Adenovirus Infection and Transplantation

Abstract

Adenoviruses result in a wide array of clinical presentations, including primarily respiratory, gastrointestinal, genitourinary or systemic infections. While adenovirus causes mild disease limited to a single organ system in immunocompetent individuals, severe and life-threatening infections do rarely occur. Disseminated disease and severe localized disease resulting in significant morbidity and mortality have been well described in the immunocompromised populations. While asymptomatic viremia, respiratory tract and gastrointestinal infections are the most common disease in most transplant patients, renal transplant patients more commonly experience urinary tract infections, including hemorrhagic cystitis or nephritis. Diagnosis requires astute clinical awareness of the patient’s clinical presentation that would be compatible with adenovirus combined with cultures, molecular testing, PCR and tissue sampling. There is no FDA-approved treatment for adenovirus, however several studies have evaluated therapeutic options including cidofovir, brincidofovir and immunotherapy. This article will summarize our current understanding of adenovirus in the transplant population.

Introduction and Epidemiology

Adenoviruses (AdV) are nonenveloped, double-stranded DNA viruses associated with a wide range of clinical syndromes in humans.¹ There are currently 103 unique human genotype types of adenovirus divided into 7 species, A to G [http://hadvwg.gmu.edu/] based on hemagglutinin properties, DNA homology, oncogenic potential in rodents, and clinical disease (see Table 1).¹ The disease is globally distributed, with higher rates in regions with limited sanitation,² and has no seasonality to infection.^3,4 Eighty percent of the general population is infected by at least 1 serotype by the age of 6. Infection is more common in children than in adults. Among adults, risk is greatest among those living in close quarters, such as college or military barracks and patients who are immunocompromised.¹

Table 1.

Infections associated with adenovirus species and serotype.⁵

Species	Serotype	Major site of infection
A	12, 18, 31, 61	GI track
B	3, 7, 11, 14, 16, 21, 34, 35, 50, 55, 66, 68, 76–79	Respiratory, urinary
C	1, 2, 5, 6, 57, 89	Respiratory
D	8–10, 13, 15, 17, 19, 20, 22–30, 32, 33, 36–39,42–49, 51, 53, 54, 56, 58, 59, 60, 63, 64, 65, 67, 69–75, 80–88, 90–1038	Eye, GI track
E	4	Respiratory
F	40, 41	GI
G	52	GI

Transmission can occur via inhalation of aerosolized droplets, direct conjunctival inoculation, fecal-oral spread, or exposure to infected tissue or blood.^1,3 Incubation period is dependent on the viral serotype and the mechanism of transmission and can range from 2 days to 2 weeks.^1,3 In the healthcare setting, patients should be placed on contact and droplet precautions.⁶ Among the immunocompromised, shedding is typically prolonged compared to otherwise healthy patients.^1,3 Acute infection in the transplant population has been associated with donor-derived infection in addition to reactivation of latent infection.⁷ Reactivation occurs because adenoviruses can establish lifelong asymptomatic infections in lympho-epithelial tissues,⁷ renal parenchyma, tonsils, adenoids and gastrointestinal tract.^1,8–10 Severe infection has been most commonly described in the hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) populations.

Hematopoietic Stem Cell Transplant Recipients

In the stem cell transplant population, the incidence of disease due to adenovirus ranges from 3–47%.^3,9 Available data suggest that adenoviral infections are more frequent in allogeneic stem cell transplant recipients compared to those receiving autologous grafts (8.5–30% vs. 2–12%); in children compared to adults (20–47% vs. 6–13.6%); in patients who receive T cell depleted grafts (45% vs. 11%); with use of alemtuzumab, cord blood donor, patients with acute graft versus host disease (GVHD) and HLA mismatch.^3,9,10 More selective T cell depletion agents are associated with less risk of infection.¹⁰ Most retrospective studies have documented the onset of adenovirus disease primarily during the first 100 days following HSCT (median 36–90 days),^3,9,10 although adenovirus disease after 100 days has also been documented, especially in adults.^11,12

In HSCT recipients, adenovirus can cause a wide range of disease including focal organ disease including upper and/or lower respiratory tract infection, gastrointestinal disease, hepatitis, and cystitis or disseminated disease.^3,8–10 Certain adenovirus serotypes are more commonly associated with certain disease manifestations (See Table 1).^5,13 Adenovirus gastrointestinal disease is common in the pediatric SCT population, which may be related to concerns that adenovirus may lay dormant in the gut mucosa prior to transplant.^8,14

Adenoviral disease can result from primary infection or reactivation of latent infection, with higher rates of infection in pediatric age groups because of a greater incidence of de novo infections.^3,9,10,15 Keratoconjunctivitis caries a range of disease from self-limited conjunctivitis, a sequala of pharyngoconjunctival fever or rather severe endemic keratoconjunctivitis (EKC).^1,9 Respiratory tract disease ranges from mild upper tract involvement, typically with nonspecific cold-like symptoms, to severe pneumonia.^3,9,10 Gastrointestinal disease ranges from mild diarrhea to hemorrhagic colitis; severe hepatitis has also been described.^12,16,17 Diarrhea can be caused by viruses that are limited to the GI tract (i.e. AdV 40, 41, and 52) or a manifestation of GI involvement of disseminated disease (i.e. AdV 11, 34 and 35) (see Table 1). While genitourinary (GU) disease is more common in renal transplantation, hemorrhagic cystitis (HC) has been described in HSCT patients and should be tested even if other potential causes are found.^3,9,10

Adenovirus infections may also be associated with graft failure or delayed engraftment. Additionally, co-infection with cytomegalovirus (CMV), Aspergillus, or bacteria frequently occurs and may contribute to poor outcomes associated with adenovirus disease.¹³ Untreated, the mortality for HSCT patients approaches 26% for all symptomatic patients while pneumonia and disseminated disease portend more ominous outcomes (50% and 80% mortality respectively).^9,10

Solid Organ Transplant Recipients

Adenovirus infections, although infrequent, have been reported in all solid organ transplant (SOT) populations, with the highest incidence among intestinal, lung and kidney recipients.^14,18–20 Among SOT recipients, risk factors for adenovirus infection include small bowel and liver transplant recipients, pediatric transplant recipients, patients who receive antilymphocyte antibodies, and patients with donor-positive/recipient-negative adenovirus status.¹⁸ Among children, recipients aged less than 5 years have the highest rates of infection while adolescents have a lower prevalence of disease related complications.¹⁴ Severe disease has been associated with isolation of the virus in the first month after transplant, detection of the virus from more than 1 site, persistent viremia and high viral loads.¹⁴ Asymptomatic adenovirus DNA-emia is common among SOT recipients and generally is not associated with progression to symptomatic disease. 6.5%, 6.7%, 8.3%, and 22.5% of adult kidney, heart, liver, and lung recipients, respectively were DNA-emic in the first-year posttransplant, generally without clinical evidence of disease.^21,22 Invasive disease occurs in up to 10% of these patients.^14,18–20

Among SOT recipients, hemorrhagic cystitis, nephritis, pneumonia, hepatitis, enterocolitis, and disseminated disease have been described.^{13,14,18–20} With the exception of HC, the most common form of symptomatic disease in renal transplant recipients, the transplanted organ is typically the site of infection: pneumonia is most frequent in lung transplant recipients, hepatitis is most frequent in liver transplant recipients, and enterocolitis, which may mimic rejection, is most frequent in small bowel recipients.^{13,14,19,20,23}

Most forms of infection outside the urinary tract have the potential to progress and cause clinically significant disease and may rarely result in death. In contradistinction, HC and adenovirus nephritis in kidney transplant recipients is generally self-limited if immunosuppression can be reduced. Patients with HC typically present with fever, hematura and voiding complaints, which may be confused for a bacterial infection. As such, clinicians seeing patients with fever and hematuria should always consider adenovirus and send for PCR testing of the urine, particularly if urine cultures are negative for bacteria. HC may progress to involve the kidney, which may lead to graft disfunction and granulomatous interstitial nephritis seen on biopsy.^18,20 Serum creatinine elevation is often seen as well, with return to baseline upon resolution of HC/nephritis.^20,23 Even with reduction of immunosuppression, symptoms may persist for several weeks, so patience and close monitoring of blood and urinary viral load are critical.^18–20

Diagnostic Approaches

Screening of blood, urine or stool has been found to predict development of disease in pediatric HSCT recipients.²⁴ While some centers begin screening immediately prior to transplant, most programs begin after chemotherapy has started. Screening of stool results in more frequent positivity but is less correlated with clinical disease unless there is rising viral loads over time. Screening of blood and/or stool is recommended weekly until at least 100 days after HCT or until CD3þ T cells are more than 300/ml. Given that there is less data supporting screening in adults, there is greater variability in approaches across centers.^10,24–26 In solid organ transplant populations, there is no role for routine screening of asymptomatic patients for adenovirus given high rates of detection and lack of risk of progression to clinically significant illness.^21,22

Diagnostic modalities for detection for AdV have evolved over time. Historically, culture and antigen tests were commonly utilized to diagnose adenoviral infections. Owing to poor sensitivity of antigen testing in transplant recipients and improved yield with polymerase chain reaction (PCR) testing, most contemporary diagnosis is focused on PCR-based testing and pathology. Throat swabs, nasal washes, conjunctival swabs or scrapings, anal swabs, stool, urine, and blood may be collected for testing.³ Sample types should correspond to clinically evident sites of infection (stool for GI disease, urine for GU disease, for example). Blood is often also screened irrespective of site of symptomatic disease to assess for disseminated disease and to increase diagnostic yield. It should be noted that respiratory viral testing may miss disseminated disease, viremia or infection outside the upper respiratory infection; as such, multiple sites should be tested if there is concern for adenovirus infection. Further, given the ability of adenovirus to remain latent in various tissues, biopsy is often required to document lytic infection in the tissue of interest.

Once clinical disease is established, serial monitoring by quantitative PCR of relevant samples, including blood or other sources that were initially positive can inform response to therapy.^{3,10,14,19,20} Patients who do not have a significant decline in viral load after 1–2 weeks of an intervention (reduction of immunosuppression or cidofovir) may need an alternative approach to management. Likewise, viral load monitoring can inform timing of enhancing immunosuppression if relevant.

Viral subtyping and serotyping can be accomplished through immunologic or nucleic acid sequence-based methods.^27–29 These techniques are currently in use predominantly for epidemiologic studies and other research applications and is generally not needed clinically for the evaluation and management of patients.

Histopathology

On biopsy of infected tissue, characteristic intra-nuclear inclusions are very suggestive of the diagnosis, in addition to nonspecific degrees of inflammation (Figure 1).^30,31 In patients with adenoviral nephritis, which is most commonly seen in renal transplant recipients, enlarged tubular cells with amphophilic glassy nuclear inclusions and granuloma formations are most commonly noted (Figure 1).^20,31 Immunohistochemistry (IHC) or in situ hybridization (ISH) techniques as an adjunct to morphologic examination may help definitively identify adenovirus infection in tissue sections, improving the sensitivity of detection, while also localizing disease and providing evidence for causality.^3,20,31 As Adv enteritis may mimic rejection, histopathology may be particularly useful, especially in small bowel transplantation.^3,13,14

Figure 1.

Histopathology of adenovirus nephritis in a transplant recipients. A, Hematoxylin and eosin stains demonstrating glassy inclusions within enlarged tubular epithelial cell nuclei (400x). B, Immunohistochemical staining of adenovirus in tubular epithelial cells.

Polymerase Chain Reaction (PCR)

Serum PCR has become the significant screening method with proven impact on pediatric and adult HSCT recipients.^10,24,25 Any time that adenovirus disease is considered, blood specimens should be sent for quantitative viral load measurements. Serum PCR is highly sensitive for disseminated AdV PCR detection. PCR can also be performed on stool, sputum and biopsy specimens.^3,9,10 If PCR is utilized to monitor clinical responses to treatment or to trend patients over time, the same assay should be utilized and the same compartment (whole blood vs. plasma) should be assessed, since there are no international standard and variation in quantitative virology across assays is significant.³

Multiplex PCR assays on respiratory samples to detect respiratory viruses from upper and lower respiratory tract samples generally have excellent sensitivities and specificities. However, each assay has divergent pathogen-specific sensitivities especially for different species and/or serotypes of adenoviruses.³² Further, some assays may not detect all subtypes of adenoviruses.³ Lastly, if the respiratory tract is not the primary site of infection, testing of respiratory specimens, particularly upper tract specimens, may yield negative results despite ongoing replication elsewhere.

There are also a number of multiplex assays for detection of adenovirus from the stool of patients.³ Quantitative PCR assays have been developed to monitor trends in viral shedding in the stool and replication in the blood. Although false-negative results have been reported, these molecular methods have improved sensitivity over traditional methods.³

Quantitative viral load measurements contribute to the diagnosis of infection and act as a surrogate that correlates with clinical response to therapy.^3,9 Increased viral load measurements are associated with an increased likelihood of death.^3,9,10,13,14

Antiviral Susceptibility Testing

Few labs are able to perform antiviral susceptibility testing and its use in routine clinical care is not recommended.³ There are no standard methods that have been universally agreed upon. In vitro resistance does not clearly correlate with clinical outcomes in the management of adenovirus.^33–36

Clinical Approach

When adenovirus infection is considered, PCR-based testing of relevant source should be performed. If there are respiratory symptoms, blood and respiratory specimens (nasal swab or BAL) should be sent. If urinary symptoms are noted, would send blood and urine samples. If there is diarrhea or gastrointestinal involvement, including hepatitis, would send stool and blood testing. Quantitative testing is preferred as it can be followed to assess clinical progression. Patients with progressive illness or rising viral loads despite time and reduction of immunosuppression should be considered for antiviral therapy. Testing should be done no more frequently than once per week. Significant increase is a 0.5 log or greater change in quantitative viral load.

Treatment

Mainstay of management of infections consists of reduction of immunosuppression. Reduction of immunosuppression is the treatment of choice for more limited disease, including urinary tract infections, including HC and adenovirus nephritis. Which agent to reduce and degree of reduction of immunosuppression should be discussed by the transplant and transplant infectious diseases teams as there is no clear guidelines. While no optimal approach has been studied, our institution often starts with reduction of the antimetabolite. This reduced immunosuppression is generally continued until undetectable viral loads or persistent low level viral loads in the urine if stably low for several weeks. With this approach, patients may have persistent signs and symptoms but typically have a reduction in viral load in the blood and/or urine within 2 weeks. Treatment approach depends on a number of factors including net state of immunosuppression, site of infection and degree of dissemination. For example, even with symptomatic adenovirus HC and transplant nephritis with viremia, reduction of immunosuppression is likely all that is needed for most patients. Given the significant toxicity of alternative agents, antivirals are typically reserved for patients with progressive or life-threatening infections. Preemptive therapy has been shown to improve outcomes for HSCT patients but in general is not recommended for SOT patients. Treatment durations are extended until resolution of symptoms and 2 consecutive negative detection of virus from original site of infection at least 1 week apart.¹⁴

There are limited options for therapy of adenovirus infection. There have been few prospective studies to-date, and the optimal timing for therapeutic intervention during the course of illness is unclear.^5,13 In HSCT, treatment is often considered depending on the level of immunosuppression in relation to the viral load, those severely immunosuppressed may warrant therapy at 100 cp/mL viral load detection, while the relatively more immune-reconstituted patients may have a higher threshold of 10,000 cp/mL.³⁷ While in SOT, therapy may be considered in the setting of severe disease or > 1.0 logarithmic increase in viral load.¹⁴ Of the available agents, most studies have focused on ribavirin and cidofovir; existing data suggests that cidofovir and its lipid ester analogue, brincidofovir, may provide the highest likelihood of antiviral efficacy.^10,14

When therapy is needed, most utilize cidofovir despite its potential toxicity. Cidofovir must be given intravenously and can be dosed as 5 mg/kg every 1–2 weeks or 1 mg/kg 3 times per week.⁹ Most studies performed on HSCT patients show equivalent results in dosing including a pediatric nonrandomized retrospective trial.^10,38,39 One nonrandomized retrospective SOT pediatric study suggested that perhaps the more frequent dosing may have higher rates of viral clearance without significant difference in toxicity.⁴⁰ However, this study was skewed due to outliers with significantly higher viral loads in the weekly dosing group and concluded that the dosing was likely equivalent. Regardless of the severity of illness, viremia versus systemic illness, dosing remains the same. Despite documented in vitro and in vivo efficacy, significant toxicity has so far limited the use of cidofovir more broadly.⁴¹ Toxicities include nephrotoxicity, myelosuppression and uveitis. To avoid renal toxicity, it is critical to ensure that the patient gets adequate hydration around dosing with at least 500mL normal saline before and after infusions. Additionally, 2 grams of probenecid should be given 3 hours prior to and 1 gram 2 and 8 hours after cidofovir administration.^10,14,26 No clear guidelines exist if patients experience nephrotoxicity, rather continuation of cidofovir should be based off benefit risk assessment due to severity of illness. Because of the risk of renal toxicity, it is critical to only use this therapy in patients who are unlikely to recover without therapy. Use of cidofovir has been associated with breakthrough CMV infections and development of CMV resistance when lower dose regiments are utilized.¹⁰ Duration is dependent of clearance of detectable virus and clinical response. While most treated patients will respond to therapy (see Table 2), some have progressive and often fatal disease.

Table 2.

Studies of cidofovir for the treatment of adenovirus in solid organ transplant recipients.

Study	Patients (N)	Adult/pediatric	Organ transplant	Disease	Cidofovir dose	Viral clearance	Clinical outcome
42	1	P	Liver	Hepatitis/sepsis	6mg/kg QW	Yes	Recovered
40	21	P	Liver, kidney, intestine, MV	Adv viremia +/− GI (30%), hepatitis (18%), pneumonia (8%), disseminated (4%)	5mg/kg QW or 1mg/kg TIW	Yes	All recovered
43	2	P	Liver	Disseminated disease + ARDS	1mg/kg TIW	Pts 1, 2: yes	Patient 1: chronic rejection Patient 2: recovered
44	1	P	Liver	Viremia + hepatitis + pancreatitis	1mg/kg TIW	Yes	Recovered
45	4	P	Lung	Pneumonia	1 mg/kg QOD or TIW	Pts 1, 2, 3: Yes	Patient 1,2,3: recovered Patient 4: developed rejection; died with persistent ADV
41	3	P	1 Liver - SB 2 Liver 3 Liver - SB	Patient 1, 2: Viremia + GI Patient 3: Viremia + GI + pneumonia	5 mg/kg QW	Pts 1, 2: Yes	Patient 1,2: recovered Patient 3: died with persistent ADV
46	3	P	Liver	Viremia + disseminated multiorgan disease	5 mg/kg QW	No	Died and did not clear ADV
47	5	P	1: Lung, 2: Heart 3: Kidney-liver, 4, 5: MV	1: asymptomatic viremia 2: fevers + sepsis 3: Pneumonia 4: GI disease 5: GI disease + rejection	5mg/kg QW or 1mg/kg TIW	Yes	Recovered
48	2	A	Kidney	Disseminated multiorgan	5mg/kg QW or 1mg/kg TIW	Yes	Recovered
49	6	P	SB; liver-SB	Symptomatic ADV	5mg/kg QW	Pts 1,2,3,4: Yes	Patients 1,2,3,4: recovered Patient 5: died from ADV
50	1	P	SB	Intestine allograft + hepatitis	5mg/kg QW	Yes	Recovered
51	1	A	Heart	Pneumonia	3 mg/kg QD	Yes	Recovered
52	1	A	Kidney	Nephritis	5 mg/kg, then at 1 mg/kg TIW	Yes	Recovered
53	1	A	Heart-kidney	Disseminated, pneumonia + HC + nephritis	NA	Yes	Recovered
54	1	A	Lung	Pneumonia	1 mg/kg TIW	Yes	Recovered
55	1	A	Kidney	Nephritis, URI	1 mg/kg QW	No	Persistent viremia, no GFR or symptom improvement
56	2	A	Kidney	Disseminated	3mg/kg QW or 1mg/kg QW	Yes	Graft recovered, CDV nephrotoxicity
57	1	A	Kidney	Nephritis	2.5 mg/kg BIW	Yes	Recovered
58	1	A	Kidney	Nephritis	2mg/kg	Yes	Recovered
59	4	A	Kidney	1: HC + orchitis 2: HC + orchitis + URI 3: HC + orchitis 4: HC + orchitis + pneumonia + delayed graft function	5mg/kg or 3mg/kg QW	Pts 1,2,3: yes	Patients 1,2,3: recovered Patient 4: died
60	1	A	Kidney	Disseminated + allograft nephritis	0.5 mg/kg once	Yes	Recovered
61	1	A	Heart	Conjunctivitis + pneumonia	1 mg/kg/dose) x1, then 7 days later 5 mg/kg/dose x1	Yes	Recovered
62	1	P	Kidney	HC	.5 mg/kg once, then 1 mg/kg TIW	Yes	Recovered
63	1	A	Kidney	Nephritis	100 mg for 2 weeks	Yes	Recovered
64	1	A	Kidney-Pancreas	HC + allograft nephritis	80 mg QW	Yes	Recovered
65	1	A	Liver	ADV	3 mg/kg (renal adjustment) QW x4	Yes	Multiorgan failure resulting in death
66	1	A	Heart	Hepatitis	NA	No	Liver failure. Death
67	1	A	Kidney	Nephritis	1 mg/kg TIW	Yes	Recovered

ADV, adenovirus; ARDS, acute respiratory distress syndrome; CDV, cidofovir; GFR, glomerular filtration rate; GI, gastrointestinal; HC, hemorrhagic cytitis; MV, multivisceral transplant; NA, not applicable; QW, once weekly; SB, small bowel transplant; TIW, 3 times a week.

To overcome much of the toxicity of cidofovir and to allow oral delivery, brincidofovir was developed as a lipid ester prodrug of cidofovir. It is currently approved for the treatment of smallpox but has been used under compassionate use and in clinical studies against adenovirus.⁶⁸ Brincidofovir appears to have increased in vitro efficacy against adenovirus and has less renal and bone marrow toxicity as compared to cidofovir.^13,68–72 Furthermore, brincidofovir has excellent oral bioavailability allowing dosing once to twice weekly in addition to excellent cellular penetration. Successful clinical response has been demonstrated in both HSCT and SOT patients.^{8,10,68,73–77} In those who were treated with brincidofovir, the mean time to viral clearance was 4 weeks in patients who responded to therapy.^10,26 The major side effect of the medication is diarrhea, which appears to be dose dependent and is clinically indistinguishable from gastrointestinal GVHD, even on histology.⁷⁸ A small, randomized placebo-controlled phase II clinical trial evaluated brincidofovir as prophylaxis in post-HSCT for prevention of adenovirus disease seemed to suggest that brincidofovir was effective at reducing adenovirus disease, although the study was under powered.⁷⁹ Unfortunately, brincidofovir is no longer being developed for adenovirus.^8,10 If it is clinically available, it may be the optimal choice to treat clinically significant adenoviral infections given its enhanced safety profile compared to cidofovir.

Ribavirin but does not appear to have significant anti-adenovirus activity in humans and is generally not recommended to treat serious adenoviral infections.⁸⁰ Nitazoxanide, may have some activity as it targets the protein replication process of the virus. Limited in vitro data suggests it may be useful for treatment of enteritis or mild to moderate disease and useful in the outpatient setting.¹⁴ Other studied agents, including vidarabine, dideoxycytidine and ganciclovir may have activity but their efficacy in managing adenoviral infections remains less than promising. ^8,13 While most AdV associated conjunctivitis are self-limited, N-chlorotaurine, an anti-microbial agent, has been shown to shorten the duration of illness of EKC.¹ There is no role for IVIG for the treatment of adenovirus infection in transplant recipients.¹⁴

Given the central role of cellular immune responses in the clearance of adenovirus, approaches to reconstitute cellular responses to adenovirus are being investigated, including the use of adenovirus- and multi-virus-specific T cell infusions.^9,81 The T cells are adoptively transferred into the patients with serious adenovirus infections, with a low frequency of de novo graft-versus-host disease in HSCT patients; experience in SOT patients is more limited.^82,83 These therapies are proving to be better tolerated and have less toxicities and may even suggest mortality benefit.⁹ Seventy-four percent of patients who received the infusions had a complete or partial response in their adenovirus infection. T cells dosing depends on various factors including GVHD, HLA match and generation method, with upper doses typically of 2.5×10⁴/kg recipient body weight CD3+ cells in HLA-mismatched/ haploidentical donors and 1×105/kg in HLA-matched donors. While these exogenous “off the shelf” cells remain experimental, they show promise and are currently in phase III clinical trials.^10,81

In summary, a multidisciplinary approach to evaluate the role of reduction of immunosuppression should be the first step. Often treatment of AdV is limited to severe infections and/or disseminated disease. Treatment options are quite limited, with most institutions favoring cidofovir, or brincidofovir if available. Treatment is typically continued until 2 successive PCR tests undetectable virus followed by resuming immunosuppression.

Conclusion

In SOT and HSTC, adenovirus can cause a wide spectrum of disease, varying from asymptomatic viremia, symptomatic viremia, organ failure, rejection and even mortality. It takes proper and complete understanding of AdV to make the diagnosis, which consists of understanding which diagnostics modalities to use, when to use them and how to interpret the results. PCR seems to be the mainstay of diagnostics and allows for surveillance linked to preemptive antiviral therapy, guiding patient management and treatment with antiviral agents. Furthermore, determining treatment modalities also requires expertise in the field. Most current therapeutic focus on cidofovir and brincidofovir with AdV specific T cell infusions showing promise. Yet, we still need additional research into development of more appropriate treatment therapies and randomized control data to better understand whom best to treat, when to treat and how long to treat.

Abbreviation Page

AdV

adenovirus

FDA

Food and Drug Administration

GVHD

graft-versus-host disease

HSCT

hematopoietic stem cell transplant

SOT

solid organ transplant

EKC

endemic keratoconjunctivitis

GI

gastrointestinal

GU

genitourinary

CMV

cytomegalovirus

PCR

polymerase chain reaction

EBV

Epstein Barr Virus

HC

hemorrhagic cystitis

IHC

Immunohistochemistry

ISH

in situ hybridization

PCR

polymerase chain reaction