An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy.

BACKGROUND: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults. METHODS: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient's or family's quality of life, and death. RESULTS: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having "childhood ILD syndrome"; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research. CONCLUSIONS: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.

Rapid and progressive pulmonary fibrosis in 2 families with DNA repair deficiencies of undetermined etiology.

Known genetic causes of pediatric interstitial lung disease include disorders of surfactant metabolism, telomerase, and DNA repair. We report 4 children from 2 families with rapidly progressive and fatal pulmonary fibrosis. A novel DNA repair defect unrelated to the ataxia-telangiectasia mutated gene was found in 1 child from each family.

Interstitial lung disease in children.

PURPOSE OF REVIEW: In this review, we discuss the recent advances in our understanding of the cause, pathogenesis, presentation, diagnosis, treatment, and prognosis of interstitial lung disease (ILD) in children. RECENT FINDINGS: The classification of ILD syndromes in children greater than 2 years of age is based largely on adult classification schemes. In children less than 2 years of age, classification has been developed and evaluated pathologically. Entities can be categorized into developmental disorders, growth abnormalities, and surfactant dysfunction disorders based on pathologic findings. Two distinctive entities, neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis, present early in life with characteristic findings. These two disorders appear to have a favorable prognosis. Diagnosis of ILD syndromes is based on the summation of history and physical findings and both noninvasive and invasive studies. Newer approaches are being evaluated to decrease the need for lung biopsy. SUMMARY: Children's interstitial lung diseases are rare diffuse lung diseases resulting from a variety of pathogenic processes that include genetic factors, association with systemic disease processes, and inflammatory or fibrotic responses to stimuli. There are unique causes and presentations seen in infancy. Diagnosis in these disorders is made by the summation of clinical, radiologic, and pathologic findings.

Diagnosis and management of diffuse lung disease in children.

Diffuse lung disease [DLD] in children comprises a group of heterogeneous, rare disorders. Despite the rarity of these diseases there has been a considerable increase in our knowledge of DLD in children including their diagnosis and management. Diagnosis of these diseases requires a detailed history and physical examination, diagnostic imaging, pulmonary function testing, selected and directed laboratory testing, bronchoalveolar lavage and in most cases an open lung biopsy. Once a diagnosis is made, treatment is centred on supportive care including nutritional and supplemental oxygen therapy when needed. Medications including corticosteroids and other immunomodulatory medications are often used. Lung transplantation has been used for final treatment in some cases of DLD. Formation of research collaborations will continue to further our understanding of these diseases.

Neuroendocrine cell hyperplasia of infancy: diagnosis with high-resolution CT.

OBJECTIVE: Neuroendocrine cell hyperplasia of infancy is a form of childhood interstitial lung disease originally reported as persistent tachypnea of infancy. Reports of small series of cases and anecdotal experience have suggested that this disorder may have a consistent CT pattern. The purpose of this study was to review the CT findings in children with neuroendocrine cell hyperplasia of infancy to determine the findings at high-resolution CT, the diagnostic accuracy of CT compared with biopsy, and interrater reliability. MATERIALS AND METHODS: Images from 23 CT examinations of children with biopsy-proven neuroendocrine cell hyperplasia of infancy and six CT examinations of children with other childhood interstitial lung diseases were reviewed by two pediatric radiologists with special expertise in thoracic imaging. Identifying digital data were removed, and images were reviewed without clinical data. A CT assessment form was completed for each patient. RESULTS: Ground-glass opacification was the most common finding in patients with neuroendocrine cell hyperplasia of infancy. The right middle lobe and lingula were most commonly involved. Air trapping with a mosaic pattern was the second most common finding. Interrater reliability was very good with a kappa value of 0.93. The sensitivity and specificity of CT in the diagnosis of neuroendocrine cell hyperplasia of infancy were at least 78% and 100%. CONCLUSION: Neuroendocrine cell hyperplasia of infancy can have a characteristic appearance on high-resolution CT scans, the imaging findings being useful in differentiating neuroendocrine cell hyperplasia of infancy from other types of childhood interstitial lung disease. The appearance aids radiologists in suggesting a specific diagnosis but does not exclude this diagnosis; in 17-22% of cases, the readers in this study did not suggest the diagnosis of neuroendocrine cell hyperplasia of infancy when it was present.

Bronchiolitis obliterans in children.

PURPOSE OF REVIEW: In this review, we discuss recent advances in our understanding of the etiology, pathology and pathogenesis, clinical presentation, diagnosis, treatment, and outcome of bronchiolitis obliterans in the nontransplant, pediatric population. RECENT FINDINGS: The diagnosis of bronchiolitis obliterans in children can be made with confidence based on clinical presentation, particularly with a history of adenovirus bronchiolitis or pneumonia, fixed obstructive lung disease on pulmonary function testing, and characteristic changes of mosaic perfusion, vascular attenuation, and central bronchiectasis on chest high-resolution computed tomography, thus avoiding the need for lung biopsy in most patients. Patients with postinfectious bronchiolitis obliterans generally have chronic, nonprogressive disease; in contrast, patients with bronchiolitis obliterans from Stevens-Johnson syndrome often have progressive disease that may require lung transplantation. SUMMARY: Bronchiolitis obliterans is a rare form of chronic obstructive lung disease that follows a severe insult to the lower respiratory tract, resulting in fibrosis of the small airways. In the nontransplant pediatric population, adenovirus infection is the most common cause. Treatment is largely supportive and prognosis is mainly related to the underlying cause and to the severity of the initial insult.

Diffuse lung disease in young children: application of a novel classification scheme.

RATIONALE: Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children. OBJECTIVES: A multidisciplinary working group was formed to: (1) apply consensus terminology and diagnostic criteria for disorders presenting with diffuse lung disease in infancy; and (2) describe the distribution of disease entities, clinical features, and outcome in young children who currently undergo lung biopsy in North America. METHODS: Eleven centers provided pathologic material, clinical data, and imaging from all children less than 2 years of age who underwent lung biopsy for diffuse lung disease from 1999 to 2004. MEASUREMENTS AND MAIN RESULTS: Multidisciplinary review categorized 88% of 187 cases. Disorders more prevalent in infancy, including primary developmental and lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and surfactant-dysfunction disorders, constituted the majority of cases (60%). Lung growth disorders were often unsuspected clinically and under-recognized histologically. Cases with known surfactant mutations had characteristic pathologic features. Age at biopsy and clinical presentation varied among categories. Pulmonary hypertension, presence of a primary developmental abnormality, or ABCA3 mutation was associated with high mortality, while no deaths occurred in cases of pulmonary interstitial glycogenosis, or neuroendocrine cell hyperplasia of infancy. CONCLUSIONS: This retrospective cohort study identifies a diverse spectrum of lung disorders, largely unique to young children. Application of a classification scheme grouped clinically distinct patients with variable age of biopsy and mortality. Standardized terminology and classification will enhance accurate description and diagnosis of these disorders.

Serum KL-6 as a marker for bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans (BO) is the pathologic manifestation of chronic allograft rejection in lung transplant recipients and specific diagnosis requires invasive tests. BO causes progressive obstruction of the small airways. The term bronchiolitis obliterans syndrome (BOS) is a clinical surrogate for the histopathologic diagnosis of BO and is measured by lung function testing. KL-6 is a glycoprotein expressed on pulmonary epithelial cells and it is present in the serum of normal individuals in small amounts. Serum KL-6 has been shown to be a useful marker of disease activity in interstitial lung diseases. We demonstrated that serum levels of KL-6 are elevated in lung transplant recipients with BOS when compared with those without BOS and healthy controls. Our results indicate that serum KL-6 measurement has the potential to serve as a noninvasive diagnostic test for the detection of BO in lung transplant recipients.

Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease.

OBJECTIVE: To determine if serum KL-6, surfactant protein A (SP-A), and surfactant protein D (SP-D) levels are elevated in pediatric interstitial lung disease (ILD) and associated with pulmonary function and disease severity score. METHODS: Serum KL-6, SP-A, and SP-D levels were measured by enzyme-linked immunosorbent assay in 10 children with ILD and in 10 healthy volunteers. In the ILD group, FEV1 percentage of predicted, FVC percentage of predicted, and ILD disease severity score were measured and correlated with serum KL-6, SP-A, and SP-D levels. RESULTS: For the ILD and control groups, respectively, mean serum KL-6 was 4,523 U/mL and 206 U/mL (p = 0.007), mean serum SP-A was 133 ng/mL and 21 ng/mL (p = 0.003), and mean serum SP-D was 304 ng/mL and 75 ng/mL (p = 0.004). There was an inverse relationship between SP-A and FVC (p = 0.05), and between SP-D and FEV1 (p = 0.05). There was a direct relationship between SP-D and ILD score (p = 0.05). CONCLUSIONS: Serum KL-6, SP-D and SP-D levels are elevated in children with ILD. SP-A and SP-D levels appear to correlate with some measures of disease severity.

Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia.

We sought to determine the clinical course and histologic findings in lung biopsies from a group of children who presented with signs and symptoms of interstitial lung disease (ILD) without identified etiology. Patients were identified from the pathology files at the Texas Children's Hospital who presented below age 2 years with persistent tachypnea, hypoxia, retractions, or respiratory crackles, and with nonspecific and nondiagnostic lung biopsy findings. Age-matched lung biopsy controls were also identified. Their clinical courses were retrospectively reviewed. Biopsies were reviewed, and immunostaining with antibodies to neuroendocrine cells was done. Fifteen pediatric ILD patients and four control patients were identified for inclusion in the study. Clinically, the mean onset of symptoms was 3.8 months (range, 0-11 months). Radiographs demonstrated hyperinflation, interstitial markings, and ground-glass densities. Oxygen was initially required for prolonged periods, and medication trials did not eliminate symptoms. After a mean of 5 years, no deaths had occurred, and patients had improved. On review of the lung biopsies, all had a similar appearance, with few abnormalities noted. Immunostaining with antibodies to neuroendocrine cell products showed consistently increased bombesin staining. Subsequent morphometric analysis showed that immunoreactivity for bombesin and serotonin was significantly increased over age-matched controls. In conclusion, we believe this may represent a distinct group of pediatric patients defined by the absence of known lung diseases, clinical signs and symptoms of ILD, and idiopathic neuroendocrine cell hyperplasia of infancy. These findings may be important for the evaluation of ILD in young children.

Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme.

RATIONALE: Children's Interstitial and Diffuse Lung Disease (chILD) is a heterogeneous group of disorders that is challenging to categorize. In previous study, a classification scheme was successfully applied to children 0 to 2 years of age who underwent lung biopsies for chILD. This classification scheme has not been evaluated in children 2 to 18 years of age. OBJECTIVES: This multicenter interdisciplinary study sought to describe the spectrum of biopsy-proven chILD in North America and to apply a previously reported classification scheme in children 2 to 18 years of age. Mortality and risk factors for mortality were also assessed. METHODS: Patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease from 12 North American institutions were included. Demographic and clinical data were collected and described. The lung biopsies were reviewed by pediatric lung pathologists with expertise in diffuse lung disease and were classified by the chILD classification scheme. Logistic regression was used to determine risk factors for mortality. MEASUREMENTS AND MAIN RESULTS: A total of 191 cases were included in the final analysis. Number of biopsies varied by center (5-49 biopsies; mean, 15.8) and by age (2-18 yr; mean, 10.6 yr). The most common classification category in this cohort was Disorders of the Immunocompromised Host (40.8%), and the least common was Disorders of Infancy (4.7%). Immunocompromised patients suffered the highest mortality (52.8%). Additional associations with mortality included mechanical ventilation, worse clinical status at time of biopsy, tachypnea, hemoptysis, and crackles. Pulmonary hypertension was found to be a risk factor for mortality but only in the immunocompetent patients. CONCLUSIONS: In patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease, there were far fewer diagnoses prevalent in infancy and more overlap with adult diagnoses. Immunocompromised patients with diffuse lung disease who underwent lung biopsies had less than 50% survival at time of last follow-up.

Pediatric interstitial lung disease revisited.

The spectrum of pediatric interstitial lung disease (PILD) includes a diverse group of rare disorders characterized by diffuse infiltrates and disordered gas exchange. Children with these conditions typically present with tachypnea, crackles, and hypoxemia. Recent advances have been made in the identification of different types of PILD that are unique to infancy. More exciting has been the discovery of genetic abnormalities of surfactant function, now described in both children and adults. A systematic evaluation of the child presenting with diffuse infiltrates of unknown etiology is essential to the diagnosis. Most often, lung biopsy is required. Current treatment options remain less than satisfactory, and morbidity and mortality remain considerable.

Invasive mechanical ventilation for acute respiratory failure in children with cystic fibrosis: outcome analysis and case-control study.

The outcome for cystic fibrosis (CF) patients requiring intubation and invasive mechanical ventilation (IMV) due to acute respiratory failure (ARF) has been poor. Mortality rates have been reported as high as 60-90%. However, a review of mortality in children has not been published in 20 years. Our objectives were to study outcomes in CF patients requiring IMV due to ARF between 1988-1998, compare recent outcomes with those previously reported, and identify risk factors associated with poor outcome. We additionally attempted to identify factors suggesting an increased risk of developing ARF requiring IMV. A retrospective cohort study design was used, comparing IMV survivors and nonsurvivors with a nested case-control study to identify risk factors for ARF leading to IMV. All patients cared for at our Center who required IMV for ARF between 1988-1998 were identified. Outcome, age, steroid use, forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1)), microbiology, nutritional status, CF-related diabetes (CFRD), liver dysfunction, and history of major hemoptysis (HEM) or pneumothorax (PTX) were recorded. Cases were matched for gender and age with CF controls identified through a clinical database.Thirty-eight episodes of IMV due to ARF were reported in 33 patients. Three subjects underwent IMV on two or more occasions, but only the first episode was included in analysis. Older age was the only factor that was significantly associated with mortality: 9 subjects were <5 years of age (mortality, 22%), while 24 were 5-34 years old (mortality, 75%) (P = 0.013). There was an increased risk of having an episode of ARF requiring IMV in malnourished subjects (OR = 4.2; 95% CI = 1.66-10.51) and in those with a history of HEM (OR = 6.3; 95% CI = 1.75-22.65). Infants and young children with CF requiring IMV due to ARF have a favorable prognosis, whereas those >or=5 years of age suffer significantly higher mortality. Malnutrition and a history of HEM are important risk factors for having an episode of ARF requiring IMV.

Immunocytochemical detection of milk proteins in tracheal aspirates of ventilated infants: a pilot study.

In this study, we evaluated immunocytochemical staining for milk proteins (alpha-lactalbumin and beta-lactoglobulin) in tracheal aspirates of mechanically ventilated infants, and assessed whether this staining technique supported a clinical diagnosis of aspiration in infants receiving orogastric feedings. All newborns requiring mechanical ventilation in the neonatal intensive care unit of a major tertiary care hospital were potential subjects for this study. Tracheal aspirates were obtained prior to the introduction of enteral feeding and at various time points thereafter in newborns requiring mechanical ventilation. Cells were obtained and processed for immunocytochemical staining of alpha-lactalbumin and beta-lactoglobulin. In total, 88 specimens recovered from 34 infants were adequate for staining. Alveolar macrophages recovered from most of the infants who were never fed (true negative controls) did not display immunoreactivity for milk proteins: 4/34 or 12% of infants' aspirates demonstrated presence of milk proteins before enteral feeding was commenced. Tracheal aspirates obtained from 12 infants after introduction of enteral feedings appeared to support clinical and radiological findings suggestive of aspiration events, with positive immunostaining on several occasions. These observations support our work in a murine model and demonstrate that immunocytochemical staining of tracheal aspirates for milk proteins may enhance the ability to diagnose pulmonary aspiration. Further studies are needed to define the clinical significance of our findings and the effects of single and repeated aspiration events on respiratory status.

Desquamative interstitial pneumonia in a child related to cigarette smoke.

An 8-year-old white male was referred to our clinic for a 1-year history of decreased appetite and no weight gain. His entire workup failed to demonstrate cystic fibrosis, or any infectious or immune-related diseases. Chest imaging and clinical picture suggested parenchymal lung disease. Histopathology examination of the video-assisted thoracoscopic biopsy of his lungs showed a desquamative interstitial pneumonia (DIP)-like pattern that resembled that of adult smokers with the same disease. Genes for surfactant proteins B and C and the transporter ABCA3 were all negative. Furthermore, lack of any genetic disorder for surfactant proteins, along with his history of heavy exposure to 10 pack-years of indoor secondhand smoke suggests that this child's DIP is due to secondhand cigarette exposure. He had nearly complete resolution of his symptoms after a year of treatments with pulse steroid and hydroxycholoroquine. To the best of our knowledge this is the first case of cigarette smoke-related DIP reported in a child.

Pulmonary capillaritis in monozygotic twin boys.

Pulmonary hemorrhage can be classified as either proximal or distal (alveolar). Causes of proximal hemorrhage include infection, foreign body aspiration, pulmonary embolus, trauma, vascular malformation, and pulmonary hypertension. Causes of distal or diffuse alveolar hemorrhage are divided by the histologic presence or absence of capillaritis, which is characterized by inflammation of the alveolar interstitium and pulmonary capillary structure. Pulmonary capillaritis is a rare event in children and is associated with higher morbidity and mortality than diffuse alveolar hemorrhage without capillaritis. This is a report of 17-month-old previously healthy monozygotic twins presenting simultaneously with diffuse alveolar hemorrhage, pulmonary capillaritis, and an otherwise negative serologic workup. This suggests a role of genetic predisposition in this rare disease.

Lung transplantation for childhood diffuse lung disease.

BACKGROUND: Pediatric diffuse lung diseases comprise a heterogeneous group of rare lung disorders which may lead to end stage lung disease and referral for lung transplantation. Previous studies are limited by small numbers of patients with specific forms of diffuse lung disease. Children with all forms of diffuse lung disease who underwent lung transplantation at two pediatric centers were evaluated in terms of several pre- and post-transplant factors and compared to children with other end stage lung disorders. METHODS: A retrospective chart review was performed on all patients transplanted between October 1, 2002 and June 15, 2007 at Texas Children's Hospital and St. Louis Children's Hospital. Multiple pre-transplant characteristics and post-transplant morbidities and mortality were compared between diffuse lung disease, cystic fibrosis, and pulmonary vascular disease groups. RESULTS: There were 31 diffuse lung disease (DLD), 57 cystic fibrosis (CF), and 16 pulmonary vascular disease (PVD) patients included in our analysis. Patients with DLD had significantly higher pre-transplant morbidity including lower percent predicted of forced expiratory volume in first second (P = 0.013) and more patients with pulmonary hypertension (P = 0.001) and hypercapnia (P = 0.031). Compared to CF patients, more DLD and PVD patients required invasive ventilation (P = 0.001) and care in the pediatric intensive care unit (P = 0.001). After transplant, there was a difference among the three groups with regards to number of acute allograft rejections but statistical limitations preclude knowing between which group the difference lies. A difference in time to bronchiolitis obliterans was found between the PVD and CF groups but not when compared to the DLD patients. The three groups had similar time to post-transplant lymphoproliferative disease, rate of infections, and survival. CONCLUSION: Lung transplantation is as successful for patients with end stage diffuse lung disease as compared to other lung transplant candidates.