Sachiko Seo, MD, PhD is a hematologist in the National Cancer Research Center in Japan and an affiliate investigator at the Fred Hutchinson Cancer Research Center in Seattle Washington.
High dose steroids increase the risk of mortality.
A pivotal study, led by Michael Boeckh at the Fred Hutchinson Cancer Research Center, has determined that occult infections contribute to 57% of all cases of “idiopathic” pneumonia syndrome (IPS), a condition previously assumed to be non-infectious. HHV-6 was the dominant pathogen found, representing 29% of cases, after careful analysis of lung fluid and lung biopsies. A total of 69 stem cell transplant patients who had the syndrome were tested for 28 pathogens including 3 bacteria and 25 viruses, and fungal infection. The other occult pathogens found included Aspergillus, cytomegalovirus (CMV) and human rhinovirus. No other significant pathogens were identified used metagenomic next generation sequencing.
The authors describe HHV-6 infection as “occult” because HHV-6 is often not part of the standard testing panel. They noted that the levels of HHV-6 DNA in the serum were much lower than levels in the bronchoaveolar lavage fluid. The other pathogens also had higher levels detected in the lung fluid than in serum.
Mortality of patients who had HHV-6 or human rhinovirus had worse prognosis than those without these infections, and the outcome was similar to those infected with CMV and Aspergillus. The group also discovered that administering high dose steroids to patients with an occult infection can dramatically increase the risk of mortality. Adding high dose steroids after the diagnosis of IPS increased the risk of mortality from lung disease 6.8 fold and the risk of overall mortality 3.5 fold.
Some studies have suggested that steroids may preferentially exacerbate HHV-6 infections. For example, a Japanese study of viral reactivation in drug hypersensitivity reactions showed that steroid administration increased HHV-6 viral load by four logs, while it had only a minimal effect on CMV and EBV (Ishida 2014).
“The study suggests that centers should develop an expanded panel to detect infectious agents including HHV-6”, said Sachiko Seo, first author of the study. The American Thoracic Society currently recommends that physicians test for CMV, RSV, VZV, influenza, parainfluenza, pneumocystis carinii, adenovirus and fungi, although the guidelines suggest that testing for other pathogens be considered.
Idiopathic pneumonia is defined as pneumonia without evidence of a pathogen. The authors estimate incidence of IPS in hematopoietic cell transplant (HCT) patients to be 4-12% with a high rate of mortality of 50-90%.
A similar study done at a hospital in France. Investigators studied 636 BAL fluid samples using a less sensitive herpesvirus consensus PCR; those investigators were only able to identify a pathogen in 30% of cases, of which 17% were HHV-6 (Journeau 2012).
The authors did not differentiate HHV-6A from HHV-6B in this study. Both HHV-6A and HHV-6B have been found in low quantities in the lung tissue. In an earlier study by UW investigators found that 29 out of 29 pneumonia samples and controls were positive for HHV-6 DNA in bronchoaveolar lavage fluid and 54% were co-infected with both viruses (Cone 1996).
HHV-6 was first discovered in bronchial glands by Krueger et al in 1990, and in the lung tissue of transplant patients with interstitial pneumonitis by Carrigan et al in 1991, but few studies have been conducted in intervening 24 years.
Occult HHV-6 infections often occur in other conditions as well, in part because it is difficult to detect HHV-6 DNA in the plasma or CSF in spite of a persistent infection in organs such as the liver and heart or brain (Buyse 2013, Leveque 2011, Fotheringham 2007a).
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