1490 PART 5 Infectious Diseases

an immediate-early CMV antigen. Isolation of virus from urine, stool,

or saliva does not, by itself, constitute proof of acute infection, since

excretion from these sites may continue for months or years after illness. Detection of viremia by QNAT or antigenemia testing is a better

predictor of acute infection.

A variety of serologic assays detect antibody to CMV. An increased

level of IgG antibody to CMV may not be detectable for up to 4 weeks

after primary infection. Detection of CMV-specific IgM is sometimes

useful in the diagnosis of recent or active infection; however, circulating rheumatoid factors may result in occasional false-positive IgM

tests. Serology is more helpful when used to predict risk of CMV

infection and disease in transplant recipients and is not recommended

to diagnose acute disease.

■ PREVENTION

Prevention of CMV infection and disease in organ transplant and

HSCT recipients is usually based on one of two methods: universal prophylaxis or preemptive therapy. With universal prophylaxis, antiviral

drugs are used for a defined period, often 3 or 6 months. One clinical

trial demonstrated that, in CMV-seronegative kidney transplant recipients with seropositive donors, prophylaxis with (val)ganciclovir was

more effective at prevention when given for 200 days rather than 100

days. With preemptive therapy, patients are monitored weekly for CMV

viremia, and antiviral treatment is initiated once viremia is detected.

Because of the bone marrow–suppressive effects of universal prophylaxis, preemptive therapy has been more commonly employed in

HSCT recipients; letermovir, which has recently been approved, allows

prophylaxis in higher-risk patients. For patients with HIV infection,

CMV end-organ disease is best prevented by using antiretroviral therapy sufficient to maintain CD4+ T-cell counts above 100/μL. Primary

prophylaxis with ganciclovir or valganciclovir is not recommended.

Several additional measures are useful for the prevention of CMV

transmission to CMV-naïve, high-risk patients. The use of CMVseronegative or leukocyte-depleted blood significantly decreases the

rate of transfusion-associated transmission. In a placebo-controlled

trial, a CMV glycoprotein B vaccine reduced infection rates among

464 CMV-seronegative women; this outcome raises the possibility

that this experimental vaccine will reduce rates of congenital infection, but further studies must validate this approach. A conditionally

replication-defective virus, termed V160, is in a phase 2 clinical trial;

the vaccine was derived from the AD169 live attenuated virus and

genetically modified to restore expression of the gH/gL/pUL128-131

pentameric complex. A CMV glycoprotein B vaccine with MF59 adjuvant appeared effective in reducing the risk and duration of viremia in

both seropositive and seronegative renal transplant recipients at risk for

CMV infection. CMV immune globulin has been studied in a variety of

clinical situations (primary CMV infection in pregnancy, HSCT, solid

organ transplantation), with conflicting results, and is used much less

often in the era of multiple effective antiviral agents.

Prophylactic acyclovir or valacyclovir at high doses may reduce rates

of CMV infection and disease in renal transplant recipients; neither

drug is effective in the treatment of active CMV disease.

TREATMENT

Cytomegalovirus Infection

Ganciclovir is a guanosine derivative that has considerably more

activity against CMV than its congener acyclovir. After intracellular conversion by a viral phosphotransferase encoded by CMV

gene region UL97, ganciclovir triphosphate is a selective inhibitor

of CMV DNA polymerase. Several clinical studies have indicated

response rates of 70–90% among people with HIV who are given

ganciclovir for the treatment of CMV retinitis or colitis. In severe

infections (e.g., CMV pneumonia in HSCT recipients), ganciclovir

is sometimes combined with CMV immune globulin. Prophylactic

or suppressive ganciclovir may be useful in high-risk HSCT or

organ transplant recipients (e.g., those who are CMV-seropositive

before transplantation). In many people with HIV, persistently

low CD4+ T-cell counts, and CMV disease, clinical and virologic

relapses occur promptly if treatment with ganciclovir is discontinued. Therefore, prolonged maintenance regimens are recommended

for such patients. Resistance to ganciclovir is more common among

patients treated for >3 months and is usually related to mutations

in the CMV UL97 gene (or, less commonly, the UL54 gene). The

advent of CMV genotyping for resistance mutations has made it

possible to rapidly obtain information regarding optimal treatment

approaches against clinically resistant virus.

Valganciclovir is an orally bioavailable prodrug that is rapidly metabolized to ganciclovir in intestinal tissues and the liver.

Approximately 60–70% of an oral dose of valganciclovir is absorbed.

An oral valganciclovir dose of 900 mg results in ganciclovir blood

levels similar to those obtained with an IV ganciclovir dose of

5 mg/kg. Valganciclovir appears to be as effective as IV ganciclovir

for both CMV induction (treatment) and maintenance regimens,

also offering the advantage of oral dosing. Furthermore, the adverse

event profiles and rates of resistance for the two drugs are similar.

Ganciclovir or valganciclovir therapy for CMV disease consists of a

14- to 21-day induction course (5 mg/kg IV twice daily for ganciclovir

or 900 mg PO twice daily for valganciclovir), sometimes followed by

maintenance therapy (e.g., valganciclovir, 900 mg/d). Peripheral-blood

neutropenia develops in roughly one-quarter of treated patients but

may be ameliorated by granulocyte colony-stimulating factor or

granulocyte-macrophage colony-stimulating factor. Whether to use

maintenance therapy should depend on the overall level of immunocompromise and the risk of recurrent disease. Discontinuation

of maintenance therapy should be considered in people with HIV

who, while receiving antiretroviral therapy, have a sustained (3- to

6-month) increase in CD4+ T-cell counts to >100/μL. Compared

with shorter (6-week) courses, prolonged (6-month) courses of

valganciclovir had beneficial effects on hearing and developmental

outcomes in infants with congenital CMV infection.

For treatment of CMV retinitis, some clinicians prefer intravitreal injections of ganciclovir or foscarnet (see below) plus oral

valganciclovir to intravenous ganciclovir, although no clinical trials

have compared these approaches. Foscarnet (sodium phosphonoformate) inhibits CMV DNA polymerase. Because this agent does

not require phosphorylation to be active, it is also effective against

most ganciclovir-resistant isolates. Foscarnet is less well tolerated

than ganciclovir and causes considerable toxicity, including renal

dysfunction, hypomagnesemia, hypokalemia, hypocalcemia, genital ulcers, dysuria, nausea, and paresthesia. Moreover, foscarnet

administration requires the use of an infusion pump and close clinical monitoring. With aggressive hydration and dose adjustments

for renal dysfunction, the toxicity of foscarnet can be reduced. The

use of foscarnet should be avoided when a saline load cannot be

tolerated (e.g., in cardiomyopathy). The approved induction regimen is 60 mg/kg every 8 h for 2 weeks, although 90 mg/kg every

12 h is equally effective and no more toxic. Maintenance infusions

should deliver 90–120 mg/kg once daily. No oral preparation is

available. Foscarnet-resistant virus may emerge during extended

therapy. This drug is used more frequently after HSCT than in

other situations to avoid the myelosuppressive effects of ganciclovir; in general, foscarnet is also the first choice for infections with

ganciclovir-resistant CMV.

Cidofovir is a nucleotide analogue with a long intracellular half-life

that allows intermittent IV administration. Induction regimens of

5 mg/kg weekly for 2 weeks are followed by maintenance regimens of

3–5 mg/kg every 2 weeks. Cidofovir can cause severe nephrotoxicity

through dose-dependent proximal tubular cell injury; however, this

adverse effect can be tempered somewhat by saline hydration and

probenecid. Cidofovir is used primarily for ganciclovir-resistant virus.

Experimental therapies such as maribavir have been reported to

be effective for treatment of infection after HSCT and for resistant/

refractory CMV infections, for which a phase 3 trial is underway.

Letermovir has efficacy for prophylaxis after HSCT but induces

rapid development of resistance when used during active infection.

1491CHAPTER 195 Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8

HUMAN HERPESVIRUS (HHV)

TYPES 6, 7, AND 8

■ HHV-6 AND HHV-7

HHV-6 and -7 seropositivity rates are generally high throughout

the world. HHV-6 was first isolated in 1986 from peripheral-blood

leukocytes of six persons with various lymphoproliferative disorders.

Two genetically distinct variants (HHV-6A and HHV-6B) are now

recognized. HHV-6 appears to be transmitted by saliva and possibly

by genital secretions.

Infection with HHV-6 frequently occurs during infancy as maternal antibody wanes. The peak age of acquisition is 9–21 months; by

24 months, seropositivity rates approach 80%. Older siblings appear to

serve as a source of transmission. In addition, congenital infection may

occur, and ~1% of newborns are infected with HHV-6; placental infection with HHV-6 has been described. Congenital infection is generally

asymptomatic, although subtle neurologic defects have been described.

Most postnatally infected children develop symptoms (fever, fussiness,

and diarrhea). A minority develop exanthem subitum (roseola infantum; see Fig. A1-5), a common illness characterized by fever with

subsequent rash. In addition, ~10–20% of febrile seizures without rash

during infancy are caused by HHV-6. After initial infection, HHV-6

persists in peripheral-blood mononuclear cells as well as in the central

nervous system, salivary glands, and female genital tract.

In older age groups, HHV-6 has been associated with mononucleosis syndromes; in immunocompromised hosts, encephalitis, pneumonitis, syncytial giant-cell hepatitis, and disseminated disease are

seen. In transplant recipients, HHV-6 infection may also be associated

with graft dysfunction. Acute HHV-6-associated limbic encephalitis

has been reported in hematopoietic stem cell transplant recipients

and is characterized by memory loss, confusion, seizures, hyponatremia, and abnormal electroencephalographic and MRI results. High

plasma loads of HHV-6 DNA in HSCT recipients are associated with

allelic-mismatched donors, use of glucocorticoids, delayed monocyte

and platelet engraftment, development of limbic encephalitis, and

increased all-cause mortality rates. Mesial temporal lobe epilepsy has

been associated with HHV-6 infections, and, like many other viruses,

HHV-6 has been implicated in the pathogenesis of multiple sclerosis,

although further study is needed to distinguish between association

and etiology.

HHV-7 was isolated in 1990 from T lymphocytes from the peripheral blood of a healthy 26-year-old man. The virus is frequently

acquired during childhood, albeit at a later age than HHV-6. HHV-7

is commonly present in saliva, which is presumed to be the principal

source of infection; breast milk and cervical secretions may also carry

the virus. Viremia can be associated with either primary or reactivation infection. The most common clinical manifestations of childhood

HHV-7 infections are fever and seizures. Some children present with

respiratory or gastrointestinal signs and symptoms. An association has

been made between HHV-7 and pityriasis rosea, but evidence is insufficient to indicate a causal relationship.

Clustering of HHV-6, HHV-7, and CMV infections in transplant

recipients can make it difficult to sort out the roles of the various agents

in individual clinical syndromes. HHV-6 and HHV-7 appear to be

susceptible to ganciclovir and foscarnet, although definitive evidence

of clinical response is lacking.

■ HHV-8

Unique herpesvirus-like DNA sequences were reported during 1994

and 1995 in tissues derived from Kaposi’s sarcoma (KS) and body

cavity–based lymphoma occurring in people with HIV. The virus from

which these sequences were derived is designated HHV-8 or Kaposi’s

sarcoma–associated herpesvirus (KSHV). HHV-8, which infects B

lymphocytes, macrophages, and both endothelial and epithelial cells,

appears to be causally related not only to KS and a subgroup of

AIDS-related B cell body cavity–based lymphomas (primary effusion

lymphomas) but also to multicentric Castleman disease, a lymphoproliferative disorder of B cells. The association of HHV-8 with several

other diseases has been reported but not confirmed.

HHV-8 seropositivity occurs worldwide, with areas of high endemicity influencing rates of disease. Unlike other herpesvirus infections,

HHV-8 infection is much more common in some geographic areas (e.g.,

central and southern Africa) than in others (North America, Asia, northern Europe). In high-prevalence areas, infection occurs in childhood,

and seropositivity is associated with families having numerous children

who share eating and drinking utensils; HHV-8 may be transmitted

in saliva. In low-prevalence areas, infections typically occur in adults,

probably with sexual transmission. Concurrent epidemics of HIV-1 and

HHV-8 infections among certain populations (e.g., men who have sex

with men) in the late 1970s and early 1980s appear to have resulted in

the frequent association of AIDS and KS. Transmission of HHV-8 may

also be associated with organ transplantation, injection drug use, and

blood transfusion; however, transmission via organ transplantation or

blood transfusion in the United States appears to be quite rare.

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 neoplastic

disorders generally develop only after subsequent immunocompromise.

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 associated 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 susceptible in vitro to ganciclovir, foscarnet, and cidofovir. A small, randomized, double-blind, placebo-controlled, crossover trial suggested

that oral valganciclovir administered once daily reduced HHV-8

replication. 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 combination with chemotherapy can lead to a survival of >90% at

5 years in HHV-8–associated multicentric Castleman’s disease.

■ FURTHER READING

■ CYTOMEGALOVIRUS

Gunkel J et al: Outcome of preterm infants with postnatal cytomegalovirus infection. Pediatrics 141:e20170635, 2018.

Kimberlin DW et al: Valganciclovir for symptomatic congenital

cytomegalovirus disease. N Engl J Med 372:933, 2015.

Kotton CN et al: The third international consensus guidelines on

the management of cytomegalovirus in solid-organ transplantation.

Transplantation 102:900, 2018.

Leruez-Ville M et al: Cytomegalovirus infection during pregnancy:

State of the science. Am J Obstet Gynecol 223:330, 2020.

Plotkin SA et al: The status of vaccine development against the

human cytomegalovirus. J Infect Dis 5:S113, 2020.

Rawlinson WD et al: Congenital cytomegalovirus infection in pregnancy and the neonate: Consensus recommendations for prevention,

diagnosis, and therapy. Lancet Infect Dis 17:e177, 2017.

Whitley R (ed): Cytomegalovirus infection: Advancing strategies for

prevention and treatment. J Infect Dis 221:S1, 2020.

■ HUMAN HERPESVIRUS (HHV) TYPES 6, 7, AND 8

Cesaro S et al: Incidence and outcome of Kaposi sarcoma after

hematopoietic stem cell transplantation: A retrospective analysis and

a review of the literature, on behalf of infectious diseases working

party of EBMT. Bone Marrow Transplant 55:110, 2019.

Crabtree KL et al: Association of household food- and drink-sharing

practices with human herpesvirus 8 seroconversion in a cohort of

Zambian children. J Infect Dis 216:842, 2017.

1492 PART 5 Infectious Diseases

El-Mallawany NK et al: Kaposi sarcoma herpesvirus inflammatory

cytokine syndrome-like clinical presentation in human immunodeficiency virus-infected children in Malawi. Clin Infect Dis 69:2022,

2019.

Lurain K et al: Treatment of Kaposi sarcoma herpesvirus-associated

multicentric Castleman disease. Hematol Oncol Clin North Am

32:75, 2018.

Madan RP et al: Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation

Infectious Diseases Community of Practice. Clinical Transplantation

33:e13518, 2019.

POXVIRUSES

■ DEFINITION AND ETIOLOGY

Poxviruses 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 immune evasion genes or host interaction ORFs. The

complement of ORFs across different genera is largely responsible for

differences in disease manifestations and/or virus host range. Four genera of poxviruses include species that can infect humans; in addition,

an incompletely classified poxvirus has been reported to cause human

illness. Table 196-1 identifies these viruses, the majority of which are

zoonotic, and lists some of their epidemiologic characteristics.

■ EPIDEMIOLOGY

Most poxviruses that infect humans are spread through contact, not by

the respiratory route, and thus are less prone to cause epidemics. The

notable exceptions are species of Orthopoxvirus (variola and monkeypox viruses), which can be transmitted by both respiratory droplets

and direct contact. In what seems to have been a rare circumstance

near the end of global efforts to eradicate smallpox, it was reported that

the variola virus appeared to transmit via aerosol in a German hospital

in Meschede. Monkeypox virus is thought to be transmitted through

handling of or other direct contact with infected animals leading to

percutaneous or permucosal exposure; it then may spread between

humans by either the respiratory or the contact route.

Of concern, increasing numbers of monkeypox cases are reported

from countries where the disease is considered endemic, and more

numerous outbreaks have been reported in the past few years. Numerous cases have been reported in Nigeria, Cameroon, the Central African

Republic, and the Democratic Republic of the Congo over the past

5 years. In some instances, these are the first national reports of the

disease since it was identified in humans in the late 1970s and 1980s;

thus, the increases may possibly be attributable to greater surveillance

efforts. A recent modeling study sponsored by the World Health

Organization (WHO) looked at the effective reproductive rate (R0) and

suggested that monkeypox may now be a disease capable of spreading

as an epidemic through human interactions and that such spread does

not require repeated exposures to infected wildlife. This observation is

in contradistinction to the findings of WHO-sponsored studies completed in the 1980s as part of the certification of smallpox eradication.

196 Molluscum Contagiosum,

Monkeypox, and Other

Poxvirus Infections

Inger K. Damon

TABLE 196-1 Poxviruses Causing Infection in Humans

GENUS, SPECIES GEOGRAPHY ZOONOTIC CHARACTERISTICS

Orthopoxvirus

Variola Eradicated,

formerly

worldwide

Solely a human pathogen

Monkeypox Africa Squirrel species, Gambian rats, and

dormice implicated as potential reservoir

species; other species effective in

transmitting disease to humans (pet North

American prairie dogs); 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)

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

AK2015 United States

(Alaska)

Under investigation

Akhmeta Georgia

(country)

Woodmice (Apodemus spp.)

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; fomites?

Pseudocowpox Worldwide Handling of infected dairy cattle; fomites?

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

Unclassified poxvirus

NY-014a United States

(New York

State)

Unknown

a

Possibly an orthopoxvirus.

This spreading of disease may be, in part, due to waning immunity

provided by smallpox (vaccinia virus) vaccine.

Other orthopoxviruses (Table 196-1) are thought to spread only via

contact or percutaneous/permucosal exposures to infected animals (or

humans). Molluscum contagiosum virus (MCV) likely spreads through

direct contact with and percutaneous exposure to another infected human;

like variola virus, MCV is considered to be a pathogen of humans only.

The epidemiology of tanapox is poorly understood. Simian reservoirs are

postulated, and the potential for vector-borne infection is hypothesized.

Human infections with parapoxviruses occur through direct contact with

and percutaneous exposure to lesions developing at the site of contact.

Other epidemiologic factors are outlined in Table 196-1.

■ PATHOGENESIS

The pathogenesis of Orthopoxvirus infections is thought to involve systemic spread of disease from the site of virus inoculation to local lymph

1493CHAPTER 196 Molluscum Contagiosum, Monkeypox, and Other Poxvirus Infections

nodes, a subsequent phase in which additional lymphoreticular tissues

are seeded, and finally the development of symptomatic (febrile)

viremia that seeds the skin. The severity of disease is affected by the

degree to which the innate immune and interferon responses control

the initial stages of infection. In immunocompromised persons, more

severe systemic manifestations are seen. A case in point involves the

adverse events associated with smallpox (vaccinia virus) vaccination.

Individuals with intact immune systems develop a lesion at the inoculation site 3–4 days after vaccination; this lesion becomes vesicular and

pustular 7–10 days after inoculation. In some instances, lymphangitis,

lymphadenopathy, and/or fever are noted. After 14 days, the lesion

begins to scab over. In contrast, persons with atopic dermatitis or

eczema can develop eczema vaccinatum, and those with immunosuppression or immunocompromise can develop progressive vaccinia.

In these instances, the spread or growth of the vaccinia virus goes

unchecked, and systemic spread of disease or progressive growth of

the virus-induced lesion (the latter without an inflammatory response)

is noted. Generalized vaccinia, with dissemination of the rash, has been

documented in HIV/AIDS patients. Inflammatory rash responses are

often misclassified as generalized vaccinia. Other poxvirus infections—

with the possible exception of Yatapoxvirus 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.”

APPROACH TO THE PATIENT

Poxviruses

Usually the patient presents to the clinician with nodular or vesiculopustular lesions. Important elements of the history are travel,

occupation (with greater risk in laboratory workers, farmers, hunters, and health care workers), how the lesions have progressed, and

the history of fever with respect to rash onset. During the patient’s

assessment, contact precautions should be used, and if monkeypox

or smallpox is being considered, respiratory precautions, including

use of a negative-pressure isolation room, should be implemented.

■ CLINICAL MANIFESTATIONS

The first clinical sign of systemic poxvirus infection is fever, which is

followed by rash onset days later. With systemic Orthopoxvirus infections (specifically, smallpox and monkeypox), the rash evolves through

classic macular, papular, vesicular, and pustular phases (the last with

umbilication). A centrifugal distribution, with lesions more prominent

on the extremities than on the trunk (Fig. 196-1), is classic. Lesions

are often prominent on the palms of the hands, the soles of the feet,

and the face. Secondary or tertiary fever can develop; tertiary fever

is sometimes a hallmark of bacterial superinfection. Once the lesions

scab over and the scabs separate from the skin, the patient is no longer

infectious. Patients infected with tanapox virus initially present with

a very high fever, are often thought to have malaria, and later develop

1–10 nodular lesions. Other Orthopoxvirus infections are more localized in their presentation, with lesions likely developing directly at the

site of contact with the virus. Akhmeta, AK2015, vaccinia, and cowpox

virus infections are typically associated with a localized rash or lesion.

In immunocompromised patients, presentation of these Orthopoxvirus

infections can be protracted or disseminated.

Individuals infected with other poxviruses that cause localized

disease (parapoxviruses and MCV) seldom report a febrile phase and

instead notice the slow and gradual development of a nodular-papular

lesion or lesions. The lesion of molluscum contagiosum has a classic

pearly appearance. “Giant” Parapoxvirus infections have been reported

in immunocompromised individuals. MCV infections are painless,

without an obvious accompanying inflammatory response; they persist

but then gradually regress after 6–12 months. The differential diagnosis in poxvirus infections includes varicella, yaws, papillomavirus infection, and (particularly in Parapoxvirus infections) cutaneous anthrax.

FIGURE 196-1 These images from 1997 were obtained during an investigation into

an outbreak of monkeypox that took place in the Democratic Republic of the Congo

(formerly Zaire). These photographs from the World Health Organization show the

face, back, feet, and hands of a young boy with the characteristic maculopapular

cutaneous rash of monkeypox, which is similar in appearance to the rash caused by

smallpox virus. (Source: Centers for Disease Control and Prevention.)

■ DIAGNOSIS

Currently, the most common laboratory tool for diagnosis of poxvirus

infection involves nucleic acid testing. Nucleic acid–based diagnostics

include polymerase chain reaction and sequencing to fully characterize

the isolate in some cases. This technology has led to the identification of

a number of new poxviruses that can cause human infection, including

Akhmeta, AK2015, and NY-014. The orthopoxviruses 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 particles on negative stain if Orthopoxvirus,

Yatapoxvirus, or MCV is present. 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.

TREATMENT

Poxvirus

Treatment of poxvirus infections is largely supportive and aims to

avoid secondary bacterial infection if substantial areas of the skin

1494 PART 5 Infectious Diseases

are involved. Recently, as part of smallpox preparedness efforts,

an antiviral agent active against the orthopoxviruses has been

approved by the U.S. Food and Drug Administration (FDA) for the

treatment of smallpox. This drug, TPOXX (tecovirimat), has been

used investigationally to treat isolated cases of vaccinia virus infection associated with smallpox vaccination or laboratory exposure.

The recommended dose for adults is 600 mg twice daily for 14 days.

Bioavailability is best if the drug is taken with a fatty meal. Vaccinia

immune globulin is also licensed for the treatment of adverse reactions to smallpox (vaccinia virus) vaccine. The standard dose is

6000 U/kg IV; dosing can be repeated, and doses of up to 9000 U/kg

can be used. For treatment of orthopoxviruses, one other antiviral

drug—brincidofovir (trade name Tembexa) has been approved by

the FDA for treatment of smallpox in June 2021, and cocktails of

monoclonal antibodies are also being assessed. Treatment for MCV

infection is done on a case-by-case basis if quicker resolution is

desired; curettage, topical liquid nitrogen, and some immunomodulators have been investigated.

■ COMPLICATIONS

Orthopoxvirus infections can often seed tissues around the eye, causing keratitis and corneal infections that can lead to blindness. Careful

observation of the eye should be undertaken. Trifluridine is active

against ocular infections.

■ PROGNOSIS

In immunocompetent hosts, most poxvirus infections are self-limited;

the exceptions are the generalized Orthopoxvirus infections caused by

monkeypox virus and variola virus, whose case–fatality rates are 2–30%.

Immunocompromised hosts may have more severe Orthopoxvirus and

Parapoxvirus infections (progressive vaccinia, eczema vaccinatum) or

atypical presentations (e.g., giant orf). MCV infections can be diffuse in

immunocompromised persons. In AIDS patients, effective antiretroviral

therapy will help clear MCV. Immune reconstitution inflammatory syndrome (IRIS) has been associated with recrudescence of MCV infections.

■ PREVENTION

Awareness of occupational risks and institution of appropriate barrier

precautions effectively prevent most poxvirus infections. For prevention

of Orthopoxvirus infections, vaccination with vaccinia virus (smallpox

vaccine) is at least 85% effective. During the smallpox eradication era,

administration of a qualified vaccine 3–5 years earlier was viewed as

100% protective. During monkeypox surveillance efforts in Zaire (now

the Democratic Republic of the Congo) in the 1980s, vaccination 3–19

years earlier was 85% protective against disease among household

contacts of monkeypox patients. The duration of efficacy is unclear.

These estimates of protection were developed for the replicative forms

of vaccinia virus–based smallpox vaccines. A new replication-deficient

Orthopoxvirus vaccine, JYNNEOS, has been licensed in the United

States for the prevention of smallpox and monkeypox disease. This

vaccine, which undergoes no more than one round of replication in

mammalian cells, is less reactogenic than the historic, replication-competent vaccinia virus–based smallpox vaccines.

SELECT POXVIRUS INFECTIONS

■ MOLLUSCUM CONTAGIOSUM

Molluscum contagiosum virus is likely the most common poxvirus

infection that will be seen by practitioners in the United States. Disease

is transmitted through contact, usually through nonintact skin. Children are affected, likely transmitting disease through play activities.

In HIV or AIDS patients, disease can be severe. Genital involvement

can be seen in adults. Clinical disease is usually recognized by the

development of flesh-colored papules, sometimes umbilicated as they

mature. Little inflammation surrounds the painless lesions. Diagnosis

is usually made by the classic presentation (umbilication can be used to

differentiate from papilloma virus infections). However, skin biopsies

of lesions will demonstrate a characteristic pathology, and PCR tests

are also available for diagnostic verification. Clinical management

varies; there is no specific systemic treatment. Various localized measures have been attempted—whether physical methods to remove the

lesions or use of topical immunomodulatory agents (imiquimod). With

HIV/AIDS, a successful antiretroviral regimen that reconstitutes the

immune response is usually sufficient to clear the virus. Clearance in

immunocompetent hosts can take months. Simple barrier precautions

can prevent transmission of the virus infection.

■ MONKEYPOX VIRUS

Monkeypox disease is endemic in regions of western and central Africa

and has been exported outside of Africa a number of times in the past

20 years. Both exported disease and endemic disease have occurred in

those who have had contact with infected animals and contact with or

respiratory exposure to other humans with disease. The infected individual will likely seek medical attention when classic vesiculopustular

lesions develop. These lesions—which manifest at least a week after a

fever and that may be attributed to a flulike illness—develop at least

2 weeks after the initial exposure to infection. Lesions can be sparse or

profuse in number. As discussed previously, a centrifugal distribution

is usually seen, and palms and soles can also be affected. Lesions on the

face should be carefully evaluated, especially if near the eye; conjunctival involvement can result in corneal involvement with blindness as a

sequela. Death was reported in up to 10% of unvaccinated (with a prior

smallpox vaccination) individuals in an African study performed in the

1980s; all deaths were in children under the age of 6. Diagnosis at the

rash stage of illness is easily achieved through evaluation of scrapings

from a rash lesion or the scab from a healing rash lesion. High levels of

virus can be found and can be detected through PCR analysis of the primary material or cultures derived from the scrapings or scab. Although

there is no licensed treatment in the United States, TPOXX—licensed

for the treatment of smallpox—has activity against monkeypox virus

and other orthopoxviruses and has shown treatment benefit in animals

challenged with monkeypox. The Centers for Disease Control and

Prevention holds an Investigational New Drug license for the use of

the product to treat human laboratory-confirmed monkeypox disease.

JYNNEOS is an U.S. Food and Drug Administration-licensed vaccine

for the prevention of monkeypox disease.

■ OTHER POXVIRUS INFECTIONS OF HUMANS

With respect to other poxvirus infections (and with the exception of

tanapox disease, which may have an arthropod vector), most other poxvirus infections are initially acquired through exposure and contact with

an animal’s infection. Tanapox has rarely been seen in the United States

and is seen mostly in travelers returning from West or Central Africa.

The Orthopoxvirus infections caused by cowpox and the vaccinia-like

viruses are typically acquired initially through contact with an infected

animal. Human-to-human transmission can also occur via contact

with the lesion(s) of the infected human. In Europe, human cowpox

infections have recently been associated with the pet rat trade, and

vaccinia-like viruses (e.g., Belo Horizonte, Cantagalo, Aracatuba)

are reported in handlers of dairy cattle in South America. Similarly

buffalopox has been reported in those inhabitants of the Indian subcontinent exposed to infectious lesions on water buffalo. In the United

States, vaccinia, the virus known as the substrate for smallpox vaccine,

has caused infections in laboratory workers studying the virus in the

laboratory. Parapoxviruses are only spread to humans through contact

with an infected animal’s lesions.

Characterization of the rash can help to identify the source of the

poxvirus infection. The rash lesions of tanapox are nodular, develop

days after a high fever, and are initially often thought to be symptomatic of malaria. The rash lesions of Parapoxvirus infections begin as

erythematous papules, develop into a “target” lesion, and then become

nodular and papilloma-like. Orthopoxvirus lesions develop through

classical popular, vesicular and pustular phases before scabbing. Laboratory diagnoses can be achieved through scrapings of the rash or the

scab and nucleic acid analyses of the material; common approaches are

to use PCR or sequencing methods.

Treatment of the lesions is usually supportive; the aim is preventing secondary bacterial infections. Orthopoxvirus infections may be