Monkeypox infection: A quick glance.

Introduction

An unusual, sudden outbreak of monkeypox infection in different countries spanning the globe has recently emerged as a reason of concern. A few of the North American and European countries are already seeing a surge in the confirmed as well as suspected cases of monkeypox infection from the past few weeks. These include Canada, the United States, Spain, the United Kingdom, Italy, Germany, Portugal, Belgium, France, Sweden, and even the Australian subcontinent.[1] Data from the vaccination drives conducted in the past reveal that the smallpox vaccine was found to be nearly 85% protective against monkeypox infection.[2] However, the eradication of smallpox in 1980 led to a subsequent decline in routine vaccination drives, paving a way for monkeypox to emerge as a pathogen capable of being a possible threat.[23] This is supported by the fact that all reported cases of monkeypox infection during the 2018–2019 outbreak in Nigeria were born after 1978, the year that the worldwide smallpox immunization program was suspended.[4] In light of the current COVID-19 pandemic, that wreaked havoc all across the globe, the reemergence of monkeypox infection in several countries with an ever-increasing number of confirmed cases each passing day should not be taken lightly. India's Ministry of Health and Family Welfare and the Government of India have also recently released the guidelines for the diagnosis and management of monkeypox, which were published on May 31, 2022.[5]

History

Following two outbreaks of a disease similar to smallpox in colonies of monkeys confiscated in Malaysia and smuggled through Singapore, Preben Von Magnus found monkeypox in laboratory cynomolgus monkeys in Denmark in 1958.[6] In 1964, an epidemic of monkeypox was recorded in the Rotterdam Zoo.[7] The first known case in humans occurred in 1970, in a 9-year-old boy who was unvaccinated.[2] About 50 cases were documented between 1970 and 1979, with Zaire (the Democratic Republic of the Congo [DRC]) accounting for more than two-thirds of them.[4] By 1986, over 400 human cases had been recorded. In Central and West Africa, small virus outbreaks, with a mortality of 10% and a human-to-human infection rate of around the same amount occur on a regular basis.[8]

Etiology and Pathophysiology

The monkeypox infection is a zoonotic disease that can be transmitted through direct contact, respiratory droplets, or infected objects.[12] The monkeypox virus belongs to the genus Orthopoxvirus from the Poxviridae family.[2] It is a linear double-stranded DNA virus that lives in infected cells’ cytoplasm.[9] Monkeypox takes typically 7–14 days to incubate, although it can take anything from 5 to 21 days.[510] The infected cells most likely produce two forms of infectious virions – intracellular mature virus (IMV) and extracellular enveloped virus (EEV).[9] IMV and EEV are the most probable infections virions produced by infected cells. While internal mature viruses are responsible for cell-to-cell dissemination, EEVs are responsible for the virus's fast travel to remote portions of the body inside infected persons.[9]

The monkeypox virus has been further subdivided into two different genetic clades – the Congo Basin (CB) clade (also known as Central Africa clade) and the West African (WA) clade.[1] The CB clade has been reported from Central and Southern Cameroon to DRC, whereas the WA clade has been reported from Western Cameroon to Sierra Leone.[11] While the WA clade is the milder one, the CB clade is reported to be more virulent with very higher rates of interhuman transmission, serial transmission events, and secondary attack rates.[9] In addition, the CB clade also has the potential to persist in the human population after interhuman transmission, while the WA clade is presumed to cause outbreaks mostly through spillover from animal hosts.[9]

Epidemiology

In 1970, a 9-year-old boy from Zaire's (now DRC) equatorial area was diagnosed with monkeypox for the first time.[4] Since then, the infection has remained endemic to Western and Central Africa.[4] The cases of monkeypox infection were also reported in the Ivory Coast, Sierra Leone, Nigeria, and Liberia between 1970 and 1971. The first case of monkeypox outside Africa was reported in the United States in 2003 when the infected African rodents harboring the WA clade of the virus were imported to Texas from Ghana.[4] The outbreak was reported from 6 states in the US namely, Wisconsin, Ohio, Missouri, Kansas, Indiana, and Illinois.[4]

In recent years, the monkeypox infection reemerged in Nigeria when a case was reported in 2017 in an 11-year-old child after 39 years of no reported cases in the country.[49] The outbreak continued even in 2018–2019 with 132 confirmed cases and 7 deaths reported till January 2019.[4] Owing to the ease in human mobility in the current times, the monkeypox virus was imported to several other countries in 2018 when a traveler from Nigeria reached these countries. Three cases were reported in the UK in 2018 with two individuals having a travel history to Nigeria, while Israel and Singapore reported one case each in 2018 with a travel history to Nigeria.[411]

Travel-related cases were also reported in the US and the UK in 2021 with two and one confirmed cases, respectively.[112] A total of 32 suspected cases were reported in Nigeria from January 2021 to May 2021, out of which 7 cases were later confirmed with no reported deaths.[13] At present, 12 nonendemic countries have reported cases of monkeypox infection to the WHO since May 12, 2022, with 92 confirmed cases as of May 21, 2022.[14] These include the United States, Canada, the United Kingdom, the Netherlands, Spain, and Germany, Italy, Portugal, Belgium, France, Sweden, and Australia. The highest number of confirmed cases have been from the United Kingdom, Portugal, and Spain, the number being 21–30 confirmed cases.[14] No cases have been reported in India till May 31, 2022; however, India needs to be prepared for the same mainly due to the increasing trend of cases in nonendemic countries.[5]

Diagnosis

Clinically, monkeypox infection can be diagnosed based on the presence of rash disorders such as syphilis, measles, chickenpox, bacterial skin infections, scabies, and medication-related allergies. The occurrence of lymphadenopathy during the prodromal stage of sickness is a characteristic feature of monkeypox infection that distinguishes it from chickenpox or smallpox infection.[15] The diagnosis can further be confirmed by testing for the monkeypox virus using the polymerase chain reaction (PCR) method which is the standard laboratory test in case of skin lesion samples. PCR blood tests are frequently inconclusive as the virus cannot survive in blood for long. The date of development of fever, rash, current stage of rash, patient age, and specimen collection are all needed to interpret test findings.[15] The Indian guidelines classify the cases as suspected, probable, and confirmed. A suspected case is defined as a person of any age with a travel history to any of the affected countries within the past 21 days, presenting with an unexplained rash and one or more of the cardinal signs and symptoms (fever, headache, body ache, swollen lymph nodes, and weakness). A probable case is defined as a suspected case with a clinically compatible illness, having an epidemiological link such as face-to-face exposure of health-care workers with personal protective equipment, direct contact with skin or skin lesions, sexual contact, or contact with contaminated clothing, utensils, or bedding. While a confirmed case is defined as PCR or sequencing confirmed case of monkeypox.[5]

Indian guidelines have also proposed certain surveillance strategies to rapidly identify and control cases and clusters of infection as soon as possible, as per which even a single case of monkeypox will be considered an outbreak. Core surveillance strategies include hospital-based and targeted surveillance along with contact tracing and testing of all symptomatic cases following the detection of probable or confirmed cases.[5]

Complications

The illness is distinguishable from chickenpox, measles, and smallpox by the presence of enlarged glands. Headache, muscular discomfort, fever, and weariness are common early symptoms. Lesions often occur on the face after a few days of the fever before spreading to other areas such as the palms of the hands and soles of the feet in a centrifugal distribution.[21516] The rash usually lasts around 10 days.[2] Affected individuals may be ill for 2 to 4 weeks. When the lesions heal, they may leave pale markings before turning black scars.[17] Pneumonia, encephalitis, loss of vision, and secondary infections are all possible complications.[15] If an infection arises during pregnancy, there is a possibility of stillbirth or birth abnormalities.[18] The sickness may be milder in those who were immunized against smallpox as children.[19]

Treatment/Management

BMJ Best Practice advises the use of two Food and Drug Administration-approved drugs tecovirimat or the smallpox therapy brincidofovir as first-line antiviral treatment and supportive care (including oxygenation, antipyretic, and fluid balance).[20] If subsequent varicella-zoster or bacterial infection is suspected, empirical treatment or aciclovir may be utilized.[21] Table 1 enlists the drugs that can be considered for the treatment of monkeypox infection.[922]

Table 1

Potential drug candidates for use against monkeypox virus

Drug name	Category	Mechanism of action	Stage of testing	Reference
Cidofovir	Antiviral	Inhibit viral DNA polymerase	FDA approved for treating CMV retinitis	[23]
N-MCT	Antiviral	Nucleoside analog inhibitor	In vivo testing	[24]
KAY-2-41	Antiviral	Nucleoside analog inhibitor	In vivo testing	[25]
NIOCH-14	Antiviral	Blocks the release of intracellular virus from the cell	In vivo testing	[26]
Ribavirin	Antiviral	IMP dehydrogenase inhibitor	FDA approved for treating HCV infection	[23]
Tiazofurin	Antiviral	IMP dehydrogenase inhibitor	In vivo testing	[23]
C-ca3-Ado	Antiviral	SAH hydrolase inhibitor	In vivo testing	[23]
C3-Npc A	Antiviral	SAH hydrolase inhibitor	In vivo testing	[23]
HPMA	Antiviral	DNA polymerase inhibitor	In vivo testing	[23]
ANO	Antiviral	Blocks the translation of viral mRNAs	In vivo testing	[23]

FDA=Food and drug administration, HCV=Hepatitis C virus, SAH=S-Adenosy-L-homocysteine, IMP=Inosine monophosphate, CMV=Cytomegalovirus, N-MCT=N-methanocarbathymidine, ANO=Adenosine N1-oxide, HPMA=(S)-9-(3-hydroxy-2-[phosphonomethoxypropyl]) adenine

India so far mainly recommends supportive management and isolation of the confirmed cases, including protection of the compromised mucus membranes and skin (rash, conjunctivitis, oral, and genital ulcers), oral rehydration and adequate nutrition, and symptom alleviation of fever, nausea/vomiting, pruritus and malaise/headache using paracetamol, antihistaminics, topical ointments, antiemetics, etc. Along with this close monitoring of the complications is warranted such as pain in the eyes or blurring of vision, dyspnea, altered consciousness, seizures, poor oral intake of food, and extreme lethargy.[5]

Prevention

The smallpox vaccine has been demonstrated to be 85% effective in preventing human monkeypox in several observational studies.[15] The explanation for this might be due to the close relationship between smallpox and monkeypox viruses, and the fact that immunization protects animals in the laboratory against lethal monkeypox challenges.[27] In previously inoculated Africans, smallpox immunization has been demonstrated to reduce the incidence of monkeypox.[16] To protect against the monkeypox disease individuals investigating monkeypox outbreaks or caring for infected individuals are recommended to get the smallpox vaccine by the Centres for Disease Control and Prevention. Vaccination is also recommended for anyone who has had close or intimate contact with monkeypox-infected humans or animals.[28]

Conclusion

The sudden reemergence of the monkeypox virus in recent years and its importation to nonendemic areas is a matter of concern. With 12 countries having reported to the WHO for monkeypox cases, the physicians across the globe need to be alert to identify any possible cases. This presses the need of implementing a strict surveillance system, especially for travelers coming from different countries as well as the building of containment zones for the identified suspected cases. In the absence of vaccines as well as therapeutic interventions against the monkeypox virus, this virus has the potential to turn into a pathogen capable of posing a serious threat to the general public worldwide. With the world already dealing with the impact of the COVID-19 pandemic, the scientific fraternity needs to be prepared for any upcoming outbreak. This calls for efforts to strengthen research and development in the area of infectious diseases, with monkeypox being the area of interest at the moment. There is a dire need to understand the epidemiology, mutations, or changes that the monkeypox virus is undergoing at present as well as to focus on the development of vaccines and drugs against this reemerging virus.