Caro, J Jaime MDCM, FRCPC, FACP*; Getsios, Denis BA*; Payne, Krista MEd*; Annemans, Lieven PhD†; Neumann, Peter J. ScD‡; Trindade, Evelinda MD, MSc§
Epidemiologic data show that pertussis continues to pose a high disease burden, despite the use of effective whole cell vaccines in infant and toddler programs for >40 years [World Health Organization (WHO) 2001].1 A report issued by WHO in 2001 estimated that, globally, there are 50 million cases of pertussis and 300,000 deaths every year, mostly among infants, in whom the risk of severe morbidity and mortality is highest. In addition, recent reports have noted an increase in the incidence of pertussis among adolescents and adults, in whom it is a considerable source of cough illness. Tracking and understanding the epidemiologic trends for pertussis is thus vitally important.
In addition to understanding the epidemiology and health burden of Bordetella pertussis infection and disease, it is also important to recognize the economic burden it poses, particularly because this aspect is often a key factor in setting priorities for the introduction of new health care interventions in the current climate. Economic data on the burden of pertussis can therefore help to facilitate decisions on the introduction of expanded immunization programs aimed at controlling the transmission of B. pertussis and can aid assessment of their impact and benefits.
In this paper, we present the findings of a comprehensive review of the literature to uncover data that quantify the economic burden of pertussis. The review was performed by the Global Pertussis Initiative, a group of 37 international experts with the ultimate aim of slowing or reversing the increasing trend in pertussis incidence.2 Reports on the direct and indirect costs of pertussis were reviewed, given that both contribute to the overall economic burden of pertussis. We also consider the adequacy of these data in evaluating the potential cost effectiveness of immunization strategies
Existing health economic models were also reviewed to evaluate their utility in assisting decision making on possible future pertussis immunization strategies.
DEFINING THE ECONOMIC BURDEN OF PERTUSSIS: DIRECT AND INDIRECT COSTS
Direct medical costs are those costs that focus exclusively on health care resource utilization. For pertussis, this would include such things as hospitalizations, emergency room/physician visits, laboratory tests and medications. Direct nonmedical costs can include such things as additional child care provision or travel expenses incurred for medical consultations. Typically the direct costs of pertussis are higher in infants, for whom the disease burden is considerably greater and hospitalization is more common.
The indirect costs of pertussis are those incurred as a consequence of the illness, even though no direct expenditure has occurred. These include costs associated with time diverted from normal activities (eg, as a consequence of visits to the physician) and reduced work productivity, both of which may be caused by either individual illness or illness in a family member. Indirect costs can be expected to be relatively higher in adult cases, in whom illness is most directly linked to time lost from paid work activities, but can also be high for cases in infants and young children, where working parents are required to stay at home to care for their children.3
Two components are required to calculate the costs: the amount of resource used and the value (or “unit cost”) of that resource.
ESTIMATES OF DIRECT MEDICAL CARE COSTS
Estimates of direct medical costs that could serve as inputs for future economic models are limited, but some are available from North America3–6 and several European countries, including Denmark, Germany and Italy.7–9
The cost of pertussis is highly variable. One important aspect is whether pertussis-related complications, such as pneumonia and encephalopathy, develop. According to published German estimates,9 an uncomplicated case of pertussis is estimated to produce direct costs of €210 (∼US $257), whereas a case requiring hospitalization will be considerably more expensive, incurring an average direct cost of €1700 (∼US $2084). Pertussis-related pneumonia has been estimated to increase the direct cost to ∼€3940 (∼US $4830), and cases leading to encephalopathy were estimated at €5170 (∼US $6337).
The available studies also reveal that estimates of direct costs due to pertussis vary according to age, being highest in infants. A U.S. study estimated the direct costs of pertussis at US $2822 (€2302) for infants (0–23 months), US $308 (€251) for children (2–12 years), US $254 (€207) for adolescents (13–18 years) and US $181 (€148) for adults (19 years of age or older).3 Infant cases are considerably more costly than cases in other age groups because a large proportion of infant cases require inpatient care. In this study, infants were the only group to incur hospitalization costs, which accounted for two-thirds of their total medical costs. Although hospitalization of adolescents and adults because of pertussis is thought to be an infrequent occurrence, some studies have documented up to 7.5% of individuals 10–19 years of age and 5.7% 20 years of age or older with pertussis requiring hospitalization.10–12 Longer hospitalization stays may also be needed by those older than 50 years old compared with those 10–50 years old, as evidenced in a study by Gil et al13 (8.7 days versus 6.3 days).
A large scale U.S. study focusing on the societal costs (medical and nonmedical, excluding antibiotics to treat contacts) of pertussis in adolescents and adults found that mean direct medical costs in a cohort of 1679 adolescents (10–17 years old) and 936 adults (18 years old or older) were $242 (€339) and $326 (€456), respectively.6 Cases in adults were, on average, more severe than in adolescents, which is reflected in the average costs. Relatively few adolescents and adults with pertussis were hospitalized (0.8% of adolescents and 3% of adults). Adolescents stayed in hospital for a mean of 3.8 days, whereas adults stayed 4.6 days.
In Italy, the average annual hospitalization rate is ∼1 in 14 (7%) for infants less than 1 year of age, compared with only 1 in 145 (0.07%) for toddlers up to the age of 4 years.7 Data from the Danish study also confirm that hospitalization is unusual outside infancy: only 2% (n = 16) of the hospitalized cases were older than 15 years; and two-thirds of cases (n = 528) were in infants younger than 1 year old.8 In a German study, almost 90% of cases did not lead to hospitalization, and it was estimated that the cases would require no more than 4 visits to the physician and some inexpensive medications.9
For children, adolescents and adults, most direct costs are incurred through physician office visits.3 Farizo et al11 reported that up to 62% of older children, adolescents and adults who were eventually diagnosed with pertussis had at least 1 medical visit. Furthermore 16% visited their physician 3 or more times, commonly because the illness was misdiagnosed at earlier visits.14,15 The most recent study of costs in the United States estimated that between 36 and 43% of costs were a result of physician visits and roughly one-fourth was from prescription drugs.6 In another study, those eventually diagnosed with pertussis had a mean of 3.7 physician visits, 1.2 courses of antibiotics and 0.7 other prescriptions, including inhaled corticosteroids.16
Information on direct costs of pertussis cases in countries outside North America and Europe has not appeared in the literature; only estimates for the costs of the vaccines or of the vaccination programs exist.
ESTIMATES OF INDIRECT COSTS
Published data relating to the indirect costs of pertussis are less available than those for direct costs, but the data that are available strongly suggest that, from a societal perspective, the indirect costs of pertussis and its management are substantial, particularly among working parents and working adults with pertussis. Indeed the economic consequences of pertussis in terms of reduced work productivity and absence from work likely match or exceed direct health care costs.
A few North American-based studies have derived estimates of indirect costs, including the economic implications of time off work to care for a family member with pertussis or for medical consultation for pertussis, and the impact of pertussis on work productivity.3,5,6,17
A prospective study that assessed the costs of pertussis morbidity among 69 families (87 individuals with pertussis) in a community setting in New York State, found that parents lost an average of 6 work days (range, 1–35 days) to care for a sick child (Table 1). 3 For these parents, costs associated with work loss averaged US $767 (€626) per family. An average of 1.7 and 0.7 lost work days was accrued in taking an ill child to a physician's office and the emergency department, respectively. The majority (58%) of parents who continued to attend work while family members were ill with pertussis reported decreased work productivity, ranging from 25 to 99%. An earlier, retrospective study performed in the same community covering a 6-year period (1989–1994) also found that the economic burden on adults through illness or childcare responsibilities was substantial.5 The study reported 107 cases of pertussis in 90 households, 86 (80%) of which occurred in children 0–10 years of age. In 50 households, a single adult lost an average of 8.3 work days (range 1–45), and for 4 households, 2 adults lost an average of 44 workdays between them (range, 10–120 days). Additional child care costs ranged from US $12–$2688 (€10–€2193) per family.
The overall indirect costs associated with the 107 cases of pertussis recorded totaled US $160,657 (€131,068), equaling 42% of the total costs (US $381,052; €310,871). In contrast, in the more recent study undertaken by Lee and Pichichero,3 the overall indirect costs associated with 87 cases of pertussis totaled US $107,025 (€87,313), equaling 73% of the total costs (US $145,903; €119,031). This higher percentage of indirect costs may be caused by the different age distribution of cases in the 2 studies (29% infants versus 13% infants), different emergency room and hospitalization rates and different medication costs (US $22 versus US $206).
A more recent U.S. study found that adults had significantly higher nonmedical costs ($447) than did adolescents ($155).6 Of the latter, 83% missed a mean of 5.5 days from school (range, 0.4–32 days), and 61% of adults missed a mean of 9.8 days from work (range, 0.1–180 days) because of pertussis. The inclusion of personal time missed from non-work-related activities in adults increased nonmedical costs to an average of $320 per case in adolescents, and $1400 per case in adults.
Estimates of indirect costs related to pertussis are sparse for Europe. One estimate comes from a German study that used a simulation model to compare the costs and effects of acellular versus whole cell pertussis vaccination in children.9 For the purposes of the study, the impact of pertussis on productivity was estimated, based on replies to a questionnaire administered to pediatricians. On average, it was assumed that 10 working days were lost per parent taking care of a child suffering from pertussis. A study conducted in Sweden in the 1970s found that 14% of adults with pertussis were unable to work for >1 month.18
No studies outside North America and Europe that have specifically calculated the indirect costs of pertussis appear to have been published. However, reduced work productivity among adults diagnosed with pertussis has been reported in Australia. In a telephone survey of pertussis morbidity in 73 adults (20 years of age or older) in western Sydney, 17 (35%) of those employed reported missing >5 work days (range, 0–93 days).16 The results suggested that, in 1998, there were 15,000 lost work days caused by pertussis in Australian adults.
HEALTH ECONOMIC MODELING OF PERTUSSIS IMMUNIZATION STRATEGIES
Economic models of pertussis immunization have been published for the United States, Canada, Australia and several countries in Europe.4,9,19–29 The majority of these studies have focused primarily on pediatric vaccination rather than modeling the costs relating to vaccination beyond infancy. Three recent economic analyses have tried to assess the cost impact of expanded immunization strategies to cover adolescents and adults in North America28,29 and parents of newborns in Australia.22
North American Studies.
A Canadian analysis published in 2001 provided a detailed economic evaluation, based on a decision-analytic model, comparing a new acellular vaccine for pertussis with a whole cell vaccine, targeting children from birth to 8 years of age.21 Switching from a whole cell vaccine to an acellular vaccine was found to be the economically dominant option (ie, health was improved and costs were reduced) compared with continuing to vaccinate with the whole cell vaccine. However, the result was obtained under the assumption that the acellular vaccine was considerably more effective than the whole cell vaccine, with the relative risk of infection with the acellular vaccine estimated at 0.3 compared with the whole cell vaccine. Under this assumption, with coverage assumed equal for both vaccines (95%), the switch to an acellular vaccine from a whole cell vaccine was predicted to reduce the number of cases of pertussis by 66%. If, along with the superior adverse event profile of the acellular vaccine, the assumption about the efficacy of the acellular vaccine is tenable, then for every 100,000 people vaccinated, the savings in direct health care costs would be Can $275,585 (US $210,548; €171,770), and if the indirect costs to society are included, the savings would rise to Can $9,752,864 (US $7,451,214; €6,078,872).
A cost-benefit analysis comparing a diphtheria-tetanus toxoid-acellular pertussis (DTaP) vaccine with a diphtheria-tetanus toxoid-whole cell pertussis vaccine in the United States has also been reported.4 The investigators estimated that immunizing with a whole cell vaccine leads to a cost saving compared with no vaccination. For a cohort of 4.1 million children from birth to age 15 years, use of the acellular vaccine instead of a whole cell vaccine would increase immunization costs by US $113 million (€92.2 million) but would reduce the direct costs (caused by reduced need for adverse event management) by US $36 million (€29.4 million). Other U.S. economic analyses of pertussis vaccine have used decision-analytic cohort models, but their current applicability is somewhat limited given that they were published in the late 1970s and early 1980s.19,20
Two models have evaluated strategies in groups other than children.28,29 In Canada, the economic impact of an additional acellular pertussus booster dose in adolescents has been evaluated.28 The cost effectiveness of a combined vaccination program where DTaP would be administered at 12 years of age was compared with current practice: vaccinating adolescents with diphtheria and tetanus (dT) vaccine at 14 years of age. An economic model was developed, following a cohort of 144,000 adolescents during a 10-year period. The model assumed that the incidence in Canada was higher than reported, using an underreporting factor of 9, and that the DTaP vaccine would be 85% effective over the duration of the analysis. A secondary attack rate of 12% was also incorporated into the model, in effect, partially accounting for potential herd immunity. The analysis found that booster vaccination with DTaP at 12 years of age increased medical costs by Can $0.52 per adolescent annually (Can $742,341 in total), resulting in an incremental cost effectiveness ratio of Can $188 per pertussis case avoided (discounted at 3% annually). When productivity and leisure time losses caused by pertussis were factored into the analysis, savings of Can $0.60 per adolescent annually (Can $858,106 in total) were predicted. The model also estimated that 4428 cases of pertussis would be prevented over the study period with 50 hospital admissions averted. The analysis suggests that, from the societal perspective, administering a booster dose of DTaP at 12 years of age instead of dT at 14 years may reduce the economic burden of pertussis, at reasonable incremental costs from the perspective of the Ontario Ministry of Health. Estimates of cost per life year gained, or quality-adjusted life year (QALY) gained were not included in the analysis.
A cost-benefit analysis undertaken in the United States has evaluated the benefits of 7 alternate strategies for administering a pertussis booster, in the form of DTaP to adolescents and adults over a 10-year interval (2001–2010)29: (1) adolescents 10–19 years of age; (2) adults 20 years of age or older; (3) adults 50 years of age or older; (4) adults 18 years of age or older with chronic obstructive pulmonary disease (defined as asthma, chronic bronchitis and emphysema); (5); household caretakers of infants younger than 1 year old; (6) health care workers 20 years of age or older; (7) all persons 10 years of age or older (universal vaccination). For each strategy, break-even vaccination cost was calculated (ie, the cost per vaccination that would result in no net increase in total costs), adopting a societal perspective. (A break-even cost of $40 for a particular immunization strategy means that up to $40 per person can be spent on vaccine, education programs and vaccine administration before societal costs would outweigh benefits.) In the base case, vaccine efficacy of 88% declining over 10 years was assumed. The incidence of pertussis in infants and children was assumed to be twice that reported to the Centers for Disease Control and Prevention, whereas for adolescents and adults, it was assumed to be >100 times higher: between 370 and 620 per 100,000 person-years (compared with <5 per 100,000 person-years reported to the Centers for Disease Control and Prevention). Break-even vaccination cost for the 7 strategies ranged from $28.86 per vaccination for strategy 2 to $36.92 for strategy 1. In multivariate sensitivity analyses, low and high estimates for break-even cost ranged from ∼$10 to $200. Immunizing adolescents was found to be the most economically efficient strategy, and was estimated to prevent 0.7-1.8 million pertussis cases. The authors suggested that routine adult booster vaccinations every decade would be expensive and difficult to implement. The authors also felt that a recommendation for booster vaccinations every decade would require more information about duration of immunity, program costs, compliance and nonmedical costs associated with pertussis.
A model designed to estimate the health and cost impacts of adding a preschool pertussis booster to the existing U.K. primary vaccination series predicted that this would reduce the number of hospitalizations by ∼1400 and the number of pertussis cases by up to 28,000 at a net investment of <£13 million over a 5-year period.26
The only published European model of vaccination beyond childhood looked at the cost effectiveness of introducing acellular pertussis booster doses at 15 years of age in the United Kingdom.25 The researchers concluded that there was great uncertainty in the economic efficiency of these booster doses because of lack of precise estimates of the extent of herd immunity. In extensive simulations of the possible scenarios, about one-third of the simulations for a booster dose at 15 years of age indicated a cost per QALY of <£10,000 (US $18,442; €15,045).
Other modeling work undertaken in Europe includes research to evaluate pertussis immunization in children in Germany. A simulation model was used to compare the costs and effects of 3 different immunization strategies with “no prevention”: (1) whole cell vaccination (efficacy, 90%) at 45% coverage; (2) acellular vaccination (efficacy, 85%) at 45% coverage; and (3) acellular vaccination (efficacy, 85%) at 90% coverage.9 The following assumptions were made: both whole cell and acellular vaccine were given according to official recommendations at 3, 4 and 5 months of age for primary immunization followed by a booster dose in the second year of life. In the 2 low-coverage scenarios, expected annual savings in direct medical costs through prevention of disease were larger with a whole cell vaccine (€129 million; US $158 million) than with the acellular vaccine (€110 million; US $135 million). Higher direct costs for treating adverse events induced by whole cell vaccination did not outweigh the higher direct costs of pertussis infections not prevented with the acellular vaccine and the higher price of the acellular vaccine. Cost differences with acellular vaccine relative to the whole cell vaccine became equal, however, when coverage with acellular vaccine rose above 53% (keeping whole cell vaccine coverage fixed at 45%). At 90% coverage with the acellular vaccine, cost were significantly lower, leading the authors to conclude that introduction of the more expensive acellular vaccines is warranted if their use increases coverage by at least 7.5%. Moreover if indirect costs to parents resulting from vaccine-associated side effects were taken into account, the acellular vaccines were more economically attractive even if higher coverage could not be obtained (eg, in countries with already high whole cell vaccine coverage).
A similar approach was used to evaluate universal acellular pertussis vaccination in Italy, where, in the mid-1990s, overall coverage of pertussis immunization was estimated at only 50%.23 In the baseline calculations, it was assumed that pertussis vaccination would consist of 3 doses (given at 2–3, 4–5 and 6–7 months of age) and 1 booster dose (given during the third year of life). Incremental analyses were performed for each additional 10% increase in coverage up to 90%. The results indicate that at the prevailing 50% coverage, acellular vaccination would not be optimal on the basis of cost effectiveness considerations. Increases in coverage were found to yield health gains at modest net costs or even potential net savings to the health care sector. For example, an increase in coverage from 50% to 90% would yield direct net savings of US $42 (€34.3) per additional vaccinated child. By including indirect costs, the savings rose to >US $100 (€81.6) per child. Immunization with an acellular vaccine would be dominant over whole cell vaccination if switching led to an increase in coverage to 60%.
In Australia, an economic model was undertaken to estimate the costs and health consequences of 3 strategies to reduce pertussis in infants during the first 6 months of life.22 Vaccination of both parents after the birth of their child, as well as additional vaccination either at birth or at 1 month of age was compared with the current practice of vaccinating infants at 2, 4 and 6 months of age. Base case analyses were conducted on notified cases only, although sensitivity analyses were run under assumptions of underreporting. Only costs to the Australian health care system were considered, and disability-adjusted life-years (DALYs) were used as the primary outcome measure. Additional vaccination at birth was estimated to be the most cost-effective of the 3 strategies, costing an additional A$33.21 per infant, but reducing cases, deaths and DALYs lost by ∼45%. Vaccination at 1 month of age reduced morbidity by ∼25%. Parental vaccination reduced morbidity by the greatest amount (almost 40%) but was also the most costly option, resulting in incremental costs of $73.38 per infant, compared with current practice. The costs per DALY averted compared with current practice were relatively unfavorable at A$330,175, A$735,994 and A$787,504 for the birth, 1 month and parental vaccination strategies, respectively. When underreporting was taken into account in sensitivity analyses, by increasing hospitalizations and deaths by a factor of 3, however, cost effectiveness ratios fell by almost 70%, resulting in more acceptable economic outcomes.
Studies Performed Outside Australia, Europe and North America.
Models of pertussis immunization in other countries could not be found. Only a general model of immunization for various infectious diseases, designed by WHO, was identified.30 The model evaluated the incremental costs per QALY for activities added to the WHO health initiative.
SUMMARY AND CONCLUSIONS
Available epidemiologic and health burden data suggest that the economic burden of pertussis is substantial, though there are considerable gaps in the information required to accurately quantify this. Neither direct nor indirect costs are widely recorded and, to date, no economic analyses have attempted to estimate the national burden of pertussis in monetary terms or its contribution to total national health care expenditure.
The few studies performed in the United States and Europe suggest that the indirect economic burden of pertussis is substantial because of the economic expenditures required to care for ill family members, the prolonged recovery from illness and the consequential time lost from work.3,5 In terms of the direct costs of pertussis, hospitalization is the greatest contributor, and studies in the United States have found that direct costs are much higher for infant cases.3–5 The high hospitalization rates for infants reported in numerous non-U.S. studies suggest that this will also be true in other settings.
Although the available studies provide some estimate of medical resource use and data on work time lost due to illness, a complete picture of the economic burden of pertussis is lacking. Major obstacles to the accurate assessment of the costs of pertussis are that there are no cost estimates for countries in the developing world, the true incidence of pertussis is subject to considerable question, the severity and cost consequences of unreported and undiagnosed cases are unknown and costs by severity of symptoms have not been fully investigated.
Just as data on the economic burden of pertussis are limited, so too are data on the economic impact of pertussis vaccination strategies. The limited cost data described above, especially as they pertain to unreported and undiagnosed cases, along with considerable gaps in epidemiologic data on pertussis, hamper the economic modeling of new immunization strategies. The true incidence of pertussis and the economic consequences of unreported and undiagnosed cases are especially problematic, as assuming undiagnosed or unreported cases are just as costly and severe as reported cases would overestimate the burden of pertussis. Similarly, assuming that these cases result in no costs, or not including them in the evaluation, has the opposite effect of underestimating the health economic impact of pertussis.
Some economic modeling of various vaccination strategies has been undertaken,4,9,19–29 but most have focused on childhood vaccination. Three studies have examined routine adolescent vaccination,25,28,29 whereas 2 have looked at other extensions of current immunization practices, including vaccination of adults28,29 and neonates.22 Although childhood vaccination analyses have generally shown use of DTaP to be cost-effective, results of economic evaluations in other age groups have been less consistent, largely because of differences in estimates of the true incidence of pertussis and, to a lesser extent, of the potential herd immunity that might result from expanded immunization.
Until more data become available, new cost effectiveness analyses will have to be exploratory. Nevertheless models using existing data and adopting reasonable assumptions may provide sufficient information to aid decisions on the implementation of new immunization strategies. By outlining the conditions required for vaccination to be cost-effective, these studies, coupled with expertise on the likelihood of meeting these conditions, may provide a strong sense of whether or not new immunization strategies will be economically efficient. As such, part of the activities of the Global Pertussis Initiative included the development of an economic model that provides a flexible framework for assessing the cost effectiveness of various immunization strategies.31
In the mid- to long term, primary data should be collected for more definitive estimates to be possible. Epidemiologic, economic and demographic data for input into cost effectiveness analyses are needed. These include data on: extent of underreporting and impact of unreported cases on health and costs; extent of the contribution of undiagnosed or misdiagnosed cases to underreporting; country- and age-specific costs/case; epidemiology and costs in special populations (eg, child care workers); herd immunity; transmissibility of infection; full range of infections and clinical disease; health utilities; duration of immunity (natural and vaccine-induced); safety and efficacy of vaccines in nonpediatric populations.
More research is also needed on the optimal immunization scheme, in terms of both timing of administration and the number of administrations (boosters). The cost effectiveness of vaccination strategies should be reassessed as more data become available.
We thank Wissam El-Hadi for assistance with literature searches and with reviewing the published economic and epidemiologic research.
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