RNA respiratory viral infections in solid organ transplant recipients.

Introduction and Epidemiology

A wide range of RNA respiratory viruses have been identified as causes of significant morbidity and mortality among transplant recipients, including influenza, respiratory syncytial virus (RSV), parainfluenza virus (PIV), rhinovirus, human metapneumovirus (hMPV), coronavirus, bocavirus and polyomaviruses (1) (Table 1). Several features are common among all of these viruses in the transplant population:

Table 1

Common respiratory virus infections in solid organ transplant recipients

Virus	Isolation recommendations	Prophylactic interventions	Therapeutic alternatives
Influenza	Contact and droplet	Annual injectable vaccine	M2 inhibitor1
		Neuraminidase inhibitor2	Neuraminidase inhibitor2
RSV	Contact	RSV Ig, palivizumab	Aerosolized ribavirin3± IgIV
			RSV‐active antibodies4
PIV	Contact	None	Aerosolized ribavirin
hMPV	Contact	None	Aerosolized ribavirin ± IgIV
Rhinovirus	Contact	None	None
Coronavirus	Standard precautions except for SARS which requires contact, droplet and airborne precautions	None	None

1Amantadine or rimantadine (for susceptible viruses only).

2Oseltamivir or zanamivir (for susceptible viruses only).

3Oral or IV ribavirin can be used as well, although patients should be monitored for hemolytic anemia; less are available about the efficacy of these formulations in treating RSV than with aerosolized ribavirin.

The seasonality of respiratory viral infections among transplant recipients usually follows that of the general population (2, 3).

The viruses all cause a range of disease, from mild congestion and rhinorrhea to more severe tracheobronchitis, bronchiolitis and pneumonia. No one virus is exclusively associated with one clinical syndrome (i.e. influenza‐like illness, croup, etc.). As such, diagnostic strategies should initially be broad, attempting to screen for all recognized viruses (3, 4) with particular emphasis on ones that might be amenable to therapy. Symptoms commonly associated with a respiratory viral infection include fevers, nasal congestion, rhinorrhea, watery eyes, cough, sore throat, sputum production, wheezing, shortness of breath and fevers.

Transplant recipients often present with mild or atypical symptoms. Lung transplant recipients, for example, may initially only have subjective symptoms of shortness of breath or subtle changes in pulmonary function testing without more typical symptoms (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.

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).

Transplant recipients are at higher risk of infectious complications compared to immunocompetent hosts. In the older studies, initial evidence of or progression to lower tract involvement with viruses occurred frequently, but may in part be due to ascertainment biases as sicker patients were more likely to be seen by physicians and have specimens sent for viral assays (1). Respiratory viral infections are a significant risk factor for subsequent development of fungal and bacterial pneumonia (1). Other infections, such as CMV viremia, may complicate respiratory viral infections as well.

Respiratory viral infections appear to be a risk factor for both acute and chronic rejection with the greatest risk in lung transplant recipients (5, 7, 8, 9) (II‐2). Concurrent rejection and graft dysfunction has been documented with other solid organ transplant recipients as well, although at a lower frequency than in lung transplant recipients (1) (III). The pathogenesis of the link between respiratory viral infections and rejection is not clearly understood.

All pediatric solid organ and lung transplant recipients appear to have the greatest risk of both RNA viral infections and more severe courses and complications (1).

All are potential nosocomial pathogens which can be potentially spread by staff or visitor with mild upper respiratory illness.

There are few prospective studies of respiratory virus infections in most solid organ transplant populations, with the exception of lung transplant recipients. Most of these studies were retrospective in nature and focused on individuals who were hospitalized with infections (1). In addition, most studies evaluated patients close to the time of transplantation when specimens were more likely to be obtained for diagnosis. This likely leads to an overestimation of the severity and underestimation of the incidence of these infections among transplant recipients.

Diagnosis

Because one cannot clinically distinguish disease caused by any of the RNA viruses, diagnosis using broad ranging techniques should be considered particularly in the early period after transplantation or augmented immunosuppression and during respiratory viral season. Diagnosis can be achieved by combinations of serology, virus culture, antigen detection and nucleic acid testing. Serology is generally not clinically useful. In general, all patients with presumed respiratory viral infection should have a nasopharyngeal swab, wash or aspirate performed and sent for rapid antigen testing, if available. Although positive results for the test may be considered diagnostic, negative results do not rule out infection. Rapid antigen testing may only detect a limited number of viruses (i.e. only influenza and/or RSV) and therefore additional testing may be warranted. Negative rapid tests does not rule out infection and should trigger additional testing with polymerase chain reaction (PCR), direct florescent antibody (DFA) or culture, dependent on which is available locally. If upper tract samples fail to document the cause of the respiratory illness or if there is clinical or radiologic evidence of lower tract involvement, bronchoalveolar lavage should be considered and sent for the range of available tests. Testing of a wide range of pathogens is most important among lung transplant recipients.

Rapid antigen detection, using several different techniques, is available for influenza and RSV. Despite their speed, sensitivity may be lower than reported in licensing studies, particularly among immunocompromised patients (10). In the case of RSV, one study documented a sensitivity with one rapid test method of 15% for nasal wash specimens among immunocompromised patients; sensitivity is improved to 89% when BAL is used (11).

Although viral cultures previously were considered the preferred diagnostic tests, molecular tests tend to provide higher yields and can detect a wider range of viruses in a more timely fashion (standard cultures typically do not detect hMPV, coronaviruses, bocaviruses and polyomaviruses) (1); not all hospitals have access to molecular diagnostics for respiratory viruses, although these are increasingly available through reference laboratories. As with other diagnostic strategies, yields of cultures are dependent on the site of sampling; greatest yield is from BAL and nasal wash (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).

Influenza

Virology and epidemiology

Influenza viruses are orthomyxovirus and are associated with substantial morbidity and mortality worldwide with epidemics during the winter months. Antigenic variability gives this virus a survival advantage allowing for its continued virulence during yearly epidemics. Few studies have examined the prevalence of influenza virus infection prospectively in organ transplant recipients (1, 3, 10, 17, 18). Risk of disease and complications appear to be greatest in pediatric and lung transplant patients with variable levels of severity in other transplant populations (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.

Prevention

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). Although responses vary based vaccine year, specific influenza strains, immunosuppressant and recipient type, and while responses in transplant recipients are less robust than those of healthy controls, most recipients do have some benefit. Accordingly, annual trivalent inactivated influenza vaccination is strongly recommended for transplant recipients, their close contacts and caretakers >6 months of age (I) (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).

Treatment

There are two classes of antiviral compounds that are approved for the treatment of influenza: M2 inhibitors (amantadine and rimantadine; Table 2) which are effective against susceptible influenza A strains only, and neuraminidase inhibitors (zanamivir and oseltamivir; Table 3) which are active against susceptible influenza A and B viruses (22). Treatment with these agents in transplant recipients has been studied in case reports and is associated with reduced risk of lower respiratory tract complications (e.g. bronchiolitis, pneumonia), duration of symptoms, mortality and possibly a reduced risk of progression to bronchiolitis obliterans after infection (17) (III). Prospective studies have not been conducted, although a dose ranging study of oseltamivir is underway. There are frequent changes to the recommended management of influenza based on currently circulating strains; treatment decisions should be aligned with current recommendations as outlined by the Centers for Disease Control and Prevention (http://www.cdc.gov/flu/).

Table 2

Agents used to prevent and treat influenza: M2 inhibitors (22)

Drug	Suggested dosage	Usual adult dosage1		Dose adjustment state
		Prophylaxis	Treatment
Amantadine		100 mg b.i.d.	100 mg b.i.d.
	5 mg/kg to max of 150 mg in two divided doses			Age 1–9 years
	100 mg q.o.d.			CrCl 30–50 mL/min
	100 mg q.o.d.			CrCl 15—30 mL/min
	100 mg q. week			CrCl 10—15 mL/min
	100 mg q week			CrCl,10 mL/min
	100 mg q.o.d.			Age ≥65 years
Rimantadine		100 mg b.i.d.	100 mg b.i.d.
	5 mg/kg to max of 150 mg in two divided doses			Age 1–9 years2
	100 mg q.o.d.			CrCl,10 mL/min
	100 mg q.o.d.			Severe hepatic dysfunction
	100 mg q.o.d.			Age ≥65 years

1Duration of treatment is usually 5 days. Duration of prophylaxis depends of the clinical setting.

2Investigational: Not approved for treatment of children by the US Food and Drug Administration and Health Canada.

Table 3

Agents used to prevent and treat influenza: neuraminidase inhibitors (22)1

Drug	Dosage for treatment	Dose adjustment
		State	Dosage
Zanamivir2	2 puffs (10 mg) b.i.d.	No dose adjustment needed
Oseltamivir3	75 mg b.i.d.2	CrCl <304	75 mg QD
		12 months of age or older
	C	≤15 kg	30 mg b.i.d. (2.5 mL5)
	H	16–23 kg	45 mg b.i.d. (3.8 mL5)
	I	24–40 kg	60 mg b.i.d. (5 mL5)
	L	>40 kg	75 mg b.i.d. (6.2 mL5)
	D	<12 months of age6	3 mg/kg/dose/bid
	R
	E
	N

1Prophylaxis: Adults (normal renal function): Doses as above, but given once daily. Infants and children (normal renal function): Doses as above, but given once daily. Prophylaxis is not recommended for infants <3 months of age.

2Zanamivir is indicated for prophylaxis in children ≥5 years old and for treatment in children ≥7 years old.

3The dosing of infants less than 1 year of age remains problematic, as data are limited on appropriate dose of oseltamivir in this age group, notably neonates and those with lower body weights. Please consult current dosing recommendations available on the CDC’s web site and in any updated package insert for dose adjustments in renal impairment.

4No treatment or prophylaxis dosing recommendations are available for patients undergoing renal dialysis.

There are a number of antivirals and antiviral combinations that are currently undergoing investigation and/or are available for by compassionate use. Up to date information on these can be obtained from: http://www.clinicaltrials.gov.

5Volume of suspension—dose recommended in normal renal function.

6Per Emergency Use Authorization (http://www.cdc.gov/h1n1flu/recommendations.htm#table1).

Some key caveats about the treatment of influenza in transplant recipients should be recognized. First, patients have prolonged viral replication, even with therapy, such that the approved 5 day duration of therapy may be insufficient to treat transplant recipients (24). Likewise, immunocompromised transplant recipients may benefit from therapy even if they have had symptoms beyond 48 h before presentation. Higher doses of medications or combinations of antivirals may have benefit in transplant recipients (1). Some experts recommend treating all transplant recipients with proven influenza, irrespective of symptom onset, and continue therapy until viral replication has been documented to have ceased; culture or PCR‐based methods should be used to monitor patients for shedding (1) (III).

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). There are limited data about the use of zanamivir in lung transplant recipients; as with all patients with underlying lung disease, if zanamivir is used, rescue inhalers should be readily available and the first dose should be given in a monitored setting. Recommendations as to the optimal management of influenza are updated based on real‐time surveillance of circulating strains and their susceptibility. As such, current dosing recommendations from health authorities should be consulted regularly.

Respiratory Syncytial Virus

RSV is a paramyxovirus in the genus pneumovirus that causes seasonal annual epidemics worldwide; year‐round disease is seen in some tropical locations. By 2 years of age, virtually all children have experienced a primary infection, although reinfection can occur throughout life. Risk factors for more severe disease after organ transplantation include infection in children under a year of age or with underlying lung disease (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 Virus

Parainfluenza is a pneumovirus for which there are four types that commonly cause disease in humans (types 1–4). 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).

Human Metapneumovirus

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).

Rhinovirus

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.

Other Respiratory Viruses

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.

Future Studies

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 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 high‐risk pediatric populations. Finally, prospective therapeutic trials are needed to define the optimal timing, duration and treatment regimen of each of the viruses is needed.

Disclosures

Michaels M.: Grant Support, Sanofi Pasteur, Roche. Ison M.G.: Consultant: BioCryst, Adamas, Roche; Lectures Fees, Abbott Molecular, ViraCor; Site PI, ViraCor, BioCryst, Roche.