# Estimating the economic burden of respiratory syncytial virus infections in infants in Vietnam: a cohort study | BMC Infectious Diseases

### Study setting

A prospective cohort study was conducted at the outpatient and inpatient departments of CH1, a tertiary pediatric care facility previously involved in studies assessing LRTIs and RSV in HCMC, Vietnam [3].

In general, patients with LRTIs, defined as cough or difficulty breathing [14], initially present to the outpatient department or emergency department at CH1. Those requiring additional services may be referred for inpatient care in the respiratory department or ICU, depending on the severity of LRTI disease. For the cost analysis, based on the clinical management, children with non-severe LRTI are those treated in the outpatient clinic; severe and very severe LRTI cases are typically treated in the respiratory department and in the ICU, respectively.

### Study population

We evaluated the costs associated with LRTIs, stratified by RSV status and severity, among children under 2 years of age seeking care at CH1.

Of note, the clinical definitions of RSV severity are not standardized and differ between settings. In our study we have adapted our definitions on severity groups from World Health Organization (WHO) recommendations [15] as below:

• Mild: patients admitted only to the outpatient department

• Moderate: patients admitted to the respiratory department and who had saturation oxygen (SaO2) at admission ≥ 93 percent

• Severe: patients admitted to the respiratory department and who had saturation oxygen at admission (SaO2) < 93 percent

• Very severe: patients admitted to ICU

Children were recruited to our study prospectively. Only patients who met all inclusion criteria and did not have any exclusion criteria were enrolled. Inclusion criteria were having cough and/or difficulty breathing, a clinical diagnosis of LRTI based on WHO criteria [14], and onset of symptoms ≤ 4 days prior to hospital admission. Exclusion criteria were patients with known non-respiratory or non-infectious respiratory diseases. Due to high volumes in the facility and to limit the burden on clinical staff and families, potential participants were identified and enrolled in the study if they had been hospitalized within 48 h and timing was convenient for the study doctors.

We used the formula below, based on WHO guidelines for estimating treatment costs for diarrheal disease [16], to calculate the minimum sample sizes for the primary objective of estimating the costs of RSV-associated LRTI cases in the (1) outpatient and (2) inpatient wards (stratified by severity–i.e., respiratory department and ICU):

$$n=ceiling {\left[\left(\frac{{precision}^{2}}{{CV}^{2} \times {Z}_{1-a/2}^{2}}+\frac{1}{{N}_{o}}\right)\right]}^{-1}$$

In the formula, CV is the coefficient of variation and N is the annual case load. Annual case loads for both outpatient and inpatient calculations were based on historical data from CH1 regarding annual LRTI admissions (N = 13,650 [3]). Data on visits to the outpatient ward were unavailable, so we assumed the same annual case load for outpatients and inpatients. While the outpatient ward sees more cases of LRTI than the inpatient setting, outpatient cases are less severe and will have less variation in resource needs and costs than inpatient cases. We assumed a Z-score of 1.96 (95 percent confidence interval [CI]), margin of error of 10 percent, and coefficient of variation of 0.5. This yielded target sample sizes of 96 (rounded up to 100) and 139 (rounded up to 150) RSV-positive children in the outpatient and inpatient settings, respectively. To estimate the number needed to achieve the desired sample sizes, we assumed an RSV-positive rate of 30 to 50 percent based on previous RSV studies at CH1 [3]. This determined we needed to enroll 200 to 330 outpatients and 300 to 500 inpatients, depending on observed prevalence during the RSV season.

### Study timeline

The study began in September 2019 with three enrollment periods: September 2019–December 2019, October 2020–June 2021 and October 2021–December 2021. Due to COVID-19 pandemic, the study had to pause for two periods from January to September 2020 and from July to September 2021.

### Sample collection and RSV detection

RSV testing is not routine at CH1. A nasopharyngeal (NP) swab was collected from each study participant, within 24 h of study enrollment, to determine RSV infection status using a validated real-time RT-PCR (reverse transcription polymerase chain reaction) test [17]. NPs for RT-PCR testing were collected in RNAlater™ media (Invitrogen, Lithuania) and transported to the Pasteur Institute laboratory on wet ice within 24 h of collection where they were stored at − 80 °C until RT-PCR testing performed at the end of each study enrolment period.

A random sample of 30 percent of participants admitted to the respiratory ward department also had an additional NP swab (collected at the same time of the NP swab collection for the real-time RT-PCR). This additional NP swab was tested immediately on-site via a commercial RSV RDA test (Immuno AG1®, Fujifilm Corporation).

Although the physicians who treated patients were not aware of RSV RT-PCR results, they received results from the RDA test in real-time. All laboratory technicians who conducted the RT-PCR testing were blinded about the RSV RDA results.

### Data collection and components

Costs were estimated from the societal and household perspectives. Three components of cost and resource utilization data were collected for the study:

(1) Health care utilization and cost data from facility-level billing data.

(2) A day-of-visit parent questionnaire to assess household-level costs incurred prior to arriving at the facility. For outpatient participants, any costs due to seeking care incurred on the day of the visit were also collected.

(3) A post-discharge parent questionnaire to identify additional costs incurred by the household for the same illness 1 week after discharge from the facility.

The billing data were used to identify resource utilization as well as direct medical and overhead costs associated with care received in the facility. Data parameters collected include types of services received during the visit (ICU bed, inpatient bed, outpatient services), consultation fees, medications, laboratory tests, imaging (chest X-ray, echocardiogram, ultrasound), and other procedures (chest physiotherapy, intubations, oxygen delivery). The proportion of costs covered by the household and national health insurance system (NHIS) was also reflected on facility-level billing data. Consumption of health care was the direct medical cost that covered the total costs of disease episode.

Hence, we reported:

• The total costs per case from the societal perspective including direct medical costs (from both billing and questionnaire data), non-medical costs, and indirect costs incurred prior to admission, during the visit and after discharge.

• The household-level costs included patient-level out-of-pocket, non-medical costs (e.g., transportation to/from facility, meals, accommodations, and caregiver), and indirect costs (e.g., opportunity costs of lost income and lost leisure time) during the disease course. These costs were obtained through standardized questionnaires conducted with parents (pre- and post-discharge), as described above.

We also collected data on total costs, stratified by time of spending, using a specific questionnaire for each spending period. Pre-hospital costs include direct medical costs, non-medical costs, and indirect costs estimated from household surveys for any health care services sought before the day of outpatient visit or inpatient/ICU admission. Costs incurred during the hospital stay include direct medical costs from billing data plus non-medical and medical out-of-pocket spending (beyond the hospital charge) for the day of outpatient visit or the episode of inpatient stay, as well as indirect costs incurred during the disease episode. Similarly, follow-up visit costs include direct medical costs from billing data for follow-up visits at the hospital, as well as out-of-pocket spending and indirect costs for any care sought after the day of outpatient visit or discharge until completing a follow-up visit.

The NHIS covers a certain proportion of the direct medical cost, depending on the type of medicines and procedures received during the hospitalization or the visit. The NHIS coverage amount was reflected on the billing data collected for the study. The remaining cost was from the out-of-pocket expenditures by the patient’s family (e.g., the household-level cost).

Demographic characteristics of children and their families were also collected through questionnaires for both outpatients and inpatients.

Figure 1 represents the clinical flow process and data components collected from outpatients and inpatients.

### Data analysis

Costs were estimated by the following categories: cost per episode, cost by component (i.e., direct medical costs, direct non-medical costs, indirect costs, and relevant subcategories), and cost by RSV status and severity (outpatient, respiratory department, ICU).

In calculating indirect costs, opportunity costs of lost income due to missed work were based on the average salary reported by participants in the study, and opportunity costs of lost leisure time were based on the minimum Vietnamese income based on government data, for the study period [18]. Continuous variables were presented as the median, with interquartile ranges (IQRs) of 25 to 75 percent. Categorical variables were presented as numbers and percentages. We used the July 2022 exchange rate of 1 US dollar for 23,195 Vietnam Dong (VND) to convert VND costs to US dollars [19].

We also evaluated sensitivity, specificity, and positive and negative predictive value of the RSV antigen rapid test (compared to the validated real-time RT-PCR) and calculated 95 percent CIs. Statistical comparisons between the RSV antigen rapid test and the validated real-time RT-PCR were performed using McNemar’s test [20].

All statistical analysis was implemented using Stata version 16.0 (StataCorp LP). All statistical tests were conducted at the two-tailed 5 percent significance level.