Report: A pox presenting without pox

Abstract

A man with virally suppressed HIV presented with an erythematous, morbilliform rash without pustules in the setting of fever, fatigue, and myalgias after recent travel to Mexico and Puerto Rico. He was diagnosed with non-variola orthopoxvirus (mpox) infection. This case report highlights an atypical presentation in the 2022 outbreak.

SUMMARY:

A man with virally-suppressed HIV had an atypical presentation of mpox; he presented with an erythematous, morbilliform rash without pustules in the setting of fever after recent travel.

BACKGROUND

Non-variola orthopoxvirus infection, or mpox, has been identified in 93 countries (many with no prior history of mpox), with 37,736 cases reported as of August 18, 2022 (1). Currently, the United States has the most patients affected (13,517), particularly in New York (2,675) and California (2,356); Washington state has reported 303 (2). Most patients identify as men who have sex with men, bisexual, or gay; potentially related to rapid transmission within a highly connected population engaged with healthcare (1, 3).

Mpox virus has been previously described in Central and West Africa; the two phylogenetic clades are the West African or Congo Basin clade (3, 4). Often, a prodromal phase with fever, malaise, and lymphadenopathy occurs 5–13 days after exposure, progressing to a pustular or vesicular rash 1–4 days later (3). The rash can mimic other sexually transmitted infections (STIs) or febrile illnesses which may delay diagnosis (3, 4). Mpox virus is transmitted through close contact with skin lesions, respiratory droplets, and potentially genital fluids (5); case fatality is generally limited, but complications can occur including encephalitis, secondary bacterial infections, pharyngitis, proctitis, anorectal pain, myocarditis, and epiglottitis (4).

The first person identified in the United States outbreak was a man in his mid-30s with recent travel to Canada and unprotected sexual contact with men; he presented with perianal ulcers and developed an umbilicated lesion on his penis (6). His diagnosis was delayed given no ongoing outbreak in the United States at the time and overlap of mpox symptoms with other STIs (6). However, patients may present without the classic pustular, umbilicated lesions, further delaying diagnosis. Here we describe an atypical presentation of mpox virus infection.

CASE REPORT

In July 2022, a man in his mid-40s with virally suppressed human immunodeficiency virus (HIV) (CD4 count >900 cells per microliter (μL)) on bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy), treated for latent syphilis nine months prior, presented to the emergency department (ED) with a four day history of severe fatigue and malaise, and a one day history of sore throat, fever, and rash that began on his back and progressed to cover his entire body. In the ED, he was febrile (38.5 degrees Celsius) and tachycardic (125 beats per minute); blood pressure was 112/66 millimeters of mercury. On physical exam, he was alert and oriented, but uncomfortable. He had pharyngeal erythema and minimal exudate, a large palpable and tender right-sided cervical lymph node, and a diffuse, morbilliform, erythematous eruption with confluent areas on his trunk that spared his face, palms, and soles (Figure 1a). He had a small papular lesion on his penis that was not vesicular or umbilicated (Figure 1b). During his initial ED presentation, he had no other papular, vesicular, or pustular lesions.

Figure 1: Evolution of rash in a patient with non-variola orthopoxvirus infection.

(A, B) Initial presentation with diffuse morbilliform rash and penile papule. (C) Hospital day 2 with new abdominal lesion. (D) Hospital day 3 with evolution and umbilication of back lesion.

He traveled to Mexico and Puerto Rico one month prior but was not acutely ill while traveling or immediately upon return. The patient is sexually active with men. He was sexually active in Mexico and more recently in Washington State over the prior month. He denied any close contacts with rash or fever, recent hiking trips, pets, recreational drug use, new medications, or new supplements. He received childhood vaccinations including varicella zoster vaccine.

Initial laboratory studies demonstrated a white blood cell (WBC) count of 5,060 cells/μL; absolute eosinophils were 100 cells/μL. Platelets were 115,000 cells/μL. He had elevated serum creatinine of 1.56mg/dL, and a lactate of 2.6 mmol/L which declined after fluid resuscitation. Liver function tests were within normal limits.

Highest suspicion initially was for secondary syphilis and treponemal testing was performed. Blood cultures were obtained to rule out bacteremia and toxic shock and were negative. Additional workup included dengue, chikungunya, and Zika serologies, and mycoplasma respiratory polymerase chain reaction (PCR) testing. Initial differential diagnosis for the confluent morbilliform eruption was a viral or drug exanthem. The patient was admitted to the hospital for workup and management.

Despite atypical skin findings, his epidemiological risk factors raised concern for mpox given the ongoing outbreak. Forty-four mpox cases were reported county-wide by the time of his presentation. Only four patients within our hospital system had been both diagnosed with mpox and started on tecovirimat (TPOXX), a Centers for Disease Control and Prevention (CDC) non-research expanded access investigational new drug (EA-IND) for empiric treatment.

The patient was placed on airborne and contact precautions (per CDC guidelines at the time) (7). By hospital day (HD) 2, new skin-colored papules appeared: three on his upper back, one behind the left ear, one on the lower lip, and two on the abdomen (Figure 1c). Liver function tests were notable for elevated aspartate transaminase (AST) at 117 U/L and alanine aminotransferase (ALT) at 131 U/L. Dry swab specimens were obtained from papules on the back, penis, and lip for non-variola orthopoxvirus real-time PCR testing at the Washington State Department of Public Health Laboratory. Dermatology was consulted and were initially concerned for a viral exanthem versus a morbilliform drug eruption (omeprazole was started 1–2 months prior) with superimposed infection leading to umbilicated papules (differential diagnosis included molluscum contagiosum, cryptococcus neoformans, histoplasmosis, etc.); skin biopsies were obtained for hematoxylin and eosin staining and tissue culture.

On HD 3 and 4 the patient developed new vesicular and umbilicated lesions on his scrotum, trunk, thighs, and back, and had progression of prior lesions (Figure 1d). He endorsed worsening headache and eye pain; lumbar puncture to rule out aseptic meningitis was considered but deferred given stability and lack of meningeal signs. He developed tenesmus and proctitis, with tenderness on rectal exam. His pharyngitis progressed with right-sided tonsillar exudates. Computed tomography of the head and neck demonstrated tonsillitis without drainable abscess. He was started on ampicillin/sulbactam and vancomycin for fevers and hypotension in the setting of his tonsillitis, and then narrowed to an empiric course of amoxicillin/clavulanate.

On HD 4, real-time PCR testing confirmed non-variola orthopoxvirus infection; later identified as of the West African clade. Chlamydia was also diagnosed through urine nucleic acid amplification testing; doxycycline was prescribed for one week of therapy. Rapid plasma reagin titer was 1:2; reflective of his treated latent syphilis. Dengue IgG was elevated at 8.07; IgM was negative. Chikungunya and Zika serologies were negative.

He began treatment with tecovirimat on HD 5 with CDC approval. He tolerated therapy well and did not develop any new lesions after treatment day 2 (HD 7). He was discharged HD 9 with a plan to complete 14 days of tecovirimat. He was evaluated via telemedicine a week later (day 14 after initial presentation) and had residual fatigue and prostatic firmness on self-exam without tenesmus or proctitis. His initial lesions had healed and resolved.

DISCUSSION

We describe an atypical presentation of mpox in a person with known epidemiologic risk factors, including recent travel and sexual contact with men. The diagnosis was delayed due to initial presentation of a diffuse, erythematous, morbilliform rash rather than discrete vesicles or pustules, causing diagnostic uncertainty. Skin biopsy demonstrated epidermal spongiosis, multinucleate keratinocytes, eosinophilic cytoplasmic inclusion bodies, and ballooning degeneration (Figure 2), consistent with non-variola orthopoxvirus infection; bacterial, fungal, and atypical mycobacterial tissue cultures were negative.

Figure 2:

Biopsy demonstrating eosinophilic cytoplasmic inclusion bodies and ballooning degeneration. Pathology image courtesy of Drs. Ata Moshiri and Martin Dittmer, University of Washington Department of Pathology.

Our patient developed common complications of mpox infection, including headache, eye pain, tonsillitis, and proctitis. He responded well to tecovirimat, which at the time of his presentation required CDC approval. Given rapid improvement with treatment, also anecdotally reported in other settings (8), we recommend considering treatment early to hopefully alleviate symptoms and prevent progression, while awaiting results of more conclusive trials.

Our patient demonstrates that mpox can present with atypical skin findings, including a rash mimicking a morbilliform drug exanthem or general viral exanthem with delayed development of typical “pox” lesions, presenting diagnostic challenges in outpatient or ED settings in areas with low prevalence, or in sexual health clinics where patients may more commonly present with genital or perianal lesions.

Broad diversity of mpox presentations has been noted; in a recent case series of 528 patients across 16 countries, while 95% presented with rash, 64% had fewer than ten lesions (4). Seventy-three percent of patients had anogenital lesions (27% did not) and 58% had typical vesiculopustular lesions; however, 10% had only a single lesion like our patient, and some patients presented with a macular rash (4). Many patients had concomitant STIs (4).

We advise practitioners that mpox may present without the typical umbilicated rash in the anal or genital area; thus, mpox testing should be considered in patients with epidemiologic factors that may predispose them to exposure (travel, close personal contact, unprotected sexual activity), even with atypical rash. Though the predominant population affected includes men who have sex with men, there were nine heterosexual men diagnosed with mpox in the recent case series suggestive of ongoing community spread, further supporting that providers should test any persons with constitutional symptoms and rash, even if atypical, to optimize early identification (4). We continue to recommend broader testing and treatment strategies, and enhanced prevention efforts including vaccination in affected communities.