Monkeypox in 2022: A New Outbreak of an Old Disease

Jeannette Guarner, MD


Am J Clin Pathol. 2022;158(2):160-161. 

For over 50 years, monkeypox was considered a disease that was endemic in Central and West Africa. Rare cases presented outside the continent in persons who had traveled to endemic areas, with very rare secondary transmission to health care providers.[1] Since 2017, Nigeria has experienced an outbreak of monkeypox, with over 500 cases that have occurred primarily in young men that have lesions in the genital area.[2] The current 2022 multicountry outbreak of monkeypox has affected over 2,500 patients in more than 37 countries, with most not having traveled to Central or West Africa. The countries with most cases are England, Spain, and Germany. In the US, over 110 cases have been reported in 21 states, with most cases in California and New York. In comparison to the US multistate 2003 monkeypox outbreak linked to importation of African rodents that were brought as pets,[3] the 2022 multicountry outbreak has been observed in men who have sex with men.

The monkeypox virus belongs to the Poxviridae family, which includes the benign molluscum contagiosum and the dreaded smallpox. These are large, enveloped, double-stranded DNA viruses that have a boxcar or oval characteristic shape that can be observed when using electron microscopy to study either cultures or tissues.[4] Due to successful world vaccination campaigns that ended in the 1970s, the World Health Organization (WHO) declared the eradication of smallpox in May 1980. Smallpox caused many deaths worldwide, reaching a mortality of 60%, and was easily transmitted by aerosols and human-to-human contact. The introduction of smallpox to the American continent by Europeans decimated the native populations, making the conquest of the New World possible. Thus, smallpox is considered a bioterrorism category A agent. As smallpox disappeared worldwide, it became evident that there was another poxvirus that presented with very similar but milder clinical characteristics, and in 1970 in the Democratic Republic of Congo the first human case of monkeypox was reported. The name monkeypox is derived from the initial isolation of the virus in monkeys, though the virus also circulates in rodents. There are 2 clades of monkeypox: the West African monkeypox clade appears to cause a milder disease, while the Congo Basin/Central African clade causes a more severe disease, as the virus from this clade suppresses the inflammatory response.

Monkeypox virus is transmitted by direct contact with a patient's lesions or fomites (towels, bed linen, etc) that have been in contact with the lesions. The incubation period spans from 5 to 21 days. The disease starts with a prodrome of fever, malaise, body aches, headache, and other nonspecific symptoms. Initially, there is a maculopapular rash that progresses to umbilicated vesicles and pustules. In time, the vesicular rash ulcerates and crusts. The lesions appear in crops, mostly at the same stage and apparently at the entry site, but can be disseminated. The rash is accompanied by lymphadenopathy. The disease is self-limited, with the lesions lasting between 14 and 28 days. Eye infections, pneumonia, encephalitis, and death are complications that occur mostly in pregnant women, the immunosuppressed, and children less than 8 years of age. Mortality is quoted at 10%, though this percent is likely a reflection of access to health care in locations where the disease occurs endemically.

Clinically, other infectious agents can have similar presentations, thus the need to test these patients for a variety of diseases. During this current multicountry outbreak, herpesvirus infections and sexually transmitted diseases are at the top of the differential diagnosis. For the diagnosis of monkeypox, 2 swabs from different lesions (vesicle, pustule, or ulcer) should be obtained by vigorous swabbing and placed in a dry sterile container to be sent to a state public health laboratory (more information can be obtained from the state public health laboratory or the Centers for Disease Control and Prevention [CDC] website, which may change over time and depending on state).[5] The specimens should be stored refrigerated or frozen if not tested within 1 hour. Within the US, while the patient is under investigation (PUI), the packaging to send the sample to the referral laboratory is considered category B. Most state public health laboratories will first perform an Orthopoxvirus screening polymerase chain reaction (PCR) test that, if positive, is sent to the CDC for sequencing to define the monkeypox clade. Of interest, although not approved for use in the US, several of the PCR instruments that are currently being used for diagnosis of SARS-CoV-2 have cassettes that target monkeyox.[6] As the current outbreak evolves, and based on the number of cases seen in a particular location, it may be necessary for hospital laboratories to validate these platforms. Although molecular testing is the method of choice for diagnosis of monkeypox, other methods that can be used include serology, electron microscopy, and culture.

For other testing that may be required to take care of the patient (eg, CBC counts, chemistry panels, HIV, syphilis), it is indispensable that laboratory personnel use adequate precautions such as personal protective equipment, including masks and goggles, or a biosafety hood in case aerosols are produced during centrifugation, decapping of tubes, or testing (eg, performing a rapid plasma reagin test). However, it should be noted that there are no studies defining when monkeypox viremia occurs or the amount of virus in blood and other body fluids, which, if known, would be very useful to determine potential risks when handling specimens in the laboratory.

Because our laboratory has handled several specimens from PUIs for monkeypox, we performed a risk assessment in the core laboratory, which determined that our automation lines (those lines that centrifuge and decap specimens when needed) mitigate potential exposure to personnel for the great majority of tests ordered. Although there were questions regarding disposal of discarded material, it was determined that instruments use minimal sample for testing, which gets diluted during the testing process, thus remnants can be disposed of with other hospital waste. The only thing we are being asked to do is to keep the spent PUI samples in a safe, restricted location until the state public health laboratory and CDC testing are finalized. If the patient is infected with the Congo Basin/Central African clade, the laboratory may be asked to dispose of the sequestered samples as category A agents. Patients in the current outbreak have been infected with the West African clade, allowing laboratories to dispose of samples as usual (category B).

Obtaining biopsies may be necessary for diagnosis of other infections, though it is not recommended for monkeypox diagnosis. Histopathologic descriptions of monkeypox human skin lesions are few and include a small number of cases.[7,8] To be expected, the pathology changes based on the stage of the lesion: in the vesicular stage the epidermis shows spongiosis, acanthosis, and an inflammatory infiltrate composed of neutrophils and lymphocytes. The dermis shows edema and a band-like infiltrate of neutrophils, lymphocytes, and occasional eosinophils. In the dermoepidermal junction there are necrotic keratinocytes and rare multinucleated giant cells. In pustules, the epidermis shows abundant necrotic keratinocytes that contain intracytoplasmic eosinophilic inclusions (Guarnieri-like inclusions), necrotic debris, frequent multinucleated cells, and an abundant inflammatory infiltrate of neutrophils, lymphocytes, and eosinophils. The presence of the poxvirus in the epidermis can be highlighted by using immunohistochemistry.

Due to the infectivity of monkeypox, prevention can be challenging. Avoiding contact with lesions is necessary, thus health care workers taking care of patients should use personal protective equipment (gowns, gloves, masks, and goggles). Patients with lesions should quarantine. Smallpox vaccine can provide up to 85% protection and can be given after exposure.[9] Two licensed vaccines are available in the US Strategic National Stockpile. Treatment is mostly symptomatic, though for patients with severe disease or those at risk of complications, vaccinia immune globulin, brincidofovir, or tecovirimat can be used.[10] Use of these treatments is under an Expanded Access-Investigational New Drug (EA-IND) protocol that the CDC currently holds, so consultation with the CDC is necessary for possible treatment with antivirals.