Intestinal cow's milk allergy

Cow's milk allergy (CMA) is multifaceted disease representing systemic, skin or gastrointestinal reactions to cow's milk (CM) protein. This article shortly reviews the intestinal form of CMA (ICMA). According us the child is allergic to CM when the immunologic reaction to CM is associated with clinical symptoms. The incidence of CMA is 1.3-1.9% in general, but the ICMA only 0.6 pro mille among the children less than six months of age. The majority of infants shows symptoms within a month of starting CM feeding. The majority of children with CMA have gastrointestinal symptoms. Manx of these infants has additionally dermatological symptoms and some respiratory symptoms. The mode of onset is often acute diarrhoea and vomiting, as in acute gastroenteritis. Laboratory findings indicate iron deficiency anemia in 20-70%. Half to two thirds of infants with chronic diarrhoea have moderate to severe steatorrhoea. The morphologic lesion in the gastrointestinal tract in ICMA is widespread, often being present from stomach to rectum. Jejunal lesion is most severe in the proximal part of the intestine and nowadays most patients have only partial villous atrophy or slight changes of the villi. Both the epithelium and the lamina propria of the jejunum are infiltrated with inflammatory cells. The morphology of the small intestine speaks for a strong immune reaction which leads increased destruction of surface epithelial cells. We recommend elimination of CM proteins to the age of 1.5 to 2 years. Most patients tolerate CM by the age of 2 years without symptoms. Prolonged breast-feeding and avoidance of early contact with CM are important in reducing the severity and frequency of CMA.     

Peripheral blood immune response elicited by beta-lactoglobulin in childhood cow's milk allergy

Several studies analyzing the immune responses in patients with cow's milk allergy (CMA) have used T-cell lines or T-cell clones that require prolonged in vitro cell culturing and may result in a switched cell phenotype and function. We investigated immune responses to beta-lactoglobulin (b-LG) in peripheral blood mononuclear cells after a short in vitro antigen stimulation in children with acute CMA (both IgE-mediated and non-IgE-mediated forms) and in those who outgrew an IgE-mediated CMA. Healthy controls were also investigated. Peripheral blood mononuclear cells were assayed for IL-13, IFN-γ, IL-4, and IL-10. Although b-LG induced a cytokine production and/or cell proliferation almost in all children, included healthy controls, differences were observed among the four groups. Children with IgE-mediated CMA had a marked Th2-response, with high IL-13 production and proliferation, but low IFN-γ; by contrast, children with non-IgE-mediated CMA produced no, or very low, IL-13 and cell proliferation. Children, who outgrew CMA, showed a shift to a Th1-response, with reduced IL-13 and increased IFN-γ. IL-10-responses were high in all groups, with the highest level in healthy children; by contrast, IL-4 was undetectable in all children. This study highlights the use of shortly stimulated peripheral blood cells to investigate the food-induced immune responses.     

Immunologic disturbances in cow's milk allergy, 2: evidence for defective interferon-gamma generation

We have investigated the role of interferon-gamma (IFN-gamma) in the regulation of antigen-specific T-cell function in patients with cow's milk allergy. The study population consisted of 22 patients, aged from 7. 6 to 56. 9 months, who had challenge-proven cow's milk allergy (CMA) manifested with either skin (n=9) or gastrointestinal (n=13) symptoms. In addition, 11 age-matched children and 6 adults, mean (SD) age 31 (7) years, were studied as controls. Patients with challenge-proven CMA were rechallenged to establish whether they had acquired clinical tolerance to cow's milk. The spontaneous and mitogen-induced IFN-gamma and interleukin-4 (IL-4) generation of isolated lymphocytes was evaluated in vitro with commercial ELISA Kits at diagnosis and at reassessment. At diagnosis, the IFN-gamma production was not detectable in patients with CMA as compared with control children. IL-4 production was almost undetectable in all subjects in this study. However, at reassessment the CMA patients who had acquired clinical tolerance to cow's milk (n=16) showed enhanced IFN-gamma production, when compared with that of control children, but still lower when compared with that of healthy adults. Our results indicate that the maturation of IFN-gamma producing T-cells is delayed in CMA, which could lead to a disturbance in the regulation of T-cell function. This defect might be an important etiologic factor for CMA.     

Evidence for eosinophil activation in cow's milk allergy

To assist in identifying pathogenetic mechanisms in different clinical manifestations of cow's milk allergy (CMA), the involvement of eosinophil cells in immunoinflammatory reactions was evaluated. The study population comprised 28 patients, aged from 5.8 to 43.0 months, who had challenge-proven CMA, manifested either cutaneously (n = 17) or gastrointestinally (n = 11). A clinical cow's milk challenge was performed in hospital after a 4 week cow's milk elimination period. Eosinophil activation in vivo was studied by measuring the serum level of eosinophil cationic protein (ECP) before the oral cow's milk challenge, mean (SD) 27 (12) hours after commencing the challenge and one week later. These results were compared to those of 80 non-allergic age-matched controls. During the challenge, the level of ECP increased from 6.2 (4.5, 8.0) μg/L to 20.0 (9.5, 30, 4) μg/L in CMA patients with skin manifestations but not in those with gastrointestinal symptoms. The increase was shown to be transient. We conclude that eosinophil degranulation is an important immunologic mechanism leading to allergic inflammation in cutaneously manifested CMA.     

Serum immunoglobulin E,IgA, and IgG antibodies to different cow's milk proteins in children with cow's milk allergy: Association with prognosis and clinical manifestations

Diverse pathogenic mechanisms elicit different clinical manifestations in cow's milk allergy (CMA). Our aim was to determine the concentration of serum immunoglobulin levels to different cow's milk proteins in patients with CMA and to determine how these values were related to clinical symptoms and prognosis. Fifty children (mean age 10.9 months, range: 1–34 months) with previously confirmed CMA were enrolled in this study. All had various clinical manifestations of CMA, including gastrointestinal, skin, and respiratory symptoms. At the diagnosis of CMA the serum total and the milk‐specific immunoglobulin (Ig)E values were measured by enzyme immunoassay and fluoroimmunoassay, respectively, while the relative levels of serum IgA and IgG antibodies against different cow's milk proteins were determined by a sensitive enzyme‐linked immunosorbent assay (ELISA). The results were compared to those of 30 non‐atopic age‐matched control children. On average, after 9.2 months (range 2–31 months) on a milk‐free diet, a repeated challenge was performed in 38 children. At the re‐challenge, 12 patients had clinical symptoms while the remaining 26 children were symptom‐free. The IgG antibody level to bovine serum albumin (BSA) was significantly lower in the patients than in the controls (median: 0.36 vs. 2.94, p < 0.01). There was a close correlation among all individual IgA and IgG antibodies to different cow's milk proteins. The anti‐α‐casein IgG level (of 2.10) in children with a positive reaction at the re‐challenge was significantly higher than in those with a negative reaction (0.89) (p < 0.05). The total IgE serum concentration was also significantly higher in those who had symptoms at the re‐challenge compared to those who did not have any reaction at this time (22.9 vs. 6.8 kU/l, geometric mean, p < 0.02). There was no association between the clinical manifestations and the IgG and IgA antibody levels to the cow's milk proteins studied, except for the anti‐BSA IgA level, which was higher in patients with gastrointestinal symptoms. The serum total IgE and anti‐α‐casein IgG levels could have prognostic values; their increase at the beginning of the disease may indicate the development of tolerance to cow's milk only at a later age and after a longer duration of CMA. However, as there is considerable overlap among the values observed in different groups of patients, there is a limitation of these tests for predicting the prognosis.     

Lymphocyte response to cow's milk proteins in patients with cow's milk allergy: relationship to antigen exposure

The cellular immune response to cow's milk was measured in patients with challenge-proven cow's milk allergy (CMA), manifested with either gastrointestinal or skin symptoms. After 2–4 weeks on milk elimination, 44 children, mean (SD) age 15.7 (9.4) months, were challenged, and cow's milk-induced lymphocyte transformation was measured before the clinical challenge (Day 1) and / or one week later (Day 8). During the clinical challenge period, 17 (39%) patients showed gastrointestinal reactions, 9 (20%) had urticarial or eczematous skin eruptions, and 18 (41%) were negative to challenge. On Day 1, the mean [95% confidence interval] stimulation index for lymphocytes in patients manifesting CMA with gastrointestinal symptoms, 2.60 [1.60, 4.10], was significantly higher than that in patients with skin symptoms, 1.15 [0.60, 2.30], or patients with negative clinical challenge, 0.83 [0.64, 1.08], F = 9.0, p = 0.001. After the clinical challenge (Day 8), this cow's milk-induced lymphocyte proliferation response was abrogated. At the same time, CMA patients evidenced a significantly higher spontaneous lymphocyte proliferation response in RPMI medium-containing control cultures than those with negative clinical challenge. We conclude that in patients with CMA, the number of circulating cow's milk-sensitized lymphocytes is depleted or their function is impaired after clinical exposure to cow's milk antigens.     

Cow's milk challenge through human milk evokes immune responses in infants with cow's milk allergy.

OBJECTIVES: In order to measure the immune response evoked in breast-fed infants with cow's milk allergy (CMA) by cow's milk challenge through human milk, mothers were given increasing doses of cow's milk after they had been on a cow's milk elimination diet. Another objective was to study the secretion of beta-lactoglobulin (BLG) into human milk before and during milk challenge in relation to the appearance of symptoms in infants. STUDY DESIGN: Seventeen asymptomatic mothers who had infants with challenge-proven CMA and 10 asymptomatic mothers who had healthy infants were recruited. Infants ranged in age from 1.8 to 9.4 months. A solid-phase enzyme-linked immunoassay (ELISPOT) was used to assess the total number of immunoglobulin-secreting and specific antibody-secreting cells. Flow cytometry was used to enumerate different lymphocyte subpopulations among peripheral blood lymphocytes primed during provocation by cow's milk antigens. BLG levels were assessed in human milk before the challenge and 1, 2, 3, and 4 hours after the commencement of the challenge. RESULTS: All but one of the infants with CMA showed symptoms of CMA during cow's milk challenge through human milk. There was a significant rise in the total number of immunoglobulin-secreting cells in the IgA and IgG classes associated with a positive cow's milk challenge response, but the proportions of peripheral blood B cells bearing CD19, CD23, CD19 and 23, CD5, or CD19 and CD5 were comparable. BLG levels were comparable in both study groups. CONCLUSIONS: Most of the infants with CMA reacted to cow's milk challenge through human milk. Hypersensitivity reactions to food antigens through human milk may be more common than previously thought.     

Large number of CD19+/CD23+ B cells and small number of CD8+ T cells as early markers for cow's milk allergy (CMA)

Assessment of activation of immune mechanisms is valuable in the early diagnosis of cow's milk allergy (CMA). The purpose of this study was to evaluate peripheral blood lymphocyte subclasses in children suspected of having CMA and healthy infants in order to detect an early marker for food allergy. Altogether 47 breast-fed infants, aged from 0.4 to 10 months were followed-up prospectively from birth because of atopic heredity. Twenty-three of the infants were healthy and 24 infants had a strong suspicion of and later challenge-proven cow's milk allergy. Leucocyte subsets were determined from peripheral blood mononuclear cells by flow cytometry. In response to a clinical cow's milk challenge, seven infants developed urticaria, 11 infants had eczema, three patients had loose stools, diarrhoea or vomiting and three infants had eczema and diarrhoea, loose stools or vomiting. The total percentage of B cells and also the proportion of B cells bearing a low-affinity IgE receptor as a marker for activation were significantly higher, whereas the percentage of CD8+ T cells was significantly lower in infants with challenge-proven CMA than in healthy controIs. These results imply that infants with active CMA have a defect in regulation of B-cell function. Further, they suggest that imbalance of the ratio of suppressor and helper T cells might be an important factor in the etiopathogenesis of CMA. Our results show that large numbers of activated CD19 B cells and low numbers of CD8+ T cells could be considered as early markers for food allergy since they are already detectable in peripheral blood during the earliest symptoms of CMA.     

Soy allergy in infants and children with IgE-associated cow's milk allergy

OBJECTIVES: To determine the prevalence of soy allergy in IgE-associated cow's milk allergy (CMA). STUDY DESIGN: Children <3.5 years with documented IgE-associated CMA (n = 93) were evaluated for soy allergy by double-blind, placebo-controlled food challenge, open challenge, or convincing previous history of an anaphylactic reaction to soy. Children tolerant to soy at entry received soy formula and were followed up for 1 year. RESULTS: Of this IgE-associated CMA cohort (ages 3 to 41 months), 14% (95% CI = 7. 7%-22.7%) were determined to have soy allergy, 12 definitely at entry and 1 possibly after 1 year of soy ingestion. The latter child experienced severe failure to thrive at enrollment and exhibited improved growth while receiving soy during follow-up but was diagnosed with eosinophilic esophagitis at study completion. Improved growth (P <.05) occurred in the non-soy-allergic cohort ingesting soy formula (579 31 mL/d) during the year of follow-up. CONCLUSIONS: Soy allergy occurs in only a small minority of young children with IgE-associated CMA. As such, soy formula may provide a safe and growth-promoting alternative for the majority of children with IgE-associated CMA shown to be soy tolerant at the time of introduction of soy formula.     

Formula feeding during cow's milk allergy

Cow's milk allergy (CMA) is an immunologically mediated reaction to cow's milk proteins, which affects infant and young children. Cow milk elimination requires either breast-feeding, with or without elimination diet in mother or the use of specific formulas, based on cow's milk protein extensively hydrolyzed, which fit 90-95% of children with cow's milk allergy. In others, still reactive to allergic remnants in hydrolysates, an amino acid based formula is the optimal option. The good tolerance of soy formulas in a reasonable proportion of children with cow's milk allergy make them useful, including as a 1(st)-choice alternative, except probably for those below the age of 6 months. Any elimination diet in children is at risk of nutritional deficiency so that a constant monitoring of the growth parameters should be kept in those children.     

Defective tumor necrosis factor-α production in infants with cow’s milk allergy

As an aid to clarifying the role of immune mechanisms in the development of cow’s milk allergy (CMA) in suckling infants, we studied the capacity of peripheral blood mononuclear cells (PBMC) to produce tumor necrosis factor-α (TNF-α) in vitro. The study population consisted of 43 infants, aged 0.12–11.2 months; of these, 31 had challenge-proven cow’s milk allergy manifested with either skin or gastrointestinal symptoms or both. In addition, 12 healthy infants were studied as controls. The spontaneous, unstimulated and mitogen-induced production of TNF-α and interferon-γ (IFN-γ) by isolated peripheral blood leukocytes was evaluated. TNF-α and IFN-γ production of PBMC was significantly lower in infants with cow’s milk allergy than in healthy children. Our results indicate that, in infants with CMA, the function of TNF-α-producing cells is defective. This might disturb the development of oral tolerance and thereby lead to cow’s milk allergy. These results may help to clarify the etiopathology of CMA.     

Status of children with cow's milk allergy in infancy by 10 years of age

To assess the development of milk protein tolerance and atopic diseases in children diagnosed for cow's milk allergy (CMA) in infancy, we conducted re-examinations of 56 CMA subjects at the age of 10 y using 204 age-matched controls. The children underwent clinical examinations and skin prick tests (SPT), and their IgE-specific antibodies to milk and five other food allergens were determined. By the age of 10 y, all but four subjects had become tolerant to at least small amounts of milk protein. However, gastrointestinal symptoms relating to more abundant milk consumption were reported by 45% of the study subjects and 15% of the controls (p < 0.001). The incidence figures for asthma, allergic rhinitis and dermatitis, as well as the occurrence of recurrent otitis, were three to four times higher than in the controls. Positive SPTs were seen in two-thirds of the subjects, the figure being highest (83%) in those with dermatitis onset CMA. Seven subjects showed positive titres of IgE-class milk-specific antibodies, and five showed a clinical response. CONCLUSION: This re-examination study showed that CMA in infancy, even when properly treated, has significant clinical consequences by posing special risks for respiratory atopy and persistence of atopic dermatitis as well as positive SPT and recurrent ear infections. However, each of these clinical manifestations seems to have an independent curriculum unrelated to the persistence of CMA itself.     

Eosinophil cationic protein in human milk is associated with development of cow's milk allergy and atopic eczema in breast-fed infants

The precise role of leukocytes and mediators in human milk is still unresolved. Eosinophils are uncommonly detected in human milk and their presence has previously been associated with maternal atopy and development of cow's milk allergy (CMA) in the breast-fed infant. The purpose of this study was to examine the levels of eosinophil cationic protein (ECP) in human milk and to compare the levels with development of allergic diseases in breast-fed infants. Altogether 94 breast-feeding mothers (58 atopic, 36 nonatopic) with their babies were prospectively followed from birth for development of CMA or atopic dermatitis. Colostrum and mature milk samples (at 3 mo of lactation), together with mother's peripheral blood samples, were collected. Milk and blood leukocyte content was evaluated with a light microscope. ECP concentration in human milk was measured by commercial UniCAP method. By the end of a 2-y follow-up, 51 mothers had an infant with CMA, 24 had an infant with atopic dermatitis, and 19 had a healthy infant. ECP concentration in milk was under the detection limit (2 microg/L) in all the mothers with a healthy infant, whereas detectable levels were found in 27% of mothers with a CMA infant and in 42% of those with a baby with atopic dermatitis. Measurable ECP in milk was detected in 26% of the atopic and 25% of the nonatopic mothers. Presence of ECP in human milk is associated with development of CMA and atopic dermatitis in the breast-fed infant, but has no direct association with the maternal atopy.     

The evaluation of selected parameters of calcium and phosphorus metabolism in children with cow's milk allergy

The aim of this study was to evaluate selected parameters of calcium and phosphorus metabolism in children with CMA treated with the following milk substitute formulas: lactose-containing extensively hydrolyzed wheat protein formula, lactose-free extensively hydrolyzed casein protein formula, as well as soy-based formula. Material and methods: The study involved 66 children with CMA aged 2-5 years treated with milk-free diet for at least one year. Group I included 31 children fed with a lactose-containing formula, group II - 35 children treated with lactose-free formula. In all children the mean energy intake and nutritional value of daily food rations were assessed. Serum concentrations of calcium (Ca), phosphorus (P), sodium (Na) and magnesium (Mg) were determined using standard methods. Serum values of 25 hydroxyvitamin D (25-OH D) and parathormone (PTH) were assessed by chemiluminescence, whereas concentrations of biochemical markers of bone formation-bone alkaline phosphatase (BALP), osteocalcin (OC) and bone resorption marker-collagen type I crosslinked C-telopeptide (CTX) were determined by immunoenzymatic methods (ELISA), using specific monoclonal antibodies. Results: There were no significant differences in the mean dietary supply of calcium, phosphorus, magnesium, sodium, total protein and vitamin C in children from both groups. In the diets of children from group II, the mean content of lactose (0.5±1.0 vs 10.0±6.8 g/d) and 25-OH vitamin D (4.1±2.3 vs 8.5±4.0 ug/d) were significantly lower and dietary fibre content (14.7±3.9 vs 10.4±3.9 g/d) was higher. Calcium and vitamin D dietary supply was lower with respect to nutritional recommendations in all the studied children, whereas the dietary deficiency of vitamin D was higher in children from group II. The mean serum concentrations of evaluated biochemical parameters did not reveal any differences in children from the study groups and were in the normal ranges. There were also no differences in the mean serum concentration of 25-OH vitamin D, ALP, BALP, CTX and PTH in patients from both groups. The mean concentration of OC was significantly higher in group II (71±26.6 ng/ml) than in children from group I (61.1±23.4 ng/ml) <0.01. Positive correlation was found between OC and CTX in both study groups. Conclusions: 1. In children with CMA basic blood laboratory tests may have limited importance in the evaluation of calcium and phosphorus metabolism. 2. Our results suggest that the disturbances in the balance between bone formation and bone resorption processes may occur in children with CMA treated with lactose-free formulas. 3. In order to assure optimal conditions for achieving adequate bone mass by children with CMA, it is necessary to provide them with regular medical and nutritional care.     

Antigen absorption by the jejunal epithelium of children with cow's milk allergy

To establish if intestinal permeability to exogenous antigens is involved in cow's milk allergy (CMA) in infants, 33 children 1 to 24 months old (18 controls and 15 with CMA) were tested for intestinal permeability to the protein marker horseradish peroxidase (HRP). Jejunal biopsies were performed either during the initial period of diagnosis, at the mean (and SE) age of 3 +/- 1 months, and/or 1 yr later, at the age of 13 +/- 2 months, just before and after a milk challenge. A small fragment of the biopsy was studied for histology and the remainder was mounted in an Ussing chamber for simultaneous measurement of mucosal to serosal transport of HRP in its intact and degraded forms and electrical parameters including short-circuit current and conductance. No modification in HRP absorption was noted in control children aged from 2 months to 11 yr, indicating that gut closure probably occurred earlier in life. During the initial period of CMA, transepithelial HRP fluxes were significantly higher, about 8-fold, in children with CMA (intact HRP flux = 48.5 +/- 15.2, 95% confidence interval, 11.2 to 85.7 versus 5.9 +/- 1.2, 95% confidence interval 2.9 to 8.3, in control children). In addition, short-circuit current was increased but conductance was unchanged. After several months on a milk-free diet, HRP flux and short-circuit current returned to control values. Just after the milk challenge and independently of the clinical issue, a slight rise in HRP permeability was observed but it was not significant and remained within control values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cow's milk allergy in infants with atopic eczema is associated with aberrant production of interleukin-4 during oral cow's milk challenge

OBJECTIVES: A failure in the establishment and maintenance of oral tolerance in infancy may result in food allergy. To further assess the role of the intestinal immune system in cow's milk allergy (CMA), we investigated the systemic production of the pro-allergenic Th2 cytokine interleukin (IL)-4 and anti-allergenic cytokines IL-10, transforming growth factor (TGF)-beta1 and TGF-beta2 in infants suffering from atopic eczema with and without CMA during antigen elimination diet and oral antigen exposure. METHODS: 18 infants (mean age, 9.6 months; 95% confidence interval 8.1-11.1 months) with atopic eczema and CMA and 17 infants (mean age, 9.7 months; 95% confidence interval 8.6-10.9 months) with atopic eczema tolerant to milk as assessed by a double blind, placebo-controlled cow's milk challenge were investigated. Peripheral blood mononuclear cells were obtained during antigen elimination diet and during oral cow's milk challenge and stimulated with Concanavalin-A or cow's milk or were left unstimulated. The cytokine concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: During antigen elimination, the Concanavalin A-stimulated production of TGF-beta2 was significantly lower in infants with CMA as compared with infants without CMA: 129 pg/mL (interquartile ratio, 124-144 pg/mL) vs. 149 pg/mL (interquartile ratio, 133-169 pg/mL); P = 0.016. During oral antigen exposure, the immune responses in infants with CMA were characterized by significantly higher spontaneous production of IL-4 as compared with those without CMA: 12.0 pg/mL (interquartile ratio, 5.2-28.3 pg/mL) vs. 4.2 pg/mL (interquartile ratio, 1.5-7.6 pg/mL); P = 0.018. CONCLUSIONS: Infants with atopic eczema and CMA exhibit markedly increased systemic pro-allergenic IL-4 responses on intestinal antigen contact, which may partially be explained by a defective ability to launch anti-allergenic TGF-beta2 responses.     

Lessons from the clinical course of IgE-mediated cow milk allergy in Israel

Cow milk and milk products are the most common food products consumed in Israel; rates of allergy to cow milk exceed those of peanuts in infants and children. The aim of the present study was to evaluate retrospectively the clinical features and natural course of immunoglobulin (Ig) E-mediated cow milk allergy (CMA) in Israel. Data of children diagnosed with CMA from 1995 to 2003, were collected regarding age at first and most recent reactions, symptoms and signs, family history of atopy, other allergic diseases, emergency department visits, hospitalizations, and treatment. Patients with transient CMA were compared to those with persistent CMA (> or =3 yr old). The study group consisted of 105 patients, 43 with transient CMA (age range: 0.48-11 yr). The remaining 62 patients (age range: 3-16.5 yr) did not achieve tolerance to cow milk during the follow-up period. No differences were found between the groups in mean age and symptoms and signs at the first allergic reaction and family history of atopy. Patients with persistent CMA had a higher rate of asthma than patients with transient CMA (61.2% vs. 18.6%, p < 0.001). Fifty patients with persistent CMA had 137 subsequent allergic reactions after diagnosis, 25% of the reactions were due to oral milk challenge at the clinic and 75% due to accidental exposure, of which 13% required an emergency department visit and 8%, hospitalization. Only 19% of the reactions were treated with epinephrine injection. In conclusion, in our experience, less than half of the children diagnosed with IgE-mediated CMA during 9 yr, outgrew it. The patients with persistent CMA have a higher prevalence of asthma compared with the general population or to children with transient CMA. The high number of recurrent allergic reactions due to accidental exposure and the low rate of epinephrine usage in these patients point to a need for better education of patients and their families.     

Selectively high level of serum interleukin 5 in a newborn infant with cow's milk allergy

Cow's milk allergy (CMA) in the neonatal period is thought to include several clinical conditions, yet the pathophysiology remains unclear. We report here the case of a term newborn infant who showed hematochezia 36 hours after the first feeding with cow's milk formula. His serum immunoglobulin E levels were not elevated, although eosinophils were detected in the stool. Elimination of cow's milk formula resolved the symptoms, and from the clinical course and laboratory data the infant was diagnosed with CMA. The serum interleukin 5 (IL-5) (125 pg/mL) level in this patient was selectively elevated. However, serum levels of other T-helper 2 (Th2) cytokines (including IL-4 and IL-13), Th1 cytokines (including interferon γ), and proinflammatory cytokines (including tumor necrosis factor α) were not elevated. These findings suggest that, for this patient, IL-5 and eosinophils might have played a role in the development of neonatal CMA. Although this finding is reported from only 1 case, it highlights the need for serum IL-5 to be determined in more neonatal patients with CMA to further clarify the pathophysiology of this condition in the neonatal period.     

Immunologic disturbances in cow's milk allergy, 1: delayed maturation of suppressor activity

To assist in identifying pathogenetic mechanisms in different subtypes of cow's milk allergy (CMA), the function of immunoregulatory T-lymphocytes was studied. The study population consisted of 23 patients, mean [95% confidence interval] age of 25. 6 [19. 5, 33. 6] months, who had challenge-proven cow's milk allergy manifested with either skin (n=9) or gastrointestinal (n=14) symptoms; in addition, 13 age-matched disease controls were studied. Patients with challenge-proven CMA were rechallenged to establish whether they had acquired clinical tolerance to cow's milk. The suppressor activity of isolated lymphocytes was measured in vitro by a cell coculture at rechallenge and in 10/23 patients at diagnosis. At diagnosis, patients with CMA (n=10) showed a decreased mean [95% CI] suppressor activity, induced by either Concanavalin A, 7[-2, 15]%, or cow's milk, 3[-8, 14]% as compared with disease controls (n = 13), 19[15, 24]% and 24[17, 31]%; F = 7. 1, p = 0.004 and F = 6. 7, p = 0.005, respectively. At rechallenge the suppressor activity, induced both by Concanavalin A and cow's milk, reached the level of disease controls only in patients who had acquired clinical tolerance to cow's milk (n = 13/23), but not in those retaining CMA (n = 10/23). Our results indicate that the maturation of suppressor function is delayed in CMA, which might be of primary importance in the etiopathogenesis of CMA.     

Cow's milk allergy, incidence and pathogenetic role of early exposure to cow's milk formula

A study was performed in infants under the age of 12 months born during 1974 and admitted to St. G?ran's Children's Hospital with symptoms suggestive of cow's milk allergy (CMA). The aims of the study were to determine the role of early exposure to cow's milk formulas as a predisposing factor to CMA and to estimate the incidence of CMA in infancy. Twenty-five infants fulfilled the criteria for CMA. Available records were reviewed and a careful history was obtained from the mothers on two occasions. The patient group was compared with a control group. Sixteen of the 25 infants were exposed to cow's milk protein during their first week in the nursery for newborns, 6 were exposed before the end of the fourth week of life, and 3 infants were apparently not exposed. All infants were breast fed 3 to 26 weeks before re-exposure and occurrence of symptoms. Infants with CMA were given cow's milk formulas during their first 4 weeks of life significantly more often than infants in the control group (p less than 0.01). The incidence of CMA was approximately 1 : 200. The first 4 weeks after birth seem to be a particularly vulnerable period. Hence, in order to prevent CMA, infant formula should not be given--even occasionally--during this period.