Idiopathic interstitial pneumonia pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Synonyms and keywords:
Overview
Pathophysiology
Idiopathic pulmonary fibrosis
Pulmonary fibrosis has often been called an autoimmune disease. However, it is perhaps better characterized as an abnormal and excessive deposition of fibrotic tissue in the pulmonary interstitium with minimal associated inflammation.[1] Autoantibodies, a hallmark of autoimmune diseases, are found in a minority of patients with truly idiopathic pulmonary fibrosis. Moreover, many autoimmune diseases associated with "pulmonary fibrosis", such as scleroderma, are more frequently associated with a related but more inflammatory disease, nonspecific interstitial pneumonitis.[2] It is associated withsmoking[3] and exhibits some dependency on the amount of smoking.[4]
Idiopathic Non-specific Interstitial Pneumonia (NSIP)
There are some common associations between NSIP and usual interstitial pneumonia (UIP). Histologically patients can manifest lesions of UIP and NSIP simultaneously.[5][6] Some common factors include exposures, genetic mutations. Exact cause and nature is still unknown.
Recent studies conclude that epithelial injury and dysregulated repair play a major role.[7] Cytokines and some proteins like epimorphin (a cell surface associated protein), matrix metalloproteinases, heat shock protein, surfactant protein C, the coagulation system, intercellular adhesion molecules-1, IL-4, IL-13, IL-18, interferon-gamma, pro fibrotic chemokine, CCL7, and CCL5.[8][9][10][11][12][13][14][15][16][17][18][19][20][21] A bronchoalveloar lavage (BAL) revealed the presence of lymphocytes in the alveolar septum, which suggests the involvement of the immune system.[22][23][24][25]A greater number of dendritic cells (DC), which help in antigen presentation, are visualized in close association to CD4 and CD8 lymphocytes in biopsy in NSIS patients than UIP .[26]Fibroblasts are key pathological cells involved in fibrotic lung diseases.[27]Fibroblasts secreting transforming growth factor–Beta (TGF-β) and fibronectin are the differentiating characters in NSIS and UIP.[28]
Respiratory Bronchiolitis-Interstitial Lung Disease (RB-ILD)
Cigarette smoking could be one of the major causative agent of RB-ILD.Some radiologic studies may show a relation between the duration and the intensity of cigarette smoking and visualization of opacities on chest radiographs which could be associated to RB-ILD.[29][30][31][32]As the name suggests the pathology is in the bronchiole. It’s a more centrally distributed pathology especially in the lumen though the bronchioles, alveolar ducts and the peribronchiolar alveolar spaces may show clusters of macrophages which are dusty and brown.[33][34][35][36][37][38] Granular golden brown particles having plenty of cytoplasm may be seen. These particles are PAS-positive and Prussian blue –positive which implies increased iron content in alveolar macrophage, which might be associated to smoking.[35][37][36] A common appearance between DIP and respiratory bronchiolitis would be a combination of alveolar septal thickening, epithelial hyperplasia and pigmented macrophages in the lumen. There are lymphocytes and histiocytes present in an irregular way in the submucosa. Similar to the black pigment in the macrophage a dark black anthracotic pigment is what could be seen in the histiocytes.[34][38] Type 2 hyerplastic cells and cuboidal bronchiolar type epithelium could be seen lining the peribronchiolar fibrosis.
Desquamative Interstitial pneumonia (DIP)
DIP lacks the patchy appearance that UIP normally presents with .In DIP alveolar walls are lined with chronic inflammatory cells and dense connective tissue and alveolar spaces are filled with macrophages. In desquamative interstitial pneumonia mild fibrosis without honeycomb changes are seen. Key changes are visualization of mononuclear changes at the distal spaces. These mononuclear cells appear as finely granular brown pigment with mottled tiny black particles. These may be called as smoker’s macrophage, which are different than desquamated pneumocytes. Some common overlapping changes between DIP and respiratory bronchiolitis are seen.[39][34]
Cryptogenic-Organizing pneumonia
Cryptogenic organizing pneumonia lesions consist more of fibroblasts and myofibroblasts in the alveolar ducts and alveoli. There might be involvement of polyps in the bronchial lumen in some patients. There is excess of granulation tissue deposition and sometimes this pattern of extension may appear like a butterfly. Dysorganization of the alveolar epithelium is what causes cryptogenic organizing pneumonia. This disorganization leads to plasma protein leakage, fibroblast migration and fibrin deposition inside the lumen. Involvement of the vascular endothelial growth factors and matrix metalloproteinase also adds up to the cause.[40] Some recent studies also show that it is a rare extra-intestinal manifestation of Crohn's Disease.[41]
Acute Interstitial pneumonia (Hamman-Rich Syndrome) (AIP)
AIP has similar appearance as to diffuse alveolar damage (DAD). A majority of lung injury reacts via the same mechanism as diffuse interstitial pneumonia. It has three stages earlier exudative, then organized proliferative and last the chronic healed or fibrotic.[42][43]
- Exudative stage: Histology specimen never obtained since patient presents late and biopsy are never obtained.
- Proliferative stage: Most typical change seen. A lot of inflammatory infiltration seen in the septa with destruction and hyaline membrane formation leading to thickening of the septa and interstitium.
- Chronic or healed phase: Diffuse scarring seen. A major differentiating factor between AIP and UIP in this phase is that AIP has similar type of lesion at one point of time whereas UIP has lesions of different ages and no specific one pattern could be found out at a period of time.
Release of tumor necrosis factor alpha, interleukin 1β, monocyte chemoattractant factor and neutrophils cause further damage and release of toxic oxygen radicals and proteases. These causes exudate and cellular damage. A fibroblast proliferation and differentiation into myofibroblasts leads to collagen formation and widening of the septa. Later Hyaline membrane decrease in number and there is a rise in the number of type II epithelial cells. A few patients resolve after this stage whereas a majority progress to the next stage. AIP shows prominent myofibroblastic proliferation whereas this is finding only seen in a few cases or ARDS due to infection or drug toxicity .[44][45]
Lymphoid Interstitial Pneumonia (LIP)
Characteristic findings are lymphoid and chronic cell infiltration predominantly in seen in the alveolar septa but sometimes may appear along bronchi and vessels. Granulomas specially non –caseating, fibrotic changes, honeycombing and loss of normal lung tissue could be seen as the disease progresses.[46][47].In LIP B cell polyclonality is seen which differentiates it from pulmonary lymphoma. In HIV T cell are more predominant. Some times no specific cell type are seen though.[47][48][49] A Bcl-6 gene mutation is somewhat believed to be associated with mucosa-associated lymphoid tissue (MALT), HIV and EBV and other virus negative LIP [50]. Features like monoclonality, hilar involvement, pleural involvement, bronchial wall involvement all point towards a malignant transformation. [51]
References
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|coauthors=ignored (help) - ↑ King, Jr., Talmadge E. (2005). "Centennial review: clinical advances in the diagnosis and therapy of the interstitial lung diseases". American Journal of Respiratory and Critical Care Medicine. 172 (3): 268–79.
- ↑ Nagai, Sonoko (2000). "Smoking-related interstitial lung diseases". Current Opinion in Pulmonary Medicine. 6 (5): 415–9. PMID 10958232. Unknown parameter
|coauthors=ignored (help) - ↑ Baumgartner, KB (1997). "Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis". American Journal of Respiratory and Critical Care Medicine. 155 (1): 242–248. PMID 9001319. Unknown parameter
|coauthors=ignored (help) - ↑ Monaghan, H.; Wells, AU.; Colby, TV.; du Bois, RM.; Hansell, DM.; Nicholson, AG. (2004). "Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias". Chest. 125 (2): 522–6. PMID 14769733. Unknown parameter
|month=ignored (help) - ↑ Flaherty, KR.; Travis, WD.; Colby, TV.; Toews, GB.; Kazerooni, EA.; Gross, BH.; Jain, A.; Strawderman, RL.; Flint, A. (2001). "Histopathologic variability in usual and nonspecific interstitial pneumonias". Am J Respir Crit Care Med. 164 (9): 1722–7. doi:10.1164/ajrccm.164.9.2103074. PMID 11719316. Unknown parameter
|month=ignored (help) - ↑ Ishii, H.; Mukae, H.; Kadota, J.; Fujii, T.; Abe, K.; Ashitani, J.; Kohno, S. "Increased levels of interleukin-18 in bronchoalveolar lavage fluid of patients with idiopathic nonspecific interstitial pneumonia". Respiration. 72 (1): 39–45. doi:10.1159/000083399. PMID 15753633.
- ↑ Terasaki, Y.; Fukuda, Y.; Ishizaki, M.; Yamanaka, N. (2000). "Increased expression of epimorphin in bleomycin-induced pulmonary fibrosis in mice". Am J Respir Cell Mol Biol. 23 (2): 168–74. doi:10.1165/ajrcmb.23.2.3973. PMID 10919982. Unknown parameter
|month=ignored (help) - ↑ Suga, M.; Iyonaga, K.; Okamoto, T.; Gushima, Y.; Miyakawa, H.; Akaike, T.; Ando, M. (2000). "Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias". Am J Respir Crit Care Med. 162 (5): 1949–56. doi:10.1164/ajrccm.162.5.9906096. PMID 11069839. Unknown parameter
|month=ignored (help) - ↑ Kakugawa, T.; Mukae, H.; Hayashi, T.; Ishii, H.; Nakayama, S.; Sakamoto, N.; Yoshioka, S.; Sugiyama, K.; Mine, M. (2005). "Expression of HSP47 in usual interstitial pneumonia and nonspecific interstitial pneumonia". Respir Res. 6: 57. doi:10.1186/1465-9921-6-57. PMID 15955241.
- ↑ Thomas, AQ.; Lane, K.; Phillips, J.; Prince, M.; Markin, C.; Speer, M.; Schwartz, DA.; Gaddipati, R.; Marney, A. (2002). "Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred". Am J Respir Crit Care Med. 165 (9): 1322–8. doi:10.1164/rccm.200112-123OC. PMID 11991887. Unknown parameter
|month=ignored (help) - ↑ Brasch, F.; Griese, M.; Tredano, M.; Johnen, G.; Ochs, M.; Rieger, C.; Mulugeta, S.; Müller, KM.; Bahuau, M. (2004). "Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene". Eur Respir J. 24 (1): 30–9. PMID 15293602. Unknown parameter
|month=ignored (help) - ↑ Nogee, LM.; Dunbar, AE.; Wert, SE.; Askin, F.; Hamvas, A.; Whitsett, JA. (2001). "A mutation in the surfactant protein C gene associated with familial interstitial lung disease". N Engl J Med. 344 (8): 573–9. doi:10.1056/NEJM200102223440805. PMID 11207353. Unknown parameter
|month=ignored (help) - ↑ Stevens, PA.; Pettenazzo, A.; Brasch, F.; Mulugeta, S.; Baritussio, A.; Ochs, M.; Morrison, L.; Russo, SJ.; Beers, MF. (2005). "Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene". Pediatr Res. 57 (1): 89–98. doi:10.1203/01.PDR.0000147567.02473.5A. PMID 15557112. Unknown parameter
|month=ignored (help) - ↑ Chibbar, R.; Shih, F.; Baga, M.; Torlakovic, E.; Ramlall, K.; Skomro, R.; Cockcroft, DW.; Lemire, EG. (2004). "Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis". Mod Pathol. 17 (8): 973–80. doi:10.1038/modpathol.3800149. PMID 15133475. Unknown parameter
|month=ignored (help) - ↑ Eitzman, DT.; McCoy, RD.; Zheng, X.; Fay, WP.; Shen, T.; Ginsburg, D.; Simon, RH. (1996). "Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene". J Clin Invest. 97 (1): 232–7. doi:10.1172/JCI118396. PMID 8550840. Unknown parameter
|month=ignored (help) - ↑ Kim, KK.; Flaherty, KR.; Long, Q.; Hattori, N.; Sisson, TH.; Colby, TV.; Travis, WD.; Martinez, FJ.; Murray, S. "A plasminogen activator inhibitor-1 promoter polymorphism and idiopathic interstitial pneumonia". Mol Med. 9 (1–2): 52–6. PMID 12765340.
- ↑ Takehara, H.; Tada, S.; Kataoka, M.; Matsuo, K.; Ueno, Y.; Ozaki, S.; Miyake, T.; Fujimori, Y.; Yamadori, I. (2001). "Intercellular adhesion molecule-1 in patients with idiopathic interstitial pneumonia". Acta Med Okayama. 55 (4): 205–11. PMID 11512562. Unknown parameter
|month=ignored (help) - ↑ Jakubzick, C.; Choi, ES.; Kunkel, SL.; Evanoff, H.; Martinez, FJ.; Puri, RK.; Flaherty, KR.; Toews, GB.; Colby, TV. (2004). "Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia". J Clin Pathol. 57 (5): 477–86. PMID 15113854. Unknown parameter
|month=ignored (help) - ↑ Keogh, KA.; Limper, AH. (2005). "Characterization of lymphocyte populations in nonspecific interstitial pneumonia". Respir Res. 6: 137. doi:10.1186/1465-9921-6-137. PMID 16287509.
- ↑ Choi, ES.; Jakubzick, C.; Carpenter, KJ.; Kunkel, SL.; Evanoff, H.; Martinez, FJ.; Flaherty, KR.; Toews, GB.; Colby, TV. (2004). "Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia". Am J Respir Crit Care Med. 170 (5): 508–15. doi:10.1164/rccm.200401-002OC. PMID 15191918. Unknown parameter
|month=ignored (help) - ↑ Cottin, V.; Donsbeck, AV.; Revel, D.; Loire, R.; Cordier, JF. (1998). "Nonspecific interstitial pneumonia. Individualization of a clinicopathologic entity in a series of 12 patients". Am J Respir Crit Care Med. 158 (4): 1286–93. doi:10.1164/ajrccm.158.4.9802119. PMID 9769293. Unknown parameter
|month=ignored (help) - ↑ Fujita, J.; Yamadori, I.; Suemitsu, I.; Yoshinouchi, T.; Ohtsuki, Y.; Yamaji, Y.; Kamei, T.; Kobayashi, M.; Nakamura, Y. (1999). "Clinical features of non-specific interstitial pneumonia". Respir Med. 93 (2): 113–8. PMID 10464862. Unknown parameter
|month=ignored (help) - ↑ Nagai, S.; Kitaichi, M.; Itoh, H.; Nishimura, K.; Izumi, T.; Colby, TV. (1998). "Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP". Eur Respir J. 12 (5): 1010–9. PMID 9863989. Unknown parameter
|month=ignored (help) - ↑ Park, CS.; Jeon, JW.; Park, SW.; Lim, GI.; Jeong, SH.; Uh, ST.; Park, JS.; Choi, DL.; Jin, SY. (1996). "Nonspecific interstitial pneumonia/fibrosis: clinical manifestations, histologic and radiologic features". Korean J Intern Med. 11 (2): 122–32. PMID 8854648. Unknown parameter
|month=ignored (help) - ↑ Shimizu, S.; Yoshinouchi, T.; Ohtsuki, Y.; Fujita, J.; Sugiura, Y.; Banno, S.; Yamadori, I.; Eimoto, T.; Ueda, R. (2002). "The appearance of S-100 protein-positive dendritic cells and the distribution of lymphocyte subsets in idiopathic nonspecific interstitial pneumonia". Respir Med. 96 (10): 770–6. PMID 12412975. Unknown parameter
|month=ignored (help) - ↑ Selman, M.; King, TE.; Pardo, A. (2001). "Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy". Ann Intern Med. 134 (2): 136–51. PMID 11177318. Unknown parameter
|month=ignored (help) - ↑ Miki, H.; Mio, T.; Nagai, S.; Hoshino, Y.; Nagao, T.; Kitaichi, M.; Izumi, T. (2000). "Fibroblast contractility: usual interstitial pneumonia and nonspecific interstitial pneumonia". Am J Respir Crit Care Med. 162 (6): 2259–64. doi:10.1164/ajrccm.162.6.9812029. PMID 11112149. Unknown parameter
|month=ignored (help) - ↑ Carilli, AD.; Kotzen, LM.; Fischer, MJ. (1973). "The chest roentgenogram in smoking females". Am Rev Respir Dis. 107 (1): 133–6. PMID 4683317. Unknown parameter
|month=ignored (help) - ↑ Weiss, W. (1984). "Cigarette smoke, asbestos, and small irregular opacities". Am Rev Respir Dis. 130 (2): 293–301. PMID 6380358. Unknown parameter
|month=ignored (help) - ↑ Weiss, W. (1991). "Cigarette smoking and small irregular opacities". Br J Ind Med. 48 (12): 841–4. PMID 1772799. Unknown parameter
|month=ignored (help) - ↑ Dick, JA.; Morgan, WK.; Muir, DF.; Reger, RB.; Sargent, N. (1992). "The significance of irregular opacities on the chest roentgenogram". Chest. 102 (1): 251–60. PMID 1623762. Unknown parameter
|month=ignored (help) - ↑ Myers, JL.; Veal, CF.; Shin, MS.; Katzenstein, AL. (1987). "Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases". Am Rev Respir Dis. 135 (4): 880–4. PMID 3565934. Unknown parameter
|month=ignored (help) - ↑ 34.0 34.1 34.2 Yousem, SA.; Colby, TV.; Gaensler, EA. (1989). "Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia". Mayo Clin Proc. 64 (11): 1373–80. PMID 2593722. Unknown parameter
|month=ignored (help) - ↑ 35.0 35.1 Niewoehner, DE.; Kleinerman, J.; Rice, DB. (1974). "Pathologic changes in the peripheral airways of young cigarette smokers". N Engl J Med. 291 (15): 755–8. doi:10.1056/NEJM197410102911503. PMID 4414996. Unknown parameter
|month=ignored (help) - ↑ 36.0 36.1 Churg, A.; Müller, NL.; Wright, JL. (2010). "Respiratory bronchiolitis/interstitial lung disease: fibrosis, pulmonary function, and evolving concepts". Arch Pathol Lab Med. 134 (1): 27–32. doi:10.1043/1543-2165-134.1.27. PMID 20073602. Unknown parameter
|month=ignored (help) - ↑ 37.0 37.1 Cosio, MG.; Hale, KA.; Niewoehner, DE. (1980). "Morphologic and morphometric effects of prolonged cigarette smoking on the small airways". Am Rev Respir Dis. 122 (2): 265–21. PMID 7416603. Unknown parameter
|month=ignored (help) - ↑ 38.0 38.1 Colby, TV. (1998). "Bronchiolitis. Pathologic considerations". Am J Clin Pathol. 109 (1): 101–9. PMID 9426525. Unknown parameter
|month=ignored (help) - ↑ Moon, J.; du Bois, RM.; Colby, TV.; Hansell, DM.; Nicholson, AG. (1999). "Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease". Thorax. 54 (11): 1009–14. PMID 10525560. Unknown parameter
|month=ignored (help) - ↑ Qiu, YY.; Miao, LY.; Cai, HR.; Xiao, YL.; Ye, Q.; Meng, FQ.; Feng, AN. (2013). "[The clinicopathological features of acute fibrinous and organizing pneumonia]". Zhonghua Jie He He Hu Xi Za Zhi. 36 (6): 425–30. PMID 24103205. Unknown parameter
|month=ignored (help) - ↑ Dinneen, HS.; Samiullah, S.; Lenza, C. (2013). "Cryptogenic organizing pneumonia: A rare extra-intestinal manifestation of Crohn's disease". J Crohns Colitis. doi:10.1016/j.crohns.2013.09.006. PMID 24090908. Unknown parameter
|month=ignored (help) - ↑ Olson, J.; Colby, TV.; Elliott, CG. (1990). "Hamman-Rich syndrome revisited". Mayo Clin Proc. 65 (12): 1538–48. PMID 2255216. Unknown parameter
|month=ignored (help) - ↑ Katzenstein, AL.; Myers, JL.; Mazur, MT. (1986). "Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study". Am J Surg Pathol. 10 (4): 256–67. PMID 3706612. Unknown parameter
|month=ignored (help) - ↑ Kang, D.; Nakayama, T.; Togashi, M.; Yamamoto, M.; Takahashi, M.; Kunugi, S.; Ishizaki, M.; Fukuda, Y. (2009). "Two forms of diffuse alveolar damage in the lungs of patients with acute respiratory distress syndrome". Hum Pathol. 40 (11): 1618–27. doi:10.1016/j.humpath.2009.04.019. PMID 19647854. Unknown parameter
|month=ignored (help) - ↑ Pache, JC.; Christakos, PG.; Gannon, DE.; Mitchell, JJ.; Low, RB.; Leslie, KO. (1998). "Myofibroblasts in diffuse alveolar damage of the lung". Mod Pathol. 11 (11): 1064–70. PMID 9831203. Unknown parameter
|month=ignored (help) - ↑ "American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001". Am J Respir Crit Care Med. 165 (2): 277–304. 2002. doi:10.1164/ajrccm.165.2.ats01. PMID 11790668. Unknown parameter
|month=ignored (help) - ↑ 47.0 47.1 Koss, MN.; Hochholzer, L.; Langloss, JM.; Wehunt, WD.; Lazarus, AA. (1987). "Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases". Pathology. 19 (2): 178–85. PMID 3453998. Unknown parameter
|month=ignored (help) - ↑ Travis, WD.; Fox, CH.; Devaney, KO.; Weiss, LM.; O'Leary, TJ.; Ognibene, FP.; Suffredini, AF.; Rosen, MJ.; Cohen, MB. (1992). "Lymphoid pneumonitis in 50 adult patients infected with the human immunodeficiency virus: lymphocytic interstitial pneumonitis versus nonspecific interstitial pneumonitis". Hum Pathol. 23 (5): 529–41. PMID 1314778. Unknown parameter
|month=ignored (help) - ↑ Lin, RY.; Gruber, PJ.; Saunders, R.; Perla, EN. (1988). "Lymphocytic interstitial pneumonitis in adult HIV infection". N Y State J Med. 88 (5): 273–6. PMID 3288914. Unknown parameter
|month=ignored (help) - ↑ Kurosu, K.; Weiden, MD.; Takiguchi, Y.; Rom, WN.; Yumoto, N.; Jaishree, J.; Nakata, K.; Kasahara, Y.; Tanabe, N. (2004). "BCL-6 mutations in pulmonary lymphoproliferative disorders: demonstration of an aberrant immunological reaction in HIV-related lymphoid interstitial pneumonia". J Immunol. 172 (11): 7116–22. PMID 15153535. Unknown parameter
|month=ignored (help) - ↑ Turner, RR.; Colby, TV.; Doggett, RS. (1984). "Well-differentiated lymphocytic lymphoma. A study of 47 patients with primary manifestation in the lung". Cancer. 54 (10): 2088–96. PMID 6386139. Unknown parameter
|month=ignored (help)