Viral infections in pediatric transplant patients are associated with significant morbidity and mortality. Immunosuppression, conditioning regimens and underlying illness before transplant all contribute to transplant patients being vulnerable to reactivation and/or primary acquisition of viral infections. Potential complications of these infections include end organ damage, rejection of transplant, graft-versus-host disease (GVHD) and increased susceptibility to other infections.1 Early identification and treatment of viral infections is important because they are often detectable before the development of severe disease or overt clinical symptoms. Establishing the correct diagnosis in transplant patients is difficult, as patients commonly have nonspecific symptoms that may overlap with infectious and noninfectious etiologies. The ability to detect viral infections has improved with the availability of direct molecular assays and the shift from reliance on viral cultures and antibody detection.
Treatment options continue to advance although additional antiviral agents and research are needed. The first-line treatment for most viral infections is reduction of immunosuppression combined with antiviral therapy. However, drug toxicities, development of resistance and graft rejection are recurring challenges encountered during treatment. Fortunately, there are new therapies in clinical trials that hold immense promise. These include novel pharmaceutical agents, virus-specific cytotoxic T lymphocyte therapies (CTL) and donor lymphocyte infusions.2 The objective of this review is to summarize current strategies for diagnosis and treatment of common viral diseases in pediatric transplant patients (Table 1).
Common Viruses in Transplant Patients
Cytomegalovirus (CMV) is a ubiquitous herpesvirus that establishes latency in peripheral blood monocytes and macrophages. CMV infection may result in direct damage to the lungs, gastrointestinal system, central nervous system, as well as variety of secondary immune phenomena resulting in infections, and GVHD.
Pretransplantation CMV serology is useful for risk stratification based on the status of the donor and recipient. The highest risk patients are those with disparate donor and recipient serologic status. A CMV seronegative recipient receiving a transplant from a CMV seropositive donor (D+/R−) is at highest risk for a primary CMV infection. Likewise, a D−/R+ patient may not be able to mount an adequate immune response to latent virus, risking overwhelming viremia.
There are several approaches to manage CMV disease in transplant patients. Preemptive therapy based on detection of quantitative polymerase chain reaction (PCR; preferred) or CMV antigens (pp65 antigenemia) in the blood are common approaches to prevent CMV disease after transplantation.3 Therapy is commonly initiated upon detection of greater than 1000 copies or a 0.5 log or greater increase on serial viral load using PCR. Certain groups start therapy earlier (ie, detectable below 1000 copies) in very immunosuppressed patients such as recipients of unrelated cord blood or haploidentical transplant. Other strategies include a prophylactic approach, starting empiric antiviral prophylaxis for a predetermined period posttransplant or a hybrid approach. Although CMV infections often occur as a relatively early complication after transplantation, it is increasingly clear that late onset (greater than one-hundred days after transplant) CMV disease contributes to significant mortality.4
The first-line agent for treatment of CMV is ganciclovir (GCV), with foscarnet and cidofovir reserved for resistant cases. Ganciclovir can suppress the bone marrow and may increase risk for bacterial and fungal infection. In most cases of neutropenia foscarnet will be used first, however, renal toxicity typically is the limiting factor for foscarnet. Duration of treatment is often determined by weekly CMV surveillance with discontinuation after 2 negative studies. Transition to orally administered valganciclovir may be considered, given excellent bioavailability although pediatric data are only available in the context of congenital CMV. CMV hyperimmune globulin is used in the setting of CMV pneumonitis though there is little data supporting its use for other indications.
Mutations may confer resistance to GCV, as well as to cidofivir and foscarnet. Resistance typically presents as a slow response to therapy or relapse of infection. Other antiviral drugs under investigation include brincidofivir5 (the lipid formulation of cidofovir, orally administered), maribavir and letermovir. Immunotherapeutic strategies including donor lymphocyte infusions and ex vivo virus specific cytotoxic lymphocytes are under evaluation and available at some centers.2
Epstein–Barr virus (EBV) is a herpesvirus whose clinical presentation is often similar to CMV. EBV infection may be associated with leukopenia, thrombocytopenia, hepatitis and pneumonia. The most dreaded complication is posttransplant lymphoproliferative disorder (PTLD).
Onset of PTLD is usually preceded by increasing levels of EBV PCR in the blood associated with mononucleosis like syndrome or lymphoma. Although a markedly elevated blood EBV PCR in a setting compatible with PTLD is suggestive, tissue biopsy utilizing EBV-specific assays (eg, EBV encoded RNA staining) are needed for definitive diagnosis. PTLD may occur in any transplant type though it is most common in liver, heart and small bowel transplants. EBV reactivation is most frequent in settings of severe immunosuppression, especially when serotherapy (ie, ATG) has been used.
Current therapies for EBV are limited. Antivirals such as ganciclovir and acyclovir have minimal in vitro activity, and there is sparse evidence suggesting any clinical utility. Reduction of immunotherapy is first-line therapy. Anti-CD20 antibodies such as Rituximab are increasingly important therapeutic agent for PTLD. EBV-specific CTL are under evaluation and show significant promise, but their use is limited by availability and concerns for increasing the risk of GVHD.
Herpes Simplex Virus
Herpes simplex virus (HSV)-1 and HSV-2 infection are extremely common in the transplant population. The majority of patients who are HSV seropositive develop reactivation without antiviral prophylaxis. The spectrum of disease is broad including oral lesions, respiratory tract disease, hepatitis and encephalitis. Testing for HSV is best accomplished from skin (classically vesicular) or mucosal lesions using PCR (preferred) or direct fluorescent antibody testing of cells scraped from the base of a lesion. Cerebrospinal fluid specimens should be tested by PCR. Antiviral prophylaxis with oral or intravenous acyclovir is recommended before transplant for seropositive patients. Development of antiviral resistance is an increasing concern. If antiviral resistance is confirmed, use of agents that do not utilize the viral thymidine kinase, such as foscarnet and cidofovir, are advised. Relapse is common although subsequent infections may be susceptible to acyclovir.
Varicella Zoster Virus
Varicella zoster virus (VZV) is a highly contagious herpesvirus that establishes latency in the dorsal root ganglia and may then reactivate under certain conditions in the form of zoster. Immunocompromised individuals are at risk from primary and reactivated varicella. As with HSV, antiviral prophylaxis before and after transplant has reduced associated morbidity. Testing for VZV is best achieved by PCR (preferred) or direct fluorescent antibody of skin or mucosal lesions, whereas PCR should be used for cerebrospinal fluid.
Seronegative immunocompromised patients who are exposed to varicella should be given varicella-zoster immunoglobulin or standard immunoglobulin within 10 days of exposure.
Clinical presentation of primary VZV infection may be quite variable including fever and respiratory symptoms with vesicular rash, systemic illness, gastrointestinal tract involvement or encephalitis, with or without rash. Reactivation (zoster) generally presents as grouped vesicles in a dermatomal distribution although multiple dermatomes may be involved in disseminated disease. Intravenous acyclovir is the standard of care for treatment of VZV infections in immunocompromised hosts, with foscarnet and cidofovir as options in cases of resistant virus.
Human Herpes Virus-6
Human herpes virus (HHV)-6A and HHV-6B are herpesviruses that replicate in CD4+ lymphocytes and can result in suppressed T-cell function. They typically reactivate several weeks after transplant though only a minority of patients seem to develop symptoms such as fever, encephalitis, rash, hepatitis or delayed engraftment. A specific syndrome consisting of altered mental status, seizures and temporal lobe changes on magnetic resonance imaging termed limbic encephalitis has been associated with HHV-6 infection.6 Ganciclovir as well as foscarnet have been used to treat HHV-6 disease.
Immunocompromised patients are at high risk of progression from upper respiratory tract infection to the lower respiratory tract infection, with concomitant dramatic increases in morbidity and mortality.
Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) is a common respiratory pathogen in the immunosuppressed. Studies have shown that aggressive early treatment reduces progression to lower respiratory tract infection involvement and improved survival.7 Aerosolized ribavirin given intermittently has been shown to be as effective as continuous therapy. Early oral and intravenous ribavirin are effective in preventing progression of disease though have not been directly compared with the inhaled form. RSV-IG (IGIV with high neutralizing titer against RSV) with ribavirin and/or palivizumab is sometimes used in severely ill patients although there is a paucity of data comparing these treatment options.
Parainfluenza virus (PIV) most commonly presents as an upper and/or lower respiratory infection in the spring or fall. The diagnosis is best made by PCR (preferred), antigen detection or viral culture from nasopharyngeal swab specimens. Ribavirin in any form has little effect in PIV pneumonia. Immune globulin is often administered for treatment of PIV though the efficacy of this therapy is unclear. The investigational drug DAS 1818 is under evaluation for treatment on PIV.
Influenza infection may be devastating in immunosuppressed patients. Early and aggressive antiviral treatment is important and likely still beneficial even if treatment is delayed. Prophylaxis in transplant patients is currently not recommended. Early treatment with neuraminidase inhibitors such as oseltamivir and zanamivir is indicated and is associated with reduced risk for admission to the intensive care unit. Treatment with intravenous neuraminidase inhibitors such as intravenous (iv) zanamivir or peramivir are considered in critically ill patients. Resistance is an increasing issue and requires monitoring.9 High dose oseltamivir is recommended by some groups though there are no published studies to support this. The investigational drugs DAS 181 and favipiravir10 are under evaluation for strains that are resistant to oseltamivir.
Adenovirus (AdV) infection may arise from either latency in lymphoepithelial tissue or primary acquisition from the community. AdV is associated with significant morbidity and mortality in immunosuppressed patients. Symptoms commonly include respiratory distress or failure, gastroenteritis, keratoconjunctivitis, hepatitis, nephritis, encephalitis and/or multiorgan involvement. Detection of AdV in the blood and/or stool often precedes the development of symptoms.
Reduction of immunosuppression and cidofovir are recommended therapies for AdV, with consideration for adjunctive therapy with administration of immune globulin. Ribavirin has some activity against specific strains of AdV, whereas most other antivirals including ganciclovir are ineffective. The addition of probenecid to cidofovir significantly reduces the associated nephrotoxicity. Brincidofovir and adenovirus specific CTL show significant promise in treating this infection.2
Viral infections are a common complication of pediatric transplantation populations with high morbidity and mortality. Molecular diagnostics for surveillance and diagnosis, as well as a high degree of clinical suspicion, can help identify infection earlier and allow prompt institution of therapy to ameliorate disease.
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2. Leen AM, Christin A, Myers GD, et al. Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood. 2009;114:4283–4292
3. Yanada M, Yamamoto K, Emi N, et al. Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;32:801–807
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5. Florescu DF, Pergam SA, Neely MN, et al. Safety and efficacy of CMX001 as salvage therapy for severe adenovirus infections in immunocompromised patients. Biol Blood Marrow Transplant. 2012;18:731–738
6. Seeley WW, Marty FM, Holmes TM, et al. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology. 2007;69:156–165
7. Waghmare A, Campbell AP, Xie H, et al. Respiratory syncytial virus lower respiratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes. Clin Infect Dis. 2013;57:1731–41
8. Waghmare A, Wagner T, Andrews R, et al. Successful treatment of parainfluenza virus respiratory tract infection with DAS181 in 4 immunocompromised children. J Pediatric Infect Dis Soc. 2015;4:114–118
9. Tamura D, DeBiasi RL, Okomo-Adhiambo M, et al. Emergence of multidrug-resistant influenza A(H1N1)pdm09 virus variants in an immunocompromised child treated with oseltamivir and zanamivir. J Infect Dis. 2015;212:1209–1213
10. Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100:446–454
transplantation; viral infection; pediatrics; antiviral agents; prophylaxis