Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures.

UNLABELLED: Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies. IMPORTANCE: While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes.

Swallowing dysfunction in infants less than 1 year of age.

BACKGROUND: Gastroesophageal reflux (GER) occurs frequently in infants and children and is implicated as a trigger for reactive airways disease. While evaluating patients for GER by upper gastrointestinal studies (UGI), we frequently noticed laryngeal penetration or tracheal aspiration in infants < 1 year of age. We conducted this prospective study to assess the incidence of swallowing dysfunction in infants with vomiting or respiratory symptoms. METHODS: Between February 1994 and August 1997, 1,003 UGI in infants < 1 year of age were performed by two experienced pediatric radiologists. Fluoroscopy of swallowing using an appropriate image intensifier was observed as part of the UGI in all patients. In addition to evaluating premature infants, former premature infants, and infants with underlying conditions such as bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), esophageal atresia and/or tracheoesophageal fistula (EA), and neurologic disorders, we assessed swallowing in 472 full-term infants in the general population who had respiratory symptoms or suspected GER, but no other apparent abnormalities. Swallowing was not assessed in patients with congenital bowel obstruction. The presence of normal swallowing or swallowing dysfunction was recorded immediately following the study. Chest radiographs obtained on the same day as the UGI were evaluated in the study. Forty-four videotaped modified barium-swallow studies (MBSS) were obtained in 25 general-population infants and reviewed frame-by-frame to determine the length of time that barium could be visualized in the subglottic trachea. RESULTS: The incidence of swallowing dysfunction is significant in premature and former premature infants, those with BPD, CHD, EA, various syndromes, and neurologic abnormality. In the general population of full-term infants referred for evaluation of vomiting or respiratory symptoms, 63 (13.4 % of 472) had swallowing dysfunction. Forty-four had tracheal aspiration (TA) and 19 had laryngeal penetration (LP). Gastroesophageal reflux was found in 79.5 % with TA and in 68.4 % with LP. The MBSS confirmed swallowing dysfunction in all patients shown to have vocal cord penetration or tracheal aspiration by UGI. CONCLUSIONS: Careful evaluation of swallowing during an UGI can identify swallowing dysfunction in full-term infants who have respiratory problems, as well as in infants with an abnormality that predisposes the patient to aspiration. Episodes of tracheal aspiration may be fleeting and overlooked if swallowing is not assessed carefully. An MBSS can confirm the observation of swallowing dysfunction found during an UGI and assist in planning appropriate dietary therapy that minimizes the likelihood of tracheal aspiration during feeding.

Is tracheotomy decannulation possible in oxygen-dependent children?

OBJECTIVE: The goal was to determine whether decannulation can be safely achieved in children with persistent oxygen requirements. DESIGN: The study was a prospective evaluation of 12 oxygen-dependent children at a tertiary care academic children's medical center. METHODS: Twelve tracheotomy-dependent children with persistent oxygen requirements were evaluated for decannulation. Patients requiring more than 35% FiO(2) were not considered. Direct laryngoscopy and bronchoscopy were performed in all patients. Two required single-stage laryngotracheoplasty to correct subglottic stenosis, 1 required tracheal resection, and 7 required removal of suprastomal granulation tissue. Oxygen was administered after decannulation through a nasal cannula. RESULTS: Decannulation was successful in 92% (11 of 12) of patients. At final follow-up, oxygen requirements decreased in 58% of patients after decannulation. CONCLUSIONS: Decannulation can be successful in children who remain oxygen dependent; conversion to a more physiologic airway may be an adjunct to reducing or eliminating their oxygen demand.

Abnormalities in lymphocyte populations in infants with neural crest cardiovascular defects.

The DiGeorge syndrome has been associated with various immune deficits. Embryologically, defects of the neural crest are associated with conotruncal and aortic arch abnormalities. The objective of this study was to determine if children with neural crest congenital heart defects can have subtle but significant immunodeficiencies. Complete blood counts with differential counts and a standard lymphocyte immunophenotyping panel of selected monoclonal antibodies were performed on peripheral blood from 20 children with neural crest cardiac disease and 34 normal newborns. The children with cardiac disease were grouped as survivors and nonsurvivors. The mean total white blood cell count was similar for all groups, but the percent lymphocytes was significantly less in the nonsurvivors than in the survivors and normal newborns (p < 0. 02). The lymphocyte subsets affected were CD2, CD3, and CD4. When the cardiac patients were compared to the normal newborns, again differences in lymphocyte subsets CD2, CD3, and CD4 were seen. When comparing nonsurvivors with survivors, the mean percentages of the CD2, CD3, and CD4 T lymphocyte markers, as well as the mean lymphocyte, B cell (CD20), and natural killer cell (CD16) percentages were all lower in the nonsurvivors. It was concluded that abnormalities in specific lymphocyte populations and their subsets may be predictors of infants at greatest risk for immunodeficiency complications. Therefore children with neural crest cardiac defects should have evaluations of lymphocyte subsets at birth and be treated as if potentially immunodeficient.

Respiratory manifestations of gastroesophageal reflux in children.

Gastroesophageal reflux is often overlooked as both a cause and a complication of respiratory disease in children. The manifestations may be protean and may bear little clinical relationship to the gastrointestinal tract. However, a high index of suspicion for its potential role in unexplained respiratory symptoms may yield large benefits for the physician and patient alike.

Management of childhood asthma: more than juggling medication doses.

Optimal management of asthma in children requires a program of patient education, avoidance of triggers, prevention of airway inflammation, and symptomatic management of episodic wheezing. Use of patient-initiated interventions based on peak expiratory flow rates determined daily in the home setting promotes early interruption of symptom cycles and better assessment of severity of disease. A fully outlined management program for any given patient requires investment of time and energy on the part of the physician, but the long term rewards for both physician and patient are significant.

The value of screening for risk of exercise-induced asthma in high school athletes.

Exercise challenges were performed on 166 middle and high school student athletes (aged 12 to 18 years) to evaluate undiagnosed exercise-induced asthma (EIA). Seventy-three percent were male, 70% were white, and 30% were black. All students completed a questionnaire and were briefly interviewed to elicit risk factors for EIA. Resting spirometry, exercise treadmill provocation, and postexercise spirometry at 1, 10, 20, and 30 minutes were performed. Twenty-two students had reductions in FEV1 > or = 15% from baseline; 15 of these had FEV1 reductions > or = 20%. Of students considered at risk for EIA by history or baseline spirometry (N = 48, 29%) eight (17%) demonstrated EIA after exercise. Of students with no risk factors (N = 118, 71%), 14 (12%) demonstrated EIA after exercise, but would not have been identified without exercise challenge. The overall incidence of EIA was 12%, a rate that is consistent with previous studies of college and Olympic athletes. Sixty-four percent of students identified with EIA were not considered at risk by routine screening methods. History and spirometry alone may not be adequate as screening tools for EIA in adolescents.

Unrecognized exercise-induced bronchospasm in adolescent athletes.

OBJECTIVE--As part of their preparticipation physical examinations, 1241 middle and high school student athletes completed a questionnaire and were interviewed to elicit risk factors for unrecognized exercise-induced bronchospasm (EIB). Spirometry was then performed when the students were at rest. RESEARCH DESIGN--All participants completed a questionnaire, were interviewed, and underwent baseline testing to determine forced expiratory volume in 1 second (FEV1). SETTING--All testing was performed in a school setting. SELECTION PROCEDURES--Athletes known to have EIB who were receiving appropriate treatment (46 athletes [4%]) and athletes with no risk factors based on medical history and normal results of spirometry (847 athletes [68%]) were eliminated from further evaluation. Students with medical histories indicating risk of unrecognized EIB and students with abnormal results of spirometry were eligible for exercise challenge by standard treadmill protocol. MEASUREMENTS AND RESULTS--Of the 348 eligible students, 230 (66%) completed the exercise challenge. Sixty-six of the 230 students had greater than 15% reduction in FEV1, and 50 of the 66 students had greater than 20% reduction, representing a 29% occurrence of previously undiagnosed EIB in a population of students identified with screening to be at risk of unrecognized EIB. Of the 179 students identified to be at risk based on medical history only, 28% had EIB. Of 33 students with positive results of spirometry but no medical history that put them at risk, 15% had EIB. Of the 18 students with medical histories that put them at risk and positive results of spirometry, 61% had EIB. Including the subpopulation with reduction in FEV1 of greater than 15%, students shown to be at risk after screening, and students previously identified as having EIB, 145 students were identified as having EIB (12%). CONCLUSIONS--These data are in accord with results of previously reported studies of college and Olympic athletes. The data may have implications for more extensive screening in the adolescent population.

Allergic drug reactions: identification and management.

Any attempt to distinguish allergic drug reactions from other adverse drug reactions (ADRs) can be complicated by the fact that terminology in this area has not been standardized. True allergic reactions are those resulting from immunologic causes, and their prevalence is only 6 to 10% of all ADRs. A number of factors predispose individuals to drug allergies--the recognition of which might aid the healthcare professional in diagnosing these reactions--and other criteria can be helpful in the process. In order to successfully separate pseudoallergic from allergic from other adverse drug reactions, the clinician must proceed with caution and suspicion. When foreseeable allergic reactions cannot be prevented, measures can be taken that might reduce their impact.

Type I diabetes in an adolescent with common variable immunodeficiency.

A male adolescent with common variable immunodeficiency developed type I diabetes approximately 1 year after the initiation of immunoglobulin therapy. Immunologic evaluation revealed decreased numbers of T cells and an intrinsic B cell defect in immunoglobulin production. Lymphocytes from the patient failed to generate normal suppressor activity. There were no insulin or islet cell antibodies present in the patient's serum or in the commercial immunoglobulin preparations he received. The patient's HLA phenotype included HLA-DR3 and 4, placing him genetically at high risk for type I diabetes.

IgM deficiency: clinical spectrum and immunologic assessment.

Selective IgM deficiency has been associated with recurrent infections and enteric protein loss. We have evaluated eight patients with IgM deficiency presenting with recurrent infections and manifestation of atopy. A variety of subtle immunologic aberrations were noted, including depressed IgM and elevated IgG responses to immunization with bacteriophage OX174. Despite normal quantitative IgG in most patients, IgG antibody responses to diphtheria-tetanus and/or pneumococcal polysaccharide antigens were generally depressed. No correlation could be made between antibody responses (or lack thereof) and the nature of infections in any given patient.

Use of transfer factor in a pediatric AIDS patient with disseminated Mycobacterium avium intracellulare.

An 8-year-old male with AIDS and disseminated Mycobacterium avium intracellulare infection was treated with transfer factor (TF) prepared from maternal lymphocytes. Subsequent lymphocyte stimulation studies and repeat cultures failed to demonstrate improvement during treatment. His overall clinical status remained unchanged. No adverse effects of TF were noted.

Effect of interleukin-2 and mitogen on in vitro immunoglobulin production by peripheral blood lymphocytes from patients with selective IgM deficiency.

Immunoglobulin production by mitogen and recombinant interleukin-2-(rIL-2)-stimulated lymphocytes from IgM-deficient patients was studied. The findings were that subnormal serum IgM levels did not necessarily predict defective in vitro IgG or IgM production, lymphocytes from some IgM-deficient patients exhibited defective T cell function, and rIL-2 did not enhance defective in vitro immunoglobulin production.

Clinical and pharmacokinetic evaluation of a sustained-release liquid theophylline preparation.

Theolan Suspension is the first long-acting liquid theophylline dosage form. A crossover study comparing the pharmacokinetic and clinical response to Theolan Suspension (administered every 12 hours) with aminophylline solution (administered every 8 hours) in children younger than 12 years of age is reported. Twenty-seven patients completed the study: 17 children were aged 6 years or younger and five patients were 3 years or younger. All patients were withdrawn from bronchodilator therapy and then were titrated to clinically effective doses of study medication. There was an equivalent and significant reduction from baseline levels in the mean symptom score during administration of theophylline suspension (42%; p less than or equal to 0.001) and aminophylline solution (57%; p less than or equal to 0.001). Mean values for FEV1 (1.2 versus 1.3 L), FEV1/FVC (77% versus 79%), and reduction in acute metaproterenol use (24% versus 43%) in children receiving theophylline suspension and aminophylline solution revealed no differences between products. Adverse effects were reported more frequently for the aminophylline solution, possibly caused in part to its taste. Of children stating a taste preference, eight of 10 children chose the Theolan Suspension. The suspension demonstrated a lower peak theophylline blood level at a later time (11.6 micrograms/ml at 3 1/2 hours), compared to the solution (14.6 micrograms/ml at 1 1/2 hours; p less than or equal to 0.01). Indexes of theophylline fluctuation during the dosing interval indicated equivalent or reduced variability for the suspension. Relative bioavailability of theophylline suspension was 89% of that for the solution.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicenter, open study of the non-sedating antihistamine, terfenadine (Seldane), in the maintenance therapy of seasonal allergic rhinitis.

A multicenter open study was conducted throughout the 1984 fall pollen season to assess the possible development of tolerance or loss of efficacy to terfenadine in the maintenance therapy of patients with seasonal pollinosis. Patients with proven allergic pollinosis were entered into a 1-week initial treatment period taking terfenadine 60 mg bid and only those who responded to the initial treatment with "moderate" to "complete" relief continued on terfenadine throughout a 4 to 11-week pollen season for evaluation of continued efficacy. A total of 179 patients from five study centers were enrolled in the initial treatment period and 154 (86%) responded to terfenadine with "moderate" to "complete" relief of symptoms. Of these 154 patients who continued terfenadine treatment, approximately 90% of the patients maintained the same degree of relief throughout the pollen season. All symptoms of seasonal pollinosis including nasal congestion improved significantly the first day of treatment. This improvement in symptoms continued during the first week and remained unabated throughout the pollen season. The incidence of adverse events was low with sedation being reported by only 2.8% of patients at some time point during the study. It is concluded that terfenadine is a safe and effective non-sedating antihistamine in the maintenance therapy of seasonal allergic pollinosis and that tolerance is not noted during continued administration.

Comparison of inhaled metaproterenol, inhaled atropine sulfate, and their combination in treatment of children with acute asthma.

The separate and combined effects of inhaled metaproterenol and atropine sulfate were evaluated in the treatment of 44 episodes of acute asthma occurring in 35 children ranging in age from 13 months to 13 years. Peak expiratory flow rate and pulmonary index were measured before and after each of up to three inhalation treatments. Significant improvement in peak flow rate (P less than .04) was noted after the second inhalation of metaproterenol both with and without the combination of atropine sulfate compared with the effects of atropine alone. Patients treated with metaproterenol and metaproterenol combined with atropine also experienced fewer therapeutic failures (2/15 and 2/16, respectively) compared with those treated with atropine (6/13, P less than .02). Pulmonary index scores did not differ among the treatment groups. Inhaled metaproterenol appears to be more effective than inhaled atropine sulfate in the treatment of children with acute asthma. The addition of inhaled atropine sulfate appears to offer no advantage over treatment with inhaled metaproterenol alone.