Pleuroparenchymal fibroelastosis in an 8-year old treated for neuroblastoma

Abstract

Pleuroparenchymal fibroelastosis (PPFE), which is primarily diagnosed in adults, is a progressive lung pathology associated with significant morbidity and mortality. PPFE is characterized by pleural and subpleural parenchymal disease causing dyspnea, cough, and recurrent pneumothoraces. PPFE can be precipitated by autoimmune disorders, recurrent respiratory infections, chemotherapy, and transplant. We describe the youngest recorded patient to develop PPFE, whose symptoms began several years after treatment for neuroblastoma. Her symptoms were initially mistaken for worsening asthma, and multiple comorbidities developed during the prolonged time to recognition of PPFE and she progressed to fatal lung disease before potentially curative lung transplantation could occur.

1 |. INTRODUCTION

Interstitial lung disease is rare in children, and most develop symptoms of cough, tachypnea, and exertional dyspnea months to years before a diagnosis is confirmed. The overall prevalence of interstitial lung disease in pediatrics is not known, and there are neither standardized definitions nor robust reporting systems to help clinicians understand the impact on children. Here we report a patient who was diagnosed with pleuroparenchymal fibroelastosis (PPFE), a type of interstitial lung disease not previously described in young children.

2 |. CASE DESCRIPTION

The patient was diagnosed at age 3 with stage four, high-risk neuroblastoma. Her treatment consisted of six cycles of induction chemotherapy including cisplatin, etoposide, vincristine, cyclophosphamide, doxorubicin, and topotecan per Children’s Oncology Group (COG) protocol ANBL0532.¹ She achieved a complete response and proceeded with conditioning chemotherapy with carboplatin, etoposide, and melphalan followed by autologous stem cell rescue and radiation to her resected adrenal tumor bed. She then received immunotherapy and retinoic acid per ANBL0032.² Two years after completing therapy, she developed recurrent cough. Following assessment by pulmonology, she was given a therapeutic trial of glucocorticoids, bronchodilators, and inhaled corticosteroids for presumptive asthma with minimal response. Three months after the start of her cough, she underwent bronchoscopy, which was nondiagnostic. She had chest CT at this time which showed patchy atelectasis and scarring at the apices bilaterally. She had frequent hospitalizations due to respiratory distress, hypoxia, and failure to thrive, showing some improvement in tachypnea with supplemental oxygen. Echocardiogram 14 months after the bronchoscopy revealed elevated right ventricular pressures that were approximately half of systemic pressures, suggestive of pulmonary hypertension. There were no pulmonary venous abnormalities. At this time, she was noted to be cachectic, tachypneic, and had mild finger clubbing. Her chest CT scan was repeated following the echocardiogram report and revealed interlobular septal thickening, apical scarring, and interval worsening consistent with a probable diagnosis of PPFE (Figure 1). A multidisciplinary team that included pulmonology, cardiology, critical care, oncology, and surgery determined that definitive therapy necessitated a referral for lung transplantation assessment. As she was cachectic (<0.1 percentile) with very poor nutritional status (Figure 2), she was determined to be an unsuitable candidate for lung transplantation. Therefore, gastrostomy tube feedings were initiated with the hope to improve her nutrition. During this course, her clinical condition deteriorated with worsening respiratory distress, progressive hypoxemia, and pulmonary hypertension necessitating mechanical ventilation. She then developed multiple bilateral pneumothoraces refractory to symptomatic therapy and died shortly after she was 5 years from completion of treatment for neuroblastoma. Autopsy findings confirmed PPFE. On gross examination, the lungs were bilaterally involved with fibrous-appearing thickening of the peripheral aspect of the parenchyma, variably involving all lobes. Hematoxylin and eosin stain demonstrated fibroelastotic thickening of the pleura and subpleura as well as some fibrotic bands extending centrally with entrapment of some alveoli. Trichrome and Verhoeff’s histochemical staining supported the diagnosis. In addition, there was mild to moderate pulmonary arterial hypertensive changes. There was no evidence of recurrent or metastatic neuroblastoma.

FIGURE 1.

Multiple coronal chest computerized tomography images show progressive biapical pleural and pulmonary fibrosis/scarring consistent with pleuroparenchymal fibroelasosis (A: July 2015, B: January 2016, C: July 2017, D: April 2018)

FIGURE 2.

Sequence of clinical events including treatment, patient clinical symptoms and management along with patient’s weight changes

3 |. DISCUSSION

In 2004, a distinct form of pulmonary fibrosis was identified in five adult patients with progressive lung disease who had elastic fiber proliferation seen on histology from lung biopsies.³ The first recognized cases of the newly described Idiopathic PPFE had the clinical constellation of symptoms including dry cough, exertional dyspnea, weight loss, flat chest, and pneumothoraces. While some case reports describe PPFE developing in otherwise healthy individuals, most patients presented after exposure to chemotherapy, radiation, or transplant surgery. Median reported age of presentation in the literature is between 46 and 60 years,⁴ however, there are case reports of younger individuals, with the youngest being 14-years old, who developed features similar to PPFE after exposure to cyclophosphamide⁵ and a 16-year old with idiopathic PPFE.⁶ While more patients with high-risk neuroblastoma are surviving, thanks to intensive multimodal chemotherapy,¹ long-term follow-up studies have revealed that survivors are at a higher risk of treatment-related complications including dysfunction of musculoskeletal, neurologic, endocrinal, sensory, cardiovascular, renal, and pulmonary function in addition to increased rates of secondary malignancies.⁷ Specific pulmonary complications described include chronic respiratory symptoms, abnormal PFT, and bronchiectasis.⁷

The differential diagnosis for children who present with symptoms of chronic cough and shortness of breath, especially with a history of treatment for malignancy, is broad and the symptoms of PPFE can also overlap with multiple chronic or systemic conditions.⁸ Several predisposing factors associated with the development of PPFE have been proposed including infections, autoimmune diseases, stem cell transplantation, and chemotherapy. We cannot confirm the precise etiology of PPFE in this patient. She received multiple chemotherapy agents including cyclophosphamide and conditioning for stem cell infusion, both of which are implicated in the pathogenesis of PPFE. As some predisposing agents are used in several pediatric diseases, such as cyclophosphamide for treating autoimmune conditions, awareness of this rare complication by pediatric providers is warranted.

Due to the heterogeneous etiology and the presenting symptoms which masquerade as common complaints, time from symptom onset to diagnosis has been reported anywhere between 1 and 16 years in adults and the only curative approach is lung transplantation as medical approaches have not been shown to be effective.^3,4 Our patient was not diagnosed until 2 years after the onset of her cough, and an earlier recognition of PPFE may have made treatment by lung transplant feasible.⁹ Histopathology continues to be the gold standard for diagnosing PPFE, but lung biopsy is fraught with complications. However, recent publications suggest high-resolution CT alone with dense pleural and subpleural consolidation with a reticular pattern (apical-caudal distribution) can confirm the diagnosis if classic features are present. If validated, this would decrease the need for invasive biopsies.¹⁰ Malnutrition and pulmonary hypertension are important comorbidities associated with this disease and put affected individuals at a higher risk of mortality. Improved awareness, clinical knowledge, and early inclusion of PPFE in the differential diagnosis of patients with classical clinical symptoms should encourage multidisciplinary teams to speed diagnosis and allow for aggressive early interventions in the otherwise deadly disease.

4 |. SUMMARY

PPFE is a recently recognized and underappreciated interstitial lung disease, particularly in children. Our experience with this child highlights some of the difficulties in diagnosing this rare condition, which caused a prolonged period before definitive management. The creation of an international pediatric interstitial lung disease registry would provide for a precise understanding of the incidence of this pathology, facilitate awareness among pediatric providers, and facilitate research to determine etiology and improvements in the management of PPFE.

Abbreviations:

COG

Children’s Oncology Group

CT

computerized tomography

PPFE

pleuroparenchymal fibroelastosis