Biomarkers have the potential to become central to the clinical evaluation and monitoring of patients with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype. Here we summarize the current understanding of putative serum, BAL fluid, and genetic biomarkers in this setting, according to their hypothesized pathobiologic mechanisms: evidence of epithelial cell dysfunction (eg, Krebs von den Lungen-6 antigen), fibroblast proliferation and extracellular matrix production or turnover (eg, matrix metalloproteinase-1), or immune dysregulation (eg, CC chemokine ligand 18). While most of the available data come from idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrosing ILD, data are available in the broader patient population of chronic fibrosing ILDs. A number of these biomarkers show promise, however, none have been validated. In this review article, we assess both the status of proposed biomarkers for chronic fibrosing lung diseases with a progressive phenotype in predicting disease risk or predisposition, diagnosis, prognosis, and treatment response and provide a direct comparison between IPF and other chronic fibrotic ILDs. We also reflect on the current clinical usefulness and future direction of research for biomarkers in the setting of chronic fibrosing ILDs with a progressive phenotype.

A 34-year-old man presented to a community hospital with sudden-onset pleuritic chest pain on a background of a 12-month indolent history of progressive exertional dyspnea. He denied cough, fevers, night sweats, or weight loss. He reported some low back pain and ache. He had a history of gastroesophageal reflux and was a current smoker with a 20-pack year history. There were no known occupational or environmental exposures and there was no family history of any lung disease.

A 36-year-old woman with a history of hypertension and alcoholism reported 2 days of left upper quadrant pain and jaundice. Within hours of admission, she became somnolent and hypoxic. The patient was then intubated. She had no history of drug abuse, cigarette smoking, liver disease, autoimmune disease, or pancreatitis. She had no home medications.

A 55-year-old man presented to the ED with a 3-week history of worsening cough and shortness of breath. He had blood-tinged sputum, fever, night sweats, and a 2.7 kg weight loss within the same period. For the past few days, he had taken amoxicillin-clavulanate for presumed sinusitis. Despite this, his symptoms persisted, prompting him to seek further evaluation. His medical history was significant for ulcerative colitis and he had some bloody diarrhea for the past few weeks. Medications included aspirin, mesalamine, multivitamins, folic acid, and herbal supplements including gingko biloba, ginseng, and turmeric-ginger. He never smoked and drank alcohol occasionally. Family history was notable for stroke and myocardial infarction.

A 51-year-old nonsmoking man presented to his general practitioner with a primary complaint of 4 months of progressive hoarseness, and was subsequently referred to an otolaryngologist. He had no relevant medical or surgical history. He did not take any chronic medications or supplements. He was born in the Dominican Republic and moved to New York City when he was 36 years old. He worked in construction. In his spare time, he would return to his home country. The patient was a lifelong nonsmoker and reported no alcohol consumption. He denied shortness of breath, cough, sputum expectoration, fevers, chills, and night sweats.

A 21-year-old Chinese man presented with a nonproductive cough for the past 5 months. He denied fevers, chills, night sweats, chest pain, dyspnea, hemoptysis, or weight loss. He was an undergraduate with an unremarkable medical history. He denied any sick contacts and he never smoked. Laboratory tests showed a leukocyte count of 11,200/μL (normal range, 3,500-9,500/μL) with a high neutrophil count and a raised erythrocyte sedimentation rate of 81 mm/h. The purified protein derivative skin test result was positive, and a TB test (T.SPOT.TB; Oxford Immunotec) produced a positive result. The HIV test result was negative. The lung window of the patient's thoracic CT scan showed mottled, patchy opacification in the right lower lobe, and enlarged mediastinal and right hilar lymph nodes (Fig 1A). Bronchoscopy showed mucosal swelling and congestion (Fig 1B). A lymph node (station 11R) biopsy, obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (Fig 1C), showed nonspecific necrosis. An acid-fast bacillus smear of bronchial secretion produced negative results. He was administered empiric anti-TB therapy (ethambutol, isoniazid, pyrazinamide, and rifapentine). But his cough had not improved by 4 months later. Thus he came to our hospital for a second opinion.

Pulmonary venoocclusive disease (PVOD) is a rare form of pulmonary vascular disease with pulmonary hypertension characterized by preferential involvement of the pulmonary venous system. Hepatic venoocclusive disease (HVOD), also known as sinusoidal obstruction syndrome, is a condition that occurs in 13% to 15% of patients after hematopoietic stem cell transplantation (HSCT). Although hepatic and pulmonary venoocclusive diseases may share some pathologic features as well as some etiologies such as HSCT, these two disorders have never been described together in a single adult patient. We report the case of a patient who received HSCT and developed HVOD and PVOD within 9 months. Despite their differences, PVOD and HVOD share common risk factors and associated conditions, suggesting that in the context of HSCT, the two diseases share common pathophysiological mechanisms. Optimal treatment for HSCT-related PVOD remains to be determined.

Neurofibromatosis type 1 is a rare disorder that occurs secondary to pathogenic variants in the NF1 tumor suppressor gene on chromosome 17. Characteristic clinical manifestations include multiple hyperpigmented macules, axillary and inguinal freckling, optic gliomas, and numerous skin neurofibromas. Vasculopathies are a rare complication of this disease and can affect vessels ranging from the proximal aorta to small arterioles, with pathology including arterial stenosis, aneurysms, and arteriovenous malformations. Aneurysms in these patients are often asymptomatic, and most patients with this complication appear for treatment after vessel rupture. We describe a 33-year-old man with neurofibromatosis type 1 who presented with chest pain and was ultimately found to have a ruptured left subclavian artery branch pseudoaneurysm leading to a large hemothorax.