Lymphocytic Interstitial Pneumonia (LIP)

Lymphocytic interstitial pneumonia is a rare, slowly progressive pulmonary disorder associated with autoimmune diseases, dysgammaglobulinemia, human immunodeficiency virus infection and Epstein-Barr virus infection or it could be idiopathic. It is characterized by inflammatory alveolar infiltration leading to clinical manifestations. Imaging studies and lung biopsy are necessary to confirm the diagnosis.


Presentation

The etiology of lymphocytic interstitial pneumonia (LIP) is unknown. It is characterized by infiltration of the pulmonary alveoli by inflammatory lymphocytes, plasma cells and histiocytes [1]. LIP is often associated with autoimmune conditions like Sjögren's syndrome, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Hashimoto thyroiditis as well as immunodeficient diseases like human immunodeficiency virus infection (HIV), combined variable immunodeficiency, agammaglobulinemia, and Epstein-Barr virus (EBV) infection [2] [3] [4].

Although LIP has been reported in patients of all age groups, a majority of the patients are middle-aged and the incidence is higher amongst females [5]. If LIP occurs in a pediatric patient, then it should raise suspicion of underlying acquired immunodeficiency syndrome (AIDS).

Patients with LIP often do not present any signs of the disease and are diagnosed incidentally based on radiological findings [6]. Symptoms when present can be nonspecific such as a long-standing cough becoming worse with time, dyspnea, chest pain, rarely hemoptysis [6], anorexia, fever, night sweats and joint pain. Clinical manifestations of associated diseases like parotid enlargement, xerophthalmia and xerostomia [7] can also be present. The features in children are slightly different and can include clubbing, dyspnea, lymphadenopathy, parotid enlargement, and hepatosplenomegaly.

As the disease progresses, patients develop bronchitis, bronchiectasis and eventually, pulmonary fibrosis. The incidence of respiratory failure with cyanosis is higher amongst children with LIP.

cardiovascular
Cyanosis
  • ) Dyspnea: Cough: Pleuritic Chest Pain: Bibasilar Rales: Pulmonary HTN: late Other System Involvement: a) Lymphadenopathy: b) Keratoconjunctivitis sicca: c) Salivary Gland Enlargement: d) Hepatosplenomegaly: e) Fever: f) Weight Loss: g) Clubbing: h) Cyanosis[mdnxs.com]
  • Becomes coarser as disease progresses and ends with honeycomb lung Progressive loss of volume is characteristic of either UIP or scleroderma Clinically Symptoms include SOB, non-productive cough and fatigue Clubbing of the fingers is very common (85%) Cyanosis[learningradiology.com]
  • If the disease progresses to the end-stage respiratory failure cyanosis and clubbing may develop. [radiopaedia.org]
  • His general physical examination was normal, with pulse rate of 88/minute, blood pressure 110/68 mmHg, respiratory rate 22/minute, J.V.P. not raised, cyanosis, lymphadenopathy, clubbing, were not present.[lungindia.com]
  • But, clubbing of finger and cyanosis were absent.[kjim.org]
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  • respiratoric
    Cough
    • LIP is often mistaken for pulmonary TB (miliary) because of the chronic cough and the miliary-like pattern on chest X-ray.[books.mcai.org.uk]
    • […] may progress to lymphoma. lymphocytic interstitial pneumonia A diffuse pulmonary disease of insidious onset that is most common in middle-aged , which may be accompanied by Sjögren's disease, hyper- or hypo-gammaglobulinemia Clinical Progressive SOB, cough[medical-dictionary.thefreedictionary.com]
    • Definition Chronic lung disease characterized by interstitial lymphocytic infiltration Alternate/Historical Names LIP Lymphocytic interstitial pneumonia Diagnostic Criteria Clinical Gradual onset of dyspnea, cough Most have symptoms 6 months May occur[surgpathcriteria.stanford.edu]
    • […] general 1/3 associated with Sjögren's syndrome; also associated with AIDS, pulmonary drug reactions May occur in children with AIDS May be an IgG4 related disease May be EBV related, particularly in non HIV related cases Symptoms : shortness of breath, cough[pathologyoutlines.com]
    • Symptoms include fever, cough, and shortness of breath.[en.wikipedia.org]
    Dyspnea
    • Definition Chronic lung disease characterized by interstitial lymphocytic infiltration Alternate/Historical Names LIP Lymphocytic interstitial pneumonia Diagnostic Criteria Clinical Gradual onset of dyspnea, cough Most have symptoms 6 months May occur[surgpathcriteria.stanford.edu]
    • Patients should be instructed to seek medical attention for increased dyspnea or change in sputum.[emedicine.medscape.com]
    • […] correlates well with pathologic honeycombing 5) Pleural effusion: uncommon (suggests presence of complicating lymphoma) Hypo or hypergammaglobulinemia: may be seen Serum autoantibodies or immune complexes: may be positive Clinical Clubbing (common) Dyspnea[mdnxs.com]
    • The median duration of symptoms was 5 months (range 1–84) with class II or III dyspnea occurring in 70%(9/13) of patients.[bmcpulmmed.biomedcentral.com]
    • Symptoms are nonspecific and include cough and dyspnea.[humpath.com]
    Dry Cough
    • Breathlessness during exercise is one of the initial symptoms of these diseases, while a dry cough may also be present.[books.google.com]
    • The main symptoms are gradual onset of persistent progressive dry cough and breathlessness, which is often associated with constitutional symptoms.[lungindia.com]
    • She remained fit and well until late 2014, when she presented to her primary care physician with a six week history of a dry cough and progressive shortness of breath.[scitechnol.com]
    • A dry cough is another symptom.[healthline.com]
    • The most common symptoms of interstitial lung disease are a dry cough and shortness of breath .[medicinenet.com]
    Rales
    • Pleural effusion: uncommon (suggests presence of complicating lymphoma) Hypo or hypergammaglobulinemia: may be seen Serum autoantibodies or immune complexes: may be positive Clinical Clubbing (common) Dyspnea: Cough: Pleuritic Chest Pain: Bibasilar Rales[mdnxs.com]
    • […] loss of volume is characteristic of either UIP or scleroderma Clinically Symptoms include SOB, non-productive cough and fatigue Clubbing of the fingers is very common (85%) Cyanosis and pulmonary hypertension usually occur late in the disease “Velcro” rales[learningradiology.com]
    • […] examination findings in children may include the following: Generalized lymphadenopathy Hepatosplenomegaly Parotid enlargement Clubbing Wheezing (occasional) Physical examination findings in adults may include the following: Generalized lymphadenopathy Rales[emedicine.medscape.com]
    • Bibasilar rales are a consistent finding on lung auscultation (1,3,4,16); wheezes and decreased breath sounds may also be present (4).[path.upmc.edu]
    • On physical examination, she had bibasilar crackling rales.[kjim.org]
    Pulmonary Disorder
    • Previous Contents Next Lymphocytic interstitial pneumonitis (LIP) LIP is a non-infectious pulmonary disorder caused by white cell infiltration into alveolae.[books.mcai.org.uk]
    • Immunosuppressive and cytotoxic pharmacology for pulmonary disorders.[erj.ersjournals.com]
    Exertional Dyspnea
    • Chest radiograph of lymphocytic interstitial pneumonia in an adult who is HIV positive and has exertional dyspnea, demonstrating characteristic fine bibasilar interstitial markings In adults, honeycombing is present in up to one third of cases.[emedicine.medscape.com]
    • Symptoms are typically exertional dyspnea and variable mucus production.[clevelandclinicmeded.com]
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  • Entire body system
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  • Jaw & Teeth
    Parotid Swelling
    • The child is often asymptomatic in the early stages, but may later have a mild persistent cough, with or without difficulty in breathing, bilateral parotid swelling, persistent generalised lymphadenopathy, poor growth, hepatomegaly and other signs of[books.mcai.org.uk]
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  • Workup

    The diagnosis of LIP is often delayed due to the nonspecific symptoms. A clinical suspicion is required to detect the condition. Patients may provide a history of progressively worsening symptoms. During the physical examination, chest auscultation can reveal rales and clubbing.

    Routine laboratory tests will show elevated levels of inflammatory markers in the presence of autoimmune disease and polyclonal agammaglobulinemia or dysgammaglobulinemia on serum protein electrophoresis. Tests for HIV, EBV, RA factor, SLE, Sjögren's and Hashimoto thyroiditis should be performed to detect the disorders associated with LIP. Lactate dehydrogenase (LDH) levels are obtained in pediatric patients to differentiate LIP from pneumocystis carinii pneumonia.

    Restrictive pattern and diminished diffusion capacity are seen on pulmonary function testing [8].

    Plain X-ray chest may show bilateral basal opacities and cysts. Computed tomography (CT) scan is obtained to determine the extent of lung involvement and for subsequent follow-up of the disease. Findings include cysts, opacified nodules, bronchiectasis, bullae with air bronchogram and pulmonary fibrosis in the late stages of LIP [9] [10].

    Bronchoalveolar lavage is performed to exclude infection and is likely to reveal lymphocytic infiltrate [8].

    However, confirmation of diagnosis requires histological examination of a lung biopsy specimen [6]. The typical features of LIP are widening of the alveolar septae with extensive interstitial lymphocytic, plasma cell and histiocytic infiltration. Immunohistochemical staining and flow cytometry are required to differentiate between LIP and pulmonary lymphoma. Polyclonal infiltrate (i.e. both T and B cells) is seen in LIP, while monoclonal infiltrate with destruction/distortion of the airways and vessels and pleural involvement are a feature of lymphomas [2].

    Pathology

    Biopsy
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  • Laboratory

    Serum
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  • Imaging

    X-ray
    Pulmonary Infiltrate
    • Overview Lymphocytic interstitial pneumonia (LIP) is a syndrome of fever, cough, and dyspnea, with bibasilar pulmonary infiltrates consisting of dense interstitial accumulations of lymphocytes and plasma cells.[emedicine.medscape.com]
    • A chest radiography showed right pleural effusion with bilateral pulmonary infiltrations ( Figure 1A ).[kjim.org]
    • We report the case of a 28-year-old patient with frequent respiratory infections and nodular pulmonary infiltrates, who was diagnosed with common variable immunodeficiency and follicular bronchiolitis.[archbronconeumol.org]
    • The patient began receiving steroids, with good response, but he returned with pulmonary infiltrates after he discontinued steroid therapy.[nature.com]
    • infiltrate and eosinophilia Hydrochlorothiazide Oxygen Radiation l -Tryptophan CCNU, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea.[clevelandclinicmeded.com]
    Reticulonodular Pattern
    • […] with decreased DLCO FOB: BAL lymphocytosis ( 35%) may be seen (also seen in Sarcoid, Berylliosis, HP, drug-induced ILD, lymphoma) -Increased plasma cells and macrophages OLB: required for diagnosis in almost all cases CXR/Chest CT patterns: 1) ILD: reticulonodular[mdnxs.com]
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  • Test Results

    Pulmonary Function Test
    Decreased Lung Compliance
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  • Treatment

    Prognosis

    Complications

    Bronchiolitis Obliterans
    • obliterans and diffuse interstitial pneumonia) –favors upper lobes DIP (desquamative interstitial pneumonia) –second most common chronic interstitial pneumonia Heavy concentration of mononuclear cells rather than polys as in UIP Loss of type I alveolar[learningradiology.com]
    • obliterans Cryptogenic organizing pneumonia Desquamative interstitial pneumonia DNA repair disorders Drug-induced lung disease Eosinophilic pneumonias Follicular Bronchiolitis Growth abnormalities Hypersensitivity pneumonitis Immune-mediated lung disease[child-foundation.org]
    • obliterans with organizing pneumonia (BOOP), sometimes known as cryptogenic organizing pneumonia (COP) Usual interstitial pneumonitis (UIP) Lymphocytic interstitial pneumonitis (LIP) Desquamative interstitial pneumonitis (DIP) Sarcoidosis Lymphangiomyomatosis[rxlist.com]
    • Subsequent work has included the description of bronchiolitis obliterans and organizing pneumonia (BOOP) (Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA.[bumc.bu.edu]
    Pulmonary Lymphoma
    • Flecainide (see [[Flecainide]]) Phenytoin (see [[Phenytoin]]) Surfactant Protein C Deficiency Idiopathic Lymphocytic Interstitial Pneumonia Physiology Lymphocytic infiltration of interstitium of lung Must be differentiated from pseudolymphoma/ primary pulmonary[mdnxs.com]
    • lymphoma BALT hyperplasia Only gold members can continue reading.[radiologykey.com]
    • Malignant transformation to pulmonary lymphoma was not detected.[erj.ersjournals.com]
    • This statement also emphasized the need of excluding all known secondary causes and pulmonary lymphoma which warrants extensive investigation before arriving at a diagnosis of idiopathic disease.[omicsonline.org]
    • Although occasionally present, germinal centers are uncommonly seen in pulmonary lymphomas (14,17,20).[path.upmc.edu]

    Etiology

    Epidemiology

    Sex distribution
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    References

    1. Kim J-Y, Park S-H, Kim S-K, et al. Lymphocytic interstitial pneumonia in primary Sjogren's syndrome: a case report. Korean J Intern Med. 2011 Mar; 26 (1): 108 -111
    2. Panchabhai TS, Farver C, Highland KB. Lymphocytic interstitial pneumonia. Clin Chest Med. 2016 Sep 3; 37(3): 463-74
    3. Swigris JJ, Berry GJ, Raffin TA, Kuschner WG. Lymphoid interstitial pneumonia: a narrative review. Chest. 2002;122:2150–2164.
    4. Alkhayer M, McCann BG, Harrison BD. Lymphocytic interstitial pneumonitis in association with Sjogren's syndrome. Br J Dis Chest. 1988;82:305–309.
    5. Ferguson EC, Berkowitz EA. Lung CT: Part 2, The interstitial pneumonias-clinical, histologic, and CT manifestations. AJR Am J Roentgenol. 2012;199 (4): W464-76.
    6. Wu W, Zhou J, Di L-G, Chen H. From lymphocytic interstitial pneumonia to MALT lymphoma of lung: a case report with a 5-year diagnostic dilemma. 2015; 8(8): 9698-9702
    7. Couderc LJ, D'Agay MF, Danon F, et al. Sicca complex and infection with human immunodeficiency virus. Arch Intern Med. 1987 May; 147(5):898-901.
    8. Cha S-I, Fessler MB, Cool CD, et al. Lymphoid interstitial pneumonia: clinical features, associations, and prognosis. Eur Respir J. 2006; 28:364-369
    9. Becciolini V, Gudinchet F, Cheseaux JJ, Schnyder P. Lymphocytic interstitial pneumonia in children with AIDS: high-resolution CT findings. Eur Radiol. 2001;11(6):1015-20.
    10. Johkoh T, Ichikado K, Akira M, et al. Lymphocytic interstitial pneumonia: follow-up CT findings in 14 patients. J Thorac Imaging. 2000. Jul; 15(3):162-7.

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