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Return to Home : March 2007 : Features

Historical Perspective on Pertussis and Use of Vaccines to Prevent It

100 years of pertussis (the cough of 100 days)

 

James D. Cherry

 

James D. Cherry is  Professor of Pediatrics  at the David  Geffen School of  Medicine at the  University of California,  Los Angeles  (UCLA), Division of  Infectious Diseases,  Mattel Children’s  Hospital at  UCLA, Los Angeles,  Calif.

 

Summary 

• Although early pertussis vaccine use in the  United States sharply reduced reported disease  by more than 157-fold, the disease has been on  the rise for the past two decades—in part because  of decreased vaccine use. 

• Current treatments for pertussis involve supportive  care, avoiding factors that provoke  coughing attacks, and paying careful attention  to provide patients with fluids and nutrition. 

• What was called pertussis-vaccine encephalopathy  proved instead to be seizures attributable  to infantile epilepsy; importantly, pertussis vaccine  does not cause such illnesses. 

• Several acellular pertussis—typically, combined  with diphtheria and tetanus—vaccines that are  now licensed appear to be safe and effective not  only for infants but also for adolescents and  adults.      

 

Unlike many other severe epidemic  infectious diseases, pertussis lacks an  ancient history. Perhaps the earliest  mention of pertussis, or whooping  cough, is of a 1414 outbreak in Paris  in Moulton’s The Mirror of Health, published in  1640. A contemporary observer, Guillaume de  Baillou, described a 1578 epidemic of pertussis in  Paris and, by the middle of the 18th century,  pertussis was well recognized throughout Europe.  Carl Burger at University of Bonn, Germany,  apparently recognized Bordetella pertussis in  stained films of sputum by 1883, based on his  drawings of elliptical rods. Other observations  of bacilli in respiratory mucus followed, including  Jules Bordet and Octave Gengou who in  1900 described finding a new “ovoid bacillus”  in the sputum of a 6-month-old infant with  whooping cough. They were also the first to  cultivate the causative agent at the Pasteur Institute  in Brussels in 1906.  Before pertussis vaccines became available,  this disease caused a staggering amount of morbidity  and mortality. U.S. use of vaccines to  protect against pertussis from the 1940s to 1984  reduced the incidence of reported disease by  more than 157-fold. Nonetheless, B. pertussis  continues to circulate, with adolescents and  adults serving as a reservoir for this pathogen. In  general, the older, whole-cell-based pertussis  vaccines have greater efficacy than do the newer  acellular vaccines, but the former are also more  reactogenic. An important advantage of the  acellular vaccines is that because of their  lessened reactogenicity they can be given to  adolescents and adults, which will lead to  the better control of pertussis.      


Clinical Microbiology Practices  Past and Present      

During much of the first half of the 20th  century, B. pertussis was cultured using  Bordet-Gengou (BG) medium. Specimens  typically were collected by the “cough  plate” technique in which an agar plate was  held within 3 to 6 inches of a child’s mouth  during a coughing spell. Although this technique  was being used when I became a pediatric  house officer in 1957, William L.  Bradford and Betty Slavin earlier showed  that nasopharyngeal (NP) swabs were more  effective for culturing this pathogen.      

Several serologic tests were used during that  period, including agglutination, complement  fixation, and opsonocytophagic tests. Among  them, complement fixation was the best. Early  in the illness, it was negative; then it gave a peak  titer in four to nine weeks, but fell to a nonmeasurable  value in five to eight months. The opsonocytophagic  test measured the uptake of organisms  in neutrophils when incubated with  antibody-containing sera. The test was appealing  but nonspecific.      

Laboratory diagnosis today relies on culture,  but Regan-Lowe agar is used more often than  BG medium because of its longer shelf life. Material  for culture is obtained by NP swab or  aspirate. When the swab or aspirate comes in  contact with ciliated epithelial cells of the nasopharynx  in children who have had a paroxysmal  cough for two weeks or less, the sensitivity  is about 80%.      

Many laboratories throughout the  United States are replacing culture with  PCR tests. This test, which often uses  insertion sequences in the genome of B.  pertussis and B. parapertussis, is generally  more sensitive than culture, but  false positives can be a problem. The  biggest advance during the last two decades  has been development of ELISA  techniques to measure immunoglobulin  G (IgG) or IgA antibodies to pertussis  toxin (PT). This approach facilitates the  diagnosis of pertussis in adolescents  and adults because such individuals  rarely seek care until the third or fourth  week of the illness, when cultures and  PCR tend to be negative. Moreover, because  virtually all adolescents and adults  previously have had B. pertussis infections  or were immunized, they typically  have high antibody titers early in illness,  making single-serum diagnosis very reliable.      


Clinical Pertussis Has a Rich  History      

Pertussis typically occurs in three stages—  catarrhal, paroxysmal, and convalescent—  and lasts 4–12 weeks. Specific  manifestations include a paroxysmal  cough, lack of significant fever, no systemic  illness, profuse nasal discharge but no  significant pharyngitis, vomiting, whoop, and  leukocytosis with absolute lymphocytosis.      

Based on L. Emmett Holt’s 1902 textbook,  clinical pertussis remains remarkably constant.  However, symptoms were more pronounced  and hemorrhagic complications tended to be  more frequent a century ago. Moreover, during  summer outbreaks, infants with pertussis nearly  always also had diarrhea, and those who experienced  severe vomiting often developed malnutrition.      

No disease has a greater list of remedies  proposed and enthusiastically lauded as ‘specifics’  than pertussis,” noted Alfred Friedlander,  Professor of Medicine, College of Medicine,  University of Cincinnati, in 1925. For example,  Holt recommended treating pertussis with fresh  air, a sea voyage, small formalin lamps to prevent  reinfection, and alcohol stimulants. He also  suggested insufflation with quinine or benzoic  acid mixed with bicarbonate of sodium, talcum,  or coffee; application by spray or swab of resorcin  and carbolic acid; and inhalations with carbolic  acid, creosite, and cresolene or chloroform.  Additionally, he mentioned several drugs,  including quinine, belladonna, bromoform, antipyrine,  codeine, chloral, trional, and heroin.      

Meanwhile, Friedlander suggested a tight  abdominal binder to control vomiting. For specific  treatment, Friedlander recommended vaccine  therapy, including vaccines prepared with  whole organisms or vaccine fractions containing  undenatured bacterial antigen, topagen, and  detoxified antigen. He also mentioned the use  of high-titered animal serum and adult hyperimmune  convalescent sera. Joseph H. Lapin,  Adjunct Pediatrician, Bronx Hospital and Associate  in Contagion, Riverside Hospital for Contagious  Diseases, New York City, suggested  paying particular attention to diet and hygienic  measures, and he also suggested treating pertussis  patients with X-rays, UV rays, climatotherapy,  airplane trips, inhalations, insufflations,  and laryngeal sprays.      

Although today the treatment of pertussis  does not involve many of those more dubious  recommendations, it still suffers from lack of  effectiveness. The mainstay of supportive care is  avoiding factors that provoke coughing attacks,  including a noisy environment, unnecessary examination,  strangers, excessive brightness of  room lighting, noxious odors, and the supine  position. Careful attention to fluids and nutrition  is important. Although corticosteroids and  salbutamol are often used, their benefits are not  demonstrated.      

Hospitalized young infants should receive  gentle suction and well-humidified oxygen. In  general, infants with respiratory and cardiovascular  failure due to pulmonary hypertension  respond poorly to treatment. In such severe  cases, patients are treated with pulmonary artery  vasodialators and extracorporeal membrane  oxygenation (ECMO). According to a  recent hypothesis, pulmonary hypertension in  very young infants is due to excessive leukocytosis  with lymphocytosis. On this basis, some  patients are being treated with double-volume  exchange transfusions.      


Vaccine Use Changed the  Epidemiology of Pertussis      

Before vaccines were available, reported pertussis  occurred with an average rate of 157 cases  per 100,000 population, high death rates, and  peaks of illness every two to five years. One  peculiarity of the clinical history of pertussis is  that cases were more common among girls than  boys, unlike many other infectious diseases that  tend to predominate in boys.      

The toll of pertussis before vaccines was staggering.  For example, from 1926 to 1930, there  were 36,013 pertussis-related deaths in the  United States. The average death rates from  1940 to 1948 per 100,000 population per year  were 64 in children less than 1 year old, 6.4 in  those 1–4 years of age, and 0.2 in those 5–14  years of age. More than 90% of the reported  pertussis cases occurred in children less than 10  years of age, with about 10% of those in children  less than 1 year of age.      

By 1974, extensive use of vaccines decreased  the average annual incidence of reported pertussis  to less than 1 per 100,000 population. Although  90% of those cases still occurred among  children, the distribution shifted so that more  than 50% occurred among those less than 1 year  of age. However, by 2004, 66% of the reported  cases occurred in those older than 10 years.      

During the last 22 years there has been an  increase in reported pertussis in the United  States, peaking in 2004 at 25,827 cases. While  this increase is alarming, it should be noted  that we still have 10- to 15-fold fewer cases of  reported pertussis today than we had in the  prevaccine era. There have been a number of  suggestions for possible reasons for this “resurgence”  of reported pertussis. These suggestions  include genetic changes in B. pertussis, lessened  potency of pertussis vaccines, waning of vaccine-  induced immunity, greater awareness of  pertussis, and the general availability of better  laboratory tests. It seems apparent to me that  this increase is mainly due to the greater awareness  of pertussis now than two decades ago.  Also, in some states better diagnostic laboratory  tests are available. Another factor which may be  contributing to the increase of reported pertussis  is the fact that in general the new acellular  vaccines (DTaP vaccines) are not as efficacious  as the former whole-cell DTP vaccines. This may  have contributed to the recognition of more  recent cases in adolescents.      

Of particular importance to me is the fact that  the epidemiology of reported pertussis is vastly  different from the epidemiology of B. pertussis  infection. Over the last 20 years a number of  studies have been done to delineate the epidemiology  of B. pertussis infection. Here is a summary  of these findings:      

B. pertussis infections in adolescents and  adults are very common and endemic in the  present vaccine era. 

• Data from Germany in the early 1990s, when  few children were being immunized and pertussis  was epidemic, as well as much earlier  observations in the United States, suggest that  infections in adolescents and adults were common  and endemic in the prevaccine era. 

• Rates of reported pertussis are 40- to 160-fold  less common than actual infection rates.  • Asymptomatic infections are 4–22 times  more common than symptomatic infections. 

• Today symptomatic adolescents and adults  are the major source of infection in unvaccinated  children.       


Chaos in Formulating, Using  Early Pertussis Vaccines      

Pertussis was such a devastating disease in early  infancy that soon after B. pertussis was isolated,  many investigators made and tested a range of  candidate vaccines, including whole-cell preparations  that were washed or unwashed, mixed  vaccines containing other respiratory tract flora,  extracted vaccines, detoxified vaccines, and vaccines  enriched with “toxic factors.”      

As early as 1923 some protection was noted  in vaccine trials; however, the state of available  vaccines was in such chaos that pertussis vaccines  were withdrawn from new and nonofficial  remedies. In the 10-year period from 1933–  1942, there were many candidate vaccines and a  number of these were shown in clinical trials to  be efficacious. By 1944, pertussis immunization  was endorsed by the American Academy of Pediatrics.      

In the 1930s the following types of pertussis  vaccines existed: whole-cell preparations which  were washed or unwashed, mixed vaccines containing  other respiratory tract flora, fractionated  vaccines (extracted vaccines), detoxified  vaccines, and vaccines enriched with “toxic factors.”  At this time the only toxin that had been  identified was dermonecrotic toxin, which was  heat labile, and therefore detoxification was  easy.      

It was realized relatively early that a good  antibody response and clinical protection following  immunization depended upon the number  of organisms in the vaccine, and because of  toxicity, there was a limit to the number of  organisms that could be given in a single dose.  Many of the early vaccines contained substantial  amounts of human or animal serum, and  immunization schedules included six or seven  injections over a 2- to 3-month period to obtain a  significant dose.      

Almost from the outset, pertussis vaccines  were associated with problematic side effects  and temporally related severe events. For example,  Thorvald Madsen, State Serum Institute,  Copenhagen, Denmark, reported in 1925 that  two neonates died after receiving the second  dose of a pertussis vaccine during the first week  of life.      


Pertussis Vaccines Repeatedly  Scrutinized for Safety      

Concern about severe temporally related events  (so called vaccine encephalopathy and sudden infant  death syndrome [SIDS]) lead to a number of  observational studies shortly after vaccine use became  widespread. In 1948, Randolph K. Byers  and Frederic C. Moll of the Department of Pediatrics,  Harvard Medical School, and Infants  and Children’s Hospital, Boston, published a  report of 15 children with severe neurologic  disease which had its onset following immunization.  This was followed in 1958 by a series by  J. M. Berg, Fountain Hospital, London, with  107 cases and in 1974 by M. Kulenkampff, J. S.  Schwartzman, and J. Wilson, The Hospital for  Sick Children, Great Ormand St., London, who  noted 36 cases. This latter uncontrolled study  led to considerable media attention in England,  and immunization use dropped precipitously,  resulting in epidemic disease in 1977.      

The next group of studies were those that  attempted to determine a rate of severe neurologic  disease (“vaccine encephalopathy”) following  immunization. Justus Stro¨m of the Hospital  for Infectious Diseases, Stockholm,  Sweden, published reports in 1960 and 1967  with very alarming results. Following this in  1977 Gordon Stewart in Glasgow, Scotland,  suggested the rate of severe encephalopathy was  1 per 54,000 children. It is important to note  that in none of these studies was there control  for temporally related events due to other  causes.      

In 1978 and 1979, our group carried out an  extensive study involving more than 16,000  children which looked comparatively at the  rates of reactions following DTP vaccines versus  DT vaccines. This study showed that redness,  swelling, and pain at the injection site and fever,  drowsiness, fretfulness, vomiting, anorexia, and  persistent crying were all significantly related to  the pertussis component of the vaccine. In addition,  we noted the occurrence of hypotonichyporesponsive  episodes, febrile convulsions,  and high-pitched unusual crying in association  with DTP vaccine.      

Concern about these severe temporally related  events led to decreased use or stoppage of  immunization in England, Sweden, and Japan  and subsequent epidemics of disease occurred in  all three countries. In the United States there was  considerable media coverage that in contrast to  England, Sweden, and Japan, had little detrimental  effect on vaccine usage, but did result in  an epidemic of DTP lawsuits. At this time it was  pointed out by my close friend and colleague,  Ted Mortimer of Case Western Reserve University,  Cleveland, Ohio, that “subsequences and  consequences are not synonyms.” As an example  he said that “some people who go outside after a  rainstorm and see frogs believe it rained frogs.”      

During the period of extensive study of neurologic  events temporally related to pertussis  immunization, it became apparent to me and  others that what was being called pertussis vaccine  encephalopathy was not an encephalitislike  event, but instead was the first seizure or  seizures of infantile epilepsy. From the period  1976 to 1994 five studies were done, all of  which were controlled for temporally related  events. It is clear from these studies that there is  no such entity as pertussis vaccine encephalopathy.  This led me to write a commentary published  in 1990 entitled “Pertussis Vaccine Encephalopathy—  It Is Time to Recognize It as the  Myth That It Is.” Studies of the period show that  immunization with whole-cell pertussis vaccines  called attention to the early signs of infantile  epilepsy and perhaps moved the events forward  in time, but did not cause these illnesses.      

In regard to SIDS, the age of peak occurrence  is at about 10 weeks of age, and since the first  dose of DTP in the United States was administered  at 2 months of age, the temporal association  with immunization and SIDS would be  expected. However, in the late 1970s and 1980s  there was considerable coverage in the media of  the possibility of a cause-and-effect relationship.  However, a number of well-controlled studies  failed to show a causal relationship between  DTP immunization and SIDS. In fact, immunized  children tended to have less SIDS than  unimmunized children.      


B. pertussis Produces Several Toxins and  Other Important Antigens      

Although dermonecrotic toxin (DNT) was identified  by Bordet and Gengou in 1909, it was  not characterized until 1963. Pertussis toxin  (PT) was identified in 1948 but was not purified  until 1962. Similarly, filamentous hemagglutin  (FHA) was identified in 1947, lipopolysaccharide  (LPS) in 1960, adenylate cyclase toxin  (ACT) in 1973, tracheal cytoxin in 1982, and  pertactin (PRN) in 1982.      

From our studies of whole-cell pertussis vaccines,  we concluded that the fever, local reactions,  irritability, and persistent crying are due  to LPS. Increased serum insulin following immunization  appears to be due to PT. Although  the cause of hypotonic-hyporesponsive reactions  is not known, it may be due to hypoglycemia  from PT-associated increased serum insulin.      


Acellular Pertussis Vaccines      

The first acellular pertussis containing vaccines  (DTaP vaccines) were developed and put into  use in Japan. Using centrifugation techniques,  Yuji Sato, Department of Bacteriology, National  Institute of Health, Tokyo, Japan, and  colleagues concentrated supernatant fluid from  cultures of B. pertussis that contained PT and  other antigens, including LPS. The layers containing  LPS were separated by ultracentrifugation  and discarded, while PT was inactivated  with formalin. These vaccines, produced by six  different manufacturers, were put into general  use in Japan in 1981 and were shown to be  effective. However, because immunization was  not carried out by conventional schedules, and  the studies of reactogenicity and efficacy were  less than adequate, further studies were necessary  prior to the licensure of DTaP vaccines in  the United States and western Europe. A number  of different types of vaccines were evaluated in  studies in Europe and Africa in the early 1990s.      

These vaccines included a single PT component  vaccine, two-component vaccines with PT  and FHA, three-component vaccines with PT,  FHA, and PRN, and four-component vaccines  with PT, FHA, PRN, and fimbriae. One of these  latter vaccines, which is presently in use in the  Untied States, is called a five-component vaccine  because it contains both serotypes of fimbriae.  Studies in the mid-1990s showed that the vaccines  that contained PRN were more efficacious  than vaccines containing PT or PT-FHA.       

In 1991 the first DTaP vaccine was approved  for the fourth and fifth doses in the United  States. Subsequently, in 1996 and shortly thereafter,  a number of vaccines were approved for  the primary series (doses one, two, and three).  With two exceptions, DTaP vaccines are less  efficacious than DTP vaccines.      

Most recently we have had the licensing of  two tetanus, diphtheria, and acellular pertussis  vaccines (Tdap vaccines) for adolescents and  adults. Both of these vaccines have components  similar to their pediatric counterparts but they  contain less diphtheria and smaller amounts of  some or all of the pertussis antigens. The antibody  responses to these vaccines in adolescents  and adults are significantly greater than the responses  in children after three doses of the pediatric  vaccines. This difference suggests that these  vaccines will be highly efficacious and should  protect recipients for more than 5 years.


SUGGESTED READING

 
Cherry, J. D.
2005. The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of Bordetella pertussis infection. Pediatrics 115:1422–1427.
Cherry, J. D. 1984. The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Curr. Problems Pediatr. 14:1–78.
Cherry, J. D. 1990. ‘Pertussis vaccine encephalopathy:’ it is time to recognize it as the myth that it is. JAMA 263:1679–1680.

 

Cherry, J. D., P. A. Brunell, G. S. Golden, and D. T. Karson. 1988. Report of the task force on pertussis and pertussis immunization - 1988. Pediatrics 81(Suppl):939–984.
Cody, C. L., L. J. Baraff, J. D. Cherry, et al. 1981. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 68:650–660.
Friedlander, A. 1925. Whooping-cough (Chapter CXLIII), p. 128–147. In Pediatrics. Abt IA, Ed. W.B. Saunders Company, Philadelphia and London.

Holt, L. E. 1902. Pertussis (Chapter VI), pp. 985–96. In The diseases of infancy and childhood, 2nd ed. D. Appleton and Company, New York.
Lapin, J. H. 1943. Whooping cough. Charles Thomas, Springfield, Ill.
Mattoo, S., and J. D. Cherry. 2005. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin. Microbiol. Rev. 18:326–382. 
  

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