Review of:

"EFFECTS OF DIPHTHERIA-TETANUS-PERTUSSIS OR TETANUS
VACCINATION AND ALLERGY-RELATED RESPIRATORY
SYMPTOMS AMONG CHILDREN AND ADOLESCENTS
IN THE UNITED STATES"

Hurwirtz E, Morgenstern H.  J Manipulative Physiol Ther  2000;23:81-90


  In the Journal of Manipulative and Physiological Therapeutics, Hurwitz and Morgenstern(1) reported the results of a cross-sectional study that examined a potential association between diphtheria-tetanus-pertussis (DTP) or tetanus vaccination and subsequent allergies or respiratory symptoms in children. The authors concluded that such vaccination appears to raise the risk of allergic responses.

  The authors assert that DTP vaccine components cause a TH1-to-TH2 shift in CD4 cells, citing the works of Mu and Sewell (2) and Rook and Stanford.(3) However, the study by Mu and Sewell did not involve DTP vaccine, but actual pertussis toxin. Thus, if such a CD4 shift takes place, we would expect it to occur in active whooping cough disease, not just in the pertussis vaccine. The authors failed to note that the claims of Rook and Stanford were later refuted by Brady et al, (4) who demonstrated that whole cell pertussis vaccines do indeed induce TH1-type responses in infants. Further, the new acellular vaccines, including diphtheria and tetanus toxoids, also produce mixed TH1 /TH2 cytokine profiles. Brady et al (4) further demonstrate that allergic sensitivity is slightly increased in children with a history of pertussis infection. Thus, it appears possible pertussis infection itself, more than pertussis vaccine, that contributes to allergy sensitivity.

  Some previous papers that suggested a pertussis vaccine/asthma link suffered from limitations that prevented firm conclusions. The review by Odent and Culpin (5) was a limited, uncontrolled, in-office survey. Odent acknowledged the need for better studies. Farooqi and Hopkin (6) urged caution in the interpretation of their results, noting the possibility of confounding effects and reverse causation. The study by Kemp et al (7) suffered from a very small number of unvaccinated children (n = 23) on which to base a comparison.

  The Hurwitz and Morgenstern' study suffered similarly from having a small number of unvaccinated children (1%) for comparison.  This contributed to the wide 95% confidence intervals (CIs) reported.

  The limitaions of the Hurwitz study become clear when it is compared to what is arguably the best study to date on the topic: the 1999 study by Henderson et al (8) on pertussis vaccination and wheezing. This study had a number of positive attributes that make it worthy of consideration. It was a controlled, prospective study rather than a limited cross-sectional survey as in the Hurwitz paper.  It further had a much larger unvaccinated comparison group, which resulted in better statistical significance. Henderson also tracked age of asthma onset, and  planned a population follow-up. The larger, better, prospective Henderson  paper concluded:
"No evidence was found that pertussis vaccination increases the risk of wheezing illnesses in young children."

  A similar finding was also noted by Nilsson and Storsaeterl who failed to find any association between pertussis vaccination and asthma or allergy.  In comparing DTP vaccines against a placebo vaccine Nilsson specifically notes:
"We found no significant differences between the DTP vaccination groups in the proportions of children with reported wheezing, itchy rash, or sneezing."
And also:
"These results suggest that there is no reason to withhold pertussis vaccination because of fear of subsequent asthma or allergy."
(9)

  The Hurwitz paper can also be compared to another randomized study by Nilsson et al (10)  who examined for the effect of pertussis vaccines on atopic disease and
"...found no support for a drastic increase in allergic manifestations after pertussis vaccination."

  This is reminiscent of an earlier era in DTP's history. Two decades ago, similar limited case history and cross-sectional studies, such as the one by Baraff et al, (11) suggested a possible temporal association between pertussis vaccination and sudden infant death syndrome(SIDS). In time larger, better controlled, more sensitive prospective studies have consistently and overwhelmingly demonstrated that not only does pertussis vaccine not cause sudden infant death syndrome, it may offer a protective effect against it. (12-16)

  Similarly, the notion of an encephalopathy/DTP association has now been demonstrated to be a myth. (17)

  As additional controlled prospective studies are done, rather than limited cross-sectional studies such as the one by Hurwitz and Morgenstern, they will likely show a similar outcome in the issue of DTP/asthma: no connection.

  Authors Hurwitz and Morgenstern speculate that perhaps 50% of asthma cases could be prevented by not administering DTP vaccine. If the pertussis vaccine effect were that large, it should have readily shown up in the more sensitive prospective studies by Henderson et al (8) and Nilsson and Storsaeter.(9)  The fact that these other larger, better studies have found no such effect demonstrates the severe limitations of the Hurwitz study and brings its credibility into question.

  Further, if there were a DTP/asthma association we should be seeing exceptionally high asthma incidence in just those countries with high levels of DTP immunization. This is clearly not the case. China, as just one of several examples that could be cited, has consistently high levels of DTP immunization, typically well above 90%,(18) but its incidence of asthma is among the lowest on earth. (19)

  Another example is found in Sweden.  In 1979, amid concerns about DTP vaccine safety, Sweden suspended pertussis immunization.  This was followed by at least two major pertussis outbreaks.(20)  Pertussis immunization was not reimplemented in Sweden until the mid-1990's.  Sweden provides an ideal testbed to compare the incidence of asthma in Sweden with adjoining Scandanavian and other European countries who continued with DTP immunization programs.

  Current data demonstrates that Sweden has an incidence of asthma of 6-7% (21), which is comparable to other similar countries.  American for example has an asthma incidence of 7% (22).  Nearby Norway reports an asthma incidence of   4.6%.(23)

Obvious conclusion:  Complete suspension of DTP immunization for approximately 16 years brought absolutely no benefit to Sweden in terms of asthma incidence.

  The authors concluded a potential pertussis vaccine/asthma effect based on a limiting cross-sectional study. In better controlled prospective studies by Henderson et al (8) and Nilsson and Storsaeter,(9) however, no such effect could be found.

  No controlled prospective study has ever found any association between pertussis vaccination and asthma/allergy incidence.

  Hurwitz and Morgenstern (1) accurately state that their study design and the small number of unvaccinated children in their study preclude definitive causal inferences. It is to be predicted that the anti-vaccination community will, in typical fashion, ignore this statement and the numerous other conflicting studies that refute their position.

REFERENCES:

1. Hurwitz E, Morgenstern H. Effects of dipthera-tetanus-pertussis or tetanus vaccination
    and allergy-related respiratory symptoms among children and adolescents in the United States.
   J Manipulative Physiol Ther 2000;23:81-90.

2. Mu H, Sewell W. Enhancement of interleukin-4 production by pertussis toxin.
   Infect Immun 1993;61:2834-40.

3. Rook G, Stanford J. Give us this day our daily germs.
    Immunol Today 1998;19:113-6.

4. Brady M, Mahon B, Mills K. Pertussis infection and vaccination induces TH1 cells.
    Immunol Today 1998; 19:534.

5. Odent M, Culpin E. Pertussis vaccination and asthma: Is there a link?
   JAMA 1994;272:592-3.

6. Farooqi 1, Hopkin J. Early childhood infection and atopic disorder.
    Thorax 1998;53-927-32.

7. Kemp T, Pearce N, Fitzharris P, Crane J, Fergusson D, St George J, et al.
    Is infant immunization a risk factor for childhood asthma or allergy?
    Epidemiology 1997;8:678-80.

8. Henderson J, North K, Griffiths M, Harvey 1, Golding J.
    Pertussis vaccination and wheezing illnesses in young children: prospective cohort study.
    Br Med J 1999;318:1173-6.

9. Nilsson L, Storsaeter J.
    Lack of association between pertussis vaccination and symptoms of asthma and allergy [letter].
   JAMA 1996;275:760.

10. Nilsson L, Kjellman N, Bjorksten B. A randomized controlled trial of the effect of pertussis
      vaccines on atopic disease.
      Arch Pediatr Adolesc Med 1998; 152:734-8.

11. Baraff L, Ablon W, Weiss R.
      Possible temporal association between diphtheria-tetanus toxoid-pertussis vaccination and
      sudden infant death syndrome.
      Pediatr Infect Dis 1983;2:7-11.

12. Fujita T, Kato N.
      Risk factors for SIDS in Japan: a record-linkage study based on vital statistics.
      Acta Pediatr Jpn 1994;36:325-8.

13. Mitchell D.
      Immunization and the sudden infant death syndrome
      Archives of disease in childhood. 1995.

14. Heininger U, Stehr K, Schmidt-Schlapfer G, Penning R, Vock R, Kleemann W, et al.
      Bordetella pertussis infections and sudden unexpected deaths in children.
      Eur J Pediatr 1996; 1 55:551-3.

15. Hodder SL, Mortimer EA Jr.
      Epidemiology of pertussis and reactions to pertussis vaccine.
      Epidemiol Rev 1992;14:243-67.

16. Griffith M, Ray W, Livengood J.
      Risk of sudden infant death syndrome after immunization with the diphtheria-tetanus-per- tussis vaccine.
     N Engl J Med 1988;319:618-23.

17. Cherry J.
      Pertussis vaccine encephalopathy: It is time to recognize it as the myth that it is.
      JAMA 1990;263:1679-80.

18. http://www.who.int/vaccines-surveillance/intro.html

19. Bailin A, Somekh E, Meyetes D.
      High rate of asthma among immigrants.
      Med Hypotheses 1996;51:281-4.

20. Romanus V. et al Pertussis in Sweden after the cessation of general immunization in 1970.
      Ped Infec Dis Jrnl 1987; 6(4):364--371.

21. http://www.lef.org/protocols/abstracts/abstr-014a.html

22. http://www.ama-assn.org/special/asthma/library/readroom/pr7003.htm

23. Nystad W, Magnus P, Gulsvik A
     Increasing risk of asthma without other atopic diseases in school children:

     a repeated cross-sectional study after 13 years.
     Eur J Epidemiol 1998 Apr;14(3):247-52





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