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Archives: Medical Journal Reviews

Medical Journal Review

Posted: March 2010

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

1. Potential dangers of the indiscriminate use of first-generation H1-antihistamines.
A GA²LEN (Global Allergy and Asthma European Network) task force reviewed the literature (via Medline and Embase) and performed a media audit of coverage in the United States from 1996 to 2008 of accidents and fatal adverse events in which H1-antihistamines were implicated. The goal of the effort was to enhance consumer protection by bringing to the attention of regulatory authorities, physicians and the general public the potential dangers of the indiscriminate use of first-generation H1-antihistamines purchased over-the counter in the absence of appropriate medical supervision. They found that first-generation H1-antihistamines, all of which are sedating, are generally regarded as safe by laypersons and healthcare professionals because of their long-standing use. However, they reduce rapid eye movement (REM)-sleep, impair learning and reduce work efficiency. They have been implicated in civil aviation, motor vehicle and boating accidents. They have also been responsible for deaths as a result of accidental or intentional overdosing. In conclusion this review raises the issue of better consumer protection by recommending that older first-generation H1-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second-generation non-sedating H1-antihistamines with superior risk/benefit ratios are widely available at competitive prices.
Editor's comment: There is no rationale for sedating antihistamines as prescription-free drugs for self-medication in 2010.
Church MK, Maurer M, Simons FER et al. Risk of first-generation H1-antihistamines: a GA²LEN position paper. Allergy 2010; 65(4):459-466.

2. A mechanism by which probiotics modulate the immune system.
The authors identified a mixture of probiotics that up-regulates CD4+Foxp3+ regulatory T cells (Tregs). The administration of the probiotics mixture induced both T-cell and B-cell hyporesponsiveness and down-regulated T helper (Th) 1, Th2, and Th17 cytokines without apoptosis induction. They also induced the generation of CD4+Foxp3+ Tregs from the CD4+CD25- population and increased the suppressor activity of naturally occurring CD4+CD25+ Tregs. Conversion of T cells into Foxp3+ Tregs is directly mediated by regulatory dendritic cells (rDCs) that express high levels of IL-10, TGF-β, COX-2, and indoleamine 2,3-dioxygenase. Administration of probiotics has shown therapeutic effects in experimental inflammatory bowel disease, atopic dermatitis, and rheumatoid arthritis. The therapeutic effect of probiotics is associated with enrichment of CD4+Foxp3+ Tregs in the inflamed regions. The authors concluded that probiotics that enhance the generation of rDCs and Tregs represent a potential easily applicable treatment of inflammatory immune disorders.
Editor's comment: The beneficial effects of probiotics have been described in many diseases, but the mechanism of action has been poorly understood. This article sheds light on the possible mechanism(s) of action by these agents.
Kwon HK, Lee CG, So JS et al, Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders. PNAS (Proceedings of the National Academy of Sciences of the United States of America) 2010; 1-7:2159-2164.

3. Responses to asthma treatment according to body mass index.
The authors studied the relationship between body mass index (BMI) on responses to asthma therapy (fluticasone propionate (FP)/salmeterol via Diskus 100/50 micrograms twice daily and montelukast (MON) 10 mg daily) using a retrospective analysis of four previously reported clinical trials. BMI was classified as underweight (less than 20 kg/m²), normal (20-24.9 kg/m²), overweight (25-29.9 kg/m²), obese-1 (30-34.9 kg/m²), obese-2 (35-39.9 kg/m²), or obese-3 (at least 40 kg/m²). Outcomes assessed included forced expiratory volume in one second (FEV1), asthma symptom score, and albuterol use. FP/salmeterol produced greater improvements compared to MON in each of the asthma outcomes studied over the entire BMI range at the week-12 endpoint, with statistically significant differences noted among normal, overweight, obese-1, and obese-3 subjects. Treatment responses to FP/salmeterol were consistently greater compared to MON and persisted at higher BMI.
Editor's comment: Excess weight, especially in the obese range, diminishes the effects of all asthma treatment regimens.
Camargo CA, Boulet LP, Sutherland ER et al. Body mass index and response to asthma therapy: fluticasone propionate/salmeterol versus montelukast. Journal of Asthma 2010; 47(1):76-82.

4. The role of IgG2 deficiency in the pathogenesis of H1N1 infection.
After identification of immunoglobulin G(2) (IgG2) deficiency in one severe case, the authors assessed IgG subclass levels in a cohort of patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women. Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoalbuminemia, anemia and low levels of total IgG, IgG1, and IgG2 were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia and low mean IgG2 levels remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG2-deficient found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG2 deficient. Among 17 healthy pregnant control subjects, mildly low IgG1 and/or IgG2 levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG2. The authors concluded that severe H1N1 infection is associated with IgG2 deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG2 level may explain the increased severity of H1N1 infection in some but not all pregnant patients.
Editor's comment: Relative IgG2 deficiency may predispose to more severe H1N1 infection.
Gordon CL, Johnson PD, Permezel M et al. Association between Severe Pandemic 2009 Influenza A (H1N1) Virus Infection and Immunoglobulin G(2) Subclass Deficiency. Clinical Infectious Diseases 2010; 50(5):672-678.

5. Tonsillar hypertrophy linked to childhood wheeze and snoring.
In addition to airway inflammation, adenotonsillar hypertrophy is another factor that may increase upper airway resistance and predispose to sleep-disordered breathing (SDB) in childhood. The researchers studied 442 children (average 7.6 years old), who attended the ED for minor ailments or were referred for recurrent wheezing. They used parental questionnaires on symptoms of SDB (snoring), wheezing, use of inhaled bronchodilators or corticosteroids, tonsillectomy, and history of chronic disease. The children also underwent clinical examinations and the size of their tonsils was measured by inspection of the oropharynx. After accounting for factors such as age, gender, body mass index, and passive smoking, the researchers found that a history of wheezing was significantly associated with the presence of tonsillar hypertrophy and habitual snoring, at odds ratios (ORs) of 2.23 and 1.73, respectively. A history of wheezing was significantly associated with the presence of snoring in children with tonsillar hypertrophy (OR=2.76), but not in those without. The authors concluded that children with history of wheezing have more frequently tonsillar hypertrophy than those without wheezing.
Editor's comment: Children with a history of wheezing are more likely to have tonsillar hypertrophy which may partly explain the association between asthma and obstructive sleep-disordered breathing (SDB) in childhood.
Kaditis AG, Kalampouka E, Hatzinikolaou S et al. Associations of tonsillar hypertrophy and snoring with history of wheezing in childhood. Pediatric Pulmonology 2010; 45(3):275-280.

6. Estrogen-only hormone replacement therapy (HRT) may increase asthma risk after menopause.
The authors studied data on 57,664 postmenopausal French women who participated in the E3N study, part of the European Prospective Investigation into Cancer and Nutrition (EPIC). All the women completed questionnaires about their use of HRT and the development of asthma symptoms every 2 years between 1990 and 2002. Overall, 35.7% of the participants had never used HRT, while the remainder had used some form of HRT since experiencing menopause. In total, 569 women developed asthma during 495,448 person-years of follow-up. The researchers found that women who had ever used HRT were 1.20 times more likely to have developed asthma over the study period than those who had never used HRT. Further analysis revealed that only the use of estrogen-alone HRT was associated with a significantly increased risk for asthma, at a hazard ratio (HR) of 1.54, after accounting for potential confounding factors such as body mass index, parity, use of oral contraceptives, and type of menopause (natural/surgical/unknown). This risk was particularly elevated in never smokers (HR=1.80) and women who reported suffering from allergic disease before asthma onset (HR=1.86). The authors concluded that postmenopausal use of estrogen alone was associated with an increased rate of newly diagnosed asthma in menopausal women.
Editor's comment: The increase in asthma risk associated with estrogen hormone therapy must be judged in light of all other health effects of hormone therapy use, including its beneficial effect on the quality of life of menopausal women.
Romieu I, Fabre A, Fournier A et al. Postmenopausal hormone therapy and asthma onset in the E3N cohort. Thorax 2010 Published online first, 8 February 2010

7. Asthma Screening Questionnaire (ASQ) is a reliable instrument for diagnosing asthma in adults.
The authors developed a simple, pre-interview screening questionnaire-(ASQ)-consisting of 6 questions. Participants were asthmatics or controls, aged 18 to 65 years. All participants completed the questionnaire (self-administered and physician-administered), and underwent spirometry and a methacholine challenge test (if there was no reversibility during initial spirometry). Sensitivity, specificity, and positive and negative predictive values were calculated for each question, and the total scores of asthmatics were compared with those of controls. The degree of agreement between the self-administered and the physician-administered questionnaire was calculated. The main symptoms discriminating asthmatics from controls were cough more than average (88% vs 0%), cough from chest (72% vs 0%), shortness of breath with exercise (84% vs 16%), and chest tightness when lying down (72% vs 4%). A cutoff point of total score ≥4 was associated with the highest combination of sensitivity (96%) and specificity (100%). Substantial agreement was observed between the self-administered and the physician-administered questionnaire (κ statistic, 0.56-1.00; P<.0001). The authors concluded that ASQ is a simple, inexpensive, and efficient pre-interview screening tool to diagnose asthma.
Editor's comment: ASQ is a simple and inexpensive approach to predict which individuals are most likely to be diagnosed with asthma and for efficient pre-interview of suspected asthma patients.
Shin B, Cole Sl , Park S-J et al., A new symptom-based questionnaire for predicting the presence of asthma. Journal of Investigative Allergy and Clinical Immunology 2010; 20(1):27-34.
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8. Relationships between bacterial-specific IgE and asthma susceptibility.
The authors investigated relationships between bacterial-specific IgE amongst teenagers and asthma susceptibility measuring titres of IgE against Haemophilus influenzae(HI), Streptococcus pneumonia(SP) and Staphylococcus aureus(SA) in 1380 teenagers, and related these to asthma symptomatology and immunophenotypes. The IgE titres against SA-derived enterotoxins were highest amongst atopics and were associated with asthma risk. Surprisingly, IgE titres against HI and SP surface antigens were higher and not stratified by atopy, and independently associated with decreased asthma risk. The positive association between Type-2 immunity to SA and asthma phenotypes likely reflects IgE-mediated effector cell activation via enterotoxin antigens which are secreted in soluble form. The contrasting benign nature of Type-2 immunity to HI and SP antigens may reflect their lower availability in soluble forms that can crosslink IgE receptors. They theorized that they may be processed by antigen presenting cells and presented to Type-2 memory cells leading to mucosal secretion of IL-4/IL-13, a mechanism widely recognized in other tissues to attenuate TH1-associated bacterial-induced inflammation.
Editor's comment: This article raises intriguing questions about the possible role of bacteria in atopic diseases and notes that the IgE response to bacteria can vary with the organism involved.
Hollams E, Hales B, Bachert C et al. Th2-associated immunity to bacteria in asthma in teenagers and susceptibility to asthma. European Respiratory Journal, Published online before print 28 January 2010.

9. A CC-chemokine receptor-3 (CCR3) antagonist in allergic rhinitis.
The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation. To examine whether a dual CCR3 and H1-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis the authors subjected patients with seasonal allergic rhinitis to three, seven-day allergen challenge series. Treatment with AZD3778 was given in a placebo and loratadine-controlled design. They monitored symptoms and nasal peak inspiratory flow (PIF) in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and alpha-2-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation. AZD3778 and loratadine reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not loratadine, improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine. The authors concluded that AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis, and part of this effect can likely be attributed to CCR3-antagonism.
Editor's comment: These data are of interest with regard to the potential use of CCR3 antagonists in allergic rhinitis. They also suggest a role for eosinophils in the production of nasal obstruction since AZD3778 had a beneficial effect on PIF.
Greiff L, Ahlstrom-Emanuelsson C, Bahl A et al. Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis. Respiratory Research 2010; 11:17
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10. Intravenous montelukast (IV MON) for the treatment of acute asthma.
The authors evaluated the efficacy of IV MON as adjunctive therapy for acute asthma on 583 adults with acute asthma that were treated with standard care during a </=60-minute screening period. Patients with FEV1 </=50% predicted were randomly allocated to IV MON 7 mg (n = 291) or placebo (n = 292) in addition to standard care. This double-blind treatment period lasted until a decision for discharge, hospital admission, or discontinuation from the study. The primary efficacy endpoint was the time-weighted average change in FEV1 during 60 minutes after drug administration. Secondary endpoints included the time-weighted average change in FEV1 at various intervals (10-120 minutes) and percentage of patients with treatment failure (defined as hospitalization or lack of decision to discharge by 3 hours post administration). IV MON significantly increased FEV1 at 60 minutes postdose; the difference between change from baseline for placebo and IV MON was 0.10 L (95% CI, 0.04, 0.16). Similar improvements in FEV1-related variables were seen at all time points (all P <.05). Although treatment failure did not differ between groups (OR 0.92; 95% CI, 0.63, 1.34), a pre-specified subgroup analysis suggests likely benefit for IV MON. The authors concluded that IV MON added to standard care in adults with acute asthma produced significant relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.
Editor's comment: Intravenous montelukast may offer a new alternative for treating acute asthma.
Camargo CA, Gurner DM, Smithline HA et al. A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma. The Journal of Allergy and Clinical Immunology 2010; 125(2):374-380.

11. Role of vaccination in the development of autoimmunity in adults.
In this review the authors presented evidence for the association of vaccinations and the development of autoimmune diseases. Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Infrequently reported post-vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, the authors discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following human papilloma virus vaccine.
Editor's comment: More research is required to identify those individuals who may develop autoimmune diseases following immunizations.
Orbach H, Agmon-Levin N and Zandman-Goddard G. Vaccines and Autoimmune Diseases of the Adult, Discovery Medicine 2010; Published February 7, 2010
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12. Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis.
In this review, the authors focused on the safety of and protocols for subcutaneous and sublingual immunotherapy in the treatment of seasonal allergic rhinitis. They also described an approach to selecting allergens for the vaccines so as to avoid secondary sensitization and adverse events. They discussed the therapeutic biomarkers that are correlated with the improvement of clinical symptoms brought about by immunotherapy as well as the involvement of Tr1 and regulatory T cells in the therapeutic mechanisms. Finally they discuss the current immunotherapeutic approaches to treating Japanese cedar pollinosis, the most prevalent pollinosis in Japan, including sublingual immunotherapy with standardized extract, a transgenic rice-based edible vaccine, and an immunoregulatory liposome encapsulating recombinant fusion protein.
Editor's comment: Excellent review about the state of the art of immunotherapy in allergic rhinitis.
Fujimura T, Okamoto Y, Antigen-Specific Immunotherapy against Allergic Rhinitis: The State of the Art. Allergology International 2010; 59(1) :1-11.
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