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Abstract

Monkeypox (MPX) is a zoonotic disease caused by the MPX virus from the poxviridae family of orthopoxviruses. Typically, endemic in central and west Africa, it has now become a matter of concern since cases have been reported in non-endemic countries around mid-June 2022, especially in the European region, with the transmission not related to travel. The diagnosis is made by PCR testing of the skin lesions. Even though treatment is symptomatic, antiretrovirals, such as tecovirimat, are used in severe cases. Vaccination with second and third generation vaccines is approved for prophylaxis in high risk individuals. Unfortunately, these options of treatment and prevention are only available in high income countries at the moment. This review, through a thorough literature search of articles from 2017 onward, focuses on epidemiology, clinical manifestations, challenges, treatment, prevention and control of MPX virus and how they can be corelated with other viral outbreaks including COVID-19, Acute Hepatitis of unknown origin, Measles and Dengue, to better predict and therefore prevent its transmission. The previous COVID-19 pandemic increased the disease burden on healthcare infrastructure of low-middle income countries, therefore, this recent MPX outbreak calls for a joint effort from healthcare authorities, political figures, and NGOs to combat the disease and prevent its further spread not only in high income but also in middle- and low-income countries.

Keywords

monkey pox diagnosis epidemiology future perspective vaccination treatment prevention and control COVID-19 review overview

What do we already know about this topic

Monkeypox (MPX) virus is a member of Poxviridae family which causes human MPX. It is transmitted via direct contact with animals and presents as fever, chills, exhaustion, myalgia. backache, and rashes with lymphadenopathy being the key diagnostic feature. Diagnosed via Polymerase Chain Reaction (PCR), MPX has no specific treatment yet. However, the second and third generation smallpox vaccines have been proven effective for prevention.

How does your research contribute to the field?

Various other outbreaks including the recent COVID-19, Acute Hepatitis of Unknown Origin, measles, and dengue present with symptoms which are similar to those of MPX. This can result in misdiagnosis and, delay the beginning of treatment. As MPX cannot be clinically distinguished from other pox-like viruses and diseases with similar clinical manifestations, efficient rapid diagnostic techniques, such as the use artificial intelligence (AI) are required to control the outbreak.

What are your research’s implications toward theory, practice, or policy?

Since the transmission for the recent MPX outbreak has not been linked to travel, further research in transmission pathophysiology is required. In addition, enhanced surveillance, better safety precautions for healthcare workers, awareness programs, strict control over immunization and vaccination as per WHO guidelines, ensuring spread of only authentic information, and financial support can help tackle various challenges and prevent the spread of MPX.

Introduction

Amidst several ongoing viral outbreaks at present, monkeypox (MPX) is a cause of concern. In recent years, various viral outbreaks have affected the world, with the current ones including MPX virus (MPXV), COVID-19, Acute Hepatitis of unknown origin, and a few familiar ones that have reappeared as outbreaks, including Measles and Dengue, are more prevalent and recurring than others.¹ The common factors responsible for the viral emergence include population growth, change in diet, increased globalization, easier travel between continents, and climate change.^2,3 Prior to the 2022 outbreak, between 2003 and 2021, several sporadic cases in non-endemic regions including North America, Europe and Asia have been reported. All these cases were either linked to travel to endemic regions or through animal reservoirs such as prairie dogs. Monkeypox virus, clade 2b, is responsible for the recent cases and no definitive link with travel has been established.⁴ On 23 July 2022, the World Health Organization (WHO) declared MPX a Public Health Emergency of International Concern (PHEIC).⁵ As of 6 October 2022, 71 237 cases and over 26 deaths have been reported from around 107 countries.⁶ Increasing cases in low-income countries such as Nigeria and the Democratic Republic of Congo (DRC) and others in central and west Africa, Pakistan and Afghanistan, can prove to be a burden on the already meager resources in these regions. This narrative review critically focuses on providing updated and summarized information on the recent viral outbreak of MPX, with the aim of better understanding of these viral outbreaks, which will help reach a timely diagnosis. Moreover, by looking into the prevention and treatment strategies, this article will also provide an effective method to curb the epidemics.

Methodology

This narrative review discusses the relevant literature, including updated studies with respect to the monkeypox virus in comparison to other viral outbreaks. Literature search was performed of studies published from the year 2017 onward, using the databases PubMed and Google scholar. Reviews and meta-analysis were mainly included. The search terms used are “Monkeypox virus,” “COVID-19,” “Acute Hepatitis of unknown origin,” “Measles,” “Dengue,” “Epidemiology,” “Clinical Manifestations,” “Signs and Symptoms,” “Treatment,” “Control” and “Outbreaks.” We mainly included studies related to the 2022 global MPX outbreak and recent outbreaks such as COVID-19, Dengue, Acute Hepatitis of unknown origin and Measles. No specific age group or demographic region was targeted, in order, to have an insight on the transmission pathophysiology of the virus and predict the pattern of global spread. Furthermore, external sources such as the WHO, CDC, NHS etc. were also used for relevant information. Abstract only articles, commentaries, letter to the editor, and articles in language other than English were excluded from this review.

Monkeypox Virus

MPXV is a member of the Orthopox genus of the Poxviridae family which causes human MPX, a zoonotic disease.

Transmission and Pathogenesis

The incubation period of MPXV ranges from 5 to 21 days.⁷ MPXV invades the airway epithelial cells or the keratinocytes, fibroblasts and endothelial cells in the skin to enter the host. In the skin, the virus invades keratinocyte, resulting in ballooning degeneration in the vasicular stage, while prominent inflammotry cells and keratinocyte debris in pustule stage. The virus then spreads from these initial sites of infection to draining lymph nodes via antigen presenting cells (cells that present antigens on their surface to other immune cells in order to elicit an immune response) or by directly accessing lymphatic vessels (vessels carrying lymph and white blood cells around the lymphatic system). Replication in lymph nodes, causing primary viremia, is followed by spread of virus to organs like spleen and liver, and then further beyond to distant organs of the infected host, resulting in secondary viremia.⁴

MPXV has a variety of animal-based reservoirs like rodents, squirrels, rats, monkeys, etc. and is transmitted by direct animal contact by means of bodily fluids, blood, aerosols, and infected lesions. In 2003, prairie dogs that had been in contact with Gambian pouched rats, exported from Ghana as exotic pets, were responsible for the 71 cases reported in the USA. Import and housing together of these animal reservoirs aids transmission of the virus to non-endemic regions.⁸ Human-to-human transmission is also possible via close contact with infected individuals and respiratory droplets.⁸ Vertical transmission can too occur from mother to fetus across placenta or during childbirth, leading to high risk of miscarriages and perinatal death.^7,9 Cases also have been recently reported among men having sex with men (MSM), raising the possibility of transmission of virus via sexual route.^10-12

Epidemiology

MPX is endemic in central and western African countries but is slowly encompassing non-endemic regions as well. This virus has 2 subgenuses: West Africa and Congo Basin, with the latter contributing to severe outbreaks presented with higher mortality rates and severe illness.⁸ The first outbreak of MPX outside Africa occurred in the US in 2003, and West African clade was responsible.¹³ The West African clade has mortality rate up to around 3%, while the Congo Basin clade exhibits a mortality rate of up to 11%.^13,14 MPX cases have also been reported in UK, USA, Israel, and Singapore, which are however mostly associated with travel from Nigeria.⁸ According to recent WHO statistics, in June 2022, 3413 confirmed laboratory cases including one death were reported from 50 countries in 5 WHO regions from 1st January to 22nd June 2022. Among these, the majority of the cases were reported from the WHO European Region (86%). Others included regions of the Americas (11%), the African Region (2%), the Eastern Mediterranean Region (1%), and the Western Pacific Region (1%).¹² These cases then further increased to 16 000, being reported from 75 different countries.⁵ The general pattern shows that MPXV is more prevalent in males, especially gays and bisexuals¹¹ and the mortality rate tends to be higher in younger children than in adults.⁷ Even though the spread of MPX from its endemic regions to non-endemic regions is not clear and there is little evidence linked to travel, there is still enough data to take preventative measures. Further research in terms of transmission pathophysiology is still required to further specify prevention, diagnosis and treatment.¹⁵

Clinical Manifestations

MPX patients present with symptoms of fever, chills, exhaustion, muscle ache and backache, swollen lymph nodes, and rashes most commonly on the feet, hands, chest, genitals, or anus.¹⁶ MPX disease begins with the initial phase, lasting up to 5 days, consisting of fever, severe headache, back pain, lymphadenopathy, intense asthenia, and myalgia.⁷ Lymphadenopathy is the distinguishing characteristic that sets MPX apart from other diseases like smallpox, chickenpox, and measles.⁷ The second stage signifies rash formation on the skin at several sites which could comprise of a few to thousands of lesions involving the face and extremities more commonly than the trunk, but could also appear along the oral mucosal membrane.⁷ Approximately 95% of patients suffer from a rash that appears on the face, around 75% present with a rash on the palms of their hands and soles of their feet, oral mucosa is affected in around 70% patients, genitalia are affected by rash in 30% cases, and in about 20% of the cases conjunctiva is involved.⁷ The rash tends to change its morphology along with time from macules to papules, vesicles, pustules, and finally crusts which eventually dry up, wither, and fall off.⁷ The rash may even coalesce if the disease reaches an advanced stage.⁷ Severe cases are being reported in children as they are said to be more exposed to the virus and are immune susceptible.⁷ Typically, the clinical manifestations resolve without any treatment within 2 to 4 weeks but some patients may present with complications such as encephalitis, bronchopneumonia, sepsis, and corneal infection leading to loss of vision.⁷

Vertical Transmission

Data on effect on MPX in pregnancy is limited.¹⁷ However, a case study, conducted between 2007 and 2011, including 4 pregnant women infected with the MPXV revealed 3 babies with a fetal death and the fourth baby dying by stillbirth, with evidence suggesting vertical transmission of the MPXV via the placenta.¹⁷ The stillborn fetus was investigated, uncovering findings of diffuse cutaneous maculopapular lesions involving the skin of the head, the trunk, and the extremities along with hydrops fetalis and marked hepatomegaly with peritoneal effusion.¹⁷ In a meta-analysis by D’Antonio et al, which included 7 cases of monkeypox infection during pregnancy, concluded that it is highly associated with perinatal loss (77% of the cases) mainly due to increased vertical transmission (62% of the cases).⁹

Prevention and Treatment

According to WHO and Centers for Disease Control and Prevention (CDC) updated March 22nd 2023, there is no specific treatment for MPXV, however, certain antivirals (Tecovirimat, Cidofovir, and Brincidofovir) and JYNNEOS vaccine can prove to be effective in providing prophylaxis.^7,18 The MPX vaccines are free of cost and thus are cost-effective. However, these vaccines are for high risk individuals only and not for mass vaccination.¹⁸ Furthermore, the European Medicine Agency in 2013 and US Food and Drug Association (FDA) have also recommended vaccination by 2 smallpox vaccines (ACAM-2000 and MVA-BN) against MPX.¹⁹ The smallpox vaccine has been proven helpful as it has been shown to provide 85% protection against MPXV, therefore, the most important factor for the re-emergence of MPXV could potentially be the decline of smallpox immunity, with a vaccination rate of only 1.29% per year, as unvaccinated individuals are 2.5 times more vulnerable to this virus than vaccinated individuals.²⁰ As there is evidence of transmission of MPXV through sexual contact during the recent 2022 outbreak, population surveillance, contact tracing and ring vaccination is recommended.⁴

Investigations

Currently, genomic sequencing of viral DNA and polymerase chain reaction (PCR) assays of skin lesions are available for detection of the virus.^12,21 Even though MPXV is not highly contagious, to effectively halt the spread of this viral outbreak it will require better strategies, as recommended by WHO like public awareness, appropriate diagnostic testing, identification of infected individuals and their proper isolation, restriction on trade of wild animals, avoiding contact with infected animals and consuming properly cooked meat.¹²

Other Emerging Outbreaks

SARS-CoV-2 (COVID-19)

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) belongs to the Coronaviridae family of viruses and is responsible for the recent COVID-19 pandemic.²² On December 2019, the first case of SARS-CoV-2 was reported in the city of Wuhan, China.²³ On March 11th, 2020, WHO declared the spread of the virus as a pandemic.²⁴ The virus has spread very rapidly to most of the world since then, and as of 2 October 2022, over 615 million confirmed cases and over 6.5 million deaths have been reported worldwide.²⁵ The pandemic greatly affected public health, disrupting economy, leading to unemployment and loss of income along with feelings of isolation, depression and other mental health issues. As hospitals solely focused on COVID-19 and emergency cases, elderly, young, women, people of color and immunocomromised individuals were especially affected.²⁶ The incubation period of SARS-Cov-2 is around 2 weeks during which the patient remains asymptomatic.²⁷ The SARS-CoV-2 virus enters the target cells via ACE2 receptor, and then increases production of angiotensin-2. This increases vascularity of pulmonary vessels causing lung injury and can also give rise to multi-organ dysfunction.²⁷ Human-to-human transmission occurs either via respiratory droplets or by touching contaminated surfaces.²⁸ Case fatality rate of COVID-19 is 2.67% and the average reproduction number Ro is 2.69.²⁹

The clinical course of COVID-19 ranges from being asymptomatic to death by severe pneumonia.³⁰ Approximately 2.27% of the patients, mainly youngsters and women without comorbidities remain asymptomatic.³⁰ Initially, a fever develops (58.66%), followed by cough (54.52%) and then dyspnea (30.82%).31 Ground-glass opacities and consolidation seen in the lung periphery on chest exams and radiographs along with dyspnea are directly related to increased severity of infection.³⁰ On physical examination, individuals with the severe form of the disease have decreased breath sounds, increased respiratory rate, speech tremors, and dullness on lung percussion.³⁰ These patients also usually present with comorbidities including hypertension, diabetes, and cardiovascular disorders.^30,31 As the disease progress, fatigue, malaise, rhinitis, sputum secretion, sneezing, sore throat, chest pain, anorexia, diarrhea, myalgia, headache, dermatological manifestations and neurological manifestations including loss of taste and smell were also commonly reported.³⁰ Diagnosis is usually made using PCR tests of nasal swab samples taken from the patients.²⁷ Hospitalized patients are given supplemental oxygen therapy, especially in respiratory failure and Acute Respiratory Distress Syndrome (ARDS). Besides this, wide-spectrum antibiotics are used to prevent bacterial and fungal co-infections and the use of corticosteroids have also shown positive results with reduced risk of death.²⁷ Several public interventions including restrictions on social gatherings, travel restrictions, and social distancing have been proven to be effective in controlling the spread of the disease.³² Vaccines developed against SARS-CoV-2 have reassuring safety and have effectively reduced the mortality rate, severity, symptomatic cases, and infections across the world.³³

Acute Hepatitis of Unknown Origin

According to the WHO, the case definition of Acute Hepatitis of unknown origin is a child who is 16 years or younger, with acute hepatitis (non-hep A, B, C, D, and E), and presents with serum transaminase levels (ALT or AST) greater than 500 IU/L.^34-36 Adenovirus, which is spread via respiratory droplets,³⁷ was detected in 116 of the 170 UK cases tested, with Adenovirus type 41 being confirmed in the majority.^34,38 It is likely that immunologic injury to the liver induced by adenovirus might be causing the disease.³⁹ Most cases (76.6%) involve children who are 5 years old or younger.³⁵ As of 8 July 2022, around 1010 cases and 22 deaths of acute hepatitis of unknown etiology have been reported across 35 countries, with further 90 cases and 4 deaths being reported.³⁶ These cases have been reported from regions of America (n = 435), Western Pacific (n = 70), South-East Asia (n = 19), and Eastern Mediterranean areas (n = 2) with almost half of the cases (48%) from the WHO European Region.³⁶

The common clinical presentation of the infected individual include jaundice (68.8%), vomiting (57.6%), and light-colored stools (42.7%); the less common symptoms comprise lethargy (48.6%), fever (28.5%), respiratory symptoms (18.1%), and some gastro-intestinal symptoms that commonly appeared in the patient includes diarrhea (43.1%), nausea (25.7%) and abdominal pain (36.1%) as reported by the UK Health Security Agency (UKHSA).^34,36,38 In accordance with the Joint European Centre for Control and Prevention (ECDC)-WHO Regional Office for Europe Hepatitis of Unknown Origin in Children Surveillance Bulletin out of 279 cases with available information, 31.2% of patients were shifted to an Intensive Care Unit (ICU), and 8.4% received a liver transplant.³⁵ Diagnosis can be made by laboratory tests and imaging examinations such as abdominal ultrasound, or magnetic resonance imaging (MRI).³⁹ Although treatment solely focuses on supportive care, it is subjective to further complications including acute liver failure or hepatic encephalopathy which may ultimately necessitate liver transplantation.³⁹ Even though WHO currently has limited access to epidemiological, etiological, analytical, histopathological, and clinical data, certain preventive measures like maintaining hand hygiene, avoiding crowded areas, ensuring good ventilation, wearing masks, using clean water for drinking, regular disinfecting of surfaces, and safe food handling can be followed to limit spread.^36,38

Measles

Measles is caused by a single-stranded, enveloped RNA virus which is a member of the genus Morbillivirus in the Paramyxoviridae family.^40,41 It is a highly contagious virus that spreads via direct contact and through air droplets.^40,41 The incubation period of measles ranges from 10 to 14 days.⁴² The virus first infects the respiratory tract and then spreads throughout the body to various tissues such as lymphoid tissues, gastrointestinal tract and skin.^40,43 Direct infection and thus depletion of memory immune cells leads to measles-associated immune suppression.⁴³ In 2019, measles infected about 870 000 people globally, with 208 000 deaths reported.⁴² Most of the deaths are reported in children less than 5 years of age.⁴² Measles is endemic in the developing areas of Africa and Asia and the number of cases have decreased by 73% during the time-period from 2000 to 2018, as a result of vaccination. Strict implication of preventative techniques and vaccination is the mainstay to decrease disease burden in these regions Public awarness on first appearance of symptoms can also lead to early presentation and effective management.⁴⁰

The first symptom to appear is usually high-grade fever followed by a runny nose, cough, red and watery eyes, and small white spots inside the cheeks known as koplik’s spots.^40-42 Around 3 to 5 days after the onset of symptoms, a maculopapular rash occurs which starts from the head and then spreads throughout the body.^41,42 Fever due to measles lasts around 4 to 7 days, and the rash disappears after 5 to 6 days.⁴⁰ Complications of measles include diarrhea (8%), otitis media (7%), pneumonia (6%), encephalitis, premature birth, low birth weight, and death.^40,41 Complications are common in children less than 5 years of age, adults greater than 20 years of age, pregnant females, immunocompromised individuals, and those with vitamin A deficiency.⁴¹ One rare, but fatal, complication of measles is “subacute sclerosing panencephalitis” (SSPE) which is a degenerative disease of the central nervous system (CNS), and it leads to behavioral and intellectual deterioration and seizures that usually develop about 7 to 10 years after measles infection.⁴¹ Patients are at high risk of spreading the disease from 4 days before to 4 days after the rash appears.^40,41 Diagnosis of measles is mostly based on clinical manifestations and patient’s history but it can be confirmed by laboratory blood and tissue tests (from a throat or nose swab).⁴⁴ There is no specific antiviral treatment for measles, and it is managed by supportive care for example, good nutrition, adequate hydration, and vitamin A supplementation to prevent blindness and reduce mortality.^40,41 Antibiotics are prescribed only if a person has signs and symptoms of infection. Measles can be prevented by vaccination which contains 2 doses of MMR vaccine given at 12 months and 4 to 5 years of age in the developed world and 6 and 9 months of age in the developing world.^40,41 By 2018, it was shown that due to routine vaccination deaths due to measles went down by a huge margin (73%).⁴⁰

Dengue

Dengue is caused by the virus known as Dengue Virus (DENV) that are of 4 subtypes (DENV-1, DENV-2, DENV-3 and DENV-4), transmitted through the bite of an infected female Aedes species (A. aegypti and A. albopictus) and via human-to-mosquito transmission (mosquito becoming infected by biting an individual viremic with DENV).^45-47 DENV sub-neutralizes antibodies, a mechanism known as antibody-dependent enhancement (ADE). ADE enhances the membrane fusion efficiency of DENV virions into monocytes, macrophages and dendritic cells. This initiates an intrinsic ADE-mediated cascade in the target cells, leading to enhanced DENV production and infection.⁴⁷ According to the WHO, this virus is more prevalent in tropical and sub-tropical areas and has spread to almost all the regions of the WHO over the years.⁴⁵ Furthermore, the CDC reported that over half the population of the world (around 4 billion people) lives in areas with the risk of dengue.⁴⁶ The disease is usually mild but in some cases it can be severe and prove fatal; it presents with mortality rates of 2%−5% which is comparatively lower than that of MPX.^45,48,49 Further reports by the WHO state that dengue is endemic in more than 100 countries in the WHO regions of America, South-East Asia, Asia and many more.^45,46,48 It is of grave importance to clear breeding sites of mosquitoes along with spreading awarness among the population regarding prevention techniques, when to get tested, and avaliable treatment options.⁴⁵

The majority of dengue cases range from asymptomatic, or mild to severe disease.^45,48,50 It clinically presents with flu-like symptoms that may appear 4 to 10 days after the bite of the infected mosquito.⁴⁵ As per the reports by the WHO, the National Health Service (NHS), and the CDC, dengue is divided into 2 groups: dengue with or without symptoms (present in 1 out of 4 patients of Dengue) and severe dengue (presents in 1 out of 20 patients of Dengue).^45,48,50 As reported by the WHO and CDC, dengue should be recognized if presented with more than 2 clinical findings in a febrile person.^45,50 The signs and symptoms that are likely to be found in an infected dengue patient that is similar to MPX include severe headache, fever, nausea, vomiting, muscle aches, back pain, and rash; moreover, additional clinical findings that are present in severe dengue are pain behind the eyes, abdominal pain, loss of appetite, liver enlargement, plasma leakage, severe bleeding, rapid breathing, mucosal bleeding, fatigue, and restlessness.^45,48,50,51 Although several factors like urbanization, population density, water storage practices, lack of awareness and climate change seem to increase the risk of dengue infection, the WHO suggests some measures that include prevention of mosquito breeding by cleaning and covering of domestic water storage containers, use of larvicides in water bodies, personal protection by using screen, repellents, vaporizers and coil, spreading awareness, and establishment of strong surveillance programs that can help combat the disease.^45,48 Several diagnostic methods such as reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme linked immunosorbent assays (ELISA) have proved efficient in its diagnosis.⁴⁵ As for now, there is no specific treatment, however, according to the WHO a new vaccine CYD-TDV has proven effective in individuals who have had the dengue infection before.⁴⁵ A new tetravalent live attenuated vaccine, TAK-003, is undergoing clinical trials with promising results, and may be approved for use in future.⁵²

Figure 1.

Comparing the common presenting signs and symptoms of SARS-CoV-2, and Measles with MPX virus.

Table 1.

The Mode of Transmission, Clinical Manifestations, Diagnosis and Treatment/Prevention of all the Viral Outbreaks Discussed Above is Summarized.

Viral Outbreaks	Mode of Transmission	Clinical Manifestations	Diagnosis	Treatment/Prevention
MPX	Direct contact with animals, like rodents, squirrels, rats, monkeys etc., by the means of bodily fluids, blood, aerosols, and infected lesions. Human to human transmission is also possible via respiratory droplets.	• Fever • Chills • Exhaustion • Myalgia & backache • Swollen lymph nodes • Rashes on feet, hands, chest, genitals, anus, oral mucosa, or conjunctiva	Polymerase Chain Reaction (PCR).	No specific treatment. Antivirals (Tecovirimat, Cidofovir, and Brincidofovir) and Vaccinia vaccine can be used. Smallpox vaccine has also been proven helpful.
SARS-CoV-2	Respiratory droplets or by touching contaminated surfaces.	• Fever • Cough, sore throat, sputum secretion • Dyspnea, chest pain • Loss of taste and/or smell • Fatigue, malaise, headache, myalgia • Anorexia	PCR of nasal swabs samples.	Wide-spectrum antibiotics to prevent co-infection and corticosteroids have shown positive results. Main preventative strategy is social distancing and use of face masks.
Acute Hepatitis of Unknown Origin	Main cause is adenovirus which is spread via respiratory droplets.	• Jaundice • Vomiting • Diarrhea, light-colored stools, abdominal pain • Lethargy • Fever • Respiratory symptoms	Laboratory tests and imaging examinations such as abdominal ultrasound or magnetic resonance imaging (MRI).	Supportive care. Liver transplant in acute liver failure or hepatic encephalopathy.
Measles	Direct contact and through air droplets	• High-grade fever followed by a runny nose • Cough • Red and watery eyes • Koplik’s spots • Maculopapular rash (starts from the head and spreads throughout the body)	Diagnosis is based on clinical manifestations and history. Laboratory blood and tissue tests can be used to confirm.	Supportive care. Prevention is via vaccination.
Dengue	Vector transmission via infected female Aedes species (A. aegypti and A. albopictus)	Flu-like symptoms • Headache • Fever • Nausea, vomiting, abdominal pain, loss of appetite • Myalgia, backache • Rash • Severe bleeding (from mucosal sites) • Fatigue, restlessness, tachypnea • Pain behind eyes	Reverse transcriptase-polymerase chain reaction (RT-PCR), ELISA.	Supportive care. CYD-TDV vaccine has proven effective in individuals who have had the dengue infection before.

Discussion

MPX was identified and endemic in West and Central Africa, before it gained attention due to its spread to the high income, non-endemic countries. The emergence of above-mentioned outbreaks in developing countries and persistence of some such as dengue and measles in these regions shows that these populations might be more vulnerable and may contribute to a higher disease burden.⁵³ The middle- and low-income countries suffer most from emerging outbreaks like MPX due to several factors. Developing countries lack proper healthcare facilities, trained professionals, and have high poverty and illiteracy rates which makes it difficult for them to manage, control and prevent these outbreaks.⁵³ A high proportion of the population lives in slums and overcrowded areas where most of these outbreaks emerge from.⁵³

In a meta-analysis published by Benites-Zapata et al in August 2022, among 1958 patients from African and European countries the most common clinical manifestations were rash (93%), fever (72%), pruritus (65%), and lymphadenopathy (62%). In addition, fatigue (60%), sore throat (57%), headache (50%), cough (47%), myalgias (45%), photophobia (32%), arthralgia (26%), difficulty breathing (25%), conjunctivitis (19%), nausea/vomiting (19%) and diarrhea (4%) were also reported.⁵⁴ Even though the frequency of a rash was higher in African patients (100%) than in European patients (22%), the distribution of the rash in the groin or pelvic area was noted to be significantly higher in Europeans (75%) than in Africans (30%).⁵⁴ This associates the 2022 outbreak with a possibility of sexual transmission. For effective management of the disease, early diagnosis is of prime importance. With rash (93%) and fever (72%) being the 2 most common symptoms, differential diagnoses of MPX have broadened to include Varicella Zoster virus, Herpes simplex virus, measles, dengue, and especially sexually transmitted diseases like syphilis which consequently increases the risk of misdiagnosis. To improve the diagnosis, not only genitals but recently oral cavity is also called to be checked for lesions by dental surgeons.⁵⁴

The common presenting signs such as fever, headache, myalgia, fatigue, nausea, vomiting, abdominal pain, diarrhea, and back pain are shared by almost all the recent outbreaks mentioned above (Figure-1, Table-1). The similarity of clinical manifestations among these outbreaks can potentially result in misdiagnosis, which may lead to the progression of the disease beyond treatment. In a study conducted by Ogoina et al during the 2017 outbreak of MPXV in Nigeria, twenty-one false cases including cases of chickenpox, mosquito bites, molluscum contagiosum, impetigo, facial acne, tinea corporis, psoriasis, scabies, and petechial rash in a patient with a bleeding disorder were reported in Niger Delta University Teaching Hospital.⁵⁵ Other symptoms like groin lesion and penile rash were also reported as the first presenting symptom in the MPX cases recorded in the UK and Israel.⁵⁶ In addition, in the cases reported in Europe, the UK, and North America, the transmission is not associated with a travel history from an endemic region and shows the prevalence in MSM groups (males having sex with males) suggesting that more cases would be diagnosed at STI clinics and some communities might be more susceptible than others.⁵⁷

Despite the recent increase in MPX cases, it has little potential to become a pandemic due to several reasons. Unlike the SARS-CoV-2, MPX virus has a low mutation rate, the smallpox vaccine is available for prophylactic use in high populations and it is transmissible only after the appearance of symptoms and requires close contact, therefore, it has a low transmission rate.^12,14 According to WHO it is highly likely that MPX cases will spread to other non-endemic countries,¹² which will have serious effects on the third-world countries, unlike the European region where the spread can be controlled due to better healthcare infrastructure, government and policymakers’ involvement, better diagnostic techniques, and identification of cases transmitted from sexual contact.

As MPX cannot be clinically distinguished from other pox-like viruses and diseases with similar clinical manifestations like syphilis and varicella, efficient rapid diagnostic techniques are required to control the outbreak. Electron microscopy, immunohistochemistry, and serological testing for specific antibodies, including ELISA are techniques used for laboratory testing. RT-PCR assay is used as a method of choice for routine diagnosis. Sequencing of the whole genome is the gold standard for the characterization of Orthopoxviruses but is not used frequently, especially in developing countries as it is expensive and uses advanced technology. CDC uses non-Variola Orthopoxvirus testing, an RT-PCR primer, and a probe set assay to detect non-Variola Orthopoxviruses. FDA also recommends collecting swab samples from the lesions as blood and saliva may give false results.⁵⁸

The use of artificial intelligence (AI) through various methods for the diagnosis of MPX is discussed in a systematic review conducted by Chadaga et al. Although still a topic of further research, this automated diagnostic technique can eliminate misdiagnosis, reduce the time between PCR testing and beginning of treatment, and can be used in developing countries where there is a lack of medical facilities.⁵⁹

Although mass vaccination is not recommended, pre-exposure and post-exposure vaccination in high risk individuals prevents and reduces the severity of disease respectively. Only second and third generation vaccines can be used for this purpose.⁴ The third generation, modified vaccinia Ankara (MVA) vaccine, is preferred over the second generation ACAM2000 as it doesn’t have any adverse side effects and can also be used in immunocompromised individuals. Unfortunately, the vaccine supply is only limited to high income countries like North America and Europe. The mainstay treatment for MPX is supportive but 3 antivirals tecovirimat, cidofovir and brincidofovir originally approved for the treatment of smallpox are now also used for monkeypox.⁴ According to a systematic review by Chaudhari et al tecovirimat is the first line treatment option for patients of HIV-monkeypox coinfection.⁶⁰

In a meta-analysis by Dahanani et al across 170 000 Americans, less than two-thirds of adults were willing to accept the COVID-19 vaccine. Among these, the most common subgroups were women, Black and Hispanic Americans, youngsters, people from lower educational backgrounds, people with lower incomes, people living in rural areas, and Republicans.⁶¹ In another meta-analysis conducted by O Bhattacharya et al regarding COVID-19 vaccine hesitancy among pregnant women, data was collected from 24 147 participants from 4 continents across the globe. Vaccine acceptance prevalence in pregnant women across the globe was 49% with the lowest in the Americas and Europe (45%) compared with Africa (61%) and Asia (52%). These figures indicate the same patterns can be followed with the smallpox vaccine.⁶² It should also be noted that, as mass vaccination is not the recommended, vaccine hesitancy should only have limited effect on the control of this disease.

Such viral outbreaks have also shown to have effects on the mental health of individuals and the community as a whole. In a systematic review and meta-analysis by Rogers et al, it has been found that the SARS epidemic in Hong Kong led to an increase in suicide rates in the elderly; on the other hand, in Japan there was no change in suicides among youngsters amidst the COVID-19 pandemic.⁵³ In another review conducted by Samji et al, a significant mental health impact of the COVID-19 pandemic was found among children and the youth.⁶³ Therefore, rising MPX cases may have an impact on mental health due to the stigma attributed to the disease, isolation, and long hospital stays.

Challenges

The world recently saw COVID-19 pandemic, which brought many challenges for the concerned government bodies as well as the healthcare sectors. The rise in the number of monkeypox cases in non-endemic areas highlights the need to be ready for any foreseen challenges.

Early and correct diagnosis is essential for the control of infection, which is hindered by incidences of misdiagnosis, as well as variations in clinical presentation of the disease in different regions of the world.^55,64 Another pandemic in the form of monkeypox may lead to serious effects on the third-world countries, which lack the governing expertise, the funds, a proper reporting and monitoring system, proper healthcare facilities, trained HCWs, the basic diagnostic tools and adequate laboratory services to handle any outbreak.^12,19,53 The direct health care costs account for most of the expenses incurred in a viral pandemic, which majorly include expenses of hospital resource use, GP visits, utensils or devices, pharmaceutical costs, and costs of quarantine.⁶⁵ Regional cultural differences, social stigma, rumors and fears are major reasons of non-compliance to seeking medical treatment and seeking vaccination.⁶⁶ The HCWs in low-income countries lack the required knowledge and confidence to determine the clinical features indicating poor prognosis and thus effective treatment.⁶⁷ The HCWs also lack the necessary precautions and equipment for their own safety during an outbreak. There were significant impacts on mental health of patients, HCWs, and the whole community itself during the COVID-19 pandemic, and such problems can be a challenge in any outbreak.⁶⁸ The policy of early detection, early reporting, early isolation/quarantine, and early treatment used in China had been effective to control the COVID-19 infection.⁶⁹ The majority of world’s population lags far behind to implement such policies in response to an outbreak.

Recommendations

According to the recent guidelines by the WHO issued on 15th June 2022, it has been advised to carry out enhanced surveillance by providing better tests and lab facilities for rapid identification of MPXV in order to prevent its spread.²¹ Avoiding close contact with infected individuals, restriction on trade of wild animals and avoiding consumption of their meat will prove to be beneficial in containing the spread. It is also imperative to provide better safety precautions for HCWs.^19,21,70

Action by the global authorities, investment commitments, action plans and evidence-based guidelines is essential to combat the disease in developing countries.¹⁹ The surveillance programs like CDC Poxvirus and Rabies Branch in collaboration with DRC, Ministry of Health (MOH), and Kinshasa School of Public Health (KSPH), have helped to enhance the surveillance of MPXV.⁷⁰ Moreover, the laboratory testing done at Institute National de Biorecherche (INRB), which is also assisting other African countries for the diagnosis of MPXV, has provided supplemental information about the disease that can assist in providing rapid and better response in a state of public health concern.⁷⁰

According to a recent multi-country MPX outbreak, MSM groups are majorly affected. As these cases are more likely to be identified in sexual health clinics, awareness among clinicians in these facilities is critical. Suspected cases should be immediately reported to public health authorities so that isolation, laboratory testing and contact tracing can be initiated.⁷¹

Immunization and vaccination guidelines by WHO should be strictly followed.⁷² At this point in time uncertainty regarding the disease, especially its spread in non-endemic regions is high. Government authorities should act against the spread of rumors and to communicate authentic information to the public. Stigma and discrimination against specific communities should also be countered.

Financial support from funding programs, like the Biden-Harris Administration, is necessary to control the spread of the outbreaks. Recently, it has announced funding for its national MPX vaccine strategy, to ensure the availability of MPX vaccines to affected areas and to make testing easier for HCWs and infected individuals.⁷³ Strengthening international health regulations and global security actions against this MPX outbreak, precise and immediate clinical management, and vaccine research collaboration is an urgent necessity.¹⁹

Future Perspectives

During the current crisis, the lessons learned so far from the previous outbreaks, especially COVID-19, can lead to better future responses both in the short term and long term, on how to deal with the emerging viral outbreaks more effectively.⁷⁴ The past outbreaks have resulted in a much better surveillance network, rapid development of biologicals and funding to combat the outbreak.⁷⁵ Moreover, establishment of some organizations like the US Department of Health and Human Services, the office of the Assistant Secretary for Preparedness and Response formed in 2007, that help by supporting and purchasing medical countermeasures for pandemic threats.⁷⁵ Furthermore, various other organizations are built to raise the funds for advanced preparation of vaccines and the WHO has also formed a Department of Pandemic and Epidemic Diseases in 2011 that works for better outbreak intervention.⁷⁵ During the current MPX outbreak, enhanced control strategies, future research and studies focusing on the multiple aspects of the disease system can help in better public health response in the upcoming years.⁷⁶ With the current treatment options available for MPXV, there is still a need to assess their efficacy, hence, the National Institute of Health (NIH) is now developing a US-based RCT to determine a safer and effective treatment preference.⁷⁷ The upsurge of the viral outbreaks over the past few decades has caused a great turmoil and thus there is an urgent need for precise biosecurity, biosafety protocols, better understanding of the interactions of pathogen-host environment, monitoring molecular evolution, and genomic surveillance to promote the work of scientists all around the globe to control the outbreaks more easily in future.⁷⁸ Despite the imposed threat from the ongoing outbreaks, the technological tools available and additional systematic efforts can develop an effective intervention strategy before the next major event in the future.⁷⁵

Strengths and Limitations

This detailed narrative review can be a one-stop solution for obtaining information regarding different viral diseases from the past 3 decades in one place. Data is collected by screening multiple articles from verified sources, hence the data collected is authentic and reliable. The article contains updated information on all the recent viral outbreaks. Moreover, this article also compares MPXV to various viral diseases in terms of their clinical manifestations, signs, and symptoms which can help in reaching better diagnoses. Lastly, it can also help in establishing a better understanding of its spread, treatment, and prevention.

However, our article is not free of limitations. As the topic is very diverse hence encompassing all the relevant information is challenging. Moreover, the recent re-emergence of MPXV has led to fewer available studies, hence the literature is limited due to which the information added is not very detailed. Furthermore, its spread to other non-endemic regions, the changing epidemiology, lack of understanding of its zoonosis, and lack of evidence on its new transmission route(s), make it strenuous to compare the clinical manifestations of MPXV to other viral diseases. Our paper focuses on viral outbreaks which includes only 2 recent outbreaks that are ongoing. The sole aim of this article is to compare the clinical manifestations of MPXV with other viral outbreaks on the basis of recent information available, thus it is difficult to make an exact comparison. Lastly, no detailed data screening was done while selecting the articles during literature search. The search was simply based on the key terms that we used; thus, our study may have selection bias.

Conclusion

A recent rise in the cases of MPXV amidst ongoing COVID-19 has caused disarray and raised concerns about the impact of this outbreak and the possible harm it can have on one’s health. Although the symptoms of MPX seem alarming, overall, the virus is less severe and has low mortality compared to other diseases that present with similar symptoms as MPX. The disease has a short course with fewer complications and is self-resolving requiring supportive care only. However, more data needs to be collected and studied from areas with high incidence to better evaluate the course of this disease in order to come up with more promising advances that will assure safety and prevent the further spread of the disease.

Footnotes

Author’s Contributions

All authors equally contributed.

All authors contributed to the writing, interpretation, revision and approved the final draft of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics and Informed Consent Statement

Our study did not require an ethical board approval because it is a narrative review.

Ethical Consideration

The paper doesn’t require ethical consideration as it is a narrative review

ORCID iD

Mohammad Yasir Essar

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