Ophthalmologist may play an important role in the diagnosis and management of monkeypox: JAMA

Cognizance of monkeypox clinical features (both ophthalmic and systemic) and an appropriate index of suspicion should enable ophthalmologists to detect monkeypox cases and may also mitigate transmission by subsequent measures of prevention

The intent of this article by Aaron R. Kaufman and team was to aggregate from an ophthalmic standpoint what is presently known about monkeypox from historical outbreaks and the emerging 2022 outbreak.

Virology in Brief

Monkeypox virus (MPXV) is an enveloped double-stranded DNA virus and member of the genus Orthopoxvirus, which also includes variola virus (the cause of smallpox), vaccinia virus (from which modern smallpox vaccines are derived), and cowpox virus. The virus was named for initial identification in monkeys, but the reservoir species is thought to be an unknown rodent species (possibly Gambian pouched rats, rope squirrels, or other rodents) rather than monkeys. MPXV is divided into clades, which were historically named based on geographic associations but have recently been renamed by the WHO to reduce stigma and discrimination. Clade I (formerly Congo Basin clade) has historically caused more severedisease. Clade II (formerly West African clade) is further subdivided into 2 subclades, clade IIa and clade IIb. The ongoing 2022 international outbreak is of clade IIb. The incubation period of MPXV is typically 7 to 14 days but may be up to 21 days.

Clinical Presentation of Human Monkeypox Infection

MPXV infection typically begins with a prodromal fever, followed 2 to 3 days later by skin and oropharyngeal/mucosal eruptions. Oropharyngeal/mucosal lesions may precede skin lesions. The skin eruptions may have a centrifugal distribution (greater density of lesions on face and extremities).

Lymphadenopathy may be an important clinical feature, which may distinguish the rash from that of smallpox. The number of skin lesions may be quite variable, ranging from fewer than 25 to more than 500 lesions.

The skin lesions may follow a characteristic sequence of stages: macular, papular, vesicular, pustular, and then crusting and sloughing. An important feature in distinguishing the monkeypox rash from that of chicken pox is that for a particular affected skin region, all monkeypox lesions are typically in the same stage. Other severe complications that may result from monkeypox infection include bronchopneumonia, encephalitis, gastroenteritis, secondary skin infection, sepsis, and ocular manifestations.

In the 2022 outbreak, a majority of patients have been men who have sex with men (MSM), but women and children have also been affected. Many patients have had a history of travel (most frequently to Europe) in the month preceding symptom onset.

Monkeypox-Related Ophthalmic Disease Manifestations

Ocular findings may include external (periorbita and lid) and ocular surface lesions (blepharoconjunctivitis and keratitis). As the characteristic skin rash may occur on the face, monkeypox lesions may occur on the periorbita and eyelids.

Eyelid margin lesions occurring in association with conjunctivitis have been reported; in such co-occurrences it is not clear if the conjunctival lesions occur secondary to regional autoinoculation from the eyelid margin lesions or if the eyelid and conjunctival lesions are both due to regional eruption. Monkeypox conjunctivitis may include a conjunctival follicular reaction, discrete vesicular or papular conjunctival lesions, conjunctival ulceration, pseudomembranes, and/or subconjunctival nodules.

Corneal disease in the setting of monkeypox can include ulcerative keratitis, immune stromal keratitis, and neurotrophic keratitis and may result in corneal scarring and bacterial superinfection. Thus, MPXROD may be associated with severe ocular and visual morbidity including central corneal scarring, visual impairment, the need for corneal transplant and phthisis bulbi. Persistent MPXROD may occur as late as 6 weeks from monkeypox onset and can be severe.

Diagnosis

The diagnosis of monkeypox begins with a high index of clinical suspicion, and diagnosis can be challenging, as atypical rash presentations may resemble chicken pox/zoster, syphilitic eruptions, and other poxvirus infection.

Specimens submitted can be dry swabs, swabs in viral transport media, or lesion crusts. Two swabs should be collected from a single lesion and processed together and it may be prudent to separately sample additional lesion(s) from different parts of the body or which are different in appearance. Swabs should be synthetic (eg, Dacron, polyester, or nylon). The swab can be obtained from the surface of the lesion; it is not necessary to unroof the lesion. The swab/ specimen should be placed whole in a sterile container with gasket seal, or the end of the swab should be broken off into a 1.5- or 2-mL screw-capped tube with O-ring. Specimens should be collected, stored, and shipped refrigerated or frozen.

Treatment

As the course of infection with MPXV is typically self-limited, the management of systemic monkeypox infection is frequently supportive. Antiviral agents (tecovirimat, cidofovir, brincidofovir, and vaccinia immunoglobulin intravenous [VIGIV]) maybe used for the systemic treatment of monkeypox in patients with severe disease or who are considered at risk for severe disease. There are limited available data about the efficacy of systemic antiviral agents for monkeypox in general, and data regarding MPXROD are especially limited.

Tecovirimat, which inhibits the product of the Orthopoxvirus F13L gene, is presently the monkeypox antiviral agent used most widely in the US. Cidofovir, a DNA nucleotide analog that inhibits viral DNA polymerase, is FDA approved for the treatment of cytomegalovirus retinitis and has been shown in vitro and in animal models to have activity against orthopoxviruses, including MPXV. Brincidofovir, a prodrug of cidofovir, has also been shown to be efficacious against Orthopoxvirus species in in vitro and in animal models.

VIGIV is FDA approved for complications of vaccinia vaccination and may be used for the treatment of other orthopox viruses by an expanded-access protocol. VIGIV may be considered for severe monkeypox infection or for monkeypox post exposure prophylaxis in individuals with severe T-cell deficiency (as in HIV/AIDS); however, the efficacy of VIGIV in these patients is not yet known

There is no available topical ophthalmic antiviral agent specific for monkeypox infection. Trifluridine, 1%, ophthalmic solution, approved by the FDA for ocular herpes simplex keratitis, has been used in case reports of ocular vaccinia and has been shown in vitro to have activity against orthopoxviruses. The efficacy of trifluridine specifically in human MPXROD has not yet been reported. Historically, the management of MPXROD and ocular manifestations of other Orthopoxvirus infection have relied on generous topical lubrication and this remains an important component of supportive ocular therapy for MPXROD. Topical antibiotics for corneal ulceration and epithelial defects may be important to prevent bacterial superinfection.

Transmission and Prevention

Transmission may occur both between humans and from animals to humans (including by scratch, bite and bushmeat ingestion). Transmission may occur by contact with skin lesions, bodily fluids, or respiratory droplets from a patient with monkeypox and may enter the body through skin, mucous membranes and the respiratory tract. Of note, conjunctival viral shedding in patients with monkeypox conjunctivitis has been reported but it is not known if conjunctival viral shedding occurs in patients without conjunctivitis. Additionally, conjunctival and corneal shedding of virus has been demonstrated in monkeypox-infected Gambian pouched rats, a possible reservoir species formonkeypox. Maternal transmission of MPXV to the fetus has been reported and may result in pregnancy loss.

Current CDC recommendations for personal protective equipment for monkeypox disease include the use of a gown, gloves, eye protection (including front and side coverage), and a respirator with N95 filter or higher. The patient should be kept in a single-patient room, and movement of the patient outside of the room should be restricted.

The CDC currently recommends using a US Environmental Protection Agency–registered hospital-grade disinfectant with an emerging viral pathogen claim (formally regulated by the Environmental Protection Agency).

Patients diagnosed with monkeypox should be advised of the need to isolate at home, during which time they should restrict contact with other people and with animals (including pets). Items that are likely to be contaminated, including utensils for eating and linens/ bedding, should not be shared. Surfaces that may become contaminated should be disinfected accordingly. Isolation is recommended until the rash is fully healed, with crusts/scabs having fallen off and new skin having grown.

MPXROD may occur in human monkeypox infection and rarely leads to severe corneal sequelae. Ophthalmologists can play an important role in detecting cases and reducing visual morbidity associated with the disease. Clinical and public health recommendations regarding monkeypox continue to evolve as the outbreak progresses. Improved understanding of disease process, preventive strategies, and treatment options will help to determine optimal therapeutic and public health strategies. Clinicians should be watchful for updated guidance onmonkeypox from the CDC and the WHO.

Source: Aaron R. Kaufman, MD; James Chodosh, MD, MPH; Roberto Pineda II; JAMA Ophthalmology

doi:10.1001/jamaophthalmol.2022.4567