Poxviruses - Clinical Tree

Introduction

Since the last natural smallpox infection, reported in Somalia in 1977, human poxvirus infections (other than molluscum contagiosum) have only been observed sporadically either after vaccination with poxvirus officinalis (vaccinia virus), or due to zoonotic poxviruses, such as monkeypox, catpox, or tanapox virus. As it is highly lethal and infectious, smallpox virus is feared for its potential use by bioterrorists.

History

Smallpox epidemics have decimated whole populations since antiquity. Smallpox has been demonstrated in Egyptian mummies. Indian (Shitala) and African / Afro-American (Shapanan) divinities share the characteristics of both deadly disease and protection of the person who has already survived the disease. In 1798, Edward Jenner made use of the observation that milkers who had contracted cowpox did not suffer from smallpox. This was the beginning of vaccination – that is, the inoculation of cowpox virus in order to protect against smallpox (Latin: vacca = cow). Smallpox eradication is the greatest success story of the World Health Organization (WHO). Once eradication was declared by the WHO in May 1980, compulsory vaccination was generally abandoned. Monkeypox was initially recognized in 1958 in captive primates. The first human cases were reported in 1970 in the Congo. Since then, monkeypox has been reported sporadically in humans in Africa but not outside Africa until 2003, when the infection first appeared in the USA.

Tanapox virus was first recognized in 1957 after an outbreak among schoolchildren in Kenya, in a village of the Tana river valley. Indications for smallpox vaccination have been newly established in order to prepare for bioterroristic attacks as well as to prevent monkeypox, as this has been imported into the USA.

Epidemiology

Poxviruses that can affect humans comprise four main genera : orthopox, yatapox, parapox, and molluscipox virus ( Table 13-1 ). Orthopox viridae are endemic in many animals throughout the world. The natural hosts of poxviruses are usually rodents, which can occasionally transmit the virus to humans. Monkeypox is a zoonotic poxvirus infection endemic in Africa; it was imported from Ghana to the USA in 2003 by infected Gambia giant rats and transmitted to prairie dogs and humans. Although human-to-human transmission of monkeypox may occur, further spread among humans is limited. Other zoonotic poxvirus infections occur sporadically (e.g., cowpox or catpox). These orthopox viruses usually cause self-limited infections, but may become life threatening in immunocompromised patients or subjects suffering from a predisposing skin disease. This also applies to the virus used for vaccination against smallpox, P. officinale (vaccinia virus). This virus may sometimes be inadvertently transmitted from a smallpox vaccinee to another individual.

TABLE 13-1

Poxviruses that May Cause Disease in Humans

Genus and Species	Primary Reservoir	Other Hosts	Geographic Region	Mode of Transmission	Protection Provided by Vaccinia Vaccination
ORTHOPOX VIRUS (OPV)
Smallpox (variola major-virus), alastrim (variola minor-virus)	High-security laboratories in Russia and USA		Declared eradicated in 1980 Maintained in high-security laboratories in USA and Russia	Direct contact, respiratory droplets	Yes
Vaccinia (poxvirus officinalis) ^a	Laboratories producing dermovaccine			Direct contact, inoculation
Cowpox / catpox (OPV bovis)	Rodents	Ungulates, cats	Europe, Africa, central and northern Asia	Direct contact	Yes
Monkeypox (OPV simiae)	Rodents	Monkeys, apes, prairie dogs, other mammals (?)	Central and West Africa	Direct contact, respiratory droplets	Yes
Other OPV	Rodents	Mammals (ungulates, camels, elephants, raccoons, voles, dogs, cats), birds	Worldwide?	Direct contact	Yes
YATAPOXVIRUS (YPV)
Tanapox	Non-human primates		Central and East Africa	Direct contact	No
Yabapox	Non-human primates		Central Africa	Direct contact	No
PARAPOXVIRUS (PPV)
Pseudocowpox (milkers' nodules and paravaccinia)	Ungulates		Worldwide	Direct contact	No
Bovine papular stomatitis	Ungulates		North America, Africa, Australia, New Zealand, Europe	Direct contact	No
Orf	Ungulates		North America, New Zealand, Europe	Direct contact	No
Sealpox	Seals		Atlantic and Pacific Ocean, North Sea	Direct contact	No
MOLLUSCIPOXVIRUS
Molluscipox (molluscum contagiosum)	Humans		Worldwide	Direct contact	No

a It is not clear whether the modified orthopoxvirus cultured for smallpox vaccination originates from a cowpox or an equine orthopoxvirus.

Non-orthopox viruses comprise pseudocowpox (milker's nodules) and yatapox viruses, including tanapox virus. Human tanapox occurs sporadically in Africa or in individuals handling laboratory animals. Tanapox is acquired by direct contact with infected non-human primates, and the infection cycle appears to be maintained between primates and mosquitoes.

For molluscipox virus causing molluscum contagiosum, the distribution is worldwide, and it is not considered to be a tropical disease.

Pathogenesis and Etiology

Poxvirus penetrates into the organism by virus-containing material coming into contact with the skin or with the respiratory tract (smallpox and monkeypox). Smallpox virus replicates at the site of contact and in the local lymph nodes. Subsequently, primary viremia develops, followed by multiplication of the virus in the reticuloendothelial system during the incubation period. Secondary viremia is accompanied by fever and the cutaneous eruptions appear.

Clinical Features

Poxviruses typically produce skin lesions, initially presenting as maculae or papules that evolve to become vesicles and pustules, which eventually dry up, forming a crust. The multifaceted clinical pictures due to poxviruses and the clinical course of smallpox are shown in Figure 13-1 and Tables 13-2 to 13-3 . Complications after smallpox vaccination also share features with smallpox eruptions. When the infection is acquired by inoculation, either by inadvertent contamination of a preexisting skin injury or by vaccination, a primary lesion appears on the respective site.

Figure 13-1, Clinical evolution of smallpox.

TABLE 13-2

Clinical Presentations of Poxvirus Infections

Smallpox	Alastrim (variola minor) Smallpox in a vaccinee (varioloid) Smallpox (variola major) Non-complicated smallpox Complicated smallpox Flat (hyporeactive) smallpox Early hemorrhagic smallpox (purpura variolosa) Late hemorrhagic smallpox (variola haemorrhagica)
Vaccinia	Allergic erythema multiforme after vaccinia inoculation Bacterial superinfection (auto)inoculation Vaccinia keratitis Eczema vaccinatum Generalized vaccinia Progressive vaccinia Postvaccinial encephalitis Fetal vaccinia Myocardial damage (?)
Monkeypox and other zoonotic orthopoxvirus infections	Non-complicated orthopoxvirus infection Complicated orthopoxvirus infection
Milker's nodule and paravaccinia Tanapox	Multiple stages: usually resolve within 6 weeks

TABLE 13-3

Clinical Courses and Outcomes of Smallpox

Date	Stage	Skin Eruptions	Skin Eruptions Indicating Complications	Contagiousness	Figures
−12 (−7 to −17) to 0 days	Incubation			None
0–2	Initial / prodromal stage	High continuous fever and prostration Initial morbilliform rash and enanthem (mouth), easily overlooked	Early hemorrhagic smallpox (purpura variolosa), leading to death	Yes	Flat smallpox Purpura variolosa
2–3	M			High	Macular eruption
4–5	Eruptive stage: multiform eruptions	Different generations of M, P, V Fever recrudescence	Flat-type (rudimentary) pustules, (semi)confluent eruptions, leading to death	High	Multiform early eruptions
6–10	Uniform appearance and postulation ^a	Pu	Flat eruptions, leading to death Hemorrhage into eruptions (late hemorrhagic smallpox), leading to death	Highest	Uniform vesicles Uniform pustules Hemorrhagic vesicles (late hemorrhagic smallpox)
11–	Desiccation of eruptions	C and scarring		After scabs have fallen off, patients are no longer contagious	Crust

M, macule; P, papule; V, vesicle (cental umbilication); Pu, pustule; C, crust.

a In vaccines multiform eruptions persist.

For smallpox surveillance the Centers for Disease Control and Prevention (CDC) has established a case definition and various probability categories for smallpox ( Table 13-4 ). Monkeypox eruptions resemble those due to smallpox, but the clinical picture is usually less severe ( Figs. 13-2 and 13-3 ). In immunocompromised hosts, small children, and infants, however, monkeypox is life threatening. As with smallpox, monkeypox may present as a primarily hemorrhagic infection. The reported lethality in Africa reaches 15% and more; breast-fed infants of monkeypox-infected mothers and malnourished children are at particular risk. Also as with smallpox, generalized eruptions appear only after 2–3 days of febrile illness (see Fig. 13-3 ). In other zoonotic poxvirus infections, a primary lesion appears at the inoculation site, and the clinical course is mild if the patient is immunocompetent.

TABLE 13-4

Smallpox Criteria

CDC smallpox case definition	An illness characterized by an acute onset of fever (38.3°C / 101°F) followed 1–4 days later by a rash with firm deep-seated vesicles or pustules in the same stage of development without other apparent cause ^a
	High probability is defined by a febrile prodrome and classical smallpox lesions and uniformity of lesions (lesions at the same stage of development)
	Moderate probability of smallpox is defined by a febrile prodrome and either one other major smallpox criterion or four minor smallpox criteria
	Low probability of smallpox is defined by the presence of fewer than four smallpox criteria, whether or not preceded by a febrile prodrome
Major smallpox criteria	Febrile prodrome occurring 1–4 days before rash onset, fever ≥ 38.3°C (101°F) and at least one of the following: prostration, headache, backache, chills, vomiting, or severe abdominal pain
	Classic smallpox lesions: deep-seated firm, hard, round well-circumscribed vesicles or pustules; as they evolve, lesions become umbilicated or confluent
	Lesions in the same stage of development: on any part of the body (e.g., the face or arm); all the lesions are in the same stage of development (i.e., all are vesicles, or all are pustules) ^a
Minor smallpox criteria	Centrifugal distribution, greater concentration of lesions on the face and on distal extremities
	First lesions on the mucosal palate, face, or forearms
	Patient appears septic or moribund
	Slow evolution: lesions evolve from vesicles to papules–pustules over days (each stage lasts 1–2 days)
	Lesions on the palms and soles
CDC laboratory criteria for confirmation	PCR identification of variola DNA in clinical specimen; or
CDC laboratory criteria for confirmation	Isolation of smallpox (variola) virus from a clinical specimen (WHO smallpox reference laboratory or laboratory with appropriate reference capabilities) with variola PCR confirmation

CDC, Centers for Disease Control and Prevention.

a Authors' note: it must be emphasized that at the beginning of a rash the lesions are not yet uniform, but become so after 2 days. In vaccinees the multiform picture may persist for the whole course of the disease.

Figure 13-2, Pustules of monkeypox on the hand of a child in Wisconsin after handling an infected prairie dog.

Figure 13-3, Monkeypox is a zoonotic infection, caused by an orthopoxvirus morphologically indistinguishable from that of smallpox; it produces a relatively benign infection in humans in parts of the tropical rain forest areas of West and Central Africa. This girl from Zaire showed large numbers of papules and pustules on the trunk, head, extremities, and external genitalia. Infection is acquired by handling or eating infected monkeys.

Tanapox virus infection is usually a mild self-limiting disease that shares the febrile prodromal stage with other poxvirus infections. In tanapox, the prodrome is mild and may be accompanied by headache and myalgia. Towards the end of the febrile phase, a mostly solitary erythematous macule appears. As the fever wanes, a papule appears and this expands to a diameter of approximately 1 cm. The center may become umbilicated, develop a necrotic crust, or deepen and form a nodule. On light skins the expanding nodule is surrounded by a reddish halo ( Fig. 13-4 ). Regional lymphadenopathy appears 4–5 days after the appearance of the papule. The lesion can be extremely tender, and it may also be pruritic. The maximal diameter (approximately 2 cm) is reached at the end of the second week. From this point the lesion slowly involutes with the whole evolution–involution taking 6 weeks, leaving a small scar.

Figure 13-4, Nodule of tanapox surrounded by a red halo on the arm of a student after contact with chimpanzees near the Tana river.

Patient Evaluation, Diagnosis, and Differential Diagnosis

Smallpox is likely to be initially misdiagnosed because clinicians are no longer familiar with the features of these infections. Because of the high lethality and infectivity of smallpox, it is necessary to differentiate smallpox as soon as possible from other diseases with vesicular eruptions, especially chickenpox. The CDC has therefore provided an algorithm for the probability of smallpox and for the differential diagnosis of papulovesicular eruptions : a highly suspicious smallpox case is defined by an illness characterized by acute onset of fever (38.8°C / 101°F) followed 1–4 days later by a centrifugal rash with firm deep-seated vesicles or pustules in the same stage of development without other apparent cause (see Table 13-4 , Fig. 13-5 ). The occurrence of a febrile prodrome before generalized eruption is an equally important criterion for monkeypox and catpox / cowpox. The suspicion of zoonotic poxvirus infections is raised by contact with animals (e.g., prairie dogs, cats, or other animals) that can transmit poxviruses ( Table 13-5 ). The potentially transmitting animal must be traced and investigated for symptoms of poxvirus infection. Unique clinical features of tanapox are the nodular nature of tender lesions, the paucity of lesions, the lack of pustulation, the benign course of the disease, and the prolonged resolution of the rash. Vaccinia (disease due to inoculation of the smallpox dermovaccine) is suspected when a smallpox vaccination has been administered or when the patient was in contact with a smallpox vaccinee within less than 21 days (inadvertent inoculation). For differential diagnosis of poxvirus infection versus other papulovesicular eruptions, see Table 13-6 and Figs. 13-5 to 13-18 .

Figure 13-5, Distributions of eruptions in ( A ) smallpox and ( B ) chickenpox.

TABLE 13-5

Centers for Disease Control Case Definition for Human Monkeypox

Modified from Centers for Disease Control. Updated interim case definition for human monkeypox. CDC, 2003.

CLINICAL CRITERIA

Rash (macular, papular, vesicular, or pustular; generalized or localized; discrete or confluent)
Fever (subjective or measured temperature ≥ 37.4°C [≥ 99.3°F])
Other symptoms: chills and / or sweats, headache, backache, lymphadenopathy, sore throat, cough, shortness of breath

EPIDEMIOLOGIC CRITERIA

Exposure ^a to an exotic or wild mammalian pet ^b
With clinical signs of illness (e.g., conjunctivitis, respiratory symptoms and / or rash), and / or has been in contact with either a mammalian pet ^c or a human with monkeypox
Exposure ^d to a suspect, probable, or confirmed human case of monkeypox

LABORATORY CRITERIA

Isolation of monkeypox virus in culture
Demonstration of monkeypox virus DNA by PCR testing of a clinical specimen
Demonstration of virus morphologically consistent with an orthopoxvirus by electron microscopy in the absence of exposure to another orthopoxvirus
Demonstration of presence of orthopoxvirus in tissue using immunohistochemical testing methods in the absence of exposure to another orthopoxvirus

CASE CLASSIFICATION

Suspect Case

Meets one of the epidemiologic criteria
and
Fever or unexplained rash and two other signs or symptoms with onset of first sign or symptom ≤ 21 days after last exposure meeting epidemiologic criteria

Probable case

Meets one of the epidemiologic criteria
and
Fever and vesicular–pustular rash with onset of first sign or symptom ≤ 21 days after last exposure meeting epidemiologic criteria

CONFIRMED CASE

Meets one of the laboratory criteria

EXCLUSION CRITERIA

A case may be excluded as a suspect or probable monkeypox case if:

An alternative diagnosis can fully explain the illness ^e
The case was reported on the basis of primary or secondary exposure to an exotic or wild mammalian pet or a human (see epidemiologic criteria) subsequently determined not to have monkeypox, provided other possible epidemiologic exposure criteria are not present, or
A case without a rash does not develop a rash within 10 days of onset of clinical symptoms consistent with monkeypox ^f
The case is determined to be negative for a non-variola generic orthopoxvirus by PCR testing of a well-sampled lesion following the approved Laboratory Response Network (LRN) protocol

a Includes living in a household, petting or handling, or visiting a pet-holding facility (e.g., pet store, veterinary clinic, pet distributor).

b Includes prairie dogs, Gambian giant rats, and rope squirrels. Exposure to other exotic or non-exotic mammalian pets will be considered on a case-by-case basis; assessment should include the likelihood of contact with a mammal with monkeypox and the compatibility of clinical illness with monkeypox.

c Includes living in a household, or originating from the same pet-holding facility as another animal with monkeypox.

d Includes skin-to-skin or face-to-face contact.

e Factors that might be considered in assigning alternate diagnoses include the strength of the epidemiologic exposure criteria for monkeypox, the specificity of the diagnostic test, and the compatibility of the clinical presentation and course of illness for the alternative diagnosis.

f If possible, obtain reconvalescent-phase serum specimen from these patients. See specimen collection guidelines ( http://www.cdc.gov/poxvirus/monkeypox/clinicians/prep-collection-specimens.html ) for details on collecting serum for convalescence evaluation.

TABLE 13-6

Differential Diagnosis Between Chickenpox And Orthopoxvirus Infections

	Chickenpox	Smallpox	Smallpox in a Vaccinee (Varioloid)	Monkeypox
MEDICAL HISTORY	Contact with other individual with chickenpox	Contact with individual with smallpox Laboratory worker Suspicion of bioterrorism		Contact with pet prairie dogs or Gambia rats Close contact with humans with monkeypox
APPEARANCE OF LESIONS	At fever peaks; prodrome, if present, mild first lesion with lymph node swelling	2–3 days after onset of fever, when fever decreases		Possibly inoculation site: first lesion with lymph node swelling Generalization, 1–3 days after onset of fever
PICTURE OF RASH	Multiform rash (“starry sky”) Development of lesions, each evolving without synchronization	Transient multiform rash for 2–3 days M-P-V-Pu-C with subsequent synchronization and uniform rash	Persistent multiform rash M-P-V-Pu-C	Uniform evolution of lesions (M-)P-V-Pu-C
MORPHOLOGY OF VESICLES	Not chambered vesicle: “dewdrop on a rose petal”	Chambered deep-seated umbilicated vesicle (vesicle with “belly bottom”)	Chambered but abortive	Chambered umbilicated vesicle
DISTRIBUTION OF LESIONS	Centripetal = maximum density of lesions: trunk Rarely on palms and soles	Always centrifugal distribution of lesions Maximum density of lesions: extremities, head Lesions also appear on palms and soles	In many but not all patients there is centrifugal distribution of lesions Maximum density of lesions: extremities, head Lesions also appear on palms and soles	Centrifugal generalized rash, maximum density of lesions: extremities + lesion at inoculation site Lesions may appear on palms and soles
EVOLUTION OF LESIONS	More rapid (from vesicle to crust even within 24 h)	Slow (each stage lasts 1–2 days)		Slow (each stage lasts 1–2 days)

M, macule; P, papule; V, vesicle; Pu, pustule; C, crust.

Figure 13-7, Smallpox: day 3 (vesicles).

Figure 13-8, Smallpox: uniform vesicular eruption; distribution: eruption more concentrated on the face and extremities as compared with the trunk.

Figure 13-9, Smallpox: vesicular umbilicated lesions on the sole.

Figure 13-10, Smallpox: day 5; uniform pustular eruption.

Figure 13-11, Smallpox: depigmented scars after loss of crusts.

Figure 13-12, Smallpox: scarring after convalescence.

Figure 13-13, Complicated smallpox: flat hyporeactive smallpox in a 70-year-old man.

Figure 13-14, Complicated smallpox: early hemorrhagic smallpox, subungual hemorrhage.

Figure 13-15, Complicated smallpox: early hemorrhagic smallpox.

Figure 13-16, Complicated smallpox: early hemorrhagic smallpox, profuse conjunctival and mucosal bleeding.

Figure 13-17, Complicated smallpox: late hemorrhagic smallpox, bleeding into preexisting smallpox.

Figure 13-18, Complicated smallpox: massive excretion of poxviruses.

Other differential diagnoses comprise generalized herpes simplex or herpes zoster, impetigo, drug eruptions, and erythema multiforme. In rickettsialpox, an eschar (inoculation site with a black scar) is seen; this may sometimes be difficult to distinguish from an inoculation site of a poxvirus infection. Rickettsialpox rapidly responds to doxycycline. The typical symptom of scabies is intense itching, especially at night, whereas pox eruptions are painful and lesions are tender to palpate. Scabies and molluscum contagiosum are not accompanied by fever. Early (flat) hemorrhagic smallpox (see Figs. 13-13 to 13-16 ) and hemorrhagic monkeypox must be differentiated from fulminant meningitis, viral hemorrhagic fevers, and acquired immunodeficiency syndrome (AIDS) with thrombocytopenia and disseminated herpes virus infections.

Smallpox-vaccine-associated adverse events may be due to the vaccinia virus itself or to autoimmune processes induced by the virus, or may represent non-specific allergic side-effects to other vaccine components (erythema multiforme major / Lyell syndrome), or may be a bacterial superinfection (see Table 13-2 ). The suspicion is raised by the history of smallpox vaccination of the individual or a contact person, because inoculation of vaccinia virus may occur inadvertently from a vaccinee to another individual.

Laboratory Diagnosis

Laboratory investigation must be performed in high-security laboratories. Security criteria for vaccinia virus, monkeypox virus, and smallpox virus have been defined by the CDC. Suitable material for diagnostic examinations includes vesicle fluid from the eruptions and tissue samples. Orthopox virus belongs to the largest viruses in nature ( Fig. 13-19 ). They are visible even with an optical microscope. Electron-microscopically, orthopox viruses are brick shaped. All orthopox viruses have a similar appearance and are not morphologically distinguishable. Polymerase chain reaction (PCR) assay is performed in specialized centers. Tissue samples may be inoculated onto primary and continuous cell lines, including rhesus-monkey kidney cells, rabbit kidney cells, VERO cells, and other cells. Cytopathic changes are observed in those cell lines within 1–4 days. Samples may also be inoculated onto rabbit skin. A PCR assay that amplifies a conserved segment of the DNA polymerase gene ( E9L ) that is present in all Old-World orthopox viruses except variola allows the differentiation between monkeypox and smallpox viruses. Further combined PCR tests allow the characterization of orthopox virus species, and, for example, in monkeypox the subclassification of monkeypox virus strains. Tests for antibodies against poxviruses do not allow the differentiation between antibodies against vaccinia virus in vaccines, or between monkeypox virus and smallpox virus infection.

Figure 13-19, Electron microscopy of an orthopox virus (vaccinia virus).

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