Keywords

1 Introduction

Respiratory viruses (RVs) are increasingly recognized as a major cause of morbidity and mortality in solid organ transplant recipients, especially within the lung transplant population. Respiratory viral infections are typically caused by rhinovirus (RhVs), coronavirus (CoV), respiratory syncytial virus (RSV), influenza (FLU), parainfluenza (PIV), human metapneumovirus (hMPV), and adenovirus (AdV) (Table 9.1). Respiratory infections can also be caused by viruses less commonly associated with the respiratory tract such as cytomegalovirus (CMV), human herpesviruses (HSV1, HSV2), and varicella zoster virus (VZV) that will be discussed in another chapter (Chap. 6). A detailed discussion of other newer respiratory viruses (Table 9.1) is beyond the scope of this chapter, since they have not been widely studied in immunocompromised patients and their clinical impact is not fully understood. However, these viruses should be considered in the differential diagnosis of patients presenting with severe lower tract disease, especially if clinical history indicates potential exposure. The newer RVs are more challenging to diagnose since they are not included in the routinely available diagnostic tests and optimal management has not been defined.

Table 9.1 Classification and distribution of major and minor respiratory viral infections in SOT
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2 Clinical Manifestations

The definition of RV disease includes (1) a new onset of symptoms and (2) at least one respiratory symptom and (3) the clinician’s judgment that the illness is due to an infection [1]. An upper respiratory tract infection (URTI) is defined with the onset of sore throat, rhinorrhea, or hoarseness. A lower respiratory tract infection (LRTI) is defined as new onset of shortness of breath, cough, sputum, rales, hypoxemia, and/or wheezing. When symptoms of LRTI are associated with a new pulmonary infiltrate (on chest radiograph or chest computed tomography), pneumonia is distinguished from tracheobronchitis.

Many common respiratory viral infections in SOT patients are mild, self-limiting upper respiratory tract infection (URTI) and do not require hospitalization. However, compared to immunocompetent hosts and due to alterations in cellular and humoral immunity, infections can cause protracted symptoms with greater risk of progression to LRTI, prolonged periods of viral shedding, and increased mortality. In SOT, LRTIs have been associated with increased risk of adverse complications and subsequent development of fungal, viral, and bacterial superinfections [2]. Although these complications may appear in the context of any type of transplantation, pediatric, lung, and heart-lung transplantation recipients appear to have the greatest risk of respiratory viral infections with more severe courses and complications [2,3,4].

In addition to their direct, cytopathic, and tissue-invasive effects, RVs can create an inflammatory environment that leads to local and systemic microbially determined immune modulation (MDIM) [5]. MDIM may increase the alloimmune and autoimmune responses that increase susceptibility to other opportunistic infections and are associated with the development of acute and chronic rejection. The greatest risk appears from data in lung transplant recipients, although data on this topic in the literature are conflicting [2, 5, 6].

In transplantation overall, RhV and CoV are the most common etiological agents, causing mostly mild URTI, with LRTI less frequently described. In contrast, FLU and other paramyxovirus (RSV, PIV, and hMPV) have a greater association with LRTI and particularly acute and chronic rejection in adult lung transplant recipients [2, 5] (Tables 9.1 and 9.2). Outcomes of infection are associated strongly with site of involvement, net state of immune suppression, and availability and use of antiviral agents.

Table 9.2 Seasonality, diagnostic tools, clinical presentation, treatment regimens, prevention, and isolation precaution for major RVs
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3 Diagnosis

The clinical diagnosis of RVs can be difficult, since SOT recipients often present with mild or atypical symptoms and signs, which are often overlapping and not always specific for any one viral agent. Fever can be absent in SOT with pneumonia or can be the sole presenting sign. In addition bacterial and fungal coinfections may occur.

The distribution of RV infections throughout the year suggests that seasonal patterns of RV circulation in SOT are similar to those circulating in the general population [2, 3]. Consequently, vigilance regarding circulating community RV infections is required while caring for SOT recipients.

Rapid and reliable laboratory diagnosis is required in SOT with respiratory syndrome to significantly impact on patient care and management. The ideal method of sampling has also come into question, as the yield of viral specimen may differ depending on the specimen source. All SOTs with suspected RV infection should have a nasopharyngeal sample tested by PCR, including nasopharyngeal swab (NPS), wash, or aspirate. Between common respiratory specimens collected from the upper respiratory tract, NPS are preferred, since they are practical for widespread use and comparable in sensitivity to nasopharyngeal aspirates or bronchoalveolar lavage (BAL) for the detection of all major RVs [1, 7, 8]. NPS should be collected diligently by trained staff, using the standardized procedures of the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/urdo/downloads/speccollectionguidelines.pdf; https://www.youtube.com/watch?v=DVJNWefmHjE) [9]. If upper tract samples fail to document the RV cause of the respiratory illness and clinical or radiologic evidence of lower tract involvement exists, BAL should be performed for RV testing [7].

The array of diagnostic tools for RVs in immunocompromised patients has greatly increased over the last few years, and diagnosis can be performed using real-time PCR (RT-PCR) techniques, antigen detection, and serology (Table 9.3) [9].

Table 9.3 Laboratory methods for diagnosis of the major human respiratory viruses. From Hodinka (https://www.youtube.com/watch?v=DVJNWefmHjE) modified
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The sensitivities of contemporary molecular diagnostic techniques have been substantially improved, allowing for the rapid simultaneous detection of a wide variety of conventional and emerging RVs in respiratory samples. At present, real-time multiplex nucleic acid amplification testing (multiplex NAT) based on the RT-PCR technology is the preferred diagnostic tool for studying RVs in immunocompromised patients and is incorporated into many of the current guidelines [1, 7]. Both laboratory-developed and commercial RT-PCR assays are currently available, differing in specificity and sensitivity (ranges from 72% to 100%, with best sensitivity seen for FLU and lower sensitivities for ADV and PIV). With the aim of overcoming technical complexity of PCR-based testing, fully automated RT-PCR instrument for rapid detection of RV has been tested in immunocompromised patients with promising results with a turnaround time of approximately 1–2 h [10]. Therefore, clinicians should be aware of the performance characteristics of the assay performed (https://www.cdc.gov/urdo/downloads/speccollectionguidelines.pdf). Of note that regarding ADV, negative testing from the upper or lower airway may not exclude infections particularly for SOT with disseminated disease if there is limited to no involvement of the respiratory tract. RT-PCR should be applied on respiratory specimen, blood (quantitative viral load testing), and other compartments depending on clinical presentation (urine, cerebrospinal fluid).

It is important to remember, however, that despite the excellent sensitivity, poorly collected samples may yield false-negative results, and results may greatly vary depending on the quality of the swab. The high sensitivity of these methods also has drawbacks, such as frequent detection of viruses in asymptomatic individuals and prolonged detection of viruses in patients who have already clinically recovered [2, 3].

The major challenge is to determine association between the presence of microbial nucleic acids and a clinical syndrome in individual patients. Quantification of the virus may be a helpful result interpretation, since high viral loads are associated with the presence of symptoms and may be related to the severity of the clinical symptoms [9].

Antigen detection techniques, which include immunofluorescence (IF) and immunoassay (IA), are fast and have high specificity but are only available for specific viruses and their sensitivity less than molecular methods. This technique is not available for viral respiratory infections caused by RhV or CoV and is moderately complex, and interpretation of results is subjective [9]. A number of commercial IA are available for RSV and FLU (A and B) and require little technical expertise. However, false-negative and false-positive results can be generated. A low prevalence of circulating virus within the community decreases the positive predictive value of the test. For FLU, rapid IA has shown high specificity but low sensitivity (20–70%) as compared to other assays, making them suboptimal for SOT recipient, particularly in clinical decision-making for antiviral therapy [11].

Antiviral susceptibility testing for RVs is primarily focused on influenza, and both phenotypic and genotypic assays can be tested, although such testing is not widely available in local or commercial labs.

Antiviral resistance is of considerable concern among immunocompromised patients infected with influenza virus, and testing should be strongly considered in SOT undergoing treatment who fails to have an appropriate clinical response within 3–5 days of initiating antiviral therapy or who has a relapsing course despite ongoing therapy.

4 Treatment Options, General Considerations

In the absence of available treatment options and of strong evidence of effectiveness for any particular therapy, treatment strategies differ widely among centers [12]. Limited understanding of (1) risk factors for progression to severe LRTI and poor outcomes and (2) indirect inflammatory effects of viral infection impact opinions on appropriate interventions for respiratory viral infections. RV infections, particularly cause by influenza virus, are a risk factor for subsequent bacterial and fungal superinfections. In cases of LRTI, secondary infections must be ruled out and appropriately treated, and initiation of oral or nebulized antifungal prophylaxis to prevent invasive fungal infections should be evaluated in high-risk patients [1, 2, 12].

Management in transplant patients is generally focused on reduction of immunosuppression feasible to speed resolution of viral infection. Treatment options for RVs are limited (Tables 9.2 and 9.4). Resistance patterns may change and affect recommended antiviral strategies. Consequently, clinicians should consult national health authority regularly for updated recommendations, especially for influenza.

Table 9.4 Antiviral agents
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In our opinion treatment efforts should be always performed in any SOT with LRTI or in lung transplant and heart-lung transplantation recipients both with URTI and with LRTI, due to increased morbidity and mortality [12].

Reconstitution of the immune system appears to be important in overcoming RV infections. Clearly, the currently available treatment option is a clinical dilemma [6, 7, 13]. There are numerous reports in the literature citing the use of intravenous immunoglobulin (IVIG) as part of therapy for viral infections in immunocompromised patients. Hypogammaglobulinemia has been associated with an increased risk of opportunistic infections in SOT, but not to community-acquired RVI. However, some experts recommend considering the addition of IVIG for severe RV infection in SOT [13].

The use of monoclonal antibodies is limited to the treatment of RSV. Immunotherapy including transfer of RV-specific T lymphocytes from healthy donors is under investigation and has been reported to be safe and effective when performed early in the course of the infection for hMPV, adenovirus, RSV, and PIV. At the same time, virus-associated immune modulation may sometimes be deleterious in RVs due to local inflammatory responses. Adjunctive therapy with corticosteroids has been purposed for SOT with influenza and RSV and for lung transplant recipients with any RVs with LRTI because of the risk of both acute and chronic rejection [13].

5 Prevention, General Considerations

Treatment options for RVs are limited, and maximizing prevention measures against viral infections in SOT is mandatory.

RVs are potential community and nosocomial pathogens that can be spread by staff or visitors with mild upper respiratory illness. Overall awareness among SOT, healthcare personnel, family members, and caregivers about the potential deleterious outcomes of RV infections in SOT and the importance of early detection of infection may have a significant impact on the incidence of RV infections and risk of transmission [1].

Strict adherence to hand hygiene, contact precautions, and respiratory droplet isolation are required to reduce RV nosocomial spread and outbreaks during hospitalization (Table 9.2) (https://www.cdc.gov/infectioncontrol/guidelines/isolation/). The appropriate length of isolation for patients with laboratory proven RVs is debated, as prolonged shedding is a common finding in SOT patients, but viral load thresholds for infectivity are unknown. Infection control measures should be maintained until the patient is discharged home or until PCR is negative. Stringent hygiene precautions should be also applied in community settings, where SOT recipients should avoid close contact with individuals with respiratory tract infections [1]. The influenza virus is currently the only CARV that can be prevented with vaccination [14].

6 Prevention and Treatment of Specific RVs

6.1 Influenza

Three main viral strains have been recently associated with human infection, namely, influenza A/H1N1, influenza A/H3N2, and influenza B. Influenza infection in SOT causes significant morbidity and mortality compared to general population [15]. In studies performed in 2009 H1N1 pandemic, the proportion of patients who required hospitalization varied between 73% and 96%, and one of every five patients suffered severe complications with 7–8% mortality [15].

Treatment

The mainstay of treatment for influenza A and B are the neuraminidase inhibitors (NAI), mainly oseltamivir (Tables 9.2 and 9.4) [16]. Doubling the treatment dose of oseltamivir in hospitalized patients with influenza does not seem to increase virologic efficacy, except perhaps for influenza B infections or in case of oral absorption concerns, with no evidence of emergence of oseltamivir resistance [17, 18]. Zanamivir is used less frequently than oral oseltamivir, likely due to the inhaled delivery route, although it has shown better activity against influenza B and few cross-resistance with oseltamivir.

Regarding intravenous formulations, if available, intravenous zanamivir or peramivir can be considered in SOT recipients who are severely ill despite oral oseltamivir, in case of concerns with oral absorption, although experience with these drugs in SOT recipients is lacking [1]. Parenteral zanamivir is currently available in Europe, and a single dose intravenous peramivir has been approved in the United States for treatment of uncomplicated influenza infections. However, peramivir use in SOT likely would require repeated dosing or switching to oral oseltamivir to complete therapy.

NAI resistance is currently uncommon (0.09–1.9% of isolates), especially for influenza A/H3N2 and influenza B viruses, but remains an area of growing concern. In case of high-level oseltamivir resistance (such as H1N1 viruses strains with H275Y substitution), peramivir usually preserves reduced susceptibility, but zanamivir is usually active. Another common resistance mutation (H274Y in H3N2) confers resistance to both oseltamivir and peramivir, but not zanamivir. Therefore, peramivir should not be used in patients with oseltamivir resistance unless the isolate is proven to be susceptible [16] (Tables 9.2 and 9.4). DAS181, an inhaled sialidase potentially inhibiting influenza and parainfluenza infection, has shown promising in vitro results of activity against oseltamivir-resistant influenza strains but failed to show superiority compared to placebo in previous studies in healthy subjects with influenza infection [17].

Treatment should be initiated as soon as possible since antiviral therapy is most likely to provide benefit when initiated within the first 48 h of illness in SOT, with a reduced rate of influenza-associated complications (admission to ICU, use of invasive ventilation, and death) [15]. However, benefit has been demonstrated even with delayed treatment, and most experts endorse influenza-specific antiviral treatment at any point in the illness. Further, treatment should not be delayed while awaiting diagnostic testing results or if a rapid antigen IA test is negative when clinical symptoms are suggestive of infection due to the poor sensitivity of rapid antigen tests (Table 9.3) [19].

In general, duration of antiviral therapy should be at least 5 days for SOT patients although some data suggest that longer duration (≥10 days) may be required, particularly in critically ill patients, those with pneumonia and persistent viral shedding.

Aside from advances in supportive care, no specific adjunctive therapies are routinely recommended. Corticosteroids have been shown to decrease the need for mechanical ventilation and progression to LRTI but at the cost of prolonged viral shedding and risk for invasive fungal coinfection. Corticosteroids are not routinely recommended but should be used if indicated for another reason such as concurrent acute rejection [17].

Prevention

The main preventive strategy against influenza in SOT recipients remains the administration of yearly inactivated influenza vaccine. All transplant recipients and candidates, as well as family members, close contacts, and healthcare workers, should receive the influenza vaccine to provide herd immunity [14, 20] (Table 9.2). Influenza vaccines are available in inactivated (intramuscular or intradermal administration) and live-attenuated (intranasal) formulations. The live-attenuated vaccine is not recommended for immunocompromised recipients and close contacts, due to a potential risk of dissemination of the vaccine [14, 21].

Current guidelines recommend the standard injected inactivated influenza for SOT starting 2–6 month posttransplantation with option for administration as early as 1 month posttransplantation in an outbreak setting. If influenza vaccine was administered earlier than 2 months posttransplantation, when it is likely to be less effective, consideration may be given to administering a second dose of vaccine later in the influenza season [14, 20]. An association between vaccination and the development of the de novo antibodies and graft rejection is unproven.

A higher-dose vaccine in pediatric SOT and a booster strategy 5 weeks after standard influenza vaccination in adult SOT have shown to induce an increased antibody response compared with standard single dose. Whether or not protection is increased by use of higher-dose vaccine, adjuvants, booster doses, or quadrivalent versus trivalent vaccines constitutes an area of active research [21].

Clinical failure of influenza vaccination in SOT recipients has not been extensively studied, but most of the studies clearly suggest a reduced immune response in SOT, with a seroconversion rate that varies between 15% and 90%, although this is also dependent on the match between the vaccine and the circulating strains [20]. Vaccination has shown to attenuate adverse outcomes among SOT recipients with a lower incidence of pneumonia and shorter length of hospital stay [19, 22].

Beyond influenza vaccination, pre-exposure or postexposure chemoprophylaxis with either oseltamivir or zanamivir is approved (Tables 9.2 and 9.4) and may be considered [7]. Caution should be used with prescribing oseltamivir for prophylaxis in patients exposed to an index case because prophylaxis has been associated with emergence of resistant mutants; therefore, monitoring and empiric therapy are generally recommended in these cases [17].

6.2 Respiratory Syncytial Virus

Respiratory syncytial virus has long been recognized as a concerning pathogen in immunocompromised hosts. In SOT, RSV infection typically manifests as an URTI with progression to LRTI in 27–67%. Risk factors for more severe disease after organ transplantation include infection in children under a year of age or lung transplantation [2, 4].

Treatment

The use of ribavirin (RBV) for the treatment of RSV infection is controversial. In immunocompromised patients (mainly hematopoietic stem cell transplant recipients), RBV has been shown to decrease progression to LRTI when given to patients with URTI. Among SOT, the greatest experience with RBV is with lung transplant recipients. Based on published reports as well as self-reported treatment strategies in surveys from SOT centers, lung and heart-lung recipients often receive RBV for both RSV-related URTI and LRTI [12]. Due to lack of clear evidence of efficacy, wide variation in the management of RSV exists including variability often dependent on availability of the inhaled, intravenous, and oral RBV formulations [23]. Intravenous and inhaled RBV are not available in most European countries. Oral ribavirin appears to be an effective, well-tolerated alternative to intravenous or inhaled ribavirin, providing potential cost savings and reducing length of hospital stay [24] (Tables 9.2 and 9.4). ALN-RSV01, a small interfering RNA that targets the RSV nucleocapsid messenger RNA, has shown some early promise in potentially preventing chronic rejection in lung transplant recipients with RSV; this agent is no longer being developed clinically. In addition, there are a number of other small molecule therapies in various stages of development including early clinical trials [13].

Immunomodulators have also been investigated. Experts recommend considering the addition of an antibody preparation (palivizumab) and IVIG with or without corticosteroids for severe RSV infection in SOT, although data are limited to support this recommendation [12, 23]. A systematic review reported that any form of RBV, alone or in combination with an immunomodulatory agent, was effective in preventing progression from URTI to LRTI, with a trend toward better outcomes with inhaled RBV plus an immunomodulatory with monoclonal (palivizumab) or polyclonal antibody preparations (IVIG) (Table 9.2).

Prevention

In addition to the general preventive measures, the only FDA-approved agent for the prevention of severe RSV infection in high-risk patients under the age of 2 years is palivizumab [23, 25]. Survey data suggest that antibody-based prophylaxis is used among pediatric transplant centers in young candidates and recipients. However, guidelines regarding the use of this agent in older children and adults do not exist, and the high combined with a lack of clear evidence of efficacy in SOT recipients precludes its wide-scale use (Table 9.2).

6.3 Parainfluenza Virus

In SOT patients PIV, most commonly PIV 3, is able to cause more serious and even fatal infections, which mostly occur in patients after lung transplantation [26]. An outbreak of PIV 3 infections in a kidney transplant unit demonstrated that all infections were mild and symptoms resolved spontaneously without associated mortality [27].

Treatment

There are no currently approved antiviral treatments for parainfluenza disease. Treatment is supportive and includes reduction in immunosuppression. Oral, aerosolized, and intravenous RBV and/or IVIG and corticosteroids have been used off-label in PIV with variable results and no impact on mortality [28]. DAS181 has been used to treat PIV infections in immunocompromised patients and has shown encouraging results including reduction in PIV quantitative viral load and overall outcomes [28]. Clinical trial results are pending.

Prevention

Outbreaks caused by PIV have been reported previously [27], and patients with known or suspected PIV should be isolated with standard contact precautions. There are no approved vaccines or prophylactic antiviral agents.

6.4 Human Metapneumovirus

Human metapneumovirus has a clinical pattern similar to RSV and is a significant cause of disease in transplant recipients [3]. hMPV Has been associated with LRTI (pneumonia) and high hospitalization rates [2].

Treatment

There is no approved drug for the treatment for hMPV respiratory infection. Supportive therapy is the main treatment although RBV alone or with IVIG could be considered for the management of LRTI and severe cases of hMPV in SOT [29].

Prevention

There are no approved vaccines or prophylactic antiviral agents.

6.5 Rhinovirus

Rhinovirus has more than 100 serotypes in 3 different species: A, B, and the more recently characterized C. Rhinoviruses are the leading cause of community-acquired RV infections, and that finding is in agreement with the knowledge that this RV is the primary cause of acute viral respiratory illnesses [2, 3]. Infections with rhinovirus are usually mild and self-limiting URTI, although significant LRTI has been described in lung transplant recipients [2, 3]. Prolonged shedding for over 6 months with minimal symptoms has been reported in lung transplant recipients.

Treatment

No specific treatment is approved for rhinovirus infection.

Prevention

There are no approved vaccines or prophylactic antiviral agents.

6.6 Coronavirus

Coronavirus generally results in self-limited disease but may progress to LRTI. The most common types of HCoV are OC43, 229E, HKU1, and 25 NL63. Severe acute respiratory syndrome coronavirus (SARS-CoV) and

Middle East respiratory syndrome coronavirus (MERS-CoV) are novel coronavirus that have been responsible for recent acute respiratory syndrome epidemics.

Treatment

There are no antivirals licensed for the treatment of HCoV infections, and therapy consists of supportive care. RBV has been used for the treatment of LRTI caused by coronavirus during the outbreak of SARS, and the use of RBV in combination with interferon-α-2a on MERS-CoV has been reported. However, this combination has not been reported in SOT, and there are no specific data to recommend RBV for the treatment of CoV infection in SOT recipients [13].

Prevention

There are no approved vaccines or prophylactic antiviral agents.

6.7 Adenovirus

Adenovirus is a double-stranded DNA virus of the family Adenoviridae, with 7 subgroups (A–G) and 52 serotypes.

In contrast to many of the other community-acquired RVs, adenoviral infection can occur from primary acquisition or through reactivation. The transplanted organ is typically the site of infection, and pneumonia is most frequent in lung transplant recipients [30]. Of note, commercial RT-PCR assays differ in sensitivity and specificity for adenovirus (AdV), and quantitative AdV PCR from blood may also be obtained to aid in diagnosis (Tables 9.2 and 9.3).

Treatment

Treatment is supportive and includes reduction in immunosuppression. The optimal timing for therapeutic intervention during the course of illness is unclear. Existing data suggests that cidofovir and brincidofovir, an orally bioavailable lipid conjugate of cidofovir, may provide the highest likelihood of antiviral efficacy. Brincidofovir appears to have increased in vitro and in vivo efficacy against AdV for treatment of serious infections with less renal and bone marrow toxicity than cidofovir (Table 9.4). RBV does not appear to have significant anti-AdV activity in humans and is generally not recommended to treat serious AdV infections. The use of IVIG remains controversial because it does not appear to have a clear benefit at this time. Adoptive T-cell transfer has generally been limited to a few centers (predominantly in hematopoietic stem cell transplantation) and has been reported to be safe and effective when performed early in the course of the infection [30].

Prevention

There are no approved vaccines or prophylactic antiviral agents.

7 Conclusions

Longitudinal prospective surveillance using molecular diagnostics is needed to understand the true epidemiology and clinical spectrum of respiratory viral diseases in SOT, particularly in non-lung population. Optimal timing, duration, and treatment indication for RVs are a dilemma that needs to be clarified in clinical practice. The efficacy of adjuvant immunogenic therapies remains controversial. Maximizing prevention and infection control measures against RVs in SOT is essential (Table 9.5).

Table 9.5 Key points for RV infections in SOT
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