Assessment of phrenic nerve pacers in a patient with Congenital Central Hypoventilation SyndromeTo the Editor:A 13-year-old patient with Congenital Central Hypoventilation Syndrome (CCHS) was transported to the emergency department following an unwitnessed syncopal event with associated cyanosis. She opened her eyes within a few minutes, her mental status returned to normal, and her oxygen saturation increased back to above 95%. Her parents reported she’s had two or three similar events over the past few months. She was born at 38-week gestation with recurrent central apnea noted immediately after birth. Genetic tests revealed that she was heterozygous for a 36 base pair duplication from nucleotide 729 to 764 of the PHOX2B gene (c 729_764dup36), which encodes an additional 12 alanine residues in the polyalanine tract of the PHOX2B protein (p.Ala244_Ala255dup12). With confirmation of a diagnosis of CCHS1, a tracheotomy was performed, and she was discharged home on positive pressure ventilation. By the end of her first year of life, she was able to be weaned to just mechanical ventilation when sleepy or asleep. At 5 years of age, bilateral phrenic nerve pacers were implanted, and she was successfully decannulated and transitioned from positive to negative pressure ventilation (Avery Diaphragm Pacing System, Avery Biomedical Devices, Inc, Commack, NY. At 7 years of age, she was diagnosed with absence epilepsy and placed on levetiracetam with resolution of her seizures. At 8 years of age, prolonged sinus pauses of up to 6 seconds were documented by an implantable loop recorder, and a cardiac pacemaker was implanted.Vital signs and physical examination in the ED were unremarkable, and neuro, cardiology, and pulmonary consults were obtained. There were no signs of infection; chest x-ray and electroencephalogram were unremarkable. Her cardiac pacemaker was interrogated, and there was no evidence that her cardiac pacemaker had been activated before, during, or after her syncopal episode. A 12-lead electrocardiogram (EKG) was obtained (figure 1). This EKG suggests her phrenic nerve pacemakers are functioning normally, with a set rate of 17 breaths per minute. Approximately every 3.5 seconds, 27 electrical pulses over 1.32 seconds are noted, particularly well seen on leads II, III, aVR, aVL, aVF, and V3-V6. Iron deficiency was noted, and it was subsequently confirmed that she suffered from menorrhagia. Her syncopal episode was judged most likely vasovagal in origin, exacerbated by iron deficiency anemia. Realizing the noteworthy aspects of the case, informed consent was obtained from the patient and her family to publish this case report. This case report is exempt from IRB approval by the New York Medical College Institutional Review Board as per the policy in their manual, “If case reports are not identifiable, there is no need…to contact or to submit any documents to the IRB”.Following the seminal work of Glenn WL, et al 2, diaphragmatic pacing has been utilized in patients with spinal cord injuries or patients with amyotrophic lateral sclerosis3. Some patients with CCHS are being transitioned to ventilation with phrenic nerve pacers, thus permitting tracheostomy closure4.Syncope is not uncommon in patients with congenital central hypoventilation syndrome. Patients with CCHS are at risk for life-threatening cardiac arrhythmia and may sometimes require cardiac pacemakers. Patients being ventilated with phrenic nerve pacers without a tracheostomy, are also at risk for obstructive sleep apnea. Patients with CCHS are prone to fainting, and tilt-table testing confirms they are prone to greater orthostatic decreases in blood pressure than healthy control patients.The artefact due to phrenic nerve pacer discharge in figure 1 has been previously demonstrated in the literature. In 1987, Auerbach and Dobelle reported trans telephonic monitoring of patients with implanted neurostimulators, including a similar figure to ours, using 2 EKG leads5. A similar figure was published in a case report of a patient who developed ventricular tachycardia and cardiac arrest during diaphragmatic pacing, and on polysomnography in a patient with CCHS.In conclusion, a routine EKG may be an easy and quick way to determine if phrenic nerve pacers are functioning properly. Both the frequency and amplitude of phrenic nerve stimulation can be estimated on an EKG.

Asthma is a significant public health concern, particularly in low- and middle-income countries (LMICs), which are predominantly located in regions such as North Africa, sub-Saharan Africa, South, Central, and East Asia, the Middle East, Latin America, the Caribbean, and certain parts of Europe. According to the World Health Organization (WHO), nearly 300 million individuals globally suffer from asthma. Data from the GAN Phase I study indicates that approximately one in ten children are asthmatic, with one in twenty experiencing severe asthma. Moreover, in children, 40% in LMICs have poor asthma control, compared to 19.9% in HICs.(1) It is estimated that 90% of the global burden of asthma is borne by individuals in LMICs, where death rates due to asthma are also the highest.(2) Also, in LMICs, children make up a larger proportion of the population compared to higher-income nations, which results in a correspondingly greater burden for those countries on health services due to childhood diseases. Estimates suggest that high proportion of asthma patients reside in LMICs, its prevalence over the past two decades is only increasing or remaining high, and morbidity-mortality rates associated with the condition are disproportionately higher compared to its counterpart high-income countries (HICs). (3)

Indoor air pollution represents a major health problem in developing countries. Common sources of household contaminants in these settings include gas or wood-fired stoves and ovens, heaters, fireplaces, tobacco smoke, dust mites, pets, mold, insecticides, and cleaning products. The use of biomass fuels or coal for daily activities, such as cooking, heating and lighting, are still common practices among many Latin American countries because of cultural behaviors, geographical conditions and limited access to cleaner energy sources. Inefficient combustion of these substances results in the release of toxic products, mainly nitrogen dioxide (NO2), carbon monoxide (CO), particulate matter (PM) and volatile organic compounds (VOC). Additionally, tobacco consumption is frequent in the region and is a well-known cause of air pollution, while electronic cigarettes have also gained popularity worldwide and are now a new source of airborne chemicals. Exposure to all these substances has been associated with an increased risk of health issues, particularly in children, such as growth impairment, respiratory infections, asthma, reduced lung function, and development of adult lung diseases (e.g., cancer and COPD) (1).

To the editor:

Introduction – Uncontrolled asthma is common in children and is associated with a decline in lung function. Repeated personalised assessments of the reasons for inadequate control should including evaluations of the patients’ surroundings. This can be support by Indoor Environmental Advisors (IEAs). This cohort study aimed to assess the impact on asthma control of routine assessment of children’s home by IEAs. Methods – Children aged 4 to 18 years who had asthma severity grades of 3 to 5 according to Global Initiative for Asthma guidelines were enrolled. Asthma control was evaluated using the standardized Asthma Control Test (ACT) before and 3 months after the IEA visit. Results – We enrolled 15 children with moderate-to-severe asthma. Asthma control improved significantly after the IEA visit (p=0.004). The percentage of children with uncontrolled asthma decreased from 64.3% before IEA visit to 27.3% at 3 months, and none of the patients had 2 exacerbations or more within the 3 months after the visit. IEA identified environmental issues whose remediation could likely contribute to improve asthma control. However, there are still barriers to the implementation of IEA that would be beneficial to remove. Conclusion – Our results support the inclusion of IEA interventions as part of the standard care pathway for children with asthma.

home NIV for children must consider the key role of the interface, in addition to selecting the ventilatory mode and settings. Acceptance and adherence to NIV often depend on the time spent selecting the right mask, as well as on regular and careful attention to preventing and addressing various issues that arise during NIV

last year's publications constitute an important step in the care of children with oSDB. The time has come to abandon the sacrosanct Apnea-Hypopnea Index as the sole marker on which we base all decisions for managing children with oSDB. We are entering a new era where better phenotyping of oSDB in children will enable personalized medicine

From Dyspnea to Diagnosis: A Pediatric Case Report on an Unexpected ConditionYotam Ophir, MD1, Marketa Bloomfield, MD, PhD2, Jana Tukova, MD, PhD1Department of Pediatric and Inherited Metabolic disorders, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic.2 Department of Immunology, Motol University Hospital, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.

A Protocol for Treating Atelectasis in the Chronically Ventilated Pediatric PatientEliezer Be’eri MBBCh, Nitay Fraenkel MD, Orit Bartov BSc. MPt. Ped, Noah Eisenberg BPT, Rachelle Lavi B Physio, Ofra Ginat BPT, Ma’ayan Shoffer BPT.Department of Respiratory RehabilitationAlyn Pediatric Rehabilitation HospitalJerusalem, IsraelPresented at the 2nd meeting of the International Society of Pediatric Respiratory Diseases (INSPiRED), 2024.ORCID ID (Eliezer Be’eri): 0000-0003-4935-6000Email addresses of authors:Eliezer Be’eri: ebeeri@alyn.orgNitay Fraenkel: nitay@alyn.orgOrit Bartov: obartov@alyn.orgRachelle Lavi: rlavi@alyn.orgNoah Eisenberg: noaeis@gmail.comOfra Ginat: ofraginat@gmail.comMa’ayan Shoffer: maayan.shoffer@gmail.comCorrespondence should be addressed to:Eliezer Be’eri, MDALYN Hospital84 Shmaryahu Levin Street, Jerusalem, Israel 91090Phone: +972 546871183ebeeri@alyn.orgKey words: Atelectasis, physiotherapy, tracheostomy, mechanical ventilationAbbreviated title: Protocol for treating atelectasisTo the editor,Lung atelectasis is an important complication occurring in children and adolescents who are ventilator-dependent due to neuromuscular respiratory failure. It may occur if a “low tidal volume” ventilation strategy is used, as is commonly done to avoid barotrauma when ventilating subjects with parenchymal respiratory failure. However, the patient in respiratory failure due to neuromuscular disease, in contrast to the subject with parenchymal respiratory failure, is primarily at risk for alveolar de-recruitment, rather than barotrauma. Some authorities have therefore advocated using a “high tidal volume strategy” \RL1. In the short term, atelectasis causes ventilation-perfusion mismatch, but if left untreated it may become a focus of recurrent infection and eventual bronchiectasis. When atelectasis is identified, it is therefore essential to re-recruit the atelectatic lung segment as early as possible, prior to the atelectasis becoming permanent.A standardized protocol for treating newly diagnosed atelectasis in ventilator-dependent children has been developed and implemented in the Respiratory Rehabilitation Department of Alyn Pediatric Rehabilitation Hospital in Jerusalem, Israel. The protocol aims to achieve rational medical and physiotherapy (PT) resource management in a stepwise and time-limited manner. The protocol employs the full spectrum of medical and physiotherapy modalities available at Alyn Hospital, including alveolar recruitment by means of prolonged “sigh” inhalations, mechanical inexsufflation (MIE), intrapulmonary percussive ventilation (IPPV), Vest therapy, negative-pressure cuirass ventilation (RTX), “green-bag” manual hyperinflation and bronchoscopy, and is detailed in diagram 1.The initial step is to maximize the ventilator parameters (peak inspiratory pressure (PIP) or tidal volume (Vti), and peak end expiratory pressure (PEEP)) and add a sigh recruitment manoeuvre of 40 cmH2O for 10 seconds every 20 minutes. In our experience, addition of the sigh recruitment maneuver often succeeds in opening the atelectatic segment, and no further therapy is needed. After 24 hours a chest Xray is performed. If no clinical (oxygen saturation above 94% or return to pre-atelectasis baseline) or radiological improvement has occurred, physiotherapy treatments are then added in a stepwise manner every 48 hours. Our initial physiotherapy protocol comprises manual chest vibration and ventilation-enhancement maneuvers combined with patient positioning to enhance postural drainage. Such positioning may be prone, or lying on the side with the atelectatic lung superior, and may include use of an abdominal belt to improve diaphragmatic function. Manual physiotherapy is combined with MIE and either IPPV (for tracheostomized subjects) or Vest therapies (if the subject is using non-invasive positive-pressure ventilation (NIPPV)), all performed three times a day. Whereas the Vest and IPPV achieve secretion mobilization (essentially, shaking secretions free of the tracheo-bronchial wall), MIE performs secretion removal (moving the secretions up the airways towards the pharynx). The protocol aims to combine mobilization and removal modalities synergistically. If no clinical improvement has occurred after 48 hours, the physiotherapy modality is changed to use of a negative-pressure cuirass (RTX) in secretion removal mode. Our rationale in choosing this technique is that during negative-pressure ventilation, chest wall expansion occurs in a manner that is morphologically different from the manner in which the thorax expands during positive-pressure ventilation, reflecting the difference between “inflating” the lungs from within versus expanding the chest wall from without. We postulate that this morphological difference manifests also at the level of the airways, meaning that there may be differences between positive-pressure and negative-pressure ventilation in terms of how airways physically expand when exposed to these two modalities. If that is in fact true, negative-pressure ventilation may succeed in achieving alveolar recruitment when positive-pressure ventilation has failed to do so. Indeed, in our experience we have witnessed successful recruitment of an atelectatic segment within 24 hours of initiating negative-pressure ventilation, in cases in which the initial positive-pressure ventilation combined with secretion-mobilization methodologies for 72 hours had failed to achieve such. In particularly resistant cases we have also combined RTX ventilation with simultaneous and synchronous positive-pressure ventilation.In children younger than 2 years of age it may be difficult to successfully fit a negative-pressure cuirass to a small thorax, which precludes using that therapy as a next step after failure of first-line PT techniques. In such circumstances, we employ a technique for achieving prolonged lung insufflation using an anesthesiology “green bag” manual resuscitator. In this technique, a slow, prolonged inspiration with a sustained inspiratory pause is followed by rapid release during the expiratory phase. As small children generally still have a pliable chest wall, this technique can often be effective in achieving sustained and high PEEP levels, encouraging alveolar recruitment.We reserve bronchoscopy for those cases in which no ongoing improvement has been achieved after one week of recruitment-enhancing therapies. This is due to a combination of the invasiveness of the procedure with the low likelihood (in our experience) that bronchoscopy alone will achieve re-expansion of an atelectatic lung segment (unless such atelectasis has been caused by a solid, aspirated foreign body that can be removed).In summary, the described protocol is a pathway for opening a newly diagnosed atelectasis in a chronically ventilated child, in a manner that maximizes the number of potentially beneficial treatment modalities employed in a time-limited and rational framework.Abbreviations:PT: physiotherapyMIE: mechanical inexsufflationIPPV: intrapulmonary percussive ventilationNIPPV: non-invasive positive-pressure ventilationRTX: negative-pressure cuirass ventilationPIP: peak inspiratory pressureVti: inspired tidal volumePEEP: peak end expiratory pressure

Wheeze is the musical continuous sound produced by oscillations in any critically narrowed airways, and heard mostly on expiration. It is common in preschool age, about half of all children will experience an episode of wheezing by their sixth birthday. Asthma is usually characterized by cough, wheeze, chest tightness and fast breathing. It is a significant global health issue and affects both children and adults. The prevalence is on the increase, especially in LMIC. Studies from different populations have revealed the key role influencing the progression from preschool wheezing to childhood asthma. Recurrent wheezing is four or more episodes in the preceding year and has a spectrum of phenotypes and with heterogeneous features. Phenotypes of wheezing were proposed to facilitate the identification of young children who are at risk of subsequent development of asthma. The epidemiology and environmental determinants of recurrent wheezing and asthma are discussed.

not-yet-known not-yet-known not-yet-known unknown Pneumonia is an infection affecting the lower airway, where the air sacs are filled with mucus and pus; and typically presents with cough, fever, and fast breathing. Pneumonia is estimated to be the leading cause of mortality in children under five worldwide with 120 million episodes result in one million deaths globally. 1 The Low-Income and Middle-Income Countries (LMICs) are more affected. In a study in southeast Nigeria, 2 bronchopneumonia accounted for 41.9%, of the cases admitted in the tertiary hospitals and in another hospital based study among children, 3 pneumonia had the highest respiratory admission rates at 34.0%. Pneumonia can be caused by various organisms: Bacterial (Streptococcus, staphylococcus etc), Viral (RSV) and recently COVID 19 pneumonia. RSV has been noted globally to be a major cause of childhood lower respiratory tract infection, with morbidity/mortality occurring in 99% of (LMICs). 4 Some of the long term sequalae are discussed

TITLE: Post-infectious bronchiolitis obliterans in children after the end of the COVID-19 pandemic.To the Editor,Bronchiolitis obliterans (BO) is a rare disease in which the main characteristic is chronic obstruction of the small airways. Post-infectious is the most common cause in children, mainly due to adenovirus (ADV), followed by other viruses such as respiratory syncytial virus (RSV), influenza or parainfluenza. Histologically, inflammation and fibrosis of the terminal bronchioles occurs, with total or partial obliteration of their lumen. The diagnosis of post-infectious bronchiolitis obliterans (PIBO) relies on a compatible clinical history of previous respiratory infection, usually severe, followed by chronic symptoms such as cough, tachypnea, intercostal retractions, hypoxemia and/or pathological auscultation with bilateral or unilateral fine crackles. Computed tomography (CT) of the lungs shows signs of mosaic perfusion pattern, with or without bronchiectasis, and pulmonary function tests with fixed airflow obstruction1. Treatment consists of a combination of anti-inflammatory drugs, oxygen therapy, bronchodilators, respiratory physiotherapy and antibiotics in case of acute infections2.Different authors have described their PIBO cases, highlighting ADV as the main microorganism involved. The highest incidence and prevalence are found in different South American countries with an Amerindian population, such as Argentina, probably related to the presence in these individuals of a characteristic HLA haplotype (DR8-DQB1*0302). The prevalence of PIBO reported in patients developing the disease with severe pneumonia was 30.3% in the province of Jilin, China, after an epidemic outbreak of ADV that occurred in the period from 2018 to 20203. To date, the increase in the number of PIBO cases after the end of the COVID-19 pandemic and the lockdown measures imposed to stop its spread remains unpublished for any geographic area.The epidemiological, etiological, clinical, diagnostic and evolutionary characteristics of 18 pediatric cases with PIBO over a period of 15 years in our center (January 2008 to January 2023) are described. Using the Shapiro-Wilk test, we described quantitative variables as mean and standard deviation (SD) when having a normal distribution, and median and interquartile range (IQR) if they corresponded to non-parametric variables.Of 18 patients diagnosed with PIBO, most are male (67%) and Caucasians (90%). Regarding the causal infection, it occurred at a median age of 1.76 years (IQR 0.96-3.02), with the time interval between October 2022 and January 2023 having the highest number of cases (10 cases) (Figure 1). The most frequent symptoms were cough (100%), fever (94%) and respiratory distress (94%); 100% were diagnosed with bronchitis and 71% with bronchitis and pneumonia. In 11 cases (61%) ADV was isolated as a causal agent, and in the remaining 7 cases ADV could not be confirmed (not analyzed in 5 and unknown in 2). The most frequent findings on chest radiography were pulmonary hyperinflation with unilateral (47%) or bilateral (33%) infiltrate. Hospital admission was required in 94%, out of which 11% were serious infections admitted to the Intensive Care Unit (ICU). Hospitalization time was 9 days (IQR 6.3-14.8 days). Treatment of acute infection was with short-acting beta2-agonist (SABA) nebulization (100%), systemic corticosteroids (SCS) (79%), antibiotics (93%) and oxygen therapy (93%). Two patients required non-invasive mechanical ventilation and 1 endotracheal intubation with invasive mechanical ventilation (IMV).The characteristic clinical history (persistent obstructive respiratory symptoms after a severe infectious condition) and typical radiological findings (mosaic perfusion pattern on CT of the lungs) is the basis for diagnosis. The median age at diagnosis was 3.10 years (IQR 1.89-6.34), with a median time between the causal infection and diagnosis in the entire sample of 1.21 years (IQR 0.65-3.38) and of those infected in 2022-23 of 0.65 years (IQR 0.48-0.78). The most frequent clinical finding after the acute infection was persistent pathological lung auscultation (89%) and recurrent bronchitis (61%). All cases showed a mosaic perfusion pattern on CT of the lungs, 83% bilateral and 17% unilateral (Swyer-James syndrome). A valid forced spirometry test was possible in 56%, all of them showing an obstructive airflow pattern defined by a Z-Score lower than –1.64 (lower limit of normality) of the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (FEV1/FVC ratio). The mean Z score (±SD) values of forced spirometry are FVC -1.75 (±1.59); FEV1 -3.25 (±1.22); FEV1/FVC -2.66 (±0.59); and the forced expiratory flow at 25-75% (FEF25-75%) is -3.34 (±0.68). The maintenance treatments they received are inhaled corticosteroids (ICS) (28%); ICS with long-acting bronchodilators (LABA) (56%), oral azithromycin (56%); leukotriene-receptor antagonist (78%); SABA rescue inhalers (100%) and 11% do not receive any maintenance treatment. The median course of the disease is 1.30 years (IQR 1.21-8.18).In summary, most cases with PIBO diagnosed in our center had the causal infection with less than 2 years of age, with ADV being the main virus involved, isolated or in coinfection with other viruses such as RSV. Seventeen patients required hospital admission and the most common diagnosis was bronchitis with bilateral pneumonia. Two patients required admission to the ICU due to severe respiratory failure, one of them requiring orotracheal intubation. The basis of the diagnosis is persistent symptoms after the initial infectious condition, supported by the involvement of ADV and an obstructive pattern in spirometry. CT of the lungs with mosaic perfusion pattern served as diagnostic confirmation in all patients. No lung biopsy was required in any of them. The time from the initial injury to the diagnosis of PIBO in our series is approximately 1 year with a disease progression time of 1.3 years. The treatments used, the most in the chronic phase, are ICS with or without LABA, montelukast and oral azithromycin. Only one patient currently requires home oxygen therapy (Table 1).The authors would like to highlight the significant increase in the number of pediatric cases of PIBO in our geographical area, the Autonomous Community of Aragón (Spain), during the months of October 2022 to January 2023 after the end of health restrictions for the recent COVID-19 pandemic. This phenomenon to our knowledge in not published or documented by other authors. Of the 18 cases, 7 had the initial infection related to ADV during this period, and in 2 patients the involvement of ADV is unknown. We are unable to demonstrate in our center an increase in the incidence of serious ADV infections after the COVID-19 pandemic. Regardless, we believe that, as has happened with other microorganisms such as Streptococcus pyogenes group A4 or RSV5, the end of COVID-19 restrictions has led to the appearance of more aggressive infections, in atypical epidemic seasons, a phenomenon known as “immunity debt”6. A recent hypothesis is that children born during the COVID-19 pandemic, where there was a clear decrease in the circulation of viruses, lowered physiological development of immunity due to minimal contact with these infectious agents. After returning to “normality”, the usual infections have appeared in greater numbers and aggressiveness. Analyzing the subgroup of patients infected after the pandemic, all of them were born during the lockdown periods (2020-2022), the disease began at an age of 1.35 years, and the time until diagnosis was shorter than in the total number of patients, 0.65 years. Another interesting fact extracted from our series is that, unlike what other authors describe, most of our patients did not require oxygen therapy for more than 60 days, so we believe that this criterion is not essential for the diagnosis, relying more on other variables such as persistent pathological lung auscultation and subsequent severe bronchitis.

not-yet-known not-yet-known not-yet-known unknown Objective: To investigate the prevalence of clinical manifestations of post COVID-19 condition, also known as long COVID, in children hospitalized with COVID-19. Methods: This is a systematic review of observational studies. We conducted the search on the databases of PUBMED and EMBASE (up to March 15, 2023). We used the following search strategy: ”long COVID” OR ”post COVID-19” OR ”post-acute COVID-19” OR ”long-term COVID” OR ”COVID-19 sequelae” OR ”persistent COVID-19” OR ”chronic COVID-19”. We included observational studies (case-control, cross-sectional, cohort, or case series) that investigated the clinical manifestations of post COVID-19 condition in children (<18 years) admitted with COVID-19. We used the WHO case definition of post COVID-19 condition (ICD-10 U09). Four authors independently assessed the studies. We performed the meta-analysis of prevalence using a random-effects model. Results: Eleven studies involving 2279 patients were included. In the period between ≥3 months and <12 months after acute COVID-19, the most frequent symptom was exercise intolerance with a pooled prevalence of 29% (95% CI: 7-57%), followed by nonspecific respiratory symptoms (12%, 95% CI: 0-48%) and nonspecific gastrointestinal symptoms (10%, 95% CI: 0-37%). In the period ≥12 months after the initial infection, the pooled prevalence of post COVID symptoms was lower, with 6% (95% CI: 2-10%) for exercise intolerance and 3% (95% CI: 0-8%) for fatigue. Conclusions: Clinical manifestations of post COVID condition in hospitalized children include symptoms across multiple organ systems, with higher prevalence in the period up to 12 months after the acute phase of COVID-19.

A document by Emily McInnes. Click on the document to view its contents.

Many children treated with cystic fibrosis transmembrane conductance regulator (CFTR) modulators increase their body mass index (BMI). To extend this observation, we prospectively monitored rates of change for growth, body mass and composition indices and z scores, forearm strength, and FEV1 during ETI therapy for a cohort of 27 children, ages 6-11, assessed potential risk factors for concerning change rates; and documented variability of individual change rates. Body composition was assessed by bioelectrical impedance analysis (BIA). Z score calculations used matched data from US children. Outcomes rates of change were analyzed using a linear mixed effects regression model. At enrollment, median BMI z-score was 0.6, percent body fat was 22.7, and percent predicted (pp) FEV1 was 100. During ETI treatment, mean z scores for annualized change rates of BMI (0.02±0.07), fat mass index (FMI) (0.02±0.08), and fat free mass index (-0.03±0.07) were not different from zero. Percent increase of FMI (mean:12.0±29.0) often exceeded that for skeletal muscle mass index (SMMI)(4.7±4.9). Older children and girls experienced the largest weight gain. Individual body mass and composition index rates of change varied extensively. FEV1 increase was independent of body composition and muscle strength change rates. Preadolescent children, as a group, experienced growth and body composition trajectories expected of US children, adding muscle mass, but preferentially adding fat mass when treated with ETI. Individual outcomes variation suggests potential benefit for body composition monitoring and interventions to promote healthy physical maturation during ETI therapy.

Title: Living with Alveolar capillary dysplasia with misalignment of the pulmonary veins – case reportAuthorsRenata Wrobel Folescu CohenInstituto Fernandes Figueira IFF/FIOCRUZ Rio de Janeiro, RJ, BrazilUniversidade do Estado do Rio de Janeiro (UERJ) Rio de Janeiro, RJ, BrazilFlavio SztajnbokUniversidade Federal do Rio de Janeiro (UFRJ) Rio de Janeiro, RJ, BrazilUniversidade do Estado do Rio de Janeiro (UERJ) Rio de Janeiro, RJ, BrazilEvanice Lima de MarcaHospital Pediátrico Jutta Batista, Rede Dor Rio de Janeiro, RJ, BrazilVera Luiza CapelozziUniversidade do Estado de São Paulo, São Paulo, SP, BrazilDafne Dain Gandelman HorovitzInstituto Fernandes Figueira IFF/FIOCRUZ, Rio de Janeiro, RJ, BrazilEloa NunezHospital Pediátrico Jutta Batista, Rede Dor, Rio de Janeiro, RJ, BrazilHenrique de Campos Reis GalvãoDiagnósticos da América S.A., DASA, São Paulo, SP, Brazil.Joselito SobreiraDiagnósticos da América S.A., DASA, São Paulo, SP, Brazil.Diana Carolina Salazar BermeoDiagnósticos da América S.A., DASA, São Paulo, SP, Brazil.Tania Wrobel FolescuInstituto Fernandes Figueira IFF/FIOCRUZ, Rio de Janeiro, RJ, BrazilTo the editor,Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare and lethal disorder mainly involving the vascular development of the lungs. The clinical presentation is characterized by respiratory distress and cyanosis caused by severe pulmonary hypertension (PH) and insufficient oxygen uptake. 95% of ACD/MPV patients are born at full term with normal Apgar scores and develop symptoms within the first 24 hrs of life. In up to 80% of the cases, associated malformations are found, for which surgery is occasionally needed1. These malformations predominantly affect the gastrointestinal tract, but also may affect the cardiovascular and urogenital systems. The mortality of ACD/MPV is almost 100%1. Atypical, milder cases of ACD/MPV patients that present after 24 hrs of life or survive beyond the neonatal period have occasionally been described2. The current gold standard to unambiguously diagnose ACD/MPV is histological examination of the lungs. In most studies, cases were diagnosed postmortem by autopsy3.It is postulated that the milder phenotype of atypical ACD/MPV patients, including late presenters and long-term survivors, is correlated with the extent of affected lung tissue. A recent study showed a heterogeneous non-uniform distribution of histological findings in all atypical ACD/MPV patients4.Recently, Sen et al5 have reported genomic deletions and point mutations in the FOXF1 gene (OMIM 601089) in chromosome 16q24.1 in unrelated patients with histopathological verified ACD/MPV. So far, 42 FOXF1 variants and 24 genomic and genic deletions identified in the 16q24.1 region have been reported. All patients have died in the first 4 months of life.This case report describes a patient as a late presenter and long-term survivor of ACD/MPV with a non previously described de novo variant in FOXF1. Informed consent statement was obtained from parents. Written informed consent to participate in this study was provided by the participant legal guardian. This study was approved by the Instituto Fernandes Figueira Ethical Committee, under the ethical approval number 59963822.0.2001.5269 (chILD - RJ).CASE REPORT:Full-term female born to non-consanguineous parents. GII/PII mother was 38yo and pregnancy was uneventful; Apgar scores 9/10, phototherapy needed for 4 days due to jaundice. There was no respiratory distress, nor congenital abnormalities were detected. Pulse oximetry was 98% (upper end lower limbs), transfontanelle and doppler ultrasound were normal. Family history negative for congenital cardiac or lung disease.At nine months she presented cough and wheezing and received salbutamol and prednisolone at home. At 14mo, there was a new respiratory distress, with no response to Salbutamol, Prednisolone and antibiotics, requiring her first ICU admission: Her weight was 8.4kg; pulse oximetry:96% with oxygen therapy support. She presented increased AP diameter, intercostal retraction, reduced air flow with crackling sounds in both lungs and hepatosplenomegaly.On admission, laboratorial exams revealed: Hb:10.6g/dL; Hto:34%; RDW:18,4%; platelets:196000/mm3; WBC:2100/mm3; Reticulocytes:13,4%; Serum iron:17mcg/dL; Ferritin:24ng/ml; Transferrin:267mg/dL; HIV and mycoplasma serology were negative. Nasopharyngeal material was negative for SARASCOV2, RSV, Influenza A and B. Immunoglobulin and lymphocytes were normal for age.Echocardiogram presented situs solicitus; levocardia; concordant atrioventricular and arterial ventricle connections; intact interatrial and interventricular septa; pulmonary trunks and branches were confluent and without obstruction; pulmonary venous drainage to the right atrium; dilation of the right cavities; significant right ventricular (RV) systolic overload; mild RV systolic dysfunction, normal left ventricular function. Systolic pressure in the pulmonary artery (SPPA) was 70mmHg. Inferior vena cava with normal caliber.Thorax high resolution computed tomography (HRCT) showed extensive diffuse ground-glass opacity in both lungs (FIG1-A,B). Bronchoscopy revealed: hyperemia and moderate mucosal edema with thick and yellowish secretion in the main bronchi. The secretion collected from bronchial lavage was negative for pyogenic germs, fungi, mycobacteria, andPneumocystis jirovecci. She was discharged home using sildenafil, captopril, furosemide + hydrochlorothiazide, spironolactone and carvedilol.She progressed with worsening respiratory pattern and hypoxemia, being readmitted at 16mo. New exams showed negative viral and SARSCOV-2 panel; negative blood cultures; echocardiogram: SPPA 88-100mmHg. Salbutamol, fluticasone, sildenafil, Captopril furosemide, hydrochlorothiazide, spironolactone and carvedilol were maintained. A new HRCT scan detected ground-glass opacities affecting both lungs (FIG1-C,D), with the appearance of septal thickening and diffuse thickening of the bronchial walls.After this, she underwent a lung biopsy and the histopathological report (FIG2) showed muscular hypertrophy of the middle layer of medium and small pulmonary arteries; reduction of capillary loops in the microcirculation along the alveolar septa; ectasia and tortuosity of pulmonary veins and lymphatics; misalignment of pulmonary veins adjacent to the terminal bronchiole; discrete inflammatory infiltrate represented mainly by small lymphocytes; there were no signs of malignancy. Perls staining was positive for macrophages with hemosiderin. Electron microscopy showed abnormal lamellar bodies of varying shapes and sizes with dense inclusions inside. Heteromorphic mitochondria with cristae fusion. There was no evidence of glycogenosis or storage diseases. No ciliary abnormalities were detected.She was discharged with regular monitoring by a pediatric cardiologist and pulmonologist, and receiving sildenafil, captopril and furosemide, spironolactone, carvedilol, hydrochlorothiazide, salbutamol and fluticasone.In parallel, exome analysis was carried out. A heterozygous variant in the FOXF1 gene was identified (NM_001451.3: c.359A>T; p.(His120Leu)), classified as probably pathogenic, considering that the variant is absent on populational databases, in silico algorithms predict damaging impact of the variant on protein function, parental testing for the variant was negative and this indivudual phenotype is highly specific for the disease.Thus, the diagnosis of alveolar-capillary dysplasia with misalignment of pulmonary vessels was confirmed.During the last two years, she has been receiving the same medication, and was admitted in hospital por 3 times due to respiratory exacerbation following viral infection. She needed during admission period, oxygen supplementation, non invasive ventilation, antibiotics and systemic corticosteroids. Cardiac catheterization at 3yo showed a high pulmonary artery pressure (100mmHg) and Bosentana was started after this exam.CONCLUSIONInfants affected with ACD/MPV usually develop respiratory distress and severe pulmonary hypertension, have no sustained response to supportive treatments, and die early in life. Few patients with ACD/MPV have been reported beyond the neonatal period. One report describing two siblings shows that a patient with less severe symptoms has a patchy pattern of capillary deficiency and abnormal distal air space, which may be correlated with the late onset. All infants with pathogenic/probably pathogenic variants in the FOXF1 gene, responsible for ACD/MPV, have died in the first 4 months of life. Our case, however, shows a 3yo girl with ACD/MPV carrying a de novo variant in FOXF1, which configurates quite a long survival with ACD/MPV. This is a missense mutation, absent in population databases with predicted in silico impact in the protein function. Based in normal parental investigation and compatible pathologic study, we considered it as phenotype-causing. Further studies will be needed to clarify the phenotypic difference between the above patient and the previously reported cases. Although phenotypical differences are present, genetic testing could contribute to earlier detection and allows adequate consultation about the prognosis and the process of decision-making.

Objective: To determine the impact and best management sequence between adenotonsillectomy (AT) and rapid maxillary expansion (RME) on the apnea-hypopnea index (AHI) and minimum oxygen saturation (MinSaO 2) in non-obese pediatric obstructive sleep apnea (OSA) patients presenting relatively normal sagittal and vertical craniofacial features. Study Design/Methods: Thirty-two children with a mean age of 8.8 years, with a graded III/IV tonsillar hypertrophy and maxillary constriction, participated in a cross-over randomized controlled trial. As the first intervention, one group underwent AT while the other underwent RME. After six months, interventions were switched in those groups, but only to participants with an AHI > 1 after the first intervention. Polysomnography (PSG) was conducted before (T 0), six months after the first (T 1) and the second (T 2) intervention. The influence of sex, adenotonsillar hypertrophy degree, initial AHI and MinSaO 2 severity, and intervention sequence were evaluated using linear regression analysis. Intra- and inter-group comparisons for AHI and MinSaO 2 were performed using ANOVA and Tukey´s test. Results: The initial AHI severity and intervention sequence (AT first) explained 94.9% of AHI improvement. AT caused more significant AHI improvements than RME. The initial MinSaO 2 severity accounted for 83.1% of MinSaO 2 improvement changes. Most AHI reductions and MinSaO 2 improvements were due to AT than RME. In most cases, RME had a marginal effect on AHI and MinSaO 2 when adjusted for confounders. Conclusions: Initial AHI severity and AT as the first intervention accounted for most of the AHI improvement. The initial MinSaO 2 severity alone accounted for the most changes in MinSaO 2 increase.

Background Cystic fibrosis (CF) is a multisystemic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene, resulting in defective synthesis or function of the CFTR protein. Historically, CF treatment focused on managing symptoms and complications. Fortunately, modulator drugs are now available to directly target the defective CFTR protein. However, in some countries, such as Turkey, these drugs are not covered by social insurance. Consequently, many CF patients face barriers to accessing modulatory therapies or must interrupt their treatment. This study demonstrates the impact of interrupting modulator therapy on pulmonary function, emphasizing the need for uninterrupted continuous treatment. Methods In this study, 39 CF patients receiving elexacaftor-tezacaftor-ivacaftor (ETI) at our clinic were retrospectively analyzed. Among the patients, 18 experienced one or more interruptions, ranging from 15 to 210 days during ETI treatment. We analyzed pulmonary function test results from 27 interruption periods. Results At the beginning of the interruption, the mean percent predicted FEV1 (ppFEV1) was 69.59 ± 25.87%, which decreased to 64.96 ± 24.52% by the end of the interruption. There was a significant decrease with a mean change of 4.62 ± 8.49 (p = 0.008). However, no significant correlation was found between the interruption duration and FEV1 change. Conclusion Our results demonstrate that pulmonary functions are adversely affected by interruption periods, regardless of their duration. Even short interruptions have a significant impact on pulmonary functions. This underscores the need for uninterrupted continuation of modulatory treatment and for improved policies to ensure equitable access to treatment.