Telemedicine-supported penicillin allergy delabeling in low-risk patients

Introduction

Background

Telemedicine (TM) has become a crucial tool in modern healthcare, particularly in managing chronic diseases such as allergies and immunological conditions (1-3). Allergic diseases, including allergic rhinitis and asthma, along with food and drug allergies, affect millions worldwide (4). The adoption of TM has led to significant improvements in both patient outcomes and satisfaction while also reducing healthcare costs (5). TM is crucial in overcoming the barriers to effectively managing allergic conditions (1). The primary aim of TM is not to completely replace in-person consultations but to serve as a tool that enhances patient monitoring and care in particular circumstances. TM encompasses various methods, including audio-visual consultations, remote monitoring of cutaneous and vital signs (e.g., blood pressure, heart rate), and the use of electronic medical records (EMR), which facilitate seamless communication and information sharing between patients and healthcare providers (1,6). This approach enables remote monitoring of patients, providing real-time insights that would otherwise require frequent in-person visits. By integrating TM, healthcare systems can extend their reach to patients in remote or underserved areas, ensuring that they receive timely care and reducing the burden of travel and hospital visits. It also supports patients in maintaining their treatment regimen more consistently, leading to improved outcomes without negatively affecting the quality of care (7,8). As a disruptive innovation, TM challenges traditional healthcare delivery models, necessitating robust evidence to confirm its efficacy and safety (1). Ensuring that TM maintains or enhances diagnostic accuracy and therapeutic outcomes is essential for its successful integration into standard practice.

Drug hypersensitivity reactions are increasingly accounting for referrals to allergy departments worldwide. Drug provocation testing, also known as drug challenge, is the gold standard of investigation (9). The advancement of TM practices has enabled greater access for allergists to evaluate suspected drug allergies (10).

Although drug challenges may appear unsuitable for TM due to the need for close patient monitoring and immediate access to emergency care, it is important not to shy away from discussing the potential of specific types of drug challenges in TM settings. This open dialogue is crucial for exploring new possibilities for improving patient care.

In long-term care facilities and other remote settings, the lack of access to specialists presents an opportunity to connect with allergists for remote supervision and consultation through TM. Moreover, the unprecedented circumstances of the coronavirus disease 2019 (COVID-19) pandemic have accelerated the need for a comprehensive exploration of the feasibility and safety of specific drug challenges conducted via TM. Delabeling, a related concept, refers to the process of modifying or removing incorrect clinical labels, such as misdiagnosed allergies, to ensure more accurate treatment and reduce unnecessary medical interventions. This is particularly indicated in cases of penicillin allergy, as part of antibiotic stewardship efforts aimed at reducing antibiotic resistance. Nowadays, it has become essential to determine whether such procedures, preceded by risk mitigation strategies, can be supported by or partially adapted to remote medical assistance without compromising patient safety (11-15).

Rationale and knowledge gap

The rationale is based on the fact that different TM tools are utilized in allergology (1,16-20). Digital interventions enhance disease outcomes by equipping patients with the knowledge to actively engage in their care and make informed decisions (21). TM is also used in clinical immunology (22,23) and for monitoring drug efficacy (24-28). Safety monitoring via telehealth has promising potential with high consumer acceptability (29). TM was used for initial drug allergy assessment for antibiotics (11-13,30,31), including severe cutaneous adverse drug reactions (SCARs) (14,32). Drug allergy delabeling is a concept introduced for penicillin antibiotics (33-38) and other drugs (39-41).

The overwhelming burden of incorrect penicillin allergy labels is a global public health concern. The consequences of administering non-beta-lactam antibiotics in the case of an erroneously reported penicillin allergy include delayed administration of antibiotic therapy, poorer efficacy and more frequent treatment failures, prolonged hospital stays and higher re-hospitalisation rates, higher risk of adverse events from the use of broad-spectrum and reserve antibiotics, such as Clostridium difficile infections, resistance due to their use, higher rates of transfer to an intensive care unit and higher mortality, poor patient outcomes and higher treatment costs. Depending on the country, the prevalence of beta-lactam allergy in the general population is estimated to be about 5–10%. However, in over 90% of those who reported a penicillin allergy, allergy workups, including provocation tests, are unable to confirm it (42-44).

In some regions, there is limited access to allergy services or specialists, which hinders the capacity for penicillin allergy delabeling. Moreover, “preemptive” routine drug skin testing among patients without a history of drug allergy (or even exposure) may lead to inappropriate labeling (45,46).

Patient assessment by a specialist, questionnaires to stratify risks, and appropriate drug allergy testing are instrumental in both adult and pediatric patients (47,48). Therefore, TM in drug allergy is considered an emerging and applicable procedure (14). Still, knowledge gaps and ongoing discussions persist in the field of TM-supported direct drug challenges in allergy management. The principal concern related to the perplexity surrounding ethical involvement in assessing penicillin allergy with TM often arises from balancing the imperative to provide accurate diagnoses with the patient’s autonomy and the potential risks of in vivo allergy assessments.

Objective

The objective of this manuscript is to create a clinical practice review on direct amoxicillin challenges performed in low-risk patients for TM-guided penicillin allergy delabeling. This concise narrative review is not intended to substitute for a referral for an in-person consultation with an allergy expert with experience in drug-allergic reactions, with allergy skin testing and in vitro tests, if necessary. It is intended for information purposes only. Data presented here cannot be held liable or responsible for inappropriate health care associated with the improper use of this paper. When assessing patients and making therapeutic decisions, healthcare professionals are strongly recommended to use their professional judgment and to ensure compliance with all local and national legal and regulatory requirements. The medical setting is rapidly evolving, and not all recommendations will be suitable or valid for all patients; they may also change over time (49).

Methods

Search strategy

A comprehensive literature search was performed across the following online databases: PubMed, Scopus, Web of Science, and Google Scholar. The search covered studies published between January 2000 and May 2025. References were selected from those identified by the following keywords and Boolean operators: “penicillin allergy” AND “provocation” AND “telemedicine” OR “outpatient” OR “low-risk”, along with “beta-lactam” AND “allergy” AND “risk stratification” AND “drug provocation”, and through citation tracking and manual searching of references. Penicillin allergy delabeling or de-labeling (common versions in American English), also spelt penicillin allergy delabelling or de-labelling (British English versions), is the process of removing penicillin allergy labels from patients’ medical records after confirming they are not truly allergic to penicillin. Many people carry such an erroneous label based on outdated or unclear information. We focused on direct oral amoxicillin challenges/provocations (skipping allergy skin testing) in outpatient settings, including patients’ homes, long-term care facilities (e.g., nursing homes, assisted living facilities), and other remote settings, such as mobile clinics or community centers, as a fast delabeling strategy, because low-risk patients and patients with non-immune-mediated adverse reactions could be evaluated outside the hospital/allergy setting or with TM guiding care (50).

TM-enabled delabeling of penicillin allergy in low-risk patients

The implementation of TM in the management of allergic and immunological conditions varies depending on the healthcare provider and clinical setting. TM consultations can be conducted by both allergists and non-allergist healthcare professionals, depending on the complexity of the case and the availability of specialists. In many scenarios, allergists are primarily responsible for supervising diagnostic and therapeutic interventions, including remote drug challenges or desensitization protocols in carefully selected cases. In cases where patients are required to ingest a drug under supervision, the logistics and safety protocols are meticulously planned. For example, the medication is typically mailed to the patient with detailed instructions, and ingestion is monitored in real-time via a video consultation. To address the risk of adverse events, the patient must be accompanied by at least an available caretaker and, if possible, a trained nurse or another healthcare professional who can provide immediate assistance if needed. Alternatively, the patient may be required to conduct the procedure at a satellite clinic or facility equipped to handle emergencies, ensuring safety while utilizing TM for supervision. By clearly delineating roles and ensuring the presence of appropriate safeguards, TM can be effectively integrated into clinical practice without compromising patient safety or the quality of care, as stated in a recent position paper by the European Academy of Allergy and Clinical Immunology (EAACI) (1). Recently, TM has been used to triage, assess, label and delabel drug hypersensitivity reactions, as mentioned in several publications. This approach delabels penicillin allergy at lower costs while reducing the use of second-line antibiotics and maintaining patient satisfaction. Drug allergy consults, in several circumstances, do not necessitate an in-person evaluation for adverse drug reaction assessment and may therefore be well-suited for TM. A classic example is a patient labeled as allergic to penicillin in childhood by their family doctor or by medical doctors without training in allergology, a labeling that is often maintained over time, despite the fact that the patient subsequently tolerated amoxicillin, a penicillin-class antibacterial, with or without clavulanate potassium, a beta-lactamase inhibitor, without experiencing a hypersensitivity adverse drug reaction. Other low-risk features include previously told allergy test positive but no history of reaction, other allergies to non-related drugs (such as non-beta-lactams) only, nonspecific (nonimmunological) adverse reactions, and family history of penicillin allergy only (44).

The COVID-19 pandemic health crisis suggested the feasibility of remote evaluation of some adverse drug reactions, with the delabeling of low-risk subjects in selected cases. Such TM monitoring of direct amoxicillin challenges has been reported in pediatric and adult patients (12,15,47,48,51-53).

Using TM for virtual care in drug hypersensitivity management may allow healthcare providers to remotely assess, supervise and follow up patients for specific drug challenges only after careful risk stratification and specialist risk-benefit assessment. Even though there is a need to evaluate many erroneously labelled patients in clinical practice, recent programs target only those considered to be most likely to benefit from the removal of inaccurate antibiotic allergy labels, those with beta-lactam hypersensitivities and high-risk subjects likely to need beta-lactam antibiotics as first-line treatment, especially perioperative and immunocompromised patients (12,14,15,54,55).

Most patients who claim to have a penicillin allergy can tolerate penicillins. This highlights the need to proactively assess undocumented penicillin allergy in healthy patients, including children and pregnant women, during regular consultations before they might need beta-lactam antibiotics (56). The gold standard for delabeling is an oral challenge with the suspected drug. Increasing evidence supports the use of direct oral amoxicillin provocation without skin testing in patients with an appropriate low-risk clinical history (42,57-60). Patients labeled as allergic to penicillin/aminopenicillin have been recruited in several publications mentioning this practice using TM (12,15,51-53).

The TM approach offers several advantages, including improved access to specialist evaluation, particularly for patients in rural, remote, or underserved areas or those with limited mobility. It also provides patient convenience by reducing travel time and costs, limiting exposure and promoting social distancing for vulnerable individuals, especially during infectious disease outbreaks, epidemics, or pandemics. Additionally, it offers real-time personalized guidance via secure video TM platforms during low-risk drug challenges, reassurance for alleviating patient concerns and anxiety, improved compliance, convenient, flexible, and efficient initial and follow-up remote consultations with timely interventions, enhanced continuity of care, less environmental impact, minimizing the need for in-person visits, and cost-effectiveness. The latter depends on the specifics of healthcare coverage, as well as local and national regulations (12,15,48,61,62).

While in-person evaluation of penicillin allergy is conducted through in-depth interviews, a safe and pragmatic protocol for TM assessing and delabeling patients with suspected penicillin allergy is required. Few studies have proposed such a protocol for TM approaches, and they need validation. A plan and checklist for a virtually supported amoxicillin oral challenge include an initial visit for TM consultation and patient assessment, followed by a second visit for a TM-supported low-risk home oral provocation challenge (15,63).

TM drug allergy consults for penicillin allergy delabeling without skin tests or drug provocation testing are feasible in the case of non-hypersensitivity reactions, such as well-known non-allergic adverse drug effects; full dose of same drug tolerated after initial reaction; allergy only suspected in a close relative (9).

Regarding the risk stratification for a practical procedure in cases of suspected non-SCAR beta-lactam antibiotic allergy not identified with certainty and an urgent indication for beta-lactam antibiotic therapy, TM consultants may recommend administering cefazolin (if the index reaction was to an oral beta-lactam) or carbapenems at full dose (43). This recommendation may be crucial for antibiotic prophylaxis in obstetrics and gynaecology, as well as for perioperative use in orthopaedics. The risk of allergic cross-reaction is highest between beta-lactam antibiotics with identical or similar R1 groups. Aminopenicillins (ampicillin, amoxicillin) are considered to be almost 100% cross-reactive due to their very similar R1 side chain (aminobenzyl group). Some of the individuals sensitized to aminopenicillins also show cross-reactivity with aminocephalosporins such as cefaclor, cefadroxil, and cefalexin, which can also cross-react with each other. The methoxyimino cephalosporins cefuroxime, ceftriaxone, cefotaxime, and ceftazidime also show a certain degree of cross-reactivity with each other via their side chains. Cefazolin is a first-generation cephalosporin with a unique R1 side chain and appears to have very low cross-reactivity with penicillins (64). However, it should be avoided in patients who have a history of severe delayed hypersensitivity reactions, such as end-organ involvement, such as hemolytic anemia, hepatitis, nephritis, serum sickness-like reaction, or SCAR (56,64-67). The prevalence of cefazolin perioperative anaphylaxis does not significantly differ between patients with and without penicillin allergy labels, and the incidence remains remarkably low. Therefore, it is advisable to consider cefazolin as an acceptable choice for antibiotic prophylaxis in patients carrying a penicillin allergy label. It is also recently suggested that in patients with a history of penicillin or cephalosporin allergy, a carbapenem may be administered without testing or additional precautions (64,68).

The results of a systematic review, which found limited professional liability for clinicians who prescribed a cephalosporin or a carbapenem to a patient with a known penicillin allergy, may alleviate the litigation fears of practitioners and risk managers within healthcare systems (69). By utilizing the published and internationally validated tool PEN-FAST [penicillin (PEN) allergy, an occurrence of five or fewer years ago (F), anaphylaxis or angioedema (A), severe cutaneous adverse reaction/SCAR (S), and treatment required for allergic reaction (T)] for low-risk penicillin allergy, CEPH-FAST [cephalosporin (CEPH) allergy, an occurrence of five or fewer years ago (F), anaphylaxis or angioedema (A), severe cutaneous adverse reaction/SCAR (S), and treatment required for allergic reaction (T)] was recently validated using the same criteria with minor modifications for low-risk cephalosporin allergies (70).

An overview of TM-supported penicillin allergy delabeling is presented in Figure 1.

Figure 1 Schematic overview of TM-supported penicillin allergy delabeling in low-risk patients. TM, telemedicine.

Initial TM visit for penicillin allergy delabeling in low-risk patients

The initial TM consultation is conducted on a secure video and audio platform, allowing the physician to obtain a baseline appreciation of the patient’s health status within the limitations of virtual visits. Personal history is obtained in detail to determine the characteristics of the index reaction, risk of true allergy and risk of adverse reaction to a provocation challenge (15).

There is no strict consensus on risk stratification criteria (9). Several penicillin allergy risk assessment tools with clinical significance must be mentioned. The most recent one is the EAACI/European Network on Drug Allergy (ENDA) strategy (71). Others emerged from research conducted in the United States, such as the Blumenthal strategy (72), Australia, with the PEN-FAST strategy/score (59), and Europe, including the Chiriac strategy/score (73) and a Combined score (74).

According to the recent EAACI task force on drug provocation testing, low-risk patient profile comprises an exanthema that is not urticarial, with onset more than 6 h after drug intake, involving less than 50% of the body surface, of less than 7 days duration, without danger signs (no fever, lymphadenopathy, systemic involvement, blisters, mucosal involvement or eosinophilia), not requiring hospitalization or systemic treatment other than H1 antihistamines. In such patients, skin testing is optional before drug challenge, depending on individual case information (9), and they may be suitable for TM penicillin allergy delabeling.

Patients considered eligible for TM-supported amoxicillin oral challenge may include such patients with low-risk profiles, in which the reaction was isolated to cutaneous involvement (non-SCAR), particularly if the index reaction occurred in childhood or more than ten years prior in adults (15,42). High- and intermediate-risk patients who need allergy skin tests performed before drug provocation testing (9) are not eligible for TM-supported direct amoxicillin oral provocation.

Regarding immediate hypersensitivity reactions, the high-risk patient profile comprises anaphylaxis, hypotension, laryngeal edema, bronchospasm, urticaria within one hour after drug exposure, and/or angioedema, generalised flushing/erythema. The intermediate risk profile includes non-severe immediate reactions, such as generalised pruritus. Regarding non-immediate hypersensitivity reactions, high-risk patient profile include SCARs: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), generalized bullous fixed drug eruption, and non-SCAR reactions including drug-induced autoimmune disease such as systemic vasculitis or linear IgA bullous dermatosis, and specific drug-induced organ failures (e.g., hepatic, renal, pulmonary). The intermediate risk patient profile comprises moderate maculopapular exanthemas (lasting more than 7 days or requiring systemic or highly potent topical corticosteroids, involving more than 50% of the body surface, without systemic symptoms and danger signs), and delayed urticaria with onset more than one hour after drug exposure. Danger signs in non-immediate reactions, include: intense facial involvement, atypical target lesions, bullous lesions, dark red erythema, extensive pustulosis, painful skin, mucosal involvement, generalized lymphadenopathy, elevated liver enzymes, impaired renal function tests, fever >38.5 ℃, alterations in blood cell counts (i.e., anemia, granulocytopenia, thrombocytopenia, neutrophilia, eosinophilia), hypocomplementemia, hepatitis, nephritis, and pneumonitis (9,75).

PEN-FAST is a concise validated clinical decision score to identify adults with low-risk penicillin allergy that does not require formal allergy testing. A PEN-FAST score of less than three is associated with a high negative predictive value. Clinicians and antimicrobial stewardship programs may use it to identify low-risk patients at the point-of-care. A penicillin allergy is considered to involve at least one of the following beta-lactam antibiotics: unspecified penicillin; natural penicillins: benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V); aminopenicillins: amoxicillin, ampicillin; penicillinase-resistant penicillins: dicloxacillin, flucloxacillin, nafcillin; beta-lactam/beta-lactamase inhibitor combinations: amoxicillin and clavulanate, ampicillin and sulbactam, piperacillin and tazobactam, ticarcillin and clavulanate. The mnemonic PEN-FAST represents penicillin (PEN) allergy, an occurrence of five or fewer years ago (F), anaphylaxis or angioedema (A), severe cutaneous adverse reaction/SCAR (S), and treatment required for allergic reaction (T). The primary criteria include an allergy event occurring five or fewer years ago (yes +2 points) and anaphylaxis or angioedema or severe cutaneous adverse reaction/SCAR (yes +2); the minor criterion is treatment required for reaction (including unknown) (yes +1). Four risk groups are established: very low risk (0 points), with a risk of allergy of <1%; low risk (1 or 2 points), with a risk of 5%; moderate risk (3 points), with a risk of 20%; and high risk (4 or 5 points), with a 50% probability of having a positive penicillin test result. A cutoff of less than 3 points for PEN-FAST is chosen to classify low-risk subjects (59). This score was validated in cohorts of adults with predominantly immediate hypersensitivity (76). To improve performance, two new criteria were added to PEN-FAST (PEN-FAST+) based on a retrospective analysis of misclassified patients: skin rash lasting more than 7 days (being indicative of delayed hypersensitivity), and immediate reaction occurring in less than one hour, with palmoplantar, genital, ear, and/or head, or generalized itching/tingling/heat feeling (suggesting true immediate hypersensitivity) (77).

The EAACI/ENDA strategy has the advantage of providing practical recommendations based on recent literature and expert opinion from task force members, all of whom have significant experience in both immediate and non-immediate drug hypersensitivity. For low-risk patients, PEN-FAST and other scoring strategies, such as the Chiriac score or the Combined score, can be employed to verify whether the patient is indeed low-risk and are highly efficient for delabeling (78).

According to the Canadian Society of Allergy and Clinical Immunology (CSACI) risk stratification and PEN-FAST clinical decision rule, a virtual penicillin allergy delabeling study during COVID-19 restrictions was performed in the Vancouver area. Twenty-three patients, including both adults and children, underwent a TM-supported oral challenge with 250–500 mg of amoxicillin, and all of them tolerated the aminopenicillin with no adverse reaction. The majority of patients had a personal history of maculopapular rash or localized rash to amoxicillin. Patients with immediate reactions in adulthood in the last ten years, immediate reactions after the first dose of course, meeting criteria for anaphylaxis at any time, allergist confirmed penicillin allergy, delayed hypersensitivity reaction such as serum sickness-like reaction, SCARs or a reaction requiring urgent or emergent care or admission to hospital were not considered eligible for the TM procedure (15,42).

Of the selected patients, only those who complete the initial TM visit with adequate quality can reliably contact the physician if any signs of reaction occur. As previously mentioned, the patient must be accompanied by at least one available caregiver and, if possible, a trained nurse or another healthcare professional who can provide immediate assistance if needed. An emergency plan must be in place in case of an adverse reaction which may occur during the challenge. An individual’s cardiovascular and respiratory reserve, as well as their subsequent ability to tolerate minor reactions and anaphylaxis, should always be considered and balanced against the morbidity and mortality associated with inappropriate antimicrobial use. Pregnancy and patients with severe comorbidities, such as uncontrolled asthma, severe chronic obstructive airways disease, and severe ischemic heart disease, represent contraindications for TM-supported direct amoxicillin oral challenges (9,15). The risks and benefits of TM-supported amoxicillin oral provocation must be discussed, and the patient must provide informed consent while being offered instructions for the virtual challenge during the second visit (15).

If a patient tolerated a full dose of the same antibiotic (with the same or different trade name or formulation) after the index reaction, TM delabeling without skin testing or drug provocation is recommended (9). If the patient has received amoxicillin or other penicillin without any reaction in the past, subsequent to the index reaction, if the patient has a family history of penicillin allergy, or presents non-hypersensitivity adverse reactions such as headache, fatigue or exclusive gastrointestinal manifestations such as nausea, vomiting, diarrhea, or abdominal pain, there is a minimal risk for penicillin allergy, while an unknown and remote reaction (more than 10 years in the past) or if the patient denies hypersensitivity adverse reaction but has documented allergy, then it is considered to be low risk for penicillin allergy (42,71,79) and eligible for TM-supported penicillin allergy delabeling.

According to the newly released position paper of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Society for Pediatric Allergology (GPA), Austrian Society for Allergology and Immunology (ÖGAI) and the Swiss Society for Allergology and Immunology (SGAI), similar cases with no evidence of allergy to beta-lactam antibiotics, including isolated gastrointestinal reactions (nausea, vomiting, diarrhea, distinguished from their occurrence in systemic reactions along with other anaphylactic symptoms), isolated non-specific reactions such as dizziness, headache, fatigue, and palpitations and/or rhinoconjunctivitis associated with fear of drug hypersensitivity, delayed urticaria with occurrence more than 1 day after discontinuation or persisting for days after discontinuation, mild exanthema occurring more than 1 week after discontinuation, positive family history without personal allergy history, personal history of tolerance of the suspected beta-lactam antibiotic administered accidentally or the case of allergy documentation but denied by patient, a direct administration of beta-lactam antibiotic may be recommended for delabeling, without prior in vivo and in vitro allergy workup (43), therefore suitable for TM-enabled beta-lactam allergy delabeling.

It is essential to keep in mind that despite some disagreements in classifying clinical entities in risk categories, limitations of point-of-care clinical scores to stratify risks and some controversies regarding assessing patients at low-risk, recent evidence is increasingly supporting fast penicillin allergy delabeling strategies with direct amoxicillin oral provocation which has been proven safe and effective, delabeling the vast majority of low-risk cases (77,80,81).

Although very recently it was suggested that direct single-dose amoxicillin-provocation test is safe in hospital setting for delabelling adults assessed by the latest EAACI/ENDA strategy as low-risk patients such as mild maculopapular exanthema (less than 7 days of duration without systemic symptoms) along with those with intermediate risk such as maculopapular exanthema that lasts more than 7 days and delayed urticaria (81), we suggest that both high- and intermediate-risk patients, according to EAACI/ENDA (9), are to be considered ineligible for TM-supported direct amoxicillin oral challenge.

TM visit in case of direct amoxicillin oral provocation in low-risk patients

The second TM consultation is conducted on the same secure video and audio platform as the first, allowing the healthcare providers to document that patients/caregivers have been informed of all aspects regarding the procedure and have agreed to proceed. There is a need for clear documentation on TM interactions, including any reported clinical manifestations, advice offered, and decisions made regarding patient care. Since the allergist cannot physically direct examine and interact with the patient face-to-face, which may limit the ability to assess specific symptoms remotely, clear communication is critical to minimize the potential for miscommunication. Because remote TM monitoring relies on the patient’s/caregiver’s ability to accurately recognize and report symptoms, education should be provided to enhance self-reporting. Moreover, patients and their companions or caregivers should be trained to keep rescue medication readily accessible for immediate administration, recognize signs of adverse hypersensitivity reactions, and know when and how to call emergency services. TM monitoring relies on their ability to identify and respond to emergencies, so clear, step-by-step instructions on what to do during and after the test are critical (1,12,15,82,83).

Allergists are involved in TM-supported penicillin allergy delabeling practices because they can perform careful risk stratification and adequate benefit-risk assessment for the patient. Allergy-trained primary care physicians may also be involved in children evaluation, but a paediatric allergist should be available for discussions and supervision. After obtaining informed consent, eligible patients are prescribed the appropriate dose of amoxicillin for the oral challenge. The drug is obtained from a community pharmacy, where the prescription is called or faxed and secured before the day of the drug provocation. Oral H1 antihistamines are recommended for symptomatic relief if needed. The benefits of acquiring an epinephrine autoinjector solely for the challenge are an excellent juncture for shared decision-making. Sometimes, it is not provided for the amoxicillin oral challenge alone if the risk of anaphylaxis is considered low enough according to the individual index history (12,13,15,84).

The oral challenge is scheduled to ensure that the patient will not be interrupted and has no other commitments during that time. Physicians will be easily accessible during the monitored period, and emergency means of contact will be provided in addition to the virtual platform. On the scheduled day for the amoxicillin challenge, patients remotely encounter the supervising allergist specialist on a secure video TM platform. The TM-monitored oral provocations may be performed in outpatient departments, long-term care facilities, mobile temporary clinics, or other remote settings, and even at the patient’s residence. An appraisal of their health status is performed, including temperature, weight and cardiorespiratory assessment, and patients should verbally confirm that they are clinically well. A digital thermometer (oral, forehead, or ear), an accurate and comfortable blood pressure monitor, a digital or analogue scale for weight measurement, and a finger pulse oximeter to display heart rate and oxygen saturation are usually required. The patient’s, parent’s, or caregiver’s written or verbal informed consent must be reviewed before administering the drug, and a single-step oral challenge is completed. For a virtually-monitored penicillin oral provocation, amoxicillin, a semisynthetic amino-penicillin, is given orally 250–500 mg as an adult single dose or weight-calculated pediatric single dose, with the aim of delabelling low-risk patients self-reporting penicillin allergy or previously non-allergist labeled as penicillin/aminopenicillin-allergic, without prior allergy skin testing or in vitro blood testing. The physician must be available via the TM platform for 60–120 minutes to monitor and discuss any patient concern regarding a potential allergic reaction or for immediate assistance and guidance in case of a reaction. Visual and verbal assessment is usually performed every 30 minutes for 2 hours, and following this, the patient verbally confirms as being clinically well. Patients are required to have a capable friend, family member, or guardian available in their vicinity to function as a caretaker, and counselling is provided on when, how and where to seek immediate medical support in the event of an adverse reaction requiring immediate care. No additional personnel is generally required (12,15), although a trained nurse or another healthcare professional may be present to provide immediate assistance if needed.

TM follow-up and monitoring

After the challenge test, the TM specialist can schedule a follow-up TM visit to review any immediate and delayed manifestations, guide symptom management, and reinforce any necessary precautions. Immediate reactions are defined as IgE-mediated hypersensitivity reactions that occur within two hours of the first dose of medication and usually last less than 24 hours. Some drug reactions can manifest hours or even days after the initial test. Delayed hypersensitivity reactions are defined as non-IgE-mediated hypersensitivity reactions that typically take more than 24 hours to develop and raise concern for end-organ involvement (cytopenias, renal/hepatic dysfunction, serum sickness), or SCARs (skin desquamation, purpura, mucosal lesions, SJS/TEN, DRESS, AGEP). In the case of prolonged drug challenges, delayed adverse reactions are usually mild maculopapular cutaneous ones, which alone would not be a contraindication to the antibiotic (15).

Through TM, healthcare providers can monitor patients during this period, guiding them on what symptoms to watch for and when to seek further care. Based on the test results, TM can be used for counseling on results by discussing the outcomes of the challenge test, clarifying any uncertainties for the patient, and helping them understand what the results mean for their future medication regimens or treatment options. If the oral amoxicillin challenge is completed, patients are counselled on the low risk of delayed reactions and when to seek medical care if required. They are advised to notify their attending physician and are provided with instructions in the event of any reaction thought to be due to the single-step oral challenge or to a course of a penicillin antibiotic taken for a subsequent infection after delabeling. For clinicians who adopt TM-based penicillin allergy delabelling, steps can be taken to mitigate the potential for adverse outcomes, even if not adopted in the already published studies. In summary, a cost-saving approach to delabeling penicillin allergy using TM and outpatient resources for low-probability cases should be considered (13,15).

Discussion

Technological barriers

The growth of TM has been remarkable, yet its full potential is hindered by several technological barriers, which limit its effectiveness and accessibility. Several critical challenges demand meticulous consideration and strategic interventions to overcome. Infrastructure and access barriers pose significant challenges, especially in rural and low-income areas (85-87). It is also crucial to prioritize user-friendliness and digital literacy to overcome technological barriers. Many patients and providers, particularly seniors or those with limited digital literacy, may struggle with technology. Complex logins, complicated interfaces, and technical jargon can create barriers to effective TM for non-tech-savvy users. Specific requirements should be provided for deaf or hard-of-hearing persons, patients with vision impairment or blindness, persons with speech difficulties, mobility impairments, mental health conditions and psychosocial disabilities, developmental and intellectual disabilities, and learning disabilities (88-90). Limited or unstable access to high-speed internet can lead to poor communication and interrupted TM services, affecting the accuracy and effectiveness of consultations. Blockchain-based smart contracts, bandwidth and data-intensive consumption costs, and patients’ or providers’ limited data plans can discourage some users from frequently utilizing TM services (1,91-93). The lack of standardized TM platforms to meet regulatory standards can create challenges for training and usage. Moreover, the lack of interoperability between TM platforms and electronic health record systems, or the incompatibility of these systems, often makes it difficult to deliver comprehensive care and share important information between healthcare providers. The use of TM is also hindered by device limitations, such as the lack of updated hardware or software capable of supporting TM applications, the lack of necessary cameras, microphones, smartphones, tablets, or computers, outdated technology systems, network crashes caused by power outages, and computer viruses or hardware failures (1,87,94-96). Inadequate technical support and maintenance reduce patient satisfaction and lead to care delays. At the same time, data privacy and security concerns, including those related to data breaches or cyberattacks, can hinder adoption and trust in TM services (97-99).

Reliable technology, including a stable internet connection, a working camera, and audio equipment, is critical for effective TM use in drug challenges. Secure, compliant platforms are also necessary to protect patient privacy and confidentiality. Furthermore, ensuring the safety and efficacy of therapeutic drug monitoring may also necessitate, in some cases, the use of wearable sensors and sensing technologies. Therefore, incompatibility between medical devices for remote monitoring and the TM platforms can hinder real-time monitoring and accurate data transmission (100). Addressing all these technological barriers requires investment in infrastructure, improved technology, and policy support to make TM more accessible, reliable, and user-friendly for patients and providers (89,101,102).

Clinical limitations

TM frequently relies on audio or video consultations, limiting the physician’s ability to perform a complete physical examination, essential for assessing drug effects or adverse drug reactions. Moreover, remote monitoring is associated with limited access to diagnostic tools, such as skin testing for drugs, which are frequently necessary for assessing hypersensitivity reactions (1,103-105). Although there is sometimes a limited need for face-to-face visits, this is not the case for certain patients, such as those with intermediate- and high-risk or primary immunodeficiencies (61). Additionally, TM can be challenging to use for managing complex cases that involve multiple health conditions or special groups such as elderly individuals, people with limited language abilities, or those unfamiliar with digital technology. This is because it requires careful clinical assessment and frequent monitoring. In such circumstances, TM could even worsen healthcare disparities (106,107). When it comes to TM approaches, it is crucial to engage in extensive discussions and transparent decision-making about the risks and benefits involved. No allergy provocation/challenge is without risks (15). TM platforms and remote monitoring devices have the potential to streamline non-adherence to medication, lack of objective diagnostic tests, and poor engagement with allergy and asthma services. However, without artificial intelligence (AI) algorithms, it is very hard to analyze vast amounts of patient data to predict adherence, treatment safety, and disease prognosis (108). Integrating AI in telemonitoring applications offers potential for data analysis, pattern recognition, and personalized treatment plans. However, maintaining a balance between AI-enabled insights and human expertise is crucial for optimizing the benefits of telemonitoring (109). Without monitoring devices, patients may not accurately report symptoms or adverse reactions remotely, leading to incomplete or inaccurate monitoring data. Utilizing TM with monitoring strategies may become an important aspect of self-care and preventive medicine. The data provided may allow for the provision of personalized tools and tailored solutions to improve patient health, as well as help to enhance accurate symptom reports, improve the accuracy of diagnosis, and streamline appropriate specialty referrals. Using e-health through mobile apps, TM, and monitoring devices can increase adherence to treatment, with good acceptance by the patients; however, benefits were not always found (110-113). Nevertheless, significant limitations are related to the need for more scientific evidence regarding their contribution to patient care, their insufficient reliability and validation, and even their endorsement by some patients. Acceptance of connected devices may vary between wealthy and disadvantaged patients, potentially exacerbating care inequalities. Furthermore, transmitting sensitive medical information over TM platforms raises concerns about data privacy and security, potentially eroding patient trust and compliance, a critical issue that needs to be addressed (114,115). While TM cannot replace in-person oral drug challenge tests for intermediate- and high-risk patients, it can be useful for certain selected low-risk cases, making the process more convenient for both patients and healthcare providers. Informed consent is also vital because patients must understand the scope and limitations of such virtual procedures, as well as the associated risks (1,12,15,82,83).

Legal and regulatory issues

TM-supported drug hypersensitivity assessments and drug allergy delabeling by drug challenges raise many specific legal and regulatory issues and complex challenges as they involve patient management, monitoring and safety. Key areas of concern include identifying which services within the specialty of allergology can be delivered via TM, the conditions that must be met for providing these services, and the specific regulations governing their delivery. Moreover, many other essential aspects comprise provider licensure, professional formation and jurisdictional compliance; patient privacy and data security in compliance with data protection laws such as General Data Protection Regulation (GDPR) (in the EU) or Health Insurance Portability and Accountability Act (HIPAA) (in the US); informed consent with details about the benefits and risks of remote drug monitoring, data collection, and the potential limitations compared to in-person monitoring that necessitate careful consideration and planning; accuracy of documentation and record keeping, medication management and safety with provider adherence to regulation on remote e-prescriptions and drug monitoring; professional-patient relationship and standard of care for accurate tracking of patient adverse drug reactions and adherence to treatment with potential liability for malpractice; fee splitting and other potential factors leading to conflicts of interest which may affect the quality of patient care; regulatory standards for remote monitoring medical devices and technology standards; along with adherence to national, interstate and international regulatory frameworks. Together with infrastructure and access barriers, operational complexities and communication challenges, legislative and regulatory hurdles can impede effective healthcare delivery via TM (86,116,117).

TM practitioners should adhere to applicable facility, national, regional and international practice regulations and collaborate with malpractice insurers to ensure proper coverage. Similar ethical, conflict of interest, and personal health information protection obligations exist for practising TM and in-person medicine. Clear data transfer and privacy guidelines are essential for legal compliance and equitable access to TM, including cloud-based TM platforms (13).

Adequate legal regulations are needed for transmitting and storing confidential data. Moreover, modern medico-legal frameworks shape healthcare authorization profiles (116,118). To ensure secure and legally compliant data exchange in TM, it is crucial to establish a clear and well-defined legal framework for data protection. This includes developing and organizing a data protection policy and conducting regular audits and assessments of the data protection framework (1). In European legislative regulations, TM is considered a health and information service. Therefore, both sets of regulations apply. There are no standard specific regulations at the European level regarding healthcare and the practice of medical specialties (119).

Although TM-enabled delabeling of penicillin allergy by amoxicillin challenges may not seem suitable for TM due to the need for close patient observation and rapid access to emergency care, it is important not to shy away from discussing the potential for certain types of drug hypersensitivity assessments and even drug provocations via TM support, but this must adhere to diverse regulatory standards and legal requirements across different jurisdictions this potentially creating more obstacles (89). Constantly evolving regulations and the need for regulatory compliance significantly impede the widespread adoption and sustainability of such TM services. However, various legal and educational, technical, and economic concerns can be addressed and resolved. In that case, the TM has the potential to be sustainable and beneficial not just during pandemics but also in the long term. This optimistic future is within our reach, and stakeholders play a crucial role in making it a reality (85,117,120).

In clinical practice, TM can significantly improve patient care related to some drug hypersensitivity assessments and low-risk drug challenges for patients suspected of being erroneously labelled, by providing timely, convenient, and accessible support. While there are several limitations, TM may offer a valuable approach to practically adjusting healthcare plans and educating patients and their caregivers, companions, and family members. As previously mentioned, it is necessary to consider whether TM should be limited to periods of health crises or whether it could become a new approach to practising medicine in selected patients, and to keep in mind that TM lacks specific regulations and has loopholes that leave physicians with a considerable degree of insecurity (12,15,121).

The current regulatory landscape of the European Health Data Space, initiatives such as the European Electronic Health Record Exchange Format, and interoperability challenges, including legal, technical, and semantic issues, all highlight the need for a comprehensive assessment of cross-border trade mark and related data movements (122).

Although still limited, the integration of AI in healthcare has rapidly developed in the past few years, and it appears that it will play a prominent role in enhancing the efficiency, accessibility, and effectiveness of TM. Even so, there are significant regulatory needs for targeted curricular interventions to bolster AI literacy and proper clinician training to optimise AI algorithms while ensuring patient safety. Additionally, significant concerns exist regarding the integration of generative conversational and agentic AI platforms in TM, particularly in relation to clinical responsibilities and legal frameworks, data security and privacy, as well as beneficence and trust (123,124).

Conclusions

TM offers significant potential for advancing allergy management, primarily by expanding access to care, enhancing patient monitoring, and facilitating follow-up. Despite these advantages, TM’s role in drug allergy assessment and provocation testing remains challenging due to the critical need for direct clinical supervision in many cases and the risks due to hypersensitivity adverse reactions. The safe implementation of TM-enabled penicillin allergy labelling and TM-supported direct amoxicillin oral challenges in low-risk patients, for example, requires careful patient selection and eligibility evaluations, with allergists playing a vital role in risk stratification and assessing the benefits versus risks. Secure video and audio platforms are crucial for real-time virtual monitoring and post-challenge follow-up and monitoring. While future developments may support remote or hybrid protocols under specific conditions, even with AI involvement, robust guidelines, specified legal and regulatory issues, and prioritization of patient safety are critical. This review is intended for informational purposes only and it is not intended to replace in any way the professional expertise of an allergist during in-person visits when needed. Physicians assessing suspected drug hypersensitivity reactions are advised to use their medical judgment, following local and national guidelines, as well as legal and regulatory considerations, and to update their medical information periodically.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://mhealth.amegroups.com/article/view/10.21037/mhealth-24-89/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://mhealth.amegroups.com/article/view/10.21037/mhealth-24-89/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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