CONTENTS

• Constrictive bronchiolitis:
  • Bronchiolitis obliterans
    • Epidemiology
    • Clinical presentation
    • Radiology
    • Pulmonary function tests
    • Bronchoscopy
    • Diagnostic criteria
    • Treatment
  • DIPNECH (diffuse idiopathic pulmonary neuroendocrine cell hyperplasia)
• Cellular bronchiolitis:
  • Aspiration bronchiolitis
  • Diffuse panbronchiolitis
  • Infectious bronchiolitis ➡️
  • RBILD (Respiratory bronchiolitis interstitial lung disease) ➡️
  • Follicular bronchiolitis ➡️
• Questions & discussion

abbreviations used in the pulmonary section: 2

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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bronchiolitis obliterans

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bronchiolitis obliterans (BO)

• Bronchiolitis obliterans involves a chronic, progressive process which causes obstruction of the bronchioles.
• This is also known as “constrictive bronchiolitis” or “obliterative bronchiolitis.”

bronchiolitis obliterans syndrome (BOS) after transplantation

• Bronchiolitis obliterans is common following lung transplantation or allogeneic stem cell transplantation:
  • In the context of lung transplantation, bronchiolitis obliterans may be conceptualized as a form of chronic lung allograft rejection.
  • In the context of allogeneic stem cell transplantation, bronchiolitis obliterans may be conceptualized as one manifestation of graft-versus-host disease (GVHD).
• Transbronchial biopsy has low yield for bronchiolitis obliterans, so a surgical biopsy would be needed to obtain a definitive pathological diagnosis. However, the risks of a surgical biopsy generally outweigh potential benefits in post-transplant patients. Consequently, if the characteristic imaging and PFT abnormalities are seen in the absence of a competing diagnosis, the patient may be clinically diagnosed with BOS (bronchiolitis obliterans syndrome). Bronchiolitis obliterans syndrome is essentially the same thing as bronchiolitis obliterans, but with the diagnosis based on non-pathological information.
  • Precise diagnostic criteria for BOS are listed below. 📖

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epidemiology of bronchiolitis obliterans

BOS after lung transplantation

• Half of post-transplant patients develop BOS within 5-years; and 75% within 10 years posttransplantation. (Murray 2022) BOS is the leading cause of death beyond one year post transplantation.
• The mean time to diagnosis is 1.3-1.6 years after transplantation. BOS is uncommon in the first six months following transplantation.
• Risk factors for BOS after lung transplantation:
  • Rejection (including both acute cellular rejection and antibody-mediated rejection).
  • Primary graft dysfunction.
  • Pneumonia (including CMV and other pathogens).
  • HLA mismatch.
  • Gastroesophageal reflux disorder.

BOS after allogeneic stem cell transplantation

• BOS occurs in ~5% of all patients, and 14% of patients with graft-versus-host disease. (Murray 2022; Shepard 2019)
• BOS usually presents within the first two years after transplantation.
• Risk factors for BOS after allogeneic stem cell transplantation:
  • Older age.
  • GVHD (graft-versus-host disease).
  • Methotrexate therapy. (Walker 2019)
  • Myeloablative/busulfan-containing conditioning regimen. (Poletti 2023)
• (BOS doesn't occur following autologous-stem cell transplantation.)

rheumatologic/paraneoplastic

• Rheumatoid arthritis is most closely associated with bronchiolitis obliterans:
  • BO usually occurs after the diagnosis of rheumatoid arthritis has been made.
  • BO may be more common in middle-aged, seropositive women.
  • This tends not to respond to therapy. (Fishman 2023)
• Lupus.
• Sjogren syndrome.
• Scleroderma.
• Mixed connective tissue disease.
• Inflammatory bowel disease (and also sulfasalazine or mesalamine therapy).
• Paraneoplastic pemphigus or paraneoplastic autoimmune multiorgan syndrome (PAMS). (29286849)

medications (also see Pneumotox.com 🌊)

• Penicillamine, gold.
• Sulfasalazine, mesalamine.
• Cancer therapeutics (afatinib, 5-fluorouracil, lomustine, carmustine, busulfan, immune checkpoint inhibitors, rituximab). (32551095)

inhaled toxins 

• Cocaine.
• Diacetyl (popcorn/food flavoring, E-cigarettes).
• Mustard gas.
• Nitrogen oxides (fertilizer production, silo filling).
• Sulfur dioxide (paper mill bleaching, sulfur mine fire).
• Sulfur mustard (chemical warfare).
• Ammonia.
• Chlorine.
• Phosgene. (31860801)

postinfectious (predominantly in children)

• Viral (adenovirus, measles, influenza, parainfluenza).
• Mycoplasma.
• (Swyer-James-Macleod syndrome: unilateral hyperlucent lobe or lung, although both lungs are usually affected to some degree). (Fishman 2023)

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clinical presentation of bronchiolitis obliterans

general presentation of bronchiolitis obliterans

• The primary symptom is insidious onset of exertional dyspnea.
• Dry cough may occur (although in advanced disease with bronchiectasis, a productive cough may develop).
• Lung auscultation is generally unremarkable. However, inspiratory crackles, wheeze, or a mid-inspiratory squeak may occur. Crackles may occur early in inspiration, due to small airways popping open. (28279286) 
• Asymptomatic BOS may be detected based on serial PFTs among post-transplant patients.

BOS after lung transplantation

• BOS may be asymptomatic initially (requiring ongoing screening with serial pulmonary function tests).
• Symptoms may include:
  • Dyspnea.
  • Cough.
  • Recurrent purulent tracheobronchitis may be seen (with sputum culture showing Pseudomonas). (Murray 2022)

BOS after allogeneic stem cell transplantation

• Other signs of graft-versus-host disease generally precede or accompany BOS: (Murray 2022)
  • Mucositis, skin rash.
  • Esophagitis.
  • Hepatic inflammation.

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radiology of bronchiolitis obliterans

chest radiograph 

• Generally unremarkable.
• Hyperinflation may be seen.

CT scan

• Mosaic attenuation 📖 due to air trapping might be the most common finding.
  • Air trapping on CT scan may precede abnormalities in pulmonary function tests (which can be relatively insensitive for small airway obstruction). (27144798)
  • ⚠️ An inspiratory CT scan without a high resolution protocol may miss this diagnosis (especially one without a high resolution protocol, such as a pulmonary embolism protocol CT). A high-resolution CT scan with inspiratory and expiratory images is optimal. (32505324)
• Additional findings: (Fishman 2023)
  • Bronchial wall thickening.
  • Bronchiectasis, bronchiolectasis.
  • Tree-in-bud opacities are typically absent, but may occasionally be visible. (Shepard 2019; Walker 2019) If a substantial number of nodules are present, consider the possibility of DIPNECH (diffuse idiopathic pulmonary neuroendocrine cell hyperplasia).
• Differential diagnoses: (Rosado-de-Christenson 2022)
  • Asthma (severe asthma can be radiographically indistinguishable from bronchiolitis obliterans).
  • Bronchiectasis with secondary air trapping.
  • Panlobular emphysema.
  • Pulmonary artery hypertension.
  • (A broader differential diagnosis of mosaic attenuation: 📖)

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pulmonary function tests

general concept: subacute development of fixed airway obstruction

• Fixed airflow obstruction evolves subacutely (over months to years).
  • Either BO or asthma may cause isolated mosaic attenuation on CT scan. Pulmonary function tests are required to sort out these possibilities (asthma causes reversible airflow obstruction, whereas BO causes fixed airflow obstruction).
• FEV 25-75 may be more sensitive for early detection, but this remains controversial.
• DLCO is often normal. 
• ⚠️ In biopsy-proven bronchiolitis, patients may have entirely normal pulmonary function tests, or an isolated reduction of DLCO. (35388671) 

PFT criteria for diagnosis of bronchiolitis obliterans syndrome (BOS)

• Bronchiolitis generally involves a persistent reduction of FEV1 by ~20-25%.
  • Following bone marrow transplantation, BOS is defined in terms of FEV1 <75% predicted, with a decline of >10% over <2 years.
  • Following lung transplantation, BOS is defined in terms of a FEV1 <80% of the patient's post-transplant baseline.

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bronchoscopy

• Transbronchial biopsy has low yield for diagnosing bronchiolitis obliterans.
• Bronchoscopy may be utilized to exclude alternative diagnostic possibilities.

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diagnostic criteria for bronchiolitis obliterans

As with any diagnostic criteria, in clinical practice these don't need to be followed precisely. However, these criteria provide some useful concepts regarding how to approach the diagnosis of BOS.

criteria for BOS following stem cell transplantation

• (1) FEV1/FVC <0.7 or below the lower limit of normal.
• (2) Post-bronchodilator FEV1 <75% of predicted, with decline of >10% over <2 years.
• (3) Absence of infection.
• (4) At least one of the following:
  • Chronic GVHD (graft-versus-host disease) involving another organ.
  • Small airway thickening or bronchiectasis on CT scan.
  • Evidence of air trapping:
    • Air trapping on expiratory CT scan.
    • Air trapping based on PFTs with residual volume >120% or RV/TLC exceeding the 90% confidence interval. (25529383; 31860801)

criteria for BOS following lung transplantation

• (1) FEV1/FVC <0.7
• (2) FEV1 <80% of post-transplant baseline that persists, despite addressing any treatable causes.
• (3) Absence of infection or other confounding conditions.
• (4) Absence of persistent radiographic pulmonary opacities (ground-glass opacity, consolidation, reticular lines) or pleural thickening that may be suggestive of restrictive allograft syndrome. (31860801)

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treatment of bronchiolitis obliterans

general treatment measures to consider

• Treatment of any underlying disorder.
• Aggressive treatment of any gastroesophageal reflux disease.
• Inhaled steroid, bronchodilators, and/or long-term therapy with azithromycin may be trialed. (35388671)

idiopathic BO

• High-dose steroid may be trialed to determine if this improves airflow. If improvement occurs, steroid may be very gradually weaned. (Fishman 2023)

BOS following lung transplantation

• Augmentation of systemic immunosuppression has been utilized, although this hasn't been shown to be effective. (Murray 2022)
• Azithromycin is widely accepted as the front-line therapy. (Fishman 2023)
  • Azithromycin may be especially effective for patients with >15% neutrophils on bronchoalveolar lavage, who have neutrophilic reversible allograft dysfunction (NRAD). Neutrophilic reversible allograft dysfunction may be suggested by finding more prominent centrilobular nodules and tree-in-bud opacities. (28362556)
  • 250 mg may be utilized daily for five days, followed by 250 mg three times per week.
  • Unfortunately, most patients have progressive disease even despite azithromycin.
• Aggressive therapy for any gastroesophageal reflux disorder.
• Re-transplantation.

BOS following hematopoietic stem cell transplantation

• Based on extrapolation from GVHD (graft-versus-host disease), steroid is often trialed:
  • Prednisone 1-1.5 mg/kg/day may be tried for 4-6 weeks to determine if this causes improvement.
  • JAK kinase inhibitors (e.g., ruxolitinib) have demonstrated efficacy in GVHD, with a potential use in BOS. (34260836) 
• Inhaled steroid with a long-acting beta-agonist (budesonide/formoterol) was associated with short-term improvement in patients with newly diagnosed BOS. (25835160)

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diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

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basics

• DIPNECH involves multifocal hyperplasia of neuroendocrine cells, causing numerous small nodules within the lung parenchyma. Neuropeptides secreted by these neuroendocrine cells may cause the development of constrictive bronchiolitis. (32892886) 
• Clinical problems that may result include:
  • (1) Obstructive respiratory failure due to constrictive bronchiolitis.
  • (2) Nodules are premalignant, with the potential to progress to carcinoid tumors.
• Like any rare obstructive lung disease, this will often initially be misdiagnosed as either asthma or COPD.

epidemiology

• DIPNECH is rare (although it's probably been historically overlooked).
• >90% of patients are women. (34246389)
• The most common age of onset is ~45-65 years old.
• Usually affects nonsmokers.

clinical presentation

• Incidental finding:
  • Small, multiple pulmonary nodules are found incidentally on CT scan.
  • Patients are asymptomatic.
• Constrictive bronchiolitis (~1/3 of patients):
  • Cough, dyspnea, and wheezing may progress insidiously over years.
  • Pulmonary function tests show obstruction.
  • Patients are often initially misdiagnosed as having asthma. (28035883)

chest radiograph

• May be normal.
• May show hyperinflation.
• Small pulmonary nodules may occasionally be seen.

CT scan

• Two key findings are mosaic attenuation and nodules:
• (1) Mosaic attenuation 📖 reflects the component of constrictive bronchiolitis.
  • Expiratory images may confirm air trapping.
  • Mosaic attenuation correlates with airflow obstruction and clinical symptoms.
• (2) Scattered nodules that represent neuroendocrine tumors.
  • Maximum intensity projection (MIP) images may help detect the true profusion of nodules.
  • Nodules are small (<5 mm).
  • The distribution is typically centrilobular.
  • Nodules may be solid or ground-glass in attenuation. (Walker 2019)
• Other less common findings may include: (32892886; 34246389)
  • Bronchial wall thickening and nodularity.
  • Mucoid impaction of airways.
  • Bronchiectasis (rarely).
• Distribution is diffuse, but the bases may be more severely involved. (32892886)

diagnosis

• Surgical biopsy is the gold standard investigation, but may not always be required.
• Bronchoscopic biopsy has a yield of only ~20%.
• If nodules are sufficiently large, transthoracic needle biopsy may be utilized to establish the presence of neuroendocrine hyperplasia. (28035883)

management

• There is no known effective treatment. A wide variety of treatments have been utilized.
  • Octreotide might be considered to suppress biogenic amine secretion from neuroendocrine cells. (34246389, 33567196)
  • Sirolimus may target molecular circuitry in the neuroendocrine cells, thereby improving pulmonary function. (29632951)
  • The use of inhaled steroid and as-needed bronchodilators may be reasonable.
• Most patients have indolent disease, with very slow decline in pulmonary function.
• Serial imaging to evaluate for the development of a carcinoid tumor is reasonable.
• Lung transplantation may be considered in patients with progressive airflow limitation.

prognosis

• DIPNECH may be slowly progressive, but long periods of stability can occur.
• DIPNECH may be a pre-neoplastic state, prior to the development of carcinoid tumor.

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aspiration bronchiolitis

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basics

• Chronic microaspiration may cause an insidious onset of bronchiolitis. This may be difficult to diagnose or suspect.

epidemiology

• Most patients have a predisposition to aspiration, for example: (28362556)
• Esophageal or gastric disease (e.g. gastroesophageal reflux disease, achalasia, large hiatus hernia, gastroparesis, gastric banding).
• Neurologic disorders (e.g., stroke, Parkinson disease).
• Medications/substances that suppress airway protection (e.g., alcoholism, substance use disorder).

clinical presentation

• Gradual onset of symptoms, which may present with:
  • Chronic cough which may be productive.
  • Wheeze.
  • Dyspnea.
• There may be recurrent episodes of dyspnea, fever, and cough.
• Symptoms may be exacerbated after or during eating.
• Examination may reveal crackles.

chest radiograph

• Diffuse small nodular shadows and nonspecific interstitial infiltrates may be present.

CT scan

• The hallmark finding is centrilobular nodules, with a tree-in-bud appearance.
• Distribution:
  • May be patchy and unilateral, or bilateral.
  • The right lung is involved most often.
  • Classically in a dependent distribution, although this may vary depending on the patient's position (e.g., supine patients will often have disease in a posterior position).
• Patchy lobular consolidations are often seen, which may progress to larger consolidations. These indicate an extension of bronchiolitis to cause bronchopneumonia. (Walker 2019)
• Gastrointestinal abnormalities may sometimes be seen (e.g., esophageal dilation, Zenker diverticulum, large hiatal hernia). (28362556)

treatment

• Treatment consists of the usual approaches to prevent aspiration.

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diffuse panbronchiolitis

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basics

• Pathologically, panbronchiolitis is characterized by a triad of findings: bronchiolocentric inflammation, lymphoid hyperplasia, and accumulation of interstitial foamy macrophages. (Murray 2022)

epidemiology

• Diffuse panbronchiolitis predominantly affects people of Asian (especially Japanese) ancestry. (Murray 2022)
• There is a male predominance (~1.5:1), with most patients presenting in their 20s-50s. (Poletti 2023)

symptoms include upper and lower respiratory tracts

• Chronic paranasal sinusitis is extremely common, usually preceding pulmonary symptoms. (Murray 2022)
• Chronic productive cough, with substantial volumes of purulent sputum (i.e. >50 ml/day).
• Dyspnea.
• Wheezing.
• Weight loss.
• Hypercapnia and cor pulmonale may eventually occur. (Fishman 2023)

radiology

• Initial findings include bronchiolitis:
  • Tree-in-bud opacities.
  • Mosaic attenuation, with air trapping on expiratory images.
• Bronchiectasis develops in more advanced disease:
  • Bronchiectasis is basal predominant.
  • Eventually, large cysts and dilated proximal bronchi develop.

laboratory findings

• Sputum often shows Haemophilus influenzae. With ongoing disease progression and bronchiectasis development, the frequency of Pseudomonas aeruginosa colonization increases.
• Cold agglutinins may be elevated (even in the absence of Mycoplasma pneumoniae).

pulmonary function tests

• The primary finding is airflow obstruction.
• DLCO may be variably reduced.
• Less often, a mixed obstructive/restrictive pattern may occur. (Murray 2022)

treatment

• Macrolide therapy (e.g., clarithromycin 200-400 mg daily or azithromycin).
  • Low-dose macrolide therapy likely acts via an immunosuppressive action, rather than an antimicrobial action.
  • Treatment should continue for at least 6 months to two years.
• Patients with bronchiectasis should receive the usual supportive care for non-CF bronchiectasis 📖.

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questions & discussion

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