Short Communication

Antiviral Therapy
February 2022: 1–5
Herpes simplex virus reactivation in © The Author(s) 2022
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DOI: 10.1177/13596535211068613
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respiratory distress syndrome: a
prospective cohort study

Alessandro F Chiesa1,2 , Micol Pallanza2,3, Gladys Martinetti4, Fabio Lanzi1,

Marco Previsdomini1, Alberto Pagnamenta1,5,6 and Luigia Elzi2,3,7

1
Department of Intensive Care Medicine, Ente Ospedaliero Cantonale, Bellinzona, Switzerland;
2
Department of Internal Medicine, Ente Ospedaliero Cantonale, Bellinzona, Switzerland;
3
Division of Infectious Diseases, Regional Hospital of Bellinzona and Locarno, Locarno, Switzerland;
4
Institute of Microbiology, Ente Ospedaliero Cantonale, Bellinzona, Switzerland;
5
Clinical Trial Unit, Ente Ospedaliero Cantonale, Bellinzona, Switzerland;
6
Division of Pneumology, University Hospital of Geneva, Geneva, Switzerland;
7
Faculty of Medicine, University of Basel, Basel, Switzerland

Abstract
Background: There is a paucity of data about the occurrence and risk factors of herpes simplex virus (HSV) reactivation
among patients with severe COVID-19 presenting with acute respiratory distress syndrome (ARDS).
Methods: We performed a nested case-control study among a cohort of SARS-CoV-2 infected patients with ARDS.
Between March and April 2020, all consecutive mechanically ventilated patients ≥18 years old with a positive PCR for SARS-
CoV-2 on mucocutaneous samples were included in the study. We collected data on demographics, medical history,
laboratory variables, administration of antivirals and other agents, respiratory and organ support procedures, microbi-
ological results, and management of ARDS with prone positioning and the use of steroids. Univariate and multivariable Cox
regression models were performed in order to identify predictors of HSV reactivation.
Results: Eighty-three patients with laboratory-confirmed SARS-CoV-2 infection were admitted to the ICU for mechanical
ventilation. 18/83 (21.7%) patients developed mucocutaneous herpes simplex virus reactivation after a median of 17 days
(IQR, 14–20). Prone positioning was the only independent risk factor for HSV reactivation (adj. hazard ratios, 1.60; 95% CI,
1.11–2.30; P = 0.009). All patients with mucocutaneous HSV reactivation were treated with antivirals. The outcome in
terms of ventilator-associated pneumonia, catheter-related bloodstream infections, and in-hospital mortality was similar
for patients with and without HSV reactivation.
Conclusions: HSV reactivation is frequent in COVID-19 patients with ARDS, especially if prolonged invasive mechanical
ventilation with prone positioning is needed. Prompt testing for HSV and initiation of antiviral therapy should be performed
in case of mucocutaneous lesions in this population.

Corresponding author:
e-mail: alessandroFelice.chiesa@eoc.ch
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2 Antiviral Therapy
Introduction
Herpes simplex virus (HSV) is a common virus that may
affect critically ill patients undergoing mechanical venti-
lation [1,2]. Depending on age and socioeconomic status,
40–90% of the human population in different countries has
antibodies to HSV [3]. Despite the presence of these an-
tibodies, the virus reactivates following local stimuli (e.-
g. tissue lesion) or systemic stimuli (e.g. fever or impairment
of the immune system). Reactivation of HSV has been as-
sociated with asymptomatic virus excretion in saliva, ulcer-
ation of the oral mucosa or herpes labialis, or more severe
disease such as herpetic oesophagitis, tracheobronchitis or
pneumonia in immunocompromised hosts [4,5]. Several
studies have shown that HSV reactivation and active repli-
cation in the respiratory tract are common in mechanically
ventilated critically ill patients even without underlying im-
munosuppression, with reported rates of 20 to 40% [1,2,5-7].
Whether HSV replication in the respiratory tract plays a
significant role in the outcome of critically ill patients remains
unclear [1,8]. It is also uncertain whether treatment with an
antiviral agent is beneficial for these patients [9-11]. Little is
known about HSV reactivation occurring in patients with
COVID-19 and acute respiratory distress syndrome (ARDS).
The aim of this study was to investigate the occurrence
and risk factors of HSV reactivation in a cohort of SARS-
CoV-2 infected patients with ARDS receiving mechanical
ventilation at the Regional Hospital of Locarno, Switzer-
land, during the first Swiss pandemic wave.
Methods
We performed a single-centre, nested case-control study to
investigate the frequency and risk factors of HSV reactivation
among patients with severe COVID-19 and ARDS who were
admitted to the ICU at the Regional Hospital of Locarno,
Switzerland, during the first wave of the Swiss COVID-19
pandemic between March and April 2020.
Local health and government officials in southern
Switzerland responded to the COVID-19 pandemic by ded-
icating one public hospital (Regional Hospital Locarno, in-
tegrated in a multisite public hospital named Ente Ospedaliero
Cantonale) exclusively to the care of patients with laboratory-
confirmed SARS-CoV-2 infection. The pre-pandemic local
ICU with eight beds was expanded to a unit with 45 beds in
order to respond to the rapidly increasing number of COVID-
19 patients requiring invasive respiratory support. We applied
standard of care in accordance with the most recent guidelines
to the entire cohort [12]. Specific treatments of COVID-19,
including lopinavir/ritonavir, hydroxychloroquine, tocilizu-
mab and remdesivir, were administered according to current
national and international guidelines [13,14]. All consecutive
mechanically ventilated patients ≥18 years old with a positive
PCR for SARS-CoV-2 on mucocutaneous samples were
included in this study. We collected data on demographics,
medical history, laboratory variables, administration of anti-
virals and other agents, respiratory and organ support pro-
cedures, microbiological results, and management of ARDS
with prone positioning and the use of steroids.
The primary endpoint was the frequency of mucocu-
taneous HSV reactivation after orotracheal intubation,
defined as detection of HSV by qualitative specific PCR
from a skin or mucosal lesion. We did not obtain HSV
cultures. Secondary endpoints included the time to HSV
reactivation from orotracheal intubation; risk factors of
HSV reactivation according to demographic and clinical
characteristics, disease severity (SOFA score at ICU ad-
mission), the use of steroids, prone positioning; and the
impact of HSV reactivation on the incidence of ventilator-
associated pneumonia (VAP), catheter-related bloodstream
infections and in-hospital mortality.
Data were compared using the chi-square test or Fisher’s
exact test for categorical variables, and the Mann-Whitney
test for continuous variables. We used Kaplan-Meier
curves to describe the cumulative incidence of HSV re-
activation according to all variables collected, and the
curves were compared using the log-rank test. Uni- and
multivariable Cox regression analysis was used to inves-
tigate risk factors of HSV reactivation. All patients were
censored at discharge from ICU if no HSV reactivation or
death had occurred. All tests have been conducted two-
sided and P-values <0.05 were considered statistically
significant. All analyses were performed using commer-
cially available software (STATA version 13.1 for Win-
dows, StataCorp, College Station, TX, USA).
We followed the principles of the Strengthening the Re-
porting of Observational Studies in Epidemiology (STROBE)
guidelines for reporting our research [15]. The regional Ethics
Committee of Canton Ticino, Bellinzona, Switzerland, ap-
proved the study protocol (Project ID: 2020-01429 CE 3665).
Due to the observational nature of the study, the Ethics
Committee waived the need for informed consent.
Results
Between March 6 and 5 April 2020, 83 patients with
laboratory-confirmed SARS-CoV-2 infection were admit-
ted to our ICU for mechanical ventilation. Of these, 18
(21.7%) patients developed mucocutaneous HSV re-
activation after a median of 17 days (IQR, 14–20). All
patients diagnosed with oral or labial HSV reactivation
were started on intravenous acyclovir or oral valacyclovir
for 5 to 7 days. Patients’ characteristics according to HSV
reactivation are shown in Table 1. The median age was
69 years, and most patients were males (73%). No dif-
ferences in co-morbidities, specific COVID-19 treatment
(lopinavir/ritonavir, hydroxychloroquine, remdesivir and
tocilizumab) and SOFA score at ICU admission were
Chiesa et al. 3

Table 1. General characteristics of the study population (n = 83) according to herpes simplex virus (HSV) reactivation.

Variable HSV reactivation (N = 18) No HSV reactivation (N = 65) P-value

Age 69(62–75) 69(61–73) 0.855

Male sex 12(66.7) 49(75.4) 0.458
Body mass index, kg m-2 30(27–34) 29(26–32) 0.143
Comorbidity 13(72.2) 50(76.9) 0.680
Arterial hypertension 10(55.6) 39(60.1) 0.734
Diabetes mellitus 7(38.9) 19(29.3) 0.434
Cardiovascular disease 4(22.2) 21(32.3.9) 0.303
Immunodeficiency 3(4.6) 0 —
White blood cells count, ×109 l-1 5.1(4.4–7.1) 6(4.8–7.8) 0.306
Lymphocytes count, ×109 l-1 0.8(0.5–1.0) 0.7(0.6–0.9) 0.726
Minimum lymphocytes count, x109 l-1 0.5(0.4–0.7) 0.6(0.5–0.7) 0.377
C-reactive protein, mg l-1 83(40–214) 95(57–158) 0.907
Maximum C-reactive protein, mg l-1 373(343–481) 351304–463) 0.309
SOFA score 7(78) 7(68) 0.824
Lopinavir/ritonavir 8(44.4) 32(49.3) 0.719
Remdesivir 1(5.6) 7(10.8) 0.446
Hydroxychloroquine 8(47.7) 8(44.4) 0.807
Use of tocilizumab 0 7(10.8) —
Use of steroids 13(72.2) 23(35.9) 0.006
Steroids, days 6(2–19) 6(213) 0.836
Use of prone positioning 18(100) 48(73.9) 0.009
Days of prone position 14(10–20) 5(210) <0.001
Days of mechanical ventilation 34(21–44) 20(11–30) 0.002
Ventilator-associated pneumonia 14(77.8) 39(60) 0.132
Catheter-related bloodstream infection 13(73.2) 30(46.2) 0.044
In-hospital mortality 7(38.9) 26(40.0) 0.578
Data are presented as median [IQR] and number (%).
SOFA, Sequential Organ Failure Assessment.

Table 2. Hazard ratios (HR) of herpes simplex virus reactivation, univariable and multivariable analysis.

Univariable model Multivariable model

Variable HR 95% CI p-value Adj. HRa 95% CI p-value

Age, per 10 years older 1.12 0.67–1.87 0.663 — — —

Male sex 0.57 0.21–1.52 0.260 — — —
Body mass index, per 10 kg/m2 increase 1.33 0.69–2.58 0.395 — — —
Comorbidity 0.87 0.31–2.47 0.805 — — —
Minimal lymphocyte count 0.35 0.02–4.96 0.437 — — —
Maximal C-reactive protein 1.01 0.99–1.01 0.470 — — —
SOFA score 1.08 0.82–1.44 0.570 — — —
Use of steroids 2.74 0.97–7.68.3 0.056 1.33 0.44–4.05 0.611
Time of steroids, days 0.99 0.94–1.05 0.764 — — —
Time of pronation, for each additional week 1.69 1.21–2.37 0.002 1.60 1.11–2.30 0.009
Time of mechanical ventilation, for each additional week 1.19 1.02–1.18 0.018 1.11 0.79–1.56 0.548
a
adjusted for use of steroids, time of pronation and time of mechanical ventilation.
SOFA, Sequential Organ Failure Assessment.

observed between both groups. Patients who experienced for more days with prone positioning (14 vs 5 days, P <
HSV reactivation were more frequently treated with steroids 0.001), compared to those without HSV reactivation. In the
(72.2% versus 35.9%, P = 0.006), mechanically ventilated for multivariable analysis, after adjustment for the duration of
a longer period of time (34 vs 20 days, P = 0.002) and treated mechanical ventilation and the use of steroids, prone
4 Antiviral Therapy
positioning was the only independent risk factor for HSV
reactivation (adj. HR, 1.60; 95% CI, 1.11–2.30; P = 0.009;
Table 2). The outcome in terms of ventilator-associated
pneumonia, catheter-related bloodstream infections and in-
hospital mortality was similar in both groups.
Discussion
This prospective cohort study, involving 83 patients with
severe COVID-19 and ARDS requiring mechanical ven-
tilation during the first Swiss pandemic wave, illustrates an
overall high rate of mucocutaneous HSV reactivation in
critically ill COVID-19 patients. Moreover, we identified
prone positioning, particularly the application of an ele-
vated number of pronation cycles, as the only independent
risk factor of HSV reactivation in our study population.
High prevalence of respiratory Herpesviridae re-
activation has recently been described in 38 mechanically
ventilated COVID-19 patients who were screened twice a
week by specific PCR for HSV and CMV on tracheal as-
pirates without cytologic or histologic examination [16].
The clinical relevance of Herpesviridae detection in the
lower respiratory tract remains controversial despite the
association between antiviral treatment and lower ICU
mortality has been described [1,2,4-6,8,9]. We focused on
the occurrence of herpetic orofacial lesions that have been
linked to a higher risk of bloodstream infections in the
immunocompromised host. In our study, mucocutaneous
HSV reactivation was more frequent in patients receiving
steroids and in those with more prolonged mechanical
ventilation. However, only prone positioning was an in-
dependent risk factor of HSV reactivation. We hypothesize
that the repetitive trauma to the tissues occurring during
prone position might have played a central role in the
reactivation of the virus. In fact, the endotracheal tube may
cause microtraumas to the orofacial region when a patient
is turned in the bed and lies face down onto his anterior
chest and abdomen.
Treatment with steroids and prolonged mechanical
ventilation have been previously recognized as risk factors
of HSV reactivation [1,4,6,7,9,10,16]. During the first
Swiss COVID-19 pandemic wave national and interna-
tional guidelines discouraged the administration of ste-
roids, being an option at low dosage (i.e. hydrocortisone at
a dose of 200 mg per day for 3–7 days) in case of septic
shock not responsive to fluids and vasopressor therapy.
This restrictive strategy might be the reason why steroids
were not independently associated with HSV reactivation
in our study.
Whether HSV reactivation in the setting of ARDS due to
COVID-19 has an impact on the prognosis of these patients
remains unclear and deserves to be further investigated.
In contrast to previous studies [1,4,6-8,16], we did not
observe any difference in the occurrence of ventilator-
associated pneumonia, bloodstream infections or in-
hospital death. This might be explained by the limited
sample size of the study. On the other hand, we cannot
exclude that antiherpetic treatment might have positively
influenced the clinical course of the group with HSV
reactivation in our population.
We acknowledge some limitations to our study. First,
this is a single-centre study limiting the generalizability of
our results. Second, we obtained an oropharyngeal swab
or a swab from oral or skin lesions only in case of clinical
suspicion for HSV reactivation, possibly underestimating
its occurrence. Third, the study did not evaluate
asymptomatic viral shedding, which could have influ-
enced predictive factors. However, we concentrated on
clinically relevant HSV reactivations rather than unspe-
cific viral shedding of the lower respiratory tract. Fourth,
due to the design of the study and the small sample size,
we cannot draw any definitive conclusion about the utility
of the antiherpetic treatment in case of prolonged prone
positioning. The main strengths of this study are the
prospective assessment of HSV reactivation and the
choice of a clinically relevant endpoint. To our knowl-
edge, this is the first study that investigates the problem of
mucocutaneous HSV reactivation in patients with severe
COVID-19.
In conclusion, mucocutaneous HSV reactivation is frequent
in COVID-19 patients with ARDS, especially if prolonged
invasive mechanical ventilation with prone positioning is
needed. Our findings should be confirmed in a larger study.
Prompt testing for HSV and initiation of antiviral
therapy should be performed at the occurrence of muco-
cutaneous lesions in this population.
Acknowledgements
We thank all the patients and the professionals working at our ICU
for their collaboration during this study.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with re-
spect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Alessandro F Chiesa  https://orcid.org/0000-0002-9588-4982
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