Volume 88 Number 4, part 1
Letters to the Editor
REFERENCES 1. Chrispin AR: Abnormalities ofoesophageal function: some radiological aspects, In: Wilkinson AW, editor: Recent advances in Pediatric surgery, New York, 1969, Grune & Stratton, Inc, p 137. 2. Chrispin AR, Friedland GW, and Wright DE: Some functional characteristics of the oesophageal vestibule in infants and children, Thorax 22:188, 1967. 3. Edwards DAW: The "raspberry" or "flutter" valve in the antireflux mechanism, In Smith AN, editor: Surgical physiology of the gastrointestinal tract: Proceedings of a symposium, Royal College of Surgeons of Edinburgh, 1962, pp 24-28. 4. Herbst JJ, and Johnson D J: Gastroesophageal manometry in children with gastroesophageal reflux, Pediatric Res 8:382, 1974. 5. Chrispin AR, and Friedland GW: Functional disturbance in hiatal hernia in infants and children, Thorax 22:422, 1967.
Metronidazole in treatment of amebiasis To the Editor: In his interesting review of parasitic infections 1 Dr Michael Katz commented that there had been no reported experience of metronidazole in the treatment of nonhepatic extraintestinal amebiasis. A case report from this hospitaF is thus of interest, since a young adult with an amebic hepatic abscess and cutaneous amebiasis of the overlying skin was treated with metronidazole, 2.4 gm orally, on two successive days, resulting in satisfactory resolution of the lesion. Perhaps therefore, metronidazole should remain the drug of first choice even in the uncommon manifestations of amebiasis.
D. G. Human, M.R.C.P. Senior Registrar Department of Paediatrics Mpilo Central Hospital P.O. Box 2096 Bulawayo Rhodesia REFERENCES 1. Katz M: Parasitic infections, J PEDIATR 87:165, 1975. 2. Thomas JEP: Cutaneous amoebiasis due to liver abscess, Cent Air J Med 18:190, 1972.
Reply To the Editor: I am grateful to Dr. Human for calling my attention to a report with which I was unfamiliar. There have been other, single case reports about the effectiveness of metronidazole in the treatment of non-hepatic extra-intestinal amebiasis, but all of them have
695
dealt with individual cases. My statement that there has not been "reported experience" was meant to convey that a critical study has not yet been published.
Michael Katz, M.D. Division of Tropical Medicine College of Physicians and Surgeons of Columbia University New York, N.Y. 10032
Diuretic therapy in infants and children To the Editor: Dr. Loggie and colleagues ~confined their discussion of diuretic therapy to treatment of fluid retention due to heart and kidney disease. They failed to discuss fluid retention in chronic liver disease which presents certain special problems. Extrahepatic biliary atresia is by far the most frequent cause of cirrhosis leading to fluid retention in infants and young children. A few other children develop ascites and edema in the course of progressive forms of hepatic parenchymal damage with cirrhosis. In both these situations the effective treatment of ascites can alleviate a very uncomfortable symptom in a dismal progressive disease. Ascites and edema can also be present at the time of presentation in children with treatable forms of liver disease (e.g., Wilson disease) and incorrect use of diuretics can be life threatening in these situations. There are two special features to the fluid retention of liver disease. (1) Hyperaldosteronism and renal tubular damage are both commonly present in liver disease and both lead to potassium loss and hypokalemia. Overenthusiastic use of diuretics like furosemide or thiazides can be quite dangerous. (2) The fluid accumulates predominantly in the peritoneal cavity from which it can be reabsorbed for excretion only fairly slowly. This makes it rather easy to cause dehydration by overzealous use of any diuretic. An aldosterone antagonist like spironolactone is the logical first diuretic to use in fluid retention of liver disease. I have followed this course o f action since 1960 and during this period have treated over 60 children with fluid retention due to liver disease. In at least three-quarters o f these patients spironolactone alone has produced a satisfactory diuresis within 24 to 36 hours after first administration. I have used an initial dose of 25 mg twice a day in infants under 12 months or 25 mg three times a day in infants 12 months to 2 years o f age. Serious disturbances of serum electrolytes have been so rare that I come to regard it as quite safe to start this treatment at home provided that the baby is not very ill. In infants with terminal liver failure hyponatremia is usually also present and spironolactone can aggravate this. However, the hypokalemia, which is more usually present alone in earlier cases, is usually corrected by this drug w i ~ o u t additional potassium. In about 25% of infants diuresis has not followed the use of spironolactone alone. The addition of a small dose of furosemide
696
Letters to the Editor
or a thiazide has always yielded the desired diuresis and when these drugs are given after satisfactory saturation of the patient with spironotactone, serious potassium depletion is rarely seen. These additional diuretics are also needed in the terminal phases in a number of cases. It is a great pity that no form of spironolactone suitable for parenteral administration is available because the potassiumdepleting diuretics have to be used alone in those patients who are too ill to tolerate oral drugs. Liberal supplements of potassium must then be administered intravenously with careful monitoring of the serum potassium levels. Some quite extraordinary economic arguments have been put forward against the use of spironolactone as the initial drug in the treatment of fluid retention in liver disease. While it is true that spironolactone is an expensive drug, the added cost is more than compensated by the infrequent need for serum electrolyte measurements and the ability to initiate and carry out treatment at home rather than in hospital.
David M. Danks, M.D., F.R.A.C.P. Head, Genetics Research Unit Royal Children's Hospital Research Foundation Melbourne, 3052, Victoria, A ustralia Professor of Paediatrics University of Melbourne REFERENCE
1. Loggie JMH, Kleinman LI, and Van Maanen EF: Renal function and diuretic therapy in infants and children. Part 1II, J PEDIATR 86:825, 1975.
Immune response in iron-deficient children To the Editor: In a recent publication from South Africa, MacDougall and associates ~ described significant deficits in both cell-mediated immune response and bactericidal-killing function of polymorphonuclear leukocytes in children with iron-deficiency anemia and latent iron deficiency. Chandra '2. reported similar findings in an article from India. The fact that their data and interpretations directly contradict those of Kulapongs and associates:' and Gross and associates 4 indicates that additional studies are required before one can conclude that either of these two immune systems are uniformly depressed in children with iron-deficiency anemia. One must look very closely at the data from these studies to determine why their results and interpretations differ. Obviously, variations in patient populations and laboratory techniques could be factors. As Dr. Buckley pointed out in her editorial, ~ th,e *Dr. A.K. Saraya requested his name be deleted from authorship (see erratum, J PEDIATR87:676, 1975).
The Journal of Pediatrics April 1976
nutritional status of the children studied and the presence of intercurrent infections also may have influenced the findings. In the study by MacDougall and associates, 1 it is noteworthy that nutritional status differed significantly between the anemic patients and the control subjects. The authors stated, however, that the nutritional differences were irrelevant, because seven patients with latent iron deficiency had the same nutritional status as the controls, and had deficits in lymphocyte and phagocyte functions similar to those found in the anemic children. Although the statement regarding the deficit in lymphocyte function may be true, there are no data to indicate that the deficit in bactericidal killing function found in the anemic patients was also found in the latent group. Therefore, one cannot rule out the effects of nutritional status on phagocytic-killing function. It is also important to note that for technical reasons, the investigators were unable to study, let alone demonstrate, improvement in phagocytic-killing function after iron therapy. To cloud further the issue of phagocytic function in iron-deficiency anemia, MacDougall and associates ~ reported no significant difference between the control and iron-deficient groups on the NBT test, while Chandra ~ reported a significant impairment in NBT reduction in the iron-deficient children he studied. In evaluating in vitro lymphocyte transformation to PHA and Candida, MacDougall and associates ~ used a five-day culture, after which [3H]-methyl thymidine was added to the media. The resulting control stimulation indices for PHA were significantly lower than those reported by either Kulapongs and associates :~or Chandra.'-' As Buckley ~ pointed out, MacDougall and associates ~ harvested the lymphocytes after the peak responses had occurred-a factor that may have been responsible for the very low stimulation indices reported by these investigators. MacDougall and associates ~also indicated that the question of infection was obviated by the fact that the children were studied seven to ten days after completion of three to ten days of penicillin or sulfonamide therapy. It is interesting to note that the anemic patients tended to have higher white blood cell counts than the controls, and that, though the group with latent iron deficiency had no evidence of infection either by history or physical examination, they had higher white blood cell counts than the controls or the anemic children. Leukocytosis, either by itself or accompanying an infection, has been associated with a significant degree of anergy. 6 It is also well known that an infectious agent can affect cellular immunity for a longer time than the seven- to ten-day interval allowed by MacDougall and associates 1 between the completion of therapy and the evalution of immune status. Of the 20"patients studied by Chandra,'-' five presented with recurrent infection, five with abdominal pain, and two with chronic moniliasis. Again, infection may have been an important factor in the depressed celtular immunity. On the other hand, the patients studied by Kulapongs and associates 3 had evidence of hookworm infestation on admission, but no other evidence of intercurrent infection at the time of the study. It is also interesting that Gross and associates ~ found impaired cell-mediated immunity in folate-deficient patients, but not in iron-deficient subjects. The patients studied by Kulapongs and associates~ had normal folate levels. Unfortunately, folate deft-
Letters to the Editor
REFERENCES 1. Chrispin AR: Abnormalities ofoesophageal function: some radiological aspects, In: Wilkinson AW, editor: Recent advances in Pediatric surgery, New York, 1969, Grune & Stratton, Inc, p 137. 2. Chrispin AR, Friedland GW, and Wright DE: Some functional characteristics of the oesophageal vestibule in infants and children, Thorax 22:188, 1967. 3. Edwards DAW: The "raspberry" or "flutter" valve in the antireflux mechanism, In Smith AN, editor: Surgical physiology of the gastrointestinal tract: Proceedings of a symposium, Royal College of Surgeons of Edinburgh, 1962, pp 24-28. 4. Herbst JJ, and Johnson D J: Gastroesophageal manometry in children with gastroesophageal reflux, Pediatric Res 8:382, 1974. 5. Chrispin AR, and Friedland GW: Functional disturbance in hiatal hernia in infants and children, Thorax 22:422, 1967.
Metronidazole in treatment of amebiasis To the Editor: In his interesting review of parasitic infections 1 Dr Michael Katz commented that there had been no reported experience of metronidazole in the treatment of nonhepatic extraintestinal amebiasis. A case report from this hospitaF is thus of interest, since a young adult with an amebic hepatic abscess and cutaneous amebiasis of the overlying skin was treated with metronidazole, 2.4 gm orally, on two successive days, resulting in satisfactory resolution of the lesion. Perhaps therefore, metronidazole should remain the drug of first choice even in the uncommon manifestations of amebiasis.
D. G. Human, M.R.C.P. Senior Registrar Department of Paediatrics Mpilo Central Hospital P.O. Box 2096 Bulawayo Rhodesia REFERENCES 1. Katz M: Parasitic infections, J PEDIATR 87:165, 1975. 2. Thomas JEP: Cutaneous amoebiasis due to liver abscess, Cent Air J Med 18:190, 1972.
Reply To the Editor: I am grateful to Dr. Human for calling my attention to a report with which I was unfamiliar. There have been other, single case reports about the effectiveness of metronidazole in the treatment of non-hepatic extra-intestinal amebiasis, but all of them have
695
dealt with individual cases. My statement that there has not been "reported experience" was meant to convey that a critical study has not yet been published.
Michael Katz, M.D. Division of Tropical Medicine College of Physicians and Surgeons of Columbia University New York, N.Y. 10032
Diuretic therapy in infants and children To the Editor: Dr. Loggie and colleagues ~confined their discussion of diuretic therapy to treatment of fluid retention due to heart and kidney disease. They failed to discuss fluid retention in chronic liver disease which presents certain special problems. Extrahepatic biliary atresia is by far the most frequent cause of cirrhosis leading to fluid retention in infants and young children. A few other children develop ascites and edema in the course of progressive forms of hepatic parenchymal damage with cirrhosis. In both these situations the effective treatment of ascites can alleviate a very uncomfortable symptom in a dismal progressive disease. Ascites and edema can also be present at the time of presentation in children with treatable forms of liver disease (e.g., Wilson disease) and incorrect use of diuretics can be life threatening in these situations. There are two special features to the fluid retention of liver disease. (1) Hyperaldosteronism and renal tubular damage are both commonly present in liver disease and both lead to potassium loss and hypokalemia. Overenthusiastic use of diuretics like furosemide or thiazides can be quite dangerous. (2) The fluid accumulates predominantly in the peritoneal cavity from which it can be reabsorbed for excretion only fairly slowly. This makes it rather easy to cause dehydration by overzealous use of any diuretic. An aldosterone antagonist like spironolactone is the logical first diuretic to use in fluid retention of liver disease. I have followed this course o f action since 1960 and during this period have treated over 60 children with fluid retention due to liver disease. In at least three-quarters o f these patients spironolactone alone has produced a satisfactory diuresis within 24 to 36 hours after first administration. I have used an initial dose of 25 mg twice a day in infants under 12 months or 25 mg three times a day in infants 12 months to 2 years o f age. Serious disturbances of serum electrolytes have been so rare that I come to regard it as quite safe to start this treatment at home provided that the baby is not very ill. In infants with terminal liver failure hyponatremia is usually also present and spironolactone can aggravate this. However, the hypokalemia, which is more usually present alone in earlier cases, is usually corrected by this drug w i ~ o u t additional potassium. In about 25% of infants diuresis has not followed the use of spironolactone alone. The addition of a small dose of furosemide
696
Letters to the Editor
or a thiazide has always yielded the desired diuresis and when these drugs are given after satisfactory saturation of the patient with spironotactone, serious potassium depletion is rarely seen. These additional diuretics are also needed in the terminal phases in a number of cases. It is a great pity that no form of spironolactone suitable for parenteral administration is available because the potassiumdepleting diuretics have to be used alone in those patients who are too ill to tolerate oral drugs. Liberal supplements of potassium must then be administered intravenously with careful monitoring of the serum potassium levels. Some quite extraordinary economic arguments have been put forward against the use of spironolactone as the initial drug in the treatment of fluid retention in liver disease. While it is true that spironolactone is an expensive drug, the added cost is more than compensated by the infrequent need for serum electrolyte measurements and the ability to initiate and carry out treatment at home rather than in hospital.
David M. Danks, M.D., F.R.A.C.P. Head, Genetics Research Unit Royal Children's Hospital Research Foundation Melbourne, 3052, Victoria, A ustralia Professor of Paediatrics University of Melbourne REFERENCE
1. Loggie JMH, Kleinman LI, and Van Maanen EF: Renal function and diuretic therapy in infants and children. Part 1II, J PEDIATR 86:825, 1975.
Immune response in iron-deficient children To the Editor: In a recent publication from South Africa, MacDougall and associates ~ described significant deficits in both cell-mediated immune response and bactericidal-killing function of polymorphonuclear leukocytes in children with iron-deficiency anemia and latent iron deficiency. Chandra '2. reported similar findings in an article from India. The fact that their data and interpretations directly contradict those of Kulapongs and associates:' and Gross and associates 4 indicates that additional studies are required before one can conclude that either of these two immune systems are uniformly depressed in children with iron-deficiency anemia. One must look very closely at the data from these studies to determine why their results and interpretations differ. Obviously, variations in patient populations and laboratory techniques could be factors. As Dr. Buckley pointed out in her editorial, ~ th,e *Dr. A.K. Saraya requested his name be deleted from authorship (see erratum, J PEDIATR87:676, 1975).
The Journal of Pediatrics April 1976
nutritional status of the children studied and the presence of intercurrent infections also may have influenced the findings. In the study by MacDougall and associates, 1 it is noteworthy that nutritional status differed significantly between the anemic patients and the control subjects. The authors stated, however, that the nutritional differences were irrelevant, because seven patients with latent iron deficiency had the same nutritional status as the controls, and had deficits in lymphocyte and phagocyte functions similar to those found in the anemic children. Although the statement regarding the deficit in lymphocyte function may be true, there are no data to indicate that the deficit in bactericidal killing function found in the anemic patients was also found in the latent group. Therefore, one cannot rule out the effects of nutritional status on phagocytic-killing function. It is also important to note that for technical reasons, the investigators were unable to study, let alone demonstrate, improvement in phagocytic-killing function after iron therapy. To cloud further the issue of phagocytic function in iron-deficiency anemia, MacDougall and associates ~ reported no significant difference between the control and iron-deficient groups on the NBT test, while Chandra ~ reported a significant impairment in NBT reduction in the iron-deficient children he studied. In evaluating in vitro lymphocyte transformation to PHA and Candida, MacDougall and associates ~ used a five-day culture, after which [3H]-methyl thymidine was added to the media. The resulting control stimulation indices for PHA were significantly lower than those reported by either Kulapongs and associates :~or Chandra.'-' As Buckley ~ pointed out, MacDougall and associates ~ harvested the lymphocytes after the peak responses had occurred-a factor that may have been responsible for the very low stimulation indices reported by these investigators. MacDougall and associates ~also indicated that the question of infection was obviated by the fact that the children were studied seven to ten days after completion of three to ten days of penicillin or sulfonamide therapy. It is interesting to note that the anemic patients tended to have higher white blood cell counts than the controls, and that, though the group with latent iron deficiency had no evidence of infection either by history or physical examination, they had higher white blood cell counts than the controls or the anemic children. Leukocytosis, either by itself or accompanying an infection, has been associated with a significant degree of anergy. 6 It is also well known that an infectious agent can affect cellular immunity for a longer time than the seven- to ten-day interval allowed by MacDougall and associates 1 between the completion of therapy and the evalution of immune status. Of the 20"patients studied by Chandra,'-' five presented with recurrent infection, five with abdominal pain, and two with chronic moniliasis. Again, infection may have been an important factor in the depressed celtular immunity. On the other hand, the patients studied by Kulapongs and associates 3 had evidence of hookworm infestation on admission, but no other evidence of intercurrent infection at the time of the study. It is also interesting that Gross and associates ~ found impaired cell-mediated immunity in folate-deficient patients, but not in iron-deficient subjects. The patients studied by Kulapongs and associates~ had normal folate levels. Unfortunately, folate deft-
