The vitamins and resistance to infection

THE VITAMINS AND RESISTANCE TO INFECTION ELIZABETH CHANT ROBERTSON From the Department of Paediatrics, University of Toronto CONTENTS I. Introduction……………………………………………………………………. 123 II. Vitamins A and D…………………………………………………………… .... 124 III. Vitamin A……………………………………………………………………. ... 145 IV. Vitamin D……………………………………………………………………. .... 157 V. Vitamin B……………………………………………………………………. .. 175 VI. Vitamin C……………………………………………………………………. ... 190 VII. Vitamin E……………………………………………………………………. ... 206 This text is restricted to vitamin C. Location of this file: https://doi.org/10.5281/zenodo.1449692 The whole review is available at: https://journals.lww.com/md-journal/citation/1934/05000/the_vitamins_and_resistance_to_infection.1.aspx INTRODUCTION In many of the investigations on the relation between the vitamins and resistance to infection rations lacking in several essentials have been employed, usually in an effort to test the effect of inadequate human dietaries. Although such investigations have yielded results of practical value, they do not disclose the roles played by the diverse missing substances. More definite information on this question can be obtained from experiments in which diets deficient in one vitamin only are utilized and the following review has been limited, with very few exceptions, to the discussion of such work. Very numerous papers on this subject have appeared and some no doubt have been overlooked by the author. Wherever possible the investigations have been described in sufficient detail for the reader critically to appraise them. Unfortunately many of the experiments have been carried out on such small numbers of animals that the results are not statistically significant. 123 MEDICINE, VOL. 13, NO. 2 190 ELIZABETH CHANT ROBERTSON VITAMIN C 1. Variations in the natural immune bodies or tissue reactions in vitamin C deficiency (a) Results indicating that these are reduced. Fortenato (1) reported in 1921 that the opsonic index was lower in scorbutic than in normal guinea pigs. In the following year, Leichentritt and Zielaskowski (2) measured the trypanocidal substance in the blood of guinea pigs suffering with scurvy and found that it was reduced. Höjer (3) however criticized the latter's experiments on the grounds that they were carried out on too few animals. According to Prausnitz and Schilf (4) tuberculous scorbutic guinea pigs show considerably smaller tuberculin reactions, which also dis- VITAMINS AND RESISTANCE TO INFECTION 191 appear more quickly than those in tuberculous guinea pigs subsisting on normal diets. The febrile reaction after the tuberculin injection was also less marked in the scorbutic animals. This reduced skin reactivity was not correlated with a generalized unsusceptibility to tuberculin (5) as the animals with scurvy died more frequently than the normal controls when this substance was injected subcutaneously in large amounts (5 cc.). In addition, Bieling (6) and also Arkwright and Zilva (7) found that markedly scorbutic guinea pigs gave smaller skin reactions to diphtheria toxin than normal. The former author noted that the necrosis of the skin was slower coming on, and that the subcutaneous oedema was absent or very slight. The latter authors reported that animals on diets which contained suboptimal amounts of vitamin C, but enough to allow a gain in weight of about 25 per cent, still showed large Schick reactions, whereas if this vitamin was further reduced so that a loss of about the same magnitude occurred, the reactions were very small. Scorbutic guinea pigs however are definitely more susceptible to large doses of diphtheria toxin and die earlier than normal animals according to Bieling. A possible clinical application of these findings was provided by Hess (8) in 1932. He had encountered nasal diphtheria very commonly in children with scurvy. The Schick reactions were regularly negative, although the patients showed the bloody mucous nasal discharge which is typical of this disease, and one child apparently died from it. In three cases, virulence tests showed the bacilli to be virulent. The last of these three cases gave no skin reaction to dilutions of from 1/50 to 1/5 M.L.D. of toxin. In his brief review the author does not discuss the possibility of these cases being carriers, already self-immunized. He suggests that in scurvy the pharyngeal mucous membrane loses its immunity to the diphtheria bacilli, whereas the general immunity as reflected by the negative Schick test is still maintained. A simpler explanation however might be that the scorbutic skin does not react in the usual manner to the toxin, although the organism as a whole is not immune to it. Lawrynowicz (9) suggests that scurvy may so reduce the resistance that a carrier may become the victim of bacteria which it previously carried with impunity. For example, a guinea pig that had been well 192 ELIZABETH CHANT ROBERTSON for one month after it had been used in a crude test for B. diphtheria was placed on a scorbutic diet. Thirty-seven days later it died. The post-mortem showed the changes found in diphtheritic deaths and the organism was recovered from the spleen. When Vercellana (10) injected strychnine nitrate or aqueous extracts of poisonous fungi subcutaneously into scorbutic guinea pigs, he found that they were killed more frequently by these substances than controls fed normal diets. The ration of the deficient animals consisted of oats exclusively. Also aleuronat, broth, peptone, cinnabar and other substances, when injected by Dluzewski (11) into the peritoneal cavities of scorbutic animals, did not provoke the normal inflammatory reaction with the outpouring of leucocytes. (b) Results indicating that these are not reduced. In contrast to some of the above findings, Lawrynowicz and Bohdanowicz (9) state that they have never established any difference between the Schick reactions of normal and scorbutic guinea pigs. In 1919, Zilva (12) determined the complement titres in normal and scorbutic guinea pigs and found that they were the same. Four years later, Hamburger and Goldschmidt (13) reported that the complement titres were not lowered in scorbutic children and guinea pigs. In fact, some of the latter animals showed increased complement titres, which were apparently correlated with high albumin concentrations in the serum. Koch and Smith (14) found consistently increased complement titres in a series of twelve scorbutic guinea pigs. When an antiscorbutic was added to the diet, the titres fell, but still remained somewhat higher than they had been before the onset of the scurvy. On the other hand, Bohdanowicz and Lawrynowicz (9) found that complement did not show any constant or characteristic changes in guinea pig scurvy. The phagocytic indices in scorbutic guinea pigs were reported by Werkman et al. (15) to be unaltered. Hamburger and Goldschmidt (13) also determined the bactericidal titres of the sera of scorbutic and normal guinea pigs and of scorbutic and normal children to the same strain of colon bacillus and found that they were similar. This organism was used because the pyelonephritis which frequently complicates guinea pig scurvy is usually caused by it. VITAMINS AND RESISTANCE TO INFECTION 193 2. Variations in acquired immune bodies due to vitamin C deficiency (a) Results indicating that these immune bodies are altered. When scorbutic guinea pigs were sensitized to horse serum, or red blood corpuscles, Zolog (16) found that they were much less sensitive to anaphylactic shock than normal diet controls. The minimum lethal dose was three to ten times higher in the animals with scurvy. Sereni (17), on the other hand, reported that scorbutic guinea pigs showed much more severe anaphylactic shock than the control animals. Hurwitz and Wessels (18) went further into the question and found that the uterine muscles of sensitized vitamin C deficient guinea pigs would not react either to the specific antigen or to smooth muscle stimulants, whereas the bronchial muscles of such animals reacted normally. In addition, when Bieling (5) immunized scorbutic guinea pigs with diphtheria toxin, he found that they did not produce as much antitoxin as the adequately fed controls. (b) Results indicating that these immune bodies are not reduced. Scorbutic and normal guinea pigs produced agglutinins to B. typhosus equally well according to both Zilva (12) and Werkman (15). In addition, the former author stated that amboceptors to the same organism were also produced in normal amounts by guinea pigs on vitamin C deficient diets, and the same findings also held true for the rat. In 1922, Hess (19) reported that the diphtheria antitoxin production in scorbutic guinea pigs was as good as that in normal controls. Summary of immunological investigations. I. Non-immune animals. In several of these studies conflicting results have been obtained. For example, Werkman reported that the opsonic indices of non-immune scorbutic guinea pigs were as high as those of normal animals, whereas Fortenato found them reduced. And again, Lawrynowicz stated that the presence or absence of scurvy did not affect the size of the Schick reaction in guinea pigs, whereas Bieling and also Arkwright found these reactions considerably reduced when scurvy was present. Other workers reported that tuberculin reactions were also considerably decreased. As the immunological significance of the Schick and tuberculin reactions are entirely different, one would infer that the general reactivity of scorbutic skin was depressed. The smaller Schick reactions were not due to any increased antitoxin in the animal, as Bieling 194 ELIZABETH CHANT ROBERTSON showed that these guinea pigs died more frequently and more quickly after the injection of large amounts of toxin. In fact, scorbutic guinea pigs seem more susceptible to the subcutaneous injections of toxic substances generally, e.g., to tuberculin, strychnine and poisonous fungus extract. Lawrynowicz suggests, on evidence gathered from the study of one animal only, that scurvy so lowers the resistance of a healthy carrier that it may become the prey of bacteria which formerly did not harm it. This sequence of events however might have occurred without the aid of the scurvy-producing diet. Leichentritt found that the substance in the blood which destroyed trypanosomes was reduced in scurvy, and further evidence of the reduced capacity of the scorbutic animal to cope with infections was provided by Dluzewski, who reported that the inflammatory reactions which followed the injection of foreign substances into the peritoneum were much reduced. Two authors stated that the complement titre was unchanged in scurvy, but a similar number of investigators found it increased. One of the latter however did not find it consistently raised, but at least it was never lowered. II. Immune animals. Comparatively few studies have been carried out on such animals, and many of the results are conflicting. For instance, Hess found that scorbutic guinea pigs could produce diphtheria antitoxin as well as normal animals, whereas Bieling states that this is not the case. Zilva and Werkman were not able to demonstrate any difference between the amounts of anti-typhoid antibodies produced by guinea pigs and rats lacking vitamin C and those fed adequate diets. The results of the anaphylaxis experiments are of interest because most of them suggest a reduced activity in the tissues of animals suffering from scurvy, analogous to the lessened skin reactions. 3. Occurrence of spontaneous infections in vitamin C deficiency (a) Infections indicating a reduced resistance. I. Experimental. In 1932, Suzuki (20) stated that the nasal mucous membrane and glands were atrophied and showed catarrhal inflammation in vitamin C deficient guinea pigs. The crushed oats, autoclaved milk diet that McCarrison (21) fed his guinea pigs is mainly lacking in vitamin C. He VITAMINS AND RESISTANCE TO INFECTION 195 found that the bladders in such animals at postmortem examination were tightly contracted and that the mucous membrane of this organ was congested and necrotic. The duodenum was also intensely congested and punched out ulcers were present in the intestines and sometimes in the stomach. Mackie and Chitre (22) gave their monkeys very small amounts of orange juice, but most of them developed scurvy, and in addition they showed in their large intestines very marked necrotic and ulcerated lesions, which were laden with common intestinal bacteria. These various pathological findings provide possible explanations for some of the frequent secondary infections that occur in cases of human scurvy. In Höjer's (3) series only about 30 per cent of his severely scorbutic guinea pigs showed infections. This low figure may be partly explained by the fact that they survived for just a few weeks. On the other hand, 50 per cent of the animals with mild scurvy developed infectious lesions, and about 20 per cent of the much longer-lived normal animals showed similar lesions. In the course of his experiments, Heymann (23) reported that he lost a large number of scorbutic guinea pigs with pneumococcic pneumonia. II. Clinical—latent scurvy. Even before the onset of definite symptoms of human scurvy, in the so-called period of latent scurvy, the affected individual is particulaly susceptible to infections (24) and if these are contracted they run an unusually severe course. In 1919, Wiltshire (25) described the occurrence of small conical swellings in the hair follicles of the legs of scorbutic Serbian troops and he also found them during the scurvy season (January and June) in apparently normal individuals. The latter were probably suffering from latent scurvy. One of the most typical pathological lesions in scurvy is the increased permeability of the blood vessel wall which allows the blood to ooze into the tissues. Gothlin (26) was able to devise a method of measuring the permeability of the cutaneous capillaries. In 1931, he found that 18 per cent of a group of apparently healthy Swedish country school children (11 to 14 years) were suffering from vitamin C undernourishment. Hopkins (27) was able to associate a period of ill 196 ELIZABETH CHANT ROBERTSON health in boys in a preparatory school with a lack of fresh fruit and vegetables during the winter months. When a little fresh fruit was supplied, the minor ailments and the listlessness disappeared. In children who are suffering from undiagnosed latent scurvy, vaccination may precipitate acute scorbutic symptoms (28, 29). Abels (29) quotes the case of an anemic, atrophic ten months old child who developed both scurvy and a high prolonged fever after vaccination. This may explain the reluctance of parents in backward regions of Austria towards having their children vaccinated in the winter, when no doubt their diets are partially deficient in this vitamin. In such children, coryza and pharyngitis may be surprisingly severe and may usher in evident scurvy, and skin ulcers and cystitis are also very prevalent. In fact, this author has gone so far as to say that manifest scurvy is always preceded by an infection. Other investigators (30) however have found this sequence of events to occur frequently, but not invariably. The increased metabolism caused by the infection probably accentuates the vitamin deficiency and hastens the appearance of active scurvy. As in the case of the other deficiency diseases, there seems to be some predisposition to scurvy, as only a certain number of those on a uniformly deficient diet develop it (24b). Manifest scurvy. Infections are very commonly associated with active scurvy (31), and Von Niedner (31) reported that scorbutic soldiers succumb to the slightest infection. Numerous authors (29, 32) have found respiratory infections, including grippe and pneumonia, to be very common in such individuals. One of these authors, Erdheim (33), stated that such diseases were frequently very grave and persistent in scorbutic children. Tuberculosis was also very prevalent in several series (32b, 34). In one of these, Salle and Rosenberg (34) found that all the deaths (17) in their 461 cases were from tuberculosis and that 9 to 22 per cent of their different groups of scorbutic patients suffered from this disease. They also remarked on the great frequency with which cases of infantile scurvy were complicated by florid tuberculosis. Diphtheria (8, 32b, 34b) and dysentery and typhoid (29, 34a, 35) were also very often encountered by various clinicians in scorbutic individuals. Mackie (22) described an epidemic of dysentery (Shiga) among scorbutic war refugees in the near East, which was almost as VITAMINS AND RESISTANCE TO INFECTION 197 virulent as cholera. Many investigators (32b, 35, 36) have reported that cystopyelitis and nephritis were very common, and that furuncles, paronychia and gun shot wounds (2, 32b, 35, 36) were often very difficult to clear up in scorbutic patients. In 1927, Funk (37) stated that an epidemic of pneumonia in the Sudan disappeared when antiscorbutic treatment was given to the numerous cases of scurvy which appeared at about the same time. This would suggest that scurvy lowered the resistance to this infection. Oral infections. If a guinea pig is kept on a completely vitamin C free diet for even two days, marked abnormalities are seen in its teeth (3, 30), and if such a diet is kept up for a few weeks, the teeth may become devitalized. Apical abscesses are prone to appear in such teeth later on. The same processes may occur in man (38), and the resistance to infection may be indirectly lowered by the presence of these bacterial foci. Höjer and Westin (30) also found that although enough vitamin C was given (1.2 minimum protective doses of orange juice) to prevent the appearance of any scorbutic changes in the teeth, except perhaps an uncertain hyperemia in the pulp cavity, the animals were still markedly susceptible to infection. After analyzing the diets of groups of individuals, Hanke (39) stated that those whose diets were complete suffered from dental caries, gingival irritation or pyorrhoea much less frequently than those whose diets were deficient in either or both vitamin C and vitamin D. The details of the diets were unfortunately not given. Spongy gums, associated with infections, were cleared up by the use of an adequate diet plus 1 pint of orange juice, the juice of a lemon and from one-fourth to one-half a head of lettuce daily. The resistance to other infections, especially to colds, was raised at the same time, and in one individual a long standing osteo-myelitis was also cured. When pyorrhoea was present surgical measures had usually to be combined with the dietetic treatment unless the condition was very mild. 4. Susceptibility to artificially induced infections (a) Reduced resistance in vitamin C deficient animals. In 1923, Findlay (40) reported that guinea pigs fed on a vitamin C deficient diet died more frequently after intraperitoneal injections of bacteria than 204 ELIZABETH CHANT ROBERTSON whooping cough cases, for although scurvy is very rare in Strassburg, they saw four cases of whooping cough and scurvy together. McConkey (56) reported that the administration of cod liver oil and tomato juice has a favorable effect on intestinal tuberculosis which was secondary to a pulmonary infection. In order to determine whether the vitamin C was of value he gave three patients on normal diets a cod liver oil concentrate alone. No change could be seen until orange juice was added also, when two of them began to show satisfactory improvement. In a second test, he gave two cases irradiated brewer's yeast. Again they did not improve until the orange juice was administered also. The possibility that the good effects were due to the combination of the vitamins can not be ruled out, as none of the patients were given vitamin C alone. Bloch (57) is of the opinion that vitamin A is of more importance than vitamin C in the treatment of tuberculosis, but other authors (31) claim that generous amounts of vitamin C are essential in the treatment of such cases. Summary. The results which have been published up to date suggest that this factor plays a very important rôle in the combatting of tuberculous infections, but further investigations will be necessary before this can be conclusively settled. 6. The mechanism underlying the decreased resistance in scurvy According to Höjer (3), the decreased resistance in scurvy is due to the atrophy of the various organs in the body that protect it against infections. These organs include the lymph nodes, spleen and bone marrow. Findlay (40) had previously ascribed the low resistance which he found in scorbutic animals to the changes that were present in the bone marrow. C references (1) FORTENATO: Quoted by J. A. HÖJER: Act. Pediat., 1924, 3, supplement: 121. (2) LEICHENTRITT AND ZIELASKOWSKI, 1922, quoted by HÖJER, as above. (3) HÖJER, J. A.: Act. Pediat., 1924, 3, supplement. (4) PRAUSNITZ, C., AND SCHILF, F.: Deutsch. med. Wchnschr., 1924, 50: 102; and SCHILF, F.: Cent. f. Bakt., Abt. 1, Orig., 1924, 91: 512. (5) (a) BIELING, R.: Deutsche med. Wchnschr., 1927, 53: 182 and 228. (b) MOURIQUAND, G., ROCHAIX, A., AND MICHEL, P.: C. rend. de Soc. de Biol., 1924, 91: 208. (6) BIELING, R.: Zeit. f. Hyg., 1925, 104: 518. VITAMINS AND RESISTANCE TO INFECTION 205 (7) ARKWRIGHT, J. A., AND ZILVA, S. S.: J. Path. and Bact., 1923–4, 27: 346. (8) See Ref. 86 under "Vitamin A and D." (9) LAWRYNOWICZ, M. A.: J. de Physiol. et de Path. gen., 1931, 29: 270. (10) VERCELLANA, G.: Ann. d'Igiene, 1928, 38: 364. (11) DLUZEWSKI, ST.: See Ref. 9 above. (12) See Ref. 8 under "Vitamin A and D." ZILVA SS. Bioch. J., 1919, 13: 172. (13) HAMBURGER, R., AND GOLDSCHMIDT, L.: Jahrb. f. Kinderheilk, 1923, 100: 210. (14) KOCH, M. L., AND SMITH, A. H.: Proc. Soc. Exp. Biol. and Med., 1924, 21: 366. (15) WERKMAN, C. H., NELSON, V. E., AND FULMER, E. I.: J. Infect. Dis., 1924, 34: 447. (16) ZOLOG, M.: C. rend. Soc. de Biol., 1924, 91: 215. (17) SERENI, E.: Boll. Soc. Biol. sper., 1927, 2: 254. Quoted by FRANK: See Ref. 24 (c) below. (18) HURWITZ, S. H., AND WESSELS, A. L.: Proc. Soc. Biol. and Med., 1931, 29: 122. (19) HESS: Quoted by HAMBURGER AND GOLDSCHMIDT: See Ref. 13 above. (20) SUZUKI, S.: Mitteil. a. d. med. Akad. zu Kioto, 1932, 6: 2533. (21) MCCARRISON, R.: Ind. J. Med. Res., 1919-20, 7: 167 and 188. (22) MACKIE, F. P., AND CHITRE, G. D.: Ind. J. Med. Res., 1928-29, 16: 77. (23) HEYMANN, B.: Klin.Woch., 1926, 5: 59. (24) (a) HESS, A. F., AND FISH, M.: Am. J. Dis. Child., 1914, 8: 385. (b) HESS, A. F.: Scurvy, Past and Present, Lippincott, Philadelphia, 1920, p. 18. (c) FRANK, A.: Ergeb. d. inn. med. u. Kinderh., 1930, 38: 513. (25) WILTSHIRE, H.: Lancet, 1919, 197: 564. (26) GÖTHLIN, G. F.: Skand. Arch. Physiol., 1931, 61: 225. (27) HOPKINS, F. G.: Lancet, 1921, 200: 1. (28) STERN, R.: Zeit. f. Kinderheilk., 1923, 36: 32. (29) ABELS, H.: Ergeb. d. inn. Med. u. Kinderheilk., 1924, 26: 733. (30) HÖJER, J. A., AND WESTIN, G.: Dental Cosmos, 1925, 67: 1. (31) (a) NASSAU, E., AND SINGER, M. J.: Jahrb. f. Kinderheilk., 1922, 98: 44. (b) VON NIEDNER: Med. Klinik., 1918, 14: 333. (32) (a) HESS, A. F.: Am. J. Dis. Child., 1917, 14: 337. (b) ASCHOFF, L., AND KOCH, W.: Quoted by HÖJER: See Ref. 3. (33) Quoted by ABELS: See Ref. 29. (34) (a) SALLE, V., AND ROSENBERG, M.: Ergeb. der. inn. Med. u. Kinderheilk., 1921, 19: 31. (b) STEPP, W.: Wien. klin. Wchnschr., 1930, 43: 65. (c) SCHAGAN, B.: Jahr. f. Kinderheilk, 1924, 104: 225. (35) ABELS, H.: Wien. klin. Wchnschr., 1930, 43: 1350. (36) HEHIR, P.: Ind. J. Med. Res., Spec. Number, Sixth Ind. Sci. Congr., 1919: 79. (37) FUNK, C.: Quoted by E. BROWNING, The Vitamins, Bailliere, Tindall & Cox, London, 1931: 98. [The latter refers to FUNK 1927, which is in French] (38) MCCOLLUM, E. V.: See Ref. 15 under "Vitamin D." (39) HANKE, M. T.: J. Am. Dent. Assoc., 1930, 17: 957; J. Nutr., 1930–31, 3: 433. (40) FINDLAY, G. M.: J. of Path. and Bact., 1923, 26: 1. (41) ABELS, quoted by FRANK: Ergeb. d. inn. Med. u. Kinderheilk., 1930, 38: 601. (42) See Ref. 60 under "Vitamin A and D." GRANT AH. J. Infect. Dis., 1926, 39: 502. (43) SCHMIDT-WEYLAND, P., AND KÖLTZSCH, W.: Zeit. f. Hyg. u. Infekt., 1928, 108: 199. (44) NASSAU, E., AND SCHERZER, M.: Klin. Woch., 1924, 3: 314. 206 ELIZABETH CHANT ROBERTSON (45) COULARD, E.: Presse med., 1923, 31: 611, 11 July. (46) MCCONKEY, M.: Science News Letter, June 15, 1929. (47) MOURIQUAND, G., ROCHAIX, A., AND DOSDET, L.: C. rend. de Soc. de Biol., 1925, 93: 901. MOURIQUAND, G., AND LEULIER, A.: Paris med., 1927, 63: 436. (48) LEICHENTRITT, B.: Zeit. f. Hyg., 1924, 102: 388. (49) HERICOURT AND RICHET, quoted by J. A. HÖJER: Act. Paediat., 1924, 3, supplement. (50) GRANT, A. H.: Am. Rev. of Tub., 1930, 21: 115. (51) MOURIQUAND, G., MICHEL, P., AND BERTOYE, P.: C. rend. de Soc. de Biol., 1922, 87: 537. (52) JAFFE, H. L.: J. Infect. Dis., 1927, 40: 502. (53) BAJ, L.: Chir. degli Organi di Movimento, 1929–30, 14: 477. (54) See Ref. 50 under "Vitamin A and D." HOTTA Y. Centralbl. f. Bakt., 1 Abt., Orig., 1928, 32: 519. (55) WORINGER, P., AND SALA, T.: Rev. franc. Pediat., 1927, 3: 668. (56) MCCONKEY, M.: Trans, of 25th Ann. Meeting of Nat. Tub. Assoc., 1929, p. 105, in Am. Rev. Tuberc., 1930, 21: 627. (57) BLOCH, C. E.: Ungeskrift f. Laeger, 1928, 90: 185.