Diagnosis of Herpes Simplex Virus-Induced Erythema Multiforme Confounded by Previous Infection With Mycoplasma Pneumonia

An 18 year-old male presented with 1 week of painful oral lesions accompanied by fever, cough and photophobia. Physical examination revealed an ill appearing male with bilateral conjunctivitis and hemorrhagic crusting on the lips (Figure 1). There were no lesions on the hands or genitalia. Blood, eye, sputum and throat cultures were unremarkable. Mycoplasma pneumoniae (MP) serology showed elevated IgM (1.51 g/l) and IgG (4.92 g/l), and he was successfully treated with azithromycin and prednisone for presumed MP-induced erythema multiforme (EM).

One year later, he presented with oral ulcers and targetoid macules on the penis. MP IgM and IgG were again elevated at 1.68 g/l and 6.03 g/l, respectively. HSV serologies were normal except for elevated HSV-1 IgG, suggesting previous exposure or infection, and he responded to treatment with azithromycin and prednisone for presumed recurrent MP-induced EM.

One month later, he returned with bilateral conjunctivitis, clustered vesicles on the lips (Figure 2), oral white plaques (Figure 3), and targetoid macules on the penis (Figure 3). Repeat HSV serologies were normal except for elevated HSV-1 IgG and HSV-1 direct fluorescent antibody (DFA) testing from a lip lesion was positive. A diagnosis of recurrent HSV-induced EM was made and he was treated with valacyclovir without further recurrences.

Erythema multiforme is an immune-mediated hypersensitivity reaction usually due to infection (up to 90% of cases) or rarely, medications (less than 10% of cases). Infection-induced EM is typically self-limited and commonly caused by HSV or MP; recurrent EM is almost always associated with HSV. However, identifying the causal factor can be sometimes challenging given variations in diagnostic methods. Herein, we present a concise overview of diagnostic techniques for HSV and MP (Tables 1 and 2), as repeatedly elevated MP titers with normal HSV IgM in our case led to a delayed diagnosis of HSV-induced EM.

Serology can aid in the diagnosis of primary HSV infection, but is less helpful with distinguishing recurrences. HSV IgM becomes positive within 9 to 14 days of initial infection and remains elevated up to 7 weeks. However, IgM may not be produced during HSV recurrence, leading to missed diagnoses. HSV IgG becomes positive within 4 weeks and remains elevated indefinitely. Sensitivity and specificity are presented in Table 1.¹

HSV culture becomes positive within 2 to 5 days, but samples must be obtained from active vesicles during viral shedding, which lasts an average of 4 days. Cultures may be negative in over 50% of recurrent lesions, resulting in gross underdiagnoses.^{2, 3}

A comparison between DFA and viral culture found a sensitivity of 85% for DFA analysis.³ For recurrent lesions, multiple samples are recommended to maximize collection of viral particles. DFA has a rapid turnaround time and allows for differentiation between HSV and varicella zoster virus (VZV).

PCR detects DNA from ocular, oral and genital lesions, with superior specificity to culture.⁴ PCR can also detect viral copies during