TABLE 1 Pertussis characteristics in adults, 1998-2003

What do the excellent data from Massachusetts tell us about pertussis in adults and adolescents (see Table 1)? All of these patients had cough, and 48 days after the onset of the illness, 83% of them were still coughing.³ Half of them vomited in association with their cough, and some had spells of apnea. Some had the classic whoop, that intake of breath characteristic of pertussis, though not as severe as it is in children. Others had periods of cyanosis and even seizures. Complications included sleep problems in 84% and weight loss in about one third because the cough keeps people from sitting down and completing meals. Urinary incontinence among women was common, and a few patients had conjunctival hemorrhages, syncope, and cough fractures. Clearly, this is not a benign illness.

How frequently does pertussis occur in teens and adults? A number of population-based studies have been conducted, with varying findings. Pertussis goes through cycles. You may observe a higher or lower incidence, depending on the population you are studying. We have incidence estimates in the United States that range from trivial to very high. Dr Joel Ward, who has done the most elaborate study, has found some of the highest incidence rates and suggests that 0.5% of adults in the United States have symptomatic pertussis annually. That is a lot of adults.⁴ State and local health departments are struggling with outbreaks of pertussis that are occurring with increasing frequency and have had to redirect their resources to outbreak management.

We have a newly licensed vaccine for use in adolescents and adults, Tdap, which combines the full dose of the tetanus vaccine with slightly reduced doses of diphtheria and acellular pertussis vaccines. The goals are both to provide individual protection and to reduce community outbreaks.

When we protect teens and adults, we're also protecting very young infants from pertussis. Despite our attention to the appropriate immunization of infants, some remain vulnerable because they are too young to start their immunizations or because their immunizations must be delayed for one reason or another. Others remain vulnerable simply because they are exposed to the pathogen before they've completed the vaccine series. Often, a parent, sibling, or babysitter brings the Bordetella pertussis organism into the household. According to the best estimates, about 20 infants in the United States die of pertussis each year because they are inadequately immunized or were exposed before they were old enough to be immunized.¹ Members of the pediatric and family practice communities are determined to eliminate those deaths. Pertussis also has been introduced into hospitals, and we are investigating better ways of protecting health care workers.

Adacel and Boostrix, Tdap vaccines from different manufacturers, have been licensed for use as a single-dose booster. Adacel is approved for people aged 11 to 64, and Boostrix is approved for those aged 10 to 18. We anticipate that in due course the FDA will approve them for regular boosting at the conventional 10-year intervals.

The ACIP has recommended that Tdap replace the tetanus/diphtheria (Td) vaccine at the preadolescent visit and also be used at the next decennial immunization. Because the manufacturers have chosen not to market a pertussis-only acellular vaccine, we're currently faced with an important question: If children and adults have already received Td vaccine, how long should we wait before administering Tdap? We would like to boost population immunity to pertussis as much as possible, as soon as possible.

When should we do that? This has been the source of substantial debate. The prevailing notion is if patients have had Td and 5 years have passed, it is safe to give Tdap. But what is the best approach if your community has been hit by a pertussis outbreak? The ACIP says that if 18 months have elapsed since administration of Td, it is safe to give Tdap and not expect much of a reaction at the injection site. The issue is safety, not efficacy.

How should we proceed with selected subgroups? This is another source of debate. If infants are the subgroup of interest, you should think about immunizing everyone who has contact with those infants. This strategy is commonly called cocooning; the immunized people form a safety cocoon around that infant. Questions arise, however, when we think about logistics. Who should conduct the immunization? The pediatrician? How do we get the pediatrician to immunize adults? Is it the obstetrician? The obstetrician sees mom but not dad. Family physicians are in the best position to accomplish this cocooning strategy, but not all family members are their patients, and general internists need to do their part.

The ACIP is currently conducting a survey of US hospitals to assess the impact that pertussis is having on hospital employee health. In our hospital, pertussis has become the single most important infectious disease exposure (other than needlesticks), and these exposures involve a lot of investigative work.⁵ We have to determine who was exposed. We have to contact all of these people and determine whether they are candidates for antibiotic prophylaxis. This has become a regular activity of our occupational health service. We hope that the ACIP survey will tell us exactly how common these hospital-based pertussis events are and how frequently these exposures result in transmission. If the results of the survey suggest that this is a big problem, the ACIP will make recommendations for pertussis immunization of all or subsets of health care workers.

Q. Are humans the only reservoirs, and can adults become asymptomatic carriers?

Dr Schaffner: Humans are the only reservoir for B pertussis. The established notion is that the pathogen is not carried asymptomatically. If you acquire infection, you will get some degree of invasive illness and some degree of cough. I've never been 100% convinced that this is correct. This organism remains in the population, and perhaps it does circulate asymptomatically.

Q. What does the vaccine cost?

Dr. Schaffner: For children, we anticipate that both private insurance and government programs will pick it up once the ACIP recommendations put this vaccine on the routine schedule. Once a patient moves beyond the 19th birthday into adulthood, we run into characteristic problems with funding of immunization. Unfortunately, most medical insurance plans negotiate these benefits plan by plan. Most of them do not support immunizations.

Q. Does the new pertussis vaccine contain thimerosal?

Dr Schaffner: No, it does not.

MENINGOCOCCAL DISEASE

Neisseria meningitidis is the most common cause of bacterial meningitis among children and adolescents in the United States, now that the pneumococcal conjugate vaccine has substantially reduced the occurrence of pneumococcal bacteremia and meningitis in young children. Meningococcal meningitis has a mortality rate of 10% to 13%. Among survivors, the possible sequelae include deafness and amputation due to disseminated intravascular coagulation and gangrene. This ominous illness has a seemingly benign onset. It can look like influenza, but within hours it can take a fulminant course and put a healthy young person in a coma.*

*See "Identifying early meningitis symptoms for quicker diagnosis."

Meningococcal conjugate vaccine (MCV4; Menactra), licensed relatively recently, is active against 4 meningococcal serotypes (A, C, Y, and W-135) but does not contain antigen against meningococcal group B organisms. As of yet, it has not been possible to make the group B polysaccharide capsule into a vaccine. The MCV4 vaccine is quite effective, but the meningococcal vaccine will be better when it also protects against group B serotypes.

What are the advantages of a conjugate vaccine? It triggers a T-cell as well as a B-cell response, thus inducing immune memory, which promotes longer-term protection. We don't know exactly how long—at least 10 years. Most important, it permits a genuine booster response with reimmunization; patients develop a higher antibody level more quickly. When you reimmunize with a polysaccharide vaccine, you may attain the same antibody levels induced after the first immunization, but the antibody levels will not exceed those obtained after the first shot. Thus, it is not a true booster response. With a conjugate vaccine, you can expect a booster effect and long-term protection.

N meningitidis is carried in the nasopharynx asymptomatically, and the organisms are transmitted from person to person, some of whom will get invasive disease. Again, the conjugate vaccine demonstrates an advantage because it reduces, and may even eliminate, carriage. It interrupts transmission. If enough people are immunized, herd immunity may develop. This means that when many people are immune, those who are not immunized are protected because transmission of the organism has been interrupted. This is how the public health function of a vaccine is fulfilled: Both the community and the individual are protected.

The current recommendation for MCV4 specifies a single dose for any of 3 target age-groups: at the 11-12-year-old visit, at entry to high school, and at entry to freshman year of college. The immunization can also be given at other times during adolescence as vaccine supplies permit. Notice that the ACIP emphasizes preadolescents and students entering high school. Meningococcal disease has a predilection for older adolescents, who are harder to get into the office, so we try to reach them at an earlier age. We know that college freshmen living in dorms, jammed together, are at increased risk for meningococcal disease, and we now have a consensus that all college freshmen living in dorms should be immunized. Many colleges now require immunization of their freshmen with MCV4, and, in some states, legislation requires that, at the very least, all students and their parents must be educated about this illness and must formally decline the immunization, if they choose not to participate.

Actually, this vaccine is so popular that the manufacturer can't produce it fast enough. They are building a new plant, which will be online in 2008, and that will give them the capacity to manufacture MCV4 stock to meet world-wide demand.

One possible problem has emerged with MCV4. We have reports of Guillain-Barr syndrome in 6 adolescent recipients. These cases all developed within 2 to 4 weeks of vaccine administration, which makes it possible that the vaccine played a causal role. When the delay between vaccine administration and the emergence of Guillain-Barr symptoms is longer, the connection is more tenuous. All but one of the cases occurred in Ohio and the Northeast, but the vaccine has been distributed throughout the country. That is an anomaly, but sometimes in a situation like this, the early cases appear to be geographically clustered. Only later do they emerge in other areas.

We've been looking at cases now for several months; no others have appeared elsewhere in the country, and no additional cases have occurred in the Northeast. These findings make it less likely that the cases of Guillain-Barr syndrome were due to the vaccine. The FDA and CDC are continuing to investigate and monitor the situation among MCV4 recipients, however. The rates of Guillain-Barr in this population simply could be consistent with background rates. The CDC continues to urge immunization.

HEPATITIS B

FIGURE 2 Reported acute hepatitis B incidence by age-group: United States, 1990 to 2004

Although we all know about the hepatitis B vaccine (Engerix-B, Recombivax HB) and its recommendations for use, you may not know that it is a "reemerging" vaccine among young adults. A remarkable series of events has occurred since it was introduced. Hepatitis B immunization coverage was slow and steady until we decided to immunize every child. This has been an increasingly successful program, and, as a consequence, hepatitis B rates in this country have substantially diminished. Figure 2 shows the declines in hepatitis B that have occurred among children, adolescents, and young adults.

FIGURE 3 Hepatitis B incidence ≥19 y by race/ethnicity: United States, 1990 to 2004

As shown in Figure 3, the decline in hepatitis B cases has occurred in all racial and ethnic groups. Racial disparities in this infection had always been present, and persons in racial and ethnic minority groups typically had higher infection rates than Caucasians in the United States. The good news is that rates in minority groups have decreased very substantially, though we still have a disparity regarding African Americans that needs to be addressed.

What is the best way to reduce hepatitis B transmission rates across all age, ethnic, and racial groups? The population data tell us that hepatitis B has been virtually eliminated among girls and boys in the United States. This is a huge step on the road to elimination of transmission in this country. But once the threshold of the 19th birthday is crossed, infection rates increase. The means of transmission include drug use and sexual transmission, most of it by the heterosexual route.

We now have a bifurcated set of recommendations for using hepatitis B vaccine in our population. We have a policy of universal immunization until the 19th birthday, and we see how successful that is. But once a patient crosses the threshold to adulthood, during those ages when people are at greatest risk of becoming infected, we have barriers to immunization. As I like to quip, an adult must pass a test to become eligible for hepatitis B vaccination: The patient must have had multiple heterosexual partners in the past 6 months, have used drugs, or be a man who has sex with men before I can administer the vaccine. The patient has to assume the risk before he or she can get immunized. It is a strange way to proceed with a public health measure.

The ACIP currently is debating expansion of the risk groups eligible for vaccine. One recommendation under consideration is that all sexually active people who are not in a mutually monogamous relationship should receive the hepatitis B vaccine. In addition, patients who have ever been evaluated or treated for a sexually transmitted disease (STD) would be considered for immunization. My question for the ACIP is, Why not give hepatitis B vaccine to everyone aged 30 and younger? We have learned that age-based recommendations are easier to implement than those based on behavioral characteristics.

Q. Will we ever get a universal vaccination record? So many young adult patients have no idea what vaccinations they've had. At age 18 or 19 they stop seeing a pediatrician and find another doctor, and sometimes they move at this time, too.

Dr Schaffner: It's under way; the CDC is looking at this. In Florida, there is a program called Florida SHOTS (State Health Online Tracking System). This statewide centralized electronic immunization registry helps a treating physician determine which immunizations a child has had.

Q. In my community, the hepatologists are still trying to come up with a reason not to immunize against hepatitis B. Has that been your experience?

Dr Schaffner: Actually, the hepatologists I know would like to see universal immunization for hepatitis B. If that's not possible, they certainly seem to endorse immunization for anyone who has any chronic liver disease or infection. They would also like to immunize patients who are infected with hepatitis C, because those patients get sicker than others when they acquire a coinfection with the hepatitis B virus.

Q. Is there evidence that it is necessary to boost somebody who has had the hepatitis B series?

Dr Schaffner: According to the most current data, it is not necessary. The initial 3-dose series provides prolonged protection.

HERPES ZOSTER

Shingles, or herpes zoster, is a late consequence of chickenpox infection. The varicella virus finds the dorsal ganglion and goes into hibernation for reasons we don't understand. Then the infection often reemerges as shingles. This manifestation of varicella infection is a great trouble to many people. Even worse, it can cause postherpetic neuralgia (PHN). The pain syndrome, which can be prolonged for months, may be so severe that some people have been driven to considering suicide. This is not a disease that kills, and it is not an infectious disease in the conventional sense, but its consequences can be very troublesome, even grave.*

*See "Corticosteroid injection and a local anesthetic for PHN."

We are on the verge of making some progress against it, however. A randomized placebo-controlled, double-blind clinical trial was conducted at 22 sites among nearly 39,000 adults aged 60 and older who received either an enhanced potency vaccine against varicella or placebo.⁶ The goal was to determine whether the enhanced vaccine, which is 14 times more potent than the varicella vaccine that is used in children, prevents shingles. The notion is that if you boost immunity and keep the varicella virus in the dorsal ganglion, it cannot emerge to cause shingles. A remarkable 95% of subjects completed the 5-year follow-up, which required monthly call-ins. I know, because my wife and I were participants.

The bottom line is that the occurrence of shingles was reduced by 51%, and PHN was reduced by 66%. The total burden of illness due to herpes zoster was reduced by 61%.⁶ It's not yet clear exactly how long the protection lasts, and those studies are ongoing. I continue to make my monthly calls. At the end of the study, my wife and I were delighted to learn that we both had received vaccine, not placebo.

This vaccine is under review by the FDA, and I am confident it will be released and licensed in 2006. On the day after it is released, your phones will be ringing early in the morning. Patients will want this vaccine. We'll wait to see which insurance plans will pay and whether Medicare will cover it. This vaccine will bring older patients to your office asking for immunizations. While you have them there, you'll give the enhanced potency varicella vaccine in one arm and then say, "You have a free arm. You are going to get your tetanus booster, your pneumococcal vaccine, and whatever else you need." This is the vaccine around which you can construct a more comprehensive adult immunization plan for your patients.

HPV INFECTION

Infection with HPV occurs shortly after the initiation of sexual activity. A very high proportion of both men and women have been infected by age 30. The organism is cleared in more than 80% of patients, but for some this infection triggers stage 1 cervical intraepithelial neoplasia (CIN). Even this condition is self-limiting in most patients. For some, however, HPV infection is prolonged and proceeds to cervical intraepithelial neoplasia (CIN) stage 2 and 3, precursors to cervical cancer.⁷

To prevent this chain of events, human papillomavirus vaccines have been developed. One protects against HPV types 16 and 18, the types most commonly associated with cancer, whereas the other is a quadrivalent vaccine now in phase III trials. In addition to HPV types 16 and 18, this latter vaccine also targets types 6 and 11, which are implicated in causing genital warts. In a phase II trial, it reduced the incidence of HPV infection by 90% in women who received the vaccine, compared with those who received a sham vaccine.⁸ We expect approval of HPV vaccine within a year, and it will be administered as a 3-dose series. The proposed target group is preadolescent girls. Consider this an anticancer vaccine, not a vaccine against an STD. The manufacturer reports that clinical trials have shown that the vaccine not only protects against HPV infection but also helps against CIN stage 2 and 3 among sexually active adolescents.

Vaccines have played quite a minor role in adolescent and adult medicine in recent decades. That will now change considerably. The transition could be bumpy and involve issues including feasibility, education, and appropriate implementation. Remember that prevention is the highest goal in medicine and that these vaccines will provide us the opportunity to prevent much disease and disability.

Q. How far along is development of an avian flu vaccine?

Dr Schaffner: An avian influenza vaccine is now in clinical trials. First it will be tested in young healthy adults to determine if a single dose is sufficient or if 2 are necessary. Preliminary evidence suggests that each dose should be quite potent and that it should be given twice because these are completely new antigens. Trials are also starting in children, older adults, and people with chronic conditions.

Q. I'm curious about what other infectious disease vaccinations are on the horizon. Where are we with an HIV vaccine, for example?

Dr Schaffner: When people asked me about this 10 or 12 years ago, I said that we would have an HIV vaccine by now. So much for my crystal ball! Fortunately, we have antiviral agents, but we still don't have a vaccine. Furthermore, I'm afraid it's on the distant horizon.

We do have other vaccines in research, though. A new streptococcal vaccine, which may be utilized in adults more often than in children, is in development. We have the basic group B streptococcal vaccine, which can be used in or before pregnancy to protect infants. A herpes simplex vaccine is also getting some attention from scientists. As you can see, these are vaccines that primarily involve adult populations.

Q. What about tuberculosis and malaria? Those are the big killers.

Dr Schaffner: Tuberculosis and malaria vaccines are getting considerable attention. There's money available for these topics, and very good people are orchestrating research and development programs in numerous research laboratories.

Q. Our patients are going to the big drugstore chains and getting vaccinated. Meanwhile, the vaccine we ordered last February is still not available to us. We were told that the pharmacies have contracted to purchase huge amounts and that they are getting their shipments first. I can't vaccinate my patients who need it because the drugstores are doing it for people who don't need it. Can't the CDC do something?

Dr Schaffner: You are referring to influenza vaccine, of course. Your distress is the consequence of the complex entrepreneurial system of influenza vaccine distribution in this country. Although somewhat of an oversimplification, the system works this way. About half the influenza vaccine is shipped directly from the manufacturers to doctors, hospitals, and other vaccine providers. This is done on a sequential basis: Everyone gets a fraction of the order in the first shipment, and then later shipments complete the order. However, the other half of the vaccine produced is sold to distributors, who may ship directly to health care providers—or they may sell the vaccine to other distributors. All of these distributors have their own methods of supplying their customers. Thus, the timing of when vaccine will arrive in your office depends on where you've placed your order.

Things get even more complicated when, as happened recently, a company has trouble producing the vaccine and cannot fill its orders at all. The government (federal, state, and local) actually purchases only a relatively small amount of influenza vaccine. The CDC, however, has been working closely with manufacturers to address the problem of influenza vaccine distribution, especially during times of vaccine shortage.

*See "Corticosteroid injection and a local anesthetic for PHN"

Dr Schaffner discloses that he is a member of a data safety monitoring committee for Merck and the National Institute of Allergy and Infectious Diseases.

REFERENCES

1. Centers for Disease Control and Prevention. Pertussis—United States, 2001-2003. MMWR Morb Mortal Wkly Rep. 2005;54:1283-1286.

2. Dworkin MS. Adults are whooping, but are internists listening? Ann Intern Med. 2005;142:832-835.

3. Lee GM, Lett S, Schauer S, et al. Societal costs and morbidity of pertussis in adolescents and adults. Clin Infect Dis. 2004;39:1572-1580.

4. Ward JI, Cherry JD, Chang S-J, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med. 2005;353:1555-1563.

5. Friedman DS, Curtis CR, Schauer SL, et al. Surveillance for transmission and antibiotic adverse events among neonates and adults exposed to a healthcare worker with pertussis. Infect Control Hosp Epidemiol. 2004;25:967-973.

6. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352: 2271-2284.

7. Pinto AP, Crum CP. Natural history of cervical neoplasia: defining progression and its consequence. Clin Obstet Gynecol. 2000;43:352-362.

8. Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6:271-278.

Best Clinical Practices

Guidelines for selected adolescent and adult immunizations

Pertussis
Tdap replaces Td vaccine as booster dose at ages 11-12 y
Tdap for adolescents 5 y after last tetanus-containing shot (<5 y if pertussis risk high)

Meningococcal disease
One dose for any of 3 target ages:
11-12-y visit
High school entry
College entry
Other adolescents (supplies permitting)

Hepatitis B
Sexual transmission
All sexually active persons not in a mutually monogamous relationship
Persons evaluated or treated for STDs
Men who have sex with men
Sex partners of HBsAg-positive persons
Risk from blood exposure (percutaneous, mucosal)
Health care and public safety workers
Injection-drug users (current and recent)
Patients with end-stage renal disease
Household contacts of HBsAg-positive persons
Others
International travelers to areas with hepatitis B
Patients with chronic liver disease
All persons wishing protection from HBV

Key: HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; STD, sexually transmitted disease; Td, tetanus/diphtheria vaccine; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed.

Vaccines mentioned in this article

Hepatitis B vaccine (Engerix-B, Recombivax HB)
Human papillomavirus vaccine (Gardasil)*
Meningococcal conjugate vaccine (MCV4) (Menactra)
Tetanus/diphtheria (Td) vaccine
Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed (Tdap) (Boostrix)
Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed (Tdap) (Adacel)
Varicella virus vaccine (Zostavax)*
*Not FDA-approved.