Rising to the challenge of pertussis persistence

Unimmunized infants are at greatest risk for the potentially serious, even fatal, complications of this disease. New prevention measures are available.

In 1976, when 1,010 cases of pertussis were reported to the Centers for Disease Control and Prevention (CDC), it was the lowest annual total ever recorded.1 By 2004, however, that number had risen to more than 25,000—the highest level since 1959 (when a first-class stamp cost 4 cents). More than one third of the cases (38%) in 2004 occurred among adolescents 10 to 19 years of age.2,3 The actual number of pertussis cases is believed to be much higher, from 800,000 to upwards of 3 million cases a year in the United States, based on studies evaluating the percentage of all cough illness that is traceable to Bordetella pertussis.4,5

Infections with B. pertussis may be overlooked in some adults because the symptoms can be relatively mild. Or, classic symptoms of pertussis may go unrecognized, possibly because patients and clinicians think of pertussis as strictly a pediatric infection. Our goal in this article is to explore what’s behind the recent upsurge in reported pertussis cases and the shifting demographics of this disease, with an emphasis on exploring newly available means of prevention.

KEY CLINICAL FEATURES OF B. PERTUSSIS INFECTION

B. pertussis is a gram-negative coccobacillary organism that preferentially attaches to ciliated epithelial cells in the nasopharynx. It then elaborates a number of toxins that are absorbed and cause the characteristic and persistent pertussis cough. Over the past two decades, increases in reported cases of this infection have been noted in both adolescents and adults, in part because of our ability to perform serologic testing in coughing individuals. Serologic testing for B. pertussis was pioneered by the Massachusetts State Laboratory Institute.

Public health officials in Massachusetts have provided this testing for years, generating useful data on the occurrence of pertussis in the population. In addition to the spike in cases among adults and teens, increases in pertussis infection have also been observed in infants too young to be vaccinated, generally those younger than 2 months. Some of these infections in infants have been fatal.

The classic presentation

Three stages characterize the illness: catarrhal, paroxysmal, and convalescent. The catarrhal phase, which lasts approximately 7 to 10 days, is characterized by sneezing and rhinorrhea, symptoms that are indistinguishable from those of a common cold. In the latter part of the catarrhal phase, a mild cough begins. The cough progresses to a paroxysmal form with severe spasms and thick, tenacious mucus. The characteristic whoop also develops, occurring as the patient attempts to inspire against a closed glottis. Patients may experience posttussive vomiting and are often deeply exhausted. The paroxysmal stage may last six weeks or more. Gradual recovery occurs during the convalescent phase, with less frequent and less severe coughing over the course of a month or longer.

Pertussis has been called the “100-day cough,” and many patients may, in fact, have a cough for a protracted period. The cough may become severe again in patients who experience another viral upper respiratory infection during the convalescent period.

B. pertussis infection is highly contagious and is transmitted by respiratory droplets. During the catarrhal phase of illness, the nasopharynx teems with organisms. Secondary attack rates are at least 80% and may be as high as 100%.6 The incubation period is generally between 7 to 10 days with a range of 4 to 21 days. Communicability is highest during the late catarrhal and early paroxysmal phases. Thus, transmission often takes place well before the cough illness is recognized as pertussis (if it is recognized at all). B. pertussis organisms are no longer detectable in the nasopharynx approximately three weeks after the cough develops.7

B. pertussis in adolescents and adults

Many manifestations of pertussis in adolescents and adults are similar to those seen in young children.8 Cough for up to three weeks is almost a universal finding. More than half of teens and adults cough for more than nine weeks. Paroxysms occur in 73%, whooping in approximately 70%, and posttussive emesis in 65%. Teens miss an average of five days of school, and adults miss an average of seven days of work. Disrupted sleep continues for days, and many clinician visits take place for an illness that is often incorrectly diagnosed.8

Complications develop in nearly 16% of adolescents and more than 25% of adults.8 The spectrum of complications can include pneumonia, which is seen in about 2% of those aged 30 years and younger and in 5% to 9% of those over 30. Approximately 2% of those younger than 50 require hospitalization, compared with about 6% of patients aged 50 and older.8 Other reported complications include urinary incontinence (in as many as one third of women aged 50 or older), sinusitis, and otitis media.8

THE CHANGING EPIDEMIOLOGY OF PERTUSSIS

Reported rates of pertussis substantially declined in the United States as DTP vaccination of children increased, beginning in the late 1940s. The dramatic results of this vaccine effort are shown in Figure 1, which displays pertussis rates spanning the period 1922 to 2000.9 As noted, the lowest reported infection rates occurred in 1976. Rates climbed slowly in the 1980s and early 1990s and then accelerated sharply around the year 2000, topping 11,000 in 2003 and more than doubling, to 25,827, in 2004, a 45-year high (Figure 2).2,9-14 The increases in pertussis reports have occurred in all age groups, but the most dramatic changes have taken place among adolescents and adults, as shown in Figure 3.2,9,10,14, 15, 17 In comparing the single year 2004 to the period 1990-1993, the increase in reported pertussis cases approaches 20-fold in adolescents and is more than 15-fold among adults 20 years of age or older.

The recent surge in pertussis case reports is sometimes mistakenly attributed to wide use of the acellular vaccine. The older, whole-cell vaccine enjoyed a reputation for high efficacy at the cost of frequent side effects. But data gathered during an outbreak in Michigan in the 1960s cast doubt on the theory that the whole-cell vaccine provides longer-lasting immunity than acellular preparations.18 All subjects in this study had received whole-cell vaccine. The pertussis attack rate among people who had been vaccinated within the previous one to three years was 21%, compared with 95% among those who had received the vaccine 12 or more years earlier.18

FIGURE 3. Reports of pertussis in the United States, by age


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These and other data suggest that the whole-cell and acellular vaccines and even natural pertussis disease do not induce lifelong immunity.

Pertussis rates in adolescents and adults

Until recently, a child’s final pertussis vaccine was administered between 4 and 6 years of age. It appears that when this schedule is used, B. pertussis immunity reaches a nadir by adolescence. Studies conducted in Massachusetts, with its widespread serologic testing, have shown that many outbreaks occur in schools. In studies from around the world, 12% to 50% of people who have had a cough persisting for 7 to 14 days have shown evidence of current B. pertussis infection.4,19-20 Based on multiple studies, an estimated 800,000 to 3.3 million adolescent and adult cases of pertussis occur in this country every year.4

Another estimate of the prevalence of pertussis in the adolescent and adult populations comes from investigators working with physicians at a Kaiser facility in northern California. They determined the prevalence of pertussis infection among 153 adults who sought medical help because of a cough of more than two weeks’ duration.19 In this population, 12.4% had elevated antibody titers to B. pertussis. Extrapolating this figure to patients participating in Kaiser programs, the authors estimated the incidence of pertussis causing cough illness at 176 per 100,000, making pertussis as common as peptic ulcer disease in this population.19

In a similar study, researchers obtained serologies in teen and adult patients (aged 10 to 49 years) with persistent cough at an HMO in Minnesota. Approximately one in eight patients (27 of 212, 13%) had at least one positive test for pertussis; the median duration of cough in these patients was six weeks.21 The incidence of pertussis in this population was 507 cases per 100,000 person-years, but the attack rate was even higher among teenagers, in the range of more than 1,000 per 100,000, or approximately 1% of that population.21 A number of adolescent outbreaks have been reported among schoolmates, friends, and families.22

A recent efficacy study of an acellular pertussis vaccine for adolescents and adults also provides estimates of pertussis incidence.5 The study included 2,781 people aged 15 to 65 years, who were followed for a median of 22 months. Half of them received an acellular pertussis vaccine and the other half received a control (hepatitis A) vaccine. Nasopharyngeal aspirate culture and polymerase chain reaction assays along with serological tests were performed in any subject who had an illness with cough lasting more than five days. Among subjects who received the control hepatitis A vaccine, the pertussis incidence was in the range of 370 to 450 cases per 100,000 person-years.5 Extrapolating to the entire U.S. population suggests that almost 1 million cases of pertussis occur in persons 15 years of age or older each year. If probable, but not confirmed, cases are included, the total runs to more than 800,000. All possible cases might exceed 1.5 million.

Infants: vulnerable and unprotected

Rates of reported pertussis in infants have increased during the past 20 years. The trend has been especially marked in those 1 to 3 months of age, who are too young to have been vaccinated. The situation is of particular concern because these infants are highly susceptible to complications and hospitalization. Pertussis-related death rates in these youngest patients are significantly higher than in older patients.

According to the CDC, between 1997 and 2000 more than 4,500 infants younger than 6 months of age were admitted to the hospital for complications of pertussis.9 Over the four years reviewed, the spectrum of complications included nearly 850 cases of pneumonia, over 100 cases of seizures, 15 cases of encephalopathy, and 56 deaths.

Data from the same CDC study show that the number of hospitalizations in children aged 6 to 11 months caused by pertussis-related pneumonia, seizures, and encephalitis is much lower than in very young infants.9 The difference in complication and hospitalization rates between younger and older infants is probably attributable to vaccination of the older ones.

Pertussis hospitalization rates in infants younger than 6 months show no signs of diminishing. In fact, the pertussis hospitalization rate for these infants has actually increased, from 64.7 per 100,000 births (1994 to 1998) to 77.9 per 100,000 (1999 to 2003), a jump of 20%.23 Pertussis-associated deaths among young infants have also increased, a burden borne mostly by infants too young to have been protected by vaccination. As shown in Figure 4, projections suggest that if no steps are taken to change the current situation, pertussis- associated death rates for the period 2000-2009 will be higher than in the two previous decades, especially among infants aged 3 months and younger.24,25

Sources of infection in infants

Changing the course of these pertussis projections is essential. A key step is learning how B. pertussis infection is transmitted to these infants. A study conducted among children younger than 4 years of age who presented as index cases and were hospitalized at UCLA Medical Center revealed that more than 50% of the contacts of these children were older than 13 years of age.26 More than half of the people who transmitted the infection to the babies were adolescents and adults.26 Other risk factors for pertussis in infants too young for vaccination include maternal age 15 to 19 years (odds ratio 7) and maternal cough (odds ratio, 13).27 Living with other children younger than age 5 is notably not a risk factor for pertussis in young infants, further supporting the role of teens and adults in transmission.27

In another study conducted under the auspices of the CDC, investigators found a known or suspected source of infant pertussis in 264 of 616 cases (Figure 5).28 Suspected or known sources included the mother (32%), father (15%), siblings (20%), grandparents (8%), and others (25%).28

The important lesson here is that people who live with the infant are the likely source of pertussis in at least half of cases in which a known or suspected source is identified.

Health-care professionals are often involved in the transmission of pertussis; a number of outbreaks among physicians and nurses have been reported through the years.29 In some cases, infants with pertussis transmit the infection to physicians or nurses, who in turn transmit it to other health-care professionals and other infants. This underscores the importance of health-care professionals maintaining up-to-date vaccination status.

ADVANCING PERTUSSIS CONTROL BY EXPANDING IMMUNIZATION

The discovery of B. pertussis as the causative agent of pertussis in 1906 was the huge first step in controlling this serious and sometimes fatal infection. Whole-cell pertussis vaccines were combined with diphtheria and tetanus toxoids and routinely administered to children starting in the late 1940s, with excellent results. The number of annual reported cases dropped from hundreds of thousands of cases to just thousands. It is now clear, however, that much work remains to be done before this infection is adequately controlled.

Many different active antigens and virulence factors are associated with B. pertussis, including pertussis toxin (lymphocytosis-promoting factor), filamentous hemagglutinin, pertactin (69-kilodalton protein), and fimbrial agglutinogens. Pertussis toxins probably protect B. pertussis from the host’s white blood cell or other immune responses. Filamentous hemagglutinin, pertactin, and the fimbrial agglutinogens help the organism attach to respiratory epithelial cells. These and other components of B. pertussis have been harvested, purified, and combined into various vaccines.

Three diphtheria, tetanus, and acellular pertussis (DTaP) vaccines are currently available in the United States: Tripedia® vaccine, Infanrix® vaccine*, and Daptacel® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). These vaccine products differ according to the number and quantity of antigenic components (two pertussis antigens for Tripedia, three for Infanrix, and five for Daptacel vaccine). The vaccines have comparable efficacy overall, with Daptacel vaccine showing somewhat greater efficacy in preventing pertussis illness of short duration.30,31

Pertussis vaccines for adolescents and adults

In light of the increase in pertussis cases among adolescents and adults and the suspected role of these patients in spreading the infection to very young, often unimmunized infants, the spotlight has shifted to developing effective vaccines for older age groups. In 2005, two such vaccines were licensed by the FDA: Boostrix®, indicated for adolescents aged 10 to 18 years; and Adacel vaccine, indicated for adolescents and adults aged 11 to 64 years. Both are known as Tdap vaccines (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed), although amounts of specific antigens in those vaccines vary.

Boostrix contains three pertussis components, while Adacel vaccine has five pertussis components. A comparison of the antigenic components of the vaccines is shown in Table 1.

TABLE 1. Antigenic components of diphtheria, tetanus, and acellular pertussis vaccines


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Boostrix contains the same components as Infanrix vaccine, produced by the same manufacturer. The quantities of diphtheria antigens and acellular pertussis components are lower in Boostrix than Infanrix, however, as is appropriate for the older age groups.

In the clinical trials among adolescents that led to the licensing of Boostrix, the comparison vaccine was Td vaccine. The two vaccines had very similar rates of local reactions (injection-site pain, swelling, erythema) and systemic reactions (headache, fever, fatigue, GI symptoms).32 The two vaccines produced apparently equivalent immune responses against tetanus and diphtheria. Boostrix produced immune responses against B. pertussis that ranged from two to seven times higher than that obtained in infants given three doses of Infanrix in previous efficacy trials.32

Adacel vaccine is based on the manufacturer’s infant and childhood Daptacel vaccine. Adacel vaccine has lower levels of pertussis and diphtheria toxoids than Daptacel vaccine, as is appropriate for the older age groups. In clinical trials, Adacel vaccine was compared to Td vaccine not only in adolescents, but also in adults.33,34

The results of the pivotal trial leading to licensure of Adacel vaccine were published in the Journal of the American Medical Association in June 2005.34 This was a prospective, randomized, modified double-blind, comparative trial conducted in more than 4,400 people aged 11 to 64 years at 39 sites in the United States. Participants were randomized to receive Adacel vaccine or Td vaccine, and antibody titers to diphtheria and tetanus toxoids were measured before vaccination and 28 days afterward. Pertussis antibody titers were assessed and compared with titers in infants who had received the analogous pediatric vaccine, Daptacel vaccine, in previous clinical trials.

Protective antibody concentrations against diphtheria and tetanus were achieved in 94% and 100% of participants, respectively. Antibody titers to the B. pertussis components pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3 were 2.1 to 5.4 times higher in the adolescent and adult subjects in this study than in infants who had received Daptacel vaccine at 2, 4, and 6 months of age. The incidence of local and systemic reactions was similar in the Td vaccine and Adacel vaccine groups, with the exception of slightly more injection-site pain in Adacel vaccine recipients.34

Adolescent and adult immunization: The Canadian experience

Experience with Tdap vaccine in Canada over the past decade offers some insight into its effectiveness in preventing pertussis disease. Health authorities in Canada’s Northwest Territories maintain an excellent pertussis surveillance program, which revealed high rates of the infection in the early 1990s, particularly among toddlers and school-aged children.

In 1997, health officials switched from using a whole-cell vaccine to a combination vaccine called Pentacel® (Haemophilus b Conjugate Vaccine [Tetanus Protein-Conjugate] Reconstituted with Component Pertussis Vaccine and Diphtheria and Tetanus Toxoids Adsorbed Combined with Inactivated Poliomyelitis vaccine). The use of Pentacel vaccine was associated with lower rates of pertussis among young children, but rates remained high among teens, adults, and very young infants.35

Starting in late 2000, Canadian health officials began using Adacel vaccine in adolescents, and pertussis rates dropped precipitously, as illustrated in Figure 6.35

Similar results were reported in Newfoundland, where large pertussis outbreaks occurred in the mid 1990s.36 When Adacel vaccine became commercially available in Canada, it replaced a Td vaccine that had been used in school-based vaccination programs for 14-year-olds throughout Newfoundland.

Rates of pertussis declined markedly in subsequent years until another outbreak occurred in 2003.36 Importantly, none of the teens aged 14 through 17 who had received Adacel vaccine in previous years, during the routine vaccination of 14-year-olds, became ill with pertussis during the 2003 outbreak. The disease was confined to 10- to 14-year-olds who had not yet received Adacel vaccine.36 Vaccination efforts were not broad enough to stop pertussis transmission completely, and adults and small infants continue to become infected in Newfoundland. Pertussis levels are much lower, however.36

Vaccine timing

The Advisory Committee on Immunization Practices (ACIP) encourages an interval of five years between Tdap vaccine and a previous tetanus and diphtheria toxoid-containing vaccine (Td/DT). ACIP also notes, however, that shorter intervals are acceptable, in view of recent reports from Canada. The investigators sought to determine how soon Tdap vaccine could be administered after a previous Td/DT vaccination without causing significant adverse events.37

In this study, conducted on Prince Edward Island, Tdap vaccine was offered in schools to all children in grades three through 12. Participants had documentation of previous Td/DT vaccine. Reactogenicity was compared in more than 7,000 children who received Tdap vaccine at intervals ranging from 18 months to 9 years after a previous Td/DT vaccine and in those who received Td/DT vaccine 10 or more years earlier. No whole-limb swelling, Arthus-type reactions, or other serious events related to vaccine administration were reported in any of the vaccine recipients. The investigators found no clinically important differences in reactogenicity among the vaccinees and concluded that Tdap vaccine could be safely administered 18 months or more after a previous Td/DT immunization.37

ACIP recommendations for Tdap vaccine used in adults and adolescents

Current ACIP recommendations

Following licensure of the Tdap vaccines in the spring of 2005, ACIP deliberated recommendations for their use in adolescents and adults at its next three meetings (see the box on page 71).38,39 Tdap vaccine is now recommended for all youngsters at 11-12 years of age (or later in adolescence if they don’t receive it at 11-12). To replace an adult’s next booster dose of Td vaccine, ACIP recommends a single dose of Tdap vaccine for adults aged 19-64 years. The vaccine is also recommended for any adults who have close contact with infants less than 1 year of age. Women are encouraged to obtain a dose of Tdap vaccine before becoming pregnant to reduce the risk of transmission to a newborn. Women who have not received Tdap vaccine prior to giving birth are encouraged to receive it in the immediate postpartum period.

ACIP also recommended that all health-care personnel receive Tdap vaccine “as soon as feasible” to prevent transmission of the infection to susceptible infants.39 Health-care personnel are more likely than other adults to become infected and to transmit B. pertussis to others.

In conclusion

Pertussis remains a challenge in 2007 and will remain one in the immediate future. The newly licensed Tdap vaccines have a demonstrated ability to produce excellent protection against tetanus, diphtheria, and pertussis. In addition, it now seems clear that Tdap vaccine can be given much sooner after a previous tetanus and diphtheria toxoid-containing vaccine than previously recognized without any clinically important increase in adverse events. Patients who are immunized with Tdap vaccine sooner rather than later are likely to be better protected from pertussis themselves and are less likely to transmit the infections to others.

Kathryn M. Edwards, MD, is Professor of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tenn. David R. Johnson, MD, MPH, is Director, Scientific and Medical Affairs, Sanofi Pasteur Inc, Swiftwater, Pa.

References

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21. Strebel P, Nordin J, Edwards K, et al. Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995-1996. J Infect Dis. 2001;183:1353-1359.

22. Greenberg DP. Pertussis in adolescents: increasing incidence brings attention to the need for booster immunization of adolescents. Pediatr Infect Dis J. 2005;24:721-728.

23. CDC. QuickStats from the National Center for Health Statistics. MMWR. 2005;54:1027.

24. 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;22:628-634.

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31. Greco D, Salmaso S, Mastrantonio P, et al for the Progetto Pertosse Working Group. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med. 1996;334:341-348.

32. BOOSTRIX Prescribing Information. GlaxoSmithKline, Research Triangle Park, NC. March 2006.

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34. Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. JAMA. 2005;293:3003-3011.

35. Kandola K, Lea A, White W, et al. A comparison of pertussis rates in the Northwest Territories: Pre- and post-acellular pertussis vaccine introduction in children and adolescents. Can J Infect Dis Med Microbiol. 2005;16:271-274.

36. CCDR Notifiable Disease Annual Summaries. Pertussis in Newfoundland and Labrador: 1991-2004. CCDR. 2005;31(22):15.

37. 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.

38. CDC. 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. 2006;55(RR-03):1-44.

39. CDC. Preventing tetanus, diphtheria, and pertussis among adults: Use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2006;55(RR-17):1-44.

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