Varicella zoster is a highly infectious virus that causes varicella disease (chickenpox). Symptoms include a vesicular rash, headache, malaise, fever and loss of appetite.1,2 Annually, varicella infects between 2 and 16 individuals per 1000 persons worldwide,3,4 and while 90% of infections occur before the age of 9, varicella can be contracted at any age.4,5 Universal varicella vaccination programs (UVVs) have successfully lowered varicella incidence across European countries,4,6 however, less than 50% of European countries have a UVV program as of 2021.7 In France, which has yet to implement a UVV, annual incidence of varicella is still high, with an estimated total of 794,533 cases in 2018.7 The highest estimated incidence in France (13,488 in 100,000) was in children under 5 years of age.6

Most cases of varicella are mild and can be treated at home using emollients, over-the-counter analgesics (eg, paracetamol), and fluids to prevent dehydration.8,9 Primary care physicians may also prescribe antivirals, analgesics, antihistamines or antibiotics.8,10,11 More severe varicella cases have been associated with complications including, infections of the skin and soft tissue, pneumonia or encephalitis, that may result in hospitalization.1 It is estimated that complications occur in 2% to 6% of all varicella cases.12 For more severe complications, treatment with antimicrobials such as antivirals or systemic and nonsystemic antibiotics may be necessary.

The use of antibiotics in an outpatient setting for the treatment of varicella has not been extensively studied, however, a few studies have described antibiotic use for varicella. In Argentina, 22.7% of patients seen in an outpatient setting were prescribed an antibiotic, compared to 2.7% in Hungary.10 A separate study in Belgium showed 27.3% of varicella patients seen in an outpatient setting were prescribed at least one antibiotic; 19.7% were prescribed systemic antibiotics and 10.3% a topical antibiotic.11

Globally rising antibiotic use, due in part to the prescription of antibiotics without a confirmed bacterial diagnosis, is of particular concern.13 In 2019, 326 in every 1000 patients in France presenting in an outpatient setting (for any reason) were prescribed antibiotics.14 With the growing use of antibiotics, the potential for antimicrobial resistance increases.15

The aim of this study was to explore varicella-related complications, medication prescriptions (including antibiotics), healthcare resource utilization (HCRU), and costs associated with the management of pediatric varicella and its complications in the outpatient setting in France.

MATERIALS AND METHODS Study Design

This was an observational, retrospective cohort study using data extracted from the Cegedim Strategic Data-Longitudinal Patient Database (CSD-LPD), also known as The Health Improvement Network. Pediatric patients presenting with varicella to their general practitioner (GP) or an office-based specialist between January 2014 and December 2018 (indexing period) were selected for inclusion in this study. The index date was defined as the date a patient was first diagnosed with varicella. Patients were observed from diagnosis until the last database entry or the end of the study period (whichever was earliest), with a minimum follow-up period of 3 months (see Figure, Supplemental Digital Content 1, https://links.lww.com/INF/F399).

Patients under the age of 18 years with a diagnosis of varicella during the indexing period, a 6-month preindex period (if >1 year of age), and a follow-up period of 3 months postindex date recorded in the CSD-LPD, were included in this analysis. Patients with 1 or more varicella diagnoses or a varicella vaccination prior to the index date were excluded.

Data Source

The CSD-LPD is a longitudinal anonymized health record database of primary care interactions in France, comprising approximately 10% of GPs and office-based specialists covering over 4.8 million patients. The CSD-LPD has been previously described and validated as a data source.16,17 Data captured by the CSD-LPD included demographics, medical diagnoses, comorbidities and medications. Data were coded using the International Classification of Diseases version 10 (ICD-10) coding system for diagnoses, and Anatomical Therapeutic Chemical coding for medications (with prescriptions linked to a diagnosis).18 Data validation and quality assurance were performed by Cegedim and by the study’s data analysts. As this was a longitudinal retrospective study using a secondary anonymized data source, all data collected were fully anonymized and no direct subject contact occurred. As such, submission to an Institutional Review Board or Independent Ethics Committee was not required.

Study Measures

Patient demographics, such as index year, age and gender were assessed at index. Per patient, complications that occurred during the 6-month baseline period prior to the index date were documented and removed from follow-up analyses to avoid inclusion of chronic, preexisting conditions. Outcome measures assessed during follow-up included diagnosed complications, prescribed medications, HCRU and costs.

Varicella infection and complications were identified using ICD-10 codes and sorted into categories that included skin disorders, systemic bacterial infections, neurological conditions, upper and lower respiratory tract infections, ear, nose and throat conditions, musculoskeletal disorders, ophthalmic conditions and gastrointestinal disorders. Within each category, common complications associated with varicella were selected based on literature review1,12,19–31 and further validated by clinical experts (see Table, Supplemental Digital Content 2, https://links.lww.com/INF/F400).

Prescribed medications were classified as antivirals, antibiotics (systemic antibiotics and nonsystemic/topical antibiotics), emollients, analgesics or antihistamines, with further subgroup analysis performed for specific systemic antibiotics. Specific systemic antibiotics were selected from a list defined by the Haute Autorité de Santé of common antibiotics used for the treatment of pediatric patients with the complications included in our analysis.32 The number of patients prescribed each category of medication was recorded. As CSD-LPD data are linked to diagnostic codes, subgroup analysis was performed to assess whether medications were prescribed directly for varicella (using a varicella ICD-10 code), for a varicella-related complication, or for conditions that may or may not be associated with the varicella diagnosis such as common colds, coughs, unspecified fevers and asthma.

Other HCRU measures included the number of GP and office-based specialist consultations. Costs were categorized into medication costs, GP consultation costs, and specialist consultation costs. The cost of a single consultation was estimated from the conventional rates for GPs33 and specialists.34 As reimbursement data was unavailable for some patients, a standardized rate of €24 per consultation, regardless of consultation type, was applied based on a reimbursement rate of €23–€25 recorded for those with reimbursement data. The cost-per-unit for medications was derived from national tariffs compiled by Cegedim, which reported the basic price, quantity and reimbursement rate for each drug. These costs per unit were used to calculate total medication costs for the cohort.

Data Analysis

As this was a descriptive study, no formal statistical testing was performed. Categorical variables were summarized by frequencies and proportions, while counts, means, medians, standard deviations (SDs) and interquartile ranges (IQR) were reported for continuous variables.

RESULTS Patient Demographics and Clinical Characteristics

In total, 48,027 patients were diagnosed with varicella during the indexing period and met the inclusion criteria. Mean (SD) age was 3.7 (2.4) years, with the majority 2–4 years of age (58.7%, n = 28,196); 51.4% (n = 24,704) were male. Demographics were similar across complication status groups and where they were diagnosed (GP or specialist; Table 1). Overall, 37,339 patients were diagnosed by GPs and 4585 by specialists; the location of the diagnosing visit was missing for 6103 patients. Of those diagnosed by a specialist, 98.8% (n = 4532) were indexed by a pediatrician. Overall, 15.3% (n = 7369) of patients with varicella had at least one complication; reports of complications were highest among patients ≤1 year old (19.2%, n = 1291/6730) and adolescents 13–18 years old (18.1%, n = 87/480) (Fig. 1). The most common complication categories were ear, nose and throat conditions (38.0%, n = 2798), respiratory conditions (35.9%, n = 2642) and ophthalmic conditions (20.4%, n = 1502, Fig. 2), of which pharyngitis (33.6%, n = 2478), bronchitis (32.7%, n = 2412) and conjunctivitis (20.3%, n = 1498) were the most frequent complications.

TABLE 1. - Patient Demographics Overall (n = 48,027) No Complication (n = 40,658) Any Complication (n = 7369) Indexed With GP (n = 37,339) Indexed With Specialist (n = 4585) Unknown (n = 6103) Index year, n (%)  2014 12,328 (25.7) 10,406 (25.6) 1922 (26.1) 9320 (25.0) 1466 (32.0) 1542 (25.3)  2015 9384 (19.5) 7906 (19.5) 1478 (20.1) 7290 (19.5) 877 (19.1) 1217 (19.9)  2016 10,242 (21.3) 8615 (21.2) 1627 (22.2) 8058 (21.6) 902 (19.7) 1282 (21.0)  2017 7927 (16.5) 6751 (16.6) 1176 (16.0) 6414 (17.2) 503 (11.0) 1010 (16.6)  2018 8146 (17.0) 6980 (17.2) 1166 (15.8) 6257 (16.8) 837 (18.3) 1052 (17.2) Age (years) at index  Mean (SD) 3.7 (2.4) 3.8 (2.4) 3.5 (2.4) 3.9 (2.4) 2.8 (1.7) 3.6 (2.7) Categorized, n (%)  ≤1 year 6730 (14.0) 5439 (13.4) 1291 (17.5) 4495 (12.0) 1053 (23.0) 1182 (19.4)  2–4 years 28,196 (58.7) 23,812 (58.6) 4384 (59.5) 21,901 (58.7) 2912 (63.5) 3383 (55.4)  5–6 years 9028 (18.8) 7846 (19.3) 1182 (16.0) 7555 (20.2) 525 (11.5) 948 (15.5)  7–9 years 2586 (5.4) 2284 (5.6) 302 (4.1) 2167 (5.8) 82 (1.8) 337 (5.5)  10–12 years 1007 (2.1) 884 (2.2) 123 (1.7) 837 (2.2) – 160 (2.6)  13–18 years 480 (1.00) 393 (1.0) 87 (1.2) 384 (1.0) – 93 (1.5) Sex, n (%)  Female 23,323 (48.6) 19,829 (48.8) 3494 (47.4) 18,162 (48.6) 2221 (48.4) 2940 (48.2)  Male 24,704 (51.4) 20,829 (51.2) 3875 (52.6) 19,177 (51.4) 2364 (51.6) 3163 (51.8) Any complication, n (%) 7369 (15.3) – 7369 (100.0) 5847 (15.7) 706 (15.4) 816 (13.4)

GP indicates general practitioner; SD, standard deviation.

FIGURE 1.:

Complication rate by age.

FIGURE 2.:

Proportion of patients with complications by type within the overall cohort and by those with any complication recorded.

Medications

The 3 most prescribed medications across all varicella patients were antihistamines (74.1%, n = 35,574), analgesics (69.9%, n = 33,550) and antibiotics (up to 25.1%, n = 12,045), with systemic antibiotics prescribed in 18.7% (n = 8982) of all varicella cases and topical/nonsystemic antibiotics prescribed in 9.5% (n = 4545). Of patients with any complication, 68.1% (n = 5018/7369) were prescribed antibiotics, compared with 17.3% (n = 7027/40,658) of patients without complications (Fig. 3A). Antibiotic use was highest among patients ≤ 1 year old (29.5%, n = 1983/6730) and patients 13–18 years of age (20.6%, n = 99/480). Among the 8982 patients who received systemic antibiotics, amoxicillin and cefpodoxime were the most prescribed (69.4%, n = 6231 and 17.3%, n = 1552, respectively). Only 2.2% (n = 1035) of varicella cases were treated with antivirals, the majority of whom were prescribed acyclovir (see Table, Supplemental Digital Content 3, https://links.lww.com/INF/F401), with the highest usage observed among patients 13–18 years old (5.4%, n = 26/480).

FIGURE 3.:

Proportion of prescriptions of each drug class by (A) complication status and (B) prescription diagnostic code.

Most antihistamine (92.9%, n = 33,045/35,574), antiviral (87.2%, n = 903/1035), analgesic (84.1%, n = 28,246/33,550) and emollient (66.4%, n = 1343/2024) prescriptions were associated with a varicella diagnostic code or a varicella-related complication diagnostic code. Around 35.0% (n = 4210/12,045) of all antibiotic prescriptions were for a varicella diagnostic code, 32.9% (n = 3960) were prescribed for a varicella-related complication and 32.2% (n = 3875) were prescribed for other conditions, which may or may not have been related to varicella. As such, if antibiotic prescriptions for other conditions, which may or may not have been related to varicella, were excluded, the proportion of patients treated with antibiotics would be 17.0% (n = 8170/48,027) for the overall cohort, 61.6% (n = 4538/7369) for patients with a complication and 8.9% (n = 3632/40,658) for patients without a complication.

When stratified by antibiotic type, 21.5% (n = 1933/8982) of systemic antibiotic prescriptions were for a varicella diagnostic code, with 37.5% (n = 3369) prescribed for a complication, and 41.0% (n = 3680) for other conditions. Over half of nonsystemic antibiotic prescriptions (56.2%, n = 2554/4545) were for a varicella diagnostic code, 25.2% (n = 1147) for a complication and 18.6% (n = 844) for other conditions (Fig. 3B).

Healthcare Resource Utilization and Costs

In all, 87.0% (n = 41,763/48,027) of patients were seen by a GP and 11.3% (n = 5438/48,027) by a specialist on the index date or during the follow-up period. Patients who saw a GP had a median (IQR) of 2 (1,2) visits to a GP and those who saw a specialist had a median (IQR) of 2 (1,3) visits to a specialist. Patients with a complication had a numerically higher median (IQR) number of visits to a GP [2 (2,3)] or specialist [3 (2,4)] than those without a complication [1 (1,2) and 2 (1,2), respectively].

The total cost associated with varicella patients for medications and outpatient office visits was €1,576,166 (€315,233 per year for the cohort, range: €260,151 to €404,584; €32.82 per patient per year). Medications accounted for 16.1% of total varicella costs across the study period, for a total of €253,742 (€50,748 per year, range: €41,881 to €65,133), with a mean cost per patient of €5.84 (n = 42,503). The highest total contributing costs were for antihistamines (€96,880, mean €2.72 per patient), analgesics (€71,882, €2.14 per patient) and antibiotics (€58,455, €4.96 per patient) with antibiotics accounting for 23.0% of medication costs. The most expensive medication category per patient was antivirals at a mean cost of €20.72 (Table 2). The costs of GP and specialist appointments related to varicella that accrued during the study period were €1,176,768 (€234,365 per year, range: €196,488–€286,416) and €145,656 (€29,002 per year, range: €24,041–€37,388), respectively (Table 2). In all, consultations accounted for 83.9% of the total cost of varicella management, with the majority attributed to GP consultations (88.9%).

TABLE 2. - Total Cost and Cost per patient for Varicella-related Medications and Healthcare Resource Utilization Between 2014 and 2018 Total Cost Across all 5 Years (€) Cost Per Patient in €, Mean (SD) Medication  Antivirals 21,450 20.72 (8.02)  All antibiotics 58,455 4.96 (4.27)  Systemic antibiotics 44,447 4.95 (4.33)  Nonsystemic/topical antibiotics 14,008 3.08 (1.36)  Analgesics 71,882 2.14 (1.38)  Antihistamines 96,880 2.72 (1.07)  Emollients 5076 2.51 (0.69) Total varicella-related medication costs 253,742 5.84 (5.33) HCRU  GP consultations 1,176,768 25.79 (7.16)  Specialist consultations 145,656 25.18 (5.53) Total varicella-related HCRU costs 1,322,424 25.54 (6.66) Total costs 1,576,166 –

GP indicates general practitioner; HCRU, healthcare resource utilization; SD, standard deviation.

DISCUSSION

This study showed a considerable clinical burden associated with pediatric varicella, its complications and the use of antibiotics in the outpatient setting. Approximately 15% of the study cohort had at least one complication, and 17%–25% of varicella cases were prescribed antibiotics. Total costs for medications and outpatient visits accrued during the study period were €1,576,166 (€315,233 annually), with medications accounting for 16.1% of total varicella costs, of which 23.0% were for antibiotic prescriptions. HCRU (GP and specialist appointments) accounted for 83.9% of the total cost associated with varicella, of which 88.9% was attributed to GP consultation costs.

In total, 15.3% of our cohort reported at least one varicella-related complication, which is notably higher than reports in previous studies. Complication rates may vary widely, likely due to several factors including whether the study was single- or multi-country, the study setting (primary vs. secondary care), the study design, length of observation and the included complications. Indeed, studies conducted primarily among hospitalized varicella patients in France have shown complication rates of between 58.5% and 76.2%.35,36 In contrast, our study was conducted in the outpatient setting only. Studies in the primary care or outpatient setting in other European countries have shown a range of complication rates. For example, in Belgium, 12.6% of varicella patients in primary care experienced a complication, while in England, 7.7% of patients in primary or secondary care experienced a complication.11,37

Analgesics and antihistamines were the 2 most prescribed medication classes in this study cohort. Similar findings have been reported in a previous study in Argentina, which found high levels of over-the-counter medication use, which included analgesics and antihistamines.38 Conversely, antivirals were amongst the least prescribed medications, prescribed in only 2.2% of varicella cases, which concurred with previous studies in Belgium (2.7%) and England (1.5%).11,37 Over 25% of patients in the study cohort were prescribed antibiotics, which was similar to primary care/outpatient studies of varicella in Belgium (27.3%) and England (25.9%).11,37 Of the 25.1% prescribed an antibiotic in this study, 32.2% of antibiotic prescriptions were associated with a diagnostic code that could be deemed not specific to varicella. Therefore, it is possible the proportion of varicella patients prescribed antibiotics could be as low as 17%. Further study would be required to confirm if these prescriptions were indeed not specific to varicella and should be omitted from the analysis.

Our study highlights that high levels of antibiotic prescriptions are common in varicella and are partially driven by complications, with 68% of patients with complications prescribed an antibiotic compared with 17% of those without complications. UVV programs have been shown to reduce the incidence of varicella cases and complications, potentially reducing the associated burden of antibiotics.39 For example, in the United States, data from 25 years of UVV indicated a drastic reduction in severe cases of varicella, with a 92% decline in complications in hospitalized patients in the post-UVV period.40 Other childhood vaccination programs have contributed to reductions in antibiotic use; the introduction of pneumococcal vaccination programs led to reductions in antibiotic use for invasive pneumococcal disease in children, which in turn led to decreases in the development of antibiotic-resistant strains.41

In terms of economic burden, the average annual outpatient cost of varicella care including medication and healthcare consultations was €315,233, with annual costs of approximately €32.82 per patient. A study of annual varicella costs in Europe estimated average annual direct costs (including inpatient costs) in France of €41.4 million across 794,533 patients, which is approximately €52.12 per case.7 Our per-patient estimate is much lower, which is likely due to the lack of secondary care data in our sample. A recent study in England that used a similar methodology to this study found that while per person medication costs were similar to ours at around €9 (£8.10) per person, GP costs were considerably higher at approximately €102 (£89.50) per person, compared with our estimate of €25.47 per person.37 This may be due to differences in healthcare systems and methods for deriving costs. The unit costs for GP consultations in this study were derived from conventional tariffs, while the cost for consultations in England took the average annual income of a GP into account. Furthermore, costs within our study may have been underestimated as any additional fees applied by GPs (on top of the standard conventional rate of €24) were not captured.

Due to sheer prescription volume, antihistamines, analgesics and antibiotics contributed most to treatment costs in France at €96,880, €71,882 and €58,445, respectively. Mean cost per patient for antihistamines was relatively low at €2.72 compared to antibiotics (€4.95) and antivirals (€20.72). Studies have shown UVV programs to be successful at reducing medication costs; a study from the US reported estimated savings of $181 million (94.7%) for antivirals and $78 million (95.0%) for antibiotics annually with the implementation of UVV.42

LIMITATIONS

Certain limitations must be considered when interpreting these data. The CSD-LPD only covers around 10% of GPs and specialists in France potentially limiting generalizability. Though procedures are in place to ensure ICD-10 coding within the CSD-LPD is accurate, there is still the possibility for miscoding. Furthermore, study-specific code lists were developed to identify varicella cases, complications and medications; where possible, definitions were aligned with previously published studies and code lists were verified through medical input.

As we only captured varicella in the outpatient setting, we likely underestimated the burden of complications, antibiotics and costs associated with varicella. Furthermore, using a 3-month follow-up period, as opposed to a shorter period, may have overestimated varicella-related prescriptions and complications. Our data only included medications that were prescribed; over-the-counter medications were not captured. Therefore, it is possible that medication use and costs were underestimated. Finally, only confirmed consultations with a GP or specialist were included in the HCRU and cost analysis. The 6103 patients with a missing location on their index date had a varicella diagnosis, but did not have a consultation type recorded at index. We therefore may have underestimated indexed consultation costs for these patients.

In conclusion, we assessed complications, medications, HCRU, and the economic burden of pediatric varicella in an outpatient setting in France. Over 15% of patients experienced 1 or more complications during the 3-month follow-up period and a quarter of varicella patients were prescribed antibiotics. Introducing a UVV program in France is 1 potential strategy to reduce the clinical and economic burden of varicella in children and the use of antibiotics.

ACKNOWLEDGMENTS

We thank Victoria Banks for her contribution to study design. Medical writing support was provided by Daniel Green, PhD, of Adelphi Real World.

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