MEDICAL ASPECTS of VITAMIN A as an ANTI-INFECTIVE AGENT R. G . TURNER Detroit College of Medicine and Surgery, Detroit, Michigan
coccus catarrhalis, a gram-negative organism occurring among the flora of the nasal passages. These authors believed that the pathogenicity of the micrococcus was slight, though occasionally in catarrhal inflammation i t may be a causative factor. Though many investigators have carried on the struggle to determine the etiology of the so-called common cold, little is definitely known today. It is uncertain whether i t is caused by a single or by a variety of infectious agents. Streptococci, pneumococci, and numerous other organisms have been described as possible causative agents, but to none can etiological importance be conclusively attached. Kruse6 in 1914 suggested that the cold + + + + + + ' may be due to a filtrable virus. Though studies along HE prevention and cure of infections of the this line have been carried on to the present date no upper respiratory tract, middle ear, and nasal definite conclusions have been reached. These facts cavities constitutes one of the greatest problems make i t doubtful as to whether or not iniection of the of clinical investigation. Research studies may not nasal cavities and accessory sinuses is the result of a only aid in relief of those suffering from head colds, specific infection. Lawsona states that the epithelial sinus, and mastoid infections hut secondarily may be membrane lining the normal sinus is histologically beneficial in controlling other systematic conditions. similar to that found in the nasal cavities and upper Smith1 in a review on symptoms and treatment of respiratory tract. Characteristic of this membrane upper respiratory infections gave statistics showing in normal conditions is a mucous secretion covering that ninety per cent. of all acute diseases of children it, which offers resistance to bacterial invasion. From have their origin in nasal infections and that thirty data accumulated in this laboratory it is believed that per cent. of the fatal illnesses in infancy have their the condition of the mucosal lining itself is the most beginning in the same manner. Cone2 reports on the important factor. Experimental and clinical evidence has established frequency of infections of the nasal cavities in infants and children under eleven years of age when admitted the fact that deficiency of vitamin A produces a lowered to the hospital for treatment of various systematic resistance to infection. The development of various conditions. In a large number of the cases the syste- lesions appears to be a characteristic accompaniment matic conditions were removed by treatment of re- to the development of xerophthalmia, a disease of the spiratory foci alone. Dr. Cody of Houston, T e ~ a s , ~eyes occurring from lack of vitamin A. These lesions recently reported to the American Medical Association occur in the cornea, nasal passages, accessory sinuses, the beneficial effects of vitamin A therapy in acute middle ear, tongue, and upper respiratory tract. abscesses of the middle ear in infants and children. Besides lowered resistance to infection the accumulated He found that large amounts of vitamin A added to the studies of various investigators show that absence diet reduced the period of discharge, made repeated of this vitamin results in retarded growth and developincisions less frequent, lessened complications of the ment with susceptibility to infections of the salivary and lymph glands, lungs, skim, kidney, ureter, and mastoid bone, and hastened the return of hearing. The problem of acute infection among school children alimentary canal. Lack of vitamin A produces also is of a vital importance to any community. The physical weakness, failure of appetite and digestion, efforts made to combat the common cold and diseases sterility, and cornification of the epithelium cells. The artificial concentrates of this vitamin are (a) of the upper respiratory tract began with the bacteriothe non-saponifiable fraction of cod-liver oil and (b) logical studies of Ghon and Pfeiffer4 in 1890 on Microcarotene obtained from carrots or green vegetables. I D . L. Smm, South Med. J.,22,918 (1929). Recent investigations of Norwegian chemists have Animal experimentation has shown that carotene, the plant source of vitamin A , is equully as protective against infections of the upper respiratory tract and middle ear as cod-her oil, the animal source of vitamin A . Infections in these loci are encountered most jrepently when that portion of the tract is affected by a change in cell structure which takes place in the albino rat deprived of vitamin A . To combat the common cold, sinus, and mastoid infection, one must keep the mucous linings of these localities in a normul condition. This is best accomplished by consistent vitamin A intake at a liberal leuel.
T
A. J. CONE,L ~ ~ ~ ~ z ~37,lQ o s (1927). c o ~ , C. C. CODY.Sci. N m s Letter. 21.324 fMav 21. 1932).
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W .Rnuss, Miinchen Med. Wochnrchr., 61,1547 1914)
J. LAWSON, Am. Otol. Rhin. Leryng.,39,159 {1930):
shown that halibut-liver oil is a more potent source than cod-liver oil. Green and MellanbyT studied the anti-infective action of carotene (the plant source of vitamin A) and give convincing data that it confers a considerable degree of immunity against spontaneous infection in growing rats. The bacterial flora of the upper respiratory tract of white rats which receive an adequate supply of vitamin A (control animals) may show organisms similar to those encountered in the suppurations of xerophthalmic animals, those which receive no source of vitamin A. Seventy per cent. of the control animals showed positive cultures from the nasal cavities but suppuration was absent in one hundred per cent. Purulent suppurations were encountered in the nasal cavities of sixty-two per cent. of 127 animals on a diet from which this vitamin had been withdrawn. Why is it that ordinarily harmless organisms present normally in the upper respiratory tract are able in the presence of vitamin A deficiency to develop a virulence which frequently results in a fatal septicemia? Carotene administration to animals with definite vitamin A deficient symptoms, whether orally, subcutaneously, or intramuscularly, reduces the number of spontaneous suppurative lesions in the upper respiratory tract, xerophthahnia is cured in one hundred per cent.,and normal health regained in seventy-four per cent. The percentage incidence of bacteria is noticeably less than encountered in animals receiving no carotene. Of ninety-four cultures taken from the nasal cavities of thirty-two rats receiving carotene therapy sixty-three per cent. were sterile, and only seven per cent. of the loci from which the cultures were taken showed suppuration. The percentage incidence of other systematic conditions which accompany vitamin A withdrawal, such as hematuria, enteritis, calculi in the common bile duct, and jaundice, is also greatly reduced through carotene treatment. This fortifying effect of carotene against invasion of bacteria is of utmost importance and encourages the use of vegetables containing this pigment to maintain health and vigor. Progress in the chemistry of vitamin A has been rapid in the past year and has been summarized in the preceding number of TAIs JOURNAL (p. 138.). There are good prospects that a concentrate of carotene, beneficial in the prevention and cure of upper respiratory and middle ear infections, will soon be available. One of the problems confronting investigators before carotene may be used medicinally in a concentrated form is the stabilization of this pigment. Under ordinary conditions it is converted to the achrooform, yellow in color and inactive. Heat hastens this conversion. Dr. Matills of the University of Iowa
paved the way to circumvent this transformation by making a solution of carotene in ethyl laurate and adding an organic reducing agent, hydroqninone. In this solution fading did not take place during fortyfive days of exposure to the air at room temperature. He found that carotene in natural oils was relatively stable, the rate of fading comparable to that of the ethyl laurate containing hydroquinone. Recent unpublished data from this laboratory have shown that carotene can be stabilized for periods of seven months or longer at room temperature in the light under exposure to the air daily for a period of five minutes. The prospects, therefore, of obtaining a stable carotene solution for medicinal use in combating infection are hopeful. Why carotene and vitamin A promote increased resistance toward bacterial invasion and protect against the development of suppurative lesions, especially of the upper respiratory tract, is not definitely clear. It is known that the lining membrane of the sinuses is normally sterile, owing probably to a mucous secretion of the membrane which is protective against bacteria. A change in the condition of the membrane lining the sinuses and nasal cavities must be the factor leading to pathologic tissue in these localities. Such changes may be caused by numerous factors. The accumulated work of various investigators gives the general impression that lack of vitamin A in the animal body brings about changes in the cells of the membranes lining the localities in question. The change in the structure of the cells may have an influence on the secretion of protective substance or may change its character so that invading organisms gain a foothold and suppurative lesions result. In the rat metaplasia of the epithelial membrane has been reported. Wolbach and Howeg found a metaplasia of the epithelial membrane in rats suffering from deficiencies in vitamins A and D. Goldblatt and Be~ischek'~ as well as Green and Mellanby" reported similar changes following feeding of rats on diets deficient only in vitamin A. Thus it seems that infections of the upper respiratory tract are encountered most frequently when that portion of the tract is affected by a change in cell structure. To prevent diseased conditions of the nasal cavities and sinuses therapeutic measures should be such as will keep the mucous linings of these localities in a normal condition. Thus far in animal experimentation vitamin A as present in cod-liver oil or halibut-liver oil and carotene, the copper-colored pigment in carrots, has proved most beneficial. It is only a matter of continued research to determine definitely their fortifying effect on upper respiratory diseases of infants, children, and adults. *S. 8 . WOLBACX AND P. R. Horn, J. Erper. Mcd., 42, 753 ' H. N. GREENAND E. MELLANBY,British J. Exper. PatM.. (lQ951 ,---- ,. 11, 81 (1930). ID H. GOLDBLAI-I AND M . BENISCHEK, ibid., 46,699 (1927). 8 H. S. OLCOVICFI AN^ H. A. MATILL, J. B i d . Chem., 41, 105 llH. N. G ~ E AND N E. MELLANBY, British Med. I.,2, 691
(1931).
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