**7. Respiratory viruses**

ently. BKV infection is acquired in early childhood, whereas JC presents later. Transmission of BKV occurs typically via oral and respiratory routes, but data suggests transmission via cells and tissues, in particular by kidney transplantation [81]. Approximately 50%–80% of humans have seropositivity to JCV and BKV viruses due to multiple routes of transmission [82, 83]. Clinically apparent diseases in immunocompetent hosts are extremely rare and are not associated with any well-defined clinical syndrome. After primary infection, viruses remain latent possibly in the lymphoid organs, neuronal tissue, kidney, and tubular epithelial cells. About 5% of healthy individuals intermittently reactivate BKV replication with detectible viruria [84]. Under the circumstances of severe immunosuppression both viruses reactivate. BKV can cause pneumonitis, hepatitis, retinitis, and meningoencephalitis [85]. Hemorrhagic cystitis is seen in 25–60% of bone marrow transplant patients, usually 2 weeks after transplan‐ tation [86]. Up to 80% of renal transplant patients have BK viruria, and 5%–10% progress to BKV nephropathy (BKVN) [87]. Given that polyomavirus is widely latent in the kidney, renal transplantation is believed to be an important mode of infection in patients with end stage kidney disease. Graft loss rate have been reported to be as high as 30%–50% following a diagnosis of BKVN [88]. More recent data indicate that with early diagnosis of BK viremia or

viruria using regular screening, the majority of patients respond favorably [89, 90].

or when allograft dysfunction occurs is recommended [93].

viruses in human cancer [96].

112 Immunopathology and Immunomodulation

Serologic testing may be used in risk-assessment of virus transmission via organ transplanta‐ tion. The greatest risk of post-transplant viral reactivation is associated with positive serostatus of both the donor and recipient. The presence of IgG antibody to BKV-VP-1 in serum is associated with increased risk of virus transmission and disease in renal allograft recipient [91]. To detect viral replication in urine and blood, real time PCR is the method of choice for diagnosis of BKVN [92] and screening every 3 months for the first two years after transplant

The first line of treatment of BKV nephropathy is reduction of immunosupression [92, 93]. A variety of drugs with possible anti-BKV activity that are being utilized as adjuvant therapy but fraught with side-effects are cidofovir, leflunomide, and intravenous immunoglobulin [94]. Fluoroguinolons have been reported to display anti-BK activity because of its large Tantigen helicase activity [95]. Further studies are needed to firmly establish the role of polyoma

Other polyomavirus with importance of human pathology is JCV. Progressive multifocal leukoencephalopathy (PML) is a progressive demyelinating central nervous system disorder involving cerebral white matter caused by the JCV. It most often presents as an opportunistic infection in HIV patients with lymphopenia but has recently been seen with new immuno‐ suppressives. After reactivation in severely immunosuppressed states, the virus travels to the central nervous system through infected B-lymphocytes, where it produces lytic destruction of myelin producing glial cells (i.e., oligodendrocytes) and non-lytic infection of astrocytes, causing progressive disease in central nervous system. Typical PML patients have very low CD4+T cell counts even less than 200/mm2 [97, 98]. The estimated incidence of PML in HIV patients is 5%, but is decreasing with the introduction of highly active anti-retroviral therapy (HAART) [99]. The differential diagnosis of PML is HIV-associated encephalopathy and primary CNS lymphoma. Brain biopsy is the gold standard for diagnosis. Staining with

Every year, the number of patients undergoing stem cell and solid organ transplantation to treat malignancy and end-organ failure increases. Despite advances in screening and prophy‐ laxis strategies, infections remain a significant cause of morbidity and mortality among transplant recipients. From the available data, respiratory viruses remain common pathogens. The respiratory viruses, including Adenovirus, Influenza virus, Human Metapneumovirus (hMPV), Parainfluenza virus (PIV), Respiratory Syncytial virus (RSV), and Rhinovirus (HRV) are increasingly recognized as contributing to significant morbidity and mortality among hematpoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients [102]. Iimmunocompromized patients often have atypical presentation of respiratory infections and viral shedding can be prolonged [103]. Not one virus is exclusively associated with one clinical syndrome and there is a high risk of infectious complications as viral pneumonia or bronchio‐ litis obliterans following acute respiratory infection. Lymphopenia is consistently a risk factor for more serious infections. Respiratory viral infections appear to be risk factors for acute and chronic rejection, especially in lung transplant patients [104]. There is increased risk of severe respiratory viral infections and its sequels among pediatric recipients, as compared to adult recipients (103).

All respiratory viruses are extremely dangerous for lung and HSCT cell recipients with high mortality rate [105, 106]. Adenoviruses induce respiratory and gastrointestinal diseases. Disseminated infections are characterized by fever, pneumonia, diarrhea, hemorrhagic cystitis, hepatitis, and CNS involvement in up to 10% of the cases. In some patients Adenovi‐ ruses can become a reason for organ rejection. Cases of death can occur if there is co-infection with CMV and different bacteria. Adenoviruses are usually in latent condition in the human body and the infection becomes clinically manifested after reactivation of the virus (107). HRV is probably the most common respiratory viral pathogen in the upper and lower respiratory tract in transplant recipients [108].

In general, all patients with presumed respiratory viral infections have a nasopharyngeal swab, wash, or brohoalbeolar aspirate performed. Diagnosis of the respiratory viruses can be achieved by the combination of serology, virus culture, antigen detection, nucleic acid testing, and histopathology. Serology is not useful for initial diagnosis and has reduced sensitivity in transplant recipients. Viral culture can be achieved for most viruses except hMPV and Coronaviruses because special cell lines are needed. Shell vial assays allow earlier detection of viruses with application of monoclonal and polyclonal antibodies. Recently, several fixed mixture of cells (R-Mix) has become commercially available [109]. Rapid antigen detection using several different techniques is available for Influenza, RSV, and Adenovirus. Direct fluorescent antibody (DFA) testing of primary patient specimens has documented sensitivity that approached PCR [110]. Nucleic acid amplification assay appears to be the most sensitive diagnostic tool available, and most allow for simultaneous detection of a broad range of respiratory pathogens from a simple sample [111].

Treatment depends on the etiological agent. Reduction of immune suppression, if possible, is recommended for all the transplanted recipients. For infections caused by RSV, combination therapy with aerosolized ribavirin and intravenous immunoglobulins appears to have the greatest benefit in reducing mortality [103, 112]. PIV and hMPV infections are treated with oral, aerosolized, or intravenous ribavirin in a combination with intravenous immunoglobu‐ lins [113]. Adenovirus infections are treated with cidofovir, vidarabin, and gancyclovir. Lymphocyte reconstitution plays a crucial role in the clearance of Adenovirus [114]. Treatment of Rhinovirus infections is done with pleconaril and 3C-protease inhibitors, but there is insufficient experience with them and this limits their application. Topical interferon might be efficacious in moderating viral shedding and symptoms [115, 116]. Prevention of Influenza depends on aider vaccination with Influenza vaccine [117] or antiviral therapy. Vaccination is not suitable for bone marrow transplant patients 6–12 months after the transplantation. Patients with severe Influenza should be treated with both M2 inhibitors (rimantadin and amantadin) and neuraminidase inhibitors (relenza and tamiflu [118].
