Eur J Clin Microbiol Infect Dis (2017) 36:1673–1677

DOI 10.1007/s10096-017-2982-z

ORIGINAL ARTICLE

Early administration of neuraminidase inhibitors in adult

patients hospitalized for influenza does not benefit survival:
a retrospective cohort study
S.-H. Choi 1 & T. Kim 2 & K.-H. Park 3 & Y. G. Kwak 4 & J.-W. Chung 1 & M. S. Lee 3

Received: 3 March 2017 / Accepted: 4 April 2017 / Published online: 18 April 2017
# Springer-Verlag Berlin Heidelberg 2017

Abstract The administration of neuraminidase inhibitors pneumonia, and intensive care unit admission, than those
(NAIs) within 2 days after the onset of symptoms (early with early NAI therapy, the in-hospital mortality of the for-
NAI therapy) has been shown to reduce mortality in adult mer (2.9%, 8/273) did not differ from that of the latter (3.4%,
patients with severe influenza. However, there is no sufficient- 8/233) (p = 0.75). We did not find a reduction in mortality
ly solid evidence supporting the effectiveness of early NAI associated with early NAI therapy in adult patients hospital-
therapy on mortality. We reviewed the clinical data from ized for influenza. Further clinical studies including a large
506 adult patients who were hospitalized for influenza be- number of influenza B-infected patients with virus identifi-
tween March 2010 and March 2014, to investigate the impact cation using PCR methodology rather than viral culture may
of early NAI therapy on mortality. Nearly one-third of the be required to confirm the beneficial impact of early NAI
study patients were infected with influenza B (influenza A, therapy on mortality.
influenza B, and co-infection of both in 68.8%, 28.1%, and
3.2%, respectively), and were diagnosed using the polymer-
ase chain reaction (PCR) method (33.6%). Less than half Introduction
(233, 46.0%) had received early NAI therapy. Patients with
early NAI therapy were admitted to the hospital earlier, more Neuraminidase inhibitors (NAIs) have been regarded as one
frequently infected with influenza A, and more frequently of the most important therapeutic tools against influenza in-
diagnosed using rapid influenza detection tests compared to fection [1]. In adults with uncomplicated influenza, it has been
those without early NAI therapy. Although patients without reported that NAIs reduced symptom duration, prevented
early NAI therapy presented with more serious clinical man- complications, and protected patients from hospitalization
ifestations, such as an initial symptom of dyspnea, [2, 3]. For adults hospitalized with influenza or severe influ-
enza in some cases, several observational studies reported that
early administration of NAIs prevented fatal outcomes [4–8].
* J.-W. Chung
drjwchung@cau.ac.kr However, current evidence may not completely support the
outstanding clinical effectiveness of NAIs. This has been
questioned in a recent meta-analysis of adults with uncompli-
1
Division of Infectious Diseases, Department of Internal Medicine, cated influenza, which was not sponsored by any pharmaceu-
Chung-Ang University Hospital, Chung-Ang University College of
Medicine, 102 Heukseok-ro, Dongjak-gu, Seoul, Republic of Korea
tical company [9]. The effectiveness of NAIs on clinical out-
2
comes in adults with severe influenza has not been confirmed
Division of Infectious Diseases, Department of Internal Medicine,
Soonchunhyang University Bucheon Hospital, Bucheon, Republic of
by any randomized controlled trial [10]. Although a recent
Korea meta-analysis which included data from more than 29,000
3
Division of Infectious Diseases, Department of Internal Medicine,
individual patients from 78 different centers admitted for
Kyung Hee University Medical Center, Kyung Hee University H1N1 influenza during the 2009 pandemic showed a remark-
School of Medicine, Seoul, Republic of Korea able reduction in mortality for patients receiving NAIs [11],
4
Division of Infectious Diseases, Department of Internal Medicine, the study results were criticized due to methodological issues
Inje University Ilsan Paik Hospital, Goyang, Republic of Korea [12–15]. Therefore, further investigations into the clinical
1674 Eur J Clin Microbiol Infect Dis (2017) 36:1673–1677

effectiveness of NAIs are still required, especially in adults administration of NAIs ≤2 days after the onset of symptoms.
hospitalized with influenza. We reviewed the clinical data NAIs were administered as follows: one capsule (75 mg) of
from adults hospitalized with influenza to investigate the ef- oseltamivir was taken twice a day and 300 mg of peramivir
fectiveness of NAIs on their clinical outcomes. was injected once a day. This study was approved by the
Institutional Review Board of each study hospital, including
CAUH.
We compared the clinical characteristics of patients with
Patients and methods early NAI therapy to those of patients without early NAI ther-
apy. Continuous variables were compared using a Student’s t-
We identified adults (age ≥15 years) who had a positive result test or the Mann–Whitney U-test. Categorical variables were
from diagnostic tests for influenza at Chung-Ang University compared using a χ2 test or Fisher’s exact test. A p-value of
Hospital (CAUH) between March 2010 and December 2013. <0.05 was considered significant. Logistic regression analysis
From these patients, we selected those who were admitted to was performed to identify risk factors for in-hospital mortality.
the hospital for the treatment of influenza and reviewed their Statistical analyses were performed using SPSS software (ver-
medical records. We also included clinical data from adults sion 18.0; SPSS, Chicago, IL, USA).
hospitalized with influenza from our previous study [16],
which was performed between January 2014 and
March 2014 at four tertiary care centers, including CAUH.
The following parameters were investigated: baseline charac- Results
teristics including demographics and underlying disease or
condition, and clinical characteristics including symptoms, A total of 588 adults were hospitalized with influenza during
treatment, and clinical outcomes. Based on these data, patients the study period. Among these, 82 were excluded (16 received
were included in the final study analysis only if: (1) they had NAIs more than 14 days after the onset of symptoms, six were
available data on the time from the onset of symptoms to the duplicates, 12 did not have available data on the time from the
administration of NAIs and (2) the time ranged from 0 to onset of symptoms to the administration of NAIs, and 48 had
14 days. Patients who received NAIs more than 14 days after the occurrence of influenza infection 2 days after admission).
the onset of symptoms were excluded because they were as- Finally, 506 patients were included in study analyses.
sumed to have inaccurately recalled the onset of symptoms. If The distribution of study patients according to each influ-
a patient had experienced several episodes of influenza infec- enza season and the major circulating strain(s) during each
tion during the study period, only the first episode was includ- period in the Republic of Korea are presented in Table 1
ed. Pneumonia was defined as the presence of a new or pro- [17–20]. The characteristics for study patients are presented
gressive infiltrate on chest radiograph plus two or more of the in Table 2. The median patient age was 58.5 years, and more
following symptoms or signs: fever, cough, sputum produc- than half of the patients were female (312, 61.7%). More than
tion, dyspnea, and an attending physician’s diagnosis of pneu- two-thirds were infected with influenza A (348, 68.8%),
monia. A patient was considered to have Bpneumonia at followed by influenza B (142, 28.1%) and both (16, 3.2%).
presentation^ or Bearly admission to the intensive care unit Nearly one half of patients (232, 46.5%) had underlying dis-
(ICU)^ if he (or she) had pneumonia or was admitted to the eases or conditions predisposing them to influenza complica-
ICU within one day after the beginning of the influenza eval- tions. Pneumonia occurred in 143 patients (28.3%).
uation, respectively. Early NAI therapy was defined as the Admission to the ICU was observed in 38 (7.5%). There were

Table 1 Distribution of adult patients hospitalized with influenza A, influenza B, and co-infection of influenza A and B according to influenza season

Season Major strain(s) Influenza A Influenza B Influenza A/B Total no.

in Korea (no. of fatal cases) (no. of fatal cases) (no. of fatal cases) (no. of fatal cases)

2009–2010 pH1N1a, B 3 (0) 13 (0) 1 (0) 17 (0)

2010–2011 pH1N1a 16 (0) 0 (0) 0 (0) 16 (0)
2011–2012 sH3N2b, B 42 (3) 47 (2) 11 (0) 100 (5)
2012–2013 sH3N2b 75 (2) 9 (0) 1 (1) 86 (3)
2013–2014 B, sH3N2b 212 (5) 73 (3) 2 (0) 287 (8)
Total no. (no. of fatal cases) 348 (10) 142 (5) 16 (1) 506 (16)
a
Pandemic H1N1 2009
b
Seasonal H3N2
Eur J Clin Microbiol Infect Dis (2017) 36:1673–1677 1675

Table 2 Clinical characteristics for adult patients hospitalized with influenza who received neuraminidase inhibitors (NAIs) within 2 days after the
onset of symptoms and those who did not

Characteristics All patients With early NAI Without early NAI p-value
(n = 506) therapy (n = 233) therapy (n = 273)

Median age, years (range) 58.5 (15–96) 60.0 (15–93) 57.0 (15–96) 0.44
Male sex 194 (38.3) 89 (38.2) 105 (38.5) 0.95
Diagnosis of influenza <0.001
Rapid influenza detection test 341 (67.4) 186 (79.8) 155 (56.8)
PCR 108 (21.3) 20 (8.6) 88 (32.2)
Both 57 (11.3) 27 (11.6) 30 (11.0)
Type of influenza 0.01
Influenza A 348 (68.8) 176 (75.5) 172 (63.0)
Influenza B 142 (28.1) 52 (22.3) 90 (33.0)
Both 16 (3.2) 5 (2.1) 11 (4.0)
Median days from the onset of symptoms to admission (range)a 2 (0–14) 1 (0–7) 3 (0–14) <0.001
Underlying disease or condition 232 (46.5) 105 (45.1) 127 (46.5) 0.74
Diabetes mellitus 97 (19.2) 44 (18.9) 53 (19.4) 0.88
Bronchial asthma 61 (12.1) 23 (9.9) 38 (13.9) 0.16
Chronic lung disease 55 (10.9) 19 (8.2) 36 (13.2) 0.07
Solid tumor 44 (8.7) 25 (10.7) 19 (7.0) 0.13
Cerebrovascular disease 39 (7.7) 16 (6.9) 23 (8.4) 0.51
Congestive heart failure 33 (6.5) 12 (5.2) 21 (7.7) 0.25
Chronic kidney disease 28 (5.5) 13 (5.6) 15 (5.5) 0.97
Pregnancy 13 (2.6) 4 (1.7) 9 (3.3) 0.26
Liver cirrhosis 9 (1.8) 6 (2.6) 3 (1.1) 0.31
Hematologic malignancy 8 (1.6) 6 (2.6) 2 (0.7) 0.15
Dialysis 10 (2.0) 6 (2.6) 4 (1.5) 0.52
Immunosuppressive agents 15 (3.0) 9 (3.9) 6 (2.2) 0.27
Recent chemotherapy 13 (2.6) 10 (4.3) 3 (1.1) 0.02
Recent surgery 6 (1.2) 1 (0.4) 5 (1.8) 0.22
Initial symptoms
Fever 437 (85.0) 205 (88.0) 232 (85.0) 0.33
Cough 426 (84.2) 195 (83.7) 231 (84.6) 0.78
Sputum production 335/505 (66.3) 155 (66.5) 180/272 (66.2) 0.93
Dyspnea 120 (23.7) 44 (18.9) 76 (27.8) 0.02
Positive bacterial culturesb 47 (9.3) 16 (6.9) 31 (11.4) 0.08
Pneumonia 143 (28.3) 46 (19.7) 97 (35.5) <0.001
Pneumonia at presentation 131 (25.9) 40 (17.2) 91 (33.3) <0.001
ICUc admission 38 (7.5) 10 (4.3) 28 (10.3) 0.01
Early ICUc admission 33 (6.5) 9 (3.9) 24 (8.8) 0.03
Clinical management
Oxygen supplementation 130/505 (25.7) 56/232 (24.1) 74 (27.1) 0.45
Mechanical ventilation 22 (4.3) 6 (2.6) 16 (5.9) 0.07
Vasoconstrictors 22 (4.3) 9 (3.9) 13 (4.8) 0.62
NAI therapy with peramivir 24/443 (5.4) 8/233 (3.4) 16/210 (7.6) 0.05
Antibiotics 341 (67.4) 140 (60.1) 201 (73.6) 0.001
Length of hospital stay, mean days (SD)d 6.5 (7.6) 5.3 (4.5) 7.5 (2.9) 0.001
In-hospital mortality, days after the onset of symptoms 16 (3.2) 8 (3.4) 8 (2.9) 0.75
3–7 days 3 1 2
8–14 days 2 1 1
15–30 days 9 6 3
>30 days 2 0 2
Influenza-related mortality 10 (2.0) 5 (2.1) 5 (1.8) 1.00

a
The number of patients was 552
b
Positive bacterial cultures included patients with concomitant bacterial infections caused by Staphylococcus aureus (11), Escherichia coli (10),
Streptococcus pneumoniae (6), Klebsiella pneumoniae (6), Pseudomonas aeruginosa (4), Acinetobacter baumannii (4), streptococci (3), Moraxella
catarrhalis (1), Haemophilus influenzae (1), Enterobacter cloacae (1), Enterococcus faecalis (1). In one case, two organisms were found
c
Intensive care unit
d
The number of patients was 503

443 patients (87.5%) who received NAIs and 233 (52.6% of (2.0%) were assumed to be directly related to influenza infec-
443) received early NAI therapy. The median duration of hos- tion. Deaths unrelated to influenza were caused by the devel-
pital admission was 4 days (ranging from 1 to 95 days). opment of hospital-acquired infections 2 weeks after influenza
Sixteen patients (3.2%) died during admission and 10 deaths infection (n = 2), progression of malignancies (n = 1), acute
1676 Eur J Clin Microbiol Infect Dis (2017) 36:1673–1677

myocardial infarction (n = 1), acute cerebral infarction (n = 1), early NAI therapy, and received a key intervention to reduce
and asphyxia (n = 1). mortality earlier than patients without early NAI therapy.
Patients who received early NAI therapy were compared to However, the in-hospital mortality rate in patients with early
those without early NAI therapy (Table 2). The diagnosis of NAI therapy was not lower than that in those without. The
influenza by polymerase chain reaction (PCR) methodology multivariate analysis showed that early NAI therapy was not
and influenza B infection were both less commonly observed associated with in-hospital mortality. Thus, the findings from
in patients who received early NAI therapy compared to those our cohort did not reveal any impact of early NAI therapy on
who did not. Patients with early NAI therapy were also admit- mortality, which is not consistent with the results from previ-
ted to the hospital earlier. Underlying chronic illnesses were ous studies [4–8, 11]. This discrepancy may be explained by a
similar in the two groups, except for chronic lung disease, few characteristics of our study patients. First, unlike the pre-
which tended to be more common in patients without early vious studies [6–8, 11], influenza B infection was more fre-
NAI therapy, and recent chemotherapy, which was more com- quently found (sole influenza B infection in 28.1% and co-
mon in patients with early NAI therapy. Patients without early infection of influenza A/B in 3.2%) in our patients. Several
NAI therapy had dyspnea, pneumonia, pneumonia at presen- previous studies on severe influenza only investigated influ-
tation, ICU admission, early ICU admission, and antibiotic enza A-infected patients [6, 8, 11] or the study was primarily
therapy more frequently than patients who received early composed of influenza A-infected patients [7]. A few clinical
NAI therapy. The length of hospital admission was longer in studies reported that the NAI, oseltamivir, was less effective
patients without early NAI therapy. Both the in-hospital mor- against influenza B compared to influenza A [21, 22].
tality rate and the influenza-related mortality rate were not Although this finding has not been confirmed in further stud-
different between the two groups. ies, it suggests that the inclusion of more influenza B-infected
The impact of early NAI therapy on the in-hospital mortality patients in our study may have affected outcomes due to early
was evaluated in variable subgroups. Among influenza A- NAI therapy. This hypothesis could also be supported by the
infected patients (n = 348), the in-hospital mortality rate for finding that in-hospital mortality was relatively frequent in
patients with early NAI therapy was lower compared to patients influenza B-infected patients with early NAI therapy in this
without NAI therapy [4/176 (2.3%) vs. 6/172 (3.5%)], although study; there was a tendency toward more frequent in-hospital
this difference was not statistically significant (p = 0.54). Among mortality in influenza B-infected patients with early NAI ther-
influenza B-infected patients (n = 142), the rate of patients with apy even compared to patients without early NAI therapy.
early NAI therapy (4/52, 7.7%) tended to be higher than in Second, although two observational cohort studies which in-
patients without early NAI therapy (1/90, 1.1%) (p = 0.06). In cluded a relatively large number of influenza B-infected pa-
each subgroup of patients who had pneumonia at presentation tients (19% of 327 in one and 29% of 754 in the other) showed
(n = 131) and those who had early ICU admission (n = 33), in- a reduction in mortality associated with early NAI therapy [4,
hospital mortality rate of patients with early NAI therapy was 5], they did not utilize PCR methods for the diagnosis of
not lower than that of patients without early NAI therapy [7.5% influenza but used rapid influenza diagnostic tests and viral
(3/40) vs. 8.8% (8/91) in the former subgroup and 66.7% (6/9) culture instead. Compared to the PCR methods used in our
vs. 20.8% (5/24) in the latter subgroup]. study, viral cultures have been reported to have a lower sen-
Risk factors for in-hospital mortality were investigated sitivity, especially for samples with low viral loads [23]. Thus,
using univariate and multivariate analyses. The univariate only patients with relatively high viral loads may have been
analyses showed that male gender, ICU admission, pneumo- included in the two previous studies. Patients with low influ-
nia, old age (age ≥65 years), chronic lung disease, congestive enza virus-replicating activity in the respiratory tract may still
heart failure, dyspnea, positive bacterial culture, antibiotic present with severe influenza resulting from variable compli-
therapy, oxygen supplementation, mechanical ventilation, cations. If these patients were not included, the clinical effec-
and the use of vasoconstrictors were risk factors for in- tiveness of early NAI therapy might be overestimated. We
hospital mortality. The multivariate analysis showed that suggest that the impact of early NAI therapy on mortality
ICU admission was the only risk factor for in-hospital mortal- should be further evaluated in studies including a large num-
ity (adjusted odds ratio = 56.53, 95% confidence inter- ber of influenza B-infected patients using PCR methodology
val = 9.18–348.04, p < 0.001). rather than viral culture to diagnose influenza.
The shorter length of hospital admission in patients with
early NAI therapy should not be interpreted as a result of early
Discussion NAI therapy in our cohort. Patients with early NAI therapy
had pneumonia and ICU admission less frequently than pa-
Patients who received early NAI therapy had severe clinical tients without early NAI therapy, even from the early stage of
manifestations such as an initial symptom of dyspnea, pneu- their illnesses. But we could not determine which of the two—
monia, and ICU admission less frequently than those without earlier NAI therapy and less severe initial presentation—
Eur J Clin Microbiol Infect Dis (2017) 36:1673–1677 1677

affected the shorter length of hospital admission in patients 7. Lee N, Leo YS, Cao B, Chan PK, Kyaw WM, Uyeki TM, Tam
WW, Cheung CS, Yung IM, Li H, Gu L, Liu Y, Liu Z, Qu J, Hui DS
with early NAI therapy.
(2015) Neuraminidase inhibitors, superinfection and corticosteroids
This study has a few important limitations. First, laboratory affect survival of influenza patients. Eur Respir J 45:1642–1652
investigation on the influenza virus, such as subtyping, quantifi- 8. Hiba V, Chowers M, Levi-Vinograd I, Rubinovitch B, Leibovici L,
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