ACHAIKI IATRIKI | 2022; 41(2): 65–68
Ploutarchos Pastras¹, Efthymios P. Tsounis¹, Stelios F. Assimakopoulos²
1Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
2Division of Infectious Diseases, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
Received: 15 Jun 2022; Accepted: 16 Jun 2022
Corresponding author: Stelios F. Assimakopoulos, Department of Internal Medicine, University Hospital of Patras, Patras – 26504, E-mail: firstname.lastname@example.org
Key words: Monkeypox, orthopoxvirus, outbreak, treatment, therapy
Monkeypox has historically caused sporadic endemics in Central and West Africa in proximity to tropical rainforests . However, since 13 May 2022, and as of 2 June 2022, the World Health Organization (WHO) has been notified of 780 laboratory-confirmed cases of monkeypox identified in 27 non-endemic countries . The pattern of the current outbreak differs considerably from previous outbreaks outside of Africa, in which monkeypox was almost exclusively diagnosed in people with a history of travel to endemic countries, or with direct contact to infected exotic animals . As epidemiological and laboratory information is still missing and many chains of transmission remain undetected, the number of cases is possibly underestimated . This sudden and unprecedented rise in cases, simultaneously, in numerous non-endemic countries should raise the awareness of clinicians, especially in areas, where they may have never encountered a monkeypox case in the past.
Monkeypox at a glance
Monkeypox is an enveloped, double-stranded, DNA (dsDNA) virus belonging to the Orthopoxvirus genus of the Poxviridae family . Monkeypox is a zoonotic disease transmitted to people through bite, scratch, handling wild game, or use of products made from various infected wild mammals including rope squirrels, tree squirrels, and Gambian pouched rats. Human-to-human transmission is possible after direct physical contact with skin lesions or body fluids of an infected person, direct contact with contaminated materials such as bedding or after prolonged face-to-face contact through respiratory droplets. . Its clinical presentation resembles that of smallpox; however, symptoms tend to be milder. Following an incubation period of 5-21 days, monkeypox begins with a combination of the following symptoms: fever, headache, swollen lymph nodes, myalgia, and exhaustion. Lymphadenopathy can be either generalized or localized (submandibular, cervical, axillary, or inguinal) and facilitates distinguishing monkeypox from other smallpox-like syndromes . The onset of general symptoms typically precedes 1-3 days of the development of skin lesions. The lesions vary from a few to several thousand and mostly affect the face (95% of the cases) and the extremities (75%), rather than the torso. Other commonly affected areas include oral mucous membranes (in 70% of cases), genitalia (30%), and conjunctivae (20%). The rash evolves sequentially through four stages, namely macular, papular, vesicular, and pustular, followed by exfoliation and resolution of the lesions . In the current outbreak, a significant proportion of patients are men who have sex with men (MSM), who were diagnosed at sexually transmitted infection (STI) clinics or other primary, or secondary health services, suggesting a novel route of transmission via sexual intercourse [2,5]. In parallel, a peculiar clinical presentation of the disease has been described. In particular, sore throat and genital or peri-anal lesions are frequently recognized, apart from fever and lymphadenopathy. Interestingly, anogenital rash is reported to evolve before the development of general symptoms and without consistently spreading to other parts of the body .
In most cases, monkeypox is a self-limited disease lasting from 2 to 4 weeks. Secondary infections, bronchopneumonia, encephalitis, sepsis, and corneal infection, leading to loss of vision, are among the most serious disease complications. The case fatality ratio is reported to be as high as 3-6%, while certain strain variations, such as the West African clade, appear to be less virulent with a mortality rate of <1% [2,6].
Patient management: who to treat?
Most patients with monkeypox experience mild symptoms and recover without requiring any medical support. Supportive care and intravenous hydration should be considered in those patients at risk for dehydration (vomiting, nausea, geriatric patients) . Treatment should be considered in three categories of patients: (a) those with severe disease (hemorrhagic disease confluent lesions, sepsis, encephalitis or other severe complications), (b) those at high risk of severe disease, including immunocompromised individuals (e.g. patients with HIV-1 infection, hematologic or generalized solid organ malignancy, autoimmune diseases with immunodeficiency, hematopoietic stem cell or solid-organ transplant recipients, and those on immunosuppressive therapy), children < 8 years old, pregnant or breastfeeding women, patients with atopic dermatitis or other active exfoliative skin conditions, and (c) those with aberrant infections that include accidental implantation in eyes, mouth, or other anatomical sites where monkeypox might constitute a special hazard. [7-9]. There is no specific antiviral drug for monkeypox; however, certain antivirals approved for the treatment of smallpox are expected to be equally effective against human monkeypox. The efficacy of antiviral agents may be lessened in immunosuppressed patients. In general, tecovirimat is considered the treatment of choice, although some specialists support the administration of dual-combination therapy with tecovirimat and cidofovir in seriously ill patients .
Treatment and immunization
Tecovirimat (TPOXX®) is a potent inhibitor of the highly conserved among orthopoxviruses VP37 envelope protein, which is essential for the generation of egress-competent virions, and thereby, hinders the dissemination of the infectious particles into host circulation . In July 2018, tecovirimat was the first agent to be approved for the treatment of smallpox in the USA and can be administered in adults or pediatric patients weighting at least 3kg . It is important to note that this approval was based on experimental data from animal or dose-escalation studies in healthy volunteers [10,11]. Clinical trials would be very challenging to conduct considering accessibility and security issues in areas where monkeypox thrives, so this procedure is justified in the interest of public health security. Tecovirimat is available in oral (capsules of 200mg) or intravenous formulations and the recommended dosage depends upon the weight of the patient . Treatment with tecovirimat was effective in non-human primates with smallpox and well-tolerated in humans over a period of 14 days . In an expanded safety trial recruiting 361 healthy adults, administration of tecovirimat was not followed by any increase in adverse events, while the most common side effects were reported to be headache, abdominal discomfort, and nausea . In a small retrospective study, tecovirimat appeared to reduce the duration of viral shedding .
Cidofovir (Vistide®) is a monophosphate nucleotide analog that displays broad-spectrum antiviral activity by inhibiting viral DNA polymerase . It was first approved in 1996 as an intravenous therapy against cytomegalovirus retinitis in patients with AIDS . Importantly, cidofovir exhibits remarkable anti-poxvirus activity in vitro and prevents lethal monkeypox infection in animal models. However, evidence supporting its efficacy on human monkeypox infection is lacking, while its administration has been associated with significant adverse events, including nephrotoxicity [7,14].
Brincidofovir (Tembexa®) is an optimized, orally available, lipid conjugate of cidofovir. The lipid conjugation leads to higher intracellular concentrations of the active metabolite (cidofovir diphosphate), enhancing, thus, its antiviral efficacy against dsDNA virus, and lower plasma concentrations of cidofovir, preventing from drug-induced toxicity . In June 2021, brincidofovir was approved by the US FDA for the treatment of smallpox in adult and pediatric patients . Remarkably, the decision was once again based on animal studies and in vitro data supporting its potent activity against orthopoxviruses [15,16]. The safety profile of brincidofovir derived from clinical trials of the drug in the context of non-smallpox infections. The most frequently reported side effects were GI-related, such as diarrhea, vomiting, nausea, or abdominal pain . The duration of brincidofovir therapy should be closely monitored, since an increased risk for mortality was observed, when used for a longer than recommended period . Brincidofovir yielded discouraging results in a UK case series study. In three monkeypox patients, the administration of brincidofovir was not associated with any convincing clinical benefit; instead, it induced derangement of liver function tests leading to treatment discontinuation .
Previous vaccination against smallpox prevents the acquisition of monkeypox virus and, in case of infection, significantly improves symptoms and clinical outcomes [17-19]. According to a population-based surveillance study in Africa, individuals with prior smallpox vaccination presented a fivefold lower risk to be infected with monkeypox in comparison to unvaccinated persons (0.78 vs. 4.05 per 10,000) . In another study investigating 2278 close contacts of 203 primary monkeypox infections, the secondary attack rate (SAR) was highly influenced by prior immunization status against smallpox (1.3% versus 9.3% among vaccinated and unvaccinated household contacts, respectively) .
ACAM2000® and Jynneos® are the two currently approved vaccines to prevent smallpox in the USA . ACAM2000® is administered as a live vaccinia virus formulation that is inoculated into the skin and entails a risk of spreading to other parts of the body or even to other people. The newer-generation Jynneos® vaccine is based on a live, attenuated, replication-incompetent, vaccinia virus (Modified Vaccinia Ankara). The CDC recommends that individuals with occupational exposure to orthopoxviruses receive a vaccination with either ACAM2000 or JYNNEOS as pre-exposure prophylaxis (PrEP) . Post-exposure vaccination of close contacts has efficiently limited transmission in past outbreaks and can be considered in certain cases. According to the CDC, vaccination within 4 days from the date of exposure can effectively prevent monkeypox transmission, and, if delivered within days 4 to 14 from exposure, it can alleviate the symptoms of the disease . Intravenous administration of Vaccinia Immune (VIGIV) is an alternative measure for post-exposure prophylaxis, in cases in which small immunization is contraindicated, e.g., immunosuppression .
The scientific community has focused on unraveling the changing epidemiology of this monkeypox outbreak in communities outside of Africa. In the meantime, containment efforts are relied on enhanced case identification, isolation, and contact tracing. Primary care physicians, dermatologists, and those working in STI clinics should maintain a high degree of clinical suspicion. The monkeypox outbreak does not have the characteristics that could lead to a new viral pandemic since transmission occurs mainly after symptom(s) onset through visible skin lesions, therefore protection measures can be undertaken by both the patient and its potential contacts, and there is no airborne transmission. It is imperative that effective interventions and medications are already available and affordable in monkeypox-endemic low-income countries. Finally, this monkeypox outbreak should not lead to stigmatization of already vulnerable groups; instead, the real culprit is the neglect of diseases that affect the most impoverished populations.
Conflict of interest disclosure
None to declare
Declaration of funding sources
None to declare
Pastras P, Tsounis EP were responsible for the literature review analysis; Pastras P, Tsounis EP were responsible for drafting the manuscript; Assimakopoulos SF was responsible for the revision of the manuscript for important intellectual content; all authors provided final approval for the version to be submitted.
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