Introduction

Adenovirus infections have an incidence of over 20% in paediatric bone marrow transplanted recipients and result in significant morbidity and mortality.¹ Most haematopoietic stem cell transplanted (hSCT) children with adenovirus infection develop related local symptoms and around 20% of them will further develop a severe disseminated disease, which could eventually lead to death.¹ Adenoviruses from C and B species represent more than 90% of reported cases of adenoviruses infections occurring after hSCT in children, and the vast majority of fatal cases of disseminated adenovirus infection described in the literature are due to adenoviruses of C species.^{2, 3, 4, 5, 6} In recent years, cases of adenovirus A31 infection have also been reported as another cause of adenovirus infection in hSCT children. However, the origin and the particularities of adenovirus infection with A31 strains in this context have not been specifically studied.^{4, 5, 7}

The paediatric haematology unit of Necker hospital specializes in hematopoietic stem cell transplantation for children with underlying congenital immunodeficiency syndrome, haematological disease or metabolic disorders. Bone marrow protocol often includes T-cell depletion for recipients of hSCT from human lymphocyte antigen partially identical donors, and therefore a high number of those hSCT children are at a high risk for the development of adenovirus infection owing to slow immune reconstitution. Recent data suggested that a positive adenovirus DNA detection in blood plasma or serum has a good specific predictive value for the occurrence of adenovirus disseminated disease in allogeneic stem cell paediatric recipients.^{8, 9, 10} Moreover, we demonstrated that adenovirus quantitative real-time PCR in blood plasma was effective for accurate monitoring of adenovirus-disseminated infection treatment.¹¹ Based on these data, surveillance for adenovirus viraemia was implemented for hSCT children from April 2002.

Between April 2002 and April 2005, 58 hSCT children were screened for adenovirus viraemia by PCR. Within the first 11 months (April 2002 to February 2003), after implementation of our screening programme, three cases of adenovirus infection with positive viraemia were diagnosed among the children hospitalized in Necker hospital bone marrow transplant unit. Then, between February 2003 and August 2003, eight cases of adenovirus infection were reported in the unit: one child was infected with an adenovirus from C species but the other seven were infected with an adenovirus from A species. This alarming high rate of adenovirus A detection suggested the occurrence of an epidemic. Genotyping analysis showed that this epidemic was due to an adenovirus type 31 strain. Nosocomial spread of adenovirus among children hospitalized in a bone marrow unit has not been reported in the literature. However, the timing and location of cases as well as the genotyping results suggested a nosocomial origin to this adenovirus A31 strain epidemic that occurred in Necker hospital bone marrow transplant unit.

Materials and methods

Settings

There are three wards (A, B and C) on the same floor in the Paediatric Haematology Unit of Necker hospital. The outbreak developed in two wards (A and B). The nursing staff is dedicated to one ward during daytime. But the cleaning staff and the on-call staff are not dedicated to one ward. Moreover, all children's parents are sharing the same restroom in which a fridge is available to store food and beverages for them. Another fridge is available in the Unit kitchen to store food and beverages for hospitalized children.

Routine surveillance of adenovirus infection

From April 2002 onwards, blood samples of all hSCT children were screened for the presence of adenovirus species A, B or C, at least once before transplantation and then every 2 weeks after transplantation until immune recovery (CD3 count>1000/mm³).

Every 2 weeks, stool and NPA specimens were sent routinely to the laboratory in order to screen for adenovirus and other enteric or respiratory viruses. Stool specimens were screened for adenovirus with a rapid test and NPA were screened with rapid immunofluorescence staining and culture. In our routine surveillance, PCRs in stool were not carried out systematically but only in children with symptoms. However, during the epidemic (and mostly between July and October 2003), PCR tests in stools were performed every 2 weeks in all patients to screen for new cases. Stool cultures were made when the PCR was positive in order to obtain the viral strain.

Cidofovir treatment was initiated at the time of the first positive adenovirus detection in blood if the viral load was high and/or if adenovirus-related symptoms were associated or later if adenoviral blood plasma load significantly increased in further samples. Standard cidofovir regimen dosage was used with 5 mg/kg once a week for 2 weeks followed by 5 mg/kg intravenously every 2 weeks. Regimen using 3 mg/kg was used when renal function could not allow usage of the usual dose.

Patients

From April 2002 to April 2005, 58 hSCT children were screened for adenovirus viraemia by PCR on ethylenediaminetetraacetic acid blood samples specimen. The median age of these children at engraftment was 12 months (range: 3–180); underlying disease was a congenital immunodeficiency for 32 children, a haematologic disease for four children and a metabolic disorder for 22 children. A T-cell-depleted graft was given to 39 children and 44 children received antithymocyte globulin in their conditioning regimen. Donor type was matched family donor (MFD) in 20 cases, mismatched family donor (MMFD) in 23 cases, matched unrelated donor (MUD) in 12 cases and mismatched unrelated donor (MMUD) in three cases.

Methods

Adenovirus infection screening: direct detection, culture, real-time PCR

Stool samples were screened for the presence of adenovirus with a rapid test based on agglutination of dry spot latex: DIARLEX Rota-Adeno (Orion Diagnostica, Levallois Perret, France). Naso-pharyngeal aspirate (NPA) were screened for adenovirus with rapid immunofluorescence staining using an adenovirus monoclonal antibody (IMAGEN™ Adenovirus, DAKO, Trappe, France). Adenoviruses were cultured from NPA and stool samples as already described.¹¹ The adenovirus serotypes were identified by neutralization tests with specific rabbit antiserum obtained from the American Type Culture Collection (Rockville, MD, USA) until February 2003; later serotyping was no more realized because of shortage of antibodies.

Three in-house adenovirus real-time PCR assays were used in parallel: the first one allowed detection, quantification and species typing of adenovirus from species A, the second one of adenovirus from species B and third one of adenovirus from species C, as already described.¹¹

Genotyping of adenovirus A strains

Total DNA was extracted from 200 l of adenovirus A culture supernatant by the QIAamp DNA blood mini kit (Qiagen, Courtaboeuf, France). The extracted DNA was amplified using the Ampli Taq DNA Polymerase kit (Applied Biosystems, Courtaboeuf, France) with 2 U of Taq polymerase and 10 M of each primer. Published sequences of the hexon protein gene of adenovirus A31 (accession number Y17253) and of adenovirus A12 (accession number NC001460) were used to design primers for amplification of the full length of the hexon protein gene of adenovirus A species.¹² Three sets of primers were used to amplify 2732 nucleotides of the hexon gene protein. The 1367 nucleotides of the 5' end of the gene were first amplified with forward primer 5'-GCCTCGGAGTACCTGAGT-3' and reverse primer 5'-TTCATGTACTCGTAGGTGTT-3' and then a nested PCR was performed with forward primer 5'-AGTCCCGGTCTGGTGCAA-3' and reverse primer 5'TTCATGTACTCGTAGGTGTT-3'. The second set of primers allowed the amplification of further 597 nucleotides with forward primer 5'-AACACCTACGAGTACATGAA-3' and reverse primer 5'-AGGGAATGGTTCCAGAGTA-3' and then a nested PCR was performed with forward primer 5'-AACACCTACGAGTACATGAA-3' and reverse primer 5'-ACAAAGTAGGGGTCAAACC-3'. The 768 nucleotides of the 3' end of the gene were first amplified with forward primer 5'-GGTTTGACCCCTACTTTGT-3' and reverse primer 5'-TGCGCAGATAGACCGCTT-3' and then a nested PCR was performed with forward primer 5'-TACTCTGGAACCATTCCCT-3' and reverse primer 5'-TGCGCAGATAGACCGCTT-3'. Amplifications were carried out with a Perkin-Elmer Gene Amp PCR system 2400 (Perkin-Elmer). The conditions for amplification with all primer sets were 94°C for 2 min, followed by 35 cycles at 94°C for 1 min, 55°C for 45 s and 72°C for 1 min. The 35 cycles were followed by a single extension cycle at 72°C for 5 min. PCR products were purified using a QIAquick^® PCR Purification kit (Qiagen^®, Courtaboeuf, France).

DNA sequencing

The purified PCR products were sequenced using a fluorescent dideoxyterminator method (Big Dye Terminator Sequencing Kit, Applied Biosystems, Courtaboeuf, France). Sequencing products were analysed on an ABI 377 automated DNA sequencer (Applied Biosystems, Courtaboeuf, France). Sequences obtained were aligned with Sequence Navigator^® software and compared to six complete or partial sequences of the hexon protein gene of adenovirus A species published in GenBank (accession numbers X73487, NC001460, Y17253, AF161576, AY220987, AB106221).^{12, 13}

The sequences obtained were aligned with the Clustal W 1.6^® software.¹⁴ Pairwise evolutionary distances were estimated using Kimura's two parameters method, and the trees were then constructed by a neighbour joining method (neighbour program implemented in the Phylip^® package, version 3.6, University of Washington, Seattle, USA).¹⁵ The reliability of each tree topology was estimated from 100 bootstrap replicates. Trees were also inferred by using the maximum likelihood model.

Results

Description of the adenovirus outbreak in the paediatric haematology unit (Table 1)

Between April 2002 and April 2005, 15 out of 58 (26%) hSCT children developed a positive adenovirus viraemia. Between April 2002 and February 2003, three children had positive adenovirus PCR tests in blood: the first child had AdV C-positive PCR tests and was infected with an adenovirus serotype C6 in April 2002; the second child presented AdV A-positive PCR tests and was infected with an adenovirus serotype A12 in August 2002; and the third one had AdV C-positive PCR tests and was infected with an adenovirus serotype C2 in October 2002. Then, the number of adenovirus infections dramatically increased, with eight cases reported between February 2003 and August 2003. Of these eight infected children, seven had positive AdV A PCR tests and were therefore infected with an adenovirus from species A and one was infected with an adenovirus from species C. Serotyping was carried out only on the first strain isolated in February 2003, which was found to be A31; serotyping of the other strains was not carried out because we ran short of antibodies.

Table 1 - Epidemic cases of adenovirus A31 infection during spring/summer 2003.

Full table

The first patient infected with adenovirus A (patient 1) was hospitalized in ward A from February to June 2003, patients 2–4 were also hospitalized in ward A during winter and spring 2003. After June 2003, patient 1 was transferred to ward B where patients 5–7 were also hospitalized at the same period (Table 1). Because of the timing and location of the cases, a nosocomial transmission was suspected and strict preventive control was established from August 2003. Case 1 (patient 1) was the suspected index case, the other six infected children were contaminated either in the pretransplantation period or in the late transplantation period; no children were contaminated after admission in laminar flux rooms or sterile isolators, all these six children had been hospitalized for more than a month before the onset of infection. No epidemic cases happened in ward C; the index case and none of the other infected children were hospitalized in this ward at the time they shed the virus in their faeces. Standard infection control measures (septic isolation, hand-washing recommendations, wearing of gloves and gowns) were reinforced in the two wards with information and precise guidelines given to all parents and to all members of staff. Every day cleaning of the floor and the surfaces of infected children's rooms was carried out with Cidalkan^® (Alkapharm, Marly le Roi, France), an antiseptic that has shown strong antiadenovirus activity in vitro, and special measures were added such as disinfection of door knobs with Cidalkan^® three times a day. Moreover, strict recommendations were given to parents of infected children not to store any food or beverage in the Unit fridge. These measures were effective in controlling the outbreak.

No new adenovirus infection was diagnosed until February 2004. Then, four other children were infected with adenovirus C, respectively, in April 2004, July 2004, November 2004 and February 2005.

Hexon protein gene genotyping of the adenovirus species A strains (Figure 1)

The hexon protein genes of 10 adenovirus A strains were amplified and sequenced: one A strain isolated in August 2002 from a child hospitalized in the Gastro-Enterology unit of the hospital (A31-2002), the seven A strains of the epidemic (1–7) isolated from February 2003 to August 2003, one A strain isolated in February 2004 from a child hospitalized in the General Paediatric Unit of the hospital (A31-2004) and one A strain isolated in 2002 (A31-2002bis) in an hSCT child hospitalized in another hospital.

Figure 1.

Phylogenetic tree, based on the neighbour-joining method, of sequence alignment of the hexon gene sequences obtained from the seven epidemic isolates (1–7), the Ad31 strains recovered from other haematopoietic stem cell transplanted (HSCT) patients (A31-2002, A31-2004, A31-2002bis) and adenovirus strain sequences published in the literature (Ad12, X73487, NC0014, BK0004, Ad31, Y17253). Only boostrap values >70 are reported.

Full figure and legend (14K)

We obtained sequences data on the two strands for 2654 nucleotides of the hexon gene. Phylogenetic analysis showed that all 10 A strains analysed belonged to genotype 31. There were 12% nucleotides differences between the hexon gene of the Ad31 strains and of the Ad12 strains published in the literature (accession numbers NC0014, BK0004, X73487) (boostrap value=100).

The nucleotides homology was 100% among the seven isolates of the epidemic, confirming that it was only one strain that was responsible for the epidemic. Alternatively, this epidemic strain displayed 0.26% nucleotides difference with the A31-2002 strain, 0.11% with the A31-2002bis strain and 0.3% with the A31-2004 strain. The epidemic strain also displayed substantial nucleotides differences with other published adenovirus A species: 0.4, 0.3 and 1.8% differences with the three strains described in Germany in 1999 and 2003 (accession numbers AF161576, AY 220987, Y17253) and 1.3% with a strain recovered in Vietnam in 2003 (accession number AB106221).

Clinical features of the seven HSCT children with positive A31 adenovirus viraemia (Table 2)

All seven patients had adenovirus detected in their stool by PCR and culture and in their NPA by PCR. The median peak blood plasma viral load for all seven adenovirus A31-infected children was 170 000 (range: 1500–2 500 000) (5.2 (range: 3.2–6.4) log₁₀) copies/ml and the median duration of positive PCR detection in blood was 36 (range: 15–168) days.

Table 2 - Clinical features of the seven HSCT children with A31 adenovirus viraemia.

Full table

Two children had another concomitant viral infection: patient 2 was coinfected with BK virus, patient 7 was coinfected with cytomegalovirus. Three children (2, 4, 7) had a concomitant graft-versus-host disease (GvHD).

The median CD3 count/mm³ of the children infected by Ad31 strain at the time of the last positive adenovirus viraemia was 91 (range: 50–693). All seven A31-infected children received cidofovir; the median number of cidofovir injections was three (range: 2–16). None of the seven patients infected with Ad31 adenovirus died of adenoviral infection: six patients are alive, patient 7 died 1 year later from high-grade GvHD.

Discussion

Adenovirus infection in paediatric bone marrow transplanted patients is a concerning issue. Although the data on this subject are numerous, the issue of the origin of adenovirus infections in hSCT children is seldom addressed in the literature. Two main mechanisms may explain the occurrence of viral infections in immunocompromised individuals: (1) reactivation of a latent or persistent virus (2) or primary viral infection following transmission from a seropositive donor to a seronegative recipient, transmission of a virus circulating in the community or nosocomial transmission.

There are arguments in the literature in favour of a possible reactivation of endogenous adenoviruses from C species in immunocompromised persons. Indeed, the vast majority of adenovirus C primary infection occurred within the first 2 years of age¹⁶ and following primary infection, C adenoviruses induce persistent infections in tonsils, adenoids and other lymphoid tissues.^{17, 18} High levels of adenoviruses C genomes are found in the tonsils of children younger than 9 years old and it was shown that tonsil T lymphocytes can harbour species C adenoviruses in a quiescent form.¹⁹ Therefore, part of adenovirus C infection occurring in bone marrow transplanted children could be linked to the reactivation of endogenous latent or persistent infection. However, there is no information in the literature indicating if adenoviruses from other species than C are also capable of inducing a persistent or latent infection.

Primary adenoviral infection following bone marrow transplantation may be owing to the transmission of a specific adenovirus serotype from a seropositive donor to a seronegative recipient via contaminated stem cell product. However, this kind of transmission is probably rare, as adenovirus genome is usually not recovered, even by highly sensitive PCR technique, in peripheral blood monuclear cells of immunocompetent individuals.²⁰ Although adenoviruses nosocomial infections have been extensively reported in ophthalmology clinics,²¹ neonatal intensive care units and long-term paediatric care facilities,²² no nosocomial outbreak of adenovirus infection in a paediatric haematology unit has been reported in the literature. Moreover, Venart et al.²³ failed to demonstrate the nosocomial origin of an adenovirus outbreak involving adenoviruses C and non-typable strains and favoured the hypothesis of endogenous reactivation. We report here an outbreak of adenovirus A31 infections that occurred in Necker Hospital paediatric haematology unit between February and August 2003. This cluster of cases could be explained by an epidemic exposure of the seven infected children before SCT and secondary reactivation after a period of latency. However, the timing and location of the epidemic cases added to the hexon gene genotyping results strongly suggested a nosocomial origin to this epidemic. Indeed, epidemic cases occurred secondary to the hospitalization of the presumed index case first in ward A (February to June 2003) and later in ward B (June to October 2003), whereas no case occurred in the third ward. Moreover, the hexon gene nucleotide homology was 100% among the seven epidemic isolates confirming that it was the same strain that was responsible for the epidemic. Recently, a nosocomial outbreak of diarrhoea was reported in a haematology unit for adults; interestingly, this outbreak was due to another adenovirus of species A (type 12).²⁴ In our series, all children infected with the epidemic strain were contaminated either before transplantation or in the late transplantation period when the children were not isolated in septic conditions. The potential route of nosocomial transmission was not elucidated. Notably, the role of health care workers in the transmission of the infection was not investigated. The share of food and drinks facilities by children's parents may also have had a role in the spread of infection, but this possibility was not investigated by performing PCR on swabs from surfaces of parents' restroom. However, standard control measures were effective to control this outbreak.

To our knowledge, no recent epidemiological data on the spread of adenovirus strain A31 in the community are available. However, adenoviruses from species A are known to be responsible for epidemic gastrointestinal disease in immunocompetent children.¹⁷ The capacity of adenoviruses species A to disseminate from the gastrointestinal tract to other organs of immunosuppressed children is unknown. In the series of Legrand et al.⁵, none of the seven children infected with adenovirus 31 had a positive viraemia, but in our series, all A31-infected children had a positive viraemia even if the level of adenovirus viraemia was highly variable; moreover, all seven children but one had clinical symptoms consistent with adenovirus disseminated infection. However, clinical features of adenoviral infection are not specific and may be difficult to differentiate from those of other viral infections or other affection such as GvHD. In our series, three of the seven children infected with Ad31 strain had either a concomitant other viral infection or a GvHD, which could also be the cause of their symptoms.

None of the seven children infected with adenovirus Ad31 died of this infection; however, severe adenovirus infection with strain A31 may happen, as two cases of Ad31 fatal infection had been reported in the literature.^{4, 7} Whether the good outcome of the children infected with Ad31 strain in our series is explained by early antiviral therapy, by immune recovery or by both is difficult to tell. Indeed, the importance of immune reconstitution for the clearance of adenovirus viraemia has been well documented.^{25, 26} Moreover, a recent report based on a retrospective data showed that some hSCT children with adenovirus viraemia are able to clear the virus spontaneously without antiviral therapy.²⁷

Adenovirus A31 infections have been increasingly reported in hSCT children in the last few years and we reported here that this strain may be responsible for nosocomial infection in this population. Future surveillance of adenovirus A31 infections in hSCT children will be useful to obtain additional data in order to determine the exact role of these infections in this context.

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