Sex differences in febrile children with respiratory symptoms attending European emergency departments: An observational multicenter study.

OBJECTIVE: To assess sex differences in presentation and management of febrile children with respiratory symptoms attending European Emergency Departments. DESIGN AND
SETTING: An observational study in twelve Emergency Departments in eight European countries. PATIENTS: Previously healthy children aged 0-<18 years with fever (≥ 38°C) at the Emergency Department or in the consecutive three days before Emergency Department visit and respiratory symptoms were included. MAIN OUTCOME MEASURES: The main outcomes were patient characteristics and management defined as diagnostic tests, treatment and admission. Descriptive statistics were used for patient characteristics and management stratified by sex. Multivariable logistic regression analyses were performed for the association between sex and management with adjustment for age, disease severity and Emergency Department. Additionally, subgroup analyses were performed in children with upper and lower respiratory tract infections and in children below five years.
RESULTS: We included 19,781 febrile children with respiratory symptoms. The majority were boys (54%), aged 1-5 years (58%) and triaged as low urgent (67%). Girls presented less frequently with tachypnea (15% vs 16%, p = 0.002) and increased work of breathing (8% vs 12%, p<0.001) compared with boys. Girls received less inhalation medication than boys (aOR 0.82, 95% CI 0.74-0.90), but received antibiotic treatment more frequently than boys (aOR 1.09, 95% CI 1.02-1.15), which is associated with a higher prevalence of urinary tract infections. Amongst children with a lower respiratory tract infection and children below five years girls received less inhalation medication than boys (aOR 0.77, 95% CI 0.66-0.89; aOR 0.80, 95% CI 0.72-0.90).
CONCLUSIONS: Sex differences concerning presentation and management are present in previously healthy febrile children with respiratory symptoms presenting to the Emergency Department. Future research should focus on whether these differences are related to clinicians' attitudes, differences in clinical symptoms at the time of presentation and disease severity.

Introduction

Sociodemographic characteristics such as sex have been shown to influence health care delivery and outcome [1]. Identifying these differences is crucial for not only optimizing health care outcomes but also minimizing existing inequity in health care [2]. Sex is defined as a biological classification of living things as male or female according to their reproductive organs and functions [3]. Several studies have been conducted regarding sex differences in adults presenting to the Emergency Department (ED), finding clinically relevant differences. For example, a study in adults has demonstrated that men and women have a different presentation of myocardial infarction [4]. Another study has shown that sex-specific protocols for diagnosis, management, and counseling can influence patient outcomes in sport-related injury in emergency medicine [5].

Although sex differences in adults attending the ED have received increasing attention, research on sex differences in children remains scarce, especially in emergency medicine [6]. The first study to assess the role of sex in pediatric emergency medicine using a multicenter and international cohort found evidence of sex-specific differences regarding management of children after adjustment for age, triage urgency and clinical presentation. This study was conducted in a large heterogeneous population of children using pooled data and they found that boys present more frequently to the ED and receive inhalation medication more often when presenting with respiratory symptoms [7]. Additionally, it has been shown that sex hormones play a role in developmental and physiological differences in the lungs of children both before and during the neonatal period and boys have a higher risk of developing asthma than girls during childhood [8, 9]. This is also reflected in the higher incidence rate of respiratory syncytial virus bronchiolitis in boys compared with girls [10, 11].

Globally, fever and respiratory tract symptoms are one of the most common symptoms among children presenting at the ED and are responsible for 20–25% of all pediatric emergency visits [12-14]. The aim of this study is to examine sex-specific differences regarding presentation and management in a large cohort of febrile children with respiratory symptoms visiting European EDs. Insight in these sex differences may increase our understanding on the role of sex in pediatric emergency medicine and whether these are based on clinical symptoms or physician’s attitude.

Methods

Study design

The MOFICHE study (Management and Outcome of Fever In Children in Europe) is a European observational multicenter study assessing management and outcome of febrile children in Europe using routine emergency care data and is embedded in the PERFORM project (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) [15].

The study was approved by the ethical committees of all the participating hospitals: Austria (Ethikkommission Medizinische Universität Graz, ID: 28–518 ex 15/16), Germany (Ethikkommission der LMU München, ID: 699–16), Greece (Ethics committee, ID: 9683/18.07.2016), Latvia (Centrala medicinas etikas komiteja, ID: 14.07.201 6. No. Il 16–07–14), Slovenia (Republic of Slovenia National Medical Ethics Committee, ID: ID: 0120-483/2016-3), Spain (Comité Autonómico de Ética de la Investigación de Galicia, ID: 2016/331), The Netherlands (Commissie Mensgebonden onderzoek, ID: NL58103.091.16), United Kingdom (Ethics Committee, ID: 16/LO/1684, IRAS application no. 209035, Confidentiality advisory group reference: 16/CAG/0136). The need for informed consent was waived by the ethics committee. In all the participating UK settings, an additional opt-out mechanism was in place.

Study population and setting

We included children aged 0–<18 years attending the ED with fever (≥ 38°C) or a history of fever (fever within 72 hours before ED visit) and respiratory symptoms. We decided to focus on febrile children with respiratory symptoms, since the majority of children had respiratory symptoms (63%) and a previous study regarding sex-specific differences in pediatric emergency care has shown that sex differences were present in children attending the ED with respiratory symptoms [7]. Respiratory symptoms were defined as runny nose, coughing, sore throat or sneezing. Twelve EDs from eight European countries (Austria, Germany, Greece, Latvia, the Netherlands (n = 3), Spain, Slovenia and the United Kingdom (n = 3)) participated in this study. The participating hospitals were either university or large teaching hospitals. More details are described in a previous publication [16]. We excluded children with missing data on management and children with comorbidity, which was defined as having a chronic underlying condition expected to last at least one year [17].

Data collection

Data were collected from January 2017 to April 2018 for at least one year to account for seasonal variation. Data were collected as part of routine clinical care at the ED and these were extracted from patient records before being entered into electronic case report forms by the local research teams. Data collected included age, sex, triage urgency, comorbidity (as stated in the ED charts or previous history forms), presenting symptoms, vital signs (tachycardia, tachypnea, hypoxia), diagnostic tests (laboratory test, respiratory test, imaging), treatment (antibiotics, inhalation medication, oxygen therapy), disposition, focus of infection and cause of infection. Data on presenting symptoms were restricted to prespecified complaints including respiratory, gastrointestinal (diarrhea, vomiting) and neurological symptoms (seizures or focal neurological signs or meningeal signs), and children were allowed to have multiple presenting symptoms. Age-specific cut off values for vital signs according to Advanced Pediatric Life Support guidelines were used to define tachypnea, tachycardia and hypoxia [18]. The focus of infection was allocated retrospectively by the research team. We used the following categories: upper respiratory tract, lower respiratory tract, urinary tract and other (gastrointestinal tract, childhood exanthemas/flu-like illness, soft tissue or skin/musculoskeletal, sepsis/meningitis, undifferentiated fever and inflammatory illness). The cause of infection, defined as presumed bacterial (definite bacterial, probable bacterial and bacterial syndrome), unknown bacterial or viral, presumed viral (definite viral, probable viral and viral syndrome) or other (e.g. inflammatory), was determined by the research team using a previously published phenotyping algorithm, which combines clinical data, microbiology results and C-reactive protein (CRP) (S1 Fig) [19, 20].

Outcome measures

Management was defined as diagnostic tests, treatment and admission. We categorized diagnostic tests into general bloodwork (CRP, white blood cell count (WBC) and procalcitonin (PCT)), respiratory test/culture, blood culture, and chest X-ray. Treatment included antibiotic treatment, inhalation medication (salbutamol, ipratropium, epinephrine, budesonide) and oxygen therapy. Admission was defined as both admission to the ward or the Pediatric Intensive Care Unit.

Data analysis

First, descriptive statistics were used for children’s characteristics and management stratified by sex. Chi-squared tests and Mann-Whitney U tests were used assuming not normally distributed data. Second, multivariable logistic regression analyses were performed to examine the association between management and sex, with boys as reference group. We adjusted for the following covariates: age, triage urgency, ill appearance (classify as ill if ill, irritable or uncomfortable is stated in the chart written by triage nurses or physicians), duration of fever, vital signs (tachycardia, tachypnea, hypoxia), increased work of breathing and participating ED. Increased work of breathing was defined as the presence of any of chest wall retractions, nasal flaring, grunting or apnea. Third, we stratified the analyses for children with 1) the upper respiratory tract and 2) the lower respiratory tract as focus of infection. Subsequently, we performed a subgroup analysis in children up to five years to reduce the influence of pubertal sex hormones, since the rise of adrenal androgens occurs around the age of six to eight years [21, 22]. Based on our results, we performed an additional sensitivity analysis with exclusion of children with the urinary tract as focus of infection. Adjusted odds ratios (aORs) were calculated and a 95% confidence interval (CI) was given. Multiple imputation using MICE package in R were used for missing data on covariates. Statistical analyses were performed using IBM SPSS Statistics software version 25. A p-value below 0.05 was determined as statistically significant.

Results

Description of the study population

We included 19,781 previously healthy febrile children with respiratory symptoms after excluding 18% (4321/24,380) of the children due to comorbidity and subsequently excluding 1% (278/20,059) due to missing data on outcome measures. The majority were boys (54%), in the age group of 1–5 years (58%) and triaged as low urgent (67%). Sixty-four percent had an upper respiratory tract infection, 19% had a lower respiratory tract infection and most infections were of viral cause. Sixteen percent had another focus of infection, which could be due to concomitant infection next to their respiratory infection. Girls had less frequently tachypnea (15% vs 16%, p = 0.002) and increased work of breathing (8% vs 12%, p<0.001) compared with boys, whereas girls had more often tachycardia (28% vs 23%, p<0.001) (Table 1).

Table 1

Patient characteristics stratified by sex (N = 19,781).

	Boys (N = 10,870 54%)	Girls (N = 8911 46%)	Total (N = 19,781)
Age (years)
<1	2037 (19)	1481 (17)	3518 (18)
1<5	6297 (58)	5152 (58)	11,449 (58)
5<12	2030 (19)	1789 (20)	3819 (19)
12–17	506 (4)	489 (5)	995 (5)
Triage urgency *
Low urgent	7236 (67)	6078 (68)	13,313 (67)
High/intermediate urgent	3336 (31)	2556 (29)	3892 (30)
Duration of fever (days) ~	1.5 (0.5–3.0)	1.5 (0.5–3.0)	18,600 (94)
Ill appearing	1383 (13)	1144 (13)	2527 (13)
Vital signs
Tachypnea*	1770 (16)	1307 (15)	3077 (16)
Tachycardia*	2509 (23)	2510 (28)	5019 (25)
Hypoxia	272 (3)	207 (2)	479 (2)
Increased work of breathing*	1260 (12)	743 (8)	2003 (10)
Focus of infection ¥ *
Upper respiratory tract	6897 (64)	5657 (64)	12,554 (64)
Lower respiratory tract	2218 (20)	1590 (18)	3808 (19)
Urinary tract	64 (0.6)	217 (2.4)	281 (1.4)
Other	1691 (16)	1447 (16)	3138 (16)
Cause of infection *
Presumed bacterial	2153 (20)	2040 (23)	4211 (21)
Unknown bacterial or viral	1438 (13)	1226 (14)	2664 (14)
Presumed viral	6758 (62)	5244 (59)	12,002 (61)
Other	420 (4)	336 (4)	756 (4)

Absolute numbers and percentages (%) are shown

~ median and interquartile range (IQR) 25–75

*p-value <0.05

¥ Most clinically relevant focus of infection was assigned

Missing data: <3% triage urgency, ill appearing, cause of infection, 6–14% duration of fever, tachycardia, hypoxia, increased work of breathing, 23% tachypnea

Management stratified by sex is shown in Table 2 and the range per ED is shown in S1 Table. Simple diagnostics were performed in 39% in boys and in 40% in girls of which the majority consisted of CRP and WBC. Advanced diagnostic tests were performed in 35% in boys and in 36% in girls of which chest X-rays were most often performed. Antibiotics were prescribed in boys and girls in 31% and 33%, inhalation medication in 13% and 10%, oxygen therapy in 3% and 2%, respectively, and both boys and girls were admitted in 20%.

Table 2

Management stratified by sex (N = 19,781).

	Boys (N = 10,870)	Girls (N = 8911)
Diagnostics
CRP	4204 (39)	3529 (40)
WBC	4193 (39)	3526 (40)
PCTμ	178 (2)	100 (1)
Respiratory test/culture	2113 (19)	1802 (20)
Blood culture	681 (6)	577 (7)
Chest X-ray	1850 (17)	1524 (17)
Antibiotic treatment	3316 (31)	2923 (33)
Inhalation medication	1399 (13)	883 (10)
Oxygen therapy	282 (3)	203 (2)
Admission	2214 (20)	1751 (20)

Absolute numbers and percentages (%) are shown

μ PCT was performed in 7 out of 12 ED settings

Association between sex and management

In the total group of 19,781 children, girls received less inhalation medication compared with boys (aOR 0.82, 95% CI 0.74–0.90), but girls received antibiotic treatment more often compared with boys (aOR 1.08, 95% CI 1.02–1.15) as shown in Fig 1. The unadjusted odds ratios are shown in S2 Table.

Fig 1

Association between sex and management for all febrile children presenting with respiratory symptoms (N = 19,781).

Boys as reference group. Adjusted for age, triage urgency, ill appearance, tachypnea, tachycardia, hypoxia, work of breathing, duration of fever, ED.

In the upper respiratory tract subgroup of 12,554 children no significant associations were found between sex and management as shown in Fig 2. The unadjusted odds ratios are shown in S3 Table.

Fig 2

Association between sex and management in the upper respiratory tract group (N = 12,554).

Boys as reference group. Adjusted for age, triage urgency, ill appearance, tachypnea, tachycardia, hypoxia, work of breathing, duration of fever, ED.

In the lower respiratory tract subgroup of 3808 children, girls received less inhalation therapy compared with boys (aOR 0.77, 95% CI 0.66–0.89) as shown in Fig 3. The unadjusted odds ratios are shown in S4 Table.

Fig 3

Association between sex and management in the lower respiratory tract group (N = 3808).

Boys as reference group. Adjusted for age, triage urgency, ill appearance, tachypnea, tachycardia, hypoxia, work of breathing, duration of fever, ED.

In the 14,967 children below five years of age, girls received less inhalation medication compared with boys (aOR 0.80, 95% CI 0.72–0.90) as shown in S2 Fig and S5 Table.

Discussion

Main findings

Sex differences regarding presentation and management are present in a large cohort of febrile children with respiratory symptoms attending European EDs. Girls present less often to the ED with fever and respiratory symptoms, and when they do so they have less frequently tachypnea (15% vs 16%) and increased work of breathing (8% vs 12%) compared with boys. Few differences in management between boys and girls exist, but we observed consistently lower proportions of girls receiving inhalation medication after adjustment for patient characteristics and markers of disease severity (aOR 0.82, 95% CI 0.74–0.90). This is in line with a previous study in which girls received less inhalation medication compared with boys in children with respiratory symptoms attending the ED (pooled OR 0.79, 95% CI 0.73 to 0.86) [7]. However, these children had respiratory symptoms in general and did not look at febrile children specifically. The lower proportion of girls receiving inhalation medication could be explained by boys having higher rates of wheezing and bronchial hyperresponsiveness during childhood than girls [23, 24]. However, children with comorbidity including asthma were excluded in our study, so this group does not contribute to the sex-specific differences. In the total group we also found that girls more often received antibiotic treatment (aOR 1.08, 95% CI 1.02–1.15) compared with boys. This might be explained by a higher prevalence of a urinary tract infection in girls than boys (2.4% vs 0.6%). A sensitivity analysis where we excluded children with a urinary tract infection (N = 281) did not show a significant difference in antibiotic prescription in girls and boys (aOR 1.03, 95% CI 0.97–1.10). There was no significant difference in antibiotic prescription rates between boys and girls in the subgroup analyses performed. In addition, no sex differences were found regarding diagnostic tests, treatment with oxygen therapy and admission. This is in contrast to a previous study where differences were present between girls and boys, with the proportion of children receiving laboratory tests and imaging during ED visits for respiratory problems was higher in girls. However, in this previous study subgroup analyses in children with respiratory symptoms and children with fever were performed separately and they have adjusted for other covariates including age, triage urgency and clinical presentation [7].

Strengths and limitations

This is the first study to examine sex differences in carefully phenotyped febrile children with respiratory symptoms in a large multicenter cohort in twelve European EDs, which makes the results generalizable to the majority of European countries. Clinical data was extensively collected with detailed information on clinical presentation and management. Additionally, we performed subgroup analyses to describe the observed sex differences in the total group more in depth. However, this study has some limitations which should be mentioned. First, data on respiratory symptoms related to the upper respiratory tract such as runny nose and coughing were collected but data on findings of physical examination such as wheezing or focal abnormalities on auscultation were not collected, which is important since wheezing is often associated with a viral infection and clinicians may tend to start inhalation medication in these children [25]. Second, we did not take into account gender, which might play a role in how girls and boys present themselves, clinician’s perception and therefore management. Gender refers to a person’s self-presentation as male or female and the influence of the social and cultural environment [3]. However, we have performed a subgroup analysis in children up to five years to reduce behavioral factors associated with gender. Third, we did not adjust for other determinants such as parental concern, clinicians’ experience or gut feeling and sociocultural factors. However, we have adjusted our analysis for important clinical factors related to disease severity including tachypnea and increased work of breathing. This is a first step in providing insight in the role of sex in management in febrile children with respiratory symptoms in emergency medicine. Future research should focus on to what extend the observed differences between boys and girls are related to clinicians’ attitudes or to differences in clinical symptoms at the time of presentation and disease severity.

Conclusion

In a large cohort of previously healthy febrile children with respiratory symptoms attending European EDs, girls present less frequently with tachypnea and increased work of breathing compared with boys. Girls receive inhalation medication less frequently than boys, especially when they have a lower respiratory tract infection and are below five years of age. However, no sex differences were found regarding diagnostic tests, oxygen therapy and admission. Insight in these sex differences may lead to better understanding of the role of sex in pediatric emergency medicine.

Phenotyping algorithm cause of infection.

*Patients could have a identified viral co-infection.

(PDF)

Click here for additional data file.

Association between sex and management in children below five years (N = 14,967).

(PDF)

Click here for additional data file.

Management stratified by sex with range per ED (N = 19,781).

Boys as reference group. Absolute numbers and percentages (%) are shown.

(PDF)

Click here for additional data file.

Association between sex and management (N = 19,781).

(PDF)

Click here for additional data file.

Association between sex and management in children with an upper respiratory tract infection (N = 12,554).

(PDF)

Click here for additional data file.

Association between sex and management in children with a lower respiratory tract infection (N = 3808).

(PDF)

Click here for additional data file.

Subgroup analysis in children below five years (N = 14,967).

(PDF)

Click here for additional data file.

PERFORM consortium authors list.

(PDF)

Click here for additional data file.

(PDF)

Click here for additional data file.

19 May 2022

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Reviewer #1: In their paper, Sex differences in febrile children with respiratory symptoms attending European Emergency Departments: an observational multicenter study, the study authors aim to assess sex differences in presentation and management of febrile children with respiratory symptoms across twelve different European emergency departments in a roughly one-year period of time. The data set is quite large and finds statistically significant differences in both work of breathing on arrival and interventional therapies, but has some underlying issues with the methodology that need to be addressed.

Major comments:

- Is there a reason that you didn’t just look at children with respiratory symptoms? Why combine fever and respiratory? I would put in a statement explaining this choice, given that there are many patients with URI/LRI who don’t also have fever.

- The exclusion criteria should be re-explored. The authors excluded anyone with a co-morbidity, including asthma, but kept in patients who presented with other non-respiratory infections or neurologic complaints, such as seizure, which would seem to alter ER management and muddy the picture more than the presence of an underlying comorbidity. I think you need to decide to look at all-comers and then do subanalyses or decide you want to look to only at otherwise healthy children who are presenting with URI/LRI without another major presenting complaint. One of the main findings was that girls get more antibiotics overall, but this disappears when looking only at URI/LRI and can likely be explained by the higher prevalence of UTI – though we don’t have this data (only that girls have more co-infections of some kind). If you are truly looking at management of respiratory disease and trying to get at underlying sex differences, these kids need to be pulled out of the data.

- I would clarify further the purpose of this study – it’s hard for me to piece together the clinical significance. The last sentence of the introduction says that finding differences in how these children present “may improve diagnosis and treatment” – but there is no further discussion of this and it’s hard to say how this data would do this. The last sentence of the discussion seems more reasonable – that there are differences in care and next step is to determine if these are based on clinical symptoms or physicians’ attitudes (ie, some type of implicit bias). I think I would stick with this theme, that this is purely descriptive, but more work needs to be done to figure out why there are differences.

Minor comments:

Abstract

-Line 83: I’d include p values (or ORs) with these statistics, particularly since the differences are so small.

Introduction

- Line 97: Small point, but I’d replace “inequality” with “inequity” – there are many reasons that different groups receive different treatments, but the goal should be to provide equitable care – which is what I think you are trying to get at here.

- Line 100: Would change “adults in emergency medicine” to “adults presenting to the emergency department”

- Line 107: “research on sex differences in children remains scarce” – I don’t think this is true. If you look at the reference list for the next paper you talk about, there are multiple studies there. Much of the research coming out of pediatric EM will contain demographic data and comment on any sex difference in presentation. You may be able to say that we need more research into differences in emergency management by sex – since I agree, there’s not as much out there about management in particular.

- Line 108: “The first study to assess the role of sex in pediatric emergency…” I would definitely talk more about this study – ie, what they found. I think it leads nice into your study and puts it into more context. They looked into a huge group of kids and found that boy present more frequently to the ED, get more inhalational medications, and girls get more labs – but this was all pooled data and didn’t look at a specific population. Here, you are attempting to only look at febrile kids with respiratory symptoms so you can really get to whether or not there are differences that exist here. This will also make your next sentences about sex different in asthma/bronchiolitis make more sense since they seem a bit disconnected currently.

- Line 123: “may improve diagnosis and treatment” – this doesn’t seem to be the goal of your paper overall based on the discussion and conclusions. I think you mean the role of sex in the management of children in the emergency department. There is no discussion in the paper at all around improving diagnosis or improving treatments since there is no information on outcomes (ie did they receive a correct diagnosis or was that treatment useful), only descriptive information on who presented and what was done.

Methods

- Line 150: “We excluded children with missing data on management and children with comorbidity.” Two things

1. I would move your source for what defines a comorbidity here. It looks like the source is referencing a paper that uses ICD-9 codes (though your study was done during the ICD-10 era, so I would use an updated source – looks like there have been two newer versions, PMID: 29496546). Were these codes only present at the index visit? Or if the patient ever had this code?

2. Why did you exclude these children? Seems like if these are large university hospitals you are going to have a lot of kids with comorbidities. Particularly in a study that is looking at the use of inhalational medications which should be mostly used in children who carry a diagnosis of asthma (or should). Is it possible to include them and then do a subanalysis of children who did not have comorbidities? Or look at all the data and then control for the number of kids with asthma? If not – I would at least include information on how many kids (what %) you excluded due to a comorbidity.

- Line 160: “Children could have had gastrointestinal (diarrhea or vomiting) or neurological (seizures or focal neurological signs or meningeal signs) symptoms in addition to their respiratory symptoms.” Were they allowed to have other symptoms as well? Or were they excluded if they had other symptoms except fever, respiratory and possibly GI/neuro. I would clarify what you mean here.

- Line 174: “We categorized diagnostic tests into simple and advance.” This classification seems a bit arbitrary – there are many kids with fever/respiratory who get a CXR and go home on antibiotics. I wouldn’t consider that more advanced than doing bloodwork (which is often reserved for kids who are actually sicker since it’s a more invasive intervention). I would get rid of this distinction and just split into “imaging,” “bloodwork,” and “respiratory test/culture”.

- Line 186: How was ill appearance defined? Triage nursing? Physicians note?

- Line 193: It’s unclear to me what “behavioral and psychological processes” means and has to do with fever/respiratory symptoms and ED management. Please clarify what you mean here.

- Line 194: Please change odds ratios to adjusted odds ratios

Results

- Line 205: Please include the p value for these numbers, particularly since they are so similar between groups. Or, even better, include the odds ratio with the confidence interval.

- Table 1:

I think you should include the actual p values here instead of just the asterisk that it’s <0.05. Again – I think having an odds ratio with a confidence interval would also provide much more information than a p value. I also can’t tell what is significant – eg focus of infection is labeled as significant, but I can’t tell if one sex is more likely to have an “other” focus of infection, which will likely affect management. Same with cause of infection.

- Table 2/Figure 1.

I would combine this with Figure 1. It looks strange to have this table without any statistics on the significance – you have to then go to Figure 1 to find the actual aORs – but Figure 1 doesn’t include all of the variables in Table 2… so I still don’t know what the aOR of getting a CXR was. It’s a pretty figure, but I think it makes more sense to just add this information to a fourth column in Table 2 if editor agrees.

I would control for presence of another source of infection other than respiratory. This is certainly going to change management. As you say – more females had UTIs and they are going to then get antibiotics that are not for their respiratory disease. Instead of just adding as a limitation, you can control for this, particularly since one of your main findings that barely reached significance was antibiotic use. You should also consider removing these patients (making it an exclusion criteria) since this will so strongly affect management (I think this is the better option).

As a side note – the number of children who are getting interventions seem really high to me. From your S1_Table – it looks like one of your EDs sends blood work on 93% of the patients it sees with fever/respiratory symptoms which seems outrageous to me, particularly since you include any rhinorrhea or sore throat as a respiratory symptom and most of these patients are low-acuity. Is this correct? It feels like it can’t possibly be the same patient population.

Discussion

- Line 264: “This is in line with a previous study in which girls received less inhalation medication compared with boys in children with respiratory symptoms attending the ED (pooled OR 0.79, 95% CI 0.73 to 0.86).” Please move your reference for these statistics to after this line.

- Line 270: I’m having some trouble with this argument – please clarify here. It seems like you are saying that boys are more likely to wheeze, which is why they get more inhalational therapies – but then say this can’t be because we excluded kids with asthma. I think the truth is that if you are getting bronchodilators and are over the age of 2, you are going to get a diagnosis of asthma (since having wheeze/cough responsive to bronchodilators is essentially the definition). The kids in this study who received bronchodilators probably fell into one of two categories – either they just hadn’t had an ICD-10 code for asthma put on their chart yet, or they were under 2 years old and wheezing, so had a tentative diagnosis of viral induced wheeze and may or may not later be diagnosed with asthma. Either way – both of these are more prevalent in males (as you point out), which likely explains why they are getting more inhalational therapy.

- Line 274: Agree with this argument for more antibiotics in girls – but this is why you should exclude these patients with other reasons to get antibiotics if you really want to looks at management of respiratory complaints.

Other Figures

- See comments in results for Tables 1&2 and Figure 1

- I don’t think you need supplemental tables 2-4 – they are the same as Figures 1-3 with the inclusion of the unadjusted odds ratio, which you don’t need to include – though will leave to editor.

- No comments on other figures/tables

Reviewer #2: General comments:

The authors have performed an observational study evaluating the association of sex with characteristics of children visiting Emergency Departments for febrile respiratory illness. Strengths of the study include the inclusion of multiple centers, large number of subjects, and depth of available data.

Overall, the expected implications and intended applications of the study findings are unclear. Were the authors intending the inform the incorporation of patient sex into clinical decision making or even the development of a clinical decision rule? Or were they intending to shed light in potential sex-based disparities in emergency care, particularly with respect to management? There are parts of the introduction that suggest either objective. The authors' proposed significance of this study could be stated more clearly in the introduction and discussion.

Abstract

General: The conclusions are largely a reiteration of the results and instead could be nbetter used to discuss the implications of the results.

70: "0-18 years" could be interpreted to be inclusive of 18-year-olds, whom the study presumably excluded based on the age groups in Table 1.

79: Could mention that subgroups analyses were performed by upper versus lower respiratory tract infection

83: See comment on 205.

Methods

144: See comment on 70.

146: Why were shortness of breath, tachypnea, or wheezing not included as respiratory symptoms? These symptoms would capture children with greater illness severity who would be of higher interest clinically to pediatric emergency physicians than those with only fever and sore throat.

151: Exclusion of children with comorbidity needs to be explained more. What level of comorbidity was excluded, complex illness or all chronic conditions including even mild intermittent asthma? If all children who have received a diagnosis of asthma are excluded, it should be noted that there is significant variability as to which children with prior respiratory illnesses have received a chronic diagnosis of asthma versus only acute diagnoses of "bronchiolitis," "wheeze," etc. that may confound the study results.

Given the high prevalence of asthma and other chronic conditions in among children, the exclusion of children with comorbidity significantly limits the applicability of these results to the overall ED population. If this is intentional, the authors could be more explicit in stating that their study focuses only on previously healthy children.

164: How were children with concurrent infections allocated? Given that the percentages in Table 1 add up to 100%, presumably only one focus of infection was assigned to each child, but if one were to present with influenza and urinary tract infection, both are clinically significant and worth accounting for. The categories perhaps should not be treated as mutually exclusive.

187: Unclear what is meant by ED setting.

Results

200: In addition to the study sample size, this sentence should include the total initial number of febrile children with respiratory symptoms and the number that were excluded due to missing data or presence of morbidity.

205: The statement that girls had lower frequency of tachypnea is repeated multiple times across the manuscript but is questionable. The difference by sex, while perhaps statistically significant with the large sample size, is too small to be considered clinically important.

Discussion

General: The entirety of the discussion is in one large paragraph and may be more easily readable in divided into multiple paragraphs by topic.

257-264: These lines are largely a reiteration of the results, which seems unnecessary and better off being cut.

272: The authors hypothesize that the higher antibiotic prescription rate for girls may be due to a higher rate of urinary tract infections. This hypothesis could have been tested with their data by including a third subgroup for stratification for children with a non-respiratory focus of infection.

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29 Jun 2022

Manuscript reference number: PONE-D-22-05605

Title: Sex differences in febrile children with respiratory symptoms attending European Emergency Departments: an observational multicenter study

Dear dr. Emily Chenette and reviewers,

Thank you for reviewing our paper titled: "Sex differences in febrile children with respiratory symptoms attending European Emergency Departments: an observational multicenter study". We are very pleased to hear that a revised version of our manuscript is considered for publication in PLOS ONE. We sincerely thank the reviewers for their extensive comments to improve the paper, and have revised our manuscript according to their recommendations. The comments and suggestions on how to clarify the methodology and implications of our study were especially valuable. We hope that the revisions made to these sections made the overall paper more clear, and made it reproducible and more understandable for first-time readers. We feel that we were able to address all comments in the revised version and that our paper has improved significantly. Our point to point response to the individual review comments can be found below.

All co-authors have read and agreed upon the current submitted version.

Yours Sincerely, on behalf of all co-authors,

Prof. dr. H.A. Moll and dr. J.M. Zachariasse

Submitted filename: Rebuttal letter_SexDifferences_PLOSONE.docx

Click here for additional data file.

11 Jul 2022

Sex differences in febrile children with respiratory symptoms attending European Emergency Departments: an observational multicenter study

PONE-D-22-05605R1

Dear Dr. Zachariasse,

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Additional Editor Comments (optional):

Thank you for addressing reviewer concerns. I share some of reviewer 1's concerns about specific exclusions but appreciate the overall reframing of the article and inclusion of the UTI sensitivity analysis, which eliminates a disparity in antibiotic use.

Reviewers' comments:

26 Jul 2022

PONE-D-22-05605R1

Sex differences in febrile children with respiratory symptoms attending European Emergency Departments: an observational multicenter study

Dear Dr. Zachariasse:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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