JAMA, The Journal of the American Medical Association

Wednesday, November 14, 1990

Vol. 264, No. 18, ISSN: 0098-7484

Pertussis vaccine encephalopathy. (includes replies) (letter to the editor)

James E. Lewis John H. Menkes Vincent Garbitelli John A. Tilelli Robert L. Manniello Marie R. Griffin Wayne A. Ray William Schaffner Gerald M. Fenichel, Edward A., Jr. Mortimer James D. Cherry

To the Editor. - In his editorial proclaiming the myth" of pertussis vaccine encephalopathies, Cherry' fails to recognize the paucity of conceptually and methodologically sound research on the insidious neurotoxic effects of the whole cell" pertussis vaccine. There is little scientific dispute that the pertussis toxin can produce acute local and systemic reactions. The more heated controversy has focused on whether these acute symptoms also involve lasting central nervous system effects, or, as Cherry's referenced studies describe, permanent brain damage" and "serious neurologic illness. "

At a minimum, a conceptually sound cause-and-effect study of hypothesized pertussis vaccine encephalopathies would specify and operationally define the full range of potential sequelae, ie, mild, moderate, and severe pertussis vaccine encephalopathies. An animal experimental paradigm employed by Goh and Pennefather recently identified a significant neuropathologic mechanism of pertussis toxin, the functional "uncoupling" of G-type proteins in a hippocampal region, effecting disruption of long-term synaptic potentiation. Given that a human analogue of long-term synaptic potentiation disruption would include disturbance of immediate memory and related attention processes, a conceptually sound study of pertussis vaccine encephalopathies should include examination for higher cerebral dysfunction. A methodologically sound study of pertussis vaccine encephalopathies should include neuropsychometric and other behavioral neurotoxicity measures that are capable of detecting the full range of suspected sequelae and not simply be content defining only the tail of the distribution of likely pertussis toxin effects (eg, so-called serious neurological illness).

The studies endorsed by Cherry as proving no permanent brain damage from pertussis toxin have never operationally defined comprehensively or examined with reliable detection measures the full range of pertussis toxin-produced encephalopathies. Neither office neurological examinations nor Medicaid mothers' reporting of frank or partial complex seizures is a reliable system of measurement for detecting mild to moderate pertussis vaccine encephalopathies (with arguable sensitivity for the identification of severe pertussis vaccine encephalopathies). Pertussis vaccine encephalopathies researchers and editorial writers should note the Topics in Radiology article by Jordan and Zimmerman' that precedes Cherry's JAMA editorial. Though pertussis toxin-affected children are not meant herein to be precisely compared with brain-injured boxers, there is an analogous lesson. "Subtle" encephalopathies from boxing "trivial" concussions) were long thought to be a myth when evidence of suspected brain damage was limited to "hard" signs on neurological examination or on clear-cut computed tomographic findings. Jordan and Zimmerman and the studies they reference demonstrate the presence of subtle structural and central nervous system functional abnormalities through use of magnetic resonance imaging and neuropsychometric measures. Insidious pertussis toxin-induced permanent brain damage, but with nonetheless significant devastation of central nervous system function, is not impossible to investigate.'

Finally, Pizza et al' have produced nonneurotoxic vaccine strains with immunogenic properties equal or superior to those of the current vaccine, removing a major obstacle in the switch over" to a safer vaccine. Cherry's editorial, sensationalized in international news media, could have better served the public if the proselytizing had had a different thrust: toward a worldwide interdisciplinary effort among the medical arts and sciences, animal neuroscience investigators, and clinical neuropsychologists to seek the "whole truth" about the effects of the "whole cell" pertussis vaccine.

James E. Lewis, PhD Clinton, Md

1. Cherry JD. Pertussis vaccine encephalopathy: it is time to recognize it as the myth that it is. JAMA. 1990;263:16791680.

2. Goh J, Pennefather P. Pertussis toxin-sensitive G protein in hippocampal long-term potentiation. Science. 1989; 244:980-982.

3. Jordan BD, Zimmerman RD. Computer tomography and magnetic resonance imaging comparisons in boxers. JAMA. 1990;263:1670-1674.

4. Lewis JE. Neuropsychological toxicology in pertussis vaccine

encephalopathies: renewed public health controversy. Clin Neuropsychol. In press.

5. Pizza M, Covacci A, Bartoloni A, etal. Mutants of pertussis toxin suitable for vaccine development. Science 1989;246:497499.

To the Editor. -There is scarcely a subject in pediatric neurology that has evoked more controversy among both professional and lay groups than the neurological complications that have been encountered following pertussis immunization. It would therefore have been prudent on the part of THE JOURNAL to provide its readers with more than one point of view.

Cherry,' in his editorial, calls for an end to the "myth of pertussis vaccine encephalopathy." Before we heed his call, the following facts

must be considered.

Pertussis toxin, whose concentration in pertussis vaccine varies from one batch to the next, is not a harmless substance. It can attach itself to neuronal membrane receptors and by adenosine diphosphate-ribosylation modify the adenylate cyclase system in such a way as to impair the action of inhibitory neurotransmitters and enhance the action of excitatory neurotransmitters."' Whereas in the vast majority of instances the blood-brain barrier prevents entry of the toxin into the brain, temporary disruption of the barrier by one or more of several factors, including concurrent viral disease or fever, could facilitate access of toxin to nerve cells and result in seizures, neuronal death, or both.

None of the epidemiologic studies have exonerated pertussis vaccine from inducing permanent brain damage. All are confounded by the relatively low incidence of permanent neurological complications and by the differences in pertussis vaccine as used at different times and in different locales. The study by Griffin et al' evaluated the risks for seizures and other serious neurological events in 38,171 children who received 107,154 doses of vaccine. Based on the incidence of encephalopathy derived from the British National Childhood Encephalopathy Study, we would expect to see 0.3 cases of permanent damage. Therefore, as conceded by the authors, the study by Griffin et al was far too small to disprove any causal relationship between pertussis vaccination and permanent encephalopathy. Furthermore, Griffin et al recorded only six febrile seizures within 72 hours of vaccination (1/17 859), one tenth the incidence of febrile seizures (1/1750 vaccine doses) encountered by Cherry's 'group. The Puget Sound Study,' cited by Cherry as one of several studies in which no permanent neurological damage followed pertussis vaccination, actually reported the case of one child who developed a prolonged seizure within 24 hours of pertussis vaccination, with subsequent uncontrolled focal seizures.

The National Childhood Encephalopathy Study remains the best available inquiry into neurological complications associated with pertussis vaccine. It suggested, but did not prove, that the vaccine rarely causes permanent neurological damage. Although the National Childhood Encephalopathy Study has been found to have several biases, these tend to balance each other. Ib focus on one set of biases, and to dismiss this study by reassessment of selected cases, is contrary to the scientific principles of the study and therefore unacceptable.'

Finally, for a pediatric neurologist, pertussis vaccine encephalopathy is not a myth but instead is a rarely encountered reality in that there are a small number of previously normal infants who develop a permanent neurological disorder in very close temporal proximity to pertussis vaccination, and in whom extensive diagnostic studies do not uncover any other underlying cause.

This controversy should not deter the practitioner from vaccination of infants; rather, it should alert him to an ongoing confrontation between science and ideology. Such confrontation is not unique; only the ideologies differ. "E pur si move.!"'

John H. Menkes, MD Beverly Hills, Calif

1. Cherry JD. Pertussis vaccine encephalopathy: it is time to recognize it as the myth that it is. JAMA. 1990;263:16791680.

2. Dolphin AC. Nucleotide binding proteins in signal transduction and disease. Trends Neurosci. 1987; 10:53-57.

3. Black WJ, Munoz, JJ, Peacock MG, et al. ADP-ribosyl-transferase activity of pertussis toxin and immunomodulation by Bordella pertussis.

Science. 1988;240:656-659.

4. Giffin MR, Ray WS, Mortimer EA, Penichel GM, Schaffner W. Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-petussi, vaccine. JAMA. 1990;263:1641-1645.

5. Cody CL, Baraff L.T, Cherry JD, Marcy SM, Manclark CR. Nature and rate of adverse reactions associated with DTP and DT immunization in infants and children. Pediatrics. 1981;68:650-660.

6. Walker AM, Jick H, Perera DR, Knauss TA, Thompson RS. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatrics 1988;81:345-349.

7. Miller DL, Wadsworth MJH. Petussis vaccine and severe acute neurological illness. Vaccine. 1989;7:487-489.

8. But it does move. The remark attributed to Galileo immediately after he was forced to recant his views on the earth's motion before the Inquisition, 1633.

To the Editor. - It seems that Dr Cherryl almost misses the point of the pertussis vaccine controversy. In the last line of his editorial he states, "New vaccines are needed ... to decrease the many disquieting reactions such as high fever, persistent uncontrollable crying, and hypotonic, hyporesponsive state, that do occur. . . . " That is the point. Because an infant cannot ever describe an awful headache, the infant would behave in exactly the "disquieting" manner that Dr Cherry describes. Like most diagnoses in medicine, encephalopathy is a clinical diagnosis. At this point in medicine, no computed tomographic scan, magnetic resonance imaging, or spinal tap could really prove the diagnosis. What is clear is that those babies reacting to the pertussis vaccine are sick and probably do have an encephalopathy. Most physicians do recognize that a sequence of events does not mean that one event caused a subsequent event, but clinical diagnosis is based on allowing physicians to make inferential judgments with an index of suspicion that one event may indeed have caused a subsequent event.

In fact, the observation of an adverse reaction to a vaccine, a drug, or anything else is a basic part of the scientific mind-set. Of course, it is understood that a rare adverse reaction will be difficult to prove (as to causation), but that does not mean the reaction is mythical. In addition, it is the disquieting" reactions that do occur regularly with the whole cell pertussis vaccine that have prompted the call for a better vaccine. Rather than berate those who suspect there is a pertussis vaccine encephalopathy (demonstrated by Cherry's disquieting symptoms), Dr Cherry should keep an open mind and accept that the possibility exists. Calling something mythical because you don't believe it exists is sophistry. I don't believe in myths either, but I do believe in possibilities.

Vincent Garbitelli, MD East Williston, NY

1. Cherry JD. Pertussis vaccine encephalopathy: it is time to recognize it as the myth that it is. JAMA. 1990;263:16791680.

To the Editor.-We read with interest the article by Griffin et al' that recently appeared in JAMA and concur with the authors that the incidence of encephalopathy with permanent neurological sequelae after diphtheria-tetanus-pertussis (DTP) immunization is low, and is probably lower than that calculated from the often-quoted British National Childhood Encephalopathy Study. These data reinforce the conclusion that DTP vaccination is safe in an overwhelming number of children. We believe, however, that it is hazardous to draw the conclusion, as the authors do, that DTP immunization might never cause permanent neurological disease. The absence in this population of unexplained encephalopathy does not help to reconcile the reports of such events in the case literature and of their continued observation by individual pediatricians. It has been suggested that most of these events are coincidental occurrences,' but none were observed in this prospective

study: their absence does not shed light on whether they are real. Indeed, the report of the Committee on Infectious Diseases implies that the diagnosis of vaccine-associated encephalopathy is established when a temporal relationship of new neurological disease without apparent cause to a DTP immunization is present.'

We furthermore take exception to the editorial comments of Dr Cherry'in the same issue stating that these data prove pertussis vaccine encephalopathy to be a myth, and claiming that the National Vaccine Injury Compensation Program is nonsense. The aggregation of prospectively collected data is at best statistically hazardous and does nothing to satisfy the objection cited above. This study does not justify the termination of the program. As our society mandates the benefits of universal vaccination, it must be prepared to compensate the rarely injured individual, whether or not prospectively obtained data

are able to define the precise risk.

Finally, we are concerned about allegations in the popular press that several of the authors of these articles had undisclosed financial ties to the manufacturers of the vaccine at the time of writing (Los Angeles Times. March 24, 1990). The specter that the publication and review of these data might be self-serving has implications beyond the DTP debate that affect physicians everywhere who are trying to make therapeutic decisions based on published prospective and anecdotal data, as well as personal experience. As supporters of the compensation program, and as witnesses to what we believe are the victims of what these authors allege does not occur, we urge that prudent reserve be observed in the collection and interpretation of data defining reaction rates to DTP vaccine on the way to the development of a safer, more effective vaccine.

John Tilelli, MD

Robert L Manniello, MD

Arnold Palmer Hospital for Children and Women

Orlando, Fla

1. Giffin MR, Ray WA, Mortimer EA, Fenichel GM, Schaffher W. Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine. JAMA. 1990;263:1641-1645.

2. Miller DL, Ross EM, Alderslade R, et al. Pertussis immunization and serious acute neurological illness, in children. BMJ. 1981;282:1595-1599.

3. Cherry JD, Brynell PA, Golde, GS, Kan DT. Report of the Task Force on Pertussis Immunization - 1988. Pediatrics, 1988;81(suppl):939-984.

4. American Academy of Pediatrics, Committee on Infectious Diseases,. Pertussis (whooping cough). I,: Report of the Committee an Infectious Diseases. 20th ed. Elk Grove Village, Ill: American Academy of pediatries; 1986:266-275. 5. Cherry JD. Pertussis vaccine

encephalopathy: it is time to recognize it a, the myth that it is. JAMA. 19%;263:16791680.

In Reply. -We agree that our data do not prove DTP immunization never causes encephalopathy; our study of 38,171 children with 107,154 immunizations did not have sufficient power to detect rare events.

However, the consistency of our findings with those of two other recent controlled studies of this question'-' led us to comment that if there are encephalopathies caused by DTP immunization, they must be rare. We disagree with the presumption of Tilelli and Manniello that it is established that DTP immunization can cause encephalopathies.

Uncontrolled case reports and observations by individual pediatricians do not constitute a scientific basis for establishing causality. The information cited from the 1986 "Redbook"' is based on the British National Childhood Encephalopathy Study; recent reanalysis of these data have cast doubt on the original finding of an association between DTP immunization and permanent neurological damage. Thus, the extant data are consistent with either no association or a weak association between DTP vaccine and encephalopathy.

Marie R. Griffin, MD

Wayne A. Ray, PhD

William Schaffher, MD

Gerald M. Fenichel, MD

Edward A. Mortimer, Jr, MD

Vanderbilt University School of Medicine Nashville, Tenn

1. Walker AM, Jick H, Pererra DR, et al. Neurologic events following diphtheria tetanus pertussis immunization. Pediatrics. 1988;81:345-349.

2. Shields WD, Nielsen C, Buch D, et al. Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. J Pediatr 1988;113:801805.

3. American Academy of Pediatrics, Committee on Infectious Diseases. Pertussis(whooping cough). In: Report of the Committee on Infectious Disease. 20th ed. Elk Grove Village, Ill: America, Academy of pediatrics; 1986:266-275,

4. Stephenson JBP. Pertussis vaccine on trial; science vs the law (High Court of London). In: FEM-Symposium Pertussis: Proceedings of the Conference Organized by the Society of Microbiology and Epidemiology of the GDR; April 20-22, 1988; Berlin, Federal Republic of Germany.

In Reply. -The letters of Lewis, Menkes, Garbitelli, and Tilelli and Manniello all contain errors of fact and reasoning and seem to be aimed at preserving the myth of pertussis vaccine encephalopathy. Dr Menkes implies that in my assessment of the National Childhood Encephalopathy Study I focused on one set of biases. This is not true. Even though there clearly were biases that tended to exaggerate the calculated risks, the original data alone do not indicate a cause-and-effect relationship but only the redistribution of events over time.' If you believe that the increased number of vaccinations in cases during the 0- to 3-day period indicates a causative effect of vaccine, then by the same reasoning you must believe that the increased number of vaccinations in the controls during the rest of the observation period was protective against disease.

Since after considerable study there is no epidemiologic evidence that supports the idea that pertussis vaccine causes brain damage, there is little sense in seriously considering the various animal and laboratory systems that describe mechanisms by which pertussis toxin, or lymphocytosis-promoting factor, is perceived to cause brain damage. Dr Lewis states that "there is little scientific dispute that the pertussis toxin can produce acute local and systemic reactions." While it is true that pertussis vaccine causes local and systemic reactions, there is no evidence at the present time that indicates that the reactions are due to pertussis toxin. In the only study that I am aware of, the intravenous injection of purified pertussis toxin in large doses (0.5 and 1.0 [Lg/kg) to adult volunteers resulted in no adverse effects.' Although the report by Goh and Pennefatheris of considerable scientific interest, it is also a perfect example of how the myth of pertussis vaccine encephalopathy is perpetuated. The authors of that study state, "Pertussis toxin (PT) is the causative agent in pertussis vaccine encephalopathy," but their reference for this pronouncement is in reality one that describes a model of anaphylaxis.' It should also be pointed out that in the mouse protection test in which live Bordetella pertussis organisms are inoculated intracerebrally, the susceptible animals die of infection and not of a toxic encephalopathy.

Dr Menkes also assumes that pertussis toxin-animal model systems can in some way be translated into facts relating to vaccinated children. Wardlaw' has adequately shown the fallacy in this extrapolation of data from the studies referenced by Menkes to the immunization of infants.

The amount of pertussis toxin that is liberated in the body during whooping cough is magnitudes greater and present longer than that resulting from immunization. If pertussis toxin is as neurotoxic as the letter writers believe, every child with pertussis should suffer brain damage. To date, the only verified manifestations of pertussis toxin in B pertussis-infected humans are lymphocytosis and perhaps mild hyperinsulinemia.'

Finally, the results of the recent controlled studies on the risks of pertussis vaccines can be likened to the discoveries in previous decades that linked smoking and lung cancer. The only major group today that suggests that smoking is not harmful consists of those making money from tobacco sales. Similarly, those who are working the hardest to preserve the myth of pertussis vaccine encephalopathy are the special interest groups (segments of the news media and plaintiff lawyers and their clients and professional experts) who profit from a continuation of the controversy.

All handicapped children and their families have enormous problems. Would it not be better to have a national program to provide services to all children with handicaps rather than the present program that offers support to a few children in whom the onset of illness was temporally related to immunization? All of us who express advocacy for children should work toward this goal.

James D. Cherry, MD

University of California at Los Angeles School of Medicine

1. Cherry JD. Pertussis and the vaccine controversy. In: Hoot RK, Warren KS, Griffiss JM, Sande MA, eds. Immunization: Cotepory Issms in Infectios Diseases. New York, NY: Churchill Livingstone Inc; 1989;8:47-63.

2. Toyota T, Kai Y, Kaldzaki M, et al. Effects of is-letactivating protein (IAP) on blood glucose and plasma insulin in healthy volunteers

phase 1 studies). Tohok, J Exp Med. 1980;130:105-116.

3. Goh JW, Pennefather PS. A pertussis toxin-sensitive G protein in hippocampal long-term potentiation. Science. 1989;244:980-983.

4. Wardlaw AC. Laboratory aspects of the UK pertussis vaccine test case.

In: FEMS-Symposium Pertussis: Proceedings of the Conference Organized by the Society of Microbiology and Epidemiology of the GDR; April 20-22, 1988; Berlin, Federal Republic of Germany.

5. Furman BL, Walker E, Sidey FM, Wardlaw AC. Slight hyperinsulinemia but no hypoglycemia in pertussis patients. J Md Microbiol. 1988;25:183-186.

Editorial Note. -Because numerous allegations of conflict of interest have been made, we asked the above authors to enlarge upon the financial conflict of interest forms that all had signed. Some of their statements were long, but in brief: Dr Cherry's work has been supported by grants from Wyeth and Lederie, and he has been a consultant to Lederle (see also JAMA 1990;263: 2182). Dr Menkes has received grants from Abbott Laboratories, CIBA-Geigy, and Roche Laboratories. Dr Mortimers laboratory receives support from Lederle. The other authors state that they have not received any grants from pharmaceutical companies.

Dr Lewis has testified about the condition of one of his own patients. Drs Menkes, Tilelli. Cherry, and Mortimer have given testimony concerning the effects of the vaccine: Dr Menkes in approximately 25 cases (for which he received compensation), Dr Tilelli (who is employed as a consultant to groups seeking compensation) in approximately 39 cases, Dr Cherry in approximately 12 cases, and Dr Mortimer in approximately 20 cases, Drs Mortimer and Cherry note that any fees went to their institutions.

Drs Griffin, Ray, Schaffner, and Fenichel's financial disclosure forms were filed at the time their article was published, and it was thought by the editors that no disclosure to our readers was required. Neither they nor Dr Garbitelli or Dr Manniello have testified on this i2,

Drummond Rennie, MD