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Immunological preparations
B. Hofman and H.P. Lansberg
34
Immunological preparations
GENERAL A rare complication of DTP inoculation has been described b y Omokoku and Castells (le). Two siblings received trivalent DTP and developed cervical lyrnphadenitis; a contamination with viral or bacterial agents could be ruled out. One of the children had a recurrence of lymphadenitis following half a booster dose of DTP six months later. The complication was presumed to be an immune reaction to the DPT vaccine or to adjuvants. Laude reports a case of pityriasis rosea in a four-year-old girl, who three days after a booster dose of DTP developed a 'herald patch' over the site of the injection. A week later symptoms of pityriasis rosea appeared on the trunk and extremities, sparing the face (2e). INDIVIDUAL PRODUCTS
Antithymocyte #obulin In a trial by Doney et al. (3R), comparing antithymocyte globulin (ATG) and corticosteroids, side effects of antithymocyte globulin were found to be more frequent. Two ATG preparations were given. Horse ATG infusion was followed by fever and chills, sometimes with extreme hyperpyrexia. One patient had a decrease in the platelet and granulocyte count after three doses of ATG. Other reactions included nausea, vomiting and urticaria. Rabbit ATG effects cited were pain and erythema at the injection site and in one instance polyarthritis with urticaria. Prophylactic vaccination Could there be a link between BCG vaccination and cancer in later life? This question has triggered several trials. As pointed out earlier (SEDA-3,261; SEDA-4, 226) research has been performed to detect any possible positive, protective influence of vaccination as regards cancer in childhood. Other epidemiological studies followed (4R, 5R, 6R).
From these investigations, and especially from a paper by Kendrick and Comstock (7R), another conclusion has come to the fore, i.e. that among vaccinees no more and no less cancer is found with the exception of the group lymphoma-Hodgkin's diseaseleukemia. More cases of these disorders than expected were found among vaccinees. Kendrick concludes: 'Whatever the explanation may be for the unexpected excess of lymphoma-Hodgkin's disease-leukemia cases (among vaccinees) in this study and in other studies, additional evidence has been provided against the notion that vaccination with BCG might prevent leukemia'. A rare complication is mentioned by Bonnetblanc et al. (8c). Three months after BCG vaccination by scarification a small papule was noted at the treatment site. More than a year later it had grown into a tumor that proved to be a typical Spitz melanoma with an underlying lymphocytic inflammatory infiltration. The author concludes that tumors arising at the site of scarification are, in view of their rareness, probably coincidental, but careful assessment is suggested, particularly in patients in whom BCG is used as immunoprophylaxis. Two cases of lupus vulgaris, a rare but rather serious complication, have been reported by Lal (9c). There is also a study from India by Kader and Nair concerning the relation between BCG and keloid (1 oR). Thirty-seven patients were followed over a period of two years. In this and in a survey among schoolchildren a correlation between keloid formation and BCG vaccination was found. BCG induces keloid not only at the treatment site, but also at other sites that may be subsequently subjected to injury. Other recent publications include known side effects such as osteomyelitis (11 cr, 12 c, 130.
Immunotherapy In two reports and the ensuing discussions at the 60th and 61st meetings of the American Association for
324
B. Herman and H.P. Lansberg
Thoracic Surgery, a difference in reaction to BCG therapy between patients with a positive PPD test and a negative one was noted. PPD-positive patients suffered more side effects and showed less favorable therapeutic results. On the other hand, the therapeutic result was better and the side effects were milder in PPD-negative individuals (14 R, 15R). The same applies to the MER (methanol extraction residue BCG) therapy for advanced, recurrent Hodgkin's disease. Furthermore, the results were extremely poor (16R). BCG Cell Wall Skeleton (BCG-CWS), which is a non-viable BCG extract attached to oil microduplets, has been used in malignant effusions. The primary toxic effects were pain and fever. When it was used in peritoneal effusions, patients also experienced nausea, vomiting and diarrhea as described by Richman and Hersh (17R). A preliminary study by Yamamura "et al. with cell wall skeleton of Nocardia rubra (N-CWS) along the lines set by previous BCG-CWS studies gives as the most common adverse reaction fever, which was persistent after intratumoral or intrapleural injections. The next most common effect was the occurrence of skin lesions at the injection sites (18R).
has been investigated further. After the mass-vaccination campaigns of 1976 a relation between the two was found, but a survey following the influenza vaccination in the period between September 1978 and March 1979 showed that influenza vaccination in this perod was not associated with a statistically significant excess risk of GBS. The composition of the vaccine used in the latter season was A/USSR/77 H1N1, A/Texax/77 H3N2 and B/Hongkong/72. Further analyses in the coming years will be needed to determine whether the apparent causal relation of GBS with influenza vaccination with A/New Jersey swine virus in 1976 was a unique phenomenon due to this specific strain (21 c ). A case of pericarditis one week after vaccination with influenza vaccine containing A/Bangkok/1/79 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore[222/79 has been described (22e). A recurrence of vasculitis was described in a 55-year-old woman 10 days after administration of influenza vaccine (23e). Using administration of (14C)aminopydne and a subsequent determination of carbon dioxide 14 in the breath, relatively low values for the latter were found after influenza vaccination. This reflects a depressed
Corynebaeterium parvum
effect persisted for three weeks and levels were comparable with those seen in alcoholic liver disease, although other indicators of hepatic function remained normal. The clinical importance of this finding is that influenza vaccine may impair the pharmacokinetics of several drugs, as is mentioned for warfarin (24 C). In relation to the phenomenon described above some equivocal results from Canadian observations may be worth attention. After influenza vaccination one group of researchers found a decrease of blood theophylline levels in patients and volunteers treated with this substance. A second group could not confirm these results. The discrepancy may have been due to the fact that theophylline levels were measured only one day after administration of influenza vaccine, and another possibility is the difference between brands of influenza vaccine. It is to be hoped that further observations will throw more light on these phenomena, but it is advisable to monitor carefully the effects of influenza vaccine in patients treated with various drugs (36 c ).
hepatic (14C)aminopyrine metabolism. The
Corynebacterium parvum used as an adjuvant therapy for malignant melanoma proved to have no effect on the outcome of the disease; this was the conclusion of Hilal et al. (19R). With intravenous administration 93%of the patients had chills and fever and 76% hypertension. These are known side effects. Less frequent adverse reactions were hypotension and peripheral cyanosis. Subcutaneous injection gave almost only local reactions. Comparison by Mitcheson and Priestman of two formulations of Corynebacterium parvum in the treatment of bronchogenic carcinoma showed that the formalin-killed wet-filled preparation caused more side effects than did the heat-killed freeze-dried type (20 c).
Influenza The association between influenza vaccination and Guillain-Barr~ syndrome (GBS)
Immunological preparations Measles Three children presented an immediate reaction within 30 minutes after the administration of live attenuated measles virus (Schwarz strain). The symptoms were vomiting, fever and rash. Moreover, two of these children showed cyanosis. AU three children recovered completely (25c). A 15-month-old child who suffered minor scalding during the febrile response after vaccination with attenuated measles virus died from 'adult respiratory distress syndrome', which might have been due to a depressed immune response to the viremia (26c). Pertussis In a letter to the editor two Indian authors (27 c) have reported a side effect that may easily escape attention. Twenty hours after his third DTP injection an eightmonth-old male child developed a bulging fontanelle. As the child had undergone his ritual headshaving a week prior to the injection the bulging anterior fontanelle was clearly visible. He also had an axillary temperature of 38~ Forty-eight hours after the injection he was afebrile and the fontanelle was normal. Otherwise the child was asymptomatic, and the bulging of the fontanelle might not have been observed if his head had not been shaven. Only once has a similar observation been recorded (by Jacob and Mamine, 28e). The complication may be missed unless specially looked for. As the pertussis component of DTP vaccine has been the only one reporteu as being implicated in neurological complications, it seems probable that this component is the one responsible for the reported side effect. A very substantial study from the USA (29 R) describes a project Undertaken to determine accurately the rates of both minor and more serious reactions in 15,752 children 0 - 6 years of age to DTP vaccine as licensed in the USA; a control group of 784 children received DT-vaccine. The ratio of minor reactions associated with DTP and DT respectively was: local redness 37.4%/ 7.6%; local swelling 40.7%/7.6%; pain 50~9%/9.9%; fever 46.5%/9.3%; drowsiness 31.5%/14.9%; fitfulness 53.4%/22.6%; vomiting 6.2%/2.6%; anorexia 20.9%/7.0% and
325 persistent crying 3.1%/0.7%, high-pitched unusual cry 0.1%/0.0%. The reactions after DT were not only less frequent but also less severe. Convulsions and hypotonic hyporesponsive episodes each occurred in 1:1750 immunizations. No evidence of encephalopathy or permanent brain damage was seen and there were no fatalities. In view of the lack of neurological sequelae and death the conclusion was that the risk/benefit ratio of pertussis vaccine clearly favors routine immunization. The battle as to risk/benefit, however, goes on (30 r, 3 lr).
Rubella To answer the question as to how frequently fetal infection has occurred after rubella vaccination of pregnant women and what consequences it had for the fetus, the (US) Centers for Disease Control (CDC) have operated two programs from 1969 onwards. The results to date show that 94 susceptible women receiving either Cendehill of HPV-77 rubella vaccine all gave birth to healthy infants. Moreover, 17 susceptible women who received RA 27/3 vaccine delivered babies free from abnormalities which could be compatible with congenital rubella. From these figures it is calculated that the potential risk of severe congenital malformations is less than 3%. Because this is not zero it remains advisable not to vaccinate women known to be pregnant (32 C , 33R).
Tetanus Taking 740 patients with a history of adverse reactions to tetanus toxoid immunization, Jacobs et al. (34 c ) provide an analysis of the original symptoms and of those following skin testing and diphtheria tetanus booster. The historical data are given in Table 1. 730 of the 740 patients were non-reactive to skin testing or booster. Of the 10 others, four reacted to skin testing, two of them refused the booster, two responded negatively to the booster. Of the six non-reactors to skin testing, three reacted to the booster in that they were hypersensitive to the mercury in thiomersal. The three remaining cases had large local indurated erythematous lesions
326
B. Hofman and H.P. Lansberg
Table 1. Adverse reactions to tetanus toxoid immunization Symptom
Number of patients (%)
Anaphylactoid reaction Local swelling, erythema, tenderness Immediate (<2 hr) Delayed ( 4 - 8 hr) Late (>12 hr) Unknown time frame Fever Immediate ( 1 - 3 hr) Delayed (>4 hr) Nausea and vomiting Constitutional symptoms (malaise, fatigue, etc.) Generalized non-specific rash Acute dizziness Syncope Arthralgias Miscellaneous Localized urticaria at injection site; vesicles at injection site; shock (delayed time frame); phlebitis; seizure; 'red spots all over arms'; sleepwalking; chest wall swelling (delayed); 'hallucinations'; paralysis (generalized, transient)
95 (13.0) 248 (33.6) 37 76 72 113 30 83 84 57
(5.0) (10.1) (9.5) (15.3) (4.1) (11.2) (11.4) (7.8)
38 (5.2) 22 (3.0) 11 (1.5) 7 (1.0) (Each <1)
at the site of injection, that persisted for several days. In conclusion: A history o f an adverse reaction to t e t a n u s t o x o i d does not preclude future i m m u n i z a t i o n to this same material. Tuberculin
A n unusual reaction to a PPD skin test has b e e n r e p o r t e d b y Lavey and Pearl (35c). A 35-year-old V i e t n a m e s e w o m a n had an injection w i t h liquid silicone in her face in 1973. Three years later she suffered f r o m i n f l a m m a t i o n s in the injected area; all cultures were negative. N i n e m o n t h s after recovery she received a M a n t o u x PPD skin test; after 48 hours swelling and inflammation of the glabella and at the site o f the skin test occurred. O n e w e e k later all sympt o m s were gone. T h e authors came to t h e conclusion that t h e m o s t likely e x p l a n a t i o n was a non-specific response o f l y m p h o c y t e s initiated by the tuberculin test; activated l y m p h o c y t e s might cross-react with some antigen in the silicone-injected tissue.
Several patients described more than one symptom and data are therefore presented as a percentage of total complaints.
REFERENCES 1. Omokoku, B. and Castells, S. (1981): Post-DPT inoculation cervical lymphadenitis in children. N. Y. St. J. Med., Oct., 1667. 2. Laude, T.A. (1981): Herald patch in a DPT injection site. J. Amer. Acad. Dermatol., 5, 475. 3. Doney, K.C., Weiden, P.L. et aL (1981): Treatment of graft-verms-host disease in human allogenic marrow graft recipients: a randomized trial comparing antithymocyte globulin and corticosteroids.Amer. J. Haematol., 11, 1. 4. Skegg, D.C. (1978): BCG vaccination and the incidence of lymphomas and leukaemia. Y. Cancer, 21, 18. 5. Lilienfeld, A.M., Pedersen, E. et aL (1967): Cancer Epidemiology: Methods of Study, at p. 72. Johns Hopkins Press, Baltimore. 6. Snider, D.E., Comstock, G.W. et al. (1978): Efficacy of BCG vaccination in prevention of cancer. An update: brief communication. J. nat. Cancerlnst., 60, 785. 7. Kendrick, M.A. and Comstock, G.W. (1981): BCG vaccination and the subsequent development of cancer in humans. J. nat. Cancer Inst., 66, 431.
8. Bonnetblanc, J.M., Gualde, N. et al. (1981): Juvenile melanoma after BCG vaccination. Dermatologie, 163, 195. 9. Lal, H. (1981): BCG-Lupus. Ind. J, Tuberc., XXVII, 130. 10. Kader, M.A. and N a i l V.J. (1981): BCGinduced keloid. Int. J. Stag., 43, 430. 11. Well, L. and Torklus, D. (1981): Osteomyelitis nach BCG-Impfung. Z. Orthop., 119, 297. 12. Berges, O., Boccon-Gibod, L. et al. (1981). Case Report 165. Skel. Radiol., 7, 75. 13. Mulder, J.C. (1982): Complicaties van BCG vaccinatie b~ kinderen van buitenlandse worknemers.Ned. T. Geneesk., 126, 468. 14. McKneally, F., Mayer, C. et al. (1981): Fouryear follow-up on the Albany experience with intrapleural BCG in lung cancer. J. thorac. cardiovasc. Surg., 81,485. 15. Mountain, F. and Gaff, M.H. (1981): Surgical adjuvant intrapleural BCG treatment for stage I non ~nall cell lung cancer. J. thorac, cardiovasc. Surg., 82,649. 16. Vinciguerra, V. and Coleman, M. (1981): MER immunotherapy and combination chemo-
Immunological preparations therapy for advanced, recurrent Hodgkin's disease. Cancer din. Trials, 4, 99. 17. Richman, S.P. and Hersh, E.M. (1981): Administration of BCG cell wall skeleton into malignant effusions: toxic and therapeutic effects. Cancer Treatm. Rep., 65, 383. 18. Yamamura, Y., Ogura, T. et al. (1981): Phase I study with cell wall skeleton of Nocardia rubra. Cancer Treatm. Rep., 65, 707. 19. Hflal, E.Y.,Pinsky, C.M. et aL (1981): Surgical adjuvant therapy of malignant melanoma with corynebacterium parvum. Cancer, 2, 245. 20. Mitcheson, H.D. and Priestman, T.J. (1981): A comparison of the toxicity of two formulations of Corynebacterium parvum in a double blind cross-over trial in patients with bronchogenic carcinoma. Clin. Oncol., 7, 179. 21. Hurwitz, E.S., Schonberger, L.B. et al. (1981): Guillain-Barr~ syndrome and the 1 9 7 8 - 1 9 7 9 influenza vaccine. New Engl. J. Med., 26, 1557. 22. Streifler, J.J., Dux, S. et al. (1981): Recurrent pericarditis: a rare complication of influenza vaccination. Brit. reed. Z, 283, 526. 23. Cannata, J., Cuesta, V. et al. (1981): Reactivation of vasculitis after influenza vaccination. Brit. reed. I., 283,526. 24. Kramer, P. and McClain, C.J. (1981): Depression of aminopyrine metabolism by influenza vaccination. New Engi. J. Med., 21, 1262. 25. Van Asperen, P.P., McEniery, J. et al. (1981): Immediate reactions following live attenuated measles vaccine. Med. J. Aust., Oct., 330. 26. Pfenninger, J. and Zimmermann, A. (1981):
327 Fatal adult respiratory distress syndrome in a scalded child after immunization with attenuated virus (measles, rattraps and rubella). Paediat. Acta, 36, 371. 27. Mathur, R. and Kumari, S. (1981): Bulging fontanel following triple vaccine. Int. Pediat., 18, 417. 28. Jacob, J. and Mamine, F. (1979): Increased intracranial pressure after Diphtheria-tetanus and pertussis immunisation. Amer. Z Dis. Chad., 133, 217. 29. Cody, L.C., Baraff, L.J. et al (1981): Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics, 68, 650. 30. Robinson, R.J. (1981): The whooping-cough immunisation controversy. Arch. Dis. Chad., 56, 577. 31. Stuart-Harris, Ch. and Ehrengut, W. (1981): Pertussis vaccine. Brit. reed. Z, 283,494. 32. Preblud, S.R., Harrison, C. et al. (1981): Fetal risk associated with rubella vaccine. Z Amer. mea~ Ass., 246, 1413. 33. Fox, J.P. (1981): Fetal perspective of rubella vaccine efficacy and safety. Z Amer. reed. Ass., 246, 1444. 34. Jacobs, R.L. et al. (1982): Adverse reactions to tetanus toxoid immunization Z Amer. reed. Ass., 247, 40. 35. Lavey, E.B. and Pearl, R.B. (1981): Inflammation in a silicone-induced granuloma caused by a tuberculosis skin test. Ann. plast. Surg., 7, 152.
34
Immunological preparations
GENERAL A rare complication of DTP inoculation has been described b y Omokoku and Castells (le). Two siblings received trivalent DTP and developed cervical lyrnphadenitis; a contamination with viral or bacterial agents could be ruled out. One of the children had a recurrence of lymphadenitis following half a booster dose of DTP six months later. The complication was presumed to be an immune reaction to the DPT vaccine or to adjuvants. Laude reports a case of pityriasis rosea in a four-year-old girl, who three days after a booster dose of DTP developed a 'herald patch' over the site of the injection. A week later symptoms of pityriasis rosea appeared on the trunk and extremities, sparing the face (2e). INDIVIDUAL PRODUCTS
Antithymocyte #obulin In a trial by Doney et al. (3R), comparing antithymocyte globulin (ATG) and corticosteroids, side effects of antithymocyte globulin were found to be more frequent. Two ATG preparations were given. Horse ATG infusion was followed by fever and chills, sometimes with extreme hyperpyrexia. One patient had a decrease in the platelet and granulocyte count after three doses of ATG. Other reactions included nausea, vomiting and urticaria. Rabbit ATG effects cited were pain and erythema at the injection site and in one instance polyarthritis with urticaria. Prophylactic vaccination Could there be a link between BCG vaccination and cancer in later life? This question has triggered several trials. As pointed out earlier (SEDA-3,261; SEDA-4, 226) research has been performed to detect any possible positive, protective influence of vaccination as regards cancer in childhood. Other epidemiological studies followed (4R, 5R, 6R).
From these investigations, and especially from a paper by Kendrick and Comstock (7R), another conclusion has come to the fore, i.e. that among vaccinees no more and no less cancer is found with the exception of the group lymphoma-Hodgkin's diseaseleukemia. More cases of these disorders than expected were found among vaccinees. Kendrick concludes: 'Whatever the explanation may be for the unexpected excess of lymphoma-Hodgkin's disease-leukemia cases (among vaccinees) in this study and in other studies, additional evidence has been provided against the notion that vaccination with BCG might prevent leukemia'. A rare complication is mentioned by Bonnetblanc et al. (8c). Three months after BCG vaccination by scarification a small papule was noted at the treatment site. More than a year later it had grown into a tumor that proved to be a typical Spitz melanoma with an underlying lymphocytic inflammatory infiltration. The author concludes that tumors arising at the site of scarification are, in view of their rareness, probably coincidental, but careful assessment is suggested, particularly in patients in whom BCG is used as immunoprophylaxis. Two cases of lupus vulgaris, a rare but rather serious complication, have been reported by Lal (9c). There is also a study from India by Kader and Nair concerning the relation between BCG and keloid (1 oR). Thirty-seven patients were followed over a period of two years. In this and in a survey among schoolchildren a correlation between keloid formation and BCG vaccination was found. BCG induces keloid not only at the treatment site, but also at other sites that may be subsequently subjected to injury. Other recent publications include known side effects such as osteomyelitis (11 cr, 12 c, 130.
Immunotherapy In two reports and the ensuing discussions at the 60th and 61st meetings of the American Association for
324
B. Herman and H.P. Lansberg
Thoracic Surgery, a difference in reaction to BCG therapy between patients with a positive PPD test and a negative one was noted. PPD-positive patients suffered more side effects and showed less favorable therapeutic results. On the other hand, the therapeutic result was better and the side effects were milder in PPD-negative individuals (14 R, 15R). The same applies to the MER (methanol extraction residue BCG) therapy for advanced, recurrent Hodgkin's disease. Furthermore, the results were extremely poor (16R). BCG Cell Wall Skeleton (BCG-CWS), which is a non-viable BCG extract attached to oil microduplets, has been used in malignant effusions. The primary toxic effects were pain and fever. When it was used in peritoneal effusions, patients also experienced nausea, vomiting and diarrhea as described by Richman and Hersh (17R). A preliminary study by Yamamura "et al. with cell wall skeleton of Nocardia rubra (N-CWS) along the lines set by previous BCG-CWS studies gives as the most common adverse reaction fever, which was persistent after intratumoral or intrapleural injections. The next most common effect was the occurrence of skin lesions at the injection sites (18R).
has been investigated further. After the mass-vaccination campaigns of 1976 a relation between the two was found, but a survey following the influenza vaccination in the period between September 1978 and March 1979 showed that influenza vaccination in this perod was not associated with a statistically significant excess risk of GBS. The composition of the vaccine used in the latter season was A/USSR/77 H1N1, A/Texax/77 H3N2 and B/Hongkong/72. Further analyses in the coming years will be needed to determine whether the apparent causal relation of GBS with influenza vaccination with A/New Jersey swine virus in 1976 was a unique phenomenon due to this specific strain (21 c ). A case of pericarditis one week after vaccination with influenza vaccine containing A/Bangkok/1/79 (H3N2), A/Brazil/11/78 (H1N1) and B/Singapore[222/79 has been described (22e). A recurrence of vasculitis was described in a 55-year-old woman 10 days after administration of influenza vaccine (23e). Using administration of (14C)aminopydne and a subsequent determination of carbon dioxide 14 in the breath, relatively low values for the latter were found after influenza vaccination. This reflects a depressed
Corynebaeterium parvum
effect persisted for three weeks and levels were comparable with those seen in alcoholic liver disease, although other indicators of hepatic function remained normal. The clinical importance of this finding is that influenza vaccine may impair the pharmacokinetics of several drugs, as is mentioned for warfarin (24 C). In relation to the phenomenon described above some equivocal results from Canadian observations may be worth attention. After influenza vaccination one group of researchers found a decrease of blood theophylline levels in patients and volunteers treated with this substance. A second group could not confirm these results. The discrepancy may have been due to the fact that theophylline levels were measured only one day after administration of influenza vaccine, and another possibility is the difference between brands of influenza vaccine. It is to be hoped that further observations will throw more light on these phenomena, but it is advisable to monitor carefully the effects of influenza vaccine in patients treated with various drugs (36 c ).
hepatic (14C)aminopyrine metabolism. The
Corynebacterium parvum used as an adjuvant therapy for malignant melanoma proved to have no effect on the outcome of the disease; this was the conclusion of Hilal et al. (19R). With intravenous administration 93%of the patients had chills and fever and 76% hypertension. These are known side effects. Less frequent adverse reactions were hypotension and peripheral cyanosis. Subcutaneous injection gave almost only local reactions. Comparison by Mitcheson and Priestman of two formulations of Corynebacterium parvum in the treatment of bronchogenic carcinoma showed that the formalin-killed wet-filled preparation caused more side effects than did the heat-killed freeze-dried type (20 c).
Influenza The association between influenza vaccination and Guillain-Barr~ syndrome (GBS)
Immunological preparations Measles Three children presented an immediate reaction within 30 minutes after the administration of live attenuated measles virus (Schwarz strain). The symptoms were vomiting, fever and rash. Moreover, two of these children showed cyanosis. AU three children recovered completely (25c). A 15-month-old child who suffered minor scalding during the febrile response after vaccination with attenuated measles virus died from 'adult respiratory distress syndrome', which might have been due to a depressed immune response to the viremia (26c). Pertussis In a letter to the editor two Indian authors (27 c) have reported a side effect that may easily escape attention. Twenty hours after his third DTP injection an eightmonth-old male child developed a bulging fontanelle. As the child had undergone his ritual headshaving a week prior to the injection the bulging anterior fontanelle was clearly visible. He also had an axillary temperature of 38~ Forty-eight hours after the injection he was afebrile and the fontanelle was normal. Otherwise the child was asymptomatic, and the bulging of the fontanelle might not have been observed if his head had not been shaven. Only once has a similar observation been recorded (by Jacob and Mamine, 28e). The complication may be missed unless specially looked for. As the pertussis component of DTP vaccine has been the only one reporteu as being implicated in neurological complications, it seems probable that this component is the one responsible for the reported side effect. A very substantial study from the USA (29 R) describes a project Undertaken to determine accurately the rates of both minor and more serious reactions in 15,752 children 0 - 6 years of age to DTP vaccine as licensed in the USA; a control group of 784 children received DT-vaccine. The ratio of minor reactions associated with DTP and DT respectively was: local redness 37.4%/ 7.6%; local swelling 40.7%/7.6%; pain 50~9%/9.9%; fever 46.5%/9.3%; drowsiness 31.5%/14.9%; fitfulness 53.4%/22.6%; vomiting 6.2%/2.6%; anorexia 20.9%/7.0% and
325 persistent crying 3.1%/0.7%, high-pitched unusual cry 0.1%/0.0%. The reactions after DT were not only less frequent but also less severe. Convulsions and hypotonic hyporesponsive episodes each occurred in 1:1750 immunizations. No evidence of encephalopathy or permanent brain damage was seen and there were no fatalities. In view of the lack of neurological sequelae and death the conclusion was that the risk/benefit ratio of pertussis vaccine clearly favors routine immunization. The battle as to risk/benefit, however, goes on (30 r, 3 lr).
Rubella To answer the question as to how frequently fetal infection has occurred after rubella vaccination of pregnant women and what consequences it had for the fetus, the (US) Centers for Disease Control (CDC) have operated two programs from 1969 onwards. The results to date show that 94 susceptible women receiving either Cendehill of HPV-77 rubella vaccine all gave birth to healthy infants. Moreover, 17 susceptible women who received RA 27/3 vaccine delivered babies free from abnormalities which could be compatible with congenital rubella. From these figures it is calculated that the potential risk of severe congenital malformations is less than 3%. Because this is not zero it remains advisable not to vaccinate women known to be pregnant (32 C , 33R).
Tetanus Taking 740 patients with a history of adverse reactions to tetanus toxoid immunization, Jacobs et al. (34 c ) provide an analysis of the original symptoms and of those following skin testing and diphtheria tetanus booster. The historical data are given in Table 1. 730 of the 740 patients were non-reactive to skin testing or booster. Of the 10 others, four reacted to skin testing, two of them refused the booster, two responded negatively to the booster. Of the six non-reactors to skin testing, three reacted to the booster in that they were hypersensitive to the mercury in thiomersal. The three remaining cases had large local indurated erythematous lesions
326
B. Hofman and H.P. Lansberg
Table 1. Adverse reactions to tetanus toxoid immunization Symptom
Number of patients (%)
Anaphylactoid reaction Local swelling, erythema, tenderness Immediate (<2 hr) Delayed ( 4 - 8 hr) Late (>12 hr) Unknown time frame Fever Immediate ( 1 - 3 hr) Delayed (>4 hr) Nausea and vomiting Constitutional symptoms (malaise, fatigue, etc.) Generalized non-specific rash Acute dizziness Syncope Arthralgias Miscellaneous Localized urticaria at injection site; vesicles at injection site; shock (delayed time frame); phlebitis; seizure; 'red spots all over arms'; sleepwalking; chest wall swelling (delayed); 'hallucinations'; paralysis (generalized, transient)
95 (13.0) 248 (33.6) 37 76 72 113 30 83 84 57
(5.0) (10.1) (9.5) (15.3) (4.1) (11.2) (11.4) (7.8)
38 (5.2) 22 (3.0) 11 (1.5) 7 (1.0) (Each <1)
at the site of injection, that persisted for several days. In conclusion: A history o f an adverse reaction to t e t a n u s t o x o i d does not preclude future i m m u n i z a t i o n to this same material. Tuberculin
A n unusual reaction to a PPD skin test has b e e n r e p o r t e d b y Lavey and Pearl (35c). A 35-year-old V i e t n a m e s e w o m a n had an injection w i t h liquid silicone in her face in 1973. Three years later she suffered f r o m i n f l a m m a t i o n s in the injected area; all cultures were negative. N i n e m o n t h s after recovery she received a M a n t o u x PPD skin test; after 48 hours swelling and inflammation of the glabella and at the site o f the skin test occurred. O n e w e e k later all sympt o m s were gone. T h e authors came to t h e conclusion that t h e m o s t likely e x p l a n a t i o n was a non-specific response o f l y m p h o c y t e s initiated by the tuberculin test; activated l y m p h o c y t e s might cross-react with some antigen in the silicone-injected tissue.
Several patients described more than one symptom and data are therefore presented as a percentage of total complaints.
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