Impact of Respiratory Viral Infections in Transplant Recipients Free

Abstract

Respiratory viral infections (RVIs) are among the leading cause of morbidity and mortality in pediatric hematopoietic stem cell transplant (HCT) and solid organ transplant (SOT) recipients. Transplant recipients remain at high risk for super imposed bacterial and fungal pneumonia, chronic graft dysfunction, and graft failure as a result of RVIs. Recent multicenter retrospective studies and prospective studies utilizing contemporary molecular diagnostic techniques have better delineated the epidemiology and outcomes of RVIs in pediatric transplant recipients and have advanced the development of preventative vaccines and treatment interventions in this population. In this review, we will define the epidemiology and outcomes of RVIs in SOT and HSCT recipients, describe the available assays for diagnosing a suspected RVI, highlight evolving management and vaccination strategies, review the risk of donor derived RVI in SOT recipients, and discuss considerations for delaying transplantation in the presence of an RVI.

INTRODUCTION

Respiratory viral infections (RVIs) are among the leading causes of morbidity and mortality in pediatric hematopoietic stem cell transplant (HCT) and solid organ transplant (SOT) recipients and have been associated with chronic graft dysfunction and graft failure in SOT recipients, particularly in lung transplant recipients [1–3]. Transplant recipients remain at high risk for progression from upper respiratory tract infection to lower respiratory tract infection, with higher rates of pneumonia and bacterial and fungal superinfection compared to nonimmunocompromised children [4]. Rates of hospitalization are also higher among transplant recipients, with data suggesting that 14.5% of pediatric SOT recipients had at least one RVI that required hospitalization within 12 months of transplant, while only 4% of otherwise healthy children experienced hospitalization as a result of respiratory viral infection [5, 6]. Community-acquired respiratory viruses such as influenza, respiratory syncytial virus (RSV), parainfluenza, adenovirus, rhinovirus, endemic coronaviruses, SARS-CoV-2, and human metapneumovirus are particularly challenging due to frequent exposures both pre- and post-transplant, as well as the potential for nosocomial transmission. Until recently, the majority of the available data on RVIs in HCT and SOT recipients was limited to single-center retrospective reports. However, recent multicenter retrospective studies and prospective studies utilizing contemporary molecular diagnostic techniques have better delineated the epidemiology and outcomes of RVIs in symptomatic pediatric transplant recipients requiring hospitalization for influenza, adenovirus, and RSV disease in pediatric transplant recipients.

DIAGNOSIS

Early detection of RVIs in transplant recipients may reduce antibiotic exposure, prompt timely initiation of antiviral therapies, and allow for appropriate infection control measures to mitigate nosocomial transmission. Specific RVIs are clinically indistinguishable from one another, and transplant recipients often have atypical presentations due to lifelong immunosuppression [1, 7]. Comprehensive molecular diagnostic testing should be employed to screen for recognized viruses when a RVI is suspected.

Nucleic acid amplification assays are the preferred diagnostic test for immunocompromised children due to their high sensitivity, specificity, and rapidity of results. Multiplex polymerase chain reaction (PCR) assays are commercially available and allow simultaneous detection of a variety of recognized viral respiratory pathogens, although specific assays differ in sensitivity and specificity [8]. While PCR is a powerful and widely used technique for the diagnosis of RVIs, it does have limitations. Timing of sample collection is crucial as poorly collected specimens can yield false negative results [9]. Likewise, anterior nasal swab testing may be negative in patients with lower respiratory tract infections [10]. Guidelines suggest that patients suspected to have a RVI should have a nasal swab sent for testing [1]. If there is clinical concern for lower respiratory tract infection, including with other non-RVI pathogens, bronchoalveolar lavage can be considered after weighing risks and benefits in a given patient [1, 8].

Viral shedding can be prolonged in immunocompromised patients despite use of appropriate antivirals, but the clinical and epidemiologic importance of prolonged excretion of virus is unclear [11]. PCR testing does not distinguish between viable and nonviable virus, which can lead to challenges in interpreting a positive result [12]. Monitoring of viral replication by PCR should generally not be used to guide duration of antiviral therapy. Rather, continuation of antiviral therapy depends on clinical symptoms [1]. Recent data indicate that PCR cycle threshold values correlate with infectivity for SARS-CoV-2, however, data are limited regarding the clinical correlation for SARS-CoV-2 cycle threshold in immunocompromised hosts. In one cohort of five adult SOT recipients with serial SARS-CoV-2 PCR testing, cycle threshold values of <35 were detected >27 days after symptom onset in two patients [13]. Further investigation is needed to determine whether cycle threshold data can help inform strategies for prevention and treatment of RVIs in transplant recipients, especially in the context of prolonged viral shedding [14, 15]. Absolute quantification of viral load can be performed but is not widely available outside of research settings.

Rapid antigen detection directly identifies proteins produced by viruses in respiratory secretions. This method is available for influenza, RSV, and SARS-CoV-2. Rapid antigen detection offers a number of advantages over molecular assays, as it is relatively inexpensive, easy to perform, and allows for rapid results within minutes. Of note, rapid antigen detection tests have suboptimal sensitivity, with reports varying between 50 and 60% for RSV and influenza [16–18]. The sensitivity of an antigen test for SARS-CoV-2 is 30-40% lower when compared with PCR [19]. Despite the lower sensitivity, rapid antigen detection can be helpful in guiding patient management decisions as well as large-scale public health interventions. Rapid antigen tests for SARS-CoV-2 for home testing are widely available and may reduce the need for extra testing visits in the clinic.

Prior to the advent of molecular tests, respiratory viruses were diagnosed by serology or viral culture. A variety of serologic assays testing acute and convalescent-phase serum for diagnosing respiratory infections have been used, and in the case of influenza, hemagglutination inhibition tests are able to subtype the virus. However, serology is no longer used for diagnosis as it is slower and less specific than rapid antigen testing and molecular assays. Serological testing for RVI in transplant patients is rarely used and is especially unreliable in the setting of poor antibody response to infection. Likewise, viral culture is rarely used in clinical practice as secondary to low sensitivity for some viruses, inability to test for multiple viruses at one time, need for technical expertise, and prolonged time to diagnosis compared to rapid diagnostic techniques [1, 7].

EPIDEMIOLOGY

Recent retrospective multicenter cohort studies of the epidemiology of RVIs in pediatric SOT and HCT recipients have documented that approximately 14.5% of SOT recipients and 16.6% of HCT recipients have had at least one RVI that required hospitalization within 12 months of transplant [5]. The seasonality of RVIs in the transplant population is similar to that in the general community, with epidemiologic patterns of RVI detection being comparable between HCT and SOT recipients. RSV and human metapneumovirus typically circulate in winter. Parainfluenza virus and influenza virus seasonality varies by type, and epidemiology can vary from year to year. Human rhinoviruses and endemic coronaviruses are typically present year-round at low to moderate levels [20]. With the emergence of SARS-CoV-2, there have been notable disruptions to the typical seasonal circulation of RVIs in the community [21]. Prior studies have described the outcomes of specific RVIs in various transplant populations, however, these data have been limited to single-center studies and are biased toward patients who are hospitalized, who are potentially more likely to be symptomatic and to develop complications [22, 23].

RVI in Renal Transplantation

The epidemiology of infections following pediatric renal transplantation has evolved over time. In the past few decades, an increase in bacterial infections has been observed, with a relative decrease in the incidence of reported respiratory viral infections [24, 25]. RVIs have been reported to occur at a rate of 5.5% in the first year after transplant [5]. Unlike other pediatric solid organ transplant recipients, symptomatic RSV infection is not commonly diagnosed in pediatric renal transplant patients [26]. Furthermore, the course of RSV infection did not differ from that reported in otherwise healthy children, with no increased mortality observed in renal transplant recipients. One retrospective study examining the incidence and outcome of RSV in 173 pediatric renal transplant recipients noted that of the 5 patients (3%) with RSV, 3 developed biopsy-proven acute rejection during or immediately following RSV diagnosis. Allograft dysfunction and acute rejection have also been described after severe cases of influenza in adult renal transplant recipients, but this association between RVIs and acute rejection warrants further study in pediatric renal transplant recipients [27].

RVI in Liver Transplantation

RVIs have been identified as important pathogens among pediatric liver transplant recipients, but the true incidence and burden of these infections remain poorly defined [28]. A large, multicenter consortium of 448 pediatric liver transplant recipients described a RVI rate of 15.6% within the first year after transplant. No deaths were attributable to RVI in isolated liver transplant recipients, and only one recipient developed a respiratory complication (pulmonary hemorrhage) within three months of RVI onset [5]. Contrarily, RSV infection in particular has been associated with significant morbidity in pediatric liver transplant recipients and is associated with an increased rate of hospitalization compared to the general pediatric population, with a death rate of 4.5%. Factors associated with a more severe RSV course included preexisting lung disease and RSV diagnosis within 20 days of transplant [29]. RSV infection in liver transplant recipients occurs during peak epidemic months, with nosocomial transmission accounting for a significant proportion of cases [30]. One report of RSV infection in pediatric liver transplant recipients documented that nosocomial transmission accounted for 13 out of 17 RSV cases in this population.

Studies have not reported severe SARS-CoV-2 disease in pediatric liver transplant recipients. In a multicenter observation registry including 180 pediatric liver transplant recipients with confirmed SARS-CoV-2 infection, no recipient required mechanical ventilation or died [31].

Disseminated adenovirus infection has been documented to occur in 3.5-38% of pediatric liver transplant recipients, with clinical manifestations ranging from asymptomatic to fulminant disease [32]. In liver transplant recipients, adenovirus can affect the respiratory tract as well as the gastrointestinal and urinary tracts. However, hepatitis is the most common manifestation in this population.

RVI in Heart Transplantation

RVIs occur frequently after pediatric heart transplantation and are associated with significant rates of hospitalization and high health care costs [33]. A retrospective study of 251 pediatric heart transplant recipients documented a RVI rate of 18.3% within the first year after transplant [5]. A study using the Pediatric Health Information System (PHIS) database found similar rates of infection in 3815 pediatric heart transplant recipients, with RSV and influenza being the most commonly identified infections in the post-transplant period. Patients who were <2 years of age, who required mechanical circulatory support, or who received an induction regimen containing >2 immunosuppressive agents had an increased incidence of RVI in the first year after transplant. Data regarding outcomes of RVIs in this population are limited, but infection with respiratory viruses has not been significantly associated with graft rejection [33]. As seen with pediatric lung transplant recipients, heart transplant recipients who contract SARS-CoV-2 infection tend to have quick resolution of their illness and with no reported long-term sequelae [34].

RVI in Lung Transplantation

Infection accounts for nearly 40% of post-transplant mortality in lung transplant recipients, with RVIs reported in 1.4-66% of recipients. RVIs occur frequently in the early post-transplant period, with reported rates up to 13.8% within the first year after transplant [5]. A recent multicenter retrospective study of pediatric lung transplant recipients reported that the most frequently encountered viral pathogens were adenovirus (24.8%), human rhinovirus (21.8%), RSV (20.8%), and parainfluenza virus (18.8%). Seasonal distribution was observed for influenza and RSV, with peak recovery of these viruses in the winter months. Adenovirus occurred more frequently in the spring months, and parainfluenza and rhinovirus were reported year-round, with peaks in both the fall and spring. Infections were documented during seasons in which the viruses are known to circulate in the community. Younger age at the time of transplant and an underlying disease process other than cystic fibrosis were found to be significant risk factors for the development of a RVI [35].

Lung transplant recipients are particularly prone to complications related to RVIs. Studies in adult lung transplant recipients have linked RVIs to bronchiolitis obliterans syndrome [36], but the relationship between graft dysfunction and RVIs in the pediatric population remains less clear. Some small studies of pediatric lung transplant recipients have not identified an association between RVIs and the development of chronic allograft rejection or death [37]. However, adenovirus respiratory infection was associated with graft failure and death in a separate cohort [38]. Similarly, a large retrospective analysis of RVIs in a cohort of nearly 600 pediatric lung transplant recipients reported that development of a RVI within the first year of transplant was a predictor of death or re-transplantation due to graft failure [35, 36, 39].

In comparison to adult lung transplant recipients, pediatric lung transplant recipients seem less likely to develop severe disease secondary to SARS-CoV-2. A recent single-center study did not report severe disease, graft-related complications, or deaths related to SARS-CoV-2 infection in a cohort of 51 pediatric lung transplant recipients [40, 41].

RVI in Intestinal/Multivisceral Transplantation

A multicenter, retrospective study of 1096 pediatric heart, lung, kidney, liver, and intestinal/multivisceral transplant recipients reported that intestinal/multivisceral transplant recipients were at highest risk for symptomatic RVI, with 38% of recipients experiencing at least one RVI event within one year of transplant [5]. Human rhinovirus was the most commonly detected virus. A prior single-center report of 25 children who had undergone intestinal and/or liver transplant reported that the overall mortality associated with lower respiratory tract RVIs was as high as 13%; no deaths were attributed to rhinovirus disease in this study [42]. A recent retrospective analysis assessing the impact of RSV, adenovirus, influenza, and parainfluenza infection in pediatric SOT patients documented a total of eight RVIs in children with multivisceral transplants, with four of those being parainfluenza, and four being RSV. Almost all documented RVIs were associated with hospitalization, and one of the eight patients had death or disability attributed to a RVI [23]. Adenovirus has been found at high rates (up to 57%) in intestinal or multivisceral transplant recipients [43], but seems to be more localized to the transplanted organ [44]. The clinical consequences of adenovirus respiratory tract infection in pediatric intestinal transplant recipients remain poorly understood.

RVI in HCT

Pediatric HCT recipients are at increased risk for morbidity and mortality from RVIs due to the extent and duration of their immunosuppression. Small, single-center cohorts have reported incidence rates of RVIs in this population between 5.1 and 21% [45–48]. However, a large, multicenter retrospective study followed a cohort of 1560 HCT recipients reported an incidence rate of inpatient symptomatic RVI as high as 16.6% within 1 year post-transplant, with no significant differences reported between allogeneic and autologous HSCT recipients (17.4 vs 14.2%, respectively) [2]. Human rhinovirus was the most commonly detected pathogen, followed by parainfluenza virus and RSV. Seasonality of RVIs in pediatric HCT recipients is similar to that observed in the general pediatric population, with most RVIs occurring between October and March [45, 47]. Significant mortality due to acquisition of a RVI in the first year following transplant has been documented, with RVI-attributable mortality rates between 0.6 and 10% [45, 47, 49]. Risk factors for poor outcomes include allogeneic transplant, graft versus host disease (GVHD), use of immunosuppressive agents, and steroid exposure [50].

PREVENTION

General Measures

Preventing RVIs is paramount to reducing morbidity and mortality associated with these infections. Nosocomial transmission can be avoided by isolation precautions, meticulous hand washing, and limiting sick visitors. Vaccination prior to transplantation should be pursued when available and feasible, as vaccine responses are often impaired in the post-transplant period. Post-transplant vaccination should also be considered; timing and dosing may depend on transplant type.

Pathogen-Specific Vaccination

Influenza

Influenza vaccination is the mainstay of influenza disease prevention and has been shown to decrease influenza-related morbidity and mortality in transplant recipients [51]. Annual vaccination with standard-dose inactivated influenza vaccine is recommended for SOT recipients 6 months of age and older, although a pilot study in pediatric SOT recipients showed that a higher percentage of individuals achieved seroconversion after receiving high-dose influenza vaccine compared to standard-dose vaccine [52, 53]. Similarly, a recent randomized controlled trial in 170 pediatric HCT recipients reported that two doses of high-dose influenza vaccine resulted in significantly higher geometric mean titers to A/H1N1 and A/H3N2, with numerically higher titers to B/Victoria when compared to two doses of standard-dose vaccine. The overall safety profile was comparable, with a slightly higher number of injection-site reactions after the second dose of high-dose vaccine when compared to the second standard-dose vaccine. These results are similar to prior influenza vaccine trials conducted primarily in immunocompromised adults that also demonstrated high-dose influenza vaccine to be more immunogenic compared to standard dose. A phase I study of adult HCT recipients found that a single dose of high-dose vaccine produced higher geometric mean titers to A/H3N2 compared to a single dose of standard-dose vaccine [54, 55]. These data suggest the need for investigation of alternative vaccination strategies to determine the optimal timing and number of doses for transplant recipients.

COVID-19

A primary series of two doses of COVID-19 vaccine in transplant patients does not generate an immune response as robust as that seen in nonimmunocompromised hosts [56, 57]. Both humoral and cellular immune responses are significantly augmented after receiving a third vaccine dose [57]. Recommendations for COVID vaccination in transplant recipients are anticipated to evolve as variants emerge and providers should refer to the most updated recommendations from the CDC and/or professional societies.

RSV

A RSV vaccine was recently approved for adults 60 years of age and older to reduce the risk of RSV-associated lower respiratory tract disease [58]. Several other trials are underway in pregnant women and older adults. However, there are currently no studies to evaluate RSV vaccination in transplant recipients.

Pre-Exposure Prophylaxis

Pre-exposure prophylaxis is one strategy to prevent disease and/or infection in transplant recipients who may not mount an adequate immune response to vaccination. Monoclonal antibodies have been shown to be effective as pre-exposure prophylaxis for both RSV and SARS-CoV-2 in certain populations. Palivizumab is a humanized monoclonal antibody licensed for RSV prophylaxis in high-risk children younger than 24 months and has been shown to be effective in reducing hospitalization from RSV [59–61], although supportive data are limited for its use in pediatric transplant recipients [62]. One retrospective study of pediatric HSCT recipients showed that adapting a restrictive approach to palivizumab use did not result in increased RSV incidence or severity, suggesting that palivizumab should not routinely be used, but rather use should be limited to transplant recipients who are at the highest risk for severe disease [63]. Despite a paucity of evidence, survey data indicate that palivizumab prophylaxis is commonly used among pediatric transplant centers [64, 65]. Nirsevimab, a novel RSV monoclonal antibody with higher potency and a prolonged half-life compared to palivizumab, has demonstrated efficacy in infants against medically attended and hospitalization for RSV-associated LRTI and severe RSV and has recently been approved by the Food and Drug Administration (FDA) [66, 67]. Transplant-specific data are lacking, but trials in immunocompromised hosts are ongoing (NCT04484935).

The only product shown to be effective for pre-exposure prophylaxis for SARS-CoV-2 is tixagevimab plus cilgavimab [68]. The authorization of this combination of monoclonal antibodies was based on clinical trial data from a group of largely nonimmunocompromised adults, but retrospective studies of immunocompromised patients demonstrated efficacy against COVID-19 complications [69, 70]. With the emergence of SARS-CoV-2 variants, tixagevimab-cilgavimab authorization was revoked due to its limited activity against circulating variants. Novel monoclonal antibodies with activity against newer variants are under investigation.

Post-Exposure Prophylaxis

In transplant recipients for whom influenza vaccination is either contraindicated or ineffective due to diminished immune response, antiviral prophylaxis may be considered following documented exposure to influenza. Prophylaxis with oseltamivir is generally well-tolerated and been shown to be ~80% effective in reducing incidence of influenza in adult SOT patients [1, 71].

Monoclonal antibodies to the spike protein of SARS-CoV-2 received emergency use authorization for post-exposure prophylaxis in children ≥12 years of age who are at increased risk for progression to severe disease. While these therapies were well-tolerated, they are no longer available due to the development of resistant SARS-CoV-2 variants [72].

MANAGEMENT

The management of RVIs in transplant recipients includes supportive care and, when available, antiviral medications and monoclonal antibodies, especially in patients who are at higher risk for progression to lower respiratory tract involvement. As with most infections in transplant recipients, the feasibility of reduction of immunosuppression should be considered, as this may shorten the duration and lessen the severity of illness.

Influenza

Neuraminidase inhibitors including oral oseltamivir, inhaled zanamivir, and IV peramivir are approved for the treatment of influenza. Early use of oseltamivir in transplant recipients is associated with decreased risks of mortality, progression to lower respiratory tract disease, and ICU admission [73–77]. Minimal data are available for zanamavir and peramivir in transplant patients. Baloxavir is a single-dose FDA-approved therapy which selectively inhibits the influenza cap-dependent endonuclease. Baloxavir has been demonstrated to be efficacious in treating influenza in clinical trials conducted in healthy adolescents and adults, although antiviral resistance following baloxavir has been documented in clinical trials [78]. There is a paucity of data for its use in transplant recipients, but observational studies and case series have shown that baloxavir alone and in combination with oseltamivir was successful in treating adult HCT patients with influenza [79, 80]. Most experts would not use baloxavir as monotherapy in transplant recipients; combination therapy should be considered on a case-by-case basis.

Given the benefits of early treatment, it is recommended that antiviral therapy be administered empirically to transplant recipients with clinical presentation consistent with influenza, prior to molecular diagnostic or rapid antigen confirmation [1]. Although treatment is most beneficial within 24-48 hours of symptom onset, benefit has been demonstrated even with delayed treatment, and it is therefore recommended that antivirals be administered to SOT and HCT recipients with influenza at any point in their illness [81]. Due to reduced immunologic response to influenza vaccination, antiviral chemoprophylaxis has been recommended as an alternative therapy to vaccination in SOT recipients after receipt of lymphocyte depletion therapy [1]. A randomized controlled trial in HCT and SOT recipients found that antiviral prophylaxis with oseltamivir for 12 weeks significantly reduced the frequency of proven influenza infection [82].

Resistance to neuraminidase inhibitors has been documented and appears to occur more commonly among immunocompromised patients [83, 84]. These patients with resistant influenza have a higher rate of progression to lower respiratory tract involvement and death. Most resistance in influenza viruses in patients exposed to neuraminidase inhibitors is caused by a mutation in H275Y, which results in resistance to oseltamivir and peramivir, but retains zanamivir activity [85]. As resistance patterns may evolve and affect antiviral activity and recommendations, clinicians should consult national health authorities for up-to-date guidance on treatment and vaccination.

COVID-19

Available therapeutics for the treatment of COVID-19 have evolved over the course of the pandemic as resistant SARS-CoV-2 strains have emerged. Available data suggest that the majority of pediatric transplant recipients do not progress to severe disease, and published literature is limited regarding the use of antivirals and monoclonal antibodies in the pediatric transplant population [86–88]. Recommendations are therefore largely based on extrapolation from adult studies. Historically, different preparations of monoclonal antibodies have received emergency use authorization to prevent progression to severe disease, but there are currently no approved monoclonal antibody products, as the most recently circulating SARS-CoV-2 subvariants are not susceptible to these products. Remdesivir was the first antiviral to be authorized to treat COVID-19 in adults and children aged ≥28 days, but the literature in pediatric transplant recipients is limited to case reports. Nevertheless, guidance documents support the use of remdesivir for use in hospitalized patients who require supplemental oxygen and in nonhospitalized patients who are at high risk of progressing to severe disease [89, 90]. Remdesivir should be administered for three days in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease, whereas hospitalized patients should receive remdesivir for 5 days or until hospital discharge [91]. Ritonavir-boosted nirmatrelvir is an additional antiviral approved in patients 12 years and older that is used as outpatient therapy for COVID-19 in high-risk patients early in disease. However, due to significant interactions with calcineurin inhibitors, the American Society of Transplantation recommends the early use of outpatient intravenous remdesivir as the preferable first-line therapy to prevent disease progression [92]. Molnupiravir, while not approved for treatment of COVID-19 in the pediatric population, retains antiviral activity against all known variants of SARS-CoV-2 and is an oral treatment option for adult SOT recipients. A recent clinical trial showed that patients treated with molnupiravir had faster time to recover and reduced viral load [93]. Molnupiravir has not shown any interactions with calcineurin or mTOR inhibitors and may be a more practical option for nonhospitalized adult SOT recipients [94].

RSV

Although several options have been considered for the treatment of RSV, consensus in transplant recipients remains unsettled, as there are no placebo-controlled, randomized trials that favor RSV treatment in this population. Available therapies include ribavirin, intravenous immunoglobulin, and palivizumab. Currently, ribavirin is the only approved drug for the treatment of RSV-attributed lower respiratory tract disease in high-risk patients [95]. Due to paucity of evidence, management strategies across transplant centers are not uniform [65]. Guidance documents have been published based on the best available data and recommend treatment with either aerosolized or oral ribavirin in lung transplant recipients with upper or lower respiratory tract infection, with consideration for the addition of corticosteroids and IVIG [1]. Treatment with ribavirin in nonlung solid organ recipients with lower respiratory tract disease may be considered, although data to support this recommendation are limited. Prospective and retrospective studies have reported improved outcomes in HCT recipients with inhaled, oral, and IV ribavirin as well as with combinations of ribavirin with IVIG and palivizumab [81, 96–99]. However, ribavirin in HCT recipients with RSV infection remains controversial. Despite limited availability of effective therapeutics, overall outcomes of RSV infection in transplant patients have clearly improved over time. This may be attributable to early diagnosis of disease, improved supportive care, changes in transplant practices and/or increased use of antivirals. A recent report in pediatric HCT recipients showed lower rates of RSV-attributable lower respiratory tract disease and reduced mortality rates, compared to historical populations [100].

Adenovirus

Few effective therapeutic options exist for the treatment of adenovirus disease and there are currently no approved drugs for the specific indication of treating adenovirus infection. The mainstay of therapy consists of reduction of immunosuppression if feasible. Ribavirin, IVIG, and cidofovir have all been used as treatment strategies in transplant patients, but their effective use is limited by drug toxicity, variable success of therapy, and lack of data from controlled trials [101, 102]. Although there is limited clinical data specifically evaluating the efficacy of cidofovir in pediatric transplant recipients, case reports and case series in both SOT and HCT patients report successful off-label use of cidofovir to treat disseminated adenovirus [102–105]. When therapy is needed, most use cidofovir despite potential toxicity [106]. Cidofovir must be given intravenously and can be dosed either as 5 mg/kg every 1-2 weeks or 1 mg/kg three times per week. One retrospective study in pediatric SOT recipients comparing the two dosing regimens reported that the 1mg/kg three times weekly dosing had improved viral load clearance without significant difference in nephrotoxicity [107].

Brincidofovir is a prodrug of cidofovir with increased in vitro efficacy against adenovirus and a more favorable side effect profile compared to cidofovir. Brincidofovir has been used successfully for the treatment of disseminated adenovirus [106]. A phase II trial including pediatric and adult HCT recipients demonstrated that patients who received brincidofovir had better control of adenovirus viremia, with improved mortality over placebo [108]. Additionally, a case series among four pediatric SOT recipients demonstrated successful treatment with brincidofovir with limited adverse side effects, suggesting that it might be a viable treatment option [109]. Currently, brincidovir is still under investigation and access is limited to investigational and compassionate use, therefore it cannot be routinely considered for adenoviral infections [106, 110].

Viral-specific T cells are also under investigation for the treatment of disseminated adenovirus in pediatric HCT recipients (NCT02532452). Further information regarding virus-specific T cells for the treatment of systemic infections following transplantation can be found elsewhere in this supplement [111].

Parainfluenza and Human Metapneumovirus

Case reports of adult SOT recipients with parainfluenza and human metapneumovirus infection have reported successful outcomes with a combination of ribavirin and intravenous immunoglobulin (IVIG), however, no randomized trials exist to determine the efficacy of this regimen in transplant recipients [1, 35, 112]. Regardless, current recommendations suggest consideration of treatment of lung transplant recipients with ribavirin [1].

Risk for Donor-Derived Disease in SOT

Despite laboratory screening of potential donors, transmission of RVIs from donor to recipient remains an inherent risk of solid organ transplantation, with the highest risk in lung transplant recipients. A recent report of donor-derived diseases from the Disease Transmission Advisory Committee described 9 lung transplant recipients known to be exposed to respiratory viruses from donors. Symptomatic disease developed in all 9 of the lung recipients, compared to only 1 of 26 exposed, nonlung recipients [113]. Similarly, emerging data suggest that the risk of donor-derived COVID-19 is highest among lung transplant recipients [114]. The American Society of Transplantation (AST) recommends that all donors should be tested for SARS-CoV-2 infection from the upper respiratory tract using nucleic acid testing and as close to organ recovery as possible. Nonlung donors with positive SARS-CoV-2 PCR should be considered for organ acceptance. The use of lung donors with positive bronchoalveolar lavage PCR should be avoided [114]. Donor-derived influenza A and B infection has also been documented in lung transplant recipients [115–118]. These transmission events have informed guidelines discouraging transplanting lungs from influenza-positive donors until a course of antiviral therapy has been completed in the donor [119]. Although several reports of excellent short-term outcomes following nonlung SOT transplantation from influenza-positive donors exist, guidance on the use of organs from influenza-infected donors is limited. Most current guidelines recommend 10 days of antiviral post-exposure prophylaxis following the recipient of any organ from a donor infected with influenza [77, 117, 118, 120, 121].

Considerations for Delaying Transplantation

Diagnosis of RVI in the pretransplant period may complicate the timing of planned transplantation and may increase the risk of post-transplant complications. Efforts should be made to mitigate risk of infection prior to transplantation, including vaccination and prophylaxis when appropriate. In some situations, transplantation must be delayed. The decision to delay transplantation in the presence of a RVI is influenced by the urgency of transplant, and by the severity and nature of the RVI. Definitive guidance is lacking, but expert opinion is available to guide decision-making. In the case of an identifiable upper respiratory tract infection in a child who requires urgent SOT, most experts recommended no delay in the timing of transplant. Conversely, in the presence of a lower respiratory tract infection, recommendations vary depending on the severity of infection, organ to be transplanted, and urgency of transplant. Intermediate delay in transplantation is recommended in the presence of a mild to moderate lower respiratory tract infection, with a prolonged delay favored in the event of severe lower respiratory tract infection [122], although the risks and benefits of deferred transplantation require careful analysis and must be determined on a case-by-case basis. Similar considerations should be evaluated for HCT transplant candidates with pretransplant RVIs, with most experts recommending possible delay for certain viruses (RSV, influenza, PIV, hMPV, SARS-CoV-2) and in those with certain risk factors (LRTI due to any virus, myeloablative conditioning) [123, 124].

FUTURE DIRECTIONS

In the era of advanced molecular diagnostic techniques, RVIs are increasingly recognized as important causes of morbidity and mortality in transplant recipients. However, knowledge gaps remain, requiring ongoing studies to assess the impact of these viruses. Prospective, multicenter studies evaluating the long-term outcomes of RVIs in pediatric transplant recipients are needed to improve understanding of potential complications including effects on graft function. Continued development of vaccines specifically targeting the transplant population as well as optimization of immunizations schedules are essential to improve protection against RVIs. Novel antiviral therapies targeting specific respiratory viruses are under development and could provide effective treatment options for pediatric transplant recipients. Additionally, virus-specific T cells are an emerging therapeutic modality, but prospective trials are needed to understand the optimal treatment regimen for these viruses.

Note

Supplement sponsorship. This article appears as part of the supplement “Advances in Pediatric Transplant Infectious Diseases,” sponsored by Eurofins Viracor.

References