Table 1. Summary of reports describing pediatric patients without known immunodeficiency with presumed central nervous system infection caused by human adenovirus published during the last 40 years

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Table 1. Summary of reports describing pediatric patients without known immunodeficiency with presumed central nervous system infection caused by human adenovirus published during the last 40 years

Author (Year), Country

No. of cases with HAdV infection and CNS

involvement (total no. of study

participants)

Mean/median age in years

(Range) Male/female

Clinical manifestation Sample types and method CSF WCC (cells/mm³)

Immunolo-‐

gical investi-‐

gations

Antiviral treatment

Outcome Comments

Huang YC et al.

(2013), Taiwan **

Encephalitis: 28 Meningitis: 9 Meningoencephalitis: 3 Others neurological manifestations: 19 (n= 3298)

4.43 34/25

Seizure: 19 (32.2%);

Altered level of consciousness: 11 (18.6%);

Headache: 13 (22%);

Hallucination: 10 (16.9%);

Other neurological symptoms: 13 (22%)

Culture of nasopharyngeal or throat swab.

[LP only done in 28 cases:

CSF culture for bacterial (n=28) and viral pathogens (n=17) were negative in all cases in whom these tests had been performed] *

Pleocytosis (WCC> 10) in 6 of 28 cases

None None Epilepsy: 3

Obstructive hydrocephalus: 1 Vegetative state: 1 Hemiplegia: 1

Retrospective study of 3298 children with HAdV infection detected by culturing nasopharyngeal or throat swab. 109 of these (3.3%) had CNS manifestations.

However, this included 52 cases with febrile convulsion, without evidence of CNS infection (ie meningitis or encephalitis). ‘Other neurological manifestations’

included: afebrile seizure (n=12), status epilepticus (n=2), acute flaccid paralysis (n=2), cerebellitis (n=1), ADEM (n=1) and extrapyramidal syndrome (n=1).

Lai CY et al.

(2013), Taiwan

Encephalitis: 7 (n=45)

2.75 (0.08-‐15.4)*

28/17*

N: 10 (22%) * RS: 40 (89%) * GI: 21 (47%) *

Culture or RT-‐PCR Sample types not specified

LP done in 9 cases; no pleocytosis in CSF in any case*

ND ND 10 cases (22%) died; all reported to

have had “major underlying diseases”*

Retrospective study of children with severe HAdV infection.

De Ory F et al.

(2013), Spain

Meningitis: 1 Cerebellitis: 1 (n=581)

ND N: 2 (100%)

RS: ND GI: ND

PCR on CSF

(study included testing for other pathogens)

ND ND ND ND Prospective observational study of acute viral CNS

infections (encephalitis, meningitis or

meningoencephalitis) in children and adults involving 17 Spanish hospitals.

Dupuis M. et al (2011), USA **

Encephalitis: 1 (n=ND)

1.1 yrs 0/1

N: lethargy, reduced level of consciousness RS: wheeze, shortness of breath

Known sickle cell disease;

profound anemia on admission (Hb 1.7 g/dl).

RT-‐PCR on CSF (CSF of HAdV case also positive for HHV-‐6)

ND ND ND Died (diagnosis established post-‐

mortem)

Study of 2357 CSF specimens from patients diagnosed with meningitis or encephalitis in hospitals in New York State over 40-‐month-‐period; HAdV PCR only added after first 12 months. Report included one additional adult case of HAdV encephalitis (aged 21 years).

Khetsuriani N et al.

(2009), Thailand **

Meningoencephalitis: 1 (n=1)

0.8 yrs 1/0

Seizures, ataxia, maculopapular rash

PCR on CSF 100 WCC (60% neu)

ND No Full recovery Case report. Notably, the patient was also diagnosed

with Haemophilus influenzae sepsis/meningitis (based on positive blood and CSF cultures obtained 4 days and 2 days prior to the detection of HAdV, respectively).

Krous HF et al.

(2007), USA

1.7 yrs 1/0

Pyrexia, irritability Swabs of anus and brain (taken post-‐mortem) grew HAdV in culture

ND No No Died Report of 2 cases with sudden death.

Lema CL et al.

(2005), Argentina **

Case 1: 0.5 yrs Case 2: 12 yrs 1/1

Case 1: bronchiolitis (later sepsis syndrome) Case 2: ND

PCR on CSF ND ND Case 1: acyclovir

Case 2: ND

Case 1: developmental delay Case 2: full recovery

Cohort study of 108 cases with neurological diseases, including encephalitis (n=79) and meningitis (n=7). The report includes a further 4 adult cases with HAdV CNS disease, all of which were immunocompromised.

Chuang YY et al.

(2003), Taiwan **

Case1: 1.3 yrs Case 2: 1.7 yrs Case 3: 4.2 yrs 2/1

N: 3 (100%) RS: 3 (100%) GI: ND

Culture of nasopharyngeal swabs, bronchoalveolar lavage fluid and stool

No LPs performed None None Died: 1 (33%)

Survived: 2 (66%)

Case series of nine cases with severe adenovirus infection at a single hospital in Taiwan. All cases with encephalitis had an altered level of consciousness and seizures.

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* Figures refer to entire study cohort (rather than cases with CNS disease specifically). ** Contains additional data not contained in the original manuscript provided by the author(s).

Clinical manifestation: N: neurological; GI: gastrointestinal; RS: respiratory. HSM: hepatosplenomegaly, IVIG: intravenous immunoglobulin, Leu: leukocytes, LN: lymph nodes, Lymph: lymphocytes, ND: No data provided in manuscript, Neu: neutrophils, NPA:

nasopharyngeal aspirate, RT-‐PCR: real-‐time PCR, WCC: white cell count, yrs: years.

Lee TC et al.

(2003), Taiwan **

4.2 (0.5-‐17.2) 3/2

Acute psychosis: 2 (40%) Paralysis: 2 (40%) Convulsion: 2 (40%) Meningeal signs: 3 (60%)

PCR on CSF (n=1) or blood (n=4)

Case 1+2: 0 WCC Case 3: 20 WCC (5% neu) Case 4: 200 WCC (6% neu) Case 5: 230 WCC (36% neu)

No (n=5) No (n=5) Died: 1 (20%) Survived: 4 (80%)

Multicenter study of pediatric and adult cases with acute encephalitis in 30 Taiwanese hospitals, which included testing for 14 different viruses.

Straussberg R et al.

(2001), Israel

Encephalopathy: 7 (n=7)

1.6 yrs (0.6-‐2.8) 3/4

N: 7 (100%) RS: 7 (100%) GI: 4 (57%)

Shell vial assays on sputum, nasopharyngeal, conjunctival and rectal swabs

No cases with pleocytosis ND Acyclovir: 2 Full recovery (n=7) Case series of 7 pediatric patients with encephalopathy seen at a single healthcare institution in Israel during four years (1983, 1984, 1998, 1999). Neurological symptoms mainly comprised reduced level of consciousness; none of the cases had seizures.

Sakata H et al.

(1998), Japan **

2.1 yrs (0.9-‐2.9) 4/2

N: 6 (100%) RS: 6 (100%)

Culture of pharyngeal swabs, stool, pleural effusion fluid or CSF

Range of WCC (in 4 cases):

1-‐10 (all 100% lymph)

IgG, IgA and IgM within normal limits in all cases

None (all cases)

Died: 1 (17%) Facial palsy: 1 (17%) Full recovery: 4 (67%)

Report of a nosocomial outbreak of adenovirus infections in a pediatric ward in a Japanese hospital. No definition for ‘encephalitis’ provided in the manuscript.

Only 4 of the 6 cases with HAdV encephalitis underwent lumbar puncture; in none of these cases HAdV was grown from the CSF.

Berlin LE et al.

(1993), USA **

Meningitis: 1 (n=274)

ND N: 1 (100%) Culture of pharyngeal swab ND No None ND Prospective study of children (< 2 years of age) with

aseptic meningitis presenting at 3 hospitals in Baltimore, U.S. No clinical data provided on the case with HAdV meningitis.

Osamura T et al.

(1993), Japan

0.02 yrs Pneumonia, HSM,

abnormal clotting, seizures, coma

Culture of lung, hiliar LN and brain tissue.

Electron microscopy of lung showed HAdV virions.

ND No (normal

histology of thymus and LN)

None (but IVIG)

Died Case report of infant who presented at 9 days of age.

HAdV identified at post-‐mortem examination.

Kumar R et al.

(1990), India **

Encephalopathy: 5 (n=740)

ND Pyrexia and altered level of consciousness: 5 (100%)

Culture of throat swabs ND None

(all cases)

None (all cases)

ND Prospective study of encephalopathy in children

presenting to a single hospital in India over a 3-‐year-‐

period.

Mak S et al.

(1990), Taiwan

Meningitis (clinically): 1 (n=124)

7 yrs “Signs of meningitis” Culture of CSF 3 WCC ND ND ND Retrospective study of cases with suspected meningitis

at a single healthcare institution in Taiwan. HAdV type 3 was isolated from the CSF in only one patient.

Wong V et al.

(1987), Hong Kong

ND ND ND ND ND ND ND Retrospective study of paediatric encephalitis cases

presenting to a single hospital in Hong Kong over an 11-‐

year-‐period.

Kelsey DS (1978), USA

6.3 yrs (4-‐10) 2/2

N: 4 (100%) RS: 2 (50%)

Culture of CSF Case 1: 370 (93% neu) Case 2: 23 (93% neu) Case 3: 1019 (79% neu) Case 4: 172 (100% lymph)

ND ND Died: 1 (25%)

Ataxia and intention tremor: 1 (25%) Full recovery: 2 (50%)

Case series of 4 children with HAdV meningo-‐

encephalitis. Case 3 had ataxia and intention tremor prior to onset of illness (due to resection of cerebellar astrocytoma). Case 4 had lymphocytic leukemia (potential cause of the CSF pleocytosis).

Sutton RN et al.

(1976), UK

Encephalitis: 1 Meningitis (clinically): 1 (n=42)

6 yrs (n=2) 2/0

N: 2 (100%) RS: 1 (50%)

Culture

(Case 1: site not detailed;

Case 2: stool specimen)

Case 1: ND Case 2: 5 WCC

Case 1:

normal IgA and IgM levels Case 2: ND

ND Case 1: partial recovery, cerebellar signs remained

Case 2: full recovery (but dyslexia)

Retrospective cohort study of patients with adenovirus type 7 infections in England & Wales. Report mentions a total of 9 cases with suspected meningitis, and 4 cases with suspected encephalitis; however, the age of those cases is unclear (except in 2 cases that are described in detail).