Ibuprofen as risk-factor for complications of acute anterior sinusitis in children

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Original article

Ibuprofen as risk-factor for complications of acute anterior sinusitis in children R. Nicollas a,∗ , E. Moreddu a , C. Le Treut-Gay a , J. Mancini c , M. Akkari d , M. Mondain d , D. Scavarda b , G. Hosanna e , P. Fayoux e , S. Pondaven-Letourmy f , E. Lescanne f , J.-M. Triglia a a Aix-Marseille University, Department of Pediatric Otolaryngology Head and Neck Surgery, La Timone Children’s Hospital, 264, rue St Pierre, 13385 Marseille cedex 5, France b Aix-Marseille University, Department of Pediatric Neurosurgery, La Timone Children’s Hospital, 264, rue St Pierre, 13385 Marseille cedex 5, France c Aix-Marseille University Department of Biostatistics and Communication and Information Technologies, BiosTIC, La Timone Hospital, Inserm, IRD, UMR912 SESSTIMF, 264, rue Saint Pierre, 13385 Marseille cedex 5, France d Department of Otolaryngology Head and Neck Surgery, Gui de Chauliac Hospital, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 5, France e Department of Otolaryngology Head and Neck Surgery, avenue Eugène-Avinée, 59037 Lille, France f Department of Otolaryngology Head and Neck Surgery, Gatien Clocheville Children’s Hospital, 49, boulevard Béranger, 37000 Tours, France

a r t i c l e Keywords: Ibuprofen NSAID Acute sinusitis Complication Empyema

i n f o

a b s t r a c t Importance: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to inhibit chemotaxis, oxidative burst and phagocytosis, bacterial killing in granulocytes as well as inhibiting neutrophil aggregation or degranulation, thereby interfering with the function of lymphocytes. On the other hand, ibuprofen is widely prescribed in pediatrics for its powerful analgesic and antipyretic effects. To our knowledge, no previous publication outlines the relationship between Ibuprofen therapy and an increased risk of intracranial and/or orbital complications of acute fronto-ethmoidal sinusitis in childhood. Objective: To look for a relationship between ibuprofen and occurrence of intra-cranial and/or orbital complications of acute fronto-ethmoidal sinusitis in pediatrics. Setting and methods: The medical charts of patients younger than 18 years admitted into the E.N.T. departments of 4 academic care centers during 2 consecutive years for fronto ethmoidal sinusitis were reviewed retrospectively. The history of ibuprofen intake, the occurrence of complication (orbital or intracranial) as well as the usual demographic data were noted. A statistical analysis was performed in order to ascertain whether a relationship between taking NSAIDs and the onset of an intracranial and/or orbital complication exists. Results: Intake of ibuprofen appeared to be a risk-factor of intracranial complications or associated orbital and intracranial complications of acute fronto-ethmoidal sinusitis in children. Neither gender nor age nor initial pain intensity were statistically related to the onset of complications. Conclusion and relevance: This retrospective multicenter cohort study appears to suggest that ibuprofen increases the risk of orbital and/or intracranial complications of acute fronto-ethmoidal sinusitis in childhood. Therefore, we recommend not prescribing ibuprofen if one suspects an acute sinusitis in a child or adolescent. © 2019 Elsevier Masson SAS. All rights reserved.

1. Introduction NSAIDs are known to inhibit chemotaxis, oxidative burst and phagocytosis, bacterial killing in granulocytes as well as inhibiting neutrophil aggregation or degranulation [1,2], so interfering

∗ Corresponding author at: Department of Pediatric Otolaryngology Head and Neck Surgery, La Timone Children’s Hospital, 264, rue St Pierre, 13385 Marseille cedex 5, France. E-mail address: [email protected] (R. Nicollas).

with the function of lymphocytes. Many cases are reported suggesting a relationship between intake of NSAIDs and worsening of necrotizing fasciitis[3–6], between exposure to NSAIDs at the beginning of acute pneumonia and the development of pleuro-pulmonary complications[7–9] and between intake of antiinflammatory drugs and pharyngitis complications[10]. The aim of this article is to look for any relationship between taking NAIDs and an increased risk of intracranial and/or intra-orbital complications of acute fronto-ethmoidal sinusitis in childhood as to our knowledge, no previous publication did it.

https://doi.org/10.1016/j.anorl.2019.10.004 1879-7296/© 2019 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Nicollas R, et al. Ibuprofen as risk-factor for complications of acute anterior sinusitis in children. European Annals of Otorhinolaryngology, Head and Neck diseases (2019), https://doi.org/10.1016/j.anorl.2019.10.004

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2. Patients and methods 2.1. Ethical considerations The risk of severe complications precluded ethically a prospective randomised study using two groups (with and without NSAIDs); we therefore decided to undertake a multicenter retrospective study of all patients under 18 years of age admitted with acute ethmoidal and/or frontal sinusitis. The study and its design were approved by the Review Board of the “Pediatric medicine and surgery department” of our institution. 2.2. Patients and methods The medical charts of children referred to 4 French academic care centers with ethmoidal and/or frontal acute sinusitis over a 2 years-period were reviewed. As ibuprofen is the most frequently prescribed NSAID, especially in pediatrics, for its powerful analgesic and antipyretic effects, the study focused on this drug. The patients were separated retrospectively into 2 groups according to whether or not ibuprofen had been used before referral to our center. The demographic data (age and gender) were studied in each group and compared, as well as the initial pain, fever and intake of antibiotics before hospitalization. As the initial pain was evaluated using 3 different scales according to the retrospective appreciation of the parents (and children when possible), we decided to define this pain as mild, moderate or severe. The evaluations were reported either using a verbal scale (from 1 to 10, 1 being the lack of pain and 10 the most intense pain you can imagine), using a self-evaluation with an analogue visual scale or with a hetero-evaluation using the Evendol [11] when patients’ age did not allow them to answer correctly. The pain was defined “mild” if located in first third part of the scales, “moderate” if located in the middle third part of the scales, and “severe” over this level (Fig. 1). The rates of loco-regional complications were compared between the two groups and were also studied separately (global loco-regional, orbital and/or intracranial, purely orbital and purely intracranial). 2.3. Statistical Analysis Data are expressed as mean ± standard deviation for continuous data and as counts (%) for categorical data. Bivariate analyses were conducted with the use of two-tailed Student’s t-tests for continuous data and a two-tailed ␹2 or Fisher’s exact test for categorical data when appropriate. All these statistical analyses were performed using IBM SPSS Statistics 20.0 (IBM Inc.,

New York, USA), and P-values of less than 0.05 were considered to indicate statistical significance. The association between NSAIDs prescriptions before hospitalization and the occurrence of complications during hospitalization was studied using a binary logistic regression model making systematic adjustments for age, initial pain intensity and antibiotics during the pre-hospital period. 3. Results 125 children (56 F/69 M) with median age of 8 years (9 months to 18 years) were referred to our 4 centers. All of them began their history with fever associated with headache, and all were referred after a mean of 6 days of at home treatment with increasing headache and persisting fever. In 5 cases, data about intake of ibuprofen were not available and the patients were excluded of the study. Of 120 patients, 30 (14 F/16 M) had a history of ibuprofen intake and were labelled Group A. Ibuprofen was prescribed for a mean duration of 6.2 days (1–10) at the recommended posology according to their weight. In this group, 22 patients were ordered antibiotics; as 6 different molecules were given, a significant analysis could not be performed. The group of 90 patients who did not take ibuprofen (40 F/50 M) was labelled group B. In group A, the sex ratio was 14 F/16 M. The global loco-regional complication rate was 80% (n = 24). The purely orbital complication rate was 46.7% (n = 14) and the purely intra-cranial complication rate was 43% (n = 12). In group B, the sex ratio was 40 F/50 M. The global locoregional complication rate was 44.4% (n = 40). The purely orbital complication rate was 28.9% (n = 26) and the purely intra-cranial complication rate was 17.6% (n = 16). Comparing the two groups, it can be observed that: the sexratio is not statistically different (P = 0.903). Mean age was 4.55 years for the group A and 11.48 years for the group B (P = 0.003). Age greater than 10 y seemed in isolation to increase the risk of intracranial complication (P = 0.005). Performing a binary logistic regression model, age was found not to any have effect on the occurrence of such complications and had to be considered as a confounding factor, though ibuprofen intake retained a significant difference (P = 0.001; O.R. = 3.992; Confidence Interval CI : 1.808-8.812) for intracranial and global loco-regional complications. The incidence of loco-regional complications is significantly higher in group A than B (P = 0.002; OR = 4.8; CI: 1.76-12.84) (Table 1). Group A shows an increased risk of purely intra-cranial complications (P = 0.015; OR = 3.08; CI 1.24–7.65) (Table 2), but

Fig. 1. EVENDOL Scale from 0 to 15 (on left) and its harmonization with the Analog Visual Scale from 0 to 10 (on right).

Please cite this article in press as: Nicollas R, et al. Ibuprofen as risk-factor for complications of acute anterior sinusitis in children. European Annals of Otorhinolaryngology, Head and Neck diseases (2019), https://doi.org/10.1016/j.anorl.2019.10.004

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Table 1 Uni- and multivariate analysis for occurrence of Global Loco-regional Complications according to intake of NSAID, gender, age and initial pain.

NSAIDs No Yes Gender Male Female Age ≤ 10 y.o > 10 y.o Initial Pain Severe Mild/moderate

Global Loco-regional Complications Yes No n = 64 n = 56

Univariate Analysis OR CI-

CI+

P

Multivariate Analysis OR CI-

CI+

P

50 (55.6%) 6 (20.0%)

40 (44.4%) 24 (80.0%)

1 5.0

1.864

13.409

0.001

1 4.8

1.76

12.84

0.002

30 (46.2%) 26 (47.3%)

35 (53.8%) 29 (52.7%)

1 0.956

0.465

1.964

0.903

0.95

0.45

2.04

0.903

43 (59.7%) 13 (27.1%)

29 (40.3%) 35 (72.9%)

1 3.992

1.808

8.812

0.001

27 (55.1%) 29 (40.8%)

22 (44.9%) 42 (59.2%)

1.777 1

0.852

3.708

0.125

1.58

0.73

3.41

0.203

Table 2 Uni- and multivariate analysis for occurrence of intra-cranial complications according to intake of NSAID, gender, age and initial pain.

NSAID’s No Yes Gender Male Female Age ≤ 10 y.o > 10 y.o Initial Pain Severe Mild/moderate

IntraCranial Complications No Yes n = 92 n = 28

Univariate Analysis OR CI-

CI+

P

Multivariate Analysis OR CI-

CI+

P

74 (82.2%) 18 (60.0%)

16 (17.8%) 12 (42.9%)

1 3.08

1.24

7.65

0.015

2.82

1.11

7.17

0.029

49 (75.4%) 43 (78.2%)

16 (24.6%) 12 (21.8%)

1 0.855

0.364

2.006

0.718

0.83

0.334

2.03

0.676

68 (94.4%) 24 (50.0%)

4 (5.6%) 24 (50.0%)

1 17

5.349

54.027

< 0.001

49 (69.0%) 43 (87.8%)

22 (31.0%) 6 (12.2%)

3.218 1

1.194

8.67

0.021

2.96

1.08

8.12

0.035

not of purely intra-orbital complications (P = 0.077; OR = 2.2; CI 0.921–5.039) (Table 3). When splitting the complications into subgroups, it appears that for the NSAIDs group, no statistical relationship was found between initial pain intensity and the onset of intra-orbital complication (P = 0.617); a statistical relationship was found with intracranial complication and severe initial pain (P = 0.035). No statistical link appeared between global loco-regional complications (P = 0.203; OR = 1.58; CI: 0.73-3.41) (Table 1) and between initial pain intensity and NSAID intake (P = 0.124) (Table 4). 10 different antibiotics

were prescribed during the pre-hospital period in widely different dosages; no accurate statistical analysis was possible. 4. Discussion The clinical and observational data gathered in this study strongly suggest a relationship between the intake of Ibuprofen during frontal and/or ethmoidal sinusitis and the occurrence of loco-regional and especially intracranial complications in children. Many models and series can be found in the literature to

Table 3 Uni- and multivariate analysis for occurrence of orbital complications according to intake of NSAID, gender, age and initial pain.

NSAIDs No Yes Gender Male Female Age ≤ 10 y.o > 10 y.o Initial Pain Severe Mild/moderate

Orbital Complications Yes No n = 40 n = 78

Univariate Analysis OR CI-

CI+

P

Multivariate Analysis OR CI-

CI+

P

64 (71.1%) 16 (53.3%)

26 (28.9%) 14 (46.7%)

1 2.2

0.921

5.039

0.077

2.2

0.94

5.25

0.069

44 (67.7%) 36 (65.5%)

21 (32.3%) 19 (34.5%)

1 1.106

0.517

2.367

0.796

1.1

0.51

2.38

0.81

45 (62.5%) 35 (72.9%)

27 (37.5%) 13 (27.1%)

1 0.619

0.279

1.372

0.237

32 (65.3%) 48 (67.6%)

17 (34.7%) 23 (32.4%)

0.902 1

0.418

1.948

0.793

0.82

0.37

1.8

0.617

Please cite this article in press as: Nicollas R, et al. Ibuprofen as risk-factor for complications of acute anterior sinusitis in children. European Annals of Otorhinolaryngology, Head and Neck diseases (2019), https://doi.org/10.1016/j.anorl.2019.10.004

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Table 4 Analysis for relationship between pain intensity and intake of NSAID.

NSAID No Yes Total

Pain Mild/moderate Obs Exp

Severe Obs

Exp

Total Obs

Exp

46 9 55

23 10 33

25.9 7.1 33.0

69 19 88

69.0 19.0 88.0

43.1 11.9 55.0

P value

0.124

explain why ibuprofen can be a risk-factor for the extension of an infectious process. In vitro and in vivo data demonstrate that NSAIDs may inhibit neutrophil aggregation or degranulation, and so interfere with the function of lymphocytes and inhibit monocyte superoxide production [6,10]. Some studies provide evidence that NSAIDs can increase production of TNF-␣, IL-1, and IL-6, which are pro-inflammatory cytokines and so may increase the spread of infection [1,4]. It has also been clearly demonstrated that, in vitro, NSAIDs inhibit the function of neutrophil polymorphonuclear cells, which constitute the first-line of defense against pathogenic agents [12]. Cheung [10] found that TNF-␣ and IL-6 peaked at the third day of exposure to Ibuprofen in his murine model, concomitant of an increase of wound necrosis and death. Many cases are reported of what seemed to be a relationship between intake of NSAIDs and worsening of necrotizing fasciitis [3,5], including pharyngitis [3]. A prospective cohort of patients with community-acquired pneumonia suggested that exposure to NSAIDs at the beginning of acute community-acquired pneumonia was associated with the development of pleuro-pulmonary complications, especially empyema [7]. All these data were confirmed by further studies in adults and children [8,9]. Recently, in a series of 163 patients, it appeared that anti-inflammatory drugs (steroids as well as NSAIDs) seemed to increase the risk of pharyngitis complications [8]. To our knowledge, no publication states how NSAIDs do or do not modify the onset of complications in a case of acute sinusitis in children. For this reason, it will not be easy to compare these results with other series. A clinical report of a bilateral epidural empyema in a teenager as complication of an acute sinusitis was published in 1994 [13]. In this unusual presentation, the ibuprofen medication was reported in the patient’s history but was not discussed further. In our experience, we felt that most of our patients with an intracranial complication of an acute sinusitis in pediatric population were prescribed NSAIDs. As it was ethically impossible to perform a random prospective study to evaluate the relative risk, we decided to perform this multicenter retrospective study. Age could initially appear as a risk factor for intracranial complications. However, if we consider this parameter as a confounding factor and perform a binary logistic regression, it appears not to be related to a complication event (loco-regional, strictly intra-orbital or strictly intracranial). The same analysis was performed with ibuprofen intake and then with the age, to verify whether it was a confusing factor or if it kept a statistical link with the complications. Ibuprofen intake appeared related to the onset of a loco-regional and strictly intra-cranial complications of acute anterior sinusitis, and age was clearly a confounding factor. As initial pain intensity could be a confounding factor, being eventually the symptom of an initial blocked-sinusitis or even empyema, and not a drug-induced complication, the pain evaluations were studied after homogenizing the scales used. Considering the intracranial complications, the initial pain was severe in most cases. The discussion can be: was the initial pain related to an initial intracranial complication or was the complication related to the intake of more ibuprofen? When the relation between initial pain

intensity and intake of NSAID is studied, it appears that no statistical link can be found. So, the answer to the question is that pain is also a confounding factor. The main fact, merging from the analysis of our study is that intake of NSAID appears as a risk factor for intracranial complications in children presenting with an ethmoido-frontal acute sinusitis. The Odds Ratio is 2.82 (with a CI: 1.11–7.17 and P value at 0.029) for strictly intracranial complications and 4.8 (with a CI: 1.76–12.84 and P value at 0.002) for loco-regional complications. In the case of isolated orbital complication, the Odds ratio is 2.2 (with a CI: 0.921-5.39 and P value at 0.069). This slight lack of significance may be due to a lack of power due to the somewhat limited number of patients and would need a larger study. Last, as stated by guidelines of the French Society of Oto-RhinoLaryngology and HNS, if NSAIDs have not, for the moment, any proved responsibility in complications of usual ENT infections in pediatrics, it is recommended not to prescribe them in nonmaxillary sinusitis, and, in all other cases, not more than 2 days [14]. 5. Conclusion Clinical data and statistical analysis of this study strongly suggest that ibuprofen is a risk factor for the loco-regional and especially intracranial complications of acute sinusitis in childhood. Consequently, we recommend avoidance of this drug in cases of feverish headache in childhood and prefer paracetamol or acetaminophen until it is proved that there is no documented acute sinusitis. Disclosure of interest The authors declare that they have no competing interest. References [1] Stevens DL. Could nonsteroidal anti-inflammatory drugs (NSAIDs) enhance the progression of bacterial infections to toxic shock syndrome? Clin Infect Dis 1995;21:977–80. [2] Kaplan HB, Edelson HS, Korchak HM, Given WP, Abramson S, Weissmann G. Effects of non-steroidal anti-inflammatory agents on human neutrophil functions in vitro and in vivo. Biochem Pharmacol 1984;33:371–8. [3] Veenstra RP, Manson WE, van der Werf TS, Fijen JW, Tulleken JE, Zijlstra JG, et al. Fulminant necrotizing fasciitis and nonsteroidal anti-inflammatory drugs. Intensive Care Med 2001;27(11):1831. [4] Childers BJ, Potyondy LD, Nachreiner R, Rogers FR, Childers ER, Oberg KC, et al. Necrotizing fasciitis: a fourteen year retrospective study of 163 consecutive patients. Am Surg 2002;68:109–16. [5] Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M. Severe necrotizing softtissue infections and nonsteroidal antiinflammatory drugs. Clin Exp Dermatol 2008;33:249–55. [6] Weng TC, Chen CC, Toh HS, Tang HJ. Ibuprofen worsens Streptococcus pyogenes soft tissue infections in mice. J Microbiol Immunol Infect 2011;44(6): 418–23. [7] Voiriot G, Dury S, Parrot A, Mayot C, Fartoukh M. Non-steroidal antiinflammatory drugs may affect the presentation and course of communityacquired pneumonia. Chest 2011;139(2):387–94. [8] Franc¸ois P, Desrumaux A, Cans C, Pin I, Pavese P, Labarère J. Prevalence and risk factors of suppurative complications in children with pneumonia. Acta Paediatr 2010;99(6):861–6. [9] Dirou S, Voiriot G. Anti-inflammatoires et pneumonie aiguë communautaire. Rev Mal Respir 2015;32(8):841–4. [10] Demeslay J, De Bonnecaze G, Vairel B, Chaput B, Pessey JJ, Serrano E, et al. Possible role of anti-inflammatory drugs in complications of pharyngitis. A retrospective analysis of 163 cases. Europ Ann Otorhinolaryngol Head Neck Dis 2014;131:299–303. [11] Fournier-Charrière E, Tourniaire B, Carbajal R, Cimerman P, Lassauge F, Ricard C, et al. EVENDOL, a new behavioral pain scale for children ages 0 to 7 years in the emergency department: design and validation. Pain 2012;153(8): 1573–82. [12] Cheung EV, Tidball JG. Administration of the non-steroidal anti-inflammatory drug ibuprofen increases macrophage concentrations but reduces necrosis during modified muscle use. Inflamm Res 2003;52:170–6.

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anti-inflammatory drugs (NSAIDs) and pediatric ENT infections. Short version. Eur Ann Otol Rhinol Laryngol 2019 [in press].

Please cite this article in press as: Nicollas R, et al. Ibuprofen as risk-factor for complications of acute anterior sinusitis in children. European Annals of Otorhinolaryngology, Head and Neck diseases (2019), https://doi.org/10.1016/j.anorl.2019.10.004