Interstitial Lung Disease In Children Research Articles

The pathogenesis of interstitial lung diseases in children.

The pathological changes observed in interstitial lung disease (ILD) are characterised by derangements of the alveolar walls. For a long time, the prevailing hypothesis has emphasised the key role of a persistent alveolitis that injures the lung and modulates fibrogenesis, regardless of initiating agents. The current concept on ILD pathogenesis relies on an epithelial/fibroblastic pathway with epithelial injury and activation, formation of subepithelial fibroblast/myofibroblast foci and excessive accumulation of extracellular matrix. An essential step in the restoration of alveolar integrity is the rapid re-epithelialisation of the altered surface, mainly through epithelial proliferation and migration. In the context of lung growth and development in paediatric ILD, it is suggested that the programmed production of mitogenic factors may promote the process of re-epithelialisation and may help to counteract the altered secretion of mediators involved in migration and proliferation of fibroblasts and differentiation into myofibroblasts. This is supported by clinical observations indicating that paediatric ILD is more responsive to therapeutic strategies than adult ILD.

Serum KL‐6 levels in pediatric patients: Reference values for children and levels in pneumonia, asthma, and measles patients

Serum KL-6 reflects alveolar damage and regeneration of type II pneumocytes, indicating disease activity in various interstitial lung diseases. We conducted a descriptive and observational multiple case-control study to determine the distribution of serum KL-6 levels in pediatric patients with or without respiratory diseases. Subjects were recruited from the patients of a teaching hospital in the suburb of Tokyo. A consecutive series of 401 children (0-16 years old) underwent blood sampling for many clinical reasons. They comprised the following four groups: pneumonia (n = 96), bronchial asthma (n = 101), measles (n = 102), and nonrespiratory diseases (n = 102) as a control group. Standard upper limits of serum KL-6 in a group of children with nonrespiratory disease were 250 U/mL, or half the adult level. No gender or age differences were observed. Elevated serum KL-6 concentrations were observed in severe pneumonia, acute exacerbations of asthma, and measles pneumonia. In the measles group, KL-6 values reflected the presence and severity of complicating pneumonia. We conclude that serum KL-6 levels exceeding 250 U/mL were rarely observed in children without respiratory diseases. In contrast, a substantial proportion of children with common respiratory diseases showed mild to moderate increases in serum KL-6 levels. Elevated serum KL-6 in these children may reflect the presence of alveolar damage, followed by regeneration of type II pneumocytes. However, in order to use serum KL-6 as a marker of interstitial lung diseases in children, a cutoff level should be determined separately.

Evaluation of Interstitial Lung Disease in Children

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Pediatric bronchoscopy.

Diagnostic flexible endoscopy for pediatric respiratory diseases is performed in many centers. Technical advances have resulted in performance of interventional bronchoscopies, and new diagnostic indications are being explored. Indications with documented clinical benefit include congenital or acquired progressive or unexplained airway obstruction. Pulmonary infections in immunodeficient children who do not respond to empirical antibiotic treatment may be diagnosed by bronchoscopy and bronchoalveolar lavage (BAL). The potential usefulness of bronchoscopy and BAL for managing chronic cough, wheeze, or selected cases with asthma or cystic fibrosis requires further study. The use of transbronchial biopsies (TBB) is established in pediatric lung transplantation. The role of TBB in the diagnosis of chronic interstitial lung disease in children remains to be determined. For a number of interventional applications, rigid endoscopy is required, and pediatric bronchoscopists should be trained in its use. Complications in pediatric bronchoscopy are rare, but severe nosocomial infection or overdosing with local anesthetics has occurred. The issues of quality control, video documentation, interobserver variability of findings, and educational standards will have to be addressed in the future as bronchoscopy use becomes less restricted to only large pediatric pulmonary units.

Interstitial lung disease in children: a multicentre survey on diagnostic approach

Chronic interstitial lung disease (ILD) is a rare disorder in the paediatric age group, with a poor prognosis. The diagnostic approach to ILD is based on more or less invasive methods. This study was implemented to verify which methods are the most often used in children. Questionnaires (333) were sent to members of the European Respiratory Society Paediatric Assembly belonging to 187 European and non-European centres. Questions concerned the use of noninvasive diagnostic methods, e.g. history taking, physical examination, routine laboratory tests, respiratory function tests and radiology (chest radiography, high-resolution computed tomography (HRCT)), and the use of invasive techniques such as bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), open lung biopsy (OLB), video-assisted thoracoscopic biopsy (VAT) and HRCT with fine-needle aspiration biopsy (FNAB). Thirty eight centres returned the questionnaires and 131 children with ILD were studied. A diagnosis of ILD was achieved in five (3.8%) patients using noninvasive techniques alone. Using the various biopsy methods, histological assessment was performed on a total of 98 (74.8%) children. The most frequently used invasive technique both alone and in combination was BAL (83, 63.3%), followed by OLB (64, 48.8%), TBB (26, 19.8%) and VAT (11, 8.4%); FNAB was used in one patient. In conclusion a diagnosis of interstitial lung disease was reached on the basis of aetiological and/or histological findings in 117 (89%) of the 131 patients studied.

Computed Tomography of Diffuse Interstitial Lung Disease in Children: Review

Unlike diseases of the airways, interstitial lung diseases in childhood are exceedingly rare and are usually associated with significant morbidity and mortality. Interstitial lung disease in the paediatric age group is a particular diagnostic challenge because the clinical presentation and radiographic features are so non-specific. High resolution computed tomography (HRCT) has proved its worth in adults with interstitial lung disease and has a role, albeit more limited, in the non-invasive evaluation of paediatric interstitial lung disease.Koh, D. M. & Hansell, D. M. (2000). Clinical Radiology55, 659–667.

Current concepts on interstitial lung disease in children.

Pediatric interstitial lung disease comprises a diverse group of rare conditions characterized by an infiltrative process, abnormal gas exchange, and restrictive lung disease. Although the disorder is similar to its adult counterpart, its course is complicated by the continued need for lung growth and differentiation in infants and children. Knowledge about the pathogenesis, prognosis, and treatment of pediatric interstitial lung disease is limited. Investigators are focusing on defining the cellular mediators of the interstitial damage and describing the role of viral infections in and possible genetic predisposition to interstitial lung disease. Clinicians continue to define the various types of interstitial lung disease and to evaluate the roles of bronchoalveolar lavage, radiography, and biopsy in diagnosis. Together, investigators are working toward the development of specific, targeted therapy that will reduce the significant morbidity and mortality seen in pediatric interstitial lung disease.

Interstitial lung disease in children: An overview

Interstitial lung disease in children: An overview

Interstitial lung disease in children: An overview

Interstitial lung disease in children: An overview

Chronic interstitial lung disease in children: Response to high‐dose intravenous methylprednisolone pulses

The prognosis for children with chronic interstitial lung disease is poor and the mortality rate is high, especially in infants. This explains the many therapeutical protocols which have been proposed and investigated by several authors. In the present work, we evaluated the response of three infants with idiopathic pulmonary fibrosis to high-dose intravenous prednisolone pulses. The patients were referred to the department at the age of 4, 17, and 3 months, respectively. The diagnosis was confirmed by open lung biopsy and intravenous pulse methyl prednisolone therapy was started with the following protocol: 300 mg/m2 methylprednisolone daily for 3 days, repeated every 4 to 6 weeks. Because of the extreme severity of the respiratory distress at the time of diagnosis, the intravenous pulse treatments were initially complemented by oral prednisone. Clinical improvement was noticed within 6 months with progressive correction of hypoxemia. After follow-up for 3.5 to 4 years, with a total number of pulses of 37, 26, and 32, respectively, the children are symptom-free and do not require oxygen supplementation. During this period, no side effects and no adrenal insufficiency could be documented. Based on current knowledge of steroid action, it can be speculated that the response to intermittent high-dose intravenous methylprednisolone may explain the ability of this mode of hormone administration to maintain an adequate level of glucocorticoid receptor expression. More information and trials through multicenter collaborations are needed to assess therapeutical protocols of repeated high-dose intravenous steroid treatment. Pediatr Pulmonol. 1998; 26:332–338. © 1998 Wiley-Liss, Inc.

Chronic interstitial lung disease in children: response to high-dose intravenous methylprednisolone pulses.

The prognosis for children with chronic interstitial lung disease is poor and the mortality rate is high, especially in infants. This explains the many therapeutical protocols which have been proposed and investigated by several authors. In the present work, we evaluated the response of three infants with idiopathic pulmonary fibrosis to high-dose intravenous prednisolone pulses. The patients were referred to the department at the age of 4, 17, and 3 months, respectively. The diagnosis was confirmed by open lung biopsy and intravenous pulse methyl prednisolone therapy was started with the following protocol: 300 mg/m2 methylprednisolone daily for 3 days, repeated every 4 to 6 weeks. Because of the extreme severity of the respiratory distress at the time of diagnosis, the intravenous pulse treatments were initially complemented by oral prednisone. Clinical improvement was noticed within 6 months with progressive correction of hypoxemia. After follow-up for 3.5 to 4 years, with a total number of pulses of 37, 26, and 32, respectively, the children are symptom-free and do not require oxygen supplementation. During this period, no side effects and no adrenal insufficiency could be documented. Based on current knowledge of steroid action, it can be speculated that the response to intermittent high-dose intravenous methylprednisolone may explain the ability of this mode of hormone administration to maintain an adequate level of glucocorticoid receptor expression. More information and trials through multicenter collaborations are needed to assess therapeutical protocols of repeated high-dose intravenous steroid treatment.

Chronic interstitial lung diseases in childhood--an overview

The spectrum of chronic interstitial lung disease in children includes a large and heterogeneous group of rare disorders. This paper reviews these disorders by focussing on basic pathophysiological mechanisms, and by discussing the difficulties in the classification of these diseases. Diagnostic and therapeutic approaches are also listed. The overall prognosis is dubious and mortality remains high.

Interstitial lung disease.

Interstitial lung disease in children is a complex group of disorders whose etiology and pathogenesis is not entirely clear. Although the basic pathogenesis has been extrapolated from adult studies, its relevance in the pediatric population can be questioned. Several classifications of this condition have been put forward but Liebow's histologic classification is well accepted. Clinical manifestations are non-specific and can vary from no symptoms and a positive chest X-ray to more characteristic signs and symptoms. The triad of tachypnea, intercostal retractions and dry crackles is characteristic. Chest roentgenograms are a useful diagnostic tool and CT scans help to stage disease severity. Spirometry classically shows a restrictive pattern. Lung biopsy is the gold standard for establishing a diagnosis. Corticosteroids are the cornerstone of treatment in this condition. Thus, in view of the multifactorial nature of this disease, more extensive multi-centre prospective studies are required in order to better understand this rather complex group of disorders.

BAL in Children: A Controlled Study of Differential Cytology and Cytokine Expression Profiles by Alveolar Cells in Pediatric Sarcoidosis

<h3>Study objective</h3> The development of BAL in children for both research and clinical purposes has been limited so far by the difficulty in establishing reference values. The aim of the study was (1) to define composition of BAL cellular components in control children and to evaluate the ability of these cells to express various cytokines, and (2) to study modifications of differential cytology and BAL cell cytokine responses in children with interstitial lung disorders. <h3>Populations and methods</h3> Two groups were investigated: a control group of 16 children who were concluded to be free of parenchymal lung disease after complete pulmonary investigation, and a group of 11 children with pulmonary sarcoidosis. Differential cytology was evaluated by standard techniques. BAL cell cytokine expression was studied at the level of messenger RNA (mRNA) by reverse transcription-polymerase chain reaction (RT-PCR) methods. <h3>Results</h3> In the control group, differential cell counts appeared to be similar to values reported in adult populations with normal distribution of the data and no influence of age. In this group, no transcripts for interleukin-1β (IL-lβ), tumor necrosis factor-a (TNF-a), IL-6, and tranforming growth factor-β (TGF-P) could be detected. In children with sarcoidosis, different profiles of IL-1β, TNF-α, IL-6, and TGF- β expression were individualized which seemed to be related to the activity and/or severity of the disease, IL-6 and TGF-β mRNA being observed only in the more severe forms. <h3>Conclusion</h3> These data provide information on BAL cell number and function in children. Characterization of BAL cytokine expression patterns during the course of interstitial lung diseases in children may be of great interest for evaluation of disease activity and/or severity and therefore for planning of therapy.

Role of bronchoalveolar lavage in children with lung disease

The aim of the present study was to evaluate the clinical role of bronchoscopic and nonbronchoscopic bronchoalveolar lavage (BAL) in the diagnosis of infectious and interstitial lung disease in children. BAL was performed using three 1 mL.kg-1 aliquots of normal saline, with the flexible bronchoscope (Olympus 3.6 or 4.8 mm) wedged in a segmental or subsegmental bronchus of the lobe that showed most abnormality on chest radiograph. In seven children with severe diffuse lung disease who were intubated, a nonbronchoscopic suction catheter lavage was performed. Fluid cultures and cellularity were evaluated using identical methods for both techniques. Between January 1993 and April 1994, 41 BAL were performed in 32 children aged 2 months to 17 yrs (median 8 yrs). Of these lavages, 14 were in heart and heart-lung transplant recipients, 11 in children known to be immunocompromised, and 16 in children who had a lung biopsy for interstitial lung disease or who had presumed infective lung disease. Transbronchial biopsies (TBB) or open lung biopsies were performed coincident with 19 BAL procedures. In all transplant recipients without clinical symptoms, BAL and TBB cultures were negative and BAL cellularity was normal. TBB did not reveal infection or rejection in any of these patients. A diagnosis of infection was made by BAL in 1 out of 8 transplant recipients with clinical symptoms, and a diagnosis of rejection was made by TBB in 3 out of 8 patients. In 6 out of 11 BAL in immunocompromised children, an infectious agent was found in the BAL fluid. In three other patients who had an open lung biopsy, an interstitial lung disease was diagnosed. In these patients, BAL was abnormal but not diagnostic. In summary, BAL proved helpful in the diagnosis of infective lung disease, but had little value in the diagnosis of rejection or parenchymal noninfective lung disease in children.

Chloroquine treatment of interstitial lung disease in children

Seven children aged 3 months to 11 years with histologically confirmed interstitial lung disease (ILD) [6 with desquamative interstitial pneumonitis (DIP) and 1 with chronic interstitial pneumonitis] were treated with chloroquine, 10 mg/kg/day. One patient, diagnosed late in the course of the disease, died after three weeks of treatment, despite the addition of systemic corticosteroids. Another patient responded to combined therapy with chloroquine and prednisone and had a normal lung biopsy after 6 months of treatment. He underwent surgical repair of mitral valve stenosis and died after extensive brain infarction. The other 5 patients responded well to chloroquine therapy with major improvement in oxygenation within a few weeks and in lung function over the next few months. They remained well clinically and physiologically, including a normal response to incremental exercise, during a mean follow-up period of 9.8 years (range 3.5 to 15.7 years). None of the patients has developed retinopathy or any other ocular complication. Bronchoalveolar lavage was a useful tool for evaluation of the activity of the disease (predominance of neutrophils) in 3 out of 4 patients. We suggest that chloroquine should be considered as an effective treatment in ILD in children. Incremental exercise test may be helpful for routine follow-up and evaluation of the efficacy of a specific treatment.

280 HYDROXYCHLOROQUINE IN THE TREATMENT OF CHRONIC

We report on our experience in 8 patients with different forms of chronic interstitial lung disease. These included lymphocytic interstitial pneumonitis and chronic bronchiolitis. Clinical presentation consisted in tachypnoea, cyanosis, cough, crepitant rales and failure to thrive. Diagnostic work up included lung function studies in all patients, bronchoscopy with bronchoalveolar lavage (BAL) in 7 patients and open lung biopsy in 4 patients. Therapy included oral and inhaled steroids, inhalation with bronchodilators and oral hydroxychloroquine. While most of the patients did not respond to steroids alone, hydroxychloroquine improved the clinical and laboratory findings in a majority of our patients. Conclusion: Further controlled studies are required for propper evaluation of the effect of hydroxychloroquine in the treatment of chronic interstitial lung disease in children.

Interstitial Lung Disease in Children

Interstitial lung disease in children is a heterogeneous group of disorders of both known and unknown causes that share a common histologic characteristic (i.e., inflammation of the pulmonary interstitium that may resolve completely, partially, or progress to derangement of alveolar structures with varying degrees of fibrosis). The inflammatory process, evoked as a result of injury to alveolar epithelium and/or the endothelium, is responsible for alveolar wall thickening that is the histologic marker of ILD. This article extrapolates some of the known pathogenic mechanisms of ILD from adult and animal models and applies this information for a better understanding of the pathogenesis of ILD in children. The clinical manifestations vary and are often subtle and nonspecific. There is no consensus on specific criteria for the clinical diagnosis of ILD in children. There are no pathognomonic laboratory criteria for the diagnosis of ILD in children other than the characteristic findings on histologic examination of the lung. It is important to make the diagnosis early to minimize lung damage. Therapy is directed toward the reduction of the inflammatory response to minimize or prevent the progression to fibrosis. ILD suffers from lack of uniform guidelines for diagnostic evaluation, therapy, and prognostic indicators essential for critical monitoring of disease activity. No one medical center has enough cases of ILD in children to allow objective evaluation of a significant number of cases with adequate longitudinal follow-up to determine guidelines for optimal management and to identify accurate prognostic indicators. The organization of a multicenter approach will guide us towards a better understanding of ILD in children.

Interstitial Lung Disease in Children: An Orphan Lung Disease

Interstitial lung disease (ILD) in children represents a heterogeneous group of disorders that result from inflammation of the pulmonary interstitium and perialveolar tissues and share common histologic, radiologic, and clinical characteristics. The histologic marker of ILD, thickening of the alveolar wall, result from responses of the lung to injury from known and unknown causes with recruitment of inflammatory and immunoregulatory cells. The inflammatory responses in the pulmonary interstitium can be completely or partially reversible or can progress to flbrosis and/or to irreversible "end-stage lung" disease. Unlike asthma, another inflammatory disease of the respiratory system, ILD in children has not attracted enough interest or financial support for critical scientific efforts to advance the knowledge of this "orphan lung disease." This review emphasizes the pathogenesis, classification, diagnostic evaluation, and general principles of monitoring and treatment.

Chronic interstitial lung disease in children.

Chronic interstitial lung disease in children.