Pediatric Bone Marrow Transplantation: Current Progress and Future Prospects

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REFERENCES

1. Shahar E, Feigl A, Barzilay Z, et al: Amiodarone in control of sustained tachyarrhythmias in children with the Wolff-Parkinson-White syndrome. Pediatrics 1983;72:813-816 2. Rosenbaum MB, Chiale PA, Halpern MS, et al: Clinical

efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 1976;38:934

3. Wheeler PJ, Puritz R, Ingram DV, et al: Amiodarone in the treatment of refractory supraventricular and ventricular arrhythmias. Postgrad Med J 1979;55:1-9

4. Leak D, Eydt JN: Control of refractory cardiac arrhythmias with amiodarone. Arch Intern Med 1979;139:425-428 5. Ward DE, Camm AJ, Spurrell RAJ: Clinical antiarrhythmic

effects of amiodarone in patients with resistant paroxysmal tachycardias. Br Heart J 1980;44:91-95

6. Sicart M, Besse P, Choussat A, et al: Action hemodynamique de l’amiodarone intra-veineuse chez l’homme. Arch Mal Coeur 1977;70:219-277

7. Sobol SM, Rakita L: Amiodarone, letter. Circulation

1979;60:1426-1427

8. Sobol SM, Rakita L: Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: A possible compli-cation of a new antiarrhythmic drug. Circulation 1982;

65:819-824

9. Harris L, McKenna WJ, Rowland E, et al: Side effects of long-term amiodarone therapy. Circulation 1983;67:45-51 10. McGovern B, Garan H, Kelly E, et al: Life-threatening

reactions during amiodarone therapy, abstracted.

Circula-tion 1983;66:II-224

11. Greene HL, Graham EL, Sears GK, et al: Extracardiac effects of amiodarone therapy, abstracted. Circulation 1983;66:II-224

12. Koren G, Hesslein PS, MacLeod SM: Digoxin-Toxicity due to amiodarone in children. J Pediatr, in press 1984 13. Costigan DC, Holland FJ, Hesslein PS, et al: The effects of

amiodarone (AM) on thyroid function in children, ab-stracted. Pediatr Res 1983;17:161A

14. Gillette PC, Garson A, Kugler JD, et al: Surgical treatment of supraventricular tachycardia in infants and children. Am J Cardiol 1980;46:781

818 PEDIATRICS Vol. 72 No. 6 December 1983

drome for which amiodarone therapy was preferred. Fortunately, medically refractory and surgically in-accessible Kent bundles are exceedingly rare, and long-term amiodarone therapy is, therefore, not often necessary.

PETER S. HESSLEIN, MD, FRCP(C)

Division of Cardiology Department of Paediatrics

University of Toronto and The Hospital for Sick Children Toronto

Pediatric

Bone

Marrow

Transplantation:

Current

Progress

and Future

Prospects

Allogeneic bone marrow transplantation (BMT) has been applied with increasing frequency and

success to the treatment of children with severe immune deficiency disease,”2 aplastic anemia,3’4 and the acute leukemias.58 Patients with these

otherwise rapidly fatal diseases receive an intrave-nous infusion of marrow from a healthy donor. The healthy marrow either “replaces” the deficient

mar-row of children with immune deficiency or aplastic anemia, or “rescues” the marrow of children who have received ablative antileukemic therapy. The resultant engraftment makes the patient a chimera, with reconstitution of mature hematopoietic and immunologic cells of donor origin. When successful, this results in long-term survival with normal mar-row function, no recurrence of the original disease, and a return to normal childhood activity and func-tion with only a few irreversible but major side

effects (such as infertility following total body ir-radiation).9

This desired result occurs in approximately half of the patients currently receiving transplantation under optimal circumstances for the above

dis-eases.’#{176}These successes depend on four major fac-tors.

First, the immune system of the recipient must not be allowed to reject the donor’s bone marrow.

Potent immunosuppressive pretransplant “condi-tioning” is required, but is not always effective. This includes varying combinations of cyclophos-phamide and busulfan or total body irradiation, depending on the patient’s disease and immune status.

Second, the T lymphocytes included with the donor bone marrow must not be allowed to recog-nize and destroy host tissues; otherwise the condi-tion recognized as graft versus host disease will occur. A major factor in preventing graft versus host disease involves the avoidance of any foreign major histocompatibility (HLA) antigens which may serve as targets for donor T-lymphocyte at-tack.” This is currently accomplished by only transplanting marrow from an HLA identical

sib-Reprint requests to (P.M.S.) University of Wisconsin, Clinical Science Center, 600 Highland Aye, Rm K4/448, Madison, WI 53792.

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820 PEDIATRICS Vol. 72 No. 6 December 1983

on their ability to bind soybean agglutinin and

sheep RBCs. Initial results with immunodeficient children receiving T-lymphocyte-depleted HLA mismatched marrow prepared by this approach have been encouraging, although graft versus host disease has not been totally avoided.24 This result has stimulated the development of other

ap-proaches designed to thoroughly remove T

lympho-cytes from marrow using a more convenient treat-ment to allow T-cell depletion of the larger volumes of marrow needed for BMT of adults and older children with leukemia or aplastic anemia.

A number of monoclonal antibodies specific for human T cells have been identified. Several centers

have shown that in vitro pretreatment of bone marrow with anti-T-cell monoclonal antibody alone

does not abrogate graft versus host disease; appar-ently, viable antibody-coated T cells are not en-tirely removed by the host’s reticuloendothelial sys-tem and can therefore still cause graft versus host disease.2527 Thus the T cells must be destroyed or removed prior to infusion. The in vitro addition of baby rabbit serum as a complement source to mar-row treated with anti-T-cell antibody can effi-ciently deplete T cells and abrogate T-cell func-tion.2’ This may enable the infusion of HLA-matched or mismatched marrow with little or no resultant graft versus host disease. Preliminary

en-couraging results with this approach have been reported.29’3#{176} We are continuing with this technique, and so far have found far less graft versus host disease than anticipated, both with matched and mismatched donors. Other similar approaches may utilize monoclonal anti-T-cell antibodies bound to potent toxins to deplete conveniently marrow of T cells in vitro. This is a new area of clinical research.

As the graft versus host disease problem is avoided by T-cell depletion techniques, new unforseen

prob-lems may arise. The stability of hematopoietic en-graftment and the recovery of normal T-cell func-tion following a T-depleted BMT are both concerns

that will require more detailed evaluation.

LEUKEMIC RELAPSE

Presently, leukemic patients receive total body irradiation and cyclophosphamide prior to most transplants. The goal is to eliminate all leukemic cells prior to hematopoietic rescue with allogeneic marrow. That leukemia recurs for many patients

with acute lymphoblastic leukemia, and a smaller proportion of those with acute myelogenous leuke-mia, is indicative of survival of leukemic cells

re-sistant to radiation and cyclophosphamide. Many centers are trying to enhance the ablation of these residual leukemia cells by increasing the dose of total body irradiation, while avoiding increased ra-diation toxicity by fractionating this higher

radia-tion dose. One center has replaced cyclophospha-mide (a good immunoablative drug that has only moderate activity against lymphoid leukemias) with the more potent antileukemic agent, cytosine ara-binoside.3’ Another ongoing trial is providing pa-tients “maintenance” chemotherapy posttransplan-tation.15 The rationale for further chemotherapy is that the few remaining leukemic cells may be sen-sitive to maintenance 6-mercaptopurine despite re-sistance to cyclophosphamide and total body irra-diation. Preliminary data with all three of these approaches suggest some benefit.

A retrospective analysis by the Seattle Bone Mar-row Transplantation team demonstrated a surpris-ing result.32 Patients with moderate or severe graft versus host disease following an HLA-matched sib-ling BMT for acute leukemia have fewer leukemic relapses than patients with mild or no graft versus host disease. As treatment for graft versus host disease has improved, the Seattle team (but not some others) have found that the decreased mci-dence of leukemic relapses in patients with graft versus host disease is also associated with a better chance for survival. This may potentially be due to the “antileukemic” effect ofthe immunosuppressive

drugs used to treat the active graft versus host disease. In contrast, this may result from an

anti-leukemic immune response triggered in parallel with the graft versus host disease. This graft versus

leukemia effect has been directly observed in some patients,33 and clearly demonstrated in murine bone marrow transplants for leukemia.34 In fact, the T cells that mediate this murine graft versus leukemia effect can be effective when given alone without need for hematopoietic ablation and subsequent reconstitution of marrow function by BMT. Under appropriate experimental conditions, this form of “adoptive immunotherapy” can eliminate all resid-ual (chemotherapy-resistant) leukemic cells, and supercede the need for a bone marrow transplant.35 It remains unclear whether these graft versus leu-kemia responses may be directed against leukemia-specific antigens, or minor locus histocompatibility antigens preferentially expressed on the leukemia cells.3638

In man, parallel antileukemic immune responses can be triggered and quantitated in vitro.394’ If effective and controllable, this form of intentional T-cell transfer may become included as a routine component of allogeneic bone marrow transplants for patients with leukemia. Conceivably, conven-tional chemotherapy combined with effective adop-tive immunotherapy could replace the need of leu-kemia patients for BMT.

SUMMARY

Ongoing clinical and laboratory research is being

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COMMENTARIES 819

ling. Any healthy sibling has a 25% chance of being completely identical with the patient for both the maternal and paternal HLA haplotypes. Yet even with perfectly matched sibling donors, clinically significant (moderate or severe) graft versus host disease causes morbidity or mortality in nearly 50% of transplants despite the post-BMT use of im-munosuppressive drug regimens designed to pre-vent graft versus host disease.’#{176}

Third, numerous potentially life-threatening complications require vigilant supportive care prior to the acquisition of complete and normal chimeric bone marrow function. Two to 4 weeks are required

before the transplanted marrow can begin to

sup-port neutrophil production adequate to protect against bacterial infections. Platelet production ad-equate to stabilize counts and prevent bleeding requires a comparable time. During this 1-month period, an aggressive approach by a multidiscipli-nary team is required to provide irradiated blood products, treat incipient infections, prevent oppor-tunistic infections, and maintain a stable physio-logic environment to allow for recovery of orophar-ynx, lungs, liver, gastrointestinal tract, skin, mus-des, and psyche-all of which are subject to revers-ible injury by the intense pretransplant condition-ing regimens.’3 A far longer period (as much as 1 year) is required to regain normal immune func-tion.’4 Thus, delayed viral and fungal infections are frequent following myeloid and platelet recovery, and they require diligent prophylaxis, screening, and treatment.

Fourth, the underlying disease can recur. This is unfortunately most common for patients with re-lapsed acute lymphoblastic leukemia treated by transplantation in second remission.’5 Even though these patients receive transplantation while in re-mission, nearly 50% are at risk for recurrence of

acute lymphoblastic leukemia, most often within 12 months following BMT. This leukemia is usually of the same karyotype and histology as the prior leukemia, and suggests that a small cohort of leu-kemic cells present during remission were resistant to the supralethal chemoradiotherapy condition-ing.7

Our transplant team is currently testing newer approaches toward transplanting across HLA bar-riers, and preventing leukemic relapse.

TRANSPLANTATION FOR PATIENTS WHO DO

NOT HAVE AN HLA IDENTICAL SIBLING

The HLA system is the most polymorphic genetic region so far identified in the human genome. Given the large number of alleles at each of the five currently typable loci (HLA-A, B, C, D, and DR), there are more than 3 x 108 distinct genotypes possible.16 Because some alleles at one locus are

associated with particular alleles at another locus

more frequently than anticipated by chance (link-age disequilibrium), the odds are somewhat better than one in 3

x

108 that a randomly selected unre-lated individual can be a perfect match for a

poten-tial BMT recipient. Advantage can be taken of the fact that some blood banks have files of thousands

of potential on-call platelet donors who have been HLA typed for the A and B loci. By computer screening, it is possible to find a handful of donors from such a pool who are closely matched to the A

and B alleles for a potential recipient. Provided that these healthy individuals are willing to be considered as potential BMT donors (a major

eth-ical and administrative issue), they can be asked to consider further matching with the potential recip-ient by HLA DR typing and mixed lymphocyte

culture reactivity to quantitate D locus disparity. If these matching tests demonstrate minimal dispar-ity, then some centers have proceeded with BMT.

A few such transplants using HLA-simi!ar

unre-lated donors,’7 and more using HLA-similar (but not perfectly matched) relatives,’8 have been per-formed worldwide. The degree of graft versus host disease is clearly greater than with perfectly matched siblings; however, some of these patients are surviving. The posttransplant addition of cy-closporin A, an effective immunosuppressive agent, with no myelosuppressive effect, may potentially ameliorate the magnitude of graft versus host dis-ease observed when HLA matching is not perfect.’9 It is, however, noteworthy that a similar matching program to provide HLA A-, B-, and DR-matched cadaver kidneys was unable to reproduce the excel-lent graft survival results obtained for the recipients of renal allografts from HLA identical siblings.20 This further confirms the distinction between sib-lings who are identical by descent for the entire HLA region, and unrelated individuals who are identical (or similar) only for typable loci. The HLA identical siblings, unlike the HLA “identical” un-related donors, share the entire HLA region with one another. The unrelated “matches” in all like-lihood differ from one another for alleles at other loci that are important in the allograft reaction, but are not currently being identified by standard HLA typing.21’22

One potential solution is suggested from animal studies. Mice receiving mismatched marrow con-taming mature immune cells succumb to graft ver-sus host disease. If mature T lymphocytes are re-moved from the marrow inoculum, the fatal graft

versus host reaction is avoided.23 Clinically, the

depletion of mature T lymphocytes from the donor marrow infusate should produce the same beneficial result. Initial attempts to “purge” human marrow have involved sequential depletion of T cells based

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COMMENTARIES 821

directed at the many problems and complications associated with clinical bone marrow transplanta-tion. The most important goals are to increase the

long-term survival of patients receiving bone mar-row transplants, decrease the morbidity associated with the process, and extend this therapeutic mo-dality to patients in need of a transplant, but with-out an HLA identical sibling. In addition, as these problems are resolved,42 and the toxicity of BMT is

controlled, this form of therapy may become the treatment of choice for a number of inherited and acquired hematologic,’#{176} immunologic, and

meta-bolic43 disorders that are chronically progressive but ultimately fatal, yet are not now routinely

treated with BMT due to the acute morbidity and mortality associated with this major procedure.

ACKNOWLEDGMENTS

This research was supported, in part, by grants

CH-237 of the American Cancer Society and CA-32685 of the National Institutes of Health.

Dr Sondel is a Scholar of the Leukemia Society of America, and a J. L. and G. A. Hartford Foundation Fellow. Drs Trigg, Finlay, and Bozdech are American Cancer Society Junior Faculty Clinical Fellows.

The authors thank Drs J. A. Hank and P. C. Kohler for critical scientific discussions and review, Dr R. Billing for providing CT-2 monoclonal antibody, Grace Baumans for preparing this manuscript, and the many clinical and research staff members helping to perform successful bone marrow transplantation at the University of

Wis-consin Hospital.

REFERENCES

PAUL M. SONDEL, MD, PHD

MICHAEL E. TRIGG, MD

RICHARD HONG, MD

JONATHAN L. FINLAY, MB, CHB

MAREK J. BOZDECH, MD

Departments of Pediatrics, Human Oncology, Genetics, and Medicine University of Wisconsin

Madison

1. Parkman R, Rappeport J, Geha R, et al: Complete correction

ofthe Wiskott Aldrich syndrome by allogeneic bone marrow transplantation. N Engl J Med 1978;298:921

2. Bortin MM, Rimm AA: Severe combined immune deficiency disease: Characterization of the disease and results of trans-plantation. JAMA 1977;238:591

3. Gluckman E, Barrett AJ, Arcese W, et al: Bone marrow transplantation in severe aplastic anemia: A survey of the European group for bone marrow transplantation. Br J

Haematol 1981;49:165

4. Bortin MM, Gale RP, Rimm AA: Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. JAMA 1981;245:1132

5. Gale RP, Kay HEM, Rimm AA, et al: Bone marrow trans-plantation for acute leukemia in first remission. Lancet

1982;2: 1006

6. Sanders JE, Thomas ED: Marrow transplantation for chil-dren with acute nonlymphocytic leukemia in first remission. Med Pediatr Oncol 1981;9:423

7. Johnson F: Marrow transplantation in the treatment of acute childhood leukemia: Historical development and cur-rent approaches. Am J Pediatr Hematol Oncol 1981;3:389 8. Beutler E, McMillan R, Spruce W: The role of bone marrow

transplantation in the treatment of acute leukemia in re-mission. Blood 1982;59:1115

9. Barret AJ. Bone marrow transplantation. Arch Dis Child

1980;55:750

10. Storb R, Thomas ED: Allogeneic bone marrow transplan-tation. Immunol Rev 1983;71:77

1 1. Feig SA: Histocompatibility barriers in human marrow transplantation. Am J Pediatr Hematol Oncol 1980;2:273 12. Bach FH, Bach ML, Sondel PM: Differential function of

major histocompatibility complex antigens in T lymphocyte activation. Nature 1976;259:273

13. Patenaude AF, Rappeport JM: Surviving bone marrow transplantation: The patient in the other bed. Ann Intern Med 1982;97:915

14. Witherspoon RP, Lum LG, Storb R, et al: In vitro regulation of immunoglobulin synthesis after human marrow trans-plantation: II. Deficient T and non-T lymphocyte function within 3-4 months of allogeneic, syngeneic, or autologous marrow grafting for hematologic malignancy. Blood

1982;59:844

15. Woods WG, Nesbit ME, Ramsay NKC, et al: Intensive therapy followed by bone marrow transplantation for pa-tients with acute lymphocytic leukemia in second or subse-quent remission: Determination of prognostic factors. Blood 1983;61:1 182

16. Bodmer W, Thomson G: Population genetics and evolution

of the HLA system, in Dausset J, Svejgaard A (eds): HLA

and Disease. Baltimore, Williams & Wilkins, 1977, p 286 17. Duquesnoy BA, Zeevi A, Marrari M, et al: Bone marrow

transplantation for severe aplastic anemia using a pheno-typically HLA identical SB-compatible, unrelated donor. Transplantation 1983;35:566

18. Hansen JA, Clift RA, Mickelson EM, et al: Marrow trans-plantation from donors other than HLA identical siblings. Hum Immunol 1981;2:31

19. Powles RL, Kay HEM, Clink HM, et al: Mismatched family donors for bone marrow transplantation as treatment for acute leukemia. Lancet 1983;1:612

20. Albrectsen D, Moen T, Flatmark A, et al: Influence of HLA-A, B, C, D, and DR matching in renal transplantation. Transplant Proc 1981;13:924

21. Sondel PM, Bach FH: Immunogenetic complexity of HLA-D. Transplant Proc 1977;9:401

22. Grover JP, Watson AJ, Bach FH: DW/LD related molecular polymorphism of DR 4 fichains. J Exp Med 1983;157:1687 23. Rodt H, Thierfelder 5, Eulity M: Antilymphocyte antibodies

and marrow transplantation: III. Effect of heterologous anti brain antibodies on acute secondary disease in mice. Eur J

Immunol 1974;4:25

24. Reisner Y, Kapoor N, Kirkpatrick D, et al: Transplantation for severe combined immunodeficiency with HLA-A, B, D, DR incompatible parental marrow cells fractionated by soy-bean agglutinin and sheep red blood cells. Blood 1983;61:341 25. Hayward AR, Murphy 5, Athens J, et al: Failure of a

pan-reactive anti T cell antibody, OKT3, to prevent graft versus host disease in severe combined immunodeficiency. J Pe-diatr 1982;100:665

26. Prentice HG, Blacklock HA, Janossy G, et al: Use of anti-T cell monoclonal antibody OKT3 to prevent acute graft versus host disease in allogeneic bone marrow transplanta-tion for acute leukemia. Lancet 1982;1:700

27. Filipovich AH, Ramsay NKC, Warkentin P1, et al: Pretreat-ment of donor bone marrow with monoclonal antibody OKT3 for prevention of acute graft versus host disease in allogeneic, histocompatible, bone marrow transplantation. Lancet 1982;1:1266

28. Granger 5, Janossy G, Francis G, et al: Elimination of T lymphocytes from human bone marrow with monoclonal T antibodies and cytolytic complement. Br J Haematol 1982;50:367

29. Reinherz EL, Geha R, Rappeport JM, et al: Reconstitution after transplantation with T lymphocyte depleted HLA

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822 PEDIATRICS Vol. 72 No. 6 December 1983 lotype mismatched bone marrow for severe combined im-munodeficiency. Proc NatI Acad Sci USA 1982;79:6047 30. Trigg ME, Billing R, Sondel PM, et al: In vitro treatment

of donor bone marrow with anti-E rosette antibody and complement prior to transplantation, abstracted. J Cell

Bio-chem 1983;7A:57

31. Coccia PF, Strandjord SE, Gordon EM, et al: High dose cytosine arabinoside and fractionated total body irradiation as preparation for bone marrow transplantation for child-hood acute leukemia in remission-a preliminary report. Proc Am Soc Clin Oncol 1983;2:175

32. Weiden P1, Sullivan KM, Flournoy N, et al: Antileukemic effect of chronic graft versus host disease: Contribution to improved survival after allogeneic marrow transplantation. N EngI J Med 1981;304:1529

33. Odom LF, August CS, Githens JH, et al: Remission of relapsed leukemia during a graft versus host reaction. Lancet

1978;2:537

34. Bortin MM, Truitt RC, Rimm AA: Graft versus leukemia reactivity induced by alloimmunization without augmenta-tion of graft versus host reactivity. Nature 1979;281:490 35. Cheever MA, Greenberg PD, Fefer A, et al: Augmentation

of the antitumor therapeutic efficacy of long term cultured T lymphocytes by in vivo administration of purified inter-leukin-2. J Exp Med 1982;155:968

36. Meredith RF, Okunewick JP: Possibility of graft versus leukemia determinants independent of the major histocom-patibility complex in allogeneic marrow transplantation. Transplantation 1983;35:378

37. Zarling JM, McKeaugh M, Reich P, et al: Generation of cytoxic lymphocytes in vitro against autologous leukemia cells. Nature 1976;262:691

38. Sondel PM, Hank JA, Wendel T, et al: HLA identical leukemia cells and T cell growth factor activate cytotoxic T cell recognition of minor locus histocompatibility antigens in vitro. J Clin Invest 1983;71:101

39. Lotze MT, Line BR, Mathisen DJ, et al: The in vivo distri-bution of autologous human and murine lymphoid cells grown in T cell growth factor (TCGF): Implications for adoptive immunotherapy of tumors. J Immunol 1980;

125:1487

40. Kohler PC, Hank JA, Lieberman L, et al: Adoptive che-moimmunotherapy with cyclophosphamide and alloimmu-nized haploidentical lymphocytes. Proc Am Asso Cancer Res

1983;24:232

41. Sondel PM, Hank JA, Kohler PC, et al: Adoptive immuno-therapy with alloactivated TCGF expanded human lympho-cytes. Transplant Proc 1983;15:1872

42. Good RA: Toward safer marrow transplantation. N Engl J Med 1982;306:421

43. Hobbs JR: Bone marrow transplantation for inborn errors. Lancet 1981;2:735

Impact

of Litigation

on

Immunization

of Children

There have been an increasing number of

law-suits claiming compensation for injuries related to

vaccines. Increased litigation can be expected to result in reluctance on the part of some

practition-ers to use certain vaccines, consideration in changes in recommendations for immunization, and

in-creased cost of vaccines.

The costs of oral polio vaccine (OPV) and diph-theria-tetanus-pertussis (DTP) vaccine have been increased markedly presumably because of

litiga-tion. It is estimated that the nearly tenfold increase in DTP vaccine charged by one manufacturer could add approximately $50 million per year to the cost of protecting children against these diseases. Man-ufacturers have been leaving the vaccine business and now only a few remain. It is conceivable that there may be no producers of vaccines in the future, and the government will have to intervene in order to maintain protection against these diseases. In addition, the fear of litigation may be retarding the

development of a new pertussis vaccine.

Paralysis due to polio has decreased from tens of thousands of cases prior to the introduction of the polio vaccine to approximately a dozen cases per annum in recent years. The fact that approximately half of these cases have been associated with ad-ministration of OPV has led to a consideration of change in recommendations for immunization. The much more expensive inactivated polio vaccine may be used in addition to OPV or to replace OPV. There is no assurance, however, that administering millions of doses of inactivated polio vaccine will result in fewer lawsuits or less morbidity.

The fear of pertussis immunization in England has led to decreased acceptance of this vaccine, which has resulted in two massive epidemics of pertussis in that country. Thus far, there has been speculation that there has been decreased accept-ance of pertussis vaccine in this country, but there is no objective evidence that this is the case. Indeed, there has been no significant increase in the sale of diphtheria-tetanus (DT) vaccine, which suggests that physicians have not shifted from DTP to DT to avoid pertussis vaccine reactions. It may be too early to be certain that there has not been decreased utilization of pertussis vaccine, as epidemics of this disease tend to occur in 3-year cycles.

The obvious solution to the problem of lawsuits is to produce vaccines that are reaction-free. The

restriction of funding for medical research and the litigious climate are not conducive to development

of new vaccines. Moreover, drug manufacturers ap-pear to be diverting their efforts to produce prod-ucts that are more likely to yield larger profits, eg, tranquilizers, antibiotics, etc. Even if it were pos-sible to produce vaccines that were free of reactions, this would still not eliminate suits due to

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1983;72;818

Pediatrics

and MAREK J. BOZDECH

PAUL M. SONDEL, MICHAEL E. TRIGG, RICHARD HONG, JONATHAN L. FINLAY