624
IgE ANTIBODIES TO COW’S MILK IN INFANTS FED
Letters
to
BREAST MILK AND MILK FORMULÆ
the- Editor
ANION-EXCHANGE RESINS IN PSEUDOMEMBRANOUS COLITIS
SIR,-Dr Te Wen Chang and colleagues (July 29,
p.
258)
report the in-vitro binding of Clostridium difficile toxin to anion-exchange resins. Their in-vitro studies indicate that colestipol is more active than cholestyramine, which might suggest that colestipol would be more effective clinically. In our experience the pH of faecal fluid from patients with pseudomembranous colitis can be as low as pH 6. Is the activity of the resins unaffected by pH? In the same issue Dr Tedesco and colleagues (July 29, p. 236) report the effective treatment of pseudomembranous colitis with vancomycin. Would combined therapy with an anion-exchange resin be compatible? We report here the results of laboratory studies to answer these
SIR,-Jarrett suggested that allergies due to a boostable IgE response may result from an initial exposure to a small rather than a large quantity of antigen together with an adjuvant.’ This hypothesis was based on experiments with rats and mice. We have evidence indicating that mechanisms like this may also act in the human neonate. We have followed up 95 healthy infants until one year of age. The infants belonged to two feeding categories :2 in the breast-milk group breast milk was the source of milk until 6 months of age. We tried to exclude cow’s milk-containing foods from the diet as far as possible by frequent advice to the mothers. As a notable exception, an unknown, probably large, number of infants received proprietary milk formula in the hospital nursery at night. In the cow’s-milk group regular use of cow’s milk-based formulae was started before one month of age.
questions. Cholestyramine (Bristol Laboratories) and colestipol hydrochloride (Upjohn) were suspended in 0.1mol/1 phosphate buffer at pH 6.4 and 7.2 to give w/v concentrations ranging from 6-25 g/l to 100 g/1. Mixtures of 1 part fsecal fluid and 9 parts resin suspension were agitated in a shaking water bath at 37°C for varying periods, and the supernatant was removed after centrifugation. Solutions were titrated for residual toxic activity on monolayers of hela cells. Resin-free controls were similarly treated. To determine whether vancomycin was bound to resin, vancomycin solutions were similarly treated. To determine the relative affinity of the resins for toxin and vancomycin a mixture of fxcal fluid with added vancomycin and resin was used. Vancomycin assay was performed by an agar plate method incorporating Bacillus subtilis NCTC 10073 as the test organism.
TABLE I-INFANTS FROM THE BREAST-MILK GROUP WITH IGE ANTIBODIES TO
Our studies of the binding of toxin at pH 7.2 are essentially in accord with those of Te Wen Chang et al. although we found complete binding by colestipol at 15 min. Studies at pH 6.4, however, showed a greater degree of binding by both resins. Both resins produced a thousandfold reduction in titre within 15 min when used at a concentration of 12.5g/1 at pH 6.4. These findings suggest to us that cholestyramine and colestipol would probably be of equal activity in vivo. Binding of vancomycin was not appreciably affected by change in pH and both compounds produced a similar and substantial fall in concentration when a resin concentration of 100 g/1 was tested:
place. Department of Microbiology Birmingham Children’s Hospital Birmingham B16 SET Department of Microbiology, General Hospital, Birmingham B4 6NH
I Ii
Insufficient sample prevented some assays. *Significant difference between groups Cy2=5
D. J. YOUNGS
E. M. JOHNSON D. W. BURDON
1_11
.00, r=0025).
The infants were seen seven times during the first year of life. Serum-total-IgE was determined with the ’Phadebas IgE PRIST’ kit, and IgE antibodies to cow’s milk with the ’Phadebas RAST’ kit. The 0 to 4 radioallergosorbent test score system was modified to include the score -2k, defined as the antibody concentration giving a count rate at least twice the
sample background. Cow’s milk-specific IgE could be detected only in infants from the breast milk group (table i). At six months of age the proportion of infants with milk-specific IgE was higher in the breast-milk group than in the cow’s milk group (P=0025). There were no differences between the groups in respect of family. history of atopy, atopic symptoms during the first year of or the incidence of high (100 u/ml) total IgE values (table 11). On the other hand, the mean total IgE concentration was lower in the breast-milk group up to 4 months of age
life,
R. H. GEORGE
MILK
TABLE II-SIGNS OF ATOPY IN THE TWO FEEDING GROUPS
i
Experiments pH 6.4with fsecal fluid containing toxin and vancomycin showed that significant binding of toxin still occurred at concentrations of resin which did not significantly reduce the vancomycin concentration. This indicates a greater affinity for the toxin than for vancomycin, but in the clinical situation where the toxin titre can exceed 105 these concentrations of resin would be insufficient. These results suggest that in vivo the affinity between anion-exchange resins and vancomycin might interfere with the therapeutic action of vancomycin. In the light of this binding we wonder whether other drugs administered orally could be similarly bound by anionexchange resins. It would seem prudent to allow several hours between giving the resin and another drug which is known to be rapidly absorbed. With poorly absorbed drugs studies should be done to determine whether significant binding takes at
COW’S
(unpublished). 1. 2.
Jarrett, E E. E. Lancet, 1977, ii, 223. Saarinen, U.M.J. Pediat. 1978, 93, 177.
625 We believe that breast
feeding
in
early infancy
is
a com-
mendable practice. If, however, prevention of the formation of is sought, the elimination of cow’s milk from be thorough. We regard with suspicion the common procedure of feeding neonates with cow’s milk-based formulas at delivery hospitals in the night-time. Our study shows that minor quantities of cow’s milk protein can elicit the production of milk-specific IgE. Our data even suggest that large quantities of antigen might inhibit this response.
milk-specific IgE the diet
must
We thank Pharmacia for reagents. for Allergic Diseases and Children’s Hospital,
Hospital
FRED BJÖRKSTÉN ULLA M. SAARINEN
University of Helsinki, SF-00250 Helsinki 25, Finland
PROPHYLACTIC CO-TRIMOXAZOLE IN LEUKÆMIA
SIR,-Dr Enno and colleagues show (Aug. 19, p. 395) that co-trimoxazole reduces the incidence of infection in neutropenic patients being treated for acute leukaemia. They also show that giving prophylactic non-absorbable antibiotics and nursing their neutropenic patients in single rooms with reverse isolation is a waste of time, since 94% of their controls became infected despite these measures. It seems that prophylactic cotrimoxazole should be used to replace other expensive and labour-intensive measures, not to supplement them. Pathology Department, Royal West Sussex Hospital, Chichester, West Sussex
C.
PO19 4SE
**This letter has been shown lows.-ED.L.
to
Dr
Catovsky,
J. T. BATEMAN whose
reply fol-
SIR,-Dr Bateman concludes from our study that because the addition of co-trimoxazole was useful in reducing the incidence of infection, the other prophylactic measures were not necessary. Previous controlled studies have shown the value of gut prophylaxis and reverse isolation in the management of patients with acute myeloid leukaemia (A.M.L.).1-4 Recent studies at the Baltimore Cancer Center (Dr P. Wiernik, personal communication) have shown that co-trimoxazole alone may be as effective as gut prophylaxis with oral gentamicin, vancomycin, and nystatin in preventing infection in A.M.L. A study in Winnipeg,5 on the other hand, showed that co-trimoxazole was better than no prophylaxis in neutropenic patients. A formal trial to see whether the non-absorbable antibiotics used for gut prophylaxis may be redundant if co-trimoxazole is used has not yet been carried out, but we are about to do so. Although the end-point of our study was the development of fever and infection, the final outcome (i.e., the successful treatment of the infection and clinical remission) is the most important objective and should be kept in perspective. Serious infections in patients with A.M.L. are most commonly due to gram-negative bacteria thought to be derived from the patient’s own gut flora. Gut prophylaxis may not only reduce the rate of infection but also may reduce the number of invading organisms and thus prevent overwhelming septicxmia and death from shock, for this has been uncommon in our unit since the routine use of oral non-absorbable antibiotics. We now rarely see serious perianal infections, a common and fatal problem in the past. Although the need for additional gut prophylaxis was not tested in our controlled study, we do not yet feel able to aban1. Schimpff, S. C.,
Greene, W. H., Young, V. M., Fortner, C. L., Jepsen, L., Cusack, N., Block, J. B., Wiernik, P. H. Ann. intern. Med. 1975, 82, 351. 2 Storring, R. A, McElwain, T. J., Jameson, B., Wiltshaw, E., Spiers, A. S. D., Gaya, H. Lancet, 1977, ii, 837. 3. Levine, A. S. Clins Hemat. 1976, 5, 409. 4. Rodriguez, V., Bodey, G. P., Freireich, E. J., McCredie, K. B., Gutterman, J. U., Keating, M J., Smith, T. L., Gehan, E. A. Medicine, 1978, 57, 253. 5. Gurwith, M J. Antimicrob. Chemother. 1978, 4, 302.
don this and other in previous studies.
prophylactic
measures
shown
to
be useful
,
M.R.C. Leukæmia Unit and Department of Bacteriology,
A. ENNO
D. CATOVSKY
Royal Postgraduate Medical School,
J. DARRELL
London W12 0HS
HEALTH SCREENING IN RESIDENTIAL HOMES
SIR,—Iwas interested in the paper by Professor Brocklehurst and his colleagues (July 15, p. 141) as I have just participated in a survey of four local-authority residential homes in this district.’ We were studying, not new -referrals, but an established population in the homes, and no clear indication was available as to the fitness of individuals at the time of their admission. Nevertheless, the results are revealing. 183 residents were examined medically and assessed for daily living activities. Even in this "captive" group, for whom one might reasonably have expected a greater degree of awareness and thoroughness of surveillance on the part of their medical attendants, 763 significant medical conditions were found of which only 299 were apparently known (or at any rate heeded) by the doctors concerned. Most of the previously unknown conditions were minor, but at least two-thirds of them were treatable. Furthermore, over 1 in 4 residents had conditions which needed prompt referral to their general practitioners. 15 residents were regarded as below standard for residential care, and 6 of them were accepted (or referred) for admission to hospital immediately. For a variety of reasons and after discussion with home staff it was decided to leave the remainder in the homes. At the other end of the scale 27 individuals were judged fit for less sheltered accommodation. The implications of this finding at first led to some misunderstanding with the local social services department, as it was seen as a criticism of the judgment of social workers. This was not our intention, and I’ am glad to say that amity has been restored. Clearly, health and fitness are major considerations in assessing need for part m accommodation but equally clearly doctors must allow the social services sovereignty of final decision in their own departments. Locally, we now hope to cooperate even more closely in the more rational assessment and allocation of scarce residential places. Trinity Hospital, PETER F. ROE
Taunton, Somerset
S!R,—The importance of medical screening of elderly people who are on the verge of moving from independence to institutional living was demonstrated by Professor Brocklehurst and his colleagues in your issue of July 15. In Copenhagen such medical screening has been assured since 1973 as a consequence of a regulation, passed by the municipal authorities, to the effect that no elderly person can be accepted for institutional care without having been examined at one of the five geriatric departments in the city, either in outpatient departments or after hospital admission. The geriatric department concerned receives two referral documents for every pensioner referred-one filled in by the elderly person’s general practitioner and the other by the district nursing services. An analysis of 196 consecutive referrals2 revealed the following items. Disability affecting the elderly person’s ability to cope independently were recorded many times, the most common being difficulty in walking (38%), vertigo, falls, or fainting (35%), mental disturbances (dementia, psychosis, neurosis) (27%), decreased vision (20%), cardiopulmonary troubles (dyspnoea, angina pectoris) (18%), decreased hearing (13%), urinary incontinence (12%), compromised function of upper 1. Roe, P F., Guillem, V. L. Hlth Soc Serv. 2. Krakauer, R. Ugeskr. Læg. (in the press).
J. 1978, 88,
168.
IgE ANTIBODIES TO COW’S MILK IN INFANTS FED
Letters
to
BREAST MILK AND MILK FORMULÆ
the- Editor
ANION-EXCHANGE RESINS IN PSEUDOMEMBRANOUS COLITIS
SIR,-Dr Te Wen Chang and colleagues (July 29,
p.
258)
report the in-vitro binding of Clostridium difficile toxin to anion-exchange resins. Their in-vitro studies indicate that colestipol is more active than cholestyramine, which might suggest that colestipol would be more effective clinically. In our experience the pH of faecal fluid from patients with pseudomembranous colitis can be as low as pH 6. Is the activity of the resins unaffected by pH? In the same issue Dr Tedesco and colleagues (July 29, p. 236) report the effective treatment of pseudomembranous colitis with vancomycin. Would combined therapy with an anion-exchange resin be compatible? We report here the results of laboratory studies to answer these
SIR,-Jarrett suggested that allergies due to a boostable IgE response may result from an initial exposure to a small rather than a large quantity of antigen together with an adjuvant.’ This hypothesis was based on experiments with rats and mice. We have evidence indicating that mechanisms like this may also act in the human neonate. We have followed up 95 healthy infants until one year of age. The infants belonged to two feeding categories :2 in the breast-milk group breast milk was the source of milk until 6 months of age. We tried to exclude cow’s milk-containing foods from the diet as far as possible by frequent advice to the mothers. As a notable exception, an unknown, probably large, number of infants received proprietary milk formula in the hospital nursery at night. In the cow’s-milk group regular use of cow’s milk-based formulae was started before one month of age.
questions. Cholestyramine (Bristol Laboratories) and colestipol hydrochloride (Upjohn) were suspended in 0.1mol/1 phosphate buffer at pH 6.4 and 7.2 to give w/v concentrations ranging from 6-25 g/l to 100 g/1. Mixtures of 1 part fsecal fluid and 9 parts resin suspension were agitated in a shaking water bath at 37°C for varying periods, and the supernatant was removed after centrifugation. Solutions were titrated for residual toxic activity on monolayers of hela cells. Resin-free controls were similarly treated. To determine whether vancomycin was bound to resin, vancomycin solutions were similarly treated. To determine the relative affinity of the resins for toxin and vancomycin a mixture of fxcal fluid with added vancomycin and resin was used. Vancomycin assay was performed by an agar plate method incorporating Bacillus subtilis NCTC 10073 as the test organism.
TABLE I-INFANTS FROM THE BREAST-MILK GROUP WITH IGE ANTIBODIES TO
Our studies of the binding of toxin at pH 7.2 are essentially in accord with those of Te Wen Chang et al. although we found complete binding by colestipol at 15 min. Studies at pH 6.4, however, showed a greater degree of binding by both resins. Both resins produced a thousandfold reduction in titre within 15 min when used at a concentration of 12.5g/1 at pH 6.4. These findings suggest to us that cholestyramine and colestipol would probably be of equal activity in vivo. Binding of vancomycin was not appreciably affected by change in pH and both compounds produced a similar and substantial fall in concentration when a resin concentration of 100 g/1 was tested:
place. Department of Microbiology Birmingham Children’s Hospital Birmingham B16 SET Department of Microbiology, General Hospital, Birmingham B4 6NH
I Ii
Insufficient sample prevented some assays. *Significant difference between groups Cy2=5
D. J. YOUNGS
E. M. JOHNSON D. W. BURDON
1_11
.00, r=0025).
The infants were seen seven times during the first year of life. Serum-total-IgE was determined with the ’Phadebas IgE PRIST’ kit, and IgE antibodies to cow’s milk with the ’Phadebas RAST’ kit. The 0 to 4 radioallergosorbent test score system was modified to include the score -2k, defined as the antibody concentration giving a count rate at least twice the
sample background. Cow’s milk-specific IgE could be detected only in infants from the breast milk group (table i). At six months of age the proportion of infants with milk-specific IgE was higher in the breast-milk group than in the cow’s milk group (P=0025). There were no differences between the groups in respect of family. history of atopy, atopic symptoms during the first year of or the incidence of high (100 u/ml) total IgE values (table 11). On the other hand, the mean total IgE concentration was lower in the breast-milk group up to 4 months of age
life,
R. H. GEORGE
MILK
TABLE II-SIGNS OF ATOPY IN THE TWO FEEDING GROUPS
i
Experiments pH 6.4with fsecal fluid containing toxin and vancomycin showed that significant binding of toxin still occurred at concentrations of resin which did not significantly reduce the vancomycin concentration. This indicates a greater affinity for the toxin than for vancomycin, but in the clinical situation where the toxin titre can exceed 105 these concentrations of resin would be insufficient. These results suggest that in vivo the affinity between anion-exchange resins and vancomycin might interfere with the therapeutic action of vancomycin. In the light of this binding we wonder whether other drugs administered orally could be similarly bound by anionexchange resins. It would seem prudent to allow several hours between giving the resin and another drug which is known to be rapidly absorbed. With poorly absorbed drugs studies should be done to determine whether significant binding takes at
COW’S
(unpublished). 1. 2.
Jarrett, E E. E. Lancet, 1977, ii, 223. Saarinen, U.M.J. Pediat. 1978, 93, 177.
625 We believe that breast
feeding
in
early infancy
is
a com-
mendable practice. If, however, prevention of the formation of is sought, the elimination of cow’s milk from be thorough. We regard with suspicion the common procedure of feeding neonates with cow’s milk-based formulas at delivery hospitals in the night-time. Our study shows that minor quantities of cow’s milk protein can elicit the production of milk-specific IgE. Our data even suggest that large quantities of antigen might inhibit this response.
milk-specific IgE the diet
must
We thank Pharmacia for reagents. for Allergic Diseases and Children’s Hospital,
Hospital
FRED BJÖRKSTÉN ULLA M. SAARINEN
University of Helsinki, SF-00250 Helsinki 25, Finland
PROPHYLACTIC CO-TRIMOXAZOLE IN LEUKÆMIA
SIR,-Dr Enno and colleagues show (Aug. 19, p. 395) that co-trimoxazole reduces the incidence of infection in neutropenic patients being treated for acute leukaemia. They also show that giving prophylactic non-absorbable antibiotics and nursing their neutropenic patients in single rooms with reverse isolation is a waste of time, since 94% of their controls became infected despite these measures. It seems that prophylactic cotrimoxazole should be used to replace other expensive and labour-intensive measures, not to supplement them. Pathology Department, Royal West Sussex Hospital, Chichester, West Sussex
C.
PO19 4SE
**This letter has been shown lows.-ED.L.
to
Dr
Catovsky,
J. T. BATEMAN whose
reply fol-
SIR,-Dr Bateman concludes from our study that because the addition of co-trimoxazole was useful in reducing the incidence of infection, the other prophylactic measures were not necessary. Previous controlled studies have shown the value of gut prophylaxis and reverse isolation in the management of patients with acute myeloid leukaemia (A.M.L.).1-4 Recent studies at the Baltimore Cancer Center (Dr P. Wiernik, personal communication) have shown that co-trimoxazole alone may be as effective as gut prophylaxis with oral gentamicin, vancomycin, and nystatin in preventing infection in A.M.L. A study in Winnipeg,5 on the other hand, showed that co-trimoxazole was better than no prophylaxis in neutropenic patients. A formal trial to see whether the non-absorbable antibiotics used for gut prophylaxis may be redundant if co-trimoxazole is used has not yet been carried out, but we are about to do so. Although the end-point of our study was the development of fever and infection, the final outcome (i.e., the successful treatment of the infection and clinical remission) is the most important objective and should be kept in perspective. Serious infections in patients with A.M.L. are most commonly due to gram-negative bacteria thought to be derived from the patient’s own gut flora. Gut prophylaxis may not only reduce the rate of infection but also may reduce the number of invading organisms and thus prevent overwhelming septicxmia and death from shock, for this has been uncommon in our unit since the routine use of oral non-absorbable antibiotics. We now rarely see serious perianal infections, a common and fatal problem in the past. Although the need for additional gut prophylaxis was not tested in our controlled study, we do not yet feel able to aban1. Schimpff, S. C.,
Greene, W. H., Young, V. M., Fortner, C. L., Jepsen, L., Cusack, N., Block, J. B., Wiernik, P. H. Ann. intern. Med. 1975, 82, 351. 2 Storring, R. A, McElwain, T. J., Jameson, B., Wiltshaw, E., Spiers, A. S. D., Gaya, H. Lancet, 1977, ii, 837. 3. Levine, A. S. Clins Hemat. 1976, 5, 409. 4. Rodriguez, V., Bodey, G. P., Freireich, E. J., McCredie, K. B., Gutterman, J. U., Keating, M J., Smith, T. L., Gehan, E. A. Medicine, 1978, 57, 253. 5. Gurwith, M J. Antimicrob. Chemother. 1978, 4, 302.
don this and other in previous studies.
prophylactic
measures
shown
to
be useful
,
M.R.C. Leukæmia Unit and Department of Bacteriology,
A. ENNO
D. CATOVSKY
Royal Postgraduate Medical School,
J. DARRELL
London W12 0HS
HEALTH SCREENING IN RESIDENTIAL HOMES
SIR,—Iwas interested in the paper by Professor Brocklehurst and his colleagues (July 15, p. 141) as I have just participated in a survey of four local-authority residential homes in this district.’ We were studying, not new -referrals, but an established population in the homes, and no clear indication was available as to the fitness of individuals at the time of their admission. Nevertheless, the results are revealing. 183 residents were examined medically and assessed for daily living activities. Even in this "captive" group, for whom one might reasonably have expected a greater degree of awareness and thoroughness of surveillance on the part of their medical attendants, 763 significant medical conditions were found of which only 299 were apparently known (or at any rate heeded) by the doctors concerned. Most of the previously unknown conditions were minor, but at least two-thirds of them were treatable. Furthermore, over 1 in 4 residents had conditions which needed prompt referral to their general practitioners. 15 residents were regarded as below standard for residential care, and 6 of them were accepted (or referred) for admission to hospital immediately. For a variety of reasons and after discussion with home staff it was decided to leave the remainder in the homes. At the other end of the scale 27 individuals were judged fit for less sheltered accommodation. The implications of this finding at first led to some misunderstanding with the local social services department, as it was seen as a criticism of the judgment of social workers. This was not our intention, and I’ am glad to say that amity has been restored. Clearly, health and fitness are major considerations in assessing need for part m accommodation but equally clearly doctors must allow the social services sovereignty of final decision in their own departments. Locally, we now hope to cooperate even more closely in the more rational assessment and allocation of scarce residential places. Trinity Hospital, PETER F. ROE
Taunton, Somerset
S!R,—The importance of medical screening of elderly people who are on the verge of moving from independence to institutional living was demonstrated by Professor Brocklehurst and his colleagues in your issue of July 15. In Copenhagen such medical screening has been assured since 1973 as a consequence of a regulation, passed by the municipal authorities, to the effect that no elderly person can be accepted for institutional care without having been examined at one of the five geriatric departments in the city, either in outpatient departments or after hospital admission. The geriatric department concerned receives two referral documents for every pensioner referred-one filled in by the elderly person’s general practitioner and the other by the district nursing services. An analysis of 196 consecutive referrals2 revealed the following items. Disability affecting the elderly person’s ability to cope independently were recorded many times, the most common being difficulty in walking (38%), vertigo, falls, or fainting (35%), mental disturbances (dementia, psychosis, neurosis) (27%), decreased vision (20%), cardiopulmonary troubles (dyspnoea, angina pectoris) (18%), decreased hearing (13%), urinary incontinence (12%), compromised function of upper 1. Roe, P F., Guillem, V. L. Hlth Soc Serv. 2. Krakauer, R. Ugeskr. Læg. (in the press).
J. 1978, 88,
168.
