A “New Age” in Pertussis Prevention

Research Articles

A “New Age” in Pertussis Prevention New Opportunities Through Adult Vaccination Margaret M. Cortese, MD, Andrew L. Baughman, PhD, Kristin Brown, BS, Pamela Srivastava, MS Background: For the first time, pertussis vaccines for adolescents and adults (combined with tetanus and diphtheria toxoids [Tdap]) became available in the United States in 2005. Despite a fully implemented U.S. childhood pertussis vaccination program, substantial morbidity because of pertussis continues to occur. To reduce this morbidity, the Advisory Committee on Immunization Practices recommended Tdap for all adolescents and adults in place of the next tetanus-diphtheria booster. As background for the basis of these recommendations, we summarize data on the morbidity and incidence of pertussis in U.S. adults and the role of adults in transmitting pertussis to young infants. Methods:

A MEDLINE search was performed in March 2006 for data on pertussis incidence rates and cough illness because of pertussis among U.S. adults (prospective, nonoutbreak studies were selected) and pertussis complications in adults. Data from the national passive surveillance system were also analyzed in October 2005.

Results:

The true adult burden is estimated at more than 600,000 cases annually in the United States. Adults with pertussis commonly cough for 2– 4 months, often resulting in repeated medical visits and missed work. Complications include pneumonia, rib fractures, and cough syncope. Adults are an important source of pertussis for young infants, who have the highest risk of hospitalization and death.

Conclusions: The morbidity from pertussis in adults can be substantial, the incidence of pertussis in U.S. adults is high, and adults transmit infection to young infants. Providers now have the opportunity to reduce the burden of pertussis by vaccinating adults with Tdap. (Am J Prev Med 2007;32(3):177–185) © 2007 American Journal of Preventive Medicine

Introduction

F

or the first time in more than 50 years, dramatically new opportunities to reduce the morbidity in the United States from pertussis became available in 2005. The Food and Drug Administration (FDA) licensed two new tetanus, diphtheria, and acellular pertussis (Tdap) vaccines: ADACEL (sanofi pasteur) with age indication of 11– 64 years,1 and BOOSTRIX (GlaxoSmithKline) for those aged 10 –18 years.2 In late 2005 and early 2006, the Advisory Committee on Immunization Practices (ACIP) recommended Tdap for all adolescents in place of the first dose of tetanus and diphtheria (Td) vaccine3 and for all adults aged 19 – 64 years, replacing the next Td booster.4 Accelerated uptake was recommended for those in close contact with young infants and for healthcare workers.4 The primary objective of the adult Tdap program is to From the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Address correspondence to: Margaret M. Cortese, MD, CDR, United States Public Health Service, Centers for Disease Control and Prevention, 1600 Clifton Road, MS A47, Atlanta GA 30333. E-mail: [email protected]. The full text of this article is available via AJPM Online at www.ajpm-online.net.

protect the vaccinated adult against the morbidity of pertussis; the secondary objective is to reduce the reservoir of pertussis in the population at large.5 The new Tdap vaccines will prevent many cases of pertussis. More than 25,000 cases of pertussis were reported to the national passive reporting system at the Centers for Disease Control and Prevention (CDC) in 2004 (the highest reported since 1959; Figure 1), but passive data greatly underestimate the incidence of pertussis. The true adult burden is estimated to be as high as 600,000 cases annually. This burden occurs against the backdrop of a fully implemented infant/ childhood immunization program; since 1994, ⱖ90% coverage for ⱖ3 doses of pertussis-containing vaccine has been achieved in U.S. children aged 19 –35 months.6 Improved control of pertussis will require high uptake of the new adolescent/adult Tdap vaccines, with practitioners aware of the need to prevent pertussis and recommending the vaccines to their patients. As with other vaccines, nontraditional avenues to reach adults should be pursued, including communitybased and occupation-based vaccination programs. Recommendations for Tdap in adults may not be fully appreciated by clinicians because of the significant challenges in diagnosing pertussis. Even though most

Am J Prev Med 2007;32(3) © 2007 American Journal of Preventive Medicine • Published by Elsevier Inc.

0749-3797/07/$–see front matter doi:10.1016/j.amepre.2006.10.015

177

300,000

Number of cases

30,000 25,000

250,000

DTP

200,000

20,000

> 19 y

15,000

11– 18 y < 11 y

10,000 5,000

150,000

0 1990

1995

2000

100,000 50,000 0

1922 1930

1940

1950

1960

1970

1980

1990

2000

Year

Figure 1. Reported cases of pertussis, United States 1922– 2004.* *NNDSS, CDC, 2005 (1950 –2004). Passive reports to the Public Health Service (1922–1949).

internists and family physicians have likely cared for adults with pertussis, and perhaps developed pertussis themselves, they are often simply not aware of it.7 This paper summarizes the data on pertussis in adults, focusing on pertussis morbidity and incidence estimates. Because a secondary objective of the adult Tdap program is to reduce the pertussis reservoir and thereby reduce transmission to infants, data are also presented on infant pertussis and source of transmission. Last, aspects of Tdap vaccines are highlighted.

Background Bordetella pertussis is a fastidious, Gram-negative coccobacillus that naturally infects only humans, and is transmitted person to person primarily through respiratory droplets generated by coughing and sneezing. Precisely how B. pertussis causes the prolonged cough is not known. Pertussis toxin (PT) is believed to have a major, although not exclusive, role, yet its target cells are still uncertain.8 –11 Most complications that occur beyond the neonatal period are because of the forceful, prolonged coughing episodes. Once infection has occurred and the patient’s cough is well established, neither antibiotics nor any other known intervention reduces symptoms.12,13 In practice, therefore, antibiotics for treatment of pertussis are primarily recommended for those people who may still be infectious (i.e., within 21 days of cough onset) to eradicate the organism and reduce communicability. Use of chemoprophylaxis (i.e., providing antibiotics to asymptomatic individuals believed to be close contacts of a casepatient) as a general public health response has limited effectiveness, largely because most cases are diagnosed late after substantial pertussis transmission has already occurred.14,15 Therefore, vaccination before exposure is the only effective way to prevent pertussis morbidity and mortality in the population at large. Laboratory confirmation of pertussis in adults is challenging for both the clinician and the researcher.3,16 178

Although detection of B. pertussis by culture or by polymerase chain reaction of a nasopharyngeal specimen may be possible early in cough illness, these tests are likely to be negative by the time adults seek care for persistent cough. A standardized single-point serologic assay for elevated antibody against a specific B. pertussis antigen (i.e., PT) is not commercially available; the Massachusetts State Laboratory, however, does have an in-state standardized assay for IgG against PT, and CDC and FDA are developing such an assay for wider use.17 Pertussis in adults, therefore, is frequently not laboratory confirmed, but diagnosed by an epidemiologic link to a confirmed or suspected case.

Morbidity and Incidence of Pertussis in Adults Data sources A MEDLINE search was performed in March 2006 for data on pertussis incidence rates and cough illness from pertussis among U.S. adults, and complications in adults. The search specified English-language articles published from 1966 to March 2006, containing the term “pertussis” and including adults aged ⱖ19 years. Bibliographies of pertinent articles were also reviewed. Prospective, nonoutbreak studies were emphasized for the pertussis incidence summary. In October 2005, data from two studies18,19 were reanalyzed for specific age groups, and an incidence rate confidence interval (CI) was calculated for one result.20 Data from the national passive surveillance system were analyzed. This system collects data reported from state and local health departments: the National Notifiable Diseases Surveillance System (NNDSS) and the more detailed case information from the Supplementary Pertussis Surveillance System.21,22 Additionally, data were analyzed from the Massachusetts Department of Public Health and that on U.S. pertussis deaths from NNDSS reports and cases reported directly to the National Immunization Program, CDC.

Morbidity of Pertussis The clinical outcome after a specific exposure to B. pertussis depends in large part on the level of immunity at the time of exposure. Immunity may be vaccineinduced or from prior exposure to B. pertussis, and immunity wanes over time.23–25 Depending on the level of immunity, adult infection can be asymptomatic, or can result in disease anywhere from mild cough illness (which may have a prolonged duration) to classic pertussis with paroxysmal cough, post-tussive vomiting, and whoop.26 –28 Although severe cough illness has more impact on the individual, even mild pertussis cough illness is consequential because those with mild illness can still transmit B. pertussis via respiratory droplets.

American Journal of Preventive Medicine, Volume 32, Number 3

www.ajpm-online.net

Additional information on the clinical manifestations and impact of adult pertussis are available from the literature and from more than 19,000 cases reported to the U.S. national surveillance system in 1996 –2004 (Appendix A).29 –32 Overall, the great majority (⬎80%) of adults reported with pertussis have paroxysmal cough, and approximately half have post-tussive vomiting (may be lower in older adults: 27% of 984 nonMassachusetts U.S. adults aged ⱖ65 years reported post-tussive vomiting). Loss of consciousness from severe paroxysms (“cough syncope”)33 is reported in up to 6% of adults, pneumonia in up to 5%, rib fractures in up to 4%, and hospitalization in up to 3%; rates of pneumonia and hospitalization may be higher in older adults (8% and 12%, respectively, in non-Massachusetts U.S. adults aged ⱖ 65 years). Urinary incontinence with cough (particularly in women) and weight loss were also frequently reported in the two studies that specifically solicited this information.29,30 The wide range in the proportion of adults reported with apnea (32%– 85%) or whoop (33%– 82%) may reflect differences in definition and interpretation of these clinical features. Most of the large studies on adult pertussis (including those in Appendix A, found online at www.ajpmonline.net) are based on passive surveillance data; these data likely better represent the more classic or severe cases because they are based mainly on cases diagnosed by medical providers and meet surveillance system case definition criteria. The substantial proportion of clinically milder cases that do not come to medical attention would not be routinely captured. Nonetheless, these data demonstrate that clinically significant adult pertussis is not rare, and complications do occur. In the United States, ⬎1000 pertussis cases in adults aged ⱖ19 years have been reported to NNDSS each year since 1996. Cases from Massachusetts figure prominently in U.S. data on adult pertussis. A serologic assay for IgG antibody against PT used in Massachusetts17 greatly enhances the ability for clinicians and Massachusetts Department of Public Health investigators to document adult pertussis. Clinical data from other countries show findings similar to the U.S. data, and provide information on characteristics not routinely quantified.29,31,32 Anecdotal reports in the literature describe other complications from pertussis in adults. Complications include those because of the high pressure generated during coughing attacks (in addition to rib fracture, cough syncope, and urinary incontinence): pneumothorax,32,34 aspiration,35 herniated lumbar disc,36 inguinal hernia,30,35 and subconjunctival hemorrhage.31,37 One patient was reported with carotid dissection as a possible consequence of pertussis.38 Respiratory tract complications other than pneumonia include sinusitis,29 otitis media,29,35 and hemoptysis.37 Neurologic and other complications of pertussis in adults have also been described: pertussis encephalopathy (characterized March 2007

as seizures triggered by only minor coughing),39 migraine exacerbation,40 loss of concentration/memory,37 sweating attacks,29,35 angina,32 and severe weight loss.35 Prolonged cough is a very common feature among adults reported with pertussis. The median cough duration from five published non-U.S. studies was approximately 2 months; some adults coughed for much longer (up to 32 weeks) (Appendix B, found online at www.ajpmonline.net).29,31,32,35,37 To supplement these non-U.S. data, cough-duration data were analyzed on 2004 surveillance forms from 620 Massachusetts adults aged ⱖ19 years with laboratory-confirmed pertussis. A survival analysis was performed using reported cough duration from those who had stopped coughing by the last interview and those who were still coughing at last interview. The Kaplan-Meier estimate was 53% of adults with pertussis still coughing 16 weeks after cough onset (Appendix B, found online at www.ajpm-online.net). Cough duration data also show that the diagnosis and treatment of pertussis are delayed in adults. Surveillance data from 2206 Massachusetts adults reported during 1988 –2003 showed that 50% had been coughing 1 month or longer at the time of laboratory diagnosis. Additionally, of the 90% (1837 of 2048) of cases with complete information, 43% of Massachusetts adults aged ⱖ19 years reported during 2000 –2004 were not treated with an antibiotic effective against pertussis within 21 days of cough onset. This common delay allows for continued transmission of B. pertussis, because untreated patients may remain infectious through approximately the first 21 days of cough. The prolonged nature of the cough illness has additional consequences. Adults may undergo extensive medical evaluations by providers in search of a diagnosis if pertussis is not considered,35 and patients make repeated visits for care. Of 2472 Massachusetts adults with pertussis reported during 1988 –2003, 31% had one; 31% had two; and 35% had three or more medical visits during their illness. Adults with pertussis also miss work. In Massachusetts, 78% of 158 employed adults with pertussis missed work for an average of 9.8 days (range 0.1–180 days).30 Data from other countries showed work loss can be prolonged, with 10% (Australia)31 and 16% (Sweden)32 of adults missing more than 1 month of work. Additionally, other adults in the case-patients’ household may miss work.29,31 Pertussis-associated deaths in adults have rarely been reported. It is likely that adult pertussis deaths are underreported in the United States for the same reasons that adult pertussis disease is under-reported: namely, limited availability of accurate diagnostics and overall underappreciation of this illness in adults. During 1990 –2004, five pertussis-associated deaths in adults were reported to the CDC, and all occurred since 1997; patients were aged 49 – 82 years, and all had serious underlying medical conditions (one each with severe diabetes, severe multiple sclerosis with asthma, multiple Am J Prev Med 2007;32(3)

179

myeloma on immunosuppressive therapy, myelofibrosis, and chronic obstructive pulmonary disease).41,42 Although it is not known if adults with specific medical conditions are at higher risk of developing pertussis or suffering its complications, it is conceivable that adults with severe cardiac or pulmonary disease, or the elderly, for example, could be seriously affected by severe coughing paroxysms or cough syncope.29,43 In a 1992 outbreak of pertussis among older women in a religious institution in The Netherlands, 4 of 75 residents were reported to have suffered pertussis-associated deaths: one aged ⬍75 years and three aged ⱖ75 years.44 Based on clinical assessments, three of the four deaths were attributed to intracranial hemorrhage during pertussis cough illnesses that had lasted more than 100 days.

Incidence of Pertussis In 2004, some 25,827 pertussis cases among all ages were reported to the national surveillance system, with 7029 cases in adults aged 19 – 64 years (incidence 3.9 per 100,000). Passive surveillance data, however, greatly underestimate the true burden of adult pertussis for several reasons, including limited availability of accurate laboratory diagnostics, limited physician awareness of pertussis in adults, and when not classic disease, the limited ability to clinically distinguish it from other respiratory illnesses. As previously described, pertussis can also have a mild enough course in adults that medical care is not sought. Therefore, populationbased, active surveillance studies for pertussis with laboratory confirmation are critical for addressing this issue. Four such studies have been performed in the U.S.19,20,45,46 (Table 1). If the incidence estimates from the population-based studies that included adults in a broad age range are applied to the 2000 U.S. census population for adults 19 – 64 years, approximately 299,000 to 626,000 adults in this age group develop clinical illness from pertussis annually, up to 89 times more than the number reported to the passive system. Additionally, three of the four studies19,45,46 started at the point of patients seeking medical care, missing milder cases that still result in pertussis transmission. In the study by Ward et al.20 (annual pertussis incidence 368 per 100,000 person-years), however, participants were contacted by phone every 2 weeks for 2 years and tested for pertussis if they reported any cough illness lasting ⱖ5 days, so milder case were also detected. Other aspects of the studies are useful to highlight. The studies differed in age groups studied, specific laboratory tests used to confirm pertussis, and methods to define person-years at risk. Although the clinical features of all the cases are not detailed individually, the clinical information provided, and the fact that three of the four studies19,45,46 enrolled patients only after they sought medical care suggest that the high incidence estimates are not based merely on very mild 180

illnesses. Because of the unique study design in Ward et al.,20 the population at risk could be carefully quantified, allowing for more accurate incidence estimates. These studies were performed in different regions and calendar years. None were described as occurring during a period of markedly increased regional pertussis activity, which could have limited the generalizability of the estimates. Interestingly, Van Rie et al.49 predicted a similar incidence rate for adult pertussis from a mathematical model that divided the U.S. population by age and epidemiologic class (pertussis susceptible, infectious, and immune), and used estimates of demographic and epidemiologic parameters available in the literature. The incidence of symptomatic pertussis infection in U.S. adults in 2002 was predicted to be 438 per 100,000, within the range of results from active surveillance studies.49 The population-based studies and additional active surveillance U.S. studies that did not have a population base numerated also provide estimates of the proportion of adult cough illness because of B. pertussis (Table 1). Results range from 1% to 16% when criteria for laboratory confirmation were restricted to the most pertussis-specific, and higher estimates were obtained with additional (but less pertussis-specific) serologic assays. As Cherry23 notes, regardless of exact population source, year, or U.S. region, everyone who looks for pertussis in coughing adults finds it. Finally, an additional population-based study that estimates pertussis infection rates in U.S. adults is a large serologic survey from individuals in the National Health and Nutrition Examination Survey III, 1991– 1994.18 This survey was designed to be representative of the U.S. civilian, noninstitutionalized population. Antibodies (IgG) against pertussis antigens were measured in 5409 adults from across the United States, and the proportion with elevated anti-PT antibody, suggesting recent pertussis infection, was determined. No clinical information on cough illness was available. The prevalence estimate of recent pertussis infection (including asymptomatic infection) in people aged 20 – 49 years was 2.67% (95% CI⫽1.76%–3.89%) or 2670 per 100,000 population (data reanalyzed for this age group). Although it is not possible from this study to determine the number of clinically significant infections, the study supports the concept that pertussis infection is indeed endemic in U.S. adults.

Pertussis in Infants and Adults as Source of Transmission Although pertussis in adults can cause substantial morbidity, pertussis in very young infants is life threatening. Infants with pertussis frequently require hospitalization or develop pneumonia or other complications, and the youngest have the highest risk of fatal pertussis. During

American Journal of Preventive Medicine, Volume 32, Number 3

www.ajpm-online.net

March 2007 Table 1. Prospective U.S. studies: estimated incidence of pertussis in U.S. adults and proportion of cough illness confirmed as pertussis

Study

Years

Population-based studies Ward20 1997–2000 Strebel19

1995–6

Nenning45

1994–5

Mink46

1986–9

Other studies** Jansen47 1993–4 Wright48

1992–4

Setting/location

Age group (years)

Minimum cough duration for enrollment (days)

Number tested

Number cases pertussis (lab-confirmed)*

Cough illness ⴝ pertussis* (%)

Annual incidence per 100,000 person years (95% CI)

Annual U.S. cases in age 19–64 yearsa

Vaccine trial control group, 8 sites in 8 states HMO primary care St. Paul/ Minneapolis, MN HMO primary care San Francisco, CA College primary care facility Los Angeles, CA

15–65

5

1284b

9

1%

368 (168–699)c

⬃626,000

20–49d

7

155

15

10%

361 (176–546)

⬃614,000

14

153

19

12%

176 (97–255)

⬃299,000

College students

6

130

17–34

13%–26%

35–69

—

Marine training outpatient clinics San Diego, CA Emergency room Nashville, TN

Marines 18–29

7

120

1–20

1%–17%

—

—

14

75

12–16

16%–21%

—

—

ⱖ18

ⱖ18

—, not available. *Based on positive laboratory results from:

Am J Prev Med 2007;32(3)

Strebel: pertussis culture (cx), PCR, or anti-PT (pertussis-toxin) serology (PT). Ward: cx, PCR, PT, or positive results in at least 2 non-PT serologic assays. Nenning: PT. Mink: low value: cx or PT (see also ref 23); high value: also includes positive results from at least 1 non-PT serologic assay or direct fluorescent antibody (DFA) assay. Jansen: low value: cx, PCR, or PT; high value: also includes positive results from at least 2 non-PT serologic assays. Wright: low value: cx or PT; high value: also includes positive results from 1 non-PT serologic assay. Cases ⫽ Incidence ⫻ 170,064,743 (U.S. population aged 19 – 64 years, U.S. Census 2000). Not calculated for Mink due to limited age group studied. Number of cough episodes (in 1390 persons monitored) for which pertussis testing was performed. c Exact Poisson confidence interval; CDC, 2005. d Data re-analyzed for this age group; CDC, 2005. **Excludes studies without PT serology or studies that took place during an outbreak. a

b

181

Cases per 100,000 population

250

0 –2 months

200 3–4 months

150 100

5– 6 months

50 7–11 months

0 1984

1988

1992

1996

2000

2004

Year

Figure 2. Reported pertussis incidence in U.S. infants, by age in months, 1984 –2004.* *Tanaka et al.21 (1984 –1999). NNDSS, CDC, 2005 (2000 – 2004).

2000 –2004, 10,720 pertussis cases were reported in U.S. infants aged ⬍6 months. Of the cases with complete information, 68% (5868 of 8619) were hospitalized; 13% (995 of 7395) had radiographically confirmed pneumonia; and 2% (139 of 8545) had seizures. Surveillance data suggest that the incidence of pertussis in the youngest infants (those too young to be protected by the pertussis vaccines on the routine immunization schedule) has increased since the 1980s (Figure 2).21 The number of pertussis deaths reported in U.S. infants has also increased since the 1980s (Figure 3). Although the infant pertussis mortality rate increased from the 1980s to the 1990s, the case-fatality rate did not change.42 The most advanced medical therapies currently available have not improved the dismal survival rate in very young infants critically ill from pertussis.50 –52 During 2000 –2004, 90 of the 100 reported U.S. pertussis deaths occurred in infants aged ⱕ2 months. By improving the ability to detect B. pertussis, wider use of polymerase chain reaction may contribute to the continuing increase in reported deaths. Nonetheless,

pertussis deaths in U.S. infants are under-reported: Vitek estimated that only 65% of diagnosed pertussis deaths in infants during 1990 –1999 were reported to the national surveillance system.25,42 As documented in the United Kingdom, severe pertussis in infants is under-recognized,53 and it is likely that this extends to pertussis deaths as well. Understanding how infants are exposed to pertussis can inform new strategies to better protect them. Bisgard et al.54 reviewed information from a large number of U.S. infants with pertussis where pertussis source was ascertained by parental report during routine investigations. The source was defined as the person with acute cough illness who had contact with the infant 7–20 days before the infant’s cough onset. If more than one possible source was identified, the person who spent the most time with the infant was considered the source. For this review, the data were reanalyzed for infants with the greatest risk of mortality: those aged ⱕ2 months. No source could be identified by the parent in 57% of the 413 cases aged ⱕ2 months, and the source was reported to be the mother, father, or grandparent in 26% of the cases (Table 2). When classified by source age, 22% of the sources were aged ⱖ20 years (with 62% of infant cases having source of unknown age). It is not known if source reported through such surveillance investigations is accurate. Additionally, who infected the large proportion of infants who did not have a source reported? These infants may have been infected by close contacts the parent did not want to identify, by close contacts with mild illness not recalled by the parent, or by persons beyond the usual circle of contacts who could not be identified. Additional smaller studies from the U.S.55,56 and other countries26,57 support the finding that close adult family or household members are important sources of pertussis for infants. Providing pertussis vaccination to adults in close contact or anticipating

Figure 3. Reported pertussis deaths in young U.S. children, by age and time period.* *Vitek et al.42 (1980 –1999). NNDSS and National Immunization Program, CDC, 2005 (2000 –2004).

182

American Journal of Preventive Medicine, Volume 32, Number 3

www.ajpm-online.net

Table 2. Relationship and age of reported source for 413 U.S. infants aged ⱕ2 months with pertussis, 1999 –200252a Relationship (to infant) of source Unknown Mother Father Grandparent Sibling Other Total Age of source (years) Unknown 0–9 10–19 20–29 30–39 40–49 50–59 60–64 65⫹ Total

Number

% of total

236 67 27 14 28 41 413

57 16 7 3 7 10 100

269 30 30 33 32 11 7 0 1 413

62 7 7 8 8 3 2 0 0.7 98b

Data from Bisgard et al.52 re-analyzed for infants aged ⱕ2 months; CDC 2006. Parents/guardians of 413/522 (79%) infants with pertussis interviewed for source information. b Less than 100% due to rounding. a

close contact with infants is a targeted strategy recommended by the ACIP to reduce pertussis morbidity and mortality.

The New Tdap Vaccines Whole-cell pertussis vaccines became available for routine use to protect against childhood pertussis in the 1940s. Local and systemic adverse events were common. As reviewed by Keitel,58,59 whole-cell vaccines were generally considered too reactogenic for use in adults, with risks outweighing perceived benefits. With the goal of providing pertussis protection comparable to that from most whole-cell vaccines but reducing adverse reactions, purified acellular pertussis vaccines were developed and licensed for infants/children in the United States in the 1990s. As Orenstein60 describes, the safety and efficacy of the infant acellular pertussis vaccines (some of which had been previously studied in adults in Phase-1 trials),59 and increased attention on adult pertussis, led to optimism that similar vaccines could be used in adults. In 2004, biologic license applications for Tdap vaccines for adolescents/adults were submitted to the FDA. The pertussis components in these vaccines are similar (but in reduced quantity for some or all of the antigens) to those used in the respective manufacturers’ infant/childhood DTaP vaccines.3 After meeting safety and efficacy criteria, the Tdap vaccines were licensed for single-dose use by the FDA in 2005. Compared to Td, overall safety profiles of the Tdap vaccines were comparable, and antibody responses to the tetanus and diphtheria components March 2007

were noninferior.61– 63 Because no established correlate of immunity exists for pertussis, efficacy for the pertussis components was met in adolescents and/or adults by demonstrating antibody responses to the pertussis antigens that were noninferior to those measured in infants during the infant acellular pertussis vaccine trials (where clinical efficacy against pertussis was documented).61– 63 Although not part of an FDA licensure application, one clinical efficacy trial was performed in 2781 people aged 15– 65 years using an acellular pertussis vaccine that contained the same pertussis antigens as those in Boostrix (without tetanus or diphtheria toxoids).20 The efficacy against laboratory-confirmed pertussis over the 2-year monitoring period was 92% (95% CI⫽32%–99%). Although no studies have yet determined duration of protection from a single Tdap dose, repeat doses will likely be necessary in adulthood to optimally maintain pertussis protection.20,64,65 Three economic analyses have been performed to estimate the costs, risks and benefits of Tdap vaccination in the U.S., including adult vaccination.66 – 68 Although methodologies and assumptions differed in these analyses, results were favorable toward a general adult Tdap vaccination program in the two studies66,68 using adult pertussis incidence rates in the range of those from the active surveillance studies. A sensitivity analysis in the most recent report by Lee et al.66 found adult vaccination to be cost effective at an annual incidence rate of 120 per 100,000 population, or higher. The ACIP has now recommended that all adults aged 19 – 64 years receive a single dose of Tdap to replace their next Td booster if their last dose of Td was ⱖ10 years earlier.4 Tdap may be given at an interval shorter than 10 years since last Td to provide pertussis protection; the safety of an interval as short as approximately 2 years between last tetanus-containing vaccine and Tdap has been reported in a Canadian study.69 Accelerated uptake is recommended for high priority groups, including adults who have or who anticipate having close contact with an infant aged ⬍12 months, and healthcare workers with direct patient contact. Adults who have never received tetanus and diphtheria toxoid-containing vaccine should receive one dose of Tdap and two doses of Td to complete the schedule. The separate provisional recommendations addressing Tdap in pregnancy are available at the NIP Web site.70

Summary Adult pertussis is common in the U.S., with as many as 600,000 cases occurring annually. Adults with pertussis can often have substantial morbidity; the majority of adults reported with pertussis cough for many weeks and half have post-tussive vomiting. Severe coughing in some patients causes rib fractures or loss of consciousness, and some adults develop pneumonia or require Am J Prev Med 2007;32(3)

183

hospitalization. Repeated medical visits and work loss frequently result. Adults are a source of pertussis for infants; young infants have the highest reported incidence of pertussis among all age groups and the greatest risk of mortality. Vaccination before exposure is the only effective way to reduce the morbidity and mortality from pertussis in the population at large. With licensure of Tdap, the opportunity now exists to prevent a significant proportion of adult pertussis and reduce the overall morbidity and mortality from pertussis that still occurs every year. This long-awaited milestone challenges all who provide adult care to strengthen our adult immunization program through traditional and less-traditional avenues, and deliver these services to our patients. Those who care for infants also have a critical role in advocating that these goals be realized. The authors gratefully acknowledge Susan Lett, MD, MPH, and Areche Arquimedes, MPH, for providing data from the Massachusetts Department of Public Health; Kristine Bisgard, DVM, MPH, for providing infant source data; Trudy Murphy, MD, and Martha Roper, MD, MSTPH, for review of the manuscript; and the assistance of Grace Lee, MD, MPH, Karen Broder, MD, Amanda Cohn, MD, and Katrina Kretsinger, MD, MA. No financial conflict of interest was reported by the authors of this paper.

References 1. Food and Drug Administration. Product approval information—licensing action, approval letter: ADACEL. Rockville MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research; 2005. Available at: http://www.fda.gov/cber/ approvltr/tdapave061005L.htm (Accessed June 10, 2005). 2. Food and Drug Administration. Product approval information—licensing action, approval letter: BOOSTRIX. Rockville MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Available at: http://www.fda.gov/cber/ approvltr/tdapgla050305L.htm (Accessed May 3, 2005). 3. Broder KR, Cortese MM, Iskander JK, et al. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:1–34. 4. Advisory Committee on Immunization Practices. ACIP votes to recommend use of combined tetanus, diphtheria and pertussis (Tdap) vaccine for adults. Available at: http://www.cdc.gov/nip/vaccine/tdap/tdap_adult_ recs.pdf. 5. Morita J. ACIP Pertussis Vaccine Tdap Working Group Overview, October 26, 2005. Record of the meeting of the Advisory Committee on Immunization Practices. Available at: http://www.cdc.gov/nip/ACIP/minutes/ acip-min-oct05.pdf. 6. CDC. National, state, and urban area vaccination coverage among children aged 19 –35 months—United States, 2004. MMWR Morb Mortal Wkly Rep 2005;54:717–21. 7. Dworkin MS. Adults are whooping, but are internists listening? Ann Intern Med 2005;142:832–5. 8. Hewlett EL. Pertussis: current concepts of pathogenesis and prevention. Pediatr Infect Dis J 1997;16(4 Suppl):S78 – 84. 9. Hewlett EL. A commentary on the pathogenesis of pertussis. Clin Infect Dis 1999;28(Suppl 2):S94 – 8. 10. Long SS, Edwards KM. Bordetella pertussis (pertussis) and other species. In: Long S, Pickering L, Prober C, eds. Principles and practice of pediatric infectious diseases, 2nd ed. London: Churchill Livingstone; 2003:880 – 888.

184

11. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev 2005;18:326 – 82. 12. Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev 2005;1:CD004404. 13. Pillay V, Swingler G. Symptomatic treatment of the cough in whooping cough. Cochrane Database Syst Rev 2003;4:CD003257. 14. DeSerres G, Boulianne N, Duval B. Field effectiveness of erythromycin prophylaxis to prevent pertussis within families. Pediatr Infect Dis J 1995;14:969 –75. 15. Halperin SA, Bortolussi R, Langley JM, Eastwood BJ, De SG. A randomized, placebo-controlled trial of erythromycin estolate chemoprophylaxis for household contacts of children with culture-positive Bordetella pertussis infection. Pediatrics 1999;104:e42. 16. Hewlett EL, Edwards KM. Clinical practice. Pertussis—not just for kids. N Engl J Med 2005;24;352:1215–22. 17. Marchant CD, Loughlin AM, Lett SM, et al. Pertussis in Massachusetts, 1981–1991: incidence, serologic diagnosis, and vaccine effectiveness. J Infect Dis 1994;169:1297–305. 18. Baughman AL, Bisgard KM, Edwards KM, et al. Establishment of diagnostic cutoff points for levels of serum antibodies to pertussis toxin, filamentous hemagglutinin, and fimbriae in adolescents and adults in the United States. Clin Diagn Lab Immunol 2004;11:1045–53. 19. Strebel P, Nordin J, Edwards K, et al. Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995–1996. J Infect Dis 2001;183:1353–9. 20. Ward JI, Cherry JD, Chang SJ, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005;353:1555– 63. 21. Tanaka M, Vitek CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis among infants in the United States, 1980 –1999. JAMA 2003; 290:2968 –75. 22. Wharton M SP. National surveillance of vaccine-preventable diseases. Manual for the surveillance of vaccine-preventable diseases, 3rd ed. Atlanta GA: Centers for Disease Control and Prevention; 2006. 23. Cherry JD. The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection. Pediatrics 2005;115:1422–7. 24. Wendelboe AM, Van RA, Salmaso S, Englund JA. Duration of immunity against pertussis after natural infection or vaccination. Pediatr Infect Dis J 2005;24(5 Suppl):S58 – 61. 25. Edwards KM. Overview of pertussis: focus on epidemiology, sources of infection, and long-term protection after infant vaccination. Pediatr Infect Dis J 2005;24(6 Suppl):S104 – 8. 26. Aoyama T, Takeuchi Y, Goto A, Iwai H, Murase Y, Iwata T. Pertussis in adults. Am J Dis Child 1992;146:163– 6. 27. Schmitt-Grohe S, Cherry JD, Heininger U, Uberall MA, Pineda E, Stehr K. Pertussis in German adults. Clin Infect Dis 1995;21:860 – 6. 28. Wirsing von Konig CH, Postels-Multani S, Bock HL, Schmitt HJ. Pertussis in adults: frequency of transmission after household exposure. Lancet 1995; 346:1326 –9. 29. De Serres G, Shadmani R, Duval B, Boulianne N, Dery P, Douville FM. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000; 182:174 –9. 30. Lee GM, Lett S, Schauer S, et al. Societal costs and morbidity of pertussis in adolescents and adults. Clin Infect Dis 2004;39:1572– 80. 31. Thomas PF, McIntyre PB, Jalaludin BB. Survey of pertussis morbidity in adults in western Sydney. Med J Aust 2000;173:74 – 6. 32. Trollfors B, Rabo E. Whooping cough in adults. Br Med J (Clin Res Ed) 1981;283:696 –7. 33. Jenkins P, Clarke SW. Cough syncope: a complication of adult whooping cough. Br J Dis Chest 1981;75:311–3. 34. Wright SW. Pertussis infection in adults. South Med J 1998;91:702– 8. 35. Postels-Multani S, Schmitt HJ, Wirsing von Konig CH, Bock HL, Bogaerts H. Symptoms and complications of pertussis in adults. Infection 1995; 23:139 – 42. 36. Shvartzman P, Mader R, Stopler T. Herniated lumbar disc associated with pertussis. J Fam Pract 1989;28:224 –5. 37. MacLean DW. Adults with pertussis. J R Coll Gen Pract 1982;32:298 –300. 38. Skowronski DM, Buxton JA, Hestrin M, Keyes RD, Lynch K, Halperin SA. Carotid artery dissection as a possible severe complication of pertussis in an adult: clinical case report and review. Clin Infect Dis 2003;36:e1– 4. 39. Halperin SA, Marrie TJ. Pertussis encephalopathy in an adult: case report and review. Rev Infect Dis 1991;13:1043–7. 40. Eidlitz-Markus T, Zeharia A. Bordetella pertussis as a trigger of migraine without aura. Pediatr Neurol 2005;33:283– 4.

American Journal of Preventive Medicine, Volume 32, Number 3

www.ajpm-online.net

41. CDC. Fatal case of unsuspected pertussis diagnosed from a blood culture— Minnesota, 2003. MMWR Morb Mortal Wkly Rep 2004;53:131–2. 42. Vitek CR, Pascual FB, Baughman AL, Murphy TV. Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis J 2003;22:628 –34. 43. Schellekens J, von Konig CH, Gardner P. Pertussis sources of infection and routes of transmission in the vaccination era. Pediatr Infect Dis J 2005; 24(5 Suppl):S19 –24. 44. Mertens PL, Stals FS, Schellekens JF, Houben AW, Huisman J. An epidemic of pertussis among elderly people in a religious institution in The Netherlands. Eur J Clin Microbiol Infect Dis 1999;18:242–7. 45. Nennig ME, Shinefield HR, Edwards KM, Black SB, Fireman BH. Prevalence and incidence of adult pertussis in an urban population. JAMA 1996;275:1672– 4. 46. Mink CM, Cherry JD, Christenson P, et al. A search for Bordetella pertussis infection in university students. Clin Infect Dis 1992;14:464 –71. 47. Jansen DL, Gray GC, Putnam SD, Lynn F, Meade BD. Evaluation of pertussis in U.S. Marine Corps trainees. Clin Infect Dis 1997;25:1099 –107. 48. Wright SW, Edwards KM, Decker MD, Zeldin MH. Pertussis infection in adults with persistent cough. JAMA 1995;273:1044 – 6. 49. Van Rie A, Hethcote HW. Adolescent and adult pertussis vaccination: computer simulations of five new strategies. Vaccine 2004;22:3154 – 65. 50. Halasa NB, Barr FE, Johnson JE, Edwards KM. Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal membrane oxygenation have a role? Pediatrics 2003;112(6 Pt 1):1274 – 8. 51. Smith C, Vyas H. Early infantile pertussis; increasingly prevalent and potentially fatal. Eur J Pediatr 2000;159:898 –900. 52. Williams GD, Numa A, Sokol J, Tobias V, Duffy BJ. ECLS in pertussis: does it have a role? Intensive Care Med 1998;24:1089 –92. 53. Crowcroft NS, Booy R, Harrison T, et al. Severe and unrecognised: pertussis in UK infants. Arch Dis Child 2003;88:802– 6. 54. Bisgard KM, Pascual FB, Ehresmann KR, et al. Infant pertussis: who was the source? Pediatr Infect Dis J 2004;23:985–9. 55. Nelson JD. The changing epidemiology of pertussis in young infants: the role of adults as reservoirs of infection. Am J Dis Child 1978;132:371–3. 56. Izurieta HS, Kenyon TA, Strebel PM, Baughman AL, Shulman ST, Wharton M. Risk factors for pertussis in young infants during an outbreak in Chicago in 1993. Clin Infect Dis 1996;22:503–7. 57. Elliott E, McIntyre P, Ridley G, et al. National study of infants hospitalized with pertussis in the acellular vaccine era. Pediatr Infect Dis J 2004; 23:246 –52.

March 2007

58. Keitel WA, Edwards KM. Pertussis in adolescents and adults: time to reimmunize? Semin Respir Infect 1995;10:51–7. 59. Keitel WA. Cellular and acellular pertussis vaccines in adults. Clin Infect Dis 1999;28(Suppl 2):S118 –23. 60. Orenstein WA. Pertussis in adults: epidemiology, signs, symptoms, and implications for vaccination. Clin Infect Dis 1999;28(Suppl 2):S147–50. 61. Food and Drug Administration. Sanofi pasteur. ADACEL briefing document. Bethesda MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologic Evaluation and Research. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/ 2005– 4097B1_6.pdf (Accessed March 15, 2005). 62. Food and Drug Administration. GlaxoSmithKline (GSK) Biologicals. BOOSTRIX briefing document. Bethesda MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologic Evaluation and Research. Available at: http://www.fda.gov.ohrms/ac/05/ briefing/2005– 4097B1_3.pdf (Accessed March 15, 2005). 63. Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. JAMA 2005;293:3003–11. 64. Le T, Cherry JD, Chang SJ, et al. Immune responses and antibody decay after immunization of adolescents and adults with an acellular pertussis vaccine: the APERT Study. J Infect Dis 2004;190:535– 44. 65. McIntyre PB, Turnbull FM, Egan AM, Burgess MA, Wolter JM, Schuerman LM. High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria–tetanus–acellular pertussis vaccine. Vaccine 2004;23:380 –5. 66. Lee GM, Murphy TV, Lett S, et al. Cost-effectiveness of pertussis vaccination in adults. Am J Prev Med 2007;32. 67. Lee GM, LeBaron C, Murphy TV, Lett S, Schauer S, Lieu TA. Pertussis in adolescents and adults: should we vaccinate? Pediatrics 2005;115:1675– 84. 68. Purdy KW, Hay JW, Botteman MF, Ward JI. Evaluation of strategies for use of acellular pertussis vaccine in adolescents and adults: a cost– benefit analysis. Clin Infect Dis 2004;39:20 – 8. 69. Halperin SA, Sweet L, Baxendale D, et al. How soon after a prior tetanus– diphtheria vaccination can one give adult formulation tetanus– diphtheria–acellular pertussis vaccine? Pediatr Infect Dis J 2006;25: 195–200. 70. Prevention of tetanus, diphtheria and pertussis among pregnant women: provisional ACIP recommendations for the use of Tdap vaccine. Available at: http://www.cdc.gov/nip/recs/provisional_recs/tdap-preg. pdf.

Am J Prev Med 2007;32(3)

185

Appendix A—Clinical characteristics and complications in adults with pertussis (percent with characteristic) Massachusetts1 U.S. without Massachusetts

Data source Age (years) No. Cases Year Paroxysmal cough Difficulty sleeping Difficulty breathing Post-tussive vomiting Whoop Apnea Weight loss Urinary incontinence Pneumonia Hospitalization

19–64 18,243a 1996–2004 89 — — 45 37 32 — — 3c 3

Rib fracture Loss of consciousness Seizure

— — 0.6

ⱖ65 984b 1996–2004 86 — — 27 33 32 — — 8c 12

Cohort 1

Cohort 2

Quebec, Canada2

Sweden3

Australia4

ⱖ18 936 2001–2003 86 — — 47 41 44 — —

ⱖ18 203 1998–2000 84 84 86 54 — — 33 28

ⱖ18 384 1998 99

ⱖ20 155 1976–1978 — — — 50 82 — — —

ⱖ8 73 1997–1998 82 84 — 62 45 — 33 —

2 3

5 —

— —

— —

0.2

0.3

4 6 —

— — 61 70 85 3 (34% in women ⱖ50 years) 5 2 (6% in ⱖ50 years) (4% in women) 3 0

0.60 2

5 0

1 0

0

0

0

—

*Pertussis cases reported by states as confirmed or probable; NETSS and SPSS, CDC, 2006. CDC and CSTE (Council of State and Territorial Epidemiologists) pertussis case definition: clinical case: a cough illness lasting at least 2 weeks with one of the following: paroxysms of coughing, inspiratory “whoop,” or post-tussive vomiting, and without other apparent cause (as reported by a healthcare professional). Laboratory criteria for diagnosis: isolation of B. pertussis from a clinical specimen or positive PCR assay for B. pertussis. Confirmed case: an acute cough illness of any duration with B. pertussis isolation, or a case that meets the clinical case definition and is confirmed by PCR, or a case that meets the clinical definition and is epidemiologically linked directly to a case confirmed by culture or PCR. Probable case: a case that meets the clinical case definition, is not laboratory confirmed by culture or PCR, and is not epidemiologically linked directly to a laboratory-confirmed case. a Percent based on reports with data available. Percent of total reports with data missing for the following characteristics: paroxysmal cough 13%, vomiting 14%, whoop 17%, apnea 17%, pneumonia 23%, hospitalization 16%, seizure 16%. b Percent based on reports with data available. Percent of total reports with data missing for the following characteristics: paroxysmal cough 15%, vomiting 17%, whoop 19%, apnea 19%, pneumonia 25%, hospitalization 18%, seizure 18%. c Radiographically confirmed. — ⫽ not available.

Appendix B—Cough duration in adults with pertussis

Cough ⱖ3 weeks Median (range), weeks

Massachusetts nⴝ620a

Quebec, Canada2 nⴝ384

96%d 16e (––,––)

97% 12f (––, ––)

Sweden3 nⴝ155b

Germany5 nⴝ79

United Kingdom6 nⴝ77

Australia4 nⴝ63c

–– 8 (2–26)

80% 7 (––, 32)

100% ––g (3–32)

–– 8.6 (0.5–21)

a

Lab confirmed: 569 (92%) MA serology; 54 (9%) culture; 3 (0.5%) PCR. Data from MDPH, 2006. Patients with late or no erythromycin treatment. Cases for which cough had resolved by time of final interview. d Kaplan–Meier estimate, CDC, 2006. e Kaplan–Meier estimate: 53% still coughing at 16 weeks, which was longest cough duration among the 107 (17%) of cases who had stopped coughing by last interview. CDC, 2006. f Mean; 55% with cough ⬎9 weeks. g 47% with cough ⱖ6 weeks. — ⫽ not available. b c

Appendix References 1. Lee GM, Lett S, Schauer S, et al. Societal costs and morbidity of pertussis in adolescents and adults. Clin Infect Dis 2004;9:1572– 80. 2. De Serres G, Shadmani R, Duval B, Boulianne N, Dery P, Douville FM. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000;182:174 –9. 3. Trollfors B, Rabo E. Whooping cough in adults. Br Med J (Clin Res Ed) 1981;283:696 –7.

185.e1

4. Thomas PF, McIntyre PB, Jalaludin BB. Survey of pertussis morbidity in adults in western Sydney. Med J Aust 2000;173:74 – 6. 5. Postels-Multani S, Schmitt HJ, Wirsing von Konig CH, Bock HL, Bogaerts H. Symptoms and complications of pertussis in adults. Infection 1995;3: 139 – 42. 6. MacLean DW. Adults with pertussis. J R Coll Gen Pract 1982;32:298 – 300.

American Journal of Preventive Medicine, Volume 32, Number 3