Postexercise immune correlates in children with and without cystic fibrosis.

INTRODUCTION: Previous studies have shown that children with cystic fibrosis (CF) are capable of mounting a normal immune response after the stress of exercise. However, few data are available regarding the underlying mechanisms by which this immune modulation occurs. METHODS: In this study, lymphocyte and leukocyte cell counts were measured before and immediately after a single bout of exhaustive exercise in 25 children (ages 8-17 yr; 12 with CF and 13 healthy controls). Catecholamine, cortisol, and insulin levels, age, nutritional parameters, and static and dynamic lung function were measured as potential correlates for immune modulation. We hypothesized that catecholamine levels would be associated with the immune changes seen after exercise in children with CF. RESULTS: Our results demonstrated positive correlations between age and the change in cell counts after exercise for white blood cells (r = 0.44, P < 0.03), lymphocytes (r = 0.60, P < 0.002), monocytes (r = 0.43, P < 0.03), and CD3-CD16+CD56+ cells (r = 0.61, P < 0.002). Lower increases in the lymphocyte and CD3-CD16+CD56+ cells were observed in the CF group. Changes in pre- and post-exercise norepinephrine levels were weakly correlated with the changes in granulocyte, lymphocyte, and monocyte cell counts. Changes in cortisol levels correlated with lymphocyte and CD19+ cell count changes for the CF group but not for the healthy controls. Within the CF group, the severity of lung disease (as indicated by a FEV1) was negatively correlated with changes in lymphocyte (r = -0.66, P < 0.02) and CD3-CD16+CD56+ cell counts (r = -0.67, P < 0.02). CONCLUSION: The results suggest that postexercise changes in cell counts occur in an age dependent, norepinephrine associated manner. Disease severity for children with CF also appears to enhance the postexercise leukocytosis with pronounced increases seen in natural killer cells.

Immune modulation following aerobic exercise in children with cystic fibrosis.

Previous studies have demonstrated altered immune response following exercise in healthy adults and children. As data are lacking in children with cystic fibrosis, we evaluated the immune response following acute exercise and hypothesized that acute increases in cellular changes would be seen but would be blunted in subjects with CF. Leukocytes, lymphocytes, and their subsets as well as natural killer cell number and activity were determined before, immediately after, and one hour post exhaustive exercise in 15 children with cystic fibrosis (8-21 yrs, FEV1 69.5+/-18.0%, colonized with P aeruginosa) and 15 healthy controls (8-18 yrs, FEV1 107.5+/-10.7%). At baseline the cystic fibrosis group had greater leukocytes (9.25+/-2.83 vs. 5.17+/-0.96 x 10(9) cells/liter). Immediately post exercise, the cystic fibrosis group demonstrated increases in cell counts for leukocytes (32.4%), lymphocytes (61.8%), granulocytes (36.4%), monocytes (76.2%), and natural killer cells (315%). Similar percentage increases were seen in cell counts for the controls (leukocytes: 39.5%, lymphocytes: 78.5%, granulocytes: 32.0%, monocytes: 75.9%, and NK cells: 442%). Natural killer cell activity also increased by 57.9% in the group with cystic fibrosis and by 43.6% in the healthy controls. Except for elevated leukocyte and granulocyte counts, values returned to baseline at one hour post-exercise. In conclusion, the cellular immune response to acute exercise in children with mild to moderate cystic fibrosis appears normal.

Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation.

Chronic bacterial infection and neutrophilic inflammation characterize cystic fibrosis (CF) pulmonary disease. In many disorders, inflammation and angiogenesis are codependent phenomena. We previously noted excessive angiogenesis in CF tissues and elevated vascular endothelial growth factor (VEGF) in random serum samples from subjects with CF. To further explore this finding, we measured serum VEGF in 38 subjects with stable CF and in 25 subjects with other pulmonary diseases. Mean VEGF was elevated in both groups compared with reference values, but it was higher in CF: 403 +/- 280 versus 255 +/- 169 pg/ml, p = 0.02. VEGF was negatively correlated with FEV(1) in CF, r = -0.51, p = 0.007. To assess the effect of airway infection on VEGF, 10 subjects with CF were studied before and after intravenous antibiotic therapy for pulmonary exacerbation. VEGF levels decreased with antibiotic therapy, from 537 +/- 220 to 259 +/- 176 pg/ml, p = 0.001. We conclude that circulating VEGF is increased in subjects with CF and other inflammatory pulmonary disorders. In CF, VEGF elevation is related to airway infection. We speculate that increased circulating VEGF is related to chronic inflammation, which is robust in CF. Elevated circulating VEGF may result in tissue angiogenesis, furthering the progression of pulmonary disease.

Energy metabolism during anaerobic exercise in children with cystic fibrosis and asthma.

PURPOSE: The nature of a child's daily physical activity requires both aerobic and anaerobic energy metabolism. Aerobic exercise becomes compromised with advancing airway obstruction in children with cystic fibrosis (CF) and asthma (AS). Whether children with CF will have altered metabolic responses to supramaximal exercise when compared with asthmatics or healthy controls is still undetermined. METHODS: Twenty-five children with CF, 22 with AS, and 23 healthy controls (CN) performed an incremental graded aerobic and Wingate anaerobic test (WAnT) on a cycle ergometer. Analysis of gas exchange and ventilatory data was collected and averaged every 5 s to estimate ventilatory kinetics and energy system contributions during both tests. RESULTS: The CF and AS groups had mild lower airway obstruction (FEF25-75% < 80%) as compared with the CN. All three groups demonstrated similar anaerobic (mean and peak power during the WAnT) and aerobic exercise performance (peak oxygen consumption). In contrast to the AS or CN groups, children with CF used a lower percentage of their peak VO2 and V(E) during each phase of the WAnT, suggesting a preferential use of ATP/phosphocreatine and glycolytic energy stores compared with aerobic pathways. Greater reliance on anaerobic pathways during the WAnT in children with CF could be due to the physiologic sequelae underlying chronic obstructive lung disease. CONCLUSIONS: Oxygen uptake kinetics appeared similar for all three groups. Although the energy needed to perform the WAnT can be met by subjects with CF, abnormalities in energy metabolism may exist for this group during exercise.

Parental attitudes about exercise regarding their children with cystic fibrosis.

Despite the well-recognized benefits of exercise on general health and pulmonary function, lack of participation in regular exercise remains a concern with respect to children with cystic fibrosis (CF). Data are lacking regarding parental perceptions about exercise in children and adolescents with CF. Sixty-nine parents of children with CF and 70 parents of healthy children completed the 'Exercise Benefits/Barrier Scale" self administered inventory. Fifteen additional items addressing exercise issues for people with CF were also included. Data were reported as total score, and subdivided into barriers and benefits scales for analysis. Data on the CF specific questions were also reported. Parents of children with CF scored lower on both the total score and benefits portion of the inventory and scored slightly greater on the barriers portion (p < .05) representing less favorable perception of the benefits of exercise along with increased barriers. The presence of a healthy child in addition to a child with CF appeared to increase both the total score and benefits score as well as resulting in a more positive outlook on exercise related uses in CF. It appears that significant differences in parental perceptions regarding exercise indeed exist not only when compared to healthy children but within varying intra-structures of families with a child who has CF.

Anaerobic exercise testing in children with asthma.

Twenty-two males with asthma and 22 healthy males (7-18 years old) performed a Wingate Anaerobic Test. The subjects with asthma had a lower mid-maximal expiratory flow rate (78.3+/-25.3 vs. 100.1+/-24.5%, p < 0.01) than the controls. Aerobic and anaerobic exercise performance (peak power: PP; mean power: MP) were similar for the two groups whether expressed in absolute or relative terms to body weight. The subgroup with asthma with a lower percent body fat (<25%) had a higher PP and MP than the subjects with a higher percent body fat (>25%). Pulmonary function or maturation were not independent correlates of anaerobic power. Our results fail to show differences in anaerobic exercise performance in children with asthma compared to healthy controls. Nutrition appears to be an important factor for performance during this test.

Allergic bronchopulmonary mycosis to Fusarium vasinfectum in a child.

BACKGROUND: A 12-year-old boy with asthma and 6 years of recurrent pneumonias who had normal serum immunoglobulin concentrations was suspected of having allergic bronchopulmonary aspergillosis (ABPA). OBJECTIVE: To search for and secure a fungal etiology for a child who did not have ABPA but was suspected of having an allergic bronchopulmonary mycosis. METHODS: Immediate skin testing with fungal extracts, high resolution computerized tomography, and establishment of an ELISA procedure to detect serum IgE and IgG antibodies to Fusarium vasinfectum. RESULTS: Immediate skin reactivity was present for Fusarium, Cladosporium, Helminthosporium, and Aspergillus fumigatus. The ELISA demonstrated serum IgE and IgG antibodies to Fusarium vasinfectum 8.5 and 5.6 times nonatopic control sera. CONCLUSIONS: This 12-year-old with asthma has sufficient criteria for a diagnosis of allergic bronchopulmonary mycosis (ABPM) to Fusarium vasinfectum. Bronchiectasis was not present despite recurrent pneumonias and hemoptysis. This case appears to be the first pediatric example of ABPM to Fusarium species, a fungus more recognized for causing rotting of tomatoes and melons than human disease.

Exercise recommendations for individuals with cystic fibrosis.

The role of exercise in the treatment of cystic fibrosis has received increasing attention over the past 15 to 20 years. As a group, physical fitness is reduced for people with cystic fibrosis, although tremendous individual variability exists. Limitations in exercise performance appear related to the extent of lung disease and compromised nutritional status. Exercise testing with subsequent development of individualised exercise programmes offers this unique population an opportunity to attain the well-recognised benefits of exercise.

Airway function tests and vocal cord paralysis in lung transplant recipients.

Maximum expiratory and inspiratory flow-volume (MEFV, MIFV) curves, specific airway conductance (sGaw), and flexible fiberoptic laryngoscopy were examined in 8 pediatric lung transplant recipients with vocal cord paralysis (VCP). Six were heart-lung (H-L) and 2 double-lung (D-L) recipients, 7 had left VCP, and 1 had right VCP. Based on the pulmonary function tests (PFT), 2 subgroups could be distinguished in the 8 recipients with VCP. Group A (5/8 recipients; mean age, 13 +/- 3.4 years; mean height, 144.3 +/- 12.3 cm) had significantly reduced specific airway conductance (sGaw; < 2 SD from predicted) and normal MEF25, MEF50, peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV1), and %FEV1/forced vital capacity (FVC); this pattern suggested variable extrathoracic airway obstruction. PIF was normal in 4/5 and reduced in 1/5 of these recipients. Group B (3/8 recipients with VCP; mean age, 17 +/- 2.4 years; mean height, 156.3 +/- 12.0 cm) had significantly reduced sGaw, MEF25, MEF50, PEF, FEV1, and %FEV1/FVC, implying primarily small airway obstruction. These recipients had bronchiolitis obliterans. The results suggest that a pattern of reduced sGaw and normal MEFs, PEF, FEV1, and PIF should raise the possibility of VCP in patients after lung transplantation. sGaw is more sensitive than PIF and PEF in identifying airway obstruction due to VCP, and should be routinely included in the follow-up evaluation of lung transplant recipients.

Effects of anaerobic exercise on the immune system in eight- to seventeen-year-old trained and untrained boys.

OBJECTIVES: To determine the immunologic response to a brief bout of intense exercise in children and to determine the effects of prolonged activity and maturation level of the subjects on this response. STUDY DESIGN: We determined counts of leukocytes and their subsets, counts of lymphocytes and their subsets, and natural killer (NK) cell activity and cell number before and 3 and 60 minutes after a Wingate anaerobic test (WAnT) in 16 male swimmers (9 to 17 years of age) and 17 male nonswimmers (9 to 17 years of age). Subjects were also categorized by pubertal status based on Tanner staging and by level of physical activity. The Student t test and analysis of variance were used to determine statistical significance, with values expressed as mean +/- SEM. RESULTS: Three minutes after the WAnT, all children had increases in leukocytes (28%), lymphocytes (43%), and NK cells (395%) (p < 0.01). Swimmers had less baseline NK cell activity (54 +/- 6 cytolytic units) than nonswimmers (87 +/- 10 cytolytic units) after the WAnT (p < 0.01), although both groups showed an increase to similar levels of NK activity 3 minutes after exercise. Pubertal effects on these responses were not significant. CONCLUSIONS: Our results demonstrate transient leukocytosis, lymphocytosis, and increases in NK cell number and activity in 8- to 17-year-old boys after a brief bout of intense exercise. Formal athletic training appears to be associated with a lower baseline NK cell activity, and yet such activity is still within the normal range for this age group. Further investigations are necessary to determine the impact of such training on overall health and the ability to fight infection.

Evolution of airway hyperresponsiveness in infants with severe congenital diaphragmatic hernia.

Infants born with severe congenital diaphragmatic hernia (DH) characteristically have pulmonary hypoplasia. Airway hyperresponsiveness during the first 4 weeks of life can be demonstrated in most of these neonates. Early postnatal pulmonary development in infants with severe DH has not been well characterized. We examined lung growth in patients with congenital DH by using the forced deflation method to study pulmonary function in 18 infants on mechanical ventilation who survived neonatal repair of their congenital DH. Thirteen infants without primary pulmonary pathology who required general anesthesia for other surgery served as controls. Infants were further divided according to age at the time of testing into early (age < or = 7 days at time of testing) and late (age > or = 29 days) groups, yielding four groups of subjects: early diaphragmatic hernia (EDH): n = 9; mean age, 4.2 days; range, 1-7 days; early controls (EC): n = 8; mean age, 3.1 days; range, 1-6 days; late diaphragmatic hernia (LDH): n = 11; mean age, 57.7 days, range, 28-120 days; and late controls (LC); n = 5; mean age, 52.2 days; range 32-90 days. All infants were studied once, with the exception of two infants with DH who were studied on two occasions at EDH and LDH stages. A marked reduction in weight-corrected forced vital capacity (FVC) was seen in the EDH group (13.9 +/- 3.9 ml/kg) as compared to the EC group (44.4 +/- 4.9 ml/kg). During the ensuing 4 months of life, FVC in patients with LDH (24.5 +/- 1.9 ml/kg) was much higher than FVC in patients with EDH (P < 0.05). These findings demonstrate the presence of pulmonary hypoplasia in the EDH group and suggest subsequent rapid postnatal lung growth. An index of rate constant, MEF25/FVC, as compared with control groups was abnormally elevated in EDH subjects (1.87 +/- 0.30/second vs 1.16 +/- 0.32/ second, P < 0.05), indicating significantly increased lower airway caliber relative to lung volume. The severe reduction of the rate constant in the LDH group (0.36 +/- 0.05/second vs 0.73 +/- 0.07/second, P < 0.05) suggests the development of lower airway obstruction. After the administration of a nebulized bronchodilator (BD), an increase in MEF25 (32.9%) in the EDH group was not significant, but an increase of 134.7% in the LDH group was significant (P < 0.05). Although the study utilized a cross-sectional design with most of the infants in either the early or late group, present findings suggest that infants with EDH have lung restriction reflecting pulmonary hypoplasia. These infants developed lower airway obstruction and airway hyperresponsiveness with only mild fixed obstruction over the first 4 months of life.

Interferon-alpha affects the immune response in post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is associated with Epstein-Barr virus (EBV) and characterized by fever, lymphadenopathy, and graft dysfunction. We describe the clinical course of an EBV seronegative 11-yr-old boy who underwent double lung transplantation and subsequently developed PTLD in the graft. A reduction in immunosuppression and the addition of acyclovir did not result in improvement. Treatment with interferon-alpha (IFN-alpha), however, led to dramatic clinical, radiographic, and histologic improvement. Semiquantitative measurements of cytokine mRNA in his bronchoalveolar lavage cells prior to therapy with IFN-alpha revealed high levels of IL-4 and IL-10 mRNA, which decreased significantly with treatment. We speculate that the beneficial effect of IFN-alpha in the treatment of PTLD is directly related to the inhibition of type 2 helper (Th2-like) T-cells.

Factors limiting anaerobic performance in adolescent males with cystic fibrosis.

Forty-one adolescent males (11.1-18.3 yr) with cystic fibrosis (CF) and 37 healthy adolescent males (11.1-17.9 yr) performed a Wingate Anaerobic Test (WAnT). The group with CF was subdivided by sexual maturity, nutritional status, and degree of airway obstruction. The subjects with CF had lower absolute power outputs than the healthy controls [mean power in Watts (mean +/- SD): 350.2 +/- 135.9 vs 424.5 +/- 120.4, P < 0.001; peak power: 525.2 +/- 178.4 vs 665.9 +/- 191.3, P < 0.001). When absolute power was corrected for lean body mass, the subjects with CF had lower power outputs than the healthy controls (mean power in W.kg-1: 8.9 +/- 1.7 vs 9.6 +/- 0.9, P < 0.05; peak power: 13.4 +/- 2.1 vs 15.0 +/- 1.6, P < 0.05). The subgroup with CF with a higher body mass index (BMI > 17.5 kg.m-2) had higher peak and mean power output than subjects with CF with a lower BMI in both absolute power and when power was expressed per lean body mass. When sexual maturation was considered, subjects with CF with salivary testosterone greater than 4.0 ng.dl-1 had a higher mean and peak power in both absolute terms and relative to lean body mass than subjects with CF with salivary testosterone less than 4.0 ng.dl-1. Multiple regression analysis indicated that the nutritional factor accounted for 70%-80% of the variability in power output in the subjects with CF, while testosterone accounted for 10% of the variability. Pulmonary function was not a significant independent correlate of anaerobic power. Our results suggest that nutritional status, and to a lesser extent maturational factors, may play a more important role than pulmonary function in determining anaerobic fitness in male adolescents with CF.

Salivary testosterone levels in male adolescents with cystic fibrosis.

PURPOSE: Salivary testosterone concentrations have been used for monitoring testosterone levels in male adolescents and have been found to correlate closely with serum values. Data are lacking on such measurements in male adolescents with cystic fibrosis (CF), in which salivary gland abnormalities are commonly seen. Delayed sexual maturation occurs in many patients with CF, particularly those with severe disease. We examined the usefulness of salivary testosterone collection and measurement in male adolescents with CF. METHODS: Forty boys with CF and 35 healthy control boys participated in the study. All boys were Tanner staged and had serum and salivary testosterone concentrations measured. Testosterone assays were performed using standard radioimmunoassay techniques. RESULTS: The boys with CF were slight older, lighter in body weight, and shorter. Serum and salivary testosterone concentrations were lower in the CF group than in the control group. A significant correlation was found between serum and salivary testosterone levels for boys with CF (r = .84) and for the control boys (r = .86). Mean salivary testosterone increased as age progressed and as Tanner stage advanced. CONCLUSIONS: These results demonstrate that salivary testosterone measurements correlate well with serum values in male adolescents with CF and can be used in the monitoring of pubertal status.

Validity of self-assessment of sexual maturation in adolescent male patients with cystic fibrosis.

PURPOSE: Self-assessment of sexual maturity by healthy male adolescents has been found to correlate closely with physician ratings. Data are lacking, however, in adolescents with cystic fibrosis (CF), where an altered body image may affect self-assessment. Delayed sexual maturation occurs in many patients with CF, particularly those with severe disease. We hypothesized that self-assessment of sexual maturation by adolescents with CF would agree with physician ratings. METHODS: Using Tanner's standard photographs for pubic hair (PH) and genital (G) development, we compared self-assessment of sexual maturation to physician rating in 34 adolescent male patients with CF and 27 healthy male controls (C). RESULTS: The two groups did not differ in age. All subjects were initially examined and Tanner-staged by a physician (SRB), and instructed in self-assessment using the Tanner photographs; they then performed a self-assessment. Scores by physician and subjects were assessed for inter-observer agreement by Kappa analysis. For the CF group, 29 of 34 PH assessments and 21 of 34 G assessments demonstrated exact inter-observer agreement between physician and subject ratings. The Kappa coefficient, kappa, (weighted for the degree of closeness between two observers) was 0.946 for PH and 0.840 for G and the C group, kappa was 0.905 for PH and 0.737 for G. Repeat analysis combining stages 3 and 4 PH and G development yielded higher inter-observer agreement in the CF group (33 of 34 PH assessments and 26 of 34 G assessments) and in the C group (24 of 27 PH assessments and 18 of 27 G assessments). CONCLUSIONS: Self-assessment is a valid method to assess sexual maturity in clinical evaluation and as a research tool in the study of patients with CF.

Hypertrophic osteoarthropathy in a child with follicular bronchiolitis.

Hypertrophic osteoarthropathy (HOA) is a syndrome affecting the bones, soft tissue, and joints, often occurring in association with chronic pulmonary disorders. Radiography has traditionally been the imaging modality employed to confirm this diagnosis. However, radionuclide bone imaging provides a sensitive method for the detection of HOA and correlates well with the clinical manifestations. The authors's describe the case of a child with HOA in association with follicular bronchiolitis, a rare chronic pulmonary disorder, whose HOA was diagnosed by radionuclide imaging.

Pediatric lung transplantation for graft-versus-host disease following bone marrow transplantation.

Nine years after receiving a bone marrow transplant for aplastic anemia, a 14-year-old girl with severe pulmonary disease associated with graft-versus-host disease received a double lung transplant. Subsequent to lung transplant, her lung function improved dramatically (FEV1 increasing from 20 to 73 percent predicted normal, residual volume decreasing from 316 to 130 percent predicted normal values). The patient is currently well 15 months after transplant, while receiving immunosuppression consisting of FK506 and azathioprine. Double lung transplantation may offer a therapeutic option for the treatment of graft-versus-host pulmonary disease in selected patients.