Monkeypox and its pandemic potential: what the anaesthetist should know

Editor—Monkeypox is a viral zoonosis endemic to certain parts of Africa. As with other diseases caused by pox viruses, its principal manifestations are fever and skin lesions. However, a minor portion of patients may develop severe disease with multisystemic involvement, often proving fatal. Monkeypox has recently gained international interest and concern as a result of a sudden outbreak of cases detected outside its endemic zone. The monkeypox virus is an enveloped double-stranded DNA virus of the Poxviridae family and is closely related to the smallpox (variola) virus. The first human case of monkeypox was identified in 1970 in the Democratic Republic of the Congo.¹ Since then, there have been multiple outbreaks, mostly affecting African countries. Gradually, cases were reported from countries outside Africa as well and it became a disease of public health importance. The World Health Organisation (WHO) has recently confirmed an atypical outbreak of monkeypox from multiple non-endemic countries with increasing numbers of cases everyday.² This raises the potential that anaesthetists will again be called into action in leading frontline care to critically ill patients with potentially lethal infectious disease as occurred with COVID-19.3, 4, 5

The word ‘monkeypox’ is a misnomer. Although first detected in monkeys transported for research purposes from Africa to Denmark, it was later found in almost 14 species of African rodents including Gambian giant pouched rats, squirrels, and dormice. The natural host reservoir of monkeypox is still not known.⁶ The chief mode of transmission is animal-to-human from direct contact with infected animals and by handling their raw meat. Human-to-human transmission is possible via respiratory droplets, sexual intercourse, contact with body fluids including saliva, and transplacental transfer from mother to the baby. Monkeypox is classified as a High Consequence Infectious Disease (HCID) in the UK.⁷ Two different strains of monkeypox have been described, namely Central African (or Congo basin) and West African, of which the Central African variety has a higher case fatality rate of ∼10% compared with ∼3% for the West African clade.^{8 , 9}

The current resurgence includes 780 confirmed cases in 27 non-endemic countries between May 13 and June 2, 2022, surpassing earlier outbreaks.² Reasons for this surprisingly high rate of spread in comparison to previous recorded outbreaks are unknown. Whether the virus has mutated to enhance human transmission is a question that needs further research. A significant number of monkeypox cases were identified from sexually transmitted infection clinics among men who have sex with men, presenting with a peri-anal or genital rash.² This raises the possibility that monkeypox may be exploiting specific social groups via sexual transmission. This preliminary observation, however, needs validation, and should in no way lead to social stigma or homophobia.

Another alarming observation is that many of the recent confirmed monkeypox cases did not have a history of travel to the endemic areas in Africa, or history of contact.^{2 , 6} It points towards the possibility of unidentified human-to-human transmission of the infection that has been going on for some time. Genome sequencing has revealed that the predominant strain in the current outbreak is the less virulent West African variety.¹⁰ Being a rare disease confined to a fairly remote and underdeveloped region of the world, monkeypox has failed to gain the attention of anaesthesiologists until now. As a result, there is a paucity of available literature from the perspective of anaesthesiologists and critical care physicians in suspecting, identifying, and dealing with the disease. We have reviewed the existing literature to explore the perioperative concerns of the disease and to outline necessary preparedness measures.

Identifying the early signs and symptoms of the disease is vital in preventing occupational exposure and spread. The usual incubation period of monkeypox is 6–13 days. Initial non-specific symptoms include fever, headache, myalgia, body ache, and chills. Prominent cervical and axillary lymphadenopathy is a characteristic feature of the initial viral invasion period and distinguishes monkeypox from smallpox. Centrifugal rashes start appearing in 1–3 days of the fever and progress through macules, papules, vesicles, pustules, and scabs. The lesions can be distributed over the face, scalp, trunk, limbs, palms and soles (including nail beds), and anogenital areas.² Patients may have painful oral sores, conjunctivitis, eyelid oedema, pharyngitis, deep abscesses, painful subungual lesions, and ulcerated inguinal lymph nodes. Corneal involvement may result in permanent opacities. Patients often develop neuropsychiatric manifestations including emotional lability and depression. The illness usually resolves in 2–4 weeks but often leaves significant scarring that can be both disfiguring and debilitating.8, 9, 10, 11

Diagnosis involves isolation of viral DNA in body fluid samples or samples collected from the lesions using polymerase chain reaction. Samples used for detection include blood, urine, fluid swab from active lesions, and upper respiratory tract swabs.¹¹ During the 2003 monkeypox outbreak in the USA, electron microscopy, immunohistochemistry, culture of samples from lesions, and serological testing for specific antibodies were other modalities used. Chickenpox, smallpox, measles, scabies, syphilis, and allergic skin reactions are the common differential diagnoses of monkeypox.¹² Raised total leukocyte counts, elevated liver enzymes, low blood urea nitrogen level and low albumin levels are non-specific findings in blood tests.¹³

The search for a vaccine with an acceptable safety profile for monkeypox in endemic areas still continues.¹⁴ Theoretically, because of the genetic similarity between the smallpox virus and the monkeypox virus, smallpox vaccine may offer some degree of protection against monkeypox. Personnel coming in close contact with monkeypox patients and those investigating monkeypox outbreaks are being inoculated with smallpox vaccine in a few countries.² The risk of antibody-dependent enhancement of the disease after vaccination, which promotes viral recognition, entry, and replication in target cells, has been a matter of debate.¹⁵ Other potentially life-threatening side-effects include myocarditis and angina. Modified vaccinia Ankara–Bavarian Nordic (MVA-BN®, Bavarian Nordic A/S, Hellerup, Denmark), an attenuated poxvirus vaccine, was approved in 2019 by the US Food and Drug Administration for prevention of smallpox and monkeypox amongst healthcare workers and veterinarians at high risk of exposure.⁸

A few compounds have shown promising results against orthopoxvirus species, however their efficacy in the treatment of human monkeypox infection is largely unknown (Table 1 ). A recently published case series describes the disease course and management of seven patients who were treated for monkeypox in the UK in HCID units.¹¹ Three of the seven patients in this series received brincidofovir and one received tecovirimat, while the remaining three did not receive any antiviral therapy. All seven patients recovered completely. In an elaborate review, Reynolds and colleagues¹⁷ discuss aspects of the treatment of monkeypox and its complications. An interdisciplinary approach is needed for management of the multiple potential complications of monkeypox infection (Table 2 ). Compared with adults, paediatric patients suffer from more severe disease and higher mortality. Challenges for managing them are unique and warrant a careful multidisciplinary approach. Safety and dosing of the different antiviral agents are still not confirmed for paediatric patients.¹¹

Table 1.

Drugs used for treatment of human monkeypox and their perioperative implications.

Drug	Dosage and duration of treatment	Response to treatment	Mechanism of action	Side-effects and perioperative concerns
Brincidofovir11	200 mg orally once a week for 3 weeks 100 mg tablets and oral suspension available No patient has completed treatment yet	Transient reduction of upper respiratory tract viral load after second dose	DNA polymerase inhibitor	Newer drug prepared as a lipid conjugate of cidofovir Authorised by US FDA in June 2021 for adults and paediatric patients (including neonates) Yet to be approved in EU Lesser side-effects, particularly lacks nephrotoxicity Elevated liver enzymes
Tecovirimat16	200–600 mg twice daily orally for 2 weeks US FDA recently approved i.v. formulation	Not completely clear Early treatment (<6 days within exposure) improves survival in animal studies	Inhibition of intracellular virus release by targeting membrane protein VP37	Approved from January 2022 for use in exceptional situations in EU Most side-effects are mild (headache, nausea, abdominal pain) and non-lethal No organ toxicity reported No cross-reaction or antagonism with brincidofovir suits dual therapy

EU, European Union; US FDA, United States Food and Drug Administration.

Table 2.

Organ system specific concerns and management options in monkeypox infection.

Affected system	Concerns	Management modalities
Respiratory system	Prevention of infection and atelectasis Maintain airway patency	Deep breathing exercises Chest physiotherapy Bronchodilators, appropriate antibiotics Suctioning of secretions Close monitoring of respiratory functions Noninvasive and invasive ventilation as per clinical decision
Gastrointestinal system	Minimise fluid losses from diarrhoea, vomiting Analgesia to improve food intake and promote healing for oral and throat sores	Antiemetics, appropriate anti-diarrhoea drugs Oral, topical analgesics, adequate hydration and nutrition
Skin	Risk of secondary bacterial infection Insensible fluid loss	Antibiotics as required Wound care Incision and drainage of abscess
Eyes	Corneal scarring Vision loss	Antibiotics/antivirals, steroids, tear substitutes, after consulting with ophthalmologist Document visual acuity preoperatively
Central nervous system	Encephalitis Seizures Fever Headache	Admission to intensive care unit Provide high-quality care accordingly

MVA-BN® can also be considered for post-exposure prophylaxis in selected patients, ideally within 4 days of high-grade exposure.¹⁸ As live vaccines are contraindicated in immunocompromised patients, vaccinia immunoglobulin may be considered, although data on its effectiveness are unclear.¹⁹

WHO has defined severe disease as having more than 100 skin lesions and very severe disease as having more than 250 skin lesions.²⁰ Such patients are unable to perform their daily activities and require nursing help. They are also at high risk of systemic complications and death. Little is known about the potential systemic effects of monkeypox. Animal studies with inoculated monkeypox virus show pulmonary changes on positron emission tomography scan similar to severe acute respiratory distress syndrome, including multifocal patchy consolidation and ground glass opacities.²¹ The exact incidence of pulmonary involvement is unknown. Organ biopsies have confirmed the presence of monkeypox virus in deep organs including liver, spleen, kidneys, and the gonads. Elevated liver enzymes and low blood urea nitrogen levels frequently observed in cases of monkeypox infection may be manifestations of hepatic dysfunction. Thus, severe cases may potentially result in acute liver failure. As with other pox viruses, monkeypox may show neurotropism leading to encephalitis, and secondary immune-mediated neurological insults such as Guillain–Barré syndrome and acute disseminated encephalomyelitis.¹³ Extensive skin lesions and lymphadenopathy may lead to deep abscesses and secondary bacterial infection including sepsis.^{8 , 11} Similar to other viral infections, multisystem involvement may be more severe in immunocompromised patients. Infection during pregnancy may be especially dangerous because of altered immune status, and transplacental transmission may lead to birth defects and fetal loss.²²

In anticipation of a potential monkeypox outbreak, hospitals need to have a strategic plan in place for effective containment and management of the infection. The UK Health Security Agency has recently declared monkeypox a notifiable disease.²³ Experience gained during the COVID-19 pandemic should provide valuable insights in planning the safe and effective care of patients with monkeypox. Depending on the case load, adequate logistics and isolation facilities should be ensured, with the provision for rapidly ramping up capacity if needed. Since the outbreak is still in a very nascent stage, strict quarantine and isolation protocols are of paramount importance. Suspected patients should be kept in negative air pressure isolation rooms, or, if such a facility is unavailable, private rooms. Contacts of confirmed cases should self-isolate for a period of 21 days since last exposure. Hand hygiene and appropriate waste disposal should always be followed in taking care of patients with monkeypox. Personal protective equipment (PPE) including a waterproof surgical gown, plastic apron, plastic visor, filtering face piece 3 respirator (FFP3), rubber boots, hood, and three pairs of latex gloves are recommended. Supervised donning-doffing protocols are suggested.¹¹ However, experience drawn from the COVID-19 pandemic suggests that such stringent PPE protocols may not be cost-effective as the infectivity of monkeypox still appears to be low. Ongoing research should inform regarding selective use of PPE in specific high-risk situations. Until then, local experience and institution-specific protocols should guide use of PPE. An effective testing strategy has yet to be formulated. Finally, public education about the disease and its prevention is critical.

The ‘safe’ time period for delaying an elective surgery in cured patients is unclear. All patients scheduled for surgery should be screened for early signs of the disease. Patients with any degree of suspicion should then proceed for testing. Blanket screening of all surgical patients is not warranted at the moment because of the low prevalence. Testing strategy may need to be altered depending on the epidemiological kinetics of the disease. Based on our knowledge of chickenpox, elective surgery should be deferred until all skin lesion crusts have fallen off. This typically takes about 3 weeks from onset. After recovery from the disease, fitness for surgery should be evaluated on a case-by-case basis, including assessment of possible systemic complications. For a person who has come in close contact with a confirmed case of monkeypox, elective surgery should be deferred by at least 2 weeks to account for the subclinical course of the disease.

Anaesthetic precautions must start from the point of first contact with the patient, which includes preanaesthetic assessment. All patients, whether symptomatic or not, should be considered potentially infectious. Preventing droplet and aerosol exposure during airway examination and manipulation is of utmost importance. If feasible, preoperative assessment may be done via remote means such as videoconference. Bag-mask ventilation and airway procedures are the time of greatest exposure risk for anaesthetists. Universal use of circuit microbial filters, eye protection, and FFP3 respirator masks should be mandatory during such situations. Videolaryngoscopy may help avoid the need for close proximity of the anaesthetist's face to the patient during tracheal intubation. More extensive precautions, including full body PPE, should be taken while dealing with patients having suspected or confirmed active monkeypox infection undergoing emergency surgery. Proper disinfection of anaesthetic equipment must be ensured. Wherever feasible, disposable equipment, including linen and drapes, should be used.

In summary, monkeypox, a viral zoonosis mainly limited to parts of Africa, is now rapidly emerging as a global public health concern. Strain mutations may be responsible for its rapid spread outside endemic zones. Transmission of monkeypox is probably through droplets or direct contact with body fluids. Vaccines are under development and may provide some protection. Antivirals are being studied and may reduce disease severity. Monkeypox has the potential to unfold as a global pandemic and health infrastructure preparedness is warranted. Anaesthetists and intensivists, because of the nature of their clinical duties, are at high risk of exposure to infection, particularly given its potential for respiratory transmission, and therefore need to be vigilant and take adequate precautions. The disfiguring, debilitating, and potentially deadly consequences of the disease, and the lack of proved medical therapy, means that prevention rather than cure takes precedence.

Declarations of interest

The authors declare that they have no conflicts of interest.