Pertussis Vaccination and Serious Central Nervous System Disorders:
Early Case Series Evidence and Public Reaction

Margaret Ann Goetz

©1997 by Margaret Ann Goetz. All rights reserved


Wide-scale inoculation against pertussis began nearly five decades ago in Great Britain and other industrialized countries. Since that time, pertussis vaccination has been at the center of controversy both in terms of efficacy and its association with complications of the central nervous system. This review will be limited to consideration of the association of pertussis vaccination with serious neurologic complications as documented in early case series through Kulenkampff (1974), with an exploration of the subsequent public outcry and pertussis epidemic in Great Britain in the late 1970s.

Background: Pertussis

Pertussis is a highly contagious respiratory disease spread by airborne droplet. Pertussis is primarily a disease of young children, although cases have been reported in all age groups (Krugman et al., 1977). 10 percent of all cases and 70 percent of all deaths occur in infants under one year of age; approximately two-thirds of cases occur in children under eight years of age. Both incidence and fatality rates are higher among females. Incidence rates appear to be similar in white and non-whites (Institute of Medicine, 1991).

The infection is called 'whooping cough' due to the 'whoop' or high-pitched wheeze accompanied by coughing and vomiting during the paroxysmal stage of pertussis. Duration of the illness is typically 6-10 weeks in uncomplicated cases. Complications include secondary respiratory tract infections such as pneumonia, and neurologic complications such as convulsions, paralysis, seizure and movement disorders, and mental retardation (CDC Pedbase, 1994; Coulter and Fisher, 1985).

Pertussis is caused by Bordetella pertussis, first isolated in 1906 by bacteriologists Bordet and Gengou (Cherry, 1996). Despite intensive study since that time, much remains unknown regarding the organism's biology and pathogenesis. B. pertussis, a polymorphic bacillus, contains a number of allergenic components. Of these, the effect of the component pertussis toxin is thought to be associated with the rapid adverse events occurring after vaccination, although the pathophysiologic responses related to specific clinical symptoms is not clearly defined (Pittman, 1986).

Development of pertussis vaccine

Whole-cell pertussis vaccine was first used on a large scale by Madsen, during a 1925 epidemic in the Faroe Islands. Madsen reported that manifestation of pertussis among vaccinated cases was less severe than among unvaccinated cases (Madsen, 1925).

In the 1930s and 1940s, early concerns regarding pertussis vaccine were primarily those of efficacy. To understand the support for the early pertussis vaccine, it is important to characterize the morbidity and mortality associated with pertussis at the time vaccine became available. In Great Britain, pertussis incidence and mortality rates increased in the early 1940s: in 1940, 53,545 notifications and 678 deaths were reported, figures which more than tripled in 1941 (173,249 notifications and 2383 deaths) (Joint Committee, 1977).

Concerns regarding efficacy of the pertussis vaccine were soon overshadowed by reports of adverse reactions to the vaccine. Early case series and case reports on serious adverse reactions to pertussis vaccine document neurological complications ranging from convulsions and behavioral changes to recurrent seizures, paralysis, cerebral palsy, and death.
[Footnote: In many instances, a case series will refer to one or several of the aforementioned acute events as encephalopathy, which has been variously defined in the literature. Toomey (1949) acknowledges the difficulty in references to encephalopathy as an outcome and attempts to restrict outcomes in his own case series to seizures. This review traces the most groundbreaking case series, which in many instances, involve presentation of both clinical symptoms as well as use of the term encephalopathy.]

Madsen's 1933 report of the death of two infants following pertussis vaccination was among the first published accounts of serious adverse effects associated with the vaccine. Both infants had received initial subcutaneous injections within eight days of birth, leading Madsen to recommend against vaccination of infants under 1 month old. Both infants exhibited cyanosis prior to death; one infant experienced convulsions (Madsen, 1933).

From 1942 to 1944, the Whooping Cough Immunization Committee of the Medical Research Council of Great Britain conducted a small series of cohort studies in day nurseries and infant welfare clinics to assess the effectiveness of the vaccine, the results of which failed to demonstrate vaccine efficacy (McFarlan et al., 1945). Additional trials involving nearly 36,000 children and 19 vaccines with two to three years of follow-up demonstrated a reduced rate of infection among those exposed in the home. These trials were concerned with efficacy, not adverse reactions, but are important in characterizing the initial ambiguities surrounding the vaccine in Great Britain (Coulter and Fisher, 1985).

Due in large part to the groundbreaking 1940s research of Kendrick, pertussis vaccine began to be administered in combination with diphtheria and tetanus toxoids (the DPT combination vaccine). In 1957, Great Britain was immunizing children on a national scale. By 1958, 470,290 children had reportedly completed basic courses of pertussis immunizations; in that same year, a striking fall in incidence and mortality rates associated with whooping cough in Great Britain was documented (Joint Committee, 1977). Whether the decline could be attributed to immunization or to improvements in sanitary practice and care was a much-debated issue (see, e.g., Stewart, 1977).

In 1947, Brody and Sorley documented neurologic complications observed in an infant who experienced five episodes of generalized hypotonia and weakness followed by paralysis, four of which occurred subsequent to an injection of pertussis vaccine. Severe flaccid paralysis followed by respiratory complications and bronchopneumonia ultimately resulted in death. Brody and Sorley hypothesized that these neurovascular sequelae were the result of an in vivo agglutination phenomenon, and recommended against inoculating children with any central nervous system disease or previous neurologic reactions to vaccination (Brody and Sorley,1947).

In 1948, Byers and Moll presented a watershed case series of adverse reactions to pertussis vaccine. This report was crucial to practitioner recognition of the possibility that adverse risks could be associated with pertussis vaccination. Retrospective chart reviews revealed 15 such cases of children, ages 5 to 18 months at time of inoculation, who were admitted or treated as outpatients at Children's Hospital between 1938 and 1947. 14 of the 15 cases identified experienced severe reactions, and had no notable medical history. The common precipitant to neurologic complications was pertussis vaccination, although variation included: time from injection to reaction (mean time 13.3 hours); administration; manufacturer; and duration of reaction. All cases experienced convulsions and changes in consciousness. While follow-up varied, 11 of the 13 surviving children suffered from recurrent convulsions more than one year after vaccination; six children were suffering from cerebral palsy. Recommendations included review or modification of the vaccine or inoculation practices (Byers and Moll, 1948). At the time this study was published, approximately one dozen pharmaceutical companies were manufacturing DPT vaccines (Coulter and Fisher, 1985).

In 1949, Toomey surveyed Ohio pediatricians and select additional practitioners, to identify cases of convulsive reactions attributed to pertussis vaccination. Its myriad of potential biases and limitations aside, the survey identified 38 cases of convulsive reactions subsequent to vaccination and recommended lower dosages of the vaccine for children with a history of CNS disease (Toomey, 1949).

Also in 1949, Globus and Kohn documented the reactions of two male infants who experienced convulsions and unresponsiveness subsequent to pertussis vaccination. One infant (9 months old) continued to experience convulsive episodes at follow-up; the second infant, experienced convulsions, became comatose, and subsequently died; autopsy revealed evidence of degenerative processes in the brain. The authors concluded that an allergic form of encephalopathy was caused by an antigen-antibody reaction (Globus and Kohn, 1949).

In 1958, Berg summarized the findings of 25 case reports or case series of adverse effects of pertussis vaccine, and one personally observed case. His review, encompassing 107 cases of neurological sequelae of pertussis immunization, characterized: patient medical history; dosage and type of pertussis vaccine; clinical features of reaction (time interval, presence of convulsion, paralysis); and outcome (recovery, mental retardation, death). Berg's report highlighted early onset of neurological symptoms, convulsions, and changes of consciousness. An overall recovery rate of 50%, a persistent morbidity rate of 30%, and a mortality rate of 15% are cited (Berg, 1958).

At the time of Berg's report, pertussis vaccination programs were being implemented in nearly all industrialized nations (Coulter and Fisher, 1985). In 1960, over 626,000 children in England and Wales had completed basic courses of pertussis immunizations. By 1962, the number of notifications of pertussis in these countries had decreased to 8,343, with 24 associated deaths, from 24,469 in 1961 (Joint Committee, 1977). Decreased morbidity was also reported in Sweden. Strom's reports of milder symptoms and decreased mortality, versus the neurological risks associated with vaccination, questioned the need for universal vaccination (Strom, 1960). Strom's position and research were controversial, amid claims that he overestimated incidence of encephalopathic complications by including cases with pre-existing abnormalities (Kulenkampff, 1974).

In 1974, Kulenkampff retrospectively examined the medical records of 36 children who presented at the Hospital for Sick Children, London, between 1961 and 1972 with neurological illness (defined as convulsions, infantile spasms, unconsciousness) thought to be associated with pertussis inoculation. Cases with only screaming and fever, and those in which the events occurred more than two weeks following inoculation, were excluded. Of the 36 cases, two died within six months of onset, four experienced a complete recovery, and the remainder experienced paralysis, epilepsy, and/or moderate to severe mental retardation. Despite the retrospective nature of his series, Kulenkampff dismissed the possibility of a chance association between inoculation and the onset of neurologic complications due to the consistent temporal relationship. However, one third of subjects had a previous history of "fits" or family history of seizures, previous reactions to inoculation, recent illness, or previous developmental issues, and Kulenkampff recommended against vaccination of infants with any of these conditions (Kulenkampff, 1974).

Kulenkampff's findings were relayed to the lay public via newspaper accounts and a television broadcast. Additional reports (Dick, 1974; Stewart, 1977) documenting adverse reactions and questioning risk versus benefits of immunization, respectively, contributed to the surge in publicity surrounding the efficacy and risk debate. Stewart estimated the prevalence or risk of children who had suffered adverse reactions to pertussis vaccination in the U.K. to be as high as one in 10,000, a risk exceeding that of death or permanent damage from pertussis itself (Stewart, 1977).

The Chief Medical Officers for England, Wales, and Scotland sent notifications to all physicians alerting them of the possibility that decreased public confidence could lead to decreased vaccination rates (Stewart, 1977). Supported by the 1977 report of the Joint Committee on Vaccination and Immunization, which definitively advocated vaccine use (Joint Committee, 1977), these notifications recommended continuation of DPT vaccination.

Despite official encouragement, and on the heels of adverse media coverage and editorials, Great Britain experienced a subsequent decline in immunizations (Joint Committee, 1977; BMJ editorial, 1981). From 1974-1978, vaccine acceptance rates for pertussis fell from around 80% to 31% (Fenichel, 1983). West Glamorgan, where previous vaccination rates had been about half the national average, documented a vaccination rate of 9.5% of children born in 1974 (Royal College of General Practitioners, 1981).

Beginning in 1977, a sharp rise in notified cases of pertussis became apparent in certain Area Health Authorities (AHAs) in England and Wales. Over the next two years, all AHAs experienced increased rates of notifications. Overall, the notification rate during the 1977-1979 outbreak was about 4 times that of 1974-1975, with the highest rate in children aged 1-4 years (Pollard, 1980). In England and Wales, 5,000 children with pertussis were admitted to hospital (Fenichel, 1983).

As a result of public outcry, additional research efforts on both efficacy and adverse events were launched. Researchers concerned primarily with efficacy used the 1977 outbreak to support claims that the decrease in whooping-cough vaccination rates were the principal cause of increased incidence rates (Pollard, 1980; Church, 1979). The Association of Parents of Vaccine Damaged Children claimed that pertussis vaccine was responsible for 182 of 281 total cases documented by their organization, and sought compensation for families (Church, 1979). In 1976, the British government, prompted by the acknowledged inadequacies of voluntary reporting and the difficulties in establishing causal relationships without controlled trials (Grady, 1978), funded the National Childhood Encephalopathy Study (NCES). A three-year case-control study, NCES was designed to assess the risks of neurological disorders associated with immunization.


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