By the mid-1700's European and Revolutionary War physicians inoculated material from smallpox pustules into uninfected individuals. Although "variolation" caused a mild form of smallpox, it prevented significant morbidity and mortality. Edward Jenner (1749-1823) discovered that cutaneous injection of cowpox would prevent smallpox by conferring passive immunity. Jenner coined the term vaccination from the Latin for cow (vacca). Smallpox vaccination was initially used to curtail disease outbreaks, but was routinely given to children in most developing countries by the 20^th century.

In 1967 the United Nations World Health Organization (WHO) launched a worldwide vaccination campaign against smallpox; at that time, 10 to 15 million cases of the disease occurred each year, with more than 2 million deaths. The last case of endemic smallpox occurred in Somalia in 1977. In 1979, after two years without a reported case of smallpox, WHO marked the disappearance of smallpox from the earth and recommended that countries stop vaccinating against the disease. The total cost of smallpox eradication was $315 million between 1967-80; $30 million was from the United States and the rest from developing countries. Since the eradication of smallpox in 1977, the US Public Health Service estimates a monthly savings of more than $30 million in material and human resources (cost of production, administration of the vaccine, treatment of adverse reactions, record-keeping and surveillance, immigration control, quarantine, and education) (personal communication, Joel Breman).

Clinical Features
The virus is transmitted via the respiratory tract mucous membranes. There is a short viremia followed a variable period of clinical latency when the virus replicates in the lymphoreticular system. The incubation period averages 10-12 days but may range from 7 to 17 or more days. The onset is abrupt and is characterized by fever (up to 104^o F), chills, severe headache, and back pain. The symptoms tend to subside in three to five days, when the eruption begins to develop. Lesions of the mouth and oropharynx precede the rash by a day. The rash appears first on the palms, soles, forehead, and the backs of the wrists. It spreads quickly to the arms, face, and thorax and tends to be least pronounced on the abdomen and thighs. The exanthem begins as a petechial, scarlatiniform or morbilliform rash, soon becomes a papular eruption, and in five to six days the individual lesions develop into multiloculated pustules. The pustules become umbilicated and progressively desiccate forming a crust. Crust a shed as a small highly infectious "seed" that separates from each lesion. Lesions are at the same stage of development and have a predominately peripheral distribution.

At the pustular stage, there is an opportunity for secondary bacterial infection. Other complications include laryngitis, bronchitis, bronchopneumonia, variolous keratitis and iridocyclitis, otitis media, osteomyelitis, encephalitis, orchitis, and oopheritis.

The disease has been classified on the basis of the character of the rash into the discrete, confluent and hemorrhagic forms. The mortality in the first type is from one percent to six percent; in the confluent variety, the rate rises sharply to about 40%. The severest form of the disease is the hemorrhagic of black smallpox. The hemorrhagic diathesis is manifested in the skin, renal pelvis and other viscera. In this intensely fulminating variety, the patient may not survive long enough to develop the vesicular or pustular phases of the eruption.

Pathology
The early lesions of the skin and upper respiratory tract show similar changes; within the papillary dermis there is capillary dilatation, endothelial swelling and a lymphohistiocytic infiltrate. As skin lesions progress lesions undergo vacuolar degeneration of the mid-epidermis; infected cells contain slightly basophilic, intracytoplasmic Guarnieri bodies (2-8 micros). Multilocular vesicles form in the mid-epidermis. In the pustular stage, the serous and fibrinous contents of the vesicle are replaced by polymorphonuclear leukocytes sometimes in association with pyogenic bacteria. With healing, there is crust formation with parakeratosis. There is degeneration of the superficial hair follicles and scaring of the sebaceous glands – the classic pox scars are most prominent on the face.

Respiratory and digestive lesions have similar early histology, but are more likely to ulcerate. Pseudomembranes can be seen in the larynx and trachea. Focal hepatitis, orchitis, oopheritis, leptomeningitis, and encephalitis may be found in virulent infections.

(a detailed description of organ-specific pathology is found in ref 7).

Diagnosis and Reporting
A case of suspected smallpox would be an emergency of international importance and should be reported immediately to public health officials. Diagnosis would require BSL 4 laboratory and vaccinated staff.⁶ 

The differential clinical diagnoses in suspect cases would include other eruptive dermatoses (Table 1) and chicken pox, varicella virus (Table 2).

Skin scrapings of lesions at the various states, oropharyngeal or tonsillar swabs should be sent to the CDC for testing.

Serologic testing can be done one to two weeks following onset of the rash. The immune response in non-vaccinated persons appears after a week of illness. Cytotoxic T-cells and B-cells, neutralizing antibodies help to limit spread and progression of the infection in all but the most severe cases. Hemagglutination inhibition (IH) and complement fixation antibodies (CF) are detectable at 2 weeks after onset of symptoms and for one or more years. Neutralizing antibodies persist for several years.

References

1. Lillie RD. Smallpox and Vaccinia. The Pathologic Histology. Arch Path 1940;10:241-191.
2. Ash JE, Spitz S. Pathology of Tropical Disease: An Atlas. American Registry of Pathology, Wash DC, 1945.
3. Strano AJ. Smallpox. In Pathology of Tropical and Extraordinary Diseases. Binford CH and Connor DH, Eds. Washington DC, AFIP 1976.
4. Henderson DA. The eradication of smallpox. Sci Am, 1976;235:25-33.
5. Breman JG, Arita I. The confirmation and maintenance of smallpox eradication. N Engl J Med, 1980;303:1263-75.
6. Breman JG, Henderson DA. Current concepts: Smallpox diagnosis and management. N Engl J Med, 2002;346:1300-8.
7. Smallpox. http://www.afip.org/Departments/infectious/sp/text/1_1.htm (histologic description with multiple images)

TABLE 2 (from ref 6): Differential diagnosis of patients with smallpox and chickenpox

Evaluation criteria	Smallpox	Chickenpox
History
Recent contact with smallpox	+ + +	-
Recent contact with chickenpox	-	+ + +
Prior vaccination against smallpox*	- or +	- or +
Prior vaccination against chickenpox	+ or -	-
Incubation period (range)	10-12 days (7-17)	14-16 days
Prodrome**	2-4 days	0-2 days
Fever	+ + +	+ or -
Headache, backache	+ + +	+
Muscle pain, malaise	+ +	+
Pallor, transient rash	+ or -	-
Physical Examination
Vaccination scar against smallpox*	- or +	- or +
Skin Eruption**
Distribution	Peripheral	Central
Peak	7-10 days	3-5 days
Evolution of lesions	Same stage	Different stages
Size	4-6 mm	2-4 mm
Shape	Round	Oval
Depth	Deep	Superficial
Desquamation from eruption onset	14-21 days	6-14 days
Palms and soles - complications	Common	Uncommon
Skin infection	+ or -	- or +
Facial scarring	+ +	- (rare)
Pneumonia	+ or -	- (rare)
Blindness	+	-
Encephalitis	+ or -	- (rare)
Case Fatality Rate
Variola major, v. minor	30%, <1%	<1%
Children <1 year	40-60%	20%†
Laboratory Diagnosis
Antigen or nucleic acid detection	Variola virus	Varicella-zoster virus
Electron microscope	Poxvirus particles	Herpes-varicella
Culture on chorioallantoic membrane	Characteristic pocks	Does not grow
Serology	Rise in antibody to orthopoxvirus	Rise in antibody to varicella virus

* Routine vaccinations against smallpox stopped in 1971 in the United States and in the early 1980s in other countries, except for laboratorians working with orthopoxviruses; the vaccination scar may fade with time.

** Patients with a prior smallpox vaccination may have attenuated disease.

† Neonatal chickenpox has a 20 percent case fatality rate.

TABLE 3 (Ref 6) Complication rates from vaccinia by vaccination status and age derived from a survey of 10 states in the United States, 1968* Vaccination status and rate per million vaccinations

Condition	Vaccination status and rate per million vaccinations
	Primary vaccination				Revaccination**
	0-4yrs	5-19yrs	≥ 20 yrs	Total	1-4yrs	5-19yrs	≥ 20 yrs	Total
Accidental Infection	642	371	606	529	198	48	25	42
Generalized Vaccinia	564	140	212	242	------	10	9	9
Erythema Multiforma	209	87	30	165	73	2	9	10
Eczema Vaccinatum	39	35	30	39	------	2	5	3
Post-vaccinial Encephalitis	15	9	-------	12	------	-------	5	2
Progressive Vaccinia	3	------	-------	2	------	-------	5	2
Other	222	214	636	266	18	24	55	39
TOTAL	1572	856	1515	1254	200	86	114	108

*Modified from ref 41; 650,000 primary vaccinations and 998,000 revaccinations were given; no deaths occurred.

** No revaccinations in children <1year old

---- No conditions reported