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Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus

Oropharyngeal Reactivation: A Randomized Clinical Trial

Article in JAMA Internal Medicine · December 2019

DOI: 10.1001/jamainternmed.2019.5713

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 Research

JAMA Internal Medicine | Original Investigation

Acyclovir for Mechanically Ventilated Patients

With Herpes Simplex Virus Oropharyngeal Reactivation
A Randomized Clinical Trial
Charles-Edouard Luyt, MD, PhD; Jean-Marie Forel, MD, PhD; David Hajage, MD, PhD; Samir Jaber, MD, PhD;
Sophie Cayot-Constantin, MD; Thomas Rimmelé, MD, PhD; Elisabeth Coupez, MD; Qin Lu, MD, PhD;
Mamadou Hassimiou Diallo, MSc; Christine Penot-Ragon, PhD; Marc Clavel, MD; Carole Schwebel, MD, PhD;
Jean-François Timsit, MD, PhD; Jean-Pierre Bedos, MD; Caroline Hauw-Berlemont, MD; Jérémy Bourenne, MD;
Julien Mayaux, MD; Jean-Yves Lefrant, MD; Jean-Paul Mira, MD, PhD; Alain Combes, MD, PhD; Michel Wolff, MD;
Jean Chastre, MD; Laurent Papazian, MD, PhD; for the Preemptive Treatment for Herpesviridae Study Group,
Réseau Européen de recherche en Ventilation Artificielle Network

Invited Commentary page 272

IMPORTANCE The role of herpes simplex virus (HSV) reactivation on morbidity and mortality Supplemental content
in patients in the intensive care unit requiring mechanical ventilation remains unknown.

OBJECTIVE To determine whether preemptive treatment with intravenous acyclovir reduces

the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation.

DESIGN, SETTING, AND PARTICIPANTS A double-blind, placebo-controlled randomized clinical

trial was conducted in 16 intensive care units in France. Participants included 239 adults (age,
>18 years) who received mechanical ventilation for at least 96 hours and continued to receive
mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients
were enrolled between February 2, 2014, and February 22, 2018.

INTERVENTIONS Participants were randomized to receive intravenous acyclovir, 5 mg/kg,

3 times daily for 14 days or a matching placebo.

MAIN OUTCOMES AND MEASURES The primary end point was ventilator-free days from
randomization to day 60. Prespecified secondary outcomes included mortality at 60 days.
Main analyses were conducted on an intention-to-treat basis.

RESULTS Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238
patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR]
age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day
60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients
and 36 (0-50]) for controls (P = .17 for between-group comparison). Among secondary
outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11,
95% CI, –0.004 to 0.22, P = .06). The adverse event frequency was similar for both groups
(28% in the acyclovir group and 23% in the placebo group, P = .40), particularly acute renal
failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four
patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for
treatment-related adverse events.

CONCLUSIONS AND RELEVANCE In patients receiving mechanical ventilation for 96 hours or

more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days,
did not increase the number of ventilator-free days at day 60, compared with placebo. These Author Affiliations: Author
affiliations are listed at the end of this
findings do not appear to support routine preemptive use of acyclovir in this setting.
article.
TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02152358 Group Information: Members of the
Preemptive Treatment for
Herpesviridae Study Group, Réseau
Européen de recherche en Ventilation
Artificielle Network are listed at the
end of the article.
Corresponding Author:
Charles-Edouard Luyt, MD, PhD,
Médecine Intensive Réanimation,
ICAN, Groupe Hospitalier Pitié–
Salpêtrière, 47-83, boulevard de
JAMA Intern Med. 2020;180(2):263-272. doi:10.1001/jamainternmed.2019.5713 l’Hôpital, 75651 Paris Cedex 13, France
Published online December 16, 2019. ([email protected]).

(Reprinted) 263
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 Research Original Investigation Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation

A
mong the Herpesviridae responsible for infections in
humans, herpes simplex virus (HSV) is one of the Key Points
most frequent, with 50% to 80% of healthy adults
Question Does preemptive treatment with acyclovir reduce the
being infected, most during childhood, and carrying the duration of mechanical ventilation in critically ill patients with
virus. Critical illness and mechanical ventilation, with endo- herpes simplex virus oropharyngeal reactivation?
tracheal tube–induced microtrauma, are factors strongly
Findings In this multicenter, randomized clinical trial of 238
associated with reactivation HSV in nonimmunocompro-
adults, treatment with intravenous acyclovir vs placebo during
mised patients. Oropharyngeal HSV reactivation occurs in 14 days did not significantly reduce ventilator-free days at day 60.
20% to 50% of mechanically ventilated patients, with the Compared with placebo, intravenous acyclovir was not associated
virus being detectable in up to 64% of patients receiving pro- with higher incidence of adverse events.
longed mechanical ventilation. Some patients develop true
Meaning The findings of this study do not appear to support
HSV bronchopneumonitis.1,2 Moreover, HSV detection in the routine preemptive use of acyclovir in this setting.
lower respiratory tract and HSV bronchopneumonitis seem to
be associated with poorer outcomes in observational studies
and a meta-analysis.1-4 However, whether HSV reactivation
in intensive care unit (ICU) patients occurs in the most Exclusion criteria were use of acyclovir, ganciclovir, or an-
severely ill patients, thus considered a marker of severity, or other antiviral with anti-HSV activity (eg, cidofovir or foscavir)
is associated with morbidity and mortality and treatment at the time of randomization; known hypersensitivity to acy-
with acyclovir could improve the prognosis remain to be clovir; active HSV or CMV infection treated during the preced-
determined. We designed the Preemptive Treatment for Her- ing month; pregnancy or lactation; pancytopenia; solid-
pesviridae trial to determine whether treating mechanically organ or bone-marrow transplant; immunosuppressant therapy
ventilated HSV-reactivation–positive patients with acyclovir (including corticosteroids at doses ≥0.5 mg/kg per day of pred-
would improve their outcomes. nisone or its equivalent for >1 month); HIV infection; mori-
bund condition, defined as a preinclusion Simplified Acute
Physiology Score (SAPS) II of 75 or higher (possible score, 0-163;
where higher scores indicate greater disease severity)6; deci-
Methods sion made to withhold or withdraw life-sustaining therapies;
Study Design and ICU readmission during the same hospital stay.
This randomized, multicenter, double-blind, placebo-
controlled trial was conducted in 16 intensive care units (ICUs) Randomization
in France from February 2, 2014, to February 22, 2018. An in- A centralized, secure, web-based randomization system using
dependent ethics committee (Comité de Protection des Per- minimization assigned patients at a 1:1 ratio, with stratifica-
sonnes Sud Méditerranée 5) approved the study protocol, tion by study site, prerandomization mechanical ventilation
which is available with the statistical analysis plan in Supple- duration (≤14 or >14 days), and number of organ failures ac-
ment 1. Written informed consent was obtained from the cording to the Sequential Organ-Failure Assessment7 (SOFA)
patient or his or her legally authorized representative. For the score (<2 or ≥2). The SOFA score was calculated from 6 vari-
latter, the patient’s follow-up informed consent was obtained ables the day of randomization, taking into account the worst
when possible. Participants did not receive financial compen- values of each parameter in the 24 hours preceding the ran-
sation. This study followed the Consolidated Standards domization. Scores range from 0 to 24, with higher scores in-
of Reporting Trials (CONSORT) reporting guideline for dicating more severe organ failure and higher mortality risk.
randomized clinical trials.5 Organ and system failure were deemed present when the cor-
During the study period, potentially eligible patients (ie, responding SOFA score was greater than 2. All investigators,
those mechanically ventilated for ≥96 hours) were screened statisticians, and data analysts were blinded to arm assign-
twice weekly with quantitative polymerase chain reaction per- ments until the study and analysis were completed.
formed on whole blood for cytomegalovirus (CMV) and quali-
tative polymerase chain reaction performed on oropharyn- Study Interventions
geal swabs for HSV reactivations. Patients with HSV-positive Patients were randomized to receive intravenous acyclovir,
oropharyngeal swabs were potentially eligible for this trial. Pa- 5 mg/kg, 3 times daily or a matching placebo preparation (con-
tients could not be included in another study. Patients and/or trols) every 8 hours for a maximum duration of 14 days. That
their relatives were informed of this screening until Decem- dose was chosen because it is recommended to treat immu-
ber 18, 2015, when screening became routine care and French nocompromised patients’ cutaneous HSV infections and has
law rendered informing them no longer necessary. been shown to effectively prevent HSV reactivation in a pre-
vious randomized clinical trial.8 For extubated patients dis-
Study Participants charged from the ICU before day 14 post randomization, the
Patients aged 18 years or older who had been receiving me- study agent was stopped at discharge. Acyclovir doses were
chanical ventilation for 96 hours or more, with a predicted me- adjusted to renal function according to the manufacturer’s
chanical ventilation duration of 48 hours or more and an HSV- recommendations.9 Placebo and acyclovir powders were con-
positive oropharyngeal swab, were eligible for enrollment. ditioned in similar opaque bottles that were distributed post

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 Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation Original Investigation Research

randomization and reconstituted in saline by the nurses be- spectively to calculate day 90 mortality, day 90 ventilator-
fore each administration. free days, and mechanical ventilation duration.
By November 16, 2016, although 206 patients had been ran-
domized, the dates of validity of the initially manufactured Statistical Analysis
opaque bottles that contained either the placebo or acyclovir According to a previous study evaluating HSV reactivation in
powder had expired. Because funding for replacing the pow- patients with prolonged mechanical ventilation, the ex-
ders was not available, it was decided to continue the trial only pected SD of ventilator-free days for controls was 20 days.2 We
in the 2 centers with the highest inclusion rates—Hôpitaux hypothesized that preemptive acyclovir administration could
Universitaires Pitié Salpêtrière-Charles Foix and Hôpitaux de increase the number of ventilator-free days by 8 days. To have
Marseille—and to use a different placebo and acyclovir distri- 80% power with a 5% α level, 112 patients had to be included
bution procedure that would keep investigators blind with- per group after applying a correcting coefficient of 0.864 to
out requiring additional budget. Accordingly, from Novem- adjust for asymptotic test efficiency.12 To account for poten-
ber 16, 2016, to the end of the trial, when a patient was tial losses to follow-up, that number was raised to 120 per
randomized in the trial, acyclovir was reconstituted in saline group, meaning that 240 patients had to be included. Be-
bags by a pharmacist or an independent research nurse (both cause 1 patient withdrew consent, the database was reset at
not blinded to the randomization arm) outside of the ICU. The 241 patients for stopping the inclusions. Two patients were in-
same process was used for the placebo, and bags were distrib- advertently entered into the web randomization system but
uted to the nurse in charge of the patient. All bags were la- were not randomized because they fulfilled an exclusion cri-
beled using protocol labels of Preemptive Treatment for Her- terion. When 241 patients were included in the web random-
pesviridae study drug. As such, the nurses and physicians in ization system, the data manager stopped the inclusions, leav-
charge of the patients in the ICU were not aware of the study ing 239 patients randomized and 2 not randomized.
drug during the entire study period. As proposed recently, we recalculated ventilator-free days
in such a manner that death constituted a worse outcome than
Study Outcomes fewer days off the ventilator.13 Each patient was compared with
The primary outcome was the number of ventilator-free days every other patient in the study and assigned a score (tie: 0,
at day 60 (ie, days alive without mechanical ventilation). For win: +1, loss: −1) for each pairwise comparison based on who
patients who died before day 60, that number was zero, re- fared better. If one patient survived and the other did not,
gardless of mechanical ventilation duration. For patients with scores of +1 and −1 were assigned, respectively, for that pair-
multiple mechanical ventilation episodes during the 60-day wise comparison. If both patients in the pairwise comparison
follow-up period, days without mechanical ventilation were survived, the assigned score depended on which patient had
considered only after the last weaning process of mechanical more days free from mechanical ventilation: the patient with
ventilation. Secondary outcomes included day 60 mortality more days off the ventilator received a score of +1, and the pa-
rate; mechanical ventilation duration; occurrence of HSV tient with fewer days received a score of −1. If both patients
bronchopneumonitis2 or active CMV infection; secondary bac- survived and had the same number of days off the ventilator
terial pneumonia, bacteremia, or fungemia; acute respira- or if both patients died, they both were assigned a score of 0
tory distress syndrome; and septic shock post randomiza- for that pairwise comparison. For each patient, scores for all
tion. The main safety end points were acute renal failure and pairwise comparisons were summed, resulting in a cumula-
neurotoxicity. The protocol specified that acyclovir could be tive score for each patient. These cumulative scores were
stopped for stage 3 acute kidney injury as defined by the acute ranked and compared between treatment groups via the Mann-
kidney injury network, if the treating physician judged it to be Whitney technique. The probability of more favorable out-
study agent related.10 Potential neurologic complications were come is a ranked composite incorporating death and days free
accorded special attention. Physicians recorded other safety from mechanical ventilation among survivors. It represents the
concerns in the electronic case report form. estimated probability that an individual randomly selected
The following post hoc analyses were conducted: per- from 1 treatment group will have a higher score (more favor-
protocol analysis, including patients who had received the able outcome) than an individual randomly selected from the
study agent for 7 days or more; subgroup analyses according other group. It is mathematically equivalent to the area un-
to the number of organ failures at randomization (≤2 or >2) and der the receiver operating characteristic curve for the Mann-
number of prerandomization days on mechanical ventilation Whitney test. A value of 50% indicates no difference be-
(defined according to the median value of 10 days); subgroup tween groups.13
analyses according to the time of randomization (ie, before and Data are expressed as median (interquartile range [IQR]),
after November 16, 2016, corresponding to the time of dispen- mean (SD), or mean (95% CI), as appropriate. Between-group
sation of study drug changed); and sensitivity analysis com- comparisons used a t test or the Mann-Whitney test for con-
paring the cumulative incidence of each event (mechanical tinuous variables according to the variable distribution (ie, nor-
ventilation weaning and death) to take into account the com- mal or not). The normality assumption was tested for each
petition between these 2 events (ie, the occurrence of one type quantitative variable using a Shapiro test if 1 of the numbers
of event [eg, death] will prevent the occurrence of the other was less than 50 or an Anderson-Darling test. If normality was
[mechanical ventilation weaning]).11 Data on day 90 status and not rejected, we used the t test; otherwise, the Mann-
day 60 to 90 mechanical ventilation use were collected retro- Whitney test was used. For categorical variables, between-

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 Research Original Investigation Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation

sons for discontinuation were 25 deaths (acyclovir, 9; control,

Figure 1. Study Flowchart
16), 41 ICU discharges (acyclovir, 21; control, 20), 4 acyclovir-
related adverse events, HSV bronchopneumonitis in a control
1621 Adult patients ventilated >96 h
screened for HSV reactivation patient, active CMV infection or herpes zoster in 2 control
patients, 9 physicians’ decisions (acyclovir, 4; control, 5), 4 er-
1382 Excluded rors (acyclovir, 3; control, 1), 3 unavailable study agents (acy-
908 Extubated or died
before positivity clovir, 2; control, 1), and 1 unknown reason in a control patient.
123 Care withdrawal decided
96 No family to give consent
77 CMV reactivation Primary and Secondary End Points
72 Included in another study On day 60, the median (IQR) numbers of ventilator-free days
54 SAPS II score >75 were 35 (0-53) for acyclovir recipients and 36 (0-50) for con-
50 Refused their consent
2 Eligible but not trols (P = .17 for between-group comparison).
randomized On day 60, 26 acyclovir recipients (22%) and 39 controls
(33%) had died (risk difference, 0.11; 95% CI, –0.004 to 0.22;
239 Randomized P = .06). The hazard ratio for death within 60 days post ran-
domization for the acyclovir group vs controls was 0.61 (95%
119 Randomized to acyclovir 120 Randomized to placebo
CI, 0.37-0.99; P = .047) (Figure 2). No significant violation from
the proportional hazards assumption was observed (P = .25).
1 Withdrew consent On day 60, 33 acyclovir recipients (28%) and 48 control pa-
tients (40%) had died or were still receiving mechanical ven-
119 Included in the primary analysis 119 Included in the primary analysis tilation (P = .08). Median (IQR) mechanical ventilation dura-
tion for day-60 survivors was 17 (6-32) days for acyclovir
The Simplified Acute Physiology Score (SAPS) II is assessed on a scale ranging recipients and 14 (825) days for controls (P = .89). Other sec-
from 0 to 163, with higher scores indicating greater disease severity. ondary end points (Table 3) did not differ between groups. Time
CMV indicates cytomegalovirus; HSV, herpes simplex virus. to weaning from mechanical ventilation was comparable for
the 2 groups (eFigure 1 in Supplement 2).
group comparisons used χ2 or Fischer exact tests. Censored out- Patients’ clinical courses, as assessed by temperature,
comes (time to death and time to weaning-off mechanical white blood cell count, radiologic score, 15 and modified
ventilation) were described with the Kaplan-Meier method, Clinical Pulmonary Infection Score16 from randomization to
with between-group log-rank test comparisons. Proportional day 14, and SOFA score and PaO2/fraction of inspired oxygen
hazards assumption was evaluated graphically using Shoen- ratio kinetics from randomization to day 28 were also com-
feld residuals and the Harrell test. Main analyses were con- parable for the 2 study groups (eFigures 2-7 in Supple-
ducted on an intention-to-treat basis. ment 2). Microorganisms responsible for bacteremia/
All analyses were computed with R software, version 3.5.1 fungemia post randomization were also similar between
(R Project for Statistical Computing), at a 2-sided, 5% α level groups (eTable 1 in Supplement 2).
of significance.
Post Hoc Analyses
The ranked composite end point, incorporating death and days
free from mechanical ventilation through day 28, was not sig-
Results nificantly different between treatment groups (Table 3). The
Among the 1621 patients screened for HSV and CMV, 239 were probability of more favorable outcome with acyclovir com-
randomized (Figure 1). One placebo-group patient withdrew pared with placebo was 51%. Subgroup analyses, reported in
consent, leaving 238 assessable patients: 119 acyclovir and 119 eTable 2, eTable 3, and eFigure 8 in Supplement 2, showed a
placebo recipients. Participants’ baseline characteristics at ICU significant interaction between day 60 mortality and number
admission (Table 1) differed significantly only for body mass of organ failures at randomization but not mechanical venti-
index, which was lower for controls (median [IQR]: acyclovir, lation duration before randomization, no significant interac-
29.3 [26.1-34.3] vs control: 27.2 [23.5-32.1]; calculated as weight tion between ventilator-free days and the number of organ fail-
in kilograms divided by height in meters squared). Their char- ures at randomization or mechanical ventilation duration
acteristics at randomization were also comparable (Table 2). before randomization, and no significant interaction be-
The median (IQR) prerandomization mechanical ventilation tween time of randomization and ventilator-free days or day
duration was 10 (8-14) days for both groups. 60 mortality. Sensitivity analysis comparing the cumulative
incidence of mechanical ventilation weaning and death dis-
Study Drug played similar results (eFigure 9 in Supplement 2).
All patients received 1 or more doses of a study agent. Median On day 90, 33 acyclovir recipients (28%) and 41 controls
(IQR) treatment durations were comparable (Table 3): 14 (34%) had died (P = .26 for between-group comparison) (eFig-
(11-14) days for acyclovir recipients and 14 (10-14) days for con- ure 10 in Supplement 2). The median (IQR) numbers of day 90
trols (P = .69). Ninety patients (43 acyclovir recipients and 47 ventilator-free days were comparable for acyclovir recipients
controls) stopped the study agent earlier than scheduled. Rea- (32 [0-53]) and controls (36 [0-50]) (P = .43).

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 Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation Original Investigation Research

Table 1. Patient Characteristics at ICU Admissiona

Study Group
Acyclovir Placebo
Characteristic (n = 119) (n = 119)
Age, median (IQR), y 61 (52-68) 61 (48-71)
Men, No. (%) 78 (66) 84 (71)
Women, No. (%) 41 (34) 35 (29)
BMI, median (IQR) 29.3 (26.1-34.3) 27.2 (23.5-32.1)
McCabe and Jackson score >2, No. (%)b 30 (25) 26 (22)
Preexisting disease, No. (%)
NYHA III or IV heart failure 5 (4) 8 (7)
Cancer/hemopathy 19 (16) 16 (13)
Diabetes 24 (20) 31 (26)
COPD 23 (19) 14 (12)
Cirrhosis 2 (2) 4 (3)
Chronic renal failurec 16 (13) 13 (11)
Admission category, No. (%)
Medical 99 (83) 96 (81)
Emergency surgery 12 (10) 14 (12)
Planned surgery 8 (7) 9 (8)
Primary reason for mechanical ventilation, No. (%)
Septic shock 16 (13) 17 (14)
Cardiogenic shock 12 (10) 14 (12)
Shock, other 1 (1) 2 (2)
Acute respiratory failure 31 (26) 25 (21)
Postoperative acute respiratory failure 6 (5) 12 (10)
Exacerbation of chronic respiratory disease 12 (10) 9 (8)
Trauma 5 (4) 5 (4)
Coma 6 (5) 9 (8)
Cardiac arrest 5 (4) 5 (4)
Other 25 (21) 21 (18)
SAPS II, median (IQR)d 45 (35-57) 46 (37-57)
SOFA score, median (IQR)e 10 (6-13) 9 (7-12)
Organ or system failure, No. (%)f
Cardiovascular 72/117 (62) 77/117 (66)
Respiratory 82/112 (73) 80/113 (71)
Renal 47 (40) 43 (36)
Central nervous 23/117 (20) 27 (23)
Hepatic 1 (1) 4 (3)
Coagulation 6 (5 8 (7)
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided 1.7 mg/dL (to convert to micromoles per liter, multiply by 88.4), or chronic
by height in meters squared); COPD, chronic obstructive pulmonary disease; dialysis.
ICU, intensive care unit; IQR, interquartile range; NYHA, New York Heart d
Possible score, 0 to 163; higher scores indicate greater disease severity.
Association; SAPS, Simplified Acute Physiology Score; SOFA, Sequential e
Calculated from 6 variables the day of randomization, taking into account the
Organ-Failure Assessment.
worst values of each parameter in the 24 hours preceding the randomization.
a
There were no significant between-group differences in characteristics at ICU Scores range from 0 to 24, with higher scores indicating more severe organ
admission, except for body mass index (P = .002). failure and higher mortality risk. Patients with a SOFA score of 10 have a
b
Denotes the severity of underlying medical conditions: 0 indicates no predicted mean chance of survival between 40% and 50%.
underlying disease; 1, nonfatal underlying disease; 2, ultimately fatal (survival f
Organ or system failure was deemed present when the corresponding SOFA
>1 to <5 years) underlying disease; and 3, rapidly fatal (survival <1 year) score was greater than 2. When data regarding organ/system failure were
underlying disease. missing, number of assessable patients is reported.
c
Creatinine clearance less than 60 mL/min, serum creatinine level greater than

The per-protocol analysis that included patients treated for days were 31 (0-50) for acyclovir recipients and 34 (0-50) for con-
7 days or more retained 227 patients: 111 acyclovir recipients and trols (P = .42). Among those 237 patients, 26 acyclovir recipients
116 controls. On day 60, the median numbers of ventilator-free (23%) and 39 controls (34%) had died by day 60 (P = .09).

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 Research Original Investigation Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation

Table 2. Patient Characteristics at Randomizationa

Study Group
Acyclovir Placebo
Characteristic (n = 119) (n = 119)
MV duration before inclusion, median (IQR), d 10 (8-14) 10 (8-14)
Time between positive HSV test and randomization, median (IQR), d 3 (1-4) 2 (1-5)
Ongoing antimicrobial treatment, No. (%) 88 (74) 84 (71)
ECMO use, No. (%) 40 (34) 31 (26)
Renal replacement therapy, No. (%) 36 (30) 29 (24)
SOFA score, median (IQR)b 7 (5-10) 8 (5-11)
Organ or system failure, No. (%)c
Cardiovascular 47 (40) 53 (45)
Respiratory 69 (58) 76 (64)
Renal 38 (32) 32 (27)
Central nervous 19 (16) 26 (22)
Hepatic 7 (6) 7 (6)
Coagulation 13 (11) 9 (8)
Temperature, median (IQR), °C 37.6 (36.6-38.2) 37.8 (37.1-38.5)
White blood cell count, median (IQR), /μL 12 900 (10 100-17 700) 13 900 (10 400-20 300)
Neutrophil count, median (IQR), /μL 9900 (7500-14 200) 11 500 (8700-16 900)
PaO2/FiO2, median (IQR), mm Hg 178 (87-246) 174 (114-230)
Radiologic score, median (IQR) 5 (2-8) 6 (3-8)
b
Abbreviations: ECMO, extracorporeal membrane oxygenation; HSV, herpes Calculated from 6 variables the day of randomization, taking into account the
simplex virus; IQR, interquartile range; MV, mechanical ventilation; PaO2/FiO2 worst values of each parameter in the 24 hours preceding the randomization.
(fraction of inspired oxygen), partial oxygen pressure in arterial blood/fraction Scores range from 0 to 24, with higher scores indicating more severe organ
of inspired oxygen ratio; SOFA, Sequential Organ-Failure Assessment. failure and higher mortality risk. Patients with a SOFA score of 7 to 8 have
SI conversion: To convert neutrophils and white blood cells to ×109 per liter, a predicted mean chance of survival between 15% and 20%.
c
multiply by 0.001. Organ or system failure was deemed present when the corresponding SOFA
a
There were no significant between-group differences in characteristics at score was greater than 2.
randomization.

Safety by the number of ventilator-free days. Moreover, other sec-

The adverse event rates were comparable for the 2 groups ondary outcomes did not differ between acyclovir recipients
(eTable 4 in Supplement 2), notably with 3 acyclovir recipi- and controls. Nonsignificant lower day 60 mortality was ob-
ents (3%) and 2 controls (2%) experiencing acute renal failure served for acyclovir recipients compared with controls. Acy-
after randomization. Moreover, creatinine levels from ran- clovir was well tolerated at the dose administered (5 mg/kg
domization to day 14 for the 2 groups did not differ signifi- 3 times daily), without renal or neurologic adverse events,
cantly (eFigure 11 in Supplement 2) and the percentages of pa- although our study was underpowered to assess such major
tients requiring renal replacement therapy from randomization complications.
to end of treatment were comparable (eTable 5 in Supple- Reactivation of HSV is frequent in ICU patients and asso-
ment 2). No neurologic adverse event was reported by the in- ciated with increased morbidity2 and mortality.4 However, the
vestigators during the study, and Glasgow Coma Scale score exact effect of HSV reactivation in ICU patients remains con-
changes from day 1 to day 14 were comparable for the groups troversial: it could be a bystander (ie, a marker of disease se-
(eFigure 12 in Supplement 2). Total bilirubin levels and plate- verity) effect or a pathogen with independent morbidity and
let counts from day 1 to day 28 did not differ between groups mortality.17,18 Reactivation of HSV is the first step before HSV-
(eFigure 13 and eFigure 14 in Supplement 2, respectively). Four associated bronchopneumonitis, which can worsen lung in-
patients (3%) in the acyclovir group vs none in the placebo flammation or injury and pave the way for nosocomial bacte-
group stopped the study drug for treatment-related adverse rial pneumonia, thereby prolonging mechanical ventilation.2,19
events. Research on HSV reactivation and its prognosis has
been published4; however, to our knowledge, Tuxen et al8
conducted the only randomized, double-blind, placebo-
controlled trial on acyclovir efficacy against HSV reactiva-
Discussion tion. They randomized 45 patients with acute respiratory dis-
Our study results show that preemptive acyclovir administra- tress syndrome to receive prophylactic acyclovir or placebo and
tion, compared with placebo for mechanically ventilated pa- found that acyclovir was associated with significantly less HSV
tients with oropharyngeal HSV reactivation, was not associ- reactivation (6% vs 71%, P < .001), but not with shorter me-
ated with shorter mechanical ventilation durations, as assessed chanical ventilation durations or lower mortality. Because some

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 Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation Original Investigation Research

Table 3. Outcomes

Study Group
Acyclovir Placebo
Parameter (n = 119) (n = 119) P Value
Primary outcome
Ventilator-free days at day 60, median (IQR) 35 (0-53) 36 (0-50) .17
Secondary outcomes post randomization
Day 60 mortality, No. (%) 26 (22) 39 (33) .06
Duration of MV, median (IQR) 17 (7-30) 13 (7-23) .41
Probability of more favorable outcome, %a 50.78 40.48 .16
ICU length of stay, median (IQR) 20 (12-41) 17 (11-31) .10
HSV bronchopneumonitis, No. (%) 1 (1) 4 (3) .37
Cytomegalovirus infection, No. (%) 1 (1) 5 (4) .21
Hospital-acquired bacterial pneumonia, No. (%) 58 (49) 53 (45) .52
Secondary bacteremia or fungemia, No. (%) 29 (24) 27 (23) .75
ARDS postrandomization, No. (%)b 14 (12) 7 (6)
Mild 2 0
Moderate 7 2 .11
Severe 5 4
Septic shock post randomization, No. (%) 22 (18) 27 (23) .42
No. of days with study drug, median (IQR) 14 (11-14) 14 (10-14) .69
Abbreviations: ARDS, acute respiratory distress syndrome; HSV, herpes simplex than an individual randomly selected from the other group. It is
virus; ICU, intensive care unit; IQR, interquartile range; MV, mechanical mathematically equivalent to the area under the receiver operating
ventilation; PaO2/FiO2 (fraction of inspired oxygen) partial oxygen pressure in characteristic curve for the Mann-Whitney test. A value of 50% indicates no
arterial blood/fraction of inspired oxygen ratio; PEEP positive end-expiratory difference between groups.13
pressure. b
The Berlin definition of ARDS is as follows: mild: PaO2/FiO2 greater than 200
a
Probability of more favorable outcome is a ranked composite incorporating but 300 or less, with positive end expiratory pressure (PEEP) or continuous
death and days free from mechanical ventilation among survivors. It positive airway pressure (CPAP) 5 cm H2O or more; moderate: PaO2/FiO2
represents the estimated probability that an individual randomly selected greater than 100 but 200 or less, with PEEP or CPAP 5 cm H2O or more;
from 1 treatment group will have a higher score (more favorable outcome) severe: PaO2/FiO2 100 or less with PEEP 5 cm H2O or more.14

patients, even those who are HSV seropositive, will never ex- Figure 2. Survival Analysis Through 60 Days
perience virus reactivation during their ICU stays, this pro-
phylactic strategy of treating before reactivation may unnec- 1.00

essarily expose patients to acyclovir. Because of renal and Acyclovir

neurologic toxic effects,20,21 the applicability of prophylactic 0.75
Survival Probability

acyclovir may be questionable. Luyt et al2 compared 42 ICU

Placebo
patients who developed HSV bronchopneumonitis—19 pa- 0.50
tients given acyclovir, 10 mg/kg, 3 times per day for 5 to 14 days
and 23 patients without antiviral treatment. The investiga-
0.25
tors found that the clinical courses of all patients were simi-
Log-rank P =.045
lar, including hospital mortality rates (acyclovir, 37%; con-
0
trol, 57%). However, the criteria for treating patients with 0 10 20 30 40 50 60
acyclovir were not defined by the authors. Although treating Days
No. at risk
only patients with documented HSV bronchopneumonitis has 119 106 90 86 85 82
Placebo 80
the advantage of limiting acyclovir exposure to patients with Acyclovir 119 113 104 101 96 94 93
true disease, it raises several issues, including a complicated
definition of disease.2 In addition, Traen et al19 retrospec- Survival estimates in the intention-to-treat population.

tively analyzed 212 patients with HSV-1–positive respiratory

tract or bronchoalveolar lavage-fluid cultures and compared To our knowledge, no published study has evaluated the
the outcomes of acyclovir recipients (n = 106) vs those not effect of a preemptive strategy for ICU patients with HSV re-
given the drug (n = 106). Acyclovir was associated with lower activation. Such a strategy has several advantages. First, acy-
in-ICU and in-hospital mortality rates, even after adjustment clovir is given only to patients with HSV reactivation, there-
in multivariable Cox or propensity-score analyses. However, fore, not exposing those without reactivation to this potentially
that analysis was retrospective and, despite adjustment, po- toxic drug. Second, patients are treated before lung disease oc-
tential confounders might not have been taken into account curs, and some authors have suggested that HSV might in-
(notably, the decision to administer acyclovir based on un- duce lung injury, paving the way for bacterial infection.2,17 This
known criteria). kind of strategy is applied successfully for CMV in solid-

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 Research Original Investigation Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation

organ recipients; preemptive treatment of CMV reactivation exponential increase to reach very high HSV peaks (106-1010
seems to be, at least for some transplanted organs, noninfe- copies/mL) in 78% of the HSV DNA-positive patients.24 There-
rior to a prophylactic approach.22 However, use of preemp- fore, although we cannot exclude that patients with HSV oro-
tive treatment implies implementing regular screening of pa- pharyngeal reactivation could evolve toward a rapid, sponta-
tients susceptible to HSV reactivation. neous resolution of HSV reactivation without acyclovir, this
We were unable to demonstrate any beneficial effect of acy- resolution appears to be uncommon in ICU patients requiring
clovir in ICU patients. This result could have been due to a lack prolonged mechanical ventilation. Conversely, we cannot be
of power of our study. As indicated above, some investigators sure whether acyclovir, 5 mg/kg, 3 times daily was able to stop
have postulated that acyclovir could improve the prognosis of virus reactivation and prevent lower respiratory tract coloni-
ICU patients having reactivated HSV by limiting the bronchio- zation and/or infection in our study, although this dose has
alveolar damage secondary to viral infection, and/or by pre- been shown to be effective to prevent HSV reactivation in a pre-
venting CMV replication, even the anti-CMV effect of acyclo- vious randomized clinical trial.8
vir is usually observed with higher doses than the ones used Our study has other limitations. First, whether the study
in our study.1,2,4,17 Although the acyclovir group had a non- population and standard of care in the ICUs that participated
significant lower day 60 mortality, the number of ventilator- in the Preemptive Treatment for Herpesviridae trial were simi-
free days was comparable to that of placebo-treated patients, lar to those observed elsewhere could be debatable. However,
implying that survivors in the acyclovir group had a longer me- patients’ clinical characteristics in our study were comparable
chanical ventilation duration (ie, fewer ventilator-free days) to those reported in a large, nonselected database of patients
than the placebo recipient survivors. This longer duration of who were mechanically ventilated.25 Second, although our treat-
mechanical ventilation in acyclovir survivors might be due to ment groups did not differ significantly, acyclovir recipients re-
the higher number of patients with extracorporeal mem- ceived slightly more frequent, but not statistically significant,
brane oxygenation support and the higher percentage of pa- extracorporeal membrane oxygenation support and renal re-
tients developing acute respiratory distress syndrome after ran- placement therapy at randomization, and more developed acute
domization. Whether acyclovir could improve the survival of respiratory tract distress syndrome post randomization, it re-
mechanically ventilated patients with reactivated HSV at the mains unknown whether those findings could have affected the
cost of a prolonged mechanical ventilation duration is un- results. Third, using ventilator-free days as the primary out-
known and remains to be explored. Whether targeting a more come may be debated.24 Fourth, we cannot exclude the possi-
narrowly defined population (ie, patients with <2 organ bility that some patients may have had HSV viremia or HSV or-
failures) might have changed our results also remains to gan disease without previous oropharyngeal reactivation and
be determined. that we could have missed these patients. In addition, our pri-
mary hypothesis (8-day increase of ventilator-free days) was per-
Limitations haps too optimistic, and our sample size may have limited the
One major limitation of our study was the lack of serial moni- study’s ability to detect a true effect.
toring of HSV shedding in respiratory tract secretions. It is
known that HSV reactivation begins in the throat within the
first 10 days of mechanical ventilation,1 followed by a descend-
ing contamination of the bronchial tree. Using quantitative real-
Conclusions
time polymerase chain reaction testing for the quantitative de- It appears that for ICU patients with HSV reactivation in the
tection of HSV DNA, De Vos et al23 described the time-course throat while receiving mechanical ventilation for 96 hours or
of HSV shedding in lower respiratory tract secretions and found more, acyclovir, 5 mg/kg, 3 times daily compared with pla-
that HSV emerged in tracheal and bronchial aspirates after a cebo was unable to increase the day 60 number of ventilator-
median of 7 (IQR, 5-11 days) days of intubation, followed by an free days.

ARTICLE INFORMATION Information Médicale, Centre de d’Epidémiologie et de Santé Publique, AP-HP,

Accepted for Publication: September 28, 2019. Pharmacoépidémiologie, Paris, France (Hajage); Hôpitaux Universitaires Pitié Salpêtrière Charles
Réanimation Chirurgicale, Centre Hospitalier Foix, Unité de Recherche Clinique, Paris, France
Published Online: December 16, 2019. Universitaire de Montpellier, Hôpital St-Eloi, (Diallo); Pharmacie, Hôpitaux Sud, Assistance
doi:10.1001/jamainternmed.2019.5713 Montpellier, France (Jaber); Département Publique–Hôpitaux de Marseille, Marseille, France
Author Affiliations: Sorbonne Université, INSERM, de médecine periopératoire, Centre Hospitalier (Penot-Ragon); Réanimation Polyvalente, Centre
Médecine Intensive Réanimation, Institut de Universitaire Clermont-Ferrand, Clermont-Ferrand, Hospitalier Universitaire Dupuytren, Limoges,
Cardiologie, Hôpitaux Universitaires Pitié France (Cayot-Constantin); Réanimation France (Clavel); Médecine Intensive Réanimation,
Salpêtrière-Charles Foix, Assistance Publique– Chirurgicale, Hôpital Edouard-Herriot, Hospices Centre Hospitalier Universitaire Grenoble Alpes,
Hôpitaux de Paris, Paris, France (Luyt, Combes, Civils de Lyon, Lyon, France (Rimmelé); La Tronche, France (Schwebel); Médecine Intensive
Chastre); Médecine Intensive Réanimation, Réanimation Médicale, Centre Hospitalier Réanimation, Hôpital Bichat, Assistance Publique–
Aix-Marseille Université, Hôpital Nord, Assistance Universitaire Gabriel-Montpied, Clermont-Ferrand, Hôpitaux de Paris, Paris, France (Timsit); Service
Publique–Hôpitaux de Marseille, Marseille, France France (Coupez); Réanimation Chirurgicale de Réanimation, Hôpital Mignot, Versailles, France
(Forel, Papazian); Sorbonne Université, INSERM, Polyvalente, Département (Bedos); Médecine Intensive Réanimation, Hôpital
Institut Pierre Louis d’Epidémiologie et de Santé d’Anesthésie-Réanimation, Hôpitaux Universitaires Européen Georges-Pompidou, Assistance
Publique, Assistance Publique-Hôpitaux de Paris, Pitié Salpêtrière-Charles Foix, Assistance Publique– Publique–Hôpitaux de Paris, Paris, France
Hôpitaux Universitaires Pitié Salpêtrière-Charles Hôpitaux de Paris, Paris, France (Lu); Sorbonne (Hauw-Berlemont); Réanimation des Urgences et
Foix, Département Biostatistique Santé Publique et Université, INSERM, Institut Pierre Louis Médicale, Aix-Marseille Université, Hôpital Timone,

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 Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation Original Investigation Research

Assistance Publique–Hôpitaux de Marseille, Drs Brebion, Henquell, Peigue-Lafeuille. CHU de (9395):1536-1541. doi:10.1016/S0140-6736(03)
Marseille, France (Bourenne); Pneumologie, Nîmes: Réanimation Chirurgicale: Pr Lefrant; 14740-X
Médecine Intensive Réanimation, Hôpitaux Virologie: Dr Carles. CHU de Limoges Dupuytren: 2. Luyt C-E, Combes A, Deback C, et al. Herpes
Universitaires Pitié Salpêtrière-Charles Foix, Réanimation Polyvalente: Drs Clavel, François, simplex virus lung infection in patients undergoing
Assistance Publique–Hôpitaux de Paris, Paris, Vignon; Virologie: Drs Alain, Hant. CH de Versailles, prolonged mechanical ventilation. Am J Respir Crit
France (Mayaux); Réanimation Chirurgicale, Centre Hôpital Mignot: Réanimation Polyvalente: Drs Ferre, Care Med. 2007;175(9):935-942. doi:10.1164/rccm.
Hospitalier Universitaire Nîmes, Nîmes, France Bruneel, Bedos; Virologie: Dr Marque Juillet. CHU 200609-1322OC
(Lefrant); Médecine Intensive Réanimation, Hôpital de Grenoble: Médecine Intensive Réanimation:
Cochin, Assistance Publique–Hôpitaux de Paris, Drs Terzi, Schwebel; Virologie: Dr Morand. Hôpital 3. Linssen CFM, Jacobs JA, Stelma FF, et al. Herpes
Paris, France (Mira); Réanimation Timone, APHM, Marseille: Réanimation des simplex virus load in bronchoalveolar lavage fluid is
Neurochirurgicale, Hôpital Sainte-Anne, Paris, Urgences: Dr Bourenne. related to poor outcome in critically ill patients.
France (Wolff). Intensive Care Med. 2008;34(12):2202-2209.
Conflict of Interest Disclosures: Dr Luyt reported doi:10.1007/s00134-008-1231-4
Author Contributions: Dr Luyt had full access to all receiving grants from French Ministry of Health
of the data in the study and takes responsibility for during the conduct of the study; personal fees from 4. Coisel Y, Bousbia S, Forel J-M, et al.
the integrity of the data and the accuracy of the Bayer Healthcare, Carmat, Faron, Merck Sharp & Cytomegalovirus and herpes simplex virus effect on
data analysis. Dohme, ThermoFischer Brahms, and Biomérieux; the prognosis of mechanically ventilated patients
Concept and design: Luyt, Forel, Jaber, Wolff, and grants from Bayer Healthcare outside the suspected to have ventilator-associated
Chastre, Papazian. submitted work. Dr Forel reported receiving grants pneumonia. PLoS One. 2012;7(12):e51340. doi:10.
Acquisition, analysis, or interpretation of data: Luyt, from DGOS PHRCN during the conduct of the study. 1371/journal.pone.0051340
Forel, Hajage, Jaber, Samir, Cayot-Constantin, Dr Hajage reported receiving grants from the 5. Begg C, Cho M, Eastwood S, et al. Improving the
Rimmelé, Coupez, Lu, Diallo, Clavel, Schwebel, Ministry of Health during the conduct of the study. quality of reporting of randomized controlled trials.
Timsit, Bedos, Hauw-Berlemont, Bourenne, Dr Samir reported receiving personal fees from The CONSORT statement. JAMA. 1996;276(8):
Mayaux, Lefrant, Mira, Combes, Wolff, Chastre, Drager, Fisher-Paykel, Medtronic, Baxter, and 637-639. doi:10.1001/jama.1996.03540080059030
Papazian. Xenios-Fresenius outside the submitted work. 6. Le Gall JR, Lemeshow S, Saulnier F. A new
Drafting of the manuscript: Luyt, Forel, Cayot, Dr Rimmelé reported receiving grants from Baxter Simplified Acute Physiology Score (SAPS II) based
Penot-Ragon, Combes, Chastre. and personal fees from Fresenius Medical Care and on a European/North American multicenter study.
Critical revision of the manuscript for important Biomérieux outside the submitted work. Dr Timsit JAMA. 1993;270(24):2957-2963. doi:10.1001/jama.
intellectual content: Luyt, Forel, Hajage, Jaber, reported receiving grants and personal fees from 1993.03510240069035
Rimmelé, Coupez, Lu, Diallo, Clavel, Schwebel, Merck and Pfizer; personal fees from Gilead,
Timsit, Bedos, Hauw-Berlemont, Bourenne, Nabriva, and Paratek; grants from Biomerieux, and 7. Vincent JL, Moreno R, Takala J, et al. The SOFA
Mayaux, Lefrant, Mira, Combes, Wolff, Chastre, personal fees from Bayer outside the submitted (Sepsis-related Organ Failure Assessment) score to
Papazian. work. Dr Combes reported receiving grants from describe organ dysfunction/failure; on behalf of the
Statistical analysis: Forel, Hajage, Diallo, Papazian. Getinge and personal fees from Getinge and Baxter Working Group on Sepsis-Related Problems of the
Obtained funding: Luyt, Clavel, Papazian. outside the submitted work. Dr Wolff reported European Society of Intensive Care Medicine.
Administrative, technical, or material support: Luyt, receiving personal fees from Merck & Co, Pfizer, Intensive Care Med. 1996;22(7):707-710. doi:10.
Forel, Rimmelé, Coupez, Penot-Ragon, Combes, Correvio, and Inotrem outside the submitted work. 1007/BF01709751
Papazian. Dr Chastre reported receiving grants from French 8. Tuxen DV, Wilson JW, Cade JF. Prevention of
Supervision: Luyt, Forel, Hajage, Jaber, Samir, Ministry of Health during the conduct of the study; lower respiratory herpes simplex virus infection
Bedos, Lefrant, Wolff, Chastre, Papazian. personal fees from Bayer, Shionogi, Aridis, Merck, with acyclovir in patients with the adult respiratory
Group Information: Members of the Preemptive Polyphor, and Tigenix/Takeda; and grants and distress syndrome. Am Rev Respir Dis. 1987;136(2):
Treatment for Herpesviridae Study Group according personal fees from AstraZeneca outside the 402-405. doi:10.1164/ajrccm/136.2.402
to hospital: Hôpitaux Universitaires Pitié submitted work. Dr Papazian reported receiving 9. Résumé Des Caractéristiques Du Produit.
Salpêtrière-Charles Foix, APHP, Paris: Médecine grants from French Ministry of Health during the http://agence-prd.ansm.sante.fr/php/ecodex/rcp/
Intensive Réanimation: Drs Hékimian, Bréchot, conduct of the study. No other disclosures were R0229767.htm. Accessed.
Nieszkowska, Schmidt, Combes, Chastre, Luyt; reported.
10. Mehta RL, Kellum JA, Shah SV, et al; Acute
Pneumologie, Médecine Intensive Réanimation: Funding/Support: The trial was funded by the Kidney Injury Network. Acute Kidney Injury
Drs Mayaux, Demoule; Réanimation Chirurgicale Direction de la Recherche Clinique et du Network: report of an initiative to improve
Polyvalente, Département d’Anesthésie Développement and the French Ministry of Health; outcomes in acute kidney injury. Crit Care. 2007;11
Réanimation: Drs Lu, Arbelot, Vezinet, Monsel, Programme Hospitalier de Recherche Clinique 2011. (2):R31. doi:10.1186/cc5713
Rouby; Virologie: Drs Burrel, Boutolleau. Hôpital Role of the Funder/Sponsor: The funding
Nord, Marseille, APHM: Médecine Intensive 11. Gray RJ. A class of K-sample tests for comparing
organization had no role in the design and conduct the cumulative incidence of a competing risk. Ann
Réanimation: Drs Hraiech, Guervilly, Forel, Roch, of the study; collection, management, analysis, and
Papazian; Virologie: Drs Zandotti, Charrel. CHU Stat. 1988;16(3):1141-1154. doi:10.1214/aos/1176350951
interpretation of the data; preparation, review, or
de Montpellier, Hôpital St-Eloi: Réanimation approval of the manuscript; and decision to submit 12. Hollander M, Wolfe D. Nonparametric Statistical
Chirurgicale: Drs Coisel, Chanques, Jaber; Virologie: the manuscript for publication. Methods. 2nd ed. New York: John Wiley and Sons;
Drs Segondy, Foulogne, Montes. Hôpital Bichat, 1999.
APHP, Paris: Médecine Intensive Réanimation: Data Sharing Statement: See Supplement 3.
13. Beitler JR, Sarge T, Banner-Goodspeed VM,
Drs Sonneville, Timsit, Wolff (now, Réanimation Additional Contributions: Janet Jacobson helped et al; EPVent-2 Study Group. Effect of titrating
Neurochirurgicale, Hôpital Sainte-Anne) Virologie: with preparation and correction of the manuscript, positive end-expiratory pressure (PEEP) with an
Drs Houhou, Brun-Vezinet. Hôpital Cochin, APHP, for which she was compensated, and Jean-Marie esophageal pressure-guided strategy vs an
Paris: Médecine Intensive Réanimation: Drs Cariou, Chrétien and Lucie Van Eeckhoutte (Direction empirical high PEEP-FiO2 strategy on death and
Charpentier, Pene, Mira; Virologie: Dr Rozenberg. de la Recherche Clinique, Cellule Gestion des days free from mechanical ventilation among
Hôpital Européen Georges-Pompidou, APHP, Paris: Données et Évaluation, Centre patients with acute respiratory distress syndrome:
Médecine Intensive Réanimation: Drs Aissaoui, Hospitalo-Universitaire d'Angers), performed the a randomized clinical trial. JAMA. 2019;321(9):846-
Guerot, Diehl, Fagon; Virologie: Drs Bélec, data management, for which they were 857. doi:10.1001/jama.2019.0555
Si-Mohamed. Hospices Civils de Lyon, Hôpital compensated.
Edouard-Herriot: Réanimation Chirurgicale: 14. Ranieri VM, Rubenfeld GD, Thompson BT, et al;
Dr Rimmelé; Virologie: Drs Frobert, Billaud, Lina. REFERENCES ARDS Definition Task Force. Acute respiratory
CHU de Clermont-Ferrand: Réanimation Médicale, distress syndrome: the Berlin Definition. JAMA.
1. Bruynseels P, Jorens PG, Demey HE, et al. Herpes 2012;307(23):2526-2533. doi:10.1001/jama.2012.
Hôpital Gabriel-Montpied: Drs Coupez, Souweine; simplex virus in the respiratory tract of critical care
Département de médecine périopératoire, CHU 5669
patients: a prospective study. Lancet. 2003;362
de Clermont-Ferrand: Drs Constantin, 15. Weinberg PF, Matthay MA, Webster RO,
Cayot-Constantin, Jabaudon, Godet; Virologie: Roskos KV, Goldstein IM, Murray JF. Biologically

jamainternalmedicine.com (Reprinted) JAMA Internal Medicine February 2020 Volume 180, Number 2 271

© 2019 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 06/13/2022

 Research Original Investigation Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation

active products of complement and acute lung 19. Traen S, Bochanen N, Ieven M, et al. Is acyclovir 23. De Vos N, Van Hoovels L, Vankeerberghen A,
injury in patients with the sepsis syndrome. Am Rev effective among critically ill patients with herpes et al. Monitoring of herpes simplex virus in the
Respir Dis. 1984;130(5):791-796. doi:10.1164/arrd. simplex in the respiratory tract? J Clin Virol. 2014; lower respiratory tract of critically ill patients using
1984.130.5.791 60(3):215-221. doi:10.1016/j.jcv.2014.04.010 real-time PCR: a prospective study. Clin Microbiol
16. Luyt C-E, Chastre J, Fagon J-Y. Value of the 20. Ryan L, Heed A, Foster J, Valappil M, Schmid Infect. 2009;15(4):358-363. doi:10.1111/j.1469-0691.
clinical pulmonary infection score for the ML, Duncan CJA. Acute kidney injury (AKI) 2009.02704.x
identification and management of associated with intravenous aciclovir in adults: 24. Bodet-Contentin L, Frasca D, Tavernier E,
ventilator-associated pneumonia. Intensive Care Med. Incidence and risk factors in clinical practice. Int J Feuillet F, Foucher Y, Giraudeau B. Ventilator-free
2004;30(5):844-852. doi:10.1007/s00134-003- Infect Dis. 2018;74:97-99. doi:10.1016/j.ijid.2018. day outcomes can be misleading. Crit Care Med.
2125-0 07.002 2018;46(3):425-429. doi:10.1097/CCM.
17. Luyt C-E, Bréchot N, Chastre J. What role do 21. Ernst ME, Franey RJ. Acyclovir- and 0000000000002890
viruses play in nosocomial pneumonia? Curr Opin ganciclovir-induced neurotoxicity. Ann Pharmacother. 25. Bellani G, Laffey JG, Pham T, et al; LUNG SAFE
Infect Dis. 2014;27(2):194-199. doi:10.1097/QCO. 1998;32(1):111-113. doi:10.1345/aph.17135 Investigators; ESICM Trials Group. Epidemiology,
0000000000000049 22. Kotton CN, Kumar D, Caliendo AM, et al; patterns of care, and mortality for patients with
18. Forel J-M, Martin-Loeches I, Luyt C-E. Treating The Transplantation Society International CMV acute respiratory distress syndrome in intensive
HSV and CMV reactivations in critically ill patients Consensus Group. The Third International care units in 50 countries. JAMA. 2016;315(8):788-
who are not immunocompromised: pro. Intensive Consensus Guidelines on the Management of 800. doi:10.1001/jama.2016.0291
Care Med. 2014;40(12):1945-1949. doi:10.1007/ Cytomegalovirus in Solid-organ Transplantation.
s00134-014-3445-y Transplantation. 2018;102(6):900-931. doi:10.1097/
TP.0000000000002191

Invited Commentary

Preemptive Treatment of Herpes Simplex Virus Reactivation

in Critically Ill Patients?—Not Based on Current Data
David S. Y. Ong, MD, PharmD, PhD; Olaf L. Cremer, MD, PhD; Marc J. M. Bonten, MD, PhD

In a multicenter randomized clinical trial by Luyt et al1 pub- increase in ventilator-free days of 8 days with acyclovir
lished in this issue of JAMA Internal Medicine, twice-weekly treatment was not achieved.
screening for oropharyngeal reactivation of herpes simplex Do these findings then close the book on the concept of
virus (HSV) followed by preemptive treatment with acyclovir preemptive treatment of HSV reactivation forever? Maybe not,
during 14 days did not in- as preemptive treatment with acyclovir was associated with
Related article page 263
crease the number of ventila- a reduction in day-60 mortality (a secondary end point of the
tor-free days at day 60 in pa- trial) from 33% to 22% (risk difference, 0.11; 95% CI, −0.004
tients who received mechanical ventilation in the intensive care to 0.22; P = .06) and with a lower death rate in Cox regression
unit (ICU). The study informs a debate that has been ongoing analysis (hazard ratio, 0.61; 95% CI, 0.37-0.99; P = .047).1 Yet,
for decades regarding the clinical relevance of HSV reactiva- this remarkable benefit occurred without effects of acyclovir
tion in patients without an apparent prior immunocompro- treatment on any of the other outcomes. As such, the study
mised condition. underscores the difficulty in interpreting the frequently used
Herpes simplex virus reactivation occurs commonly in pa- failure-free–day end point constructs that aim to summarize
tients who receive ventilation in the ICU; published esti- the effect of an intervention on multiple competing events.
mates vary widely in frequency, from 14% to 71%.2-6 While re- Although the use of such composite outcome measures may
activation is associated with a prolonged duration of increase the statistical efficiency of a trial, these gains are re-
mechanical ventilation as well as increased morbidity and alized only if the intervention affects each component in the
mortality,4,5 it is unclear whether reactivation worsens the pa- same direction. That assumption is not met in the present
tient’s condition or is simply a marker of disease severity. study, with contrasting effects on ventilator-free days and mor-
The trial by Luyt et al1 is the first randomized interven- tality at day 60, and one might therefore argue that absolute
tion study evaluating preemptive treatment with acyclovir mortality would have been the more appropriate primary out-
on detection of HSV reactivation in the throat, to our knowl- come measure.
edge. The study was initiated after a previous small trial Can these contrasting effects be explained? Despite ran-
in 38 patients with acute respiratory distress syndrome domization, it cannot be ruled out that some imbalances be-
revealed that a prophylactic approach reduced the occur- tween both study groups affected the study outcomes. As the
rence of HSV reactivation from 71% to 6%.6 However, that authors acknowledged, the higher number of patients receiv-
study was underpowered to detect clinically important dif- ing extracorporeal membrane oxygenation at the time of ran-
ferences. The current study had 238 patients, and the multi- domization and the higher proportion developing acute re-
center design contributes to the external validity of its spiratory distress syndrome after randomization in the
results. The median (interquartile range) numbers of acyclovir group may have prolonged duration of mechanical
ventilator-free days at day 60, the primary end point in this ventilation in survivors. Possibly, acute respiratory distress syn-
study, were 35 days for acyclovir recipients and 36 days for drome occurred more frequently in patients receiving extra-
controls, convincingly demonstrating that the pursued corporeal membrane oxygenation, independent of the ran-

272 JAMA Internal Medicine February 2020 Volume 180, Number 2 (Reprinted) jamainternalmedicine.com

© 2019 American Medical Association. All rights reserved.

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