Respiratory Viral Infections in Transplant Recipients
Authors: Deepali Kumar, MSc FRCPC
Transplant recipients are at risk for community-acquired respiratory viruses. These are broadly categorized as influenza A and B, parainfluenza, respiratory syncytial virus (RSV), coronaviruses, adenovirus, and rhinovirus. In the past decade, molecular methods have allowed for the detection of new pathogens of the respiratory tract such as human metapneumovirus (hMPV), bocavirus and others (e.g. WU/KI viruses). Respiratory viral infections (RVI) occur in 8-64% of solid organ transplant recipients and are a cause of morbidity and mortality (3, 9). In lung transplant recipients, respiratory viral infections have been associated with acute rejection and a progression to bronchiolitis obliterans syndrome (31, 33). However, some viruses such as respiratory viral infection may have greater association with bronchiolitis obliterans syndrome than others (eg. hMPV) (24).
Viral infections may present with only upper respiratory tract involvement but can progress to lower respiratory tract involvement in transplant recipients. Symptoms suggestive of respiratory viral infections include sore throat, rhinorrhea, dry cough, fever, and myalgias. Gastrointestinal symptoms such as nausea, vomiting, or diarrhea may also be present. Adenovirus specifically may cause disseminated disease with pneumonitis or hepatitis. In addition, adenovirus may cause hemorrhagic cystitis in kidney transplant recipients. For most respiratory viruses, however, symptoms are similar and cannot be used to distinguish one respiratory virus from another. Bacterial superinfection can also occur and should be considered if productive cough or pulmonary infiltrate is present on chest radiograph. In transplant recipients, it is important to diagnose the specific respiratory virus since therapeutic options differ. Viral coinfections (e.g. simultaneous detection of two respiratory viruses) may also be present.
Diagnosis is made by nasopharyngeal swab or lower respiratory tract sampling where possible (e.g, bronchoalveolar lavage). Molecular methods have become widespread for the diagnosis of respiratory viral infections (20). Multiplex nucleic acid testing for a wide variety of respiratory viruses can be performed in many clinical laboratories. Direct fluorescent antibody can also provide a rapid turnaround time but lacks sensitivity and can only be used to diagnose a limited number of viruses. Serology is of limited utility in diagnosis since seroconversion is delayed. Serologic responses in transplant recipients may be delayed or completely absent. Therefore, serology is generally reserved for population-based seroepidemiology studies or instances where molecular diagnosis is not possible. Rapid diagnostic tests are also available for influenza A and B but lack sensitivity (6).
Specific antiviral therapy for respiratory viral infections is limited. In immunocompetent patients, respiratory viral infections are generally limited to the upper respiratory tract and symptomatic therapy is recommended. An exception to this is influenza where randomized trials in immunocompetent patients have shown a decrease in duration and severity of illness if antivirals are instituted within 48 hours of symptom onset (43). However, in transplant recipients, antiviral therapy should be strongly considered given the significant rate of complications. Discussion on specific viruses follows below.
Seasonal influenza and Pandemic Influenza A/H1N1 Influenza is a single stranded RNA virus that can cause upper respiratory tract infection that has a relatively high rate of progression to viral pneumonia. In addition, bacterial pneumonia, myocarditis, and myositis have been observed. Recently, there has been an increase in antiviral resistance in seasonal influenza (7). Influenza virus is likely also the most significant of the respiratory viruses due to its ability to undergo antigenic drift and antigenic shift. As well, genomic reassortment or mutation events with circulating influenza viruses in swine or avian species allows for the potential for pandemics (32). In 2009, a novel H1N1 influenza A virus was first detected in Mexico and subsequently caused a global crisis. Relatively greater rates of hospitalization and ICU admission were seen in children and pregnant women (27, 30, 35). START* Novel pandemic influenza A/H1N1 (pH1N1) was expected to be severe in transplant recipients and reviews are underway to determine morbidity and mortality in this population. The American Society of Transplantation developed a guidance document outlining recommendations for prevention, treatment, infection control issues, pediatric issues, and the potential for donor transmission of the novel virus (34). In addition, the International Society of Heart and Lung Transplantation also developed a guidance document for thoracic organ transplant (10).
ANTIVIRAL THERAPY
It is important to suspect influenza in the transplant recipient and start antiviral therapy empirically in highly suspected cases while awaiting diagnosis. In immunocompromised transplant recipients, antivirals should be started in symptomatic patients regardless of duration of illness. For influenza A (seasonal H3N2 or pH1N1) or influenza B, the drug of choice is oseltamivir, an inhibitor of viral neuraminidase (see Table 1). The standard adult oral dose is 75mg bid for 5 days (see Table 2). Oseltamivir is available in capsules or oral suspension. Dose should be reduced in patients with creatinine clearance less than 30mL/min (see Table 1). In pediatric patients, a weight-based dose is used (see Table 3 and 4). There are no clinically significant drug interactions with immunosuppressive medication and this drug is generally well tolerated in transplant recipients. Higher doses of 150mg bid have been used in severely ill transplant patients although the benefit of this is unknown. Longer durations of 10 days have also been suggested by experts for transplant recipients with persistent clinical symptoms. This strategy is limited by the potential for development of resistance (typically the H275Y mutation) to oseltamivir.
Zanamivir is also a neuraminidase inhibitor and is commercially available in the inhaled form for age greater than 7 years. The standard dose is 2 puffs bid (10mg) for 5 days. Less is known about the tolerability of zanamivir in transplant recipients and systemic exposure of the drug is limited. Nevertheless, this is an option for patients with influenza. In the event of oseltamivir or adamantane resistance, viruses have remained susceptible to zanamivir. An intravenous preparation of zanamivir is investigational and can also be obtained through emergency use authorization (21). Another investigational neuraminidase inhibitor is intravenous peramivir which is undergoing clinical trials and can also be obtained through emergency use authorization (1).
Amantadine and Rimantadine are M2 inhibitors that can also be used in transplant recipients with influenza A although their use is limited due to adverse effects and antiviral resistance. These can be used for seasonal H1N1 virus infections that are almost all resistant to oseltamivir (7).
DRUG RESISTANCE
Antiviral resistance has been noted in seasonal influenza. For the 2008/09 season, the majority of seasonal H1N1 viruses were resistant to oseltamivir but retained susceptibility to amantadine whereas H3N2 viruses were susceptible to oseltamivir but resistant to amantadine. On the other hand, pandemic H1N1 was sensitive to oseltamivir although sporadic cases of resistance are now known. Newer strategies to combat drug-resistant influenza include the use of combination antivirals. One such combination consists of oseltamivir, amantadine, and ribavirin which has good in vitro activity (37,42). In addition, agents with newer modes of action such as the sialidase fusion protein DAS181 (Fludase; Nexbio Inc.) is also under investigation (44). Practitioners can access the latest clinical trials of influenza antivirals on www.clinicaltrials.gov.
VACCINES
Commercial vaccines are available for influenza. The injectable trivalent inactivated vaccine (TIV) contains two circulating strains of influenza A and a circulating B strain and is recommended annually for all transplant recipients (11). Generally, influenza vaccine can be given starting at 3 months post-transplant although some groups recommend to immunize as early as 1 month post-transplant (28). There is limited data on whether early vaccination would be as immunogenic as late vaccination. As a whole, studies do not show an association between vaccination and the occurrence of rejection. It is also recommended to immunize household / close contacts of the transplant recipient as well as healthcare workers especially given that patients may not mount an adequate response early post-transplant. Adjuvanted influenza vaccines are generally considered safe for transplant recipients although there is very limited data on their safety in this setting (34). Specific monovalent vaccine is also available for Novel Influenza A/H1N1 and is recommended for transplant recipients starting at one month post-transplant. Live vaccines such as the intranasal live attenuated influenza vaccine should not be given to transplant recipients (11).
ANTIVIRAL PROPHYLAXIS
For influenza, antiviral prophylaxis with oseltamivir during the influenza season has been studied and shown to reduce the incidence of laboratory-confirmed influenza although the results were not statistically significant (26). Routine prophylaxis in the influenza season is generally not recommended due to emergence of oseltamivir resistance. If a transplant patient has been exposed, then consideration can be given to starting antiviral prophylaxis. Prophylaxis is generally continued till 10 days after exposure. However, antiviral resistance has emerged in this setting. Therefore, some experts suggest to diligently observe for symptoms and begin treatment doses of antivirals as soon as symptoms appear.
DONOR TRANSMISSION
Donor transmission of influenza is especially of concern during pandemics. Lung or small bowel transplantation is especially likely to transmit infection due to high viral burden in these organs (10). Careful donor screening with history should be done to rule out those with active influenza infection. However, organs from donors with known influenza that have received antivirals for at least 48 hours may be considered for transplant with appropriate antiviral therapy of the recipient(s).
Respiratory Syncytial Virus (RSV)
RSV can cause severe lower respiratory tract disease in transplant recipients. For upper tract disease with RSV, conservative management is often used. An exception to this is in the post-stem cell transplant setting where patients may be admitted to hospital for antiviral therapy. The standard antiviral therapy for RSV is Ribavirin, a nucleoside analogue. The aerosolized form of ribavirin is used for therapy of lower respiratory tract disease from RSV and in some instances to prevent progression to lower tract disease (2). The administration of aerosolized ribavirin can be logistically difficult since this form is teratogenic and a negative pressure isolation room must be used. Therefore, oral and intravenous ribavirin has also been used for RSV and small case series are described (8). Adjunctive therapies that may also have benefit include corticosteroids. In one small series of lung transplant recipients, oral ribavirin and pulse solumedrol were given for RSV LRTI and appeared beneficial. RSV immuneglobulin (Respigam, Medimmune) has also been utilized in stem cell transplant recipients for RSV infection. Some clinicians will use intravenous immuneglobulin (IVIg) if RSV-specific immuneglobulin is not available. Palivizumab, a humanized monoclonal antibody specific for RSV can also be used but is costly and was not beneficial in a small study (12). Palivizumab has also been used as immunoprophylaxis in the pediatric transplant setting. A recent survey showed about half of the pediatric solid organ transplant centers use this strategy for in children age 0-4 years. Another humanized monoclonal antibody for RSV (Motavizumab) is undergoing clinical trials. The data for adjunctive therapies in the transplant setting is limited to small case series and case reports. Not all products are readily available in all centers. Clinical trials for RSV vaccines are also ongoing but no vaccine is commercially available.
Parainfluenza
Parainfluenza (serotypes 1-4) infections occur all year round and are associated with pneumonitis but also with Guillain-Barre syndrome, acute disseminated encephalomyelitis, and parotitis. Parainfluenza-3 is especially associated with nosocomial outbreaks in transplant recipients (18). Ribavirin (aerosolized, intravenous, and oral) has been used for parainfluenza infections with conflicting results. In the stem cell transplant setting, oral ribavirin and methylprenisolone has been used with success (40). In the lung transplant setting, some clinicians will use ribavirin, IVIg, and/or pulse solumedrol in an attempt to decrease the risk of bronchiolitis obliterans in the long term. The utility of this strategy is unknown. There is no specific immuneglobulin or parainfluenza monoclonal antibody available.
Adenovirus
Adenovirus infections can cause disseminated disease in transplant recipients including pneumonitis and hepatitis. Adenovirus can also cause conjunctivitis. In addition, it is an agent of hemorrhagic cystitis in kidney transplant recipients. Peripheral blood PCR can also be done to determine the presence of adenovirus. However, interpretation of a positive PCR is difficult. Up to 7% of solid organ transplant recipients will have self-limited adenoviremia with over half being asymptomatic (25). For disseminated or end-organ disease, PCR, in situ hybridization, or immunohistochemistry can also be performed on tissue biopsy specimens. Antiviral therapy for severe adenovirus infections consists of intravenous cidofovir (15, 38). Vidarabine has in vitro activity against adenovirus and has been used to treat hemorrhagic cystitis (5). Many clinicians will also give intravenous immunoglobulin for severe disease. The dose of IVIg is not known and various dosing strategies have been used. One option is to give 500mg/kg on day 1 and day 3. Other modes of therapy include adoptive transfer of T cells and donor lymphocyte infusion (19).
Human Metapneumovirus
Human Metapneumovirus (hMPV) is increasingly recognized as a pathogen in transplant recipients although asymptomatic infections may be present (14, 16, 23). Supportive care and a reduction of immunosuppression are mainstays of treatment. Ribavirin with or without IVIg have been used in human cases (4). A recent report used an RSV protocol for hMPV, namely IV ribavirin and methylprednisolone. Vaccines for hMPV are under investigation in animal models.
Coronaviruses
Human coronavirus strains now include OC43, 229E, NL63, HKU1 and SARS (Severe acute respiratory syndrome) (Farcas 2005). There is no specific antiviral therapy for coronavirus although several patients were treated with intravenous or oral ribavirin with or without corticosteroids during the SARS outbreak in 2003. This resulted in adverse effects such as hemolytic anemia and hypocalcemia in the majority of patients with no clinical benefit (29). No vaccine is available for coronaviruses although few groups are researching this subject.
Rhinovirus
Rhinovirus is a picornavirus that is a major cause of upper respiratory infections but also causes lower respiratory tract infection in immunocompromsed hosts including rare reports of fatal cases (22). In addition, up to 20% of lung transplant recipients will have persistent detection of rhinovirus in from bronchoalveolar lavage specimens or nasopharyngeal specimens in asymptomatic patients. No specific antiviral therapy is available. Pleconaril, a specific inhibitor of picornaviruses, appeared effective in clinical trials of immunocompetent persons but is no longer commercially available. Therefore, supportive care and a reduction of immunosuppression in severe infections are the standard practices.
Bocavirus / WU/ KI
Human Bocavirus is part of Parvoviridae. Disseminated disease with this virus has been reported in a child with HCT as well as a child after both liver transplant and HCT (13, 39). It has not been found to date in adult transplant recipients. WU and KI are polyomaviruses that are associated with both upper and lower tract disease. Both viruses are found as copathogens with another respiratory virus in 70-80% of patients making the association with clinical disease debatable. In one study of 200 hospitalized patients, KI was more frequent in HCT recipients (36). No specific therapy for these viruses exists.
ENDPOINTS FOR MONITORING THERAPY
Transplant recipients may deteriorate quickly and their respiratory status should be monitored. A baseline chest radiograph should be done and subsequent chest radiographs can be done for significant clinical changes. Repeat nasopharyngeal swabs (or bronchoalveolar lavage) can be done for those with failure to improve after 7 days. However, it is important to note that transplant recipients have prolonged shedding periods and swabs may be positive in the absence of clinical disease.
INFECTION CONTROL MEASURES
Droplet precautions are suggested for all transplant recipients with respiratory viruses (41). This includes private rooms for patients with respiratory viruses. Visitors should practice good hand hygiene and wear gowns, gloves, mask, and eye protection. Airborne precautions should be used for pandemic influenza or viruses with high virulence or mortality (such as SARS-coronavirus). In an outbreak situation on a transplant ward, new admissions should be restricted and chemoprophylaxis can be offered to asymptomatic patients where possible.
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Table 1: Management of Respiratory Virus Infection in Transplant Recipients
| Respiratory Virus | Isolation Precautions (120) | Primary Therapy | Alternate Therapy | Comments |
|---|---|---|---|---|
Influenza A
Seasonal H1N1 |
Droplet | Amantadine 100mg po bid x 5 days OR Zanamivir | >99% Resistance to Oseltamivir for 2008-09 season | |
Influenza ASeasonal H3N2 |
Droplet | Oseltamivir 75-150mg po bid x 5-10 days OR Zanamivir 2 puffs bid x 5 days | 100% Resistance to Adamantanes in 2008-09 season | |
Influenza APandemic H1N1 |
Airborne | Oseltamivir 75-150mg po bid x 5-10 days OR Zanamivir 2 puffs bid x 5 days | Resistant to Adamantanes | |
| Influenza B | Oseltamivir 75mg po bid x 5 days OR Zanamivir | |||
| RSV | Droplet and Contact | Aerosolized Ribavirin 6 g over 12-18 hours daily or 2g tid | Ribavirin po 15-20 mg/kg/d in 3 divided dosesRibavirin IV 33mg/kg on day 1 then 20mg/kg/d in 3 divided dosesRSV Ig 100mg/kgPalivizumab 15mg/kg i.m.IVIgSolumedrol 5-15mg/kg daily x 3 daysIVIg (various dose regimens) > |
|
| Parainfluenza | Droplet | Ribavirin (aerosolized, po, IV) | Solumedrol 5-15mg/kg daily x 3 days | |
| Adenovirus | Droplet | Cidofovir 5mg/kg iv once weekly x 2 wks, then every 2 wks + probenecid given 3 hrs pre-dose and 3 & 9 hrs post dose | ?Ribavirin
For hemorrhagic cystitis, Intavesicular cidofovir (5mg/kg in 100mL saline)IVIgVidarabine iv 10mg/kg/d x 5 days |
Peripheral blood PCR for disseminated disease, Tissue biopsy |
| Coronavirus | DropletAirborne for SARS-CoV |
Supportive careSupportive care |
Ribavirin + corticosteroids not effective | |
| hMPV | Droplet | Supportive care | Ribavirin +IVIg | |
| Rhinovirus | Droplet | Supportive care | ||
| Bocavirus | Droplet | Supportive care | Not routinely diagnosed; method of diagnosis is NAT | |
| WU/KI viruses | Droplet | Supportive care | Not routinely diagnosed; method of diagnosis is NAT |
Table 2: Doses of oseltamivir and zanamivir
| Drug | Treatment Dose | Dose Adjustment | |
|---|---|---|---|
| CrCl (mL/min) | Dose | ||
| Zanamivir | 2 puffs (10mg) twice daily | No dose adjustment needed | |
| Oseltamivir | 75 mg twice daily | CrCl < 30 | 75mg once daily |
Table 3: Dose Recommendations for Children 12 Months of Age or Greater
| Age | Treatment (Duration = 5 days) | Chemoprophylaxis (Duration = 10 days) |
|---|---|---|
| Oseltamivir | ||
| Children ≤ 15 kg | 30 mg twice daily | 30 mg once daily |
| Children 15-23 kg | 45 mg twice daily | 45 mg once daily |
| Children 24-40 kg | 60 mg twice daily | 60 mg once daily |
| Children > 40 kg | 75 mg twice daily | 75 mg once daily |
| Zanamivir‡ | ||
| Children | Two 5-mg inhalations (10 mg total) twice daily [age, 7 years or older] | Two 5-mg inhalations (10 mg total) once daily [age, 7 years or older] |
Table 4: Dose Recommendations for Children Less than 12 Months of Age (weight-based dosing preferred)
| Age | Treatment with Oseltamivir (Duration = 5 days) | Chemoprophylaxis with Oseltamivir (Duration = 10 days) |
|---|---|---|
| < 3 months | 3 mg/kg/dose twice daily | Not recommended unless situation judged critical due to limited data on use in this age group |
| ≥ 3 months | 3 mg/kg/dose twice daily | 3 mg/kg/dose once daily |
Kneyber MC, van Woensel JB, et al. Azithromycin does not improve disease course in hospitalized infants with respiratory syncytial virus (RSV) lower respiratory tract disease: An randomized equivalence trial. 2007;Dec. 17 [Epub ahead of print].
Khanna N, et al. Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature. Clin Infect Dis. 2008 Feb 1;46(3):402-12.
Hall CB et al. The Burden of Respiratory Syncytial Virus Infection in Young Children. N Engl J Med. 2009 Feb 5;360(6):588-98.