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A New Trigger of Morbilliform Eruption in the Setting of Atypical Infectious Mononucleosis Roxanne Rajaii, DO,* Megan Furniss, DO,** John Pui, MD,*** Brett Bender, DO****

*Dermatology Resident, PGY2, Beaumont Hospital - Farmington Hills, Farmington Hills, MI **Dermatology Resident, PGY4, Beaumont Hospital - Farmington Hills, Farmington Hills, MI ***Dermatopathologist, Beaumont Hospital - Farmington Hills, Farmington Hills, MI ****Dermatologist, Beaumont Hospital - Farmington Hills, Farmington Hills, MI

Disclosures: None Correspondence: Roxanne Rajaii, DO; [email protected]

Abstract Morbilliform eruptions, also commonly referred to as exanthematous or maculopapular drug eruptions, are the most common type of hypersensitivity reaction and can vary in etiology. are a common trigger, most notably or in the setting of a concomitant and acute Epstein-Barr virus (EBV) infection. However, other antibiotics have been identified to cause a similar reaction in the setting of EBV. Cephalexin, a commonly used , is the only in its class that has been implicated in causing such a phenomenon. We present a unique case of a morbilliform eruption in the setting of EBV secondary to the use of , further outlining the importance of conservative antibiotic use and awareness of such a reaction in this specific patient population, not only with but also with a wider spectrum of antibiotics.

Introduction acquired pyelonephritis, as she had been admitted Work-up included the following laboratory tests: Epstein-Barr virus (EBV) infects more than a month prior to that for status asthmaticus. complete blood count, complete metabolic panel, 98% of the world’s adult population and is the Four days later, she presented with an urticarial anti-nuclear antibody, creatinine phosphate kinase, most common cause of infectious mononucleosis morbilliform rash. She was told she was allergic lactic acid, blood cultures, rapid plasma reagent, (IM).1,2 IM is a clinical syndrome characterized by to cefepime, was prescribed diphenhydramine immunoglobulin (Ig) G and immunoglobulin prominent fever, fatigue, malaise, lymphadenopathy, and a weeklong course of ciprofloxacin, and was M titers for rubeola, human immunodeficiency and sore throat.2 It is a self-limiting disease most discharged home the day prior to presenting at virus, cytomegalovirus, EBV, and parvo B19. All commonly seen in older children and young our hospital. labs were within normal limits and demonstrated adults. Symptoms persist over a period of weeks expected adult immunities, with the exception of On examination, the patient had a diffuse to months, typically without sequela; however, a white blood cell count of 12.4 and EBV titers morbilliform and urticarial eruption, with neurologic, hematologic, hepatic, respiratory, positive for IgM and negative for IgG, indicating accentuation on the trunk, neck and upper and psychological complications may occur. In an acute Epstein-Barr virus infection, also known as extremities. The truncal eruption had overlying this patient population, a rash can develop with infectious mononucleosis. A computed tomography marked purpura (Figure 1), while the neck and concomitant use of an antibiotic, most commonly scan of the abdomen and pelvis noted the spleen to extremity eruptions were indurated and urticarial ampicillin or amoxicillin. Clinically, a generalized be at “top normal size,” measuring 13 centimeters. in nature (Figure 2). The patient’s skin was maculopapular, urticarial, or petechial rash develops notably sensitive to touch, and she complained A skin biopsy was taken from each of the within five to 14 days of antibiotic treatment in a 1,2 of generalized itching and stinging. There was an representative areas, one purpuric and the other patient with an acute EBV infection. absence of mucosal involvement, including the urticarial. The biopsy of the left dorsal hand This eruption -- particularly in response to throat, and the face was spared. The exam was showed a focal vacuolar interface dermatitis with amoxicillin or administration -- is well also positive for left costovertebral angle pain and occasional lymphocytes present at the dermal- known amongst clinicians, especially dermatologists tenderness of the spleen on palpation. The spleen epidermal junction and a sparse underlying and infectious-disease specialists.1,2 Lesser known was palpable 1 cm below the left ribcage. superficial perivascular lymphocytic infiltrate. These is the ability of other classes of antibiotics to trigger this immunologic phenomenon. Although amoxicillin and ampicillin are most commonly the causative agents of this eruption, other penicillin derivatives and other antibiotic classes have also been cited in the literature. These include , , , cephalexin, minocycline, sulfonamides, quinolones, and macrolides including erythromycin and azithromycin. To date, although cephalexin, a commonly used cephalosporin, has been cited to cause this reaction, cefepime, another well-known cephalosporin, has not been implicated in this phenomenon, making this case report novel in adding another antibiotic to the list of potential causes for a morbilliform rash in the setting of infectious mononucleosis.1 Case Report A 29-year-old woman presented to the emergency department with left-sided back and leg pain, leg weakness, fever, rash, nausea, vomiting, and malaise and was admitted for further work-up. Approximately one week prior, she had been admitted to a nearby hospital with similar complaints plus pelvic pain and dysuria, Figure 2. Eruption on the back, diffusely for which she was treated with intravenous (IV) Figure 1. Eruption on the neck and acral sites covered in a tender, morbilliform, markedly cefepime and for presumed hospital- with an indurated, urticarial appearance. purpuric rash.

A NEW TRIGGER OF MORBILLIFORM ERUPTION IN THE SETTING OF ATYPICAL INFECTIOUS MONONUCLEOSIS findings were consistent with a morbilliform viral antibiotics as the causative agent.4 Although most rarely. Acral sites are often spared in mild cases. exanthem. The biopsy of the left lower abdomen often confined to the skin, severe cases may exhibit However, the face, palms, and soles may be affected. revealed a different histologic pattern consisting involvement of the mucosa and appendages.2,3 Aside from this maculopapular rash, patients often of a superficial to mid perivascular and interstitial experience pruritus, low-grade fever, elevation mixed-cell infiltrate composed of lymphocytes and The pathophysiology of exanthematous drug of acute-phase proteins, and mild eosinophilia.2 neutrophils with extravasated erythrocytes, with eruptions is variable. Many are believed to be a Timing of these eruptions is variable; the consensus, minimal epidermal changes. These findings were result of a delayed-type T-cell mediated (type however, is that the rash commonly develops within 5 consistent with an urticarial drug eruption. IV) immune reaction. However, the exact five to 14 days of antibiotic initiation.2 In those mechanism by which drugs cause an immune individuals who have been previously sensitized, the Based on the positive acute EBV titers, biopsy response resulting in a maculopapular eruption eruption may appear within only two or three days. results, and clinical presentation, the patient was is poorly understood. The number of drugs that diagnosed with acute infectious mononucleosis have been cited as culprits for such a reaction is If antibiotics are postulated to be the causative complicated by a morbilliform drug eruption vast. The penicillins, , and agents agent, the eruption may even appear up to several elicited by administration of cefepime. The patient with sulfhydryl groups, for instance, are among days after treatment termination. Although the was treated with a two-week steroid taper, beginning the most commonly used drugs that cause a drug eruption in many individuals evolves rapidly, it with IV methylprednisolone and transitioning to eruption.1,2 These specific classes of drugs act reaches its maximum intensity approximately two oral prednisone on discharge. She was also treated as haptens, bind to macromolecules, and then days after discontinuation of the causative agent with topical corticosteroids, antipyretics, and anti- become full antigens.6 Aromatic sulfonamides and resolves within one to two weeks. Many histamines, and fared well. She was discharged (trimethoprim-sulfamethoxazole), anticonvulsant individuals experience desquamation throughout home after a five-day admission. drugs such as carbamazepine and phenytoin, some the process of resolution, and some may suffer from nonsteroidal anti-inflammatory drugs (NSAIDs), post-inflammatory hyperpigmentation. Discussion and paracetamol are other agents that are notorious Exanthematous drug eruption, also known as for causing a drug eruption. However, these specific Diagnosis is often clinical in nature and should morbilliform or maculopapular drug eruption, is the drug classes require biotransformation to form be suspected in an individual who is receiving most common type of hypersensitivity reaction and reactive metabolites.1,6 drug therapy and presents with a new-onset can have a variety of etiologies.5 It often manifests rash.1,2 History of present illness, clinical features, as a diffuse and symmetric eruption of erythematous Although drugs play a crucial role in exanthematous laboratory testing, and sometimes histopathologic macules or small papules that can be triggered within drug eruptions, concomitant diseases, namely viral examination of a skin biopsy are used to confirm approximately one week of drug initiation.3,4 Roughly infections, may predispose an individual to such a suspected diagnosis.15 Treatment involves 2% of individuals exposed to drugs will experience an eruption as well.7-9 Diseases cited in current prompt withdrawal of the offending drug along a cutaneous drug reaction, most commonly with literature that increase an individual’s risk of with symptomatic treatment including topical such an eruption include infection with Epstein- corticosteroids and oral antihistamines for the Barr virus, cytomegalovirus, and human herpes pruritic eruption. Systemic corticosteroids are viruses 6 and 7. In the setting of EBV-caused typically only indicated in severe cases. infectious mononucleosis, a maculopapular rash almost always occurs following the administration This case demonstrates the importance of accurate of ampicillin or amoxicillin.2 In addition, diagnosis and early identification of mononucleosis, immunocompromised patients, namely those particularly in the setting of a new-onset rash after afflicted with human immunodeficiency virus antibiotic initiation. Although not among the (HIV) infection, cystic fibrosis, and autoimmune numerous antibiotics previously reported to cause a disorders, are also at increased risk of developing maculopapular eruption in individuals infected with an exanthematous drug eruption.7,11,12 EBV, this case demonstrates that cefepime can be added to the long that can cause an While the pathophysiology is not fully understood, immune response in this patient population. While the histopathology of these drug eruptions has been this reaction can be severe, it is important to note better described.13 At the dermoepidermal junction, that it does not imply a true allergy to that specific Figure 3. H&E (200x): Skin biopsy of the left a vacuolar interface dermatitis with scattered antibiotic or even the general drug class, as patients dyskeratotic keratinocytes is often observed. A often tolerate the antibiotic of concern without an dorsal hand showing a focal vacuolar interface 3 superficial perivascular and interstitial infiltrate of adverse reaction in the absence of mononucleosis. dermatitis with occasional lymphocytes lymphocytes, neutrophils, and eosinophils is often In this case, the marked reaction to the antibiotic present at the dermal/epidermal junction and seen under histology as well. Other features that provided a clue to pursuing the correct diagnosis a sparse underlying superficial perivascular may be seen include extravasation of erythrocytes, in a less-than-typical presentation of acute lymphocytic infiltrate. foci of lymphocytes at the dermoepidermal mononucleosis. Ultimately, the severity and sudden junction, and fibrin deposition within the blood onset of the rash after antibiotic administration was vessel walls of the papillary plexus. the key clue to the unifying diagnosis. Epstein-Barr virus is the most common cause of Conclusion infectious mononucleosis, which is characterized by This case report documents a new and previously prominent fever, fatigue, malaise, lymphadenopathy, undocumented trigger of morbilliform eruption, and sore throat.2 However, other viruses, such as cefepime, in the setting of infectious mononucleosis. cytomegalovirus (CMV), HIV, human herpesvirus While antibiotics such as amoxicillin and type 6 (HHV-6), and hepatitis B virus (HBV), can ampicillin have commonly been associated with the also spread through bodily fluids and cause this development of a maculopapular rash in the setting disease.15 Symptoms of infectious mononucleosis of an acute EBV infection, this clinical scenario persist over a period of weeks to months, typically demonstrates the important role other antibiotic without sequela; however, neurologic, hematologic, classes may play in similar drug eruptions. This hepatic, splenic, respiratory, and psychological further supports the importance of conservative complications can arise.2,15 antibiotic use and awareness of such a reaction Figure 4. H&E (200x): Skin biopsy of the left in this patient population with all antibiotics, not lower abdomen showing a superficial to mid- In patients with infectious mononucleosis, a rash just the penicillins. Further reports documenting can develop with concomitant use of an antibiotic, a morbilliform eruption after treatment with perivascular and interstitial mixed-cell infiltrate 14 most commonly ampicillin and amoxicillin. The cefepime in the setting of infectious mononucleosis composed of lymphocytes and neutrophils with rash presents as erythematous macules and papules, are needed for a more definitive association. extravasated erythrocytes; minimal epidermal closely resembling eruptions of viral exanthems. changes are noted. Pustules and bullae may be seen, although very

RAJAII, FURNISS, PUI, BENDER, References Acknowledgment 1. Dakdouki GK, Obeid KH, Kanj SS. Azithromycin- Author Contributions: Drs. Rajaii and Furniss had induced rash in infectious mononucleosis. Scand J full access to all of the data in the study and take Infect Dis. 2002; 34(12):939-41. responsibility for the integrity of the data and the accuracy of the data analysis. 2. Jenson HB. Acute complications of Epstein-Barr virus infectious mononucleosis. Curr Opin Pediatr. Study concept and design: Drs. Rajaii, Furniss 2000;12(3):263-8. and Bender

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Abbreviations and acronyms: EBV: Epstein Barr Virus CMV: Cytomegalovirus IM: Infectious mononucleosis CBC: Complete blood count UA: Urinalysis CMP: Complete metabolic panel CT: Computed Tomography ANA: Anti-nuclear anti-body CPK: Creatinine phosphate kinase HIV: Human Immunodeficiency virus RPR: Rapid plasma reagent

A NEW TRIGGER OF MORBILLIFORM ERUPTION IN THE SETTING OF ATYPICAL INFECTIOUS MONONUCLEOSIS