Megan K. Dishop

Pulmonary Manifestations in Children with Invasive Community-Acquired Staphylococcus aureus Infection

BACKGROUND Primary pneumonia and metastatic pulmonary infection have become more common in patients with invasive community-acquired Staphylococcus aureus disease at Texas Childrens Hospital (TCH; Houston). METHODS In this study, we sought to describe pulmonary involvement in children with community-acquired S. aureus invasive infection and to determine whether the presence of genes encoding Panton-Valentine leukocidin (PVL) (luk-S-PV and luk-F-PV) and collagen adhesin (cna) is correlated with pulmonary manifestations. Patients with invasive staphylococcal infections admitted to TCH between 1 August 2001 and 30 June 2004 were studied. Chest imaging and postmortem examination reports were reviewed. Isolates were tested for the presence of genes encoding PVL and collagen adhesin by PCR. RESULTS A total of 47 of 70 patients with community-acquired methicillin-resistant S. aureus (MRSA) infection had abnormal pulmonary imaging findings, compared with 12 of 43 patients with community-acquired methicillin-susceptible S. aureus (MSSA) infection (P < .001). Pneumonia and/or empyema, in addition to septic emboli, were the most common findings. Metastatic pulmonary disease occurred more frequently among patients with osteomyelitis. Severe necrotizing pneumonia was present in 3 children coinfected with influenza and parainfluenza virus. The presence of genes encoding PVL was investigated in 67 MRSA and 36 MSSA isolates. Abnormal chest imaging findings were observed for 51 of 80 patients with PVL-positive isolates, compared with 2 of 23 patients with PVL-negative isolates (P < .001). Only 2 isolates (both of which were MSSA) from patients with abnormal chest radiograph findings carried cna. PVL remained independently associated with abnormal chest imaging findings in patients with secondary pneumonia in a multivariate analysis (P = .03). CONCLUSIONS Pulmonary involvement is commonly observed in patients with invasive community-acquired S. aureus infections. Community-acquired MRSA may cause primary community-acquired pneumonia, as well as metastatic pulmonary disease. The presence of genes encoding PVL is highly associated with pulmonary involvement by S. aureus.

Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA

Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.

Clinical, radiological and pathological features of ABCA3 mutations in children

Background: Mutations in the ABCA3 gene can result in fatal surfactant deficiency in term newborn infants and chronic interstitial lung disease in older children. Previous studies on ABCA3 mutations have focused primarily on the genetic abnormalities and reported limited clinical information about the resultant disease. A study was undertaken to analyse systematically the clinical presentation, pulmonary function, diagnostic imaging, pathological features and outcomes of children with ABCA3 mutations. Methods: The records of nine children with ABCA3 mutations evaluated at Texas Children’s Hospital between 1992 and 2005 were reviewed and their current clinical status updated. Previous diagnostic imaging studies and lung biopsy specimens were re-examined. The results of DNA analyses were confirmed. Results: Age at symptom onset ranged from birth to 4 years. Cough, crackles, failure to thrive and clubbing were frequent findings. Mean lung function was low but tended to remain static. CT scans commonly revealed ground-glass opacification, septal thickening, parenchymal cysts and pectus excavatum. Histopathological patterns included pulmonary alveolar proteinosis, desquamative interstitial pneumonitis and non-specific interstitial pneumonitis, and varied with age. Dense abnormalities of lamellar bodies, characteristic of ABCA3 mutations, were seen by electron microscopy in all adequate specimens. Outcomes varied with the age at which the severity of lung disease warranted open lung biopsy, and some patients have had prolonged survival without lung transplantation. Conclusions: The presentation and course of interstitial lung disease due to ABCA3 mutations are variable, and open lung biopsy and genetic testing are warranted early in the evaluation of children with a consistent clinical picture.

Extending the phenotypes associated with DICER1 mutations

DICER1 is crucial for embryogenesis and early development. Forty different heterozygous germline DICER1 mutations have been reported worldwide in 42 probands that developed as children or young adults, pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord‐stromal tumors (especially Sertoli‐Leydig cell tumor [SLCT]), and/or multinodular goiter (MNG). We report DICER1 mutations in seven additional families that manifested uterine cervix embryonal rhabdomyosarcoma (cERMS, four cases) and primitive neuroectodermal tumor (cPNET, one case), Wilms tumor (WT, three cases), pulmonary sequestration (PS, one case), and juvenile intestinal polyp (one case). One carrier developed (age 25 years) a pleomorphic sarcoma of the thigh; another carrier had transposition of great arteries (TGA). These observations show that cERMS, cPNET, WT, PS, and juvenile polyps fall within the spectrum of DICER1‐related diseases. DICER1 appears to be the first gene implicated in the etiology of cERMS, cPNET, and PS. Young adulthood sarcomas and perhaps congenital malformations such as TGA may also be associated. 32:1381–1384, 2011. ©2011 Wiley Periodicals, Inc.

Primary and Metastatic Lung Tumors in the Pediatric Population: A Review and 25-Year Experience at a Large Children's Hospital

CONTEXT Primary lung neoplasms are rare in children, but they comprise a broad and interesting spectrum of lesions, some of which are familiar from other tissue sites, and some of which are unique to the pediatric lung. OBJECTIVE To determine the relative incidence of primary and metastatic lung tumors in children and adolescents through a single-institution case series, to compare these data to reports in the medical literature, to discuss the clinical and pathologic features of primary tumors of the tracheobronchial tree and lung parenchyma in children, and to provide recommendations for handling pediatric lung cysts and tumors. DATA SOURCES A 25-year single institutional experience with pediatric lung tumors, based on surgical biopsies and resections at Texas Childrens Hospital from June 1982 to May 2007, an additional 40 lung tumors referred in consultation, and a review of the medical literature. CONCLUSIONS A total of 204 pediatric lung tumors were diagnosed at our institution, including 20 primary benign lesions (9.8%), 14 primary malignant lesions (6.9%), and 170 secondary lung lesions (83.3%). The ratio of primary benign to primary malignant to secondary malignant neoplasms is 1.4:1:11.6. The common types of lung cancer in adults are exceptional occurrences in the pediatric population. The most common primary lung malignancies in children are pleuropulmonary blastoma and carcinoid tumor. Other primary pediatric lung tumors include congenital peribronchial myofibroblastic tumor and other myofibroblastic lesions, sarcomas, carcinoma, and mesothelioma. Children with primary or acquired immunodeficiency are at risk for Epstein-Barr virus-related smooth muscle tumors, lymphoma, and lymphoproliferative disorders. Metastatic lung tumors are relatively common in children and also comprise a spectrum of neoplasia distinct from the adult population.

Successful treatment of inflammatory myofibroblastic tumor with malignant transformation by surgical resection and chemotherapy.

Inflammatory myofibroblastic tumor (IMT) is a tumor composed of myofibroblasts and a mixed inflammatory infiltrate that rarely undergoes malignant transformation. The authors present the case of a 7-year-old boy with an abdominal mass diagnosed as IMT with malignant transformation. The tumor recurred twice after attempts at resection and was initially treated with vincristine and etoposide. After a third recurrence and incomplete resection, he was treated with cisplatin, Adriamycin, and methotrexate. He is disease-free after 2 years, representing successful combined surgery and chemotherapy in the treatment of malignant IMT. The use of chemotherapy for aggressive myofibroblastic tumors is reviewed.

Successful Treatment of Bronchiolitis Obliterans in a Bone Marrow Transplant Patient With Tumor Necrosis Factor-α Blockade

Bronchiolitis obliterans (BO) in children is a rare, inflammatory/fibrosing process involving the small airways that often results in progressive, irreversible obstructive pulmonary disease. Because treatment has focused mainly on supportive care and generally unsuccessful immunosuppression, children with BO experience significant morbidity and mortality. We report a case of biopsy-proven BO after bone marrow transplantation in a child who, after failed corticosteroid therapy, was treated with infliximab, a monoclonal antibody with binding specificity for human tumor necrosis factor-α. With initiation of treatment, her pulmonary symptoms and radiographic and spirometric evidence of BO resolved. Nine months later, she remains asymptomatic and shows no evidence of pulmonary decompensation. This case illustrates a successful treatment of BO with selective tumor necrosis factor-α blockade.

A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathology co-operative group.

This is the first of a series on pediatric pulmonary disease that will appear as Perspectives in Pediatric Pathology over the coming months. The series will include practical issues, such as this protocol for handling lung biopsies and another on bronchoalveolar lavage in childhood, as well as reviews of advances in various areas in pediatric pulmonary pathology. It has been 11 years since the last Perspectives on pulmonary disease. Much has happened since then in this area, and this collection will highlight some emerging and rapidly advancing areas in pediatric lung disease. These will include a review of molecular mechanisms of lung development, and another of mechanisms of pulmonary vascular development. The surfactant system and its disorders, as well as recent advances in the biology of the pulmonary neuroendocrine system and mechanisms of respiratory viral disease, will be addressed. Articles on pulmonary hypertension, pulmonary neoplasia, and pediatric lung transplantation, with their implications for the pediatric pathologist, are also planned. The contributors to this series are a diverse group with special interests and expertise in these areas. As Dr. William Thurlbeck noted in his foreword to the previous volume, Pulmonary Disease, volume 18 of Perspectives in Pediatric Pathology, pediatric pathology had been largely concerned with phenomenology, rather than with mechanisms, model systems, and experimental investigation. I think he would have been pleased to see the changes that have occurred over the past 10 years in pediatric lung biology and pathology in particular, because these were particularly favored interests of his later years.

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

BACKGROUND Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. METHODS Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available. RESULTS We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth. CONCLUSIONS Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease.

Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies.

Thoracoscopic and open lung biopsies are being performed with increasing frequency in neonates and infants and are an important component of the diagnostic evaluation of respiratory compromise in these very young children. Diffuse lung disease in infancy includes a wide spectrum of developmental, genetic, inflammatory, infectious, and reactive disorders. The majority of the entities diagnosed in infancy (68%) in this retrospective lung biopsy series are seen almost exclusively in this age group and not in older children and adults. These include primary disorders of pulmonary and pulmonary vascular development, secondary disorders affecting prenatal and/ or postnatal lung growth, genetic disorders of surfactant function, pulmonary interstitial glycogenosis, and neuroendocrine cell hyperplasia of infancy. Although the diagnostic approach to infant lung biopsies is guided primarily by the clinical history and imaging findings, all cases require careful assessment of alveolar growth, vascular architecture, interstitial cellularity, and histologic patterns associated with genetic abnormalities of surfactant metabolism. Recognition of one or more of these processes assists not only in treatment planning but also in further diagnostic evaluation and prognostication and may have implications for subsequent siblings and other family members. In this study, we have applied a classification system developed by a North American multicenter multidisciplinary group to lung biopsies seen at our institution and have used this material to describe and illustrate the spectrum of diffuse lung disease in infancy.