Infections are the cause of significant morbidity and mortality after transplantation, both in the immediate post-operative period and beyond ( Fig. 19.1 ). Anti-infection strategies include preventive measures, such as antimicrobial prophylaxis or vaccination (see Chapter 6 ), and also effective therapy. However, pharmacokinetics, interactions, lack of evidence-based data in this population (transplant and/or pediatric), and availability of pediatric-compatible formulations make treatment options often difficult. Drug doses will not be discussed here because their availability varies between countries, and many centers have their own handbook with recommended doses of medications for prophylaxis or treatment, which can differ significantly between centers. Furthermore, customized dose adjustment is often needed based on liver or kidney function of the transplant recipient, as well as on the interactions with other medications (whether antimicrobials, immunosuppressants, or others).
This chapter will be divided into five subchapters: respiratory viruses, herpes viruses, other viruses, bacterial infections, and fungal infections.
Adamantanes (Amantadine and Rimantadine)
Mechanism of Action
Adamantanes are tricyclic amines that inhibit the M2 protein whose ion channel function is important in several stages of viral replication.
Amantadine and rimantadine are orally administered and well absorbed. Amantadine is eliminated essentially unchanged by the kidneys, whereas rimantadine undergoes extensive hepatic metabolism before renal excretion.
Adamantanes are usually well tolerated. Most side effects are mild gastrointestinal symptoms, such as lack of appetite or nausea, or central nervous system (CNS) complaints, such as anxiety, dizziness, confusion, insomnia, and difficulty concentrating. Most effects spontaneously resolve even if treatment is maintained. CNS adverse events are increased with the concomitant use of antidepressants, antihistamines, and anticholinergic medications. Rimantadine is usually better tolerated than amantadine.
At concentrations compatible with clinical use, adamantanes are only effective against influenza A and not influenza B.
Most circulating influenza A/H3N2 viruses have developed resistance to adamantanes because of point mutations in the M2 protein. Since the 2009 pandemic, most A/H1N1 circulating strains are also resistant to adamantanes.
Mechanism of Action
Oseltamivir phosphate is a prodrug that is converted by the hepatic esterases to the sialic acid analog oseltamivir carboxylate. The prodrug allows for the increased bioavailability by masking the molecule’s polarity. Zanamivir is also a sialic acid analog. Both are potent inhibitors of influenza A and B neuraminidases and competitively inhibit the neuraminidase active site, therefore preventing cleavage of sialic acid residues and the release of virions.
Oseltamivir is available in oral formulation with an oral bioavailability of around 75%. Elimination after conversion to oseltamivir carboxylate is almost entirely renal. Zanamivir is available in inhaled or intravenous (IV) formulations but not in an oral formulation because of a bioavailability of around 5%.
Oseltamivir is usually well tolerated. Dose-related gastrointestinal symptoms (nausea, epigastric pain, vomiting) are usually self-resolving, even in the absence of drug discontinuation. In the pediatric population particularly, neuropsychiatric adverse events, such as nightmares and delirium, have been reported. Intravenous and inhaled zanamivir are usually well tolerated, with headaches, gastrointestinal symptoms, and fatigue frequently reported, although there is a potential risk for bronchospasm during the use of the inhaled form.
Neuraminidase inhibitors (NAIs) are active against all neuraminidases of both influenza A and B. Oseltamivir is more effective in vitro and in clinical studies against influenza A than B viruses. Zanamivir has been shown to be more active against influenza B than oseltamivir in the clinical setting.
NAIs are the only antivirals effective against influenza B. Because of uniform resistance of influenza A to adamantanes, NAIs are the first-line agents for influenza, regardless of the type and/or subtype. Mutations conferring resistance to NAIs most commonly involve the neuraminidase, and because they are close to the active site, they tend to alter viral fitness, explaining why mutant viruses have not become dominant in the absence of antiviral pressure. Risk factors for resistance to NAIs are immunosuppression and current or previous antiviral treatment.
The H275Y mutation in the neuraminidase is the most frequent mutation conferring resistance in N1 viruses, whereas mutations E119V and R292K are more frequently found in N2 viruses. Most point mutations confer only resistance to one NAI: for example, H275Y and E119V mutations confer resistance to oseltamivir only. Cross-resistance to two or more NAIs has been reported. For example, R292K mutations confer resistance to oseltamivir and, to a lesser extent, zanamivir in H3N2 viruses, whereas the E119D mutation has been shown to confer various degrees of resistance to all NAIs.
Resistance to zanamivir is rarer than resistance to oseltamivir. It may be because of the intrinsic properties of the drug or the fact that mutations significantly reduce viral fitness, rather than because of the lower frequency of use. Mutations conferring resistance to oseltamivir do not usually affect zanamivir, although cross-resistance has been reported. Similarly, mutations conferring resistance to zanamivir do not usually confer resistance to oseltamivir.
Influenza Prevention and Treatment
Risk factors for influenza severity in the solid organ transplant (SOT) setting are T-cell-depleting agents, pneumonia, coinfection, and early post-transplant infection.
Because of increased mortality and morbidity in the adult and pediatric SOT setting, annual immunization with the injectable inactivated vaccine (IIV) is recommended for SOT patients. Children younger than 9 years should receive two doses 4 weeks apart, whereas those over 9 years should receive one dose. Children 6 to 36 months of age should receive two half-doses 4 weeks apart. The live-attenuated vaccine is contraindicated because of the risk of vaccine-derived influenza. Even though immunization is not fully protective, it has been shown to reduce disease severity in adult SOT patients.
If the IIV is contraindicated or unlikely to be effective (therapy for acute rejection, early transplantation, patient unlikely to mount an immune response before the end of the season), some experts consider antiviral prophylaxis starting at the beginning of the influenza season and continued for up to 12 weeks. However, the only randomized controlled trial (RCT) performed showed a reduction in influenza-diagnosed cases but not in influenza disease among adult SOT recipients.
In case of exposure, prophylaxis for at least 7 days has been shown to be about 80% efficient to prevent influenza in adult SOT recipients.
All infected patients should be treated, and early treatment has been shown to improve outcome. Recommended treatment duration is 5 days, although longer courses (up to 10 days) can be considered in case of suboptimal response or persistent viral shedding.
Respiratory Viruses Other Than Influenza
Mechanism of Action
Ribavirin is a guanosine analog inhibiting replication of a wide range of DNA and RNA viruses.
Ribavirin exists in aerosolized, oral, and IV formulations. Aerosol formulations seem to be the most efficient administration route in animal studies. Oral bioavailability ranges from 45% to 60%. Elimination requires both renal and, to a lesser extent, hepatic metabolism.
Dose-related hemolytic anemia is reported after systemic administration, especially in the case of concomitant kidney disease. Oral administration can lead to hyperbilirubinemia, increased uric acid, and iron. Ribavirin can also cause myalgia, pruritus, rash, as well as neuropsychiatric side effects. Intravenous administration is associated with headaches, hypocalcemia, and hypomagnesemia. Inhaled ribavirin can cause conjunctivitis, rash, and bronchospasm but is usually not associated with anemia.
Ribavirin has efficacy against a wide range of DNA and RNA viruses, such as respiratory syncytial virus (RSV), influenza, human metapneumovirus, parainfluenza virus (PIV), coronaviruses, adenoviruses, and herpesviruses.
Resistance to ribavirin has not been documented in respiratory viruses so far.
Prevention and Treatment
Respiratory Syncytial Virus
Although prophylactic palivizumab has not been evaluated in pediatric liver transplantation (PLT), this strategy seems to be frequently used in pediatric transplant recipients less than 2 years old on a monthly basis during RSV season.
RSV infection has been associated with high mortality rates after pediatric SOT. Supportive care with reduction of immunosuppression when possible is recommended. Because of the lack of data, there is no consensus on the use of ribavirin in SOT. Most SOT data come from adult lung transplant recipients and mostly with the aerosolized formulation. Expert opinions support the use of aerosolized ribavirin with IV immunoglobulins (IVIGs) and possibly IV steroids for severe RSV infection only.
There is no effective method to prevent PIV infection in PLT.
The mainstay of treatment is supportive, with reduction in immunosuppression when possible. As for RSV, most SOT data come from adult lung transplant recipients. In the absence of consensus, some experts recommend the use of ribavirin, IVIGs, and/or IV steroids.
There is no effective method to prevent PIV infection in PLT.
The mainstay of treatment is supportive, with reduction in immunosuppression when possible. Data are scarce in liver transplantation (LT), and most available data either come from adult hematopoietic stem cell transplant (HSCT) or from adult lung transplant recipients. These data suggest a potential benefit of ribavirin ± IVIG in severe disease.
Mechanism of Action
Acyclovir (ACV) and valacyclovir (VACV) are deoxyguanosine analogs. VACV is a prodrug with enhanced oral bioavailability, which is transformed in the active ACV by esterase. ACV requires transformation to ACV monophosphate by the viral herpes simplex virus (HSV) or varicella-zoster virus (VZV) viral thymidine kinase. ACV monophosphate is then transformed into ACV triphosphate by cellular kinases. The acyclic chain of ACV competitively inhibits the viral DNA polymerase by preventing the addition of subsequent nucleic acid, therefore causing premature chain termination ( Fig. 19.2 ).
ACV is available in topical, PO (bioavailability of 15%–21%), or IV formulation, whereas VACV that has been specifically designed to enhance oral bioavailability is available in PO formulation only (bioavailability of 60%–75%).
The safety profile of guanosine analogs is good. The most frequently reported side effects are gastrointestinal, such as nausea and vomiting, but headache, hematuria, and rash are also reported. Topical ACV can cause some burning at the site of application. IV injection can cause phlebitis when extravasation occurs, nephrotoxicity (interstitial nephritis, crystalluria), and neurotoxicity (1%–4%, usually 1–3 days after treatment onset and especially in patients with renal dysfunction).
ACV is mostly effective against alpha-herpesviruses, such as HSV1, HSV2, and VZV. The half-maximal inhibitory concentration (IC 50 ) for HSV is two to eight times lower than for VZV and even more so for cytomegalovirus (CMV).
HSV resistance to (V)ACV is rare in the general population (0.1–0.7%). In the SOT setting, the incidence of HSV resistance is estimated to be between 2.5 and 10%. Resistance should be considered when there is a poor clinical response to (V)ACV. Risk factors for resistance are high viral load and prolonged or intermittent antiviral therapy. The risk is usually bimodal, strains being either sensitive or resistant to (V)ACV. In HSV, about 95% of mutations affect the UL23 gene encoding the viral thymidine kinase, whereas about 5% of mutations affect UL30 encoding the viral DNA polymerase. Mutations in viral thymidine kinase will confer resistance to (V)ACV but not foscarnet (FOS) or cidofovir (CDV). Mutation in the DNA polymerase can confer resistance not only to (V)ACV but also to FOS and CDV. However, given that (V)ACV and CDV target the same site of the DNA polymerase (deoxynucleotide triphosphate–binding site), a mutation of the DNA polymerase conferring resistance to (V)ACV is more likely to confer resistance to CDV than FOS, which targets the pyrophosphate-binding site ( Fig. 19.2 ).
(V)ACV-resistant VZV is rarer than for HSV, and there are no data in the SOT setting. Data in other immunocompromised hosts show that, as for HSV, resistance to VZV mostly affects the viral thymidine kinase ( Fig. 19.2 ).
Testing can be performed by phenotypic or genotypic assays. Phenotypic assay is a plaque reduction assay–requiring culture that can identify resistant strains, but it is labor intensive and can potentially introduce a selection bias. Alternatively, genotypic testing is faster but can either identify clinically insignificant mutations or miss unknown mutations. Both techniques can be used for HSV, whereas the genotypic assay is usually preferred for VZV because of the lower sensitivity of culture. More recently, a technique known as recombinant phenotyping, where identified mutant thymidine kinases are transferred into a baseline viral strain before being tested for drug susceptibility in culture, was able to link phenotypic and genotypic results.
Mechanism of Action
Like ACV, ganciclovir (GCV) is a guanosine analog with an additional hydroxymethyl group. Valganciclovir (VGCV) is a prodrug rapidly converted into GCV after oral administration. GCV is transformed into GCV monophosphate by the viral thymidine kinase (encoded by the UL97 gene in CMV) before being again transformed into GCV triphosphate by cellular kinases. GCV triphosphate is then incorporated in the DNA and competitively inhibits the viral DNA polymerase. Unlike ACV, which is an obligate chain terminator, GCV causes either chain termination or production of short, noninfectious viral DNA segments ( Fig. 19.2 ).
Bioavailability of oral GCV is about 8% to 9% when taken with meals, whereas VGCV bioavailability is about 60%. About 90% of (V)GCV is eliminated by the kidney.
Compared with ACV, GCV has increased toxicity owing to its potential for incorporation into cellular DNA. Dose-dependent myelotoxicity is frequent, with neutropenia and thrombopenia being the most frequently affected lineages. This is related to the accumulation of GCV triphosphate in bone marrow progenitor cells. Although neutropenia usually resolves within 7 to 10 days following discontinuation of (V)GCV, patients sometimes require the use of granulocyte-macrophage colony-stimulating factor. Headaches, behavioral changes, and seizures are described in about 5%, whereas anemia, fever, rash, nausea, and vomiting are seen less frequently. Intravenous GCV use can be associated with phlebitis.
GCV is active against herpesviruses, but unlike the other nucleoside analogs, it is a potent agent against CMV. The lower IC 50 against CMV when compared with ACV is related to the fact that GCV triphosphate reaches intracellular concentrations about 10 times higher than ACV triphosphate and has a much longer half-life.
GCV resistance has been described in up to 14% of SOT patients receiving prophylaxis. In LT recipients, GCV resistance was identified in 2% of patients during prophylaxis but in up to 15% of patients during treatment. Most resistance to GCV occurs in either previously or currently exposed patients, but usually not in GCV-naïve patients. As for ACV, risk factors for resistance include prolonged or intermittent exposure, subtherapeutic dosages, profound immunosuppression, inadequate drug delivery, and Donor (D) +/Recipient (R)- CMV serostatus. Resistance to GCV is in 90% of cases because of mutations in the viral thymidine kinase (UL97 for CMV; UL23 for HSV), but it can also occur in mutations in the DNA polymerase (UL54 for CMV; UL30 for HSV). A low to medium level of resistance to GCV is usually associated with UL97 mutations, which do not confer cross-resistance to CDV or FOS. High-level resistance to GCV is usually associated with mutations in both UL97 and UL54 and tend to confer resistance to CDV, which also targets the deoxynucleotide triphosphate–binding site, but not resistance to FOS, which targets the pyrophosphate-binding site of the DNA polymerase ( Fig. 19.2 ). As for HSV, resistance testing can be done using either genotypic or phenotypic assays.
Mechanism of Action
FOS is a pyrophosphate analog that noncompetitively inhibits the viral DNA polymerase by blocking the pyrophosphate-binding site of the enzyme and preventing cleavage of pyrophosphate from the deoxynucleotide triphosphate ( Fig. 19.2 ).
Oral bioavailability is low (5%–7%), limiting administration to IV only. FOS elimination is mostly renal.
Nephrotoxicity is a frequent adverse event (25%) and is usually reversible in a few weeks for most patients. Hyperhydration can help, but probenecid has not been shown to be efficient at preventing nephrotoxicity. Metabolic disturbances, such as hypo-/hypercalcemia, hypokalemia, hypomagnesemia, and hypo-/hyperphosphatemia, are not uncommon and require close monitoring. Neurotoxicity, such as headaches and dystonia, but also seizures and tremor, are frequently described, especially in case of coadministration with calcineurin inhibitors. Other possible side effects are rash, diarrhea, nausea and vomiting, fever, elevated liver enzymes, fatigue, and mucosal ulcerations in the genital area.
All herpesviruses are susceptible to FOS.
Resistance is rare and mostly related to mutations of the viral DNA polymerase. FOS is frequently the first-line therapy in cases of suspected resistant herpesvirus infection because most ACV- and GCV-resistant viruses remain susceptible to FOS because mutation in the viral thymidine kinase does not affect FOS and because FOS acts at the pyrophosphate-binding site of the DNA polymerase, whereas ACV, GCV, and CDV target the deoxynucleotide triphosphate–binding site of the enzyme. This explains why mutations in DNA polymerase affecting ACV and GCV can confer resistance to CDV but are unlikely to confer cross-resistance to FOS ( Fig. 19.2 ).
Mechanism of Action
CDV is a nucleotide analog of monophosphate deoxycytidine. Its mechanism of action is similar to ACV, but because CDV is already monophosphorylated, it doesn’t require phosphorylation by the viral thymidine kinase. It still requires transformation to CDV diphosphate by cellular kinase before competitively inhibiting the DNA polymerase ( Fig. 19.2 ). Brincidofovir (BCDV) (also known as CMX001) is an oral prodrug of CDV.
BCDV exists in oral formulation. Oral bioavailability of CDV is greater than 5%, which explains why it can be only administered IV or topically. CDV elimination is mostly renal. BCDV is well absorbed orally.
IV CDV is associated with significant dose-dependent nephrotoxicity because of the induction of apoptosis in renal tubular cells. Nephrotoxicity mostly presents as proteinuria or glycosuria. Creatinine clearance under 55 mL/mn or proteinuria 2 + contraindicate the use of CDV. Concomitant use of probenecid and IV hydration reduces the incidence and severity of nephrotoxicity. Neutropenia affects up to 25% of patients. Other side effects seen during concomitant use of probenecid are drug-induced fever, nausea and vomiting, diarrhea, rash, fatigue headache, as well as ophthalmologic side effects (iritis, uveitis). Topical CDV is almost never associated with systemic side effects, although local side effects are reported, such as burning or itching on the site of application. BCVD is not nephrotoxic. The most common side effect of BCDV is diarrhea.
CDV has activity against all herpesviruses, as well as other DNA viruses, such as polyomaviruses, poxviruses, adenoviruses, and HPV.
Resistance to CDV is rare and mostly related to mutations in the viral DNA polymerase. A viral thymidine kinase mutation does not impair CDV activity. Most CDV-resistant herpesviruses are also resistant to ACV or GCV because these compounds act at the same deoxynucleotide triphosphate–binding site of the DNA polymerase. These isolates are usually sensitive to FOS, which targets the pyrophosphate-binding site of the DNA polymerase ( Fig. 19.2 ).
Mechanism of Action
Letermovir (LTM) inhibits the viral terminase complex of CMV.
LTM is orally administered and has good oral bioavailability.
The safety profile of LTM is good, and the absence of myelotoxicity has made it an interesting candidate for CMV prophylaxis in HSCT. There is a lack of data for SOT. Spectrum. LTM is effective against CMV but not against other herpesviruses.
Because LTM does not inhibit the viral thymidine kinase or the DNA polymerase, it is effective against GCV-resistant strains. However, in vitro studies have shown a low threshold for resistance in the case of point mutations in the terminase complex.
Prevention and Treatment
In the preprophylaxis era, about 40% of PLT recipients developed CMV infection, among which more than 80% were invasive infections. More recently, the incidence of CMV disease in PLT recipients has been estimated to be between 0% and 10% using either prophylaxis, preemptive therapy, or hybrid strategies.
The donor and recipient serostatus at the time of SOT is a major determinant of prevention strategy. For children under 18 months, the passive transfer of maternal antibodies can yield some false-positive results. Therefore the guidelines from the American Society of Transplantation (AST) recommends urine CMV DNA testing by polymerase chain reaction (PCR) in seropositive children younger than 18 months. If the urine is positive, the patient should be considered R +, whereas if the urine is negative, the patient should be allocated to the highest-risk group. The more recent guidelines from The Transplantation Society (TTS) recommend that children under 12 months should be allocated to the highest-risk group, regardless of urine testing. For example, seropositive infants receiving a seropositive organ will be allocated D +/R-, whereas seropositive infants receiving a seronegative organ will be allocated D-/R +.
Current guidelines recommend two different approaches for CMV prevention based on the D/R constellation: preemptive therapy and prophylaxis ( Table 19.1 ). Preemptive therapy is based on regular monitoring of CMV viremia by PCR and the use of antiviral treatment once viremia reaches a certain threshold to prevent CMV disease. Prophylaxis consists of giving antiviral therapy immediately after SOT for a given duration and is the preferred approach in high-risk patients, such as D +/R- configuration. Compared with prophylaxis, preemptive therapy is associated with lower drug costs, lower toxicity, and potentially lower risk of resistance, but higher laboratory costs. Prophylaxis is associated with decreased risk of graft loss, mortality, other herpesvirus infections, and opportunistic infections, but delays the reconstitution of CMV-specific immunity and therefore increases the risk of late CMV disease after discontinuation of antivirals. The doubling time of CMV viral load without treatment has been estimated to be between around 1 to 3 days, and therefore the safety of the preemptive approach requires the availability of weekly PCR testing. The efficacy of prophylaxis in adults has been clearly demonstrated in RCTs, as well as the benefit of longer durations of prophylaxis. VGCV has been shown to be noninferior to GCV in adult SOT recipients and is currently the preferred option. In children, there is a lack of data about the efficacy of preemptive therapy. Few RCTs have directly compared preemptive therapy and prophylaxis in adult kidney transplant recipients and have not shown any significant difference in efficacy as long as frequent PCR monitoring was performed in the preemptive group. For LT recipients, no RCT has been performed, but metaanalyses suggest similar results. Similarly, there are no RCTs comparing preemptive therapy and prophylaxis in pediatric SOT, but favorable outcomes have been reported using either strategy.
|Early CMV infection
|Late-onset CMV infection
|More difficult, needs infrastructure to allow for regular PCR monitoring. Threshold to start antivirals not standardized
|Prevention of other herpesvirus
|Other opportunistic infections
The current AST recommendations suggest 3 to 6 months of prophylaxis over preemptive therapy for D +/R- LT recipients. For R + LT recipients, AST suggests either 3 to 6 months of prophylaxis or preemptive therapy. In the case of combined transplantation involving the liver and other organs, 3 to 6 months prophylaxis is preferred regardless of the D/R constellation. One to 3 months of prophylaxis is also recommended during the use of lymphocyte-depleting agents for induction or treatment of rejection. CMV prophylaxis is not recommended in D-/R- PLT as long as they receive leukocyte-depleted or CMV-negative blood products.
The more recent consensus guidelines from TTS do not recommend 3 (to 6) months of prophylaxis over preemptive therapy for D +/R- adult liver recipients. For R + LT recipients, TTS suggests 3 months of prophylaxis or preemptive therapy. In the case of combined transplantation involving the liver and other organs, 3 to 6 months prophylaxis is preferred regardless of the D/R constellation, with a more recent emphasis on 6 months in case of D +/R- constellation. The pediatric chapter of TTS recommends 2 to 4 weeks of prophylaxis with surveillance after prophylaxis or 3 to 4 months of prophylaxis or preemptive therapy in all D/R constellations except D-/R-. One to 3 months of prophylaxis is also recommended during use of lymphocyte-depleting agents for induction or treatment of rejection. CMV prophylaxis is not recommended in D-/R- PLT.
The author’s approach to CMV prevention typically follows the 2018 TTS recommendations, with a tendency for 2 to 4 weeks of prophylaxis with surveillance after prophylaxis for intermediate-risk groups (R +) and 3 to 4 months of prophylaxis for high-risk groups (D +/R-).
Because of their increased likelihood of D +/R- constellation, children are at increased risk for primary CMV infection and CMV disease after SOT. VGCV or GCV can be used for the treatment of CMV infection. Symptomatic CMV infections require antiviral treatment, regardless of viral load; for asymptomatic viremia, there is no standardized threshold above which antiviral therapy is recommended. In the literature, thresholds range between 1500 IU/mL in D +/R- to 4000 IU/mL in R + patients. In children, there is a lack of data about VGCV efficacy in CMV disease treatment. Recent data have shown that VCGV was effective at clearing viral load (VL) in children with asymptomatic viremia, suggesting it might be effective at treating symptomatic infection. In adults, VGCV has been shown to be noninferior to GCV for the treatment of CMV disease. Criteria for the initial use of IV GCV instead of PO VGCV are severe disease, high viral load, and suboptimal gastrointestinal absorption. Transition to oral VGCV can be made after clinical response. Treatment is usually continued at full dose until resolution of symptoms and a negative viral load for 2 consecutive weeks. Although benefits of IVIG or CMV-IgG has not been clearly demonstrated, their use as an adjunctive therapy can be considered in severe disease but is not routinely recommended. Whenever possible, immunosuppression should be reduced, especially in the case of severe disease, high viral load, leukopenia, and inadequate clinical or viral response. Secondary prophylaxis can also be considered after discontinuation of antiviral treatment in specific situations such as profound immunosuppression or increased risk of disease recurrence, even though it is not routinely recommended, given the lack of benefit shown in retrospective studies.
Treatment of V(GCV)-resistant Infections
Resistance to V(GCV) should be suspected in the case of persistent or recurrent viremia or disease despite adequate treatment. In case of suspected resistant infection after 2 weeks of adequate therapy, the AST and TTS recommend to send samples for resistance testing, to reduce immunosuppression if possible, and add or switch to FOS. For mild to moderate infection, high-dose GCV IV is an alternative regimen, given the fact that some UL97 mutations conferring low-level resistance can be overcome by the use of high-dose GCV.
Herpes Simplex Virus
Most HSV infections after transplant result from endogenous reactivation and occur in the first month after SOT, although donor-derived infections and posttransplant horizontal acquisition are also described.
V(ACV) has been shown to prevent HSV disease after SOT. Therefore prophylaxis should be considered in HSV-1 or -2 seropositive recipients who do not require CMV prophylaxis. Patients receiving CMV prophylaxis do not require specific HSV prophylaxis because HSV is covered by V(GCV). Similarly, patients requiring Epstein-Barr virus (EBV) prophylaxis but not CMV prophylaxis do not usually need specific HSV prophylaxis. The recommended duration of HSV prophylaxis is at least 1 month because most severe HSV infections occur in the first month after SOT. Prophylaxis should also be considered in the case of rejection requiring T-cell-depleting agents, as well as in cases of clinically significant recurrences, for at least 1 month or until reduction of the net state of immunosuppression.
Early treatment of HSV disease improves outcomes in adult SOT patients. Mild to moderate mucocutaneous infection can be treated orally, whereas severe mucocutaneous, visceral, disseminated, or CNS infections require IV treatment. Treatment of mucocutaneous infection is usually given for a minimum of 7 to 14 days or until complete healing. Severe, visceral, disseminated, or CNS infections usually require 14 days of IV treatment followed by oral treatment to complete a minimum course of 21 days, except for CNS infection, which requires 21 days of IV treatment. Whenever possible, immunosuppression should be reduced. The first-line treatment when (V)ACV resistance is suspected is FOS, whereas CDV is the second-line treatment. Some experts recommend switching first to high-dose IV ACV before considering FOS or CDV.
Because of the lower seropositivity rates at the time of SOT compared with adults, primary VZV infection is more frequent in pediatric SOT recipients, whereas zoster is less frequent.
Patients requiring anti-CMV prophylaxis do not require specific VZV prophylaxis because V(GCV) is efficient against VZV. For patients not requiring anti-CMV prophylaxis but requiring HSV prophylaxis, the HSV regimen is likely effective at preventing VZV infection despite the higher IC 50 of VZV. There are no data for VZV prophylaxis in patients requiring neither HSV nor CMV prophylaxis, but the same strategies as for HSV should be considered during the highest-risk periods (first month post-SOT, T-cell-depleting agents for rejection). After primary infection, SOT patients remain at risk lifelong for zoster, but there are currently no data to justify long-term prophylaxis.
Post-exposure prophylaxis should be provided in seronegative patients only. Postexposure prophylaxis consists of varicella-specific immunoglobulin (VZIG) and should be only be administered in the first 10 days following exposure, although its efficacy is best in the first 96 hours following exposure. IVIG can be considered as an alternative in case VZIG is not available. Oral antivirals can be given for 7 days as an adjunctive measure to immunoglobulins, if immunoglobulins are not available, or if a patient has been exposed more than 10 days prior.
As for HSV, early treatment of VZV infection improves the outcome in SOT. Chickenpox and zoster are usually treated with IV antivirals for approximately 7 to 10 days, but at least until all lesions are crusted. Oral treatment can be considered for localized zoster in selected cases. Severe disease, children under 2 years of age, evidence of dissemination, tissue invasion, and zoster ophthalmicus or oticus require IV therapy. In patients treated with IV antivirals, some experts consider transitioning to oral therapy after significant clinical improvement. Immunosuppression should also be reduced whenever possible.
Prophylaxis can prevent primary infection in D +/R- pediatric SOT recipients. Despite the lack of data, some centers recommend prophylaxis for D +/R- SOT recipients, with a preference for (V)GCV over ACV. It is unclear whether antiviral prophylaxis, with or without adjunctive IV CMV IgG, significantly reduces the risk of post-transplant lymphoproliferative disorder (PTLD). Preemptive strategies using regular PCR monitoring are an alternative for high-risk patients, although the frequency of PCR testing is still debated.
For treatment of EBV infection and PTLD, please refer to the PTLD chapter.
Human Herpesvirus 6 and Human Herpesvirus 7
Prophylaxis against human herpesvirus 6 (HHV6) and HHV7 is not recommended.
Treatment of asymptomatic viremia is not recommended. In less than 2% of patients, HHV6 is chromosomally integrated. These otherwise asymptomatic patients should not be treated. A viral load above 5.5 log10 copies/mL or 1 or more copy/cell, as well as the detection of HHV-6 in all tissues (such as hair follicles), is suggestive of chromosomal integration. Antiviral treatment associated with reduction of immunosuppression whenever possible is, however, strongly recommended for HHV6 encephalitis and should be considered for other HHV6- and HHV7-related syndromes. Because of the lack of RCT or direct comparison, the choice of antiviral treatment remains debated. FOS, GCV, and CDV all have activity against HHV6, although HHV6A tends to show reduced susceptibility to GCV. FOS or CDV are the treatment of choice for HHV7. Concomitant infection with CMV and HHV6 or HHV7 does not require specific HHV6 or HHV7 treatment if the patient is treated for CMV.
Being a child and receiving an LT are both risk factors for adenovirus infection.
Because of the lack of data, prophylaxis against adenovirus is not recommended in the SOT setting.
The mainstay of treatment of adenovirus consists of reducing immunosuppression and can be sufficient for clearing the infection. No RCT has compared antivirals in the transplant setting, but CDV, ribavirin, and GCV have been used in SOT. IV CDV is usually the preferred approach in the case of severe infection. BCDV has shown promising results in HSCT patients, but data in SOT patients are lacking.
BK virus is rare in LT unless in the case of a concomitant kidney transplant. The prevalence of BK viruria and viremia in LT recipients is estimated to be between 15% to 17% and 2% to 4%, respectively. No case of disease related to BK has been reported so far in the LT setting. BK is a frequent pathogen in the HSCT setting, where it usually presents as hemorrhagic cystitis. In the case of combined liver/stem cell transplant, BK prevention relies on hyperhydration and bladder irrigation; antiviral prophylaxis is not available, and fluoroquinolones are not recommended. BK treatment is also based on hyperhydration, and bladder irrigation in addition to pain relievers and, if needed, platelet transfusions to reduce bleeding. The reduction of immunosuppression can be considered but must be weighed against the risk of graft-versus-host disease. Because of the lack of RCTs, IV CDV for BK treatment is controversial.
The outcome of rotavirus infection in the SOT setting is variable, although symptomatology tends to be more severe than in healthy patients. Moreover, rotavirus infection has been associated with acute cellular rejection in SOT patients, especially in the case of bowel transplantation; this is suspected to occur through the infiltration of the gut-associated lymphoid tissue. Norovirus also tends to be more severe in SOT recipients and has a higher tendency to cause outbreaks in hospital units. Unlike in healthy patients, it can present as chronic diarrhea in SOT patients. Management requires symptomatic treatment and reduction in immunosuppression whenever possible, although some centers have treated patients with nitazoxanide or enteral or IV immunoglobulins with inconsistent results.
Other Emerging Viruses
Data are scarce on arboviruses in the SOT setting. Chikungunya infection in SOT patients is not necessarily associated with a more severe presentation than in the general population. Whether dengue infection is more severe in SOT patients than in healthy patients remains debated. Zika virus infection has a tendency for unusual clinical presentations and increased complications in SOT patients. For chikungunya, dengue, and Zika infections, management is mostly symptomatic, and clinicians should consider reducing immunosuppression whenever possible.
Although donor-derived West Nile virus infection is not rare, most cases in SOT patients are related to mosquito bites. The likelihood of West Nile neuroinvasive disease is significantly higher in SOT than healthy patients. Management is mostly supportive with reduction of immunosuppression, although IVIG can be considered.
For other emerging viruses such as astroviruses or torque teno viruses, consultation with the pediatric infectious disease team is highly recommended because of the lack of data showing clear correlations between the identification of those viruses and clinical symptoms.
Timeline of Infections
Typically, in the immediate posttransplant period (< 1 month), bacterial infections are mostly caused by surgical site infections and device-related infections (e.g., indwelling catheters and endotracheal tubes) that lead to bacterial infections ( Fig. 19.1 ). Additional risks in pediatric LT include longer surgical time (owing to technical difficulties, for example), anastomotic leak, or thrombosis. Prophylaxis has an important role in decreasing this early risk, and guidelines are available, although a variety of practices exist. In general, good antibiotic stewardship involves some or all of the following: knowledge of the local epidemiology and risk factors, minimizing time of antibiotic prophylaxis, adapting dosage to period of highest risk, and narrowing the spectrum within the range of what is feasible. Most centers would currently recommend giving up to 24 hours prophylaxis of either piperacillin-tazobactam or a combination of third-generation cephalosporin and amoxicillin (alternatively, vancomycin or clindamycin with gentamicin or aztreonam) to cover both skin and gastrointestinal flora including Gram-positive organisms (such as Staphylococcus aureus and Enterococcus spp.) and Gram-negative enterobacteria.
In the intermediate period post-transplantation (1–6 months), more problematic bacterial infections include Nocardia, Clostridium difficile , and Listeria . However, depending on the specific conditions and risk factors, bacteria from the early post-transplant period can still trigger infections. Pediatric LT patients are at an increased risk for C. difficile infection (> 10% in pediatric SOT) compared with other children following SOT and other hospitalized children. Recommended prophylaxis in this period is trimethoprim-sulfamethoxazole (TMP-SMX), which has the advantage of significantly decreasing the risk for Pneumocystis jirovecii pneumonia (PCP), and also has a protective effect against Nocardia and Listeria . Furthermore, it is inexpensive, easy to administer orally, and usually well tolerated. In general, the duration of treatment is less than 1 year.
In the later period (> 6 months), community-acquired bacteria can lead to significant infections. Specific vaccination to prevent Streptococcus pneumoniae infections should be considered, as well as all usually recommended age-appropriate vaccines. Vaccine seroresponses can help clinicians to decide whether a booster dose is necessary or not after transplantation (see Chapter 6 ).
Multidrug-resistant (MDR) bacteria are defined as bacteria resistant to at least one agent in at least three different antibiotic classes. They are associated with increased mortality and an increased risk of recurrent infection. They are also linked with increased use of hospital resources via extended hospital stays, more frequent laboratory tests, more frequent medical consultations, and costly medications. Compared with the adult data, less is known about the prevalence of MDR organisms in the pediatric LT population.
Methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) are the most studied MDR organisms and have contributed to the implementation of infection control practices in healthcare settings and to the awareness of the need for antimicrobial stewardship and for new drug development.
Methicillin-Resistant S. Aureus
Overall rates of invasive MRSA have been declining since approximately 2005, including in the transplant population. Prevention measures for MRSA acquisition and infection include hospital-based programs and antimicrobial stewardship. Nasal carriage increases the risk for subsequent infection, and a metaanalysis in adults reported a pre- and post-LT MRSA colonization rate between 10 and 15%, with a 6- to 11-fold increase in MRSA infection in carriers. Peritransplant prophylaxis should be adapted in case of MRSA carriage by expanding the coverage provided. Decolonization, preferably already before LT, is recommended. It usually includes mupirocin nasal ointment and full-body wash with chlorhexidine soap for several days. This regimen can be repeated in case of failure, but recurrent/persistent carriage is frequent.
Treatment of MRSA infection usually includes vancomycin. Alternatives include linezolid (an oxazolidinone, mostly a bacteriostatic agent with a unique mechanism of action, available for IV or oral use, with activity against Gram-positive bacteria) and daptomycin (a cyclic lipopeptide, concentration-dependent bactericidal agent with activity against a wide range of Gram-positive bacteria), but resistance to both antimicrobials has been reported. Furthermore, data in pediatrics are still limited, although increasing clinical experience is gained over time. The most common side effects of linezolid include diarrhea, loose stools, nausea, vomiting, headache, rash, itching, and fever. Additional side effects include cytopenia and development of peripheral and optic neuropathy symptoms. These should all be monitored during treatment. The most common side effects of daptomycin include changes in liver function tests, electrolyte imbalance, nausea, vomiting, diarrhea, dyspnea, and headache. New agents such as lipoglycopeptides, antistaphylococcal cephalosporins, or new oxazolidinones (tedizolid) are currently being investigated, with the anticipated risk that pediatric data won’t be available rapidly.
Vancomycin-intermediate and heteroresistant vancomycin-intermediate S. aureus have been described in hospitals, albeit not in the LT population, and are usually secondary to a clonal transmission. Treatment strategies would include using alternative antimicrobials described above, according to available sensitivity testing.
The prevalence of VRE colonization was recently estimated in a metaanalysis as high as 22% in adult LT patients. Pre-LT and post-LT colonization was also associated with an increased risk of VRE infection. Again, peri-transplant prophylaxis should consider if the patient is colonized with VRE. However, decolonization strategies for VRE before or after transplantation have been unconvincing. Treatment of VRE invasive infection usually consists of either linezolid or daptomycin with the same limitations as above. Other antimicrobials with potential activity against VRE include ceftaroline, a new cephalosporin, and telavancin, a novel semisynthetic lipoglycopeptide agent, but both have limited activity against Enterococcus faecium , and data in pediatric LT recipients are anecdotal.
Enterobacteriaceae in the intestinal flora have acquired an increasing number of resistance elements against antimicrobials, including in the pediatric transplant population, sometimes associated with increased mortality rates. Extended-spectrum β-lactamase–producing Enterobacteriaceae is a common cause of resistance present in the community and healthcare settings. Eradication is currently not recommended when carriage, even carriage of multiple resistance determinants, is recognized, but infection control measures (contact isolation) should be implemented and maintained during hospitalization to avoid cross transmission. Carbapenems are the treatment of choice when infection occurs. Continuous or extended infusions have occasionally been demonstrated as beneficial compared with traditional intermittent infusions in adult settings, but there are limited data in children.
This group includes many different resistance mechanisms and has been increasingly described. The most commonly reported in the (adult) transplant population is Klebsiella pneumoniae, with a recent increase in prevalence and high mortality rates. Carbapenem-resistant Acinetobacter baumanii has also been reported increasingly in organ transplantation. Again, infection control measures are paramount to avoid spread and should be implemented very strictly. Prophylaxis or decontamination are not available. Treatment of carbapenem-resistant organisms is extremely complex and requires the involvement of infectious disease specialists. It usually uses a combination therapy, taking into account specific sensitivity and genetic testing, risk of side effects, and site of infection. Polymyxins, aminoglycosides, specific combination cephalosporins, tigecyclines, and sometimes even carbapenems may be used. New agents, such as cephalosporin/β-lactamase inhibitors, fluorocyclines, new aminoglycosides, and combination carbapenems/β-lactamase inhibitors, may, in the future, add some possibilities to the treatment of these resistant microorganisms.
Fungal infections are associated with high mortality rates; prevention and early treatment are therefore paramount. However, antifungals have several disadvantages: they come with the risk of hepatotoxicity, and resistance emergence is frequent. Therefore targeting the antifungal spectrum, using it at the right time and for the right duration, is particularly important. Costs of antifungals are also a significant issue. The difference between fungicidal, that is, agents that kill 99.9% of the pathogen in vitro , versus fungistatic, that is, agents that allow regrowth after they are resistant Gram-negative bacteria stopped, is less straightforward than with antibacterial agents. One can summarize that amphotericin B in vitro is listed as a fungicidal drug. Triazoles are listed as mixed; fluconazole, for example, is fungistatic, and voriconazole shows fungicidal activity against Aspergillus . Echinocandins are also considered as mixed, with both fungicidal activity against Candida species and fungistatic activity toward Aspergillus . Therefore a thorough and up-to-date knowledge of the pathogen-specific literature is necessary before deciding which is the best antifungal therapy.
Prophylaxis against PCP has significantly changed the morbidity/mortality linked with this infection. TMP-SMX prophylaxis, dosed three times weekly, is therefore recommended and usually continued, if well tolerated, 6 to 12 months. In several centers, treatment can be continued indefinitely, especially in patients with a prior history of PCP or with chronic CMV disease. The risk of PCP remains even after the first 2 post-transplant years, although the highest risk is within the first 2 to 6 months. Alternative agents include atovaquone, dapsone, and pentamidine. However, TMP-SMX is the preferred treatment, given that the efficacy data for these drugs is extrapolated from children with human immunodeficiency virus or cancer, and adults following SOT. Reinitiation of PCP prophylaxis should be considered when immunosuppression is increased, for example, with the administration of corticosteroids, rituximab, bortezomib, alemtuzumab, and tumor necrosis factor-alpha inhibitors such as infliximab and etanercept. The duration of prophylaxis should depend on the overall degree of immunosuppression and clinical setting.
TMP-SMX is the first-line treatment of PCP. Oral treatment can be considered in nonsevere cases, thanks to its excellent oral bioavailability. As a second-line therapy, pentamidine should be used; however, it has many toxicities, leading to drug withdrawal in many cases. The duration of therapy is usually 14 days but may be extended in severe infections or slow clinical improvement. Other available antimicrobials seem to be either less efficacious or have less supportive data. The AST guidelines recommend the use of adjunctive corticosteroids for SOT recipients with moderate to severe PCP, ideally within the first 3 days of treatment, even if solid data in pediatric and adult LT are lacking. Reduction of immunosuppression when feasible should also be considered.
The most common invasive fungal infection is candidiasis (up to 60% of all fungal infections), with Candida albicans , a normal commensal in the gastrointestinal tract, the most frequent among the Candida species, including in LT patients. The benefit of prophylaxis for non-high-risk children for invasive Candida infection is still debated. Limited data make the following unresolved issues: (a) the emergence of non-albicans Candida in patients on prophylactic treatment; (b) drug-drug interactions; and (c) the risk of toxicity. De Luca et al. reported that to prevent one invasive candidiasis, they would have to give prophylactic antifungals to 40 patients, which seems unreasonable. Risk factors for candidiasis in LT recipients include prolonged or repeat operation, retransplantation, renal failure, high transfusion requirement, choledochojejunostomy, and Candida colonization in the perioperative period. Patients with at least two of these factors should probably receive prophylaxis. For those at high risk, two options are available for prophylaxis: general prophylaxis versus targeted prophylaxis (i.e., to a selected subgroup of patients). For both, it should be determined if Candida is the only target or if prophylaxis should also prevent mold infections. For Candida alone, fluconazole remains a sensible choice. Lipid formulation of amphotericin B is an alternative option with the additional benefit of protecting against other fungi when needed. Nonabsorbable preparations such as nystatin are commonly used in infant transplant recipients, regardless of organ, to decrease colonization with yeast species. Duration of prophylaxis is not clearly determined but is sometimes maintained for up to 4 weeks.
Treatment of invasive Candida infection usually starts with echinocandins (caspofungin, micafungin, or anidulafungin). Patients without previous azole exposure who are stable and nonneutropenic may also be treated with fluconazole. Some Candida species, such as Candida parapsilosis and Candida guilliermondii , demonstrate less in vitro susceptibility to the echinocandins and may need alternative agents. Alternative agents include lipid formulations of amphotericin B or voriconazole. Once stabilized and depending on susceptibility testing, a switch to fluconazole may also be possible. Removal of infected or possibly infected devices, such as central lines, should be strongly suggested. The duration of therapy should be at least 2 weeks after clearance of the bloodstream cultures and resolution of symptoms attributable to candidemia.
Although Aspergillus infection is common after transplantation, it is still associated with high mortality and morbidity. Currently, prophylaxis is not routinely recommended for SOT recipients. However, targeted prophylaxis with a lipid formulation of amphotericin B or an echinocandin may be considered in high-risk patients (fulminant hepatic failure, retransplantation, renal failure, reoperation) or if the local epidemiology suggests it. Duration is unclear but usually is extended to the time of the hospital stay or the first month after transplant.
Treatment of Aspergillus in LT follows the available data in adult settings. Early treatment is associated with better survival. Currently, the preferred treatment is voriconazole in most cases, although pharmacokinetic data for young children, in particular, are lacking. Therapeutic drug monitoring should be used to obtain appropriate levels of antifungals because children metabolize voriconazole quickly, and higher doses may be needed. An alternative treatment would be liposomal amphotericin B. Data in children are lacking for most of the other antifungals used in adults. Echinocandins, such as caspofungin or micafungin, cannot be used for treating CNS disease and are not recommended as a first-line monotherapy. Combining several antifungals (usually voriconazole and echinocandins) has shown limited beneficial results and is currently reserved for salvage therapy.
Duration of treatment of invasive Aspergillus infection should be a minimum of 6 to 12 weeks and depends on the degree and duration of immunosuppression, site of disease, and evidence of clinical improvement. Decreasing, when possible, immunosuppressive drugs should be considered, as it may also improve outcome.
Other Molds, Dimorphics, and Fungi
There are a few case reports, mostly in adults, of rare fungal infections in SOT recipients, including Cryptococcus neoformans , Mucormycosis , Scedosporium spp., and Fusarium spp. In the study by Pasternak and colleagues, 10 invasive fungal infections were reported among 81 pediatric LT recipients, including 1 with mucormycosis. Although data are limited to make definitive recommendations, in practice, prophylaxis against Candida spp is often extended to protect against other fungi or molds. Often, for the prevention of candidiasis, coverage is extended by using an agent with broader spectrum of anti-fungal activity to treat other fungi or molds.
There is no recommendation for the treatment of cryptococcal infection in children. In adults, the treatment of cryptococcal infection depends on its localization, emphasizing the fact that the workup has to be performed thoroughly. For meningitis, amphotericin B is the preferred antibiotic, in particular the liposomal form. Monitoring of drug levels is essential. Association with 5-flucytosine is often also recommended in transplant recipients. Fluconazole is usually the preferred treatment for maintenance and consolidation. The optimal duration of therapy is unclear, but some authors recommend lifelong treatment. When possible, reduction of immunosuppression should be combined with antifungals.
Treatment of mucormycosis is usually based on liposomal amphotericin B as a first-line treatment. A second-line agent is posaconazole. First-line treatment of mucormycosis is usually liposomal amphotericin B. Posaconazole is the generally accepted as second-line treatment.
Voriconazole is the mainstay of treatment against Scedosporium spp. except for Scedosporium prolificans , now called Lomentospora prolificans , which is resistant to most antifungals. Combination of several antifungal agents has been used and showed synergy in vitro, but data in humans is extremely limited and warrants consultation with specialists.
Treatment of Fusarium spp. is based on liposomal amphotericin B or voriconazole, as well as resection of necrotic material.
A comprehensive list of drug interactions with azoles can be found in Gavalda’s review.
Dimorphic fungi—very rare diseases in SOT recipients—can present as subclinical respiratory infections to life-threatening systemic diseases. Pathogens such as Histoplasma, Blastomyces, Paracoccidioides , and Coccidioides will need antifungal compounds, but treatment is complicated by the fact that diagnosis is often delayed. The pathogen may reside within immune cells, hiding them from the host’s response. These organisms have a natural resistance to the echinocandins; treatments should all be systemic and prolonged (often more than a year); and drug susceptibilities are difficult to obtain. Patients with former active histoplasmosis or Paracoccidioidomycosis (last 2 years before transplantation) may be considered for itraconazole prophylaxis. Treatment should be discussed with a pediatric infectious diseases specialist.
Infections following LT are frequent, and their prevalence is influenced by several factors, such as time since transplant, net state of immunosuppression, immunization status, and comorbidities. For many pathogens, there is a lack of data specific to PLT, and management is often extrapolated from studies in either adult LT recipients or healthy children. For these reasons, the involvement of a pediatric infectious disease specialist early in the course of the infection can help, providing the best expert opinion on atypical infections.