What Do Hospitalists Need to Know About Monkeypox?

What is monkeypox? Monkeypox is a rare infection caused by the monkeypox virus. Monkeypox virus belongs to the Orthopoxvirus genus in the family Poxviridae. The Orthopoxvirus genus also includes variola virus (which causes smallpox), vaccinia virus (used in the smallpox vaccine), and cowpox virus.¹ It was first isolated in 1958 and identified as causing human disease in 1970. This pathogen was endemic in central and western African countries up until recently. Between 2018 to May 2022, about nine cases of monkeypox were confirmed in a few non-endemic countries.²

There are two strains of monkeypox:

• West African monkeypox is associated with milder disease, fewer deaths (4%), and limited human-to-human transmission
• Central African monkeypox virus clade is typically more severe, has a higher mortality rate (11 %), and higher person-to-person spread³

As of June 13, 2022, 1,678 cases have been confirmed in 35 countries with 470 cases in the U.K., 200+ cases in Spain and Portugal, and 100+ cases in Germany and Canada.

In the U.S., we have 65 confirmed cases in 18 states and the District of Columbia. California has recorded 15 cases followed by New York with 11 confirmed cases.¹ U.S. Map and Case Count.

Remarkably, during this outbreak, the majority (but not all) of the cases are among men who identify as gay, bisexual, or men who have sex with men.² In the U.S., these patients were between 23 to 76 years old, with a median age of 38 years old (which is what is being seen in other countries).⁴

Why are we seeing it now? According to the World Health Organization (WHO), about 40 years ago, around 80% of the population was vaccinated against smallpox and now that number is nearer to 30%. Termination of this routine smallpox vaccination has resulted in the populations becoming more vulnerable to monkeypox. People who were vaccinated against smallpox in childhood may have some cross-protection against monkeypox.³

What is the case definition by the Centers for Disease Control and Prevention for monkeypox?¹

• Suspect case
  • New characteristic rash* OR
  • Meets one of the epidemiologic criteria and has a high clinical suspicion† for monkeypox
• Probable case
  • No suspicion of other recent Orthopoxvirus exposure (e.g., Vaccinia virus in ACAM2000 vaccination) AND demonstration of the presence of Orthopoxvirus DNA by a polymerase chain reaction of a clinical specimen OR
  • Orthopoxvirus using immunohistochemical or electron microscopy testing methods OR
  • Demonstration of detectable levels of anti-Orthopoxvirus IgM antibody during the period of four to 56 days after rash onset
• Confirmed case
  • Demonstration of the presence of Monkeypox virus DNA by polymerase chain reaction testing or Next-Generation sequencing of a clinical specimen OR
  • Isolation of Monkeypox virus in culture from a clinical specimen

Epidemiologic criteria

Within 21 days of illness onset:

• Reports having contact with a person or people with a similar-appearing rash or who received a diagnosis of confirmed or probable monkeypox OR
• Had close or intimate in-person contact with individuals in a social network experiencing monkeypox activity, this includes men who have sex with men (MSM) who meet partners through an online website, digital application (“app”), or social event (e.g., a bar or party) OR
• Traveled outside the U.S. to a country with confirmed cases of monkeypox or where monkeypox virus is endemic OR
• Had contact with a dead or live wild animal or exotic pet that is an African endemic species or used a product derived from such animals (e.g., game meat, creams, lotions, powders, etc.)

Exclusion criteria for monkeypox¹

• An alternative diagnosis can fully explain the illness OR
• An individual with symptoms consistent with monkeypox but who does not develop a rash within five days of illness onset OR
• A case where specimens do not demonstrate the presence of Orthopoxvirus or monkeypox virus or antibodies to Orthopoxvirus

How does it spread?^1,5 Primary infection is from the animal-to-human (zoonotic virus) transmission can occur either through hunting or through contact with an infected animal (bite or scratch) or contaminated animal products. Secondary infection is from the human-to-human transmission and can occur either through contact with infected people or from mother to fetus.

Modes of transmission

• Close skin-to-skin contact with:
  • respiratory droplets, through kissing and other face-to-face contacts
  • lesion material, rash, sores, or scabs
  • body fluids
  • contaminated materials and surfaces (clothing, bedding, towels, surfaces) that have been used by someone with monkeypox)
• The virus can enter through:
  • respiratory tract
  • mucous membranes (eyes and mouth)
  • broken skin (e.g., animal bites)

At this time, it is not known if monkeypox can spread through semen or vaginal fluids. Hence, in the typical sense, monkeypox is not a sexually transmitted infection.

Paradoxically, monkeypox is not spread by monkeys.³ African rodents are suspected to play a part in monkeypox transmission to humans. However, we don’t yet know what animal maintains the virus.⁶ The WHO is considering renaming the virus to avoid the stigma associated with this infection.

What are the risk factors for contracting monkeypox during the current outbreak?

• Reported contact with a person who has a similar rash or received a diagnosis of confirmed or suspected monkeypox; and
• Traveled (within 21 days) to an area where monkeypox cases or exposures have been reported
• Persons self-identifying as men who have sex with men (MSM)

What are the signs and symptoms?^1,5 The symptoms of monkeypox are similar yet milder than the symptoms of smallpox, however, the presence of lymphadenopathy differentiates it from smallpox disease.

They are usually divided into four phases:

1. Incubation periods range from five to 21 days with no symptoms, but viremia might begin before the febrile stage.
2. Febrile stage or flu-like illness can range from one to four days and the patient begins to have fever malaise, lymphadenopathy, headache, chills, sore throat, and fatigue. The virus can be identified in the blood at this stage. Patients may also begin to show small lesions in the mouth (enanthem).
3. After one to three days of the febrile stage, the patient develops a rash that often begins on the face and eventually spreads to other parts of the body. This rash stage can last from two to four weeks, where the lesions evolve and progress through four stages—macular, papular, vesicular, to pustular—before scabbing over and resolving. The virus is present in the skin lesions and antibodies become detectable in this stage. Lesions are typically of similar size and become umbilicated. A person is contagious from the onset of the enanthem through the scab stage.
4. The illness typically lasts for two to four weeks, and recovery can take days to weeks. Patients will continue to have antibodies and the pitted scars and/or areas of lighter or darker skin may remain. The patient is no longer contagious after all scabs have fallen off. Lesions are often described as painful until the healing phase when they become itchy (crusts).

What are the key characteristic features of monkeypox prior to this outbreak?⁵

• Lesions are well-circumscribed, deep-seated, and often develop umbilication (resembles a dot on the top of the lesion)
• Lesions are relatively the same size and same stage of development on a single site of the body (ex: pustules on the face or vesicles on the legs)
• Fever before rash ​
• Lymphadenopathy common ​
• The disseminated rash is centrifugal (more lesions on extremities, face) ​
• Lesions on palms, soles​

Images of monkeypox rashes from the CDC.

What are the atypical features of monkeypox in the current outbreak?⁴

• Co-infections with sexually transmitted infections
• Mild or absent prodromal phase or prodromal phase occurring after the rash development
• Absence of fever and/or lymphadenopathy
• Presentation with a rash or an anthem only
• Lesions may be at different phases of development on the same side or opposite sides of the body
• The lesions can either be diffuse all over the body or limited to one body site or one mucosal area
• The patient may present only with rectal pain or tenesmus without any visible rash However, a physical exam may reveal lesion(s) in the genital and/or perianal areas
• The size of lesions may be smaller (unlike the 2003 outbreak in the U.S., where the cases had bigger lesions)
• The rash phase is shorter i.e., lesions go through the stages much faster

How does the disease progress?⁵ The course of illness depends on a person’s overall health status, the route of exposure, and the strain of the infecting virus (West African versus Central African virus genetic groups, or clades). Previous vaccination with smallpox appears to be a protective factor.

What are the risk factors for severe illness?^1,5

• People with severe disease (e.g., hemorrhagic disease, confluent lesions, sepsis, encephalitis, or other conditions requiring hospitalization)
• People who may be at high risk of severe disease:
  • Immunocompromised individuals (e.g., human immunodeficiency virus/acquired immune deficiency syndrome infection, leukemia, lymphoma, generalized malignancy, solid organ transplantation, therapy with alkylating agents, antimetabolites, radiation, tumor necrosis factor inhibitors, high-dose corticosteroids, being a recipient with hematopoietic stem cell transplant <24 months post-transplant or ≥24 months but with graft-versus-host disease or disease relapse, or having an autoimmune disease with immunodeficiency as a clinical component)
  • Pediatric populations, particularly patients younger than 8 years of age
  • Pregnant or breastfeeding women
  • People with a history or presence of atopic dermatitis, people with other active exfoliative skin conditions (e.g., eczema, burns, impetigo, varicella zoster virus infection, herpes simplex virus infection, severe acne, severe diaper dermatitis with extensive areas of denuded skin, psoriasis, or Darier disease [keratosis follicularis])
  • People with one or more complications (e.g., secondary bacterial skin infection; gastroenteritis with severe nausea/vomiting, diarrhea, or dehydration; bronchopneumonia; concurrent disease or other comorbidities)
• Invasive route of infection
• Congo Basin clade variant (mortality about 10%)

What are the complications and danger signs of monkeypox?⁵

• Complications and long-term sequelae
  • Bacterial infection of the eyes (4%) or skin (20%)
  • Diarrhea and vomiting leading to dehydration (7%)
  • Abscess with airway obstruction
  • Bronchopneumonia
  • Encephalitis (<1%), sepsis (<1%)
  • Pockmarks, scarring, or loss of pigmentation
  • Corneal ulcers and blindness
• Complications of pregnancy
  • Bleeding, miscarriage, or stillbirth
• Danger signs
  • Loss of vision
  • Delirium, loss of consciousness, convulsions
  • Respiratory distress
  • Bleeding, inability to produce urine
  • Signs of sepsis

In Africa, monkeypox has been shown to cause death in as many as one in 10 persons who contract the disease. However, this may be different in western countries with sophisticated health care facilities and resources.

What are the differential diagnoses?^2,4

• Genital Ulcer Disease:
  • Infectious: Herpes simplex virus (HSV), syphilis (primary [chancre] and secondary [condyloma lata]), chancroid, lymphogranuloma venereum [LGV], granuloma inguinale
  • Non-infectious: recurrent aphthous stomatitis, Behcet’s Disease, trauma, squamous cell carcinoma, drug-induced, etc.
• Diffuse Rash: Varicella-zoster virus, molluscum contagiosum (umbilication of rash), disseminated cryptococcal infections (umbilication of rash), disseminated herpes, syphilis, other pox viruses, disseminated gonococcal infection
• Proctitis: Gonorrhea, chlamydia (including LGV), HSV

How do we confirm the diagnosis? The best diagnostic specimens are directly from the rash—skin, fluid, or crusts, or biopsy where feasible. Antigen and antibody detection methods may not be useful as they do not distinguish between Orthopoxviruses. The CDC has advised a two-step process for testing specimens.

1. Test to be done by the state labs that are part of the Laboratory Response Network to perform OPX (Orthopoxvirus) generic test which confirms the presence of OPX DNA from rash lesions.
2. Test ID the confirmatory testing by real-time PCR (only available at the CDC) to confirm the monkeypox case.²

For this outbreak, given the anticipated delay in getting the confirmation test results, any case showing positive OPX test results is considered monkeypox for time being.⁴ Please reach out to your local health department for guidance concerning the collection of samples and processing.

Who needs treatment and how do we treat monkeypox?^1,2 While many patients have a mild, self-limiting disease course in the absence of specific therapy, the overall prognosis depends on multiple factors such as previous vaccination status, initial health status, concurrent illnesses, and comorbidities.

People who should be considered for treatment following consultation with the CDC might include:

• People with severe disease and people who may be at high risk of severe disease. (Please refer to risk factors).
• People with unusual monkeypox virus infections include its accidental implantation in the eyes, mouth, or other anatomical areas where monkeypox virus infection might constitute a special hazard (e.g., the genitals or anus).

As of now, there is no precise treatment approved for monkeypox virus infections.

Essentials of patient care include:⁵

• Fever and pain management
• Skin, eye, and mouth care
• Respiratory care
• Hydration and nutritional support
• Mental health support
• Prevention and treatment of complications
• Infection prevention and control

Medical countermeasures are currently available from the Strategic National Stockpile (SNS) as options for the treatment of monkeypox include:^1,2

• Tecovirimat (also known as TPOXX), is available as a pill or an injection. It is an antiviral medication that has been approved for the treatment of smallpox in adults and children.
• Vaccinia Immune Globulin Intravenous (VIGIV) is used for the treatment of complications due to vaccinia vaccination.
• Cidofovir (also known as Vistide) is an antiviral medication used for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
• Brincidofovir (also known as Tembexa) is an antiviral medication that is being used for the treatment of human smallpox disease in adult and pediatric patients, including neonates. Brincidofovir is not currently available from the SNS.

Vaccine administration after exposure can prevent or reduce the severity of the disease. Limited amounts of two vaccines are available in the U.S. for adults:

• ACAM2000 is a live vaccinia virus vaccine and is indicated for active immunization against smallpox disease for persons determined to be at high risk for smallpox infection.
• JYNNEOS (also known as IMVAMUNE, IMVANEX, MVA) is a live vaccine produced from the strain Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), an attenuated, nonreplicating Orthopoxvirus. It is indicated for the prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection.

Past data from Africa suggests that the smallpox vaccine (JYNNEOS) is at least 85% effective in preventing monkeypox.⁶ 

*Both ACAM2000 and Dryvax are derived from the New York City Board of Health strain of vaccinia; ACAM2000 is a “second generation” smallpox vaccine derived from a clone of Dryvax, purified, and produced using modern cell culture technology.²

Revaccination after exposure¹ Persons exposed to the monkeypox virus and who have not received the smallpox vaccine within the last three years should consider getting vaccinated. The sooner the person receives the vaccine, the more effective it will be in protecting against the monkeypox virus.

What are the prophylaxis measures for monkeypox?^1,2

Pre-exposure prophylaxis

Vaccination for selected persons at risk for occupational exposure to Orthopoxviruses has been suggested based on shared clinical decision-making, these include:

• Research laboratory personnel
• Clinical laboratory personnel performing diagnostic testing for Orthopoxviruses
• Designated response team members at risk for occupational exposure to Orthopoxviruses
• Health care personnel who administer ACAM2000
• Care for patients infected with replication competent Orthopoxviruses

Post-exposure prophylaxis

Prolonged close interaction with a symptomatic individual can lead to transmission of monkeypox. Short-term interactions and those conducted using appropriate PPE following standard precautions are not high risk and generally do not warrant post-exposure prophylaxis.

Receiving vaccine after exposure to monkeypox virus

• The sooner an exposed person gets the vaccine, the better.
• To prevent the onset of the disease, the CDC recommends that the vaccine be given within four days from the date of exposure. If given between four and 14 days after the date of exposure, vaccination may reduce the symptoms of the disease, but may not prevent the disease.

How can we prevent/control monkeypox in a health care setting? What are the CDC infection prevention recommendations for hospitalized patients?¹

• Isolate infected patients from others who could be at risk for infection. Isolation precautions should be maintained until all lesions have crusted, those crusts have separated, and a fresh layer of healthy skin has formed underneath.
• Intubation and extubation, and any procedures likely to spread oral secretions, should be performed in an airborne infection isolation room.
• Activities that could resuspend dried material from lesions, e.g., use of portable fans, dry dusting, sweeping, or vacuuming should be avoided
• Health care setting requires standard precautions like using gloves, NIOSH-approved particulate respirator equipped with N95 filters or higher, eye protection, and other personal protective clothing and equipment while taking care of the sick, whether in a health facility or the home is required.
• Practice good hand hygiene after contact with infected animals or humans by washing your hands with soap and water or using an alcohol-based hand sanitizer.
• Decisions regarding the discontinuation of isolation precautions in a healthcare facility should be made in consultation with the local or state health department.

What do clinicians need to know about the monkeypox outbreak?

The focus now is on identifying all cases and mange accordingly as the disease has the potential to cause significant morbidity and mortality in high-risk individuals. So, the physicians are required to know:

• That most patients are expected to be presenting in outpatient settings
• The atypical presentations of monkeypox in the current outbreak
• Maintain a high index of suspicion and a low- threshold for testing suspected lesions
• The close clinical mimics
• Most infections in this outbreak so far are self-limited, and most patients make a full recovery
• That monkeypox can occur in anyone
• Case definitions from the CDC
• Contact tracing
• Exposure risk assessment
• Guidance for monitoring exposed persons
• Infection control
• Specimen collection
• Treatment considerations

References:

1. https://www.cdc.gov/poxvirus/monkeypox/about.html
2. Webinar May 24, 2022 – What Clinicians Need to Know about Monkeypox in the United States and Other Countries https://emergency.cdc.gov/coca/calls/2022/callinfo_052422.asp
3. Harris E. What to Know About Monkeypox. JAMA. Published online May 27, 2022. doi:10.1001/jama.2022.9499
4. https://www.idsociety.org/multimedia/all-videos/monkeypox-in-the-u.s.-an-update/
5. Monkeypox: Epidemiology, preparedness and response for African outbreak contexts https://openwho.org/courses/monkeypox-intermediate
6. https://www.who.int/news-room/fact-sheets/detail/monkeypox