed using spatial mapping software. A total of 145 patients from the CHLA's CF center were characterized by a dichotomous exacerbation category. No significant association was determined between the frequency of exacerbations and exposure to fine particulate matter and ozone levels. Residential proximity to US-designated highways and freeways also did not achieve significance (p = 0.3777) but was noted to be correlated with major arterial roadways (p = 0.0420). Associations of environmental exposures may have important implications for future predictive models of CF clinical outcomes.

Sleep fragmentation and intermittent hypoxemia are associated with decreased insulin sensitivity in obese adolescent Latino males.

BACKGROUND: Although sleep-related breathing disorder (SRBD) has been linked to insulin resistance in adults, this has not been as well established in children. We hypothesized that the severity of SRBD in adolescents was associated with metabolic impairment. METHODS: Polysomnography was performed on obese, Latino males referred for snoring. The frequently sampled intravenous glucose tolerance test was used to assess glucose homeostasis. Total-body dual-energy X-ray absorptiometry was used to quantify adiposity. RESULTS: A total of 22 males (mean age ± SD: 13.4 ± 2.1 y, BMI z-score 2.4 ± 0.3, obstructive apnea hypopnea index 4.1 ± 3.2) were studied. After correcting for age and adiposity in multiple-regression models, Log frequency of desaturation (defined as ≥3% drop in oxygen saturation from baseline) negatively correlated with insulin sensitivity. Sleep efficiency was positively correlated with glucose effectiveness (S(G), the capacity of glucose to mediate its own disposal). The Log total arousal index was positively correlated with Log homeostasis model assessment-estimated insulin resistance. CONCLUSION: Sleep fragmentation and intermittent hypoxemia are associated with metabolic impairment in obese adolescent Latino males independent of age and adiposity. We speculate that SRBD potentiates the risk for development of metabolic syndrome and type 2 diabetes in the obese adolescent population.