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Neonatal Cow Milk Sensitization in 143 Case-Reports Role of Early Exposure to Cow's Milk Formula

Authored by  Arnaldo Cantani

Abstract

Objective: Cow's milk (CM) allergy (CMA) is a disease of infancy, usually appearing in the first months of life. Symptoms triggered by CM at first introduction are not completely defined. The evaluation of infants for possible CMA is one of the more common problems encountered by pediatricians. Purpose of this study was to investigate the prevalence of severe reaction to CM and clinical manifestation triggered by CM administration in the nurseries.

Materials and Methods: The series includes 143 prospectively studied CM-allergic babies.

Results: At the first introduction of CM, at the age of 1-8 months (median 4 months) all infants had immediate symptoms the babies were probably sensitized during the first days of life. Particularly sensitizing appears to be the exposure to CM formulas in the neonatal nursery.

Discussion: Little doses of allergens are more sensitizing than larger ones. We provide clear evidence of the immunological effects of oral antigen administration during the neonatal period, and discuss the possible critical allergen trans-mission to the nursing baby via breast milk (BM).

Keywords: Cow's milk allergy; Neonate; Neonatal nurseries; Severe reactions; CM sensitization; Breast milk

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Introduction

A major cause of sensitization to CM in genetically predisposed neonates is the (in) advertent administration of CM in neonatal nurseries. Neonatal care should include 49-100% of such infants given supplements of CM or hydrolysate formulas (HFs) during the first 3-4 days of life [1-5]. Among these babies CM allergy (CMA) was more frequent [6], until to 100% of infants, none of them had symptoms at the first CM administration [3]. Im-mediate reactions at the subsequent CM feeding bring into focus a delayed effect of the "hidden bottle" [2]. H0st et al [3] documented that the 40-860 ml of CM received from 39 neonates during the first three days contained 0, 4-7,4 g of fê-lactoglobulin (fêLG). Feeding half of babies with a CM formula and half with HFs for 1-4 days and then with BM, if necessary supplemented with HFs until the third month, total IgE titres were at the 5th day signific-antly related to the dose and frequency of supplements received (200-500ml) [7], maintaining significances until 12 months [8] especially in at-risk babies.

In at-risk children, prospectively followed-up from birth during 18 months [9] and re-evaluated at age 4-6 [10], the cumulative prevalence of atopy was 18% in CM-fed or 33% in wholly BM-fed babies, and in at-risk children the incidence was as high as 11 or 61%, respectively [9]. Newborns with 2742 week gestational age and 2 SDs (standard deviation) below the mean normal weight at birth correspond to prematures responding in a different manner to sensitization and onset of atopic manifestations. During the follow-up, the prevalence of atopy was nearly similar in both groups, yet skin prick tests (SPT) positive for CM significantly correlated with RAST only in CM-fed infants [10]. We have also studied four additional at risk infants who were exposed in the nursery to a first HF dose during their first days of life, and elicited acute allergic symptoms when fed again this HF at the end of an exclusive breastfeeding (data not shown).

Healthy newborns accidentally exposed to CM in a nursery develop a modest and transient antibody production (primary immune response). Such initial responses are self-limited and gradually resolve due to development of tolerance despite unremitting allergen exposures. At the second encounter, CD4 clones from non-atopic infants have a Th1 profile, whereas in atopic infants provide help for IgE synthesis (secondary immune response) [11]. Remarkably, there appears to be a consensus that BM-feeding for at least 4-6 months will delay, if not prevent allergy [12-48], although a case of apparent sensitization via BM has been reported [48].

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Materials and Methods

We have prospectively studied 143 CM-allergic babies, 79 males and 64 females aged 4-8 months (median 5 months) with IgE-mediated CMA, who attended between June 1997 and December 1999 the Allergy and Clinical Immunology Division of Rome University "La Sapienza". The diagnosis was based on SPTs, all positive to CM, and oral food challenges (OFCs) done in a hospital setting which were positive to CM in 74 babies, to egg in one baby, and to a HF in 50. In total, 125 out of 143 babies (87.4%) were positive to OFCs. Parents of each child gave details of their allergic disease (if any) and their informed consent. The babies were defined at risk of atopy when at least one parent had or had had diagnosed and treated atopic disease. Data were statistically analyzed using the Student t and the X2 tests.

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Results

At the first introduction of CM, at the age of 1-8 months (median 4 months) all infants had immediate symptoms, as follows: anaphylactic shock (9 cases), urticaria-angioedema (37 cases = 25.9%), skin rash (13 cases = 9.1%), diarrhea (25 cases = 17.5%), vomiting (19 cases = 13.3%), respiratory manifestations (wheezing or rhinitis) (18 cases = 12.6%), and worsening of atopic dermatitis (AD) (59 cases = 41.2%). Several children had more than one allergic manifestation. All children but twelve (82.8%) had positive family history for atopy (p = 0.0001). Only 10/143 infants (14.3%) were fed CM since birth; the other 133 were BM-fed for 3-8 months (median 4.5 months). Two children breastfed from birth were probably sensitized to CM proteins present in BM since their conditions improved when the nursing mothers followed dietetic restrictions. Analysing the clinical charts of the infants and interviewing the parents, we learned that 133 (93%) of the CM-allergic babies were fed a CM formula in the neonatal nursery in the first days of life. (p = 0.0001)

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Discussion

In this prospective study we learned that as many as 133 newborns were fed CM in the newborn nurseries, and this data tallies well with previously alluded to studies. As a result of OFCs, a larger proportion of babies (41.2%) had a worsening of AD symptoms, however it is remarkable that 12.6% presented with respiratory manifestations. As previously reported, there is a large consensus that BM-feeding for at least 4-6 months will delay, if not prevent allergy [12-48]. A note of caution is their unmatched results owing to methodological differences. Given that CM and egg allergens are present in BM, it was also thought that a maternal diet excluding the above allergens may be important in atopy prevention [13,34,42]. A typical case was reported by Lifschitz et al [48], an anaphylactic shock due to CM protein hypersensitivity in a newborn who was mistakenly fed BM that had been expressed before CM products were eliminated from his mother's diet, as it is correctly shown in the title [48]. More than 70 years ago Talbot documented that AD in a fully breast-fed infant could be related to chocolate ingested by the mother, and that AD cleared up when the nursing mother avoided the offending food [49], a phenomenon recently confirmed [3]

However, IgE-mediated sensitization through BM is rather rare: 0.042% [50] or 0, 28% [3]. Therefore, inadvertent exposure to CM appears to be far more important than the very low CM amounts transmitted via BM [51]. A note regarding a study based on HFs for allergy prevention [17]: the frequency of BM- feeding was high (98%), and in 232 not randomized such babies the incidence of CMA was 1.3%. The study is far more important because newborns who received a CM formula in the nursery were not included into the program [17]. We have stressed the negative effects of the maternity wards. To avoid the possible risks it should be clearly stated that giving any formula in the first few days of life is strictly forbidden unless prescribed by a pediatrician or de-manded by a mother who is unwilling or incapable to breastfeed her baby [41].

A new front was unexpectedly opened up by the significant report that a 22- week-old fetus responds to a great variety of oral and inhalant allergens including CM ßLG, and egg ovalbumin [52]. That is why reducing intake of highly allergenic foods in the last trimester has not been found to be worthwhile in atopy prevention in at-risk babies [51,53-55]. In conclusion, as early as in 1935 Ratner [56] recommended that isolated CM feedings to BM-fed infants should be avoided during the newborn period.

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Old Wine in New Bottles: Drug Repurposing

Authored by  Shahper N Khan*

Editorial

Above 90% of lead molecules first tested in phase I studies often fails to reach the market. Many thousands of compounds do not even complete clinical trials, which further add to the cost burden to new drug discovery projects. Faced with scientific and economical challenges the possibility of finding new indications of existing drugs is an attractive proposition. Hence, recently the field of drug repurposing or repositioning has fuelled extensive research in academic as well as industrial sector [1-3].

Previously, it was a serendipitous process wherein chance observations suggest new indications for an approved drug or drug candidate. In recent years, molecules rejected in drug company pipelines due to lack of efficacy or unwanted toxicity have received adequate endorsement for repurposing. Such compounds could be exceptional assets as they already have detailed safety and activity profiles. Indeed, repurposed drugs can be approved faster with as little as ~60% the cost and with three times lower attrition rates than a drug from a traditional drug discovery approaches [4]. Though it can be questioned as not to depict an absolute innovation, like the discovery of some novel molecular target would have represent. Nevertheless, these new indications from available drugs will pace our progress toward achieving the cure for a disease at much faster rate.

However, the low available data on mechanistic action of traditional drug-repositioning methods makes it difficult to reach unmet medical goals by successfully repositioning a huge number of existing drugs. In recent years, the frequency of drug- repositioning methods and its acceptance has dramatically increased. It is essential to better understand these existing methods and prioritize them based on specific studies [51]. Application of an efficient drug-repositioning pipeline to a specific study needs identification of feasible methods based on available information of the drugs or diseases of interest.

Among the various popular approaches evolved computational drug repurposing is far more efficient. These methods focus on various orientations, predicted by available data and reported mechanisms either on drug, disease pathology or treatment outcomes. These in silico drug-repositioning methods enable researchers to examine nearly all drug candidates and test on a relatively large number of diseases within drastically shortened time lines. They can be classified as target-based, knowledge-based, signature-based and network-based and can be chosen as per the need of the study [6]. Whereas most of the abovementioned computational drug repurposing methods rely on different types of structured data sets, Persidis et al. [7] showed the significance of literature mining and its use in extracting applicable data from freely available texts [7]. Such data can subsequently be mined and visualized for identifying novel indications for existing drugs. In a comprehensive review by Hong et al. [8] prospects of drug repositioning employing network pharmacology are well discussed [8]. Wherein they focused on drug off-targets discovery and relationship between drug targets and disease-associated proteins.

Besides implementing the right strategy for successful drug repositioning, it is also very important to know which drug or drug target needs to be focused. With a medicine like aspirin, it is easy to see why we are mostly not interested in researching a new therapeutic property unless it can be used as leverage for the consumers to choose it over the existing brand. And many would reconsider the ethics of doing so, as why to bring an expensive repositioned product, when an affordable option exists.

Future emphasis need to be made that drug repositioning studies have to be solidly grounded on science to get a successful end result. Furthermore, the field needs better development of more in-depth mechanistic approaches that can easily be translated into drug repositioning pipelines that integrate computational and experimental methods seamlessly to ensure high success rates of repositioned drugs.

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Pigments of Pseudomonas aeruginosa

Authored by  Chateen I Ali Pambuk*

Editorial

Pseudomonas aeruginosa is an opportunistic pathogen that causes extensive morbidity and mortality in individuals who are immunocompromised or have underlying medical conditions such as, urinary tract, respiratory tract and skin infections and primarily causes of nosocomial infections [1]. It’s a non sporulating, gram negative, oxidase positive motile bacterium with apolar flagellum [2], P. aeruginosa is a common nosocomial pathogen because it is capable of thriving in awide variety of environmental niches [3]. It is a leading cause of hospital associated infections in the seriously ill, and the primary agent of chronic lung infections in cystic fibrosis patients [4]. They exist in very large numbers in the human environment and animal gut, they are capable of inhabiting/contaminating water, moist surface and sewage, hospital environment usually have resident P. aeruginosa [5].

Despite the apparent ubiquity of P aeruginosa in the natural environment and the vast array of potential virulence factors, the incidence of community-acquired infections in healthy subjects is relatively low. However, in the hospital environment, particularly in immunosuppressed, debilitated and burns patients, the incidence of P. aeruginosa infection is high [6]. It produces many numbers of extracellular toxins, which include phytotoxic factor, pigments, hydrocyanic acid, proteolytic enzymes, phospholipase enterotoxin, exotoxin and slim [1].

P. aeruginosa grows well on media and most strains elaborate the blue phenazine pigment pyocyanin and fluorescein(yellow), which together impart the characteristic blue-green coloration to agar cultures [5]. Pyocyanin is a blue redox-active secondary metabolite [7], which induces rapid apoptosis of human neutrophils, with a10 fold acceleration of constitutive neutrophil apoptosis in vitro but no apoptosis of epithelial cell or macrophages [8]. The redox active exotoxin pyocyanin is produced in the concentration up to 100mol/l during the infection of CF patient and other bronchiectatic airways. The contributions of pyocyanin during infection of bronchiectatic airways are not appreciated [9]. Notably pyocyanin mediated ROS inhibit catalase activity, deplete cellular antioxidant reduced glutathione and increased the oxidized reduced glutathione in the bronchiolar epithelial cell [10,11]. Excessive and continuous producing of ROS and inhibit of antioxidant mechanisims overwhelm the antioxidant capacity, leading to tissue damage, also pyocyanin inhibit ciliary beating of the airway epithelial cell [12]. Pyocyanin. Also increases apoptosis and inactivates 1-protease inhibitor. reducing agents such as GSH and NADPH can reduce pyocyanin to pyocyanin radical, which then mono-or divalently reduce O2 to form superoxide anion O2- or H2O2 [13].

Pyoverdin per contra is the main siderophore in iron gathering capacity its function as a powerful iron chelator, solubilizing and transporting iron through the bacterial membrane via specific receptor proteins at the level of outer membranes. Pyoverdin is important because it has a high affinity for iron, with an affinity constant of 10(32) [14]. Moreover, has been shown to remove iron from transferrin in serum, probably assisting growth within, and ultimate colonization of the human host by P. aeruginosa [15]. Moreover experiments studying the burned models of P. aeruginosa infections have shown that ferric-pyoverdine is reuired infection and /or colonization, underlining the importance of ferric-pyoverdin to virulence of P.aeruginosa [14].

Pyomelanin, a dark brown/black pigment, is a potential target for anti-virulence compounds which is a negatively charged extracellular pigment of high molecular weight, derived from the tyrosine catabolism pathway [16]. Pyomelanin production has been reported in P. aeruginosa isolates from urinary tract infections and chronically infected Cystic Fibrosis (CF) patients [17]. Pyomelanin is one of the many forms of melanin that is produced by a wide variety of organisms. Production of pyomelanin is reported to provide a survival advantage, scavenge free radicals, bind various drugs, give resistance to light and reactive oxygen species, and is involved in iron reduction and acquisition, and extracellular electron transfer [18]. Non-pyomelanogenic strains of Burkholderiacepacia are more sensitive to externally generated oxidative stress and show reduced survival in phagocytic cells [19]. In P. aeruginosa, pyomelanin production results in increased persistence and virulence in mouse infection models.

P aeruginosa it is highly resist to antibiotics this resistance can be conferred by the outer membrane which provides an effective intrinsic barrier in the cell wall (or) cytoplasmic membrane (or) within the cytoplasm and modifications in outer membrane permeability via alternations in porin protein channel represent a component of many resistance mechanisms. In addition in activating enzymes released from the inner membrane can function more efficiently within the confines of the periplasmic space, the mechanisms by which intracellular concentrations of drugs are limited include decreased permeability through the outer membrane and active efflux back out across the cytoplasmic membrane [20]. The production of B-lactamase is the most prevalent mechanisms of resistance to B-lactam antibiotics, the B-lactamase have been reported to hydrolyze all anti pseudomonal agents. Moreover, P. aeruginosa cell particularly in patients with chronic infections can develop a biofilm, In which bacterial cells are enmeshed into a mucoi dexo polysaccharide becoming more resistant to beta-lactams as well as decrease the outer membrane permeability that enable bacteria to gain resistance development [21].

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