# 90 - 201 Monkeypox, Molluscum Contagiosum, and Other Poxvirus Infections

### 201 Monkeypox, Molluscum Contagiosum, and Other Poxvirus Infections

Primary HHV-8 infection in immunocompetent children may 
manifest as fever and maculopapular rash. Among individuals with 
intact immunity, chronic asymptomatic infection is the rule, and neo­
plastic disorders generally develop only after subsequent immunocom­
promise. Immunocompromised persons with primary infection may 
present with fever, splenomegaly, lymphoid hyperplasia, pancytopenia, 
or rapid-onset KS. Quantitative analysis of HHV-8 DNA suggests a 
predominance of latently infected cells in KS lesions and frequent 
lytic replication in multicentric Castleman disease. The KS-associated 
herpesvirus inflammatory cytokine syndrome (KICS)—consisting of 
fever, lymphadenopathy, hepatosplenomegaly, cytopenias, and high 
levels of HHV-8, human and viral interleukin 6, and human interleukin 
10—has been described in some HIV-infected patients and is associ­
ated with a high mortality rate.
Effective antiretroviral therapy for HIV-infected individuals has led 
to a marked reduction in rates of KS among persons dually infected 
with HHV-8 and HIV in resource-rich areas. HHV-8 itself is suscep­
tible in vitro to ganciclovir, foscarnet, and cidofovir. A small, random­
ized, double-blind, placebo-controlled, crossover trial suggested that 
oral valganciclovir administered once daily reduced HHV-8 replica­
tion. However, clinical benefits of valganciclovir or other drugs in 
HHV-8 infection have not yet been demonstrated. Sirolimus inhibits 
the progression of dermal KS in kidney transplant recipients while 
providing effective immunosuppression. Rituximab alone or in combi­
nation with chemotherapy can lead to a survival of >90% at 5 years in 
HHV-8–associated multicentric Castleman disease.
■
■FURTHER READING
Cytomegalovirus
Avery RK et al: Maribavir for refractory cytomegalovirus infections 
with or without resistance post-transplant: Results from a Phase 3 
randomized clinical trial. Clin Infect Dis 75:690, 2022.
Chatzakis C et al: The effect of valacyclovir on secondary prevention 
of congenital cytomegalovirus infection, following primary maternal 
infection acquired periconceptionally or in the first trimester of 
pregnancy. An individual data meta-analysis. Am J Obstet Gynecol 
230:109, 2024.
Das R et al: Safety, efficacy, and immunogenicity of a replicationdeficient human cytomegalovirus vaccine, V160, in cytomegalovirusseronegative women: a double-blind, randomized, placebo-controlled, 
phase 2b trial. Lancet Infect Dis 23:1383, 2023.
Drutman SB et al: Fatal cytomegalovirus infection in an adult with 
inherited NOS2 deficiency. N Engl J Med 382:437, 2020.
Fang M et al: High cytomegalovirus viral load is associated with 182day all-cause mortality in hospitalized people with human immuno­
deficiency virus. Clin Infect Dis 76:1266, 2023.
Hughes BL et al: A trial of hyperimmune globulin to prevent congeni­
tal cytomegalovirus infection. N Engl J Med 385:436, 2021.
Kotton CN et al: The Third International Consensus Guidelines on 
the management of cytomegalovirus in solid-organ transplantation. 
Transplantation 102:900, 2018.
Limaye AP et al: Letermovir vs valganciclovir for prophylaxis of cyto­
megalovirus in high-risk kidney transplant recipients: A randomized 
clinical trial. JAMA 330:33, 2023.
Ssentongo P et al: Congenital cytomegalovirus infection burden and 
epidemiologic risk factors in countries with universal screening: A 
systematic review and meta-analysis. JAMA Netw Open 4:e2120736, 
2021.
Human Herpesvirus (HHV) Types 6, 7, and 8
Gabrielli L et al: Inherited chromosomally integrated human herpes­
virus 6: Laboratory and clinical features. Microrganisms 11:548, 2023.
Gaccioli F et al: Fetal inheritance of chromosomally integrated 
human herpesvirus 6 predisposes the mother to pre-eclampsia. Nat 
Microbiol 5:901, 2020.
Kampouri E et al: Human herpesvirus-6 reactivation and disease after 
allogeneic haematopoietic cell transplantation in the era of letermovir 
for cytomegalovirus prophylaxis. Clin Microbiol Infect 29:1450.e1, 
2023. 

Knights SM et al: High seroprevalence of Kaposi sarcoma–associated 

herpesvirus in men with HIV in the southern United States. Open 
Forum Infect Dis 10:ofad160, 2023.
Miura H et al: Inherited chromosomally integrated human herpesvi­
rus 6 is a risk factor for spontaneous abortion. J Infect Dis 223:1717, 
2021.
Pellett Madan R et al: Human herpesvirus 6, 7, and 8 in solid organ 
transplantation: Guidelines from the American Society of Transplan­
tation Infectious Diseases Community of Practice. Clin Transplant 
33:e13518, 2019.
Faisal Syed Minhaj, Christina L. Hutson

Monkeypox, Molluscum 

Contagiosum, and Other 
Poxvirus Infections
POXVIRUSES
CHAPTER 201
■
■DEFINITION AND ETIOLOGY
Poxviruses (Poxviridae) are a family of double-stranded DNA viruses 
whose genomic structure is generally conserved across subfamilies, 
genera, and species. The central portion of the genome, which can 
range up to 200 kb, encodes the open reading frames (ORFs) required 
for replication or packaging of virions. The left and right ends of 
the genome encode genes with predicted functions in immune eva­
sion, host interaction, or unknown roles. The complement of ORFs 
across different genera is largely responsible for differences in disease 
manifestations and/or virus host range. Four genera of poxviruses 
(Orthopoxvirus, Parapoxvirus, Yatapoxvirus, and Molluscipoxvirus) 
include species that can infect humans. Additionally, a currently 
unclassified poxvirus has been reported to cause human illness. 
Table 201-1 identifies these viruses, the majority of which are zoonotic, 
and lists some of their epidemiologic characteristics.
Monkeypox, Molluscum Contagiosum, and Other Poxvirus Infections 
■
■EPIDEMIOLOGY
Most poxviruses that infect humans are spread through direct contact; 
notable exceptions are some species of Orthopoxvirus (i.e., variola 
and monkeypox viruses [MPXV]). Variola virus (the virus that causes 
smallpox) is transmitted primarily by close contact and via respira­
tory secretions. In what seems to have been a rare circumstance near 
the end of global efforts to eradicate smallpox, it was reported that 
variola virus appeared to transmit via aerosol in a German hospital in 
Meschede. The degree to which potential aerosols had a role in small­
pox transmission remains debated.
There are two geographically, genetically, and clinically distinct 
clades of MPXV. Clade I (formally Congo Basin clade) is endemic to 
Central Africa (Democratic Republic of the Congo, Republic of the 
Congo, Central African Republic, Cameroon, Gabon). Clade II (for­
mally West African clade) is endemic to West Africa (Nigeria, Liberia, 
Sierra Leone, Cameroon, Cote d’Ivoire). Clade I MPXV causes a higher 
proportion of individuals with severe disease than Clade II, which is 
further subdivided into clade IIa, found endemically in West Africa, 
and clade IIb, which spread worldwide in 2022, with low levels of virus 
circulation continuing to date. In endemic areas, MPXV infections 
historically clustered around rural villages and within households with 
significant wildlife exposure. Spread to humans is primarily through 
direct contact (e.g., handling during food preparation) with infected 
animals leading to percutaneous or permucosal exposure. Human-tohuman spread historically was primarily via close skin-to-skin contact;

TABLE 201-1  Poxviruses Causing Infection in Humans
GENUS, SPECIES
GEOGRAPHY
ZOONOTIC CHARACTERISTICS
Orthopoxvirus
Variola (smallpox)
Eradicated, formerly 
worldwide
Solely a human pathogen
Monkeypox
Historically endemic 
to West and Central 
Africa, but spread 
worldwide in 2022
Squirrel species, Gambian rats, and 
dormice implicated as potential 
reservoir species; other species 
effective in transmitting disease to 
humans (pet North American prairie 
dogs, non-human primates); can be 
acquired during hunting/preparation 
of African wildlife for nutritional 
protein source
Cowpox
Europe
Rodents as reservoir; outbreaks 
associated with rodent pet trade; cats 
also effective transmitters of illness; 
previously, dairy cow teat lesions 
linked to human cutaneous lesions
Vaccinia and 
vaccinia-like 
viruses (e.g., 
buffalopox, 
Cantagalo, 
Araçatuba)
Europe, India, and 
South America
Rodents suspected as a potential 
reservoir; localized lesions on cattle 
or other ruminants (e.g., water buffalo 
for buffalopox) responsible for most 
human infections
Borealpox 
(formally known 
as Alaskapox)
United States 
(Alaska)
Northern red-backed voles, 
squirrels, and shrews suspected as 
potential reservoir species; potential 
transmission to humans suspected 
from contact of above species or 
pets (e.g., cats, dogs) who were 
infected
PART 5
Infectious Diseases
Akhmeta
Georgia (country)
Woodmice (Apodemus spp.); cows 
can be infected and possibly transmit 
to humans.
Molluscipoxvirus
Molluscum 
contagiosum
Worldwide
Thought to be solely a human 
pathogen; closely related viruses 
described in other mammals
Parapoxvirus
Orf
Worldwide
Handling of infected sheep and goats 
primarily responsible for transmission 
to humans
Pseudocowpox
Worldwide
Handling of infected dairy cattle
Bovine papular 
stomatitis
Worldwide
Handling of infected beef cattle
Deerpox
U.S. deer herds
Handling of infected deer
Sealpox
Seal/pinniped 
colonies worldwide
Handling of infected pinnipeds
Yatapoxvirus
Tanapox
Africa
Possible nonhuman primate reservoir; 
potential arthropod mediator
Unclassified poxvirus
NY-014a
United States (New 
York State)
Unknown
aPossibly an orthopoxvirus.
however, spread via respiratory secretions also was believed to occur. 
After decades without detection of MPXV infections, Nigeria expe­
rienced a rapid increase in mpox cases in 2017. As routine smallpox 
vaccination (which provides cross-protection for mpox) ended in 
1980, it is unclear what role waning orthopoxvirus immunity played 
in its reemergence. These cases in Nigeria were unusual in that they 
occurred in urban centers in persons without known animal con­
tact. In 2021, eight travel-associated mpox cases in persons who flew 
from Nigeria were identified in four countries (United States, United 
Kingdom, Israel, and Singapore), with limited subsequent human-tohuman transmission. In 2022, clade IIb mpox spread globally, with 

transmission occurring primarily via close, intimate (e.g., sexual) 
contact and predominantly affecting gay, bisexual, and other men who 
have sex with men (MSM). MSM, particularly Black and Hispanic 
MSM in the United States, remain disproportionately affected by mpox 
to date. Additionally, up to 50% of those diagnosed with mpox in this 
outbreak are also living with HIV.
Other orthopoxviruses (apart from variola virus) (Table 201-1) are 
thought to spread only via direct contact or percutaneous/permucosal 
exposures to infected animals (or humans). The orthopoxvirus infec­
tions caused by cowpox and the vaccinia-like viruses are typically 
acquired initially through contact with an infected animal. Humanto-human transmission can also occur via contact with the lesion(s) of 
the infected human. In Europe, human cowpox infections have been 
associated with the pet rat trade, and vaccinia-like viruses (e.g., Belo 
Horizonte, Cantagalo, Araçatuba) are reported in handlers of dairy 
cattle in South America. Similarly, buffalopox has been reported in 
inhabitants of the Indian subcontinent exposed to infectious lesions 
on water buffalo. In the United States, vaccinia, the virus historically 
known as the substrate for smallpox vaccine, has caused infections in 
laboratory workers studying the virus. With all orthopoxvirus infec­
tions, the illness is considered infectious from symptom onset until all 
lesions have crusted, the crust(s) have separated from the skin, and a 
fresh layer of healthy skin has formed underneath.
The most common poxvirus encountered in practice is molluscum 
contagiosum virus (MCV), which is a molluscipoxvirus. MCV likely 
spreads through direct contact with and percutaneous exposure to 
another infected human. Like variola virus (an orthopoxvirus), MCV 
is considered to be a pathogen of humans only. Infections are com­
monly seen in pediatrics where transmission occurs through play 
activities. In adults, the disease can manifest similarly, but genital 
involvement also is noted as transmission often occurs through 
sexual exposure.
The epidemiology of tanapox (a yatapoxvirus) is poorly under­
stood. Simian reservoirs and the potential for an arthropod vector are 
hypothesized. Rare cases of tanapox have only been seen in the United 
States from travelers returning from West or Central Africa. Human 
infections with parapoxviruses occur through direct contact with and 
percutaneous exposure to lesions developing at the site of contact with 
an infected animal.
■
■PATHOGENESIS
The pathogenesis of orthopoxvirus infections is thought to involve sys­
temic spread of disease from the site of virus inoculation to local lymph 
nodes, lymphoreticular tissue seeding, and finally the development of 
symptomatic (febrile) viremia and viral skin tropism. Disease severity 
is affected by the degree to which the innate immune and interferon 
responses control the initial stages of infection. During illness, patients 
may experience lymphadenopathy, fever, pain, and malaise. In immu­
nocompromised persons more severe systemic manifestations are 
seen. Cases exemplifying this were seen throughout the global mpox 
outbreak in 2022. Individuals with intact immune systems develop 
lesions (often at the exposure site) about 1 week after exposure; these 
lesions progress through specified stages over the next 7–14 days, fol­
lowed by scabbing and complete resolution by 14–21 days after rash 
onset. Lesion scabs contain viable virus, and it is only once all lesions 
scab over, the scabs separate from the skin, and newly formed intact 
skin forms that the infectious period ends. In contrast, persons with 
severe immunocompromised states (e.g., advanced HIV [i.e., CD4 
T cell count <200 cells/mm3], organ transplantation) can develop 
severe mpox. In these instances, the spread or growth of MPXV goes 
unchecked, and systemic spread of disease results in wide dissemina­
tion of the rash, with large confluent lesions persisting for months and 
additional organ involvement.
Other poxvirus infections—with the possible exception of yatapox­
virus infection, in which disease pathogenesis is poorly understood—
likely involve only local growth of the virus at the site of inoculation or 
reinoculation. In some immunocompromised hosts, the lesions caused 
by Parapoxvirus infections can become quite large; such lesions are 
referred to as “giant orf.”

■
■CLINICAL MANIFESTATIONS
Systemic poxvirus infections (i.e., Variola Virus, Monkeypox Virus 
[Orthopoxvirus genome] and Tanapox [Yatapoxvirus genome])
Following exposure, both smallpox and mpox have a similar incuba­
tion period of up to 17 days. Classically, smallpox and mpox present as 
follows: the first clinical sign is fever, which is followed by rash onset 
days later. Other prodromal symptoms include malaise, sore throat, 
and headache. When lymphadenopathy was present during this stage 
and throughout illness, it was a key differentiating factor between 
smallpox (absent) and mpox (present) in endemic countries. The rash 
evolves through classic macular, papular, vesicular, and pustular phases 
(the last with central umbilication), with each stage lasting 2–3 days 
and lesions in the same anatomic location typically in the same stage 
of development. Diffuse, well-circumscribed, centrifugally distributed 
(i.e., lesions more prominent on the face and extremities, including 
palms and soles, than on the trunk) lesions are classic. Lesions are typi­
cally painful as they emerge and subsequently become pruritic during 
later stages. However, during the emergence of clade IIb mpox in 2022, 
several clinical manifestations differed from this classic presentation.
During the clade IIb outbreak, patients often presented with rash as 
their first sign or symptom of disease or concurrently or in the absence 
of prodromal symptoms; lesions were frequently localized, primarily 
in the anogenital region (Fig. 201-1). The lesions themselves were 
smaller, fewer in number (often <10), and often in different stages at 
the same anatomic site. There does not appear to be an increase in 
disease severity in those without severe immunocompromise (i.e., HIV 
with CD4 T cell count >200 cells/mL). However, a minority of patients 
have developed severe manifestations of mpox, many of whom who are 
severely immunocompromised (e.g., advanced HIV, organ transplanta­
tion, comparable severe immunocompromise).
Severe Mpox 
Rare severe manifestations of mpox include ocular 
infection, neurologic complications, myopericarditis, and uncontrolled 
viral replication in severely immunocompromised patients. Mpoxrelated ocular disease can occur via autoinoculation (i.e., touching a 
lesion then the eye) or local spread from a nearby lesion. Symptoms 
include eye pain, redness, vision changes or loss, or periorbital swell­
ing. Ocular disease can manifest as blepharitis, conjunctivitis, con­
junctival lesions, keratitis, and vision loss. Neurologic complications 
include rare reports of encephalitis and myelitis. Patients may have 
severe headache, neck pain, altered mentation, or focal deficits. Myo­
pericarditis has been reported in some patients with mpox, including 
complaints of shortness of breath or palpitations with elevations in car­
diac biomarkers and electrocardiographic changes. Mucosal complica­
tions can affect alimentation, urination, or defecation due to painful 
or obstructive lesions. These can lead to strictures, edema, and severe 
lymphadenopathy. Complications from uncontrolled viral replication 
commonly occur in severely immunocompromised persons such as 
those with advanced HIV or organ transplantation. These patients 
often develop numerous large, coalescing, or necrotic lesions and can 
have other organ involvement including the gastrointestinal tract, liver, 
lungs, and brain, which can manifest as organ dysfunction. These 
patients may have disease lasting many months in which immune 
system optimization is crucial to recovery. Most deaths have occurred 
in the United States, predominantly among people with advanced HIV 
with CD4 <50 cells/mm3.
Tanapox 
Patients infected with tanapox virus initially present with 
a very high fever, are often thought to have malaria (given the endemic 
location), and later develop 1–10 nodular lesions. These nodules are 
often in anatomic areas not typically covered by clothing. Lesions are 
seldom filled with fluid and more often contain necrotic tissue. The 
lesion size peaks around 2 weeks after initial formation, and lesions 
typically disappear spontaneously within 6 weeks.
Other Orthopoxvirus Infections 
Other orthopoxvirus infec­
tions are more localized in their presentation, with lesions likely devel­
oping directly at the site of contact with the virus. Akhmeta, Borealpox 
(formally known as Alaskapox), vaccinia, vaccinia-like, and cowpox 
virus infections are typically associated with a localized rash or lesion 

evolving through classical papular, vesicular, and pustular phases. In 
immunocompromised patients, presentation of these orthopoxvirus 
infections can be protracted or disseminated and, rarely, lead to death.

Other Poxvirus Infections 
Individuals infected with other pox­
viruses that cause localized disease (parapoxviruses and MCV) seldom 
report a febrile phase and instead experience slow and gradual devel­
opment of a lesion or lesions. The lesion of molluscum contagiosum 
has a classic pearly appearance that sometimes umbilicates as it 
matures (Fig. 201-2). There is little inflammation that surrounds the 
painless lesions, which persist for months but gradually regress after 
6–12 months. Patients with immunocompromised status can have 
severe and prolonged disease; in patients with uncontrolled HIV and 
advanced HIV, immune reconstitution is usually sufficient to clear 
the virus. The rash lesions of parapoxvirus infections begin as ery­
thematous papules, develop into a “target” lesion, and then become 
nodular and papilloma-like. “Giant” parapoxvirus infections have been 
reported in immunocompromised individuals.
■
■DIFFERENTIAL DIAGNOSIS
A patient usually presents to the clinician with nodular or vesicu­
lopustular lesions. Important elements of the history include travel, 
occupation (with risk varying dependent on the poxvirus; greater risk 
is in laboratory workers working with poxviruses, farmers, hunters, 
and sex workers), animal exposures, lesion evolution, sexual history, 
and symptom timing with respect to rash onset. Additionally, given 
the appearance and location, mpox lesions in the anogenital area may 
resemble common sexually transmitted infections (STIs) such as gon­
orrhea, chlamydia, or syphilis; up to 10% of patients with mpox may be 
coinfected with an STI. Other differential diagnoses in poxvirus infec­
tions include varicella, yaws, papillomavirus infection, herpes simplex 
virus, and (particularly in parapoxvirus infections) cutaneous anthrax. 
While the characteristic lesions of poxvirus infection coupled with an 
indicative exposure history are helpful in narrowing the differential, 
laboratory testing is needed to confirm the diagnosis.
CHAPTER 201
Monkeypox, Molluscum Contagiosum, and Other Poxvirus Infections 
Currently, the most common laboratory tool for diagnosis of pox­
virus infection involves nucleic acid (i.e., molecular) testing. Nucleic 
acid–based diagnostics include polymerase chain reaction (PCR) and 
sequencing to fully characterize the isolate in some cases. This technol­
ogy has led to the identification of a number of new poxviruses that can 
cause human infection, including Akhmeta, Borealpox, and NY-014. 
Orthopoxvirus molecular testing options drastically expanded during 
the global 2022 mpox outbreak that was caused by clade IIb MPXV. 
Prior to the outbreak, only select PCR assays (developed by the Centers 
for Disease Control and Prevention [CDC] for smallpox prepared­
ness) were available within a subset of the Public Health Laboratories 
(PHL) within the Laboratory Response Network. During the 2022 
outbreak, CDC and the U.S. Food and Drug Administration (FDA) 
collaborated to increase testing availability in commercial laboratories 
within the United States. PCR assays specific to non-variola ortho­
poxvirus (NVO), orthopoxvirus generic, generic mpox, and mpox 
clade II are now readily available for testing of most orthopoxviruses. 
Other countries experienced similar growth in orthopoxvirus testing 
options. Many laboratories have also introduced multiplex testing 
options that include both NVO- and MPXV-specific targets. Some 
laboratories (U.S. Government and PHL) offer mpox clade-specific 
testing. The orthopoxviruses also grow well in most standard clinical 
laboratory tissue cultures. The parapoxviruses are difficult to isolate via 
culture (primary cells are best), and MCV cannot be cultured. Electron 
microscopy identifies the characteristic large, brick-shaped virus par­
ticles on negative stain if orthopoxvirus, yatapoxvirus, or MCV is pres­
ent. Parapoxviruses have an ovoid structure with crisscross spicules 
on negative-stain electron microscopy. MCV has a classic appearance, 
with Henderson-Patterson bodies, on pathologic analysis of a biopsy 
sample. Serologic assays can demonstrate orthopoxvirus reactivity, but 
most are unable to distinguish between orthopoxvirus species because 
of their broad antigenic similarity. Efforts in serology tests during the 
mpox outbreak are ongoing in order to differentiate infection from 
vaccination.

PART 5
Infectious Diseases
A
 
D
B
 
E
C
 
F
FIGURE 201-1  Mpox lesions. A–D. Standard lesions seen in mpox. Notice the well-circumscribed nature of the lesions even on mucosal surfaces; many of the lesions display 
the central umbilication unique to poxviruses, which often develop in later stages of illness. E and F. Severe mpox manifestations in a patient with advanced HIV. Notice the large 
coalescing lesion on the back, where the large lesion border is composed of individual lesions; additionally, large healing lesions are seen on the neck and hands. (Source: CDC.)

A
 
B
FIGURE 201-2  Molluscum contagiosum lesions. Notice the classic pearly 
appearance of molluscum contagiosum in A and B. B also displays central 
umbilication. (Source: CDC.)
TREATMENT
Poxvirus
Treatment of poxvirus infection is largely supportive. Typical sup­
portive care goals include prevention of autoinoculation to sec­
ondary sites and bacterial superinfection, pain control, and scar 
minimization. Disease-specific therapies are generally reserved for 
severe illness. Recently, as part of smallpox preparedness efforts, 
two antiviral agents active against the orthopoxviruses have been 
approved by FDA for the treatment of smallpox. As these agents 
did not require comparative human trials, their role in human 
orthopoxvirus infections continues to be investigated. Both anti­
viral agents are virustatic; therefore an immune response is crucial 
to recovery for any orthopoxvirus infection. For mpox specifically, 
given the high proportion of individuals coinfected with HIV, a key 
aspect of management is initiation, continuation, or reinitiation of 
antiretroviral therapy. The degree of HIV control is directly corre­
lated with hospitalization, severe mpox manifestations, and mortal­
ity. As in other etiologies of immunosuppression, immune system 
optimization is critical for recovery. Immunosuppressive agents 
should be avoided or held if possible during illness.
Tecovirimat is an inhibitor of a viral egress protein that prevents 
cell-to-cell dissemination of mature virions; it is virustatic, so 
concomitant optimized immune function is essential to favorable 
clinical outcomes. It was used as an investigational drug in isolated 
cases of vaccinia, cowpox, and borealpox, and used extensively dur­
ing the global mpox outbreak. It has a favorable safety profile and 
is the drug of choice for severe orthopoxviral infections; however, 
its effectiveness for treatment of human orthopoxvirus infections 
has not been systematically evaluated. Tecovirimat is dosed 600 mg 
orally or 200 mg intravenously every 12 h (with higher or more 
frequent dosing depending on patient weight) typically for 2 weeks. 
A fatty meal is necessary to optimize enteral bioavailability. For 
patients with severe immunocompromise and severe manifesta­
tions of mpox, the benefits of a prolonged treatment course (i.e., 
beyond the standard 14-day duration) may outweigh the harms 
(tecovirimat resistance). Importantly, a single-point amino acid 
change in the viral target of the drug can confer resistance to teco­
virimat; therefore it should be reserved for severe orthopoxvirus 
infections given its primary purpose as therapy during a smallpox 
incident. Additionally, genotypic tecovirimat resistance does not 

consistently correlate with phenotypic resistance. To complicate 
tecovirimat resistance further, there have been different ranges of 
resistant virus observed, and it is unclear how these results should 
be interpreted for clinical treatment purposes. It is also unknown 
if resistance observed within one lesion specimen correlates with 
viral populations throughout the infected individual, and it has 
been observed that resistance develops differently (with different 
viral mutations detected) in swabs from different parts of the body. 
Therefore, it is reasonable to continue therapy even when resistance 
is suspected or detected in a specimen.

The other FDA-approved therapy for smallpox is brincidofovir, a 
prodrug of cidofovir. Either cidofovir or brincidofovir can be given 
along with tecovirimat for severe poxviral infections. Brincidofovir 
is only available orally and dosed at 200 mg weekly for two doses. 
Cidofovir can be used if intravenous therapy is required at 5 mg/kg 
weekly with concurrent probenecid. Limited animal data suggest 
that brincidofovir may be synergistic with tecovirimat in orthopox­
virus disease. Therefore, combination therapy can be considered in 
severe infections. Cidofovir and brincidofovir have higher barriers 
to resistance, therefore, it is less likely to occur. Topical cidofovir 
has been used in orthopoxvirus and MCV infections with mixed 
results.
Vaccinia immune globulin (VIG) is licensed for the treatment of 
adverse reactions to live, replicating smallpox (vaccinia virus) vac­
cine. The standard dose is 6000 U/kg intravenously; dosing can be 
repeated, and doses of up to 9000 U/kg can be used. Given antigenic 
similarities across the orthopoxvirus genus, VIG was used exten­
sively for severe mpox with unclear efficacy. It is used primarily for 
people who may not be able to mount a sufficiently robust immune 
response to clear virus in patients with severe immunocompromise. 
Monoclonal antibodies similar to VIG are currently being studied 
for variola virus.
CHAPTER 201
Trifluridine is active against ocular orthopoxviral infections and 
can be administered for treatment or ocular prophylaxis for peri­
orbital lesions. Treatment dosing is instillation of one drop into the 
affected eye(s) every 2 h while awake for the first 2 weeks and then 
four times daily for an additional 2 weeks.
Monkeypox, Molluscum Contagiosum, and Other Poxvirus Infections 
Treatment for MCV infection is on a case-by-case basis. Immu­
nomodulatory therapies such as imiquimod have been used. If 
quicker resolution is desired, curettage and topical liquid nitrogen 
is available along with the FDA-approved agent cantharidin, which 
is applied by a clinician to lesions every 21 days for up to four doses.
■
■PROGNOSIS
In immunocompetent hosts most poxvirus infections are self-limited, 
resolving in weeks or, in the case of molluscum contagiosum, months. 
The exceptions are the generalized orthopoxvirus infections caused 
by MPXV and variola virus, whose case–fatality rates are greater. In 
unvaccinated individuals smallpox carries a mortality of up to 30%, 
and MPXV clade I, IIa, and IIb mortality rates are 1.4–10%, 1%, and 
<1%, respectively. Immunocompromised hosts may have more severe 
orthopoxvirus and parapoxvirus infections (e.g., severe mpox, pro­
gressive vaccinia, eczema vaccinatum, severe borealpox) leading to 
higher mortality, or they may have atypical presentations (e.g., giant 
orf). In patients with advanced HIV, effective antiretroviral therapy is 
essential to favorable clinical outcomes. MCV infections can be diffuse 
in immunocompromised persons. Immune reconstitution inflamma­
tory syndrome (IRIS) has been associated with recrudescence of MCV 
infections. Poxvirus reinfections are seldom reported.
■
■PREVENTION
ACAM2000 is a live, replicating vaccinia virus vaccine administered as 
a single dose via a percutaneous needle. JYNNEOS is a live, nonrepli­
cating, modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine 
administered via two subcutaneous doses 28 days apart. Awareness of 
occupational risks and adherence to appropriate barrier precautions 
effectively prevent most poxvirus infections. Pre-exposure vaccination 
is recommended for specific persons at risk of occupational exposure