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Journal of Clinical Microbiology, June 2000, p. 2087-2096, Vol. 38, No. 6
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Persistence of Human Papillomavirus DNA in Benign
and (Pre)malignant Skin Lesions from Renal Transplant
Recipients
Ron J. M.
Berkhout,1
Jan N.
Bouwes
Bavinck,2 and
Jan
ter Schegget1,*
Department of Virology, University of
Amsterdam, Academic Medical Center, Amsterdam,1
and Department of Dermatology, Leiden University Medical
Center, Leiden,2 The Netherlands
Received 28 September 1999/Returned for modification 28 December
1999/Accepted 10 March 2000
 |
ABSTRACT |
An extremely diverse group of human papillomavirus (HPV) types
consisting of epidermodysplasia verruciformis (EV)-associated HPV types
and other cutaneous HPV types (e.g., HPV types 2 and 3) is associated
with nonmelanoma cancers and benign lesions of the skin. The frequent
presence of multiple HPV types in single skin biopsy specimens of renal
transplant recipients prompted us to develop PCR techniques for the
detection of distinct (sub)groups of genotypically related cutaneous
HPV types, i.e., three subgroups of EV-associated HPV types and two
groups (A2 and A4) of other cutaneous HPV types. This approach
generally allowed a reliable identification of HPV genotypes by direct
sequencing of the PCR products, despite the frequent occurrence of
multiple infections. The targeted spectrum of HPV types comprises 66 cutaneous HPV types including 21 putative novel HPV types. We also
detected 17 putative novel HPV subtypes. We demonstrated that the skin of nearly all renal transplant recipients who developed various benign
and (pre)malignant skin lesions was persistently infected with one or
more EV-associated HPV types and/or HPV types belonging to groups A2
and A4. The frequency and distribution of EV-associated HPV and HPV
types belonging to groups A2 and A4 were similar in biopsy specimens
from hyperkeratotic papillomas (77.5%), squamous cell carcinomas
(77.8%), and actinic keratoses (67.9%) but appeared to be lower in
specimens of basal cell carcinomas (35.7%), benign lesions (38.5%),
and clinically normal skin (32.3%). These findings suggest that renal
transplant recipients are prone to persistent cutaneous HPV infection.
Our data do not support the existence of high-risk cutaneous HPV types.
| |
INTRODUCTION |
Human papillomaviruses (HPVs) are
small, circular DNA viruses which are confined to the epithelial cells
of both mucosa and skin (27). Recent epidemiological studies
by PCR techniques demonstrated a strong association of certain
high-risk genital HPV types, e.g., HPV type 16 (HPV-16), with cervical
dysplasia and carcinoma. Molecular biological studies confirmed their
role in the pathogenesis of cervical dysplasia and carcinoma
(27). The association of many cutaneous HPV types with
specific skin lesions in general and nonmelanoma skin cancer in
particular remains enigmatic, partly because of the large number of
cutaneous HPV types identified so far.
The earliest evidence for the involvement of specific HPV types in
human skin cancer originates from observations for patients suffering
from a hereditary disorder, epidermodysplasia verruciformis (EV)
(17). About one-third of the EV patients develop multifocal cutaneous squamous cell carcinomas mainly on sun-exposed parts of the
body. These patients are commonly infected with a group of
genotypically related HPV types (EV-associated HPVs) that induce characteristic, macular skin lesions disseminated over the body (17).
Previously, we and others described broad-spectrum PCR methods, each of
which enabled the detection of a large number of genotypically related
HPV types, e.g., all EV-associated HPV types (1, 10, 22,
25). The nested PCR approach was shown to be highly specific and
sensitive and circumvented the problem that DNA similarity is small
even in highly conserved regions of the different HPV genotypes
(10). A high prevalence of EV-associated HPV DNA was reported in squamous cell carcinomas and actinic keratoses from both
renal transplant recipients (RTRs), and a slightly lower prevalence was
reported in immunocompetent patients (1, 6, 7, 10, 22, 24,
25).
We and others used direct sequence analysis of amplified PCR products
for HPV typing (1, 10, 22). The presence of multiple HPV
types in a single biopsy specimen or smear complicates reliable typing
by this method. Therefore, we intended to design PCR techniques which
are specific for smaller subgroups of cutaneous HPV types. On the basis
of phylogenetic studies, genotypically related HPV types have been
united into groups of HPVs (5). For some of these groups a
similar tropism has been determined (15, 26). We describe
three nested EV-associated HPV (group B1) subgroup-specific PCRs and a
PCR targeted to amplification of a subgroup of HPV types belonging to
groups A2 and A4 (5). These PCR techniques enabled the
characterization of multiple coinfecting HPV types in biopsy specimens
from various benign and (pre)malignant skin lesions and normal skin.
The value of the newly developed PCR approaches was also established by
the identification of a series of new putative novel HPV types and
subtypes. Furthermore, it was established that in renal transplant
recipients specific cutaneous HPV types do not appear to be confined to
specific skin lesions. Notably, no evidence was generated for the
association of specific HPV types with skin cancers, in contrast to an
earlier report (8). Interestingly, in most of the renal
transplant recipients one or two HPV types among the other HPV types
infecting the skin were consistently detectable in biopsy specimens
which had been collected through the years from different types of skin
lesions. This indicates that most RTRs with benign or (pre)malignant
skin lesions are persistently infected with cutaneous HPV types.
| |
MATERIALS AND METHODS |
Tissue samples.
Biopsy specimens (n = 351)
were collected from a group of Dutch RTRs. Half of the biopsy specimens
were obtained when the RTR presented at the outpatient dermatology
clinic (Leiden University Medical Center [LUMC], Leiden, The
Netherlands) with lesions suspect for skin cancer. The other part of
the lesions were collected in the same clinic as part of a case-control
clinical study (7). Investigations were approved by the
local institutional review board (LUMC).
Lesions were characterized according to the histological picture into
squamous cell carcinomas, keratoacanthomas, Bowen's disease, basal
cell carcinomas, actinic keratoses, hyperkeratotic papillomas, verrucae
vulgares, verrucae planae, verrucae seborrheicae, and benign lesions
such as dermatitis, cysts, and nevi. All biopsy specimens were divided
into two: one half was processed for routine histology, the other half
was snap-frozen in liquid nitrogen and stored at 
70°C prior to DNA
preparation. Clinically normal skin was not assessed for histology, and
the complete biopsy specimens were snap-frozen and stored.
DNA extraction.
Tissue specimens were minced and treated
overnight with proteinase K (100 µg/ml) and sodium dodecyl sulfate
(0.5% [wt/vol]) at 56°C. DNA was extracted after heat inactivation
of the proteinase K (10 min at 95°C) by a guanidium
isothiocyanate-diatom based method (2).
PCR approaches.
The nested EV-associated HPV PCR approaches
(PCR-A, PCR-B, and PCR-C) developed to target the three different
subgroups of EV-associated HPV types (group B1 [5])
are indicated in Table 1. The nucleotide
sequences and the annealing sites of the common 5' EV-specific primer
(CP62) and the 3' subgroup-specific primers (CP71A, -B, and -C) are
indicated in Table 2. The CP62-CP71 (A, B, and C) primer set amplifies 874- to 908-bp products, depending on
the target HPV type and the 3' primer used. For the second-step PCR, a
common nested primer set consisting of two primers (primers CP64 and
CP70A) with annealing sites that matched all HPV types mentioned above
was designed (Table 1).
The primers (primers CP61M and CP70M) and the respective annealing
sites for the first step of the so-called 2/3-PCR targeted
to HPV
groups A2 and A4 are also indicated in Table
1. The CP61M-CP70M
primer
set amplifies 800- to 1,006-bp product depending on the
target HPV
type. The second step of the 2/3-PCR is performed with
primers CP62M
and CP69M (Table
1).
PCR amplification.
Amplification reactions in both the
first- and second-step PCRs were performed by the method of Saiki et
al. (19) in 50 µl of a reaction mixture containing 50 mM
KCl, 10 mM Tris-HCl (pH 8.8), 3.6 mM MgCl2, 0.1 mg of
bovine serum albumin per ml, each deoxynucleoside triphosphate at a
concentration of 0.2 mM (Pharmacia), 1 U of Taq DNA
polymerase (Perkin-Elmer Cetus), and 150 ng of both primers. In the
first-step PCR, 5 µl of DNA (0.5 to 2% of total DNA extractable from
the biopsy specimen) was used as input. The subsequent 40 cycles of
amplification were performed for 1 min at 95°C, 1 min at 55°C, and
2 min at 72°C. In the nested PCR, 3 µl of the first-step PCR was
used as input. In this PCR, 35 cycles of amplification were performed
(1 min at 95°C, 1 min at 55°C, and 2 min at 72°C). All PCRs were
performed in a Perkin-Elmer Cetus thermal cycler. For every two samples
a negative control (water instead of DNA) was included. These controls
were processed in the same way as the tissue specimens throughout the
DNA preparation and the first- and second-step PCRs, and they were
never found to be positive for HPV. All tissue samples were randomly
analyzed. The investigator (R.J.M.B.) who performed the PCR analysis
was blinded to the clinical data.
Sequence analysis.
The PCR products of the second-step PCR
were reamplified by a PCR with a T7 primer extended nested primer set,
T7CP65 (5'-TAA TAC GAC TCA CTA TAG GGC A[A/G]G GGT CA[C/T]
AA[C/T] AAT GG[C/T] AT-3') and CP69A (5'-TC[A/T] GT[C/T]
AT[A/G] TCT ACA T[C/T]C CA-3'). Ten to 50 ng of the PCR product was
used as input, and the amplification was performed for 30 cycles as
described above. Sequencing was done on an ABI 370/373 automated
sequencer with the Sequence Navigator computer program (Macintosh). DNA
labeling and sampling were performed according to the manufacturer's protocol.
Phylogenetic analysis.
Alignment of the sequences were done
by using the Clustal program (11) and was corrected by hand.
The phylogenetic analyses were done by the neighbor-joining method as
implemented in the MEGA package (20). All data were sorted
by use of the Microsoft Office package.
Nucleotide sequence accession numbers.
The following
putative novel sequences were submitted to GenBank (available at
http://www.hpv-web.lanl.gov): HPV-X13 to HPV-X15 (accession nos.
[ACs] AF054873, AF054874, and AF054876, respectively), HPV-X20 to
HPV-X27 (ACs AF054877, AF054878, L38914, AF054879, AF054881, AF054882,
AF054883, and AF054884, respectively), HPV-X29 (AC AF054885), HPV-X32 to HPV-X35 (ACs AF054886, AF054887, AF055710, and AF055711, respectively), HPV-XS1 to HPV-XS5 (ACs AF091448, AF091449, AF091450,
AF091451, and AF091452, respectively), HPV-5c (AC AF091436), HPV-15b
(AC AF091457), HPV-17b (AC AF097699), HPV-20b (AC AF091438), HPV-22b
(AC AF091439), HPV-23b (AC AF091440), HPV-24b (AC AF091441), HPV-36b
(AC AF091442), HPV-38b (AC AF091443), HPV-38c (AC AF091444), HPV-X2b
(AC AF097700), HPV-X4b (AC AF091445), HPV-X10b (AC AF091446), HPV-X11b
(AC AF091447), HPV-X11c (AC AF097701), HPV-X14b (AC AF154875), and
HPV-X23b (AC AF054880).
| |
RESULTS |
HPV primer design.
A phylogenetic tree was constructed for all
EV-associated HPV types of group B1 belonging to supergroup B, as
defined earlier (5) (Fig. 1).
Subsequently, three different first-step PCR primer sets were created
for three nonoverlapping subgroups that, when combined, comprise the
entire spectrum of the EV-associated HPV types. These subgroups were
subgroup A (HPV-5, -8, -12, -14, -19, -20, -21, -25, -36, and -47),
subgroup B (HPV-9, -15, -17, -22, -23, -37, -38, and -49), and subgroup
C (HPV-24). The first-step PCR for the three EV-associated HPV
subgroups was performed with one common 5' primer and three different
3' primers (see Table 1 and Materials and Methods). In a similar
fashion, a nested PCR approach (referred to as 2/3-PCR) was designed
for HPV types belonging to groups A2 and A4 (5) (HPV-2, -3, -10, -27, -28, -29, and -57).
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FIG. 1.
A neighbor-joining tree based on the 92-amino-acid
sequence of the PCR-amplified part of the L1 open reading frame of all
EV-associated HPV types including the putative novel (sub)types (see
Materials and Methods).
|
|
Analysis of clinical specimens.
The HPV group- and
subgroup-specific PCRs were conducted with a large number (n = 351) of skin biopsy specimens from Dutch RTRs. These skin biopsy
specimens were taken from 81 squamous cell carcinomas, 14 basal cell
carcinomas, 56 actinic keratoses, 102 hyperkeratotic papillomas, 12 verrucae vulgares, 17 verrucae planae, 16 verrucae seborrheicae, 5 keratoacanthomas, 14 Bowen's disease, and 13 benign lesions
(dermatitis, cysts, and nevi); and 31 biopsy specimens were taken from
clinically normal skin. Two hundred thirty-six of 351 (67.2%) lesions
were found to be positive for HPV. None of the HPV (sub)groups were
clearly associated with a particular type of lesion (Table
3). The frequency of HPV DNA in biopsy
specimens from squamous cell carcinomas (77.8%) appeared to be higher
than that in biopsy specimens from basal cell carcinomas (35.7%). HPV
types belonging to EV-specific subgroup B were most frequently found
(n = 149; 42.5%). The other subgroups were also
frequently encountered: EV-specific subgroup A in 113 (32.5%) biopsy
specimens, EV-specific subgroup C in 81 (23.1%) biopsy specimens, and
the 2/3 group in 97 (27.6%) biopsy specimens. The frequencies of the
HPV types in the different lesions from which less than 80 biopsy
specimens were collected are shown in Table 3. The frequencies in
squamous cell carcinomas, actinic keratoses, hyperkeratotic papillomas,
and all biopsy specimens together are shown in Fig.
2.
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FIG. 2.
The frequency distribution of HPV types in all skin
biopsy specimens, actinic keratoses, squamous cell carcinomas, and
hyperkeratotic papillomas. The number of HPVs detected is indicated in
the middle of the pie charts. Undefined, the HPV type is unknown. The
EV-associated HPV subgroups are depicted in different grey scales and
by shading.
|
|
From twenty-three RTRs, four or more biopsy specimens which had been
taken over a period of months to years were analyzed
by the four PCR
approaches. Only two of these patients did not
have any HPV-positive
biopsy specimens. All other patients were
infected at least at one site
(Table
4). In nearly all RTRs one
or more
HPV types were consistently detected in biopsy
specimens
taken at different time points.
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TABLE 4.
HPV types detected in RTRs from whom four or more biopsy
specimens were available, organized by frequency of HPV infection
|
|
Specificities of the PCR approaches for subgroups of HPV
types.
The different PCR approaches generally proved to be
specific for the respective targeted (sub)groups of HPV types, despite the frequent finding of multiple HPV types in a single biopsy specimen.
Only infrequently EV-associated HPV types belonging to either subgroup
A, B, or C were amplified by a PCR not mediated by the corresponding
subgroup-specific primer pair (see, e.g., Table 4, patients 15, 17, 18, 19, and 20). No EV-associated HPV types were detected by the 2/3-PCR
designed to detect groups A2 and A4.
Novel HPV types and subtypes.
HPV typing was generally
performed by direct sequence analysis of a PCR-amplified 264- to
276-nucleotide fragment and by applying a 10% distance at the
nucleotide level for definition of a novel type (5). In
those RTRs in whom more than one HPV type was detected by one of the
four PCR approaches (Table 4), the PCR product was molecularly cloned
before sequence analysis. Sixteen new putative novel EV-associated HPV
types were identified in this study (HPV-X13 to HPV-X15, HPV-X20 to
HPV-X27, HPV-X29, and HPV-X32 to HPV-X35) and five new putative novel
HPV types belonging to the A2 and A4 group (HPV-XS1 to HPV-XS5) were
identified (Tables 3 and 4). Also, 17 novel subtypes of 14 EV-associated HPV types were identified, and these differed by 2 to
10% at nucleotide level. The nucleotide sequences of the novel
(sub)types have been submitted to GenBank (see Materials and Methods).
All new putative novel EV-associated HPV (sub)types appeared to fit
into the phytogenetic tree shown in Fig.
1. This provided
evidence that
the unknown sequences were amplified from novel
EV-associated HPV
(sub)types distinct from all known
(sub)types.
| |
DISCUSSION |
HPV subgroup-specific PCR methods.
In an effort to develop an
HPV DNA detection method which allows the efficient identification of
multiple HPV types within a single lesion and also of novel HPV types,
we designed four PCR approaches mediated by nested primer sets which
targeted specific HPV (sub)groups. One PCR approach targeted the HPV
types belonging to the A2 and A4 HPV groups (HPV types 2 and 3 and
related types) (5). The other three targeted subgroups that
have been chosen from within the B1 group of EV-associated HPV types
(5). For the detection of the subgroups of EV-associated HPV
types, broad-spectrum PCR primers were designed with an annealing site
in the L1 open reading frames of all HPV types, including previously
identified novel HPV sequences. The 3' primers were chosen from
sequences in the long control region, since the conserved binding sites for transcription regulatory proteins in this region served well as
target sites for these subgroup-specific primers.
An advantage of these nested PCR approaches was the potential to
identify the different HPV types present in a single lesion
by direct
sequence analysis of the PCR products in general without
the necessity
of molecular cloning. The PCR fragment of 264 to
276 nucleotides which
was used for EV-associated HPV (sub)typing
as described before
(
1) encompasses variable and conserved
genomic segments of
the L1 open reading frame. The conserved part
of this fragment overlaps
the DNA segment amplified by PCR with
the MY09-MY11 primer pair
(
13), which is commonly used for the
identification of
mucosal HPV types. Putative novel types were
identified as sequences
with dissimilarities of more than 10%
compared to all other known
sequences, as defined previously (
1,
5,
9,
15). The typing
protocol by sequencing resulted
in unambiguous signals when one HPV
type was present. When direct
sequencing indicated that more than one
HPV type was present,
molecular cloning of the PCR product was
performed to identify
the HPV types. In general, the nested PCR
approaches appeared
to be specific for the targeted HPV subgroups,
since positive
PCR signals were only infrequently obtained from
nontargeted HPV
types. This problem occurred only when PCR methods were
used for
the detection of the EV-associated HPV subgroups. This is
probably
due to the presence of a relatively high EV-associated HPV
copy
number in some lesions. RTRs with lesions that contain such a
high
copy number of HPV appear to be uncommon (Table
4, patients
15, 17, 18, 19, and
20).
Different numbers of HPV types were detected by the respective
EV-associated HPV subgroup-specific PCR approaches. Subgroup
B is very
large, with a high continuous diversity throughout the
cluster;
subgroup A is less diverse, with a characteristic subdivision
into
clades; and subgroup C started out from only HPV-24 and in
this study
is found to comprise only one phylogenetically related
group of HPVs
(Fig.
1).
Novel HPV types, subtypes, and variants.
The usefulness of the
nested PCR approaches was also borne out by the detection of about 16 new putative novel EV-associated HPV types, 5 new putative novel HPV
types belonging to the A2 and A4 groups (HPV-XS1 to HPV-XS5), and 17 HPV subtypes (see Materials and Methods). Of several HPV types two or
three distinct subtypes with dissimilarities of 2 to 10% at the
nucleotide level from their reference HPV type could be identified
(data not shown). These dissimilar nucleotides were not concentrated
within the variable segment but were randomly distributed. Most of the
mismatching nucleotides were silent substitutions (data not shown). The
occurrence of subtypes was not limited to EV-associated HPV types since
subtypes of HPV-57 were also found. Besides subtypes, variants were
identified with a low level of sequence diversity (
2%) (data not
shown). This degree of diversity has previously been observed among
most HPV types that have been investigated more thoroughly and is
generally used to describe variants (5). In our study we
found a similar degree of variability within EV-associated HPV types,
but this variability was only occasionally observed in HPV-2, HPV-3, or related HPV types (Table 4 and data not shown). A recent study of
HPV-2, -27, and -57, however, describes large numbers of variants of
these three HPV types (4).
HPV DNA persists in the skin of RTRs.
Epidemiological studies
by broad consensus PCRs clearly indicate that EV-associated HPV is
commonly found in skin lesions from RTRs and are also frequently
detected throughout the population of immunocompetent individuals (for
a review, see reference 18). Our previous studies
revealed the presence of EV-associated HPV in about 80% of the biopsy
specimens from (pre)malignant skin lesions from a group of Dutch RTRs
(1, 6, 7). In the study described in this report we
demonstrated in most of the RTRs the persistence of one or two HPV
types, since we detected these types in biopsy specimens collected over
a period of months to years from benign, premalignant, and malignant
lesions and also from normal skin (Table 4, patients 4 to 19 and 21).
Notably, the frequency and distribution of the detected HPV types in
the different lesions, i.e., in hyperkeratotic papillomata, squamous cell carcinomas, and actinic keratoses, were very similar (Table 3;
Fig. 2). The frequency of EV-associated HPV detection in basal cell
carcinomas appeared to be comparable to the frequency of HPV detection
in benign lesions and clinically normal skin but lower than the
frequency of HPV detection in cutaneous squamous cell carcinomas and
hyperkeratotic lesions (Table 3).
In the present report a persistent and frequent association of HPV
types belonging to groups A2 and A4 with benign lesions,
(pre)malignant
lesions, and normal skin of some individual patients
has been found
(Table
4, patients 10, 11, 12, and 21). It extends
a previous
observation that, in particular, HPV-3 and related
types were
frequently detected in benign lesions from immunocompromised
patients
(
16). These data suggest that RTRs are sensitive to
infection with one of these HPV types, probably due to failing
immune
surveillance. This observation must be corroborated by
more extensive
epidemiological
studies.
Some groups demonstrated the presence of still other HPV types
(
22; for a review, see reference
18), but in this and previous
studies we failed to
detect them. These include mucosal HPV types
(groups A1, A3, and A5 to
A11) that are associated with genital
carcinomas (i.e., HPV-16 and -56)
and cutaneous HPV types without
a known widespread histopathological
association (i.e., HPV-41
and -48). In our previous attempts to detect
HPV in skin lesions
we also failed to detect mucosal HPV types using
multiple broad
consensus PCR methods (
1,
6,
25). The PCR
method for the
detection of HPV-2 and -3, and related types (groups A2
and A4)
described here has been found to detect mucosal HPV types in
cervical
smears, but these HPV types were not found in skin lesions
from
RTRs (data not shown). Preliminary PCR studies also targeted other
cutaneous HPV types, including HPV-1, -4, and -65, that have been
regularly detected in skin warts of immunocompetent patients
(
12).
Also, these HPV types have not been detected in biopsy
specimens
from skin lesions from RTRs (data not
shown).
In conclusion, we report that nearly all RTRs who develop benign or
(pre)malignant skin lesions are persistently infected
with at least one
HPV type, often for long periods. Recently,
it was reported that
high-risk genital HPV types often persist
in immunocompromised human
immunodeficiency virus-infected patients
(
14,
23). An
increased HPV persistence may explain the higher
prevalence of genital
HPV infections as well as the increased
risk of cervical neoplasia in
human immunodeficiency virus-infected
women (
21). It will be
important to investigate whether cutaneous
HPV types also persist more
frequently in the skin of immunocompromised
patients than in the skin
of immunocompetent individuals. Such
studies will be very difficult to
perform by analyzing multiple
lesions from a large number of
immunosuppressed and immunocompetent
individuals. Our recent detection
of EV-associated HPV types in
plucked hairs in a considerable part of
the population (
3,
3a) may facilitate these kinds of
studies.
| |
ACKNOWLEDGMENTS |
We thank Ingeborg Boxman and Cees Sol for helpful suggestions and
critical reading of the manuscript, Wim van Est for preparing the
figures, and Anneke Wiersma for typing the manuscript.
The research was supported by the Dutch Kidney Foundation (grant
C94-1390).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Academic Medical
Center, Department of Virology, University of Amsterdam (L1-158), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone:
31-20-5664857. Fax: 31-20-6979271. E-mail:
J.terschegget{at}inter.nl.net.
| |
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Journal of Clinical Microbiology, June 2000, p. 2087-2096, Vol. 38, No. 6
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Abstract
Introduction
