key: cord-0010322-vtgm46xt
authors: Lynch, Joseph P.; Kajon, Adriana E.
title: Adenovirus: Epidemiology, Global Spread of Novel Serotypes, and Advances in Treatment and Prevention
date: 2016-08-03
journal: Semin Respir Crit Care Med
DOI: 10.1055/s-0036-1584923
sha: 79ef7db8567a80406b8d83a80d72448242361073
doc_id: 10322
cord_uid: vtgm46xt

Adenoviruses (AdVs) are DNA viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal tract, or conjunctiva. Rare manifestations of AdV infections include hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, or meningoencephalitis. AdV infections are more common in young children, due to lack of humoral immunity. Epidemics of AdV infection may occur in healthy children or adults in closed or crowded settings (particularly military recruits). The disease is more severe and dissemination is more likely in patients with impaired immunity (e.g., organ transplant recipients, human immunodeficiency virus infection). Fatality rates for untreated severe AdV pneumonia or disseminated disease may exceed 50%. More than 50 serotypes of AdV have been identified. Different serotypes display different tissue tropisms that correlate with clinical manifestations of infection. The predominant serotypes circulating at a given time differ among countries or regions, and change over time. Transmission of novel strains between countries or across continents and replacement of dominant viruses by new strains may occur. Treatment of AdV infections is controversial, as prospective, randomized therapeutic trials have not been conducted. Cidofovir is the drug of choice for severe AdV infections, but not all patients require treatment. Live oral vaccines are highly efficacious in reducing the risk of respiratory AdV infection and are in routine use in the military in the United States, but currently are not available to civilians.

Human AdVs are a group of double-stranded nonenveloped DNA viruses belonging to the genus Mastadenovirus of the Adenoviridae family. 29, 30 Currently, 51 serotypes, and over 70 genotypes defined by bioinformatics analysis of complete genomic sequences and designated with consecutive numbers (52, 53, 54, etc.) have been described and classified within 7 species (HAdV-A through HAdV-G). 31-37 Species A, B, C, D, E, and F circulate globally, and have been implicated in outbreaks of infection in humans. 1 Different genome types (or genomic variants) can be distinguished within the same serotype by restriction enzyme analysis of genomic DNA. [38] [39] [40] Approximately one-third of the described serotypes are associated with human disease. 24,26,29,31,41-44 Different serotypes display different tissue tropisms that correlate with clinical manifestations of infection 2,26,31,33 (discussed in detail in the next sections).

AdVs may cause epidemics of febrile respiratory illness (FRI), pharyngoconjunctival fever, 45 keratoconjunctivitis (KC), [46] [47] [48] [49] or gastroenteritis and diarrheal illness. 50-61 Severe or disseminated AdV infections may occur in immunocompromised hosts 7,9,62-64 and rarely in immunocompetent patients. 23, 65 Most epidemics occur in the winter or early spring, 6 but infections occur throughout the year with no clear seasonality. 2 Infection can result from exposure to infected individuals (inhalation of aerosolized droplets, conjunctival inoculation, fecal oral spread), 1,2,66,67 acquisition from exogenous sources (e.g., pillows, linens, lockers, guns), 68, 69 or reactivation. 2,26 Incubation period ranges from 2 to 14 days. 2 Importantly, latent AdV may reside in lymphoid tissue, 7,70 renal parenchyma, 71 or other tissues for years; reactivation may occur in severely immunosuppressed patients. 7, 70, 71 Asymptomatic carriage of AdV may persist for weeks or months. 31, 72, 73 Epidemics may spread rapidly among closed populations 16, 17, 20, 33, 40, 44, 68, [74] [75] [76] (e.g., hospitals, 6,67,77 neonatal nurseries, 78 psychiatric 77,79 or longterm care facilities, 48,66,80 job training centers, 21 boarding schools or dormitories, 81 a children's home, 82 orphanages, 83 public swimming pools 84, 85 ). In institutionalized settings, infection control measures and cohorting may be essential to limit spread. 66, 67, 86 AdV is resistant to many disinfectants 87 but 95% ethanol solution is an effective disinfectant. 73 

AdV accounts for at least 5 to 10% of pediatric and 1 to 7% of adult respiratory tract infections (RTIs). 2,31 Typical symptoms of AdV RTI include fever, pharyngitis, tonsillitis, cough, and sore throat. 3,19 GI symptoms may be present concomitantly, particularly in children. 3, 13, 19, 88 In immunocompetent patients, symptoms usually abate spontaneously (within 2 weeks) and infection induces type-specific immunity. 2 Pneumonia occurs in up to 20% of newborns and infants, 3,10,12,88,89 but is uncommon in immunocompetent adults. 2,16,17,77,79,90,91 However, fatalities due to AdV pneumonia have been described in previously healthy children 10 or adults. 19, 23, 65, 79, 90 In immunocompromised persons, dissemination and/or severe respiratory failure develop in 10 to 30% of cases 2,9,27,38 and fatality rates for severe AdV pneumonia may exceed 50% 2,9,90 (►Fig. 1).

In children, long-term respiratory sequela of AdV RTI include bronchiectasis, bronchiolitis obliterans, and hyperlucent lung. [92] [93] [94] AdVs have a propensity to establish latent or persistent infection within the upper 95 and lower respiratory tracts. 96 Persistent AdV infection in children may elicit chronic neutrophilic inflammation within the airways, protracted bacterial bronchitis and bronchiectasis. [97] [98] [99] HAdVs (particularly types 1-5, 7, 14, and 21) have been associated with small airways dysfunction 96 and bronchiectasis in children 94, 98 and chronic obstructive pulmonary disease in adults. 100, 101 These various studies suggest that HAdV is not an innocent bystander in the lower airways, but may play a role in the pathogenesis of chronic suppurative endobronchial and lung disease.

Manifestations of ocular AdV infection include: epidemic KC (EKC), pharyngoconjunctival fever, and nonspecific conjunctivitis. 49, [102] [103] [104] [105] [106] The most common serotypes associated with EKC are AdV-8, -19, and -37, 49,103,105-112 but other serotypes (e.g., AdV-3, -4, -7, -11, and -14) can also cause conjunctivitis. 46,47, 105, 106, 108, 113, 114 Outbreaks of EKC can occur in hospitals or outpatient clinics, 102, 103, 115 chronic care facilities, 66, 116 and closed settings. 117 Nosocomial transmission has been noted in eye clinics or hospitals via environmental contamination (ophthalmic instruments, eyedrops). 103, 115, 118 Rigorous sterilization of instruments and strict infection control were essential to curb epidemics. 103, 115 The recently described genotypes 53, 54, and 56 of species HAdV-D have been reported in association with outbreaks of EKC. [119] [120] [121] [122] [123] [124] 

AdV infections can cause GI symptoms even when the primary site of involvement is the respiratory tract (particularly in young children). 3,13,88,125 Some serotypes (notably AdV-40 and -41) have an affinity for the GI tract, 50,53,54,57 with predominant symptoms of gastroenteritis or diarrhea. 126 Rare complications include hemorrhagic colitis, 2,27,127 hepatitis, 27,128-131 cholecystitis, 132 and pancreatitis. 133, 134 Urinary Tract Involvement AdV may cause urinary tract infections (UTIs), 135 particularly among hematopoietic stem cell transplant (HSCT) 71, [136] [137] [138] [139] and solid organ transplant (SOT) recipients. [140] [141] [142] [143] Typical manifestations include dysuria, hematuria, hemorrhagic cystitis (HC), and renal allograft dysfunction. 141, 142, 144, 145 Most AdV UTIs (including HC) are self-limiting 43,71,140,144 but fatal or dialysis-dependent renal failure, 146-148 fatal dissemination, 149, 150 necrotizing tubulointerstitial nephritis, 148, 151 or obstructive uropathy 151 have been described. Most common serotypes associated with HC include: AdV-11, -34, -35, -3, -7, and -21. 2, 142, 144, 148 The diagnosis may be confirmed by culture or polymerase chain reaction (PCR) in urine, or serology. 2,137,142 Renal biopsy may demonstrate viral infection of tubular epithelial cells, with "smudge cells" and intranuclear inclusions. 147, 148 AdV urethritis has also been described. 152 

Disseminated AdV infections are rare among immunocompetent hosts, but dissemination occurs in 10 to 30% of HSCT recipients with AdV infection. 2,25,26,38,153-155 Diagnosis is made by PCR in blood 150 and/or detection (or recovery) of AdV from more than one site. Among HSCT recipients with symptomatic AdV disease, fatality rates range from 12 to 70%. 25, 153, [156] [157] [158] Case fatality rates for AdV pneumonia may exceed 50%. 27,90

Rare manifestations of AdV infections include: encephalitis [159] [160] [161] [162] [163] ; meningitis 162, 164, 165 ; myocarditis and cardiomyopathy 166, 167 ;mononucleosis-like syndromes 168 76 Peak illness rates occur during weeks 3 to 5 of training. 20 In a prospective study of 271 new military recruits in training, 25% developed an acute FRI due to AdV-4 over a 6-week period; all FRIs occurred among recruits with an initial AdV antibody titer of < 1:4. 69 Serum antibodies to AdV-4 were present in 34% at enrollment, and 97% by 6 weeks. 69 Following completion of basic training, recruits are dispersed to secondary sites, paving the way for epidemic spread. 86 Historically, serotypes AdV-7 and -4 predominated as a cause of FRIs in the military in the United States. 16, 17, 40 Beginning in 1971, all recruits in the United States military were vaccinated with live enteric-coated AdV-4 and -7 vaccines. 174 Following this strategy, the incidence of AdV infections in the military setting plummeted. 174 In 1995, the sole manufacturer of the AdV vaccines ceased production; existing supplies were completely depleted by 1999. 19 In 1996, the last year AdV vaccines were given to recruits year round, AdV-21 was the most prevalent type, implicated in 58% of AdV infections; AdV-4 and -7 were each implicated in only 4%. 175 The lack of availability of vaccines led to re-emergence of Beginning in October 2011, after a 12-year hiatus, the administration of live nonattenuated oral vaccines against AdV-4 and -7 to U. S. military recruits was resumed. 179 From 1996 to 2013, FRI surveillance was performed at eight military training centers in the United States. 175 During the 2 years after reintroduction of the vaccine, AdV burden declined 100-fold (from 5.8 to 0.02 cases per 1,000 person weeks, p < 0.001). 175 Although the percentage of type 14 increased following reintroduction of the vaccine, the mean annual number of AdV-14 infections decreased (from 610 in 2000 to 2011 to 44 in 2013). 175 Continuing to vaccinate all incoming recruits will reduce cases among trainees, and may reduce transmission to other geographical locations and to civilians. 175 Future surveillance studies will monitor AdV infection rates and pay attention to emergence of AdV types not targeted by the vaccines.

The incidence of AdV infections among HSCT recipients is highly variable (range, 3-47%). 2,4,25-28,42, [153] [154] [155] [156] [180] [181] [182] [183] [184] The incidence is much higher among allogeneic (range, 5-47%) 4 compared with autologous (range, 2.5-14%) [185] [186] [187] HSCT recipients. Higher rates of AdV infections reflect prospective studies with regular (often weekly) sampling of plasma for AdV DNA (by PCR). 153, 188 The incidence is 2 to 3.5 times higher in children (> 20%) compared with < 10% in adults. 38, 181, 182, 189, 190 Additional risk factors for AdV infections among HSCT recipients include: allogeneic HSCT 4,38,182 ; graft versus host disease (GVHD) 2,25,27,28, 153, 154, 156, 182, 191 ; severe T-cell depletion 28, 38, 191 ; human leukocyte antigen (HLA) mismatch. 38, 192 Infection can reflect primary infection (e.g., community or nosocomial acquisition) 73 or reactivation of latent infection. 70, 73 AdV in HSCT recipients is usually detected within 100 days of transplant. 38, 193 The disease is usually localized (e.g., urinary tract, gastroenteritis, upper or lower respiratory tract) but dissemination occurs in 10 to 30% of cases. 28, 38, 181, 189 In this context, mortality rates are high. 38 Among 76 adult HSCT recipients with symptomatic AdV infections, mortality rate was 26%. 182 Mortality rates were higher among patients with pneumonia (73%) and disseminated disease (61%). 182 Severe lymphopenia, 2,38 severe GVHD, 28,182 isolation from more than one site, 38 and high AdV viral loads in plasma 194, 195 correlate with higher mortality. In one study of 123 consecutive pediatric allogeneic HSCT recipients, 12.3% developed symptomatic AdV infections. 183 Overall survival was much worse in patients with AdV infections (15.4%) compared with noninfected subjects (50%; p < 0.03). In multivariate analysis, the most important risk factor for mortality was AdV infection (hazard ratio, 3.15; p < 0.001). 183 However, prognosis may be good, particularly when the viral load is low. A retrospective study in pediatric HSCT recipients detected AdV in blood (by PCR) in 11/26 (42%); viremia cleared in 7 (63%) without antiviral therapy. 43 In another study of 116 adult HSCT recipients who had weekly screening for AdV in blood by PCR, 14 (12.1%) developed AdV viremia. 193 Only five were treated with cidofovir (CDV); only one died as a result of AdV infection. In another study of pediatric HSCT recipients, weekly sampling of plasma PCR identified 57 patients with AdV infections; 8 (14%) patients had disseminated disease. All 57 patients were treated with intravenous CDV; clinical and microbiological cure was achieved in 56 (98%). One patient died of AdV pneumonia. 188 Quantification of AdV DNA load by real-time PCR in plasma of HSCT recipients may identify patients at high risk for dissemination 189, 194 or assess response to therapy. 189, 194 However, indications for, and duration of therapy, with CDV are controversial.

The incidence of AdV infections among SOT recipients is 5 to 22%, usually within the first 6 months posttransplantation. 2,4,38, 156, 196, 197 AdV infections have been noted in liver, 198, 199 renal, 140,142,146,200-202 heart, 196,203,204 intestinal, 205, 206 and lung 207-209 transplant recipients. Among SOT recipients, risk factors for AdV include: pediatric age 4,38,198 ; donor-positive/recipient-negative AdV status 38 ; receipt of antilymphocyte antibodies. 38 In a prospective study, AdV viremia (by PCR) was detected within 12 months of transplant in 19/263 (7.3%) SOT recipients including: liver, 10/121 (8.3%); kidney, 6/92 (6.5%); heart, 3/45 (6.7%). 196 At the time of viremia, 11 (58%) were asymptomatic. All recovered spontaneously without sequela. In a retrospective review of 484 pediatric liver transplant recipients, 49 (10%) developed AdV infections; 9 died of invasive AdV infection. 198 In another retrospective review of 191 adult liver transplant recipients, 11 (5.8%) had AdV infection, and 2 AdV-associated deaths were documented. 199 Clinical manifestations of AdV infection are protean, but the primary site of disease in SOT recipients is often related to the transplanted organ. 38, 210 In liver transplant recipients, AdV typically causes hepatitis, jaundice, and hepatomegaly. 38 In renal transplant patients, HC is the principal symptom; further, AdV may target the renal allograft, leading to graft failure. 142, 146, 200 In pediatric heart transplant recipients, the presence of AdV in posttransplant endomyocardial biopsies increased the risk for graft loss and posttransplant coronary artery disease. [211] [212] [213] In a cohort of 383 lung transplant recipients (LTRs), only 4 AdV infections were identified; incidence was 3/40 (8%) among pediatric LTR and 1/268 (0.4%) among adult LTR. 207 However, all four developed severe hemorrhagic, necrotizing AdV pneumonia; all died within 45 days of transplant. In another study of 19 pediatric LTR, 8 developed AdV, resulting in 2 early deaths, as well as late graft loss and obliterative bronchiolitis. 200 A case of fatal AdV pneumonia in an adult LTR 4 years posttransplant was described. 214 Although AdV can cause fatal infections in SOT recipients, indications for treatment with CDV for mild infections have not been established. AdV viremia may be asymptomatic, and may clear spontaneously. 196 Routine PCR surveillance is not recommended in adult SOT recipients. Further, treatment (with CDV) should be reserved for symptomatic patients or those with pneumonia or disseminated infection.

AdV infections occur in 12 to 28% of human immunodeficiency virus (HIV)-infected patients. 215, 216 In one prospective study of 63 HIVþ patients, 18 (28%) developed AdV infections within 1 year (17% if CD 4 count was > 200/mm 3 vs. 38% if the CD 4 count was < 200/mm 3 ). 216 In Nigeria, 39% of 184 HIV-infected patients had serological evidence for AdV infection. 217 The GI tract is involved in > 90%, but most patients are asymptomatic or have mild symptoms (e.g., diarrhea). 216 UTIs occur in up to 20% of AIDS patients, 218 but HC is rare. 38 Serotype D is associated with GI infection whereas UTIs are usually caused by serotypes B or D. 216 AdV (particularly serotypes 1 to 3) may cause fatal cases in HIV-infected patients. 38, 197 Since the availability of highly active antiretroviral therapy, AdV disease is uncommon in HIV/AIDS patients until immune system deterioration occurs. 38

AdV infection may complicate congenital immunodeficiency disorders such as severe combined immunodeficiency syndrome, common variable immunodeficiency, agammaglobulinemia, immunoglobulin A deficiency, and others. 38, 64, 197, 219 In patients with severe immunodeficiency, AdV tends to cause severe and recurrent pulmonary infections, disseminated disease, and even death. 38

Globally, serotypes 1 to 5, 7, 21, and 41 are most commonly associated with human disease (►Table 1). Different serotypes display different tissue tropisms and clinical manifestations of infection. 2,26,31,33 Among children, the most common AdV serotypes associated with RTI are types 1 to 7 and an intertypic recombinant H11F14 designated as genotype 55. 31,220 In adults, serotypes most often implicated in FRI include: AdV-1 to 7, -21, and -14. 10,16-18,24,33,40,41,75,221,222 AdV-55 was implicated in outbreaks of FRI in China, 81 Singapore, 44 the Middle East, 223 United States, 21 and South America. 224 AdV-11 may cause UTIs or HC in children or transplant recipients. 33,38 Other serotypes associated with HC include: AdV-7, -33, -34, and -35. 33,225

AdV-8, -19, and -37 are frequent causative agents of KC. 31, 105, 226 Gastroenteritis is most frequently associated with infection by enteric AdV-40 and -41, 9,227 but has also been reported in association with AdV-12, -18, and -31, 9 and AdV-52 32 infection. AdV-5, -31, -34, -35, and -39 have been implicated in infections in immunocompromised patients 43,51,180,220,228 (particularly HSCT 2,43, 128, 229, 230 or SOT 142,231 recipients). Hepatitis has been reported associated with infection by serotypes 1 to 3, 5, and 7. 38,225

Different genome types within serotypes have been identified by restriction enzyme analysis, 39,40,232 multiplex PCR techniques targeting fiber genes or hexon genes 233 or sequencing of the fiber genes 29,234 and hexon genes. 29,31, 235 The widely used genome typing system was proposed and modified by Li et al. 12, 236 The prototype AdV strain is designated "p"; other genome types within the serotype are designated "a" through "k" based on their distinct BamHI digestion profiles. Genome types may be further distinguished by restriction pattern with additional selected enzymes (e.g., AdV-7p, AdV-7p1, etc.). 12,40, 80 This system has been used to correlate intraserotypic genetic variability with geographic distribution and pathogenic potential. 40

Rapidly advancing sequencing technologies at affordable costs have allowed relatively easy access to complete genomic sequence data for human AdV strains expanding the information on the genetic makeup of several viruses of medical importance and contributing to a better understanding of AdV evolution. 35, [237] [238] [239] [240] Novel genomes representing cases of intertypic recombination or viruses with truly novel hexon, penton base or fiber genes have been under consideration as candidate new types and designated with numbers consecutive to the original set Serotypes 1 to 7 account for > 80% of AdV infections in infants and children. 31, 247 The most common serotypes reported in the United States, 161 Canada, 5 the United Kingdom, 248 Taiwan, 11 and South Korea 31 are displayed in ►Table 1. Striking differences in distribution of serotypes have been noted in civilian and military populations 161 (►Table 1).

In South America, AdV-7 has been a predominant strain associated with RTI requiring hospitalization in many countries. 10, 224 In Brazil, AdV-7 was the predominant serotype for decades, but an outbreak of AdV-3 occurred in 2000. 10 In Asia, AdV-3 and -7 have been the predominant serotypes associated with RTI in children. 3,11-13, 249 Documented changes in relative prevalence of serotypes and genomic variants among geographic regions underscore the potential for new strains to emerge and replace existing strains. 10-12,40, 65, 244, 246, [250] [251] [252] For interested readers, we discussed the epidemiology and temporal changes in circulating genomic variants globally in greater detail in a review in 2011. 1

Given the large number of AdV serotypes, a discussion of each serotype is beyond the scope of this review. However, we will discuss a few of the commonly detected serotypes (e.g., AdV-1, -2, -3, -4, -7, and -21), additional serotypes associated with specific clinical syndromes (e.g., AdV-8, -37, -40, -41, and -55) and the recent emergence of AdV-14 in the United States.

Serotypes AdV-1 and -2 (both species C) are common causes of acute FRI worldwide, but appear to be less virulent than AdV-7 11,224,246 or -3. 88, 224 However, a nosocomial outbreak of severe pneumonia in immunocompetent hosts due to AdV-1 was recently described in France. 253 The prevalence of AdV-1 and -2 varies among different geographic regions and populations. In the United States (2004-2006) , AdV-1 and -2 accounted for 17.6 and 24.3% of AdV clinical respiratory isolates among civilians (children or adults), respectively, but only 0.4 and 0.4% among military recruits. 161 The prevalence of these serotypes at other sites is variable: that is, Toronto, Canada (2007-2008), AdV-1 (18%); AdV-2 (26%) 5 ; United Kingdom (1982) (1983) (1984) (1985) (1986) (1987) (1988) (1989) (1990) (1991) (1992) (1993) (1994) (1995) (1996) , AdV-1 (12.1%); AdV-2 (18.6%) 248 ; Buenos Aires (1984) (1985) (1986) (1987) (1988) ; AdV-1 (10%); AdV-2 (20%) 246 ; Seoul, Korea (1990-98); AdV-1 (9.2%); AdV-2 (11.2%). 88

Globally, AdV-3 is among the most common serotypes implicated in AdV infections in children and adults. 

Globally, AdV-7 was the third most common serotype reported to the World Health Organization from 1967 through 1976, following AdV-1 and -2 84 and remains one of the leading serotypes detected in association with disease globally. 31,40,258 AdV-7 infections manifest as FRI, pharyngoconjunctival fever, bronchitis, necrotizing bronchiolitis, or pneumonia. 40, 224, 259 AdV-7 appears to be more virulent than other serotypes. 11, 88, 224, 242, 249, [260] [261] [262] Fatal pneumonias may occur in immunocompetent children 6,224,250,263,264 and adults. 23, 265 Epidemic AdV-7 infections have been reported in the United States, 6,264,266 Canada, 263 Latin America, 224, 267 Australia, 268 Israel, 243 Korea, 75,88 Japan, 242, 259 China, 12,262 the Philippines, 261 and globally. 161, 243 Outbreaks typically occur in closed settings (e.g., military barracks 18,39 ; chronic care facilities 80 ; hospitals 6, 78, 269, 270 ). In the late 1960s, AdV-7 and -4 accounted for most cases of FRI among military recruits in the United States. 80, 256 Following routine vaccination of military recruits in the United States beginning in 1971, 174, 257 no epidemics of FRI were attributed to AdV-7 or -4 from 1984 through 1994. 80 However, in 1997 (after the vaccine supply was depleted), an epidemic (> 500 cases) of AdV FRI in a U. S. Navy training site was attributed to serotypes AdV-7 (70%) and AdV-3 (24%), respectively. 19 Since 2007, AdV-7 has largely disappeared as a cause of FRI in U. S. military settings (possibly replaced by AdV-14). 33 The prevalence of AdV-7 varies according to geographic regions and over time, and depends on strain genome type, herd immunity in the region, and epidemiological settings. 6, 80, 161, 264 In the United States from 2004 to 2006, AdV-7 accounted for only 5/581 (0.9%) of clinical AdV respiratory isolates in military facilities and 48/1,653 (2.9%) isolates in civilian settings. 161 By contrast, AdV-7 was a prominent cause of FRI in South America in the 1990s 224,267 and Asia. 12,13,31,88,242,258 AdV-7 has been recently reported in association with severe disease in several provinces of China. 262,265,271 AdV-7 was the leading cause of death due to AdV pneumonia in South America in the 1980s and 1990s. 224, 267 In a study of 165 AdV RTIs in children in Argentina and Uruguay, AdV-7 accounted for 62.2% of isolates and was responsible for 17 of 18 fatalities. 224 The prevalence of AdV-7 as a cause of AdV FRI is Asia is variable, ranging from < 1 242 to > 60%. 75 In Seoul, Korea from 1990 to 1998, AdV-7 accounted for 41% of RTI (followed by AdV-3 [15%] and AdV-2 [15%]). 88 From 1991 to 2007 in Seoul, AdV-7 accounted for 23.3% of pediatric respiratory AdV isolates, second only to AdV-3 (37.0%) (►Table 1). 31 In a survey of 200 military recruits in South Korea in 2006, 122 recruits (61%) developed AdV infections; all 122 isolates were AdV-7. 75 In Taiwan, AdV-7 emerged as the predominant serotype (45%) in 1999 to 2000, but fell drastically to 1% in 2001 (replaced by AdV-4). 11 In Beijing, China, AdV-7 and -3 were the most common serotypes causing pneumonia from 1958 to 1990. 12 At least 27 genome types of AdV-7 have been identified by restriction enzyme fragment analysis 80 ; shifts or replacement of predominant genome types may occur. 40, 161, 243, 244 In some cases, new genomic variants exhibit an apparent heightened virulence or transmissibility compared with earlier strains. For interested readers, the epidemiology, global shifts, and changing genotypes of AdV-7 were discussed in detail in our previous review. 1

AdV-8 accounts for < 1% of AdV infections, 5,31,88,161 but is a common cause of EKC. 88, 105, 107, 111, 116, 272, 273 In four studies in Asia and the Middle East, AdV-8 accounted for 64 to 79% of EKC due to AdV. 105, 106, 109, 117 In a neonatal intensive care unit in Turkey, cases of conjunctivitis due to AdV-8 were linked to a contaminated eyelid speculum. 272

AdV-11 is relatively uncommon, but may cause hemorrhagic conjunctivitis 45-47, 81 different geographic locations confirmed that all isolates were identical. 33 These isolates represented a new genomic type designated AdV-14p1 (formerly known as 14a). 33 The complete genetic sequence of AdV-14p1 indicates a close relationship to AdV-11a, suggesting recombination between AdV-14 and -11 strains. 41 AdV-14p1 was implicated in outbreaks of severe pneumonias in the United States 33 and Ireland. 279 AdV-14p1 has an increased potential for high attack rates and rates of transmission, owing to the lack of herd immunity. 41

AdV-21 was associated with epidemics of FRIs in military recruits in the Netherlands in the 1960s, 280 but only sporadic cases were reported over the next two decades. 281 In 1984 and 1985, outbreaks of AdV-21 infections in children in the Netherlands and Germany were published. 281 AdV-21 has been associated with pharyngitis and conjunctivitis 282 and FRI 228 but is uncommon. 31 In the United States from 2004 to 2006, AdV-21 accounted for 2.0 and 2.4% of AdV RTI in civilians and military recruits, respectively. 161 In Toronto, Canada (2007) (2008) , AdV-21 accounted for 5.5% of clinical respiratory AdV isolates. By contrast, AdV-21 was never isolated in 741 pediatric respiratory isolates from Korea from 1991 to 2007. 31 Interestingly, Adv-21 may be less transmissible than other AdV serotypes. 283 However, a highly virulent strain of AdV-21 was associated with severe pneumonia cases in Germany 34 and neurological 284 and cardiac 285 manifestations in Malaysia. Similar strains were found to circulate in the United States over the last 3 decades 39 with no apparent association with severe disease among the infected young adults.

AdV-31 may cause gastroenteritis in healthy children, and has been associated with severe (sometimes) fatal infections in HSCT recipients. 28,157,286-288 Nosocomial transmission (seven cases) in a pediatric SCT unit was described. 288

AdV-37 accounts for < 1% of AdV infections, 5,31,88,161 but may cause EKC. 88, 103, [105] [106] [107] [108] [109] 

AdV of species F (serotypes 40 and 41) typically cause gastroenteritis and diarrheal illness in children. 50-61 Fatalities may occur as a result of dehydration in infants. 50,51 In immunocompromised hosts, fatal dissemination may occur. 73, 289 Epidemics have been cited in schools 56 and hospitals. 73 Endogenous reactivation originating from AdV persistent in mucosal lymphoid cells may occur. 70 Nosocomial transmission may occur due to high AdV levels in feces. 73 Shedding of these viruses may be prolonged in immunosuppressed patients. 73

Infections due to AdV-55 of species B are rare, but this virus has been implicated in outbreaks of severe pneumonia and acute respiratory distress syndrome in China since 2006. 89, 91, 290, 291 This type is an intertypic recombinant with an AdV-11-like hexon gene and an AdV-14-like fiber gene. 240 Several reports describing cases of respiratory infection by this unique AdV under other designations (AdV-11, 14-11 or genome type 11a, depending on the typing approach) can be found in the literature. 44,292-294

AdV can be detected in affected sites (e.g., nasopharyngeal aspirates, swabs, washings, bronchoalveolar lavage, urine, stool, blood) by direct or indirect immunofluorescence, conventional or shell vial cultures, or PCR. 31 Viral cultures by conventional techniques are the gold standard, but could be insensitive for certain samples (e.g., blood) and may take up to 21 days to develop the cytopathic effect. 2,31 Biopsy of involved tissues may reveal AdV nuclear inclusions 2 ; immunohistochemical stains may identify the AdV hexon antigen in tissue. 146 PCR of AdV DNA in plasma, urine, or other clinical specimens is currently the most frequently used approach to establish the diagnosis, 2,194 and is highly sensitive for disseminated disease. 295, 296 Quantification of the viral load using real-time PCR is a useful marker to assess response to therapy. 189, 295 Among transplant recipients, serial PCR assays of blood and stool weekly may detect AdV disease before the onset of symptoms, and facilitate early "preemptive" therapy. 26, 153, 188, 196 In one study of 138 pediatric allogeneic SCT recipients, AdV was detected in stool samples at median of 11 days before AdV viremia. 297 The role of routine surveillance is controversial although it has been increasingly used in high-risk patients (particularly HSCT recipients 2 ). Quantitative viral loads may not correlate with clinical presentation or disease severity. 43 Molecular typing is not routinely performed on AdV-positive clinical specimens in clinical diagnostic laboratories but has been the focus of several recently reported studies investigating the epidemiology of AdV-associated disease. Serological tests may be useful in epidemiological investigations, but are of limited practical value in individual patients. 38 Determination of serotype by seroneutralization with reference sera is laborious and time-consuming and currently only performed at a few reference public health laboratories around the world. PCR-based techniques targeting the fiber genes 233 or hypervariable regions of the hexon 235,298 and/or sequencing of hexon genes allow definitive identification of the type/species. 29,31 Molecular typing by PCR amplification and sequencing of both hexon and fiber genes has proved to be extremely valuable for the identification of intertypic recombinants. 299, 300 Therapy No antiviral drug has been approved to treat AdV. 38 Prospective randomized controlled trials are lacking. 14 CDV, a cytosine nucleotide analogue that inhibits DNA polymerase, has the greatest in vitro activity against AdV among currently available antiviral agents [301] [302] [303] and is the preferred therapeutic agent. 2 CDV is available only intravenously. 2 Regimens (dosing, frequency, and duration) are variable. Standard doses include 5 mg/kg every 1 to 2 weeks 38,188 or 1 mg/kg twice weekly. 38,158,188 Duration of therapy is variable (weeks to months) and depends upon clinical response and persistence or eradication of AdV. 158, 188 CDV is generally well tolerated, 153,188,304 but adverse effects include nephrotoxicity, myelosuppression, and uveitis. 2,38 Hydration and probenecid may minimize nephrotoxicity. 2, 143, 153, 201, 209 Careful monitoring of renal function (serum creatinine, proteinuria) is critical. Hexadecyloxy propyl-CDV or brincidofovir (CMX001), an orally active lipophilic form of CDV, has potent activity against AdV in vitro 305 and in animal models, 306 Adenovirus: Treatment and Prevention Lynch, Kajon 593 series. 308, 309 Compared with CDV, CMX001 appears be less nephrotoxic. 310 An open-label phase 3 trial to assess safety and efficacy of CMX001 for treating AdV infections in immunosuppressed patients is in progress (Clinical Trials.gov identifier: NCT02087306).

Numerous nonrandomized studies in HSCT and SOT recipients documented favorable responses to CDV. 25, 26, 28, 153, 158, 188, 192, 209, 231, [311] [312] [313] [314] [315] [316] [317] Three studies of allogeneic HSCT recipients with AdV infections cited improvement with CDV in 20/29 (69%), 311 10/14 (77%), 318 and 8/10 (80%) patients, respectively. 192 However, given the lack of controlled trials, indications for, and efficacy of CDV remain controversial. 27 Interpretation of these studies is confounded by heterogeneous patient populations, differing extent and sites of disease, and degree of immunosuppression or immune reconstitution. 38 Intravenous immunoglobulin has been used (together with CDV), but data are insufficient to assess efficacy. 25, 316 Immune reconstitution plays a critical role in controlling AdV infection. 38 Increases in lymphocyte counts or CD 4 counts were associated with clearance of AdV infection 319,320 and improved survival. 320, 321 Serotypic-specific neutralizing antibodies correlate with clearance of AdV. 38,320 Reduction of immunosuppression, 146, 153 immune reconstitution of HSCT recipients, 25,38 or donor leukocyte infusions 28 may have adjunctive roles to treat serious or recalcitrant AdV infections. T cells are important to eradicate AdV. Adoptive transfer of AdV antigen-specific T cells may reconstitute immunity against AdV. 322, 323 In a recent clinical trial of HSCT recipients with AdV disease refractory to therapy, ex vivo adoptive T-cell transfer with predominantly TH-1 phenotype was highly effective in clearing viremia and markedly reduced mortality. 324 Importantly, not all patients with AdV infections or viremia require treatment. 2,14,43,201 High-mortality rates in retrospective studies in part reflect that virtually all patients had symptomatic AdV infections. Prospective studies in SOT 196 or HSCT 43 recipients using plasma PCR at regular intervals noted that up to 58% were asymptomatic at the time of viremia, and spontaneous resolution without sequela was common. In a cohort of SOT recipients with AdV viremia, all 19 recovered spontaneously without sequela. 196 Similarly, in a cohort of 26 pediatric HSCT recipients, 11 (42%) developed AdV viremia that cleared without therapy in 7 (64%). 43 Two children died as a result of AdV infections. Antiviral treatment should be considered for the following indications: disseminated (! 2 sites) disease; pneumonia; high viral loads in blood; virulence or tropism of the viral strain; persistent severe lymphopenia or immune deficits. Further, "preemptive" therapy may have a role in viremic but asymptomatic organ transplant recipients at high risk for dissemination. Prospective, randomized trials are needed to elucidate indications for therapy in both symptomatic and asymptomatic patients with AdV infections.

Oral vaccines against AdV types 4 and 7 developed for the U. S. military in 1971 20 were depleted by 1999. 20 Produced by a new manufacturer, and after a new round of clinical trials 179 the same live nonattenuated vaccine formulation for AdV-4 and -7 was successfully reintroduced for military use in the United States in October 2011. 39 Importantly, antibodies to AdV-4 and -7 may cross protect against other serotypes (e.g., AdV-3 and -14). 86 

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Prevalence of enteric adenoviruses among children with diarrhea in four Brazilian cities

Healthcare-associated viral gastroenteritis among children in a large pediatric hospital

Structured surveillance of infantile gastroenteritis in East Anglia, UK: incidence of infection with common viral gastroenteric pathogens

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Severe diffuse adenovirus 7a pneumonia in a child with combined immunodeficiency: possible therapeutic effect of human immune serum globulin containing specific neutralizing antibody

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Nosocomial adenovirus infection: molecular epidemiology of an outbreak

Health care transmission of a newly emergent adenovirus serotype in health care personnel at a military hospital in Texas

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Prevalence and quantitation of species C adenovirus DNA in human mucosal lymphocytes

Hematuria due to adenoviral infection in bone marrow transplant recipients

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An adenovirus type F41 outbreak in a pediatric bone marrow transplant unit: analysis of clinical impact and preventive strategies

Epidemic spread of adenovirus type 4-associated acute respiratory disease between U.S. Army installations

High isolation rate of adenovirus serotype 7 from South Korean military recruits with mild acute respiratory disease

Retrospective analysis of demographic and clinical factors associated with etiology of febrile respiratory illness among US military basic trainees

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An epidemic of adenovirus 7a infection in a neonatal nursery: course, morbidity, and management

Multiple cases of life-threatening adenovirus pneumonia in a mental health care center

Outbreak of adenovirus genome type 7d2 infection in a pediatric chronic-care facility and tertiary-care hospital

Outbreak of acute respiratory disease in China caused by B2 species of adenovirus type 11

Viruses and disease. 3. An outbreak of adenovirus type 7A in a children's home

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Epidemiology of human adenovirus and molecular characterization of human adenovirus 55 in China

Severe adenovirus pneumonia in immunocompetent adults: a case report and review of the literature

Emergence of community-acquired adenovirus type 55 as a cause of community-onset pneumonia

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Textbook of Pediatric Infectious Diseases

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Molecular epidemiology of adenoviral keratoconjunctivitis in Saudi Arabia

A twenty-one year surveillance of adenoviral conjunctivitis in Sapporo

The change of etiological agents and clinical signs of epidemic viral conjunctivitis over an 18-year period in southern Taiwan

Isolation and identification of adenovirus from conjunctival scrapings over a two-year period

Molecular epidemiology of adenoviral conjunctivitis in Hanoi, Vietnam

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Human adenovirus type 8 epidemic keratoconjunctivitis with large corneal epithelial fulllayer detachment: an endemic outbreak with uncommon manifestations

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Detection and prevalence of adenoviral conjunctivitis among hospital employees using real-time polymerase chain reaction as an infection prevention tool

Recombination analysis of intermediate human adenovirus type 53 in Japan by complete genome sequence

Outbreak of epidemic keratoconjunctivitis caused by human adenovirus type 56

Isolation of an intertypic recombinant human adenovirus (candidate type 56) from the pharyngeal swab of a patient with pharyngoconjunctival fever

Evidence of molecular evolution driven by recombination events influencing tropism in a novel human adenovirus that causes epidemic keratoconjunctivitis

Epidemiological and virological features of epidemic keratoconjunctivitis due to new human adenovirus type 54 in Japan

Molecular epidemiology of human adenoviruses d associated with epidemic keratoconjunctivitis in

Prevalence and molecular characterisation of human adenovirus in diarrhoeic children in Tanzania; a case control study

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Adenovirus colitis in the acquired immunodeficiency syndrome

Fulminant adenovirus hepatitis following bone marrow transplantation. A case report and brief review of the literature

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Acute pancreatitis after severe opthalmic adenoviral infection

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Adenovirus is a key pathogen in hemorrhagic cystitis associated with bone marrow transplantation

Adenoviral infection in hematopoietic stem cell transplantation: early diagnosis with quantitative detection of the viral genome in serum and urine

Successful ribavirin therapy for severe adenovirus hemorrhagic cystitis after allogeneic marrow transplant from close HLA donors rather than distant donors

Adenovirus: Treatment and Prevention Lynch, Kajon 597 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited

Intravesical instillation of cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient

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Hemorrhagic cystitis secondary to adenovirus or herpes simplex virus infection following renal transplantation: four case reports

Acute hemorrhagic cystitis caused by adenovirus after kidney transplantation

Adenovirus-associated hemorrhagic cystitis in a pediatric renal transplant recipient

Acute hemorrhagic cystitis caused by adenovirus following renal transplantation: review of the literature

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Acute renal failure due to adenovirus-associated obstructive uropathy and necrotizing tubulointerstitial nephritis in a bone marrow transplant recipient

Adenovirus urethritis and concurrent conjunctivitis: a case series and review of the literature

Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention

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Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation

Adenovirus meningoencephalitis

Extrapulmonary manifestations of adenovirus type 7 pneumonia simulating Reye syndrome and the possible role of an adenovirus toxin

Genotype prevalence and risk factors for severe clinical adenovirus infection, United States

Adenovirus infection associated with central nervous system dysfunction in children

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Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults

First report on fatal myocarditis associated with adenovirus infection in Cuba

Involvement of adenovirus in clinical mononucleosis-like syndromes in young children

Detection of microorganisms in the tracheal aspirates of preterm infants by polymerase chain reaction: association of adenovirus infection with bronchopulmonary dysplasia

Intestinal intussusception associated with adenovirus infection in Mexican children

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Large, persistent epidemic of adenovirus type 4-associated acute respiratory disease in U.S. army trainees

orphaned vaccines precipitates military respiratory disease epidemics

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AST Infectious Diseases Community of Practice

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Association of viral genome with graft loss in children after cardiac transplantation

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Analysis of 15 different genome types of adenovirus type 7 isolated on five continents

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Computational analysis and identification of an emergent human adenovirus pathogen implicated in a respiratory fatality

Genome sequence of human adenovirus type 55, a re-emergent acute respiratory disease pathogen in China

Using the whole-genome sequence to characterize and name human adenoviruses

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Molecular epidemiology of adenoviruses: global distribution of adenovirus 7 genome types

PCR analysis of egyptian respiratory adenovirus isolates, including identification of species, serotypes, and coinfections

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The epidemiology of adenovirus infections in Greater Manchester, UK 1982-96

Genome type analysis of adenovirus types 3 and 7 isolated during successive outbreaks of lower respiratory tract infections in children

Adenovirus type 7h respiratory infections: a report of 29 cases of acute lower respiratory disease

Comparison of 17 genome types of adenovirus type 3 identified among strains recovered from six continents

Molecular epidemiology and restriction site mapping of adenovirus type 3 genome types

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Immunization with live types 7 and 4 adenovirus vaccines. II. Antibody response Seminars in Respiratory and Critical Care Medicine

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Molecular and epidemiological analyses of human adenovirus type 7 strains isolated from the 1995 nationwide outbreak in Japan

Pneumonia and massive pleural effusion associated with adenovirus type 7

Impact of human adenovirus serotype 7 in hospitalized children with severe fatal pneumonia in the Philippines

Re-emergent human adenovirus genome type 7d caused an acute respiratory disease outbreak in Southern China after a twenty-one year absence

An outbreak of adenovirus type 7 infection in children in Montreal

Epidemic outbreaks of adenovirus 7 with special reference to the pathogenicity of adenovirus genome type 7b

Human adenovirus type 7 infection associated with severe and fatal acute lower respiratory illness and nosocomial transmission

Adenovirus type 7 outbreak in a pediatric chronic-care facility-Pennsylvania

Genome analysis of South American adenovirus strains of serotype 7 collected over a 7-year period

Adenovirus type 7 infections in children in New South Wales, Australia

Adenovirus type 7b in a children's hospital

Outbreak of severe infection due to adenovirus type 7 in a paediatric ward in Japan

Adenovirus serotype 7 associated with a severe lower respiratory tract disease outbreak in infants in Shaanxi Province

Outbreak of adenovirus serotype 8 conjunctivitis in preterm infants in a neonatal intensive care unit

Human adenovirus type 8: the major agent of epidemic keratoconjunctivitis (EKC)

Abrupt emergence of diverse species B adenoviruses at US military recruit training centers

Adenovirus infection of a renal allograft

Pharyngo-conjunctival fever; school outbreaks in England during the summer of 1955 associated with adenovirus types 3, 7, and 14

Outbreak of severe respiratory disease associated with emergent human adenovirus serotype 14 at a US air force training facility in 2007

A community-based outbreak of severe respiratory illness caused by human adenovirus serotype 14

First reported cases of human adenovirus serotype 14p1 infection

Association of type 21 adenovirus with acute respiratory illness in military recruits

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Hospital-associated epidemic of pharyngitis and conjunctivitis caused by adenovirus (21/H21 þ 35)

Adenovirus 21 infection in an isolated antarctic station: transmission of the virus and susceptibility of the population

Adenovirus type 21-associated acute flaccid paralysis during an outbreak of hand-foot-andmouth disease in Sarawak, Malaysia

Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-associated hand, foot, and mouth disease in

Monitoring of adenovirus infection in pediatric transplant recipients by quantitative PCR: report of six cases and review of the literature

Improved outcome for children with disseminated adenoviral infection following allogeneic stem cell transplantation

Description of an adenovirus A31 outbreak in a paediatric haematology unit

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An outbreak of acute respiratory disease in China caused by human adenovirus type B55 in a physical training facility

Emergent severe acute respiratory distress syndrome caused by adenovirus type 55 in immunocompetent adults in 2013: a prospective observational study

Molecular and serological characterization of species B2 adenovirus strains isolated from children hospitalized with acute respiratory disease in

Antigenic characterization of intermediate adenovirus 14-11 strains associated with upper respiratory illness in a military camp

Genetic relationship between thirteen genome types of adenovirus 11, 34, and 35 with different tropisms

Quantitative real-time polymerase chain reaction for detection of adenovirus after T Seminars in Respiratory

cell-replete hematopoietic cell transplantation: viral load as a marker for invasive disease

Effect of ribavirin on the plasma viral DNA load in patients with disseminating adenovirus infection

Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation

Comprehensive detection and serotyping of human adenoviruses by PCR and sequencing

Molecular characterization of an adenovirus 3-16 intertypic recombinant isolated in Argentina from an infant hospitalized with acute respiratory infection

Identification of a novel intertypic recombinant species D human adenovirus in a pediatric stem cell transplant recipient

Antiadenovirus activities of several classes of nucleoside and nucleotide analogues

In vitro susceptibility of adenovirus to antiviral drugs is species-dependent

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Safety and tolerability of cidofovir in high-risk pediatric patients

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Eradication of disseminated adenovirus infection in a pediatric hematopoietic stem cell transplantation recipient using the novel antiviral agent CMX001

CMX001-201 Clinical Study Group. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation

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Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children

Patient, virus, and treatment-related risk factors in pediatric adenovirus infection after stem cell transplantation: results of a routine monitoring program

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Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients

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Immune reconstitution and clearance of human adenovirus viremia in pediatric stem-cell recipients

Adenovirus infection in children after allogeneic stem cell transplantation: diagnosis, treatment and immunity

Activity of broadspectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT

Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant

Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT

Emergence of adenovirus type 14 in US military recruits-a new challenge