CONTENTS
- Basics
- Epidemiology
- Symptoms
- Radiology
- Additional testing
- Diagnostic process
- Management
- Prognosis
- 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 📖
Follicular bronchiolitis (FP) and lymphoid interstitial pneumonia (LIP) are part of a group of three conditions that involve reactive (non-neoplastic) lymphoid lesions in the lung. All three of these entities display significant overlap: (26500941)
- FB (follicular bronchiolitis) involves excessive growth of lymphoid germinal centers in the bronchiolar submucosa. This is also known as bronchus-associated lymphoid tissue hyperplasia (BALT hyperplasia) or bronchiolar nodular lymphoid hyperplasia.
- LIP (lymphoid interstitial pneumonia) involves more diffuse lymphocytic infiltration into the lung parenchyma.
- DHL (diffuse lymphoid hyperplasia) refers to a combination of LIP plus FB.
Since the original definition of LIP, some divergence has evolved between the way pathologists and radiologists view LIP:
- Radiologists often view cysts as a hallmark feature of LIP, which often helps to suggest the diagnosis.
- Pathologists view LIP as a disorder which is predominantly marked by DELI (diffuse expansile lymphoid infiltrates).
A recent multi-institutional review of 201 cases found that there was frequently little overlap between patients with pathological features of LIP versus radiological features of LIP (defined here to require the presence of lung cysts)(figure below). (36597787) Please note that the ATS/ERS consensus radiologic criteria doesn't actually require the presence of cysts, so if the ATS/ERS radiologic criteria had been used to define “radiologic LIP,” there would be greater overlap between pathological and “radiological LIP.”

The authors of this study recommended that LIP should be abandoned as a pathologic and radiological diagnosis. (36597787) Thus, it's quite likely that these disorders will undergo reorganization in the near term. However, until such reorganization occurs, the remainder of this chapter will be written using current terminology.
epidemiology of FB (follicular bronchiolitis)
epidemiology of FB
- Follicular bronchiolitis usually occurs as a response to chronic airway inflammation or infection (affecting patients with a broad age range).
- Idiopathic follicular bronchiolitis is rare. (31200868)
disorders associated with FB
- Autoimmune disease:
- Rheumatoid arthritis.
- Sjogren syndrome.
- Lupus.
- Other autoimmune disorders:
- Evans syndrome (autoimmune hemolytic anemia and immune thrombocytopenia).
- Pernicious anemia.
- Immunodeficiency:
- HIV.
- IgA deficiency.
- CVID (combined variable immunodeficiency).
- Coatomer-associated protein subunit alpha syndrome (COPA syndrome).
- Infection:
- Mycobacterium avium complex.
- Legionella.
- Pneumocystis.
- Interstitial lung diseases:
- HP (hypersensitivity pneumonitis).
- LIP (lymphoid interstitial pneumonia).
- NISP (nonspecific interstitial pneumonia).
- RB-ILD (respiratory bronchiolitis interstitial lung disease).
- DIP (desquamative interstitial pneumonitis).
- OP (organizing pneumonia).
- Airway inflammatory diseases:
- Bronchiectasis.
- Asthma.
- COPD. (26500941)
epidemiology of LIP (lymphoid interstitial pneumonia)
general incidence
- LIP may occur at any age (mean age of onset ~55 years old).
- LIP most often occurs in the context of rheumatologic disease, with a two-fold female predominance. (Walker 2019)
- Idiopathic LIP is extremely rare (if it exists at all). Nearly all patients have LIP associated with another disorder (as listed below). “Idiopathic” cases previously reported in the literature have largely been reclassified as either low-grade B-cell lymphoma or cellular NSIP (nonspecific interstitial pneumonitis). (27514593)
disorders associated with LIP
- Autoimmune disease:
- Connective tissue disease:
- Sjogren syndrome (LIP occurs in ~1% of patients with Sjogren syndrome. Among adults with LIP, ~30% have Sjogren syndrome).
- Rheumatoid arthritis.
- Lupus.
- Polymyositis.
- IPAF (interstitial pneumonia with autoimmune features). 📖
- Hashimoto thyroiditis.
- Autoimmune hemolytic anemia, pernicious anemia.
- Myasthenia gravis.
- Primary biliary cholangitis, inflammatory bowel disease, celiac sprue.
- Connective tissue disease:
- Immunodeficiency:
- HIV (more often in younger patients).
- CVID (combined variable immunodeficiency).
- Hypogammaglobulinemia.
- Chronic viral infection:
- HIV.
- EBV.
- HHV-8 (human herpesvirus 8).
- HBV.
- HCV.
- HTLV-1.
- Drug reactions (e.g., phenytoin, captopril).
- GVHD (graft versus host disease).
FB (follicular bronchiolitis)
- Dyspnea on exertion may be the most common symptom.
- Cough may occur.
- Other symptoms can include fever and weight loss.
- Symptoms are often mild overall.
LIP (lymphoid interstitial pneumonia)
- Gradual insidious onset of dyspnea and dry cough usually occurs (e.g., over years).
- Fever, weight loss, chest pain, and arthralgias have been reported. Such features may, however, suggest the possibility of an underlying rheumatologic disorder.
ground glass nodules
- Distribution:
- Usually in a centrilobular, tree-in-bud configuration.
- Less often, nodules may additionally be distributed in a peribronchial and/or subpleural pattern. (Walker 2019)
- Often predominantly in the lower lobes.
- Size:
- Typically small (~1-3 mm).
- Some patients may have larger nodules as well (3-12 mm in size). These may have an indistinct “cotton-in-bud” appearance (figure below).
other findings
- Small airway involvement: (Shepard 2019)
- Bronchial wall thickening.
- Bronchiolectasis, bronchiectasis.
- Occasionally mosaic attenuation may be seen, with lobular air trapping on expiratory CT scan. (Walker 2019)
- Parenchymal cysts (similar in character to those seen in LIP, as discussed in the section below).
- Cyst formation in FB is predominantly seen in patients with underlying Sjogren syndrome.
- Interlobular septal thickening.


cysts
- Cysts occur in ~75% of cases. (34099156) Cysts may be the only radiographic finding, leading to confusion with other cystic lung disorders. (Fishman 2023)
- Thin-walled cysts range from roughly 5 mm to ~3 cm in size.
- Overall, cysts usually involve <10% of the lung volume. (27180915)
- Distribution:
- Often favors the mid- or lower-lung zones.
- Cysts can occur in a subpleural or peribronchovascular distribution.
- Cysts may contain internal septations and structures. (Fishman 2023)
larger areas of GGO (ground glass opacity)
- Ground glass opacities may be patchy or diffuse.
- There may be a lower lung predominance.
- Isolated ground glass opacity occurs occasionally, which renders the diagnosis of LIP very challenging. (35131079)
- Eventually GGO may progress to basilar reticulation. However, frank fibrosis is uncommon (traction bronchiectasis, honeycombing, and architectural distortion). (Shepard 2019)
ground glass nodules
- These may have characteristics similar to “cotton-in-bud” lesions seen in FB (as discussed in further detail in the section above on FB).
- If encountered, these nodules are diagnostically useful (e.g., to differentiate LIP from other cystic lung diseases, such as lymphangioleiomyomatosis).
additional findings may include
- Bronchial wall thickening.
- Perilymphatic nodules mimicking lymphangitic carcinomatosis. (27180915)
- Interlobular septal thickening commonly occurs.
features that may raise concern for lymphoma
- 🚩 Consolidation.
- 🚩 Large nodules (>10 mm).
- 🚩 Pleural effusions.
- 🚩 Bulky lymphadenopathy (although some degree of lymphadenopathy is commonly seen in LIP).
- 🚩 Absence of cysts. (27514593)



PFTs (pulmonary function testing)
- Both FB and LIP may cause restriction and diffusion limitation.
- Only FB is associated with obstruction and air trapping.
bronchoscopy
- Bronchoscopy in LIP will usually show a high fraction of lymphocytes (>15%) with a normal CD4/CD8 ratio, but this is a nonspecific finding. (27514593) 📖 Mild elevation of eosinophils may be seen.
laboratory studies
- Laboratory abnormalities in LIP:
- Dysgammaglobulinemia:
- 80% of patients have polyclonal hypergammaglobulinemia.
- 10% have hypogammaglobulinemia (e.g., as may occur in combined variable immunodeficiency syndrome). (Walker 2019; 27514593)
- If detected, a monoclonal proliferation may suggest the possibility of non-Hodgkin lymphoma. ( 27514593)
- Dysgammaglobulinemia:
- For a patient who appears to have FB or LIP of unclear etiology, the following studies should be considered to evaluate for an underlying etiology:(27514593)
- ANA (antinuclear antibody).
- RF (rheumatoid factor) and anti-cyclic citrullinated peptide antibody.
- Anti-Ro and Anti-La antibodies.
- Thyroid function studies.
- HIV.
- EBV titers.
- Human T-cell lymphotropic virus.
- Quantitative immunoglobulins.
- SPEP (serum protein electrophoresis) and UPEP (urine protein electrophoresis).
tissue diagnosis (either FB or LIP)
- Transbronchial biopsies have low yield.
- Surgical biopsy or cryobiopsy is preferred to obtain histology.
diagnosis of FB
- Among patients with an underlying etiology (e.g., Sjogren syndrome), a combination of nodules and cysts may be extremely suggestive. However, amyloidosis and lymphoma may also merit consideration.
- Confident diagnosis generally requires a lung biopsy. However, this should be undertaken only if it would alter management.
diagnosis of LIP
- LIP may be provisionally diagnosed based on characteristic CT findings in a patient known to have an underlying condition that causes LIP.
- If there is no established disorder that causes LIP, then histology is needed to secure the diagnosis. The differential diagnosis may include pulmonary lymphoma and pulmonary amyloidosis. (26761531)
most important intervention: management of any underlying disease process
- Immunodeficiency syndromes should be treated appropriately. For patients with underlying CVID (combined variable immunodeficiency syndrome), management may resemble the treatment of GLILD (granulomatous and lymphocytic interstitial lung disease). 📖
- Connective tissue disorders may be managed as described in the chapter on CTD-ILD (connective tissue disorder-related ILD): 📖
additional treatments for LIP
- Asymptomatic patients with mild disease may be followed without treatment.
- Steroid is the usual treatment for LIP that is severe or progressive. Initial therapy may be 0.75-1 mg/kg/day prednisone for 8-12 weeks, followed by repeat pulmonary function tests and CT scan. Steroid-responsive patients may be managed with a gradual steroid taper over several months, whereas steroid-refractory patients might be trialed on an alternative agent (e.g., azathioprine). Unfortunately, there is no high-quality evidence regarding these therapies. Immunosuppression is best justified among patients with more severe disease and/or underlying rheumatologic disorders. (Fishman 2023)
additional treatments for FB
- Prolonged therapy with low-dose macrolides might be beneficial. (Fishman 2023)
- Steroid might be considered in severe cases, but there is little evidence regarding this.
prognosis of LIP
- About half of patients improve, 10% remain stable, and 40% die within two years (even despite therapy with immunosuppressives). (Fishman 2023)
- Other risks:
- ~5% of patients progress to develop pulmonary MALT lymphoma (mucosa-associated lymphoid tissue lymphoma). This is usually well-differentiated and slow growing. Lymphoma may be associated with underlying Sjogren syndrome, rather than the LIP itself.
- Infection (e.g., related to immunosuppression).
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References
- 26500941 Tashtoush B, Okafor NC, Ramirez JF, Smolley L. Follicular Bronchiolitis: A Literature Review. J Clin Diagn Res. 2015 Sep;9(9):OE01-5. doi: 10.7860/JCDR/2015/13873.6496 [PubMed]
- 26761531 Sirajuddin A, Raparia K, Lewis VA, Franks TJ, Dhand S, Galvin JR, White CS. Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings. Radiographics. 2016 Jan-Feb;36(1):53-70. doi: 10.1148/rg.2016140339 [PubMed]
- 27180915 Raoof S, Bondalapati P, Vydyula R, Ryu JH, Gupta N, Raoof S, Galvin J, Rosen MJ, Lynch D, Travis W, Mehta S, Lazzaro R, Naidich D. Cystic Lung Diseases: Algorithmic Approach. Chest. 2016 Oct;150(4):945-965. doi: 10.1016/j.chest.2016.04.026 [PubMed]
- 27231864 Arcadu A, Moua T, Yi ES, Ryu JH. Lymphoid Interstitial Pneumonia and Other Benign Lymphoid Disorders. Semin Respir Crit Care Med. 2016 Jun;37(3):406-20. doi: 10.1055/s-0036-1580691 [PubMed]
- 27514593 Panchabhai TS, Farver C, Highland KB. Lymphocytic Interstitial Pneumonia. Clin Chest Med. 2016 Sep;37(3):463-74. doi: 10.1016/j.ccm.2016.04.009 [PubMed]
- 31200868 Ko JP, Girvin F, Moore W, Naidich DP. Approach to Peribronchovascular Disease on CT. Semin Ultrasound CT MR. 2019 Jun;40(3):187-199. doi: 10.1053/j.sult.2018.12.002 [PubMed]
- 34099156 Kinoshita Y, Ikeda T, Ueda Y, Sasaki T, Kushima H, Ishii H. A 63-Year-Old Woman With an Acute Exacerbation of Interstitial Pneumonia. Chest. 2021 Jun;159(6):e389-e394. doi: 10.1016/j.chest.2021.01.018 [PubMed]
- 35131079 Walker A, Rupal A, Jani C, Al Omari O, Singh H, Patel D, Perrino C, McCannon J. Longstanding Phenytoin Use as a Cause of Progressive Dyspnea. Chest. 2022 Feb;161(2):e91-e96. doi: 10.1016/j.chest.2021.08.079 [PubMed]
- 36597787 Fraune C, Churg A, Yi ES, Khoor A, Kelemen K, Larsen BT, Butt YM, Smith ML, Gotway MB, Ryu JH, Tazelaar HD. Lymphoid Interstitial Pneumonia (LIP) Revisited: A Critical Reappraisal of the Histologic Spectrum of “Radiologic” and “Pathologic” LIP in the Context of Diffuse Benign Lymphoid Proliferations of the Lung. Am J Surg Pathol. 2023 Mar 1;47(3):281-295. doi: 10.1097/PAS.0000000000002014 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.