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High doses of Antisecretory Factor stop diarrhea fast without recurrence for six weeks post treatment

Open AccessPublished:April 03, 2018DOI:https://doi.org/10.1016/j.ijid.2018.03.015

      Highlights

      • Antisecretory Factor in the form of Salovum was given perorally as 2 sachets (Group A) and 4 sachets ((Group B) to children 6–24 months of age presenting with diarrhea.
      • Eighty percent of the patients in Group B responded with a firm faecal consistency 30 min after the end of the Salovum treatment, while 30% of the patients in Group A (2 sachets) responded likewise, p = 0.004.
      • The number of diarrheal stools decreased over this time from seven to one/two over 4 hours in the two groups (p = 0.234). None of the forty patients reported with any new episodes of diarrhea during the follow-up period.
      • No adverse effects were noted.

      Abstract

      Background

      Diarrheal illnesses in young children cause morbidity and preventable deaths in developing countries. We evaluated two high doses of Salovum® [Antisecretory Factor] to treat diarrhea in young children and followed up for recurrence 6 weeks post treatment.

      Methods

      Forty children, 6-24 months old, admitted with acute diarrhea, to the Outpatient Department of Children’s Hospital in Lahore, Pakistan were selected. The patients were randomly allocated to either Group A given 2 sachets, or to Group B, given 4 sachets. Each sachet contained 4 gram of Salovum® and was mixed with Oral Rehydration Salt solution. This mixture was administered perorally within the first 30 min of treatment. The trained nursing staff observed them for number of stools and consistency over every half hour for a total of 4 hours. Follow up for 6 weeks was done daily by telephone, or visits by the mothers. The results demonstrate that Salovum provides a protective effect irrespective of the diarrhea causes.

      Results

      Group B, given 4 sachets of Salovum® showed improved fecal consistency in 80% of the children compared to 50% in Group A within 30 minutes of treatment, p = 0.004. The number of diarrheal stools decreased over this time from seven to one/two over 4 hours in the two groups [p = 0.234]. None of the children showed a recurrence of diarrhea over the follow up period.

      Conclusion

      Peroral high doses of Salovum® rapidly and safely counteract diarrhea in children followed by a diarrhea-free period of 6 weeks.

      Keywords

      Introduction

      Diarrheal disease of various etiologies is one of the leading causes of infant morbidity and mortality in developing countries. More than one million deaths from diarrhea are reported each year (UNICEF. The state of the world’s children 2016). Nearly 15% of the acute diarrheal episodes have been shown to continue for a longer duration going into persistent/chronic diarrhea and later into a chronic stage. Such development of chronic diarrhea often has a fatal outcome, or leads to severe and longstanding sequelae, with a total, negative impact on the time needed for a sufficient rehabilitation period (
      • Mahmud A.
      • Jalil F.
      • Karlberg J.
      • Lindblad B.S.
      Early child health in Lahore, Pakistan: VII. Diarrhoea.
      ).
      Specific medical intervention of the diarrhea induced dehydration can be effectively and rapidly performed by means of oral rehydration solutions or by an adequate intravenous therapy. In most rural areas in developing countries, however, this form of therapy is not available for several reasons including economics. Moreover, various forms of vaccination programs against childhood diarrhea have, worldwide, demonstrated a rather limited progress. This restricted progress is probably caused by the multiple varieties of pathogenic agents causing pathological intestinal secretion. Thus; there is an urgent need for effective and specific treatment schedules, capable of a rapid and effective treatment for all forms of agents causing childhood diarrheal disease.
      The Antisecretory Factor [AF] is an endogenously produced protein found in all mammalian tissues investigated so far. AF is secreted into blood, milk and bile (
      • Lange S.
      • Lonnroth I.
      The antisecretory factor: synthesis, anatomical and cellular distribution, and biological action in experimental and clinical studies.
      ). AF acts in vivo by a regulation of water and ion transport across cellular membranes, but AF also mediates a potent anti-inflammatory effect (
      • Eriksson A.
      • Shafazand M.
      • Jennische E.
      • Lange S.
      Effect of antisecretory factor in ulcerative colitis on histological and laborative outcome: a short period clinical trial.
      ,
      • Johansson E.
      • Jennische E.
      • Lange S.
      • Lonnroth I.
      Antisecretory factor suppresses intestinal inflammation and hypersecretion.
      ,
      • Lange S.
      • Lonnroth I.
      The antisecretory factor: synthesis, anatomical and cellular distribution, and biological action in experimental and clinical studies.
      ). Controlled clinical studies have proven a beneficial effect of AF concerning the clinical outcome of Meniere’s disease (
      • Hanner P.
      • Jennische E.
      • Lange S.
      • Lonnroth I.
      • Wahlstrom B.
      Increased antisecretory factor reduces vertigo in patients with Meniere’s disease: a pilot study.
      ,
      • Leong S.C.
      • Narayan S.
      • Lesser T.H.
      Antisecretory factor-inducing therapy improves patient-reported functional levels in Meniere’s disease.
      ), ulcerative colitis (
      • Bjorck S.
      • Bosaeus I.
      • Ek E.
      • Jennische E.
      • Lonnroth I.
      • Johansson E.
      • et al.
      Food induced stimulation of the antisecretory factor can improve symptoms in human inflammatory bowel disease: a study of a concept.
      ,
      • Eriksson A.
      • Shafazand M.
      • Jennische E.
      • Lange S.
      Effect of antisecretory factor in ulcerative colitis on histological and laborative outcome: a short period clinical trial.
      ), Crohn’s disease (
      • Bjorck S.
      • Bosaeus I.
      • Ek E.
      • Jennische E.
      • Lonnroth I.
      • Johansson E.
      • et al.
      Food induced stimulation of the antisecretory factor can improve symptoms in human inflammatory bowel disease: a study of a concept.
      ,
      • Eriksson A.
      • Shafazand M.
      • Jennische E.
      • Lonnroth I.
      • Lange S.
      Antisecretory factor-induced regression of Crohn’s disease in a weak responder to conventional pharmacological treatment.
      ) and mastitis (
      • Svensson K.
      • Lange S.
      • Lonnroth I.
      • Widstrom A.M.
      • Hanson L.A.
      Induction of anti-secretory factor in human milk may prevent mastitis.
      ). The AF protein can be endogenously stimulated by either intestinal exposure to bacterial toxins or to the intake of specific food components (
      • Bjorck S.
      • Bosaeus I.
      • Ek E.
      • Jennische E.
      • Lonnroth I.
      • Johansson E.
      • et al.
      Food induced stimulation of the antisecretory factor can improve symptoms in human inflammatory bowel disease: a study of a concept.
      ,
      • Lange S.
      • Lonnroth I.
      The antisecretory factor: synthesis, anatomical and cellular distribution, and biological action in experimental and clinical studies.
      ,
      • Lonnroth I.
      • Lange S.
      • Skadhauge E.
      The antisecretory factors: inducible proteins which modulate secretion in the small intestine.
      ). Furthermore, preformed AF can also be passively administered to the patient by peroral intake of Salovum, a spray dried egg yolk with a high content of the AF protein (
      • Kaya I.
      • Johansson E.
      • Lange S.
      • Malmberg P.
      Antisecretory Factor (AF) egg-yolk peptides reflects the intake of AF-activating feed in hens.
      ). The “active site” of AF, i.e. the part of the protein regulating water secretion and the inflammatory response, is located in the N-terminal part of the protein (
      • Johansson E.
      • Lange S.
      • Lonnroth I.
      Identification of an active site in the antisecretory factor protein.
      ).
      We have previously shown that peroral treatment of children with Salovum effectively counteracts diarrheal diseases of various etiologies (
      • Zaman S.
      • Aamir K.
      • Lange S.
      • Jennische E.
      • Silfverdal S.A.
      • Hanson L.A.
      Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo-controlled, randomised study.
      ,
      • Zaman S.
      • Lange S.
      • Jennische E.
      • Aamir K.
      • Silfverdal S.A.
      • Hanson L.A.
      The antisecretory factor—an efficient tool for rapid recovery from early childhood diarrhoea.
      ,
      • Zaman S.
      • Mannan J.
      • Lange S.
      • Lonnroth I.
      • Hanson L.A.
      B 221, a medical food containing antisecretory factor reduces child diarrhoea: a placebo controlled trial.
      ). A registration of the children’s health status, with a focus on diarrheal diseases recurrence during the diarrhea rehabilitation period has, however, not been performed.
      The primary objective was to achieve an early recovery from diarrheal illness in children from 6-24 months of age using two different doses of Salovum. The secondary objective was to document the recurrence of diarrhea in these children 6 weeks post treatment of the acute diarrheal episode. The aim was to keep these children free from recurrence of diarrheal disease, thereby eliminating the risk for the development of chronic diarrhea, malnutrition and/or death.

      Material and methods

      Study population

      Children, 6-24 months of age, were selected from the Outpatients Department [OPD] of the Children’s Hospital, Lahore over a period of 12 months covering the diarrheal seasons from March 2016 to March 2017.
      The desired number of children included in the study was obtained after screening from 68 children reporting acute watery diarrhea. All children between the ages of 6 to 24 months who had reported with a history of passage of 3, or more than 3, watery stools during the last 24 hours only and did not show any signs of moderate to severe dehydration were included. Patients with a history of taking antibiotics or anti-diarrheal drugs previously were excluded. They were also screened for any known allergy to eggs. Twenty-eight children were excluded based on the above inclusion criteria and refusal [n = 2] to participate in the study. Forty children were then randomized to either of the groups A or B with two doses of AF [Figure 1]. The nursing staff, but not the pediatricians, were blinded to the treatment groups. The number and consistency of stools were noted every half hour during the stay in the OPD by a trained group of senior nurses. Any vomiting or refusal to drink was also noted. The nurses were supervised by the pediatrician on call.

      Sample size

      At a 95% confidence interval, assessing at a power of 90% for obtaining a consistency of stools with a difference of 50% as a successful outcome initially in the two groups, we calculated a sample size of 20 in each group (
      • Zaman S.
      • Aamir K.
      • Lange S.
      • Jennische E.
      • Silfverdal S.A.
      • Hanson L.A.
      Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo-controlled, randomised study.
      ,
      • Zaman S.
      • Lange S.
      • Jennische E.
      • Aamir K.
      • Silfverdal S.A.
      • Hanson L.A.
      The antisecretory factor—an efficient tool for rapid recovery from early childhood diarrhoea.
      ,
      • Zaman S.
      • Mannan J.
      • Lange S.
      • Lonnroth I.
      • Hanson L.A.
      B 221, a medical food containing antisecretory factor reduces child diarrhoea: a placebo controlled trial.
      ). All of the children received the standard diarrheal treatment as outpatients.

      Sampling technique

      Simple random sampling by computer generation of random numbers was used. Two groups of patients were allocated to either 2 sachets, 8 gram [Group A] – or to 4 sachets, 16 gram [Group B] of Salovum. Each sachet contained 4 grams of the spray dried egg yolk Salovum. Thus, the treatment started with either 2 sachets or 4 sachets of Salovum mixed together with 300 ml of Oral Rehydration Solution [ORS] and given perorally to the diarrhea patient during a 30 min long start up period using a cup and a spoon.

      Data collection method

      The Ethics Committee of the Children’s Hospital approved the study. The investigators obtained a signed consent from the parent/s of the identified patient after providing them with complete information regarding the treatment with Salovum. They were then placed into the group given either 2 sachets or 4 sachets of Salovum. The nurses were responsible for preparing them with 300 ml of ORS and immediately thereafter administered perorally using a sterilized steel spoon to the patient during a 30 min long period. During this period, the number of stools as well as consistency of stools was registered by the nurse observing the patients’ diapers and asking the mothers. The mothers, if breastfeeding, continued to do so. The children not breast-fed were allowed to take formula milk/semi solids with cup and spoon prepared by the nurses during the time of stay. All forms of standard diarrheal treatment continued as per protocol of the OPD. After the child was clinically stabilized, the number of stools reduced and the consistency improved over the 4 hours period, the patients were sent home with a mobile phone contact with the hospital.
      The follow up contact consisted of a daily conversation between the nurse in-charge and the mothers via the mobile phone. Furthermore, the mothers were asked to immediately call if the child once more had developed acute diarrhea. During the following 6 weeks, follow up was done on a daily basis for all the patients.

      Data analysis

      The background data of the study children was achieved by bivariate analysis. The numbers and consistency of stools were compared before and after the peroral Salovum treatment in the two groups using a t-test/Wilcoxson’s Rank sum test for differences in the means of the two groups and a Chi Square test for differences in the proportions. The alpha level was defined at 0.05 in two tails. SPSS version 24 was used for analysis.

      Results

      Baseline demographic and clinical characteristics of the two groups of selected patients are shown in Table 1. Significantly more females [80%] were in group B [4 sachets] than in group A [50%, 2 sachets], p = 0.0495. The age of the patients was also significantly higher [16.35 ± 6.59 months] in Group B than in Group A [11.40 ± 4.97 months], p = 0.011. The nutritional status was examined in terms of the weight for age and height/length for age and presented as Z scores using the WHO standards for growth (
      • de Onis M.
      • Garza C.
      • Victora C.G.
      • Onyango A.W.
      • Frongillo E.A.
      • Martines J.
      The WHO Multicentre Growth Reference Study: planning, study design, and methodology.
      ). The mean WAZ and HAZ scores were not different in the two groups [p = 0.398 and p = 0.2189]. The patients in the two groups reported similar mean numbers of stools passed during the last 24 hours, varying from 7.1–7.5. The consistency of the stools was the same in Group A [95%] and in Group B [90%], i.e., loose or loose and watery, at the start of the peroral Salovum treatment [p = 0.553]. One patient from Group A and two patients from group B had reported an episode of vomiting before reporting to the hospital [data not shown].
      Table 1Descriptive analysis of the baseline demographic and clinical characteristics of patients selected in the two groups, Group A (given 2 sachets) and Group B (given 4 sachets) of Salovum for the diarrhea study.
      VariablesGroup A (n = 20)Group B (n = 20)p value
      Gender
      Males, n (%)10 (50)4 (20)
      Females n (%)10 (50)16 (80)0.0495
      Age in months, Mean ±  SD11.40 ± 4.9716.35 ± 6.590.0109
      Nutritional Status
      Weight for age (Z scores) Mean ± SD-1.0645 ± 1.440-1.435 ± 1.290.3978
      Length/Height for Age (Z scores) Mean ± SD-0.3980 ± 1.889-1.10 ± 1.6470.2181
      No. of loose, watery stools at the time of reporting Mean ± SD7.1 ± 2.87.5 ± 3.00.287
      Consistency of stools at the time of reporting, n (%)
      Loose watery19 (95)18 (90)
      Loose1 (5)2 (10)0.553
      Note: The significance testing was done using either t-test or Wilcoxon’s Rank Sum test for two independent samples or a Chi Square test or Fisher’s exact test for differences in two proportions, with significance level at 0.05 in two tails.
      The consistency of the stools rapidly changed from loose to firm and normal within 30 min after finishing of the peroral treatment with Salovum. The results demonstrated in Figure 2 showed that about 80% of the patients in Group B [4 sachets] responded with a firm fecal consistency already 30 min after the end of the Salovum treatment, while less than 30% of the patients in Group A [2 sachets] responded likewise, p = 0.004. The transformation of loose into firm stools continued in both groups over each of the coming next 30 minutes during the 4-hr-long registration period. The last stool registration was performed after 4 hrs. Thereafter the patients were sent home, but with a mobile phone contact with the hospital.
      Figure 2
      Figure 2Showing the proportion (percentage) of children with change in the consistency of stools from watery to firm/solid after each half hour of treatment in the two groups of patients belonging to either Group A (given 8 gram) or Group B (given 16 gram) of Salovum. Group B demonstrated a significantly better initial response after the first 30 min of treatment when compared to Group A (p = 0.0044).
      Figure 3 shows the proportion of children with diarrheal stools reduced as the proportion of children without diarrhea increased with time, measured every half hour while still in the OPD. The initial differences in the proportions were not significantly different in the two groups given either two times or four times the original dose of Salovum [p = 0.2347]. With time, the number of stools had reduced, but also the consistency had changed significantly.
      Figure 3
      Figure 3Percentage of children showing no diarrheal stool after the treatment with Salovum in Group A (given 8 gram) and in Group B (given 16 gram). No statistical differences were registered between group A and group B.
      The results in Figure 4 demonstrate the decrease in the mean numbers of stools, whether diarrheal or normal stools, reported at the start and at various times during the next 24 hours, after 3 days, 1 week and 6 weeks long rehabilitation period. After the initial 30–90 minutes, the stools reported by the mothers were of firm consistency and did not exceed more than one during the follow-up period. During this period, none of the children had reported with any recurrence of diarrheal disease. No adverse effects were noted during the stay in the OPD or during the 6 week long follow up period.
      Figure 4
      Figure 4This figure shows the mean number of stools, with normal or loose consistency, passed during the period after treatment in the two groups given either 2 or 4 sachets of Salovum (over a 30 min. Interval) for the first 4 hours and followed at 24 hours, 3 days, one and 6 weeks. No statistical differences were registered between group A and group B.
      Note: None of the mothers reported loose, watery stools after the first 30–90 minutes in the two groups.

      Discussion

      The present study showed how the endogenous protein AF efficiently terminated diarrhea in young children 6-24 months of age while being treated at the OPD clinic during a period of 4 hours after an initial dose of Salovum in 2 times or 4 times the original dose of 4 grams. The consistency of stools rapidly reverted to normal, starting after a 30 min long treatment period, in both of the groups. Group B (4 sachets) showed a more rapid improvement than group A (2 sachets). These findings demonstrate that the faster clinical response to Salovum was dose-dependent. The mean number of stools also rapidly decreased likewise over time in the two groups. When contacted at different time intervals during the rehabilitation period, none of the children showed a recurrence of diarrhea. This indicates the long-term effect of AF when fed to these children.
      The response to AF agrees with previous studies in man and in animals (
      • Finkel Y.
      • Bjarnason I.
      • Lindblad A.
      • Lange S.
      Specially processed cereals: a clinical innovation for children suffering from inflammatory bowel disease?.
      ,
      • Lange S.
      • Martinsson K.
      • Lonnroth I.
      • Goransson L.
      Plasma level of antisecretory factor (ASF) and its relation to post-weaning diarrhoea in piglets.
      ,
      • Laurenius A.
      • Wangberg B.
      • Lange S.
      • Jennische E.
      • Lundgren B.K.
      • Bosaeus I.
      Antisecretory factor counteracts secretory diarrhoea of endocrine origin.
      ,
      • Zaman S.
      • Aamir K.
      • Lange S.
      • Jennische E.
      • Silfverdal S.A.
      • Hanson L.A.
      Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo-controlled, randomised study.
      ,
      • Zaman S.
      • Lange S.
      • Jennische E.
      • Aamir K.
      • Silfverdal S.A.
      • Hanson L.A.
      The antisecretory factor—an efficient tool for rapid recovery from early childhood diarrhoea.
      ,
      • Zaman S.
      • Mannan J.
      • Lange S.
      • Lonnroth I.
      • Hanson L.A.
      B 221, a medical food containing antisecretory factor reduces child diarrhoea: a placebo controlled trial.
      ). The randomization of the children resulted in an uneven distribution of age and gender. Thus, the patients in group B were almost twice as old as those in group A. The faster recovery in group B could consequently be a random occurrence due to this difference in age. However, the children in both the groups were equally well-nourished and they were frequently breastfed. Consequently, these factors could, therefore, not explain the difference between group A and group B in the response to the Salovum treatment.
      One of the weaknesses of the study was that controls, i.e., children being treated using the standard regime only at the outpatient level or for the follow up, were not selected for the current study because we knew from our previous experience that the response is significant to Salovum using the different doses. Moreover, we had to restrict the follow-up to only 6 weeks because of the logistic reasons considering the burden on the staff and the increasing load of patients reporting to the Outpatients with other diseases as well. However, we would expect a longer duration of diarrhea-free period with the higher dose of Salovum post treatment. This was not addressed in the current study.
      Based on our previous studies (
      • Zaman S.
      • Aamir K.
      • Lange S.
      • Jennische E.
      • Silfverdal S.A.
      • Hanson L.A.
      Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo-controlled, randomised study.
      ), the sample size was adequately selected due to a known level of outcome. The follow up was close and intensive, carried out by the pediatrician in charge and the appointed nursing staff that was present throughout the treatment time. The staff was trained beforehand in the collection of the information and observing the progress. Despite their training and supervision, they did not know which group was getting 2 or 4 sachets since only the pediatrician in charge knew the dispensation. The follow up was completed with daily contacts between the mothers and care-givers.
      Moreover, the number of sick children in the area of the study is high during the year. It is of importance to counteract diarrhea as fast as possible in order to restore the body water and ion balance. The faster this clinical goal is achieved, the less is the risk for the diarrhea to develop further into a chronic or fatal diarrheal disease. This can also prevent the usage of any anti-diarrheal or antibiotics drugs, which can pose the danger of further damage to the gut.
      The two and four-times increase in the dose of Salovum indicates the dose-response, suggesting that such diarrheal episodes can be treated as outpatients but, if made available, even can be used by the mothers at home in the absence of any side-effects (
      • Zaman S.
      • Aamir K.
      • Lange S.
      • Jennische E.
      • Silfverdal S.A.
      • Hanson L.A.
      Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo-controlled, randomised study.
      ,
      • Zaman S.
      • Lange S.
      • Jennische E.
      • Aamir K.
      • Silfverdal S.A.
      • Hanson L.A.
      The antisecretory factor—an efficient tool for rapid recovery from early childhood diarrhoea.
      ,
      • Zaman S.
      • Mannan J.
      • Lange S.
      • Lonnroth I.
      • Hanson L.A.
      B 221, a medical food containing antisecretory factor reduces child diarrhoea: a placebo controlled trial.
      ). We have previously shown the reduction in diarrhea in young children occurring within a mean of 17 hours even when the dosage was less than the present one. The consistency of stools was also seen to revert to normal in 19 hours with the same dosage. So, high doses may provide a greater benefit to these patients in much less time.
      The rapid, clinical action of Salovum noted in the presented diarrhea patients cannot be satisfactory scientifically explained. Thus, a detailed biological mechanism of action in vivo of the various AF peptides remains to be described. Experimental studies demonstrate that the AF peptide, AF-16, suppresses increased intracranial pressure in rats, and also decreases a high intratumoral pressure in rat mammary cancer (
      • Al-Olama M.
      • Lange S.
      • Lonnroth I.
      • Gatzinsky K.
      • Jennische E.
      Uptake of the antisecretory factor peptide AF-16 in rat blood and cerebrospinal fluid and effects on elevated intracranial pressure.
      ,
      • Al-Olama M.
      • Wallgren A.
      • Andersson B.
      • Gatzinsky K.
      • Hultborn R.
      • Karlsson-Parra A.
      • et al.
      The peptide AF-16 decreases high interstitial fluid pressure in solid tumors.
      ). The registered suppression of the increased intracranial as well as intratumoral pressure is noted within minutes. Ongoing research has demonstrated an interaction in vivo between AF-16 and the flotillin-1 structure located to the inside of the cellular membrane. This interaction might directly influence the cellular membrane transport capacity for water and ions, which consequently should be reflected by an immediate decrease of the pressure. A similar mode of AF action in the affected intestine of the children with diseased diarrhea could partly explain the rapid mode of clinical action of Salovum in the diarrhea diseased patients.
      Since no fecal bacteriological evaluations were performed on the patients in the present study, the diarrheal etiology in the different patients could, therefore, not be defined. It is most likely that the causative agents may be variable, ranging from viral to bacterial. This agrees with the fact that AF functions as a principal regulator of intestinal water and ion transport and performs its action irrespectively of the diarrhea-inducing mechanisms (
      • Lange S.
      • Lonnroth I.
      The antisecretory factor: synthesis, anatomical and cellular distribution, and biological action in experimental and clinical studies.
      ).
      The protective and regulating influence of AF is presumably mediated via its capacity to normalize secretions and possibly also via its anti-inflammatory capacity as shown in several studies. The response to higher doses of Salovum did not cause any side-effects like vomiting or increase in secretory response showing worsening of diarrhea, but a prolonged, protective effect was notable in these children who returned to the same environment and remained diarrhea-free for 6 weeks in both of the groups. This suggests a prolonged resistance to diarrheal diseases initiated by Salovum.
      Moreover, we had added Salovum to the oral rehydration salts routinely used in the management of acute diarrhea. None of the patients showed any aversion to either the salts or to the egg yolk mixed in it. A more longstanding and continuous stimulation of the endogenous AF system can be achieved by feeding the children with SPC-Flakes either as finely ground and mixed with milk or ordinary food, or as a muesli (
      • Finkel Y.
      • Bjarnason I.
      • Lindblad A.
      • Lange S.
      Specially processed cereals: a clinical innovation for children suffering from inflammatory bowel disease?.
      ). Consequently, induction of increased AF production achieved via intake of SPC-Flakes over time might reduce the risk for infants and children in impoverished areas to the threat of repeated diarrheal diseases of varied etiology.

      Conflict of interest

      The authors have no conflicts of interest to declare.
      Meetings where the information has previously been presented: None.

      Funding

      This study was supported by the Swedish Government under the LUA/ALF Agreement [Grant 71570 ], Sahlgrenska University Hospital [Grant 83030 , Lantmännen AS-Faktor AB, and Lantmännens Forskningsstiftelse [Grant no 2016S004 ].

      Ethical approval

      The study was approved by the Ethics Committee of the Children's Hospital and Institute of Child Health, Lahore, Pakistan. An informed consent with Thumb impressions and contact details were also obtained before the patients were included for the study. The parents were free to withdraw from the study at their own will.

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