Respiratory Viruses in Invasively Ventilated Critically Ill Patients—A Prospective Multicenter Observational Study Frank van Someren Gréve, MD1,2; Nicole P. Juffermans, MD, PhD1; Lieuwe D. J. Bos, PhD1; Jan M. Binnekade, PhD1; Annemarije Braber, MD, PhD3; Olaf L. Cremer, MD, PhD4; Evert de Jonge, MD, PhD5; Richard Molenkamp, PhD2; David S. Y. Ong, MD, PhD, PharmD4,6; Sjoerd P.H. Rebers, BASc2; Angelique M. E. Spoelstra–de Man, MD, PhD7; Koenraad F. van der Sluijs, PhD1; Peter E. Spronk, MD, PhD3; Kirsten D. Verheul, BASc2; Monique C. de Waard, PhD7; Rob B. P. de Wilde, PhD5; Tineke Winters, CCRN1; Menno D. de Jong, MD, PhD2; Marcus J. Schultz, MD, PhD1
Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands. 2 Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands. 3 Department of Intensive Care, Gelre Hospitals, Apeldoorn, The Netherlands. 4 Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. 5 Department of Intensive Care, Leiden University Medical Center, Leiden, The Netherlands. 6 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. 7 Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal). Supported, in part, by the Academic Medical Center (University of Amsterdam, Amsterdam, the Netherlands), Crucell Holland BV (Leiden, the Netherlands), and EU FP7 project PREPARE (grant number 602525). Crucell Holland BV was involved in the study design but had neither a role in collection, management, analysis, and interpretation of the data nor in preparation, review, and the decision to submit the article. Drs. van Someren Gréve and Cremer’s institutions received funding from Crucell Holland BV (Leiden, the Netherlands), EU FP7 project Platform for European Preparedness Against (Re-)emerging Epidemics (grant number 602525). Dr. Bos’ institution received funding from Maquet (unrestrictive research grant) and Dutch Lung Foundation (research grant), and he received funding from GlaxoSmithKline (GSK) (honorarium for presentation) and Bayer (advisory board). Dr. Spoelstra-de Man’s institution received funding from Academic Medical Centre, Amsterdam, the Netherlands. Dr. de Jong’s institution received funding from Crucell B.V. (unrestricted grant), Janssen Pharmaceuticals (Scientific Advisory Board and Independent Data and Safety Monitoring Board), MedImmune (Scientific Advisory Board), and GSK (Independent Data and Safety Monitoring Board). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]; [email protected] 1
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000002752
Critical Care Medicine
Objectives: The presence of respiratory viruses and the association with outcomes were assessed in invasively ventilated ICU patients, stratified by admission diagnosis. Design: Prospective observational study. Setting: Five ICUs in the Netherlands. Patients: Between September 1, 2013, and April 30, 2014, 1,407 acutely admitted and invasively ventilated patients were included. Interventions: None. Measurements and Main Results: Nasopharyngeal swabs and tracheobronchial aspirates were collected upon intubation and tested for 14 respiratory viruses. Out of 1,407 patients, 156 were admitted because of a severe acute respiratory infection and 1,251 for other reasons (non–severe acute respiratory infection). Respiratory viruses were detected in 28.8% of severe acute respiratory infection patients and 17.0% in non–severe acute respiratory infection (p < 0.001). In one third, viruses were exclusively detected in tracheobronchial aspirates. Rhinovirus and human metapneumovirus were more prevalent in severe acute respiratory infection patients (9.6% and 2.6% vs 4.5 and 0.2%; p = 0.006 and p < 0.001). In both groups, there were no associations between the presence of viruses and the number of ICUfree days at day 28, crude mortality, and mortality in multivariate regression analyses. Conclusions: Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients. (Crit Care Med 2017; XX:00–00) Key Words: critical illness; intensive care units; pneumonia; prospective studies; virus diseases; viral respiratory tract infections
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T
he prevalence of viral respiratory tract infections in adult ICU patients is uncertain (1). Most prospective studies have focused on patients with pneumonia as their primary reason for ICU admission and reported prevalence ranges from 9% to as high as 49% (2–8). However, previous studies suffered from small sample sizes (3, 6, 7), reliance on only upper airway sampling (5, 6), and/or incomplete microbiological diagnostic efforts (2, 4, 6, 8). In addition to limited insights in their prevalence, it remains challenging to determine the clinical relevance of detecting respiratory viruses in the ICU setting, especially for noninfluenza viruses. First, a viral respiratory tract infection may be associated with only mild or no symptoms; hence, detection of a virus might be a coincidental finding and unrelated to the reason for ICU admission. Therefore, determining the background prevalence of respiratory viruses in patients admitted to the ICU for other reasons than severe acute respiratory infections (SARIs) is essential but has not been addressed in epidemiologic studies to date. Furthermore, since the relevance of virus detection in only the upper airways is uncertain (9), there is an unmet need for studies that systematically compare the presence of viruses in upper and lower airways. Finally, associations between presence of a virus and outcomes remain to be determined in patients admitted to the ICU, especially for noninfluenza viruses. Although a large retrospective study showed an association with increased risk of death and complications in ICU patients with detection of influenza virus or respiratory syncytial virus (RSV) (10), this effect has not been observed in smaller prospective studies to date. Three prospective studies in ICU patients admitted with SARI showed no differences in crude mortality between patients with and without detection of viruses at admission (2, 6, 8), whereas one study in patients admitted with acute respiratory failure showed a higher cumulative survival and lower adjusted hazard ratio for mortality associated with virus detection (11). We designed the “Clinical Outcomes of and viRal ShEdding patterns during viral infection in ICU patients” study: a multicenter prospective observational study in acutely admitted ICU patients in need of invasive ventilation, irrespective of the reason for admission. The specific aims were to assess the prevalence of respiratory viruses in invasively ventilated patients admitted with SARI and in those admitted for other reasons, to compare detection in the upper and lower respiratory tract, and to determine the association between the presence of a virus and duration of invasive ventilation, length of stay in the ICU, and mortality.
MATERIALS AND METHODS Study Design This was an investigator-initiated, multicenter, prospective observational study conducted in the ICUs of five hospitals in the Netherlands: the Academic Medical Center (AMC) and VU University Medical Center in Amsterdam; Gelre Hospitals, Apeldoorn; Leiden University Medical Center, Leiden; and University Medical Center Utrecht, Utrecht. All five ICUs 2
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served a mixed surgical-medical population. Study design was published previously (12) and registered in the Dutch Trial Register (NTR4102) (13). The Institutional Review Board of the AMC provided a waiver from the Medical Research Involving Human Subjects Act in Dutch law, due to the noninvasiveness of all study procedures. Patients and/or their legal representatives were provided with written information about the study at ICU admission and could withdraw participation via opt-out procedure. In- and Exclusion Criteria Consecutive patients admitted to participating ICUs were screened for eligibility between September 1, 2013, and April 30, 2014. Acutely admitted adults (≥ 18 yr old) requiring invasive mechanical ventilation were included. Excluded were patients with an elective ICU admission (e.g., after planned surgery), patients who were moribund at ICU admission, and those who did not require invasive ventilation. Data Collection Patient characteristics were collected at the time of ICU admission, including age, gender, medical history, admission type, and referring specialty. Severity scores included the Acute Physiology and Chronic Health Evaluation (APACHE) II score (14) and the Simplified Acute Physiology Score (SAPS) II (15). For each patient, after 24 hours the attending ICU physician chose one or more diagnoses from a list of APACHE II diagnostic categories, using medical history, clinical findings, and the results of diagnostic procedures. These were collected by the Dutch National Intensive Care Evaluation foundation (16, 17). The full list of APACHE II diagnosis categories is listed in the online supplement (Supplemental Digital Content 1, http://links.lww.com/CCM/C898). The diagnosis “respiratory infection” was selected to categorize each patient as having a clinical diagnosis of SARI; all other diagnoses were categorized as non-SARI. Routine microbiological diagnostic results were collected in SARI patients, which according to standard practice in Dutch ICUs include blood culture and bacterial culture of at least one lower respiratory specimen (sputum, pleural fluid, and/or bronchoalveolar lavage fluid). For all SARI patients, the details on initial antimicrobial treatment were collected, including the types of antibiotic and antiviral agents. Clinical outcome variables collected at hospital discharge were duration of invasive ventilation, length of ICU stay, and ICU and hospital mortality, if applicable. Sampling and Microbiological Testing A transnasal nasopharyngeal flocked swab was obtained in virus transport medium (Copan Diagnostics, Brescia, Italy), and a tracheobronchial aspirate (TA) was collected using a suction catheter into a sterile container (Medisize BV, Hillegom, the Netherlands) within 48 hours following intubation. Samples were stored and processed as described in the online supplement (Supplemental Digital Content 1, http://links. lww.com/CCM/C898) and analyzed by a semiquantitative XXX 2017 • Volume XX • Number XXX
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Clinical Investigation
multiplex reverse-transcriptase polymerase chain reaction on the LightCycler 480 (Roche Diagnostics, Penzberg, Germany), using a validated protocol for influenza A and B virus, parainfluenza virus 1–4, RSV, human metapneumovirus (hMPV), human bocavirus, human coronavirus, human rhinovirus, enterovirus, parechovirus, and adenovirus (18). Analysis Patients admitted because of SARI were compared with those admitted because of other reasons (non-SARI). The primary outcome was prevalence of respiratory virus detection, expressed as a percentage of enrolled patients categorized by virus type. The distribution of virus detection per sampling site was described as 1) exclusively in TAs 2), both in TAs and nasopharyngeal swabs, and 3) exclusively in nasopharyngeal swabs. Clinical outcomes of patients with the presence of a virus were compared with those without, and included ventilatorfree days and alive at day 28 (VFD28), ICU-free days and alive at day 28 (ICUFD28), ICU mortality, and hospital mortality. Definitions of VFD28 and ICUFD28 are described in the online supplement (Supplemental Digital Content 1, http:// links.lww.com/CCM/C898). Additional post hoc subgroup analyses on outcomes were performed between patients with 1) presence of influenza virus A or B, rhinovirus, RSV, or hMPV, compared with presence of other viruses, and no viruses; 2) virus detection in TAs, compared with detection exclusively in the nasopharynx, and no viruses; 3) SARI patients with combined viral and bacterial detection, viral or bacterial detection alone, and those in whom no pathogens were detected. In one additional post hoc competing risk regression model, we used age as a separate confounder. Statistical Analysis Baseline characteristics were presented as medians with interquartile range or as proportion. Mann-Whitney U, chi-square, or Fisher exact tests were used to compare groups. Survival between patients with and without the detection of a respiratory virus was compared with Kaplan-Meier analysis. To identify associations between the presence of a respiratory virus and duration of invasive ventilation and mortality, a multivariate competing risk survival model was used (19) as described in the online supplement (Supplemental Digital Content 1, http://links.lww.com/CCM/C898). A p value of less than 0.05 was considered statistically significant, and Bonferroni’s post hoc multiple comparison test was used where appropriate. Analysis was performed in R, version 3.2.2 R Foundation For Statistical Computing, Vienna, Austria, 2014), and additional graphs were made with GraphPad Prism, version 5.01 (Graphpad Software Inc., San Diego, CA).
RESULTS Patient Characteristics During the study period, 1,964 eligible patients were admitted, of whom 1,407 (72%) were included in the study (Fig. S1, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). Critical Care Medicine
In 1,279 inclusions (91%), a combined nasopharyngeal and TA sample was obtained, in the remaining patients only a nasopharyngeal swab or only a TA sample. A total of 156 patients (11%) were admitted to the ICU because of SARI, 1,251 (89%) because of other reasons (non-SARI). Patient characteristics are presented in Table 1. Almost all SARI patients were medical admissions; of non-SARI patients, about one third was a surgical admission. Patients were severely ill according to their median APACHE II score and SAPS. All SARI patients had received antibiotics during the first 48 hours of inclusion; 126 (81%) were treated with a second- or third-generation cephalosporin, and 24 (15%) received oseltamivir (Table S1, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). Prevalence and Distribution of Viruses In 258 of 1,407 patients (18.3%), one or more respiratory viruses were detected in nasopharyngeal swabs and/or TAs. The most prevalent were parainfluenza virus type 3 (PIV-3), rhinovirus, and coronavirus (6.0%, 5.0%, and 2.9%, respectively). More viruses were detected in SARI compared with non-SARI (28.8% vs 17.0%; p < 0.001). For individual viruses, differences in prevalence rates between SARI and non-SARI were observed for rhinovirus and hMPV (9.6% and 2.6% vs 4.5% and 0.2%, respectively, p = 0.006 and p < 0.001), whereas rates were similar for PIV-3 and bocavirus (Fig. 1; and Table S2, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). A respiratory virus was detected in 34 of 167 immunocompromised patients (20%) (chronic immunosuppression, AIDS, neoplasm, and/or hematologic malignancy) versus 224 of 1,240 immunocompetent patients (18%) (p = 0.4715). Viruses were detected in 38 of 169 chronic obstructive pulmonary disease (COPD) patients (22%) versus 216 of 1,224 patients without COPD (18%) (p = 0.1260). Viruses were detected in patients across all categories of admission diagnoses, including in seven of 11 patients (64%) admitted with an acute exacerbation of COPD (Table S3, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). In 64 of 156 SARI patients (41%), bacterial pathogens were cultured in blood and/or respiratory material (Table S4, Supplemental Digital Content 1, http://links.lww.com/CCM/C898); 16 (25%) showed detection of both bacteria and a virus, 29 (19%) only a virus, 48 (31%) only bacteria, and in 63 (40%) no pathogen was detected. Detection of Viruses in Upper and Lower Respiratory Tracts In 164 of 258 patients (64%), viruses were detected in nasopharyngeal swabs, and in 172 patients (67%) in TAs. In 93 patients (36%), viruses were exclusively detected in TAs. SARI patients more frequently had a virus-positive TA, as well as presence of a virus simultaneously in nasopharyngeal and TA, compared with non-SARI patients (80% vs 64%; p = 0.037 and 51% vs 26%; p = 0.001, respectively) (Table 2). Rhinovirus detection in nasopharyngeal swabs and TA did not differ between SARI and non-SARI patients (respectively, 86.7 vs 85.7%; p = 0.9283 in nasopharyngeal swabs and 80.0 vs 55.4%; p = 0.0836 in TA) www.ccmjournal.org
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TABLE 1.
Patient Characteristics
Variables
Age (yr)a, median (IQR)
SARI, n = 156
Non-SARI, n = 1,251
65 (51–72)
63 (51–72)
< 40, n/total no. of patients (%)
12/155 (8)
156/1,222 (13)
40–59, n/total no. of patients (%)
43/155 (28)
348/1,222 (28)
60–79, n/total no. of patients (%)
79/155 (51)
611/1,222 (50)
≥ 80, n/total no. of patients (%)
21/155 (14)
107/1,222 (9)
Men, n/total no. of patients (%)
105/156 (67)
765/1,242 (62)
1/153 (1)
6/1,206 (0)
Never
39/100 (39)
281/639 (44)
Former
22/100 (22)
123/639 (19)
Current
39/100 (39)
235/639 (37)
None
36/89 (40)
234/582 (40)
0–2 units
34/89 (38)
178/582 (31)
> 2 units
19/89 (21)
170/582 (29)
35/155 (21)
134/1,238 (11)
7/153 (5)
35/1,236 (3)
20/154 (13)
164/1,213 (14)
AIDS
1/154 (1)
6/1,213 (0)
Chronic cardiovascular insufficiency
5/154 (3)
85/1,213 (7)
Chronic immunosuppression
25/154 (16)
83/1,213 (7)
Chronic renal insufficiency
14/154 (9)
78/1,213 (6)
5/154 (3)
22/1,213 (2)
19/154 (12)
41/1,213 (3)
Neoplasm
5/154 (3)
32/1,213 (3)
Liver cirrhosis
3/154 (2)
36/1,213 (3)
Medical
151/154 (98)
842/1,213 (69)
Surgical
3/154 (2)
371/1,213 (31)
Cardiology
12/155 (8)
230/1,215 (19)
Hematology
12/155 (8)
23/1,215 (2)
Internal medicine
53/155 (34)
144/1,215 (12)
Pregnant, n/total no. of patients (%) Smoking status, n/total no. of patients (%)
Active alcohol use, n/total no. of patients (%)
Comorbidities, n/total no. of patients (%) Chronic obstructive pulmonary disease Asthma Diabetes mellitus
Chronic renal replacement therapy Hematologic malignancy
Admission type, n/total no. of patients (%)
Referring specialty, n/total no. of patients (%)
Neurology
7/155 (5)
143/1,215 (12)
29/155 (19)
41/1,215 (3)
3/155 (2)
46/1,215 (4)
General surgery
12/155 (8)
278/1,215 (23)
Neurosurgery
11/155 (7)
149/1,215 (12)
Other
17/155 (11)
197/1,215 (16)
Pulmonary medicine Cardiopulmonary surgery
(Continued) 4
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Clinical Investigation
TABLE 1.
(Continued). Patient Characteristics SARI, n = 156
Non-SARI, n = 1,251
Acute Physiology and Chronic Health Evaluation II scoreb
23 (19–30)
23 (17–29)
Simplified Acute Physiology Score IIc
49 (39–61)
49 (38–62)
Variables
Severity scores at ICU admission, median (IQR)
117/154 (76)
Vasoactive medication at admission, n/total no. of patients (%)
844/1,213 (70)
IQR = interquartile range, SARI = severe acute respiratory infection (at ICU admission). a Calculated from 1,377 cases. b Calculated from 1,271 cases. c Calculated from 1,351 cases.
Post hoc Subgroup Analysis Post hoc subgroup analysis per virus category, site of virus detection, and bacterial coinfections showed no statistically significant associations between the presence of a virus and clinical outcomes in any of the subgroups (Tables S7–S9, Supplemental Digital Content 1, http://links.lww.com/CCM/ C898). The post hoc regression model with age as a separate covariate also showed no associations between virus presences and clinical outcomes (Table S10, Supplemental Digital Content 1, http://links.lww.com/CCM/C898).
DISCUSSION
Figure 1. Distribution of respiratory viruses in severe acute respiratory infection (SARI) and non-SARI patients. In 17 patients, two viruses were detected, and in two patients, three viruses were detected; **p = 0.006; ***p < 0.001. hMPV = human metapneumovirus, PIV = parainfluenza virus, RSV = respiratory syncytial virus.
(Table S5, Supplemental Digital Content 1, http://links.lww. com/CCM/C898). Site of virus detection per virus is shown in Figure S2 (Supplemental Digital Content 1, http://links.lww. com/CCM/C898). Associations Between Virus Presence and Outcomes In SARI patients, the number of VFD28 was higher in patients with the presence of a virus compared with those without (22 [5–24] vs 17 [0–23] d; p = 0.04), but the number of ICUFD28 was not different (Table S6, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). In non-SARI patients, there were no differences in VFD28 and ICUFD28 between patients with and without the presence of a virus. In neither group, virus detection was associated with ICU or hospital mortality nor were there differences in cumulative survival between patients with and without the presence of a virus (Fig. 2). Unadjusted and adjusted competing risk regression showed no associations between virus presence and time to successful weaning of invasive ventilation or death while on invasive ventilation (Table 3). Critical Care Medicine
The results of this observational study in five ICUs in the Netherlands can be summarized as follows: 1) respiratory viruses are commonly detected in acutely admitted ICU patients who need invasive ventilation, irrespective of admission diagnosis, but are more frequently observed in patients admitted with a SARI; 2) in approximately one third of patients, viruses are detected exclusively in TA, and frequency of detection in TA is higher in SARI patients; and 3) although the presence of a respiratory virus at intubation is not associated with worse clinical outcomes in either SARI or non-SARI patients, the higher prevalence of rhinovirus and hMPV in SARI patients may be indicative of a causal role of these viruses in the development of severe respiratory infection in at least a proportion of patients. The prevalence of viruses in SARI patients in the present study is in line with previous studies focusing on SARI (2, 5, 7, 8), although much lower prevalence has also been reported (4, 6). Incompleteness of sampling and/or testing in the latter studies may explain the lower observed prevalence, but this could also result from geographic and seasonal variations. Indeed, rhinoviruses were highly prevalent in the present study as well as in two other studies in Korea and France (2, 11), but their prevalence was very low in one Scandinavian study (6). Influenza virus was uncommon in the present study, which can be explained by the low influenza activity in the Netherlands in the 2013–2014 winter season. The epidemic threshold of influenza-like illness in the Dutch general population (51 cases per 100,000 residents) was reached for only a few weeks with a rather low peak occurrence rate (86 per 100,000 residents) compared with preceding seasons (20). www.ccmjournal.org
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TABLE 2.
Site of Virus Detection
Site of Virus Detection
SARI, n = 45 (%)
Non-SARI, n = 213 (%)
p
Nasopharyngeal swab
32 (71)
133 (62)
TA
36 (80)
136 (64)
Exclusive nasopharyngeal
9 (20)
77 (36)
Both nasopharyngeal/TA
23 (51)
56 (26)
25% (9–41%)
0.001
Exclusive TA
13 (29)
80 (38)
–9% (–23% to 6%)
0.271
Difference (95% CI)
9% (–6% to 23%)
0.271
16% (3–64%)
0.037
–16% (–29% to –3%)
0.037
SARI = severe acute respiratory infection (at ICU admission), TA = tracheobronchial aspirate.
Figure 2. Cumulative survival probability stratified by virus detection in patients admitted with a clinical diagnosis of severe acute respiratory infection (SARI) at ICU admission and those with other clinical diagnoses (non-SARI) at ICU admission.
TABLE 3.
Associations Between Detection of Respiratory Viruses and Clinical Outcomes SARI, n = 156
Non-SARI, n = 1,251
Successful Death on Death on MeSuccessful Death on MeDeath on MechanWeaning, CSHR Mechanical Ventila- chanical Ventilation, Weaning, CSHR chanical Ventilation, ical Ventilation, (95% CI) tion, CSHR (95% CI) SDHR (95% CI) (95% CI) CSHR (95% CI) SDHR (95% CI)
Model
Any virus detected (crude model)
1.36 (0.92–2.03)
0.67 (0.32–1.41)
0.52 (0.26–1.08)
0.95 (0.79–1.13)
1.03 (0.79–1.34)
0.96 (0.81–1.34)
Any virus detected (adjusted model)a
1.30 (0.85–1.97)
0.65 (0.31–1.39)
0.56 (0.27–1.16)
0.97 (0.81–1.17)
0.99 (0.75–1.30)
0.93 (0.72–1.19)
CSHR = cause-specific hazard ratio, SARI = severe acute respiratory infection (at ICU admission), SDHR = subdistribution hazard ratio. a Adjusted for Acute Physiology and Chronic Health Evaluation II score, gender, history of chronic obstructive pulmonary disease, history of asthma.
In agreement with a smaller study in ICU patients admitted for nonrespiratory reasons (11), the present study shows that the background prevalence of viral respiratory tract infections is high in critically ill patients who need invasive ventilation. Respiratory viruses were detected in approximately one fifth of non-SARI patients, including patients admitted after general surgery or because of neurologic diseases. Of note, in our study the prevalence of virus detection in immunocompromised patients and patients with COPD was similar in those 6
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without these comorbidities. Although an indirect causative role cannot be excluded in some of these patients, for example, those admitted because of an exacerbation of chronic pulmonary disease, virus detection in most of the non-SARI patients likely represents a coincidental mild viral infection unrelated to the critical illness that warranted ICU admission and therefore likely reflects the population background prevalence. The prevalence of respiratory viruses in SARI patients should be weighed against this background prevalence. It remains to be XXX 2017 • Volume XX • Number XXX
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Clinical Investigation
determined whether detection of these viruses should warrant infection control measures. The U.S. Healthcare Infection Control Practices Advisory Committee recommends droplet isolation for infections with influenza virus, adenovirus, and rhinovirus, as well as contact isolation for adenovirus infections in immunocompromised adults (21). However, it is likely that a large proportion of these viral infections in non-SARI are mild or asymptomatic. Interestingly, rhinovirus and hMPV were found significantly more often in SARI patients, while other viruses such as parainfluenza virus were detected equally often in nonSARI patients. This indicates a possible causative role of rhinovirus and hMPV in development of severe pneumonia in at least a proportion of patients. However, as this is only an observational study, the role of these viruses in severe infection requires further evaluation in future studies. Several studies on the prevalence of respiratory viruses in adult ICU patients also included lower airway samples but relied on incomplete sample sets obtained from routine care (2, 4, 8) or exclusively tested the lower airways (3, 11, 22). The present study shows that in SARI patients, viruses are more frequently detected in the lower airways compared with nonSARI patients. Of note, rhinovirus detection in nasopharyngeal swabs and TA did not differ between SARI and non-SARI patients. This indicates that the difference in rhinovirus prevalence between SARI and non-SARI cannot be explained by higher detection in TA; however, the groups sizes for this comparison were too small for firm conclusions. Besides suggesting that there is more frequent lower airway detection of respiratory viruses in SARI patients, these observations indicate substantial added value of TAs. Although international guidelines remain unclear with regard to the optimal choice of respiratory tract sampling for virus diagnostics in adult ICU patients (23– 25), the present study indicates that approximately one third of respiratory viruses will remain undetected if solely relying on upper respiratory tract samples. This finding is in line with one study in ICU patients admitted with pneumonia (7). The presence of respiratory viruses was neither associated with longer duration of invasive ventilation or ICU stay nor with higher mortality, mirroring observations from previous smaller studies (2, 6, 11, 26). Also after multivariate regression to correct for possible confounding at baseline, there were no associations between virus presence and outcomes. Although these findings may seem surprising given the undebated impact of influenza (27, 28), it should be noted that the number of influenza patients in the present cohort was very low. However, our findings suggest that, compared with uninfected patients, noninfluenza virus detection at admission has no additional impact on important clinical outcomes in ICU patients who need invasive ventilation, even when respiratory infection is the reason for admission. Of note, the current study was insufficiently powered to look into specific viruses or risk groups such as immunocompromised patients or those admitted because of an acute exacerbation of COPD and was not designed to address the impact of nosocomial transmission of respiratory viruses on the adult ICU. Critical Care Medicine
There are several additional limitations to be acknowledged. First, as the study sites were all in the Netherlands and the study covered only a single winter season, prevalence rates are not necessarily representative to other regions and seasons. Also, about one fourth of eligible patients were missed in the screening process. Not all participating ICUs did have full-time research staff available for this study, which may have led to nonenrollment of patients during weekends and holidays. However, assuming that there are no major differences between acutely admitted patients during the week and during weekends, it is unlikely that this introduced significant bias. Furthermore, it should be noted that choices in initial antimicrobial therapy could have been affected by the supposed presence of other infections than SARI. Lastly, only the upper or only the lower airways were sampled in 9% of subjects, which may have led to misclassifications as virus-negative or exclusive upper or lower detection in some patients.
CONCLUSIONS Respiratory viruses were commonly detected in acutely admitted ICU patients who need invasive ventilation, irrespective of reason admission, but are more often found in patients admitted with SARI. One third of respiratory viruses was exclusively detected in TAs, which implies that these viruses will be missed when solely relying on upper airway sampling for detection. Although the presence of a virus was not associated with clinically relevant outcomes, rhinovirus and hMPV were more frequently found in patients admitted with a SARI, suggesting that these viruses may play a causative role in the development of severe pneumonia.
ACKNOWLEDGMENTS We thank all the physicians, nurses, and research staff of the participating centers for their help in data and sample acquisition.
REFERENCES
1. WHO: Battle Against Respiratory Viruses (BRaVe) Initiative, 2013. Available at: http://www.who.int/influenza/patient_care/clinical/brave/ en/. Accessed September 19, 2016 2. Choi SH, Hong SB, Ko GB, et al: Viral infection in patients with severe pneumonia requiring intensive care unit admission. Am J Respir Crit Care Med 2012; 186:325–332 3. Legoff , Guérot E, Matta M, et al: High prevalence of respiratory viral infections in patients hospitalized in an intensive care unit for acute respiratory infections as detected by nucleic acid-based assays high. J Clin Microbiol 2005; 43:455–457 4. Cillóniz C, Ewig S, Ferrer M, et al: Community-acquired polymicrobial pneumonia in the intensive care unit: Aetiology and prognosis. Crit Care 2011; 15:R209 5. Wiemken T, Peyrani P, Bryant K, et al: Incidence of respiratory viruses in patients with community-acquired pneumonia admitted to the intensive care unit: Results from the Severe Influenza Pneumonia Surveillance (SIPS) project. Eur J Clin Microbiol Infect Dis 2013; 32:705–710 6. Østby AC, Gubbels S, Baake G, et al: Respiratory virology and microbiology in intensive care units: A prospective cohort study. APMIS 2013; 121:1097–1108 www.ccmjournal.org
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van Someren Gréve et al 7. Karhu J, Ala-Kokko TI, Vuorinen T, et al: Lower respiratory tract virus findings in mechanically ventilated patients with severe communityacquired pneumonia. Clin Infect Dis 2014; 59:62–70 8. Hong HL, Hong SB, Ko GB, et al: Viral infection is not uncommon in adult patients with severe hospital-acquired pneumonia. PLoS One 2014; 9:e95865 9. Burk M, El-Kersh K, Saad M, et al: Viral infection in communityacquired pneumonia: A systematic review and meta-analysis. Eur Respir Rev 2016; 25:178–188 10. Miggins M, Hasan A, Hohmann S, et al: The potential influence of common viral infections diagnosed during hospitalization among critically ill patients in the United States. PLoS One 2011; 6:e18890 11. Daubin C, Parienti JJ, Vincent S, et al: Epidemiology and clinical outcome of virus-positive respiratory samples in ventilated patients: A prospective cohort study. Crit Care 2006; 10:R142 12. van Someren Gréve F, van der Sluijs K, Binnekade J, et al: Course – prevalence, clinical outcomes and viral shedding patterns during viral respiratory tract infections in intubated intensive care unit–patients: Design and protocol. J Clin Trials 2014; 4:185 13. Dutch Trial Register; Nederlands Trial Register, 2004. Available at: http://www.trialregister.nl/. Accessed September 19, 2016 14. Knaus WA, Draper EA, Wagner DP, et al: APACHE II: A severity of disease classification system. Crit Care Med 1985; 13:818–829 15. Le Gall JR, Lemeshow S, Saulnier F: A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270:2957–2963 16. van de Klundert N, Holman R, Dongelmans DA, et al: Data Resource Profile: The Dutch National Intensive Care Evaluation (NICE) Registry of admissions to adult intensive care units. Int J Epidemiol 2015; 44:1850–1850h 17. Koetsier A, van Asten L, Dijkstra F, et al: Do intensive care data on respiratory infections reflect influenza epidemics? PLoS One 2013; 8:e83854 18. Jansen RR, Schinkel J, Koekkoek S, et al: Development and evaluation of a four-tube real time multiplex PCR assay covering fourteen respiratory viruses, and comparison to its corresponding single target counterparts. J Clin Virol 2011; 51:179–185 19. Scrucca L, Santucci A, Aversa F: Regression modeling of competing risk using R: An in depth guide for clinicians. Bone Marrow Transplant 2010; 45:1388–1395 20. Tweede Influenza Nieuwsbrief 2013–2014 - NIVEL Zorgregistraties Eerste Lijn - Surveillance. Last update: January 8, 2015. [cited
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August 17, 2016] Available at: https://www.nivel.nl/sites/default/files/ NB_13_14_no_2.pdf 21. Siegel JD, Rhinehart E, Jackson M, et al; Health Care Infection Control Practices Advisory Committee: 2007 guideline for isolation precautions: Preventing transmission of infectious agents in health care settings. Am J Infect Control 2007; 35:S65–S164 22. Giannella M, Rodríguez-Sánchez B, Roa PL, et al; Gregorio Marañón Task Force for Pneumonia GANG: Should lower respiratory tract secretions from intensive care patients be systematically screened for influenza virus during the influenza season? Crit Care 2012; 16:R104 23. Baron EJ, Miller JM, Weinstein MP, et al: Executive summary: a guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM) (a). Clin Infect Dis 2013; 57:485–488 24. Dellinger RP, Levy MM, Carlet JM, et al; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296–327 25. Woodhead M, Blasi F, Ewig S, et al; Joint Taskforce of the European Respiratory Society and European Society for Clinical Microbiology and Infectious Diseases: Guidelines for the management of adult lower respiratory tract infections–full version. Clin Microbiol Infect 2011; 17 (Suppl 6):E1–59 26. Carrat F, Leruez-Ville M, Tonnellier M, et al: A virologic survey of patients admitted to a critical care unit for acute cardiorespiratory failure. Intensive Care Med 2006; 32:156–159 27. Belongia EA, Irving SA, Waring SC, et al: Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 2008-2009 (H1N1), and 2007-2008 (H3N2) infections. JAMA 2010; 304:1091–1098 28. Napolitano LM, Angus DC, Uyeki TM: Critically ill patients with influenza A(H1N1)pdm09 virus infection in 2014. JAMA 2014; 311:1289–1290
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Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands. 2 Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands. 3 Department of Intensive Care, Gelre Hospitals, Apeldoorn, The Netherlands. 4 Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. 5 Department of Intensive Care, Leiden University Medical Center, Leiden, The Netherlands. 6 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. 7 Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal). Supported, in part, by the Academic Medical Center (University of Amsterdam, Amsterdam, the Netherlands), Crucell Holland BV (Leiden, the Netherlands), and EU FP7 project PREPARE (grant number 602525). Crucell Holland BV was involved in the study design but had neither a role in collection, management, analysis, and interpretation of the data nor in preparation, review, and the decision to submit the article. Drs. van Someren Gréve and Cremer’s institutions received funding from Crucell Holland BV (Leiden, the Netherlands), EU FP7 project Platform for European Preparedness Against (Re-)emerging Epidemics (grant number 602525). Dr. Bos’ institution received funding from Maquet (unrestrictive research grant) and Dutch Lung Foundation (research grant), and he received funding from GlaxoSmithKline (GSK) (honorarium for presentation) and Bayer (advisory board). Dr. Spoelstra-de Man’s institution received funding from Academic Medical Centre, Amsterdam, the Netherlands. Dr. de Jong’s institution received funding from Crucell B.V. (unrestricted grant), Janssen Pharmaceuticals (Scientific Advisory Board and Independent Data and Safety Monitoring Board), MedImmune (Scientific Advisory Board), and GSK (Independent Data and Safety Monitoring Board). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]; [email protected] 1
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000002752
Critical Care Medicine
Objectives: The presence of respiratory viruses and the association with outcomes were assessed in invasively ventilated ICU patients, stratified by admission diagnosis. Design: Prospective observational study. Setting: Five ICUs in the Netherlands. Patients: Between September 1, 2013, and April 30, 2014, 1,407 acutely admitted and invasively ventilated patients were included. Interventions: None. Measurements and Main Results: Nasopharyngeal swabs and tracheobronchial aspirates were collected upon intubation and tested for 14 respiratory viruses. Out of 1,407 patients, 156 were admitted because of a severe acute respiratory infection and 1,251 for other reasons (non–severe acute respiratory infection). Respiratory viruses were detected in 28.8% of severe acute respiratory infection patients and 17.0% in non–severe acute respiratory infection (p < 0.001). In one third, viruses were exclusively detected in tracheobronchial aspirates. Rhinovirus and human metapneumovirus were more prevalent in severe acute respiratory infection patients (9.6% and 2.6% vs 4.5 and 0.2%; p = 0.006 and p < 0.001). In both groups, there were no associations between the presence of viruses and the number of ICUfree days at day 28, crude mortality, and mortality in multivariate regression analyses. Conclusions: Respiratory viruses are frequently detected in acutely admitted and invasively ventilated patients. Rhinovirus and human metapneumovirus are more frequently found in severe acute respiratory infection patients. Detection of respiratory viruses is not associated with worse clinically relevant outcomes in the studied cohort of patients. (Crit Care Med 2017; XX:00–00) Key Words: critical illness; intensive care units; pneumonia; prospective studies; virus diseases; viral respiratory tract infections
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T
he prevalence of viral respiratory tract infections in adult ICU patients is uncertain (1). Most prospective studies have focused on patients with pneumonia as their primary reason for ICU admission and reported prevalence ranges from 9% to as high as 49% (2–8). However, previous studies suffered from small sample sizes (3, 6, 7), reliance on only upper airway sampling (5, 6), and/or incomplete microbiological diagnostic efforts (2, 4, 6, 8). In addition to limited insights in their prevalence, it remains challenging to determine the clinical relevance of detecting respiratory viruses in the ICU setting, especially for noninfluenza viruses. First, a viral respiratory tract infection may be associated with only mild or no symptoms; hence, detection of a virus might be a coincidental finding and unrelated to the reason for ICU admission. Therefore, determining the background prevalence of respiratory viruses in patients admitted to the ICU for other reasons than severe acute respiratory infections (SARIs) is essential but has not been addressed in epidemiologic studies to date. Furthermore, since the relevance of virus detection in only the upper airways is uncertain (9), there is an unmet need for studies that systematically compare the presence of viruses in upper and lower airways. Finally, associations between presence of a virus and outcomes remain to be determined in patients admitted to the ICU, especially for noninfluenza viruses. Although a large retrospective study showed an association with increased risk of death and complications in ICU patients with detection of influenza virus or respiratory syncytial virus (RSV) (10), this effect has not been observed in smaller prospective studies to date. Three prospective studies in ICU patients admitted with SARI showed no differences in crude mortality between patients with and without detection of viruses at admission (2, 6, 8), whereas one study in patients admitted with acute respiratory failure showed a higher cumulative survival and lower adjusted hazard ratio for mortality associated with virus detection (11). We designed the “Clinical Outcomes of and viRal ShEdding patterns during viral infection in ICU patients” study: a multicenter prospective observational study in acutely admitted ICU patients in need of invasive ventilation, irrespective of the reason for admission. The specific aims were to assess the prevalence of respiratory viruses in invasively ventilated patients admitted with SARI and in those admitted for other reasons, to compare detection in the upper and lower respiratory tract, and to determine the association between the presence of a virus and duration of invasive ventilation, length of stay in the ICU, and mortality.
MATERIALS AND METHODS Study Design This was an investigator-initiated, multicenter, prospective observational study conducted in the ICUs of five hospitals in the Netherlands: the Academic Medical Center (AMC) and VU University Medical Center in Amsterdam; Gelre Hospitals, Apeldoorn; Leiden University Medical Center, Leiden; and University Medical Center Utrecht, Utrecht. All five ICUs 2
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served a mixed surgical-medical population. Study design was published previously (12) and registered in the Dutch Trial Register (NTR4102) (13). The Institutional Review Board of the AMC provided a waiver from the Medical Research Involving Human Subjects Act in Dutch law, due to the noninvasiveness of all study procedures. Patients and/or their legal representatives were provided with written information about the study at ICU admission and could withdraw participation via opt-out procedure. In- and Exclusion Criteria Consecutive patients admitted to participating ICUs were screened for eligibility between September 1, 2013, and April 30, 2014. Acutely admitted adults (≥ 18 yr old) requiring invasive mechanical ventilation were included. Excluded were patients with an elective ICU admission (e.g., after planned surgery), patients who were moribund at ICU admission, and those who did not require invasive ventilation. Data Collection Patient characteristics were collected at the time of ICU admission, including age, gender, medical history, admission type, and referring specialty. Severity scores included the Acute Physiology and Chronic Health Evaluation (APACHE) II score (14) and the Simplified Acute Physiology Score (SAPS) II (15). For each patient, after 24 hours the attending ICU physician chose one or more diagnoses from a list of APACHE II diagnostic categories, using medical history, clinical findings, and the results of diagnostic procedures. These were collected by the Dutch National Intensive Care Evaluation foundation (16, 17). The full list of APACHE II diagnosis categories is listed in the online supplement (Supplemental Digital Content 1, http://links.lww.com/CCM/C898). The diagnosis “respiratory infection” was selected to categorize each patient as having a clinical diagnosis of SARI; all other diagnoses were categorized as non-SARI. Routine microbiological diagnostic results were collected in SARI patients, which according to standard practice in Dutch ICUs include blood culture and bacterial culture of at least one lower respiratory specimen (sputum, pleural fluid, and/or bronchoalveolar lavage fluid). For all SARI patients, the details on initial antimicrobial treatment were collected, including the types of antibiotic and antiviral agents. Clinical outcome variables collected at hospital discharge were duration of invasive ventilation, length of ICU stay, and ICU and hospital mortality, if applicable. Sampling and Microbiological Testing A transnasal nasopharyngeal flocked swab was obtained in virus transport medium (Copan Diagnostics, Brescia, Italy), and a tracheobronchial aspirate (TA) was collected using a suction catheter into a sterile container (Medisize BV, Hillegom, the Netherlands) within 48 hours following intubation. Samples were stored and processed as described in the online supplement (Supplemental Digital Content 1, http://links. lww.com/CCM/C898) and analyzed by a semiquantitative XXX 2017 • Volume XX • Number XXX
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Clinical Investigation
multiplex reverse-transcriptase polymerase chain reaction on the LightCycler 480 (Roche Diagnostics, Penzberg, Germany), using a validated protocol for influenza A and B virus, parainfluenza virus 1–4, RSV, human metapneumovirus (hMPV), human bocavirus, human coronavirus, human rhinovirus, enterovirus, parechovirus, and adenovirus (18). Analysis Patients admitted because of SARI were compared with those admitted because of other reasons (non-SARI). The primary outcome was prevalence of respiratory virus detection, expressed as a percentage of enrolled patients categorized by virus type. The distribution of virus detection per sampling site was described as 1) exclusively in TAs 2), both in TAs and nasopharyngeal swabs, and 3) exclusively in nasopharyngeal swabs. Clinical outcomes of patients with the presence of a virus were compared with those without, and included ventilatorfree days and alive at day 28 (VFD28), ICU-free days and alive at day 28 (ICUFD28), ICU mortality, and hospital mortality. Definitions of VFD28 and ICUFD28 are described in the online supplement (Supplemental Digital Content 1, http:// links.lww.com/CCM/C898). Additional post hoc subgroup analyses on outcomes were performed between patients with 1) presence of influenza virus A or B, rhinovirus, RSV, or hMPV, compared with presence of other viruses, and no viruses; 2) virus detection in TAs, compared with detection exclusively in the nasopharynx, and no viruses; 3) SARI patients with combined viral and bacterial detection, viral or bacterial detection alone, and those in whom no pathogens were detected. In one additional post hoc competing risk regression model, we used age as a separate confounder. Statistical Analysis Baseline characteristics were presented as medians with interquartile range or as proportion. Mann-Whitney U, chi-square, or Fisher exact tests were used to compare groups. Survival between patients with and without the detection of a respiratory virus was compared with Kaplan-Meier analysis. To identify associations between the presence of a respiratory virus and duration of invasive ventilation and mortality, a multivariate competing risk survival model was used (19) as described in the online supplement (Supplemental Digital Content 1, http://links.lww.com/CCM/C898). A p value of less than 0.05 was considered statistically significant, and Bonferroni’s post hoc multiple comparison test was used where appropriate. Analysis was performed in R, version 3.2.2 R Foundation For Statistical Computing, Vienna, Austria, 2014), and additional graphs were made with GraphPad Prism, version 5.01 (Graphpad Software Inc., San Diego, CA).
RESULTS Patient Characteristics During the study period, 1,964 eligible patients were admitted, of whom 1,407 (72%) were included in the study (Fig. S1, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). Critical Care Medicine
In 1,279 inclusions (91%), a combined nasopharyngeal and TA sample was obtained, in the remaining patients only a nasopharyngeal swab or only a TA sample. A total of 156 patients (11%) were admitted to the ICU because of SARI, 1,251 (89%) because of other reasons (non-SARI). Patient characteristics are presented in Table 1. Almost all SARI patients were medical admissions; of non-SARI patients, about one third was a surgical admission. Patients were severely ill according to their median APACHE II score and SAPS. All SARI patients had received antibiotics during the first 48 hours of inclusion; 126 (81%) were treated with a second- or third-generation cephalosporin, and 24 (15%) received oseltamivir (Table S1, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). Prevalence and Distribution of Viruses In 258 of 1,407 patients (18.3%), one or more respiratory viruses were detected in nasopharyngeal swabs and/or TAs. The most prevalent were parainfluenza virus type 3 (PIV-3), rhinovirus, and coronavirus (6.0%, 5.0%, and 2.9%, respectively). More viruses were detected in SARI compared with non-SARI (28.8% vs 17.0%; p < 0.001). For individual viruses, differences in prevalence rates between SARI and non-SARI were observed for rhinovirus and hMPV (9.6% and 2.6% vs 4.5% and 0.2%, respectively, p = 0.006 and p < 0.001), whereas rates were similar for PIV-3 and bocavirus (Fig. 1; and Table S2, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). A respiratory virus was detected in 34 of 167 immunocompromised patients (20%) (chronic immunosuppression, AIDS, neoplasm, and/or hematologic malignancy) versus 224 of 1,240 immunocompetent patients (18%) (p = 0.4715). Viruses were detected in 38 of 169 chronic obstructive pulmonary disease (COPD) patients (22%) versus 216 of 1,224 patients without COPD (18%) (p = 0.1260). Viruses were detected in patients across all categories of admission diagnoses, including in seven of 11 patients (64%) admitted with an acute exacerbation of COPD (Table S3, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). In 64 of 156 SARI patients (41%), bacterial pathogens were cultured in blood and/or respiratory material (Table S4, Supplemental Digital Content 1, http://links.lww.com/CCM/C898); 16 (25%) showed detection of both bacteria and a virus, 29 (19%) only a virus, 48 (31%) only bacteria, and in 63 (40%) no pathogen was detected. Detection of Viruses in Upper and Lower Respiratory Tracts In 164 of 258 patients (64%), viruses were detected in nasopharyngeal swabs, and in 172 patients (67%) in TAs. In 93 patients (36%), viruses were exclusively detected in TAs. SARI patients more frequently had a virus-positive TA, as well as presence of a virus simultaneously in nasopharyngeal and TA, compared with non-SARI patients (80% vs 64%; p = 0.037 and 51% vs 26%; p = 0.001, respectively) (Table 2). Rhinovirus detection in nasopharyngeal swabs and TA did not differ between SARI and non-SARI patients (respectively, 86.7 vs 85.7%; p = 0.9283 in nasopharyngeal swabs and 80.0 vs 55.4%; p = 0.0836 in TA) www.ccmjournal.org
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TABLE 1.
Patient Characteristics
Variables
Age (yr)a, median (IQR)
SARI, n = 156
Non-SARI, n = 1,251
65 (51–72)
63 (51–72)
< 40, n/total no. of patients (%)
12/155 (8)
156/1,222 (13)
40–59, n/total no. of patients (%)
43/155 (28)
348/1,222 (28)
60–79, n/total no. of patients (%)
79/155 (51)
611/1,222 (50)
≥ 80, n/total no. of patients (%)
21/155 (14)
107/1,222 (9)
Men, n/total no. of patients (%)
105/156 (67)
765/1,242 (62)
1/153 (1)
6/1,206 (0)
Never
39/100 (39)
281/639 (44)
Former
22/100 (22)
123/639 (19)
Current
39/100 (39)
235/639 (37)
None
36/89 (40)
234/582 (40)
0–2 units
34/89 (38)
178/582 (31)
> 2 units
19/89 (21)
170/582 (29)
35/155 (21)
134/1,238 (11)
7/153 (5)
35/1,236 (3)
20/154 (13)
164/1,213 (14)
AIDS
1/154 (1)
6/1,213 (0)
Chronic cardiovascular insufficiency
5/154 (3)
85/1,213 (7)
Chronic immunosuppression
25/154 (16)
83/1,213 (7)
Chronic renal insufficiency
14/154 (9)
78/1,213 (6)
5/154 (3)
22/1,213 (2)
19/154 (12)
41/1,213 (3)
Neoplasm
5/154 (3)
32/1,213 (3)
Liver cirrhosis
3/154 (2)
36/1,213 (3)
Medical
151/154 (98)
842/1,213 (69)
Surgical
3/154 (2)
371/1,213 (31)
Cardiology
12/155 (8)
230/1,215 (19)
Hematology
12/155 (8)
23/1,215 (2)
Internal medicine
53/155 (34)
144/1,215 (12)
Pregnant, n/total no. of patients (%) Smoking status, n/total no. of patients (%)
Active alcohol use, n/total no. of patients (%)
Comorbidities, n/total no. of patients (%) Chronic obstructive pulmonary disease Asthma Diabetes mellitus
Chronic renal replacement therapy Hematologic malignancy
Admission type, n/total no. of patients (%)
Referring specialty, n/total no. of patients (%)
Neurology
7/155 (5)
143/1,215 (12)
29/155 (19)
41/1,215 (3)
3/155 (2)
46/1,215 (4)
General surgery
12/155 (8)
278/1,215 (23)
Neurosurgery
11/155 (7)
149/1,215 (12)
Other
17/155 (11)
197/1,215 (16)
Pulmonary medicine Cardiopulmonary surgery
(Continued) 4
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XXX 2017 • Volume XX • Number XXX
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Clinical Investigation
TABLE 1.
(Continued). Patient Characteristics SARI, n = 156
Non-SARI, n = 1,251
Acute Physiology and Chronic Health Evaluation II scoreb
23 (19–30)
23 (17–29)
Simplified Acute Physiology Score IIc
49 (39–61)
49 (38–62)
Variables
Severity scores at ICU admission, median (IQR)
117/154 (76)
Vasoactive medication at admission, n/total no. of patients (%)
844/1,213 (70)
IQR = interquartile range, SARI = severe acute respiratory infection (at ICU admission). a Calculated from 1,377 cases. b Calculated from 1,271 cases. c Calculated from 1,351 cases.
Post hoc Subgroup Analysis Post hoc subgroup analysis per virus category, site of virus detection, and bacterial coinfections showed no statistically significant associations between the presence of a virus and clinical outcomes in any of the subgroups (Tables S7–S9, Supplemental Digital Content 1, http://links.lww.com/CCM/ C898). The post hoc regression model with age as a separate covariate also showed no associations between virus presences and clinical outcomes (Table S10, Supplemental Digital Content 1, http://links.lww.com/CCM/C898).
DISCUSSION
Figure 1. Distribution of respiratory viruses in severe acute respiratory infection (SARI) and non-SARI patients. In 17 patients, two viruses were detected, and in two patients, three viruses were detected; **p = 0.006; ***p < 0.001. hMPV = human metapneumovirus, PIV = parainfluenza virus, RSV = respiratory syncytial virus.
(Table S5, Supplemental Digital Content 1, http://links.lww. com/CCM/C898). Site of virus detection per virus is shown in Figure S2 (Supplemental Digital Content 1, http://links.lww. com/CCM/C898). Associations Between Virus Presence and Outcomes In SARI patients, the number of VFD28 was higher in patients with the presence of a virus compared with those without (22 [5–24] vs 17 [0–23] d; p = 0.04), but the number of ICUFD28 was not different (Table S6, Supplemental Digital Content 1, http://links.lww.com/CCM/C898). In non-SARI patients, there were no differences in VFD28 and ICUFD28 between patients with and without the presence of a virus. In neither group, virus detection was associated with ICU or hospital mortality nor were there differences in cumulative survival between patients with and without the presence of a virus (Fig. 2). Unadjusted and adjusted competing risk regression showed no associations between virus presence and time to successful weaning of invasive ventilation or death while on invasive ventilation (Table 3). Critical Care Medicine
The results of this observational study in five ICUs in the Netherlands can be summarized as follows: 1) respiratory viruses are commonly detected in acutely admitted ICU patients who need invasive ventilation, irrespective of admission diagnosis, but are more frequently observed in patients admitted with a SARI; 2) in approximately one third of patients, viruses are detected exclusively in TA, and frequency of detection in TA is higher in SARI patients; and 3) although the presence of a respiratory virus at intubation is not associated with worse clinical outcomes in either SARI or non-SARI patients, the higher prevalence of rhinovirus and hMPV in SARI patients may be indicative of a causal role of these viruses in the development of severe respiratory infection in at least a proportion of patients. The prevalence of viruses in SARI patients in the present study is in line with previous studies focusing on SARI (2, 5, 7, 8), although much lower prevalence has also been reported (4, 6). Incompleteness of sampling and/or testing in the latter studies may explain the lower observed prevalence, but this could also result from geographic and seasonal variations. Indeed, rhinoviruses were highly prevalent in the present study as well as in two other studies in Korea and France (2, 11), but their prevalence was very low in one Scandinavian study (6). Influenza virus was uncommon in the present study, which can be explained by the low influenza activity in the Netherlands in the 2013–2014 winter season. The epidemic threshold of influenza-like illness in the Dutch general population (51 cases per 100,000 residents) was reached for only a few weeks with a rather low peak occurrence rate (86 per 100,000 residents) compared with preceding seasons (20). www.ccmjournal.org
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TABLE 2.
Site of Virus Detection
Site of Virus Detection
SARI, n = 45 (%)
Non-SARI, n = 213 (%)
p
Nasopharyngeal swab
32 (71)
133 (62)
TA
36 (80)
136 (64)
Exclusive nasopharyngeal
9 (20)
77 (36)
Both nasopharyngeal/TA
23 (51)
56 (26)
25% (9–41%)
0.001
Exclusive TA
13 (29)
80 (38)
–9% (–23% to 6%)
0.271
Difference (95% CI)
9% (–6% to 23%)
0.271
16% (3–64%)
0.037
–16% (–29% to –3%)
0.037
SARI = severe acute respiratory infection (at ICU admission), TA = tracheobronchial aspirate.
Figure 2. Cumulative survival probability stratified by virus detection in patients admitted with a clinical diagnosis of severe acute respiratory infection (SARI) at ICU admission and those with other clinical diagnoses (non-SARI) at ICU admission.
TABLE 3.
Associations Between Detection of Respiratory Viruses and Clinical Outcomes SARI, n = 156
Non-SARI, n = 1,251
Successful Death on Death on MeSuccessful Death on MeDeath on MechanWeaning, CSHR Mechanical Ventila- chanical Ventilation, Weaning, CSHR chanical Ventilation, ical Ventilation, (95% CI) tion, CSHR (95% CI) SDHR (95% CI) (95% CI) CSHR (95% CI) SDHR (95% CI)
Model
Any virus detected (crude model)
1.36 (0.92–2.03)
0.67 (0.32–1.41)
0.52 (0.26–1.08)
0.95 (0.79–1.13)
1.03 (0.79–1.34)
0.96 (0.81–1.34)
Any virus detected (adjusted model)a
1.30 (0.85–1.97)
0.65 (0.31–1.39)
0.56 (0.27–1.16)
0.97 (0.81–1.17)
0.99 (0.75–1.30)
0.93 (0.72–1.19)
CSHR = cause-specific hazard ratio, SARI = severe acute respiratory infection (at ICU admission), SDHR = subdistribution hazard ratio. a Adjusted for Acute Physiology and Chronic Health Evaluation II score, gender, history of chronic obstructive pulmonary disease, history of asthma.
In agreement with a smaller study in ICU patients admitted for nonrespiratory reasons (11), the present study shows that the background prevalence of viral respiratory tract infections is high in critically ill patients who need invasive ventilation. Respiratory viruses were detected in approximately one fifth of non-SARI patients, including patients admitted after general surgery or because of neurologic diseases. Of note, in our study the prevalence of virus detection in immunocompromised patients and patients with COPD was similar in those 6
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without these comorbidities. Although an indirect causative role cannot be excluded in some of these patients, for example, those admitted because of an exacerbation of chronic pulmonary disease, virus detection in most of the non-SARI patients likely represents a coincidental mild viral infection unrelated to the critical illness that warranted ICU admission and therefore likely reflects the population background prevalence. The prevalence of respiratory viruses in SARI patients should be weighed against this background prevalence. It remains to be XXX 2017 • Volume XX • Number XXX
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Clinical Investigation
determined whether detection of these viruses should warrant infection control measures. The U.S. Healthcare Infection Control Practices Advisory Committee recommends droplet isolation for infections with influenza virus, adenovirus, and rhinovirus, as well as contact isolation for adenovirus infections in immunocompromised adults (21). However, it is likely that a large proportion of these viral infections in non-SARI are mild or asymptomatic. Interestingly, rhinovirus and hMPV were found significantly more often in SARI patients, while other viruses such as parainfluenza virus were detected equally often in nonSARI patients. This indicates a possible causative role of rhinovirus and hMPV in development of severe pneumonia in at least a proportion of patients. However, as this is only an observational study, the role of these viruses in severe infection requires further evaluation in future studies. Several studies on the prevalence of respiratory viruses in adult ICU patients also included lower airway samples but relied on incomplete sample sets obtained from routine care (2, 4, 8) or exclusively tested the lower airways (3, 11, 22). The present study shows that in SARI patients, viruses are more frequently detected in the lower airways compared with nonSARI patients. Of note, rhinovirus detection in nasopharyngeal swabs and TA did not differ between SARI and non-SARI patients. This indicates that the difference in rhinovirus prevalence between SARI and non-SARI cannot be explained by higher detection in TA; however, the groups sizes for this comparison were too small for firm conclusions. Besides suggesting that there is more frequent lower airway detection of respiratory viruses in SARI patients, these observations indicate substantial added value of TAs. Although international guidelines remain unclear with regard to the optimal choice of respiratory tract sampling for virus diagnostics in adult ICU patients (23– 25), the present study indicates that approximately one third of respiratory viruses will remain undetected if solely relying on upper respiratory tract samples. This finding is in line with one study in ICU patients admitted with pneumonia (7). The presence of respiratory viruses was neither associated with longer duration of invasive ventilation or ICU stay nor with higher mortality, mirroring observations from previous smaller studies (2, 6, 11, 26). Also after multivariate regression to correct for possible confounding at baseline, there were no associations between virus presence and outcomes. Although these findings may seem surprising given the undebated impact of influenza (27, 28), it should be noted that the number of influenza patients in the present cohort was very low. However, our findings suggest that, compared with uninfected patients, noninfluenza virus detection at admission has no additional impact on important clinical outcomes in ICU patients who need invasive ventilation, even when respiratory infection is the reason for admission. Of note, the current study was insufficiently powered to look into specific viruses or risk groups such as immunocompromised patients or those admitted because of an acute exacerbation of COPD and was not designed to address the impact of nosocomial transmission of respiratory viruses on the adult ICU. Critical Care Medicine
There are several additional limitations to be acknowledged. First, as the study sites were all in the Netherlands and the study covered only a single winter season, prevalence rates are not necessarily representative to other regions and seasons. Also, about one fourth of eligible patients were missed in the screening process. Not all participating ICUs did have full-time research staff available for this study, which may have led to nonenrollment of patients during weekends and holidays. However, assuming that there are no major differences between acutely admitted patients during the week and during weekends, it is unlikely that this introduced significant bias. Furthermore, it should be noted that choices in initial antimicrobial therapy could have been affected by the supposed presence of other infections than SARI. Lastly, only the upper or only the lower airways were sampled in 9% of subjects, which may have led to misclassifications as virus-negative or exclusive upper or lower detection in some patients.
CONCLUSIONS Respiratory viruses were commonly detected in acutely admitted ICU patients who need invasive ventilation, irrespective of reason admission, but are more often found in patients admitted with SARI. One third of respiratory viruses was exclusively detected in TAs, which implies that these viruses will be missed when solely relying on upper airway sampling for detection. Although the presence of a virus was not associated with clinically relevant outcomes, rhinovirus and hMPV were more frequently found in patients admitted with a SARI, suggesting that these viruses may play a causative role in the development of severe pneumonia.
ACKNOWLEDGMENTS We thank all the physicians, nurses, and research staff of the participating centers for their help in data and sample acquisition.
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