CorrespondenceTitle: An oversight regarding the Club cell?To the Editor,I was surprised to a see a title including the outdated term “Clara Cell” protein, in reference to CC16, in the title and body of the article by Rallis et al recently published in Pediatric Pulmonology (1). It appears that there needs to be an ongoing reminder that due to the association of Dr. Max Clara with the Third Reich and his unethical medical research practices which lead to the identification of this cell type (2-4) that his name was removed in 2013.In 2012, Editorial boards of American Thoracic Society, the European Respiratory Society and the American College of Chest Physicians, based on recommendations from an expert panel assembled by the Forum of International Respiratory Societies, agreed to convert to use of the terms “club cell (Clara)” and “club cell secretory protein (Clara), and after January 1, 2013, completely transitioning out the use of the (Clara) eponym.In our day, where cancel culture is so predominant, questions have been raised about what lessons are lost when history is erased. Assuming an oversight was made by the authors, editors and reviewers in not utilizing the now accepted terms “Club cell secretory protein” or bronchiolar exocrine cells, it would only be acceptable to mention the prior term in the setting of an asterisked description explaining the context and involvement of concentration camp prisoners and their association with the prior eponym, for educational purposes.Rallis D, Baltogianni M, Dermitzaki N, Balomenou F, Papastergiou E, Maragoudaki E, Tsabouri S, Makis A, Giapros V. Clara cell protein expression amongst infants with respiratory distress syndrome. Pediatr Pulmonol. 2022 Mar 18.Woywodt A, Lefrak S, Matteson E. Tainted eponyms in medicine: the ”Clara” cell joins the list. Eur Respir J. 2010 Oct;36(4):706-8Winkelmann A, Noack T. The Clara cell: a ”Third Reich eponym”? Eur Respir J. 2010 Oct;36(4):722-7.Irwin RS, Augustyn N, French CT, Rice J, Tedeschi V, Welch SJ; Editorial Leadership Team. Spread the word about the journal in 2013: from citation manipulation to invalidation of patient-reported outcomes measures to renaming the Clara cell to new journal features. Chest. 2013 Jan;143(1):1-4.
To our knowledge this is the first published case of NP associated with COVID-19 in an individual with CF and the first associated with Nocardia infection. We suspect the combination of cystic fibrosis, COVID-19 pneumonitis and co-infection with Nocardia farcinia caused this young man’s NP and ultimately his untimely death. We hope this case will highlight individuals with CF of all ages are at risk of severe COVID-19 infection.
Foreign body aspiration is rare in children below 6 months of age. Very young children presenting with stridor, atypical croup presentation, and not responding accordingly, subglottic foreign body aspiration should be considered. These may not always be visible with bedside flexible endoscopy and may need investigation under anesthesia. We report 2 cases of devil's thorn aspiration in young infants. These children were left on the floor to play and devils thorn may be a danger lurking as the they have been deposited unknowingly by the shoes people wear and pick up by these young infants.
Background: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods: We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2.org). Regression-based models tested for association between CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.
An eight-year-old girl with cystic fibrosis (CF) developed a left upper lobe collapse failing to resolve with initial conventional antibiotic treatment, mucolytics and intensified physiotherapy. Mycobacterium abscessus was isolated from her sputum. Bronchoscopy revealed thick viscous mucus plugging of the left upper lobe bronchus with complete obliteration. Three bronchoscopies with saline lavage and Dornase alfa, a rhDNase, at the end of each procedure resulted in removal of this mucus plug and the re-inflation of the affected lobe, with clinical and radiological resolution. The use of flexible bronchoscopy as a ‘secondary’ treatment with 0.9% saline lavage and instillation of rhDNase is described sparsely in the literature. This is the first reported successful therapeutic resolution of a lung collapse in a CF patient with Mycobacterium abscessus, with sequential therapeutic bronchoscopies with instillation of Dornase alfa. This should be considered for lobar collapse in CF not responding to the standard therapeutic regime.
We read with great interest recent research by Anderson et al.1 on how NICU respiratory support affects infant feeding, and by Behnke et al.2 on the potential interference of infant feeding with successful respiratory stabilization of the preterm infant. Since both preclinical and human studies have established that nutrition plays a key role in preterm lung growth and development, a crucial aspect of any research undertaken in the field of neonatal respiratory outcomes should be the breastfeeding history. It is now becoming well established that human milk feeding actively contributes in limiting lung injury among vulnerable neonates.
People with cystic fibrosis (CF) have an amazing outlook with the treatment availability of highly effective modulators. Unfortunately, not all PwCF are eligible for modulators leading to continued pulmonary exacerbations and advanced lung disease. Additionally, optimizing diagnosis and evaluation for CF in the newborn period continues to be an area of focus for research. This review article will work to cover articles published in 2021 with high clinical relevance related to the above topics, however due to the extensive body of research published, this review will not be comprehensive.
Introduction: Infants and children diagnosed with BPD have a higher likelihood of recurrent hospitalizations and asthma-like symptoms. Socio-environmental factors that influence frequency and severity of pulmonary symptoms in these children during the pre-school age are poorly under-stood. In this study, we used the Area Deprivation Index (ADI) to evaluate the relationship between the socio-environmental exposures in children with BPD and respiratory outcomes during the first few years of life. Methods: A registry of subjects recruited from outpatient BPD clinics at Johns Hopkins University (n=909) and the Children’s Hospital of Philadelphia (n=125) between January 2008 and October 2021 was used. Subjects were separated into tertiles by ADI scores aggregated to ZIP codes. Care-giver questionnaires were used to assess the frequency of respiratory morbidities and acute care usage for respiratory symptoms. Results: The mean gestational age of subjects was 26.8±2.6 weeks with a mean birthweight of 909±404 grams. The highest tertile (most deprived) of ADI was significantly associated with emer-gency department visits (aOR 1.72; p=0.009), hospital readmissions (aOR 1.66; p=0.030), and activi-ty limitations (aOR 1.55; p=0.048) compared to the lowest tertile. No association was seen with steroid, antibiotic or rescue medication use, trouble breathing, or nighttime symptoms. Conclusion: In this study, children with BPD who lived in neighborhoods of higher deprivation were more likely to be re-hospitalized and have ED visits for respiratory reasons. Identifying socio-environmental factors that contribute to adverse pulmonary outcomes in children with BPD may provide opportunities for earlier interventions to improve long-term pulmonary outcomes.
The diagnosis of primary ciliary dyskinesia (PCD) is made through a combination of clinical features supported by a panel of diagnostic tests. Our cases highlight the similarities in the clinical presentation of patients with the specific immunodeficiency activated phosphatidylinositol 3-kinase delta syndrome 1 (APDS1 or PIK3CD) and PCD. We highlight the importance of repeating nasal nitric oxide testing (nNO) when PCD has not been confirmed by genetic or ciliary electron micrograph (EM) analysis in the setting of an expanded suppurative lung disease differential that includes considerations for immunodeficiency as well as PCD.
Pediatric Pulmonology , LetterElevated serum TARC/CCL17 levels are associated with childhood interstitial lung disease in patients with SFTPC gene mutationYuto Otsubo MD1; Yuji Fujita MD1; Yusuke Ando MD, PhD1; George Imataka MD, PhD1; Shigemi Yoshihara MD, PhD11Department of Pediatrics, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0207, JapanCorresponding author:Yuto OtsuboDepartment of Pediatrics, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, JapanTel: +81-0282-86-1111Fax: +81-0282-86-7152E-mail: email@example.comKeywords:Childhood interstitial lung disease; TARC/CCL17; SFTPCRunning head:Childhood ILD and increased TARC/CCL17 levelTo the Editor,Childhood interstitial lung disease (ILD) is a serious and often life-threatening disease that causes interstitial lung lesion formation during childhood. Several causative genes of childhood ILD, such asSFTPC , SFTPB , and ABCA3 , have been identified in some children. The pathogenesis of ILD caused by SFTPC mutations may include the accumulation of surfactant protein C (SP-C) in vesicles, inhibition of pulmonary surfactant reuptake, and decreased secretion of SP-C, but this remains to be confirmed.1Thymus and activation-regulated chemokine/C-C motif chemokine ligand 17 (TARC/CCL17) is a known disease marker of atopic dermatitis. Recently, an association between idiopathic pulmonary fibrosis, a representative disease with pulmonary interstitial lesions, and TARC/CCL17 has been reported,2 but none between childhood ILD and TARC/CCL17.Here we report our experience of a case of childhood ILD in which the patient had an SFTPC mutation and an elevated TARC/CCL17 level at disease onset that decreased as the patient improved with treatment. TARC/CCL17 may be involved in the pathogenesis of ILD in children withSFTPC mutation, which is different from the pathogenesis of atopic dermatitis.An otherwise healthy 15-month-old girl was admitted to our hospital with fever, difficulty breathing, and poor oral intake. Nine days prior to the visit, nasal discharge and cough appeared and gradually worsened; subsequently, poor oral intake appeared. No fine crackles were noted. The patient required supplemental oxygen and was admitted to the hospital. She had no history of respiratory impairment at birth, but she had a family history of ILD in her maternal grandmother. Informed consent was obtained from the patient’s guardians for the publication of this case report.Laboratory tests showed a white blood cell count of 941 × 109/L, neutrophil count of 58%, C-reactive protein level of 0.01 mg/dL, lactate dehydrogenase level of 929 IU/L, Krebs von den Lungen-6 (KL-6) level of 909 U/mL (normal range < 500 U/mL), surfactant protein A level of 2770 ng/mL (normal <43.8 ng/mL), and surfactant protein D level of 319 ng/mL (normal <43 ng/mL), which were suspicious findings for ILD (Table 1). ß-D-glucan level was 7.9 pg/mL (normal <20 pg/mL) and cytomegalovirus antibodies were negative for both IgG and IgM. Chest radiography showed bilateral frosted shadows (Fig. 1), and a chest computed tomography scan showed bilateral diffuse frosted shadows (Fig. 2), leading to ILD diagnosis.Although prednisolone was started on the 2nd day of admission, the patient’s respiratory status did not sufficiently improve, and oxygen supplementation was required. Therefore, methylprednisolone (30 mg/kg/day) was administered twice for 3 consecutive days on days 13-15 and 19-21; however, the respiratory status remained poor. Hydroxychloroquine (10 mg/kg/day) was then started on day 21, and azithromycin (10 mg/kg/day) three times a week was started on day 56, following which the respiratory status gradually improved. On drinking cold water, the patient often coughed and sometimes vomited. When the water was warmed from 4°C to approximately 20°C, coughing and cough-induced vomiting drastically decreased. On day 66 of hospitalization, the patient was discharged with home-based oxygen. Respiratory status, oxygenation, and laboratory data for ILD markers such as KL-6 gradually improved (Table 1).Genetic analysis of SFTPB , SFTPC , ABCA3 ,CSF2RA , and CSF2RB showed SFTPC mutation and p.I73T (c.218T>C), and the ILD was determined to be caused by theSFTPC mutation.Additional examination revealed elevated TARC/CCL17 level at 10,270 pg/mL (normal <998 pg/mL), but IgE (24.2 IU/mL; normal <173 IU/mL) and IL-4 (2.7 pg/mL; normal <6 pg/mL) levels were not elevated in the early stages of treatment. TARC/CCL17 level decreased to 2,122 pg/mL on day 131 after the admission. Granulocyte-macrophage colony-stimulating factor (GM-CSF) level was measured twice on days 11 and 83, and on both, the GM-CSF level was under 5 pg/mL without significant elevation. Anti-GM-CSF antibody (0.3 U/mL; normal <1.7 U/mL) was negative.It has been hypothesized that many of these effector cell populations are recruited by TARC/CCL17 and act profibrogenically, but the details remain largely unknown.3) SFTPC mutations increase the number of abnormal alveolar type 2 epithelial cells (AT2) due to impaired metabolism of SP-C. A knock-in mouse model capable of regulating the expression of an isoleucine-to-threonine substitution at codon 73 (p.I73T) in SFTPC, at the same site as in the present case, showed persistently elevated TARC/CCL17 level in the bronchoalveolar lavage fluid (BALF). Furthermore, the same study also reported that TARC/CCL17 is specifically released by AT2.3 In ILD caused by SFTPC mutations, its pathogenesis involves AT2 hyperplasia. The decrease in TARC/CCL17 level in our patient suggests that either AT2 itself or TARC/CCL17 production from AT2 itself decreased with treatment. In this case, we report, for the first time, elevated serum TARC/CCL17 level in a patient with SFTPC mutation, which decreased with treatment.Our patient showed no symptoms of atopic dermatitis, and she had no skin condition, and no elevation of IgE and IL-4 levels. In the SFTPC p.I73T mouse model mentioned above, no significant level of IL-4 or IL-13 was detected in BALF, and no involvement of the Th2 response was observed.This high TARC/CCL17 level was not considered to be a result of the GM-CSF cascade. TARC/CCL17 is released from macrophages as a product of the GM-CSF cascade.4) GM-CSF is also known to be produced by AT2.5) However, in this case, serum GM-CSF levels were normal and not elevated, both at the beginning of treatment and after improvement.The limitation of this case is that bronchoalveolar lavage was not performed; therefore, the evaluation was based on serum level rather than local lung findings.This case suggests that TARC/CCL17 is involved in ILD pathogenesis. Further elucidation of the chemokine and receptor signaling cascade may lead to the targeting of some stages for therapy, which may be an important issue for future medical treatment. Therefore, elucidation of this pathogenesis is desirable.References1) Beers MF, Mulugeta S. Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol 2005;67:663-696.2) Sivakumar P, Ammar R, Thompson JR, Luo Y, Streltsov D, Porteous M, McCoubrey C, Ill EC, Beers MF, Jarai G, et al. Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis. Respir Res 2021;22;273:1-13.3) Nureki SI, Tomer Y, Venosa A, Katzen J, Russo SJ, Jamil S, Barrett M, Nguyen V, Kopp M, Mulugeta S, et al. Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis. J Clin Invest 2018;128:4008-4024.4) Hamilton JA. GM-CSF-dependent inflammatory pathways. Front Immunol 2019;10;2055:1-8.5) Woo YD, Jeong D, Chung DH. Development and functions of alveolar macrophages. Mol Cells 2021;44:292-300.Conflicts of interest:The authors disclose no conflicts.Contributors:YO cared for the patient, conceived the concept of the case report, and drafted the initial manuscript. YF, YA, GI, and SY critically reviewed the manuscript for intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. All authors have read and approved the final manuscript.Acknowledgment:We would like to thank Editage (www.editage.com) for English language editing.We thank Dr. Goro Koinuma, Division of Pulmonology, National Center for Child Health and Development, Tokyo, Japan, for his invaluable expert opinion regarding the diagnosis and treatment of the patients.Sources of funding:No funding was obtained for this study.
Background: Children should be weaned from the ventilator once their clinical condition improves. Extubation failure is associated with poorer clinical outcomes in children. Predictive indicators of successful extubation are needed. This study aims to evaluate the predictive value of ultrasonographic diaphragm imaging could help predict weaning success. Methods: In this prospective, observational study conducted between March and December 2021, children between 1 month and 10 years of age who were mechanically ventilated for more than 48 hours were included. Diaphragm ultrasound (DUS) examinations were performed at the end of 2-hour extubation readiness test (ERT). The end-inspiratory thickness, end-expiratory thickness, diaphragmatic thickening fraction, diaphragmatic excursion, inspiratory slope and expiratory slope were evaluated. Results: Twenty-four (60%) patients were successfully extubated, while 16 (40%) required invasive or non-invasive mechanical ventilation support which were classified as failed extubation group. Three of the sixteen patients in the failed extubation group required re-intubation. Diaphragm thickening fraction was significantly greater in the successful weaning group (55,05 ± 23,75% vs. 30,9 ± 10,38%) (p<0,001). Diaphragm excursion was significantly greater in the SW group (14 ± 4,4 mm vs 11,05 ± 3,25 mm) (p<0,001). DTF and DE were found to have a sensitivity and specificity of 91.67 %, 87.50 %, and 83.33 %, 81.25 %, respectively. Conclusion: Diaphragm ultrasound is a feasible and promising tool to guide physicians during weaning from IMV. Among all DUS measurements, the DE and DTF indexes showed better performance in extubation failure than other diaphragmatic parameters.
Background: Cystic fibrosis is a common cause of pancreatic exocrine insufficiency. Clinically pancreatic insufficiency is treated as a permanent problem. However, new cystic fibrosis transmembrane conductance regulator (CFTR) protein modulator therapies, like ivacaftor, can change pancreatic function in children. Also, children with residual CFTR function mutations may be pancreatic insufficient in infancy and spontaneously become pancreatic sufficient. Aims: To evaluate the benefit of reviewing pancreatic function, testing and diagnosis, of a cohort and repeat testing to patients with the potential to change function. Methods: all children with cystic fibrosis managed at Perth Children’s Hospital at the end of 2019 were reviewed for pancreatic function testing at diagnosis, genotype and current modulator and pancreatic enzyme replacement therapy use. Children with the potential to change pancreatic function were offered repeat testing. Results: 204 children were included. 11 children were prescribed ivacaftor and four of these became pancreatic sufficient. Five children with a residual CFTR function mutation were pancreatic insufficient at diagnosis. Four became pancreatic sufficient. Conclusion: there is benefit in re-evaluating pancreatic function in children with cystic fibrosis regularly, especially if on ivacaftor or pancreatic insufficient with a residual CFTR function mutation.
Successful Extubation in Preterm InfantsTo the Editor,I read with great interest the article by O’Connor et al1 describing factors that lower the likelihood of successful extubation by day 14 in mechanically ventilated neonates with or at risk of developing bronchopulmonary dysplasia (BPD), born at <30week gestational age (GA). These factors were younger GA at birth, and at the time of commencing steroids had higher MAPs and had higher oxygen requirements. They studied 287 neonates and noted that each additional week of GA at birth led to a 1.53 increase in the odds of successful extubation. Higher average fraction of inspired oxygen (FiO2) requirements in the preceding 24 h resulted in a 0.94 decrease in the odds of successful extubation and higher mean airway pressure (MAP) resulted in 0.76 decrease in odds of successful extubation.I have been using the probability of successful extubation calculator (http://extubation.net/), which incorporates the same factors as described by Connor et al 1. The calculator was described earlier by Gupta et al 2. They incorporated GA, MAP and FiO2 in the calculation, same as Connor et al 1. The only difference was the inclusion of the respiratory severity score (RSS), which is nothing but a product of MAP and FiO2 [(RSS= mean airway pressure (cm H2O) x FiO2 (0.21-1.00)].Although, we have a probability score model for successful extubation among preterm infants, as described by Gupta et al 2, I do agree with Connor et al 1 that we need to develop prognostic scoring model for intubated preterm infants.References:O’Connor K, Hurst C, Llewellyn S, Davies M. Factors associated with successful extubation following the first course of systemic dexamethasone in ventilator-dependent preterm infants with or at risk of developing bronchopulmonary dysplasia [published online ahead of print, 2022 Jan 7]. Pediatr Pulmonol . 2022;10.1002/ppul.25821. doi:10.1002/ppul.25821Gupta D, Greenberg RG, Sharma A, et al. A predictive model for extubation readiness in extremely preterm infants. J Perinatol . 2019;39(12):1663-1669. doi:10.1038/s41372-019-0475-xAuthor:Shabih Manzar, MDLouisiana State University Health Sciences CenterDepartment of Pediatrics1501 Kings HighwayShreveport, LA 71103Phone: 318-626-1623Fax: 318-675-6059Email: firstname.lastname@example.orgAuthor contribution: Dr. Manzar wrote the draft.Funding and financial support: NoneConflict of interest: None
Introduction: Point of care ultrasound (POCUS) is a useful tool to determine endotracheal tube placement; however, few studies have compared it with standard methods of confirmation. We evaluated the diagnostic accuracy of POCUS and time-to-interpretation for correct identification of tracheal versus esophageal intubations compared to a composite of standard-of-care methods in neonates. Methods: A cross-sectional study was conducted in the Neonatal Intensive Care Unit (NICU) at Aga Khan University Hospital Karachi Pakistan. All required intubations were performed as per NICU guidelines. The ETT placement was determined using standard-of-care methods (auscultation, colorimetric capnography, and chest X-ray) by a clinical team, and simultaneously by POCUS. Timings were recorded for each method by independent study staff. Results: A total of 348 neonates were enrolled in the study. More than half (58%) of intubations were in an emergency scenario. Using an expert as the reference standard, POCUS user interpretation showed 100% sensitivity and 94% specificity. We found a 99.4% agreement (Kappa: 0.96; p<0.001) between the POCUS user and expert. Diagnostic accuracy of POCUS compared with at least two standard-of-care methods demonstrated 99.7% sensitivity, 91% specificity, and 98.9% agreement (Kappa:0.93; p<0.001). The median time required for POCUS interpretation was 3.0 (IQR 3.0 -4.0) seconds for tracheal intubation. The time recorded for auscultation and capnography was 6.0 (IQR 5.0 -7.0) and 3.0 (IQR 3.0-4.0) respectively. Conclusion: POCUS is a rapid and reliable method of identifying ETT placement in neonates. Early and correct identification of airway management is critical to save lives and prevent mortality and morbidity.
Nutritional support is essential in the critical care of the very preterm infant, however, study of the potential role of nutrition in the multifactorial pathogenesis of bronchopulmonary dysplasia (BPD) is limited. Achievement of full enteral feeding faster has not been shown to be harmful and may be of benefit in extremely preterm infants. This commentary discusses the studied risk and potential benefits of more rapid enteral feeding advancement in extremely preterm infants.
Introduction Spirometry plays an important role in the assessment of possible respiratory failure in children with neuromuscular disorders (NMDs). However, obtaining reliable spirometry results is a major challenge. We studied the relation between Forced Oscillation Technique (FOT) and spirometry results. FOT is an easy, non-invasive method to measure respiratory mechanics, i.e. respiratory resistance R and respiratory reactance X. We hypothesized an increased resistance R and reduced reactance X in patients with more reduced lung function. Methods In this prospective single center study we included all children with NMDs able to perform spirometry. We consecutively measured respiratory resistance R and reactance X at 5, 11 and 19 Hz and (Forced) Vital Capacity, Peak Expiratory Flow. Spearman correlation coefficients were calculated and regression curves were estimated. Results We included 148 patients, with a median age of 13 years (IQR 8-16). All correlation coefficients were statistically significant with p = 0.000. A negative correlation was found between resistance R and spirometry outcomes (spearman correlation coefficient (ρ) between -0.5 and -0.6). A positive correlation was found between reactance X (i.e. less negative outcomes) and spirometry outcomes (ρ between 0.4 and 0.6). Highest correlation was found at lower frequencies. Regression analysis showed a non-linear relation between FOT and spirometry results. Conclusion We found a non-linear relation between FOT and spirometry results with increased resistance R and reduced reactance X in patients with more restrictive lung function decline. Given the difficulties with performing spirometry, FOT may be a promising surrogate measure of lung function.
Pilot Study of Nuclear Scintigraphy To Assess Cough Clearance in DMDTo the Editor:Respiratory muscle weakness as a consequence of neuromuscular disease results in ineffective cough, atelectasis, and pneumonia. Augmented airway clearance treatments such as mechanical in-exsufflation and high frequency chest compression have been shown to decrease morbidity and mortality in children with neuromuscular disease, although the evidence supporting these therapies in clearance of airway secretions is indirect.We sought to pilot the use of nuclear imaging of the clearance of pulmonary secretions before and after voluntary coughing and airway clearance treatment to explore the role of measures of pulmonary function to predict airway clearance. This technique has been used for some time in patients with cystic fibrosis but has not been applied to patients with neuromuscular disease or to assess the utility of airway clearance devices. To this end, we recruited 7 outpatient subjects (7.8-21 years of age) with Duchenne Muscular Dystrophy when clinically well and categorized as “Early Ambulatory” (requiring minimal assistive devices, n=4); “Early Non-ambulatory” (using wheelchair some of time, n=2); and “Late Non-Ambulatory” (always using wheelchair, n=1). This study was approved by local Institutional Review Board.Spirometry was performed according to ATS specifications and normalized using Global Lung Initiative equations. Peak cough flow was measured from total lung capacity (TLC) and data was normalized with previously published equations. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were measured at the mouth using a hand-held pressure manometer and maximal pressure from FRC was also be measured at the nares (SNIP) during a sniff maneuver using a small nasal occluder and handheld transducer Maximal static pressures and SNIP pressures were normalized using previously published data.For imaging of mucus clearance, 4 mCi of Technetium [Tc-99m] sulfur-colloid particles in 2 ml of normal saline were delivered by nebulizer using a defined breathing pattern for 2 minutes . During continuous imaging, subjects were asked to voluntarily cough every 10 seconds for 1 minute using guidance from a metronome, and this sequence was repeated 3 times. The subject then received an airway clearance treatment for 30 minutes using a high frequency chest compression device with pressure adjusted between 80-100% of maximum, and compression frequencies cycled between 5Hz-15Hz. The device was paused every 10 minutes at which time the patient was asked to cough every 10 seconds over 1 minute.Image analysis was performed according to previously published methods. Measurements of radioactivity in the right lung were corrected for background and radioactive decay and normalized by starting radioactive counts. A single retention curve was generated from the initial cough clearance period and the period during which the high frequency chest compression device was operated. Cough clearance (CC) represents the percent of total deposited radioactivity cleared during the associated period. We designated the percentage cleared by 18 voluntary coughs over 3 minutes as CCvol, and the percentage cleared during three 10 min periods of HFCC and 18 voluntary coughs over 3 minutes as CCHFCC. CCvol and CCHFCCwere correlated with physiologic measures including peak cough flow (PCF), MIP/MEP, and SNIP using Spearman’s correlation.Pulmonary function was overall well preserved (FVC 92% ± 35%). Respiratory muscle strength (in cmH2O) decreased with disease severity (e.g. MIP EA 73.5 ± 26, ENA 62.5 ± 14.8, LNA 47). Peak cough flow (% predicted) decreased with severity (EA 94±11, ENA 79±9, LNA 46). Complete details are provided in the online supplement.Representative imaging of two subjects is shown (Figure 1). Significant intra-subject differences were seen in clearance with voluntary cough and with cough augmented with HFCC vest (Figure 2). Voluntary cough was responsible for 46-96% of the total clearance and HFCC-augmented clearance for 3-53% of total clearance. For most patients, the kinetics of clearance with HFCC-augmented cough did not appear very different than for voluntary cough.Statistical comparisons between disease stages were hampered by the small sample size in each group. Nonetheless, while there appeared to be a trend for decreasing CCvol with stage of disease (Figure 2), age, and PCF, we found no statistically significant correlations between voluntary cough clearance and measures of pulmonary function (FVC, r=0.39), respiratory muscle strength (PCF, r=-0.63; SNIP r=-0.12, MIP r=0.43, MEP r=0.29), age (r=-0.57), height (r=-0.49), weight (r=-0.37). Additionally, we did not find statistically significant correlations between augmented cough clearance and measures of pulmonary function (FVC, r=0.40), respiratory muscle strength (PCF, r=-0.08; SNIP r=-.02, MIP r=-0.07, MEP r=0.05), age (r=-0.39), height (r=-0.75), weight (r=-0.03).This study is the first we are aware of to directly examine cough clearance of secretions using nuclear scintigraphy in patients with DMD. Importantly, the measurements were well tolerated by subjects. We did not find a relationship between CPF, respiratory muscle strength, or spirometry and voluntary cough clearance. However, these results must be qualified based on the small number of enrolled subjects. We do note that many of the patients had good cough clearance. Additionally, HFCC did not consistently alter the rate of secretion clearance above noted with voluntary cough.While Bach et al showed that PCF >160 L/min was a predictor of successful tracheal decannulation in adults with neuromuscular disease, Airen et al found that the majority of healthy children <13 years old generated PCFs < 270 l/min despite having the ability to generate MEP > 60 cmH2O. This suggests that PCF may change with age and that an absolute threshold cannot be used across the age span. There are no studies specifically examining use of HFCC in patients with DMD. As patients with DMD are expected to have impairment in cough, mechanical in-exsufflation would be expected to assist with airway clearance by replacing the function of weak respiratory muscles in a way that HFCC does not. Lechtzin et al showed that in adults with neuromuscular diseases, HFCC decreased inpatient costs and costs for treating pneumonia compared to the year prior to initiating HFCC. Measures of pulmonary function, including PCF, were not assessed. It would be of interest to examine secretion removal with in-exsufflation using this nuclear imaging method.While we were not able to demonstrate a relationship between cough clearance and measures of respiratory muscle strength, peak cough flow, or FVC, it is possible that this relationship exists and would be demonstrated in a larger population. However, the longstanding assumption that PCF is a reliable indicator of need for airway clearance, especially in children, is not supported by these data. The biggest limitation of our pilot study is the small sample size. We suspect enrollment was limited due to preference for interventional studies. Another limitation is that for our population, the impairment of respiratory muscle strength was mild for most subjects. Additional subjects with more advanced weakness may have helped clarify the relationship between respiratory muscle strength and airway clearance. Finally, there can be day-to-day variations of clearance.There are now a number of airway clearance technologies being proposed for patients with neuromuscular and airway diseases (e.g. cystic fibrosis, ciliary dyskinesia). These include high frequency chest compression vests, battery-powered vests, in-exsufflation devices (with or without oscillation), intrapulmonary percussive ventilation devices, and handheld oscillating positive expiratory pressure devices. We propose that the imaging methodology used in this study could be utilized to compare these different techniques, some of which are costly and with limited or no comparison data. In addition, there are patients that will be unable to cooperate with pulmonary function measurements and an imaging assessment of airway clearance may be useful to determine optimal strategies.In conclusion, we demonstrated that use of nuclear scintigraphy is a feasible technique to examine airway clearance for patients with respiratory muscle weakness, as it has been used for patients with cystic fibrosis. Additional studies will be needed to further examine the relationship between pulmonary function measures and secretion removal.Daniel J. Weiner MD1,Hoda Abdel Hamid MD2,Timothy E. Corcoran PhD3Divisions of Pediatric Pulmonology1 and Neurology2, Department of PediatricsUPMC Children’s Hospital of PittsburghDivision of Pulmonary, Allergy and Critical Care Medicine3, Department of MedicineUniversity of Pittsburgh School of Medicine