Self-reported allergy to parenterally administered penicillin

Introduction: Penicillin and penicillin products are in use in everyday medical practice. The most frequently reported ad­ verse drug reactions are those to penicillin. New penicillin al­ lergies occur more often with parenteral than oral treatment. In patients who are allergic to penicillin, prescribed therapy is more often the one of antibiotics of broad spectrum, and this therapy is more expensive. The allergies to penicillin are im­ munologically mediated.


Introduction:
Penicillin and penicillin products are in use in everyday medical practice. The most frequently reported adverse drug reac tions are those to penicillin (1).
When patient states that he is allergic to penicillin, this means that in his therapy we cannot include drugs from this group be cause the patient would be placed under health risks and this could endanger his life. In such cases, the use of cephalosporins is also questionable because of cross reactivity. Cross-reactivity exists between penicillin and the first generation of cepha losporins, with a risk of 0.5%, but there is no evidence of cross-reactivity for most cephalosporins of the second and third generation (2,3). Depending on the research, in subjects with a documented IgE-mediated hypersensitivity to penicillin, a rate of posi tive responses to allergy tests with cepha losporins ranging from 0% to 27% have been found (4). "Penicillin allergy is often diagnosed early in life, and the history of penicillin allergy persists in a patient's medi cal record for many years without verifica tion. Some physicians' consideration of a patient having penicillin allergy is based on patient experience that may have occurred early in childhood" (5). Penicillin allergy remains the most common drug allergy re ported, with a prevalence of ~8-12% de pending on the specific population evalu ated, and in the USA there is a reported prevalence of 10% (6). In the research con ducted in Boston, USA, " 35.5% of patients had at least one reported drug allergy with an average of 1.95 drug allergies per patient. The most commonly reported drug allergies in this population were to penicillin (12.8%)" (7). Allergic reactions to penicillin occur in about 0.4-5% of patients and can be fatal in 0.002% patients (8). In Vićentijevic's research the most frequent allergies are to penicillin with 46% of patients reporting allergies to drugs(9) or in Dmitrović R. and Zivanovic S.(10) research 56.13% of pa tients are reporting allergies to drugs.
Patients allergic to penicillin use more of wide-spectrum antibiotics, more fluoroqui nolones, and have a higher estimated Clos tridium difficile risk (12). Treatment of pa tients allergic to penicillin with a wide spectrum of antibiotics leads to multiple side effects, higher costs and the creation of multi-resistant strains (13). "In patients with an allergy to penicillin documented in their medical records the total number of pre scriptions increases. "Total number of pre scriptions were increased in patients with a PenA record. PenA records are common in the general population and associated with increased/altered antibiotic prescribing and worse health outcomes" (14). "Prevalence of Pen-A registration in hospitalized patients is high, has high impact on antibiotic pre scribing, and is associated with a higher risk of readmission. Verification of the Pen A in hospitalized patients might restrict the use of reserve antibiotics and improve pa tient outcome" (15). In literature, manifesta tions that are reported as allergic reactions to penicillin are listed according to fre quency: rash, unknown/undocumented, hives, swelling/angioedema, anaphylaxis, as well as itching, dyspnea, nausea/ vomiting, diarrhea, palpitations, headache and ocular toxicity.
According to the CDC, the following symptoms can be clas sified as IgE-mediated reaction to penicil lin: reactions that occur immediately or usually within one hour, hives, angioedema, wheezing and difficulty breathing, symp toms and signs of anaphylactic reactionsaffecting at least two of the following sys tems -Skin: hives, redness, itch and/or angioedema; Respiratory: cough, congestion, difficulty breathing, chest tightness, wheez ing, constriction of airways/closing of the throat, change in voice quality; Cardiovas cular: hypotension, tachycardia or less fre quently bradycardia, tunnel vision, chest pain, sense of imminent death, loss of con sciousness; Gastrointestinal: nausea, vomit ing, stomach cramps, diarrhoea (16).

Scope:
The scope of study was to evaluate patients' statements on adverse reactions they experienced after receiving parenteral penicillin and what was later diagnosed as a true allergic reaction.

Methodology:
The study is a cross-sectional study, a retrospective analysis of the work of one doctor in the City Institute for EMS Bel grade from 27.07.2017 to 28.12 2018 on a total of 2481 patients.
When a patient contacts our call centre, we start a paper protocol and an electronic form in MS Access database which is later printed as a report. In taking their history patients are asked whether they are allergic to any drugs, i.e. if there are any drugs they should not take. If the answer is yes, and one or more drugs are cited, then they are asked what happened the last time when they took the drug, i.e. what reaction oc curred, so that it was diagnosed as an al lergy. For example, an allergy diagnosis made by a doctor who told the patient after an adverse reaction that she was allergic to the drug and that she should no longer use it. Sometimes they state that they had an ad verse reaction in their childhood, which is when they were told that they were allergic to the drug, i.e. they can't explain exactly what happened. The allergy data obtained are entered in the corresponding field, i.e. drug allergy field, which is then analyzed.
Patients who responded that they should not take penicillin products because of the al lergic reaction experienced after parenteral administration of penicillin were taken into consideration as those were considered con firmed allergic reactions.
Inclusion criteria: if a patient has experi enced a reaction after receiving parenteral penicillin, and at another time in a separate event they experienced an adverse reaction to another drug, they were included in the study.
Exclusion criteria: if a patient received penicillin and another drug at the same time, then that patient was not included in the study. Oral penicillin preparations and their related adverse reactions were not taken into account. They were recorded separately when entering data about pa tients. When running queries a few patients showed up more than once. Their claims of having drug allergies were compared. If their answers to the question about drug allergies were consistent each time, only one entry was made and the rest were de leted. If, on separate occasions, their an swers were inconsistent all the entries for those patients were deleted as we consid ered them unreliable.
In the end there were 242 patients left for analysis, accounting for 9.8% of the total number of patients examined. The data was then exported to an Excel spreadsheet, where the sort and count search was per formed. Statistical testing of %2 test contin gency tables and descriptive statistics in SPSS 11 for Windows.
In the end there were 242 patients left for analysis, accounting for 9.8% of the total number of patients examined. The data was then exported to an Excel spreadsheet, where the sort and count search was per formed. Statistical testing of %2 test contin gency tables and descriptive statistics in SPSS 11 for Windows.

Results:
Of the 2481 patients, 242 stated they had experienced some adverse reactions to parenteral penicillin, which was diagnosed by a physician as an allergic event.
Of that number 82 patients did not know what happened. Of the 71 who were de clared allergic to penicillin in their child hood, only 9 were able to explain what reac tion exactly occurred.
Therefore, for the analysis we were left with 160 patients who were able to explain what exactly happened and they listed 204 ad verse reactions in total.

Discussion:
Out of 242 patients, 160 were able to explain what kind of reaction they had after drug administration. The group had an aver age age of 49.64, with the majority of them being female and with most commonly re ported reactions being skin reactions like rash, hives, redness, blisters or itchiness, then loss of consciousness, eyelid, face or mouth swelling, as well as swelling of the arms or hands. They experienced dyspnea, ringing or pulsing in the ears, then less fre quently they reported fainting, blackouts, dizziness, coma, mouth distortion, vomiting,tongue tingling, heart palpitations etc. The limitation of our study is in the fact that our data was taken verbally from the pa tients who described in their own words the adverse reactions they experienced that were later diagnosed as penicillin allergy, i.e. we were not in the position to verify their self reported allergies as we had no access to their medical records.
Depending on a study, the number of pa tients reporting penicillin allergy is ranging from 8-12% depending on the populations evaluated (6). In a study from Boston, USA, "again, the most commonly reported drug intolerances, in this somewhat older popula tion, were to penicillins, with 12.8% report ing an "allergy" (7). In a study from France, 9.4% of patients stated they were allergic to penicillin (17). In 7 -15% of children there is a suspected allergic/hypersensitivity (HS) reaction to drugs, especially antibiotics (18). In Great Britain, based on a study on medi cal records of 2.3 million of adult patients the prevalence to penicillin allergy is at 5.9%, more frequently in older patients, fe males and patients with co-morbidities as stated by their GPs (14). In our study, that percentage is at about 10%.
In the research from Macy E, Romano A, Khan D it is stated that "antibiotic allergy prevalence increases with increasing age and is more common in hospitalized popu lations and in populations that use more an tibiotics"^) .
In the study by Macy et al there is a larger representation of females 9.46% as com pared to males 5.93%(1). "Antibiotic al lergy incidence rates are sex dependent, higher in females than in males" (19). The most common allergic reactions were rash (37%), unknown/undocumented (20.2%), hives (18.9%), swelling/angioedema (11.8%)" (6). Most commonly exhibited ad verse reactions to administration of par enteral penicillin are skin rashes and itchi ness, dyspnea and wheezing, swelling of eyelids, face or mouth, tongue swelling or redness, fever or shivering, joint pains, sud den drop in blood pressure (8).
According to CDC (16), out of all adverse reactions that can be categorized as allergic reactions according to drug information sheets, in our study we had redness, itchi ness, hives, rash, swelling of eyelids, face, mouth, tongue, dyspnea, loss of conscious ness, fainting, blackout or blurred vision, nausea, vomiting, tingling of tongue, palpi tations, hand tingling, seeing stars, shock, drop in BP, sinking feeling, numbness, tight throat feeling, Table number 1. As many as 82 of our patients of the total of 242, i.e. 33.9%, state they are allergic to penicillin but are unable to list even one symptom of what happened in their allergic reaction. 71 patients of 242, i.e. 29%, state they have penicillin allergy since childhood. Other researchers also state this as a fact, i.e. that a large percentage of patients who are re porting penicillin allergy have had it since childhood (5).
The most common allergic reaction is rash, as stated in multiple studies. "Overall, im proved referral to an allergist will help to identify patients who have penicillin allergy requiring avoidance" (6). In the study by Branelec A et al, skin rash is present in 58.6% of cases and 13.1%have reported se rious adverse reactions such as coma or ur gent hospitalization with anaphylactic shock being the case in 8.8% (17). Only one of our patients reported having been in 'shock' even though conditions like unconscious ness, coma and shock account for 33.9% of total adverse reactions.
"Diagnosis of drug allergy is largely based on clinical history because diagnostic tests are limited. Most patients who are labelled as having penicillin allergy can tolerate penicillins after allergy evaluation" (20). Many patients report being allergic to peni cillin, but only very few of them have clini cally significant reactions (21). Even in our study we had somewhat lighter adverse re actions reported after administration of peni cillin, i.e. skin rash, itchiness or redness of skin, dizziness, tongue numbness etc. Table  number 1.
In the study of Kusic et al it is stated that "the most common initial symptoms were rash(exanthema) and angioedema. None of the patients with self-reported allergic reac tion to penicillin had positive in vitro tests. Total number of patients with positive in vivo tests is 2/81 (2.5%)" (13)."Something completely else, but clearly not an immu nologically mediated reaction, such as a pharmacologic reaction, expected side ef fect, headache, yeast infection, gastrointesti nal upset, viral exanthem, other benign reac tion or association, fear, or some unknown reaction, account for the majority of penicil lin "allergies" reported in the electronic health record (EHR), approximately 95% to 97%"(1). In our study we had a good por tion of such reactions. Table number 1. Not all self-reported allergies are true drug al lergies. Adverse reactions can be truly aller gic but also pseudo-allergic such as: dizzi ness, palpitations, visual and hearing distur bances, change in consciousness, skin changes (8). Among the adverse reactions we have recorded and that fall under the pseudo-allergic procaine reaction or other immunological reaction cited in the drug information sheet or a neurotoxic reaction (8) are: dizziness, buzzing or pulsing in the ears, feeling of numbness in tongue and arms, heart palpitations, stiffness, mouth distortion, foaming at the mouth, seeing stars, palsy, hearing sounds, 'wave' going through the body, twisted tongue, increased epilepsy symptoms, etc. Table number 1. These reactions are not listed in the drug information sheets but could be the result of Hoigne's syndrome, which occurs after in tramuscular administration of penicillin G procaine. Hoigne's syndrome manifests it self as severe psychomotor agitation with confusion, a sense of disintegration, deper sonalization and derealization, a sense of change in body shape, visual and auditory hallucinations, panicked fear of death, changes in consciousness and epileptic seizure (8). Only one in 1543 patiens (0.065%) with oral administration and one in 1030 (0.097%) with parenteral penicillin associ ated administration were confirmed as cases of anaphylaxis (11), and only one of our pa tients stated that he experienced "shock", but several of them stated they wereunconscious which could indicate a serious reac tion or perhaps even an anaphylaxis, Table number 1. "Most patients who report peni cillin allergy can tolerate penicillins without having an adverse or hypersensitivity reac tion. Unfortunately, most patients do not undergo penicillin allergy testing, which leads to use of alternative antibiotics that result in increased morbidity. This increased morbidity leads to a significant detrimental economic effect on health care. In patients with negative test results, most recurrent reactions are benign rashes. There is always a fear that an anaphylactic reaction would occur on re-exposure to a penicillin; how ever, multiple studies have found that this is an extremely rare occurrence" (22). Al though anaphylaxis is a rare occurrence, it is not possible to remove responsibility for ad ministering penicillin to patients who indi cate that they are allergic to penicillin.
Penicillin allergy may be a serious adverse reaction that affects the possibility of anti bacterial treatment. Although it is often re corded in medical records, only a minority of patients with a recorded penicillin allergy actually have a confirmed allergy. "The term 'allergy' may be incorrectly applied to adverse reactions that do not have an immu nological basis and inappropriate labelling of penicillin allergy can lead to the unneces sary avoidance of penicillins and other betalactam antibacterials" (23). Given the in creasing resistance to antibiotics, and that penicillin remains a highly effective medi cine in the fight against many infections, the fact that the number of reported allergies is more than 10 times higher than the number of actual allergies is a serious health problem (16).
Most children who report an allergy to a multi-class drug or a family of antibiotics are not allergic to these drugs. In these chil dren, one would think of allergic or non allergic intolerance or hypersensitivity to other drugs, often given in addition to anti biotics (non-opioid analgesics, antipyretics and non-steroidal anti-inflammatory drugs in particular) (18).
"Verification of the penicillin allergy in hospitalized patients might restrict the use of reserve antibiotics and improve patient outcome" (15).
"Establishing true penicillin allergy status (e.g. oral challenge testing) would allow more people to be prescribed first-line anti biotics, potentially improving health outcomes" (14). "Seven to 15% of children re port suspected allergic/hypersensitivity (HS) reactions to drugs, antibiotics espe cially, but studies based on clinical history, skin tests (ST) and drug challenge/ provocation tests (DPT) have shown that only 10-15% of these children were truly allergic, except for the children reporting immediate and/or severe reactions" (18).
About 10% of the population reports an al lergy to penicillin, but after testing, up to 90% of these patients do not have an al lergy to penicillin (24).
"Antibiotics are the commonest cause of life-threatening immune-mediated drug re actions and many antibiotic reactions docu mented as allergies were unknown or not remembered by the patient. Antibiotic al lergy labels result in displacement of firstline therapies for antibiotic prophylaxis and treatment which is associated with in creased use of broad-spectrum and non-Plactam antibiotics, which results in in creased adverse events and antibiotic resis tance. Most patients labelled as allergic to penicillins are not allergic when appropri ately stratified for risk, tested, and rechallenged" (25). "An unconfirmed penicil lin "allergy" is a significant health risk and testing can significantly lower this risk" (7).
In the study of Kusic et al "adverse effects to penicillin were reported by 70/81 (86.4%) tested patients. None of the 70 pa tients with self-reported allergic reaction to penicillin had positive in vitro tests. Total number of patients with positive in vivo tests is 2/81 (2.5%)" (13).
Penicillin allergy testing is an intervention that through the analysis of assumed sensi tivity is a less expensive option and saves money (12).
Establishing the true status of penicillin al lergy will allow more people to be pre scribed the first line of antibiotics and possi bly improve patient health outcomes.
The best method for determining IgEmediated penicillin allergy is a skin test (13). Skin testing is associated with frequent false positives and false negatives(1).
The negative predictive value of the skin test is more than 95%, and when checked with a single oral dose of the drug it is close to 100% while the positive predictive value is between 40% and 100% (16). Vićentijević states that in 23% of patients, drug allergy has been further tested and confirmed by analysis(9). However, only 6% of patients who report an allergy have a confirmed report from an al lergy specialist. All in all, a confirmed con sultation with an allergist helps to detect pa tients with penicillin allergy and require drug avoidance" (6). Still, the problem is that there are millions of patients with the need to have their penicillin allergy either con firmed or dismissed.
Doctors and patients who should be given penicillin are in favour of testing, although all those who have been labeled as allergic are not convinced about the benefit of the study.
The problem with allergy to penicillin and other drugs could also be in the legal regula tions, i.e. in the actual reporting process. In order to report an allergy to the drug, it is sufficient that a doctor suspects it based on the adverse reaction.

Conclusion:
The most common reactions after ad ministration of parenteral penicillin are cu taneous manifestations, loss of conscious ness, swelling of the tongue and face, dysp nea. About 40% of what our patients report is a serious reaction like loss of conscious ness and dyspnea. One portion of all re ported reactions could be classified as non allergic reactions or adverse drug reactions.