MARIN OUTBREAK: Pertussis: It’s Not Just for Babies Anymore

Paul Katz, MD, MPH

Only three years ago pertussis was a dusty memory. For physicians, the idea of pertussis (whooping cough) called up long-ago medical school lectures, visions of old and rarely used cough plates, and an arcane consideration in cases of unexplained chronic cough. Whooping cough seemed to be one of those maladies vanquished by immunizations--another victory over infant death. Then, in 2010, pertussis came back in a big way, and Marin County was ground zero: the epicenter of a whooping cough outbreak that was by far the largest and most sweeping in California in 50 years. In its wake, 10 infants throughout the state died preventable deaths, and many lives were thrown into turmoil.

Since the outbreak, physicians in Marin County have learned much more about pertussis in the 21st century and why an apparently preventable illness surged first here and now around the country. The biology of pertussis has not changed all that much over the years, but the population that is susceptible to the illness certainly has. And now a new question looms: Will the burden of future outbreaks be just with infants and children?

To tell the story of Marin’s pertussis outbreak and what it means, let me begin with a brief personal narrative. In January and February 2010, my pediatric colleagues and I at Kaiser Permanente in San Rafael noted several cases of an odd, persistent, even paroxysmal cough in several of our patients. First there was one case of pertussis verified by the nasopharyngeal PCR (polymerase chain reaction) test, then two, then more. Each week, we sent one or two Confidential Morbidity Reports for pertussis to the Public Health Department. More and more family members were being treated for prophylaxis, and some were tested for their own coughs.

Around that time, Dr. David Witt of Kaiser’s Infectious Diseases Service and I noted a cluster of cases in a West Marin community. The cluster seemed to be centered around the adolescents and preadolescents in school there. The community also happened to have a high rate of vaccine refusers and of Personal Belief Exemptions for vaccines in the local schools. When I encouraged parents to raise awareness of pertussis in the community and the school, I heard several times from them that their children’s peers had been to their doctors and had not been tested for pertussis for emerging paroxysmal coughs. What those parents heard was that if their child was immunized they were not at risk for whooping cough or that pertussis was not really a problem for older children or teens. Of course, what families heard may not have been exactly what the doctors said, but clearly those beliefs were out there.

Two issues bothered me deeply. First, pertussis vaccine was even then known to be imperfect. At the time, the effectiveness of the vaccine was thought to be 90% in optimal conditions. Second, the North American acellular pertussis vaccine that had been around since 1991 and had fully replaced the original whole-cell pertussis vaccine by 2001 had never been studied in an outbreak situation. Would that 90% effectiveness measured in the usual background of rare endemic exposure hold up to a classroom where two or three children are coughing actively with pertussis for weeks before being treated or considered for treatment? Would density of exposure affect the efficacy of the vaccine?

By the start of March, we were sending in two Confidential Morbidity Reports per day for pertussis rather than one or two per week. Clearly this was not just a few cases, but was in fact an outbreak. Fortunately, we had good tools in our practice. We had access to the PCR test on nasopharyngeal specimens with a 24-hour turnaround time. We had a large known population at Kaiser (40% of the insured population of Marin County) that would get its medical care only though our system. We had systems and a workflow in place to rapidly treat suspected cases and their contacts. Finally, we had dedicated pediatricians and child health providers who were used to working together as a team.

In March, we established a Practice Agreement at Kaiser San Rafael to test and treat for possible pertussis uniformly during the outbreak. All pediatric patients with a persistent cough for more than a week without other explanation (e.g., asthma, pneumonia, sinusitis) were to be assessed with a PCR test. All close or family contacts of known cases with any cough symptoms of any duration were also to be tested. The Practice Agreement not only allowed us to test and manage pertussis clinically in a public health crisis, but also to look at pertussis attack rates in an outbreak without selection bias based on immunization status. Pediatricians only decided whether or not to test for pertussis based on the clinical situation--not on whether the patient was up to date on pertussis vaccine.

Despite identifying more than 200 cases of pertussis by the end of 2010, when the outbreak came to an end, we had no deaths and almost no hospitalization of our patients for pertussis. However, when Dr. Witt, our research assistant (his son Max) and I looked at our attack rates, something jumped out: pertussis peaked in older school children and preadolescents, not in teens and not in babies. Pertussis vaccine effectiveness in the outbreak was hugely different by the age of the child. The effectiveness in 13-18 year olds was 79%, meaning that a fully immunized 14-year-old, for example, had 79% less chance of getting pertussis than an underimmunized or unimmunized 14-year-old. In contrast, the vaccine effectiveness for 8-12 year olds was only 24%.

When we compared our results to the nationally recommended vaccine schedule and looked at the length of time from last vaccine to cases, we found that the immunity of the acellular pertussis vaccine seemed to wane in our outbreak at about three years after vaccination. Most children finished their kindergarten vaccines at 4 or 5 years old and were not to be boosted until at least 11 years old (and often not until 12 or 13). As a result, children from 8-12 years old would be fully vaccinated by the recommended schedule but still quite susceptible to pertussis in an outbreak situation. We presented our findings at the American Society of Microbiology meetings in the fall of 2011 and published them in March 2012.[1]

So why did the pertussis outbreak seem to start in Marin County? And why in 2010? To answer these questions, we need to go back in history. Pertussis was a frequent cause of infant death in the United States during the first half of the 20th century. Between 1926 and 1930, for example, more than 36,000 American children died of whooping cough. In the 1930s, Pearl Kendrick and Grace Eldering developed the whole-cell pertussis vaccine at the Michigan Department of Health by inactivating pertussis bacilli with thimerosal for more than a week in a cold but not frozen temperature. The vaccine was recommended for routine use by the American Academy of Pediatrics in 1943, and by 1948, pertussis mortality had dropped to near zero.

Concerns about rare but severe neurologic adverse effects led to decreasing acceptance of the pertussis vaccine during the late 1970s and 1980s. The scientific community and pharmaceutical industry responded by developing the acellular pertussis vaccine. The new vaccine seemed effective in studies lasting up to 22 months after administration. Measurable antibody levels to the targeted antigen in pertussis were similar to the whole-cell vaccine. In 1991, the acellular vaccine came on the market as a childhood booster. By 1997, the acellular had supplanted the whole-cell vaccine in most practices and was inserted into the same schedule as the whole-cell vaccine. By 2001, the whole-cell vaccine was no longer available.

For the next nine years, pertussis continued to occur in low endemic rates of illness, and no prominent outbreak was noted. The number of families refusing vaccine on personal belief exemptions increased, however--especially in Marin County, which has the highest rate of PBEs in the state. People with similar beliefs and culture tend to cluster together, and the same is true for vaccine refusers, as witness specific communities in western Marin.

By 2010, Marin County had the perfect set-up for a pertussis outbreak. By that year, everyone under 10 and almost everyone under 14 was naive to whole-cell pertussis vaccine. Since the vaccine schedule leaves a six- to eight-year break between the kindergarten and middle-school vaccine boosters, and since we now surmise that the acellular vaccine lasts only about three years in an outbreak environment, 2010 represents the time when even fully immunized 8-12 year-olds are quite susceptible to getting the illness.

Since Marin has multiple dense clusters of unimmunized and underimmunized children, a single endemic pertussis case in the right community can start a big cluster of cases. Because schoolchildren spend time together mainly with their age peers as playmates and schoolmates, once a few 8-12 year-olds have pertussis, the whole cohort gets the illness easily even if up to date on their shots. That is exactly what happened in Marin in 2010. The unimmunized were the spark, and the fully immunized but susceptible preadolescents were the kindling and the fuel.

If our data were true outside Marin, they would predict outbreaks in other states in the same manner, more likely earlier in those with a lower vaccination rate, but eventually in all states. Washington state, Minnesota, Wisconsin and New York have all seen significant outbreaks in the last 18 months, thus proving the point. Thus far in 2012, more than 40 states have reported at least twice the rate of pertussis than in the recent past.

Scientific evidence of waning pertussis immunity keeps mounting. The CDC’s own evaluation of the Minnesota and Washington outbreaks verifies the age distribution of these outbreaks and supports the proposition of waning immunity. In a rigorous case-control study independent of our own, the Kaiser Division of Research just reported in the New England Journal of Medicine that acellular pertussis immunity wanes about 47% per year after vaccination and is significantly decreased by three years after vaccination.[2] Australian data recently published in JAMA suggest that the reason for recent outbreaks was the lesser duration of protection from acellular compared to whole-cell pertussis vaccine.[3] Finally, our group just presented a follow-up study at the Infectious Diseases Society showing that the risk of getting pertussis if fully immunized appears to be more than eight times greater for those with five doses of vaccine if they received all acellular vaccine compared to those who had one or more whole-cell vaccines. The Tdap adolescent and adult boosters seem to lessen this risk, but they do not eliminate it. In other words, Tdap boosts the whole-cell vaccine more than the acellular vaccine.

So what does this all mean? The whole-cell vaccine is gone and is not coming back. Many policy arguments are currently being made. One thing is clear: everyone who is due for the pertussis vaccine according to the schedule should get it now, especially the Tdap. Vaccine refusal remains a risk to all of us. The Advisory Committee on Immunization Practices (the vaccine-recommending body for the CDC) has recognized the validity of the evidence on waning acellular pertussis immunity and is now recommending boosting the Tdap immunization for every pregnancy a woman has, regardless of past vaccinations.

After that, policy opinions diverge. Some argue for more frequent child and adult boosters to avoid the susceptibility window. Most agree that we need to develop a better and more durable vaccine using 21st century vaccine technology. Others suggest more modest changes, such as targeted vaccine programs for when outbreaks begin or just targeting families with or about to have babies, also known as “cocooning.”

One other problem might make employers and adult-medicine providers worried: what I call the “adult morbidity conundrum.” That conundrum is the result of a long chain of events, beginning with the initial development of pertussis vaccine to eliminate infant mortality from pertussis. The vaccine also happened to lessen the whole community’s disease burden of non-lethal older childhood and adult cases--but that was 80 years ago. Times have changed. We still wish to avoid pertussis mortality, but adult morbidity may be altogether different.

In the 1930s, most adults likely had some natural immunity to the highly prevalent childhood illness of pertussis. While natural immunity is not fully protective, it does attenuate the illness. The children of these adults received whole-cell vaccine and had fairly prolonged protection from pertussis, along with likely attenuation of later cases in adulthood. Up until the last 15 or so years, this fact held true for older teens and adults.

Now we are seeing the first cohort of youngsters entering adulthood never having received whole-cell vaccine or natural immunity. Fast-forward 10 years. Imagine that a 25 year-old with a bad cough walks into his office cubicles with a bunch of other fully vaccinated but susceptible peers (unless they were recently pregnant and boosted). Imagine he has pertussis. Will the susceptible cohort just be transferred to older ages? Might there be unmitigated pertussis with 100 days of untreatable cough causing huge work loss and economic woes for individuals and workplaces? What happens when they return home to recover near their newborns? We do not know.

We have to consider that not providing sufficient vaccine immunity to the future adult cohort that has never received whole-cell vaccine might be creating outbreaks in adults of greater severity and duration than seen in the past. The objectives of the pertussis vaccine nowadays may not only be prevention of infant death, but also prevention of adult morbidity.

Whooping cough is not yet a thing of the past.

 

---

Dr. Katz is a pediatrician at Kaiser San Rafael.

Email: paul.h.katz@kp.org

References

1. Witt MA, Katz PH, Witt DJ, “Unexpectedly limited durability of immunity following acellular pertussis vaccination in pre-adolescents in a North American outbreak,” Clinical Infectious Diseases, 55:1434-35 (2012).

2. Klein NP, et al, “Waning protection after fifth dose of acellular pertussis vaccine in children,” NEJM, 367:1012-19 (2012).

3. Sheridan SL, et al, “Number and order of whole-cell pertussis vaccines in infancy and disease protection,” JAMA, 305:454-456 (2012).