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Archives: Medical Journal Reviews

Medical Journal Review

Posted: February 2010

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

1. Immunotherapy reduces healthcare costs for children with allergic rhinitis (AR).
To determine whether allergen immunotherapy reduces healthcare costs, the researchers studied Medicaid claims made in Florida between 1997 and 2007 for 2,770 children with newly diagnosed AR who received allergen immunotherapy and who were followed-up for at least 18 months. Each child in the immunotherapy group was matched for age at AR diagnosis, gender, race/ethnicity, and co-morbid asthma, conjunctivitis, or atopic dermatitis, with up to five control children with AR who did not receive immunotherapy. Analysis revealed that immunotherapy-treated children had significantly lower total healthcare costs over the 18-month period after immunotherapy administration than controls, at a median per-person cost of $3,247 (€2269) compared with $4,872 (€3404), respectively. The researchers also note that a significant difference in total healthcare costs between the two groups was evident as early as 3 months after starting immunotherapy. They concluded that this study demonstrated the potential for early and significant cost savings in children with AR treated with immunotherapy.
Editor's comment: Pharmacoeconomics is another reason to indicate immunotherapy in this age group.
Hankin C, Cox L, Lang D et al., Allergen immunotherapy and health care cost benefits for children with allergic rhinitis: a large-scale, retrospective, matched cohort study. Annals of Allergy Asthma and Immunology 2010; 104: 79-85.
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2. Secondhand smoke (SHS) exposure linked to sleep problems in asthmatic children.
The goal of this study was to analyze the association between exposure to SHS and child sleep patterns among a group of 219 children with asthma enrolled in an asthma intervention trial and who had regular exposure to tobacco smoke at home. SHS exposure was measured with serum cotinine levels, and the Children's Sleep Habits Questionnaire was used to evaluate sleep patterns based on parental reports. Statistical analyses allowed adjustment for covariates of age, sex, race, maternal marital status, education, income, prenatal tobacco exposure, maternal depression, home observation for measurement of the environment total score, household density, asthma severity, and use of asthma medications. SHS exposure was associated with longer sleep-onset delay (P = .004), sleep-disordered breathing (P = .02), parasomnias (P = .002), daytime sleepiness (P = .022), and overall sleep disturbance (P = .0002). The authors concluded that significant associations exist between SHS exposure, as measured with a biological marker (serum cotinine levels), and sleep problems in children with asthma.
Editor's comment: Reduction in SHS exposure is an area with the potential for significant impact in the pediatric population.
Yolton K, Xu Y, Khoury J et al, Associations between secondhand smoke exposure and sleep patterns in children. Pediatrics, Published online January 18, 2010 [Epub ahead of print]

3. High-dose inhaled corticosteroids (ICS) may be associated with pulmonary tuberculosis (TB).
The use of high-dose ICS in patients with chronic obstructive pulmonary disease (COPD) has recently been shown to increase the incidence of pneumonia. To investigate the impact of high-dose ICS on pulmonary TB, the authors conducted a retrospective study, including 554 patients aged more than 40 years old with irreversible airflow limitation, between August 2000 and July 2008 in a medical center in Taiwan. Among them, patients using high-dose ICS (equivalent to >500 microg/d of fluticasone) were more likely to have more severe COPD and receive oral corticosteroids than those using medium-dose, low-dose, or no ICS. Sixteen (3%) patients developed active pulmonary TB within a follow-up of 25,544 person-months. Multivariate Cox regression analysis revealed that the use of high-dose ICS, the use of 10 mg or more of prednisolone per day, and prior pulmonary TB were independent risk factors for the development of active pulmonary TB. They concluded that chest radiography and sputum smear/culture for Mycobacterium tuberculosis should be performed before initiating high-dose ICS and regularly thereafter.
Editor's comment: Although systemic administration of corticosteroids is a known risk factor for tuberculosis, this finding should alert us to this possibility.
Shu CC, Wu HD, Yu MC et al, Use of high-dose inhaled corticosteroids is associated with pulmonary tuberculosis in patients with chronic obstructive pulmonary disease. Medicine 2010; 89(1):53-61.

4. The contribution of panallergens to disease manifestation.
The authors reviewed the panallergen concept that encompasses families of related proteins, which are involved in general vital processes and thus widely distributed throughout nature. Plant panallergens share highly conserved sequence regions, structure and function. They are responsible for many IgE cross-reactions even between unrelated pollen and plant food allergen sources. Although usually considered as minor allergens, sensitization to panallergens might be problematic as it bears the risk of developing multiple sensitizations. Clinical manifestations seem to be tightly connected with geographical and exposure factors. Future population- and disease-based screenings should provide new insights on panallergens and their contribution to disease manifestations.
Editor's comment: An excellent review that proposes a novel classification of panallergens.
Hauser M, Roulias A, Ferreira F et al, Panallergens and their impact on the allergic patient. Allergy Asthma & Clinical Immunology 2010; 6(1) [Abstract published online 18 January 2010]
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5. Relieving symptoms in allergic rhinitis (AR).
The authors conducted an evidence-based review of randomized controlled trials, at least 2-week duration, to evaluate how well the medications currently approved in the United States for allergic rhinitis (AR) relieve nasal symptoms (NS). 54 randomized, placebo-controlled studies with AR met the criteria for review: 38 of seasonal allergic rhinitis (SAR; n = 11,980 adults and 946 children) and 12 of perennial allergic rhinitis (PAR; n = 3,800 adults and 366 children). The median percentage changes from baseline for total nasal symptom score for SAR were: nasal antihistamines, -22.2%; oral antihistamines, -23.5%; intranasal steroids (INSs), -40.7%; and placebo, -15.0%. For PAR, the changes were: oral antihistamines, -51.4%; INSs, -37.3%; and placebo, -24.8%. The data confirmed that INSs produced the greatest improvements in nasal symptoms in patients with SAR. In addition, INSs were effective for PAR, and oral antihistamines were equally effective for some patients.
Editor's comment: Although intranasal steroids are the best approved medications for nasal symptoms in AR, oral antihistamines are a valuable option in selected patients.
Benninger M, Farrar J, Blaiss M et al, Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Annals of Allergy, Asthma & Immunology 2010; 104(1):13-29.
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6. Allergy to local anesthetics (LA), although rare, does exist.
Local anesthetics are generally considered safe with respect to allergy. To analyze the follow-up procedures at an allergy clinic and the frequency of identified causative agents and pathogenetic mechanisms and evaluate the diagnostic conclusions, the authors reviewed the medical records of 135 cases with alleged allergic reactions to LA. Diagnoses were based on case histories, skin tests, subcutaneous challenge tests and in vitro IgE analyses. Only two events (1.5%) were diagnosed as hypersensitivity to LA, articaine-adrenaline and tetracaine-adrenaline. Ten reactions (7%) were diagnosed as IgE-mediated allergy to other substances including chlorhexidine, latex, triamcinolone and possibly hexaminolevulinate. As challenge testing was not consistently performed with the culprit LA compound, follow-ups were short of definitely refuting hypersensitivity in 61% of the cases. The reported clinical manifestations most frequent in test-positive cases were itch and generalized urticaria. The authors concluded that reactions during local anesthesia are rarely found to be an IgE-mediated LA allergy.
Editor's comment: The uncertainty of LA allergy often leads to avoidance of local anesthesia and unnecessarily painful interventions, resource-consuming general anesthesia or even the risk of re-exposure to other unidentified allergens.
Harboe T, Guttormsen AB, Aarebrot S et al, Suspected allergy to local anaesthetics: follow-up in 135 cases. Acta Anaesthesiologica Scandinavica 2010 January 6 Early View [Articles online in advance of print]

7. Are sputum eosinophils useful in monitoring asthma control in childhood?
The authors reviewed the technique and also the usefulness of induced sputum in the diagnosis and assessment of asthma, together with its ability to predict the response to treatment and to anticipate asthma exacerbations. The authors concluded that due to cost-effectiveness reasons derived from high labor costs, together with the unpleasantness of the technique and the failure to obtain adequate samples in a non-negligible percentage of children, this technique should be used only for research purposes.
Editor's comment: The sputum eosinophils strategy does not evaluate the non-eosinophilic exacerbations that are very common in childhood.
Garcia-Marcos L, Brand PL, The utility of sputum eosinophils and exhaled nitric oxide for monitoring asthma control with special attention to childhood asthma. Allergologia et Immunopatholgia 2010; 38(1):41-46.
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8. Does the duration of the diet influence the onset of tolerance to cow's milk allergy (CMA)?
To prospectively assess the dietary factors influencing disease duration, the authors randomly switched the formula of symptomatic patients from the Milan CMA Cohort to one of three groups: rice hydrolysate, extensively hydrolyzed cow's milk and soy-based formula. 72 children (mean age at diagnosis: 14.1+/-8.6 months) were followed up for a median of 26 months. 51 reached tolerance at 34.1+/-15.2 months. The mean duration of disease was 40.2+/-4.8 months with milk hydrolysate, 24.3+/-3.6 months with rice and 24.3+/-2.6 months with soy. Dietary choice independently predicted shorter duration of disease [adjusted HRs 3.09 (P=0.007) for rice, 2.54 (P=0.02) for soy, both against milk hydrolysate]. In 50 children not co-sensitized to soy, diet choice impacted the duration of disease more strongly [adjusted HRs 8.02 (P=0.006) for rice, 6.53 (P=0.015) for soy, both against milk hydrolysate]. The authors concluded that patients not exposed to cow's milk protein residue achieve cow's milk tolerance earlier than patients who follow an extensively hydrolyzed cow's milk diet probably due to residual antigenicity in hydrolyzed milks.
Editor's comment: The avoidance of cow's milk is necessary but not sufficient for the induction of tolerance
Terracciano L, Bouygue GR, Sarratud T et al, Impact of dietary regimen on the duration of cow's milk allergy: a random allocation study. Clinical & Experimental Allergy 2010 January 11 Early View (Articles online in advance of print]

9. Clinical outcomes of different particle sizes, delivery devices, and pharmacoeconomics of inhaled corticosteroids (ICS).
There are few studies directly comparing one ICS with another; and there is a paucity of data comparing economic costs of a hydrofluoroalkane (HFA) ultrafine-particle aerosolized ICS with the cost of more conventional ICS delivery devices. This article reviews particle size and delivery devices of different steroids, clinical outcomes of small- versus large-particle steroids, and the issue of pharmacoeconomics.
Editor's comment: Excellent review that sheds light on an issue of extraordinary importance in the treatment of asthma.
Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: does it matter? Journal of Allergy and Clinical Immunology 2009; 124(6):S88-93.

10. Role of plasmacytoid dendritic cells (pDCs) in the regulation of allergic inflammation.
The authors previously showed that bacillus Calmette-Guérin (BCG) inactivated by extended freeze-drying (EFD) reduces airway hyperresponsiveness, whereas live and heat-killed BCG fail to do so. Now they investigated whether EFD BCG targets pDCs potentially involved in the polarization of regulatory T cells (Tregs) and the transcriptional factors that regulate allergic inflammation. OVA-sensitized mice were subcutaneously injected with EFD, live, or heat-killed BCG. They analyzed after the injection of the various BCG preparations: 1) pDCs recruited in the draining lymph nodes (day 4); 2) transcription factors involved in inflammation and T cell commitment in spleen and lungs after OVA challenge (day 28). Airway hyperresponsiveness and transcription factors were determined after in vivo depletion of pDCs or Tregs in EFD BCG-treated and OVA-challenged mice. The authors concluded that EFD BCG reduced allergic inflammation by recruiting pDCs that promoted Tregs; EFD BCG acted as a peroxisome proliferator-activated receptor agonist and thus could be used in asthma and other inflammatory diseases.
Editor's comment: Interesting likely prospect of BCG therapy.
Lagranderie M, Abolhassani M, Vanoirbeek J et al, Mycobacterium bovis Bacillus Calmette-Guérin killed by extended freeze-drying targets plasmacytoid dendritic cells to regulate lung inflammation. The Journal of Immunology 2010; 184(2):1062-1070.

11. Effects of vitamin D on the immune system.
A review of the evidence of the role of vitamin D in the regulation of T and B cells, macrophages, dendritic cells, and keratinocytes, and providing a link between vitamin D and many autoimmune diseases, including Crohn's disease, juvenile diabetes mellitus, multiple sclerosis, asthma, and rheumatoid arthritis. Considering the influence of vitamin D on the immune system, it may have potential as a treatment for immune-mediated diseases, even if additional research is required to better quantify dosage. But the biggest obstacle to its clinical use is its potent hypercalcemic effect. The calcium status of the host may influence the effect of vitamin D on immunity.
Editor's comment: The effect of vitamin D on allergy remains controversial.
Maruotti N and Cantatore F, Vitamin D and the Immune System. The Journal of Rheumatology 2010 January 15 [Published online before print].

12. Merozoite antigens for malaria vaccine development.
The authors performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (IgG) responses to leading vaccine candidates merozoite surface protein (MSP)-142 and erythrocyte binding antigen (EBA)-175 and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-119 (responders versus non-responders, 54%, 95% confidence interval [CI] [33%-68%] and 18% [4%-30%] relative reduction in risk, respectively) and there was evidence of a dose-response relationship. Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens. The authors concluded that these findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria.
Editor's comment: An efficient immune response against merozoites would limit the severity of malarial infections and prevent many deaths.
Fowkes FJI, Richards JS, Simpson JA et al, The relationship between anti-merozoite antibodies and incidence of Plasmodium falciparum malaria: A systematic review and meta-analysis. PLoS Medicine 2010; 7(1):1-20.
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13. Biphasic reactions (BR) to allergen immunotherapy are uncommon.
To investigate the incidence, characteristics, and outcomes of immunotherapy-associated BR, the researchers studied data on 453 patients who received immunotherapy at Meir Hospital Allergy Clinic. All patients underwent peak expiratory flow (PEF) measurements before administration of immunotherapy injections. If an anaphylactic reaction occurred after an injection, the patient was asked to complete a 3-day symptom diary and undergo further PEF measurements. A BR was defined as a late decrease in PEF of more than 20%, with or without accompanying symptoms. The researchers found that just 131 anaphylactic reactions occurred after a total of 21,022 immunotherapy injections. Most uniphasic reactions and all BR occurred in patients who were being treated for allergic rhinitis. BR were also more common in patients with a low baseline PEF and those with asthma. All BR, which included nasal congestion, cough, itchy eyes, shortness of breath and chest tightness, were mild and subsided either spontaneously or after antihistamine treatment. The authors concluded that immunotherapy-induced biphasic reactions are uncommon. They tend to be mild and might be more common in patients with a low baseline PEF or concomitant asthma.
Editor's comment: An anaphylactic reaction is one of the alarming adverse effects of allergen immunotherapy.
Confino-Cohen R and Goldberg A. Allergen immunotherapy-induced biphasic systemic reactions: incidence, characteristics, and outcome: a prospective study. Annals of Allergy Asthma & Immunology 2010; 104(1):73-78.
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14. Possible role of dietary antioxidants in allergic disease (AD).
The authors reviewed the possible role, if any, of dietary antioxidants in AD. It has been hypothesized that the recent increase in AD is a consequence of declining dietary antioxidant intake, but an alternative hypothesis proposes that the increase in AD is due to increasing antioxidant intake. Animal model studies demonstrate that antioxidant supplementation at the time of primary and subsequent allergen exposure attenuates allergic inflammatory responses. The data from human studies are less clear. Most observational studies report potentially beneficial associations between dietary antioxidants and allergic outcomes, but a small minority report potentially adverse associations. Human intervention studies suggest that single antioxidant supplements confer minimal, if any clinical benefit in adults with asthma, however, there is still scope for studies in children, atopic dermatitis, allergic rhinitis (AR) and of antioxidant combinations. The available epidemiological, animal, molecular and immunological data suggest that there are associations between antioxidants and asthma and to a much lesser extent, atopic dermatitis and AR. However, the exact nature of the relationships and the potential for therapeutic intervention remain unclear.
Editor's comment: Comprehensive review on a topic that is still unclear and controversial.
Allan K, Kelly FJ and Devereux G, Antioxidants and allergic disease: a case of too little or too much? Clinical & Experimental Allergy 2010; 40(3):370-380.

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