Efficacy of Low-Dose Versus Traditional Buprenorphine Induction in the Hospital: A Quantitative and Qualitative Study.

BACKGROUND: Emerging evidence suggests low-dose buprenorphine (LDB) induction can expand opportunities for buprenorphine induction in patients who are taking taking methadone, short-acting opioid agonists, or who have anxiety about opioid withdrawal. STUDY QUESTION: How is a rapid LDB protocol using transdermal buprenorphine tolerated in the hospital? STUDY DESIGN: A prospective study of 20 patient encounters (n = 20 patients) with traditional buprenorphine induction before implementation of study protocol (control group) and 37 patient encounters (n = 34 patients) with LDB induction protocol (pilot group). Summary statistics were used to describe demographics, clinical opioid withdrawal scale and pain scores within 24 hours preprotocol and within 24 hours postprotocol initiation, hospital length of stay after protocol initiation, receipt of a buprenorphine prescription at discharge, and prescription activity at 30 days. T test and chi-square tests were used to analyze comparisons. A subset of pilot group patients completed a survey about their experience. RESULTS: There were no statistically significant differences in pain and clinical opioid withdrawal scale scores between the pilot and control groups. There were 5 instances of precipitated withdrawal in the pilot group. There was no statistically significant difference in mean discharge time after protocol initiation between the pilot and control groups (P = 0.60). Most patients surveyed described a positive experience with LDB induction. CONCLUSION: Hospitalization is a critical time to initiate buprenorphine for patients with opioid use disorder. Our data adds to the growing evidence that LDB induction is feasible for patients taking methadone and short-acting opioid agonists, and that a more rapid induction protocol is generally well-tolerated by patients although precipitated withdrawal is a risk. Finally, our rapid induction protocol did not seem to increase hospital length of stay compared with traditional induction.

Pre-Paid Phone Distribution: A Tool for Improving Healthcare Engagement for People with Substance Use Disorder.

BACKGROUND: The COVID-19 pandemic drove significant disruptions in access to substance use disorder (SUD) treatment and harm reduction services. Healthcare delivery via telemedicine has increasingly become the norm, rendering access to a phone essential for engagement in care. METHODS: Adult patients with SUD who lacked phones (n = 181) received a free, pre-paid phone during encounters with inpatient and outpatient SUD programs. We evaluated changes in healthcare engagement including completed in-person and telemedicine outpatient visits and telephone encounters 30 days before and after phone receipt. We used descriptive statistics, where appropriate, and paired t-tests to assess the change in healthcare engagement measures. RESULTS: Patients were predominantly male (64%) and white (62%) with high rates of homelessness (81%) and opioid use disorder (89%). When comparing 30 days before to 30 days after phone receipt, there was a significant increased change in number of telemedicine visits by 0.3 (95% CL [0.1,0.4], p < 0.001) and telephone encounters by 0.2 (95% CL [0.1,0.3], p = 0.004). There was no statistically significant change in in-person outpatient visits observed. CONCLUSIONS: Pre-paid phone distribution to patients with SUD was associated with an increased healthcare engagement including telemedicine visits and encounters.

Text-messaging to promote smoking cessation among individuals with opioid use disorder: quantitative and qualitative evaluation.

INTRODUCTION: Individuals with opioid use disorder (OUD) who smoke cigarettes have high tobacco-related comorbidities, lack of access to tobacco treatment, lack of inclusion in smoking cessation trials, and remain understudied in the mobile health field. The purpose of this study was to understand patients' with OUD perceptions of 1) text message programs to promote smoking cessation, 2) content and features to include in such a program, and 3) how message content should be framed. METHODS: From December 2018 to February 2019, we recruited 20 hospitalized individuals with a concurrent diagnosis of OUD and tobacco dependence at Boston Medical Center (BMC), the largest safety-net hospital in New England. We surveyed participants' cell phone use, their interest in a text message program to promote smoking cessation, and their reactions to and ratings of a series of 26 prototype texts. We then conducted open-ended interviews to elicit content and suggestions on how text message interventions can improve motivation to increase smoking cessation among individuals with OUD. The interviews also included open-ended inquiries exploring message ratings and message content, inquiries about preferences for message duration, frequency, and personalization. RESULTS: Quantitative analysis of questionnaire data indicated that the majority of participants owned a cell phone (95%, 19/20). Most participants (60%, 12/20) reported that they would be interested or very interested in receiving text messages about smoking cessation. Text messages about the health benefits of quitting were rated the highest among various categories of text messages. Qualitative analysis showed that almost every participant felt that text messages would help motivate smoking cessation given the support it would provide. CONCLUSIONS: This study demonstrates that individuals with OUD who smoke cigarettes perceive that a text message program designed to promote smoking cessation would motivate and support smoking cessation efforts. Our findings demonstrate that such a program is feasible as participants own cell phones, frequently send and receive text messages, and have unlimited text message plans. Findings from this study provide valuable insight into content and features to include when developing text message programs to address barriers to smoking cessation in individuals who have OUD and smoke cigarettes.

Dismantling racism against Black, Indigenous, and people of color across the substance use continuum: A position statement of the association for multidisciplinary education and research in substance use and addiction.

The Association for Multidisciplinary Education and Research in Substance Use and Addiction (AMERSA) acknowledges that racism profoundly affects persons who use alcohol and other drugs. Racism's deadly effects compounded with other social determinants of health result in a cascade of negative impacts. The AMERSA Board of Directors (BOD) proposes an initial set of strategies to promote diversity, equity, and inclusion using a framework that speaks to four key AMERSA experiences: engagement, education, mentorship, and leadership. Through these strategies, AMERSA commits to promoting equity and inclusion to dismantle the individual, institutional, and structural racism that has permeated the United States for centuries.

Neurological Complications of Endocarditis: A Multidisciplinary Review with Focus on Surgical Decision Making.

Infective endocarditis (IE) is a systemic disease with many potential neurologic manifestations including ischemic and hemorrhagic strokes, cerebral microbleeding, infectious intracranial aneurysms, meningitis, brain abscesses, and encephalopathy. The majority of left-sided (heart) IE patients have brain lesions that may alter management decisions, warranting the systematic use of magnetic resonance imaging. Many patients require surgical treatment of valvular disease, and central nervous system lesions weigh into decision making. Data regarding the timing of surgery are conflicting, but earlier surgery appears to be safe in most ischemic strokes, while ideally surgery should be delayed for 3 to 4 weeks in patients with hemorrhagic strokes. IE requires a multidisciplinary team to collaboratively care for the patient. In this article, we review the current understanding and management of the neurological complications of IE and their impact on the performance and timing of cardiac surgery.

Optimising health and safety of people who inject drugs during transition from acute to outpatient care: narrative review with clinical checklist.

The opioid epidemic in the USA continues to worsen. Medical providers are faced with the challenge of addressing complications from opioid use disorders and associated injection drug use. Unsafe injection practices among people who inject drugs (PWID) can lead to several complications requiring acute care encounters in the emergency department and inpatient hospital. Our objective is to provide a narrative review to help medical providers recognise and address key health issues in PWID, who are being released from the emergency department and inpatient hospital. In the midst of rises in overdose deaths and infections such as hepatitis C, we highlight several health issues for PWID, including overdose and infection prevention. We provide a clinical checklist of actions to help guide providers in the care of these complex patients. The clinical checklist includes strategies also applicable to low-resource settings, which may lack addiction treatment options. Our review and clinical checklist highlight key aspects of optimising the health and safety of PWID.

A Clinical Guide to Support the Implementation of Addiction Consult Services and the Value of Teaching and Technical Assistance.

ABSTRACT: People with substance use disorders (SUDs) are increasingly admitted to general hospitals; however, many hospital systems lack both formal structures and skilled staff to provide high-quality care for inpatients with SUDs. Inpatient addiction consult services (ACSs), which are increasingly being implemented around the country, are an evidence-based strategy to add focused care for people with SUDs into the general medical setting. In 2018, New York City Health + Hospitals (H + H) launched an ACS program called Consult for Addiction Care and Treatment in Hospitals in six hospitals, supported by a team of addiction consult experts to deliver teaching and technical assistance (TTA) for the Consult for Addiction Care and Treatment in Hospitals ACSs. This commentary describes the TTA, which included site visits, introductory educational lectures, case conferences, ad hoc support, implementation assistance, and the creation of an addiction care guide. Similar TTA services could be used in the future when hospitals or systems want to launch novel clinical programs.

Patient and Clinician Experiences with the Implementation of Telemedicine and Related Adaptations in Office-Based Buprenorphine Treatment During the COVID-19 Pandemic: A Qualitative Study.

Background: Deaths from opioid overdose have increased dramatically in the past decade, representing an epidemic in the United States. For individuals with opioid use disorder (OUD), agonist medications such as methadone and buprenorphine reduce opioid-related morbidity and mortality. Historically, the provision of buprenorphine treatment in office-based settings has relied on frequent in-person contact, likely influencing patients' access to and retention in care. In response to the COVID-19 pandemic, providers of office-based buprenorphine treatment rapidly adapted their care processes, increasingly relying on telemedicine visits. To date, relatively few prior studies have combined patient and clinician perspectives to examine the implementation of telemedicine and related care adaptations, particularly in safety-net settings. Methods: Qualitative methods were used to explore clinician and patient experiences with telemedicine in an office-based buprenorphine treatment clinic affiliated with an urban safety-net hospital. From this clinic, we interviewed 25 patients and 16 clinicians (including prescribers and non-prescribers) to understand how telemedicine impacted treatment quality and engagement in care, as well as preferences for using telemedicine moving forward. Results: Five themes regarding the implementation of telemedicine and other COVID-19-related care adaptations arose from patient and clinician perspectives: 1) telemedicine integration precipitated openness to more flexibility in care practices, 2) concerns regarding telemedicine-related adaptations centered around safety and accountability, 3) telemedicine encounters required rapport and trust between patients and clinicians to facilitate open communication, 4) safety-net patient populations experienced unique challenges when using telemedicine, particularly in terms of the technology required and the need for privacy, and 5) there is an important role for telemedicine in office-based buprenorphine treatment moving forward, primarily through its use in hybrid models of care. Conclusions: Telemedicine implementation within office-based buprenorphine treatment has the potential to improve patients' engagement in care; however, our findings emphasize the need for tailored approaches to implementing telemedicine in office-based buprenorphine treatment, particularly within safety-net settings. Overall, this study supports the maintenance of changes to policy and practice that facilitate the use of telemedicine in office-based buprenorphine treatment beyond the COVID-19 public health emergency.

Offering nurse care management for opioid use disorder in primary care: Impact on emergency and hospital utilization in a cluster-randomized implementation trial.

BACKGROUND: Patients with opioid use disorder (OUD) have increased emergency and hospital utilization. The PROUD trial showed that implementation of office-based addiction treatment (OBAT) increased OUD medication treatment compared to usual care, but did not decrease acute care utilization in patients with OUD documented pre-randomization (clinicaltrials.gov/study/NCT03407638). This paper reports secondary emergency and hospital utilization outcomes in patients with documented OUD in the PROUD trial. METHODS: This cluster-randomized implementation trial was conducted in 12 clinics from 6 diverse health systems (March 2015-February 2020). Patients who visited trial clinics and had an OUD diagnosis within 3 years pre-randomization were included in primary analyses; secondary analyses added patients with OUD who were new to the clinic or with newly-documented OUD post-randomization. Outcomes included days of emergency care and hospital utilization over 2 years post-randomization. Explanatory outcomes included measures of OUD treatment. Patient-level analyses used mixed-effect regression with clinic-specific random intercepts. RESULTS: Among 1988 patients with documented OUD seen pre-randomization (mean age 49, 53 % female), days of emergency care or hospitalization did not differ between intervention and usual care; OUD treatment also did not differ. In secondary analyses among 1347 patients with OUD post-randomization, there remained no difference in emergency or hospital utilization despite intervention patients receiving 32.2 (95 % CI 4.7, 59.7) more days of OUD treatment relative to usual care. CONCLUSIONS: Implementation of OBAT did not reduce emergency or hospital utilization among patients with OUD, even in the sample with OUD first documented post-randomization in whom the intervention increased treatment.

Grayken lessons: the role of an interdisciplinary endocarditis working group in evaluating and optimizing care for a woman with opioid use disorder requiring a second tricuspid valve replacement.

BACKGROUND: Injection drug use-related endocarditis is increasingly common among hospitalized patients in the United States, and associated morbidity and mortality are rising. CASE PRESENTATION: Here we present the case of a 34-year-old woman with severe opioid use disorder and multiple episodes of infective endocarditis requiring prosthetic tricuspid valve replacement, who developed worsening dyspnea on exertion. Her echocardiogram demonstrated severe tricuspid regurgitation with a flail prosthetic valve leaflet, without concurrent endocarditis, necessitating a repeat valve replacement. Her care was overseen by our institution's Endocarditis Working Group, a multidisciplinary team that includes providers from addiction medicine, cardiology, infectious disease, cardiothoracic surgery, and neurocritical care. The team worked together to evaluate her, develop a treatment plan for her substance use disorder in tandem with her other medical conditions, and advocate for her candidacy for valve replacement. CONCLUSIONS: Multidisciplinary endocarditis teams such as these are important emerging innovations, which have demonstrated improvements in outcomes for patients with infective endocarditis and substance use disorders, and have the potential to reduce bias by promoting standard-of-care treatment.

Developing a Women's Health track within addiction medicine fellowship: reflections and inspirations.

BACKGROUND: Women who use drugs face sexism and intersectional stigma that influence their drug use experiences and treatment needs. There is a need to build the capacity of addiction medicine specialists who can deliver gender-responsive services and advance research and policy in women-focused addiction care. We describe the development of a Women's Health track within an addiction medicine fellowship program and reflect on successes, challenges, and future directions. MAIN BODY: The Women's Health track was developed in collaboration between program leaders in Addiction Medicine and Obstetrics/Gynecology. Implementing the track led to the development of women-focused rotations and continuity clinics, as well as enrichment of women's health didactic education for all fellows. The fellowship track spurred interdepartmental mentorship and collaboration on research and advocacy projects. CONCLUSION: Addiction medicine fellowships can replicate this curriculum model to advance women-focused education, research, and policy. Future curricula should focus on structural sexism in drug use and addiction treatment throughout a woman's life course.

Strokes in Patients With Injection Drug Use and Tricuspid Valve Endocarditis - A Case Series.

Research Design: In this study, we describe patients from a tertiary care safety-net hospital endocarditis registry with tricuspid valve infective endocarditis (TVIE), and concomitant acute or subacute ischemic stroke predominantly associated with injection drug use (IDU). We retrospectively obtained data pertinent to neurologic examinations, history of injection drug use (IDU), blood cultures, transthoracic/transesophageal echocardiography (TTE/TEE), neuroimaging, and Modified Rankin Scale (mRS) scores at discharge. Only those patients with bacteremia, tricuspid valve vegetations, and neuroimaging consistent with acute to subacute ischemic infarction and microhemorrhages in two cases were included in this series. Results: Of 188 patients in the registry, 66 patients had TVIE and 10 of these were complicated by ischemic stroke. Neurologic symptoms were largely non-specific, eight patients had altered mental status and only 3 had focal deficits. Nine cases were associated with IDU. Two patients had evidence of a patent foramen ovale on echocardiography. Blood cultures grew S. aureus species in 9 of the patients, all associated with IDU. Three patients died during hospitalization. The mRS score at discharge for survivors ranged 0-4. Conclusions: Patients with strokes from TVIE had heterogeneous presentations and putative mechanisms. We noted that robust neuroimaging is lacking for patients with TVIE from IDU and that such patients may benefit from neuroimaging as a screen for strokes to assist peri-operative management. Further inquiry is needed to elucidate stroke mechanisms in these patients.

Nurse Care Management for Opioid Use Disorder Treatment: The PROUD Cluster Randomized Clinical Trial.

Importance: Few primary care (PC) practices treat patients with medications for opioid use disorder (OUD) despite availability of effective treatments. Objective: To assess whether implementation of the Massachusetts model of nurse care management for OUD in PC increases OUD treatment with buprenorphine or extended-release injectable naltrexone and secondarily decreases acute care utilization. Design, Setting, and Participants: The Primary Care Opioid Use Disorders Treatment (PROUD) trial was a mixed-methods, implementation-effectiveness cluster randomized clinical trial conducted in 6 diverse health systems across 5 US states (New York, Florida, Michigan, Texas, and Washington). Two PC clinics in each system were randomized to intervention or usual care (UC) stratified by system (5 systems were notified on February 28, 2018, and 1 system with delayed data use agreement on August 31, 2018). Data were obtained from electronic health records and insurance claims. An implementation monitoring team collected qualitative data. Primary care patients were included if they were 16 to 90 years old and visited a participating clinic from up to 3 years before a system's randomization date through 2 years after. Intervention: The PROUD intervention included 3 components: (1) salary for a full-time OUD nurse care manager; (2) training and technical assistance for nurse care managers; and (3) 3 or more PC clinicians agreeing to prescribe buprenorphine. Main Outcomes and Measures: The primary outcome was a clinic-level measure of patient-years of OUD treatment (buprenorphine or extended-release injectable naltrexone) per 10 000 PC patients during the 2 years postrandomization (follow-up). The secondary outcome, among patients with OUD prerandomization, was a patient-level measure of the number of days of acute care utilization during follow-up. Results: During the baseline period, a total of 130 623 patients were seen in intervention clinics (mean [SD] age, 48.6 [17.7] years; 59.7% female), and 159 459 patients were seen in UC clinics (mean [SD] age, 47.2 [17.5] years; 63.0% female). Intervention clinics provided 8.2 (95% CI, 5.4-∞) more patient-years of OUD treatment per 10 000 PC patients compared with UC clinics (P = .002). Most of the benefit accrued in 2 health systems and in patients new to clinics (5.8 [95% CI, 1.3-∞] more patient-years) or newly treated for OUD postrandomization (8.3 [95% CI, 4.3-∞] more patient-years). Qualitative data indicated that keys to successful implementation included broad commitment to treat OUD in PC from system leaders and PC teams, full financial coverage for OUD treatment, and straightforward pathways for patients to access nurse care managers. Acute care utilization did not differ between intervention and UC clinics (relative rate, 1.16; 95% CI, 0.47-2.92; P = .70). Conclusions and Relevance: The PROUD cluster randomized clinical trial intervention meaningfully increased PC OUD treatment, albeit unevenly across health systems; however, it did not decrease acute care utilization among patients with OUD. Trial Registration: ClinicalTrials.gov Identifier: NCT03407638.

Adapting methadone inductions to the fentanyl era.

Since 2013, fentanyl and fentanyl analogs, which are significantly more potent than heroin, have been increasingly prevalent in the opioid drug supply. A need exists to adapt methadone dosing from opioid treatment programs (OTPs) in this era. Current methadone protocols at many clinics in the United States are based on expert consensus documents that were created prior to the introduction of fentanyl into the drug supply and are relatively conservative. To date, most OTP reform efforts have focused on relaxation of regulations for take-homes and have not addressed the need to adapt methadone induction schedules to be more rapid in the fentanyl era, as allowed by current regulations. Written by OTP and inpatient consult service addiction medicine physicians with expertise in OUD treatment from across the United States, the aims of the perspective piece are to: 1) highlight the need to improve OTP care by adapting methadone inductions to the fentanyl era, 2) cite emerging evidence for and examples of experiences of OTPs using more aggressive methadone inductions, and 3) call for research and updated guidelines on safety and best practices for methadone induction.

Permanent Methadone Treatment Reform Needed to Combat the Opioid Crisis and Structural Racism.

Since early 2020 COVID-19 has swept across the United States, exposing shortcomings in the current healthcare delivery system. Although some interim efforts have been made to mitigate the spread of infection and maintain access to treatment for opioid use disorder, more permanent changes are needed to combat the ongoing opioid crisis. In this commentary, we describe the regulatory barriers to methadone maintenance treatment that disproportionately impact communities of color. We then discuss strategies supporting more equitable access to this proven treatment for opioid use disorder.

Current Best Practices for Acute and Chronic Management of Patients with Opioid Use Disorder.

This comprehensive review on opioids summarizes the scope of the current opioid epidemic, the diagnosis and treatment of opioid use disorder, and the medical and psychiatric complications of opioid use.

Northeast Postacute Medical Facilities Disproportionately Reject Referrals For Patients With Opioid Use Disorder.

Referrals of hospitalized patients with opioid use disorder (OUD) to postacute medical care facilities are commonly rejected. We linked all electronic referrals from a Boston safety-net hospital in 2018 to clinical data and used multivariable logistic regression to examine the association between OUD diagnosis and rejection from postacute medical care. Hospitalized patients with OUD were referred to more facilities than patients without OUD (8.2 versus 6.6 per hospitalization), were rejected a greater proportion of the time (83.3 percent versus 65.5 percent), and in adjusted analyses had greater odds of rejection from postacute care (adjusted odds ratio, 2.2). In addition, people with OUD were referred disproportionately to a small subset of facilities with a higher likelihood of acceptance. Our findings document disparities in postacute care admissions for people with OUD. Efforts to ensure equitable access to medically necessary postacute medical care for people with OUD are needed.

Management of opioid use disorder and associated conditions among hospitalized adults: A Consensus Statement from the Society of Hospital Medicine.

Hospital-based clinicians frequently care for patients with opioid withdrawal or opioid use disorder (OUD) and are well-positioned to identify and initiate treatment for these patients. With rising numbers of hospitalizations related to opioid use and opioid-related overdose, the Society of Hospital Medicine convened a working group to develop a Consensus Statement on the management of OUD and associated conditions among hospitalized adults. The guidance statement is intended for clinicians practicing medicine in the inpatient setting (e.g., hospitalists, primary care physicians, family physicians, advanced practice nurses, and physician assistants) and is intended to apply to hospitalized adults at risk for, or diagnosed with, OUD. To develop the Consensus Statement, the working group conducted a systematic review of relevant guidelines and composed a draft statement based on extracted recommendations. Next, the working group obtained feedback on the draft statement from external experts in addiction medicine, SHM members, professional societies, harm reduction organizations and advocacy groups, and peer reviewers. The iterative development process resulted in a final Consensus Statement consisting of 18 recommendations covering the following topics: (1) identification and treatment of OUD and opioid withdrawal, (2) perioperative and acute pain management in patients with OUD, and (3) methods to optimize care transitions at hospital discharge for patients with OUD. Most recommendations in the Consensus Statement were derived from guidelines based on observational studies and expert consensus. Due to the lack of rigorous evidence supporting key aspects of OUD-related care, the working group identified important issues necessitating future research and exploration.

Clinical impact, costs, and cost-effectiveness of hospital-based strategies for addressing the US opioid epidemic: a modelling study.

BACKGROUND: The syndemic of injection drug use and serious injection-related infections is leading to increasing mortality in the USA. Although outpatient treatment with medications for opioid use disorder reduces overdose risk and recurrent infections, hospitalisation remains common. We evaluated the clinical impact, costs, and cost-effectiveness of hospital-based strategies to address the US opioid epidemic. METHODS: We developed a microsimulation model to compare the cost-effectiveness of: standard hospital care-detoxification for opioids, no addiction consult service (status quo); expanded inpatient prescribing of medications for opioid use disorder, including bridge prescriptions (ie, medication until they can see an outpatient provider) when possible (medications for opioid use disorder with bridge); implementation of addiction consult services within the hospital (addiction consult services alone); and a combined medication for opioid use disorder with addiction consult services strategy (combined). We used clinical trials and observational cohorts to inform model inputs. Outcomes were life-years, discounted costs, incremental cost-effectiveness ratios, hospitalisations, and deaths. We did deterministic sensitivity analyses on key model inputs related to costs and sequelae of drug use and probabilistic sensitivity analysis to further address uncertainty. FINDINGS: Among people who inject opioids in the USA, we estimated that expanding medications for opioid use disorder with bridge prescriptions would reduce hospitalisations and overdose deaths by 3·2% and 3·6%, respectively, and the combination of expanded medications with opioid use disorder along with addiction consult sevices would reduce hospitalisations and overdoses by 5·2% and 6·6%, respectively, compared with the status quo. Mean lifetime costs ranged from US$731 400 (95% credible interval 447 911-859 189 for the medications for opioid use disorder strategy) to $741 200 (470 930-868 551 for the combined strategy) per person. Assuming a willingness-to-pay threshold of $100 000 per life-year gained, medications for opioid use disorder with bridge and combined strategies were cost-effective ($7600 and $14 300, respectively). A scenario that assumed ideal access to harm reduction services came to the same conclusions as the base case and our results were robust in deterministic and probabilistic sensitivity analyses. INTERPRETATION: The combined interventions of expanding hospital-based prescribing of medications for opioid use disorder and implementing addiction consult services could improve life expectancy, be cost-effective, and could be the basis for a comprehensive hospital-based strategy for addressing the opioid epidemic in the USA and countries with similar opioid epidemics. FUNDING: National Institute on Drug Abuse and National Institute of Allergy and Infectious Diseases.