Pediatric Annals

Special Issue Article 

Full-Term Neonatal Respiratory Distress and Chronic Lung Disease

Naema Chowdhury, MD; B. Louise Giles, MD, FRCPC; Sharon D. Dell, BEng, MD, FRCPC

Abstract

Respiratory distress occurs in 5% to 7% of live births at term gestation. Most cases are mild and transient and can be attributed to transient tachypnea of the newborn or “wet lung.” Severe respiratory distress is often due to nonpulmonary causes such as sepsis or congenital heart disease. Occasionally, term neonatal respiratory distress is associated with an inherited primary lung disease such as primary ciliary dyskinesia or surfactant metabolism defects. These lung diseases have characteristic presentations in the neonatal period and are important to recognize, as they necessitate different management approaches and have lifelong implications. Suspicion for these diseases should prompt referral to a pediatric pulmonologist. [Pediatr Ann. 2019;48(4):e175–e181.]

Abstract

Respiratory distress occurs in 5% to 7% of live births at term gestation. Most cases are mild and transient and can be attributed to transient tachypnea of the newborn or “wet lung.” Severe respiratory distress is often due to nonpulmonary causes such as sepsis or congenital heart disease. Occasionally, term neonatal respiratory distress is associated with an inherited primary lung disease such as primary ciliary dyskinesia or surfactant metabolism defects. These lung diseases have characteristic presentations in the neonatal period and are important to recognize, as they necessitate different management approaches and have lifelong implications. Suspicion for these diseases should prompt referral to a pediatric pulmonologist. [Pediatr Ann. 2019;48(4):e175–e181.]

Neonatal respiratory distress (NRD) is common in preterm infants with incomplete lung development; however, it also occurs with a relatively high frequency (5%–10%) in term infants.1 The signs of neonatal respiratory distress are tachypnea (respiratory rate >60 breaths per minute), intercostal/subcostal retractions, expiratory grunting, and hypoxemia with or without cyanosis.

The transition to extra-uterine life involves three main processes: (1) clearance of alveolar fluid and replacement with air, (2) increased pulmonary blood flow as systemic vascular resistance increases and pulmonary vascular resistance decreases, and (3) initiation of regular breathing. The successful completion of these processes results in an increase in partial pressure of oxygen (PaO2) from 25 to 60 to 80 mm Hg within the first few minutes of postnatal life.2 The process of clearing alveolar fluid begins before birth and continues through labor and delivery. During late gestation, the lung epithelium switches from an active chloride and liquid secreting surface to a sodium and water resorption surface.2 Increased PaO2 at birth further enhances this process. In addition, passive resorption of lung fluid continues after birth as the lung expands and creates an oncotic pressure difference between the air spaces, interstitium, and blood vessels. Prematurity is associated with both reduced pulmonary surfactant production and reduced function of the sodium channel that contributes to the inability of immature lungs to clear fluid, but both these processes can be upregulated by glucocorticoids.3 Although mature alveoli are present at 36 weeks of gestation, a great deal of alveolar septation and microvascular maturation occur postnatally. The lungs are not fully developed until age 2 to 8 years.

NRD has many causes that are illustrated in Figure 1. In term infants, it is usually a transient phenomenon attributed to either aberration in the transition to extra-uterine life (eg, transient tachypnea of the newborn [TTN] or persistent pulmonary hypertension [PPHN]) or adverse external environmental influences on the fetus/newborn (eg, maternally transmitted infection, early passage, aspiration of meconium, and excessive resuscitative efforts with positive pressure ventilation).1 Most conditions either self-resolve or require interventions in the neonatal unit (eg, antibiotics, chest tubes, oxygen therapy) for a limited period after which there is complete resolution of the respiratory distress and no expected long-term pulmonary sequelae. Some congenital malformations require surgical intervention (eg, tracheo-esophageal fistula, congenital diaphragmatic hernia, congenital pulmonary airways malformation), which if successful has minimal long-term pulmonary sequelae.1 Occasionally respiratory distress is due to serious life-threatening, nonpulmonary causes, such as sepsis, metabolic disease, or congenital heart disease. Rarely is NRD due to an inherited chronic lung disease that presents at birth and has lifelong lung health implications.1

Decision tree and differential diagnosis of respiratory distress in the term newborn.

Figure 1.

Decision tree and differential diagnosis of respiratory distress in the term newborn.

Respiratory distress syndrome in preterm infants is predominantly caused by surfactant deficiency. Because the focus of this review is on term infants, we will not further discuss respiratory distress syndrome, but many reviews are available.1,4–6

The objectives of this review article are to (1) review the common causes of term NRD (2) alert the pediatrician to the distinguishing clinical manifestations of primary ciliary dyskinesia (PCD) and children's interstitial lung disease (ChILD), and (3) outline the current diagnostic testing algorithms and management guidelines for these diseases.

General Approach to Term Neonatal Respiratory Distress

As stated above, the most common causes of neonatal respiratory distress include TTN, meconium aspiration syndrome (MAS), neonatal pneumonia, and pneumothorax. Differential diagnosis is based primarily on clinical history, radiographic findings, and the evolving clinical course.

For all cases of NRD, early management includes a neutral thermal environment, supportive respiratory care, and nutritional support. It is important to evaluate the neonate for the possibility of sepsis and cardiac disease (consider echocardiogram studies if severe hypoxemia is present). Empiric antibiotic coverage should be considered if there is progressive respiratory distress or risk factors for sepsis are present. Differentiation of the disease is based on radiographic imaging, clinical presentation, and risk factors. Prolonged cases of respiratory failure and distress without clear clinical indications require further evaluation for more rare etiologies of NRD.

Transient Tachypnea of the Newborn

TTN or “wet lung” occurs when there is delayed resorption and clearance of alveolar fluid at birth. Pulmonary edema occurs as liquid fluid from the alveolar spaces moves into the lung interstitium where it pools in the interlobar fissures and perivascular tissues until it is cleared by lymphatic or vascular circulation. The incidence of TTN is 5.7 to 5.9 per 1,000 term singleton births.7,8 Preterm birth and cesarean delivery bypass mechanisms to reabsorb alveolar fluid and are the strongest risk factors for TTN. Other risk factors include male sex,8 small or large for gestational age,8 and infants of mothers with diabetes,9 obesity,10 or asthma.11

Infants usually present with onset of tachypnea at or within 2 hours of birth. They may also have hypoxemia and increased work of breathing (ie, nasal flaring, intercostal and subcostal retractions, grunting). Symptoms usually resolve within 24 hours, often within 4 to 6 hours, but may persist as long as 72 hours in severe cases. TTN is a clinical diagnosis of exclusion. If TTN does not resolve within 24 hours, respiratory distress is severe (more than 40% inspired oxygen concentration or mechanical ventilation is needed) or there are atypical signs/laboratory results (eg, atypical chest radiograph, abnormal complete blood count and differential) other diagnoses should be considered, especially sepsis, pneumonia, and cardiac disease in a term baby.

Treatment is supportive with administering oxygen as needed to keep saturations above 90% and/or nasal continuous positive airway pressure. Diuretics,12,13 beta agonist therapy,14 and inhaled corticosteroid therapy15 are not helpful. If tachypnea persists longer than 4 to 6 hours or if initial complete blood count and differential are abnormal, then it may be prudent to obtain a blood culture and begin antibiotic coverage with ampicillin and gentamicin while awaiting the results. TTN is generally considered a benign and self-limited disorder, although there are data to suggest that it increases a newborn's risk for future wheezing.16

Meconium Aspiration Syndrome

Meconium aspiration occurs in term infants, typically in those born >40 weeks of gestation and occurs in 3% to 4% of all births with meconium-stained amniotic fluid.5,17 Aspiration of meconium leads to a chemical pneumonitis with mild to moderate airway obstruction. Additionally, meconium inactivates surfactant, inhibiting the natural process of lung expansion and resulting in atelectasis.18 Lastly, meconium activates the complement cascade causing further inflammation and constriction of pulmonary veins.19 Remodeling of pulmonary vasculature can predispose patients to pulmonary vascular hyperreactivity, eventual vasoconstriction, and increased pulmonary vascular resistance.

Initial examination is significant for the presence of meconium at birth, tachypnea with increased work of breathing, hypoxemia, and cyanosis. Imaging will often reveal hyperinflation and asymmetric opacities due to air-trapping and atelectasis.20 As with TTN, presentation may vary from mild to severe and is usually managed with supportive oxygenation and/or positive pressure ventilation (noninvasive or invasive).5,21 Severe cases may require high frequency oscillation ventilation22 or extracorporeal membrane oxygenation.5 Other considerations in management may include the administration of exogenous surfactant (to replace the chemically inactivated surfactant)23 and antibiotics as patients are at a higher risk of infection.

Neonatal Pneumonia

Pneumonia is a significant cause of respiratory distress in newborns and is often difficult to diagnose and often mimics other causes of respiratory distress including respiratory distress syndrome, MAS, and TTN.5,20,24 Early pneumonia occurs within the first 6 days of postnatal life, often having onset at birth, and infection is maternally transmitted either intrauterine or intrapartum. Late neonatal pneumonia is often nosocomial. The common pathogens that typically cause infection include group B Streptococcus, Staphylococcus aureus, Gram-negative bacteria (Escheria coli, Klebsiella pneumoniae), and viruses (respiratory syncytial virus, herpes simplex virus, adenovirus).5,24 Clinical presentation often includes signs of sepsis (lethargy, apnea, fever, and tachycardia) in addition to signs of respiratory distress. Chest radiograph (CXR) imaging may show an alveolar filling pattern with air bronchograms or patchy infiltrates and may look similar to the CXR of a premature baby with respiratory distress syndrome. Risk factors for neonatal pneumonia include prolonged rupture of membranes, maternal fever, and chorioamnionitis. Premature babies are at increased risk of late-onset pneumonia.

Persistent Pulmonary Hypertension of Newborn

Although TTN and MAS occur due to ineffective lung expansion during birth, pulmonary hypertension of the newborn is characterized by persistently elevated pulmonary vascular resistance.24 The failure of pulmonary vasculature resistance to decrease at birth results in suboptimal pulmonary vasodilation and decreased pulmonary blood flow. This failure could be primary abnormal pulmonary vasculature, structural remodeling of pulmonary musculature, lung hypoplasia, and poor response to vasodilators or secondary to systemic or exogenous disease.24 The risk of developing PPHN can be multifactorial and can occur in the prenatal, perinatal, and postnatal life.25

Infants with PPHN present with hypoxemic respiratory failure that may or may not respond to supplemental oxygen. Diagnosis is usually confirmed with echocardiogram showing evidence of elevated arterial pressures such as right ventricular enlargement, deviation of interventricular septum, tricuspid regurgitation, and right-to-left shunting across patent foramen ovale and/or patent ductus arteriosis.24

Management of PPHN focuses on pulmonary vasodilation to allow for effective gas exchange. Potent vasodilators include oxygen and nitric oxide,26 which remain the primary therapy for PPHN. Severe cases of PPHN, with significant oxygen requirement are often treated with systemic vasodilators such as sildenafil and ionotropic support.24

Primary Ciliary Dyskinesia

PCD is a genetic lung disease caused by defects in the structure and/or function of the motile cilia lining the upper and lower respiratory tract. Impaired mucociliary clearance leads to progressive bronchiectasis and lung function decline, which may necessitate lung transplant by mid-adulthood. Additional morbidities include hearing loss due to chronic otitis media with effusion, chronic rhinorrhea and sinusitis, and infertility. About one-half of patients with PCD have laterality defects, due to defects of the embryonal nodal cilia.27–29 The most common laterality defect is situs inversus totalis, which is a complete mirror image of thoracic and abdominal organs with no functional consequences. However complex cardiac defects may also occasionally be associated with PCD.

More than 85% of patients with PCD present with neonatal respiratory distress,27 offering an opportunity for early diagnosis. However, the average age of PCD diagnosis is between 10 and 12 years27,28 (Table 1). The issue seems to stem from a lack of recognition of the disease during infancy. In a case control study27 of 46 children with a confirmed diagnosis of PCD and a history of term NRD, a review of neonatal health records revealed that PCD was rarely suspected; instead diagnoses of “atypical” transient tachypnea of the newborn, neonatal pneumonia, and meconium aspiration syndrome were commonly assigned, despite CXR appearance being incongruent with these diagnoses.27 Several clinical manifestations distinguish clinical PCD from other causes of term neonatal respiratory distress, namely delayed onset of symptoms (average, prolonged oxygen need >2 days), migratory lobar collapse on CXR (predominantly upper lobes), and laterality defects.27 Infants who manifest these features should be referred to a pediatric pulmonologist for further testing.

Clinical Manifestations of Primary Ciliary Dyskinesia by Age of Onset

Table 1.

Clinical Manifestations of Primary Ciliary Dyskinesia by Age of Onset

Diagnosis of PCD is confirmed by demonstrating classic ultrastructural defects on ciliary electron microscopy or two bi-allelic pathogenic variants in a known PCD causing gene. Few centers have the necessary expertise to process and interpret cilia electron microscopy. Comprehensive clinical genetic testing is available at several Clinical Laboratory Improvement Amendment-certified genetic laboratories. Sensitivity of genetic testing is currently about 70%29 and the cost of the test is slowly decreasing.30

Management of neonatal respiratory distress due to PCD is supportive. There are no PCD specific therapies and much has been extrapolated from cystic fibrosis management. Infants often benefit from continuous positive airway pressure and the average duration of oxygen need is 15 days. It is unclear whether infants benefit from the initiation of chest physiotherapy in the neonatal period. Airway clearance and prevention of infection are the mainstays of therapy.27

Mirroring the multidisciplinary approach to CF and other chronic disease management, PCD clinical centers have been established. Early diagnosis facilitates early referral for disease management and offers the best opportunity to minimize the long-term pulmonary and otologic morbidity associated with the disease. Although there are no standard treatment plans, the consensus is to monitor respiratory function through spirometry, surveillance of respiratory culture, and hearing and speech evaluation. Through the PCD Foundation, a clinical network has been established with the goal to identify potential patients for clinical trials and further research.29,30

Children's Interstitial Lung Disease

ChILD refers to a heterogeneous collection of disorders defined by abnormal gas exchange due to aberrant structure of the lung interstitium.31 Previously referred to as diffuse lung disease, ChILD refers specifically to interstitial lung disease that presents in the first 2 years of life, separate from other secondary ILD that occurs later. It is associated with high morbidity and mortality. Formal diagnosis usually requires lung biopsy. It is exceedingly rare with a prevalence of 13 to 16.2 cases per 100,000.5 It classically presents as persistent NRD syndrome with refractory respiratory failure and pulmonary hypertension. The American Thoracic Society (ATS) published a guideline to classify, evaluate, and manage ChILD.32 Common causes include surfactant dysfunction (different from surfactant deficiency), neuroendocrine cell hyperplasia, alveolar capillary dysplasia, and pulmonary interstitial glycogenesis. The ATS guidelines require that for a diagnosis of ChILD the infant must have respiratory symptoms and signs, hypoxemia, and abnormal findings on CXR including chest computed tomography (CT). Symptoms include cough and dyspnea, sometimes with difficulty breathing while feeding. Common signs may include nail-bed clubbing, crackles on auscultation, retractions, and failure to thrive.32

On the initial evaluation, clinicians should exclude more common diseases (such as those noted in Figure 1), along with chronic aspiration, cystic fibrosis, immunodeficiencies, tracheoesophageal fistulas, and congenital heart disease (Table 2).

Children's Interstitial Lung Disease Presenting in the Neonatal Period

Table 2.

Children's Interstitial Lung Disease Presenting in the Neonatal Period

During the neonatal period, evaluation should focus on the severity and rate of progression of the disease, perinatal histories, and any family history of infant death, including secondary to interstitial lung disease. A high-resolution CT is usually the first step. Genetic testing can aid in providing a diagnosis of some ChILD diseases such as surfactant dysfunction disorders (problem with production ± degradation of surfactant) due to ATP (adenosine triphophate) Binding cassette subfamily A member 3 (ABCA3) or surfactant protein B (SPB) deficiency or mutation or deletion of one thyroid transcription factor 1 allele (Table 3), and abnormalities in lung development (eg, alveolar capillary dysplasia with misalignment of pulmonary veins [ACD-MPV] due to FOXF1 [Forkhead Box F1 protein] mutation or deletion), with lung biopsy as definitive diagnosis.32 As many of these diseases have a high mortality, early diagnosis in the neonatal period is imperative and can assist in choosing management options.

Surfactant Dysfunction Defects

Table 3.

Surfactant Dysfunction Defects

Presently, there are no controlled trials that describe optimal therapeutic interventions for ChILD. Therefore, patients should be referred to a specialized pediatric pulmonary center, preferable one with a pediatric lung transplant center. Supportive management includes supplementary ventilation and oxygen, and optimization of nutrition, antibiotics for suspected pneumonia, chest physiotherapy, and anti-inflammatory medications (pulse steroids, macrolides). Progress is being made in future therapies including gene therapy and alveolar macrophage transplant.33

Why It Is Important to Recognize PCD and Children's Interstitial Lung Disease

It is important for the pediatrician to recognize PCD and ChILD early in life. Many are hereditary and genetic counselling may be offered. A child with a breathing disorder without a diagnosis can increase stress and decrease quality of life for many families. Providing a diagnosis may provide relief along with knowledge of eventual outcomes. Therapy, including lung transplantation, can be offered and therapy can be expedited with knowledge of the diagnosis. Additionally, there are implications for future new therapies (eg, gene therapy) that may be open to the child and family.

Conclusion

Most cases of NRD in the term neonate are self-limited and resolve without significant long-term sequelae (as opposed to respiratory distress syndrome in preterm infants, which is associated with significant pulmonary morbidity in childhood). PCD is underrecognized and has features distinct from TTN, neonatal pneumonia, and MAS that should be recognized to begin the lifelong process of disease management for the best possible outcomes. ChILD requires a high index of suspicion and rapid referral for diagnostic testing and potential consideration for lung transplantation (for SPB, ABCA3, and ACD-MPV). Because most cases of PCD and ChILD are hereditary, diagnosis is important for prognostication, genetic counseling, and expediting therapy (including lung transplantation for SPB, ABCA3, and ACD-MPV) and may be important for new personalized medicine therapies in the future (eg, gene therapy, macrophage transfer therapy).

References

  1. Reuter S, Moser C, Baack M. Respiratory distress in the newborn. Pediatr Rev. 2014;35(10):417–428. doi:. doi:10.1542/pir.35-10-417 [CrossRef]
  2. Hooper SB, Te Pas AB, Kitchen MJ. Respiratory transition in the newborn: a three-phase process. Arch Dis Child Fetal Neonatal Ed. 2016;101(3):F266–271. doi:. doi:10.1136/archdischild-2013-305704 [CrossRef]
  3. O'Brodovich HM. Immature epithelial Na+ channel expression is one of the pathogenetic mechanisms leading to human neonatal respiratory distress syndrome. Proc Assoc Am Physicians. 1996;108(5):345–355.
  4. Sweet DG, Carnielli V, Greisen G, et al. European consensus guidelines on the management of respiratory distress syndrome - 2016 update. Neonatology. 2017;111(2):107–125. doi:. doi:10.1159/000448985 [CrossRef]
  5. Pramanik AK, Rangaswamy N, Gates T. Neonatal respiratory distress: a practical approach to its diagnosis and management. Pediatr Clin North Am. 2015;62(2):453–469. doi:. doi:10.1016/j.pcl.2014.11.008 [CrossRef]
  6. Owen LS, Manley BJ, Davis PG, Doyle LW. The evolution of modern respiratory care for preterm infants. Lancet. 2017;389(10079):1649–1659. doi:. doi:10.1016/S0140-6736(17)30312-4 [CrossRef]
  7. Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory morbidity and mode of delivery at term: influence of timing of elective caesarean section. Br J Obstet Gynaecol. 1995;102(2):101–106. doi:10.1111/j.1471-0528.1995.tb09060.x [CrossRef]
  8. Tutdibi E, Gries K, Bucheler M, Misselwitz B, Schlosser RL, Gortner L. Impact of labor on outcomes in transient tachypnea of the newborn: population-based study. Pediatrics. 2010;125(3):e577–e583. doi:. doi:10.1542/peds.2009-0314 [CrossRef]
  9. Persson B, Hanson U. Neonatal morbidities in gestational diabetes mellitus. Diabetes Care. 1998;21(suppl 2):B79–B84.
  10. Kim SS, Zhu Y, Grantz KL, et al. Obstetric and neonatal risks among obese women without chronic disease. Obstet Gynecol. 2016;128(1):104–112. doi:. doi:10.1097/AOG.0000000000001465 [CrossRef]
  11. Birnkrant DJ, Picone C, Markowitz W, El Khwad M, Shen WH, Tafari N. Association of transient tachypnea of the newborn and childhood asthma. Pediatr Pulmonol. 2006;41(10):978–984. doi:. doi:10.1002/ppul.20481 [CrossRef]
  12. Kassab M, Khriesat WM, Bawadi H, Anabrees J. Furosemide for transient tachypnoea of the newborn. Cochrane Database Syst Rev. 2013;(6):CD003064. doi:10.1002/14651858.CD003064.pub2 [CrossRef].
  13. Kassab M, Khriesat WM, Anabrees J. Diuretics for transient tachypnoea of the newborn. Cochrane Database Syst Rev. 2015;(11):CD003064. doi:10.1002/14651858.CD003064.pub3 [CrossRef].
  14. Moresco L, Bruschettini M, Cohen A, Gaiero A, Calevo MG. Salbutamol for transient tachypnea of the newborn. Cochrane Database Syst Rev. 2016;(5):CD011878. doi:10.1002/14651858.CD011878.pub2 [CrossRef].
  15. Vaisbourd Y, Abu-Raya B, Zangen S, et al. Inhaled corticosteroids in transient tachypnea of the newborn: a randomized, placebo-controlled study. Pediatr Pulmonol. 2017;52(8):1043–1050. doi:. doi:10.1002/ppul.23756 [CrossRef]
  16. Liem JJ, Huq SI, Ekuma O, Becker AB, Kozyrskyj AL. Transient tachypnea of the newborn may be an early clinical manifestation of wheezing symptoms. J Pediatr. 2007;151(1):29–33. doi:. doi:10.1016/j.jpeds.2007.02.021 [CrossRef]
  17. Dargaville PA, Copnell BAustralian and New Zealand Neonatal Network. The epidemiology of meconium aspiration syndrome: incidence, risk factors, therapies, and outcome. Pediatrics. 2006;117(5):1712–1721. doi:. doi:10.1542/peds.2005-2215 [CrossRef]
  18. Lee J, Romero R, Lee KA, et al. Meconium aspiration syndrome: a role for fetal systemic inflammation. Am J Obstet Gynecol. 2016;214(3):366.e1–9. doi:. doi:10.1016/j.ajog.2015.10.009 [CrossRef]
  19. Hofer N, Jank K, Strenger V, Pansy J, Resch B. Inflammatory indices in meconium aspiration syndrome. Pediatr Pulmonol. 2016;51(6):601–606. doi:. doi:10.1002/ppul.23349 [CrossRef]
  20. Liszewski MC, Stanescu AL, Phillips GS, Lee EY. Respiratory distress in neonates: underlying causes and current imaging assessment. Radiol Clin North Am. 2017;55(4):629–644. doi:. doi:10.1016/j.rcl.2017.02.006 [CrossRef]
  21. Montgomery KA, Rose RS. Can nasal continuous positive airway pressure be used as primary respiratory support for infants with meconium aspiration syndrome?J Perinatol. 2019;39(2):339–341. doi:. doi:10.1038/s41372-018-0256-y [CrossRef]
  22. Mikusiakova LT, Pistekova H, Kosutova P, Mikolka P, Calkovska A, Mokra D. Effects on lung function of small-volume conventional ventilation and high-frequency oscillatory ventilation in a model of meconium aspiration syndrome. Adv Exp Med Biol. 2015;866:51–59. doi:. doi:10.1007/5584_2015_138 [CrossRef]
  23. El Shahed AI, Dargaville PA, Ohlsson A, Soll R. Surfactant for meconium aspiration syndrome in term and late preterm infants. Cochrane Database Syst Rev. 2014;(12):CD002054. doi:10.1002/14651858.CD002054.pub3 [CrossRef].
  24. Edwards MO, Kotecha SJ, Kotecha S. Respiratory distress of the term newborn infant. Paediatr Respir Rev. 2013;14(1):29–36. doi:. doi:10.1016/j.prrv.2012.02.002 [CrossRef]
  25. Delaney C, Cornfield D. Risk factors for persistent pulmonary hypertension of the newborn. Pulm Circ. 2012;2(1):15–20. doi:. doi:10.4103/2045-8932.94818 [CrossRef]
  26. Blasina F, Vaamonde L, Silvera F, et al. Efficacy and safety of a novel nitric oxide generator for the treatment of neonatal pulmonary hypertension: experimental and clinical studies. Pulm Pharmacol Ther. 2019;54:68–76. doi:. doi:10.1016/j.pupt.2018.12.002 [CrossRef]
  27. Mullowney T, Manson D, Kim R, Stephens D, Shah V, Dell S. Primary ciliary dyskinesia and neonatal respiratory distress. Pediatrics. 2014;134(6):1160–1166. doi:. doi:10.1542/peds.2014-0808 [CrossRef]
  28. Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med. 2004;169(4):459–467. doi:. doi:10.1164/rccm.200303-365OC [CrossRef]
  29. Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013;188(8):913–922. doi:. doi:10.1164/rccm.201301-0059CI [CrossRef]
  30. Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;197(12):e24–e39. doi:. doi:10.1164/rccm.201805-0819ST [CrossRef]
  31. Kuo CS, Young LR. Interstitial lung disease in children. Curr Opin Pediatr. 2014;26(3):320–327. doi:. doi:10.1097/MOP.0000000000000094 [CrossRef]
  32. Kurland G, Deterding RR, Hagood JS, et al. An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med. 2013;188(3):376–394. doi:. doi:10.1164/rccm.201305-0923ST [CrossRef]
  33. Wambach JA, Young LR. New clinical practice guidelines on the classification, evaluation and management of childhood interstitial lung disease in infants: what do they mean?Expert Rev Respir Med. 2014;8(6):653–655. doi:. doi:10.1586/17476348.2014.951334 [CrossRef]

Clinical Manifestations of Primary Ciliary Dyskinesia by Age of Onset

Signs and Symptoms Age of Onset Prevalence
Organ laterality defects In-utero 50%
Neonatal respiratory distress Birth >85%
Daily nasal congestion Infancy ∼100%
Daily wet cough Infancy ∼100%
Otitis media with effusion Infancy ∼100%
Recurrent lower respiratory tract infections Preschool >95%
Pansinusitis School age ∼100%
Bronchiectasis School age ∼100% by adulthood
Male infertility Adulthood >90%

Children's Interstitial Lung Disease Presenting in the Neonatal Period

Category ACDMPV Surfactant Dysfunction Lung Growth Abnormality PIG
Presentation NRDS + PPHN Severe or mild NRDS Mild-moderate: may worsen and then improve Mild-moderate: may worsen and then improve
Hereditary basis Yes: AD Yes: AR or AD No No
Associated features None None Prematurity, CDH, CHD, Trisomy 21, other Prematurity, CHD, other
HRCT features Nonspecific diffuse changes Diffuse GGO ± cysts Architectural distortion, cystic change Variable: GGO, cysts, interstitial infiltrates
Diagnosis Lung biopsy or genetics Genetics or lung biopsy Lung biopsy, clinical context Lung biopsy, clinical context
Outcome Fatal without lung transplant Fatal (SPB ± ABCA3) or variable Variable dependent on associated features Variable dependent on associated features

Surfactant Dysfunction Defects

Affected Gene Inheritance Pattern Neonatal Presentation Childhood Presentation Extrapulmonary Findings
SPB AR Yes Extremely rare No
ABCA3 AR Yes Yesa No
SPC AD Occasional Yes No
NKX2-1 (Lung-brain-thyroid) AD Yes Yes Chorea, hypotonia, hypothyroidism
CSF2RA CSF2RB AR Rare Yes No
Authors

Naema Chowdhury, MD, is a Pediatric Pulmonology Fellow, Department of Pediatrics, The University of Chicago. B. Louise Giles, MD, FRCPC, is a Pediatric Pulmonologist, Comer Children's Hospital, The University of Chicago. Sharon D. Dell, BEng, MD, FRCPC, is a Pediatric Respirologist, Division of Respiratory Medicine, The Hospital for Sick Children, University of Toronto.

Address correspondence to Sharon D. Dell, BEng, MD, FRCPC, Division of Respiratory Medicine, Room 4543 Roy C. Hill Wing, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; email: sharon.dell@sickkids.ca.

Grant: S.D.D. received a National Institutes of Health grant (U54HL096458).

Disclosure: Sharon D. Dell discloses a financial relationship with Parion Sciences (CLEAN-PCD [primary ciliary dyskinesia] Clinical Trial). The remaining authors have no relevant financial relationships to disclose.

10.3928/19382359-20190328-01

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