Xerophthalmia, protein-calorie malnutrition, and infections in children

October 1979

The Journal o f P E D I A T R I C S

651

Xerophthalmia, protein-calorie malnutrition, and infections in children All children with evidence of xerophthalmia who were admitted to an inpatient facifity for treatment of severe protein-calorie malnutNtion and its complications were compared to other inpatients with severe P C M but free from signs or symptoms of vitamin A deficiency. Xerophthalmic inpatients were older and had more severe hypoproteinemia than inpatients without eye signs, and were more undernourished by anthropometric criteria than a comparison group matehed fo r age, sex, and type of PCM. Children with .more severe eye lesions were more retarded in growth than those with minimal ocular signs. All inpatients had high rates of bacterial infections, regardless of their vitamin status. However, xerophthalmic children had a highly significant increase in the rate of positive urine cultures. Mortality rates were similar in all study groups.

Kenneth H. Brown, M.D.,* Abdul Gaffar, M.B.B.S., and Sharif M. Alamgir, M.B.B.S.,

Dacca, Bangladesh, and Baltimore, Md.

DIETARY INSUFFICIENCY of vitamin A and its precur-

sors, as well as the consequent high prevalence of xerophthalmia, have been reported in many of the world's poorer countries. 1 An estimated 100,000 children annually develop blindness from hypovitaminosis A; it is probable that an equal number die from diseases associated with vitamin A deficiency. ~ The importance of vitamin A for normal vision, growth, and maintenance of epithelial tissue is well recogn!zed, but the biochemical roles of the vitamin outside of its action in the visual system are not well understood. 2-4. Although numerous studies also suggest the importance of vitamin A for the maintenance of normal immunologic responses and protection against From Save the Children Fund, U.K., Children's Nutrition Unit, The Cholera Research Laboratories, and The Division o f Geographic Medicine School of Medicine, The Johns Hopkins University. Supported by an International Center for Medical Research N I H grant 5 R 0 7 A l 10048-17 and the Cholera Research Laboratory, an autonomous organization created by an agreement between the governments of the people's Republic of Bangladesh and the United States of America. The laboratory receives basic support from these governments and from the governments of the United Kingdom and A ustralia. *Reprint address: Division of Geographic Medicine, BuiMing G, Baltimore City Hospitals, 4940 Eastern Ave., Baltimoi'e, MD 21224.

0022-3476/79/100651 +06500.60/0 9 1979 The C. V. Mosby Co.

infectious diseases, there is only limited direct evidence for such a role in human beings. 2,~ A difficulty in delineating such effects results from the fact that pure vitamin A deficiency is rarely, if ever, encountered in human beings, the clinical manifestations almost always being associated with some degree of protein-calorie malnutrition and other dietary deficiencies. 2 Since PCM alone predisposes to infections, it is difficult to distinguish between the individual roles of hypovitaminosis A and other forms of malnutrition. Furthermore, PCM may interfere with the normal metabolism and transport of vitamin A so that the vitamin deficiency syndrome may be of exogenous (dietary) or of endogenous (metabolic) origin. ~ Abbreviation used PCM: protein-calorie malnutrition One pathologic study which demonstrated specific types of infections at postmortem in children who died with clinical evidence of vitamin A deficiency did not distinguish among effects of the vitamin deficiency, proteln-calorie deficiency, and other underlying diseases predisposing to both vitamin A deficiency and infection (e.g., cystic fibrosis). 6 One clinical study which noted a fourfold greater mortality rate in children with severe PCM and clinical evidence of vitamin A deficiency, when compared to children with PCM alone, presented only

Vol. 95, No. 4, pp. 651-656

652

Brown, Gaffar, and Alamgir

limited information regarding the etiologies of the various infections and the diagnostic criteria employed. 7 The current study was undertaken to define further the nature of the diseases complicating xerophthalmia and severe PCM as compared to the complications of PCM alone. METHODS Background information. The study was undertaken at the Children's Nutrition Unit in Dacca. with laboratory support from the Cholera Research Laboratory. In Bangladesh. where approximately 80% of total energy intake is consumed as rice. the mean adult per capita intake of vitamin A and its precursors is about half of the FAO-WHO recommended value of 3,500 IU per day for a diet having such a large proportion of its vitamin A in the form of carotenoid provitamins. 8 There is a seasonal variation in vitamin A intake. With a modest increase iri consumption coincident with the increased availability of carotene-containing fruits in May and June. This study took place from February to December, 1976. Patient selection and diagnostic studies. All children attending the Children's Nutrition Unit's outpatient clinic were weighed and measured and classified for nutritional status as compared to a United States reference population. ~ From limited Bangladeshi village growth data TM we had estimated the median expected weight for age to be approximately 69% of the Boston median, and the median expected weight-for-height to be approximately 90% of the Boston reference data. In order to restrict hospital admission to those children who were most severely undernourished in the local context, we selected only those children who were less than 60% of the local expected weight-for-age median (i.e., 42% of the Boston median) or less than 70% of the local expected weightfor-height (i.e.. 63% of the Boston median). We also admitted to the inpatient facilities those children with the edema, hypoproteinemia, hair2 skin. and mental changes characteristic of kwashiorkor. Males and fem/~les from birth to 10 years of age were eligible for hospital admission. Children with less severe grades of undernutrition were referred to the hospital's day-care feeding program or outpatient clinic. All children known to have received antimicrobial chemotherapy just prior to the time of evaluation were excluded from the study. Nutritional diagnoses were based on the McLaren criteria for marasmus, kwashiorkor, and marasmickwashiorkor. H Inpatients with severe vitamin A deficiency were classified by primary physical signs; as discussed in the joint W H O / U S A I D report on vitamin A deficiency and xerophthalmia? Keratomalacia. corffeal xerosis, and conjunctival drying with Bitot spots were all considered as xerophthalmia. An acute history of nightblindness was

The Journal of Pediatrics October 1979

also considered separately as evidence of vitamin A deficiency. No attempt was made to distinguish between dietary vitamin A deficiency and the secondary deficiency syndrome precipitated by the metabolic derangements of PCM. Inpatients with no evidence of vitamin A deficiency by physical examination or history were available for comparison. Ward comparison subjects included all inpafients Without xerophthalmia admitted during the same time period; "matched comparison subjects" included those non-A-deficient inpatients who were matched as closely as possible for age, Sex, and PCM diagnostic category with the xerophthalmic inpatients. Rectal temperatures were recorded at least every four hours during the first week of hospitalization. Laboratory studies at the time of admission included total plasma protein by refractometer, hematocrit, urinalysis, and microscopic examinations of the stool for blood cells, ova, and parasites. Intermediate strength PPD skin tests were applied; when possible, children were transported to the Cholera Research Laboratories f o r a chest radiograph. The following specimens were routinely taken for bacteriologic cultures: throat swabs, blood, stool, and urine. Urine was obtained by percutaneous Suprapubic bladder aspiration or collection of a freshly voided specimen in the event of a "dry tap." No facilities were locally available for culturing of mycobacteria, and the yield from acid-fast stains of clinical specimens was t o o low to be clinically useful. All bacteriologic specimens were processed by the routine bacteriology laboratory of the Cholera Research Laboratory according to standard procedures. TM A rectal temperature greater than 38.1~ was considered fever and less than 35.6~ was considered hypothermia. The diagnosis of bacteriuria was based on the finding of bacterial growth greater than 100 colonies/ml of urine obtained by suprapubic tap, or greater than 100,000 colonies/ml of urine obtained from a freshly voided specimen. The clinical diagnosis of diarrhea Was based on the finding, of more l-~'an four loose or watery stools per day in children over 12 m o n t h s ' o f age, or more than six loose or watery stools per day in infants less than 12 months. Children with less than four loose stools, but With mucus and blood in the stool on gross or microscopic examination, were included in the diarrhea group. Pneumonia was identified on the basis of radiologic findings; pulmonar tuberculosis was tentatively diagnosed when a suggestive~radiograph was associated with a consistent clinical pattern such as positive family history, positive tuberculin skin test, unexplained fevers in hospital, 0r growth failure in hospital despite adequate energy intake and no clinical signs of malabsorption. During three months of the study (September to December) a series of 50 consecutive outpatients who had

Volume 95 Number 4

XeroPhthalmia, protein-calorie malnutrition, and infections

653

Table I. Severity of eye lesions in xerophthalmic inpatients and outpatients and relation to selected measurements of nutritional status

Inpatien t "s PCM category*

No.~of patients OutInOcular signs

Patient

Patient

Total

M I MK I K

Nightblindness only (no physical findings) Nigfitblindness and conjunctival lesions Xerosis corneae

9

5

14

2

3

0

36

7

43

1

5

1

5

16

21

5

6

5

0

13

13

6

5

2

i

Keratomalacia

Age (mo)'~

Total plasma protein (gm/dl)'~

% Expected wt/aget~-

Expected wt/htt~

63 (31)" 54 (29) 40 (16)b 38 (17)~

7.2 (-+2.0) d 6.7 (-+1.6)" 5.5 (-+1.3) f 5.6 (_+1.3)~

57.4 (+ 11.4)h 58.0 (+11.4) ~ 43.7 (_+ 8.7)j 41.6 (+_ 8.9)'~

78~8 (-+ 12.4)h 76.6 (-+10.3) ~ 66.2 (_+ 7.4)j 63.2 (_+ 4.8)~

%

i

-M = Marasmus; K = kwashiorkor; MK = marasmic-kwashiorkor. ]'Figures presented are ( -- 1 SD). ~:BostonReference Data? a significantlydifferentfrom b, P < 0.01. a significantlydifferent from c, P < 0.02. d and e significantlydifferentfrom f, P < 0.01. d significantlydifferent from g, P < 0.05. e significantlydifferent from g, P < 0.0i. h and i significantlydifferent from j and k, P < 0.001. Levels of significancedetermined by unpaired t-testing. physical or historical evidence of vitamin A deficiency, but with PCM of insufficient severity to warrant admission, were included in an outpatient s.tudy group. A comple!e physical examination was performed to identify whether any infections were present, and a voided urine specimen was collected for culture. Blood was obtained by venipuncture from the outpatients for serum carotene and yitamin A levels, as determined by the Bayfield modification 1~ of the method of Neeld and Pearson/~ RESULTS During the inpatient study period, 46 of 190 children (24%) admitted to the hospital with severe PCM had some clinical evidence of vitamin A deficiency. Five of these children were excluded from furthe r analyses because of pretreatment with antibiotics. During the period when the 50 consecutive A-deficient outpatients were evaluated, a total of 66 children, or approximately 1.2% of all outpa, tients seen during that period, had clinical evidence o f vitamin A deficiency. Sixteen of those patients als0 had severe PCM, were admitted to the inpatient unit, and are included among the inpatient study subjects. The eye lesions observed in all A-deficient patients are recorded in Table I; indicators of general nutritional status are listed for patients with each type of eye findings. Patients with corneal lesions had a significantly lower plasma total protein concentration and lower m e a n percent of expecte d weight-for-age and weight-for-height than patients with Conjunctival lesions or nightblindness only

(P < 0.001). The children with corneal lesions also tended to be younger than those with only night blindness (P < 0.02). The clinical characteristics of the inpatient study groups are presented in Table II. The vitamin A-deficient inpatients tended to be older and had a greater prevalence of edematous malnutrition and a lower plasm a total protein concentration than the nondeficient inpatient comparison subjects (p < 0.001). In order to control for effects of age and PCM category on types and etiologies of infections, the xerophthalmic inpatients were matched with other inpatients for age, PCM diagnosis and, when possible, for sex. A comparison of selected clinical measurements and infection rates as related to vitamin A status is shown in Table Ill for the matched groups. The vitamin-deficient inpatients were significatly more under-nourished by weight-for-age and weight-for-height criteria than. the matched comparison subjects (P < 0.05). Both A-deficient and nondeficient inpatient groups had a very high incidence of major infections. Clinical evidence of infection, as manifested by fever or leukocytosis, occurred at similar rates in Adeficient and nondeficient groups. The types and specific etiologies of infections among the children with severe PCM have been reviewed in detail previously/6 The incidences of various types of infections in each study group were different in only one important aspect: there was a very high rate of positive urine cultures among the xerophthalmic patients, and the proportion of xerophthal-

654

Brown, Gaffar, and Alamgir

The Journal of Pediatrics October 1979

Table II. Clinical characteristics of severely malnourished

Table III. Clinical characteristics, infections, and mortali-

inpatients with and without xerophthalmia

ty rates of inpatients with xerophthalmia and inpatient comparison subjects matched for age and PCM category

Patients without xerophthalmia

Patients with xerophthalmia

Number of patients 73 41 Age 25.6 (_+2!.1)?w 40.1 (__ 19.2)? PCM category 14 (34%)~ Marasmus 46 (63%). Marasmic-Kwashiorkor 17 (23%) 18 (44%) 9 (22%) Kwashiorkor 8 (11%) Sex 22 (54%) Male 40 (55%) Female 33 (45%) 19 (46%) Weight (kg) 5.4 ( • 3.0) 6.6 (• 2.4) Mean percent expected*w 43.0%(• 9.0) 43.9% (_+ 10.0) weight-for-age Plasma total protein 6.0 (• 1.3)? 5.2 (• 1.2)? (gm/dl) 27.4 (_+ 6.0) Hematocrit% 28.8 ( • 7.1) *Compared to Boston reference data? tGroups different by unpaired t-testing, P < 0.001. ~Groups different by chi-square. P < 0.001 w I+_1 SDY mic lnpatients with bacteriuria was significantly different from that in the other groups by chi square testing (p < 0.001). Eighty-one percent of the positive urine cultures were obtained by percutaneous bladder tap, and 48% of the infections occurred in males. Proteus sp, Pseudomonas sp, and Staphylococcus albus were recovered from one positive culture each: all the remaining positive urine specimens contained Escherichia coll. All of the posiuve specimens contained a single organism. The xerophthalmic outpatients had. by definition, a less severe degree of PCM than the inpatients. The mean (__ 1 SD) serum vitamin A and carotene levels were 5 ( + 5) and 39 /~g/dl ~_~26), respectively, among the outpatients, as compared to village means of 14 (_+8)~ and 87 ( + 6 1 ) reported elsewhere. 15 The relationship of bacteriuria to severity of xerophthalmia in inpatients and outpatientsis presented in Table IV. Although there is a trend toward higher rates of colonization among children with more severe eye lesions. the numbers of children in each group are too small to show statistical significance. There was no significant relationship between bacteriuria and plasma total protein level among those children with xerophthalmia. However, inpatients had greater rates of bacteriuria than outpatients with a similar degree of xerophthalmia and less ~evere PCM. In contrast to the only previously reported clinical study, 7 there was no significant difference in rates of clinical diarrhea or mortality between the xerophthalmic

Inpatiems with Xerophthalmia Number of patients Male Female Age (too) Weight (kg) Mean % expected wt/ age? Mean % expected wt/ height? Bacteriuria Diarrhea (clinically defined) Enteric infection Bacteremia _ Pneumonia (radiologically diagnosed) Pulmonary tuberculosis Number of patients with one or more major infections Mortality

Matched comparison subjects without xerophthalmia

22 19 40.1 (• 19.2)* 6.6 ( • 2.4) 43.9 (_+ 10.0)$

19 22 38.5 (• 7.3 (_+2.9) 49.2 (• 11.6)~

64.8 (_+ 8.9)w

68.6 (_+ 10.4)w

34 (78%)]I 13 (32%)

7 (.17%)11 15 (37%}

4 (10%) 1 (2%) 23/37 (62%)

8 (20%) 1 (2%)

25/41 (61%)

6 (! 5%) 38 (93%)82

6 (15%) 30 (73%)82

6 (15%)

4 (10%)

*Mean (_+ 1 SD). tCompared to Boston reference data.9 SGroups different by unpaired t testing, P < 0.01, w differentby unpaired t testing,P < 0.05, IIGroups different by chi square, P < 0.001. 82 differentby chi square, P < 0.005.

inpatients and their comparison groups. The bacteriologic etiologies of the various infections were similar in the A-deficient and nondeficient groups. DISCUSSION Clinical evidence ofnightblindness or xerophthalmia or both was used as the basis for diagnosing vitamin A deficiency because serum vitamin A levels a r e commonly deficient in Bangladeshi children 8' 1~ and are also known to be depressed i n the presence of protein-calorie malnutriti0n 17 and infection? 8 Using these clinical criteria, the study demonstrates a high rate of advanced vitamin A deficiency among Bangladeshi children with severe protein-calorie malnutrition. W h e n compared to agematched children with severe PCM, the xerophthalmic inpatients had an even more extreme degree of growth retardation. Furthermore, among all xerophthalmic patients, those children with more advanced ocular signs

Volume 95 Number 4

Xerophthalmia, protein-calorie malnutrition, and infections'

tended to have greater depression of indicators of both protein and energy nutritional status. Keratomalacia was seen only in children simultaneously suffering from severe PCM. Thus, there seems to be an important association between the clinical severity of ocular lesions and overall nutritional well being. The types, etiologies, and clinical responses to infections were generally similar in the vitamin A-deficient and non-deficient patients with severe PCM. However, there was a significantly higher rate of bacteriuria in the xerophthalmic group. The positive urine specimens were obtained at similar rates from suprapubic aspirations and voided specimens, and from both boys and girls; thus, there is strong evidence against contamination of urine cultures. All but two of the positive urine specimens, including those obtained by bladder tap, contained at least 10~ organisms per milliliter. There was no evidence of pyelonephritis by clinical signs or urinalysis, but the actual site of urinary infection was not ascertained. The pathogenesis of urinary tract infections in children is not known, even in those without nutritional disease. 19 It is possible that ~tlterations of epithelial surfaces or accumulation of epithelial debris in vitamin A deficiency and PCM creates an obstruction, or provides a nidus for growth of bacteria seeded either from the blood or by the ascending route. The high rate of infection !n males in our series suggests that blood-borne infection might be more likely. An earlier pathologic study of hypovitaminosis A demonstrated atrophy and keratinizing metaplasia of epithelial cells at many sites, including the pelvis of the kidney, but did not specifically describe the epithelial cells of the lower urinary tract2 Another study of germ-free rats maintained on an A-deficient diet reported "urinary blockages" in a number of the animals, s~ A specific abnormality in the local immune system could also explain the high rate of urinary infections, since vitamin A has been shown to have a variety of interactions with the immune system in animal studies? ~..... However, a study of nasal secretory IgA production in severely malnourished children was unable to demonstrate differences between clinically A-deficient and nondeficient subjects. 24 An alternative explanation for the association between xerophthalmia, PCM', and bacteriuria is that a primary urinary tract infection interfered with absorption of vitamin A and other nutrients or enhanced their utilization or excretion, thus precipitating the deficiency diseases. There has been a previous report of impaired vitamin A absorption and retention in the presence of infection,25and there is evidence of increased retinol excretion in infected animals. TM Increased urinary nitrogen excretion is well documented in the presence of infection.~

655

Table IV. Percent positive urine cultures in xerophthalmic inpatients and outpatients grouped by severity of ocular signs

Inpatients

Outpatients

% positive positive No. of urine No. of urine patients cultures patients cultures %

Ocular signs Nightblindness only (no physical findings) Nightblindness and conjunctival xerosis (including Bitot spots) Xerosis corneae Keratomalacia All xerophthalmic subjects (totals) Matched comparison subjects (inpatients) All nonxerophthalmic inpatients

5

4O

9

11"

7

71

36

6*

16 13 41

81 92 78t

5 0 50

41

17t

69

12t

40 -10

*These three positive cultures were identified on the basis of finding greater than 105bacterialcaloriesper milliliterof freshlyvoidedurine,and were not reconfirmed prior to antimicrobialtherapy for some other infectiousprocess. tXerophthalmicinpatientrates differentfrom other inpatientcomparison groups by chi-square(P < 0.001). Considering these alternative explanations for the association between xerophthalmia, PCM, and bacteriuria, it seems more likely that the nutrient deficiencies may be causally important. If the infections were the primary event one would expect the prevalence of positive cultures to reflect the usual prevalence rates in the age group in question, With a high preponderance among girls.! 9 The similar rates of bacteriuria among boys and girls in our series suggest that these episodes were etiologically unlike those which occur in the usual childhood populations. It is possible that the same pathologic processes which lead to drying and softening of the cornea may similarly impair local host resistance to bacterial colonization in the urinary tract. Since children with more severe eye damage also tended to be more hypoproteinemic and retarded in growth, one might hypothesize that the severity of PCM, and not the vitamin deficiency itself, was an important determinant of bacteriuria. The relatively low rates of bacteriuria among outpatients with xerophthalmia also ,\ suggest that PCM as well as the vitamin deficiency is important in the pathogenesis of urinary colonization. However, among.patients with severe PCM and xerophthalmia there was no significant difference in the nutritional status or plasma protein levels of children with and without positive urine cultures. We found no significant increase in mortality rates or

6 56

Brown, Gaffat. and A lamgir

n o n u r i n a r y infections a m o n g m a l n o u r i s h e d children with x e r o p h t h a l m i a , in contrast to results reported in a previous study. ~ However, the n u m b e r o f subjects in this study m a y h a v e b e e n too small to d e m o n s t r a t e m i n o r differences a m o n g the various study groups. W e believe that with aggressive a t t e n t i o n to infections a n d to o t h e r complications o f PCM, the excessive mortality previously attributed to v i t a m i n A deficiency can be reduced. The authors express their appreciation to Mrs. Thelma Jackson and Dr. Thad Jackson for their supervision of the clinical ward, to Dr. Brad Sack and to Dr. George Graham for their advice and support, to Mr. Imdadul Haque for his supervision of the clinical microbiology lab, and to Ms. Ethel Poplovski for her preparation of the manuscript.

The Journal of Pediatrics October 1979

12. 13.

14. 15.

16.

17.

REFERENCES 1. Oomen HAPC, McLaren DS, and Escapini H: Epidemiology and public health aspects of hypovitaminosis A, Trop Geogr Med 4:27l, 1964. 2. Vitamin A deficiency and xerophthalmia, WHO Technical Report Series, No. 590, Geneva, 1976. 3. International symposium on the metabolic function of vitamin A, George Wolf, Chairman, Am J Clin Nutr 22:903ff, 1969. 4. Rietz P: On the biological role and metabolism of vitamin A, Acta Vitaminol Enzmol 25:123, 1971. 5. Scrimshaw NS, Taylor CE, and Gordon JE: Interactions of Nutrition and Infection, WHO Monograph Series, No. 57, Geneva, 1968. 6. Blackfan KD, and Wolback SB: Vitamin A deficiency in infants, J PEDIATR 3:679, 1933. 7 . McLaren DS, Shirajian E, Tchalian M, and Khoury G: Xerophthalmia in Jordan, Am J Clin Nutr 17:117, 1965. 8. Nutrition survey of East Pakistan, March 1962-January 1964. Washington, DC, 1966, Department of Health, Education and Welfare. 9. Stuart HS, and Stevenson SS: in Nelson WE, editor: Textbook of Pediatrics Philadelphia, 1959, WB Saunders Co, p 12. 10. Cholera Research Laboratories: Unpublished data. 11. McLaren DS, Pellett PI, and Read WWC: A simple scoring

18. 19. 20.

21. 22. 23.

24.

25. 26.

system for classifying the severe forms of protein-caloriemalnutrition of early childhood, Lancet 1:533, 1967. Bayfield RF: Colorimetric determination of vitamin A with trichloroacetic acid, Anal Biochem 39:282, 1971. Neeld JB, and Pearson WN: Macro- and micro-methods for the determination of serum vitamin A using trifluoro acetic acid, J Nutr 79:454, 1963. Cruickshank R: Medical Microbiology, ed 12, Edinburgh, 1975, Churchill Livingstone. Brown KH, Rajan MM, Chakraborty J, and Aziz KMA: Failure of a large dose of vitamin A to enhance the antibody response to tetanus toxoid in children, Am J Clin Nutr (in press). Brown, KH, Gaffar A, Alamgir SM, Gilman R, and Strife J: Bacterial infections associated with severe protein-calorie malnutrition, JHU-ICMR Annual Report 1976-1977, p 38. Smith FP, Goodman DS, Zaklama MS, Gabr MK, Maraghy SE, and Patwardhan VN: Serum vitamin A, retinol-binding protein, and prealbumin concentrations in protein-calorie malnutrition. I. A functional defect in hepatic retinol release, Am J Clin Nutr 26:973, 1973. Kagan BM, and Kaiser E: Vitamin A metabolism in infection, J Nutr 57:277, 1955. Rapkin RH: Urinary tract infection in childhood, Pediatrics 60:508, 1977. Rogers WE, Bieri JG, and McDaniel EG: Vitamin A deficiency in the germfree state, Fed Proc 39:1773, 1971. Dresser DW: Adjuvanticity of vitamin A, Nature 217:527, 1968. Jurin M, and Tannoch DF: Influence of vitamin A on immunological response, Immunology 23:283, 1972. Falchuk KR, Walker WA, Perroto JL, and Isselbacher KJ: Effect of vitamin A on the systemic and local antibody responses to intra-gastrically administered bovine serum albumin, Infect Immun 17:361, 1977. Sirisinha S, Suskind R, Edelman R, Asvapaka C, and Olson RE: Secretory and serum IGA in children with proteincalorie malnutrition, Pediatrics 55:166, 1975. Sivakumar B, and Reddy V: Absorption of labelled vitamin A in children during infections, Br J Nutr 27:299, 1972. Beisel WR, Sawyer WD, Ryll ED, and Crozier D: Metabolic effects of intracellular infections in man, A n n Intern Med 67:744, 1967.