To the Editor:
We read with interest the meta-analysis conducted by Sheng et al1 in an earlier issue of CHEST (May 2020) that provides additional evidence for the role of herpetic infections in idiopathic pulmonary fibrosis (IPF). Although Epstein-Barr virus, cytomegalovirus, human herpesvirus (HHV) 7, and HHV-8 were all found to increase the risk of IPF in this analysis, HHV-6 was not. However, only four of the 20 studies in this meta-analysis checked for HHV-6, and only one study did so in BAL fluid (BALF), where it is most likely to be found. One of these studies did not detect any HHV-6 DNA. One study1 found that five of 13 patients with IPF and seven of 13 control subjects were positive for HHV-6 DNA from the cell pellets of the BAL. The remaining two studies found that HHV-6 or HHV-6B DNA from lung tissue is marginally or significantly associated with IPF. We believe that the apparent discrepancies from these studies may be due to the differences in DNA sources and methods of detection (eg, HHV-6 vs HHV-6B, polymerase chain reaction strategies). Ideally, one should use quantitative polymerase chain reaction (qPCR) to detect HHV-6B/A genomes in BALF. This approach is necessary to differentiate low-level positivity from active infection at a higher viral load. Thus, the results of the current meta-analysis should be interpreted with caution.
We encourage more case-controlled studies using qPCR to determine the association between HHV-6 and the development of IPF, especially considering other stem cell transplantation studies that suggest HHV-6 can promote interstitial lung pathology.2, 3, 4 These studies indicate that HHV-6 infection plays a significant role in lower respiratory tract disease and idiopathic pneumonia syndrome in hematopoietic cell transplant recipients.2,4 HHV-6B infects > 90% of people within the first 2 years of life and maintains latency in host cells.5 Latent HHV-6B/A can be reactivated in transplantation, during which patients are usually immunosuppressed. Although idiopathic pneumonia syndrome and lower respiratory tract disease, which commonly occur following hematopoietic cell transplantation, differ in many ways from IPF, the potential significance of HHV-6 in interstitial lung diseases should not be ignored.
HHV-6 is not commonly recognized as a pulmonary pathogen. As a result, the number of HHV-6 infections associated with interstitial lung diseases may be greatly underreported. We applaud Sheng et al1 for highlighting the importance of herpetic infections in “idiopathic” pulmonary fibrosis and encourage clinicians to consider testing for HHV-6 infection in BALF by using qPCR.
Footnotes
FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.
References
- 1.Sheng G., Chen P., Wei Y. Viral infection increases the risk of idiopathic pulmonary fibrosis: a meta-analysis. Chest. 2020;157(5):1175–1187. doi: 10.1016/j.chest.2019.10.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hill J.A., Vande Vusse L.K., Xie H. Human herpesvirus 6B and lower respiratory tract disease after hematopoietic cell transplantation. J Clin Oncol. 2019;37(29):2670–2681. doi: 10.1200/JCO.19.00908. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Zhou X., O'Dwyer D.N., Xia M. First-onset herpesviral infection and lung injury in allogeneic hematopoietic cell transplantation. Am J Respir Crit Care Med. 2019;200(1):63–74. doi: 10.1164/rccm.201809-1635OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Seo S., Renaud C., Kuypers J.M. Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies. Blood. 2015;125(24):3789–3797. doi: 10.1182/blood-2014-12-617035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zerr D.M., Meier A.S., Selke S.S. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. 2005;352(8):768–776. doi: 10.1056/NEJMoa042207. [DOI] [PubMed] [Google Scholar]