High Torquetenovirus Loads Are Correlated With
Bronchiectasis and Peripheral Airflow Limitation in Children
Massimo Pifferi, MD,* Fabrizio Maggi, MD,† Davide Caramella, MD,‡ Emanuela De Marco, MD,*
Elisabetta Andreoli, BSc,† Silvia Meschi, BSc,† Pierantonio Macchia, MD,* Mauro Bendinelli, MD,†
and Attilio L. Boner, MD§
Background: The aim of the study was to evaluate the prevalence of
torquetenovirus (TTV) infection in a group of children with recurrent
lower respiratory tract infections and radiologic evidence of bronchi-
ectasis. Correlations between TTV loads and severity of bronchiectasis
and between TTV loads and lung function were evaluated.
Methods: In 38 subjects, high-resolution computed tomography
(HRCT) and plasma tests for TTV detection and quantification were
done. In 21/38 subjects, spirometry was also performed.
Results: TTV was found in 31/38 (81.6%) patients. The correlation
between TTV loads and severity of bronchiectasis was statistically
significant (r ? 0.548; P ? 0.01). TTV loads showed inverse correla-
tion with FEF25–75%(r ? ?0.541; P ? 0.011), and FEF25–75%/FVC
(r ? ?0.512; P ? 0.018). Inverse correlation was found also between
severity of bronchiectasis and functional lung parameters: FEF25–75%
(r ? ?0.635; P ? 0.002), FEV1/FVC (r ? ?0.541; P ? 0.011), and
FEF25–75%/FVC (r ? ?0.645; P ? 0.002).
Conclusions: This study demonstrated the high prevalence of TTV
infection in children with bronchiectasis. Moreover, we have shown
a significant correlation between TTV loads and airflow limitation
within the peripheral airways, as well as between severity of bron-
chiectasis and decrease of lung function.
Key Words: emergent viruses, high-resolution computed
tomography, lung function
(Pediatr Infect Dis J 2006;25: 804–808)
genus Anellovirus.1,2It has been observed that chronic TTV
viremia is widespread among the general population worldwide
in the absence of detectable pathologic effects, leading to the
conclusion that TTV might be an apathogenic or still an “or-
phan” virus.3–7In fact, there have been uncertainties concerning
the pathogenic potential of this virus.3,4,8Recently, in children
orquetenovirus (TTV) is a circular single-stranded DNA
virus of about 3800 nucleotides classified in the new floating
hospitalized for acute respiratory diseases, it has been demon-
strated that the respiratory tract is a site of primary infection and
continual TTV replication.9Although no evidence was obtained
that TTV might be a direct cause of respiratory disease, average
TTV loads in plasma and nasal fluids were considerably higher
in children with bronchopneumonia than in patients with milder
illnesses.9Furthermore, TTV loads were inversely related to the
percentages of circulating CD3?and CD4?T cells and posi-
tively related to the percentage of B cells, suggesting that TTV
might contribute to lymphocytes imbalance, with a possible
immunosuppressive effect.10This may increase the risk of
severe lower airway infections associated with an increased
likelihood of bronchiectasis development.11
Bronchiectasis has been considered an “orphan dis-
ease” in relation to its postulated low frequency in children of
the developed world.12
To our knowledge, no study evaluating the relationship
of TTV loads in plasma and presence of bronchiectasis has
been previously reported. The aim of our study was to evaluate
the prevalence of TTV infection in a group of children with
history of recurrent lower respiratory tract infections, as well as
clinical and chest x-ray suspicion of bronchiectasis. Moreover,
we wanted to assess if there is a correlation between TTV loads
and severity of bronchiectasis, as demonstrated by HRCT and
MATERIALS AND METHODS
Patient Selection. In the period between January 2003 and June
2004, all the children consecutively referred to the pediatric
clinic for ciliary dysmotility of the University of Pisa were
considered for the study. Inclusion criteria were a history of
recurrent lower respiratory tract infections and a chest radio-
graph suggesting the presence of bronchiectasis, such as tram-
track-like patterns, bronchiolar dilatation or honeycomb patterns.
Exclusion criteria were a history of recent lower respi-
ratory tract infections, presence in the last 3 weeks of an
increase in sputum production, increased dyspnea or cough,
temperature ?37.0°C, augmented wheezing, malaise, fatigue
or decreased exercise tolerance. The information was ob-
tained by interview with parents and by referring physicians’
chart review, when available, as well by physical examina-
tion. Children treated with systemic corticosteroids in the
previous 6 months were excluded from the study. Any phar-
macologic regimen in use was stopped in the 24 hours
preceding the evaluation except chest physiotherapy, which
Accepted for publication June 8, 2006.
From the *Department of Pediatrics, †Virology Section and Retrovirus
Center, Department of Experimental Pathology, and ‡Department of
Radiology, University of Pisa, Pisa, Italy; and the §Department of
Pediatrics, University of Verona, Verona, Italy.
Address for correspondence: Massimo Pifferi, MD, Department of Pediatrics,
University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail m.pifferi@
Copyright © 2006 by Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 25, Number 9, September 2006
Immunologic and Microbiologic Evaluations. Total IgG, IgA,
and IgM and IgG subclasses were studied in all patients. Plasma
samples were also tested for antibody response to common
respiratory viruses by complement fixation assay (adenovirus,
influenza A and B, parainfluenza types 1 to 3, respiratory
syncytial virus ?RSV?) or enzyme immunoassay (cytomegalo-
virus) and to Mycoplasma pneumoniae and Chlamydia pneu-
moniae by immunofluorescence. The intradermal Mantoux test
was always performed, and sputum cultures were obtained in
The presence of atopy was evaluated by skin-prick testing
for common environmental perennial and seasonal allergens.
Investigations for Congenital Disorders. Cystic fibrosis was
evaluated by the use of sweat chloride test and by genetic
mutation screening. Primary ciliary dyskinesia (PCD) was stud-
ied by ciliary beat frequency and motion patterns evaluation of
cilia from cells obtained by nasal scrapings. Moreover, trans-
mission electron microscopy studies were performed when cil-
iary function evaluation was suggestive of a primary defect.
Serum ?1-antitripsine was measured.
Imaging Investigation. The diagnosis of bronchiectasis was
established using HRCT, which is considered the standard to
assess the severity and extent of bronchial disease.13HRCT
was performed with a spiral scanner (HiSpeed; General Electric
Medical Systems, Milwaukee, WI) using high-resolution
technique; scans were performed in the supine position in
1-mm-thick slices (100 kV, 110–150 mA), with 10-mm
spacing. In 31 out of 38 studied patients, we obtained suffi-
cient collaboration, and we instructed them to maintain in-
spiration breath-holds near total lung capacity by asking them
to continue inspiration until required. In the remaining 7
patients, anesthesia was needed. In no child was intravenous
contrast medium administered. Bronchiectasis was diagnosed
and graded using previously described methods14: 0 (absence
of bronchiectasis), 1 (mild and rare bronchial dilatations), and
2 (severe and diffuse bronchodilatation). Subjects with HRCT
score 0 served as internal controls.
Lung Function Evaluation. Maximum forced inspiratory-expi-
ratory flow-volume curves were obtained in 21 children, utiliz-
ing the standard ATS technique15: the other patients were not
evaluated due to their young age (16 subjects) or lack of
compliance (1 girl). Subjects were tested using an automated
Germany). Measured values were expressed as percentage of
predicted values according to Zapletal et al.16Lung function
studies were performed within 2 days of HRCT examination.
TTV Detection and Quantification. For TTV detection and
quantification, plasma was obtained by spinning down blood
collected under nuclease-free conditions in Na-citrate tubes.
Viral DNA was extracted from 200 ?L of plasma by using
the QIAamp DNA Mini kit (Qiagen, Chatsworth, CA). Pres-
ence and load of TTV were determined by a universal
TaqMan real-time PCR assay as described9,10that was tar-
geted to a highly conserved segment of the noncoding region
of the viral genome. The procedures used for quantification of
copy numbers and evaluation of specificity, sensitivity, intra-
and interassay precision, and reproducibility of the assay
have been described.9,10TTV loads greater than 3 log10DNA
copies/mL of plasma were considered positive samples.
Statistical Analysis. The Student t test was used to assess the
significant difference between TTV loads in subjects with
(HRCT scores ? 1 or 2) and without (HRCT score ? 0)
bronchiectasis. The ?2test was used to evaluate the association
between TTV infection (TTV loads greater than 3 log10DNA
copies/mL of plasma) and presence of bronchiectasis. The same
test was used to evaluate the association between TTV infection
and PCD. Sensitivity, specificity, positive predictive value, and
negative predictive value of TTV loads, as indicators of HRCT-
proven bronchiectasis, were calculated. The statistical signifi-
cance of correlation between TTV loads and HRCT scores was
examined using Spearman rank signed test. The statistical sig-
nificance of correlations between TTV loads and lung function
parameters (FVC, FEV1, FEF25–75%, FEV1/FVC, FEF25–75%/
FVC) were examined using Pearson correlation test. Pearson
correlation test was used to evaluate the correlation between
TTV level and age of patients; Spearman rank signed test was
used to assess the correlation between bronchiectasis score and
age of the patients. The ?2trend test was used to evaluate the
correlation between adenovirus, cytomegalovirus, RSV infec-
tions and bronchiectasis score, respectively.
Results are expressed as mean ? SD. A P value less than
0.05 was regarded as statistically significant. All statistical cal-
culations were performed using SPSS version 9.0 software for
Windows (SPSS, Inc, Chicago, IL) for personal computers.17
Approval for the study was obtained from the local hospital
ethical committee, and written parental consent was obtained
from the parents of all the children.
Thirty-eight subjects (21 male, 17 female), ranging in age
from 8 to 192 months (mean ? SD ? 83.3 ? 49.7 months),
were finally evaluated. All the children eligible for the study and
consecutively seen were enrolled into the study.
Immunologic and Microbiologic Investigations. No child had
primary immunodeficiency or pulmonary tuberculosis. Low lev-
els of total antibodies or lack of specific IgM for adenovirus,
influenza viruses A and B, parainfluenza viruses types 1 to 3,
RSV, and cytomegalovirus excluded an acute viral infection in
all children. A previous infection with adenovirus was docu-
mented in 13 (34.2%) of the patients, with cytomegalovirus in
15 (39.5%) of the children and in the same number and propor-
tion for RSV. A positive antibodies response by complement
fixation assay to influenza and parainfluenza viruses was docu-
mented, with a lower prevalence in our study population. In all
children, serum antibody assay excluded acute infection due to
M pneumoniae and C pneumoniae. The presence of common
bacterial pathogens was excluded in 3/7 patients with PCD who
were able to expectorate to perform sputum culture.
Seven patients were sensitive to house dust mites.
Congenital Disorders. No subject had cystic fibrosis or ?1-
antitrypsin deficiency; 7 subjects had PCD. The high prevalence
of patients with PCD in our study population can be explained
by the fact that our laboratory is one of the referring centers for
this disease in Italy.
Imaging Evaluation. In our study population, HRCT score was
0 in 11 patients, 1 in 15 patients, and 2 in 12 patients. In the 7
children with PCD, the HRCT score was 0 in 2 patients, 1 in 1
The Pediatric Infectious Disease Journal • Volume 25, Number 9, September 2006Airflow Limitation in Pediatric Bronchiectasis
© 2006 Lippincott Williams & Wilkins
patient, and 2 in 4 subjects. In the 7 patients with allergic
sensitization, HRCT score was 0 in 1 patient, 1 in 5 patients, and
2 in 1 patient.
Lung Function. Lung function evaluation was possible in 21
(55%) children. Spirometry was not possible in 4 out of 7
patients with PCD and in 2 out of 7 allergic patients. Reversible
airflow limitation (?12 increase in FEV1postsalbutamol) was
observed in 5 out of 6 children with no bronchiectasis, in 1
patient out of 9 with a bronchiectasis HRCT score of 1, and in
no child out of 6 with a score of 2.
Wheezing was reported in the clinical history of 21 chil-
dren (7 of the 11 children with a bronchiectasis HRCT score of
0, in 6 of the 15 patients with the score of 1, and in 8 out of the
12 subjects with a bronchiectasis score of 2).
TTV Load and Its Correlations With Other Factors. Positive
TTV blood samples were found in 31/38 (81.6%) patients. TTV
was present in 5/11 (45%) patients without bronchiectasis and in
26/27 (96%) patients with bronchiectasis (P ? 0.0002). PCD
was not a risk factor for positive TTV blood samples. The
association between TTV infection and presence of bronchiec-
tasis (HRCT scores 1–2) was, instead, highly significant (P ?
0.001). TTV loads are an indicator of HRCT-proven bronchiec-
tasis, with 83.9% sensitivity and 85.7% specificity. The positive
predictive value was 96.3%, and negative predictive value,
54.5%. In TTV-positive subjects, TTV loads (log10DNA cop-
ies/mL of plasma) were 4.3 ? 1.1 in patients without bronchi-
ectasis, 4.9 ? 1.0 in patients with HRTC score of 1, and 5.4 ?
1.1 in patients with HRTC score of 2. There was a significant
trend towards increasing TTV loads associated with increasing
severity of bronchiectasis (r ? 0.548; P ? 0.01) (Fig. 1).
Considering the presence of previous infections with other
viruses in relation to the severity of bronchiectasis, a positive
response to adenovirus was documented in 18.2%, 33.3%, and
50% of children with bronchiectasis score, respectively, of 0, 1
and 2 (P for trend ? 0.107). The values for cytomegalovirus
were, respectively, 27.3%, 33.3% and 58.3% (P for trend ?
0.123). No significant trend was also observed for RSV because
a previous infection was observed in 36.4%, 46.7%, and 41.7%
of subjects with a bronchiectasis score, respectively, of 0, 1 and
2 (P ? 0.806). In the 13 children with a positive immunologic
response to adenovirus by complement fixation assay (2 with
bronchiectasis score 0, 5 with 1, and 6 with 2), a concomitant
positive serum sample for TTV virus was found, respectively, in
zero, 4 (80%), and 6 (100%) patients with bronchiectasis score,
respectively, of 0, 1 and 2. We did not find any significant
correlation between the age of patients and TTV loads (P ?
0.555) or bronchiectasis scores (P ? 0.587).
Among the 21 patients in whom lung function tests were
performed, HRCT score was 0 in 6 patients, 1 in 9 patients, and
2 in 6 patients. In these patients, TTV loads showed inverse
correlation with FEF25–75%(r ? ?0.541; P ? 0.011), and
significant correlation was, instead, found between TTV loads
and the other spirometry parameters (FVC, FEV1, FEV1/FVC).
In these 21 patients, an inverse correlation was found also
between HRCT score (0–2) and functional lung parameters:
FEF25–75%(r ? ?0.635; P ? 0.002), FEV1/FVC (r ? ?0.541;
P ? 0.011), and FEF25–75%/FVC (r ? ?0.645; P ? 0.002) (Fig.
3). No statistically significant correlation was found between
HRCT score (0–2) and the other spirometry measures (FVC,
Airway damage with development of bronchiectasis can
occur as a result of infection by a single potent pathogen such as
adenovirus or M pneumoniae or as a consequence of recurrent
viral respiratory infections.18
In our study, we evaluated the potential association be-
tween TTV infection and severity of bronchiectasis. The re-
markably high prevalence of chronic TTV infections in healthy
FIGURE 1. Correlation between TTV loads and HRCT score.
FIGURE 2. Correlation between TTV loads and both
FEF25–75%, and FEF25–75%/FVC in 21 children.
Pifferi et al
The Pediatric Infectious Disease Journal • Volume 25, Number 9, September 2006
© 2006 Lippincott Williams & Wilkins
individuals worldwide represents a serious hurdle to the eluci-
dation of their clinical significances and natural history.19
The results of the present investigation of TTV infections
in children with recurrent lower respiratory tract infections
confirm the widespread diffusion and early acquisition of sys-
temic TTV infection because over 80% of our patients had
positive virus blood samples. This prevalence is comparable to
that previously observed in healthy adults living in the same
area19,20and in other geographic regions.21
Despite large variations in viral loads found in individual
subjects (from 103to 108DNA copies per mL of plasma in our
series), there was a significant correlation between TTV loads
and severity of bronchiectasis. This was found in absence of
immunologic finding of acute infection due to adenovirus or M
pneumoniae, two infectious agents that have been shown to be
associated with bronchiectasis.18Of course, significant correla-
tions cannot be taken as evidence of causal relationship. The
findings of the present study suggest that TTV infection might
be a contributing factor to the development of bronchiectasis
throughout an immunomodulatory effect induced by the TTV.
The observed low level of CD4?T cells associated with high
level of TTV loads10may be responsible for a reduced cellular
and humoral immune response,22with consequently more se-
vere and more frequent infections. This may lead to cumulative
airway injury, which might be aggravated by poor mucus clear-
ance usually observed in the course of viral infections.23
The pathophysiology of bronchiectasis includes airway
inflammation, mucus production and regional airway obstruc-
tion.11,18Those findings are more likely to occur with higher
virus loads. For this reason, the positive and significant (P ?
0.01) trend between the severity of bronchiectasis and level of
TTV viremia observed in our patients might have a cause-effect
Other viral infections have been suggested to be respon-
sible for bronchiectasis development such as influenza,24ade-
novirus,25and human immunodeficiency virus infection in pa-
tient with CD4?lymphopenia.26,27The CD4?lymphopenia
associated with TTV infection has no dramatic effects, but TTV
infection might render the patients more susceptible to serious
complications with other agents, as was observed for measles.28
In this case, it was suggested that measles virus may have
rendered the children more susceptible to serious complications
from infections with adenovirus. In our study population, be-
cause no acute infection with adenovirus was documented, the
reverse situation has to be considered. This seems reasonable
because bronchiectasis was documented also in children with
TTV infection and no immunologic response to adenovirus.
There is also the possibility that an impaired mucociliary
clearance activity may favor the occurrence of infection. This
does not seem to be the case because we found no statistical
difference in the prevalence of TTV infection in patients with
and without PCD, a condition with a major negative impact on
On the other hand, it is not possible to disregard the fact
that bronchiectasis by itself may have a role in ensuring persis-
tence or recurrence of viral or bacterial infections in affected
children. Because single-stranded DNA viruses require actively
is propagated throughout cycling cells such as lymphoid cells in
blood and in bone marrow. The possibility that this happens also
in basal and columnar cells of airways’ epithelium, which
proliferates in responses to injury stimuli, needs to be explored.
However, this is very likely because it was demonstrated that
TTV replicates in multiple tissue organs, including lung.29
As expected, the obstructive disease observed in our
patients was characterized by a worsening airway obstruction
affecting both large and small airways,30,31but a significant
correlation was observed only between TTV loads and airflow
limitation mainly within the peripheral airways. This was also
observed for the correlation between presence or severity of
bronchiectasis and reduced values of FEF25–75%, FEV1/FVC,
and FEF25–75%/FVC. This may be explained by an impairment
of peripheral lung function induced by the TTV infection. In
effect, our study population consists of young children in whom
any insult to the lung is potentially more effective on the distal
lung due to the disynaptic lung growth.32The possible damage
to the developing acinar tissue has more chances to exert its
effect on small airways.
In animal models, chronic latent adenoviral infection is
associated with a persistent bronchiolitis even though the ani-
mals do not appear sick.33Future studies are necessary to
investigate whether this is the case also for TTV because TTV
infection is usually chronic, with genuine virus persistence, and
is characterized by the continued presence of the virus in the
blood (reviewed in Bendinelli et al4). Chronic inflammation can
lead to structural alterations, with progressive loss of lung
function, particularly in subjects who develop bronchial hyper-
responsiveness.34,35We did not evaluate this factor, but the ratio
of FEF25–75%/FVC is negatively associated with bronchial hy-
perresponsiveness (the smaller the ratio of FEF25–75%/FVC, the
FIGURE 3. Correlation between HRCT score (0–2) and func-
tional lung parameters: FEF25–75%, FEV1/FVC, and FEF25–75%/
FVC in 21 children.
The Pediatric Infectious Disease Journal • Volume 25, Number 9, September 2006 Airflow Limitation in Pediatric Bronchiectasis
© 2006 Lippincott Williams & Wilkins
greater the percent decline in FEV1per micromole of metha- Download full-text
choline), particularly in subjects who had reported a recent
respiratory illness.36Therefore, it is reasonable to speculate that
bronchial hyperresponsiveness was present also in some of our
patients. Moreover, this correlation between TTV loads and
airflow limitation is in agreement with the significant association
demonstrated in asthmatic children between high nasal titers of
TTV and decrements in the same lung function parameters.37
There are limitations to this study. The first is that TTV
virus DNA was not evaluated in lung tissue as it was done to
demonstrate the link between adenovirus infection and bronchi-
ectasis.38Furthermore, no mediator39or specific immunologic
response40possibly involved in the pathogenesis of airway
damage was evaluated in bronchoalveolar lavage fluid. Longi-
tudinal studies in humans and animal models are necessary to
evaluate the relationship among TTV infection, host responses
and to elucidate the actual role of TTV in the pathogenesis of
bronchiectasis and lung function impairment in children with
recurrent lower respiratory tract infections. However, there is
accumulating evidence that a new player has entered in this
complex process and that TTV infection should not be under-
estimated and probably should no more be considered an orphan
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The Pediatric Infectious Disease Journal • Volume 25, Number 9, September 2006
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