Impact of Vitamin A Supplementation on the Incidence of Infection in Elderly Nursing-home Residents: A Randomized Controlled Trial SEAN MURPHY, KEITH P. WEST JR, WILLIAM B. GREENOUGH III, ELIZABETH CHEROT, JOANNE KATZ, LILIANA CLEMENT
Summary The aim of this study was to determine if vitamin A supplementation reduces the incidence of bacterial infections among elderly nursing-home residents. One hundred and nine patients were enrolled into a double-masked, placebo-controlled trial at an academically affiliated nursing home. Fifty-six patients received a single capsule containing 1000 IU of vitamin A (placebo) and 53 received a single capsule containing 200000 IU of vitamin A. Antibiotic-treated infections were enumerated for 90 days after dosing and infection rates were expressed per 1000 days of follow-up. There were 42 antibiotic-treated infections altogether, 21 in each group. The infection rates in the vitamin A and placebo groups were 4.7 and 4.3 per 1000 days of follow-up, respectively (relative risk 1.1; 95% CI 0.6, 2.0). The findings of this study do not support a role for vitamin A supplements for the prevention of infections among frail elderly nursing-home patients.
Introduction Impaired nutritional status is a recognized risk factor for bacterial infections [1], and both are common causes of morbidity and mortality among institutionalized elderly people [2, 3]. Vitamin A, termed the 'anti-infective agent' by Green and Mellanby in 1928 [4], is essential for normal immune function. Interest in vitamin A has been stimulated recently by the finding that mild deficiency is associated with an increased risk of mortality among children [5], a finding which has been attributed to an increased risk of infection [6]. Randomized trials in countries where vitamin A deficiency is endemic have shown mortality reductions of up to 54%
among children supplemented with vitamin A [7-11]. Vitamin A nutrition may be sub-optimal in elderly nursing-home patients. In North America 21-35% of nursing-home patients have been reported to consume less than two-thirds of the Recommended Daily Allowance for vitamin A [12, 13], while in the UK 60-70% of residential care and day hospital patients were reported to have intakes below recommended levels [14]. Among long-stay patients in Leeds, 23% were recently judged to be vitamin A deficient based on low serum retinol levels [15]. In the light of the above, the potential impact of vitamin A supplementation on infection rates in elderly people is of interest. We therefore Aga and Ageing 1992;21:435-439
S. MURPHY ET AL. carried out a randomized, double-masked, placebo-controlled trial to determine if a single large dose of vitamin A (200000 IU) could reduce infectious morbidity in a group of nursing-home patients during a 3-month period of observation. Methods Patients on the chronic medical and skilled/intermediate care wards of an academically affiliated nursing home were studied between January and May, 1991. The former are very frail and have a high prevalence of deep pressure sores, immobility, and multiple chronic diseases. The skilled/intermediate patients are less frail, but require daily nursing care and assistance with the activities of daily living. Patients in the rehabilitation unit were not included in the study because of their high turnover rate. Prior to the study, ethical approval was obtained from the Institutional Review Board of the Francis Scott Key Medical Centre. Informed consent for entry into a vitamin A intervention trial was obtained from 1 20 of the 190(63.2%) patients (or their proxies) residing in the nursing home in January 1991. Eleven of the 120 patients were later excluded because of renal failure (defined as a serum creatinine greater than 226 /*mol/ 1, n = 9), liver cirrhosis (n = 1) and patient withdrawal (n = 1). Participants and non-participants were comparable with regard to age, sex, duration of institutionalization, ward of residence, and prevalence of dementia, urinary incontinence, pressure sores, and multivitamin intake (data not shown). Participants had a greater mean number of listed diagnoses [mean (SD) 5.5(2.3) vs 4.7(2.2); p = 0.03] and medications [3.4(2.3) vs 2.7(1.9); p = 0.03] compared with nonparticipants. The 109 eligible patients were randomized in a double-masked fashion, in blocks of 10, to receive either a single 60000 fig retinol equivalent (200000 IU) dose of vitamin A (n = 53) or an identical placebo capsule (n = 56) containing 300 retinol equivalents (1000 IU) as retinyl palmitate in arachis oil (Roche, Basel, Switzerland). All capsules contained 40 IU of vitamin E as an antioxidant. Participants were given the contents of a single capsule either orally (n = 94) or via enteral feeding tube ( n = 1 5 ) by a research assistant who was not involved with end-point ascertainment. Patients were either seen or their primary nurse questioned daily for 3 days after dosing for clinical evidence of vitamin A toxicity (headache, confusion, vomiting). All the patients were followed for 90 days, or until death or discharge from the nursing home. The primary end-point was the incidence of antibiotic-treated bacterial infections
which were ascertained by weekly review of computerized pharmacy records. Antibiotics were prescribed by each patient's regular attending physician, as part of routine care, based on the clinical findings and laboratory investigations. Study team members were not involved in this decision-making process. Patient chart review (by S.M.) confirmed that all diagnoses of infections were in accordance with the Centres for Disease Control Definitions for Nosocomial Infections [16]. Defined infection episodes were separated by a minimum antibiotic-free interval of 48 hours. Infection rates were calculated and expressed per 1000 patient days of follow-up. Patients, their regular physicians and study team members remained masked to the capsule contents for the duration of the study. Patients receiving multivitamin preparations at the onset of the trial continued to receive them. No patient was commenced on vitamin A-containing supplements during the follow-up period. To provide a measure of vitamin A status in this population, a fasting blood sample was drawn after an overnight fast in 94 of the subjects (47 in each group) prior to dosing. After separating the serum, samples were frozen at — 20°C until assayed. Serum retinol was measured by high-pressure liquid chromatography using a modification of the method of Bieri et al. [17]. Statistical analyses were carried out using SAS software (SAS Institute Inc., Cary, NC). The•/}test was used to compare differences between proportions and the Student's t test for comparison of means. Relative risks of infection and 95% confidence limits were derived by standard methods [18].
Results The vitamin A and placebo groups were similar on numerous factors prior to randomization, including baseline serum retinol level (Table I). Only age was significantly different between groups, with the vitamin A treated patients being on average 4.8 years older than the placebo controls; [mean (SD) 75.7(12.2) vs 70.9(12.7) years; p = 0.05]. During the followup period 24 patients were treated with antibiotics; 10/56 (17.9%) in the placebo group during 4931 days of follow-up and 14/53 (26.4%) patients in the vitamin A group during 4498 days of follow-up. There were 42 antibiotic-treated infections in total; 21 in each group. The sites of infection were as follows: urinary tract (17), upper respiratory (3), lower
VITAMIN A AND INFECTIONS IN THE ELDERLY
437
Table I. Baseline comparison of vitamin A and placebo groups Vitamin A Number of subjects Chronic medical Skilled/intermediate Mean age Female Mean duration of stay*')" Mean no. of diagnoses! Mean no. of drugsf Diagnosis of dementia Diabetes mellirus Urinary incontinence Pressure sores present Multivitamin use Fasting serum retinol (//g/dl)f
Placebo
53
56
5 (38%) 48 (50%) 75.7(12.2) 38 (72%) 31.1 (30.6) 5.0(2.4) 3.0(1.8) 30 (57%) 6(11%) 35 (66%) 20 (38%) 16(30%) 54.4(28.4)
8 (62%) 48 (50%) 70.9(12.7) 38 (68%) 35.4(52.1) 5.6(2.1) 3.6(2.6) 26 (46%) 13(23%) 39 (70%) 15(27%) 22 (39%) 56.9(20.1)
P
0.99 0.99 0.05 0.60 0.60 0.20 0.20 0.30 0.30 0.20 0.20 0.30 0.62
* Duration of institutionalization (months) prior to study. fMean(SD). Table II. Sites of antibiotic-treated infections Vitamin A Site of infection Urinary tract Upper respiratory Lower respiratory Skin/soft tissue Clostridium difficile
Others Total
8 0 3 7 2
Table III. Infection rates among vitamin A 3O recipients*
Placebo
1
9 3 2 5 1 1
21
21
respiratory (5), skin and soft tissue (12), Clostridium difficile enteritis (3), and miscellaneous (2) and there were no differences between the vitamin A and placebo groups (Table II). Table III shows both the overall infection rates in the two groups, the relative risk of infection, and the 95% confidence limits. As can be seen there was no detectable beneficial effect of vitamin A supplementation on infection rates. Analyses after stratification by sex and by prior use of multivitamins produced similar results. No patient exhibited symptoms or signs suggestive of acute hypervitaminosis A.
No. of subjects No. of infections Days of follow-up Infection ratef
Vitamin A
Placebo
53 21 4498 4.7
56 21 4931 4.3
• Infection rate expressed per 1000 days of follow-up. t Relative risk 1.1; 95% confidence limits 0.6-2.0.
Six patients died during the follow-up period; four in the vitamin A and two in the placebo group. Two patients (both vitamin A recipients) were discharged home before their 90 days of follow-up were complete and were lost to follow-up.
Discussion The impact of nutritional interventions on immune function of elderly people has been
438
S. MURPHY ET AL.
receiving increasing attention. Recent studies have shown positive effects of zinc [19], betacarotene [20], vitamin E [21], and a combination of vitamins A, C and E [15] on cellmediated immune function in elderly subjects. Vitamin A supplementation may prevent postoperative immunosuppression in adults [22], and enhance cell-mediated immune function in lung cancer patients [23]. However, the relevance and potential impact of nutritional interventions in terms of reducing the incidence of infections in frail elderly patients has not been adequately tested to date. To the best of our knowledge, this intervention trial is the first to study the impact of giving a single, large dose of vitamin A on the incidence rate of infections in elderly people. Our results do not support a role for vitamin A for this purpose among nursinghome patients. We believe that enumerating antibiotictreated infections is a satisfactory method for estimating the incidence of bacterial infections at our facility as antibiotics are rarely withheld from patients thought to be infected and because all antibiotics are dispensed from a single pharmacy so ensuring completeness of case ascertainment. In addition, physicians are available daily to see acutely ill patients. Limitations of our study include a modest sample size with attendant low statistical power (power greater than or equal to 80% to detect a 62% or larger reduction in incident infections). The effect of vitamin A supplementation on the severity or duration of infections was also not measured. There are a number of possible reasons why we were unable to detect a clinically significant effect of vitamin A. First, it is possible that a positive effect may not be detectable among elderly individuals with a high burden of chronic and often end-stage diseases. In this group, homoeostatic reserves are impaired to such an extent that any potential beneficial effect may not emerge. Secondly, it appears, from fasting serum retinol levels, that the majority of subjects in this study were vitamin A replete. Only 11 of 94 (11.7%) subjects had a serum retinol level less than 30 pg/dl, the cut-off used by Penn et al. in Leeds to define deficiency [15]. It is not clear whether beneficial effects of vitamin A supplements on immune function are confined
to those regarded as vitamin A deficient. The study was carried out at an academically affiliated nursing home where a full-time dietitian is employed and where patients' dietary intake and nutritional status are closely monitored. The vitamin A replete status of our subjects may be related in part to this. It is also possible that a different mode of dosing (e.g. daily supplement) might give different results. In any event, our findings suggest that a demonstrable benefit of nutritional supplements on immune function in elderly people may not translate into a clinically important reduction in infection risk. Although we failed to demonstrate a beneficial effect of vitamin A supplementation on the incidence of bacterial infections in institutionalized elderly patients, we believe that further studies are justified among those elderly individuals specifically identified as being vitamin A deficient and those who are non-institutionalized and less impaired. Acknowledgements Grant Support: Cooperative Agreement No. DAN0045 between DCPO and the Office of Nutrition, US Agency for International Development, NIH Grant No. S10-RR04O60, and the John A. Hartford Foundation, New York City, NY, USA. References 1. Gross RL, Newberne PM. Nutrition and immunologic function. Physiol Rev 1980;60:188-302. 2. Rudman D, Mattson DE, Nagraj HS, et al. Antecedents of death in the men of Veterans Administration nursing home. J Am Geriatr Soc 1987;35:496-502. 3. Rudman D, Feller AG. Protein-calorie undernutrition in the nursing home. J Am Geriatr Soc 1989;37:173-83. 4. Green HN, Mellanby E. Vitamin A as an antiinfective agent. Br MedJ 1928;20:691-6. 5. Sommer A, Tarwotjo I, Hussaini G, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983;ii:585-8. 6. Sommer A, KatzJ, Tarwotjo I. Increased risk of respiratory disease and diarrhea in children with preexisting mild vitamin A deficiency. AmJClin ATu*r 1984;40:1090-5. 7. Sommer A, Tarwotjo I, Djunaedi E, el al. Impact of vitamin A supplementation on child-
VITAMIN A AND INFECTIONS IN THE ELDERLY
8.
9.
10. 11.
12. 13. 14.
15.
16. 17.
hood mortality: A randomised controlled community trial. Lancet 1986;i:l 169—73. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. AmJ ClinNutr 1988;48:1271-6. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990;323:929-3S. West KP, Jr, Pokhrel RP, Katz J, et al. Effect of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991 ;ii:67-71. Daulaire NMP, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. Br Med J 1992;304: 207-10. Brown PT, Bergan JG, Parsons EP, Krol I. Dietary status of elderly people. J Am Diet Assoc 1977;71:41-5. Harrill I, Cervone N. Vitamin status of older women. Am J Clin Nutr 1977;30:431^0. Kennedy RD. Nutrition in the elderly in residential care. In: Caird FI, Grimley Evans J, eds. Advanced geriatric medicine 3. London: Pitman, 1983;21-8. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with Vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing 1991;20:169-74. Garner JS, Jarvis WR, Emori T G , et al. CDC definitions for nosocomial infections, 1988. AmJ Infect Control 1988; 16:128-40. Bieri JG, Tolliver TJ, Catignani GL. Simultaneous determination of alpha-tocopherol and retinol in plasma or red cells by high pressure liquid chromatography. Am J Clin Nutr 1979;32:2143-9.
439
18. Kahn HA, Sempos CT. Statistical methods in epidemiology. Oxford: Oxford University Press, 1989;62-4. 19. Duchateau J, Delepesse G, Vrijens R, Collet H. Beneficial effects of oral zinc supplementation on the immune response of old people. Am J Med 20. Watson RR, Prabhala RH, Plezia PM, Alberts DS. Effect of beta-carotene on lymphocyte subpopulations in elderly humans: evidence for a dose—response relationship. Am J Clin Nutr 1991;53:90-4. 21. Meydani SN, Barklund MP, Liu S, et al. Vitamin E supplementation enhances cellmediated immunity in healthy elderly subjects. AmJ Clin Nutr 1990;52:557-63. 22. Cohen BE, Gill G, Cullen PR, Morris PJ. Reversal of postoperative immunosuppression in man by vitamin A. Surg Gynecol Obstet 1979;149:658-62. 23. Micksche E, Cerni C, Kokron O, Titscher R, Wrba H. Stimulation of immune response in lung cancer patients by vitamin A therapy. Oncology 1977;34:234-8.
Authors addresses S. Murphy*, E. Cherot, W. B. Greenough Division of Geriatric Medicine and Gerontology, The Johns Hopkins Geriatrics Centre, K. P. West, Jr, J. Katz, L. Clement The Dana Center for Preventive Ophthalmology and Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA •Address correspondence to: Dr S. Murphy, Clinical Gerontology Unit, F & G Block, Level 2, Addenbrooke's Hospital, Cambridge CB2 2QQ Received 27 February 1992
Summary The aim of this study was to determine if vitamin A supplementation reduces the incidence of bacterial infections among elderly nursing-home residents. One hundred and nine patients were enrolled into a double-masked, placebo-controlled trial at an academically affiliated nursing home. Fifty-six patients received a single capsule containing 1000 IU of vitamin A (placebo) and 53 received a single capsule containing 200000 IU of vitamin A. Antibiotic-treated infections were enumerated for 90 days after dosing and infection rates were expressed per 1000 days of follow-up. There were 42 antibiotic-treated infections altogether, 21 in each group. The infection rates in the vitamin A and placebo groups were 4.7 and 4.3 per 1000 days of follow-up, respectively (relative risk 1.1; 95% CI 0.6, 2.0). The findings of this study do not support a role for vitamin A supplements for the prevention of infections among frail elderly nursing-home patients.
Introduction Impaired nutritional status is a recognized risk factor for bacterial infections [1], and both are common causes of morbidity and mortality among institutionalized elderly people [2, 3]. Vitamin A, termed the 'anti-infective agent' by Green and Mellanby in 1928 [4], is essential for normal immune function. Interest in vitamin A has been stimulated recently by the finding that mild deficiency is associated with an increased risk of mortality among children [5], a finding which has been attributed to an increased risk of infection [6]. Randomized trials in countries where vitamin A deficiency is endemic have shown mortality reductions of up to 54%
among children supplemented with vitamin A [7-11]. Vitamin A nutrition may be sub-optimal in elderly nursing-home patients. In North America 21-35% of nursing-home patients have been reported to consume less than two-thirds of the Recommended Daily Allowance for vitamin A [12, 13], while in the UK 60-70% of residential care and day hospital patients were reported to have intakes below recommended levels [14]. Among long-stay patients in Leeds, 23% were recently judged to be vitamin A deficient based on low serum retinol levels [15]. In the light of the above, the potential impact of vitamin A supplementation on infection rates in elderly people is of interest. We therefore Aga and Ageing 1992;21:435-439
S. MURPHY ET AL. carried out a randomized, double-masked, placebo-controlled trial to determine if a single large dose of vitamin A (200000 IU) could reduce infectious morbidity in a group of nursing-home patients during a 3-month period of observation. Methods Patients on the chronic medical and skilled/intermediate care wards of an academically affiliated nursing home were studied between January and May, 1991. The former are very frail and have a high prevalence of deep pressure sores, immobility, and multiple chronic diseases. The skilled/intermediate patients are less frail, but require daily nursing care and assistance with the activities of daily living. Patients in the rehabilitation unit were not included in the study because of their high turnover rate. Prior to the study, ethical approval was obtained from the Institutional Review Board of the Francis Scott Key Medical Centre. Informed consent for entry into a vitamin A intervention trial was obtained from 1 20 of the 190(63.2%) patients (or their proxies) residing in the nursing home in January 1991. Eleven of the 120 patients were later excluded because of renal failure (defined as a serum creatinine greater than 226 /*mol/ 1, n = 9), liver cirrhosis (n = 1) and patient withdrawal (n = 1). Participants and non-participants were comparable with regard to age, sex, duration of institutionalization, ward of residence, and prevalence of dementia, urinary incontinence, pressure sores, and multivitamin intake (data not shown). Participants had a greater mean number of listed diagnoses [mean (SD) 5.5(2.3) vs 4.7(2.2); p = 0.03] and medications [3.4(2.3) vs 2.7(1.9); p = 0.03] compared with nonparticipants. The 109 eligible patients were randomized in a double-masked fashion, in blocks of 10, to receive either a single 60000 fig retinol equivalent (200000 IU) dose of vitamin A (n = 53) or an identical placebo capsule (n = 56) containing 300 retinol equivalents (1000 IU) as retinyl palmitate in arachis oil (Roche, Basel, Switzerland). All capsules contained 40 IU of vitamin E as an antioxidant. Participants were given the contents of a single capsule either orally (n = 94) or via enteral feeding tube ( n = 1 5 ) by a research assistant who was not involved with end-point ascertainment. Patients were either seen or their primary nurse questioned daily for 3 days after dosing for clinical evidence of vitamin A toxicity (headache, confusion, vomiting). All the patients were followed for 90 days, or until death or discharge from the nursing home. The primary end-point was the incidence of antibiotic-treated bacterial infections
which were ascertained by weekly review of computerized pharmacy records. Antibiotics were prescribed by each patient's regular attending physician, as part of routine care, based on the clinical findings and laboratory investigations. Study team members were not involved in this decision-making process. Patient chart review (by S.M.) confirmed that all diagnoses of infections were in accordance with the Centres for Disease Control Definitions for Nosocomial Infections [16]. Defined infection episodes were separated by a minimum antibiotic-free interval of 48 hours. Infection rates were calculated and expressed per 1000 patient days of follow-up. Patients, their regular physicians and study team members remained masked to the capsule contents for the duration of the study. Patients receiving multivitamin preparations at the onset of the trial continued to receive them. No patient was commenced on vitamin A-containing supplements during the follow-up period. To provide a measure of vitamin A status in this population, a fasting blood sample was drawn after an overnight fast in 94 of the subjects (47 in each group) prior to dosing. After separating the serum, samples were frozen at — 20°C until assayed. Serum retinol was measured by high-pressure liquid chromatography using a modification of the method of Bieri et al. [17]. Statistical analyses were carried out using SAS software (SAS Institute Inc., Cary, NC). The•/}test was used to compare differences between proportions and the Student's t test for comparison of means. Relative risks of infection and 95% confidence limits were derived by standard methods [18].
Results The vitamin A and placebo groups were similar on numerous factors prior to randomization, including baseline serum retinol level (Table I). Only age was significantly different between groups, with the vitamin A treated patients being on average 4.8 years older than the placebo controls; [mean (SD) 75.7(12.2) vs 70.9(12.7) years; p = 0.05]. During the followup period 24 patients were treated with antibiotics; 10/56 (17.9%) in the placebo group during 4931 days of follow-up and 14/53 (26.4%) patients in the vitamin A group during 4498 days of follow-up. There were 42 antibiotic-treated infections in total; 21 in each group. The sites of infection were as follows: urinary tract (17), upper respiratory (3), lower
VITAMIN A AND INFECTIONS IN THE ELDERLY
437
Table I. Baseline comparison of vitamin A and placebo groups Vitamin A Number of subjects Chronic medical Skilled/intermediate Mean age Female Mean duration of stay*')" Mean no. of diagnoses! Mean no. of drugsf Diagnosis of dementia Diabetes mellirus Urinary incontinence Pressure sores present Multivitamin use Fasting serum retinol (//g/dl)f
Placebo
53
56
5 (38%) 48 (50%) 75.7(12.2) 38 (72%) 31.1 (30.6) 5.0(2.4) 3.0(1.8) 30 (57%) 6(11%) 35 (66%) 20 (38%) 16(30%) 54.4(28.4)
8 (62%) 48 (50%) 70.9(12.7) 38 (68%) 35.4(52.1) 5.6(2.1) 3.6(2.6) 26 (46%) 13(23%) 39 (70%) 15(27%) 22 (39%) 56.9(20.1)
P
0.99 0.99 0.05 0.60 0.60 0.20 0.20 0.30 0.30 0.20 0.20 0.30 0.62
* Duration of institutionalization (months) prior to study. fMean(SD). Table II. Sites of antibiotic-treated infections Vitamin A Site of infection Urinary tract Upper respiratory Lower respiratory Skin/soft tissue Clostridium difficile
Others Total
8 0 3 7 2
Table III. Infection rates among vitamin A 3O recipients*
Placebo
1
9 3 2 5 1 1
21
21
respiratory (5), skin and soft tissue (12), Clostridium difficile enteritis (3), and miscellaneous (2) and there were no differences between the vitamin A and placebo groups (Table II). Table III shows both the overall infection rates in the two groups, the relative risk of infection, and the 95% confidence limits. As can be seen there was no detectable beneficial effect of vitamin A supplementation on infection rates. Analyses after stratification by sex and by prior use of multivitamins produced similar results. No patient exhibited symptoms or signs suggestive of acute hypervitaminosis A.
No. of subjects No. of infections Days of follow-up Infection ratef
Vitamin A
Placebo
53 21 4498 4.7
56 21 4931 4.3
• Infection rate expressed per 1000 days of follow-up. t Relative risk 1.1; 95% confidence limits 0.6-2.0.
Six patients died during the follow-up period; four in the vitamin A and two in the placebo group. Two patients (both vitamin A recipients) were discharged home before their 90 days of follow-up were complete and were lost to follow-up.
Discussion The impact of nutritional interventions on immune function of elderly people has been
438
S. MURPHY ET AL.
receiving increasing attention. Recent studies have shown positive effects of zinc [19], betacarotene [20], vitamin E [21], and a combination of vitamins A, C and E [15] on cellmediated immune function in elderly subjects. Vitamin A supplementation may prevent postoperative immunosuppression in adults [22], and enhance cell-mediated immune function in lung cancer patients [23]. However, the relevance and potential impact of nutritional interventions in terms of reducing the incidence of infections in frail elderly patients has not been adequately tested to date. To the best of our knowledge, this intervention trial is the first to study the impact of giving a single, large dose of vitamin A on the incidence rate of infections in elderly people. Our results do not support a role for vitamin A for this purpose among nursinghome patients. We believe that enumerating antibiotictreated infections is a satisfactory method for estimating the incidence of bacterial infections at our facility as antibiotics are rarely withheld from patients thought to be infected and because all antibiotics are dispensed from a single pharmacy so ensuring completeness of case ascertainment. In addition, physicians are available daily to see acutely ill patients. Limitations of our study include a modest sample size with attendant low statistical power (power greater than or equal to 80% to detect a 62% or larger reduction in incident infections). The effect of vitamin A supplementation on the severity or duration of infections was also not measured. There are a number of possible reasons why we were unable to detect a clinically significant effect of vitamin A. First, it is possible that a positive effect may not be detectable among elderly individuals with a high burden of chronic and often end-stage diseases. In this group, homoeostatic reserves are impaired to such an extent that any potential beneficial effect may not emerge. Secondly, it appears, from fasting serum retinol levels, that the majority of subjects in this study were vitamin A replete. Only 11 of 94 (11.7%) subjects had a serum retinol level less than 30 pg/dl, the cut-off used by Penn et al. in Leeds to define deficiency [15]. It is not clear whether beneficial effects of vitamin A supplements on immune function are confined
to those regarded as vitamin A deficient. The study was carried out at an academically affiliated nursing home where a full-time dietitian is employed and where patients' dietary intake and nutritional status are closely monitored. The vitamin A replete status of our subjects may be related in part to this. It is also possible that a different mode of dosing (e.g. daily supplement) might give different results. In any event, our findings suggest that a demonstrable benefit of nutritional supplements on immune function in elderly people may not translate into a clinically important reduction in infection risk. Although we failed to demonstrate a beneficial effect of vitamin A supplementation on the incidence of bacterial infections in institutionalized elderly patients, we believe that further studies are justified among those elderly individuals specifically identified as being vitamin A deficient and those who are non-institutionalized and less impaired. Acknowledgements Grant Support: Cooperative Agreement No. DAN0045 between DCPO and the Office of Nutrition, US Agency for International Development, NIH Grant No. S10-RR04O60, and the John A. Hartford Foundation, New York City, NY, USA. References 1. Gross RL, Newberne PM. Nutrition and immunologic function. Physiol Rev 1980;60:188-302. 2. Rudman D, Mattson DE, Nagraj HS, et al. Antecedents of death in the men of Veterans Administration nursing home. J Am Geriatr Soc 1987;35:496-502. 3. Rudman D, Feller AG. Protein-calorie undernutrition in the nursing home. J Am Geriatr Soc 1989;37:173-83. 4. Green HN, Mellanby E. Vitamin A as an antiinfective agent. Br MedJ 1928;20:691-6. 5. Sommer A, Tarwotjo I, Hussaini G, Susanto D. Increased mortality in children with mild vitamin A deficiency. Lancet 1983;ii:585-8. 6. Sommer A, KatzJ, Tarwotjo I. Increased risk of respiratory disease and diarrhea in children with preexisting mild vitamin A deficiency. AmJClin ATu*r 1984;40:1090-5. 7. Sommer A, Tarwotjo I, Djunaedi E, el al. Impact of vitamin A supplementation on child-
VITAMIN A AND INFECTIONS IN THE ELDERLY
8.
9.
10. 11.
12. 13. 14.
15.
16. 17.
hood mortality: A randomised controlled community trial. Lancet 1986;i:l 169—73. Muhilal, Permeisih D, Idjradinata YR, Muherdiyantiningsih, Karyadi D. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. AmJ ClinNutr 1988;48:1271-6. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990;323:929-3S. West KP, Jr, Pokhrel RP, Katz J, et al. Effect of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991 ;ii:67-71. Daulaire NMP, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. Br Med J 1992;304: 207-10. Brown PT, Bergan JG, Parsons EP, Krol I. Dietary status of elderly people. J Am Diet Assoc 1977;71:41-5. Harrill I, Cervone N. Vitamin status of older women. Am J Clin Nutr 1977;30:431^0. Kennedy RD. Nutrition in the elderly in residential care. In: Caird FI, Grimley Evans J, eds. Advanced geriatric medicine 3. London: Pitman, 1983;21-8. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with Vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing 1991;20:169-74. Garner JS, Jarvis WR, Emori T G , et al. CDC definitions for nosocomial infections, 1988. AmJ Infect Control 1988; 16:128-40. Bieri JG, Tolliver TJ, Catignani GL. Simultaneous determination of alpha-tocopherol and retinol in plasma or red cells by high pressure liquid chromatography. Am J Clin Nutr 1979;32:2143-9.
439
18. Kahn HA, Sempos CT. Statistical methods in epidemiology. Oxford: Oxford University Press, 1989;62-4. 19. Duchateau J, Delepesse G, Vrijens R, Collet H. Beneficial effects of oral zinc supplementation on the immune response of old people. Am J Med 20. Watson RR, Prabhala RH, Plezia PM, Alberts DS. Effect of beta-carotene on lymphocyte subpopulations in elderly humans: evidence for a dose—response relationship. Am J Clin Nutr 1991;53:90-4. 21. Meydani SN, Barklund MP, Liu S, et al. Vitamin E supplementation enhances cellmediated immunity in healthy elderly subjects. AmJ Clin Nutr 1990;52:557-63. 22. Cohen BE, Gill G, Cullen PR, Morris PJ. Reversal of postoperative immunosuppression in man by vitamin A. Surg Gynecol Obstet 1979;149:658-62. 23. Micksche E, Cerni C, Kokron O, Titscher R, Wrba H. Stimulation of immune response in lung cancer patients by vitamin A therapy. Oncology 1977;34:234-8.
Authors addresses S. Murphy*, E. Cherot, W. B. Greenough Division of Geriatric Medicine and Gerontology, The Johns Hopkins Geriatrics Centre, K. P. West, Jr, J. Katz, L. Clement The Dana Center for Preventive Ophthalmology and Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA •Address correspondence to: Dr S. Murphy, Clinical Gerontology Unit, F & G Block, Level 2, Addenbrooke's Hospital, Cambridge CB2 2QQ Received 27 February 1992
