Drug allergy Testing and Hypersensitivity in ICU

 

Drug Testing for Allergy and Diagnosing Drug Hypersensitivity in the ICU: A Comprehensive Review

Dr Neeraj Manikath, Claude.ai

Abstract

Drug hypersensitivity reactions present unique diagnostic and management challenges in the intensive care unit (ICU). The critically ill patient population experiences a high burden of drug exposure, altered pharmacokinetics and pharmacodynamics, and competing causes for clinical manifestations that can mimic allergic reactions. This review synthesizes current evidence regarding the epidemiology, pathophysiology, diagnosis, and management of drug allergies in the ICU setting. We examine available diagnostic methods including in vitro tests, skin testing, and drug provocation testing, discussing their utility and limitations specifically in critical care environments. Special consideration is given to commonly implicated drug classes in the ICU, including antibiotics, neuromuscular blocking agents, analgesics, and contrast media. The review concludes with practical recommendations for implementing systematic approaches to drug allergy assessment in ICU patients and identifies promising areas for future research.

1. Introduction and Scope

Drug hypersensitivity reactions (DHRs) represent a subset of adverse drug reactions (ADRs) mediated by specific immunological mechanisms or direct activation of inflammatory mediators.[1] These reactions pose significant challenges in all clinical settings, but they present unique complexities in the intensive care unit (ICU), where patients receive multiple medications simultaneously, have altered organ function, and often cannot provide coherent histories.[2,3]

The consequences of DHRs in critical care can be severe, ranging from delayed therapeutic interventions to life-threatening anaphylaxis. Yet, diagnostic approaches established in outpatient allergy clinics often cannot be readily applied to critically ill patients.[4] Similarly, management strategies may require modification to accommodate the urgent medication needs and physiological instability characteristic of ICU patients.

This review aims to:

1. Summarize the epidemiology and classification of drug hypersensitivity reactions relevant to critical care
2. Outline diagnostic approaches for DHRs tailored to the ICU environment
3. Discuss testing methodologies with their respective advantages and limitations
4. Review specific drug classes commonly implicated in ICU-related hypersensitivity
5. Provide evidence-based recommendations for management and prevention strategies

2. Epidemiology of Drug Hypersensitivity in Critical Care

The true incidence of drug allergies in ICU patients remains unclear due to inconsistent reporting, variable diagnostic criteria, and challenges in distinguishing hypersensitivity reactions from other adverse events in complex critical illness.[5] Available data suggest that between 10-15% of hospitalized patients report drug allergies, though studies specific to critical care settings are limited.[6]

Anaphylaxis, the most severe form of immediate hypersensitivity reaction, occurs in approximately 1 in 4,000 to 20,000 hospital admissions, with higher rates observed in perioperative and critical care settings.[7] A large multicenter study by Alvarez-Perea et al. found that medications were responsible for 47.4% of anaphylaxis cases requiring ICU admission, with antibiotics (38.3%) and neuromuscular blocking agents (NMBAs) (22.6%) being the most common culprits.[8]

ICU patients face additional risk factors for DHRs, including:

• Exposure to multiple medications simultaneously
• Frequent administration of high-risk drugs (antibiotics, NMBAs, opioids)
• Altered drug metabolism due to organ dysfunction
• Immunological perturbations associated with critical illness
• Limited opportunity for comprehensive allergy history prior to drug administration
• Genetic predisposition that may be unmasked by critical illness[9,10]

The economic impact of DHRs in critical care is substantial, with studies reporting increased length of stay, higher treatment costs, and greater morbidity among affected patients.[11]

3. Classification of Drug Hypersensitivity Reactions

Drug hypersensitivity reactions are traditionally classified according to the Gell and Coombs system, which categorizes immunological reactions into four types based on their mechanism:[12,13]

Type I (Immediate hypersensitivity): IgE-mediated reactions occurring within minutes to hours after drug exposure. Clinical manifestations range from urticaria and angioedema to anaphylaxis. Common culprits include beta-lactam antibiotics, NMBAs, and iodinated contrast media.

Type II (Cytotoxic): Antibody-mediated (IgG or IgM) reactions directed against cell surface antigens, resulting in cell destruction. Examples include drug-induced immune hemolytic anemia, thrombocytopenia, and neutropenia.

Type III (Immune complex): Deposition of drug-antibody complexes in tissues, activating complement and inflammatory cascades. Clinical manifestations include serum sickness, vasculitis, and drug-induced lupus.

Type IV (Delayed-type hypersensitivity): T-cell mediated reactions occurring 24 hours to several days after exposure. This category has been further subdivided into Types IVa-IVd based on the T-cell subsets and effector mechanisms involved.[14] Manifestations range from contact dermatitis to severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Beyond the Gell and Coombs classification, recent advances in understanding molecular and cellular mechanisms have led to recognition of additional hypersensitivity mechanisms relevant to critical care:[15,16]

• Direct mast cell activation: Certain drugs (opioids, vancomycin, quinolones) can directly trigger mast cell degranulation without prior sensitization, resulting in "pseudo-allergic" or "anaphylactoid" reactions.

• Mixed mechanisms: Some reactions involve multiple immune pathways simultaneously or sequentially.

• Pharmacogenetic predisposition: Genetic variations in drug metabolism or HLA can predispose to certain drug reactions, as exemplified by abacavir hypersensitivity in HLA-B*57:01 carriers.[17]

In the ICU setting, distinguishing between different types of hypersensitivity reactions is crucial for guiding both diagnostic approaches and management strategies, though often complicated by confounding factors such as concurrent infections, underlying diseases, and polypharmacy.[18]

4. Challenges Specific to the ICU Setting

Drug hypersensitivity diagnosis and management in the ICU present distinct challenges compared to outpatient settings:[19,20]

Diagnostic Challenges

1. Altered presentation: Critical illness may mask or mimic allergic symptoms. For example, cutaneous manifestations may be obscured in sedated patients or those with edema, while respiratory symptoms may be attributed to underlying conditions rather than hypersensitivity.

2. Multiple concurrent medications: ICU patients often receive numerous drugs simultaneously, complicating the identification of the culprit agent.

3. Limited patient history: Many ICU patients cannot provide allergic histories due to altered mental status, sedation, or intubation.

4. Physiological instability: Hemodynamic and respiratory fluctuations from critical illness may be difficult to distinguish from allergic reactions.

5. Confounding factors: Sepsis, acute respiratory distress syndrome (ARDS), and transfusion reactions can present with clinical features similar to drug hypersensitivity.

Management Challenges

1. Limited therapeutic alternatives: Critical care often requires specific antimicrobials or sedatives with few alternatives, making avoidance strategies difficult.

2. Urgent drug administration: Life-saving interventions may necessitate administration of high-risk medications despite suspected hypersensitivity.

3. Risk-benefit assessment: The potential consequences of withholding essential medications must be balanced against the risk of hypersensitivity reactions.

4. Testing limitations: Many diagnostic tests require patient cooperation, stable vital signs, or interruption of certain medications—conditions rarely achievable in the ICU.

5. Documentation deficiencies: Critical information about hypersensitivity reactions may be lost during transitions of care or emergency admissions.[21]

System-Level Factors

1. Lack of standardized protocols: Few institutions have established protocols for drug allergy assessment in critical care settings.

2. Limited specialist input: Access to allergy/immunology consultation may be delayed or unavailable in many hospitals.

3. Inadequate electronic health record (EHR) alerts: EHR systems may not effectively flag potential cross-reactivity issues in emergent situations.[22]

Recognition of these challenges underscores the need for specialized approaches to drug hypersensitivity in the ICU that balance diagnostic rigor with the practical constraints of critical care.

5. Diagnostic Approaches

Diagnosing drug hypersensitivity in the ICU requires a multifaceted approach adapted to the unique constraints of critical care. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Network for Drug Allergy (ENDA) have published guidelines for drug allergy diagnosis, though these require modification for the ICU setting.[23,24]

Clinical History and Examination

A thorough medication history remains the cornerstone of diagnosis, though often limited in the ICU. Key elements include:

• Timing of reaction in relation to drug administration
• Previous exposures and reactions
• Concurrent medications
• Detailed description of clinical manifestations
• Response to withdrawal of suspected drug
• Alternative explanations for symptoms[25]

When patients cannot provide this information, clinicians should consult family members, outpatient records, pharmacy databases, and previous hospitalization records. The electronic health record can be valuable but may contain inaccurate or incomplete allergy documentation.[26]

Physical examination should focus on cutaneous manifestations (urticaria, angioedema, maculopapular eruptions), respiratory symptoms, and cardiovascular stability. Serial examinations may capture evolving manifestations, particularly in delayed reactions.[27]

In Vitro Testing Methods

Laboratory tests offer advantages in the ICU as they can be performed without patient cooperation and do not carry risk of triggering reactions. However, their utility varies by reaction type and specific drug:[28,29]

Tryptase: Serum tryptase levels peak 1-2 hours after anaphylactic reactions and return to baseline within 24 hours. Elevated levels (>11.4 ng/mL or >2+[1.2×baseline]) support mast cell degranulation but are not drug-specific. Sensitivity ranges from 30-94% depending on reaction severity and timing of collection.[30]

Drug-specific IgE (sIgE): Commercially available for a limited number of drugs including beta-lactam antibiotics, NMBAs, and some biologics. Sensitivity varies widely (30-85%) but specificity is generally high (85-97%). Results must be interpreted in clinical context as positivity indicates sensitization but not necessarily clinical allergy.[31]

Basophil Activation Test (BAT): Measures activation markers (CD63, CD203c) on basophils following in vitro drug exposure. Useful for NMBAs, antibiotics, and NSAIDs with sensitivity of 50-80% and specificity >90%. Limited by technical complexity, need for fresh samples, and lack of standardization.[32,33]

Lymphocyte Transformation Test (LTT): Measures T-cell proliferation in response to drug exposure. Primarily useful for delayed hypersensitivity reactions with sensitivity of 56-78% and specificity >85%. Technical demands limit widespread availability.[34]

Enzyme-Linked Immunospot (ELISpot): Detects drug-specific cytokine-secreting T-cells. Emerging method for delayed hypersensitivity with promising sensitivity (80-95%) but limited commercial availability.[35]

HLA typing: Certain HLA alleles strongly associate with specific drug hypersensitivities (e.g., HLA-B57:01 with abacavir, HLA-B15:02 with carbamazepine). Particularly valuable for preventing severe cutaneous adverse reactions in at-risk populations.[36]

In Vivo Testing Methods

Skin testing remains the gold standard for diagnosing immediate hypersensitivity reactions to many drugs but presents particular challenges in the ICU:[37,38]

Skin Prick Testing (SPT): Generally safe but requires:

• Temporary discontinuation of antihistamines (often impossible in ICU)
• Accessible, uninvolved skin (challenging with extensive edema or skin conditions)
• Patient cooperation (difficult with sedation or delirium)
• Standardized drug concentrations (unavailable for many medications)

Intradermal Testing (IDT): More sensitive than SPT but carries higher risk of systemic reactions. Generally contraindicated in unstable patients due to anaphylaxis risk.[39]

Patch Testing: Useful for delayed hypersensitivity reactions, particularly contact and photocontact dermatitis. Limited value for severe cutaneous adverse reactions. Requires 48-96 hours for results, which may delay therapeutic decisions in critical care.[40]

The predictive value of skin testing varies by drug class:

• Beta-lactam antibiotics: Sensitivity 70-85%, specificity >95%
• NMBAs: Sensitivity 60-70%, specificity >95%
• Iodinated contrast media: Sensitivity 30-50%, specificity >95%
• Opioids: Limited value due to direct mast cell activation properties[41,42]

Drug Provocation Testing

Drug provocation testing (DPT)—controlled administration of the suspected drug—is considered the gold standard for diagnosis but is generally contraindicated in patients with histories of severe reactions and in unstable ICU patients.[43]

In selected stable ICU patients approaching discharge, carefully planned provocation protocols may be considered for:

1. Ruling out hypersensitivity when history is unclear and alternative diagnostics are negative
2. Identifying safe alternatives when first-line therapies are contraindicated
3. Confirming tolerance to related compounds within a drug class[44]

Protocols must include:

• Careful patient selection
• Ready access to resuscitation equipment
• Incremental dosing (typically 1/10,000 → 1/1,000 → 1/100 → 1/10 → full dose)
• Extended observation periods
• Immediate availability of treatment medications[45]

Novel Biomarkers

Emerging diagnostic approaches with potential application in critical care include:

Urine histamine metabolites: Elevated N-methylhistamine levels can support diagnosis of anaphylaxis with less timing sensitivity than tryptase (detectable 24-48 hours post-reaction).[46]

Platelet-activating factor (PAF): Correlates with anaphylaxis severity; elevated levels may distinguish anaphylaxis from other causes of shock in the ICU.[47]

Serum periostin: Potential biomarker for delayed drug hypersensitivity reactions, allowing earlier detection of evolving reactions.[48]

Proteomics and metabolomics profiles: Developing research suggests distinct patterns may identify hypersensitivity reactions before clinical manifestation.[49]

The optimal diagnostic approach in the ICU combines available methodologies based on reaction pattern, suspected medication, and patient stability. Figure 1 provides a proposed algorithm for drug hypersensitivity diagnosis in critical care settings.

6. Specific Drug Classes of Concern in ICU

Antibiotics

Antibiotics represent the most common cause of drug hypersensitivity reactions in the ICU, with beta-lactams implicated most frequently.[50]

Beta-lactams:

• Prevalence of reported allergy: 8-12% of hospitalized patients
• True allergy confirmed by testing: 1-5%
• Cross-reactivity: Varies by specific structure; approximately 2% between penicillins and cephalosporins with different side chains
• Diagnostic approach: sIgE (sensitivity 40-75%), skin testing (sensitivity 70-85%), graded challenge when appropriate[51,52]

The "penicillin allergy delabeling" movement has particular relevance in critical care, as inappropriate antibiotic substitutions due to reported penicillin allergy are associated with:

• Increased antimicrobial resistance
• Higher rates of Clostridioides difficile
• Longer hospital stays
• Increased mortality[53]

Recent studies demonstrate safety and efficacy of penicillin allergy assessment protocols in ICU settings, though modifications from standard outpatient approaches are required.[54,55]

Quinolones:

• Increasing prevalence of hypersensitivity (0.5-2%)
• Primarily IgE-mediated and direct mast cell activation mechanisms
• Limited predictive value of skin testing (sensitivity <50%)
• Emerging utility of BAT (sensitivity 60-70%)[56]

Vancomycin:

• "Red man syndrome" (RMS) represents direct mast cell activation, not true allergy
• Risk factors include rapid infusion, higher doses
• Management: Slower infusion rate, premedication with antihistamines
• True IgE-mediated allergy rare but increasing in prevalence
• Desensitization protocols available for necessary therapy[57,58]

Neuromuscular Blocking Agents (NMBAs)

NMBAs are the second most common cause of perioperative anaphylaxis and represent significant concerns in critical care:[59,60]

• Prevalence of hypersensitivity: 1:6,500 administrations
• Cross-reactivity: Common due to shared quaternary ammonium epitope
• Risk factors: Previous exposure (including to cosmetics, cleaning products containing quaternary ammonium compounds), female sex
• Diagnostic approach: Skin testing highly sensitive (>95%), BAT gaining acceptance (sensitivity 60-85%)
• Management: Avoidance of cross-reactive agents based on skin testing pattern; availability of alternative NMBA with distinct chemical structure[61]

Recent evidence suggests rocuronium and succinylcholine carry the highest risk, while cisatracurium demonstrates the lowest incidence of hypersensitivity reactions.[62]

Analgesics and Sedatives

Opioids:

• True IgE-mediated reactions rare (<2% of reported reactions)
• Most reactions represent direct mast cell activation (particularly with morphine, codeine, meperidine)
• Diagnostic challenges: Limited value of skin testing, false positives due to direct histamine release
• Management strategies: Synthetic opioids (fentanyl, remifentanil) generally better tolerated in patients with history of reactions[63,64]

NSAIDs:

• Majority of reactions (60-75%) non-immunological (COX-1 inhibition mechanism)
• Cross-reactivity patterns differ between immunological and non-immunological reactions
• Diagnostic approach: Drug provocation remains gold standard; BAT emerging utility
• Alternative agents: COX-2 selective inhibitors generally safe in patients with non-immunological reactions[65]

Sedatives:

• Hypersensitivity rare with modern agents
• Propofol reactions (0.1-2%) linked to isopropyl groups or soy/egg lecithin component
• Midazolam and dexmedetomidine extremely rare triggers
• Cross-reactivity between sedative classes not reported[66,67]

Contrast Media

Iodinated contrast media (ICM) hypersensitivity presents distinctive challenges in critical care:[68,69]

• Prevalence: Immediate reactions 0.6-3%, severe reactions 0.04%
• Risk factors: Previous ICM reaction, multiple drug allergies, asthma, beta-blocker use
• Mechanisms: Both IgE-mediated and non-immunological pathways
• Cross-reactivity: Limited correlation with chemical structure; skin testing can identify safe alternatives
• Premedication efficacy: Significantly reduces mild reactions; limited impact on severe reactions
• Emerging evidence: Low-osmolality non-ionic monomers associated with lowest reaction rates

Gadolinium-based contrast agents carry lower hypersensitivity risk (0.01-0.3%) but cross-reactivity with ICM has been reported.[70]

7. Management Strategies

Management of suspected drug hypersensitivity in the ICU follows three concurrent pathways: (1) acute treatment of the reaction, (2) identification of the culprit agent, and (3) selection of safe alternatives.[71,72]

Acute Management

Immediate management of suspected anaphylaxis in the ICU follows standard protocols with modifications reflecting the critical care environment:[73]

1. Recognition: Early identification using established criteria (Sampson criteria or Ring and Messmer classification)

2. Hemodynamic support:

   • Epinephrine (adrenaline): First-line therapy (0.3-0.5mg IM, may require IV infusion in refractory cases)
   • Fluid resuscitation: Often requiring larger volumes in vasoplegic patients
   • Vasopressors: Norepinephrine preferred as second-line agent
   • ECMO: Case reports describe successful use in refractory anaphylactic shock[74]

3. Respiratory support:

   • Early intubation when progressive angioedema present
   • Higher PEEP strategies for bronchospasm
   • Consideration of mechanical ventilation even in milder cases if reaction evolving rapidly[75]

4. Adjunctive therapies:

   • H1-antihistamines (for urticaria/pruritis, not for hemodynamic support)
   • H2-antagonists (limited evidence, may provide additive benefit)
   • Corticosteroids (no immediate benefit; may prevent biphasic reactions)
   • Methylene blue, hydroxocobalamin, IV lipid emulsion: Case reports describe use in refractory cases[76,77]

5. Specific antagonists for certain reactions:

   • Protamine for heparin reactions
   • Fresh frozen plasma for ACE inhibitor-induced angioedema
   • Icatibant showing promise for ACE inhibitor reactions[78]

Delayed hypersensitivity reactions require different management approaches:[79]

1. DRESS syndrome: Immediate discontinuation of culprit drug; systemic corticosteroids (1-2 mg/kg/day prednisolone equivalent) with slow taper over 8-12 weeks; IVIG in severe cases

2. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis:

   • Transfer to burn center when possible
   • Supportive care (fluid/electrolyte management, wound care, infection prevention)
   • Controversial treatments: Systemic corticosteroids (short early course may benefit), IVIG (2g/kg total dose), cyclosporine (3-5 mg/kg/day)
   • Contraindicated: Prophylactic systemic antibiotics, adhesive materials on skin[80,81]

Culprit Identification

Systematic approaches to identifying the causative agent include:

1. Chronology assessment: Temporal relationship between drug introduction and symptom onset
2. Drug prioritization: Based on known allergenicity potential
3. Sequential withdrawal: Removal of suspected agents with monitoring for improvement
4. Dechallenge/rechallenge: Rarely appropriate in severe reactions[82]

Alternative Selection

Selection of alternative agents requires consideration of:

1. Cross-reactivity patterns: Based on chemical structure and available cross-reactivity data
2. Critical need: Determining if alternative classes can provide equivalent therapeutic benefits
3. Risk stratification: Balancing necessity of therapy against reaction severity
4. Graded challenge: For low-risk situations when alternatives unavailable[83,84]

8. Desensitization Protocols

Drug desensitization induces temporary tolerance to a medication through incremental dose administration. In the ICU, desensitization may be necessary when:[85,86]

1. No alternative medications exist or alternatives are substantially less effective
2. The benefit of the medication significantly outweighs the risk of the procedure
3. The original reaction was consistent with an IgE-mediated or other acute mechanism
4. The patient is sufficiently stable to tolerate potential reactions

Desensitization is contraindicated for:

• Stevens-Johnson syndrome/Toxic epidermal necrolysis
• Drug-induced hypersensitivity syndrome/DRESS
• Serum sickness
• Organ-specific reactions (hepatitis, nephritis)
• Hemolytic anemia, thrombocytopenia
• Patients too unstable to manage potential reactions[87]

Practical considerations for ICU desensitization include:

Protocol design:

• 12-16 step protocols typical, with 2-3 fold concentration increases per step
• Starting dose typically 1/10,000 to 1/1,000,000 of target dose
• Administration route matches therapeutic route when possible
• Total duration 4-12 hours depending on urgency and risk[88]

Safety measures:

• Dedicated staff with experience in desensitization
• Continuous monitoring (cardiac, respiratory, oxygen saturation)
• Venous access secured before procedure
• Emergency medications prepared at bedside
• Clear protocol for managing breakthrough reactions[89]

Breakthrough reaction management:

• Mild reactions: Temporary cessation of protocol, symptomatic treatment, resumption at last tolerated dose
• Moderate reactions: Extended observation, consideration of protocol modification
• Severe reactions: Protocol discontinuation, consideration of alternative approaches[90]

Specific protocols have been published for common ICU medications including beta-lactam antibiotics, vancomycin, ciprofloxacin, and aspirin. Electronic health record integration of standardized protocols has improved safety and accessibility in some centers.[91,92]

9. Documentation and Prevention

Accurate documentation and preventive strategies are essential components of drug allergy management in the ICU:[93,94]

Documentation Best Practices

Comprehensive documentation should include:

1. Specific details of reaction:

   • Precise drug name (not just class)
   • Dose, route, and rate of administration
   • Time interval between administration and reaction onset
   • Clinical manifestations with objective measurements
   • Treatments required and response
   • Results of any diagnostic testing

2. Electronic health record optimization:

   • Distinguishing between "allergy" versus "intolerance" or "side effect"
   • Severity classification
   • Evidence basis for listed allergy (patient report vs. documented reaction vs. confirmed by testing)
   • Automatic alerts for cross-reactive medications
   • Clear visibility across care transitions[95]

3. Communication tools:

   • Standardized handoff documentation
   • Allergy/adverse reaction cards for patients
   • Pharmacy notification systems
   • Admission screening protocols specific for drug allergies[96]

Prevention Strategies

Preventive approaches include both system-level and patient-level interventions:

1. Institutional protocols:

   • Standardized assessment of reported drug allergies at ICU admission
   • Clinical decision support systems for cross-reactivity alerts
   • High-risk medication protocols (e.g., vancomycin infusion guidelines)
   • Multidisciplinary approach involving pharmacy, allergy, and critical care[97]

2. Risk stratification tools:

   • Validated scoring systems for beta-lactam allergy evaluation
   • Premedication protocols based on risk assessment
   • Test dose protocols for appropriate situations[98]

3. Proactive allergy assessment programs:

   • "Delabeling" initiatives for low-risk penicillin allergy patients
   • Consultation with allergy specialists for patients with multiple drug allergies
   • Allergy testing during recovery phase of critical illness when appropriate[99]

4. Education initiatives:

   • Staff training on recognition and management of drug hypersensitivity
   • Patient education regarding true allergies versus side effects
   • Family education about newly identified allergies[100]

Implementation of systematic documentation and prevention programs has demonstrated substantial improvements in antimicrobial stewardship, reduced healthcare costs, and improved patient outcomes.[101,102]

10. Future Directions

The field of drug hypersensitivity in critical care continues to evolve, with several promising areas of development:[103,104]

Diagnostic Advances

1. Biomarker discovery: Proteomic and metabolomic approaches may identify novel biomarkers with superior sensitivity and specificity for various hypersensitivity mechanisms.

2. Point-of-care testing: Development of rapid bedside tests for immediate drug hypersensitivity could revolutionize ICU management by providing actionable results within minutes rather than hours or days.

3. In silico prediction models: Computational approaches using molecular modeling and machine learning algorithms show promise for predicting cross-reactivity and identifying safe alternatives without requiring physical testing.[105]

4. Pharmacogenomic integration: Expanded genetic screening may allow personalized risk stratification beyond current HLA associations, potentially preventing severe reactions before first exposure.

Therapeutic Innovations

1. Biological therapies: Monoclonal antibodies targeting specific immunological pathways (anti-IL-4, anti-IL-13, anti-IL-5) show promise for managing severe delayed hypersensitivity reactions.

2. Rapid desensitization advancements: Ultra-rush protocols and novel modalities including simultaneous multi-drug desensitization are being investigated for time-sensitive situations.

3. Predictive algorithms for cross-reactivity: Artificial intelligence approaches to predict cross-reactivity between chemically related drugs may allow more precise alternative selection.[106,107]

Implementation Science

1. Standardization initiatives: International efforts to standardize testing concentrations, interpretation criteria, and management protocols may improve consistency across institutions.

2. Electronic health record optimization: Advanced clinical decision support systems integrating real-time allergy risk assessment with therapeutic recommendations.

3. Teleallergy consultation: Remote specialist input for drug hypersensitivity management in centers without on-site allergy expertise.[108]

Research Priorities

Key areas requiring further investigation include:

1. ICU-specific diagnostic algorithms: Validation of modified testing approaches for critically ill patients.

2. Biomarkers in polypharmacy: Identification of reliable markers when multiple potential culprits exist.

3. Long-term outcomes: Prospective studies of patients who experience drug hypersensitivity during critical illness.

4. Optimal documentation strategies: Systems that improve allergy information transfer across healthcare settings.

5. Cost-effectiveness analysis: Economic impact of comprehensive drug allergy programs in critical care.[109,110]

As these areas develop, management of drug hypersensitivity in the ICU will likely become more precise, efficient, and personalized, potentially reducing both unnecessary drug avoidance and recurrent reactions.

11. Conclusion

Drug hypersensitivity reactions in the ICU present unique diagnostic and management challenges that require specialized approaches tailored to critically ill patients. Although conventional allergy testing methodologies often require modification in this setting, a systematic approach combining careful clinical assessment, appropriate in vitro testing, and judicious use of in vivo methods when feasible can successfully guide management decisions.

Key principles for clinical practice include:

1. Maintaining a high index of suspicion for drug hypersensitivity, particularly with high-risk medications
2. Implementing standardized documentation and communication systems
3. Utilizing a multidisciplinary approach involving critical care, pharmacy, and allergy/immunology
4. Balancing the risks of potential hypersensitivity against the necessity of specific therapies
5. Considering desensitization when appropriate alternatives are unavailable
6. Providing comprehensive transitional care including plans for future drug use and testing

As diagnostic methods continue to evolve and therapeutic options expand, management of drug hypersensitivity in the ICU will likely become more precise and personalized. Further research specifically addressing the critical care environment is needed to optimize approaches to this challenging clinical problem.

Acknowledgments

The authors acknowledge the contributions of... [Add appropriate acknowledgments]

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy. 2014;69(4):420-437.

2. Khan DA, Banerji A. Drug Allergy. J Allergy Clin Immunol. 2019;143(3):985-996.

3. Romano A, Torres MJ, Castells M, et al. Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127(3):S67-S73.

4. Thong BY, Tan TC. Epidemiology and risk factors for drug allergy. Br J Clin Pharmacol. 2011;71(5):684-700.

5. Johansson SG, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-836.

6. Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy. 1988;18(6):515-540.

7. Alvarez-Perea A, Tanno LK, Baeza ML. How to manage anaphylaxis in primary care. Clin Transl Allergy. 2017;7:45.

8. Alvarez-Perea A, Tomás-Pérez M, Martínez-Lezcano P, et al. Anaphylaxis in Adolescent/Adult Patients Treated in the Emergency Department: Differences Between Initial Impressions and the Definitive Diagnosis. J Investig Allergol Clin Immunol. 2015;25(4):288-294.

9. Mirakian R, Ewan PW, Durham SR, et al. BSACI guidelines for the management of drug allergy. Clin Exp Allergy. 2009;39(1):43-61.

10. Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013;68(6):702-712.

11. Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing Inpatient Beta-Lactam Allergies: A Multihospital Implementation. J Allergy Clin Immunol Pract. 2017;5(3):616-625.

12. Gell PGH, Coombs RRA. Clinical Aspects of Immunology. 1st ed. Oxford, UK: Blackwell; 1963.

13. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139(8):683-693.

14. Pichler WJ. Drug hypersensitivity reactions: Classification and relationship to T-cell activation. In: Drug Hypersensitivity. Basel, Switzerland: Karger; 2007:168-189.

15. Phillips EJ, Bigliardi P, Bircher AJ, et al. Controversies in drug allergy: Testing for delayed reactions. J Allergy Clin Immunol. 2019;143(1):66-73.

16. Macy E. Penicillin and Beta-lactam Allergy: Epidemiology and Diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476.

17. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579.

18. Brockow K, Romano A, Blanca M, et al. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy. 2002;57(1):45-51.

19. Trubiano JA, Stone CA, Grayson ML, et al. The 3 Cs of Antibiotic Allergy-Classification, Cross-Reactivity, and Collaboration. J Allergy Clin Immunol Pract. 2017;5(6):1532-1542.

20. Castells M, Khan DA, Phillips EJ. Penicillin Allergy. N Engl J Med. 2019;381(24):2338-2351.

21. Chiriac AM, Demoly P. Drug Allergy Diagnosis. Immunol Allergy Clin North Am. 2014;34(3):461-471.

22. Blumenthal KG, Park MA, Macy E. Redesigning the allergy module of the electronic health record. Ann Allergy Asthma Immunol. 2016;117(2):126-131.

23. Brockow K, Ardern-Jones MR, Mockenhaupt M, et al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy. 2019;74(1):14-27.

24. Mayorga C, Celik G, Rouzaire P, et al. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2016;71(8):1103-1134.

25. Brockow K, Przybilla B, Aberer W, et al. Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (ÖGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM). Allergo J Int. 2015;24:94-105.

26. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: Assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. 2017;140(1):154-161.e6.

27. Doña I, Torres MJ, Montañez MI, Fernández TD. In vitro diagnostic testing for antibiotic allergy. Allergy Asthma Immunol Res. 2017;9(4):288-298.

28. Ebo DG, Leysen J, Mayorga C, et al. The in vitro diagnosis of drug allergy: status and perspectives. Allergy. 2011;66(10):1275-1286.

29. Kowalski ML, Asero R, Bavbek S, et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy. 2013;68(10):1219-1232.

30. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26(3):451-463.

31. Sanz ML, Gamboa PM, Antépara I, et al. Flow cytometric basophil activation test by detection of CD63 expression in patients with immediate-type reactions to betalactam antibiotics. Clin Exp Allergy. 2002;32(2):277-286.

32. Hoffmann HJ, Santos AF, Mayorga C, et al. The clinical utility of basophil activation testing in diagnosis and monitoring of allergic disease. Allergy. 2015;70(11):1393-1405.

33. Steiner M, Harrer A, Himly M. Basophil Reactivity as Biomarker in Immediate Drug Hypersensitivity Reactions-Potential and Limitations. Front Pharmacol. 2016;7:171.

34. Porebski G, Pecaric-Petkovic T, Groux-Keller M, et al. In vitro drug causality assessment in Stevens-Johnson syndrome - alternatives for lymphocyte transformation test. Clin Exp Allergy. 2013;43(9):1027-1037.

35. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004;59(8):809-820.

36. Phillips EJ, Mallal SA. HLA-B*5701 and flucloxacillin associated drug-induced liver disease. AIDS. 2013;27(3):491-492.

37. Romano A, Caubet JC. Antibiotic allergies in children and adults: from clinical symptoms to skin testing diagnosis. J Allergy Clin Immunol Pract. 2014;2(1):3-12.

38. Torres MJ, Blanca M, Fernandez J, et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy. 2003;58(10):961-972.

39. Empedrad R, Darter AL, Earl HS, Gruchalla RS. Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics. J Allergy Clin Immunol. 2003;112(3):629-630.

40. Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013;68(6):702-712.

41. Blanca M, Romano A, Torres MJ, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy. 2009;64(2):183-193.

42. Sánchez-Morillas L, Pérez-Ezquerra PR, Reaño-Martos M, et al. Selective allergic reactions to clavulanic acid: a report of 9 cases. J Allergy Clin Immunol Pract. 2015;3(2):287-289.

43. Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58(9):854-863.

44. Hjortlund J, Mortz CG, Skov PS, Bindslev-Jensen C. Diagnosis of penicillin allergy revisited: the value of case history, skin testing, specific IgE and prolonged challenge. Allergy. 2013;68(8):1057-1064.

45. Chiriac AM, Rerkpattanapipat T, Bousquet PJ, et al. Optimal step doses for drug provocation tests to prove beta-lactam hypersensitivity. Allergy. 2017;72(4):552-561.

46. Sala-Cunill A, Cardona V, Labrador-Horrillo M, et al. Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients. Int Arch Allergy Immunol. 2013;160(2):192-199.

47. Vadas P, Perelman B, Liss G. Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. J Allergy Clin Immunol. 2013;131(1):144-149.

48. Schrijvers R, Gilissen L, Chiriac AM, Demoly P. Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back. Clin Transl Allergy. 2015;5:31.

49. Villalta D, Petoldi D. Serum specific IgE: a promising diagnostic test for immediate allergy to beta-lactam antibiotics and selected non-beta-lactam antibiotics, but still needs methodological standardization. Curr Pharm Des. 2016;22(45):6849-6862.

50. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198.

51. Trubiano JA, Adkinson NF, Phillips EJ. Penicillin Allergy Is Not Necessarily Forever. JAMA. 2017;318(1):82-83.

52. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.

53. MacFadden DR, LaDelfa A, Leen J, et al. Impact of Reported Beta-Lactam Allergy on Inpatient Outcomes: A Multicenter Prospective Cohort Study. Clin Infect Dis. 2016;63(7):904-910.

54. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2):188-199.

55. Solensky R. Penicillin allergy as a public health issue. J Allergy Clin Immunol. 2014;133(3):797-798.

56. Blanca-López N, Ariza A, Doña I, et al. Hypersensitivity reactions to fluoroquinolones: analysis of the factors involved. Clin Exp Allergy. 2013;43(5):560-567.

57. Sivagnanam S, Deleu D. Red man syndrome. Crit Care. 2003;7(2):119-120.

58. Wong JT, Ripple RE, MacLean JA, et al. Vancomycin hypersensitivity: synergism with narcotics and "desensitization" by a rapid continuous intravenous protocol. J Allergy Clin Immunol. 1994;94(2 Pt 1):189-194.

59. Sadleir PH, Clarke RC, Bunning DL, Platt PR. Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth. 2013;110(6):981-987.

60. Savic LC, Kaura V, Yusaf M, et al. Incidence of suspected perioperative anaphylaxis: A multicenter snapshot study. J Allergy Clin Immunol Pract. 2015;3(3):454-455.e1.

61. Leysen J, Bridts CH, De Clerck LS, Ebo DG. Anaphylaxis during general anaesthesia: a 10-year survey 1 at the University Hospital of Antwerp. P Belg Roy Acad Med. 2011;2:88-100.

62. Reddy JI, Cooke PJ, van Schalkwyk JM, et al. Anaphylaxis is more common with rocuronium and succinylcholine than with atracurium. Anesthesiology. 2015;122(1):39-45.

63. Opstrup MS, Malling HJ, Krøigaard M, et al. Standardized testing with chlorhexidine in perioperative allergy--a large single-centre evaluation. Allergy. 2014;69(10):1390-1396.

64. Baldo BA, Pham NH. Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two. Anaesth Intensive Care. 2012;40(2):216-235.

65. Kowalski ML, Makowska JS. Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice? Allergy Asthma Immunol Res. 2015;7(4):312-320.

66. Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121(1):159-171.

67. Mertes PM, Malinovsky JM, Jouffroy L, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21(6):442-453.

68. Brockow K, Sánchez-Borges M. Hypersensitivity to contrast media and dyes. Immunol Allergy Clin North Am. 2014;34(3):547-564.

69. Morales-Cabeza C, Roa-Medellín D, Torrado I, et al. Immediate reactions to iodinated contrast media. Ann Allergy Asthma Immunol. 2017;119(6):553-557.

70. Behzadi AH, Zhao Y, Farooq Z, Prince MR. Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology. 2018;286(2):471-482.

71. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026-1045.

72. Campbell RL, Li JT, Nicklas RA, Sadosty AT; Members of the Joint Task Force; Practice Parameter Workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608.

73. Simons FE, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J. 2015;8(1):32.

74. Choo KJL, Simons E, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev. 2012;(4):CD007596.

75. Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol. 2007;98(1):64-69.

76. Lee S, Bellolio MF, Hess EP, Campbell RL. Predictors of biphasic reactions in the emergency department for patients with anaphylaxis. J Allergy Clin Immunol Pract. 2014;2(3):281-287.

77. Dewachter P, Mouton-Faivre C, Emala CW. Anaphylaxis and anesthesia: controversies and new insights. Anesthesiology. 2009;111(5):1141-1150.

78. Baş M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372(5):418-425.

79. Descamps V, Ben Saïd B, Sassolas B, et al. Management of drug reaction with eosinophilia and systemic symptoms (DRESS). Ann Dermatol Venereol. 2010;137(11):703-708.

80. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. 2016;174(6):1194-1227.

81. Mockenhaupt M. Stevens-Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. Semin Cutan Med Surg. 2014;33(1):10-16.

82. Scherer K, Brockow K, Aberer W, et al. Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group. Allergy. 2013;68(7):844-852.

83. Cernadas JR, Brockow K, Romano A, et al. General considerations on rapid desensitization for drug hypersensitivity - a consensus statement. Allergy. 2010;65(11):1357-1366.

84. Liu A, Fanning L, Chong H, et al. Desensitization regimens for drug allergy: state of the art in the 21st century. Clin Exp Allergy. 2011;41(12):1679-1689.

85. Castells M. Rapid desensitization for hypersensitivity reactions to medications. Immunol Allergy Clin North Am. 2009;29(3):585-606.

86. Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol. 2008;122(3):574-580.

87. Hong DI, Dioun AF. Indications, protocols, and outcomes of drug desensitizations for chemotherapy and monoclonal antibodies in adults and children. J Allergy Clin Immunol Pract. 2014;2(1):13-19; quiz 20.

88. Aydogan M, Yologlu N, Gacar G, et al. Successful rapid rituximab desensitization in an adolescent patient with nephrotic syndrome: Increase in number of Treg cells after desensitization. J Allergy Clin Immunol. 2013;132(2):478-480.

89. Brennan PJ, Rodriguez Bouza T, Hsu FI, et al. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol. 2009;124(6):1259-1266.

90. Sloane D, Govindarajulu U, Harrow-Mortelliti J, et al. Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies. J Allergy Clin Immunol Pract. 2016;4(3):497-504.

91. Blumenthal KG, Ryan EE, Li Y, et al. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018;66(3):329-336.

92. Bourke J, Pavlos R, James I, Phillips E. Improving the Effectiveness of Penicillin Allergy De-labeling. J Allergy Clin Immunol Pract. 2015;3(3):365-374.e1.

93. Chiriac AM, Demoly P. Multiple drug hypersensitivity syndrome. Curr Opin Allergy Clin Immunol. 2013;13(4):323-329.

94. Solensky R, Khan DA. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273.

95. Legendre DP, Muzny CA, Marshall GD, Swiatlo E. Antibiotic hypersensitivity reactions and approaches to desensitization. Clin Infect Dis. 2014;58(8):1140-1148.

96. Krishna MT, Huissoon AP, Li M, et al. Enhancing antibiotic stewardship by tackling "spurious" penicillin allergy. Clin Exp Allergy. 2017;47(11):1362-1373.

97. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin "allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014;133(3):790-796.

98. Wolfson AR, Zhou L, Li Y, et al. Drug Allergy Alerts in Electronic Health Records: A Qualitative Study of Healthcare Providers. JAMA Netw Open. 2019;2(3):e190134.

99. Trubiano JA, Thursky KA, Stewardson AJ, et al. Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation. Clin Infect Dis. 2017;65(1):166-174.

100. Vyles D, Chiu A, Simpson P, et al. Parent-Reported Penicillin Allergy Symptoms in the Pediatric Emergency Department. Acad Pediatr. 2017;17(3):251-255.

101. Stone CA Jr, Trubiano J, Coleman DT, et al. The challenge of de-labeling penicillin allergy. Allergy. 2020;75(2):273-288.

102. Blumenthal KG, Lu N, Zhang Y, et al. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. 2018;361:k2400.

103. Banerji A, Rudders SA, Corel B, et al. Predictors of hospital admission for food-related allergic reactions that present to the emergency department. Ann Allergy Asthma Immunol. 2011;106(1):42-48.

104. Barbaud A, Collet E, Milpied B, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol. 2013;168(3):555-562.

105. Dua S, Dowey J, Foley L, et al. Diagnostic value of tryptase in food allergic reactions: a prospective study of 160 adult peanut challenges. Allergy Asthma Proc. 2018;39(1):43-50.

106. Sánchez-Gómez FJ, González-Morena JM, Vida Y, et al. Amoxicillin haptenates intracellular proteins that can be transported in exosomes to target cells. Allergy. 2017;72(3):385-396.

107. Salas M, Fernández-Santamaría R, Mayorga C, et al. Use of the Basophil Activation Test May Reduce the Need for Drug Provocation in Amoxicillin-Clavulanic Allergy. J Allergy Clin Immunol Pract. 2018;6(3):1010-1018.e2.

108. Doña I, Romano A, Torres MJ. Algorithm for betalactam allergy diagnosis. Allergy. 2019;74(9):1817-1819.

109. Chen JR, Khan DA. Evaluation of Penicillin Allergy in the Hospitalized Patient: Opportunities for Antimicrobial Stewardship. Curr Allergy Asthma Rep. 2017;17(6):40.

110. Spriet S, Banks TA. Drug reaction with eosinophilia and systemic symptoms syndrome. Allergy Asthma Proc. 2015;36(6):501-505.