Beitr. Path. Bd. 158,212-224 (1976)
Case Reports
Pathologisches Institut (Ludwig-Aschoff-Haus) der Universitat Freiburg i. Br. (Direktor: Prof. Dr. W. Sandritter)
Lethal Complications of Typhoid-CholeraVaccination (Case Report and Review of the Literature) Todlicher Zwischenfall nach Typhus- und Choleraimpfung (Ein Fallbericht und Literaturiiberblick) CH. MITTERMAYER With
2
Figures and
I
Table' Received January 4, 1974 . Accepted February
28,
1974
Key words: Typhoid-ChoLera-Vaccination - Endotoxic-shock - LethaL complications of Vaccination - AnaphyLactic Shock - Myocarditis
Summary Simultaneous parenteral vaccination against typhoid and cholera lead to death through either anaphylactic shock or endotoxic shock in a 36-year-old male. At autopsy the characteristic features of shock as well as chronic interstitial myocarditis were noted. Moreover, fresh histiocytic and lymphocytic nodules were found in the liver, heart and meninges. A review of the literature dealing with lethal complications following parenteral typhoid vaccinations shows an increased risk in debilitated persons (emaciation, stress, cold). Most of the fatalities occurred in persons who had previous disturbances of the cardiovascular system, as in the case reviewed here. Cardiac failure, Landry's paralysis, renal failure and disturbances of skin, joints and intestines may also follow typhoid vaccinations. However, these latter complications are usually not lethal. The patients presented here had many of the conditions which are known to aggravate the situation and to lead to a lethal culmination. The review of this case and the discussion following it shows that only healthy persons should receive the parenteral typhoid vaccination. Hopefully, the presentation of this material will help prevent fatalities of this type in the future.
Lethal Complications of Typhoid-Cholera-Vaccination .
2I
3
Cholera and typhoid vaccinations, in present day form, are of undisputed value. Side effects occur only rarely after initial application of the vaccine. Symptoms are reversible and usually recovery is perfect. Occasionally, however, fatalities can occur following typhoid vaccination. Of the millions of German army soldiers vaccinated during World War II, 31 died as a result of this procedure (Klinge, 1944). Comparable statistics are not available from World War I, but are probably of the same order (Askanasy, 1921). In the Swiss Army only one fatality was reported, whereas in the English Army, seven deaths were reported in World War II. From these data, the chances of death following a vaccination are estimated to be between in 1 in 106 to 1 in 108• In spite of the relatively low fatality rate, the following questions should be raised. First, which factors contribute to the development of lethal complications and, second, whether or not the analysis of a clinical case history in light of the findings recorded in the literature would help to prevent these types of fatalities in the future. In this respect, pathology may fullfill its part in preventive medicine (Sandritter, 1973). This paper pursues such a purpose by presenting a case history and the relevant literature.
Case history The patient, who died at the age of 36, had according to his mother an enlarged heart since the age of twelve. No auscultatory abnormalities were ever noted at regular routine physical examinations. These began at age 24 and were conducted at university and private clinics in the United States. When the patient was 27 years old, he developed cough, cold, hoarseness, and tonsillitis. Repeated electrocardiograms were normal. Blood pressure, urine, and differential blood counts were always normal. Four years before death, the patient was vaccinated against smallpox. Subcutaneous typhoid vaccinations were performed on May 3, 1961, May 12, 1961, and on June 13, 1961, thus, 12 years before his death.
Summary of x-ray findings 1966: slightly enlarged heart, but within normal limits; 1970: the left ventricle of the heart appeared unusually large, probably due to patient's size; 1972: Abnormally enlarged heart, probably constitutional.
2 14 .
Ch. Mittermayer
Vaccination At 10.00 A.M. on July 2, 1973, the patient was inoculated with a dose of cholera vaccine subcutaneously in the right upper arm (2 X 10 9 inactivated bacteria per 1 ml of Vibrio cholerae Inaba, Ogawa, Inaba - Biotyp EI Tor and Ogawa - Biotyp EI Tor with 2.5 mg phenol as preservative). Simultaneously, he received a dose (1 ml) of TAB-vaccine (typoid-paratypoid-adsorbate-vaccine). This vaccine contains inactivated Salmonella typhi (5 X 108), Salmonella paratyphi A (1.25 X 108), Salmonella paratyphi B (1.25 X 108) in 1.5 mg aluminum-hydroxide as adjuvant and sodium timerfonate as preservative (Behring, 1974-1975). Both vaccines were fresh and delivered directly from the pharmacy, and, used immediately. The attending physician reported that the patient said he felt healthy and that he had never experienced complications from previous vaccinations. He had no allergies. Through a weight reduction diet, the patient had lost much unnecessary weight; during the week of the vaccination he had lost five kilograms. Until three years previously the patient had been a heavy smoker, had worked a great deal and had slept very little. A year before his death, he had collapsed during a hike. His ECG, however, showed no abnormalities (recordings no longer available). Immediately after the vaccination, the patient felt ill and experienced auditory and equilibrium disturbances. Twenty-eight hous later, his wife was awakened by death rattling. He lost consciousness immediately thereafter. Tachycardia and arrhythmia followed by cardiac arrest were diagnosed by the doctor who had been called. Mouth-to-nose resuscitation and heart massage proved unsuccessful. He was admitted to the university hospital one hour before death. The patient was pale, although not livid. His extremities were cool and his pupils dilated. His heart beat was inaudible. After 30 minutes of continous effort at resuscitation one could only see slight deviations from the base line in electrocardiogram. In spite of the application of an external pacemaker, the patient died 36 hours after the vaccination. The clinical diagnosis was: cardiac arrest following suspected myocardial infarction or cardiac arrest due to anaphylactic shock.
Pathological diagnosis (Autopsy Number: SN 148/73) Chronic, interstitial myocarditis with predominantly histiocytic and plasmacellular infiltrations, especially in the subendocardial layers of the left cardiac ventricle (Fig. I). Dilatation of the right cardiac ventricle.
Lethal Complications of Typhoid-Cholera-Vaccination·
215
Fig. 1. Chronic interstitial myocarditis with several subendocardial (a) and intramural (b) lympho-histiocytic infiltrations; HE; X 36. Abb. 1. Chronische interstitielle Myokarditis mit einigen frischen lymphohistiozytaren Infiltraten subendokardial (a) und intramural (b). HE; X 36.
Slight pericardial adhesions. Focal necroses and myocardial fibrillolysis. Endocardial lesions, platelet- and granulocytic thrombi and perivascular edema of the coronary vessels. Uncoagulated blood in all arteries. Severe pulmonary congestion. Acute overinflation and local atelectasis of both lungs. Slight chronic bronchitis. Slight pleural adhesions. Severe hepatic congestion. Numerous histiocyte nodules in the hepatic parenchyma (Fig. 2). Fatty degeneration (20%) of the liver parenchyma. Activation of the reticuloendothelial system and swelling of the pericytes in the liver. 200 ml hematinic content in the ectatic stomach. Solitary adenomatous polyp of the sigmoid colon. Numerous petechial hemorrhages in the brain with lympho-histiocytic nodules in the meninges. Body length: 180 cm; Body weight: 92 kg; spleen: 430 g; heart: 510 g; liver: 1,350 g; lungs: 850 g; left kidney: 180 g; right kidney: 170 g; brain: 1,52 0 g.
116 .
Ch. Mittermayer
Fig. 2. Lympho-histiocytic nodule in the liver. HE; X 1,040. Abb.2. Lympho-histiozytiires Knotchen in der Leber. HE; X
1040.
Discussion The patient died due to protracted shock which was recognized too late to be successfully treated. The pathological-anatomical findings point to this diagnosis because of perivascular and perisinusoidal edema, platelet thrombi, endothelial defects, acute overinflation of the lung, cerebral edema, and fresh myocardial necroses. The latter probably could have been the cause of death. Similar results were found in animal experiments with immunologically induced forms of shock (Henson and Cochrane, 1969). Because our patient received a parenteral typhoid vaccination 12 years before his death, the reaction can be interpreted as anaphylactic shock. This type of reaction to typhoid-paratyphoid-vaccine is unusually rare. The frequency in Western Europe can only be estimated on the basis of published cases. Accordingly, our patient is the second recorded case since 1945 in Western Europe; the first such case was reported in England and this patient died from anaphylactic shock (Joekes et al., I972). There may be a number of unofficially registered or published cases. Exact data
Lethal Complications of Typhoid-Cholera-Vaccination .
2I7
for Western Germany are not available since the Federal Statistical Record Office classifies such deaths according to international classification of diseases (lCD 1968) under section E933-936 as "Complications resulting from vaccinations and not therapeutic measures". This constitutes a total count. For example, 16 fatalities were recorded in 1970 (Statistisches Bundesamt 1970). No special mention is made of death following typhoidparathypoid-vaccination. No detailed information could be obtained from the Federal Ministry for Youth, Family and Health (AZ: 134-4390oo-H) and the documentation of a state ministry (Dokumentation 1972). The USSR is the only nation among those represented in the World Health Organization, which systematically records vaccination deaths. According to their record, four patients died from typhoid-paratyphoid-vaccine within a 3 year period, two due to anaphylactic (endotoxin) shock and one due to acute kidney failure following "necronephrosis" (Ozerezkowsky, 1973). The paucity of information from contemporary material makes it necessary to review older literature in order to evaluate this case. A complete summary is included in the appendix. A few general rules may be obtained from these studies. I. Side effects following TAB-vaccination involve mainly the skin, joints, kidneys, and the nervous and cardiovascular systems (Baerthlein, 1931). 2. The cholera vaccine causes extremely rarely slight and reversible side effects on the skin (Wenderroth, 1943). Cholera vaccine can be administered at the same time as TAB vaccine (Behring-Codex, 197475 ). 3. Those patients who are receiving the vaccine for the first time or those who are debiliated (suffering from hunger or unusual strain) (Salge, 1915; Hiltmann, 1915) seem to be particularly suspectible to complications following typhoid-parathyphoid vaccination (Raettig, 1952). 4. Fatalities following typhoid vaccination result from acute kidney failure, Landry's paralysis and cardiovascular failure (Shock) (Gunther, 19 6 5). 5. Cardiovascular complications are the most common cause of death. About one third of the patients who died after vaccination had experienced previous heart damage (Klinge, 1944). This was also true of the first typhoid vaccine fatality reported in the literature (Askanasy, 1916). 6. A typhoid-paratyphoid-vaccine is composed of inactivated bacterial cells and not of serum; therefore, the ensuing shock must be due to toxic substances or due to antigen-antibody complex formation. There is evidence in the literature for both possibilities (Wilson, 1967).
2 18
. Ch. Mittermayer
7. In most cases an antigen-antibody reaction seems to precipitate shock. The vascular changes are lesions histologically similar to those of the generalized Shwartzman-reaction (Mittermayer, Pfrieme and Schonbach, 1970)' There is no difference between these changes and those resulting from experimentally induced soluble antigen-antibody complexes (Dixon et aI., 1958). 8. Following typhoid-paratyphoid vaccination, a conspicuous tissue reactions may be present in different organs, especially in the liver and myocardium. In the liver and myocardium (Meesen and Merkel, 1942) actual "typhomas" can be observed or smalllympho-histocytic nodules can be seen. This phenomenon occurring in the absence of living bacteria was considered as evidence for not only a humoral but also a cellular immunological reaction following typhoid-paratyphoid vaccination. (Donat, 1946; Watjen, 1947). Indication for a more generalized reaction comes from Salfelder and Sand ritter, who found such histiocytic nodules in myocardium in a series of infectious diseases which were other than typhoid fever but distinctly different from rheumatic granuloma. Hamperl (1953) called them "retothelial nodules" and considers their presence to idicate an unspecific reaction to toxic-infectious damage. In the case presented here, a number of aggravating factors have probably occurred simultaneously: the typhoid-paratyphoid vaccine was fresh and was applied simultaneously with cholera vaccine; the patient had recently been on a diet and additionally was suffering from chronic interstitial myocarditis. Indicative for a cellular immunological response are histiocytic nodules in the liver. The death resulted from protracted anaphylactic or endotoxic shock. There is a high probability that a causal relationship exists between the vaccination and the death (Berufsgenossenschaft Feinmechanik und Elektronik, Stuttgart, AZ: 73909950-1). The study of this case, from a practical medical viewpoint, is informative in so far as it describes another case, among many, in which death followed typhoid vaccination. It again emphasizes the need for careful evaluation of the patient's health before administering the typhoid-cholera vaccine.
Zusammenfassung Anhand eines todlichen Impfzwischenfalles nach subkutaner Typhus-Paratyphus-Choleraschutzimpfung werden die bisher in der Weltliteratur gesammelten Falle studiert. Die Erfahrung zeigt, daB unter I Million bis 10 Millionen Impflingen Todesfa11e auftreten, und zwar vor allem dann, wenn eine kardiovaskuHire Vorschadigung vorliegt, Abmagerung, StreB und Strapazen vorangegangen waren und sehr frischer Impfstoff verwendet wurde. Alle drei Faktoren trafen bei dem hier beschriebenen 36jahrigen Patienten zu.
Lethal Complications of Typhoid-Cholera-Vaccination'
219
I thank Prof. Dr. W. Gerok and Dr. L. Herkel (Medizinische Universitatsklinik) and Dr. E. Auch (Eichstetten) for use of patients records and Prof. Dr. A. Vogt and Doz. Dr. F. Fehrenbach (Hygiene Institut, Universitat Freiburg) for valuable suggestions. The English text was improved by cando med. Tom]. Campen.
Table
1.
Complications following parenteral Typhoid vaccination
Skin Bertarelli
19 151r6
Erythema
Hemt
19 15
Allergic rashes
Matko
19 1 5h6
Scarlatiniform Exanthema
Frieboes
19 16
Erythema
Vaternahm
19 16
Impetigo
Lintz
19 17
Fever, Exanthema
Nicolas and Gate
19 23
Scleroderma
Morel and Grupper
194 0
Dermatosis
Wenderoth
1943
Allergic Dermatitis
Sohier et al.
1944
Dermatosis
Raettig
1952
Allergic diseases
Rethy und Losonczy
1959
Urticaria
Nervous System
Gubb
19 15
Encephalomyelitis
Jumentie
19 16
Polyneuritis
Roussy and Cornil
19 19
Polyneuritis
Roussy
19 19
Polyneuritis
Souques
19 19
Polyneuritis
Guillain and Barre
19 19
Landry's Paralysis
Preti
19 19
Blindness
Bury
19 20
Ataxia
Knapp
19 22
Neuritis
220 .
Ch. Mittermayer
Gayle and Bowen
Landry's Paralysis, Polyneuritis
Benon
Depression
Kennedy
Neuritis
Noica
19J2
3 cases of partial or total paralysis of extremities, hemianopsia, aphonia, deafness
Gerloff
Neuritis, 3 cases
Peacher, Robertson
Transverse lesion with paraplegia
Pette
Transverse lesion with paraplegia
1943
Acute Paraplegia
1947
Acute Lethal Hemorrhagic Leptomeningitis
Keyserlingk
1947
Neuritis
Bannwarth
194 8
Allergic Neuritis
Giffin et al.
1948
Lethal case of Hemiplegia
Miller and Schapira
1952/59
Multiple Sclerosis
Miller und Stanton
1954
10 cases Landry's Paralysis, 20 cases of cerebral and meningeal complications
Putnam
Andre-Balisaux
Encephalitis
Weimann and Winter
Hemorrhagic Necrosis of Spine
Rieder
Transverse lesion with paraplegia
Georgiev, Y ordanov and Chukova-Bojinova
Polyneuritis (3 cases)
Mitkov and Halatchev
Allergic Diencephalitis (I case) and Neuritis (5 cases)
Cardiovascular System
Toeniessen
19 15
Venous Thrombosis
Ott
19 15
Venous Thrombosis
Askanasy
19 16
Venous Thrombosis
Gruber
19 16
Syphilitic Myocarditis
H ering
19 16
Syphilitic Myocarditis
Oberndorfer
19 16
Syphilitic Myocarditis
Hoke
19 26
Lethal Allergic Shock
Terrien
1935
Peripheral Neuropathy of the Extremities
Lethal Complications of Typhoid-Cholera-Vaccination .
221
Ziskind and Schottenburg
193 8
Anaphylactic Shock
British Ministry of Health (quoted by Wilson)
193 8/4 6
10 cases of acute Anaphylaxis, 7 letal
Hornung
1939
Shock, Anuria
Holzmann
1940
Cardiogenic Shock, Coronary Occlusion
Vogt
194 0
Peripheral Gangrene
Meesen and Merkel
1942
Cardiac Shock, Typhoid Nodules
Urbach et al.
1945
Generalized Shwartzman-Reaction
Love and Driscoll
1945
Generalized Shwartzman-Reaction
Hansen
1947
Hemorrhage
Rahn
1949
Sudden Cardiac Death; Coronary Artery Sclerosis
Strauss
1951
Allergic Bone Marrow Depression
Raettig
1952
Circulatory Failures
Marzani
19 69
Complete Cardiac Atrioventricular Block
Kidney, Joints
Polyarthritis
DreyfuB Vaivel
1937
Nephritis
Goudet Bernard et al.
Polyarthritis
1959
Nephritis Acute Renal Insufficiency
Joekes et al.
Gastro-/ntestinal-Tract
Matko
19 15/r6
Diarrhea
Koch
19 16
Acute Allergic Diarrhea
Stefansky
1917
Acute Allergic Diarrhea
Lembke
19 24
Acute Allergic Diarrhea
Muller
194 0
Acute Allergic Diarrhea
de Morsier
1947
Acute Allergic Diarrhea
Bannwarth
194 8
Acute Allergic Diarrhea
-------------------------------------------------------------------
222 .
Ch. Mittermayer
Literatur Askanasy, M.: Dtsch. med. Wschr. 62, 897 (1916) Askanasy, M.: Allgemeines uber die Morphologie der Immunitatsreaktionen. In: Handbuch der arztlichen Erfahrungen im Weltkrieg, Hrsg.: Schjerning, 8, 197 (1921) Andre-Balisaux, G.: Acta neurol. Belg. 54, 249 (1959) Baerthlein, K.: Immunitat bei Typhus. In: Handbuch der pathogenen Mikroorganismen, Band III, 1279-1376 (1931) Bannwarth, A.: Arztl. Wschr. 3,581 und 620 (1948) Bannwarth, A.: Arch. Psychiatr. 180, 531 (1948) Benon, R.: Paris med. fl, 94 (1924) Behringcodex 1974, Hrsg. Behringwerke Marburg Bernard,]. G., Laaban,]., et Lechat, S.: Pre sse med. 67,1511 (1959) Bertarelli, E.: Riv. di Igiene e di San. Pub. 16,4 (1915) Bertarelli, E.: Riv. di Igiene e di San. Pub. 27, 5 (1916) Bury,]. S.: Lancet II, 844 (1920) Dixon, F. ]., Vazques, ]. J., Weigle, W. W., and Cochrane, C. G.: Arch. Path. 65, 18 (1958) Dokumentation zur Beurteilung von Impfschaden und Impferfolgen. Heft I (1972), Hrsg.: Minister fur Arbeit, Gesundheit und Soziales des Landes Nordrhein-Westfalen Donat, R.: Dtsch. Gesundh.-Wes. I, 186 (1946) DreyfuB, E.: Ober klinische Begleiterscheinungen der Typhusschutzimpfung. Inaug. Diss., StraBburg (1915) Frieboes, W.: Munch. med. Wschr. 63, 228 (1916) Gayle, R. F., and Bowen, R. A.:]. nerv. ment. Dis. 78, 221 (1924) Georgiev, I., Yordanov, B., and Chukova-Bojinova, T.: Neurol. Psihiatr. i. neurohirug. (Bulg.) 10,382 (1971) Gerloff: Munch. med. Wschr. 87, 386 (1940) Giffin, M. E., Rogers, H. M., und Kernahan, ]. W.: Arch. Neural. Psychiat. 59, 233 (194 8) Goudet, M.: Zbl. ges. Hyg. I. Ref. 135, 378 (1940) Gruber, B. G.: Dtsch. med. Wschr. 62, 898 (1916) Gubb, A. S.: Med. Press 100, 371 (1915) Gunther, 0.: Handbuch der Schutzimpfungen. Hrsg. A. Herrlich, Typhusschutzimpfung, Choleraschutzimpfung, S. 542 und 580. Springer Verlag, Berlin-Heidelberg-New York (19 6 5) Guillain, G., und Barre, ]. A.: Rev. Neurol. 26, 595 (1919) Hamperl, H.: Klin. Wschr. jI, 681 (1953) Hansen, K.: Dtsch. med. Wschr. 72, 209 (1947) Hecht, H.: Prag. med. Wschr. 40, 287 (1915) Henson, P. M., and Cochrane, C. G.: In: Cellular and Humoral Mechanism III Anaphylaxis and Allergy. Hrsg.: H. Z. Movat, S. Karger, Basel (1969) Hering, H.: Dtsch. med. Wschr. 62, 898 (1916) Hiltmann, V: Munch. med. Wschr. 62,125 (1915) Hoke, E.: Med. Klinik 22,577 (1926) Holzmann, M.: Schweiz. med. Wschr. 70, 676 (1940) Hornung, H.: Chirurg I I , 543 (1939) Joekes, A. M., Gabriel, ]. R. T., and Goggin, M. ].: Nephron 9, 162 (1973) Jumentie, J.: Rev. Neurol. 23, 582 (1916)
Lethal Complications of Typhoid-Cholera-Vaccination .
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Kennedy, F.: Amer. J. med. Sci. 177, 555 (1929) Keyserlingk, H. von: Med. Klin. 42,189 (1947) Klinge, F.: Virchows Arch. 313,89 (1944) Koch, R.: Munch. med. Wschr. 63, 645 (1916) Knapp, A.: Dtsch. med. Wschr. 48, 659 (1922) Krauss, K.: Z. ges. inn. Med. 2, 160 (1947) Lembke, W.: Z. H yg. 103, 340 (1924) Love, J., and Driscoll, R. H.: Nav. med. Bull. 45, 1104 (1945) Lintz, W.: J. Amer. med. Ass. 681, 1319 (1917) Marzani, P. c.: Minerva Medica 60,1394 (1969) Matko, ].: Wien. med. Wschr. 65,1266-1312 (1915) Matko, J.: Wien. med. Wschr. 66, 1423 (1916) Meesen, H., und Merkel, H . H.: Beitr. path. Anat. 106, 385 (1942) Miller, H., and Schapira, K.: Brit. med. ]. 737, 2124 (1959) Miller, H ., and Schapira, K.: Brit. med. ]. 81 1,.2125 (1952) Miller, H., and Stanton, ]. B.: Quart. ]. Med. N. S. 23, I (1954) Mitkov, V., and Halatchev, N .: NeuroI. Psihiatr. i. neurohirurg. (Bulg.) 10, 379 (1971) Mittermayer, Ch., Pfrieme, B., und Schonbach, G.: Beitr. Path. 141, 155 (1970) Morel, A., und Grupper, c.: Zbl. Bakt., 1. Abt. Ref. 92,138 (1940) Morsier, G. de: Rev. mlid. Suisse Rom. 67, 607 (1947) Muller, K. H.: Dtsch. med. Wschr. 66, 1208 (1940) Nicolas, ]., und Gate, ].: Zbl. ges. Hyg. 3, 401 (1923) Noica, D.: Bull. Mem. Soc. med. Hap. Paris 48,1026 (1932) Oberndorfer, S.: Dtsch. mil. Z. 47,286 (1918) Ott, W.: Munch. Med. 62, 39 (1915) Ozerezkowsky, N.: Personliche Mitteilung, The State Institute for Standardization and Control of Medical Biological Preparations (Tarasevic's Institute) Moskau, USSR (1973) Peacher, W. G., and Robertson, R. C. L.: J. nerv. ment. Dis . 101, 515 (1945) Pette, H. : Klin. Wschr. 24, 25, 897 (1946/47) Preti, L.: Atti Soc. Lombarda Sci. med. bioI. 8, 85 (1919) Putnam, T. ].: Bull. N. Y. Acad. Med. 19, 301 (1943) Raettig, H.: Typhusimmunitat und Schutzimpfung, S. 143-147. VEB Gustav Fischer Verlag, lena (1952) Rahn, J.: Z. ges. inn. Med. 4, 490 (1949) Rethy, L., und Losonczy, G.: Ann. Immunol. Hung. 2, 65 (1959) Rieder, R. T.: Munch. med. Wschr. 104, II80 (1962) Roussy, G., und Corni!, L.: Rev. Neurol. 26, 453 (1919) Roussy, G.: Rev. Neurol. 26, 505 (1919) Salfelder, K., und Sandritter, W.: Frankf. Z. Path. 62, 88 (1951) Salge: Dtsch. med. Wschr. 41,180 (1915) Sandritter, W.: Gesundheitsfursorge 3,82 (1973) Sohier, R., Alaize, M., und Proust, R.: Zbl. Bakt., 1. Abt. Ref. 144, 214 (1944) Souques, A.: Rev. Neurol. 26, 501 (1919) Statistisches Bundesamt Wiesbaden, Mitteilungen. Verlag W. Kohlhammer, Stuttgart (1973) Stefansky, V. R.: Off. intern. Hyg. publ. 7,1279 (1917) Strauss, E.: Dtsch. med. Wschr. 76, 931 (1951) Terrien, E.: ZbI. Bakt., 1. Abt. Ref. 117,227 (1935) Toeniessen, E.: Munch. med. Wschr. 62, 429 (1915) Urbach, E., Goldburgh, H. L., and Gottlieb, P. M.: Nav. med. Bull. 45, IIo4 (1945)
224 . Ch. Mittermayer Vaivel,].: Zbl. ges. Hyg. 38, 698 (1937) Vaternahm, Th.: Munch. med. Wschr. 63,851 (1916) Vogt: Dtsch. med. Wschr. 66,700 (1940) Watjen,].: Dtsch. Gesundh.-Wes. 2, 155 (1947) Weimann, G., und Winter, H.: Med. Welt 12, 2048 (1961) Wilson, Sir G.: The Hazards of Immunization. Athlonc Press (1967) Wenderoth, H.: Dtsch. med. Wschr. 69, 445 (1943) Ziskind, ]., and Schottenburg, H. ].: Arch. intern. Med. 62, 813 (1938) Prof. Dr. Christian Mittermayer, Pathologisches Institut (Ludwig-Aschoff-Haus), Albertstr. 19, D-78oo Freiburg i. Br.
Case Reports
Pathologisches Institut (Ludwig-Aschoff-Haus) der Universitat Freiburg i. Br. (Direktor: Prof. Dr. W. Sandritter)
Lethal Complications of Typhoid-CholeraVaccination (Case Report and Review of the Literature) Todlicher Zwischenfall nach Typhus- und Choleraimpfung (Ein Fallbericht und Literaturiiberblick) CH. MITTERMAYER With
2
Figures and
I
Table' Received January 4, 1974 . Accepted February
28,
1974
Key words: Typhoid-ChoLera-Vaccination - Endotoxic-shock - LethaL complications of Vaccination - AnaphyLactic Shock - Myocarditis
Summary Simultaneous parenteral vaccination against typhoid and cholera lead to death through either anaphylactic shock or endotoxic shock in a 36-year-old male. At autopsy the characteristic features of shock as well as chronic interstitial myocarditis were noted. Moreover, fresh histiocytic and lymphocytic nodules were found in the liver, heart and meninges. A review of the literature dealing with lethal complications following parenteral typhoid vaccinations shows an increased risk in debilitated persons (emaciation, stress, cold). Most of the fatalities occurred in persons who had previous disturbances of the cardiovascular system, as in the case reviewed here. Cardiac failure, Landry's paralysis, renal failure and disturbances of skin, joints and intestines may also follow typhoid vaccinations. However, these latter complications are usually not lethal. The patients presented here had many of the conditions which are known to aggravate the situation and to lead to a lethal culmination. The review of this case and the discussion following it shows that only healthy persons should receive the parenteral typhoid vaccination. Hopefully, the presentation of this material will help prevent fatalities of this type in the future.
Lethal Complications of Typhoid-Cholera-Vaccination .
2I
3
Cholera and typhoid vaccinations, in present day form, are of undisputed value. Side effects occur only rarely after initial application of the vaccine. Symptoms are reversible and usually recovery is perfect. Occasionally, however, fatalities can occur following typhoid vaccination. Of the millions of German army soldiers vaccinated during World War II, 31 died as a result of this procedure (Klinge, 1944). Comparable statistics are not available from World War I, but are probably of the same order (Askanasy, 1921). In the Swiss Army only one fatality was reported, whereas in the English Army, seven deaths were reported in World War II. From these data, the chances of death following a vaccination are estimated to be between in 1 in 106 to 1 in 108• In spite of the relatively low fatality rate, the following questions should be raised. First, which factors contribute to the development of lethal complications and, second, whether or not the analysis of a clinical case history in light of the findings recorded in the literature would help to prevent these types of fatalities in the future. In this respect, pathology may fullfill its part in preventive medicine (Sandritter, 1973). This paper pursues such a purpose by presenting a case history and the relevant literature.
Case history The patient, who died at the age of 36, had according to his mother an enlarged heart since the age of twelve. No auscultatory abnormalities were ever noted at regular routine physical examinations. These began at age 24 and were conducted at university and private clinics in the United States. When the patient was 27 years old, he developed cough, cold, hoarseness, and tonsillitis. Repeated electrocardiograms were normal. Blood pressure, urine, and differential blood counts were always normal. Four years before death, the patient was vaccinated against smallpox. Subcutaneous typhoid vaccinations were performed on May 3, 1961, May 12, 1961, and on June 13, 1961, thus, 12 years before his death.
Summary of x-ray findings 1966: slightly enlarged heart, but within normal limits; 1970: the left ventricle of the heart appeared unusually large, probably due to patient's size; 1972: Abnormally enlarged heart, probably constitutional.
2 14 .
Ch. Mittermayer
Vaccination At 10.00 A.M. on July 2, 1973, the patient was inoculated with a dose of cholera vaccine subcutaneously in the right upper arm (2 X 10 9 inactivated bacteria per 1 ml of Vibrio cholerae Inaba, Ogawa, Inaba - Biotyp EI Tor and Ogawa - Biotyp EI Tor with 2.5 mg phenol as preservative). Simultaneously, he received a dose (1 ml) of TAB-vaccine (typoid-paratypoid-adsorbate-vaccine). This vaccine contains inactivated Salmonella typhi (5 X 108), Salmonella paratyphi A (1.25 X 108), Salmonella paratyphi B (1.25 X 108) in 1.5 mg aluminum-hydroxide as adjuvant and sodium timerfonate as preservative (Behring, 1974-1975). Both vaccines were fresh and delivered directly from the pharmacy, and, used immediately. The attending physician reported that the patient said he felt healthy and that he had never experienced complications from previous vaccinations. He had no allergies. Through a weight reduction diet, the patient had lost much unnecessary weight; during the week of the vaccination he had lost five kilograms. Until three years previously the patient had been a heavy smoker, had worked a great deal and had slept very little. A year before his death, he had collapsed during a hike. His ECG, however, showed no abnormalities (recordings no longer available). Immediately after the vaccination, the patient felt ill and experienced auditory and equilibrium disturbances. Twenty-eight hous later, his wife was awakened by death rattling. He lost consciousness immediately thereafter. Tachycardia and arrhythmia followed by cardiac arrest were diagnosed by the doctor who had been called. Mouth-to-nose resuscitation and heart massage proved unsuccessful. He was admitted to the university hospital one hour before death. The patient was pale, although not livid. His extremities were cool and his pupils dilated. His heart beat was inaudible. After 30 minutes of continous effort at resuscitation one could only see slight deviations from the base line in electrocardiogram. In spite of the application of an external pacemaker, the patient died 36 hours after the vaccination. The clinical diagnosis was: cardiac arrest following suspected myocardial infarction or cardiac arrest due to anaphylactic shock.
Pathological diagnosis (Autopsy Number: SN 148/73) Chronic, interstitial myocarditis with predominantly histiocytic and plasmacellular infiltrations, especially in the subendocardial layers of the left cardiac ventricle (Fig. I). Dilatation of the right cardiac ventricle.
Lethal Complications of Typhoid-Cholera-Vaccination·
215
Fig. 1. Chronic interstitial myocarditis with several subendocardial (a) and intramural (b) lympho-histiocytic infiltrations; HE; X 36. Abb. 1. Chronische interstitielle Myokarditis mit einigen frischen lymphohistiozytaren Infiltraten subendokardial (a) und intramural (b). HE; X 36.
Slight pericardial adhesions. Focal necroses and myocardial fibrillolysis. Endocardial lesions, platelet- and granulocytic thrombi and perivascular edema of the coronary vessels. Uncoagulated blood in all arteries. Severe pulmonary congestion. Acute overinflation and local atelectasis of both lungs. Slight chronic bronchitis. Slight pleural adhesions. Severe hepatic congestion. Numerous histiocyte nodules in the hepatic parenchyma (Fig. 2). Fatty degeneration (20%) of the liver parenchyma. Activation of the reticuloendothelial system and swelling of the pericytes in the liver. 200 ml hematinic content in the ectatic stomach. Solitary adenomatous polyp of the sigmoid colon. Numerous petechial hemorrhages in the brain with lympho-histiocytic nodules in the meninges. Body length: 180 cm; Body weight: 92 kg; spleen: 430 g; heart: 510 g; liver: 1,350 g; lungs: 850 g; left kidney: 180 g; right kidney: 170 g; brain: 1,52 0 g.
116 .
Ch. Mittermayer
Fig. 2. Lympho-histiocytic nodule in the liver. HE; X 1,040. Abb.2. Lympho-histiozytiires Knotchen in der Leber. HE; X
1040.
Discussion The patient died due to protracted shock which was recognized too late to be successfully treated. The pathological-anatomical findings point to this diagnosis because of perivascular and perisinusoidal edema, platelet thrombi, endothelial defects, acute overinflation of the lung, cerebral edema, and fresh myocardial necroses. The latter probably could have been the cause of death. Similar results were found in animal experiments with immunologically induced forms of shock (Henson and Cochrane, 1969). Because our patient received a parenteral typhoid vaccination 12 years before his death, the reaction can be interpreted as anaphylactic shock. This type of reaction to typhoid-paratyphoid-vaccine is unusually rare. The frequency in Western Europe can only be estimated on the basis of published cases. Accordingly, our patient is the second recorded case since 1945 in Western Europe; the first such case was reported in England and this patient died from anaphylactic shock (Joekes et al., I972). There may be a number of unofficially registered or published cases. Exact data
Lethal Complications of Typhoid-Cholera-Vaccination .
2I7
for Western Germany are not available since the Federal Statistical Record Office classifies such deaths according to international classification of diseases (lCD 1968) under section E933-936 as "Complications resulting from vaccinations and not therapeutic measures". This constitutes a total count. For example, 16 fatalities were recorded in 1970 (Statistisches Bundesamt 1970). No special mention is made of death following typhoidparathypoid-vaccination. No detailed information could be obtained from the Federal Ministry for Youth, Family and Health (AZ: 134-4390oo-H) and the documentation of a state ministry (Dokumentation 1972). The USSR is the only nation among those represented in the World Health Organization, which systematically records vaccination deaths. According to their record, four patients died from typhoid-paratyphoid-vaccine within a 3 year period, two due to anaphylactic (endotoxin) shock and one due to acute kidney failure following "necronephrosis" (Ozerezkowsky, 1973). The paucity of information from contemporary material makes it necessary to review older literature in order to evaluate this case. A complete summary is included in the appendix. A few general rules may be obtained from these studies. I. Side effects following TAB-vaccination involve mainly the skin, joints, kidneys, and the nervous and cardiovascular systems (Baerthlein, 1931). 2. The cholera vaccine causes extremely rarely slight and reversible side effects on the skin (Wenderroth, 1943). Cholera vaccine can be administered at the same time as TAB vaccine (Behring-Codex, 197475 ). 3. Those patients who are receiving the vaccine for the first time or those who are debiliated (suffering from hunger or unusual strain) (Salge, 1915; Hiltmann, 1915) seem to be particularly suspectible to complications following typhoid-parathyphoid vaccination (Raettig, 1952). 4. Fatalities following typhoid vaccination result from acute kidney failure, Landry's paralysis and cardiovascular failure (Shock) (Gunther, 19 6 5). 5. Cardiovascular complications are the most common cause of death. About one third of the patients who died after vaccination had experienced previous heart damage (Klinge, 1944). This was also true of the first typhoid vaccine fatality reported in the literature (Askanasy, 1916). 6. A typhoid-paratyphoid-vaccine is composed of inactivated bacterial cells and not of serum; therefore, the ensuing shock must be due to toxic substances or due to antigen-antibody complex formation. There is evidence in the literature for both possibilities (Wilson, 1967).
2 18
. Ch. Mittermayer
7. In most cases an antigen-antibody reaction seems to precipitate shock. The vascular changes are lesions histologically similar to those of the generalized Shwartzman-reaction (Mittermayer, Pfrieme and Schonbach, 1970)' There is no difference between these changes and those resulting from experimentally induced soluble antigen-antibody complexes (Dixon et aI., 1958). 8. Following typhoid-paratyphoid vaccination, a conspicuous tissue reactions may be present in different organs, especially in the liver and myocardium. In the liver and myocardium (Meesen and Merkel, 1942) actual "typhomas" can be observed or smalllympho-histocytic nodules can be seen. This phenomenon occurring in the absence of living bacteria was considered as evidence for not only a humoral but also a cellular immunological reaction following typhoid-paratyphoid vaccination. (Donat, 1946; Watjen, 1947). Indication for a more generalized reaction comes from Salfelder and Sand ritter, who found such histiocytic nodules in myocardium in a series of infectious diseases which were other than typhoid fever but distinctly different from rheumatic granuloma. Hamperl (1953) called them "retothelial nodules" and considers their presence to idicate an unspecific reaction to toxic-infectious damage. In the case presented here, a number of aggravating factors have probably occurred simultaneously: the typhoid-paratyphoid vaccine was fresh and was applied simultaneously with cholera vaccine; the patient had recently been on a diet and additionally was suffering from chronic interstitial myocarditis. Indicative for a cellular immunological response are histiocytic nodules in the liver. The death resulted from protracted anaphylactic or endotoxic shock. There is a high probability that a causal relationship exists between the vaccination and the death (Berufsgenossenschaft Feinmechanik und Elektronik, Stuttgart, AZ: 73909950-1). The study of this case, from a practical medical viewpoint, is informative in so far as it describes another case, among many, in which death followed typhoid vaccination. It again emphasizes the need for careful evaluation of the patient's health before administering the typhoid-cholera vaccine.
Zusammenfassung Anhand eines todlichen Impfzwischenfalles nach subkutaner Typhus-Paratyphus-Choleraschutzimpfung werden die bisher in der Weltliteratur gesammelten Falle studiert. Die Erfahrung zeigt, daB unter I Million bis 10 Millionen Impflingen Todesfa11e auftreten, und zwar vor allem dann, wenn eine kardiovaskuHire Vorschadigung vorliegt, Abmagerung, StreB und Strapazen vorangegangen waren und sehr frischer Impfstoff verwendet wurde. Alle drei Faktoren trafen bei dem hier beschriebenen 36jahrigen Patienten zu.
Lethal Complications of Typhoid-Cholera-Vaccination'
219
I thank Prof. Dr. W. Gerok and Dr. L. Herkel (Medizinische Universitatsklinik) and Dr. E. Auch (Eichstetten) for use of patients records and Prof. Dr. A. Vogt and Doz. Dr. F. Fehrenbach (Hygiene Institut, Universitat Freiburg) for valuable suggestions. The English text was improved by cando med. Tom]. Campen.
Table
1.
Complications following parenteral Typhoid vaccination
Skin Bertarelli
19 151r6
Erythema
Hemt
19 15
Allergic rashes
Matko
19 1 5h6
Scarlatiniform Exanthema
Frieboes
19 16
Erythema
Vaternahm
19 16
Impetigo
Lintz
19 17
Fever, Exanthema
Nicolas and Gate
19 23
Scleroderma
Morel and Grupper
194 0
Dermatosis
Wenderoth
1943
Allergic Dermatitis
Sohier et al.
1944
Dermatosis
Raettig
1952
Allergic diseases
Rethy und Losonczy
1959
Urticaria
Nervous System
Gubb
19 15
Encephalomyelitis
Jumentie
19 16
Polyneuritis
Roussy and Cornil
19 19
Polyneuritis
Roussy
19 19
Polyneuritis
Souques
19 19
Polyneuritis
Guillain and Barre
19 19
Landry's Paralysis
Preti
19 19
Blindness
Bury
19 20
Ataxia
Knapp
19 22
Neuritis
220 .
Ch. Mittermayer
Gayle and Bowen
Landry's Paralysis, Polyneuritis
Benon
Depression
Kennedy
Neuritis
Noica
19J2
3 cases of partial or total paralysis of extremities, hemianopsia, aphonia, deafness
Gerloff
Neuritis, 3 cases
Peacher, Robertson
Transverse lesion with paraplegia
Pette
Transverse lesion with paraplegia
1943
Acute Paraplegia
1947
Acute Lethal Hemorrhagic Leptomeningitis
Keyserlingk
1947
Neuritis
Bannwarth
194 8
Allergic Neuritis
Giffin et al.
1948
Lethal case of Hemiplegia
Miller and Schapira
1952/59
Multiple Sclerosis
Miller und Stanton
1954
10 cases Landry's Paralysis, 20 cases of cerebral and meningeal complications
Putnam
Andre-Balisaux
Encephalitis
Weimann and Winter
Hemorrhagic Necrosis of Spine
Rieder
Transverse lesion with paraplegia
Georgiev, Y ordanov and Chukova-Bojinova
Polyneuritis (3 cases)
Mitkov and Halatchev
Allergic Diencephalitis (I case) and Neuritis (5 cases)
Cardiovascular System
Toeniessen
19 15
Venous Thrombosis
Ott
19 15
Venous Thrombosis
Askanasy
19 16
Venous Thrombosis
Gruber
19 16
Syphilitic Myocarditis
H ering
19 16
Syphilitic Myocarditis
Oberndorfer
19 16
Syphilitic Myocarditis
Hoke
19 26
Lethal Allergic Shock
Terrien
1935
Peripheral Neuropathy of the Extremities
Lethal Complications of Typhoid-Cholera-Vaccination .
221
Ziskind and Schottenburg
193 8
Anaphylactic Shock
British Ministry of Health (quoted by Wilson)
193 8/4 6
10 cases of acute Anaphylaxis, 7 letal
Hornung
1939
Shock, Anuria
Holzmann
1940
Cardiogenic Shock, Coronary Occlusion
Vogt
194 0
Peripheral Gangrene
Meesen and Merkel
1942
Cardiac Shock, Typhoid Nodules
Urbach et al.
1945
Generalized Shwartzman-Reaction
Love and Driscoll
1945
Generalized Shwartzman-Reaction
Hansen
1947
Hemorrhage
Rahn
1949
Sudden Cardiac Death; Coronary Artery Sclerosis
Strauss
1951
Allergic Bone Marrow Depression
Raettig
1952
Circulatory Failures
Marzani
19 69
Complete Cardiac Atrioventricular Block
Kidney, Joints
Polyarthritis
DreyfuB Vaivel
1937
Nephritis
Goudet Bernard et al.
Polyarthritis
1959
Nephritis Acute Renal Insufficiency
Joekes et al.
Gastro-/ntestinal-Tract
Matko
19 15/r6
Diarrhea
Koch
19 16
Acute Allergic Diarrhea
Stefansky
1917
Acute Allergic Diarrhea
Lembke
19 24
Acute Allergic Diarrhea
Muller
194 0
Acute Allergic Diarrhea
de Morsier
1947
Acute Allergic Diarrhea
Bannwarth
194 8
Acute Allergic Diarrhea
-------------------------------------------------------------------
222 .
Ch. Mittermayer
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224 . Ch. Mittermayer Vaivel,].: Zbl. ges. Hyg. 38, 698 (1937) Vaternahm, Th.: Munch. med. Wschr. 63,851 (1916) Vogt: Dtsch. med. Wschr. 66,700 (1940) Watjen,].: Dtsch. Gesundh.-Wes. 2, 155 (1947) Weimann, G., und Winter, H.: Med. Welt 12, 2048 (1961) Wilson, Sir G.: The Hazards of Immunization. Athlonc Press (1967) Wenderoth, H.: Dtsch. med. Wschr. 69, 445 (1943) Ziskind, ]., and Schottenburg, H. ].: Arch. intern. Med. 62, 813 (1938) Prof. Dr. Christian Mittermayer, Pathologisches Institut (Ludwig-Aschoff-Haus), Albertstr. 19, D-78oo Freiburg i. Br.
