Interstitial Lung Disease In Children Research Articles

Hydroxychloroquine in children with interstitial (diffuse parenchymal) lung diseases.

Hydroxychloroquine (HCQ) is one of the drugs frequently used for the treatment of interstitial lung disease (ILD) in children (chILD). This use is off-label and studies to analyze the effect and safety of HCQ in chILD are lacking. Therefore, a literature research on the usage of chloroquine (CQ) and HCQ in these conditions was done. Eighty-five case reports and small series in the period from 1984 to 2013 were identified in which children with different diagnoses of ILD were treated with CQ or HCQ, sometimes in combination with other medication including steroids. A favorable response to HCQ or CQ was reported in 35 cases, whereas in the other cases the effect was negative or not clear. The dose of HCQ used was between 5 and 10 mg/kg body weight/day (bw/d). No pharmacokinetic studies have been done. The side effect profile in children seemed to be similar to that in adults. Most often gastrointestinal symptoms were reported. Three patients were found developing retinal changes during the treatment with CQ, whereas in none of the patients treated with HCQ retinal changes were reported. Based on retrospective case reports and small series likely to be reported with bias, the use of HCQ in chILD might be classified as safe. As no prospective data on efficacy and safety of HCQ in chILD are available, systematic collection is necessary. This may be achieved by web-based registers like the European Management Platform for Childhood Interstitial Lung Diseases. Prospective and controlled investigations of HCQ in patients with chILD are mandatory.

Genetic Causes of Interstitial Lung Disease in Children

Interstitial lung diseases (ILDs) occur through out childhood and adult life. In neonates and infants, defects in lung development and growth and defects in surfactant production and function are common features with the environmental factors being less important. For older children, genetic background combined with environmental exposure is central to the pathophysiology of ILD. In adults, environmental exposure becomes more critical to mechanism of disease with genetic background becoming less essential. Thus ILDs are often multifactorial in origin but recently molecular genetic defects have been described, especially in children. Thus, genetic testing is a non-invasive investigation that is likely to identify the genetic underpinning of childhood interstitial lung diseases (chILD). This is likely to provide insights into the mechanism of disease, which that may be helpful for treatment and defining the prognosis. This review summarizes genetic defects that can lead to ILDs, and highlights the recent advances in several kinds of chILD.

Genotype-phenotype correlations for infants and children with ABCA3 deficiency.

Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private. To determine genotype-phenotype correlations for recessive ABCA3 mutations. We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001). Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.

Interstitial lung disease in children.

There has been tremendous progress in the approach to childhood interstitial lung diseases (chILD), with particular recognition that interstitial lung disease (ILD) in infants is often distinct from the forms that occur in older children and adults. Diagnosis is challenging because of the rarity of ILD and the fact that the presenting symptoms of ILD often overlap those of common respiratory disorders. This review summarizes the newly published recommendations for diagnosis and management, and highlights the recent scientific advances in several specific forms of chILD. Clinical practice guidelines emphasize the role for chest computed tomography, genetic testing, and lung biopsy in the diagnostic evaluation of children with suspected ILD. Recent studies have better defined the characteristics and molecular understanding of several different forms of ILD, including neuroendocrine cell hyperplasia of infancy and ILD, due to mutations in genes affecting surfactant production and metabolism. Despite significant progress, definitive therapies are often lacking. chILD encompasses a collection of rare, diffuse lung diseases. Timely recognition of children with suspected ILD and initiation of appropriate diagnostic evaluations will facilitate medical management. Systematic approaches to clinical care and further studies are needed to improve the outcomes of children with these rare disorders.

GPs Meet Rare Lung Disorders Task Force factsheet: childhood interstitial lung disease

Definition Childhood interstitial lung disease (chILD) includes a range of rare disorders of the lung parenchyma (and, sometimes, airways) that have certain clinical features in common. Specific conditions within chILD include surfactant protein B or C deficiency, alveolar capillary dysplasia with misalignment of lung veins, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia, hypersensitivity pneumonitis, eosinophilic pneumonia, lymphocytic interstitial pneumonia, alveolar proteinosis, granulomatosis with polyangiitis, sarcoidosis, lung alveolar proteinosis, and Langerhans’ cell histiocytosis. chILD may complicate other disorders including inflammatory bowel disease and liver disease. In many children with chILD, no specific diagnosis can be made. Key messages Think about chILD if a child has chronic, unremitting tachypnoea, retractions, crackles and failure to thrive. Symptoms of early chILD are very unspecific and may be missed unless there is a high level of suspicion. Refer the patient to a specialist centre in paediatric pulmonology. Follow your patient longitudinally in collaboration with the reference centre, and be alert to comorbidities, complications of disease or treatment, or signs of recurrent or worsening lung disease.

A Rare Presentation Of Surfactant Deficiency In a Term Neonate

S A T U R D A Y 1 A Rare Presentation Of Surfactant Deficiency In a Term Neonate Dr. Nisha N. Shah, MD, Dr. Heena Shah, MD, Dr. Kenneth Paris, MD, MPH; LSU Health Sciences Center New Orleans, New Orleans, LA, Louisiana State University, New Orleans, LA, LSU Health Sciences Center, New Orleans, New Orleans, LA. RATIONALE: It is important to consider non infectious, and non allergic causes of chronic pulmonary inflammation in a term neonate. We describe a rare case of surfactant deficiency in a term neonate. METHODS: Surfactant protein C gene sequencing done at JohnsHopkins DNA laboratory. RESULTS: A 5 week old full term female with a history of failure to thrive, formula intolerance, intermittent tachypnea, hypoxia, and leukocytosis presented to our hospital. The patient was born full term via Cesarean section without complication. Serial chest radiography showed persistent bilateral lung infiltrates. An extensive workup showed no underlying cardiac, gastrointestinal, or infectious pathology. After 6 weeks of hospitalization she continued to have leukocytosis, persistent hypoxia on room air, and poor weight gain on elemental formula. Allergic and immunologic workup included negative skin prick testing to cow’s milk, undetectable IgE to cow’s milk, normal immunoglobulin levels, and normal lymphocyte subpopulations. A high resolution CT revealed scattered ground glass opacities concentrated in the lower lobes. Lung biopsy revealed alveolar changes consistent with childhood interstitial lung disease. Genetic testing ultimately revealed an inherited mutation in the gene coding for surfactant C. CONCLUSIONS: A mutational surfactant deficiency can present in the term neonate and lead to the pro-inflammatory cascade causing chronic lung disease well studied in premature neonates. Childhood interstitial lung diseases can be missed in the newborn period. Its non specific presentation can mimic muchmore common causes of respiratory distress. Early interventionwith steroid therapy can delay the progression of disease and improve quality of life.

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Diffuse lung disease in infancy and childhood: expanding the chILD classification

Diffuse parenchymal lung diseases (DPLD) in children comprise a wide spectrum of rare disorders. In 2007 the Children's Interstitial Lung Disease (chILD) Research Cooperative proposed a classification system for DPLD in children <2 years of age. The aims of our study were to determine the utility and reproducibility of this system in children <2 years of age, and test its extension to 18 years of age. Of 211 cases, 93 were <2 years of age at presentation and 58% were included in the chILD classification. In 118 cases aged between 2 and 18 years there was a wider distribution of disorders, overlapping with those seen in adults, necessitating expansion of the chILD classification types to encompass all reviewed cases, in particular patients with 'adult' diffuse lung diseases. Many cases showed mixed histological patterns, overlap often being between groups of disorders more prevalent in infancy. Concordance between reporting pathologists was 90%. The chILD scheme allows classification of conditions more common in children <2 years of age. It can be applied to children of any age, although additional entities need to be included. We propose a more histologically based system for use when assessing biopsies in this context.

Childhood Interstitial Lung Diseases: An 18-year Retrospective Analysis

Childhood interstitial lung diseases (ILD) occur in a variety of clinical contexts. Advances in the understanding of disease pathogenesis and use of standardized terminology have facilitated increased case ascertainment. However, as all studies have been performed at specialized referral centers, the applicability of these findings to general pulmonary practice has been uncertain. The objective of this study was to determine the historical occurrence of childhood ILD to provide information reflecting general pediatric pulmonary practice patterns. Childhood ILD cases seen at Vanderbilt Children's Hospital from 1994 to 2011 were retrospectively reviewed and classified according to the current pediatric diffuse lung disease histopathologic classification system. A total of 93 cases were identified, of which 91.4% were classifiable. A total of 68.8% (64/93) of subjects underwent lung biopsy in their evaluations. The largest classification categories were disorders related to systemic disease processes (24.7%), disorders of the immunocompromised host (24.7%), and disorders more prevalent in infancy (22.6%). Eight cases of neuroendocrine cell hyperplasia of infancy (NEHI) were identified, including 5 that were previously unrecognized before this review. Our findings demonstrate the general scope of childhood ILD and that these cases present within a variety of pediatric subspecialties. Retrospective review was valuable in recognizing more recently described forms of childhood ILD. As a significant portion of cases were classifiable based on clinical, genetic, and/or radiographic criteria, we urge greater consideration to noninvasive diagnostic approaches and suggest modification to the current childhood ILD classification scheme to accommodate the increasing number of cases diagnosed without lung biopsy.

A Mutation in TTF1/NKX2.1 Is Associated With Familial Neuroendocrine Cell Hyperplasia of Infancy

Neuroendocrine cell hyperplasia of infancy (NEHI) is a childhood diffuse lung disease of unknown etiology. We investigated the mechanism for lung disease in a subject whose clinical, imaging, and lung biopsy specimen findings were consistent with NEHI; the subject's extended family and eight other unrelated patients with NEHI were also investigated. The proband's lung biopsy specimen (at age 7 months) and serial CT scans were diagnostic of NEHI. Her mother, an aunt, an uncle, and two first cousins had failure to thrive in infancy and chronic respiratory symptoms that improved with age. Genes associated with autosomal-dominant forms of childhood interstitial lung disease were sequenced. A heterozygous NKX2.1 mutation was identified in the proband and the four other adult family members with histories of childhood lung disease. The mutation results in a nonconservative amino acid substitution in the homeodomain in a codon extensively conserved through evolution. None of these individuals have thyroid disease or movement disorders. NKX2.1 mutations were not identified by sequence analysis in eight other unrelated subjects with NEHI. The nature of the mutation and its segregation with disease support that it is disease-causing. Previously reported NKX2.1 mutations have been associated with "brain-thyroid-lung" syndrome and a spectrum of more severe pulmonary phenotypes. We conclude that genetic mechanisms may cause NEHI and that NKX2.1 mutations may result in, but are not the predominant cause of, this phenotype. We speculate that altered expression of NKX2.1 target genes other than those in the surfactant system may be responsible for the pulmonary pathophysiology of NEHI.

Diagnostic criteria and follow-up in neuroendocrine cell hyperplasia of infancy: a case series

OBJECTIVE: Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease characterized by tachypnea, retractions, crackles, and hypoxia. The aim of this study was to report and discuss the clinical, imaging, and histopathological findings in a series of NEHI cases at a tertiary pediatric hospital, with an emphasis on diagnostic criteria and clinical outcomes. METHODS: Between 2003 and 2011, 12 full-term infants were diagnosed with NEHI, based on clinical and tomographic findings. Those infants were followed for 1-91 months. Four infants were biopsied, and the histopathological specimens were stained with bombesin antibody. RESULTS: In this case series, symptoms appeared at birth in 6 infants and by 3 months of age in the remaining 6. In all of the cases, NEHI was associated with acute respiratory infection. The most common initial chest HRCT findings were ground-glass opacities that were in the middle lobe/lingula in 12 patients and in other medullary areas in 10. Air trapping was the second most common finding, being observed in 7 patients. Follow-up HRCT scans (performed in 10 patients) revealed normal results in 1 patient and improvement in 9. The biopsy findings were nonspecific, and the staining was positive for bombesin in all samples. Confirmation of NEHI was primarily based on clinical and tomographic findings. Symptoms improved during the follow-up period (mean, 41 months). A clinical cure was achieved in 4 patients. CONCLUSIONS: In this sample of patients, the diagnosis of NEHI was made on the basis of the clinical and tomographic findings, independent of the lung biopsy results. Most of the patients showed clinical improvement and persistent tomographic changes during the follow-up period, regardless of the initial severity of the disease or type of treatment.

Interstitial lung disease in children

Children's interstitial lung disease (ILD) includes a wide range of rare respiratory disorders associated with high morbidity and mortality.Genetic factors, systemic disease processes, nonspecific inflammatory or fibrotic patterns of repair seen in a number of clinical settings are involved in the ILD pathogenesis.Specific disorders more prevalent in young children include diffuse developmental disorders, alveolar growth abnormalities, genetic surfactant disorders, pulmonary interstitial glycogenosis and neuroendocrine cell hyperplasia of infancy.It may be difficult to recognize these entities and this can lead to delayed treatment. The diagnostic approach is based on a combination of history/physical examinations, imaging studies, pulmonary function testing, genetic testing, bronchoalveolar lavage (BAL) and in most cases an open lung biopsy.Although some disease types overlap with those seen in adults, in this review emphasis is placed on entities unique to the pediatric population focusing on clinical characteristics, histologic definitions, radiologic–pathologic correlation and therapeutic strategies.

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

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. 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. 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. 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.

Dynamic changes of serum cytokines and prognosis of interstitial lung disease in children

Dynamic changes of serum cytokines and prognosis of interstitial lung disease in children

Diffuse lung disease in children: Summary of a scientific conference

A multi-disciplinary scientific conference focused on diffuse and interstitial lung diseases in children was held in La Jolla, CA in June 2012. The conference brought together clinicians (including Pediatric and Adult Pulmonologists, Neonatologists, Pathologists, and Radiologists), clinical researchers, basic scientists, government agency representatives, patient advocates, as well as children affected by diffuse lung disease (DLD) and their families, to review recent scientific developments and emerging concepts in the pathophysiology of childhood DLD. Invited speakers discussed translational approaches, including genetics and proteomics, epigenetics and epigenomics, models of DLD, including animal models and induced pluripotent stem cells, and regenerative medicine approaches. The presentations of the invited speakers are summarized here.

Inhalation Toxicity of Humidifier Disinfectants as a Risk Factor of Children’s Interstitial Lung Disease in Korea: A Case-Control Study

BackgroundThe occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD.MethodsThis retrospective, 1∶3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire.ResultsThe median age of the affected children (43.8% male) was 26 months (18.25–36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.41–5.90, P = 0.00) were independently associated with an increased risk.ConclusionsThis study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals.

Interstitial lung disease in children

Interstitial lung disease in children

Toxic Inhalational Injury-Associated Interstitial Lung Disease in Children

Interstitial lung disease in children (chILD) is a group of disorders characterized by lung inflammation and interstitial fibrosis. In the past recent years, we noted an outbreak of child in Korea, which is possibly associated with inhalation toxicity. Here, we report a series of cases involving toxic inhalational injury-associated chILD with bronchiolitis obliterans pattern in Korean children. This study included 16 pediatric patients confirmed by lung biopsy and chest computed tomography, between February 2006 and May 2011 at Asan Medical Center Children's Hospital. The most common presenting symptoms were cough and dyspnea. The median age at presentation was 26 months (range: 12-47 months), with high mortality (44%). Histopathological analysis showed bronchiolar destruction and centrilobular distribution of alveolar destruction by inflammatory and fibroproliferative process with subpleural sparing. Chest computed tomography showed ground-glass opacities and consolidation in the early phase and diffuse centrilobular nodular opacity in the late phase. Air leak with severe respiratory difficulty was associated with poor prognosis. Although respiratory chemicals such as humidifier disinfectants were strongly considered as a cause of this disease, further studies are needed to understand the etiology and pathophysiology of the disease to improve the prognosis and allow early diagnosis and treatment.

The Value of Retrospective Case Review in Childhood Interstitial Lung Disease

The Value of Retrospective Case Review in Childhood Interstitial Lung Disease

Diffuse and interstitial lung disease and childhood rheumatologic disorders

Advances in genetics and clinical diagnostics, along with recently described clinical entities and refined classification schemes, have improved our understanding of diffuse and interstitial lung diseases in children. This review presents recent updates in these disorders in the context of systemic inflammatory conditions. Classification of childhood diffuse lung disease (DLD) using adult paradigms is not useful. Distinct clinical-pathologic entities exist in children. Infants are more likely to present with genetic and developmental disorders, and older children with inflammatory and immune-mediated conditions. A combination of clinical evaluation, high-resolution computed tomography scanning, pulmonary function testing and serology, with bronchoscopy and surgical lung biopsy in selected cases, is most useful in the evaluation of DLD in the context of rheumatologic conditions. Common causes of DLD, such as infection, especially in the setting of immunodeficiency, must be ruled out. Optimal therapy for specific disorders will require careful analysis of data from national registries. Emerging use of biomarkers and high-throughput molecular analysis will yield novel insight into these disorders. In the setting of known or suspected rheumatologic disorders, diagnosis and management of DLD are challenging, and require close collaboration among rheumatologists, pulmonologists, and other specialists.