EBV Causes Interstitial Lung Disease


Facts and controversies in the classification of idiopathic interstitial pneumonias. V Poletti, M Kitaichi. Sarcoidosis Vasc Diffuse Lung Dis 2000 Oct;17(3):229-238. "Idiopathic interstitial pneumonias are defined from the pathological point of view as non granulomatous intralobar inflammatory and fibrotic processes involving the alveolar walls. More than thirty years ago Liebow and Carrington pioneered the notion that morphological characteristics could be used with benefit in separating the different entities found in this group, which present with typical, but not pathognomonic clinical features. In the mid-1980s some entities, including giant cell interstitial pneumonia (GIP) and lymphocytic interstitial pneumonia (LIP), were removed from this group and considered as peculiar forms. In the early 90s the concept of cellular or nonspecific interstitial pneumonia was reconsidered, leading to an in depth revision of various types of interstitial pneumonia of unknown etiology. The histological pattern observed in patients with idiopathic pulmonary fibrosis is now referred to as usual interstitial pneumonia (UIP). Other entities that have been revised during the last ten years are desquamative interstitial pneumonia/alveolar acute interstitial pneumonia (DIP/AMP), respiratory bronchiolitis-interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP) and nonspecific interstitial pneumonia (NSIP). This paper provides a detailed description of pulmonary disorders which have been included in the new classification systems of idiopathic interstitial pneumonias..."

Poletti - Sarcoidosis Vasc Diffuse Lung Dis 2000 abstract / PubMed

Idiopathic Pulmonary Fibrosis

(Also called Cryptogenic Fibrosing Alveolitis)

Cryptogenic fibrosing alveolitis and Epstein-Barr virus: an association? JM Vergnon, M Vincent, G de The, JF Mornex, P Weynants, J Brune. Lancet 1984 Oct 6;2(8406):768-771. IgA against EBV VCA in 13/13 CFA patients, versus 1/12 patients with lung disease of known cause.

Vergnon - Lancet 1984 abstract / PubMed

Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis. JJ Egan, JP Stewart, PS Hasleton, JR Arrand, KB Carroll, AA Woodcock. Thorax 1995 Dec;50(12):1234-1239. 20 patients, 21 controls. "Fourteen (70%) of the 20 patients with cryptogenic fibrosing alveolitis were positive for both EBV VCA and gp 340/220 compared with two (9%) of the 21 controls. In the patients with cryptogenic fibrosing alveolitis viral replication was localised to pulmonary epithelial cells using epithelial cell markers, and immunohistochemical analysis confirmed the staining to be within type II alveolar cells."

Egan - Thorax 1995 full article / PubMed Central

Elevation of antibodies to cytomegalovirus and other herpes viruses in pulmonary fibrosis. M Yonemaru, I Kasuga, H Kosumoto, A Kunisawa, S Kuwabara, Y Ichinose, K Toyama. Eur Respir J 1997 Sep;10(9):2040-2045. 43 patients with IPF, 7 collagen vascular disease related interstitial pneumonitis, 22 sarcoidosis, 17 emphysema, 35 normal controls. CMV and EBV were elevated in IPF and CVD-IP versus others.

Yonemaru - Eur Respir J 1997 abstract / PubMed
Yonemaru - Eur Respir J 1997 Full Article (pdf, 6pp)

Cryptogenic fibrosing alveolitis: lack of association with Epstein-Barr virus infection. A Wangoo, RJ Shaw, TC Diss, PJ Farrell, RM du Bois, AG Nicholson. Thorax 1997 Oct;52(10):888-891. No EBV found in any CFA patients, with or without systemic sclerosis; patients with other pulmonary diseases; or normal lung.

Wangoo - Thorax 1997 abstract / PubMed

The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis. JP Stewart, JJ Egan, AJ Ross, BG Kelly, SS Lok, PS Hasleton, AA Woodcock. Am J Respir Crit Care Med 1999;159(4):1336-1341. 27 IPF patients vs 28 controls, positive by both IHC + PCR, p=0.001. "The presence of IgA antibodies to EBV VCA has been correlated with a diagnosis of IPF. This marker is an indicator of active EBV replication at an epithelial surface. Our previous and current finding of active EBV replication therefore corroborates the IgA serology, and this study confirms previous immunohistochemical observations. EBV antigens and DNA in the lower respiratory tract were significantly associated with a diagnosis of IPF." They also note that formalin fixation of samples can cause protein degradation and thus loss of detection in samples. Re Wangoo et al: "The inability of Wangoo and colleagues to identify any EBV DNA in lung tissue is perhaps more surprising. Even if EBV were not associated with IPF one would expect to find a low-level background of EBV DNA in lung tissue simply because of the blood volume in this organ."

Stewart - Am J Respir Crit Care Med 1999 full article

Chronic interstitial lung disease due to Epstein-Barr virus infection in two infants. A Pfleger, E Eber, H Popper, MS Zach. Eur Respir J 2000 Apr;15(4):803-806.

Pfleger - Eur Respir J 2000 abstract / PubMed
Pfleger - Eur Respir J 2000 Full Article (pdf, 4pp)

Involvement of Epstein-Barr virus latent membrane protein 1 in disease progression in patients with idiopathic pulmonary fibrosis. K Tsukamoto, H Hayakawa, A Sato, K Chida, H Nakamura, K Miura. Thorax 2000 Nov;55(11):958-961. 29 IPF patients, 5 systemic sclerosis with pulmonary fibrosis, 15 controls. IPF vs controls OR=9.60, 95% CI 0.9-96.9.

Tsukamoto - Thorax 2000 abstract / PubMed
Tsukamoto - Thorax 2000 Full Article

Epstein-Barr virus and wild p53 in idiopathic pulmonary fibrosis. SS Lok, JP Stewart, BG Kelly, PS Hasleton, JJ Egan. Respir Med 2001 Oct;95(10):787-791. Lung biopsies of 8/14 IPF patients vs 0/19 controls, P<0.01.

Lok - Respir Med 2001 abstract / PubMed

A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fibrosis. BG Kelly, SS Lok, PS Hasleton, JJ Egan, JP Stewart. Am J Respir Crit Care Med 2002;166(4):510-513. 39 patients with IPF, 26 lung transplant recipients, and 24 normal subjects. "[I]n blood-derived cells most (81–85%) of the IPF patients and control subjects tested were positive for EBV DNA and there was no significant difference in the frequency of detection of viral DNA between the groups. This is as expected because most subjects in the age ranges studied are EBV-positive and carry EBV in peripheral blood B cells (4). However, there was a highly significant association between the presence of WZhet-rearranged DNA in peripheral blood and IPF (p = 0.00001). In fact, only 1 of the 50 control samples, from a blood donor, was WZhet-positive." "WZhet-rearranged EBV is associated with productive EBV replication. Indeed, the introduction of DNA containing this rearrangement reactivates EBV from latency."

Kelly - Am J Respir Crit Care Med 2002 Full Article

Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. Y-W Tang, JE Johnson, PJ Browning, RA Cruz-Gervis, A Davis, BS Graham, KL Brigham, JA Oates Sr., JE Loyd, AA Stecenko. J Clin Microbiol 2003 Jun;41(6):2633-2640. 8 patients with familial IPF, 25 patients with sporadic IPF, and 25 patients with other diseases as controls. "One or more of four herpesviruses (cytomegalovirus [CMV], EBV, human herpesvirus 7 [HHV-7], and HHV-8) were detected in 32 of 33 (97%) subjects with IPF and in 9 of 25 (36%) controls (P < 0.0001). CMV, EBV, and HHV-8 were found more frequently in IPF patients than in controls (P < 0.05, P < 0.001, and P < 0.01 respectively). Two or more herpesviruses were detected in 19 of 33 (57%) IPF patients and in 2 of 25 (8%) controls (P < 0.001). Two or more herpesviruses and HHV-8 were found more frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05 for both comparisons), and CMV was found less frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05)."

Tang - J Clin Microbiol 2003 Full Article

HHV-8 and EBV are not commonly found in idiopathic pulmonary fibrosis. A Zamņ, V Poletti, D Reghellin, L Montagna, S Pedron, P Piccoli, M Chilosi. Sarcoidosis Vasc Diffuse Lung Dis 2005 Jun;22(2):123-128. "[I]mmunohistochemical, in-situ hybridisation and PCR results were negative for both EBV and HHV-8," no details on subjects in abstract.

Zamņ - Sarcoidosis Vasc Diffuse Lung Dis 2005 abstract / PubMed

Epstein-Barr virus DNA in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis. K Manika, S Alexiou-Daniel, D Papakosta, A Papa, T Kontakiotis, D Patakas, A Antoniadis. Sarcoidosis Vasc Diffuse Lung Dis 2007 Sep;24(2):134-140. "Statistically significant differences were observed in the frequency of IgA antibodies to viral capsid antigen among patients with idiopathic pulmonary fibrosis, patients with other interstitial lung diseases and healthy controls (60%, 24.4% and 22% respectively, p = 0.013). Epstein-Barr virus DNA was detected in the bronchoalveolar lavage fluid of 3 patients with idiopathic pulmonary fibrosis but in none of the patients with other diseases (p = 0.024). "

Manika - Sarcoidosis Vasc Diffuse Lung Dis 2007 abstract / PubMed

Viruses as co-factors for the initiation or exacerbation of lung fibrosis. KM Vannella, BB Moore. Fibrogenesis Tissue Repair 2008 Oct 13;1(1):2. REVIEW.

Vannella & Moore - Fibrogenesis Tissue Repair 2008 full article / PubMed Central
Vannella & Moore / Fibrogenesis Tissue Repair 2008 full article

The HLA class II Allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis. J Xue, BR Gochuico, AS Alawad, CA Feghali-Bostwick, I Noth, SD Nathan, GD Rosen, IO Rosas, S Dacic, I Ocak, CR Fuhrman, KT Cuenco, MA Smith, SS Jacobs, A Zeevi, PA Morel, JM Pilewski, VG Valentine, KF Gibson, N Kaminski, FC Sciurba, Y Zhang, SR Duncan. PLoS One 2011 Feb 23;6(2):e14715. "HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036)." [DRB1*1501 is also over-represented among patients with MS, another EBV-related disease - cast] Also, "Abnormal proportions of phenotypically and functionally distinct CD4+CD28null T-cells, the daughter progeny of repetitive antigen-driven lymphocyte proliferations, and a frequent and specific finding of chronic immunologic diseases are also present in the circulation (and lungs) of IPF patients singularly destined for poor outcomes." [CD4+CD28null T-cells are specific for cytomegalovirus - cast]

Xue - PLoS One 2011 full article / PubMed Central
Xue / PLoS One 2011 full article

A novel screening method detects herpesviral DNA in the idiopathic pulmonary fibrosis lung. V Pulkkinen, K Salmenkivi, VL Kinnula, E Sutinen, M Halme, U Hodgson, J Lehto, A Jääskeläinen, H Piiparinen, J Kere, I Lautenschlager, M Lappalainen, M Myllärniemi. Ann Med 2012 Mar;44(2):178-186. "11/12 IPF samples were positive for Epstein-Barr virus (EBV) and 10/12 for human herpesvirus 6B (HHV-6B) DNA. Control lung samples (n = 10) were negative for EBV DNA, whereas three samples were positive for HHV-6B. EBV-encoded RNA (EBER) was identified in nine IPF samples and localized mainly to lymphocytic aggregates. HHV-6B antigens were detected in mononuclear cells in IPF lung tissue. CD20+ B lymphocytic aggregates that were surrounded by CD3+ T cells were abundant in IPF lungs. CD23+ cells (activated B cells, EBV-transformed lymphoblasts, and dendritic cells) were observed in the aggregates. IPF patients had no signs of increased herpesviral activation after lung transplantation." Inflammatory cells are the main source of herpesviral DNA.

Pulkkinen - Ann Med 2012 abstract / PubMed

Herpes virus infection is associated with vascular remodeling and pulmonary hypertension in idiopathic pulmonary fibrosis. F Calabrese, A Kipar, F Lunardi, E Balestro, E Perissinotto, E Rossi, N Nannini, G Marulli, JP Stewart, F Rea. PLoS One 2013;8(2):e55715. 55 IPF patients and 41 controls. "Patients with IPF showed a higher frequency of viral infection than control cases (40% vs 7.3%; p = 0.0003). Normal lungs were all negative. Herpes viruses were the only detected genomes in IPF and EBV resulted as the most frequent, present in more than half of IPF patients... RNA-ISH for EBV (EBER) identified viral RNA in 40% of EBV-PCR positive IPF cases. The positivity was detected in alveolar epithelial cells other than within monocytes/macrophages (Figure 1). Real time PCR showed a high number of EBV genome copies (mean±SD:1085000±120208 copies/µl DNA)."

Calabrese - PLoS One 2013 full article / PubMed Central
Calabrese / PLoS One 2013 full article

[Lung injury associated with severe Epstein-Barr virus (EBV) infection]. Y Cui, Y Zhang, F Wang, Y Zhu, R Chen, L Xu. Zhonghua Er Ke Za Zhi 2015 Aug;53(8):586-591. 45 children with severe EBV infection (27 without lung injury, 12 lung injury without pulmonary fibrosis, 6 with pulmonary fibrosis). "EB virus infection complicated with lung injury had higher incidence of respiratory failure, pulmonary fibrosis with a fatal outcome. EBV-DNA and serum TNF-α level were found to be statistically significant indicators of pulmonary fibrosis. Pulmonary fibrosis associated with severe EB virus infection may be reversible."

Cui - Zhonghua Er Ke Za Zhi 2015 abstract / PubMed

Idiopathic Interstitial Pneumonia

[Serum antibody titers against various viruses in idiopathic interstitial pneumonia]. K Ohta, N Kobayashi, A Ishii, H Takizawa, T Miyamoto. Nihon Kyobu Shikkan Gakkai Zasshi 1989 May;27(5):604-608. 98 IIp patients, 45 normal controls. EBV-VCA IgG was higher in IIP, p < 0.01.

Ohta - Nihon Kyobu Shikkan Gakkai Zasshi 1989 abstract / PubMed

Detection of Epstein-Barr virus in lymphocytic interstitial pneumonia by in situ hybridization. JA Barbera, S Hayashi, RG Hegele, JC Hogg. Am Rev Respir Dis 1992 Apr;145(4 Pt 1):940-946. EBV found in archival samples of 9/14 LIP patients versus 2/10 IPF patients as ill-chosen controls. "We conclude that EBV may promote the proliferation of B-lymphocytes in a substantial number of patients with LIP."

Barbera - Am Rev Respir Dis 1992 abstract / PubMed

Detection of human cytomegalovirus, Epstein-Barr virus, and herpes simplex virus in diffuse interstitial pneumonia by polymerase chain reaction and immunohistochemistry. Y Oda, S Katsuda, Y Okada, EI Kawahara, A Ooi, A Kawashima, I Nakanishi. Am J Clin Pathol 1994 Oct;102(4):495-502. 54 (primary or secondary) DIP patients versus 32 non-lung disease controls. 40% of patients vs 0% of controls were CMV+; 30% of patients vs 0% of controls were EBV+.

Oda - Am J Clin Pathol 1994 abstract / PubMed

Immunohistochemical study on the infection of herpes simplex virus, human cytomegalovirus, and Epstein-Barr virus in secondary diffuse interstitial pneumonia. Y Oda, Y Okada, S Katsuda, I Nakanishi. Hum Pathol 1994 Oct;25(10):1057-1062. 61 SDIP autopsy cases versus 46 non-lung disease controls. 36.1% of cases were CMV+ and 31.1% were EBV+, vs 0% of controls.

Oda - Hum Pathol 1994 abstract / PubMed

Investigation of EB virus and cytomegalovirus in rapidly progressive interstitial pneumonitis in polymyositis/dermatomyositis by in situ hybridization and polymerase chain reaction. Y Hashimoto, Y Nawata, K Kurasawa, K Takabayashi, K Oda, A Mikata, I Iwamoto. Clin Immunol Immunopathol 1995 Dec;77(3):298-306. EBV found in 13/15 RPIP + collagen disease, versus 1/6 controls.

Hashimoto - Clin Immunol Immunopathol 1995 abstract / PubMed

Langerhans Cell Histiocytosis

(Also known as Histiocytosis-X; Eosinophilic granuloma; Hand Schuller Christian syndrome; Letterer-Siwi disease. Other terms used to describe symptoms which are considered to be Langerhans cell histiocytosis: reticuloendotheliosis; Hashimoto-Pritzker syndrome; self-healing histiocytosis; pure cutaneous histiocytosis; Langerhans cell granulomatosis; type II histiocytosis; nonlipid reticuloendotheliosis. 76 percent of cases are in children less than ten years old, but it is also seen in adults of all ages.)

Langerhans cell histiocytosis: lack of a viral etiology. K McClain, H Jin, V Gresik, B Favara. Am J Hematol 1994 Sep;47(1):16-20. 56 cases. "We sought and failed to find evidence of genomes for adenovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, human herpesvirus type 6, human immunodeficiency virus, human T-cell leukemia virus types I and II, and parvovirus" by PCR. The same criticism applied to Wangoo et al applies here.

McClain - Am J Hematol 1994 abstract / PubMed

Human cytomegalovirus infection in foci of Langerhans cell histiocytosis. Y Kawakubo, H Kishimoto, Y Sato, K Yanagimoto, T Tsuruta, Y Ogawa, T Kameya. Virchows Arch 1999 Feb;434(2):109-115. CMV was found in 10 / 27 LCH lesions by ISH.

Kawakubo - Virchows Arch 1999 abstract / PubMed

Expression of Epstein-Barr virus in Langerhans' cell histiocytosis. M Shimakage, T Sasagawa, M Kimura, T Shimakage, S Seto, K Kodama, H Sakamoto. Hum Pathol 2004 Jul;35(7):862-868. 17 LCH cases. "All cases showed positive hybridization signals by BamHIW mRNA in situ hybridization. Also, 13 and 14 cases showed positive signals for EBNA2 and EBER1 RNA in situ hybridization, respectively. Furthermore, almost all cases exhibited fluorescence after immunofluorescence staining with monoclonal anti-EBNA2 and anti-BZLF1 antibodies, and 15 cases were positive after treatment with monoclonal anti-LMP1 antibody. PCR-Southern blotting detected an amplified EBER1 sequence in all 9 cases examined. EBV expression was confirmed in LCH using in situ hybridization and immunofluorescence. Furthermore, EBV DNA was also detected by PCR-Southern blotting. These positive results of BZLF1 suggest that EBV replicates in LCH tissues."

Shimakage - Hum Pathol 2004 abstract / PubMed

Herpes-virus infection in patients with Langerhans cell histiocytosis: a case-controlled sero-epidemiological study, and in situ analysis. E Jeziorski, B Senechal, TJ Molina, F Devez, M Leruez-Ville, P Morand, C Glorion, L Mansuy, J Gaudelus, M Debre, F Jaubert, JM Seigneurin, C Thomas, I Joab, J Donadieu, F Geissmann. PLoS ONE 2008 Sep 23;3(9):e3262. 83 patients and 236 age-matched controls. "[P]revalence, serological titers, and viral load for EBV, CMV and HHV-6 did not differ between patients and controls. EBV was found by PCR in tumoral sample from 3/19 patients, however, EBV small RNAs EBERs –when positive-, were detected by in situ double staining in bystander B CD20+ CD79a+ lymphocytes and not in CD1a+ LC. HHV-6 genome was detected in the biopsies of 5/19 patients with low copy number and viral Ag could not be detected in biopsies. CMV was not detected by PCR in this series."

Jeziorski - PLoS ONE 2008 full article / PubMed Central
Jeziorski / PLoS ONE 2008 full article

Detection of Epstein-Barr Virus DNA in Langerhans Cell Histiocytosis. M Khoddami, SA Nadji, P Dehghanian, M Vahdatinia, AR Shamshiri. Jundishapur J Microbiol 2015 Dec 26;8(12):e27219. 30 patients with LCH and 30 controls. "The EBV was found by RT-PCR in 19 (63.33%) out of 30 patients and only in eight (26.7%) of 30 control samples. The P = 0.004, was calculated using chi-square test (OR: 4.75; 95% CI: 1.58 ‒ 14.25)."

Nadji - Jundishapur J Microbiol 2015 abstract / PubMed

See Also:

Epstein-Barr Virus Causes Lymphomas
EBV Causes Lymphoepithelioma-like Lung Cancer
Epstein-Barr Virus Causes Gastric Carcinoma
EBV & Socioeconomic Status
EBV Causes Nasopharyngeal Cancer
EBV and Other Diseases
EBV Causes Multiple Sclerosis
Epstein-Barr Virus Causes Sjogren’s Syndrome
EBV Causes Lupus


cast 02-14-16