What is Causing this Woman’s Rash?

Matthew Tabbut, MD, and David Effron, MD—Series Editor

A 19-year-old female with no significant history presented to the emergency department (ED) with a rash. She noted that the rash started on her face on the day of presentation and has since spread to her trunk and extremities, sparing the palms and soles. She described the rash as painless and not itching. She had no complaints of shortness of breath, difficulty swallowing, or sick contacts. She was not on any current medications, had no allergies, and denied any recent travel.


Two weeks prior to the current visit, the patient said she visited her primary care physician for periorbital swelling and a rash. She was told these findings were related to her sinuses and was prescribed amoxicillin, which she took for 4 days but discontinued due to lack of any improvement. 

She then developed right-sided neck discomfort, sore throat, headache, and fatigue. On the day prior to this current ED visit, she was seen in an urgent care facility for persistent periorbital swelling and was found to have proteinuria and a mild transaminitis. She was diagnosed with the possibility of nephrotic syndrome and referred to her primary care physician.

Physical Examination

The patient’s vital signs included a blood pressure of 109/63 mm Hg, heart rate of 105 beats per minute, respiration rate of 16 breaths per minute, temperature of 37.1°C, and oxygen saturation at 99% on room air. She had bilateral eyelid edema with no erythema. The remainder of her eye exam was unremarkable. She had no edema or erythema of the posterior pharynx and no mucosal rash. 

The patient was noted to have a tender mass on the right side of her neck and palpable hepatosplenomegaly. Her rash was a fine, flat, blanching macular rash that was distributed on the face, torso, and extremities (Figures 1-3).

Laboratory Tests

She had a normal white blood cell count with a lymphocyte count of 15% and atypical lymphs of 38%. Her alanine transaminase was 225 IU/L and aspartate aminotransferase was 230 IU/L with a normal alkaline phosphate and bilirubin. A bedside ultrasound delineated splenomegaly with the spleen measuring 12.4 cm (Figure 4).

What's Your Diagnosis?

A. Streptococcal pharyngitis
B. Measles
C. Roseola
D. Mononucleosis

Answer: Mononucleosis

The patient’s laboratory tests were significant for a positive mononucleosis screen. 

Mononucleosis is a common oropharyngeal infection in children, adolescents, and adults caused by the Epstein-Barr virus (EBV). Most cases are subclinical with up to 50% of the population seroconverting before 5 years of age. This case illustrates a common complication of providing antibiotics in the setting of mononucleosis—the development of a morbilliform rash.

Clinical Presentation

This may vary but common symptoms for EBV include a triad of fever, pharyngitis, and lymphadenopathy. The adenopathy is usually generalized and symmetric and may persist for 2 weeks. Posterior cervical node involvement is not unusual. A prodromal period, which may be present for 1 to 2 weeks, may include fever, malaise, and myalgia. In addition, the prodromal period may be absent with the patient presenting with an acute onset of infectious mononucleosis symptoms. 

In addition to the aforementioned symptoms, some patients can also present with hepatosplenomegaly (10% to 30% of cases), abnormal hepatic transaminases,1 and cephalgia. Periorbital edema has been noted in 15% to 35% of patients with infectious mononucleosis. Spontaneous splenic rupture, although not common, may be the presenting feature of patients with infectious mononucleosis.

Pharyngitis, the most prominent physical finding, often is described as a tonsillar inflammation and may contain exudates. Thus, it can be difficult to distinguish from the presentation of a bacterial pharyngitis. As a result, patients with mononucleosis are often prescribed antibiotics in the course of their illness. Palatal petechie may be noted; although not pathognomonic, they are highly suggestive of infectious mononucleosis.


EBV is shed in the oral saliva and is spread by salivary contact—hence the colloquial term “kissing disease.” Mononucleosis can also be spread by other body secretions (eg, uterine). Rare reports of transmission from blood transfusions have also been reported. 


The standard initial evaluation for a patient with a presentation concerning for mononucleosis is the heterophile antibody test. While highly specific and can confirm a diagnosis of mononucleosis, it is often insensitive requiring further antibody testing.


Mononucleosis can present with a morbilliform or maculopapular rash in up to 13% of cases. However, the incidence of the rash increases with the co-administration of antibiotics. Although there are many offending antibiotics, the most common offenders are ampicillin and amoxicillin. The incidence of rash from these agents is up to 69% in adults and nearly 100% in children.2 The rash usually appears within 5 to 9 days after antibiotic treatment.

The mechanism for the rash is not known, however, it is believed that there is an immune mediated component to the rash.1,3,4 Recent literature suggests that there may be a drug sensitization involved.2,3 


Treatment for infectious mononucleosis is generally supportive with emphasis of rest, fever control, and adequate hydration. Treatment for the rash involves discontinuing the offending agent. Symptoms usually resolve in several weeks, but fatigue has been known to persist for several months. ■

Matthew Tabbut, MD, is an attending physician in the department of emergency medicine at MetroHealth Medical Center and an assistant professor of emergency medicine at Case Western Reserve University School of Medicine, all in Cleveland, OH. 

David Effron, MD, is an assistant professor of emergency medicine at Case Western Reserve University, attending physician in the department of emergency medicine at the MetroHealth Medical Center, and consultant emergency physician at the Cleveland Clinic Foundation, all in Cleveland, OH.


Jenson HB. Epstein-Barr Virus. In: Kliegman R, Stanton B, St. Geme J, Schor N. Nelson Textbook of Pediatrics. 20th ed. Philadelphia, PA: Elsevier, Inc; 2015:1586-1590.

Renn CN, Straff W, Dorfmuller A, et al. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol. 2002;147(6):1166-1170.

Ónodi-Nagy K, Kinyó A, Meszes A, et al. Amoxicillin rash in patients with infectious mononucleosis: evidence of true drug sensitization. Allergy Asthma Clin Immunol. 2015;11(1):1.

Jappe U. Amoxicillin-induced exanthema in patients with infectious mononucleosis: allergy or transient immunostimulation? Allergy. 2007;62(12):1474-1475.