key: cord-0935339-mpif7pcx
authors: Ison, M. G.; Michaels, M. G.
title: RNA Respiratory Viral Infections in Solid Organ Transplant Recipients
date: 2009-12-16
journal: Am J Transplant
DOI: 10.1111/j.1600-6143.2009.02908.x
sha: 386755b2f4914014342e20040972e8283de8509c
doc_id: 935339
cord_uid: mpif7pcx

nan

A wide range of RNA (5) . Fever may be absent in transplant recipients with pneumonia or may be the sole presenting sign or symptom (1, 4) . As such, any fever or respiratory symptom should prompt the consideration of a respiratory viral infection as the potential cause. 4. Viral shedding is usually prolonged among transplant recipients. Prolonged shedding is seen even with the use of antivirals and therefore may contribute to the increased risk of resistant variant emergence (1, 6 (1, 10) .

Several studies of DFA testing of primary patient specimens have documented sensitivity that approached that of PCR for certain viruses (12, 13) . DFA testing is limited by lack of reagents for some of the viruses (hMPV, rhinovirus, coronavirus) (14) and appears to be less sensitive than PCR in detecting dual infections (13) . Like PCR, though, DFA testing can detect several viruses from a single specimen.

A wide range of PCR-based assays to detect respiratory virus are commercially available and many centers have locally developed assays that detect select viruses. Most of the available assays are able to screen for a wide range of pathogens in tandem and many have been tested in transplant populations (4, 9, 15, 16) . Nucleic acid amplification assays appear to be the most sensitive diagnostic tools available and most allow for simultaneous detection of a broad range of respiratory pathogens from a single sample and is therefore preferred testing method for immunocompromised patients (1 (1, 3, 10, 17, 18) . (1, 3, 10, 17, 18) . Transmission occurs through inhalation of infectious droplets or through contact with fomites; some forms of influenza, particularly avian influenza, may be spread through aerosols.

Patients with known or suspected influenza should be isolated from other patients using standard and droplet precautions (19, 20) . There are two types of influenza vaccine currently available: a number of formulations of injectable, killed vaccine and a single inhaled live, attenuated vaccine. The injectable vaccine has been studied in all transplant patients and has been found to be safe and not associated with an increased risk of rejection or adverse outcomes (21) . There is potential for replication of the live attenuated vaccine, so its use is contraindicated in highly immune suppressed patients and their close contacts (22 (22) . Antiviral chemoprophylaxis can be considered as an alternative or supplement to vaccination (I) (22) . Agents active against circulating influenza strains should be used. A randomized, double-blind study of oseltamivir prophylaxis in high-risk transplant recipients found a protective efficacy of 75%; of note, 40% also received vaccination (23) .

There are two classes of antiviral compounds that are approved for the treatment of influenza: M2 inhibitors (amantadine and rimantadine; Finally, resistance to available antivirals has complicated the routine management of influenza. In general, nearly all influenza A/H3 viruses are resistant to M2 inhibitors and this resistance affects both amantadine and rimantadine equally (25) . Many influenza A/H1 viruses have developed resistance to oseltamivir, although currently they retain susceptibility to zanamivir and most are also susceptible to M2 inhibitors (22, 26 (1, 9) . Early acquisition of RSV after transplantation or after augmented immunosuppression has been associated with increased severity of disease in some but not all studies (1, 8, (27) (28) (29) (30) (31) (32) . Transmission occurs through inhalation of infectious droplets or through contact with fomites.

Patients with known or suspected RSV should be isolated from other patients using standard contact precautions (II-2) (19, 20) . Prophylaxis with the RSV-specific monoclonal antibody (palivizumab) or high titer RSV-IVIG has been shown to be effective for specific groups of high-risk infants and young children (I) (33, 34) . However, no studies have been conducted to evaluate their use in the transplant setting and the cost of the weight adjusted dosing of these products in adults would be extremely high. Despite this, some experts would support the use of immunoprophylaxis for children less than 1 year of age who receive their transplant during the RSV season (III); survey data suggest that antibody-based prophylaxis is commonly used among pediatric transplant centers (35) . There are no approved vaccines for treatment of RSV.

Given the limited data on treatment of RSV, supportive care is recommended (II-2) and reduction of immune suppression should be considered, particularly in those with severe disease. The role of specific antiviral treatment is controversial. Ribavirin has been shown to have in vitro activity against RSV and the aerosolized form of this drug has been approved for the treatment of lower respiratory tract disease due to RSV in certain at-risk populations (36) . Despite its FDA approval, convincing data describing the clinical efficacy of this agent are lacking and a consensus on the utility of this drug in the treatment of RSV disease does not currently exist. Published data on the treatment of RSV disease in solid organ transplant recipients are very limited. Experience in stem cell transplant populations suggest that the use of aerosolized ribavirin may reduce mortality associated with severe RSV infections, particularly those affecting the lower airways (30, 36, 37) . The combination of aerosolized ribavirin and antibody-based interventions, including IgIV, RSV-Ig and palivizumab appear to have an even greater impact on mortality (1, 38) . Many experts, therefore, would recommend the use of the combination of aerosolized ribavirin and an antibody preparation for the treatment of severe RSV infections (II-2) (1, 28) . Based upon published experience from pediatric organ transplant recipients, patients without risk factors for severe disease and with only upper respiratory infections are unlikely to benefit from aerosolized ribavirin (II-2) (28) . There are published reports of successful treatment of RSV in lung transplant recipients with oral and IV ribavirin with and without corticosteroids (39, 40) . Further studies are needed to determine the clinical efficacy of these alternatives because there is a risk of adverse effects, notably hemolytic anemia.

Parainfluenza is a pneumovirus for which there are four types that commonly cause disease in humans (types [1] [2] [3] [4] . PIV types 1 and 2 tend to circulate sporadically in fall and winter months in temperate areas whereas type 3 occurs year round; type 4 is least commonly isolated and its epidemiology is still being defined (1) . Transmission occurs via person-to-person spread by direct contact with infectious secretions or fomites. Disease can be serious, particularly in pediatric transplant recipients and lung transplant recipients of any age (1, 5, 41) . Although all respiratory viruses are associated with an increased risk of progression to obliterative bronchiolitis in lung transplant recipients, the association appears to be clearest and strongest with PIV lower tract disease (5, 7, 8) .

Patients with known or suspected PIV should be isolated from other patients using standard contact precautions (19, 20) . There are no approved vaccines nor are there recognized preventative antiviral agents.

Although the use of IgIV and ribavirin are not associated with benefit in the management of PIV infections in stem cell transplant recipients, ribavirin has in vitro activity and has been used to treat lung transplant recipients with lower tract disease; some experts also consider the use of IgIV as well (30, 31, 41) .

hMPV discovered in 2001 is a relatively newly recognized pneumovirus that has clinical pattern similar to RSV and is a significant cause of disease in transplant recipients (42) . As with other pneumoviruses, there are no vaccines and prevention is focused on tight infection control measures, including contact precautions (20) . Case reports and animal data suggest that ribavirin and IgIV can be considered for the management of severe cases of hMPV but supportive care remains the mainstay of treatment (1, 43) .

Human rhinoviruses (hRV) are members of the Picornaviridae family and are the most common cause of colds in adults and children. They have been recognized to cause clinically significant disease in some transplant recipients with fatal cases described (44, 45) . Most of the fatalities are associated with coinfections. Prolonged shedding with minimal symptoms has been described, particularly in lung transplant recipients. The clinical importance of this prolonged shedding has not been fully defined, although could potentially pose a threat of nosocomial transmission (1, 8, 45, 46) . Pleconaril which was studied extensively in healthy adults with rhinoviral upper respiratory infections, was well tolerated, and led to faster resolution of symptoms, to more rapid improvement in symptom scores, and to clearance of virus from nasal mucous (47) . However, it was not approved for use by the FDA due to safety concerns (47) . Currently, there are no approved preventive or therapeutic interventions.

With the use of molecular diagnostics, a wider range of respiratory viruses have been isolated. Many of these viruses, such as newly recognized variants of coronavirus (HKU1, NL63), the polyomaviruses (WU, KI viruses) and bocavirus have not been widely studied in transplant recipients and so their clinical impact has not been fully assessed (1) . Severe and sometimes fatal cases of all of these viruses in immunocompromised patients have been recognized, so they should be considered in the differential diagnosis of patients presenting with severe lower tract disease. The newer agents are more challenging to diagnose because they are not included in the routine, clinically available diagnostic tests. In addition, optimal management of these agents has not been defined.

Although respiratory viruses are increasingly recognized as causes of morbidity and mortality in transplant recipients, there is still much to be learned about the impact RNA Respiratory Viral Infections of these viruses. Prospective studies, involving both inpatients and outpatients, using molecular diagnostics are needed to understand the true epidemiology and clinical spectrum of respiratory viral diseases. In particular, studies of the long-term consequences of infection, even with mild or asymptomatic infection, are needed, particularly in lung transplant recipients in which lower tract infection has been associated with an increased risk of chronic rejection. Prospective studies, using contemporary molecular diagnostic tools, are also needed to define the efficacy and cost of preventative interventions, particularly in highrisk pediatric populations. Finally, prospective therapeutic trials are needed to define the optimal timing, duration and treatment regimen of each of the viruses is needed. 

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