Pleuroparenchymal fibroelastosis as a late complication of childhood cancer therapy: A case series.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial pneumonia with distinct clinicopathologic features. It has been associated with exposure to hematopoietic stem cell transplantation (HSCT) and classical alkylating agents. Here, we highlight PPFE as a late complication of childhood cancer therapy by describing the cases of four survivors of childhood cancer with a diagnosis of treatment-related PPFE. All patients received high-dose alkylating agents. PPFE should be considered in the differential diagnosis of restrictive lung disease in patients with history of exposure to alkylating agents or HSCT. Development of PPFE-specific, noninvasive diagnostic tools and disease-modifying therapies will clinically benefit these patients.

Drug-Induced Interstitial Lung Diseases.

Drug-induced interstitial lung disease (DI-ILD) is an increasingly common cause of morbidity and mortality as the list of culprit drugs continues to grow. Unfortunately, DI-ILD is difficult to study, diagnose, prove, and manage. This article attempts to raise awareness of the challenges in DI-ILD and discusses the current clinical landscape.

The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19.

BACKGROUND: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19. OBJECTIVE: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2. DESIGN: Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge. SETTING: 114 centers in 10 countries. PARTICIPANTS: Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms. MEASUREMENTS: Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively. RESULTS: Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity. LIMITATIONS: Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available. CONCLUSION: Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Intussusception due to intramural jejunal splenosis.

Splenosis is defined as the growth of ectopic splenic tissue, due to its direct seeding, usually seen after traumatic or surgical procedures to the spleen. It often occurs on highly vascularized surfaces such as the omentum or the mesentery, and grows in sessile form, supplied by adjacent vessels. Intestinal splenosis with endoluminal extension is extremely rare. We present a case of intestinal splenosis with endoluminal growth in a 14-year-old boy that provoked a small bowel intussusception requiring surgical resolution.

Expert consensus on the management of adverse events and prescribing practices associated with the treatment of patients taking pirfenidone for idiopathic pulmonary fibrosis: a Delphi consensus study.

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) treated with pirfenidone (Esbriet®, Genentech USA, Inc. South San Francisco, CA.), effectively managing treatment-related adverse events (AEs) may improve adherence. Due to a lack of clinical evidence and expertise, managing these AEs can be challenging for patients and physicians alike. In the absence of evidence, consensus recommendations from physicians experienced in using pirfenidone to treat IPF are beneficial. METHODS: Using a modified Delphi process, expert recommendations were developed by a panel of physicians experienced with using pirfenidone for IPF. Over three iterations, panelists developed and refined a series of statements on the use of pirfenidone in IPF. Their agreement on each statement was ranked using a Likert scale. RESULTS: A panel of 12 physicians participated and developed a total of 286 statements on dosing and administration, special populations, drug-drug interactions, laboratory analysis, warnings and precautions, and AE management. Expert recommendations were achieved with regard to slower initial titrations and slower titrations for AEs, dosing with meal(s) or substantial meals, and adding other prescribed pharmacological agents for AEs. CONCLUSION: Until there is further clinical evidence, the resulting consensus recommendations are intended to provide direction on the practical management of IPF with pirfenidone, by encompassing a broad experience from the real world to complement data gleaned from clinical trials.

Concomitant Interstitial Lung Disease with Psoriasis.

Background: We encounter interstitial lung disease (ILD) patients with psoriasis. The aim of this case series was to examine clinical and radiographic characteristics of patients with concomitant psoriasis and ILD. Methods: This is a retrospective review of our institutional experience of ILD concomitant with psoriasis, from the database in the Advanced Lung/Interstitial Lung Disease Program at the Mount Sinai Hospital. Out of 447 ILD patients, we identified 21 (4.7%) with antecedent or concomitant diagnosis of psoriasis. Clinical, radiographic, pathological, and outcome data were abstracted from our medical records. Results: Median age was 66 years (range, 46-86) and 14 (66.7%) were male. Thirteen (61.9%) had not previously or concomitantly been exposed to immunosuppressive therapy directed against psoriasis. Two (9.5%) ultimately died. Clinical diagnosis of ILD included idiopathic pulmonary fibrosis, 11 (52.4%); nonspecific interstitial pneumonia (NSIP), 2 (9.5%); cryptogenic organizing pneumonia, 2 (9.5%); chronic hypersensitivity pneumonitis, 2 (9.5%); and the others, while radiographic diagnosis included usual interstitial pneumonia pattern, 9 (42.9%); NSIP pattern, 6 (28.6%); organizing pneumonia pattern, 4 (19.0%); hypersensitivity pneumonitis pattern, 2 (9.5%); and the others. Conclusions: We report 21 ILD cases with antecedent or concomitant diagnosis of psoriasis. Further prospective studies are required to determine the association between ILD and psoriasis.

Acute exacerbations of progressive-fibrosing interstitial lung diseases.

Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis (IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available.

An Open-Label, Phase II Study of the Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (PIPF-002).

INTRODUCTION: PIPF-002 was a phase 2, multicenter, open-label study of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) or other types of pulmonary fibrosis (PF). PIPF-002 terminated after pirfenidone became commercially available in the United States. The goal of PIPF-002 was to characterize the long-term safety of pirfenidone in these patients. METHODS: Between August 2003 and September 2006, 83 patients (IPF: 81, PF: 2) enrolled. Patients received pirfenidone in three divided doses daily, with the maintenance dose and schedule determined by enrollment group assignment. Treatment continued until patient withdrawal or study termination (2015). Treatment-emergent adverse events (TEAEs) were assessed by descriptive statistics. RESULTS: At baseline, median age was 70 years, mean percent predicted forced vital capacity was 67.7%, 33.7% of patients had cardiac disorders, 51.8% had gastroesophageal reflux disease, and 63.9% were receiving concomitant prednisone. Median pirfenidone dose and exposure duration were 2400 mg/day and 3.0 years, respectively. Cumulative total exposure was 279.7 patient-exposure years (PEY). Most patients (98.8%) reported ≥ 1 TEAE, with an overall incidence rate of 460.5 per 100 PEY. The most frequent TEAEs (incidence rate per 100 PEY) were nausea (23.6), IPF progression (16.1), fatigue (11.8), dyspnea (11.4), upper respiratory tract infection (11.4), and cough (10.7). Serious TEAEs were reported in 49 patients; the most frequent serious TEAEs were IPF progression and pneumonia. The most common reason for discontinuation was TEAEs (35 patients; 12.5 patients per 100 PEY), most frequently IPF progression and nausea. Overall, 21 patients died (7.5 per 100 PEY); 16 deaths were IPF-related. CONCLUSIONS: Long-term safety and tolerability of pirfenidone findings in this study were consistent with the known safety profile of pirfenidone; no new safety signals were identified. These data support the continued use of pirfenidone in patients with IPF. FUNDING: F. Hoffmann-La Roche Ltd./Genentech, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00080223. Plain language summary available for this article.

Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis.

Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs.

Elevated serum D-dimer level is associated with an increased risk of acute exacerbation in interstitial lung disease.

BACKGROUND: Early recognition of patients with interstitial lung disease (ILD) who have an increased risk of developing acute exacerbation (AE) or preclinical AE may be clinically useful, since AE is associated with poor outcome and preventive measures would be of interest to ILD researchers. This study evaluated the relationship between elevated serum D-dimer level (≥0.4 mcg/mL) and subsequent AE or preclinical AE in patients with ILD. METHODS: This single-center, retrospective study was performed from October 2009 through September 2015 in patients with ILD who were ≥18 years old and had idiopathic pulmonary fibrosis, other idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, ILD related to collagen tissue disease, or combined pulmonary fibrosis/emphysema. The primary outcome measure was AE development within three months from each D-dimer measurement. The secondary outcome measures were respiratory-related hospitalization, all-cause hospitalization, venous thromboembolism (VTE), and all-cause mortality within three months. RESULTS: A total of 263 patients (mean age, 64.1 years) with 374 D-dimer measurements (median, 0.44 mcg/mL) were included. The risk of developing AE was significantly higher in patients with elevated serum D-dimer level (adjusted odds ratio: 10.46; 95% CI: 1.24-88.11; p = 0.03). Patients with elevated serum D-dimer level had increased risk for respiratory-related hospitalization, all-cause hospitalization, VTE, and all-cause mortality. The other factors predictive for AE were home oxygen therapy, increased serum lactate dehydrogenase, decreased FVC, and decreased FEV1.0. CONCLUSIONS: Elevated serum D-dimer is associated with the risk of developing AE. Serum D-dimer may be used as a prognostic marker to predict AE or recognize preclinical AE.

Idiopathic interstitial pneumonias: a radiology-pathology correlation based on the revised 2013 American Thoracic Society-European Respiratory Society classification system.

The idiopathic interstitial pneumonias (IIPs) are a group of diffuse lung diseases that share many similar radiologic and pathologic features. According to the revised 2013 American Thoracic Society-European Respiratory Society classification system, these entities are now divided into major IIPs (idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, and acute interstitial pneumonia), rare IIPs (idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis), and unclassifiable idiopathic interstitial pneumonias. Some of the encountered radiologic and histologic patterns can also be seen in the setting of other disorders, which makes them a diagnostic challenge. As such, the accurate classification of IIPs remains complex and is best approached through a collaboration among clinicians, radiologists, and pathologists, as the treatment and prognosis of these conditions vary greatly.

Spectrum of fibrosing diffuse parenchymal lung disease.

The interstitial lung diseases are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the pulmonary interstitium. In 2002, the American Thoracic Society and the European Respiratory Society revised the classification of interstitial lung diseases and introduced the term diffuse parenchymal lung disease. The idiopathic interstitial pneumonias are a subtype of diffuse parenchymal lung disease. The idiopathic interstitial pneumonias are subdivided into usual interstitial pneumonia (with its clinical counterpart idiopathic interstitial pneumonia), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, and lymphocytic pneumonia. Sarcoidosis and hypersensitivity pneumonitis are the 2 most common granulomatous diffuse parenchymal lung diseases. Rheumatoid arthritis, systemic sclerosis, and dermatomyositis/polymyositis (causing antisynthetase syndrome) are diffuse parenchymal lung diseases of known association because these conditions are associated with connective tissue disease. Hermansky-Pudlak syndrome is a rare genetic diffuse parenchymal lung disease characterized by the clinical triad of pulmonary disease, oculocutaneous albinism, and bleeding diathesis. This review provides an overview of the chronic fibrosing diffuse parenchymal lung diseases. Its primary objective is to illuminate the clinical challenges encountered by clinicians who manage the diffuse parenchymal lung diseases regularly and to offer potential solutions to those challenges. Treatment for the diffuse parenchymal lung diseases is limited, and for many patients with end-stage disease, lung transplantation remains the best option. Although much has been learned about the diffuse parenchymal lung diseases during the past decade, research in these diseases is urgently needed.

Cardiac sarcoidosis.

Sarcoidosis is a systemic disease with a favorable prognosis, high remission rate, and low mortality. Cardiac involvement alters this prognosis. Clinical manifestations most commonly include arrhythmias, conduction abnormalities, and congestive heart failure. Treatment includes immunosuppressant therapy, permanent pacemakers in the setting of conduction abnormalities, and implantable cardioverter-defibrillators in patients at risk for sudden cardiac death. Risk stratification for sudden cardiac death is essential in otherwise asymptomatic patients who have suspected cardiac sarcoidosis.

Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity?

Idiopathic pleuroparenchymal fibroelastosis is a rare recently described entity likely to be under- and misdiagnosed, as awareness of this entity is not yet widespread. We report two cases that show the need to include this disease in the differential diagnosis of patients with predominantly pleural and subpleural fibrotic processes. The condition is a fibrotic thickening of the pleura and subpleural parenchyma due to elastic fiber proliferation predominantly in the upper lobes. Performing elastic fiber stains routinely in patients with fibrosis of this distribution may, therefore, aid in establishing the diagnosis and differentiating it from usual interstitial pneumonia/idiopathic pulmonary fibrosis. These patients may be prone to the development of secondary spontaneous pneumothoraces and persistent postoperative bronchopleural fistulae. Continued study of newly diagnosed cases may uncover shared characteristics or features helpful in generating an etiologic hypothesis. Only with better understanding of this disease can we hope in the future to be able to offer treatments other than supportive care and ultimately lung transplantation, which are the only therapeutic options available today.

Results of 188 whole-body fluorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis.

BACKGROUND: To study the role of whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans in the identification of occult biopsy sites and reversible granulomatous disease in patients with sarcoidosis. METHODS: A retrospective review was undertaken of 188 FDG PET scans performed in 137 patients with proven sarcoidosis. All patients had given a complete medical history and undergone a physical examination, standard chest radiograph, spirometry, diffusing capacity determination, and measurement of serum angiotensin-converting enzymes levels. RESULTS: One hundred thirty-nine whole-body scans had positive findings. The most common positive sites were mediastinal lymph nodes (54 scans), extrathoracic lymph nodes (30 scans), and lung (24 scans). The standardized uptake value (SUV) ranged from 2.0 to 15.8. Twenty occult disease sites were identified. Eleven repeat scans exhibited decreased SUV with corticosteroid therapy. The positive pulmonary FDG PET scan findings occurred in two thirds of patients with radiographic stage II and III sarcoidosis. Negative pulmonary FDG PET scan findings were common in patients with radiographic stage 0, I, and IV sarcoidosis. CONCLUSIONS: Whole-body FDG PET scans are of value in identifying occult and reversible granulomas in patients with sarcoidosis. However, a positive FDG PET scan finding, by itself, is not an indication for treatment.

Diagnosis and treatment of hepatic sarcoidosis.

The presence of granulomas in the liver raises consideration of a wide differential diagnosis, but in most Western series, sarcoidosis accounts for a majority of cases. This review will focus specifically on the diagnosis of and therapy for hepatic sarcoidosis. Sarcoidosis is a systemic granulomatous disease of unknown etiology. Hepatic involvement of sarcoidosis was described in 11.5% of 736 patients enrolled in the ACCESS study. However, presence alone of granulomas in an organ in sarcoidosis does not dictate treatment. The decision to treat should be based on symptoms and severity of disease. Although hepatic involvement usually is asymptomatic, a minority of patients progress to chronic cholestatic disease, portal hypertension, and cirrhosis that may require liver transplantation. Treatment of hepatic sarcoidosis should be reserved for patients who manifest this spectrum of disease. Glucocorticoid treatment is first-line therapy for hepatic sarcoidosis, improving symptoms and abnormal laboratory values but generally having no effect on progression of disease. In addition to glucocorticoids, immunomodulators such as azathioprine, methotrexate, hydroxychloroquine, and infliximab have been used with some positive effects on symptoms, liver enzyme abnormalities, and hepatomegaly, but none has been shown to prevent progression of disease. Ultimately, in cases of overt liver failure, liver transplantation is the definitive treatment. Overall, treatment for hepatic sarcoidosis is targeted toward alleviation of symptoms but has no curative potential at this time. Focus should be on discovering the etiology of the disease to target therapy at prevention, not cure.

Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension.

STUDY OBJECTIVE: To differentiate the clinical, radiographic, and physiologic profile in patients with sarcoidosis with and without pulmonary hypertension. DESIGN: Retrospective survey. SETTING: Tertiary care center. PATIENTS: One hundred six patients with sarcoidosis were classified by two-dimensional echocardiography into two groups: group 1, 54 patients with pulmonary hypertension; group 2, 52 patients without pulmonary hypertension. INTERVENTIONS: Patients underwent two-dimensional and Doppler echocardiography, chest radiography (CXR), pulmonary function testing, and arterial oxygen saturation determination, and the test results were compared between the two groups. Statistical analysis was performed using independent-sample t test and chi2 test, as appropriate; p < 0.05 was considered to be significant. RESULTS: Predicted spirometric values and lung diffusing capacity were significantly lower in patients in group 1 compared to patients in group 2: FVC, 54% vs 64% (p = 0.0065), FEV(1), 47% vs 61% (p = 0.0005), forced expiratory flow, midexpiratory phase, 35% vs 52% (p = 0.0363), and single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)sb), 39% vs 54% (p = 0.0001). Sixty percent of patients in group 1 had radiographic Scadding stage 4 sarcoidosis, while no radiographic stage predominated in group 2. Arterial oxygen saturation, need for oxygen supplementation, and degree of desaturation after exercise did not differ between groups. CONCLUSIONS: The presence of pulmonary hypertension in patients with sarcoidosis is associated with higher prevalence of stage 4 sarcoidosis by CXR and lower predicted spirometric and D(LCO)sb measurements.

Sarcoidosis presenting in patients older than 50 years.

BACKGROUND: Sarcoidosis occurs most often between 20 and 40 years of age, but also presents in children and older adults. Newly diagnosed sarcoidosis in older patients has received little attention. In order to characterize sarcoidosis in older patients, the clinical, radiographic and laboratory features of sarcoidosis presenting in patients aged 50 or older were compared to patients whose sarcoidosis was diagnosed at an earlier age. METHODS: The medical records of 181 consecutive patients with sarcoidosis were reviewed. They were divided into 92 patients diagnosed at 50 years of age or older (group A), and 89 whose diagnosis preceded age 50 (group B). RESULTS: Comparison of group A with group B revealed that the two groups were similar with regard to race, gender, smoking habits, common presenting symptoms, organ system involvement, pulmonary function data, radiographic stage, PPD status, and laboratory values. At the time of diagnosis, most patients in both groups presented with either respiratory symptoms or asymptomatic chest roentgenogram abnormalities. The most prevalent pulmonary function abnormality was reduced diffusing capacity in both groups. Most patients exhibited either stage I or II chest roentgenograms. Organ systems most commonly involved included lung, lymph nodes, and skin. CONCLUSION: Sarcoidosis presents with similar clinical features whether diagnosed in young adults or in patients over the age of 50. The diagnosis of sarcoidosis should be considered in patients presenting over age 50 with characteristic signs and symptoms including chest radiographic evidence of mediastinal lymphadenopathy.