Review of published studies

We aimed to identify all published studies reporting empirical cost data on the treatment of episodes of pneumonia in children aged below 5 years during a 15–year period (1998–2013). We included studies in children younger than 5 years with pneumonia managed as in–patients or out–patients (using standard treatment per local standard) in secondary and tertiary hospitals, first level facility or in community settings. Data on the cost of a single episode of severe pneumonia from the societal and health care perspectives were collected as the primary study outcome. We developed a review protocol at the beginning of this study and followed the same throughout the process.

We undertook a systematic literature review with three reviewers (PS, IK, SZ), and hand searched reference list of all included articles. We searched four databases (with online search tools) to offer maximum coverage of the relevant literature: Medline, EMBASE, The Centre for Review and Dissemination Library (incorporating the DARE, NHS EED, and NHS HTA databases); and The Cochrane Library (via the Wiley Online Library) for the period 1 January 1998 to October 31 2013. (for search strategy, see Appendix S1 in Online Supplementary Document(Online Supplementary Document) ).

Three review authors (SZ, PS, IK) independently selected potentially relevant studies based on their title and abstract. Any disagreements in study selection or data extraction were resolved after discussion with SZ and HC. The eligible studies were retrieved electronically for full–text review. We included studies that investigated all–cause pneumonia in a non–selective population sample, reported empirical cost data for pneumonia treatment (using any intervention including, but not limited to, antibiotics), and included only children younger than 5 years or reported data separately for this age group. We excluded review articles, vaccine cost–effectiveness trials, and studies considering specially selected cohorts with severe co–morbidity (Appendix S2 in Online Supplementary Document(Online Supplementary Document) ). We developed and piloted a comprehensive data extraction template. We collected data on cost per episode, cost and unit cost of medication and services, duration of hospital stay and direct medical and non–medical costs. Direct medical cost included costs related to medication, diagnostic tests, medical staff time and hospital stay. Direct non–medical costs included those relating to food, transportation and accommodation charges. Any additional data on indirect costs such as care–givers’ time and earning loss were also recorded, where available. Additionally, we extracted data on study characteristics including country, treatment setting, study type and sample size. We recorded the cost study perspective only if explicitly stated in the text of the article to avoid subjective influence. For those papers that did not explicitly state the perspective used, we noted “–“ for “unstated”.

We classified countries into high income and low–and–middle income categories based on the classification adopted by the World Bank and according to 2012 Gross National Income (GNI) per capita, calculated using the World Bank Atlas method. The groups are low–income per capita US$ 1035 or less; lower middle–income US$ 1036–US$ 4085; upper middle income US$ 4086–US$ 12 615; and high income US $12 616 or more [8].

Quality assessment

We assessed the quality of the included studies using a 13 point scale based on a modified Drummond checklist [9] for economic evaluation focusing on the methodological robustness and detail of reporting (Appendix S3 in Online Supplementary Document(Online Supplementary Document) ). Studies were considered high quality if more than 10 points were addressed, medium quality studies covered 7–9 points and low quality studies addressed less than 6 points. Studies with all quality levels were included in the final analysis.

Unpublished data collection

We collected unpublished data from 10 collaborating sites that were part of a Severe ALRI Working Group (SAWG) [6]. The study population included children under 5 years of age with a clinical diagnosis of pneumonia. We defined pneumonia using the World Health Organization’s (WHO) Integrated Mangement of Childhood Illness (ICMI) definition by three different severity categories: non–severe, severe and very severe pneumonia based on WHO pocket book for hospital care for children 2005 [10]. We included all interventions for pneumonia management as detailed in the WHO pocket–book (for community/and facility–based management) where data were available.

We designed a costing spreadsheet with detailed descriptions of case definitions and methods and used this for data collection. Actual cost of medications, supplies, personnel and average laboratory costs were collected. Methods used to gather primary cost data in these studies were recorded in the spreadsheet. Resource utilization data from patient records were also documented, where available, including length of stay in hospital, the quantity of drugs and supplies utilized by each patient, and the use of diagnostic tests and procedures. We also attempted to collect data on out–of–pocket spending (by patients) on transport and food where possible. Indirect cost of caregivers’ time and daily pay rate were also recorded. Primary data collection was conducted using the provided standardized templates and guidelines at individual study site. (Appendix S4 in Online Supplementary Document(Online Supplementary Document) ).

We used a bottom–up approach to calculate cost per episode for each level of the intervention (community, first level health facility and hospital). Costs were calculated and presented separately based on severity and service delivery channels: very severe pneumonia at hospital level (defined as pneumonia with central cyanosis, inability to breastfeed or drink, or vomiting everything, convulsions, lethargy or unconsciousness and severe respiratory distress diagnosed by doctor or physicians using WHO IMCI (2005) case definition or pneumonia cases requires critical care); severe pneumonia at hospital level (defined as pneumonia with chest indrawing using WHO IMCI definition or pneumonia need for hospital admission based on physician’s assessment); severe pneumonia at community level (based on assessment by a trained health worker at home/first level facility using WHO IMCI (2005) case definition); and non–severe pneumonia at outpatient level (defined as fast breathing for age in children aged 2 to 59 months). The costing model included direct medical cost, direct non–medical cost and indirect costs. We calculated the cost per episode based on the estimates of the unit cost per contact (eg, unit cost of an antibiotic per day) at each management level multiplied by the resource utilization proportions (eg, 80% of children took amoxicillin for 5 days), plus indirect costs. For the mean total cost of treatment per episode we summed the cost of drugs, diagnostic investigations and hospital stay, as well as transportation and opportunity cost for caregivers’ time. The formula is given in Figure 1 .

Figure 1.  Formula for the mean total cost of treatment per episode.

We reported all cost data in 2013 US$ equivalent prices. We first converted all costs to US$ and then adjusted for inflation to 2013 values. Conversions were made using the Penn World Tables 8.0 (http://www.ggdc.net/pwt) and an online inflation–calculating tool (http://usinflation.org/cpi-inflation-calculator) on 20^th October 2013.

Statistical analysis

We have stratified the cost results by country income category: high–income countries (HIC) and low– and middle–income countries (LMIC). As an important input in the costing analysis for in–patient management, length of stay (LOS) in hospital was extracted for severe hospitalized cases. Cost per episode, cost by component (direct medical, direct non–medical and indirect costs), and percentage of total cost per episode in each component were summarized. Cost per episode was synthesized by severity of diseases in each strata. The mean with 95% CI of the treatment costs and the median with interquartile range (IQR) of LOS were estimated and reported where appropriate. The 95% CIs were calculated based on 5000 bootstrap samples. Mean and median values were compared using appropriate statistical tests.

Direct medical cost in studies reported from household perspective were compared with monthly household income in respective countries to evaluate the burden on families. Monthly household incomes were derived from Gallup World Poll using annual median household income divided by 12 months [11]. These income results were based on Gallup data gathered between 2006 and 2012 in 131 populations. In two countries which annual household income data was missing, we used GNI per capita from World Bank database times the mean number of people per household instead. The percentages of direct non–medical costs and indirect cost per episode of weekly household income were also assessed to show the economic impact of pneumonia management for families when direct medical cost was not considered.

We conducted all data analyses using SPSS v.19 (IBM, New York City, NY, USA) noting that included studies showed marked heterogeneity of population, methodology, treatment procedure reporting categories and perspectives.

Search results

We identified 789 studies through database searching, of which 60 articles were eligible for full text review on the basis of title and abstract assessment ( Figure 2 ). Subsequently, only 24 papers were identified to be eligible for data extraction and analysis. The key reasons for exclusions included: no data for children below 5 years or no cost data on pneumonia management were reported. For unpublished studies, we contacted 16 sites, 10 of which had data that met our eligibility criteria and contributed to the analysis. The unpublished cost data were for the period January 2001 to August 2012. Six of these sites provided cost data using a template and guidelines designed for this project while the remainder provided unpublished data in their own formats.

Figure 2.  PRISMA flow diagram for severe pneumonia cost systematic review.

Characteristics of published and unpublished data

We identified 24 studies from the literature review and collected additional 10 data sets of unpublished studies totalling 34 studies from 21 countries across the 6 WHO regions ( Table 1 ). Over 60% of the studies (21 out of 34) were conducted in the South East Asia and Africa Regions. The included studies reported data from a variety of treatment settings: community, out–patient and in–patient care settings in primary, secondary and tertiary hospitals, and at city, district, provincial and national levels. Twenty–seven of the 34 studies were stand–alone primary cost analysis and/or cost–of–illness studies. The remaining 7 studies were designed to collect cost data alongside clinical trials or epidemiological studies.

The included studies reported cost data on a total of 97 062 children treated at facility or community levels, with a median sample size of 378 (IQR 117–741) across all studies. The age of the participants was reported in 12 studies and the median age was 12.3 months (IQR 8.20–33.20). The perspective of costing was explicitly stated in 30 of 34 studies. Of these, the most common perspectives were societal (16 out of 33, 1 study did not specify perspective), health care (11 out of 33) and household (5 out of 33). In most studies, the sources of pneumonia case definition were physician’s diagnosis according to WHO IMCI definition (29 out of 34), culture–proved pneumonia was used for case definition in 1 study, self–reported condition according to WHO IMCI definition was adopted in one study, and two studies used health workers’ diagnosis. A number of different sources were used for gathering cost data, the most common being through hospital records and costing interviews/questionnaires. Interviews and questionnaires were commonly used in studies with a household perspective to collect data on indirect costs. Other sources included a national database of costs, insurance databases, surveillance data and pharmaceutical databases. The WHO CHOICE database, expert opinion and data from pilot studies were also used to collect data on the unit cost of pneumonia treatment.

The average quality score of 24 published studies was 8.21 out of 13 on scale based on modified Drummond checklist (range 3–12) (Appendix S5 in Online Supplementary Document(Online Supplementary Document) ). The majority of the studies failed to consider discounting and did not perform sensitivity analyses. There were 6 studies considered high quality, 14 studies were medium quality, and 4 low quality studies. All studies were included into the final analysis.

Cost of management per episode of pneumonia

Cost results stratified by income category are presented in Table 2 , Table 3 and Figure 3 . In HICs, the mean cost of treatment for an episode of severe pneumonia at the hospital out–patient level was US$ 251.1 in Germany [16]. An Australian study [14] reported similar cost of US$ 254.9 for community management of severe pneumonia. Average costs of facility based case management for young children admitted in primary/sary and tertiary hospitals were US$ 2803.5 (95% CI IQR 2000.6–3683.3), and US$ 7037.2 (95% CI 4028.6–11 311.0) respectively, which was 11–28 fold higher than in those managed as out–patients. The total cost per episode for the management of non–severe pneumonia at out–patient level was also reported for three countries: US$55.8 in Uruguay [12], US$ 272.7 in Chile [12] and US$ 334.6 in the United States [36]. The cost for very severe pneumonia managed in general pediatric wards followed by intensive care unit (ICU) care was reported to be US$9151.3 in a tertiary hospital in Spain [17] and US$ 120 576.3 in the United States, which is nearly 2–17 fold of the cost for severe pneumonia management in hospital settings in HICs. The majority of studies from HIC took only direct medical costs into consideration. Only two studies included direct non–medical costs and indirect costs [16]. The mean proportion of the total cost for direct medical, direct non–medical and indirect costs were 41.5%, 19.5% and 38.5% respectively.

Figure 3.  Range of cost per episode for pneumonia management (2013 US$).

In LMICs, the cost of case management for severe pneumonia was reported across all treatment settings. The community management cost was only reported in studies conducted in South–East Asia region, with a mean cost of US$ 4.3 (95% CI 1.5–8.7) per episode. Out–patient care mean costs were US$ 51.7 (95% CI 17.4–91.0) per case. Costs for in–patient care varied by regions, level of hospitals (primary/sary/tertiary), and levels of care offered at a facility: the mean cost for primary/sary hospital care was 242.7 (95% CI 153.6–341.4) and for tertiary/teaching hospital was 559.4 (95% CI 268.9–886.3). Two groups–severe pneumonia by WHO IMCI definition and hospitalized pneumonia by physician’s diagnosis–showed similar costs in all levels of care. The in–patient care costs were 4–11 fold greater than that for out–patient care in the LMICs strata, which in turn was significantly higher than that for community management.

The costs for management of non–severe pneumonia managed at outpatient level were US$ 66.9 (95% CI 21.7–129.7), which was slightly higher than for severe cases at outpatient level. This is because the hospital short stay for non–severe pneumonia in South Africa [22] was relatively high at US$ 263.1 per episode. The mean cost for very severe cases was US$ 6496.0 (2246.2–12 007.4), which is nearly 10-fold of severe case management cost.

There were 6 studies reporting cost from household perspective, mainly from LMICs in South East Asia Region. Direct medical cost for severe pneumonia in hospital inpatient settings were 26.6%–115.8% of the monthly household income, thus demonstrating that severe pneumonia management in hospital placed a significant financial burden on families. On the other hand, outpatient and community management of severe pneumonia accounted for only 0.4%–4.1% of family’s monthly income indicating decreased burden in these settings. ( Table 4 ).

Of the papers reporting cost component of severe pneumonia management, direct medical cost was reported across all studies and accounted for 45%–100% of the total cost. The mean direct non–medical cost and indirect cost were US$ 22.0 (11.8–32.7) and US$ 27.0 (4.0–54.3) respectively, which account for 0.5%–31.0% of weekly household income ( Table 5 ).

Length of stay in hospital

The in–patient cost was determined primarily by the length of stay (LOS) and the average cost per bed day. In this review, we extracted length of stay for severe pneumonia for future costing analysis reference ( Tables 6–8 Table 7Table 8).

The mean LOS for severe pneumonia reported in individual studies ranged from 4–13.5 days, with a mean LOS 7.7 (95% CI 5.5–9.9) days and median 7.9 (IQR 5.5–9.2) days in HIC, and mean LOS 5.8 (95% CI IQR 5.3–6.4) days and median 6.4 (IQR 4.1–7.1) days in LMIC. For very severe pneumonia management in intensive care unit (ICU), LOS ranged from 7.4 to 18.3 days. The mean and median LOS were 13.7 (95% CI IQR 9.2–18.2) and 14.5 (IQR 10.1–18.1) days in HIC, and 9.5 (95%CI, 7.4–11.8) and 9.2 (IQR 6.1–12.6) days in LMIC.

Unit cost of case management

Unit cost of treatment and resource uptake should be routinely reported in cost studies. However, only 13 of the 34 included studies reported these data. Since treatment protocols (use of antibiotics, diagnostic tests, procedures and levels and intensity of care) varied between studies, this contributed to variations in costs across studies. For example, the average cost of chest radiograph in LMIC was US$ 8.4 (95% CI 4.3–27.0), which was significantly lower than US$ 185.5 (95% CI 66.3–357.7) in high income countries ( Table 9 ). We attempted to abstract unit cost data but were unable to include it in the presented direct medical costs because of paucity of information.