The outbreak of Monkeypox virus in the shadow of the pandemic

Abstract

The human monkeypox virus (MPVX) was first identified in 1959. Since then, the incidence of the disease has been sporadic. The endemic regions were identified in Africa's central and western areas. However, the infection started to spread in 2017 to the non-endemic regions such as North and South America, Europe, and Asia. Since May 2022, the non-endemic areas reported 62,635 till 20^th September 2022. Although the monkeypox virus has a mortality of ≥ 10%, it showed only 82 mortalities worldwide in 2022. The common symptoms include chills, fever, fatigue, and skin lesions, and the complications include secondary respiratory tract infections, encephalitis, blindness, and severe diarrhoea. The factors responsible for spreading the virus include improper handling and consumption of infected bushmeat, unprotected sexual intercourse, contact with an infected person, no smallpox vaccination, improper hygiene, lower diagnostic capacity, and strong travel history from the endemic regions. The therapeutic strategy is symptom-based treatment and supportive care. Antivirals and vaccines such as Tecovirimat, Brincidofovir, Cidofovir, Imvamune, and ACAM2000 have shown promising results. The primary purpose of the review is to perform an epidemiological study and investigate the pathobiology, diagnosis, prevention, treatment, and some associated complications of the monkeypox virus in 2022.

Highlights

• Since the identification of the monkeypox virus in 1959, the spread of the infection has been sporadic.
• However, there has been a multiple-country infection outbreak since May 2022.
• Currently, no established treatment options are available; only precaution, supportive and symptomatic care is necessary. 
• The World Health Organization (WHO), on 23^rd July 2022, declared monkeypox virus infection an international public health emergency. 

1. Introduction

Monkeypox virus (MPXV) was first found in cynomolgus monkeys taken from Singapore to Copenhagen, Denmark, in 1959. It was known to cause pox in those monkeys (Afshar et al. 2022). MPXV is a highly virulent orthopoxvirus with high infectivity and mortality rates (≥ 10%). In 1970, the first confirmed patient of MPXV had discovered the Democratic Republic of Congo. The symptoms resembled smallpox infection. There was a massive upsurge in the number of confirmed cases from 1981. This zoonotic disease became endemic in the rural central and western African regions. The infection has been found to be transmitted from humans and other animals such as mice, rats, prairie dogs, squirrels, and monkeys (Alakunle et al. 2020). Fifty-three confirmed cases were found in the US in 2003 due to some household prairie dogs imported from Ghana (Ahmed et al. 2022). Israel reported 1 case in 2018 from a man who travelled from Nigeria. In 2019, a single case was reported in Singapore by a traveller from Nigeria. Three members of the same family became infected with MPXV in the United Kingdom after travelling from Nigeria in May 2021. Two more confirmed cases were found in Texas and Maryland, the USA, in July and November 2021, respectively. Both of them had a travel history from Nigeria. However, 2022 reported 36,513 cases from around the world (Afshar et al. 2022). A detailed epidemiological study is difficult to be conducted due to a lack of reporting, confirmation, and similarity of the symptoms with that of smallpox.

Mostly, cases are reported from subjects with a strong travel history from central and west African countries (Au et al. 2022). However, mathematical models suggest higher animal-to-human and lower human-to-human transmission. This includes contact with animal skin lesions, bodily fluids, and respiratory droplets directly or indirectly through clothes, utensils, etc (Au et al. 2022). Human-to-human transmission is due to direct or close physical contact during sexual intercourse or other activity (Heskin et al. 2022). The risk factors include improper handling of bushmeat without proper precautions, contact with infected animals, heavily forested, rural areas, discontinuation of routine smallpox vaccination, taking care of infected individuals with MPXV without appropriate safeguards, and few cultural norms. Studies suggest that men and children have a higher risk of infection. Infected pregnant females have reported congenital anomalies and complications during childbirth (Cho and Wenner 1973).

The routes of viral entry include intradermal, oropharynx, and nasopharynx. The virus rapidly replicates and spreads to the local lymph nodes. The incubation period is generally 7–14 days (21 days maximum). The virus spreads and seeds to other organs post-incubation. Headache, fever, fatigue, profound weakness, erythema, skin hyperpigmentation, and lymph node swelling are some initial symptoms that develop post-incubation (Bragazzi et al. 2022). The progression of the disease leads to secondary infections, respiratory infections (such as pneumonia), loss of vision, encephalitis, and dehydration (through vomiting and diarrhoea). Oral mucosal lesions followed by lesions concentrated in the face, soles, palms, and rashes in the rest of the body develop within 1–2 days of initial incubation. The lesions are 2–10 mm and go through macular, papular, vesicular, and pustular phases in 2–4 weeks. 5–7 days after the pustular stage, crusts develop over lesions which fall off after 7–14 days, and the patient is declared non-infective (Cho and Wenner 1973; Bragazzi et al. 2022; Rodriguez-Morales et al. 2022). The protocol suggesting complete isolation of the patient in a standard negative pressure chamber was given by the Centers for Disease Control and Prevention (CDC). It also recommended non-contact with the patient's droplet and standard airborne precautions (Vivancos et al. 2022).

2. Structural Characteristics Of Mpxv

The virus has been categorized under the Poxviridae family (Guagliardo et al. 2020). This family's viruses include vaccinia, variola, and cowpox. The MPXV is a dumbbell-shaped, enveloped, and pleomorphic virus. The MPXV is nearly 200-250nm with a double-stranded DNA genome size of about 197kb consisting of non-overlapping open-reading frames (ORFs) > 180 nucleotides in length (Alakunle et al. 2020). It consists of homologous genes from the vaccinia viruses at the terminal position of its genome. Nevertheless, MPXV consists of four ORFs at the inverted terminal repeats, which is different from vaccinia viruses, which have no ORFs at the inverted terminal repeats 9 (Antinori et al. 2022). The genome of MPXV was analyzed by Shchelkunov et al., 2002, which showed similarity of the central conserved region with the other viruses of the orthopoxviruses (Shchelkunov et al. 2002). However, inverted terminal repetition (ITR) was found in the extreme right and left regions with tandem repeats. Simultaneous analysis and pathogenicity towards humans confirmed that MPVX showed a different genomic constitution than other orthopoxviruses (Kugelman et al. 2014).

3. Molecular Mechanism Of Infection And Pathogenesis

The MPXV is transmitted from infected animals or from infected humans to healthy humans. The virus accumulates within the nasopharyngeal, oropharyngeal, or intradermal region. The virus replicates rapidly at the primary inoculation sites and then spreads to all the lymph nodes. The virus enters healthy human cells by cellular fusion or endocytosis. Upon entering the cytosol, the viral envelope uncoats releasing the DNA. The DNA replicates and undergoes transcription and translation in successive steps to form the proteins required for viral assembly (Kaler et al. 2022). Finally, the genetic material gets packaged within the viral envelope, and the mature virions are released. This process is called Primary Viremia. The mature virions further spread to the skin (to form skin lesions) and other tertiary organs. This process is called Secondary Viremia, and the stage is called the Prodromal Stage (Kumar et al. 2022). The Central-African and Western-African strain have 173 and 171 unique functional genes and 56 and 53 virulent genes, respectively. The Central-African strain can activate T-cells by the T-cell receptor (TCR) pathway, thus inhibiting the host's immune system to some extent. The MPXV is perceived to have a lower mutation rate than other viruses like Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). However, the viral samples from the current outbreak showed 40 mutations that might have taken place in 50 years. However, most of the mutations are for the survival of the virus and are non-lethal for the host (Kaler et al. 2022).

4. Epidemiological Study Of Mpxv Infection Of 2022

MPXV is generally self-limiting in nature. The symptoms resolve within 14–21 days after the appearance of initial symptoms. Currently, two types of MPXV are found: the Western and Central-African strains. The mortality rate of the West-African type is around 3.6%, but sometimes it may cause severe illness. In contrast, the Central-African type has a high mortality of approximately 10.6%. The epidemiological study of MPXV can be divided into two parts, endemic regions, and non-endemic regions. The endemic area includes the Democratic Republic of the Congo, Nigeria, Cameroon, the Central African Republic, and the Republic of the Congo (Ladnyj et al. 1972; Cho and Wenner 1973). The non-endemic areas include Europe, America, and Asia, which reported recent cases. The first outbreak of MPXV in a non-endemic region was reported in 2003 in the US due to some infected rodents and prairie dogs imported from Ghana (Cho and Wenner 1973).

The incidence of human monkeypox was sporadically reported from 1970 till 2017. However, the number of cases increased rapidly, with 2,828 suspected cases and 69 mortalities in 5 endemic countries. In 2020, 6368 suspected cases were reported, with 231 mortalities in 7 countries. However, in 2021, more cases reduced by 49% than in 2020 (Bunge et al. 2022). The leading cause of the upsurge is still unknown, but deforestation, contact of humans with wild animals, and bushmeat consumption could be one of the major causes. 23,428 cumulative suspected cases with 589 mortalities have been reported from the endemic region since 2017 (Chakraborty et al. 2022). The fatality rate was around 2.5%. The Democratic Republic of the Congo includes approximately 96% of the cases in the endemic belt. Fatalities have been higher in young patients and HIV-infected individuals (Chakraborty et al. 2022; Oprea et al. 2022).

The first MPXV infection in 2022 outside the endemic region was reported in the United Kingdom from a patient with a travel history from Nigeria. The case was confirmed on 7th May 2022 and immediately isolated. Six more confirmed cases were reported between 13th – 15th May 2022 (https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON383). Two belonged to the same family as the case reported on 7th May. Most of the samples tested positive for the Western-African strain (Kugelman et al. 2014). At the end of May, 190 confirmed cases were recorded in the UK. The government of the UK gave particular emphasis on sexual contact, especially for patients who showed blisters within three weeks of sexual contact. On 7th June 2022, they declared MPX as a "Notifiable Disease" and emphasized diagnosis and contact tracing. The number of cases crossed a thousand by the end of June. Till 15th August 2022, a total of 3,201 confirmed cases were recorded (https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON383).

Apart from the UK, confirmed cases were reported from other European nations and non-European nations such as Argentina, Canada, French Guiana, United States of America, United Arab Emirates, Sudan, Belgium, Austria, Czechia, Denmark, France, Finland, Germany, Israel, Italy, Netherlands, Slovenia, Portugal, Spain, Switzerland, Sweden, Northern Ireland, United Kingdom of Great Britain, Australia, Benin, Poland, Latvia, Serbia, Luxemburg, and India (Oprea et al. 2022) (https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON383). Cases began to increase from May 2022 among individuals with a travel history from the endemic African countries and the UK. The Centers for Disease Control and Prevention (CDC) emphasizes contact tracing and diagnosis of infected individuals in both US and other countries. The CDC has guidelines for vaccination strategies, including post-exposure and pre-exposure prophylaxis. These vaccines include ACAM2000 and JYNNEOS, which are smallpox vaccines discussed in the later sections of this article (https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON396). India also reported a total number of 10 cases by 29th August 2022. The Ministry of Health and Family Welfare, Government of India, published the protocol for healthcare professionals and patients on 31st May 2022. However, the most alarming aspect is that the 4th confirmed case was reported from West Delhi, who had no travel history to any country (https://timesofindia.indiatimes.com/india/indias-4th-monkeypox-case-in-delhi-patient-has-no-foreign-travel history/articleshow/93096145.cms).

5. Diagnosis

The diagnosis of MPXV is generally made by polymerase chain reaction (PCR) for its sensitivity and accuracy. The sample includes skin lesions from different sites like fluid from pustules, vesicles, exudates, and crusts (Saxena et al. 2022). The samples are collected from the suspected cases and stored in clean, sterilized tubes without the viral media for transport in cold storage conditions. Further, diagnosis can be made through electron microscopy and molecular analysis of the sequenced results of PCR (Ibrahim et al. 1997; Espy et al. 2002; Nörz et al. 2022). The serological study can be conducted by specific immunoglobulin M within five days and specific immunoglobulin G within eight days (Petersen et al. 2019). But currently, several companies have launched rapid diagnostic testing kits based on IgM/IgG antibodies. These tests are based on fluorescence immunochromatography, which uses whole human blood as a sample. Rapid tests can produce accurate results within 10–15 minutes (Aden et al. 2022).

Table 3. Table showing various genes and the primers required for serological detection of MPXV by PCR and rtPCR (Ghate et al. 2022). 

Immunohistological analysis of the skin biopsies obtained from papular and vesiculopustular lesions revealed necrosis of keratinocytes, acanthosis, dermal lymphohistiocytic infiltrate, vacuolization of basal membrane, giant multinucleated epithelial cells, necrosis of epidermal layer, vasculitis and increased number of neutrophils and eosinophils (Hofer 2022). Contact tracing requires contact tracing to record patient details, including age, initial symptoms, collection of specimens, date of the first appearance of rashes, lesion stage, location, travel history, vaccination status for smallpox, and confirmation of laboratory tests (Mileto et al. 2022).

6. Prevention

The exact mechanism of transmission of MPXV has not yet been identified. Transmission due to contact with bushmeat has been identified as essential in spreading the infection in endemic areas. Direct exposure to blood, inadequate precautions, and improper cooking are considered direct routes of exposure (Cho and Wenner 1973; Dhawan et al. 2022). Healthcare workers are at comparatively more significant risk of getting infected due to close contact with patients and the lack of use of inappropriate protective clothing, such as surgical masks and gloves (Dhawan et al. 2022). Prevention of bushmeat trade such as import of non-human primates and rodents; proper precautions during handling of blood, meat, other body parts, dead or decaying animals; immediate quarantine of infected animals showing initial symptoms of monkeypox; and proper cooking of meat-based products are considered essential precautions for preventing animal-to-human transmission (Minhaj et al. 2022). It is not easy to disinfect the MPXV as the marketed phenol-based disinfectants are not active against it. Solvents such as chloroform (at 60°C) and 20 nM caprylate (at 22°C) with high lipophilicity and lower pH are only effective and can take up to 2–3 hours for complete disinfection (Di Guilo et al. 2004).

Diagnosis, contact tracing, quarantine, and isolation of human patients in controlled negative air-pressure isolation rooms with a travel history from central and western African regions are essential for breaking the chain of human-to-human transmission. Standard healthcare measurements, as recommended by CDC and WHO, are necessary (https://www.cdc.gov/poxvirus/monkeypox/clinicians/treatment.html). Standard nursing clothes and equipment should be provided to healthcare workers. The healthcare workers must be previously vaccinated with smallpox vaccines (Dhawan et al. 2022). Biological samples and specimens should be handled and transported according to the guidelines for transporting infectious materials, as provided by WHO. The government of lower- and middle-income countries, such as the countries of the endemic regions, should focus on building their healthcare infrastructure capacity. They should increase awareness among the population through surveillance programs, education, and training. Travel to the endemic regions should be highly controlled or strictly prohibited until the decrease in cases (Memariani et al. 2022).

7. Treatment

The current treatment protocol for human monkeypox infection includes only symptomatic management, secondary infection treatment, and supportive treatment because there is no specific treatment protocol available for MPXV. The Global Commission for the Certification of Smallpox Eradication (GCCSE) identified MPXV as a public health threat and recommended its vaccination, surveillance, and awareness program in 1980; WHO supported it from 1970 to 1986 (Cho and Wenner 1973). However, at the end of the smallpox eradication program, no such scientific evidence was found supporting the smallpox vaccine's effectiveness for monkeypox. However, a systematic surveillance program between 2005–2007, which divided the Democratic Republic of the Congo into nine healthcare zones, suggested a decrease in the risk of monkeypox infection by about 5.2 times among individuals vaccinated with the smallpox vaccine. It is because there are similar antigenic protein targets of smallpox and MPXV (Townsend et al. 2013).

Currently, WHO and CDC recommend the smallpox vaccine for healthcare workers, veterinary physicians, researchers, and the population. Studies suggest that viral-inhibitory and cross-neutralizing activity from immune subjects produces a heterogeneous and broad serum antibody response against MPXV, variola major virus (VARV), and vaccinia virus (Memariani et al. 2022). The only vaccine which gained marketing approval for both smallpox and monkeypox in the USA is JYNNEOS^TM, also called Imvanex or Imvamune (Memariani et al. 2022) (https://www.fda.gov/vaccines-blood-biologics/jynneos). Surveillance data from the endemic countries suggest that this vaccine provides 85% protection and prevents the progression of the infection to its severe stages through the mechanism of action provided in Fig. 6. Adequate pre-clinical and clinical trial data can offer this vaccine's effectiveness (Vivancos et al. 2022). Another vaccine is ACAM2000 but is approved under the expanded-access Investigational New Drug Application (INDA) of the Food and Drug Administration (FDA). It is constituted of live vaccinia virus and is used in only adult populations with a more significant risk of getting the smallpox virus (https://www.cdc.gov/poxvirus/monkeypox/clinicians/treatment.html).

The drugs available for treating human monkeypox infection include Tecovirimat, Brincidofovir, Cidofovir, and Vaccinia Immune Globulin (VIG) (Petersen et al., 2019). The safety and effectiveness of Tecovirimat can only be confirmed by the pre-clinical data, as no clinical study results are currently available. It has shown efficacy against orthopoxviruses in animal studies. It can only be used under expanded-access INDA. The in-vitro and in-vivo study results suggest that Brincidofovir and Cidofovir effectively treat poxviruses. However, its use in severe cases of MPXV infection cannot be confirmed due to a lack of clinical trial data (Petersen et al. 2019; Saxena et al. 2022). Nevertheless, Cidofovir shows severe renal toxicity during cytomegalovirus (CMV) infection treatment. On the other hand, VIG can only be used in prophylactic therapy in case of severe deficiency of T-cells due to smallpox and monkeypox. However, still, VIG has not shown benefit as a first-line treatment regimen for human monkeypox (Memariani et al. 2022).

8. Burden Of Mpxv Infection With Co-associated Complications

The differentiation of the disease from other diseases caused by different viruses of the orthopoxvirus family is quite difficult. The MPXV infection is self-limiting; however, it requires proper diagnosis and symptomatic and supportive therapy. Delay in treatment can cause the progression of the infection into severe complications. The presence of secondary conditions and disorders can delay the patient's recovery.

9. Few Case Studies Focusing On Mpxv Infection And Treatment

• An observational study was conducted retrospectively in the UK between 2018 and 2021, revealing the virus's transmission. One patient acquired the virus within the healthcare facility. The other patient had a travel history from endemic areas and transmitted the virus to a child and an adult within the same household. Few patients were subjected to 200 mg/week of oral Brincidofovir, which showed elevation of metabolic enzyme; however, those receiving 600 mg/twice daily of oral Tecovirimat for two weeks had a shorter treatment duration with no adverse effects (Adler et al. 2022).

• A study was conducted with 12 patients, and 147 samples from Barcelona, Spain, between May-June, 2022, which showed 67% of the cases showed viral load in feces, 75% in urine, 58% in semen, 83% in the nasopharyngeal region and 92% in the rectum (Peiró-Mestres et al. 2022).

• The risk of fatality due to MPXV increases due to HIV. However, if the viral load is kept low, then the risk decreases. A 30-year-old HIV-positive male from Melbourne, Australia, under treatment was infected with MPXV due to his recent travel from Europe. His treatment regimen consisted of Dolutegravir, Lamivudine, and Abacavir, which kept his viral load below 100 copies/mL. The patient showed genital rash after three days of initial onset of symptoms which subsided within five days (Hammerschlag et al. 2022).

• An observational study with 54 subjects (24% had HIV) in a sexual health center in London, UK, showed common symptoms such as skin lesions at 1–4 sites consisting of oropharyngeal and anogenital lesions. Other common symptoms included fever and fatigue (Girometti et al. 2022).

• The primary clinical manifestation of MPXV is skin lesions. However, asymptomatic cases have been found among patients of a male sexual health center in Belgium. 224 male subjects were used in the study, where oropharyngeal and anorectal samples were collected and tested by MPXV-specific polymerase chain reaction (PCR). The subjects tested negative after 21–37 days by PCR. However, none showed any clinical manifestations or contact with infected individuals (De Baetselier et al. 2022).

• There is a considerable shift from travel-associated MPXV cases to autochthonous cases reported between May and June 2022 in Berlin, Germany. The study considered 262 cases, out of which 21% of cases had travel history, while 79% of cases had no travel history. However, 58% of cases visited public gatherings during the infectious period (Selb et al. 2022).

10. Future Projections

Bisanzio et al., 2022 created a simulation-based model with 50 million subjects based on their location and socioeconomic status (Bisanzio and Reithinger 2022). The model emphasizes the non-endemic regions of Europe with higher income than the endemic regions of Africa. Factors such as travel background from the endemic areas, recent contact with patients, and genetic variability are considered. For the study, the researchers introduced 3, 30, and 300 infected individuals within the healthy population, and the spread of the infection will be within 18, 118, and 402 individuals. However, the spread of the disease can be limited due to vaccination and isolation of the individuals showing initial symptoms. The outbreak can last for 23–37 weeks after the initial introduction of infected individuals. Preventive measures such as vaccination, contact tracing, and isolation of infected individuals showed a reduction in the average duration of the outbreak between 60.9–75.5%. Till June 2020, no clear evidence of sexual transmission was found. However, recent cases strongly suggest sexual transmission, especially among men. Other constraints like reduction of gatherings, avoiding contact with bodily fluids, and lesions reduced the number of cases to a greater extent (Zumla et al. 2022; Bisanzio and Reithinger 2022).

11. Mpxv Infection Burden During Covid-19 Pandemic

The initial spread of Coronavirus disease (COVID-19) from Wuhan, China, in December 2019 was travel-related, just like the spread of MPXV from the endemic areas. Nevertheless, later, in the mid-2020s, a community spread of COVID-19 became a pandemic. However, there were certain differences between the spread of COVID-19 and MPXV. The first difference is that Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is an RNA virus, while MPXV is a DNA virus (Palmore and Henderson 2022). This characteristic makes SARS-CoV-2 unable to repair the mutations as quickly as other DNA viruses, and thus more new strains keep evolving within a short period (Bisanzio and Reithinger 2022). Therefore, SARS-CoV-2 has a much higher infectivity rate than MPXV. The SARS-CoV-2 was not limited to only humans but also spread to other animals (Palmore and Henderson 2022). But MPXV is only found within the bushmeat of the central and western-African regions and a few dogs imported from the endemic areas. The COVID-19 not only spreads from the droplets produced during cough but also from the aerosol which was present in the air of a contaminated area; it is found that MPXV only spreads due to close contact with patients and animals, their skin lesions, cough droplets, and consumption of infected bushmeat. Unlike COVID-19, the MPXV rarely spreads asymptomatically (Palmore and Henderson 2022).

The primary focus of the healthcare facility of a country is to build the capacity to increase the number of diagnostic tests, contact tracing, vaccination with smallpox vaccines, and create awareness among the citizen to avoid the risks of another pandemic. The primary concern with COVID-19 and MPXV is co-infection development within the population. COVID-19 is already found to develop co-infection Mycoplasma pneumoniae, Acinetobacter baumannii, Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus pneumoniae, influenza B virus, metapneumovirus, human immunodeficiency virus, and rhinovirus/enterovirus (Lai et al. 2022). Co-infection with MPXV can lead to a new and more infectious variant of SARS-CoV-2 (Farahat et al., 2022; Chatterjee et al. 2022). This can be prevented using smallpox vaccination programs in endemic-prone areas. The risk of co-infection further increases in sexual transmission, especially in the case of men (Zhu et al. 2022). There is a higher risk of HIV, COVID-19, and MPXV infection, which can cause more single-nucleotide polymorphisms (SNPs) to develop within MPXV, making it more virulent (Zhu et al. 2022). A man from California, US, recently contracted monkeypox after contracting COVID-19 in late June (Hammerschlag et al. 2022). The man had red lesions along his arms, legs, back, and neck (https://www.dailymail.co.uk/health/article-11039491/Incredibly-bad-luck-Californian-man-says-caught-Covid-monkeypox-time.html).

The endemic regions of Africa are facing significant healthcare challenges during the COVID-19 pandemic. That is because their healthcare system is currently occupied with diagnosing, treating, and preventing COVID-19, paying less attention to the emerging threat of MPXV. Lack of testing capacity, high cost of treatment, lack of animal surveillance, and lack of proper differentiation between MPXV and smallpox are causing a delay in treatment and prevention of the cases (Uwishema et al. 2022). Furthermore, the patients are stigmatized from going to the nearby healthcare facility for proper diagnosis and treatment. International organizations such as World Health Organization (WHO), World Organization for Animal Health (OIE), Food and Agriculture Organization (FAO), and One Health are collaborating to build capacity in the central and western African regions (Uwishema et al. 2022; Okyay et al. 2022).

12. Conclusion

WHO declared monkeypox virus infection as an international public health emergency on 23rd July 2022 (https://www.who.int/europe/news/item/23-07-2022-who-director-general-declares-the-ongoing-monkeypox-outbreak-a-public-health-event-of-international-concern). WHO is providing constant support for its member states in surveillance, contact tracing, clinical investigation, education, training, precaution, prevention, and treatment of the infected individuals (https://www.afro.who.int/health-topics/disease-outbreaks/outbreaks-and-other-emergencies-updates). WHO and CDC recommended and published interim guidelines for its member states to follow. Integrated Disease Surveillance and Response (IDSR) programs have been established in the endemic regions. The MPXV has been the topmost priority for this program. An enhanced surveillance system has been set up in the following states of Nigeria, River states, Bayelsa, and Delta. National Multisectoral Emergency Operations Centre has been upgraded to level II in Nigeria (Velavan and Meyer 2022). There is an increment in the number of laboratory tests in Nigeria, the Democratic Republic of Congo, and the Central African Republic. Hotspot regions have been identified and sealed off in the Central African Republic (Espy et al. 2002).

The full-length genome sequence of the MPXV has recently been published and is helping diagnose the infection in European countries. The non-endemic countries have established strict surveillance on travellers from the endemic regions (Ibrahim et al. 1997). There is an increase in diagnostic tests such as PCR capacity in countries such as Germany, Netherlands, Portugal, France, and Belgium. Recent diagnostic results revealed the presence of mainly the Western-African virus type in Europe. European Union, USA, and Canada have recently approved the vaccinia virus strain with the virus's genetically modified Ankara Bavarian Nordic (MVA-BN) strain to prevent human monkeypox (https://www.cdc.gov/poxvirus/monkeypox/clinicians/treatment.htmls; Memariani and Memariani et al. 2022; Rodriguez-Morales 2022).

Declarations

Funding

This work was not funded by any research grant. 

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author Contributions

Data Collection and original draft preparation were performed by Ankit Majie. Conceptualization and investigation of the concerned topic were performed by Rajdeep Saha. Provision of necessary resources, supervision, reviewing, and editing was done by Biswatrish Sarkar. All authors read and approved the final manuscript. 

Declaration of Competing Interests 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

Availability of data and materials section

Not applicable. 

Acknowledgments

Ankit Majie is thankful to AICTE, New Delhi, for awarding the fellowship under PG- Scholarship for qualifying Graduate Pharmacy Aptitude Test (GPAT-2021); Rajdeep Saha is thankful to Birla Institute of Technology, Mesra, for providing the Institute Research Fellowship. 

References

1. Aden TA, Blevins P, York SW, Rager S, Balachandran D, Hutson CL, et al. (2022) Rapid diagnostic testing for response to the Monkeypox outbreak - Laboratory Response Network, United States, May 17-June 30, 2022. MMWR Morb Mortal Wkly Rep. 71: 904–7. http://dx.doi.org/10.15585/mmwr.mm7128e1
2. Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, Osborne JC, Rampling T, Beadsworth MB, Duncan CJ, Dunning J, Fletcher TE, Hunter ER, Jacobs M, Khoo SH, Newsholme W, Porter D, Porter RJ, Ratcliffe L, Schmid ML, Sempe MG, Turnbridge AJ, Wingfield T, Price NM (2022) Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 22:1153–62. http://dx.doi.org/10.1016/S1473-3099(22)00228-6
3. Afshar ZM, Rostami HN, Hosseinzadeh R, Janbakhsh A, Pirzaman AT, Babazadeh A, Aryanian Z, Sio TT, Barary M, Ebrahimpour S (2022) The reemergence of monkeypox as a new potential health challenge: A critical review. Authorea Preprints. https://doi.org/10.22541/au.165446104.43472483/v1
4. Ahmed M, Naseer H, Arshad M, Ahmad A (2022) Monkeypox in 2022: A new threat in developing. Ann Med Surg. 78:103975. https://doi.org/10.1016/j.amsu.2022.103975
5. Alakunle E, Moens U, Nchinda G, Okeke MI (2020) Monkeypox virus in Nigeria: Infection biology, epidemiology, and evolution. Viruses. 12:1257. https://doi.org/10.3390/v12111257
6. Alkhalil A, Hammamieh R, Hardick J, Ichou MA, Jett M, Ibrahim S (2010). Gene expression profiling of monkeypox virus-infected cells reveals novel interfaces for host-virus interactions. Virol J. 7:173. https://doi.org/10.1186/1743-422X-7-173
7. Antinori A, Mazzotta V, Vita S, Carletti F, Tacconi D, Lapini LE, D'Abramo A, Cicalini S, Lapa D, Pittalis S, Puro V (2022) Epidemiological, clinical and virological characteristics of four cases of monkeypox support transmission through sexual contact, Italy, May 2022. Eurosurveillance. 27:2200421. https://doi.org/10.2807/1560-7917.ES.2022.27.22.2200421
8. Au NH, Portillo MT, Marwah A, Thomas-Bachli A, Demarsh PA, Khan K, Bogoch II (2022) Potential for monkeypox exportation from west and Central Africa through global travel networks. J Travel Med. https://doi.org/10.1093/jtm/taac072
9. Bhunu CP, Mushayabasa S, Hyman JM (2012) Modelling HIV/AIDS and monkeypox co-infection. Appl Math Comput. 218:9504–18. http://dx.doi.org/10.1016/j.amc.2012.03.042
10. Bisanzio D, Reithinger R (2022) Projected burden and duration of the 2022 Monkeypox outbreaks in non-endemic countries. Lancet Microbe. https://doi.org/10.1016/S2666-5247(22)00183-5
11. Bížová B, Veselý D, Trojánek M, Rob F (2022) Coinfection of syphilis and monkeypox in HIV positive man in Prague, Czech Republic. Travel Med Infect Dis. 49:102368. http://dx.doi.org/10.1016/j.tmaid.2022.102368
12. Bragazzi NL, Kong JD, Mahroum N, Tsigalou C, Khamisy-Farah R, Converti M, Wu J (2022) Epidemiological trends and clinical features of the ongoing monkeypox epidemic: a preliminary pooled data analysis and literature review. Available at SSRN. https://doi.org/10.1002/jmv.27931
13. Bunge EM, Hoet B, Chen L, Lienert F, Weidenthaler H, Baer LR, et al. (2022) The changing epidemiology of human monkeypox-A potential threat? A systematic review. PLoS Negl Trop Dis. 16:e0010141. https://doi.org/10.1371/journal.pntd.0010141
14. Centers for Disease Control and Prevention (2022) Treatment Information for Healthcare Professionals. https://www.cdc.gov/poxvirus
    /monkeypox/clinicians/treatment.html#:~:text=Tecovirimat%20(also%20known%2
    0as%20TPOXX%2C%20ST%2D246)&text=CDC%20holds%20a
    n%20expanded%20access,a%20pill%20or%20an%20inje
    ction. Accessed 8 July 2022
15. Chakraborty C, Bhattacharya M, Nandi SS, Mohapatra RK, Dhama K, Agoramoorthy G (2022) Appearance and re-appearance of zoonotic disease during the pandemic period: Long-term monitoring and analysis of zoonosis is crucial to confirm the animal origin of SARS-CoV-2 and monkeypox virus. Veterinary Quarterly. 1-1. https://doi.org/10.1080/01652176.2022.2086718
16. Chatterjee A, Saha R, Mishra A, Shilkar D, Jayaprakash V, Sharma P, et al. (2022) Molecular determinants, clinical manifestations and effects of immunization on cardiovascular health during COVID-19 pandemic era - A review. Curr Probl Cardiol. 101250: 101250. http://dx.doi.org/10.1016/j.cpcardiol.2022.101250
17. Cho CT, Wenner HA (1973) Monkeypox virus. Bacteriological reviews. 1973:1-8. https://doi.org/10.1080/22221751.2022.2095309
18. Daily Mail Online (2022) 'Incredibly bad luck': California man says he caught COVID AND monkeypox at the same time - leaving him in excruciating pain. https://www.dailymail.co.uk/health/article-11039491/Incredibly-bad-luck-Californian-man-says-caught-Covid-monkeypox-time.html. Accessed 23 July 2022
19. Davido B, D'Anglejan E, Baudoin R, Dahmane L, Chaud A, Cortier M, et al. (2022) Monkeypox outbreak 2022: an unusual case of peritonsillar abscess in a person previously vaccinated against smallpox. J Travel Med. http://dx.doi.org/10.1093/jtm/taac082
20. De Baetselier I, Van Dijck C, Kenyon C, Coppens J, Van den Bossche D, Smet H, Liesenborghs L, Fien V, Block T, Eric F, Koen V, Marjan VE (2022) Asymptomatic Monkeypox virus infections among male sexual health clinic attendees in Belgium. SSRN Electron J. http://dx.doi.org/10.2139/ssrn.4142074
21. de Sousa D, Patrocínio J, Frade J, Correia C, Borges-Costa J, Filipe P (2022) Human monkeypox coinfection with acute HIV: an exuberant presentation. Int J STD AIDS. 9564624221114998. http://dx.doi.org/10.1177/09564624221114998
22. Dhawan M, Emran TB, Islam F (2022) The resurgence of monkeypox cases: Reasons, threat assessment, and possible preventive measures. Travel medicine and infectious disease. 49:102367. https://doi.org/10.1016/j.tmaid.2022.102367
23. Dhawan M, Priyanka Choudhary OP (2022) Emergence of monkeypox: Risk assessment and containment measures. Travel Med Infect Dis. 49:102392. https://doi.org/10.1016/j.tmaid.2022.102392
24. Di Guilo DB, Eckburg PB (2004) Human Monkeypox: an emerging zoonosis. Lancet Infect. Dis 4:15-25. https://doi.org/10.1016/S1473-3099(03)00856-9
25. Espy MJ, Cockerill FR III, Meyer RF, Bowen MD, Poland GA, Hadfield TL, Smith TF (2002) Detection of smallpox virus DNA by light cycler PCR. J Clin Microbiol 40:1985-8. https://doi.org/10.1128/JCM.40.6.1985-1988.2002
26. Farahat RA, Abdelaal A, Shah J, Ghozy S, Sah R, Bonilla-Aldana DK, et al. (2022) Monkeypox outbreaks during COVID-19 pandemic: are we looking at an independent phenomenon or an overlapping pandemic? Ann Clin Microbiol Antimicrob. 21:26. http://dx.doi.org/10.1186/s12941-022-00518-2
27. Ghate SD, Suravajhala P, Patil P, Vangala RK, Shetty P, Rao RSP (2022) Molecular detection of monkeypox and related viruses – Challenges and opportunities. http://dx.doi.org/10.31219/osf.io/jtdnz
28. Girometti N, Byrne R, Bracchi M, Heskin J, McOwan A, Tittle V, Gedela K, Patel S, Gohil J, Nugent D, Suchak T, Dickinson M, Feeney M, Mora-Peris B, Stegmann K, Plaha K, Davies G, Moore LSP, Mughal N, Asboe D, Boffito M, Jone R, Whitlock G (2022) Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis. Lancet Infect Dis. http://dx.doi.org/10.1016/S1473-3099(22)00411-X
29. Guagliardo SAJ, Monroe B, Moundjoa C, Athanase A, Okpu G, Burgado J, et al. (2020) Asymptomatic Orthopoxvirus circulation in humans in the wake of a Monkeypox outbreak among chimpanzees in Cameroon. Am J Trop Med Hyg. 102:206–12. https://doi.org/10.4269/ajtmh.19-0467
30. Hammerschlag Y, MacLeod G, Papadakis G, Adan Sanchez A, Druce J, Taiaroa G, Savic I, Mumford J, Roberts J, Caly L, Friedman D, Williamson DA, Cheng AC, McMahon JH, (2022) Monkeypox infection presenting as genital rash, Australia, May 2022. Euro Surveill. 27. http://dx.doi.org/10.2807/1560-7917.ES.2022.27.22.2200411
31. Heskin J, Belfield A, Milne C, Brown N, Walters Y, Scott C, Bracchi M, Moore LS, Mughal N, Rampling T, Winston A (2022) Transmission of monkeypox virus through sexual contact–A novel route of infection. Journal of Infection. https://doi.org/10.1016/j.jinf.2022.05.028
32. Hofer U (2022) Case series of monkeypox infections. Nature Reviews Microbiology. 7:1. https://doi.org/10.1038/s41579-022-00757-2
33. Hughes C, McCollum A, Pukuta E, Karhemere S, Nguete B, Shongo Lushima R, et al. (2014) Ocular complications associated with acute monkeypox virus infection, DRC. Int J Infect Dis. 21:276–7. http://dx.doi.org/10.1016/j.ijid.2014.03.994
34. Ibrahim MS, Esposito JJ, Jahrling PB, Lofts RS (1997) The potential of 5' nuclease PCR for detecting single-base polymorphism in Orthopoxvirus. Mol Cell Probes 11:143-7. https://doi.org/10.1006/mcpr.1996.0093
35. Kaler J, Hussain A, Flores G, Kheiri S, Desrosiers D (2022) Monkeypox: A comprehensive review of transmission, pathogenesis, and manifestation. Cureus. 14:e26531. http://dx.doi.org/10.7759/cureus.26531
36. Kennedy RB, Ovsyannikova IG, Jacobson RM, & Poland GA (2009) The immunology of smallpox vaccines. Current opinion in immunology. 21:314–320. https://doi.org/10.1016/j.coi.2009.04.004
37. Kugelman JR, Johnston SC, Mulembakani PM, Kisalu N, Lee MS, Koroleva G. et al. (2014) Genomic variability of monkeypox virus among humans, Democratic Republic of the Congo. Emerg Infect Dis. 20:232–9. https://doi.org/10.3201/eid2002.130118
38. Kumar N, Acharya A, Gendelman HE, Byrareddy SN (2022) The 2022 outbreak and the pathobiology of the monkeypox virus. J Autoimmun. 131:102855. http://dx.doi.org/10.1016/j.jaut.2022.102855
39. Ladnyj ID, Ziegler P, Kima E (1972) A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ. 46:593–7.
40. Lai C-C, Wang C-Y, Hsueh P-R (2022) Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents? J Microbiol Immunol Infect. 53:505–12. http://dx.doi.org/10.1016/j.jmii.2020.05.013
41. Mathieu E, Dattani S, Ritchie H, Spooner F, Roser M (2015) Monkeypox. OurWorldInData.
42. Mayr A, Mayr B (1999) A new concept in prophylaxis and therapy: paramunization by poxvirus inducers. Pesq. Vet. Bras. 19:3-4. https://doi.org/10.1590/S0100-736X1999000300001
43. Memariani M, Memariani H (2022) Multinational monkeypox outbreak: what do we know and what should we do?. Irish Journal of Medical Science (1971-). 1-2. https://doi.org/10.1007/s11845-022-03052-4
44. Mileto D, Riva A, Cutrera M, Moschese D, Alessandro M, Meroni L, Giacomelli A, Bestetti G, Rizzardini G, Gismondo MR, Antinori S (2022) New challenges in human monkeypox outside Africa: A review and case report from Italy. Travel Med Infect Dis. 49:102386. https://doi.org/10.1016/j.tmaid.2022.102386
45. Minhaj FS, Ogale YP, Whitehill F, Schultz J, Foote M, Davidson W, Hughes CM, Wilkins K, Bachmann L, Chatelain R, Donnelly M, Mendoza R, Downes BL, Roskosky M, Barnes M, Gallagher GR, Basgoz N, Ruiz V, Kyaw N, Feldpausch A, Valderrama A, Alvarado-Ramy F, Dowell CH, Chow CC, Li Y, Quilter L, Brooks J, Daskalakis DC, McClung RP, Petersen BW, Damon I, Hutson C, McQuiston J, Rao AK, Belay E, McCollum AM (2022) Monkeypox Response Team 2022. Monkeypox Outbreak - Nine States, May 2022. MMWR. Morbidity and mortality weekly report. 71:764–769. https://doi.org/10.15585/mmwr.mm7123e1
46. Moyron-Quiroz JE, McCausland MM, Kageyama R, Sette A, Crotty S (2009) The smallpox vaccine induces an early neutralizing IgM response. Vaccine. 28:140–147. https://doi.org/10.1016/j.vaccine.2009.09.086
47. Nature (2022) Monkeypox goes global: why scientists are on alert. https://doi.org/10.1038/d41586-022-01421-8. Accessed 25 May 2022
48. Nature (2022) Monkeypox vaccination begins — can the global outbreaks be contained? https://doi.org/10.1038/d41586-022-01587-1. Accessed 9 July 2022
49. Nörz D, Brehm TT, Tang HT, Grewe I, Hermanussen L, Matthews H, et al. (2022) Clinical characteristics and comparison of longitudinal qPCR results from different specimen types in a cohort of ambulatory and hospitalized patients infected with monkeypox virus, J Clin Virol. 105254. http://dx.doi.org/10.1016/j.jcv.2022.105254
50. Okyay RA, Bayrak E, Kaya E, Şahin AR, Koçyiğit BF, Taşdoğan AM, Avcı A, Sümbül HE (2022) Another Epidemic in the Shadow of Covid 19 Pandemic: A Review of Monkeypox. proteins. 7:10. https://doi.org/10.14744/ejmo.2022.2022
51. Oprea C, Ianache I, Piscu S, Tardei G, Nica M, Ceausu E, et al. (2022) First report of monkeypox in a patient living with HIV from Romania. Travel Med Infect Dis. 49:102395. https://doi.org/10.1016/j.tmaid.2022.102395
52. Palmore TN, Henderson DK (2022) Adding New Fuel to the Fire: Monkeypox in the Time of COVID-19-Implications for Health Care Personnel. Annals of internal medicine. M22-1763. Advance online publication. https://doi.org/10.7326/M22-1763
53. Peiró-Mestres A, Fuertes I, Camprubí-Ferrer D, Marcos MÁ, Vilella A, Navarro M, Rodriguez-Elena L, Riera J, Català A, Martinez MJ, Blanco JL (2022) Frequent detection of monkeypox virus DNA in saliva, semen, and other clinical samples from 12 patients, Barcelona, Spain, May to June 2022. Euro Surveill. 27. http://dx.doi.org/10.2807/1560-7917.ES.2022.27.28.2200503
54. Petersen E, Kantele A, Koopmans M, Asogun D, Yinka-Ogunleye A, Ihekweazu C, et al. (2019) Human Monkeypox: Epidemiologic and clinical characteristics, diagnosis, and prevention. Infect Dis Clin North Am. 33:1027–43. https://doi.org/10.1016/j.idc.2019.03.001
55. Rodriguez-Morales AJ (2022) Monkeypox and the importance of cutaneous manifestations for disease suspicion. Microbes, Infection and Chemotherapy. 2:e1450. https://doi.org/10.54034/mic.e1450
56. Saxena SK, Ansari S, Maurya VK, Kumar S, Jain A, Paweska JT, et al. (2022) Re-emerging human monkeypox: A major public-health debacle. J Med Virol. https://doi.org/10.1002/jmv.27902
57. Selb R, Werber D, Falkenhorst G, Steffen G, Lachmann R, Ruscher C, McFarland S, Bartel A, Hemmers L, Koppe U, Stark K, Bremer V, Jansen K (2022) A shift from travel-associated cases to autochthonous transmission with Berlin as epicentre of the monkeypox outbreak in Germany, May to June 2022. Euro Surveill. 27. http://dx.doi.org/10.2807/1560
58. Shafaati M, Zandi M (2022) Monkeypox virus neurological manifestations in comparison to other orthopoxviruses. Travel Med Infect Dis. 49:102414. http://dx.doi.org/10.1016/j.tmaid.2022.102414
59. Shchelkunov SN, Totmenin AV, Safronov PF, Mikheev MV, Gutorov VV, Ryazankina OI, et al. (2002) Analysis of the monkeypox virus genome. Virology. 2002:172–94. https://doi.org/10.1006/viro.2002.1446
60. The Times of India (2022) India’s 4th monkeypox case in Delhi, patient has no foreign travel history. https://timesofindia.indiatimes.com/india/indias-4th-monkeypox-case-in-delhi-patient-has-no-foreign-travel history/articleshow/93096145.cms. Accessed 1 August 2022
61. Townsend MB, Keckler MS, Patel N, Davies DH, Felgner P, Damon IK, Karem KL (2013) Humoral immunity to smallpox vaccines and monkeypox virus challenge: proteomic assessment and clinical correlations. J Virol. 87:900–11. http://dx.doi.org/10.1128/JVI.02089-12
62. U.S. Food & Drug Administration, 2021. JYNNEOS. https://www.fda.gov/vaccines-blood-biologics/jynneos (accessed 15 August 2022).
63. Uwishema O, Adekunbi O, Peñamante CA, Bekele BK, Khoury C, Mhanna M, et al. (2022) The burden of monkeypox virus amidst the Covid-19 pandemic in Africa: A double battle for Africa. Ann Med Surg (Lond). 80:104197. http://dx.doi.org/10.1016/j.amsu.2022.104197
64. Velavan TP, Meyer CG (2022) Monkeypox 2022 outbreak: an update. Tropical Medicine & International Health. 27:604-605. https://doi.org/10.1111/tmi.13785
65. Vivancos R, Anderson C, Blomquist P, Balasegaram S, Bell A, Bishop L, Brown CS, Chow Y, Edeghere O, Florence I, Logan S (2022) Community transmission of monkeypox in the United Kingdom, April to May 2022. Eurosurveillance. 27:2200422. https://doi.org/10.2807/1560-7917.ES.2022.27.22.2200422
66. Vouga M, Nielsen-Saines K, Dashraath P, Baud D (2022) The monkeypox outbreak: risks to children and pregnant women. Lancet Child Adolesc Health. http://dx.doi.org/10.1016/S2352-4642(22)00223-1
67. World Health Organization (2022) Monkeypox - United Kingdom of Great Britain and Northern Ireland. https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON383. Accessed 8 July 2022
68. World Health Organization (2022) Multi-country monkeypox outbreak: situation update. https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON396. Accessed 12 July 2022
69. World Health Organization (2022) Outbreaks and Emergencies Bulletin. https://www.afro.who.int/health-topics/disease-outbreaks/outbreaks-and-other-emergencies-updates . Accessed 2 July 2022
70. World Health Organization (2022) WHO Director-General declares the ongoing monkeypox outbreak a Public Health Emergency of International Concern. https://www.who.int/europe/news/item/23-07-2022-who-director-general-declares-the-ongoing-monkeypox-outbreak-a-public-health-event-of-international-concern . Accessed 23 July 2022
71. Zhu F, Li L, Che D (2022) Monkeypox virus under COVID-19: Caution for sexual transmission - Correspondence. Int J Surg. 104:106768. http://dx.doi.org/10.1016/j.ijsu.2022.106768
72. Zumla A, Valdoleiros SR, Haider N, Asogun D, Ntoumi F, Petersen E, Kock R (2022) Monkeypox outbreaks outside endemic regions: scientific and social priorities. The Lancet. Infectious Diseases. 400:23. https://doi.org/10.1016/S1473-3099(22)00354-1.