Mimics of Monkeypox: Considerations for the emergency medicine clinician

3.2.1. Smallpox

Smallpox results from a primary infection with variola virus (VARV), a member of the Poxviridae family, orthopoxvirus genus alongside mpox. Responsible for approximately 500 million deaths over several hundred years, this highly infectious and lethal virus was eradicated in 1980 after a focused vaccination campaign; overlap between smallpox immunization and mpox infection has rates of cross-protection as high as 85% [[21], [22], [23], [24], [25], [26], [27], [28], [29]]. Humans are the only known host and reservoir for smallpox. The virus can persist in aerosolized form in cool, dry environments, but it is effectively killed by ultraviolet light and most common hospital disinfectants [22,24,26].

Following an incubation period of approximately 7–14 days, patients with smallpox typically have a febrile prodrome lasting 1–4 days, followed by the onset of a rash [23,24,26]. Lesions typically first occur in the oropharynx, and this early period is when respiratory concentrations have the highest potential for transmission [[22], [23], [24],26]. It is difficult to differentiate between smallpox and mpox lesions on physical examination, as both evolve from macules to papules to vesicles and then pustules, and are deep-seated, firm, and round, with central umbilication (Fig. 3 ) [22,24]. In milder cases of the variant variola minor, papules may fail to evolve to vesicles or pustules [23]. Clinically, the regional lymphadenopathy classically associated with mpox is the only distinguishing feature [24]. However, there is no significant direct comparison of the frequencies and findings in populations under surveillance for smallpox and mpox, as the latter was discovered largely after the eradication of the former [21,24]. Given its implications with regard to bioterrorism and the associated illness severity, cases of suspected smallpox mandate immediate isolation, public health notification, and confirmatory testing [24,26].

3.2.2. Varicella

Chickenpox results from a primary infection with varicella zoster virus (VZV), a member of the herpesviridae family. Unlike mpox, VZV has no known animal reservoir and is transmitted only through human-to-human contact [[30], [31], [32]]. Primary VZV infection classically presents with abrupt onset of fever coinciding with a new pruritic rash [30,32,33]. The rash of VZV infection differs from that of mpox in that it is superficial and non-umbilicated, has irregular borders, is distributed centripetally, is found in various stages throughout the body, and spares the palms and soles (Fig. 4 ) [4,30,[32], [33], [34]]. Lesions are considered contagious until crusts form, and lesions fully heal within approximately 1–2 weeks [35,36]. The rash associated with chickenpox is classically described as resembling a “dew-drop on a rose petal.” Most complications stem from a bacterial superinfection of the lesions, which occurs in approximately 5% of cases [[35], [36], [37]]. Secondary VZV infections, better known as shingles, occur due to viral reactivation within dorsal root ganglia. They can occur at any age, likely due to temporary or ongoing immunocompromise, and present with painful vesicles with surrounding erythema following a dermatomal distribution [38].

While many factors appear to clinically distinguish VZV from mpox, several studies document overlapping signs and symptoms. In fact, up to 50% of patients in Africa who were misdiagnosed as mpox were found to have VZV instead [39,40]. Even more challenging, previous epidemiologic studies document lesion polymerase chain reaction (PCR) testing being simultaneously positive for VZV and mpox in up to 12% of patients [[30], [31], [32], [33]]. Several theories exist regarding potential coinfection, including simultaneous onset of VZV and mpox, mpox infection with secondary shingles, and immunocompromise from one virus leading to secondary infection with either mpox or primary VZV [[30], [31], [32], [33]]. Many documented cases describe an “atypical Varicella” manifestation, which includes up to 86% with lesions on the palms or soles, 85% with uniform size and stage of lesions, and 70% with the predominant lymphadenopathy usually considered pathognomonic for mpox [30,33,34]. These discoveries further emphasize the importance of lesion testing to correlate with clinical findings.

3.3.1. Syphilis

Syphilis is a bacterial infection caused by Treponema pallidum [[41], [42], [43]]. The organisms gain access to subcutaneous tissues through a small abrasion, resulting in infection at the location of inoculation. The mean inoculation phase is 21 days but can last up to 90 days [43]. Organisms evade the local host immune response and cause a primary chancre at the initial inoculation site, which is known as primary syphilis. The lesion starts as a papule that is usually painless, which then ulcerates to form the classic primary chancre [42,43]. This chancre is 1–2 cm with a nonexudative base and is typically isolated, indurated, and sharply demarcated [44,45]. Regional lymphadenopathy is often present. Patients who are immunocompromised may have several lesions.

The primary lesion most commonly resolves in 6 weeks. Following the primary chancre, syphilis becomes systemic in 20–25% of cases, resulting in secondary syphilis 4–8 weeks after the primary chancre [46]. Signs and symptoms of secondary syphilis include a rash involving the palms and soles, which is the most characteristic finding (Fig. 5 ). However, over 20% of patients do not notice this rash [44,45]. The rash can take any form but is classically diffuse and symmetric, with macular or papular eruptions on the trunk and extremities [42,43,47]. Early secondary lesions are macular, flat, pale, and pink to brown in color; 4–30 mm in diameter; and elliptical in shape [42,43,47]. The central area is typically discolored, while the periphery blends into normal skin. Small papular or pustular lesions may be present, as are follicular, vesicular, and lichenoid lesions. Late secondary lesions are large, papular, and flattened. Annular lesions may also be present [42,43,47].

3.3.2. Acute retroviral syndrome

HIV was first described in 1985 [48]. The disease has been reported in a variety of patient populations, including injection drug users, MSM, recipients of blood products, and healthcare workers with needle-stick or body fluid exposure [49]. The time to development of symptoms after exposure is usually 2–4 weeks. The constellation of signs and symptoms is known as acute retroviral syndrome, which typically includes fever, sore throat, lymphadenopathy, rash, myalgias, headache, diarrhea, and weight loss [[50], [51], [52], [53], [54], [55]]. Painful mucocutaneous ulcers may also be present. These are usually shallow and sharply demarcated ulcers, characterized by an area of erythema surrounding a white base. They are often found on the anus, oral mucosa, penis, and esophagus [56]. A generalized rash may occur 2–3 days after fever onset and lasts 5–8 days [56]. The rash is characterized by 5–10 mm well-circumscribed, pink or red macules or maculopapules on the trunk, face, and extremities. The palms and soles may also be involved [56]. Lesions can be mildly pruritic, and pustules, vesicles, and urticaria can also be present [[57], [58], [59], [60]]. While no sign or symptom is specific for the diagnosis, a prolonged symptom duration and mucocutaneous ulcers are suggestive of HIV. Considering the disease is integral to diagnosis.

3.3.3. Genital herpes

Herpes simplex virus is a significant public health issue and includes both herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) [61,62]. Both strains may cause genital herpes, though HSV-2 is the predominant cause. Transmission occurs during sexual intercourse, and most transmissions occur when the patient is unaware they are infected [63,64]. Primary infection occurs when the patient does not have antibodies to HSV-1 or HSV-2. The incubation period ranges from 2 to 12 days, and the presentation varies significantly [62,65,66]. Skin lesions start as 2–4 mm vesicles with underlying erythema appearing in groups. These progress to vesicles, pustules, erosions, and then areas of ulceration. The vesicles and pustules can have an umbilicated appearance [65,66]. These lesions resolve on average within 19 days [65,66]. Women tend to have more severe symptoms. The lesions are typically painful but may be pruritic. Up to 98% have pain and pruritus along the lesions, 80% of patients have tender lymphadenopathy, 67% have systemic systems (e.g., headache, malaise, fever, myalgias), and 63% have dysuria [62,65,66]. Recurrent infection occurs with reactivation of genital HSV, which is typically less severe with shorter duration of symptoms [62,[65], [66], [67]].