Isolated abnormal FEF75% detects unsuspected bronchiolar obstruction in CF children.

BACKGROUND: Physiologic detection of bronchiolar obstruction in children with cystic fibrosis (CF) may be clinically unsuspected because of normal routine spirometry despite bronchiectasis on lung CT. METHODS: Children from two accredited CF facilities had spirometry obtained every 3 months when clinically stable. Pre-bronchodilator maximum expiratory flow volume curves were retrospectively analyzed over 16 years to detect an isolated abnormal FEF75%, despite normal routine spirometry. RESULTS: At Miller Children's and Women's Hospital (MCWH), an abnormal FEF75% was initially detected in 26 CF children at age 7.5 ± 4 (SD) years despite normal routine spirometry initially. FEF75% remained an isolated abnormality for 2.5 ± 1.5 years after it was initially detected in these 26 CF children. At Cohen Children's Medical Center (CCMC), despite normal routine spirometry initially, abnormal FEF75% occurred in 13 children at age 11.7 ± 4.5 years, and abnormal FEF25-75% in 10 children at age 11.8 ± 5.3 years. CONCLUSIONS: FEF75% was most sensitive spirometric test for diagnosing both early and isolated progressive bronchiolar obstruction. Data from CCMC in older children demonstrated the simultaneous detection of abnormal FEF75% and FEF25-75% values consistent with greater bronchiolar obstruction when serial spirometry was initiated at an older age. IMPACT: There is very little published spirometric data regarding diagnosis of isolated small airways obstruction in CF children. FEF75% can easily detect unsuspected small airways obstruction in CF children with normal routine spirometry and bronchiectasis on lung CT and optimize targeted modulatory therapies.

Inter- and intra-subject variability of nitric oxide levels in leukocyte subpopulations.

Assessment of nitric oxide (NO) dynamics in immune cells, commonly measured using NO surrogates such as inducible nitric oxide synthase (iNOS) rather than NO itself, has been effective in understanding pathophysiology across a wide range of diseases. Although the intracellular measurement of NO is now feasible, many technical issues remain unresolved. The principle aim of our study was to determine the effect of storage time of whole blood on nitric oxide (NO) level expression in leukocytes. This is important because immune cells remain chemically dynamic even after they are removed from the circulation, and the impact of storage time must be known to optimally quantify the effect of a disease or condition on NO dynamics in circulating leukocytes. We measured NO levels using the fluorescent probe, diaminofluorescein (DAF-2DA), and flow cytometry in monocytes, neutrophils, and natural killer cells from healthy subjects immediately after blood draw (Time 0) and 30, 60, and 120 min following the blood draw. There was no significant difference among the 4 study time points in NO (DAF-2) levels, though there was wide intra-subject variability at all time points. Using LPS stimulation, we compared iNOS (the more traditional surrogate marker of NO dynamics) with NO (by DAF-2) in natural killer cells and monocytes and, we found no difference in the response patterns. In summary, we did find that within a 2-hour interval from blood draw to sample processing, there was a remarkably wide intra-subject variability in expression of intracellular NO (DAF-2) in leukocytes of healthy individuals at baseline and over time. The mechanism(s) for these differences are not known but could clearly confound efforts to detect changes in NO metabolism in white blood cells. We speculate that rapid pulsatility of NO could explain the wide variability seen.

Correlation of negative skin-prick test results for tree nuts and successful tree nut challenges among children with peanut allergy.

Background: Children with peanut allergy are regularly instructed to avoid all tree nuts. However, children with peanut allergy are likely not allergic to all tree nuts. Objective: In our cohort of patients with peanut anaphylaxis and who underwent oral immunotherapy, we sought to determine the correlation of skin-prick testing (SPT) results for tree nuts and the likelihood of successfully passing a tree nut challenge. Methods: SPT was performed for peanut and tree nuts (macadamia, pine nut, coconut, hazelnut, brazil nut, cashew, pecan, walnut, pistachio, almond) in 27 patients with known peanut allergy. The probability of a negative SPT result (wheal < 3 mm) for each nut was determined. Results: All the patients demonstrated positive results in peanut allergy diagnostics in SPT, component testing, or food challenge. Only 15.4% of the patients had a positive SPT result to peanut alone. Macadamia, pine nut, and coconut SPT had a probability of negative SPT results of 0.97, 0.97, and 0.91, respectively. The odds ratio for this group having a negative SPT was 46.22. For hazelnut, brazil nut, and cashew, the probability of a negative SPT result was 0.81, 0.77, and 0.73, respectively. Pecan, walnut, and pistachio had odds ratios of 0.68, 0.68, and 0.64, respectively. All the patients with macadamia, pine nut, and coconut negative SPT results subsequently passed 9-g food challenges without oral immunotherapy. Conclusion: Despite current recommendations to avoid all tree nuts for patients with peanut allergy, the majority of patients with peanut allergy had negative SPTs and food challenges to certain tree nuts, especially macadamia, pine nut, and coconut. This pattern was seen despite most patients having multiple nut sensitizations.

Wiskott-Aldrich Syndrome: Description of a New Gene Mutation With Normal Platelet Volume.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by an increased incidence of autoimmunity, malignancy, microthrombocytes with thrombocytopenia, eczema, and recurrent infections. In this case report, we present a novel mutation, hemizygous for c.1125_1129delTGGAC mutation in the WAS gene, and a unique clinical presentation. Our patient was initially diagnosed with a milk protein allergy after presenting with a lower gastrointestinal bleed, leukopenia, and thrombocytopenia with normal platelet volume. However, signs of vasculitis and detection of microthrombocytes required additional testing and consideration of WAS. This case report illustrates the importance of retaining a high index of clinical suspicion despite normal platelet volume, as well as adding to the growing number of known mutations associated with WAS.

Immunoglobulin replacement therapy: a twenty-year review and current update.

OBJECTIVE: The expansion of immunoglobulin replacement to multiple disease entities marks a decade-long advancement in immune therapy. Parallel to its extension, the characteristics and composition of immunoglobulin products have diversified. The aim of this study was to summarize a 20-year comprehensive literature review of currently commercially available immunoglobulin products, particularly examining individual product properties in a comparative format. Data Sources/Study Selections: The literature review was performed using PubMed and Ovid, screening a time span of 2 decades. Both authors reviewed the obtained articles for acceptable quality, and the selection was narrowed down based on criteria for randomized clinical and therapeutic trials. RESULTS: Product-specific characteristics in terms of purification strategy, stabilizers, composition, and viral inactivation were found among the immunoglobulin products investigated. Such differing characteristics manifest in their variable clinical safety and efficacy as assessed by the comparative product analysis. In subgroups of patients, subcutaneous immunoglobulin therapy may be an alternative to intravenous immunoglobulin (IVIG) therapy with an equal efficacy and a lower number of systemic adverse events. CONCLUSION: Only few comprehensive clinical synopses are available to clearly demonstrate the differences in IVIG products despite the widespread clinical use of the therapy. This review defines significant characteristics of individual immunoglobulin products, noting important differences in product development and application and allowing informed clinical decisions to match a product with patients' risk factors and comorbidity. This balanced approach to gammaglobulin replacement therapy is imperative to produce the highest clinical efficacy and lowest number of adverse events.

Progression and prognostic indicators of bronchial disease in children with sickle cell disease.

PURPOSE: The pulmonary complications of sickle cell disease (SCD) are a leading cause of morbidity and mortality (MacLean et al. Am J Respir Crit Care Med 178:1055-1059, 2008; Klings et al. Am J Respir Crit Care Med 173:1264-1269, 2006; National Heart, Lung, and Blood Institute, 2009). Despite this recognition, predictive markers of lung dysfunction progression remain elusive (Klings et al. Am J Respir Crit Care Med 173:1264-1269, 2006; Platt et al. N Engl J Med 330:1639-1644, 1994; Caboot et al. Curr Opin Pediatr 20:279-287, 2008; Field et al. Am J Hematol 83:574-576, 2008; Shirlo et al. Peadiatr Respir Review 12:78-82, 2011). This study was designed describe the longitudinal progression and identify specific markers that influence bronchial disease in SCD. METHODS: A retrospective, chart review of 89 patients with SCD was conducted. All patients underwent spirometry in conjunction with body plethysmography as part of routine care. Eleven lung function variables were assessed, five of which were selected to establish patterns of normal, obstructive, restrictive, or mixed obstructive-restrictive physiology (Klings et al. Am J Respir Crit Care Med 173:1264-1269, 2006; Field et al. Am J Hematol 83:574-576, 2008). RESULTS: In the unadjusted model, forced expiratory volume in one second (FEV1)% of predicted trended downward with age, while total lung capacity (TLC)% of predicted showed a bimodal distribution and carbon monoxide diffusion capacity corrected for hemoglobin (DLCOcor)% of predicted remained stable. Adjusting for acute chest syndrome (ACS) episodes, medication status, and growth velocity (GV), the final model demonstrated that the downward trend between FEV1% of predicted with age was further influenced by the latter two factors. CONCLUSIONS: Initial decline in FEV1% of predicted is associated with worsening pulmonary dysfunction over time. Independent of ACS episodes, the factors most influential on the progression of FEV1% predicted include the introduction of medications as well as the promotion of adequate prepubertal growth. Efforts to ensure normal prepubertal GV and treatment with bronchodilators, such as short-acting beta(2) agonists and inhaled corticosteroids (ICS), should be considered at an early age to delay progression of pulmonary dysfunction.

Food anaphylaxis diagnostic marker compilation in machine learning design and validation.

BACKGROUND: Traditional food allergy assessment of anaphylaxis remains limited in accuracy and accessibility. Current methods of anaphylaxis risk assessment are costly with low predictive accuracy. The Tolerance Induction Program (TIP) for anaphylactic patients undergoing TIP immunotherapy produced large-scale diagnostic data across biosimilar proteins, which was used to develop a machine learning model for patient-specific and allergen-specific anaphylaxis assessment. In explanation of construct, this work describes the algorithm design for assignment of peanut allergen score as a quantitative measure of anaphylaxis risk. Secondarily, it confirms the accuracy of the machine learning model for a specific cohort of food anaphylactic children. METHODS AND RESULTS: Machine learning model design for allergen score prediction utilized 241 individual allergy assays per patient. Accumulation of data across total IgE subdivision served as the basis of data organization. Two regression based Generalized Linear Models (GLM) were utilized to position allergy assessment on a linear scale. The initial model was further tested with sequential patient data over time. A Bayesian method was then used to improve outcomes by calculating the adaptive weights for the results of the two GLMs of peanut allergy score prediction. A linear combination of both provided the final hybrid machine learning prediction algorithm. Specific analysis of peanut anaphylaxis within one endotype model is estimated to predict the severity of possible anaphylactic reaction to peanut with a recall of 95.2% on a dataset of 530 juvenile patients with various food allergies, including but not limited to peanut allergy. Receiver Operating Characteristic analysis yielded over 99% AUC (area under curve) results within peanut allergy prediction. CONCLUSIONS: Machine learning algorithm design established from comprehensive molecular allergy data produces high accuracy and recall in anaphylaxis risk assessment. Subsequent design of additional food protein anaphylaxis algorithms is needed to improve the precision and efficiency of clinical food allergy assessment and immunotherapy treatment.

Pediatric Patients with Tracheostomies and Its Multifacet Association with Lower Airway Infections: An 8-Year Retrospective Study in a Large Tertiary Center.

Background: Lower respiratory tract infections frequently complicate the care of children with chronic tracheostomies. Pediatric patients have significantly more risk to have tracheostomy infections than adults. Better understanding of modifiable risk factors for pulmonary exacerbations may improve the care of technology-dependent children. Methods: A retrospective single-center cohort study conducted on children with tracheostomy and chronic home ventilator to determine the incidence of pulmonary exacerbations leading to hospitalizations, emergency room (ER) visits, and antibiotic prescriptions. Oral and nebulized antibiotic prescriptions were collected and correlated to the type of exacerbation. Results: Gram-negative enteric organisms were the most common microbes seen in the lower airways, with Pseudomonas aeruginosa cultured in 86% of the subjects. P. aeruginosa presence predicted a 4-fold increased rate of pulmonary-related hospitalization. In pediatric patients with chronic respiratory failure, 64% of readmissions were pulmonary or tracheostomy related. When compared to standard care subjects on dual agent, alternating monthly nebulized antibiotic therapy (for chronic pseudomonas colonization) experienced 41% fewer hospitalizations [incidence rate ratios (IRR) 0.59 (0.18), P = 0.08], 46% fewer ER visits [IRR 0.56 (0.16), P = 0.04], and 41% fewer pulmonary-related ER visits [IRR 0.59 (0.19), P = 0.94]. Discussion: Children who require artificial airways are at an increased risk for bacterial bronchopulmonary infections. Most notable risk factors for hospitalization in tracheostomized children included neurologic impairment, dysphagia, aspiration, gastrotomy tube dependence, and gastroesophageal reflux disease. Pathogenic microbes such as P. aeruginosa species, certain gram-negative bacteria, candida, and yeast also predicted increased hospitalizations. Use of nebulized antibiotics prophylaxis in a subset of patients predicted lower rates of hospitalization or ER visits. More studies are needed to assess whether there is increased antimicrobial resistance with this strategy, and whether the benefits persist in the long-term nebulized antibiotics utilization.

Successful management of plastic bronchitis in a child post Fontan: case report and literature review.

PURPOSE: Plastic bronchitis is the occlusion of the major bronchial airways by a firm, gelatinous mucoid cast. It is a rare condition, which while classically described in asthma and sickle cell disease has greater mortality in patients with congenital heart disease. The management of this disease is obscure given the lack of clinical data regarding treatment therapies. METHODS: We describe a case of an 11-year-old female status after Fontan surgery who presented with respiratory distress secondary to atelectasis of the right lung. RESULTS: A bronchoscopy was performed demonstrating an obstructing bronchial cast with successful extraction. The plastic bronchitis continued to recur and she was placed on multiple inhaled mucolytics as well as inhaled tissue plasminogen activator with temporary resolution. Further evaluation of the etiology of her casts revealed that she had elevated pulmonary arterial pressures. Repeated bronchoscopic removal of the casts was utilized as well as continuation of the aggressive airway clearance. Ultimately fenestration of her Fontan was performed along with treatment of pulmonary vasodilators sildenafil and bosentan. Although there was improvement of the cast formation, her airway clearance could only be weaned to four times a day therapy with which she was discharged home after a 3-month hospitalization. She continues to remain on this therapy and has not required hospitalization since the initial incident over 1 year ago. CONCLUSIONS: Plastic bronchitis in a patient with Fontan physiology presents a treatment dilemma that may require comprehensive therapy in severe cases such as described.

High-frequency oscillatory ventilation in pediatric acute hypoxemic respiratory failure: disease-specific morbidity survival analysis.

BACKGROUND: Multiple ventilatory strategies for acute hypoxemic respiratory failure (AHRF) in children have been advocated, including high-frequency oscillatory ventilation (HFOV). Despite the frequent deployment of HFOV, randomized controlled trials remain elusive and currently there are no pediatric trials looking at its use. Our longitudinal study analyzed the predictive clinical outcome of HFOV in pediatric AHRF given disease-specific morbidity. METHODS: A retrospective 8-year review on pediatric intensive care unit admissions with AHRF ventilated by HFOV was performed. Primary outcomes included survival, morbidity, length of stay (LOS), and factors associated with survival or mortality. RESULTS: A total of 102 patients underwent HFOV with a 66 % overall survival rate. Survivors had a greater LOS than nonsurvivors (p = 0.001). Mortality odds ratio (OR) for patients without bronchiolitis was 8.19 (CI = 1.02, 65.43), and without pneumonia it was 3.07 (CI = 1.12, 8.39). A lower oxygenation index (OI) after HFOV commencement and at subsequent time points analyzed predicted survival. After 24 h, mortality was associated with an OI > 35 [OR = 31.11 (CI = 3.25, 297.98)]. Sepsis-related mortality was associated with a higher baseline FiO(2) (0.88 vs. 0.65), higher OI (42 vs. 22), and augmented metabolic acidosis (pH of 7.25 vs. 7.32) evaluated 4 h on HFOV (p < 0.05). CONCLUSION: High-frequency oscillatory ventilation may be safely utilized. It has a 66 % overall survival rate in pediatric AHRF of various etiologies. Patients with morbidity limited to the respiratory system and optimized oxygenation indices are most likely to survive on HFOV.

The persistent thrombus: complications, diagnosis, and novel treatment intervention.

OBJECTIVE: To review the findings and discuss the implications of the topic of pharmacomechanical thrombolysis in pediatric patients with persistent thrombus. DESIGN: A pediatric case presentation with a brief literature review on treatment of venous thrombosis and pharmacomechanical thrombolysis. INTERVENTIONS: None. MAIN RESULTS: Thrombotic events refractory to standard medical and surgical care remain a life-threatening clinical challenge in the pediatric population. Research on persistent deep venous thrombosis and treatment modalities is limited. We present a pediatric patient with a history of malignant osteosarcoma who was diagnosed with deep venous thrombosis. Despite appropriate anticoagulation therapy, the thrombus remained persistent. Pharmacomechanical thrombolysis was utilized and proved to be an effective method in providing diagnosis and treatment. CONCLUSION: Pharmacomechanical thrombolysis is a valuable and effective method in providing diagnosis and treatment of persistent thrombus.

Antidepressants in chronic idiopathic urticaria.

Chronic idiopathic urticaria (CIU) is a common disease estimated to affect 0.1% of the population and can be very difficult to treat. Many psychotropic medications have been reported to be successful in treating refractory CIU. The purpose of this article was to discuss the pathophysiology of chronic urticaria and provide practicing allergists and dermatologists alternative treatment options in the management of refractory CIU, especially in those who have concurrent psychiatric comorbidity. A review was performed of pertinent literature pertaining to the pathophysiology of CIU and the many psychotropic medications reportedly successful in disease management. Although more research is needed, this article serves to broaden the mind of the physician treating CIU.

Clinical efficacy of omalizumab in an elderly veteran population with severe asthma.

Severe asthma in elderly patients is underdiagnosed, difficult to treat, and often accompanied by atopy. This study was designed to compare clinical outcomes of omalizumab therapy in an elderly veteran population with severe allergic asthma. A retrospective, observational data analysis was performed over 2 years. Cohort outcome measures 1 year before omalizumab therapy were compared with 1 year of active treatment. Statistical analysis included two sample t-tests. The total number of patients enrolled was 17 with median age of 60 years. Omalizumab therapy was associated with a significant reduction in acute asthma exacerbations requiring prednisone treatment (p < 0.01), a significant improvement in forced expiratory volume in 1 second of 0.28 L (p < 0.01), and significantly higher Asthma Control Test (ACT) scores at 3 (p = 0.043), 6 (p = 0.039), and 12 months of therapy (p < 0.01). Two of five patients on daily prednisone for >6 months were able to discontinue systemic steroid use within 3 months of omalizumab treatment. Our study suggests elderly patients with severe atopic asthma show a significant positive clinical response to omalizumab.

Pediatric P-ANCA vasculitis following COVID-19.

BACKGROUND: Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) are associated with a multisystem vasculitis affecting small blood vessels in the body. A handful of adult patients who developed vasculitis post-COVID-19 have been reported. Although SARS-CoV-2 has been shown to drive an exaggerated immune response in the pediatric population, such as in Multisystem Inflammatory Syndrome in Children (MIS-C), only one case of vasculitis following COVID-19 has been reported previously in children. CASE PRESENTATION: Seventeen-year-old male with a past medical history of COVID-19 pneumonia two months prior presented with acute kidney injury and diffuse alveolar hemorrhage. Rheumatologic workup revealed P-ANCA and Myeloperoxidase (MPO) positivity. Kidney biopsy showed necrotizing glomerulonephritis with limited immune complex deposition. Subsequently, he was treated with steroids and plasmapheresis, and ultimately started on cyclophosphamide. CONCLUSIONS: To our knowledge, this report presents the second reported pediatric case of P-ANCA/MPO vasculitis following COVID-19.

Immune Response to SARS-CoV-2 in an Asymptomatic Pediatric Allergic Cohort.

Disease-specific COVID-19 pediatric comorbidity has not been studied effectively to date. Atopy and food anaphylaxis disease states require improved characterization of SARS-CoV-2 infection risk. To provide the first such characterization, we assessed serum samples of a highly atopic, food anaphylactic, asymptomatic pediatric cohort from across the US during the height of the pandemic. From our biobank, 172 pediatric patient serum samples were characterized specific to atopic, food anaphylactic, and immunologic markers in the US at the beginning of the pandemic, from 1 February to 20 April 2020. Clinical and demographic data were further analyzed in addition to sample analysis for SARS-CoV-2 IgM and IgG ELISA. SARS-CoV-2 antibody results were positive in six patients (4%). Nearly half of the pediatric patients had a history of asthma (49%). Total IgE, total IgG, and IgG1-3 were similar in those positive and negative to SARS-CoV-2. Median total IgG4 in the SARS-CoV-2 positive group was nearly three times (p-value = 0.02) that of the negative group. Atopy controller medications did not confer additional benefit. Our data suggest that food anaphylaxis and highly atopic children are not at increased risk for SARS-CoV-2 seropositivity. This specific population appears either at equal or potentially less risk than the general population. Total and specific IgG4 may be a novel predictor of SARS-CoV-2 infection risk specific to the allergic pediatric population.

Cystic fibrosis patients at risk for disease progression marked by decline in FEV1% predicted: development of the cystic fibrosis risk of disease progression score.

BACKGROUND: Cystic fibrosis (CF) is one of the most common recessively inherited disorders diagnosed in early childhood in the United States. Determining the phenotype of CF patients likely to experience a significant drop in FEV1% predicted will help target efforts for mitigating this deleterious disorder. METHODS: This retrospective cohort study evaluated potential risk variables that account for the decline in FEV1% predicted in 81 CF patients treated at Miller Children's and Women's Hospital, CA. Cystic fibrosis risk of disease progression (CF RD-Pro) score was evaluated as a tool to identify high-risk patients for accelerated disease progression (event = drop in FEV1% predicted ≥10 percentage points) based on risk variables identified as significant. RESULTS: ROC analysis determined classification of high versus low-moderate risk of FEV1% decline during year two based on RD-Pro score. Scores ≥2 applied as threshold for high-risk revealed relatively good validity estimates: sensitivity =82.8%, specificity =66.7%, PVP =77.4%, PVN =73.7%, and correct classification =76%. Patients with CF RD-Pro scores suggestive of high (≥2 points) vs. low-moderate (<2 points) risk were nearly 10 times more likely to experience significant disease progression (OR 9.6, 95% CI, 2.6-36.1, P=0.001). CONCLUSIONS: Identification of patients at high risk for significant decline in lung function will enable address of potential therapeutic modalities, environmental exposures, and behavioral variants that may improve outcomes in these patients. The power of the CF RD-Pro Score lies in its simplicity. Our study provides a novel readily available score, which incorporates body mass index (BMI) and Staphylococcus aureus infection, both being alterable targets for slowing CF progression.

Quantification of Aerosol Hydrofluoroalkane HFA-134a Elimination in the Exhaled Human Breath Following Inhaled Corticosteroids Administration.

Inhaled corticosteroids (ICS) and ß2-agonists are the primary pharmacotherapies of asthma management. However, suboptimal medication compliance is common in asthmatics and is associated with increased morbidity. We hypothesized that exhaled breath measurements of the aerosol used in the inhaled medications might prove useful as surrogate marker for asthma medication compliance. To explore this, 10 healthy controls were recruited and randomly assigned to ICS (Flovent HFA) or short acting bronchodilators (Proventil HFA). Both inhalers contain HFA-134a as aerosol propellant. Exhaled breath sampling and pulmonary function tests were performed prior to the inhaler medication dispersion, immediately after inhalation, then at 2, 4, 6, 8, 24, and 48 hours postadministration. At baseline, mean (SD) levels of HFA-134a in the breath were 252 (156) pptv. Immediately after inhalation, HFA-134a breath levels increased to 300 × 10(6) pptv and were still well above ambient levels 24 hours postadministration. The calculated ratio of forced expiratory volume in 1 second over forced vital capacity did not change over time following inhaler administration. This study demonstrates, for the first time, that breath HFA-134a levels can be used to assess inhaler medication compliance. It may also be used to evaluate how effectively the medicine is delivered.