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Hypoproteinemia in severe childhood atopic dermatitis: A serious complication
Pediatric Allergy and Immunology
Abstract
As a complication of atopic dermatitis (AD), the incidence of hypoproteinemia is increasing among infants with severe AD in Japan. It can be a life-threatening condition owing to hypovolemic shock as a result of hypoproteinemia and vascular infarction as a result of thrombocythemia. However, the pathophysiology of this condition remains unclear. The objectives of the present study were two-fold. The first objective was to determine the main route of protein loss, i.e. through the damaged skin or the gastrointestinal tract, or as a result of insufficient food intake. The second objective was to identify whether allergy or infection was the cause of severe skin inflammation. Fifteen patients with AD were enrolled who had serum protein levels of 3.2-5.8 g/dl. Specific immunoglobulin E (IgE) and skin test to allergens, stool eosinophils, alpha1-antitrypsin clearance, skin Staphylococcus aureus colonization and superantigens (SAgs) produced by the organism, serum SAg-specific IgE antibodies, serum interleukin (IL)-5, IL-6, IL-12, and interferon-gamma (IFN-gamma) were evaluated. Prominent serous skin discharge was seen in all of the patients and was found to have almost the same protein concentration as serum. Marked thrombocytosis, with a maximum of 1,060 x 103/ml, was seen. Skin culture revealed S. aureus colonization in all patients. SAg-producing S. aureus were found in 84.6% of the patients. The concentration of serum IL-5 was significantly increased and correlated well with the blood eosinophil count. Hence, the main route of protein loss was believed to be through damaged skin. The cause of severe inflammation was thought to be a combination of allergic inflammation and skin colonization by SAg-producing S. aureus. Serum cytokines showed a T helper 2 (Th2) T-cell-mediated pattern. To prevent hypovolemic shock, vascular occlusion, and growth retardation, it is of vital importance to diagnose hypoproteinemia at an early stage and start appropriate therapy.
... In severe cases, exudate from wet lesions can be voluminous . A few reports have described cases of atopic dermatitis associated with electrolyte abnormalities and/or hypoproteinemia23456789 and discussed its cause. We encountered an infant with severe atopic dermatitis and growth failure. ...
... Simultaneously, electrolytes abnormalities, hypoproteinemia, hypogammaglobulinemia and hyperaldosteronemia, were all improved, indicating that the voluminous exudation from the skin lesions was the underlying cause of the patient's abnormalities. Nomura et al. [8] analyzed 15 pediatric patients with atopic dermatitis who had serum protein levels of 3.2-5.8 g/dl and reported that their skin discharges contained almost the same protein concentration as serum. ...
... Occasionally, cases have been reported in which use of steroids was denied for their adverse effects, and skin lesions were not improved, leading to complications such as electrolyte abnormalities and hypoproteinemia [3, 5]. Nomura et al. [8] discussed that improvement of skin lesions is important in the treatment of severe complications of atopic dermatitis, such as hypoproteinemia and electrolyte abnormalities. In order to avoid these complications, we also stress the importance of intensive treatment of atopic dermatitis. ...
The present case is a 5-month-old female with atopic dermatitis who was brought to hospital for growth failure noted upon regular health examination. Laboratory examinations revealed hyponatremia, hyperkalemia, hypoproteinemia, hypogammaglobulinemia, elevated plasma renin activity and hyperaldosteronemia. Immune function was normal. Composition of the exudate collected from the skin lesions of atopic dermatitis was similar to that of plasma. Application of a steroid ointment improved the lesions as well as all laboratory values. These findings indicate that voluminous exudation caused by extensive atopic dermatitis can lead to hypotonic dehydration, electrolyte abnormalities, hypoproteinemia, hypogammaglobulinemia and, finally, to growth failure in infants. We conclude that intensive treatment is important for severe atopic dermatitis in infants to prevent serious complications.
... AD is a chronic inflammatory skin disease common in children, which affects 5-20% children worldwide (1). Generally, it is accepted that AD is not a life-threatening disease, but in children it can be accompanied with serious, life-threatening conditions such as hypoproteinemia, hyponatremia, thrombocytosis, hypogammaglobulinemia, serious infections, and growth retardation (2)(3)(4). Protein loss in children mostly occurs due to renal or/and intestinal disease (protein-losing enteropathy) and can cause a number of potentially life-threatening complications such as hypotension, thrombocytosis, electrolyte imbalance, cerebellar ischemia, and in extreme cases death. Recent studies suggest that patients with AD associated with hypoproteinemia have high SCORAD scores, high levels of total IgE, polysensitization to various nutritive allergens, and early sensitization to Dermatophagoides pteronyssinus (5,6). ...
... The role of damage to the skin barrier produced by S. aureus superantigens and the protein leakage worsening through the inflamed and damaged skin was previously described. Positive skin swab results for S. aureus superantigens in patients range from 66-100%, and the role of S. aureus superantigens in severe AD associated with hypoproteinemia requires further research (2,6,9). Given the age of the patient, our first therapeutic choice were topical glucocorticoids under occlusion (wet-dressings) with basic therapeutic agents (oily ointment bases), to which he responded well. ...
Protein loss is often the result of kidney or intestinal disease (protein-losing enteropathy) and can cause a number of serious, potentially life-threatening complications such as hypotension, thrombocytosis, electrolyte imbalance, and cerebellar ischemia. Recent research suggests an association between extremely severe atopic dermatitis (AD) and allergic enteropathy. An exclusively breastfed 6-month-old infant was admitted to our institution due to failure to thrive, electrolyte imbalance, and severe AD (SCORing Atopic Dermatitis; SCORAD 40). On admission, the infant was in poor general condition, dehydrated, malnourished (bodyweight 4870 g, -3.98 z-score), with exudative erythematous morphs scattered throughout the body. Initial laboratory results showed microcytic hypochromic anemia, hypoalbuminemia, hypogammaglobinemia, thrombocytosis, hyponatremia, high values of total immunoglobulin E (IgE), and eosinophilia. Polysensitization to a number of nutritional and inhalation allergens was demonstrated, and an exclusive amino acid-based formula has been introduced into the diet. During the hospital course, the patient developed superficial thrombophlebitis and methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Eosinophilia was found in a small intestine biopsy sample. Due to severe hypogammaglobulinemia, skin infections, and bacteremia, the differential diagnosis included primary immune deficiency (STAT3 deficiency, DOCK8 deficiency, PGM3 deficiency, IPEX), but all available immunological tests were unremarkable. Exclusive amino acid-based formula diet was continued in the infant, with topical corticosteroids under wet-dressing therapy and intravenous immunoglobulin replacement therapy. With the gradual improvement of the general condition, the introduction of solid foods was started according to the findings of allergy testing. At 17 months of age, the patient gained weight and his skin status has been improving, although frequent use of topical corticosteroids was necessary. There were no infections, no anemia or thrombocytosis, and albumin and immunoglobulin supplementation were no longer required. The main mechanism of protein loss in infants with extremely severe atopic dermatitis is probably due to damaged skin, and partially due to the eosinophilic inflammation of the small intestine. Immunoglobulin loss, potentiated by physiological or transient hypogammaglobulinemia in infants, poses a very high risk for severe, potentially life-threatening infections.
... Thereby, the systemic mechanism of AD is recognized to affect systemic metabolism. Nomura et al. [8] reported that infants hospitalized with severe AD had impaired mental and physical growth, protein loss through skin inflammation, and elevated serum interleukin (IL), including IL5, IL6, and IL12. Furthermore, early-onset and/or persistent AD is a known risk factor for food allergy based on a birth cohort study [3,9]. ...
... The present study speculates that severe and persistent eczema may lead to persistent skin inflammation, producing various cytokines/chemokines from the skin that may in turn affect systemic metabolism. A previous study reported that severe childhood AD led to hypoprotenemia, hyperkaremia, and hyponatremia as leaking through the skin [8]. ...
Skin inflammation leads to altered cytokine/chemokine production and causes systemic inflammation. The systemic mechanism of atopic dermatitis (AD) is recognized to affect systemic metabolism. This study aimed to examine the relationship between early-onset persistent eczema and body weight, height, and body mass index (BMI), in addition to food allergy in a birth cohort among infants. This study design was a nationwide, multicenter, prospective birth cohort study—the Japan Environment and Children’s Study (JECS). Generalized linear models were fitted for z scores of weight, height, BMI, and food allergy to evaluate the relationship between eczema and these outcomes for infants at age1, 2, and 3 years. Persistent eczema was negatively associated with height at the age of 2 years (estimated coefficient, −0.127; 95% confidence interval [CI], −0.16 to −0.095) and 3 years (−0.177; 95% CI, −0.214 to −0.139). The same tendency was also observed with weight and BMI. Early disease onset at younger than 1 year and persistent eczema had the strongest association with development of food allergy at age 3 years (OR, 11.794; 95% CI, 10.721–12.975). One phenotype of eczema with early-onset and persistent disease creates a risk of both physical growth impairment and development of food allergy. Infants who present with the early-onset and persistent type of eczema should be carefully evaluated daily for impaired physical growth and development of food allergy.
... Über ähnliche Komplikationen bei AE in geringerer Ausprägung ist vereinzelt berichtet worden [1,5,7]. In Japan wurde in diesem Zusammenhang vom SPLAD-Syndrom ("severe protein loss in atopic dermatitis") gesprochen [6], als Ursache der Hypoproteinämie und Hyponatriämie wurde das kutane Exsudat identi ziert [5]. ...
... Über ähnliche Komplikationen bei AE in geringerer Ausprägung ist vereinzelt berichtet worden [1,5,7]. In Japan wurde in diesem Zusammenhang vom SPLAD-Syndrom ("severe protein loss in atopic dermatitis") gesprochen [6], als Ursache der Hypoproteinämie und Hyponatriämie wurde das kutane Exsudat identi ziert [5]. Es kommt zur intravaskulären Dehydratation mit renaler Minderperfusion, die zur Ausschüttung von ADH (antidiuretisches Hormon) und Aktivierung des Renin-Angiotensin-Aldosteron-Systems (Pseudohypoaldosteronismus) führt. ...
Bei einem sechs Monate alten Säugling mit exsudativem atopischen Ekzem kam es zum Gewichtsverlust von 15 % des Körpergewichts mit schwerer Hyponatriämie, Hyperkaliämie, metabolischer Azidose und Hypoproteinämie. Nach parenteraler Rehydratation entwickelten sich im Verlauf ausgeprägte Ödeme mit Pleura- und Perikardergüssen sowie Aszites. Über eine Eindämmung der kutanen Elektrolyt- und Eiweißverluste mittels konsequenter externer Therapie sowie über eine orale Allergenkarenz gelang die langfristige Stabilisierung des Patienten.
... (9,11,13). Thrombocytosis was recently described as a complication of severe childhood AD with hypoproteinemia (17)(18)(19). Hypovolemia associated with hypoproteinemia may also play a role in increased platelet counts and increase the risk of thrombosis. In other studies, an infant with severe AD and hypoalbuminemia had leukocytosis, and > 60% of the patients with hypoproteinemia also had thrombocytosis and leukocytosis (11,17). ...
... Hypovolemia associated with hypoproteinemia may also play a role in increased platelet counts and increase the risk of thrombosis. In other studies, an infant with severe AD and hypoalbuminemia had leukocytosis, and > 60% of the patients with hypoproteinemia also had thrombocytosis and leukocytosis (11,17). The studies also showed that almost 90% of children with hypoalbuminemia had thrombocytosis and leukocytosis. ...
Background: Hypoalbuminemia can be a life-threatening complication of severe atopic dermatitis (AD). Objectives: The aim of this study was to evaluate correlations between clinical features and laboratory tests of AD children with scoring atopic dermatitis (SCORAD) scores ≥ 40, according to the presence of hypoalbuminemia. Methods: Children with AD between 3 and 24 months of age with SCORAD score ≥ 40 (n = 82), admitted to our unit from June 2007 to March 2016, were categorized to two groups of hypoalbuminemic (n = 27) and non-hypoalbuminemic (n = 55). A blood albumin level of ≤ 3.5 g/d on the first day of admission was considered as hypoalbuminemia. The results of clinical and laboratory tests of the two groups were evaluated and compared. Results: Significant differences were observed in different genders, age at AD onset, and duration of AD between the groups. Compared with non-hypoalbuminemia group, significantly more patients in hypoalbuminemia group had positive test results for methicillin-resistant Staphylococcus aureus (MRSA) as well as allergen sensitization (P < 0.05). After adjusting for age and gender, male gender (odds ratio (OR) 5.962; 95% confidence interval (CI) 2.136-16.644, P = 0.001), positive MRSA (OR, 10.625; 95% CI, 2.823-39.982, P < 0.001) and allergen (OR, 4.622; 95% CI, 1.573-13.578, P = 0.005) test results were strongly related to the presence of hypoalbuminemia. Conclusions: Hypoalbuminemia in AD children with SCORAD score ≥ 40 is associated with increased complications.
... We previously described the prognosis of patients with severe protein-loss in atopic dermatitis (SPLAD) who were admitted to our allergy center and treated using TCSs. 24 We concluded that proactive therapy using TCSs and AD education could achieve AD remission after 3 years with appropriate skin treatment, even in patients with SPLAD. 25 In the guidelines on AD, TCSs is first choice of the TA B L E 2 Investigator global assessment score at admission, 1 and 3 years after discharge Abbreviations: IQR, interquartile range; TARC, thymus and activation-regulated chemokine. ...
There are no data about risk factor of admission and long-term (>1 year) prognosis of proactive therapy using topical corticosteroids (TCSs) in school children. This study aims to identify the prognosis of school children over 3 years treated with proactive therapy after hospitalization due to atopic dermatitis (AD). This retrospective cohort study used electronic medical record data of schoolchildren (aged 5-19 years) with a long-term admission program for AD at the National Center for Child Health and Development from January 2008 to December 2013. Long-term prognosis at 1 and 3 years after discharge were retrospectively identified from their medical records. The most common exacerbation factor was poor adherence (51.8%). At 1 and 3 years after hospitalization, 87.3% and 74.3%, respectively, of the children used TCSs on their trunk and limbs less than twice a week. Investigator's Global Assessment of AD scores were ≤1 for 81.0%and 75.7% at 1 and 3 years after discharge, respectively. AD was well-controlled during follow-up. Rehospitalization due to AD was observed in 11.8% children. Poor adherence was biggest risk factor for admission. Children with severe AD could achieve well-controlled AD with a long-term admission AD program and home-based proactive therapy using TCSs for 3 years after discharge. Maintaining good adherence for AD treatment is required to prevent exacerbation and improve future prognosis in school children. However, we need to engage for the children who required rehospitalization.
... PLE associated with GI allergy was described in adults more than 50 years ago (8), but data on clear diagnostic criteria in infancy are limited (9), and there is no common term to define it. Several published case reports describe infants from various populations around the world, with or without other allergic comorbidities (10)(11)(12)(13)(14)(15)(16). In this study we put together our latest cases with the same clinical pattern, namely edema due to hypoproteinemia/hypoalbuminemia from enteral loss of proteins, confirmed by high values of α1 antitrypsin (α1AT) in the stools and no other pathology explaining the hypoproteinemia including normal kidney and liver function parameters, and observed them further, with the aim of establishing a distinct clinical entity. ...
Food-protein induced protein-losing enteropathy (FPIPLE) is a mixed IgE and non-IgE food allergy in infants along with eosinophilic gastrointestinal (GI) diseases (EGID). It is characterized by poor weight gain, edema, due to hypoproteinemia/hypoalbuminemia by enteral loss of proteins, anemia, eosinophilia, raised fecal α1-antitrypsin (α1AT), and specific-IgE and allergy skin prick test (SPT) positive for offending foods. Here, we describe 4 cases with the same clinical pattern (edema due to hypoproteinemia/hypoalbuminemia from enteral loss of proteins, confirmed by high α1AT in the stools and no other pathological findings explaining the hypoproteinemia including normal kidney and liver function parameters), and propose the term “food-protein induced protein-losing enteropathy” (FPIPLE) to define this clinical entity. We also propose diagnostic criteria and an empirical algorithm of a practical approach to the diagnosis and management for children suspected to have FPIPLE. These infants can be managed successfully with dietary modification. In our 4 cases, initially, an empirical elimination diet was applied, comprising the foods that had benn introduced in the infant's diet during the last month and, an extensively hydrolyzed or elemental formula was given. In a second approach, after evaluation by a pediatric allergist, an allergy test-directed dietary elimination alimentation was implemented, for mother and/or infant. It has yet to be demonstrated whether patients with FPIPLE are a subset of patients with EGID, and whether early intervention modifies the natural course.
... 20 , it was reported that 5 cases with hypogammaglobulinemia, whose eczema started at the age of 2 months, did not have exacerbation in their eczema after the immunoglobulin values returned to normal after the 12 th month. It has been suggested that a possible mechanism for the coexistence of AD and hypogammaglobulinemia may be impaired skin barrier or loss of immunoglobulin from the GIS 16,21 . Moreover, it is also thought that THI may contribute to AD exacerbations due to inadequate response to secondary infections or fluctuations in inflammatory cytokines and CD4/CD8 ratio. ...
Aim:Atopic dermatitis (AD) is the most common chronic skin disease of childhood. Although eczema may be a prominent finding in some primary immune deficiencies, there are very few studies conducted on the frequency of hypogammaglobulinemia in patients with eczema. In our study, we aimed to determine the frequency of hypogammaglobulinemia in patients with AD and the relationship between immunoglobulin levels and eczema severity.Materials and Methods:Patients between the ages of 0-18 years, who were diagnosed with AD between January 2015 and August 2018 in the Department Pediatrics Division of Pediatric Allergy and Immunology, Trakya University Faculty of Medicine, were included in the study. Hypogammaglobulinemia was defined as being less than -2 standard deviation of immunoglobulin A, M and G from normal values for age.Results:The median age of 117 patients included in the study was 11 months [interquartile range (IQR): 6.7-33 months], the median age of eczema onset was 3.5 months (IQR: 2-6 months), the median SCORingAtopicDermatitis at presentation was 13.8 (IQR): 5-32]. Thirty-six (30.8%) patients had low levels in one of the immunoglobulin isotypes and decreased levels of immunoglobulin A (IgA), M and G were found in 21 (17.9%), 18 (15.5%) and 23 (19.7%) patients, respectively. While there was no difference between mild and moderate-severe eczema groups in terms of age at presentation, age of onset of eczema, family history of allergic diseases, smoking exposure, aeroallergen sensitivity, food allergy, the number of patients having hypogammaglobulinemia, and the levels of IgA, M and G, a male predominance and higher number of eosinophils were observed in the moderate-severe eczema group.Conclusion:It is concluded that the evaluation of immunoglobulin levels independent of the severity of eczema is important for the distinction of primary immunodeficiency and the follow-up of patients in terms of transient hypogammaglobulinemia of infancy in patients with AD.
... This finding may point to new understanding of how Staphylococcal SAgs produce chronic and more severe inflammation of the skin in eczema. Nomura et al. 122 6 ...
Objectives
Our intention was to review all material published to date regarding superantigens (SAgs) and allergy from an otorhinolaryngological viewpoint to understand this association more clearly.
Methods
We identified all materials published mentioning both SAg and allergic rhinitis (AR), chronic sinusitis, asthma, and atopic dermatitis (AD) that are indexed on PubMed, Google, or the ProQuest Central databases.
Results
Staphylococcus aureus is a significant bacterial pathogen in humans and has the ability to produce enterotoxins with superantigenic features. The inflammatory response in allergy seen in both B cell and T cell may be attributed to SAgs. Sufferers of both allergic asthma with rhinitis and AR alone produce serological evidence of immunoglobulin E formation to SAgs produced by S. aureus. Perennial AR sufferers carry S. aureus more frequently and the presence of the organism within the nasal cavity may exacerbate perennial AR. SAg produced by S. aureus potentially worsens the asthmatic inflammatory response within the airway and may lead to the airways becoming hyperresponsive, as well as possibly activating T cells if asthmatic control is poor. Staphylococcal SAgs potentially increase the risk of developing chronic rhinosinusitis with nasal polyposis, additionally being a marker for more severe disease. If SAgs bring about chronic inflammatory responses in the nose and sinuses, then T cells excreting interferon-gamma may be a crucial mediator. In allergic dermatitis, S. aureus could be a key player in exacerbation of the condition. Even in younger pediatric patients with allergic dermatitis, allergic hypersensitivity to SAgs is frequent and may be a factor explaining how severe the condition becomes.
Conclusion
Just as SAgs are known to feature in many allergic conditions, they play their part in AR, chronic rhinosinusitis, asthma, and AD. Further research is required before the relationship between SAgs and allergy can be adequately explained.
... Co-morbid disorders such as AD and feeding difficulties may adversely impact nutrient intakes [27,28]. AD increases skin turnover and metabolic requirements, in relation with the disease extent and protein exudation [29][30][31], as well as agitation and sleep disturbances [32]. AD is characterized by periods of flares and remission, and multiple foods may be unnecessarily eliminated by caregivers when complementary feeding has started and the offending allergen not yet clearly determined [28]. ...
Cow's milk is one of the most common foods responsible for allergic reactions in children. Cow's milk allergy (CMA) involves immunoglobulin E (IgE)- and non-IgE-mediated reactions, the latter being both variable and nonspecific. Guidelines thus emphasize the need for physicians to recognize the specific syndromes of CMA and to respect strict diagnostic modalities. Whatever the clinical pattern of CMA, the mainstay of treatment is the elimination from the diet of cow's milk proteins. The challenge is that both the disease and the elimination diet may result in insufficient height and weight gain and bone mineralization. If, during CMA, the mother is not able or willing to breastfeed, the child must be fed a formula adapted to CMA dietary management, during infancy and later, if the disease persists. This type of formula must be adequate in terms of allergic efficacy and nutritional safety. In older children, when CMA persists, the use of cow's milk baked or heated at a sufficient temperature, frequently tolerated by children with CMA, may help alleviate the stringency of the elimination diet. Guidance on the implementation of the elimination diet by qualified healthcare professionals is always necessary. This guidance should also include advice to ensure adequate bone growth, especially relating to calcium intake. Specific attention should be given to children presenting with several risk factors for weak bone mineral density, i.e., multiple food allergies, vitamin D deficiency, poor sun exposure, steroid use, or severe eczema. When CMA is outgrown, a prolonged elimination diet may negatively impact the quality of the diet over the long term.
... Mivel a gyermekek "kinövik" ezt az immundeficienciát, feltételezhetô a THI-s csecsemôk és kisgyermekek immunológia érési zavara, ami a CD4+ T sejtszám csökkenésben, a CD19+ B sejtszám és sejtarány növekedésben, az antigén prezentáló sejtek és az antitest képzés zavarában nyilvánul meg (9,10,12). Korábbi tanulmányok felvetik, hogy a hypogammaglobulinaemia kialakulásában a gasztrointesztinális traktuson vagy a bôrön át történô IgG vesztés játszhat szerepet, mely az allergiás gyulladás okozta bélnyálkahártya és bôr károsodása következtében jön létre (13). Egyik betegünk esetében a súlyos AD-es tünetek hetekig tartó nedvedzéssel jártak az arcon és a végtagok feszítô felszínén, ami albumin és IgG vesztéssel járhatott, nagy valószínûséggel a gyulladt bélnyálkahártyán át is, kifejezett hypoproteinaemiát, hypalbuminaemiát és hypogammaglobulinaemiát eredményezve. ...
... Systemic immunosuppressive therapy for concomitant atopic diseases, for example, bronchial asthma, often results in a simultaneous improvement in AD lesions. In children with severe AD, systemic immunosuppressive therapy should be considered to allow age-appropriate physical and psychic growth and prevent complications such as hypoproteinemia resulting in growth retardation and behavioral deficits as well as improve patients' and their families' quality of life (12)(13)(14). In addition to the objective clinical signs of AD, the decision on systemic therapy is strongly dictated by subjective symptoms and the patient's complains, in particular pruritus followed by scratching, secondary restlessness and sleeplessness, anxiety about uncertain disease course, and complications as well as fear of adverse effects of topical drugs, namely TCS (15). ...
Systemic therapy for atopic dermatitis (AD) is indicated in patients with severe disease refractory to adequate topical treatment. Currently available drugs aim to decrease inflammation by suppressing and/or modulating immune responses and thus may indirectly improve skin barrier function, resulting in a decrease in clinical signs and symptoms in particular pruritus. Before considering systemic treatment, patient adherence to topical treatment including skin care has to be ensured. The selection of the drug depends on the disease severity, localization, complications, concomitant diseases, and age of the patient, but also on their availability and costs as well as the doctor's experience. Bearing in mind the potential risk of resistance, systemic therapy with antibiotics should be exclusively considered in clinically manifest infections such as in children. Here, we review recently published clinical trials and case reports on systemic therapy of pediatric and adult patients with AD to draw conclusions for clinical practice. Although AD is a common disease, controlled clinical studies investigating the efficacy of systemic drugs are scarce, except for cyclosporine, which has been approved for the therapy of severe AD.
... The main route of protein loss is believed to be through the damaged skin. It is of vital importance to diagnose hypoproteinemia at an early stage and start appropriate therapy to prevent hypovolemic shock, vascular occlusion, and growth retardation [260]. ...
Numerous factors lead to great difficulties in assessing the possible complications and diseases associated with atopic eczema (AE) [122, 248]. A major problem is correct diagnosis of AE, which has only recently been subjected to a certain standardization [29, 67a, 121, 123, 124, 125, 126, 128, 166a, 212, 273, 306a, 347]. A survey of the innumerable case reports and review articles dealing with this topic is hampered by the variable definition of AE and by imprecise description of skin lesions, particularly in the nondermatological literature, making proper classification impossible. Exact epidemiological data concerning the prevalence of atopic diseases are rare (see chapter by Schmied and Saurat, this volume). Thus, it is even more difficult to assess the frequency of diseases associated with AE, and to answer the question whether the association is incidental, rare, frequent, or constant. In addition, epidemiological studies and case reports mostly do not address the question of the causal relation between the underlying AE and the reported association. Despite these shortcomings, we will attempt to review diseases associated with AE and, if possible, discuss current ideas on causes and pathogenesis. We will omit from this review disorders dealt with in other chapters of this book (e. g. allergic contact eczema, food hypersensitivity, occupational aspects, psychosomatic abnormalities, severe immunodeficiency syndromes, side effects of glucocorticosteroids).
... Recently, Niwa et al. have been reported that atopic dermatitis is part of the spectrum of diseases related to impaired epithelial barriers and may be associated with ulcerative colitis [37]. Further, it was reported that hypoproteinemia as a complication of severe atopic dermatitis was caused by loss of protein through the gastrointestinal tract [38]. Thus, although neither erosions nor ulceration were observed in our study, latent chronic inflammation may be present in the large intestine of atopic dermatitis patients. ...
Although atopic dermatitis is known to be closely associated with food antigens, the actual changes in the gastrointestinal tract have not been clarified. The aim of this study was to investigate the macroscopic and histological features of the large intestine in patients with atopic dermatitis. We studied 15 outpatients who had generalized atopic dermatitis. Eight non-dermatitis subjects of a similar age without inflammatory bowel disease were also enrolled as controls. Total colonoscopy, pathological evaluation of biopsy specimens, and detection of Candida albicans were performed in all subjects. Four patients were re-examined after 6 months of treatment with an antifungal drug. Among the 15 patients with atopic dermatitis, 4 patients had melanosis coli. On pathological examinations, prominent infiltration of eosinophils and fragmentation of granulocyte nuclei were observed. There were no changes after an antifungal therapy. In the patients with melanosis coli, lipofuscin deposits were observed in the lamina propria. Candida albicans was not detected in any of the subjects. In conclusion, patients with atopic dermatitis may have a predisposition to develop chronic inflammation of the large intestine.
We present an infant with severe atopic dermatitis, protein loss, and subsequent failure to thrive. With proper management, the patient's laboratory findings normalized, and he gained weight appropriately. In this report, we highlight the impact that severe atopic dermatitis may have growth and development and review the genetic conditions that can result in a similar clinical presentation.
Severe atopic dermatitis (AD) may lead to various complications such as hypoproteinaemia. We describe the case of a 7-month-old male infant with severe AD complicated with protein-losing enteropathy (PLE). He was diagnosed with AD at 2 months of age; however, because of familial steroid phobia, topical corticosteroids were not administered. At 7 months of age, he was admitted to our hospital for decreased feeding, diarrhoea, reduced urine volume and recurrent vomiting. Class 3 topical corticosteroid treatment was initiated. On day 3, eczema had almost resolved. However, serum protein levels had not improved; oliguria persisted and oedema worsened. Serum albumin scintigraphy revealed radioisotopes in the distal duodenum, leading to PLE diagnosis. Systemic prednisolone and albumin were administered, with no PLE relapse after discontinuation. To our knowledge, only two infant PLE cases associated with AD were reported to date. PLE should be considered in patients with severe AD and persistent hypoproteinaemia.
Atopic dermatitis is a common, chronic inflammatory skin disorder, present in about 12% of children worldwide. Optimizing management of severe atopic dermatitis in pediatric patients is critical to reduce signs of inflammation, alleviate pruritus and sleep disturbance, minimize the development and/or impact of comorbidities, and improve the patient and caregiver's quality of life. Evaluating the longitudinal severity of pediatric atopic dermatitis is an important component of measuring therapeutic response and long-term management, and is different in clinical practice versus clinical trials. This article describes when and how to use different treatments for pediatric patients with severe atopic dermatitis, including topical medications, phototherapy, and systemic medical therapies (traditional immunosuppressants, biologics, and small molecule inhibitors). It also provides recommendations useful in clinical practice for nonpharmacologic interventions for pediatric patients with severe atopic dermatitis.
Background
Infants with atopic dermatitis who developed hyponatremia and hyperkalemia with raised aldosterone level have been repeatedly described in Japanese domestic literatures. However, similar reports from other countries are scarce.
Methods
Including our experiences, we collected reports of atopic dermatitis complicated with hyponatremia (≤130 mEq/L), written either in English or in Japanese, to delineate the characteristics and to elucidate the pathophysiology of this condition.
Results
Totally 36 patients were collected, of whom 35 were Japanese. All patients were infants younger than 9 months. Mean height SDS at presentation was ‐2.1±1.4 (n=25), with mean body mass index 14.1±1.7 (n=28). Mean sodium level was 120.7±6.1 mEq/L. While 28 patients had hyperkalemia, 7 patients showed normokalemia. Elevated aldosterone level was documented in 15 patients. Nutrition mainly with breastfeeding (97%), parental refusal of steroid ointment (77%), and the association of hypoalbuminemia (73%) were frequent findings. Diminished urinary sodium level was verified in all 12 patients tested, indicating that sodium loss from the skin exudates, with limited supply of sodium from breast‐milk, is the primary cause of hyponatremia. Hyperkalemia seems to result from decreased delivery of sodium to the distal nephron and from the mechanism of so‐called ‘aldosterone paradox’ that inhibits potassium secretion. In addition, physiological aldosterone insensitivity during infancy, low muscle volume, and impaired Na⁺,K⁺‐ATPase function due to protein deficiency seems to exaggerate the hyperkalemia.
Conclusions
Hyponatremia secondary to severe atopic dermatitis is age‐dependent manifestation, elicited by inappropriate treatment which leads to sodium loss from the damaged skin and resultant hyperkalemia via multifaceted mechanisms.
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Purpose:
The purpose of this study was to identify the causes, symptoms, and complications of hypoproteinemia to prevent hypoproteinemia and provide appropriate treatment to children with atopic dermatitis.
Methods:
Children diagnosed with atopic dermatitis with hypoproteinemia and/or hypoalbuminemia were retrospectively reviewed. The patients' medical records, including family history, weight, symptoms, treatment, complications, and laboratory test results for allergies and skin cultures, were examined.
Results:
Twenty-six patients (24 boys) were enrolled. Seven cases had growth retardation; seven, keratoconjunctivitis; six, aural discharges; five, eczema herpeticum; four, gastrointestinal tract symptoms; and two, developmental delays. In 21 cases, topical steroids were not used. According to the blood test results, the median values of each parameter were elevated: total IgE, 1864 U/mL; egg white-specific IgE, 76.5 kUA/L; milk IgE, 20.5 kUA/L; peanut IgE, 30 kUA/L; eosinophil count, 5810/μL; eosinophil cationic protein, 93.45 μg/L; and platelet count, 666.5×103/μL. Serum albumin and total protein levels decreased to 2.7 g/dL and 4.25 g/dL, respectively. Regarding electrolyte abnormality, ten patients had hyponatremia, and 12, hyperkalemia. Systemic antibiotics were used to treat all cases, and an antiviral agent was used in 12 patients. Electrolyte correction was performed in eight patients.
Conclusion:
Hypoproteinemia accompanying atopic dermatitis is common in infants younger than 1 year and may occur because of topical steroid treatment continuously being declined or because of eczema herpeticum. It may be accompanied by growth retardation, keratoconjunctivitis, aural discharge, and eczema herpeticum and can be managed through skin care and topical steroid application without intravenous albumin infusion.
Background:
Staphylococcus aureus plays a role in the pathogenesis of atopic dermatitis (AD), possibly via the expression of various virulence antigens. An altered antibody response towards these antigens might contribute to inflammation.
Objectives:
To provide an overview of the varying prevalences and odds of antibody responses against S. aureus antigens in patients with AD.
Methods:
Data were systematically obtained from Embase, MEDLINE, Web of Science, Scopus, Cochrane, PubMed and Google Scholar up to 12 February 2016. We selected all original observational and experimental studies assessing antistaphylococcal antibodies in serum of patients with AD. Prevalences and odds ratios (ORs) of IgE, IgG, IgM and IgA against S. aureus in patients with AD vs. healthy controls were pooled using the random-effects model. We calculated I2statistics to assess heterogeneity and rated study quality using the Newcastle-Ottawa Scale.
Results:
Twenty-six articles (2369 patients) were included, of which 10 were controlled studies. Study quality was fair to poor. Patients with AD had higher prevalences of IgE against staphylococcal enterotoxin (SE)A (OR 8·37, 95% confidence interval 2·93-23·92) and SEB (OR 9·34, 95% confidence interval 3·54-24·93) compared with controls. Prevalences of antistaphylococcal IgE were 33% for SEA, 35% for SEB and 16% for toxic shock syndrome toxin-1. However, study heterogeneity and imprecision should be taken into consideration when interpreting the results. Data on IgG, IgM and IgA, as well as other antigens, are limited.
Conclusions:
Patients with AD more often show an IgE antibody response directed against S. aureus superantigens than healthy controls, supporting a role for S. aureus in AD pathogenesis.
Introduction: Atopic dermatitis (AD) is a chronic inflammatory condition affecting local immunity and skin hydra-tion. Severe AD may affect growth and weight gain in infants and children but its effects on growth and nutrition in adolescents are not yet well known. Main objectives of study: To measure the effect of AD on linear growth and to evaluate some nutritional parameters in adolescents with severe AD. Methods: We studied linear growth and body mass index (BMI) in 18 adolescents with severe AD (Scoring Atopic Dermatitis-SCORAD index > 41) seen at the Pediatric Allergy and Immunology Clinic of Hamad General Hospital of Doha (Qatar) between June 2014-2015 with severe AD. Anthropometric data was collected and serum total protein, albumin, 25OHD, zinc and IgE concentrations were measured. Results: The height standard deviation score (Ht-SDS) was <-2 in 1/18 (5.5%) and <-1 in 27.8 % of them. Their BMI was 16.7 ± 3.6 Kg/m 2. In 16.7 % of adolescents with AD the BMI < 14 Kg/m 2 (BMI-SDS <-2). A hypoalbuminemia (serum albumin concentration < 4 g/dl) and a hypoproteinemia (serum total protein concentration < 64 g/dl) were found in 22.2% and 11.1 %, respectively. SCORAD was higher in adolescents with hypoalbuminemia and low BMI compared to those with normoalbumine-mia and BMI (67.9 ±22.1 vs 58.3±22.5; p = 0.045). Vitamin D deficiency and zinc deficiency (< 9.95 µmol/L) were diagnosed in 31% of patients and 33.3% of patients, respectively. Anthropometric data (Ht-SDS, BMI) and nutritional parameters (serum albumin, zinc and 25OHD concentrations) did not correlate significantly with the severity of the disease (SCORAD index). Conclusions: Adolescents with severe AD had high prevalence of hypoalbuminemia, zinc and vitamin D deficiency. Albumin loss may lead to malnutrition and low BMI in these patients. Therefore, it is mandatory to closely monitor linear growth and nutritional parameters in patients with severe AD, and to treat early any nutritional deficiency.
Atopic dermatitis (AD) is one of the most common skin disorders affecting infants and children. Food allergy is a strong risk factor for the development of AD. This study was designed to evaluate the improvement of symptoms among AD patients in the late childhood while they take the customized (organic, balanced, non-allergic, diverse vegetable, little saturated fat and trans fat free) diet.
SCORing atopic dermatitis (SCORAD) index is the best validated scoring system in atopic dermatitis (AD). But this scoring system has limitation to the interobserver and intraobserver variation. This study was designed to evaluate the correlation between the severity of AD classified by the SCORAD index and the laboratory tests.
As a complication of atopic dermatitis (AD), the incidence of hypoproteinemia is increasing among infants with severe AD. It can be a life-threatening condition owing to hypovolemic shock as a result of hypoproteinemia. The aim of this study is to investigate the clinical feature and laboratory findings in pediatric AD patients with hypoproteinemia.
Bei einem sechs Monate alten Säugling mit exsudativem atopischen Ekzem kam es zu einem Verlust von 15 % des Körpergewichts mit schwerer Hyponatriämie, Hyperkaliämie, metabolischer Azidose und Hypoproteinämie. Nach parenteraler Rehydratation entwickelten sich im Verlauf ausgeprägte Ödeme mit Pleura- und Perikard-ergüssen sowie Aszites. Über eine Eindämmung der kutanen Elektrolyt- und Eiweißverluste mittels konsequenter externer Therapie sowie über eine orale Allergenkarenz gelang die langfristige Stabilisierung des Patienten.
Patients with atopic eczema frequently experience colonization with Staphylococcus aureus that is directly correlated with the eczema severity. We hypothesized that S. aureus-secreted enterotoxins (SE) are involved in the pathophysiology of atopic keratoconjunctivitis (AKC).
A total of 45 subjects (18 with AKC, nine vernal keratoconjunctivitis (VKC), eight seasonal allergic conjunctivitis (SAC), and ten healthy volunteers) were enrolled. Slit lamp examinations, including fluorescein staining, were performed. Scraped samples were collected from the upper tarsal conjunctiva, lower conjunctival sacs, and the skin around the eyelid margins. Superantigen (SAg) genes were detected using polymerase chain reaction (PCR).
Among 45 cases, S. aureus was detected significantly more in AKC patients than VKC patients (P = 0.026), SAC patients (P = 0.0003), and healthy volunteers (P = 0.0001). SAg genes were detected in 11 patients. SEB (2/11), SEG (8/11), and SEI (8/11) were detected, but no other SE. There was a significant difference in SE detection between AKC and SAC patients (P = 0.03). In severe types of ocular allergic disease such as AKC and VKC (N = 27), SE was detected in six of ten patients with corneal ulcers and two of 17 patients without corneal ulcers. SE was detected in significantly more patients with corneal ulcers (P = 0.025).
In patients with AKC, S. aureus and SE were detected more frequently compared with other patients and healthy volunteers, especially in association with corneal ulceration suggesting a role of SE. So far, it is unknown whether SE leads to tissue damage of the cornea by initiating an immune response or has direct toxic effects.
We sought to describe the clinical outcomes of eight pediatric patients diagnosed with atopic dermatitis (AD) and hypogammaglobulinemia through retrospective review of medical records. All patients presented with severe facial AD. The mean and median ages of diagnosis of hypogammaglobulinemia were 6.2 months and 6.5 months, respectively, with a mean immunoglobulin G (IgG) level of 156 mg/dL. Seven of the eight patients identified in our search demonstrated simultaneous improvement in AD and serum IgG levels within 2 years of initial presentation, suggesting a diagnosis of transient hypogammaglobulinemia. The remaining patient demonstrated normalization by age 6, but no IgG levels had been measured between initial presentation and age 6. The five patients who were tested for specific antibody response to tetanus and Haemophilus influenzae type b vaccination all produced protective responses. All eight patients initially presented with high serum IgE levels. On initial evaluation, three patients had leukocytosis (white blood cell count >18,000 cells/μL), and six had peripheral blood eosinophilia. Three patients outgrew their AD by age 5, and five had clinically good to excellent control of their AD at their last visit, coincident with normalization of IgG levels. Although severe AD and immunoglobulin deficiency may rarely be associated with complex immunodeficiency disorders, our observations suggest that, with careful immunologic monitoring and diligent skin care, most children who present with severe AD and hypogammaglobulinemia exhibit improvement in dermatitis and serum IgG levels within 2 years of onset without major complications.
Atopic dermatitis (AD) is a common inflammatory skin disease with a T(H)2 and "T22" immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. An extensive study of nonlesional AD (ANL) skin is necessary to explore whether there is an intrinsic predisposition to barrier abnormalities, background immune activation, or both in patients with AD.
We sought to characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) skin are also reflected in ANL skin.
We performed genomic and histologic profiling of both ANL and AL skin lesions (n = 12 each) compared with normal human skin (n = 10).
We found that ANL skin is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities and that it has a cutaneous expansion of T cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the "background skin phenotype," increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the "clinical disease phenotype."
Our study implies that systemic immune activation might play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with the disease severity index.
We first report a case of protein losing enteropathy in severe atopic dermatitis in an exclusively breast-fed 5-month-old infant. Protein losing enteropathy was confirmed by fecal alpha1-antitrypsin clearance test and imaged successfully by 99mTc-human serum albumin scintigraphy. The present case highlights that protein losing enteropathy in severe infantile atopic dermatitis is being a topic of concern and also an issue even in exclusive breast feeding patients.
In recent years, there have been sporadic reports of severe atopic dermatitis (AD) with hypoproteinemia and growth impairment. The present study was conduced in order to ascertain the characteristics of patients with severe infant AD with hypoproteinemia at the initial visit and their treatment courses.
Of AD patients younger than 1 year of age who visited the department over a 27-month period from March 2002, subjects were those with severe AD accompanied by hypoproteinemia. The clinical characteristics of these patients at the initial visit and the changes in symptoms and laboratory findings were statistically analyzed.
Of the total of 119 AD patients younger than 1 year of age visited to the department during the above-mentioned period, 15 patients had severe AD with hypoproteinemia. The height and body weight of approximately half of the patients were less than 3rd percentile, and 10% and more of the patients had severe hyponatremia or hyperpotassemia. The platelet count for 60% of the patients exceeded 800 x 10(3)/microl. After visiting the department, therapy involving the use of skin care products and topical steroids and the removal of exacerbation factors quickly improved dermal symptoms and laboratory findings.
Severe AD is a disease that should be cautiously treated because of the risk of hypoproteinemia, growth impairment, electrolyte abnormalities, and thrombocytosis; however, it should be noted that appropriate treatments can improve this condition.
There is increasing concern in Japan over infants with atopic dermatitis (AD) who present with severe systemic complications, such as hypoproteinemia, electrolyte disturbances, and delayed growth and development. They are often associated with extremely increased numbers of circulating eosinophils. However, the clinical significance of eosinophil expansion has not been thoroughly investigated.
This study attempted to determine the significance of eosinophilia and eosinophil activation in infant cases of AD by comparing multiple clinical parameters, indexes of eosinophil activation, and levels of serum cytokines. CD69 expression was determined by flow cytometry. The clinical severity of AD was graded by the severity SCORing of atopic dermatitis (SCORAD) method. Patients were classified into two groups, with and without CD69 on eosinophils. Nuclear lobes were evaluated under a microscopy. Serum levels of eosinophil-derived neurotoxin (EDN), interleukin (IL)-12, IL-18, IL-4, IL-5 and interferon (IFN)-gamma were determined by enzyme-linked immunosorbent assay.
Patients with CD69-positive eosinophils had significantly higher numbers of eosinophils and platelets, total IgE, and eosinophil nuclear lobes. They also showed growth failure, developmental delay, low serum albumin, and electrolyte disturbances. EDN and IL-18 levels were significantly increased in this group, but the levels of IL-4, IL-5 and IL-12 were not significantly different between the two groups. IFN-gamma was not detectable in all patients with AD. Surface expression of CD69 indicates intense systemic allergic inflammation induced in severe cases of AD.
Evaluation of eosinophil activation and early therapeutic intervention is mandatory for the treatment of severe AD during infancy.
Although atopic dermatitis (AD) itself is regarded as a non-life threatening disease, childhood AD may be rarely accompanied by some serious complications. Six infantile AD patients who were hospitalized because of severe systemic complications, in addition to severe dermatitis on almost the entire body surface, are described. They were complicated by hypoproteinemia, hypovolemia, thrombocytosis, reduced serum immunoglobulin G, elevated serum liver enzymes and growth retardation. They had not been treated with topical corticosteroid before hospitalization. They were treated with topical corticosteroid and their eruption remarkably improved within 20 days (median) of hospitalization. Most of the abnormal clinical data including platelet numbers, serum levels of total protein, and liver enzymes had become normal at the day of discharge. After 30 +/- 4 months of follow up, their skin condition was fair with daily application of moisturizer and occasional use of topical corticosteroid, without any systemic problems. Although severe infantile AD may be accompanied by potentially life-threatening systemic complications, their prognoses concerning AD are favorable if they are treated adequately from the beginning of their infancy.
We describe an infant with atopic eczema, treated with homoeopathic medicines, who presented with erythema and limb oedema. Concentrations of urinary and plasma sodium and plasma albumin were low. On conventional treatment he made a satisfactory recovery.
In order to evaluate the importance of different thrombopoietic stimulatory cytokines in accelerating platelet recovery after bone marrow transplantation (BMT), we assayed serial plasma concentrations of three cytokines, thrombopoietin (TPO), interleukin-6 (IL-6), and IL-11 through the course of platelet nadir and recovery after BMT. Both mean TPO and IL-6 levels showed a marked rise and later fall preceding or coincident with the platelet nadir and recovery, suggesting their potential role as circulating regulators or stimulators of thrombopoiesis. In contrast, IL-11 levels remained remarkably constant through the whole course suggesting that this cytokine, though capable of stimulating thrombopoiesis, does not serve as a circulating regulator of platelet production. Additionally, we assayed the levels of these three cytokines following initial platelet transfusion to assess the capacity of transfused platelets to adsorb these thrombopoietic cytokines from the plasma and reduce their circulating levels, thus potentially modifying their availability for stimulating megakaryocyte proliferation. No consistent falls in TPO, IL-6 or IL-11 levels were observed following the initial two platelet transfusions. These data support the importance of circulating TPO and IL-6 as hormones capable of stimulating platelet production. Their physiologic relevance as in vivo regulators of thrombopoiesis and clinical utility for therapy of thrombocytopenia need further investigation.
Serum samples from 60 adults and 64 children with atopic dermatitis were tested for antistaphylococcal IgE antibodies with RAST discs coupled to cellular proteins from Wood 46 strain S. aureus. Anti-S. aureus IgE antibodies were detected in 19 (29.6%) of the children and 14 (23.3%) of the adult patients. Anti-S. aureus IgE-positive adults had more severe and prolonged disease than those who were negative. Two groups of children comprising 10 who were anti-S. aureus IgE positive and 10 who were negative were compared. Children with anti-S. aureus IgE antibodies had more severe and more extensive disease (p < 0.05), a greater prevalence of cutaneous S. aureus infections (p < 0.05), higher mean total serum IgE level (p < 0.05), a greater prevalence of specific IgE responses to food allergens (p < 0.05), and a higher percentage of helper T cells (p < 0.05) than children who were negative for these antibodies.
In staphylococcal toxic shock syndrome, hypotension and shock due to capillary leak may rapidly lead to death of the host.
To investigate its pathogenesis, the cytotoxic effects of toxic shock syndrome toxin 1 (TSST-1) on porcine aortic endothelial
cells (PAEC) were examined in vitro. TSST-l killed PAEC (as measured by 51Cr release) in a dose- and time-dependent fashion and was blocked by anti-TSST-1 antibodies. Receptor-mediated endocytosis
may be critical for the cytotoxic effects of TSST-1, as killing was inhibited by cold (4°C) and by addition of chloroquine
and methylamine. Furthermore, calcium and oxygen appeared necessary for TSST-1 effects on PAEC. Membrane receptor binding
studies indicated PAEC bind TSST-1 with high affinity (Kd = 5.7 × 10−7 M) and had 2.2 × 104 receptors/cell. Last, as measured by 125I-labeled albumin flux in a transendothelial permeability model, TSST-1 enhanced the permeability of PAEC monolayers in a
dose- and time-dependent manner.
A few patients remain severely affected by atopic dermatitis into adult life despite treatment with systemic steroids, azathioprine, and photochemotherapy. 33 patients took part in a double-blind, placebo-controlled, crossover study to assess the efficacy and safety of cyclosporin (5 mg/kg per day) in adults with severe refractory atopic dermatitis. Treatments were given for eight weeks each with one group (n = 16) receiving placebo followed by cyclosporin and another (n = 17) receiving cyclosporin and then placebo. Disease activity, extent of disease, sleep and itch, topical steroid use, and adverse events were assessed every two weeks. Both extent and activity of dermatitis were significantly improved (p less than 0.001) as were subjective measures of disease. 20 patients receiving cyclosporin reported adverse events compared with 8 taking placebo, although no patient required withdrawal from the study. Cyclosporin therapy led to an increase in the mean serum urea, creatinine, and bilirubin concentrations, although only the rise in bilirubin was significant (p = 0.001). Our results confirm that cyclosporin is a safe and effective short-term treatment for severe, refractory atopic dermatitis.
The cytokine interleukin-6, which has been shown to be increased in patients with burn injuries, is produced by activated monocytes and endothelial cells and has many in vitro activities, including stimulation of acute-phase protein synthesis in hepatocytes, immunoglobulin synthesis in B lymphocytes, and stimulation of growth of megakaryocytes. In 13 patients with a mean of 31% full-thickness burns, we studied the relation of serum interleukin-6 to clinical parameters and parameters of the acute-phase response and immunoglobulin production. Interleukin-6 was already elevated within hours after the injury was sustained, and it remained elevated for several weeks. All components of the acute-phase response were observed: fever, tachycardia, leukocytosis with an associated left shift, elevation of C-reactive protein and alpha 1-antitrypsin, and a decrease in albumin levels. In the second week after burn injury, immunoglobulin M levels peaked, followed by a prolonged elevation of immunoglobulin G levels. Thrombocyte counts initially decreased and rebounded to supranormal levels after 2 weeks. Interleukin-6 levels were positively correlated with acute-phase responses. We believe that the production of interleukin-6 induces the synthesis of acute-phase proteins. High interleukin-6 levels may also be an etiologic factor in the marked immunoglobulin response observed. Likewise, the relation between the megakaryocyte-promoting activity of interleukin-6 and the rebound thrombocytosis requires further investigation.
A 10-month-old infant is described who suffered from extensive atopic dermatitis, failure to thrive, hypoalbuminaemia and oedema. Large amounts of sticky exudate were lost through the skin and were shown to be rich in albumin. As renal and intestinal loss of protein was excluded, the patient's condition was ascribed to the loss of albumin through the skin at a rate that out-stripped the synthesis of this protein. Treatment with steroids resulted in dramatic clearing of his dermatitis, and subsequent rapid correction of his hypoalbuminaemia, oedema and anaemia.
Serum samples from 60 adults and 64 children with atopic dermatitis were tested for antistaphylococcal IgE antibodies with RAST discs coupled to cellular proteins from Wood 46 strain S. aureus. Anti-S. aureus IgE antibodies were detected in 19 (29.6%) of the children and 14 (23.3%) of the adult patients. Anti-S. aureus IgE-positive adults had more severe and prolonged disease than those who were negative. Two groups of children comprising 10 who were anti-S. aureus IgE positive and 10 who were negative were compared. Children with anti-S. aureus IgE antibodies had more severe and more extensive disease (p less than 0.05), a greater prevalence of cutaneous S. aureus infections (p less than 0.05), higher mean total serum IgE level (p less than 0.05), a greater prevalence of specific IgE responses to food allergens (p less than 0.05), and a higher percentage of helper T cells (p less than 0.05) than children who were negative for these antibodies.
In the current study, we investigated whether Staphylococcus aureus grown from affected skin of atopic dermatitis (AD) patients secreted identifiable toxins that could act as allergens to induce IgE-mediated basophil histamine release. The secreted toxins of S. aureus grown from AD patients were identified by ELISA using antibodies specific for staphylococcal enterotoxin (SE) exfoliative toxin (ET), or toxic shock syndrome toxin (TSST-1). S. aureus isolates from 24 of 42 AD patients secreted identifiable toxins with SEA, SEB, and TSST accounting for 92% of the isolates. 32 of 56 AD sera (57%) tested contained significant levels of IgE primarily to SEA, SEB, and/or TSST. In contrast, although SEA, SEB, or TSST secreting S. aureus could be recovered from the skin of psoriasis patients, their sera did not contain IgE antitoxins. Freshly isolated basophils from 10 AD patients released 5-59% of total histamine in response to SEA, SEB, or TSST-1 but only with toxins to which patients had specific IgE. Basophils from eight other AD patients and six normal controls who had no IgE antitoxin failed to demonstrate toxin-induced basophil histamine release. Stripped basophils sensitized with three AD sera containing IgE to toxin released 15-41% of total basophil histamine only when exposed to the relevant toxin, but not to other toxins. Sensitization of basophils with AD sera lacking IgE antitoxin did not result in release of histamine to any of the toxins tested. These data indicate that a subset of patients with AD mount an IgE response to SEs that can be grown from their skin. These toxins may exacerbate AD by activating mast cells, basophils, and/or other Fc epsilon-receptor bearing cells armed with the relevant IgE antitoxin.
Atopic dermatitis (AD) is a chronic skin disease associated with increased IgE synthesis and colonization with Staphylococcus aureus secreting exotoxins, such as Toxic Shock Syndrome Toxin-1 (TSST-1).
In this study, we were interested in determining the in vitro effects of TSST-1 on IgE synthesis in peripheral blood mononuclear cells from patients with AD.
We stimulated peripheral blood mononuclear cells (PBMC) from AD patients with a wide range of TSST-1 concentrations and measured IgE synthesis by enzyme-linked immunosorbent assay (ELISA) after 14 days.
We show herein that TSST-1 produced antagonistic effects on IgE synthesis by PBMC from AD patients, depending on the concentration used: IgE synthesis was inhibited at 1000 pg/mL (P < 0.05) and enhanced at 0.01 pg/mL (P < 0.01) of toxin. TSST-1 was found to induce the production of much higher amounts of interferon-gamma (IFN gamma) at 1000 pg/mL than at 0.01 pg/mL of toxin (P = 0.0001). More importantly, immunoglobulin E (IgE) synthesis was enhanced by TSST-1 at 1 pg/mL in the presence of antibodies blocking IFN gamma activity. The other immunoglobulin (Ig) isotypes were also increased after TSST-1 stimulation suggesting that the enhanced IgE synthesis was secondary to a polyclonal B cell activation rather than an isotype switch. TSST-1-stimulated IgE synthesis was T cell-dependent because purified tonsil B cells were only able to synthesize increased amounts of IgE when small numbers of T cells were added to the cultures. Anti-HLA-DR and anti-LFA-1 monoclonal antibodies (MoAb) inhibited TSST-1-enhanced IgE synthesis, suggesting that the bridging of the T cell receptor (TCR) and major histocompatibility complex (MHC) class II on B cells was necessary for activation of B cell differentiation.
These data indicate that staphylococcal superantigens are able, at concentrations inducing low amounts of IFN gamma, to stimulate IgE synthesis by PBMC from AD patients, and suggest that staphylococcal toxins may contribute to elevated IgE synthesis in AD.
A six-month old male infant with severe atopic dermatitis was admitted with hypoalbuminemia, oliguria and cyanosis of the extremities. There was marked edema and generalized eczema with foul, yellowish exudates. The patient's major clinical manifestations were attributed to the loss of albumin through the skin. Although atopic dermatitis is a common disease in children, here we want to show that systemic disturbances may arise from such condition, describe the total care given the patient, and emphasize the wholistic approach in managing cases of severe atopic dermatitis. Intensive treatment was instituted and the patient was discharged after three weeks and remained in a stable condition.
The skin of patients with atopic dermatitis exhibits a striking susceptibility to colonization and infection with Staphylococcus aureus. In this context it has been previously shown that S aureus-derived superantigens could function as classic allergens, inducing production of functionally relevant specific IgE antibodies.
The aim of this study was to determine the prevalence and the role of circulating staphylococcal enterotoxin A (SEA)- and staphylococcal enterotoxin B (SEB)-specific IgE antibodies in children with atopic dermatitis.
In a cross-sectional study of 58 children with atopic dermatitis, the presence of IgE antibodies to SEA and SEB was correlated with the severity of the disease and the total and other unrelated allergen-specific IgE titers and density of colonization with S aureus strains on atopic skin and episodes of superficial S aureus skin infections.
Twenty of 58 children (34%) were sensitized to superantigens (45% to SEB, 10% to SEA, 45% to SEA and SEB). In this group, severity of atopic dermatitis and levels of specific IgE to food and air allergens were significantly higher. The degree of disease severity correlated to a higher extent with the presence of SEA/SEB-specific antibodies than with total serum IgE levels. Density of colonization with superantigen-secreting S aureus strains was higher in the superantigen IgE-positive group. Sixty-three percent of these children experienced repeated episodes of superficialS aureus skin infections.
Sensitization to S aureus-derived superantigens may be involved in disease exacerbation. The presence of SEA/SEB-specific antibodies had additional explanatory value for disease severity and therefore may be helpful in the characterization of children with severe atopic dermatitis.
The environmental factors that contribute to the homing of T cells in skin disease is unknown. The skin lesions of atopic dermatitis (AD) are frequently colonized with superantigen (SAg), producing strains of Staphylococcus aureus. In vitro, these superantigens have the capacity to activate and expand T cells expressing specific T cell receptor BV gene segments, and also to increase their skin homing capacity via upregulation of the skin homing receptor, cutaneous lymphocyte-associated antigen (CLA). These activities have been proposed to enhance the chronic cutaneous inflammation of AD, but an in vivo role for SAg has not been conclusively demonstrated. In this study, we sought direct evidence for in vivo SAg activity by comparing the SAg profiles of S. aureus cultured from the skin of AD subjects to the T cell receptor Vbeta repertoire of their skin homing (CLA+) T cells in peripheral blood. SAg secreting S. aureus strains were identified in six of 12 AD patients, and all of these subjects manifested significant SAg-appropriate Vbeta skewing within the CLA+ subsets of both their CD4+ and their CD8+ T cells. T cell receptor Vbeta skewing was not detectable among the overall CD4+ or CD8+ T cell subsets of these subjects, and was not present within the CLA+ T cell subsets of five patients with plaque psoriasis and 10 normal controls. T cell receptor BV genes from the presumptively SAg-expanded populations of skin homing T cells were cloned and sequenced from three subjects and, consistent with a SAg-driven effect, were found to be polyclonal. We conclude that SAg can contribute to AD pathogenesis by increasing the frequency of memory T cells able to migrate to and be activated within AD lesions.
Superantigenic exotoxins produced by Staphylococcus aureus and their specific IgE antibodies are thought to be important precipitating factors of atopic dermatitis (AD), but there are few reports evaluating these 2 factors at the same time.
We examined whether the presence of the exotoxins sampled from the skin of patients with AD and the levels of anti-exotoxin IgE antibodies in their sera correlated with their severity of AD.
Patients with mild-to-severe AD, 1 to 22 years of age, were evaluated by using Leicester's scoring system. Specific IgE antibodies against these exotoxins were determined by using ELISA. S aureus was isolated from 3 different areas of the skin. We examined whether the exotoxin (staphylococcal enterotoxin [SE]A, SEB, SEC, SED, and toxic shock syndrome toxin-1) could be detected.
The levels of SEB-specific IgE were correlated with the severity of AD. Five of 6 patients having very high SEB-specific IgE antibody titers were under 6 years of age, and SEB was most frequently isolated (41%). There was no difference in severity between patients with or without exotoxin-producing S aureus. The severity of 9 patients who had both exotoxin-producing S aureus on the skin and specific IgE antibody against the same exotoxin in sera was significantly higher than that of the other patients.
Anti-SEB IgE titers correlate well with the severity of AD. The presence of exotoxin-producing S aureus may precipitate AD through its specific IgE antibody.
This review article examines the clinical aspects, epidemiology, and prognosis of atopic dermatitis.
These are studies and review articles from textbooks of dermatitis and allergy in general, as well as more recent epidemiologic surveys published in specialist journals of allergy and dermatology.
Included studies meet the criteria of being a survey of the prevalence of atopic dermatitis published recently in a respected peer-reviewed journal. Particular emphasis is placed on those that examine both the prevalence of the problem and significant causative and associated factors.
Atopic dermatitis is frequently a severe illness that develops in early infancy. It can persist beyond the childhood years and is often found in association with significant respiratory complications. The exact pathogenesis is unclear but it appears that it has a complex immunologic origin. Early surveys lack the methodologic refinements of more recent data from the mid-1990s, including the SCARPOL study. Collectively, these point to a high current prevalence rate of 10% to 15%, a figure that has risen steadily in the preceding decades. The most common associations of atopic dermatitis are a risk of developing respiratory disorders, such as allergic rhinitis and asthma (40% to 60%), and a persistence rate after puberty (40% to 60%), which is indeed much higher than previously suspected.
A clear recognition of the various disease subgroups along with intervention studies that evaluate reduction of risk are needed before more precise treatment strategies can be devised.
The skin of patients with inflammatory skin diseases such as atopic dermatitis is frequently colonized with Staphylococcus aureus. Colonization with S aureus has been reported to exacerbate atopic dermatitis. Recent studies have demonstrated that S aureus isolated from the skin of patients with atopic dermatitis releases bacterial toxins that act as superantigens. We have previously applied the staphylococcal superantigen staphylococcal enterotoxin B (SEB) on intact human skin and found that the application led to induction of dermatitis.
The purpose of the study was to determine whether superantigen-induced dermatitis is primarily due to a T cell-superantigen-mediated reaction or represents nonspecific cytokine-driven inflammation.
We applied SEB, vehicle, and sodium lauryl sulfate on normal skin in healthy (n = 6) and atopic subjects (n = 6) and biopsy specimens were taken from all treated areas. The biopsy specimens from all subjects and peripheral blood from the atopic subjects were analyzed for the T-cell receptor (TCR) Vbeta repertoire with mAbs against TCR Vbeta 2, 3, 8.1, 12, 14, and 17.
From all subjects, both healthy and patients with atopic dermatitis, skin biopsy specimens from SEB-treated areas demonstrated selective accumulation of T cells expressing SEB-reactive TCR Vbeta 12 and 17 (P <.05). This selective up-regulation was not found in the sodium lauryl sulfate-treated areas.
Our data strongly support that superantigen-induced T-cell activation is involved in the dermatitis seen after experimental application of SEB on intact skin.
The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization with Staphylococcus aureus. Some strains of S aureus secrete exotoxins with T-cell superantigen activity (toxigenic strains), and abnormal T-cell functions are known to play a critical role in AD.
Our purpose was to examine the impact of superantigen production by skin-colonizing S aureus on disease severity.
In a cross-sectional study of 74 children with AD, the presence and density of toxigenic and nontoxigenic strains of S aureus was correlated with disease severity. In a subgroup of patients the T-cell receptor Vbeta repertoire of peripheral blood and lesional T cells was investigated and correlated with individual superantigen activity of skin-colonizing S aureus.
Fifty-three percent of children with AD were colonized with toxigenic strains of S aureus producing staphylococcal enterotoxin C, staphylococcal enterotoxin A, toxic shock syndrome toxin-1, staphylococcal enterotoxin B, and staphylococcal enterotoxin D in decreasing frequency. Children colonized with toxigenic S aureus strains had higher disease severity compared with the nontoxigenic and S aureus-negative groups. Patients colonized with toxigenic S aureus exhibited shifts in the intradermal T-cell receptor Vbeta repertoire that correspond to the respective superantigen-responsive T-cell subsets.
The data demonstrate that S aureus-released exotoxins can modulate disease severity and dermal T-cell infiltration.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently predates the development of allergic rhinitis or asthma. It is an important skin condition with significant costs and morbidity to patients and their families; the disease affects more than 10% of children. Recent studies have demonstrated the complex interrelationship of genetic, environmental, skin barrier, pharmacologic, psychologic, and immunologic factors that contribute to the development and severity of AD. The current review will examine the cellular and molecular mechanisms that contribute to AD as well as the immunologic triggers involved in its pathogenesis. These insights provide new opportunities for therapeutic intervention in this common skin condition.
Infants with atopic dermatitis exhibiting hypoproteinemia
- Iguchi K Kamiya
TERADA A, FUJISAWA T, IGUCHI K, KAMIYA H. Infants with atopic dermatitis exhibiting hypoproteinemia. [In Japanese.] Jpn Soc Pediatr Allergy J 1999: 13: 38–42.
A single case report of an infant with severe atopic dermatitis suffering an associated cerebral infarction
- Tokuda R Kondo Y
- Ando
OHASHI M, KAKUMU M, URISU A, TOKUDA R, KONDO Y, ANDO H. A single case report of an infant with severe atopic dermatitis suffering an associated cerebral infarction. [In Japanese.] Arerugi no rinsho (Clin Allergy) 2000: 2: 155–9.
A single case report of an infant with severe atopic dermatitis suffering an associated cerebral infarction
- Ohashi M
Infants with atopic dermatitis exhibiting hypoproteinemia
- Terada A
Clinical aspects, epidemiology, and prognosis of atopic dermatitis
- Wuthrich