Med Microbiol Immunol

DOI 10.1007/s00430-013-0306-1

ORIGINAL INVESTIGATION

Detection of herpesvirus EBV DNA in the lower respiratory

tract of ICU patients: a marker of infection of the lower
respiratory tract?
I. Friedrichs T. Bingold O. T. Keppler
B. Pullmann C. Reinheimer A. Berger

Received: 2 April 2013 / Accepted: 11 July 2013

Springer-Verlag Berlin Heidelberg 2013

Abstract Epstein-Barr virus (EBV) is a lymphotropic

herpesvirus causing clinically self-limiting but lifelong
persisting infections. Although several severe diseases
(e.g., Hodgkin0 s disease) are associated with EBV, its role
in lower respiratory tract infections is still elusive. The
prevalence of EBV, herpes simplex virus (HSV) and
cytomegalovirus (CMV) in bronchoalveolar fluid (BAL)
samples was evaluated in a retrospective study. BAL
samples from 135 patients in the intensive or coronary care
unit (ICU/ICC) at University Hospital Frankfurt/Main
(Germany) were investigated using an in-house real-time
PCR to detect EBV-, HSV- and CMV-specific DNA.
Overall, herpesvirus DNA was detected in n = 82/135
BAL samples (60.7 %). Besides mono-infections with
either EBV or HSV, concomitant infection with EBV and
HSV DNA was most frequent, whereby the relative HSV
viral load was typically higher. Patients with HSV-positive
BAL required mechanical ventilation on average 5 days
longer than patients with HSV-negative BAL (p = 0.006).
Additionally, the proinflammatory cytokine IL-6 was significantly elevated in sera of patients positive for EBV in
comparison with patients with EBV-negative BAL
I. Friedrichs (&)  O. T. Keppler  C. Reinheimer  A. Berger
Institute of Medical Virology, University Hospital Frankfurt am
Main, Paul-Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany
e-mail: imke.friedrichs@kgu.de
T. Bingold  B. Pullmann
Clinic of Anaesthesiology, Intensive Care Medicine and Pain
Therapy, University Hospital Frankfurt am Main,
Frankfurt am Main, Germany
C. Reinheimer
Institute of Medical Microbiology and Infection Control,
University Hospital Frankfurt am Main,
Frankfurt am Main, Germany

(p = 0.01). This study demonstrates a high prevalence of

herpesviruses in BAL samples of ICU/ICC patients. The
detection of one or more herpesvirus in BAL is strongly
associated with the duration of ventilation and patient0 s
age. The association between IL-6 levels and EBV detection should be evaluated in further studies.
Keywords Herpesvirus  CMV  HSV  EBV 
Real-time PCR  BAL  IL-6

Introduction
Members of the family Herpesviridae are enveloped double-strand DNA viruses. The eight human-specific herpesviruses are denominate as human herpesviruses 1 to 8
(HHV 1-8). After primary infection, all of them remain
latent in the organism and cause a lifelong persisting
infection [1].
Their reactivation may occur in patients immunosuppressed, e.g., following hematopoietic/solid organ transplantation or in the context of an HIV infection [24]. In
case of pneumonia in immunosuppressed patients, bacteria
and fungi are frequently suggested to be the causative agent
[5]. However, DNA of herpesviruses such as Epstein-Barr
virus (HHV 4, EBV), Herpes simplex virus (HHV 1/2,
HSV-1/2) and Cytomegalovirus (HHV 5, CMV) is
detectable frequently in bronchoalveolar fluid (BAL)
samples [6].
The host cells of EBV are lymphocytes and the epithelial cells of the oropharynx. After infection of B-cells,
EBV spreads in the organism via the blood and establishes
a lifelong persistent infection [7, 8]. Under special circumstances, an EBV infection can be associated with posttransplant lymphoproliferative disease (PTLD), AIDS-

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related lymphoma, T cell and Hodgkins lymphoma, Burkitt lymphoma and nasopharyngeal carcinoma [3, 9, 10].
Because of viral persistence in the organism, detection
of herpesviruses in samples of the lower respiratory tract
does not a priori proof causality with the underlying disease manifestation. While HSV and CMV have been well
documented to cause pneumonia in immunosuppressed
patients, the role of EBV in respiratory tract infections is
still poorly understood [2, 7, 11].
The objective of this epidemiological study was to
evaluate retrospectively the prevalence of EBV-, HSV- and
CMV-specific DNA in BAL samples in critically ill
patients.

Materials and methods

Bronchoalveolar fluid samples collected from 135 consecutive patients between January 2010 and May 2011
were evaluated. All patients were treated in the intensive
care or coronary care unit [ICU/ICC] of the University
Hospital Frankfurt/Main (Germany). Sampling was performed in case of clinical suspicion of pathogen-induced
pneumonia in patients during their ICU treatment. All
patients underwent mechanical ventilation at the time of
BAL sampling.
Detection of herpesvirus DNA in BAL samples was
performed at the Institute of Medical Virology, University
Hospital Frankfurt/Main. Automated sample extraction
was done using the virus/bacteria midi kit (Qiagen, Hilden,
Germany) out of 500 ll sample on the QIASymphony
extractor (Qiagen) according to manufactures instructions.
As an internal inhibition control, cell culture supernatant
containing murine CMV (mCMV) was added together with
the lysis buffer to each sample.
For the detection of EBV, HSV and CMV DNA, an inhouse real-time PCR was performed on the ABI 7900
sequence detection system using the TaqMan GenEx
Master Mix Kit (Applied Biosystems, Darmstadt, Germany) with primers and probes specific for the EBV
BNRF1-, HSV UL52- and CMV UL89-gen region
(Table 1), respectively. Although BALs do not represent a
standardized clinical specimen, a threshold cycle
(CT) B 25 was considered as high viral load (high positive) and a CT of C35 as low viral load (low positive).
Since dilution experiments of positive control material
showed a comparable linear range of all three herpesvirus
PCRs (data not shown), the estimated CTs were compared
against each other in order to give some information of the
viral load of the investigated samples. The internal inhibition control was detected simultaneously in each reaction
using mCMV-specific primers and probe as described
previously [12].

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Patients data used for retrospective analyses were age,

gender, length of stay in hospital before ICU admission,
length of stay at ICU (LOS ICU), length of stay at ICU
before undergoing BAL sampling (LOS ICU before BAL),
days of mechanical ventilation before undergoing BAL
sampling (MV days before BAL) and hospital outcome.
Further, SAPS II Score (Simplified Acute Physiology Score
II) and SOFA Score (Sequential Organ Failure Assessment
Score) as well as levels of Interleukin 6 (IL-6), C-reactive
Protein (CRP), Lipopolysaccharid binding protein (LBP),
procalcitonin (PCT) and leukocyte count were evaluated at
day of BAL.
For statistical analysis, only the results of the patients0
first BAL at the ICU/ICC were evaluated. Statistical
analysis was done using the 95 % confidence interval
(95 %CI), chi-square test or the Fishers exact test in the
case of low sample numbers by using the program BIAS
for Windows 8.3 (Epsilon Verlag, Hochheim Darmstadt
2007). Clinical data are presented as median with 2575 %
range. MannWhitney Rank Sum Test was performed to
test differences between two groups. A two-tailed p-value
of \0.05 was considered statistically significant.

Results
Detection of herpesvirus DNA in BAL samples of ICU/
ICC patients
Overall, herpesvirus DNA (EBV, HSV or CMV) was
detectable in n = 82/135 BAL samples (60.7 %). EBV and
HSV DNA were detected most frequently, n = 48/135
(35.6 %, median CT value 33.1, IQR 30.4, 34.4) and
n = 46/135 (34.1 %, median 27.3, IQR 21.6, 32.2),
respectively, in comparison with CMV DNA with n = 21/
135 (15.6 %, median 31.8, IQR 30.1, 33.2). In 19 samples
the, CT value for HSV was B25 (high positive). A high
positive EBV load was found in only 3 BAL samples.
In 22 BAL samples, EBV DNA, but not HSV or CMV,
was detectable. HSV mono-infection was found in 22 cases
and CMV in 7 cases, respectively (Fig. 1).
In samples with dual infections, the co-detection of HSV
and EBV DNA was most frequent (n = 17). In these
samples, the median CT of EBV was 33.1 (IQR 31.1, 35.1),
and for HSV 28.9 (IQR 19.2, 32.7). The higher median CT
value of EBV in comparison with HSV indicates a lower
EBV load (Fig. 2). Co-detection of EBV/CMV and HSV/
CMV was found in 6 and 5 cases, respectively (data not
shown).
Triple infections of EBV, HSV and CMV were detectable
in 3 samples only. In all of these cases, the lower CT value of
HSV indicated a higher viral load compared to the two other
herpesviruses.

Med Microbiol Immunol

Table 1 Primer and probe sequences used for the EBV-, HSV- and CMV-real-time PCR
Name of PCR
EBV (BNFR1 Gene)

HSV 1/2 (UL52 Gene)

CMV (UL89 Gene)

Primer/probe

Sequences

EBV For

CCAgTgCTgTgATCgAgCATC

EBV Rev

CTgCTgACAAACTgCTgCATTC

EBV probe

VIC-TCTgCTgTTgTTTCTgTCTCACCTACCgg-TAMRA

HSV For

AggAgCCCgTCCCCTTTC

HSV Rev

gCCCCgCgCCTAAAgT

HSV probe

VIC-CggCTCCACgAggCCCTg-TAMRA

CMV For

CgTTggTgTTgTAgCAACTggC

CMV Rev

TgTgCTCCAAgAggTCgAgTTCC

CMV probe

VIC-CgCgAAggTgTggCggCAg-TAMRA

maltophilia were the most frequently detected agents. The

presence of bacteria/fungi in BAL samples did not significantly
influence the prevalence of the three herpesviruses (Fisher0 s
exact test p = 2.2).
Characteristics of the investigated patients

Fig. 1 Detection of HSV-, EBV- and CMV-specific DNA in BAL

samples by real-time PCR where only one viral DNA was detected.
CT (threshold cycle value)

Fig. 2 Simultaneously detection of HSV- and EBV-specific DNA in

BAL samples by real-time PCR. CT (threshold cycle value), Median
(=50th percentile), Q1 (lower quartile = 25th percentile), Q3 (upper
quartile = 75th percentile)

Bacteria and fungi were present in 71 of the 135 BAL

samples. In 47 of these samples, herpesvirus DNA was also
detected. In these samples, Candida spp. and Gram-negative
bacteria like Pseudomonas aeruginosa and Stenotrophomonas

Patients had a median age of 65 years (IQR 55; 73 years).

Patients with BAL samples positive for either HSV or
CMV were significantly older (Table 2).
The median length of stay (LOS) before admission to
ICU was 2 days (IQR 0; 7 days) with no significant difference between the groups of patients with or without
herpesvirus PCR-positive BAL. In contrast, the length of
stay before BAL sampling was performed was significantly
longer (4 and 7 days) (p = 0.02) for patients whose BAL
was diagnosed to contain CMV or HSV, respectively.
Patients were also kept under mechanical ventilation for
5 days if their BAL was HSV positive (p = 0.006)
(Table 2).
The severity of illness was estimated with the SAPS II
score and the SOFA score. The cohort of patients had a
median SAPS II score of 43 (IQR 36; 51) and a median
SOFA score of 10 (IQR 7; 14) with no statistically significant differences between all groups. The overall
severity of illness was high. A SOFA score of 10 indicates
that patients had two to three organ failures.
The overall hospital mortality was 44.8 % without differences in the different patient groups.
Severity of illness was also reflected by routine
inflammatory parameters. The median concentration of the
proinflammatory cytokine IL-6 was 134 pg/ml (IQR 56;
272 pg/ml). In support of a potential role of EBV in
shaping the severity of illness, IL-6 was significantly elevated in serum samples in patients with EBV positive
compared to EBV-negative BALs [IL-6 162 pg/ml (IQR
57; 355 pg/ml); 126 pg/ml (IQR 61; 488 pg/ml), respectively, p = 0.01]. The other inflammatory serum markers
were without statistically significant differences; median

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Med Microbiol Immunol

Table 2 Patients characteristics: Demographic data and length of
stay (LOS) before bronchoalveolar lavage (BAL) sampling; LOS in
the Intensive Care Unit (ICU); MV: Mechanical ventilation; SAPS II:
CMV

Simplified Acute Physiology Score II; SOFA: Sequential Organ

Failure Assessment score; IQR (Interquartile Range: range between
the 75th and 25th percentile)

HSV

Negative

Positive

96

21

Sign.

EBV

Negative

Positive

65

46

63

70

[54; 73]

[64; 76]

Sign.

Negative

Positive

67

48

64

69

[56; 73]

[60; 77]

Sign.

No. of patients
n
Age
Median

65

73

IQR

[55; 73]

[64; 77]

0.006

0.008

ns

Gender
Male [n]

74

16

49

39

51

39

Female [n]

22

16

16

[2; 11]

[5; 18]

[3; 11]

[4,5; 15]

15

27

20

19

[9; 25]

[12; 46]

[9; 42]

[10; 39]

[1; 8]

[4; 17]

[2; 8]

[2; 15]

LOS ICU before BAL sampling

Median

14

IQR

[2,5; 15]

[4; 24]

0.02

0.024

ns

LOS ICU
Median

20

28

IQR

[10; 39]

[22; 52]

MV (days) before BAL

Median
6
IQR

[2; 10]

10

ns

ns

[3,5; 22]

ns

0.006

ns

ns

SAPSII
Median

42

49

IQR

[33; 51]

[39,5; 55]

ns

42

43

[35; 53]

[35; 50]

10

10

[6; 15]

[7; 13]

ns

42

42

[37; 50]

[34; 51]

10

10

[7; 14]

[6; 13]

ns

SOFA
Median

10

12

IQR

[6; 14]

[9; 15]

ns

PCT 1.1 pg/dl (IQR 0.8; 5.4 pg/ml); LBP 27 pg/ml (IQR
16; 39 pg/ml), CRP 14.4 mg/dl (IQR 8.8; 23.4 mg/dl) and
14 leukocytes/nl (IQR 10.0; 19.0 leukocytes/nl).

Discussion
The present study shows a high prevalence of EBV DNA
(35.6 %) and HSV DNA (34.1 %) in BAL samples
admitted to ICU compared to a relatively low prevalence of
CMV DNA-positive samples (15.6 %).
Both HSV and CMV are known to cause pneumonia and
other severe diseases. HSV-induced pneumonia is a lifethreatening disease with high morbidity and mortality
occurring especially in patients with severe underlying
conditions frequently combined with bacterial infection
[13, 14]. Bouza et al. [13] described the occurrence of HSV
pneumonia primarily in patients with prolonged mechanical ventilation. The present results confirm this observation. Patients with BAL positive for HSV are older and
ventilated for a longer period of time compared to patients
with HSV-negative BAL. Nevertheless, patients0 BAL

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ns

ns

might be endogenously contaminated with HSV through

shedding from the upper respiratory tract (oropharynx).
HSV shedding increases, for example, following dental
procedures without presentation of clinical symptoms of
reactivation [15]. In contrast to HSV, CMV replication has
been described in epithelial cells of salivary gland and cells
of the lower respiratory tract. Therefore, besides the
detection of DNA in BAL samples, CMV pneumonia can
be confirmed by histopathology and immunohistochemistry
[16].
The pathophysiological role of EBV-induced infections
of the lower respiratory tract is still unclear. Considering
the high rate of EBV DNA-positive BALs, its clinical
relevance has to be seriously considered. Published reports
reflect a high degree of variability concerning the prevalence of EBV in BALs. For example, Costa et al. [17, 18]
reported on lower (28.2, 15.8 %) and Googskens et al. [7]
on higher (51 %) prevalence rates (range 15.851 %)
compared to our current study. Some case reports argue for
a high clinical significance of EBV in respiratory infections
[19, 20]; however, this notion is largely based on singular
cases.

Med Microbiol Immunol

So, the detection of EBV or herpesvirus DNA in general

is not strictly correlated with overt disease and thus clinical
relevance. Especially if other concomitant pathogenic
microorganism has been detected, an EBV-associated
respiratory tract disease may be doubtful. Conceivably,
BAL samples might be endogenously contaminated with
EBV or HSV DNA from cells of the oropharynx in case of
viral shedding in subclinical reactivation. Lung et al. [21]
detected EBV DNA in exfoliate cells in bronchial washing
samples and concluded that the lower respiratory tract is a
major reservoir for EBV. Thus, the detection of EBV DNA
in BAL may thus be more a marker of viral persistence
than a marker of active infection.
From a different perspective, the detection of EBV DNA
in respiratory material has been reported to be a diagnostic
tool in another disease context. Michelson et al. [22]
identified all subjects with PTLD by testing BAL samples
of pediatric lung and heart-lung transplant recipients,
whereas peripheral blood testing was positive in only one
of the three cases.
A significant correlation (p = 0.01) between elevated IL6 levels and EBV positivity of BALs was found in this study.
Further investigations of the potential correlation and
mechanistic basis between the detection of (high) EBV load
and elevated IL-6 levels are required. Various authors
showed a clinical significance of elevated serum IL-6 levels
in patients with PTLD and nasopharyngeal carcinoma [23,
24]. Furthermore, in primary EBV-infected children, elevation of this cytokine was recognized too [25].
In most cases of mixed infections of either HSV or
CMV together with EBV, the EBV load was lower than
that of the other herpesviruses. Hypothesizing that a higher
viral load is more likely correlated with a significant
clinical finding, the role of EBV DNA positivity may argue
for a lower overall importance as a pneumonia-inducing
viral pathogen. We found no correlation between any of the
clinical symptoms and the viral or microbiological findings. The detection of herpesvirus and especially EBVspecific DNA appears to be associated more with the
investigated patient cohort, which is immunosuppressed
due to its underlying diseases and undergoes artificial
ventilation. In a study of Ogata et al. [2], subclinical
reactivation of EBV was a common phenomenon in
patients under cytotoxic chemotherapy for adult T cell
leukemia. However, no disease resulting from this was
confirmed, and EBV reactivation was not associated with
reduced survival.
In conclusion, this study shows a high prevalence of
herpesvirus DNA, especially EBV and HSV, in BAL
samples of ICU/ICC patients. The detection of one or more
herpesvirus in BAL was strongly associated with time of
ventilation and patients0 age. The association between
elevated IL-6 level and EBV detection should be evaluated

in further studies. Despite sporadic reports of EBVs

association with critical illness, the overall clinical significance of EBV DNA detection in BAL seems to be low.
However, contamination of samples through viral shedding
in the upper respiratory tract or by blood cannot be
excluded for our study samples. This could be addressed in
a follow-up study by side-by-side testing of BAL, blood
and oropharyngeal swabs.
The pathogenic potential of EBV in the clinical setting
of intensive care units and severe respiratory disease has to
be discussed critically. In the context of the present data, it
is not possible to estimate if EBV is primarily a bystander
or clinical marker in critically ill patients or, in some cases,
indeed the causative agent of lower respiratory infections.

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