Thinking Fast: Addressing a Tachypneic Infant

Tachypnea is a common manifestation of respiratory distress in an infant. The differential diagnosis for tachypnea in infancy is quite broad and can range from benign conditions requiring supportive care to the initial presentation of a chronic illness requiring substantial workup and long-term management. Here, we present the case of a full-term infant who developed respiratory distress at 2 months of age. A full-term, 14-day-old male was seen by his pediatrician for a weight check and found to have slow weight gain. He was born by induced vaginal birth for maternal hypertension, had an unremarkable nursery course, and a normal newborn screen. His mother shared that he breastfed well, but spit up with every feed. His vital signs and physical examination were unremarkable, but his weight gain was below goal although not crossing any major percentiles on the growth chart. Reflux precautions and supplementation with four ounces of formula were recommended. At his 6-week follow-up, he was noted to have persistent spit ups after feeds and continued slow, but improving, weight gain. At his 2-month routine visit, his weight gain had normalized with eight ounces of supplemented formula a day, but he was noted to be tachypneic, breathing 83 times per minute. His exam was otherwise normal, with a normal oxygen saturation on room air. There was no apnea, cyanosis, stridor, wheezing, cough, significant retractions, or tiring or sweating with feeds. He was switched to a partially hydrolyzed formula and started on famotidine for treatment of reflux. Given the unclear etiology of the tachypnea, he was referred to pulmonology for further evaluation. One week later, at his initial pulmonary consultation, his mother reported intermittent, self-resolving tachypnea that would last a few minutes. She often noticed the rapid breathing during sleep or right after feeding. His vital signs revealed a respiratory rate of 78 breaths per minute while eating and 99 breaths per minute after eating. He had clear breath sounds without any accessory muscle use. Chest radiographs (Figure 1) revealed nonspecific mild opacities in both lungs and hyperinflation, but no clear etiology to explain the intermittent tachypnea (Podcast 1). A 9-week-old, full-term infant with a history of sluggish weight gain requiring formula supplementation and persistent spitting up after feeds presents for pediatric pulmonary consultation due to unexplained, intermittent tachypnea. What is most likely going on with this patient (differential diagnosis and leading diagnosis)? What would you do next and why? Listen to the Podcast 2 to hear the consortium's decision-making process. A complete blood count revealed a normal white blood cell count without evidence of anemia. A complete metabolic panel showed normal electrolytes and liver function. The patient was trialed on Dr. Brown's nipple 1 and limited pacifier use to decrease aerophagia. At 3 months of age, intermittent tachypnea continued, with respiratory rates as high as 103 breaths per minute. Given the ongoing tachypnea, a cardiology consultation, an echocardiogram, and a video fluoroscopic swallow study (VFSS) were obtained, none of which revealed the cause of the tachypnea. At the 4-month routine visit, his pediatrician noted his oxygen saturation ranged between 88% and 93%. His interval history, intermittent tachypnea, and physical examination were otherwise unchanged, and weight gain continued to be appropriate. The pediatrician referred the patient directly to the emergency room for admission and further evaluation of the tachypnea and new-onset hypoxemia. A 4-month-old infant with a history of intermittent tachypnea is admitted with new-onset hypoxemia and an otherwise unremarkable physical examination and work-up. What is most likely going on with this patient (differential diagnosis and leading diagnosis?) How would you manage this patient given his new hypoxemia? Listen to the Podcast 3 to hear the consortium's decision-making process. The patient was hospitalized for 2 days, during which he was started on 0.6–0.8 LPM of supplemental oxygen via nasal cannula, which corrected the hypoxemia. He slept more comfortably while on oxygen supplementation, with a respiratory rate of 40 to 60 breaths per minute when asleep and 60 to 80 breaths per minute when awake. There were no nocturnal desaturations while receiving supplemental oxygen. He was subsequently discharged home with oxygen to be used at all times. At pulmonary follow-up, he was noted to have ongoing tachypnea and new subcostal retractions. A repeat chest radiograph showed slightly increased nonspecific opacities in both lungs and hyperinflation. The tachypnea, hypoxemia, new onset of retractions, and findings on the chest radiograph led to a concern for childhood interstitial lung disease (chILD). Therefore, the pulmonologist sought a second opinion from a center that specializes in rare lung diseases. At the initial consultation, the patient was requiring 0.6 to 1.0 LPM of supplemental oxygen. Desaturations to the high 80's intermittently occurred with agitation and sleep. His respiratory rate was 60 breaths per minute with 100% oxygen saturation on 0.8 LPM of supplemental oxygen. His exam was notable for nasal congestion, subcostal retractions, and crackles heard over the left lower lobe on deep inspiration. There was no clubbing and weight gain was appropriate for age. A sleep study demonstrated low baseline oxygen saturations, which resolved with 0.25 LPM of oxygen, and intermittent central pauses. Findings were thought to be consistent with a low pulmonary reserve and not due to central or obstructive sleep apnea. A computed tomography (CT) of the chest obtained during the inspiratory phase of the respiratory cycle demonstrated patchy diffuse ground-glass opacities with likely atelectasis in the posterior dependent lungs bilaterally (Figure 2) (Podcast 4). A 6-month-old infant with a history of tachypnea and hypoxemia on 0.8 L supplemental oxygen is found to have patchy and diffuse ground-glass opacities on chest CT. What is most likely going on with this patient (differential diagnosis and leading diagnosis?) How would you manage this patient given the abnormalities noted on CT? Listen to the Podcast 5 to hear the consortium's decision-making process. Genetic testing for chILD included a panel of interstitial and pulmonary vascular genes. This revealed a variant of unknown significance (VUS) in BMPR1B, a gene related to autosomal dominant pulmonary artery hypertension (PAH), and a single VUS in DNAH8, a gene associated with autosomal recessive primary ciliary dyskinesia. The patient's clinical picture was concerning for chILD, with neuroendocrine hyperplasia of infancy (NEHI) being highest on the differential. To summarize, the chest CT findings were possibly, but not clearly pathognomonic for, NEHI, and the genetic testing results showed a VUS which can be seen with patients who develop PAH. Therefore, bronchoscopy with bronchoalveolar lavage (BAL), lung biopsy, and parental genetic testing was pursued. At 8 months of age, flexible bronchoscopy was grossly normal, and BAL demonstrated 80% macrophages and 20% respiratory epithelial cells. An iron stain and infectious studies were negative. Multiple wedge biopsy samples from the left lung (Figure 3) showed patchy predominantly lymphocytic airway inflammation; focal neutrophilic airway inflammation was also seen. There was a sparse patchy lymphocytic infiltrate within alveolar septa. Medium-sized pulmonary arteries showed mild concentric medial thickening. Lymphatic channels were slightly dilated. Immunostaining for bombesin highlighted prominent airway neuroendocrine cells present singly and in clusters. (Podcast 6). Despite the lack of specificity of the pathology findings, a diagnosis of NEHI was made. A full-term neonate with persistent tachypnea remained symptomatic despite dietary modifications and acid suppression. The diagnostic work-up was systematically advanced to evaluate infectious, cardiac, and aerodigestive etiologies, but the diagnosis remained elusive. Over time, symptoms progressed to include retractions and hypoxemia with an abnormal chest radiograph, prompting evaluation for chILD [1, 2], which ultimately yielded a diagnosis of NEHI. ChILD is an umbrella term for hundreds of variably well characterized rare, diffuse lung disorders that present in childhood [1-3]. ChILD disorders most prevalent in infancy have been classified into the groups “diffuse developmental disorders,” “growth abnormalities,” “surfactant dysfunction mutations and related disorders,” and “specific conditions of undefined etiology.” In this rubric, NEHI is considered a “specific condition of undefined etiology.” Clinicians should suspect chILD in a pediatric patient who has three of the following four criteria without evidence of another etiology: 1) signs of respiratory distress, including failure to thrive, 2) respiratory symptoms including cough and increased work of breathing, 3) hypoxemia, and 4) diffuse abnormalities on chest imaging [1, 2]. This patient was initially tachypneic, subsequently developed hypoxemia, and was found to have diffuse abnormalities on chest imaging. NEHI, previously called persistent tachypnea of infancy, is a type of chILD that usually presents in infancy with tachypnea, hypoxemia, retractions, and crackles. It is not typically associated with clubbing. Coughing and wheezing are often isolated to times of acute illness and respiratory tract infections. There appears to be a male predominance [4, 5] and affected patients may have comorbid gastroesophageal reflux disease, dysphagia, failure to thrive, obstructive sleep apnea, or immune abnormalities [4, 6]. Failure to thrive has been associated with more severe disease courses [6]. Clinical-radiographic-pathologic correlation is required to make this diagnosis. Histologic examination typically identifies nearly normal lung tissue, often showing only mild chronic bronchiolitis plus or minus a patchy minimal interstitial lymphoid infiltrate. Biopsy may reveal increased airway neuroendocrine cells, which can be identified by bombesin or serotonin immunostaining [1, 5, 7]. Biopsies can also show mild chronic airway inflammation, airway smooth muscle hyperplasia, and increased numbers of alveolar macrophages [7]. The pathophysiology is poorly understood. As with many other types of pediatric chronic lung disease, there are increased numbers of pulmonary neuroendocrine cells (PNEC); however, specific criteria for defining “increased” in lung biopsy samples are not established [7-9]. PNEC are abundant in fetal lungs, peaking at mid gestation, and usually rapidly regressing after birth [10]. They are thought to help regulate lung development by secreting bombesin-like peptide, serotonin, and calcitonin which lead to epithelial differentiation, fibroblast proliferation, smooth muscle hypertrophy, and alveolar macrophage cytokine expression [11]. Bombesin is a known bronchoconstrictor, and animal models have suggested a close correlation between increased bombesin staining and severity of illness in a bronchopulmonary dysplasia/prematurity model [12]. It is currently unclear why normal regression of PNEC is hindered in patients with NEHI and other chronic lung diseases in infancy and childhood, such as pulmonary hypertension, pulmonary interstitial glycogenosis, bronchopulmonary dysplasia/chronic lung disease of prematurity, follicular bronchitis, and bronchiolitis obliterans. There may be a genetic component in NEHI as some families report multiple affected children [13]. The mean age of symptom onset in NEHI is 3.8 months and ranges from 0 to 11 months [4, 6, 7]. This patient initially presented with sluggish weight gain at 2 weeks, ultimately responsive to formula supplementation, and was noted at 8 weeks to be tachypneic. The differential diagnosis for tachypnea in infancy without other pulmonary findings is broad and includes periodic breathing, reflux, recurrent aspiration, anemia, metabolic acidosis, or abdominal distension leading to decreased respiratory compliance. Given the lack of improvement with acid suppression and formula alterations, the lack of infectious findings on physical examination and chest radiograph, and reassuring labs, work-up was expanded to evaluate for cardiac and aerodigestive etiologies. Neither the VFSS nor the echocardiogram revealed the etiology of the tachypnea, reassuring providers against aspiration, intracardiac shunting, or substantial pulmonary hypertension. The combination of an unrevealing work-up for more common causes of tachypnea and the development of hypoxemia with new findings on chest radiograph at 4 months of life increased the concern for a diffusion defect. This prompted an evaluation for chILD, which included polysomnography, CT imaging and, ultimately, a lung biopsy. Chest radiographs in children with NEHI can demonstrate hyperexpansion [7] or nonspecific radiographic findings suggestive of a viral process [14, 15]. High-resolution CT (HRCT) of the chest shows characteristic imaging findings of a mosaic attenuation pattern due to underlying areas of air-trapping as well as ground-glass opacities predominantly localized in the right middle lobe, lingula and perihilar regions [5, 14, 15]. For most patients, typical history and characteristic CT findings for NEHI can confirm the diagnosis, precluding the need for a pathologic diagnosis [1-3]. Lung biopsy is typically reserved for cases with atypical symptoms or inconclusive CT findings. In this case, the radiological findings were not clearly localized to the right middle lobe, lingula and perihilar regions. Therefore, the HRCT findings were suggestive of, but not pathognomonic for, NEHI. In accordance with American Thoracic Society (ATS) guidelines [1], non-diagnostic CT findings in this setting prompted a lung biopsy. The histologic findings of minimal pathologic changes helped to rule out other types of chILD and to an extent supported the clinical impression of NEHI. However, mild pulmonary artery thickening raised the question of concomitant pulmonary hypertension that was not detected on serial echocardiograms, and a VUS detected on the pulmonary vascular genetic panel has unclear clinical significance. Management of NEHI consists of supportive care, such as supplemental oxygen. Corticosteroids, bronchodilators, and immunomodulators such as azathioprine and hydroxychloroquine, do not seem to improve symptoms [7], but there are no placebo-controlled studies. Long-term follow-up suggests that patients experience gradual improvement of their respiratory symptoms, with most experiencing resolution of hypoxemia and normalization of pulmonary function tests by 5 years of age [5, 7]. However, a persistent obstructive deficit may be found in up to 29.6% of patients [16]. A diagnosis of failure to thrive requiring nutritional support at any point during the first years of life and a biopsy proven diagnosis of NEHI is associated with longer oxygen need [5, 16]. This patient will require close monitoring for symptom progression and development of pulmonary hypertension given the VUS in the BMPR1B gene and the possibility of a multifactorial etiology to his presentation. The diagnostic uncertainty in this case highlights the limitations of a classification system for rare diseases, such as chILD, about which much is still to be learned. Specifically, there are several limitations to confirming a diagnosis of NEHI histologically, including intra- and intersubject variability when identifying the PNECs and sampling error due to the patchy nature of the disease, particularly in a small biopsy sample such as that observed herein [9]. Furthermore, the number of bombesin-positive NEC cells decreases with age, making it challenging to determine normative values [17], and other forms of chILD can present with increased number of NEC cells, particularly those associated with lung immaturity [9]. Histologic interpretation is further confounded because current practice algorithms often lead to biopsy for suspected NEHI only when clinical and/or radiologic features are not classic. Therefore, it has been difficult to establish absolute criteria for a histologic diagnosis of NEHI, and despite integration with clinical and radiographic findings, diagnosis can be uncertain. This case highlights the importance of systematically broadening the differential diagnosis as common etiologies are eliminated and the patient's symptoms and clinical picture evolve. It further illustrates the challenges and opportunities in diagnosis and management of rare pediatric disease. 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