Research Spotlight

Arroliga, M. E., A. Vazquez-Sandoval, J. Dvoracek and A. C. Arroliga (2016). “Penicillin skin testing is a safe method to guide beta-lactam administration in the intensive care unit.” Ann Allergy Asthma Immunol 116(1): 86-87.

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Geng et al. analyzed factors associated with negative histamine control reactions in patients evaluated with a penicillin skin test (PST) for allergy to β-lactams. In a case–control study of 52 patients with a negative response and 125 controls with a normal response, they used histamine dihydrochloride at a concentration of 6 mg/mL for prick or puncture skin testing but did not perform intradermal testing.1 Admission to an intensive care unit (ICU), older age, and treatment with systemic steroids and H2 blockers were associated with negative histamine responses. Geng et al1 cited our work and suggested that it was difficult to assess the precise risk of a negative histamine response during skin testing in the ICU owing to the heterogeneity of conditions, comorbidities, and medications. The response to histamine is influenced by many factors, including but not limited to age, sex, reactivity to allergens, and photoaging of the skin. Histamine response decreases with aging (>65 years), particularly in women. Patients with multiple allergen sensitizations as indicated by multiple positive skin test responses tend to have larger histamine wheals. Medications such as H2 blockers and photoaging are associated with a weaker response to histamine. These factors might be of importance in the study by Geng et al. because there were differences in age between patients with negative histamine responses and controls. Patients with negative histamine responses were older than the patients in our cohorts. There are many differences besides age between our reports and the report of Geng et al. Geng et al. did not use intradermal testing owing to concerns of subjecting patients to a higher risk of exposure to intradermal antibiotics that could lead to anaphylaxis. All our patients underwent intradermal testing as part of our PST protocol. The PST is safe provided that strict protocols are followed. Intradermal testing must be preceded by a negative prick or puncture test reaction to increase safety. Intradermal tests have higher sensitivity than prick or puncture tests when testing for penicillin allergy. Positive responses are those that have a wheal of at least 5 mm in diameter and a flare larger than the wheal with a negative response to the control saline solution and a positive response to histamine. Our studies dealt with the questions of whether patients with a history of penicillin allergy admitted to an ICU could take penicillins safely. In a cohort of 596 patients of whom 300 were admitted to the ward and 145 to the ICU, the PST was safe and helped to guide the administration of β-lactams. The PST response was negative in 88%, positive in 8%, and indeterminate (negative histamine response) in 3.4%. Most of our positive results were with PrePen intradermal injection (36 of 49) and only 0.17% of patients developed an urticarial reaction after an intradermal PST. From 39%4 to 57%9 were challenged safely with a β-lactam (the percentage of patients challenged in the ICU was 70%) with a negative predictive value for an IgE-mediated event of 99.3%. Two of 290 patients had a reaction that included flushing and urticarial and a pruritic rash within 12 hours of administration of a β-lactam. Although we did not do it in our studies, current recommendations include the administration of a single oral dose of amoxicillin to confirm adequate tolerance after a negative PST response. The PST adequately performed in patients labeled allergic to penicillins could have an important impact from the public health point of view. Patients labeled as allergic to penicillins or first-generation cephalosporins without formal evaluation have more hospital use and have increased rates of infections with Clostridium difficile, vancomycin-resistant Enterococcus species, and methicillin-resistant Staphylococcus aureus. In patients with life-threatening infections, such as methicillin-sensitive S aureus, allergy evaluation with a history-appropriate PST is preferred. In summary, the PST is safe and a very useful tool in the management of the ambulatory and hospitalized patient with a history of penicillin allergy, including the critically ill. Allergists and immunologists working together with infectious diseases specialists and critical care physicians are in a unique position to help make the correct diagnosis. Making the correct diagnosis will have financial and epidemiologic consequences for the patient and for the entire health care system.

Blum, J. L., A. Goncalves, N. Efrat, M. Debled, P. Conte, P. D. Richards, D. Richards, P. Lardelli, A. Nieto, M. Cullell-Young and S. Delaloge (2016). “A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer.” Breast Cancer Res Treat 155(2): 295-302.

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Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

Allison, J. J., H. L. Nguyen, D. A. Ha, G. Chiriboga, H. N. Ly, H. T. Tran, N. T. Phan, N. C. Vu, M. Kim and R. J. Goldberg (2016). “Culturally adaptive storytelling method to improve hypertension control in Vietnam – “We talk about our hypertension”: study protocol for a feasibility cluster-randomized controlled trial. Trials 17(1): 26.

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BACKGROUND: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. At present, the major risk factors for cardiovascular disease (CVD) are either on the rise or at alarming levels in Vietnam; inasmuch, the burden of CVD will continue to increase in this country unless effective prevention and control measures are put in place. A national survey in 2008 found that the prevalence of hypertension (HTN) was approximately 25 % among Vietnamese adults and it increased with advancing age. Therefore, novel, large-scale, and sustainable interventions for public health education to promote engagement in the process of detecting and treating HTN in Vietnam are urgently needed. METHODS: A feasibility randomized trial will be conducted in Hung Yen province, Vietnam to evaluate the feasibility and acceptability of a novel community-based intervention using the “storytelling” method to enhance the control of HTN in adults residing in four rural communities. The intervention will center on stories about living with HTN, with patients speaking in their own words. The stories will be obtained from particularly eloquent patients, or “video stars,” identified during Story Development Groups. The study will involve two phases: (i) developing a HTN intervention using the storytelling method, which is designed to empower patients to facilitate changes in their lifestyle practices, and (ii) conducting a feasibility cluster-randomized trial to investigate the feasibility, acceptability, and potential efficacy of the intervention compared with usual care in HTN control among rural residents. The trial will be conducted at four communes, and within each commune, 25 individuals 50 years or older with HTN will be enrolled in the trial resulting in a total sample size of 100 patients. DISCUSSION: This feasibility trial will provide the necessary groundwork for a subsequent large-scale, fully powered, cluster-randomized controlled trial to test the efficacy of our novel community-based intervention. Results from the full-scale trial will provide health policy makers with practical evidence on how to combat a key risk factor for CVD using a feasible, sustainable, and cost-effective intervention that could be used as a national program for controlling HTN in Vietnam and other developing countries. TRIAL REGISTRATION: ClinicalTrials.gov. REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT02483780 (registration date June 22, 2015).

Bhushan, R., M. G. Lebwohl, A. B. Gottlieb, K. Boyer, E. Hamarstrom, N. J. Korman, R. S. Kirsner, A. J. Sober and A. Menter (2016). “Translating psoriasis guidelines into practice: Important gaps revealed.” J Am Acad Dermatol. 74(3): 544-551.

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BACKGROUND: There is a well-established lack of adherence to evidence-based clinical guidelines. The American Academy of Dermatology (AAD) developed educational sessions entitled Translating Evidence into Practice based on the published guidelines for psoriasis and psoriatic arthritis. OBJECTIVE: We sought to determine the effectiveness of Translating Evidence into Practice sessions in improving patient care. METHODS: Pre- and post-session surveys were administered at Translating Evidence into Practice sessions. A follow-up was administered 6 months after completion of the most recent session, which was 2.5 years after the first session. RESULTS: At both post-session and follow-up, more than 92% of participants believed the sessions had improved their knowledge. The proportion of participants that self-reported assessing disease severity, comorbidities, and quality of life increased at follow-up. Participants’ self-reported counseling of patients and confidence in treating psoriasis and psoriatic arthritis also increased at post-session and follow-up. Greater than 97% of participants thought the sessions would have a positive impact on their practice whereas 50% reported making a change in practice. LIMITATIONS: Lack of a control group, the self-reported nature of the data, and potential participant bias are limitations. CONCLUSION: The AAD’s Translating Evidence into Practice sessions are effective and well received for improving knowledge and practice and can be useful to determine self-reported practice gaps.

Papp, K., M. A. Menter, M. Raman, D. Disch, D. E. Schlichting, C. Gaich, W. Macias, X. Zhang and J. M. Janes (2016). “A Randomized Phase 2b Trial of Baricitinib, an Oral JAK1/JAK2 Inhibitor, in Patients with Moderate-to-Severe Psoriasis.” Br J Dermatol. Jan 22. doi: 10.1111/bjd.14403. [Epub ahead of print]

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BACKGROUND: The safety and efficacy of baricitinib, an oral JAK1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis was evaluated in a randomized, double-blind, placebo-controlled, dose-ranging phase 2b study. METHODS: Patients were randomized (n=271) to receive placebo or oral baricitinib at 2, 4, 8, or 10 mg once daily for 12 weeks (Part A). Dose adjustment for 12 additional weeks was based on percentage improvement in Psoriasis Area and Severity Index (PASI) score. OBJECTIVES: Primary endpoint was PASI-75 at 12 weeks for North American patients (n=238); secondary were safety and efficacy measures in the entire population. RESULTS: At week 12, more North American patients in 8-mg (43%) and 10-mg (54%) baricitinib groups than in placebo group (17%; p<0.05) achieved PASI-75. All baricitinib-treated groups had greater mean changes from baseline in PASI score (p<0.05) at 12 weeks and (except 2 mg) had higher rates of PASI-50 than placebo group; statistically significant PASI-90 responses were achieved in the 8-mg and 10-mg groups at 8 and 12 weeks. More than 81% of PASI-75 responders maintained their scores through 24 weeks. During Part A, study discontinuations due to adverse events (AEs) were 0%, 0%, 2.8%, 6.3%, and 5.8% and treatment-emergent AE rates were 44%, 50%, 47%, 58%, and 64% for placebo and 2-, 4-, 8-, and 10-mg baricitinib groups, respectively. No opportunistic infections were observed in any treatment group. Dose-dependent changes in laboratory values were observed. CONCLUSION: Patients with moderate-to-severe psoriasis treated with baricitinib for 12 weeks achieved significant improvements in PASI-75.