After the global COVID-19 pandemic, there has been an upsurge in another dreaded viral infection caused by monkeypox (mpox) virus. From being restricted to sporadic outbreaks in Africa to affecting roughly two-thirds of the countries in the world, mpox is raising alarms. On July 23, 2022, the mpox outbreak was declared by the World Health Organization (WHO) as a public health emergency of international concern (PHEIC). The first human case was reported in a child in 1970 in the Democratic Republic of Congo (Zaire) after being reported in monkeys in 1959.[3,4] As of January 5th 2023, there were 84,318 confirmed cases of mpox in 110 different countries, with 103 countries not having historically reported mpox cases earlier. The highest cases have been reported in the USA (n = 29,913), followed by Brazil (n = 10,544) and Spain (n = 7500). Earlier in Africa, sporadic outbreaks of mpox infection were reported after contact with wildlife rodents. Despite large local outbreaks and travel-associated transmission outside Africa, the secondary spread has been limited, thus indicating limited human-to-human transmission. The recent mpox outbreak has opened gateways for extensive research to know the reason behind the limited transmission, even in high endemic areas and where the circulatory load of the virus is high. The WHO has recommended the term mpox instead of monkeypox, which will be included in International classification of diseases (ICD)-10 and ICD-11.
The mpox viral infection clinically resembles smallpox infection with an incubation period of usually 6–13 days but can range from 5 to 21 days. Besides systemic signs and symptoms, mpox infection causes a variety of ophthalmic manifestations. Although mpox is a self-limiting disease, it can result in permanent visual sequelae. Systemic mpox presents as fever, papular, pustular, vesiculopustular, and ulcerative lesions over the face and trunk, and lymphadenopathy. The reported case fatality rate is 1%–10%. Critical analysis and recent literature reveal that viral mutations, relaxation in COVID-19 guidelines, increased international travel, reduced smallpox immunity, and increased sexual transmission due to large social interactions prompted the global mpox outbreak. This review article focuses on the evidence-based available literature on mpox infections, especially highlighting the ophthalmic manifestations, systemic manifestations, investigation, management options, future direction, and how mpox differs from COVID-19 infection. The literature review shows that there is scarcity of studies highlighting the management of ocular mpox infection, and this is one of the first review articles highlighting the ophthalmic manifestations of mpox.
A literature search was done on PubMed, Google Scholar, EMBASE, Cochrane Library, MEDLINE, and PubMed Central up to September 2022 using the MESH terms which included “Monkeypox,” with variable combinations of terms like “ocular manifestations,” “eye,” “conjunctiva,” “conjunctivitis,” “epidemiology,” “clinical manifestations,” “transmission,” “lids,” “cornea,” “keratitis,” “ulceration,” “vision loss,” “posterior segment,” “retina,” “uveitis,” “treatment,” “management,” “pandemic,” and “virology,” with interposition of Boolean operators “AND” and “OR.” The references of the articles were searched for missed references.
The mpox virus (MPXV) belongs to the genus Orthopox of the Poxviridae family. It was named so as it was initially isolated from monkeys, although the reservoir is an unknown rodent species.[14,15] The virions are ovoid or brick-shaped, bounded by a lipoprotein outer membrane, and contain a linear double-stranded DNA within the dumbbell-shaped core along with enzymes and transcription factors. They measure around 200 × 250 mm. This large size makes it difficult for them to pass through gap junctions and evokes an immune response easily. They have been shown to replicate within the cytoplasm of the infected cells. Phylogenetically, there are two strains or clades, clade I and clade II. The culprit for the recent outbreak was the sublineage of the latter, clade IIb.
Transmission to humans can either be from animals, that is zoonotic, or from other humans themselves. The former occurs as a result of contact or consumption of the natural hosts. The latter occurs through respiratory droplets, contact with body fluids, and skin lesions of an infected patient. A study showed that 98% of the infected individuals were homosexual or bisexual men, and close sexual contact was reported in 95% of the infected cases. The predominant mode of spread is sexual contact; this is also supported by the fact that the most common anatomical site of the lesions is the anogenital area.[2,20] However, sexual transmission as a method of transmission is yet to be confirmed and is under investigation. Kaler et al. have highlighted that the most common mode of human-to-human transmission is respiratory droplets. The transmission and manifestations are more severe in children and adults living with acquired immunodeficiency syndrome (AIDS), immunocompromised status, and those on antiretroviral therapy (ART).
Infectious pathway and immune response
The virus first replicates at the inoculation site, followed by primary viremia and spread to regional lymph nodes. This, in turn, is followed by secondary viremia, where there is hematogenous dissemination of the virus to distant lymph nodes and organs. This encompasses the incubation period, with an average duration of 7–14 days, and is noncontagious. As the virus disseminates to the skin, lungs, eyes, gastrointestinal tract, and other organs, mucocutaneous lesions are produced due to activation of the immune response, where natural killer cells are responsible for the direct killing of the infected cells, along with activation of other cell types including T cells and dendritic cells.
The most common clinical feature is skin rash, which has been reported to occur in 95% of patients. As mentioned before, the most common site is the anogenital area, which is followed by the trunk and the limbs (65%) and the face (25%). The rash can be pleomorphic; however, vesiculopustular lesions predominate with a centrifugal distribution. The lesions range in size from 0.5 to 1 cm and usually become crusted within 2–3 weeks. Once the individual enters the desquamation phase, characterized by the scab peeling off, the patient can be considered noninfectious. Other features include lymphadenopathy, proctitis, tenesmus, diarrhea, pharyngitis, and tonsillitis. The gastrointestinal symptoms develop by the second week and contribute to dehydration, usually worsened by the presence of oropharyngeal ulcers due to their difficulty in maintaining nutrition. Nonspecific systemic features include fever, lethargy, myalgia, and headache, which are relatively common and present during the prodromal phase, roughly 3 days before the eruption of the skin rash. Co-infection with acquired immunodeficiency virus (AIDS) is common, being reported in up to 41% of the cases. This can possibly be attributed to the high prevalence of homosexual or bisexual behavior. Life-threatening complications include epiglottitis, myocarditis, bronchopneumonia, sepsis, and encephalitis. It has been reported that virological seeding from the eyes into the central nervous system can occur.
Apart from the systemic features, symptoms of ocular involvement include ocular pain, redness, watering, photophobia, discharge, swelling around the eyes, and diminished vision. Most complications, including visual, tend to occur more commonly in unvaccinated (74%) than in vaccinated (39.5%) individuals. Mpox has been reported to involve the lids, conjunctiva, cornea, and sclera. Kaufman et al. suggested the term mpox-related ophthalmic disease (MPOXROD) to encompass the spectrum of ophthalmic manifestations that might occur in association with mpox infection.
Lids and Adnexa
Lid and conjunctival involvement has been reported to occur in up to 20% of the patients, usually in the form of lid edema and ulcerative lesions along the lid margin. As the skin rash commonly involves the face, involvement of the adnexal region and the eyelid skin is not uncommon. This exanthema is pleomorphic, with macules, papules, vesicles, and pustules occurring concurrently. The rash can be a close mimic of that of herpes zoster ophthalmicus. Early lymphadenopathy in mpox differentiates it from smallpox and chickenpox. Preauricular lymphadenopathy has been reported in 71% of the patients. Scarring might result in deformation of eyelids in 2% of patients, which might have its own consequences.
Several phenotypes of conjunctivitis-associated mpox have been reported. Ulcerative, infiltrative, and vesicular lesions have been reported to occur.[33–35] Hughes et al. have also reported conjunctival pustules and phlyctenules in mpox. The contiguous spread of this pustule can result in corneal ulceration, as in smallpox. The conjunctival ulcer can be large, having regular edges and a whitish appearance. Infiltrative lesions have a serpiginous, whitish appearance with associated conjunctival thickening. Follicular reaction and a mucoid discharge can be present. Conjunctivitis in mpox can predict more severe systemic illness, with 47% of patients bedridden compared to 16% with no conjunctivitis. Jezek et al. reported that conjunctivitis was more common in patients affected with animal mpox (20.3%) compared to human mpox (16.4%). Although polymerase chain reaction (PCR) of mpox virus has tested negative in a conjunctival swab from a patient diagnosed with mpox and conjunctivitis, active secretion of the smallpox virus has been documented in tears. Therefore, conjunctivitis might be a mode of disease transmission.
Keratitis is another ocular feature reported to occur with mpox infection, although uncommonly. However, if present, it can cause vision loss due to corneal scarring and affect the quality of life. Jezek et al. reported unilateral and bilateral blindness cases, with defective vision seen in 10% of primary (animal-to-human transmission) and 5% of secondary cases (human-to-human transmission). It can include ulcerative keratitis, immune stromal keratitis, and neurotrophic keratitis. Decreased corneal sensitivity has also been observed. The major concern remains bacterial superinfection complicating corneal ulceration. The latter might eventually result in thinning, with subsequent anterior staphyloma or perforation. Such processes have been associated with smallpox. This can be prevented with the generous use of lubricants and vitamin supplementation.
Trifluridine has been used for ocular vaccinia, along with topical or systemic antibacterials. In cowpox, recrudescence has been observed months after the resolution, which is believed to occur secondary to the use of topical steroids for containing the inflammation. Mpox, associated with ocular complications, often results in persevering pain, corneal opacity, and scarring, often requiring a corneal transplant to rehabilitate the vision. Lubricants, topical antibacterials, and antiviral therapy can be considered to prevent long-term sequelae. Intraocular and posterior segment manifestations have not been reported in the literature yet [Table 1].
Finamor et al. reported a case of mpox having diffuse anterior scleritis characterized by a violet-bluish hue with scleral edema and deep congestion. This was associated with a corneal infiltrate, keratic precipitates, and 1+ cells in the anterior chamber, and it responded well to oral tecovirimat (600 mg twice daily) and a delayed introduction of topical fluorometholone (0.1%, twice daily).
The incubation period of mpox ranges from 5 to 21 days. The initial symptoms and signs include fever, chills, headaches, lethargy, asthenia, lymph node swellings, back pain, and myalgia. Once the fever sets in, rashes of varying sizes appear within 1–5 days, first on the face, then across the body, hands, legs, and feet. The size of these lesions varies from 0.5 to 1 cm in size. The rash undergoes several stages of evolution from macules, papules, vesicles, and pustules, followed by resolution over time with crusts and scabs, which drop off on recovery. Lymphadenopathy is considered to be a key distinguishing feature of mpox and can occur in the neck, groin, and submandibular region. A more severe disease is associated with pronounced illness, high viremia, and death, as observed following direct human-to-human transmission.
The complications of the disease include co-infections, respiratory disorders, encephalitis, blindness-related keratitis, and gastrointestinal symptoms like vomiting and diarrhea. Pitted scarring of the skin appears to be long-term sequela. Sepsis and septic shock may also occur due to overly exaggerated immune responses. Vaccination against smallpox offers some form of protection, with more severe complications observed among the unvaccinated patients than the vaccinated patients. In outbreaks, case fatality rates have varied between 1% and 10%, with deaths occurring primarily among young adults, children, and the immunosuppressed [Table 2].
Differential Diagnosis of Mpox
- Molluscum contagiosum
- Rickettsial infections
- Staphylococcal skin infections
- Drug reactions[26,44]
Lymphadenopathy remains the most important clinical feature in distinguishing mpox from other clinical conditions.[52,53]
The diagnosis of human mpox is mainly clinical, with typical rashes and a high index of suspicion. However, it can be challenging due to the above-mentioned differential diagnoses and their common presence in ophthalmic practice. The confirming techniques for analyzing specimens and determining mpox include genetic, phenotypic, and immunological methods. Optimal clinical specimens for laboratory analyses include specimens from skin lesions, such as swabs of vesicular lesions, exudate, or crusts, stored in a dry, sterile tubes and kept cold. An oropharyngeal or nasopharyngeal swab should obtain a viral culture. PCR or real-time PCR (RT-PCR) is the standard test for detecting mpox-specific DNA sequences due to its high accuracy and sensitivity. Serologic testing using enzyme-linked immunosorbent assay (ELISA) requires paired acute and convalescent sera for mpox-specific immunoglobulin M detection within 5 days of presentation or immunoglobulin G detection after 8 days. Positive IgM capture ELISA indicates recent exposure to the orthopoxvirus in both naive and vaccinated individuals.
In contrast, a positive IgG capture ELISA suggests that the individual has been exposed to the orthopoxvirus through vaccination or natural infection. Histology and immunohistochemistry of papular lesions may show acanthosis, individual keratinocyte necrosis, basal vacuolization, and a superficial and deep perivascular lymphohistiocytic infiltrate in the dermis. Vesicular lesions show spongiosis with reticular and ballooning degeneration, multinucleated epithelial giant cells with epidermal necrosis with numerous eosinophils and neutrophils, and features of vasculitis viral inclusions in keratinocytes. Electron microscopy can distinguish Orthopoxvirus from herpes simplex virus. The mpox virus appears as intracytoplasmic brick-shaped, lateral bodies and a central core measuring about 200–300 nm. It gives evidence that the mpox virus may belong to the Poxviridae family.[17,59] A rapid, point-of-care diagnostic (Tetracore Orthopox BioThreat Alert®) and testing tool has been developed, particularly for the field, as a valuable screening tool to prioritize samples that require further testing. The accuracy and validity of GeneXpert have been evaluated, suggesting its viability as a diagnostic platform that may expand and expedite current detection capabilities in endemic areas.
There is no specific treatment for mpox. The Centers for Disease Control and Prevention (CDC) recommends administering the smallpox vaccine within 4 days of exposure, which may prevent the disease, and within 2 weeks to reduce symptoms’ severity. US Food and Drug Administration (FDA)-approved smallpox antivirals tecovirimat and brincidofovir may be used for the treatment of mpox, but there is only limited data to prove their efficacy.
Tecovirimat is an oral intracellular viral release inhibitor that functions by interfering with a viral protein (p37) necessary for the production of mature enveloped virions. While still at various stages of clinical trials, four compounds (NIOCH-14, Cidofovir, CMX-001, and ST-246) may yield an excellent therapeutic effect. Tecovirimat is the only currently available anti-poxvirus therapeutic agent, and it is stockpiled as part of the US Strategic National Stockpile for use as a defense to treat smallpox virus infections in the event of a possible bioterrorist attack.[65,66] Tecovirimat should be used orally in the dosing of 600 mg twice a day for 2 weeks. Reported side effects include headache and nausea. It may interact with other drugs, and it is a weak inducer of cytochrome P450. Brincidofovir and cidofovir are viral DNA polymerase inhibitors which have shown activity against orthopoxviruses in animal and in vitro studies. However, due to systemic toxicity, they have fallen out of use and are largely unavailable.[68,69]
Trifluridine, available as eye drops at a concentration of 1%, is a nucleoside analog that inhibits viral DNA synthesis. It has shown activity against orthopoxviruses in vitro and is recommended by the WHO as a treatment.[70,71] Initially, it should be used every 2 h, which can be reduced to every 4 h after re-epithelialization for 7 days. The use should continue till the healing of all periocular lesions but should not exceed 21 days so as to avoid ocular toxicity. Of note, acyclovir and ganciclovir are not effective toward orthopoxviruses.
Steroids can be considered for mpox keratitis or iritis but should be avoided without topical antiviral therapy, as it leads to the risk of prolongation of virus in the ocular tissue.[24,43] Supportive and symptomatic therapy and treatment of secondary bacterial infections with antibiotics remain the basis of managing a mpox viral infection.
The CDC recommends that protection can be achieved through smallpox vaccines, which provide 85% protection against mpox via cross-immunity. Whereas first and second generations of smallpox vaccines can cause adverse side effects., third-generation vaccines like JYNNEOS have proven efficacy and safety in people infected with HIV or atopic dermatitis. ACAM2000 vaccine is approved for immunization against smallpox and mpox diseases and has been made available for use against mpox under an Expanded Access Investigational New Drug (EA-IND) protocol. It is not recommended for use in pregnant women, children less than 12 months old, and immunosuppressed individuals.
Infection control measures are vital to preventing human-to-human transmission in health care. Improved nursing (gloves, protective clothing, surgical masks) and isolation practices require education, adequate facilities, and staffing. In hospital settings, the CDC recommends that patients be isolated in negative pressure rooms, and that the health-care professionals take adequate contact and droplet precautions.[15,74] Case isolation, contact tracing, avoiding contact with animals or materials suspected of harboring the etiologic agent, isolating and euthanizing the animals suspected to be reservoirs of the virus, use of personal protective equipment, and good hand hygiene practices remain the best measures for preventing and controlling human mpox.[15,47] MPOXROD can be prevented by advising patients not to rub eyes, to prevent self-inoculation. A majority of cases have been found to be young men between the ages of 25 and 35 years, many of whom self-identify as gays and bisexuals. Whether or not mpox can be sexually transmitted in the traditional sense is being investigated. Until more clarity is gained on the role of sexual transmission, abstinence during active infection is recommended for up to 8 weeks. The public health authorities in the UK have recommended recovery as an additional precaution.
Offering the vaccine to certain high-risk groups, such as men engaging in homosexual acts with other men at risk of exposure, health-care personnel, and close contacts with mpox patients, is a promising strategy for containing the outbreak. Considering the low mutation rates of mpox and long-lasting vaccine-induced immunity, effective escape of adaptive immune responses is unlikely but cannot be completely excluded. Therefore, further studies on this re-emerging pathogen, especially the 2022 outbreak strains, are highly warranted. More clinical trials regarding the safety profile and effectiveness of the mpox vaccines and antivirals are the need of the hour. Ensuring adequate and equitable distribution and administration of mpox diagnostics, vaccines, and treatments is of prime importance.
Is Mpox Still a Threat to the Community?
Re-emerging of the mpox virus, a neglected viral zoonotic disease, is a potential global threat. The awareness of the disease dynamics remains poorly defined among all population strata. People have resisted being screened for the disease. The death rate from mpox has been higher among young adults and children, posing a significant problem to society. While evidence shows that smallpox vaccines effectively protect against mpox, the scale of the current outbreak is still too small to justify mass vaccination. No data on the clinical efficacy of the vaccines JYNNEOS or ACAM2000 for mpox disease are currently available. Also, there are only limited data regarding the effectiveness of tecovirimat and brincidofovir in the treatment of mpox. While the world is already reeling under the economic losses caused by the COVID-19 pandemic, the current rise in mpox cases in the world will also threaten economic growth prospects. The financial challenges will become more if this mpox disease is not brought under control quickly. These loopholes and uncertainties in the diagnosis and management of the disease, along with the social and economic implications, make mpox a threat to society.
COVID-19 Versus Monkey and COVID-19 and Mpox
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the mpox virus are very different. SARS-CoV-2, like all coronaviruses, is an enveloped, single-stranded RNA virus. The mpox virus is a member of the Poxviridae family – the virus is enveloped, brick-shaped, and large (220-450 nm long) with double-stranded DNA. SARS-CoV-2 is a respiratory virus, and the infection spreads through respiratory droplets. Mpox primarily spreads through direct and usually prolonged contact with an infected person and is far less transmissible than COVID-19. SARS-CoV-2 was a novel virus when it emerged in late 2019, whereas mpox is not a new disease and was discovered in 1958.
Mpox, like the COVID-19 pandemic, is a health, political, and socioeconomic crisis that will have serious consequences in society if not controlled promptly. Although most countries are fighting the COVID-19 pandemic worldwide, they should not neglect the risk of mpox. For both COVID-19 and mpox, isolating infected individuals and maintaining proper hygiene and disinfection practices are essential for preventing and slowing the spread of infection.
The recent spread of mpox during the ongoing COVID-19 pandemic can also lead to co-infection between SARS-CoV-2 and the mpox virus. This can result in changes related to infectivity patterns, severity, management, or response to vaccination in one or both diseases. This could also negatively impact the efficiency and reliability of diagnostic tests used in both diseases. The interaction between both viruses can lead to the emergence of a new variant of SARS-CoV-2 with clinical and morphological features that could further impact the current pandemic management strategies, such as the increased capability for immune evasion or escape, and burden the health-care system as a whole [Table 3]. A detailed diagnostic flowchart is given in Fig. 1 to facilitate diagnosis and treatment of mpox infection.
The ecologic, zoonotic, epidemiologic, clinical, and public health aspects of mpox remain inadequately characterized. Therefore, the mx outbreak is of great concern. Though the disease can be self-limiting, the complications of the disease can be life-threatening, and special attention needs to be given to children, the elderly, and pregnant women since they are more susceptible. It is also important to note that patients with sexually transmitted diseases (STDs) like HIV/AIDS and men having sex with men (MSM) are also at greater risk of contracting mpox. Additionally, the virus transmitted outside the high endemic areas usually masquerades as a sexually transmitted disease. Ensuring adequate, equitable distribution and administration of mpox diagnostics, vaccines, and treatments is the need of the hour. We need better public health strategies, including controlled studies of the vaccines and drugs used in mpox patients, to prevent the spread of the virus and for better management of the disease.
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