Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation.

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients.

Rituximab off-label use includes organ transplantation. We review the occurrence of infectious disease and its outcome after rituximab therapy. Between April 2004 and August 2008, 77 kidney-transplant patients received rituximab therapy [2-8 courses (median 4) of 375 mg/m2 each] for various reasons. Their results were compared with a control group (n=902) who had received no rituximab. After a median follow-up of 16.5 (1-55) months for rituximab patients and 60.9 (1.25-142.7) months for control patients, the incidence of infectious disease was 45.45% and 53.9% (ns), respectively. The incidence of bacterial infection was similar between the two groups, whereas the viral-infection rate was significantly lower, and the rate of fungal infection was significantly higher in the rituximab group. Nine out of 77 patients (11.68%) died after rituximab therapy, of which seven deaths (9.09%) were related to an infectious disease, compared to 1.55% in the controls (p=0.0007). In the whole population, the independent predictive factors for infection-induced death were the combined use of rituximab and antithymocyte-globulin given for induction or anti-rejection therapy, recipient age, and bacterial and fungal infections. After kidney transplantation, the use of rituximab is associated with a high risk of infectious disease and death related to infectious disease.

HLA class I antibodies provoke graft arteriosclerosis in human arteries transplanted into SCID/beige mice.

Antibodies toward HLA class I and/or MICA are commonly observed in transplanted patients suffering from allograft arteriosclerosis, also called chronic vascular rejection (CVR). The relative importance of cellular versus humoral alloreactivity for CVR is still disputed. We demonstrate that antibodies toward HLA class I provoke lesions typical for CVR in human arteries in vivo in the absence of cellular immunity. To show this, we grafted segments of human mesenteric arteries from 8 deceased organ donors into 36 immunodeficient SCID/beige mice in the infrarenal aortic position. Three mice died postoperatively. The remaining 33 mice received weekly i.v. injections of either a monoclonal antibody toward HLA class I, toward MICA or an irrelevant monoclonal antibody. At sacrifice after 6 weeks, mice receiving the HLA antibody showed a significant neointimal thickening in the grafted artery due to smooth muscle cell (SMC) proliferation while control mice receiving anti-MICA or irrelevant antibody showed little or no thickening. Whereas antibodies toward HLA class I were mitogenic to SMC in vitro, those directed toward MICA did not have any effect. Humoral alloreactivity toward HLA may thus play a causal role for the development of CVR and this opens new possibilities for the treatment of CVR.

Long-term evolution of lymphocytes subsets after induction therapy based on continuous versus discontinuous administration of anti-thymocyte globulins in renal-transplant patients.

UNLABELLED: The aim of our retrospective study was to assess the long-term evolution of lymphocyte subsets after two modes of administration of anti-thymocyte globulin (ATG) after renal transplantation. METHODS: Before 1993, patients (group I, n = 93) received fixed doses of RATG (1 mg/kg per day) for 8 consecutive days. Thereafter, RATG was either continued at the same dose for 15 days, in cases of delayed graft function, or was infused every other day at the same dose until the serum creatinine level became <150 micromol/L. After 1993, patients (group II, n = 66) received RATG at full dose (1 mg/kg per day) during the first 3 days and, thereafter, doses were adapted to target a CD2 T-cell count <50/mm3. RATG cumulative dose was significantly higher among group I than group II (9.7 +/- 4.5 versus 7.4 +/- 3.2 mg/kg, P = .0002). RESULTS: In both groups, total lymphocyte and T lymphocyte subset (CD4, CD8, CD2, CD3) counts decreased significantly during the first month after transplantation, increasing slowly between the first month and the third year posttransplantation. Thereafter it rose rapidly, which was greater in group II. At last follow up, total lymphocyte, T lymphocyte subsets and NK cell counts were similar to those observed before transplantation. At all monitoring times, T lymphocyte, B lymphocyte, and NK cell counts were similar in both group, except for the total lymphocyte count at 6 months and CD4 T lymphocyte count at 1 year, which were significantly higher in group II compared to group I. CONCLUSION: Induction therapy based on continuous or discontinuous administration of ATG is associated with profound depletion of T, B, and NK cells during the first 3 years, followed by a progressive reconstitution of the lymphocyte pool after 5 years.

A third renal transplantation: is it relevant and is it worth it?

INTRODUCTION: The aim of this retrospective study was to determine the outcome of third cadaveric renal transplantations performed between 1989 and 2004 among a cohort of 35 patients whose immunosuppression included induction therapy and calcineurin inhibitors. Most patients were highly sensitized with 1 (0-4) HLA (classes I + II) incompatibility between donor and recipient. RESULTS: The median follow-up time was 57 months (range, 1-190). Fourteen patients experienced delayed graft function that required posttransplantation hemodialysis. The current patient and graft survival rates were 91.4% and 82.8%, respectively. At last follow-up, 6 grafts had been lost: 1 due to primary nonfunction; 1 due to an urinary leak (day 45); 2 deaths with functioning grafts; and 2 chronic allograft nephropathies (CAN) at 85 and 60 months posttransplantation, respectively. Among the 10 patients who experienced acute rejection episodes, half were steroid-sensitive, whereas the others required OKT3 therapy. Overall, when excluding the 2 patients who presented with early loss of their grafts, 13 of 33 patients (39.4%) developed CAN, which led to the graft loss in only 2 cases. The mean creatinine clearance was 57 +/- 23 mL/min at year 5. Of the 35 recipients, 12 (34.3%) developed graft/perigraft complications, among whom 10 (83.3%) required treatment. The most frequent complication was lymphocele (M = 4; 11.4%) or infections that led to rehospitalization (n = 17). CONCLUSION: Results from third transplantations were encouraging. Thus, despite the organ shortage, a third graft was worth it!

Use of bed rest and head-down tilt to simulate spaceflight-induce immune system changes.

Bed rest, both with and without head-down tilt, has been extensively used as an earth-bound analog to study physiologic effects mimicking those occurring in weightlessness during spaceflight. We have been able to show in six subjects that 4 weeks of head-down tilt bed rest induces a significant decrease in interleukin-2 secretion by PHA-stimulated T lymphocytes. Another study, lasting 113 days, with two subjects showed a decreased interleukin-2 receptor expression in PHA-stimulated peripheral blood mononuclear cells but a decreased interleukin-2 production in one subject only. Under the same conditions, interleukin-1 production was largely increased in both subjects. Several other immune parameters were also analyzed. Increased interleukin-1 production could contribute to bone mineral loss encountered during bed rest and decreased interleukin-2 secretion could play a role in the appearance of infectious diseases often observed during bed red.

Comparison of progressive antithrombin activity and the concentration of three thrombin inhibitors in nephrotic syndrome.

In order to compare the plasmatic progressive antithrombin activity to the concentration of three thrombin inhibitors, antithrombin III (AT III), alpha 2 macroglobulin (alpha 2 M), alpha 1 anti-trypsin (alpha 1, AT) in nephrotic syndrome, a prospective study was carried out on a group of 28 children affected with the disease. A dramatic reduction of the level of AT III and of alpha 1 AT, two inhibitors of molecular weight close to that of albumin, was observed. The decreased level of AT III was counterbalanced by an increase in alpha 2 M. This phenomenon accounts for the increased progressive antithrombin activity observed in all the affected children. It is suggested that the above compensatory mechanism explains the absence of thrombotic accidents in this series and that the benefit of heparin therapy is doubtful in these conditions.

Study of the association between major histocompatibility complex class II genes and the response to interferon alpha in patients with chronic hepatitis C infection.

OBJECTIVE: The aim of the study was to determine the influence of HLA class II genes on the response to interferon-alpha (IFN-alpha) in patients with chronic hepatitis C. METHODS: The distribution of HLA DRB1 and DQB1 alleles was assessed in 170 caucasoïd patients treated with IFN-alpha for chronic hepatitis C. 50 patients had a long term sustained response to treatment whereas 120 patients were nonresponders. RESULTS: Female sex, non-1 HCV genotype particularly genotype 2 and pretreatment low serum HCV RNA level were associated with long-term sustained response to IFN-alpha. A trend towards a higher prevalence of DRB1*07 allele in non responders than in patients with sustained response (45% vs. 28%, odds ratio 2.1; P < 0.05) on the one hand and of DQB1*06 allele in HCV genotype 1 patients with sustained response than in HCV genotype 1 nonresponders (75% vs 27.3%, odds ration 7.9; P < 0.02) on the other hand, were observed. However, none of these two differences remained significant after Bonferroni's correction. CONCLUSION: Accordingly, we conclude that the response to IFN-alpha therapy is more tightly related to virus factors than to host's HLA class II genes.

A new rejection criteria in the heterotopically placed rat heart by non-invasive measurement of Dp/Dtmax.

BACKGROUND: The heterotopic heart of rats has been a useful model in the evaluation of immunomodulatory protocols. Graft palpation usually determines the day of rejection. We present in this paper an original method of graft monitoring in allograft rejection. METHODS: Heterotopic cardiac abdominal transplantation was performed in Lewis isografts (n = 15) and in ACI to Lewis allograft (n = 15). A balloon connected to a measurement device was inserted in the left ventricle, and calculation of Dp/Dtmax was possible by recording the intra-left ventricular pressure. A ten-day follow-up was achieved with a daily comparison of palaption, ECG, and Dp/Dtmax. RESULTS: In transplanted hearts, Dp/Dtmax did not change in isografts but significantly decreased in allograft on posttransplantation Day 5 (PTD 5) vs PTD 0.1 and 3 (p < .01). Dp/Dtmax values on PTD 5 and 6 were also statistically significant in allograft vs isograft group (p < .01). Histological analysis at this time showed the occurrence of acute rejection in the allograft group. Graft palpation, and ECG remained normal until PTD 10 and no difference was observed between iso and allo groups. CONCLUSION: This study shows that daily measurement of Dp/Dtmax in heterotopic heart is made possible by our implantable system without interrupting the graft, and gives a more accurate definition of graft rejection than a combination of palpation and ECG. In addition, this method would seem desirable when differences in survival may be expected to be of lesser magnitude.

Intrathecal grafting of unencapsulated adrenal medullary tissue can bring CD4 T lymphocytes into CSF: a potentially deleterious event for the graft.

Adrenal medullary tissue including chromaffin cells was grafted intrathecally in cancer patients to relieve intractable pain. The central nervous system (CNS) is considered an immune privileged site. Therefore, non-HLA-matched and unencapsulated tissue was grafted in 15 patients and 1 sham control in a series of at least 20 grafts. We observed an increase in CSF lymphocyte counts in 15/20 allografts (75%). In contrast to peripheral blood, CD4 T cells predominated in the CSF, but failed to exhibit an activated phenotype (CD25+ CD45RO+ HLA-DR+). The positive effect of graft on pain, the high met-enkephalin levels, the absence of any increase in CSF cytokine levels particularly for IFN-gamma or IL-2 (but not IL-10 and IL-6), indirectly indicated that the graft was tolerated despite the presence of CSF lymphocytes. The single treatment failure and three of four cases of partial efficacy occurred in grafts where CSF lymphocytes were present. Moreover, when assayed (n = 7), the CD4+ CSF lymphocytes still retained the capacity to exhibit ex vivo a normal or enhanced frequency of T CD4 cells producing IFN-gamma and IL-2. Taken together, our observations indicate that impairment of the local immunosuppressive balance can lead to activation of those CSF CD4 T cells and drive a rejection process. This study suggests further work on the purification and/or the immunoisolation of tissues grafted in the CNS will be necessary, particularly when the possibility of long-term and repeated grafting is considered.

Delayed hypersensitivity to human encephalitogenic protein as assayed by agarose leucocyte migration in multiple sclerosis patients.

Using a leucocyte migration test (Clausen's direct agarose gel migration method) hypersensitivity to human encephalitogenic protein has been examined in 50 multiple sclerosis patients (group 1), 50 healthy persons (group 2) and 25 patients with other neurological diseases (group 3). In group 1, 30 MS patients (60%) show an abnormal migration index, manifested either as inhibition or stimulation of migration; 29 controls in group 2 (58%), 11 O.N.D. patients in group 3 (44%) show an abnormal migration index. These results mean that lymphocyte hypersensitivity to myelin basic protein appears neither to be constant nor specific to multiple sclerosis. Three migration index curve types at different antigen concentration are obtained: monophasic curves within the normal index zones; monophasic curves staying in the inhibition or stimulation zone and biphasic curves with dose-effect relationship. Whatever the antigen used, this dose-effect relationship implies that the test must be carried out at different concentrations. The meaning of spontaneous sensitisation in healthy controls is discussed.

Value of investigation in the diagnosis of allergic fungal rhinosinusitis: results of a prospective study.

The authors report a prospective study in which the aim was to analyse the usefulness of different criteria in optimizing the diagnosis of allergic fungal rhinosinusitis. From 1995 to 1998, 165 patients were operated on for chronic rhinosinusitis. Investigations used in this study for the diagnosis of allergic Aspergillus rhinosinusitis consisted of an analysis of clinical, radiological, immuno-allergic criteria. Fourteen patients presented with allergic Aspergillus rhinosinusitis. One hundred and fifty-one patients did not present any of the necessary criteria for the diagnosis of allergic Aspergillus rhinosinusitis. The results show that the characteristic macroscopic appearance, the maxillary sinus localization, and the presence of positive specific IgE to Aspergillus fumigatus are arguments that reinforce the diagnostic certitude of allergic fungal sinusitis. No specific clinical or radiological criteria orients a diagnosis of chronic rhinosinusitis toward that of allergic fungal rhinosinusitis. The other immuno-allergic tests do not contribute to the diagnosis of allergic fungal rhinosinusitis. pathological, mycological, and

[Analysis of the cerebrospinal fluid by isoelectrofocusing on agarose in multiple sclerosis]. / Analyse du LCR par isoélectrofocalisation en agarose dans la sclérose en plaques.

Intrathecal synthesis of immunoglobulins can be proved by means of two methods: quantitatively by immunoglobulins titration in CSF, the results expressed with several ratios; qualitatively by demonstration of oligoclonal distribution of gammaglobulins. IEF is the most sensitive of the qualitative methods. From a technical point of view Agarose Isoelectrofocusing seems to be a better method than polyacrylamide isoelectrofocusing and permits, when the interpretation is difficult, immunofixation into the gel. The authors report the results of a comparative study between the evaluation of the IgG Index and agarose isoelectrofocusing of 281 CSF divided into 113 CSF from patients with Multiple Sclerosis (MS) and 168 CSF from patients with other neurological diseases (OND). Sensitivity of IEF was higher than IgG index to prove intrathecal IgG synthesis: in the group of patients with MS, 91 p. 100 of CSF were abnormal instead of 72 p. 100 of IgG Index. In the group of patients with OND, abnormalities in IEF were low (5 p. 100) but the number of inflammatory diseases was poor. These results were similar with the findings of many authors using the same methods. In our opinion, IEF is the best technique which a specialized laboratory can use in routine to prove an immunoglobulin intrathecal synthesis.

[Immunogenetic markers (BF, C2, C4, 21-OH, TNF alpha, TCR beta, Ig) and insulin-dependent diabetes in the Tunisian population: serological and molecular study]. / Marqueurs immuno-génétiques (BF, C2, C4, 21-OH, TNF alpha, TCR beta, Ig) et diabète insulino-dépendant dans une population tunisienne: études sérologique et moléculaire.

48 Tunisian people suffering from the IDDM auto-immune disease were compared to 35 control healthy persons for the polymorphisms of the complement BF, C2 and C4 proteins and genes, of the IgG (Gm allotypes) as well as of the TNF alpha and TCR C beta genes. Our study shows that the BFF1-C4A3-C4BQO and BFS-C4AQ0-C4B1 complotypes are associated to IDDM (RR of 2.97 and 3.07 respectively), as previously reported for other circummediterranean populations. The frequency of the Gm 21.28; 1.17; .. haplotype is increased, but not significantly, among the patients. The RFLP analysis reveals that the 2.65 kb SacI allelic restriction fragment of the C2 gene may be considered as a genetic marker of susceptibility to IDDM because its frequency raises to 0.206 among the patients vs 0.021 in the healthy individuals (p less than 0.001). The frequencies of the C4AQ0 and C4BQ0 alleles are more important among the IDDM patients than within the control sample, but the only C4BQ0 allele frequency is significantly increased. Both C4AQ0 and C4BQO result mainly from deletions. The frequencies of the allelic restriction fragments of the TNF alpha and TCRC beta genes are not significantly different among the patients and the controls. But the small sample size don't allow us to conclude definitively. It would be very interesting to extend the RFLP analysis to the TCR V beta and V alpha gene regions on more numerous samples.

[Allergy to hymenoptera venoms in children]. / Allergie aux venins d'hyménoptères chez l'enfant.

Incidence of hymenoptera venom allergy in children is about 0.4 to 0.8%. Clinical features usually range from urticaria to anaphylaxis. Fatal reactions can occur but with less frequency than in adults. Allergologic investigations must be performed in children with systemic or generalized reactions after hymenoptera stings, which may lead to venom immunotherapy. Venom immunotherapy is well reported, but protocols differ according to the authors: ultra-rush in 3 h, accelerated in 3 to 5 days and semi-rush in 2 to 8 weeks. Results are always excellent (90 to 100%). We report our experience with 91 children receiving venom immunotherapy. Clinical history and positivity of skin tests indicated immunotherapy. Clinical symptoms were anaphylaxis (15.3%), serious reaction (37.3%) strong reaction (34%), and mild reaction (7.6%). Changes in immunological parameters revealed wide individual variations, not differing from data in the literature, with no correlation with evolution of immunotherapy. Venom immunotherapy appeared with good tolerability in children, whatever the protocol used.

[Association between the A2 allele of the HLA system and age at onset of Alzheimer's disease]. / Association entre allèle A2 du système HLA et âge de début de la maladie d'Alzheimer.

OBJECTIVE: Alzheimer is a multifactor disease occurring in a sensitive genetic territory. The e4 allele of the apolipoprotein E (APO E) is a recognised factor of risk. Some studies have suggested an association between the A2 allele of the HLA system and an earlier onset of the disease notably when it appears before the age of 64 or after the age of 75. The aim of our study was to explore this hypothesis in an independent sample of patients. METHODS: We compared the influence of the A2 allele of the HLA system on the age at onset of the disease in two groups of Caucasian patients presenting with Alzheimer's disease: early onset if the disease appeared before the age of 60 (n= 31) and late onset if it had appeared after the age of 75 (n= 44). The influence of the e4 allele of APO E was also taken into account. RESULTS: The comparison of the patients depending on the presence or not of at least one HLA-A2 allele revealed no significant difference, whatever the group of patients studied, in the age at onset of the disease. CONCLUSION: The age at onset of Alzheimer's disease was not influenced in our study by the presence of the HLA-A2 allele.

[Study of CD45 isoforms on T CD8 lymphocytes, in the peripheral blood and the graft in patients after kidney transplantation]. / Etude chez le transplanté rénal des isoformes du CD45 sur les lymphocytes T CD8, dans le sang circulant et dans le greffon.

We report characterization of CD45 isoforms expressed by CD8+ lymphocytes in peripheral blood and in the graft of 40 kidney transplanted patients who underwent kidney biopsy on the basis of clinical signs suggesting rejection. Standard histological examination of the biopsy fragments and three-color cytofluorimetric analysis of lymphocytes extracted from the same fragments by mechanical and enzymatic treatment were performed simultaneously and compared to the peripheral blood lymphocytes. In 14/40 biopsies where lymphocyte extraction succeeded, the predominant subset was CD8 (CD4/CD8 mean ratio was 0.53). Almost all CD8+ cells were activated: among these CD8+ cells, 55 percent were HLA-DR+, and 68 percent CD45RO+, i.e. of a memory cell type with cytotoxic activity. This situation resembles the in vitro observation made during mitogenic stimulation of lymphocytes by phytohemagglutinin, OKT3 or CML ("culture mixte lymphocytaire"). Beside their evident interest for the diagnosis, these data could be useful for our understanding of the physiopathology of the rejection crisis.

[Quantitative determination of FTA abs IgM in different stages of syphilis before and after treatment]. / Apport du FTA abs IgM uantitatif aux différents stades de la syphilis avant et après traitement.

The titres of treponemal specific IgM and IgG antibodies were determined by monospecific immunofluorescence (FTA abs IgM/IgG) on 191 sera from 107 patients with treated or untreated syphilis, at various stages and from 10 neonates born from seropositive mothers. IgM antitreponemal antibody was found in all cases of untreated syphilis but two neurosyphilis. After treatment the antibody usually disappeared within one year. However it persisted in three patients treated two years ago or more. When sera from these patients were fractionated by density gradient ultracentrifugation and examined for antitreponemal antibodies of the IgM classe (FTA abs IgM 19S) they never showed detectable concentrations of IgM. False reactive results as false non reactivity due to competitive inhibition, observed with FTA abs IgM can be eliminated after separation of immunoglobulins.

[Does allergic fungal sinusitis exist? Preliminary results of a prospective study]. / La sinusite aspergillaire allergique existe-t-elle? Résultats préliminaires d'une étude prospective.

Allergic aspergillar sinusitis is a very controversial clinical feature. We present results of a prospective study aimed at evaluating the reality of allergic aspergillar sinusitis in a nosologic and clinical point of vue. During a 5 months period, 31 patients underwent surgery: 21 sino-nasal polyposis, 5 chronic sinusitis without polyposis, 5 chronic sinusitis with radiologic images evocative of mycosis. The study was carried out using clinical criteria (per-operative discovery of glue-like, thickened and viscous aspect of the secretions), pathologic criteria (the presence of elements consitutive of allergic mucin), mycological criteria (direct examination and culture), and immunoallergic criteria (specific IgE for Aspergillus fumigatus, serology for Aspergillus fumigatus and Aspergillus flavus (IgM, IgG), skin tests for Aspergillus fumigatus). In three cases we suspect an allergic aspergillar sinusitis (one patient presenting a bilateral chronic sinusitis and two patients presenting a sinonasal polyposis). In two patients presenting a sinonasal polyposis, a allergic fungal sinusitis was suspected, fungal identification was not possible.

Use of prick-tests in the screening of immediate allergy to protein: 16 cases.

BACKGROUND: Allergy to protein hydrolysates seem to be on the rise but screening is difficult because of the wide range of symptoms. The goal of our study was to improve the screening process by skin prick testing infants with an anaphylactic form of allergy to cow's milk. METHODS: We studied 92 infants who were allergic to cow's milk. The diagnosis was based on the results of skin prick tests, specific IgE assays, and oral food challenges. The skin prick tests were performed using a number of protein hydrolysate formulae and a synthetic amino acid-based formula available in France. RESULTS: We detected sensitisation to the hydrolysates in 16 infants (17.3%), 15 by positive skin prick tests and one due to persistent symptoms on protein hydrolysate formulae (gastrointestinal manifestations, atopic dermatitis, and multiple food allergies), which completely receded when the synthetic amino acid formula was used as a substitute. Two infants had a positive hydrolysate oral food challenge test. There were no statistically significant differences in terms of age, sex, breastfeeding, clinical manifestations, family history, skin reaction size, or associated allergies. The infants who were sensitised to the hydrolysates had significantly higher specific IgE levels (whole milk,(_)-lactalbumin, and casein; median = 25.6 kU/L for cow's milk, p = 0.03) than those who were allergic to cow's milk but not sensitised to the hydrolysates. CONCLUSIONS: Skin prick tests can be used to screen for sensitisation to hydrolysates in infants with IgE-mediated cow's milk allergy. They can also be used to determine the most suitable hydrolysate formula for individual infants.