By James D. Cherry MD, MSc |
As a physician I have seen pertussis cases and participated in pertussis immunization for 57 years (1).
We studied reactogenicity of DTwP vaccines in 1978-1979 and subsequent to that time I, with various colleagues, studied the epidemiology of pertussis and pertussis immunization; adolescent and adult pertussis; and carried out numerous studies with a DTaP vaccine including a DTaP vaccine efficacy trial in Germany. More recently in conjunction with investigators at the California Department of Public Health and pediatric infectious diseases colleagues we have studied severe pertussis in young infants (2, 3) and have recommendations in place for young infants who are hospitalized with pertussis.
I have analyzed why pertussis vaccines fail as well as the present resurgence of pertussis (4-7). During the last decade I have given numerous presentations to pediatricians about pertussis and pertussis immunization. During this period I have fielded many questions and in this presentation I will address many of these as well as recommendations which I think are important in 2014.
Severe Pertussis in Young Infants in California
During the period between 1998 and January 2011 there were 50 pertussis deaths in young infants in California. In the fall of 2009 a number of us presented advice relating to the diagnosis and management of pertussis in young infants to all AAP District IX members (8). Also in 2010-11 we had the opportunity to study severe pertussis in 31 infants ≤ 90 days of age and to evaluate exchange blood transfusion in the management of extreme leukocytosis with lymphocytosis (2, 3).
The following predictors of death or pulmonary hypertension were:  an early high and rapidly rising WBC count;  an early high pulse rate;  and early high respiratory rate and  the early onset of pneumonia (2). In the second study we found that for survival exchange blood transfusion, if it is performed, should be done before cardiogenic shock and organ failure has occurred (3).
This year we can expect an upswing in pertussis in California. Associated with this will be an increase of severe pertussis in young infants. In gearing up for this we have organized an observational study of all pertussis cases <4 months of age admitted to all hospitals with a Pediatric Infectious Diseases service and a PICU. The PID consultants will give standard of care advice regarding case management and when specific criteria are noted will recommend exchange blood transfusion. Since 2010 there has been only one pertussis death in California. I believe some of this success can be attributed to our 2010 Chapter IX AAP awareness campaign (8).
“Immunity following pertussis is lifelong whereas immunity following immunization (either DTwP or DTaP) is relatively short lived.”
In recent epidemics (2005, 2010, 2012) it has become very clear that protection from DTaP vaccines is short lived (9-11). Similar population data are not available for DTwP vaccines. However, in the last vaccine efficacy trial in Sweden (Sweden 2) it was found that the efficacy of a 5 component DTaP vaccine had similar efficacy for 3 years as a good DTwP vaccine (1). However, 10 year follow up noted that the DTwP vaccine had better long term efficacy than the DTaP vaccine.
Our group in Germany with investigators at Creighton University studied the antibody profiles (IgA and IgG) in 21 year old male college students (USA) and 21 year old German men participating in their required military service (12). It was assumed that the students in the US had been vaccinated in childhood whereas the Germans had not been vaccinated. Immunization generates IgG antibodies but not IgA antibodies whereas infection generates both IgA and IgG antibodies. When we compared IgA antibodies to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae-2 (FIM-2) in the Americans and the Germans they were similar; this indicated similar infection rates in the two countries.
However, in contrast those primed by vaccines (Americans) had significantly higher IgG antibody values than those primed by infection (Germans). Since IgG antibodies to PRN, FIM and PT correlate with protection (13,14) it would appear that DTwP vaccination gave better protection than natural infection.
“Pertussis in adolescents and adults is a new phenomenon due to changes in herd immunity in the vaccine era.”
In the prevaccine era pertussis was rarely reported in adults. However, many of the pertussis experts in the prevaccine era recognized that second attacks of pertussis did occur in adults but because they were atypical they, most often, did not get reported as pertussis (1, 15). In two vaccine efficiency trials in the early 1990s in West Germany it was found that adult cases were often the primary cases in the family (16, 17). Since pertussis immunization in West Germany during the 1970s and 1980s was minimal, this was the prevaccine era in West Germany.
In the prevaccine era B. pertussis infections occurred endemically in all age groups and this is true today. What may have changed over time is the clinical expression rate and also the more general awareness of pertussis in adults. At present and also in the prevaccine era there is or was no overall herd immunity. This statement is based upon the fact that the interepidemic period is the same today as it was in the prevaccine era (18). If there were significant overall herd immunity, the interepidemic periods would have lengthened in the vaccine era. To obtain herd immunity it would be necessary to repeatedly vaccinate all age groups. This today is politically impossible and recent data suggest that even if it were possible it might not occur with our present DTaP and Tdap vaccines.
“The resurgence of reported pertussis is due to the inferiority of DTaP vaccines as compared to DTwP vaccines.”
This is clearly not so because the overall attack rate of reported pertussis in the US started its upward climb in 1982 which was ~15 years before the universal use of DTaP vaccines was started (1). Clearly, the most important reason for the increase in reported pertussis over the last 32 years is greater awareness (1,5-7). Greater awareness in the 1980s was due to concern about true and perceived reactions to DTwP vaccines and many publications about studies with new DTaP vaccines. Greater pertussis awareness continued in the 1990s because of the numerous publications of the DTaP vaccine efficacy trials (1, 15). It must be stressed that greater awareness leads to the finding of more less severe cases of pertussis.
More recently the greatest contribution to the “resurgence” is the use of PCR for diagnosis (1, 5-7). This technique allows the discovery of milder cases and also cases that had previously received antimicrobial treatment. It should also be pointed out that presently most adult cases are not being correctly diagnosed. This is due to the continued view of physicians that care for adults that pertussis is a children’s disease. Also, a major contribution to the failure to diagnose pertussis in adults is the fact that adults most often do not seek care until the 3rd or 4th week of illness; at this late date PCR and culture are likely to be negative. Pertussis in adults can be reliably diagnosed by single serum serologic study (IgG and IgA antibody to PT). A highly specific test is available from Focus Laboratories (1). There are other laboratories that provide serologic tests for the diagnosis of pertussis but most of these tests lack specificity.
“The resurgence of reported pertussis is due to genetic changes in circulating B. pertussis strains”
There is some truth to this statement (1,4-7). However, at present in the US, genetic changes are far less important than greater awareness and PCR diagnosis. In the entire DTwP vaccine era, genetic change in circulating B. pertussis never contributed to vaccine failure. The reason for this is that DTwP vaccines contain ~3430 proteins and a number of these are “protective antigens”. (Antibody to them promotes bacterial killing and clearance). Therefore, mutations in 3 proteins would not be a risk factor for lack of protection because antibody to other proteins would provide adequate protection. However, our present DTaP and Tdap vaccines contain only 3 (GSK) and 5 (Sanofi pasteur) proteins. These vaccine antigens are PT, FHA and PRN in GSK vaccines and PT, FHA, PRN and FIM 2 and 3 in Sanofi pasteur vaccines.
Genetic change has not as yet occurred in FHA. However, data from two studies suggest that antibody to this protein does not contribute to protection (13, 14). Of the remaining 4 proteins (PT, PRN and FIM 2 and 3), the most important are PRN and FIM 2 and 3. At present in the US a large number (> 50%) of circulating strains are PRN deficient (19). In addition FIM 3 in circulating strains has changed FIM from 3A to FIM 3B (7). In all countries where DTaP vaccines are used the genetic makeup of PT has changed from ptx P1 to ptx P3.
It was suggested a number of years ago that the mutation of the change in PT gene had led to both vaccine failure and more severe disease in the Netherlands (1, 4). However, an analysis of the data does not support this view. Furthermore a PT toxoid single component DTaP vaccine has been used exclusively in Denmark for 16 years and pertussis attack rates are no higher in that country than in the US (7). It was shown in the initial efficacy trials in the 1990s that the PT toxoid vaccine had lesser efficacy than vaccines with more components (1).
However, the PT toxoid vaccine protected against typical pertussis (paroxysmal cough ≥ 21 days) as well as the vaccines with multiple components. I suspect that both PRN deficient mutants and the changes in FIM 3 are contributing to the present resurgence. However, since antibody to PT still protects against severe disease it will be difficult to determine the contribution of PRN and FIM mutants to vaccine failure unless careful prospective studies which look carefully for mild disease are carried out.
“The rate of reported pertussis today is ~20 fold less than in the prevaccine era.”
This fact is often overlooked today when “experts” and the media discuss the “resurgence of pertussis”. The problem is compounded by the fact that graphic data presented about the resurgence often have numbers and not rates. Since the US population has increased 3-fold since the prevaccine era, using numbers and not rates, makes the situation looks much worse than it is.
“Illness in DTaP vaccine failures is less severe than illness in similar aged unvaccinated children.”
It is important to know this when discussing DTaP vaccination with vaccine reluctant parents.
B pertussis contains many proteins that participate in the infectious process (1, 7, 15).
In contrast B pertussis clinical illness is apparently due to just two factors (7). One of these factors is PT. PT causes leukocytosis with lymphocytosis (often to extreme degrees) in unvaccinated young infants who have not received transplancentally acquired antibody to PT from the mother (2, 3). Extreme leukocytosis with lymphocytosis is a direct cause of (or a surrogate for) death in young infants. Once a person has been vaccinated or has had pertussis he/she never again get the manifestations produced by PT because they have rapid recall of antibody to PT.
The other factor which causes clinical illness is presently unknown (7). This “cough toxin” causes the unique paroxysmal cough of pertussis. In contrast with PT (which following immunization its manifestation never reoccur) immunization provides only short lived protection against cough illness. Paroxysmal cough with B pertussis infections occur throughout life in both persons who had pertussis and in those previously vaccinated.
The major cause of the “resurgence” of pertussis is greater awareness and the use of PCR for diagnosis. Many young infant pertussis deaths can be prevented by immunization of the mother in the 2nd or 3rd trimesters of pregnancy and routinely giving the first dose of DTaP vaccine at 6 weeks rather than 8 weeks of age. In addition, pertussis deaths in young infants can be prevented by early admission to a PICU at a hospital with a PID consulting team. Finally, we should see that all present DTaP and Tdap recommendations are followed.
James D. Cherry, MD, MSc, is a distinguished research professor of pediatrics at the David Geffen School of Medicine at UCLA and an attending physician specializing in pediatric infectious diseases at Mattel Children’s Hospital UCLA.
- Cherry JD and Heininger U. Pertussis and other Bordetella Infections. In: Cherry JD, Harrison GJ, Kaplan SJ, et al., ed. Feigin and Cherry’s, Textbook of Pediatric Infectious Diseases, 7th ed. Elsevier/Saunders; 2014;1616-1639.
- Murray EL, Nieves D, Bradley JS et al. Characteristics of sevre Bordetella pertussis among infants Nieves D, Bradley JS, Gargas J, et al. Exchange blood transfusion in the management of severe pertussis in young infants. The Pediatric infectious disease journal 2013;32:698-9.
- Cherry, JD. Why do pertussis Vaccines fail? Pediatrics 2012;129:968-70.
- Cherry JD. Epidemic pertussis in 2012–the resurgence of a vaccine-preventable disease. The New England journal of medicine 2012;367:785-7.
- Cherry, JD. The Epidemiology of Pertussis: A comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection. Pediatrics 2005;115:1423-7.
- Cherry JD. Pertussis: challenges today and for the future. PLoS pathogens 2013;9:e1003418.
- Cherry JD, Harrison R, Bradley JS, et al. Pertusis in Young Infants, 2010. American Academy of Pediatrics California District IX. URL: http://www.app-ca.org/clinical/pertussis/pertussis_in_young_infants.html. Date Accessed. June 9, 2010
- Winter K, Harriman K, Zipprich J, et al. California pertussis epidemic, 2010. The Journal of pediatrics 2012;161:1091-6.
- DeBolt C TA, Bardi J, et al. Pertussis Epidemic–Washington, 2012. Centers of Disease Control and Prevention MMWR 2012;61:518-22.
- Allen A. Public health. The pertussis paradox. Science 2013;341:454-5.
- Cherry JD, Beer T, Chatrand SA, et al. Comparison of values of antibody to Bordetella pertussis antigens in young German and American men. Clinical infectious diseases. 1995;20:1271-4.
- Cherry JD, Gornbein J, Heininger U, et al. A search for serologic correlates of immunity to Bordetella pertussis cough illness. Vaccine. 1998;1901-1906.
- Stosaeter J, Hallandeer HO, Gustafsson L, et al. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907-1916.
- Mattoo S CJ. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev 2005:326-82.
- Schmitt-Grohe S, Cherry JD, Heininger U, et al. Pertussis in German adults. Clin Infect Dis 1995;21:860-866.
- Wirising von Konig CH, Postels-Multani S, Block HL, et al. Pertussis in adults:frequency of transmission after household exposure. Lancet 1995;346-1329.
- Mink CM, Cherry JD, Christenson P, et al. A search for Bordetella pertussis infection in university students. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1992;14:464-71.
- Pawloski LC, Queenan AM, Cassiday PK, et al. Prevalence and molecular characterization of pertactin-deficient Bordetella pertussis in the US. Clin. Vaccine Immunol. Published online ahead of print in 20 November 2013. Clin. Vaccine Immunol. Doi:10.1128/CVI.00717-13.