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Archives: Medical Journal Reviews

Medical Journal Review

Posted: June 2010

Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.

1. Predictors of food allergy in atopic dermatitis (AD).
The authors investigated the clinical significance of blood eosinophilia as a predictor for food allergy and of late eczematous reactions in AD. 303 patients with atopic dermatitis (AD) were studied, using elimination diets and food challenge tests. Food allergy prevalence was compared between two groups of AD patients, one with high and the other with normal eosinophil levels. The effects of an elimination diet and of milk challenge producing a late eczematous reaction on the blood eosinophil fraction were evaluated. The prevalence of food allergy was 51.1% (135/264) in patients with AD. The major manifestation of food allergy in AD was late eczematous reactions. Among AD patients, 44.9% had high eosinophil levels. In patients with AD, the food allergy prevalence was 70.8% (85/120) in the high eosinophil group and 34.7% (50/144) in the normal blood eosinophil group. An elimination diet improved clinical severity and decreased blood eosinophil levels. Eosinophilia appeared to be a significant predictor of food allergy in AD and an indicating factor for diet manipulation, including an elimination diet.
Editor's comment: Food allergy may be responsible for eosinophilia in AD.
Geunwoong N, Hyunjung J, Jimin L et al., Eosinophilia as a predictor of food allergy in atopic dermatitis. Allergy and Asthma Proceedings 2010; 31(2): e18-e24.

2. Meta-analysis to determine the veracity and magnitude of the "maternal effect" on asthma.
The authors screened the medical literature from 1966 to 2009 and performed a meta-analysis to compare the effect of maternal asthma vs. paternal asthma on offspring asthma susceptibility. Aggregating data from 33 studies, the odds ratio for asthma in children of asthmatic mothers compared with non-asthmatic mothers was significantly increased at 3.04 (95% CI: 2.59-3.56). The corresponding odds ratio for asthma in children of asthmatic fathers was increased at 2.44 (2.14-2.79). When comparing the odds ratios, maternal asthma conferred greater risk of disease than did paternal asthma (3.04 vs. 2.44, p = 0.037). When analyzing the studies in which asthma was diagnosed by a physician the odds ratios were attenuated and no significant differences were observed (2.85 vs. 2.48, N = 18, p = 0.37). Similarly, no significant differences were observed between maternal and paternal odds ratios when analyzing the studies in which the patient population was 5 years or older (3.15 vs. 2.60, p = 0.14). However, in all cases the trend remained the same, that maternal asthma was a greater risk factor for asthma than paternal.
Editor´s comment: The results confirm that maternal asthma increases offspring disease risk to a greater extent than paternal disease.
Lim RH, Kobzik L, and Dahl M, Risk for Asthma in Offspring of Asthmatic Mothers versus Fathers: A Meta-Analysis. PLoS ONE 2010; 5(4): e10134
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3. Immunosuppressive drugs in pregnancy and lactation.
The aim of this review was to collect evidence regarding the safety of the most commonly used medications in rheumatic disease during pregnancy or lactation and to enable practitioners and patients to make informed decisions regarding treatment during this period in a woman's life. Most autoimmune diseases predominantly affect females. Many of these diseases occur in women who have the potential to become pregnant or wish to plan a pregnancy. The potential for fetotoxic effects of immunosuppressive medications that are commonly used to treat systemic autoimmune diseases must be weighed against the need for control of disease activity during pregnancy and the postpartum period, since active disease can be an independent risk factor for adverse pregnancy outcomes. Although far from conclusive, most data concerning the safety of medications for use during pregnancy come from case series and observational studies. It is often necessary to continue treating patients throughout pregnancy and lactation in order to control the activity of the underlying disease.
Editor´s comment: A very useful review for those who treat women with autoimmune diseases.
Elliott A and Chakravarty E, Immunosuppressive medications during pregnancy and lactation in women with autoimmune diseases. Women's Health 2010; 6(3): 431-442.
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4. Anaphylactic shock: promoting recovery from a severe allergic reaction.
New research in mice has identified a potential new drug target to counteract the widening of blood vessels that is associated with anaphylactic shock. The proteins SphK1 and SphK2 are involved in generating the soluble molecule S1P, which has effects on blood vessels and the immune system via a family of proteins (S1PR1-S1PR5). In the study, mice lacking SphK2 were found to recover more rapidly from anaphylaxis than normal mice while mice lacking SphK1 recovered poorly. Treating mice lacking SphK1 with S1P dramatically improved their recovery. As these effects of S1P were found to be mediated via S1PR2, the authors suggest that drugs that trigger S1PR2 might counteract the widening of blood vessels associated with anaphylactic shock, thereby promoting recovery.
Editor´s comment: It would be interesting to have new alternatives to treat anaphylactic shock.
Olivera A, Eisner C, Kitamura Y et al, Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice. The Journal of Clinical Investigation 2010; 120(5); 1429.
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5. Sulfasalazine (SSZ) represents an exception among allergy to antibiotic and non antibiotic sulfonamides.
Recent studies showed that patients allergic to sulfonamide antibiotics do not have a specific risk for an allergy to sulfonamide non-antibiotics. The authors analyzed in vitro the cross-reactivity between sulfamethoxazole (SMX) and the anti-inflammatory drug SSZ. PBMC from 2 patients with severe hypersensitivity syndrome to SSZ, 3 patients with SMX allergy and 5 healthy donors were isolated and incubated with medium only (negative control), 2 concentrations (10, 100 µg/ml) of sulfapyridine, 2 concentrations (100, 200 µg/ml) of SMX, and tetanus toxoid (10 µg/ml) as a positive control. After 6 days of culture, 3H-thymidine was added and cell proliferation was measured. In all patients tested, the lymphocyte transformation tests were positive for both sulfapyridine and SMX, suggesting a strong cross-reactivity between these drugs, and demonstrating that, in the case of SMX and SSZ, cross-reactivity is dependent on chemical features rather than the indication of the drugs.
Editor´s comment: Patients with hypersensitivity to SSZ or SMX should be specifically advised to avoid both drugs.
Zawodniak A, Lochmatter P, Beeler A et al. Cross-Reactivity in Drug Hypersensitivity Reactions to Sulfasalazine and Sulfamethoxazole, International Archives of Allergy and Immunology 2010; 153(2): 152-156.
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6. Asthma increases the risk for anaphylaxis.
To address the incidence of anaphylaxis-related events in patients with asthma at the population level across sex, age, and racial/ethnic groups and the impact of asthma severity on the risk of anaphylaxis, the researchers studied data from the Kaiser Permanente organization in Northern California on 526,406 patients with asthma and 526,406 without, who were matched for age, gender, and race/ethnicity. Overall, 54% of patients were female, 55% were white, and their average age was 24 years. Hospitalizations, ambulatory visits, and emergency department visits for anaphylactic shock caused by adverse food reactions, serum or other substances, as well as allergy-related diagnoses, including allergic urticaria, anaphylaxis after stings, and angioneurotic edema, were recorded for the period 1996-2006. During median follow-up of 5.2 years in asthmatic patients and 6.3 years in nonasthmatic individuals, there were 3141 and 650 anaphylactic shock events of any type, respectively. The incidence of anaphylactic shock was 109.0 per 100,000 person-years in the asthma cohort and 19.9 per 100,000 person-years in the nonasthmatic cohort. After accounting for age, ethnicity, gender, comorbidities, immunotherapy and other variables, the researchers calculated that individuals with asthma were 5.2 times more likely to suffer anaphylactic shock than those without the condition with respiratory, cutaneous, or cardiovascular complaints.
Editor´s comment: Health professionals should be aware of this connection and should have an increased level of suspicion for anaphylactic shock in asthmatic patients.
Iribarren C, Tolstykh I, Miller MK et al., Asthma and the prospective risk of anaphylactic shock and other allergy diagnoses in a large integrated health care delivery system, Annals of Allergy Asthma and Immunology 2010; 104(5): 371-377.

7. Guidance for reporting randomised controlled trials.
The CONSORT statement is used worldwide to improve the reporting of randomized controlled trials. Kenneth Schulz and colleagues describe the latest version, CONSORT 2010, which updates the reporting guideline based on new methodological evidence and accumulating experience. The CONSORT 2010 Statement includes a 25 item checklist and a flow diagram. It provides guidance for reporting all randomized controlled trials, but focuses on the most common design type-individually randomized, two group, parallel trials. Other trial designs, such as cluster randomized trials and non-inferiority trials, require varying amounts of additional information. CONSORT extensions for these designs can be found through the CONSORT website
Editor´s comment: These guidelines are extremely useful to standardize the presentation of scientific information.
Schulz KF, Altman DG and Moher D for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trial, Trials 2010; 11(1): 32
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8. Folate and vitamin B12 in asthmatic adults.
The authors studied data on 6784 individuals, 30-60 y.o., from the general population who participated in the 1999-2006 Inter99 study. All the participants supplied information on asthma diagnosis, airway symptoms, and their intake of folate and vitamin B12. The blood levels of these two vitamins were also measured. In addition, the participants underwent lung function and allergy tests, and were genotyped for the single nucleotide polymorphism (SNP) C677T in the methylene-tetrahydrofolate reductase gene (MTHFR), which is a genetic marker of impaired folate metabolism. Overall, 8.5% of participants reported a diagnosis of asthma and 13.0% reported attacks of shortness of breath. After accounting for factors such as age, gender, smoking habits, alcohol consumption, socioeconomic status, and body mass index, the researchers found that low serum folate levels (less than 6.2 nmol/l) and the TT genotype of the MTHFR C677T SNP were significantly associated with an increased risk for asthma, with odds ratios (ORs) of 1.37 and 1.52, respectively, and attacks of shortness of breath, with corresponding ORs of 1.43 and 1.47. However, serum folate levels and the MTHFR C677T SNP were not associated with lung function or atopy. The researchers also found no associations among serum levels of B12 and dietary intake of folate and B12 and asthma or atopy.
Editor´s comment: If confirmed, these findings might suggest a role of folate in asthma pathogenesis.
Thuesen BH , Husemoen LL , Ovesen L et al. Atopy, asthma, and lung function in relation to folate and vitamin B in adults, Allergy 2010; Published online 26 April (Early View: Articles online in advance of print).

9. A novel scale to measure pruritus was termed the 5-D scale.
A novel scale to measure puritus was termed the 5-D scale (degree, duration, direction, disability and distribution domains). It was administered to 234 patients with chronic pruritus due to liver disease, renal disease, dermatological disorders, HIV/AIDS and burn injuries. The 5-D questionnaire was administered at baseline and after a 6-week follow-up. A subset of 50 untreated subjects was retested after 3 days to assess test-retest reliability. The 5-D score correlated with a visual analogue scale for itch at baseline, a 3-day repeat and at follow-up (r = 0.727-0.892; P < 0.0001). There was no change in 5-D score in untreated subjects between days 1-3, but it did detect changes in pruritus over a 6-week follow-up period (P < 0.0001).
Editor´s comment : The 5-D scale is a reliable multidimensional tool to measure itching and should find application in clinical trial designs.
Elman S, Hynan LS, Gabriel V et al., The 5-D itch scale: A new measure of pruritus, British Journal of Dermatology 2010; 162(3): 587-593.

10. Suppressive role for Invariant NKT cells (iNKTc) in SLE?
The authors identified a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT-B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells was observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connected two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy.
Editor´s comment: Some evidence connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development.
Wermeling F, Lind SM, Jordö ED et al., Invariant NKT cells limit activation of autoreactive CD1d-positive B cells, Journal of Experimental Medicine 2010; 207(5): 943-952.

11. Noninvasive clinical assessments of asthma severity and response to treatment assessment using pulse oximeter plethysmograph estimate of pulsus paradoxus physiology.
To study if pulsus paradoxus estimated by dynamic change in area under the oximeter plethysmograph waveform (PEP) might provide a measure of acute asthma severity, the authors determined how well PEP correlates with forced expiratory volume in 1-second (%FEV1) (criterion validity) and change of %FEV1 (responsiveness) during treatment of pediatric patients with acute asthma exacerbations. They studied 219 subjects (median age 9 years; male 62%; African-American 56%). Correlation of PEP with %FEV1 demonstrated criterion validity (r = - 0.44, 95% confidence interval [CI], - 0.56 to - 0.30) and responsiveness at 2 hours (r = - 0.31, 95% CI, - 0.50 to - 0.09) and 4 hours (r = - 0.38, 95% CI, - 0.62 to - 0.07). PEP also correlated with airway resistance at baseline (r = 0.28 for ages 5 to 10; r = 0.45 for ages 10 to 17), but not with change over time. PEP was associated with accessory muscle use (OR 1.16, 95% CI, 1.11 to 1.21, P < 0.0001). PEP demonstrates criterion validity and responsiveness in correlations with %FEV1. PEP correlates with airway resistance at baseline and is associated with accessory muscle use at baseline and at 2 and 4 hours after initiation of treatment. Incorporation of this technology into contemporary pulse oximeters may provide clinicians improved parameters with which to make clinical assessments particularly in patients who cannot perform spirometry because of young age or severity of illness.
Editor´s comment: New technologies can assist in the objective assessment of the severity of asthma exacerbations.
Arnold DH, Cathy A Jenkins CA and Hartert TV. Noninvasive assessment of asthma severity using pulse oximeter plethysmograph estimate of pulsus paradoxus physiology, BMC Pulmonary Medicine 2010; 10:17.
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12. Acute myocardial infarction in the context of an anaphylactic episode.
Kounis syndrome has been defined as an acute coronary syndrome that manifests as unstable vasospastic or nonvasospastic angina, and even as acute myocardial infarction. It is triggered by the release of inflammatory mediators following an allergic insult. The authors reported 5 patients attended at their hospital between January 2005 and May 2008 who were diagnosed with unstable angina or acute myocardial infarction-according to analytical parameters, electrocardiographic abnormalities, and/or coronary angiography-in the context of an anaphylactic episode. At the time of the episode, ages ranged between 50 and 68 years. The results of an allergology study revealed the causal agents to be drugs in 4 cases (nonsteroidal anti-inflammatory drugs and omeprazole) and food in 1 case (kiwi). Coronary disease of a blood vessel was observed in 2 patients. Serious allergic reactions may be the cause of acute coronary syndrome in patients with healthy or altered coronary arteries and no cardiovascular risk factors.
Editor´s comment: We must take into account the serious allergic reactions in selected cases of myocardial infarction.
Gázquez V, Dalmau G, Gaig P et al., Kounis Syndrome: Report of 5 Cases, Journal of Investigational Allergology and Clinical Immunology 2010; 20(2): 162-165.
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