key: cord-0036829-5386g91w authors: Kradin, Richard L.; Fishman, Jay A.; Ferry, Judith A. title: Herpesvirus date: 2013-08-26 journal: Viruses and the Lung DOI: 10.1007/978-3-642-40605-8_6 sha: 56ff3fff3abc95aad00fd474acd24cd9e5c8e749 doc_id: 36829 cord_uid: 5386g91w Name: Herpesvirus Herpesviridae (HSV) is a DNA virus family that includes the order Herpesvirales and a number of species, some of which are addressed separately in this text. The herpesviruses cause both lytic and latent infections. Herpesviruses 1 and 2 infect the lung via the spread of virus from infected oral or esophageal lesions, by hematogenous dissemination, or via the transplantation of infected organs (Graham and Snell 1983 ; Taplitz and Jordan 2002 ; Tuxen et al. 1982 ) . Herpesviruses 6 and 8 can also produce lung pathology although their role in pathogenesis is not well elucidated. In the 1970s, the genus Herpesvirus was elevated to the order Herpesviridae . This includes three families, three subfamilies plus one unassigned subfam-ily, 17 genera, 90 species, and more than 48 as yet unassigned viruses. The naming system specifi es that each herpesvirus should be named after the taxon to which its primary host belongs. The herpesvirus is followed by an Arabic number, e.g., Herpesvirus 1. However, human herpesviruses represent an exception, as a number are better known by other names (e.g., Epstein-Barr virus) so that it is impractical to insist on a change into how they are referred. This has led to a dual nomenclature for some herpesviruses ; however, all new herpesviruses described since this system was adopted are named in accordance with it. Nine herpesviruses currently are recognized to cause human disease. Herpesviruses are large (100-110 nm) enveloped double-stranded DNA viruses with an icosahedral nucleocapsid ( Fig. 6 .1 ). The viral particle is invested with a lipid envelope as a result of viral budding at the level of the nuclear envelope (Whitley et al. 1998 ). Herpesvirus types 1 and 2 can both infect the lung (Ramsey et al. 1982 ) . HSV-1 is the most frequent cause of primary disease, whereas HSV-2 generally results from viremic spread. All herpesviruses are nuclear replicating , i.e., the viral DNA is transcribed to mRNA within the infected cell's nucleus and the mRNA gene products promote the replication of the viral DNA. Infection is initiated when a viral particle contacts a cell with specifi c types of cell surface membrane receptors. Following binding of viral envelope glycoproteins to their receptors, the virion is internalized and dismantled, so that viral DNA can migrate to the cell nucleus where replication of viral DNA and transcription of viral genes occur. During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latencyassociated transcripts (LAT) accumulate and allow the virus to persist in the host cell indefinitely. During latency, the infected host is asymptomatic, but reactivation of latent viruses can result in disease. In such case, the transcription of latency-associated LAT genes switches to that of lytic genes that lead to enhanced virus production and cell death. Symptoms and signs may include low-grade fever, headache, sore throat, and rash, as well as lymphadenopathy and reduced levels of circulating immune cells. Infection is long lived, as viral DNA persist in dormant states within sensory nerves and ganglia. HSV-1 reactivation begins in peripheral nerve cells, and viruses are transported via sensory nerve axons to mucosal surfaces, where they can produce vesicular eruptions. Young age, airway trauma, airway burns, prolonged mechanical ventilation, and immunosuppression are risk factors for developing herpetic pneumonia (Cherr et al. 2000 ; Sherry et al. 1988 ). Newborn infants are particularly at risk and may develop disseminated disease with pulmonary infi ltrates and mortality rates (even following acyclovir therapy) approaching 30 % (Kimberlin 2004 ) . In adults, HSV is isolated from secretions in ~30 % of mechanically ventilated patients, and evidence suggests that Herpesviruses may be an important factor in severe exacerbations of chronic obstructive pulmonary disease (Gu and Korteweg 2007 ) . Dyspnea, cough, and hypoxemia are common in this setting. Acute Respiratory Distress Syndrome (ARDS) can develop with virulent herpetic infection, and bacterial and fungal superinfections are both common and can be fatal when they supervene. Herpesvirus can also complicate ARDS (Byers et al. 1996 ) . The chest radiographic appearances of Herpesvirus infection range from mucosal thickening of the pulmonary airways, multifocal areas of consolidation, and diffuse bilateral pulmonary infi ltrates. Herpesvirus tracheobronchial infections tend to complicate labial and esophageal disease with virus spreading via the aspiration of oropharyngeal secretions (Corey and Spear 1986 ; Feldman and Stokes 1987 ) . Intubated patients receiving chronic ventilatory support are at risk as a consequence of local mucosal barotrauma from infl ated endotracheal tubes. The respiratory mucosa is the primary target, and Herpesvirus characteristically produces ulceration and extensive necrosis (Nash and Foley 1970 ) . The ballooning of infected cells, cell karyorrhexis, and piling up of the infected cells suggest the diagnosis. There may be a prominent neutrophilic response that mimics a pyogenic bacterial infection (Fig. 6. 2 ). Immunosuppressed patients with Herpesvirus viremia may develop miliary foci of pulmonary hemorrhagic necrosis with prominent alveolar fi brin exudates (Graham 1983 ) (Fig. 6.3 ) . The foci of infection may be paucicellular although scattered neutrophilic exudates are frequently present. Diagnostic cytopathic changes may be diffi cult to identify but will usually be visualized after detailed examination of the involved foci. The diagnosis of airway disease can be established by viral isolation from respiratory secretions, bronchoalveolar lavage fl uids, or mucosal biopsies of ulcerated sites ( Fig. 6.4 ) . As immunohistochemistry shows antigenic overlap between HSV-1 and HSV-2 infections, PCR methods may be required for accurate speciation. Diagnostic cytopathic changes include the presence of either type A or type B Cowdry nuclear inclusions, molding of adjacent cells, and multikaryon formation Fig. 6 .5 ). When there is extensive necrosis, immunohistochemistry for herpes viral antigen will often demonstrate intense background staining. While this suggests the diagnosis, it can potentially obscure it (Strickler et al. 1990 ) (Fig. 6.6b ) . The examination of paraffi nembedded tissues by electron microscopy can help to confi rm the diagnosis. Necrotizing hemorrhagic pneumonias due to Herpesviruses are similar histopathologically to those associated with varicella zoster, adenovirus, and cytomegalovirus (CMV). Helpful in making the distinction are the location and character of the viral inclusions. For example, smudge a b Fig. 6 .6 ( a ) Ulcerated tracheal lesion showing ( b ) intense immunostaining for Herpesvirus-1. The diagnosis was confi rmed by ultrastructural examination demonstrating diagnostic virions cells are strongly suspicious of adenovirus while cytomegaly is more apt to be seen in CMV infection. Immunohistochemistry plays an important role and can help to refi ne the diagnosis. Therapy is based primarily on the usage of antiviral agents such as acyclovir, valacyclovir, and famciclovir. Drug-resistant strains may respond to fosecarnet. Fosecarnet has been found effective in some acyclovir-resistant patients. Supportive therapy, hydration, and treatment of associated bacterial infection are indicated in selected patients. Herpesviruses can infect the lung as well as the mucosa of the tracheobronchial tree. Young age, airway trauma, prolonged mechanical ventilation, and immunosuppression are risk factors for development of herpetic infections. Biopsy samples from the respiratory mucosa showing ballooning of infected cells, cell karyorrhexis, and piling up of infected cells suggest the diagnosis. The diagnosis can be confi rmed with appropriate immunohistochemical stains or by identification of Cowdry type A or B in infected cells. A rare and distinctive type of malignant lymphoma occurs in patients infected with Human Herpesvirus-8. This lymphoma has equally distinctive molecular features (mutations in the 5″ noncoding regions of bcl6) that help to make the diagnosis. Studies of lung tissues and bronchoalveolar lavage specimens from patients with pneumonia have led some investigators to propose Human Herpesvirus 6 (HHV-6) as a clinical cause of pneumonia (Cone et al. 1994 ) . Cases should be referred to as " HHV-6-associated" pneumonia. Both mild and severe cases of pneumonia and bronchiolitis obliterans organizing pneumonia (BOOP) have been reported for HHV-6 infection occurring in immunosuppressed individuals with HIV or following bone marrow transplantation. No systematic evaluation of treatment regimens is currently available, and controlled prospective studies are required to confi rm HHV-6 as a primary pulmonary pathogen. In addition to its role in Kaposi's sarcoma and multicentric Castleman's disease, HHV-8 has been suggested as a cause of interstitial pneumonitis. Primary effusion lymphoma, previously called body-cavity-based lymphoma, is a rare, distinctive type of HHV8+ diffuse large B-cell lymphoma characterized by lymphomatous effusions involving pleural, pericardial, or peritoneal cavities unaccompanied by a solid mass (Ansari et al. 1996 ; Cesarman et al. 1995 ; Said and Cesarman 2008 ). Here we discuss only primary effusion lymphoma. Primary effusion lymphoma (PEL) affects young and middle-aged adults, with males more often affected than females. Nearly all patients are also HIV positive. They present late in the course of HIV infection and are profoundly immunocompromised at the time of presentation. Patients who are HIV negative are mostly elderly and often of Mediterranean origin (Ferry et al. 2008 ; Klepfi sh et al. 2001 ; Nador et al. 1996 ) . Patients present with a pleural effusion, pericardial effusion, or ascites. By defi nition, there is no discrete contiguous lymphomatous mass associated with the effusion. PEL has a poor prognosis, although among HIV+ patients, the outcome may be better for those receiving highly active antiretroviral therapy (HAART) (Boulanger et al. 2005 ) . Death is due to lymphoma, complicated by opportunistic infection and/or Kaposi's sarcoma (Carbone 2005 ). The neoplastic cells of primary effusion lymphoma are either uniform and immunoblast like or very large and pleomorphic (Fig. 6.7a, b ) . Some are multinucleated and may resemble Reed-Sternberg cells. Neoplastic cells express CD45, as well as activation antigens, including CD30, with-out expression of B-cell-specifi c markers. Despite the absence of B-cell antigens, immunoglobulin heavy and light chains are clonally rearranged, thereby supporting a B lineage. Occasionally there is aberrant expression of T-cell-associated antigens (Said and Cesarman 2008 ) . Tumor cells are often coinfected with EBV. Like HHV-8, EBV is a gamma herpesvirus closely related to HHV-8 (Cesarman et al. 1995 Knowles 1997 ; Chadburn et al. 2004 ). The neoplastic cells are also bcl6-, MUM1/IRF4+, and CD138+, corresponding to a late stage in B-cell differentiation (Carbone et al. 2000 ) . MUM1/ IRF4 has been shown to downregulate cellular response to interferon, at least in vitro. It is possible that MUM1/IRF4 expression by the neoplastic cells plays a role in allowing the virally infected tumor cells to escape from interferon-mediated control (Carbone et al. 2000 ) . HHV-8 may also downregulate expression of major histocompatibility complex (MHC) class I surface molecules, allowing HHV8-infected cells to escape killing by cytotoxic T cells (Sirianni et al. 2005 ) . HHV8 infection may be associated with impaired natural killer (NK) cell activity (Sirianni et al. 2005 ). These features, in combination with the tendency of primary effusion lymphoma to occur at a late stage in the course of HIV infection, contribute to the very poor prognosis associated with this lymphoma. Primary effusion lymphoma has distinctive molecular features. It is frequently associated with mutations in the 5′ noncoding regions of BCL6 (Antinori et al. 1999 ) as well as in the immunoglobulin gene variable ( IGV ) regions (Hamoudi et al. 2004 ) . BCL6 and IGV mutations are considered to indicate transition of B cells through the germinal center, and in conjunction with the immunophenotype, the genetic changes provide additional support for a late, post-germinal center stage of maturation for the neoplastic cells of primary effusion lymphoma in most cases. Gene expression profi le analysis shows that primary effusion lymphoma shares features of AIDSassociated immunoblastic lymphoma and plasma cell myeloma and is quite different from other types of B-cell lymphomas (Jenner and Boshoff 2002 ; Klein et al. 2003 ) . There is in addition a specifi c set of genes unique to primary effusion lymphoma (Klein et al. 2003 ) . Thus, both immunophenotype and genetic features indicate that the neoplastic cells of primary effusion lymphoma correspond to a late stage in B-cell differentiation. It is proposed that HHV8, utilizing some of the genes in the B-cell program of its host, drives the cells it occupies toward plasma cells (Jenner and Boshoff 2002 ) . Cases of HHV8+ lymphoma with morphology and immunophenotypic and genetic features similar to those of primary effusion lymphoma but producing mass lesions in lymph nodes or in extranodal sites have been described (Anagnostopoulos et al. 2008 ; Carbone 2005 ; Chadburn et al. 2004 ; DePond et al. 1997 ) . These have been called HHV-8+ or KSHV+ solid lymphomas or extracavitary primary effusion lymphomas (Carbone 2005 ; Chadburn et al. 2004 ) or KSHV+ solid immunoblastic/plasmablastic diffuse large B-cell lymphomas (Deloose et al. 2005 ) . Some patients with "solid lymphomas" also develop HHV-8+ effusion lymphomas. HHV-8+ large B-cell lymphomas can also evolve out of HHV-8+ multicentric Castleman's disease; these lymphomas mainly affect HIV+ patients and primarily involve lymph nodes and spleen. They are typically composed of monotypic cytoplasmic IgM+, EBV−, HHV8+ plasmablasts (Anagnostopoulos et al. 2008 ) . WHO classifi cation. Tumours of haematopoietic and lymphoid tissues, World Health Organization classifi cation of tumours Primary body cavity-based AIDS-related lymphomas HHV-8/ KSHV is not associated with AIDS-related primary central nervous system lymphoma Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS Pulmonary herpes simplex in burns patients KSHV/HHV-8 associated Kaposi's sarcoma in lymph nodes concurrent with Epstein-Barr virus associated Hodgkin lymphoma Expression of MUM1/IRF4 selectively clusters with primary effusion lymphoma among lymphomatous effusions: implications for disease histogenesis and pathogenesis Kaposi's sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease Kaposi's sarcoma-associated herpes virus-like DNA sequences in AIDS-related body-cavity-based lymphomas KSHVpositive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma Herpes simplex virus pneumonia in trauma patients Human herpesvirus 6 and pneumonia Infections with herpes simplex viruses (1) High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma Kaposi's sarcoma-associated herpesvirus and human herpesvirus 8 (KSHV/HHV8) -associated lymphoma of the bowel: report of two cases in HIV-positive men with secondary effusion lymphomas Varicella zoster and herpes simplex virus pneumonias Ocular adnexal lymphomas. Outcome in 181 patients Fungal autofl uorescence with ultraviolet illumination Herpes simplex virus infection of the adult lower respiratory tract Pathology and pathogenesis of severe acute respiratory syndrome Distinct cellular origins of primary effusion lymphoma with and without EBV infection The molecular pathology of Kaposi's sarcoma-associated herpesvirus Neonatal herpes simplex infection Gene expression profi le analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifi es PEL-specifi c transcripts Primary effusion lymphoma (PEL) in HIV-negative patients-a distinct clinical entity Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus Herpetic infection of the middle and lower respiratory tract Herpes simplex virus pneumonia: clinical, virologic, and pathologic features in 20 patients Primary effusion lymphoma Herpetic tracheobronchitis Downregulation of the major histocompatibility complex class I molecules by human herpesvirus type 8 and impaired natural killer cell activity in primary effusion lymphoma development Comparison of in situ hybridization and immunohistochemistry for detection of cytomegalovirus and herpes simplex virus Pneumonia caused by herpesviruses in recipients of hematopoietic cell transplants Herpes simplex virus from the lower respiratory tract in adult respiratory distress syndrome Herpes simplex viruses