Co-infections of HHV-6 commonly occurs in lung tissues at low levels (<2,000 copies/ 1 million cells) of healthy individuals. Individuals with lung disease, however, have significantly higher levels (Cone 1993, Cone 1996). The development of interstitial pneumonia and pneumonitis is often associated with HHV-6 infection/reactivation in immunocompromised patients and patients who have undergone transplantation (Cone 1994, Carrigan 1991, Hammerling 1996, Yamamoto 2005, Bommer 2009, Costa 2010, Mariotte 2011). Testing for HHV-6 on bronchoalveolar lavage fluid (BALF) should be performed on patients with acute respiratory diseases and/or patients with unexplained ground-glass attenuations on CT scanning (Jouneau 2012). Performing a CT scan around the time of neutrophil engraftment can play an important role in detecting the early phase of HHV-6 pneumonia and BAL should be considered if features consistent with HHV-6 pneumonitis are observed in patients with a risk of HHV-6 reactivation (Ishio 2015).
HHV-6 in “Idiopathic Pneumonia Syndrome”
A recent study using sophisticated testing methods demonstrated that approximately half of patients diagnosed with “idiopathic” pneumonia syndrome had pathogens detected in BAL and that HHV-6 represented 29% of the cases detected. Furthermore, detection of HHV-6 was associated with increased mortality. Thus expanding test panels to include HHV-6 can significantly increase the diagnostic precision for idiopathic pneumonia (Seo 2015).
Interstitial Pneumonia & Pneumonitis
Costa and colleagues analyzed transbronchial biopsies from 30 adult patients who underwent lung transplants and found HHV-6 DNA in 4/13 (30.8%) of samples. A 1993 study at University of Washington found that 6 of 15 transplant patients with pneumonitis had high levels of HHV-6 DNA (>20,000 copies/1 million cells) in a lung biopsy, although all 15 transplant patients and 100% of the seropositive controls were also positive for HHV-6 at low levels. (Cone 1993). Another study of bronchoalveolar lavage fluid found that 80% of CMV positive fluids were also positive for HHV-6 (Buchninder 2000). In another study by Costa and colleagues, 76 bronchoalveolar lavage and transbronchial biopsy paired samples from 27 patients were analyzed. Out of 76 samples, 6 (7.9%) cases were diagnosed with interstitial pneumonia and 5 out of 6 (83.3%) of the CMV positive samples were positive for HHV-6 (Costa 2010). Finally, in a study performed by Yamaguchi et al., BALF from 83 patients was analyzed. Out of 83 patients, 4 were diagnosed with idiopathic interstitial pneumonia. In all 4 patients diagnosed with idiopathic interstitial pneumonia, CMV and/or HHV-6 serological reactivation occurred (Yamaguchi 2003).
Organizing Pneumonia & Bronchiolitis Obliterans
Identification of HHV-6 DNA in BAL is a potential risk factor for bronchiolitis obliterates syndrome (Neurohr 2005) and organizing pneumonia in lung transplant patients. In another study by Costa and colleagues, 76 bronchoalveolar lavage and transbronchial biopsy paired samples from 27 lung transplant patients were analyzed. HHV-6 was positive in 26% of cases, and 23% of lung rejections. Organizing pneumonia was only found in four patients and HHV-6 was positive in all four (Costa 2010). In another study, of seven patients with organizing pneumonia, HHV-7 DNA was found in 7/7 (100%) with HHV-6 co-infections in 2 cases. The authors suggested that HHV-7 immune modulation may contribute to the disease process (Costa 2011).
Primary Infection
A thorough immunologic workup and early start with antiviral therapy in any patient with a life- threatening course of HHV-6 lung infection is mandatory because a severe HHV-6 infection can be the first indication of primary immunodeficiency. HHV-6 infection should be considered in infants and young children with respiratory failure or meningoencephalitis (Hennus 2009).
HHV-6 pneumonitis (Ishio 2015) and acute respiratory failure due to HHV-6 (Mariotte 2011) have been successfully treated with foscarnet antiviral therapy.

Key Papers: HHV-6 & Lung Disease