Nonprimary HHV6 infection and the respiratory tract

As more than 95% of HHV-6 infections occur during the first two years of life, most HHV-6 infections observed at later ages (especially in teens and adults) are probably reactivations of latent infections or de novo infections with a second virus (Krueger et al., 1998b; Ablashi and Krueger, 2003). Non-primary HHV-6 infections of the respiratory tract occur preferentially in immunodeficient patients, yet may occasionally also be seen in not obviously compromised persons. Any conclusion about HHV-6 being the etiological agent for a pulmonary inflammation is complicated by the fact that there is a high incidence of HHV-6 DNA in lung tissues from not obviously sick persons (Cone et al., 1996) suggesting this organ as one site of viral persistence after primary infection. The diagnosis of HHV-6 caused pneumonitis must consequently be based upon the triad, (a) evidence of an ongoing active infection (serology and/or virus isolation), (b) demonstration of replicating virus at the site of the tissue lesion (e.g. by showing p41 antigen in biopsy specimens), and (c) effectiveness of tentative anti-HHV-6 therapy (Leland and Emmanuel, 1995; Ablashi and Krueger, 2003). Finally, in any such cases, an infection or coinfection with the closely related HHV-7 should be considered (Ross et al., 2001; Yamamoto et al., 2005).

Interstitial pneumonia in not overtly immunocompromised persons

There are only very limited case reports of HHV-6 infection causing interstitial pneumonia, and most of these patients can hardly be considered immunologically "normal" (Cone, 1995). Russler and co-workers (1991) reported a case of pneumonitis in a young healthy man caused by coinfection with HHV-6 and Legionella pneumophila. He suffered from severe pulmonary, renal, hepatic and CNS dysfunctions. Legionella organisms were cultured from his lungs, yet specific antibiotic therapy produced no response. HHV-6 was isolated from the patient's blood cells, and the virus was also shown in lung biopsies with pneumonitis. Highdose corticosteroid therapy suppressed the inflammatory reaction, inhibited the HHV-6 replication and supported the clearance of the Legionella infection. It was thought that HHV-6 may have worked synergistically with Legionella in causing the severe pneumonitis. Another coinfection of HHV-6 and Pneumocystis carinii was associated with interstitial pneumonitis in a patient with hypogamma glo-bulinemia (Vuorinen et al., 2004). This patient, however, was obviously not fully immunocompetent. Similarly, antitumor chemotherapy supported the development of HHV-6-induced pneumonitis in a patient with malignant astrocytoma (Safdar and Brown, 2001). Of the four patients of Hammerling and co-workers (1996) with HHV-6-associated interstitial pneumonia, two were immunodeficient, one had congenital anomalies and one suffered from hepatitis of unknown etiology.

Totani and co-workers (2001) described an HHV-6-positive interstitial pneumonitis in a 47-year-old woman with Sjoegren's syndrome and Lupus ery-thematosus. Both autoimmune diseases were previously shown to be accompanied by higher incidences of HHV-6 reactivation (Krueger et al., 1991; De Clerck et al., 1992).

Pneumonitis in immunosuppressed patients

HHV-6 is a common latent resident in the normal lung (Cone et al., 1996), and even viral reactivation does not necessarily cause disease in immunologically competent persons. HHV-6 can be demonstrated in some 33% of bronchial lavages in healthy volunteers (Nagate et al., 2001). It may become pathogenic, though, if certain immune deficiency permits the persistent activity and replication of the virus quite similar to other "opportunistic" viruses such as Epstein-Barr virus (Purtilo et al.,

1985; Krueger and Ferrer-Argote, 1994; Singh and Carrigan, 1996; Krueger et al., 1998a).

There are large numbers of publications reporting severe and even lethal HHV-6-associated interstitial pneumonias in immunocompromised patients. These patients were preferentially various organ transplant recipients, or they suffered from HIV infection, immune deficiency or autoimmune disorders (Carrigan et al., 1991; Cone et al., 1993, 1994, 1995, 1996; Pitala et al., 1993; Knox and Carrigan, 1994; Buchbinder et al., 2000; Nagate et al., 2001; Totani et al., 2001; Michaelides et al., 2002; Taplitz and Jordan, 2002; Yata et al., 2002; Hentrich et al., 2004; Yamamoto et al., 2005). HHV-6 was usually confirmed as an etiological agent of interstitial pneumonia by showing large amounts of viral DNA in blood and lung tissue, or by finding the HHV-6 replication-associated antigen p41 at the inflammatory site in the lung. Pathologic changes are classified as non-specific interstitial pneumonitis (NIP) or lymphoid interstitial pneumonitis [LIP; (Fig. 3)]. An addition of alveolar exudates (''alveolar pneumonia'') signifies secondary superinfection or coinfection. Dual or multiple infections are not uncommon in such cases with organisms

Fig. 3 Top row: non-specific interstitial pneumonitis (NIP) in patient with acute necrotizing encephalitis following primary HHV-6 infection (Wagner et al., 1997). Bottom row: lymphoid interstitial pneumonitis (LIP) in patient with HIV infection and HHV-6 reactivation red cells immunohistochem-ical APAAP reaction for HHV-6 p41 antigen (courtesy of G. Krueger, Immunopathology Laboratory, University of Cologne, Germany). (for colour version: see colour section on page 354).

Fig. 3 Top row: non-specific interstitial pneumonitis (NIP) in patient with acute necrotizing encephalitis following primary HHV-6 infection (Wagner et al., 1997). Bottom row: lymphoid interstitial pneumonitis (LIP) in patient with HIV infection and HHV-6 reactivation red cells immunohistochem-ical APAAP reaction for HHV-6 p41 antigen (courtesy of G. Krueger, Immunopathology Laboratory, University of Cologne, Germany). (for colour version: see colour section on page 354).

including P. carinii, L. pneumophila, human cytomegalovirus, adenovirus or a co-infection with HHV-6 variant A and B (Russler et al., 1991; Cone et al., 1996; Hammerling et al., 1996; Vuorinen et al., 2004).

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