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Smallpox is an infectious disease caused by the variola virus, a DNA poxvirus and member of the orthopox family.


The incubation period of smallpox is around 7- 14 days, during which the patient appears apparently health and shows no particular signs and symptoms of this sickness.

Once the virus enters the blood and infected cells start getting destroyed, the initial prodromal symptoms begin to appear. The symptoms are similar to flu like symptoms along with muscle pain, prostration and headache. By 12th to 15th day the skin lesions begin to appear. The skin lesions first appear on the mucus membranes of the oral cavity and these lesions enlarge and rupture thereby releasing large amounts of virus into the saliva. After appearance of this enanthem within 24-48 hours the rash starts to appear on the skin. Initial presentation is macules on the forehead, whole face and spread rapidly to the trunk and the extremities.

At this point various types of smallpox can occur: the classical one, modified, malignant and the haemorrhagic one [6].

The classical presentation shows that after a day or two of appearance of macules, they become raised to form papules which later become fluid filled to form vesicles. Once the fluid gets infected it becomes pustular. This takes about 6-7 days for pustule formation. By the end of the second week, the pustules begin to leak and dry up and scab formation takes place. These scabs fall off leaving pigmented scars.

In the malignant type of smallpox the skin lesions remain flat almost and the vesicles are flat with very little fluid in them. The prodromal stage is more severe and the enanthem which appears is more extensive. This type of smallpox is almost always fatal.

The haemorrhagic type is always accompanied by severe bleeding and secondary infections. Here vesicle formation does not occur and bleeding occurs under the skin making it look dark and charred. Death usually occurs in the 5th-7th day [7].

The modified type occurs in people who were previously vaccinated and have some immunity. The prodromal stage is mild and may not be present sometimes. Fever may not occur. The skin lesions are superficial and the entire sickness is not very severe and is often mistaken with chicken pox. These cases are never fatal with a good prognosis and complete recovery [8].

  • Fever often will rise again at this time and remain high until scabs form over the bumps.[web.archive.org]
  • Once the skin sores fill with fluid, the fever may rise again and remain high until scabs form over the bumps.[cdc.gov]
  • Most of the infections spread when the rashes start and the viral shedding is low during prodromal stage.However, for preventive measures patient should be regarded infectious from the onset of the fever.[symptoma.com]
  • These patients present with fevers, and extensive rashes, and there is a 30% mortality rate.[patient.info]
  • Smallpox vaccine side-effects Usually, people vaccinated with smallpox vaccine get mild side-effects, including fever and/or body ache.[news-medical.net]
High Fever
  • In the hemorrhagic form of smallpox, petechiae and hemorrhage are associated with intense abdominal pain, headache, backache, and high fever.[logicalimages.com]
  • Smallpox was notable for the rash of pustules it caused on the skin, as well as a high fever and muscle pain.[vocabulary.com]
  • The first symptoms of smallpox are high fever, fatigue, headaches, and backaches. A rash that appears mostly on the face, arms, and legs starts about 2 to 3 days later.[medbroadcast.com]
  • They include High fever Fatigue Headache Backache A rash with flat red sores There is no treatment. Fluids and medicines for pain or fever can help control symptoms. Most people recover, but some can die. Those who do recover may have severe scars.[medlineplus.gov]
  • The initial symptoms of smallpox include a prodrome of high fever, chills, headache, backache, malaise, and vomiting. Severe abdominal pain and delirium can also be present.[logicalimages.com]
  • They may include: Backache Delirium Diarrhea Excessive bleeding Fatigue High fever Malaise Raised pink rash, turns into sores that become crusty on day 8 or 9 Severe headache Nausea and vomiting The smallpox vaccine may prevent illness or lessen symptoms[nlm.nih.gov]
  • Symptoms of variola major include high fever, malaise, head and body aches, vomiting, and rash, which starts off as small red dots on the tongue and mouth. The spots develop into sores, which then open and spread the disease.[georgiaencyclopedia.org]
  • Initial Symptoms (Prodrome) (Duration: 2 to 4 days) Sometimes contagious* The first symptoms of smallpox include fever, malaise, head and body aches, and sometimes vomiting. The fever is usually high, in the range of 101 to 104 degrees Fahrenheit.[web.archive.org]
  • The initial symptoms of smallpox include a prodrome of high fever, chills, headache, backache, malaise, and vomiting. Severe abdominal pain and delirium can also be present.[logicalimages.com]
  • However, once the incubation period (or virus development phase) was over, the following flu-like symptoms occurred: high fever chills headache severe back pain abdominal pain vomiting These symptoms would go away within two to three days.[healthline.com]
  • The committee reviewed the chilling testimony of Ken Alibek, a former first deputy director of the Soviet biowarfare agency, Biopreparat, who claimed the supposedly secure Russian smallpox stocks might have leaked to agents acting for rogue states.[web.archive.org]
  • Prodrome The first symptoms of the prodrome begin after the incubation period and include: Fever as high as 101 F to 105 F (38.3 C to 40.5 C) Malaise Prostration Headache Backache Vomiting Severe abdominal pain Chills Anorexia Pharyngitis This phase lasts[cdc.gov]
  • Salvany journeyed to various countries in South America, where the rigors of travel and work took its toll and Salvany died at 34 years of age. Fortunately, Dr. Balmis travelled to Mexico, Central America and the Philippines. In Mexico, Dr.[web.archive.org]
  • The most frequent mode of transmission was person-to-person, spread through direct deposit of infective droplets onto the nasal, oral, or pharyngeal mucosal membranes, or the alveoli of the lungs from close, face-to-face contact with an infectious person[fda.gov]
  • Prodrome The first symptoms of the prodrome begin after the incubation period and include: Fever as high as 101 F to 105 F (38.3 C to 40.5 C) Malaise Prostration Headache Backache Vomiting Severe abdominal pain Chills Anorexia Pharyngitis This phase lasts[cdc.gov]
  • These lesions first appear on the buccal and pharyngeal mucosa, and then emerge on the face, forearms and hands. The rash spreads down, and within a day the trunk and lower limbs are involved.[www2.health.vic.gov.au]
  • Although the virus can be isolated from pharyngeal washings at the onset of rash and from month-old scabs, 9 neither of these seems to be important in practice. 8 Moreover, the physical appearance of an unvaccinated person with variola major is alarming[content.nejm.org]
  • Administrative and political hiccups were never completely banished, but were dealt with by WHO and Indian federal officials with a combination of diplomacy, aggressive negotiation, hard work and significant doses of good fortune.[york.ac.uk]
  • The constitution of the patient has a lot to do with which type is 3 contracted—this is established in the first fever. 2) eruptive : from the beginning of the first fever until eruption is completed and pustules ripen.[research.history.org]
  • […] of smallpox on face Wellcome L0032957.jpg 2,777 3,794;5.12メガバイト Pustular eruption of smallpox on face Wellcome L0032958.jpg 3,260 3,287;4.87メガバイト Pustular eruption of smallpox on face Wellcome L0032959.jpg 3,950 2,704;4.89メガバイト Record of deaths of smallpox[commons.wikimedia.org]
  • ., eruptive stage) that progresses to papules 1--2 days after the rash appears; vesicles appear on the fourth or fifth day; pustules appear by the seventh day; and scab lesions appear on the fourteenth day.[fda.gov]
  • Copyright HarperCollins Publishers variolar ( vaˈriolar ) adjective C18: from Medieval Latin: disease marked by little spots, from Latin varius spotted noun any of a group of viral diseases characterized by pustular eruptions, including smallpox, cowpox[collinsdictionary.com]
  • Eczema herpeticum can clinically resemble smallpox. On the basis of the algorithm for rapid evaluation of patients with an acute generalized vesiculopustular rash illness, our patient met criteria for high risk for smallpox.[ncbi.nlm.nih.gov]
  • Eczema vaccinatum results in vaccinial skin lesions appearing on areas of active or even healed eczema.[merckmanuals.com]
  • Eczema vaccinatum occurred in vaccinated persons or unvaccinated contacts who were suffering from or had a history of eczema.[web.archive.org]
Cutaneous Manifestation
  • Cutaneous manifestations of biological warfare and related threat agents. Arch Dermatol. 1999 Mar. 135(3):311-22. [Medline]. Metzger W, Mordmueller BG. Vaccines for preventing smallpox. Cochrane Database of Systematic Reviews [database online].[emedicine.com]
Vesicular Rash
  • Therefore, CDC Poxvirus program clinical sample remainders, collected from patients presenting with pustular or vesicular rash illness but ruled negative for poxvirus infection by real-time PCR, were selected for diagnostic assay validation.[jcm.asm.org]
  • Category B contacts who develop fever and vesicular rash will be classified as probable cases and transferred to the treatment ward of the smallpox care centre.[www2.health.vic.gov.au]
  • Crusting and scab formation typically begins by the ninth day of exanthema. The crusts slough off around 14 days after rash onset. See Eruptive Stage image below.[cdc.gov]
  • The exanthema distribution is centrifugal and peripheral. The vesicles may be umbilicated. There is no lymphadenopathy present.[symptoma.com]
  • Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day[ncbi.nlm.nih.gov]
  • Fever, malaise, and myalgias are common the week after vaccination. Successful vaccination is indicated by development of a pustule by about the 7th day. Revaccination may cause only a papule surrounded by erythema, which peaks between 3 and 7 days.[merckmanuals.com]
  • These include a temperature 37.7 C in the first 3 weeks after vaccination (2%–16%); malaise, myalgia, headache, chills, nausea, and fatigue (0.3%–37%); soreness at the vaccination site (almost universal); local lymphadenopathy (25%–50%); and intense erythema[academic.oup.com]
  • Fever was observed in 11% to 22% of participants, and headache in roughly half of the participants. Fever was less frequent when new vaccines were administered, but rates of headache were similar in new and old vaccines.[ncbi.nlm.nih.gov]
  • In the hemorrhagic form of smallpox, petechiae and hemorrhage are associated with intense abdominal pain, headache, backache, and high fever.[logicalimages.com]
  • Pain/Headache: Painkillers such as Cavilo or Hydrocodone. Fever: Water and rest.[neoscavenger.wikia.com]
  • The most frequently reported side effects were headache, nausea and abdominal pain. The FDA granted this application Fast Track and Priority Review designations.[fda.gov]
  • Severe headache following smallpox vaccination seemed to be generally transient, but debilitating headache may occur ( Sejvar 2005 ).[doi.org]
  • This characterisation was not misplaced, as the country began to throw up innumerable problems, ranging from political and administrative apathy to civilian hostility, from the very outset.[york.ac.uk]
  • In the annual vaccination reports that he filed, Dukhle has described the difficulties he encountered: superstition, apathy, the belief that vaccination offered slight immunity, and ‘procrastination’.[web.archive.org]


Smallpox is easily diagnosed by a complete clinical examination and history of onset of symptoms. Typical presentation clinically will be with an acute fever followed by rash which is deep seated pustules or vesicles. The entire rash all over the body is at the same stage. The exanthema distribution is centrifugal and peripheral. The vesicles may be umbilicated. There is no lymphadenopathy present.

Microscopic examination of the the pus as well as vesicles will show the typical cytoplasmic inclusions, main one being Guarnieri bodies which are the places of replication. Blood sample and throat swabs may be taken for culture of virus.

Pulmonary Calcification
  • The late development of pulmonary calcification in one of these nurses, who is now 74 years old, is described.[ncbi.nlm.nih.gov]


Treatment is mainly symptomatic and axillary. There is no known medication for this viral illness and treatment is supportive.
Antiviral therapy is given but the efficiency is still not yet proven.

Vaccination should be given as it can reduce the severity and the complications of this sickness. Patient should be kept well hydrated. Skin lesions should be kept hygienic and care should be taken to prevent any secondary infection. Haemorrhagic and malignant types may require urgent medical care.


Smallpox cases have 30% mortality, with about one third of cases being fatal. This disease leaves severe deforming scars and pockmarks as the sequale. Blindness results if the eyes are affected.

Research suggests that medications can reduce complications and severity of the infection but as it no longer affects humans there is no recent documented evidence.

Earlier smallpox was considered a death sentence due to severe morbidity and mortality. The outcome is not good in expectant women, small children and immunocompromised individuals.
However, if by chance humans do get reinfected with this virus, the death rate and complications will be more severe.


Smallpox is caused by variola virus which is a DNA poxvirus. This virus is a member of the orthopox family.

The two classical types of smallpox are variola major and variola minor. This virus can only affect humans, the other orthopox viruses cowpox and monkey pox have the ability to infect humans as well as animals [3].

Smallpox has the unique ability to replicate in the cytoplasm of the cell than the nucleus of the cell. They produce different types of special proteins, which are very unlike other DNA viruses.
The main routes of transmission are direct contact from person to person. The virus is mainly transported by droplet infection which can be transmitted via air. This happens when an infected individual coughs, sneezes or even when talking. Infection can also spread through personal articles such as clothing, bedding, etc.

Another rare route of transmission is if the airborne infected particles travel as far as different rooms and infect other individuals. Very rare cases of congenital smallpox are reported, though transplacental transmission can occur.

Smallpox becomes infectious mainly once the rash appears on the body. The disease is not infectious during incubation and prodromal stage. There is no viral shedding during these stages. Once scab information occurs, the rate of infectivity reduces, though a patient is considered infectious till the last scab falls off.


Due to an aggressive approach small pox is completely eradicated as stated by the World Health Organisation. Smallpox was a highly dreaded disease due to the resultant deformities, scar marks and severe complications. Case fatality was around 25-30%. No other reservoir of this virus is present other than humans.

Smallpox is transmitted through droplet infection mainly airborne transmission and very few cases of fomite transmission have been documented.

The epidemiological data records state that the infectious dose is assumed to be low. Most of the infections spread when the rashes start and the viral shedding is low during prodromal stage.
However, for preventive measures patient should be regarded infectious from the onset of the fever. The patient is infectious till the scabs have fallen off. Though globally eradicated, smallpox virus samples have been retained in two World Health Organisation associated centres in Russia and the USA.

Smallpox virus poses a severe threat to public health if used as a part of bioweapon warfare especially in terrorism [4].

Smallpox affects males and females equally though younger children, pregnant women and immunosuppressed patients are at a higher risk. Patients who have had a resolved infection have lifetime immunity.

Vaccination provides immunity, but not more than 10 years, therefore in spite of vaccination all individuals are considered sensitive to this infection.

Sex distribution
Age distribution


Smallpox is a highly virulent virus. As stated earlier humans are the only reservoirs of this infection. They are the largest animal viruses 250-300 nm long, and 250 nm high almost equal to the size of a bacterial spore. Its shape is similar to a brick. It is an enveloped virus containing a double stranded DNA. Two major strains are Variola major and Variola minor [5].

The route of entry is usually through the oropharyngeal or respiratory mucosa. Very rarely does infection occur through the skin. Once it enters it spreads to the regional lymph nodes and starts to multiply. From here, it proliferates to the spleen, bone marrow and other lymph nodes.

A mild prodromal stage occurs on the 3rd and 4th day after infection during which the viral load is increasing. By 8th to 12th day secondary viraemia occurs during which fever sets in and signs of toxaemia begin to show. The rash begins to appear by day 14 and by this time large amounts of virus can be seen in the spleen, kidneys, the liver and other organs.

Due to the blood capillaries getting dilated, the cells in the epidermis become swollen and the B-inclusion bodies can be seen in the cytoplasm. These swollen cells further increase in size and finally the cell membrane ruptures which leads to vesicular lesion. Due to movement of polymorphonuclear cells into the vessel postulation occurs. With progression the pus gets desiccated leading to scab formation. Reepithelisation occurs when the scab falls off.


The most important aspect of prevention is vaccination. This vaccine is a live virus vaccine. This vaccine is not injected in the manner similar to other vaccines. It’s normally done by a long metal piece which is dipped a number of times in the vaccine and repeatedly pricked on the skin. The site of pricking will develop a blister or a vesicle which will later form a scab, thus indicating the success of the vaccine. Side-effects due to this vaccine are common [9].

Nowadays, this vaccine is not included in the immunisation schedule due to eradication of this disease. In case of smallpox outbreak, this vaccine has to be given [10].


Smallpox is a dreaded disease caused by the variola virus. This virus belongs to the genus orthopox and Poxviridae family. This disease is feared as since antiquity causing disfigurement, disability and death. Science recorded a remarkable feat on December 9, 1979 when small pox was certified as eradicated by WHO globally.

Smallpox is an airborne infection which is communicable and spread by droplet infection. It shows a wide spectrum of illness , yet the main features in majority of cases are high grade intermittent fever , wide spread deep seated centrifugal rash through macule-papule-vesicle-pustule–scab-scar stages which are consistent. Toxaemia is also present. Case fatality is around 25%.
Its annihilation was envisioned by a clinician Edward Jenner whose analysis of folklore about milkmaids being immune to smallpox, imagination to developing inoculation and courage to experiment with James Philips have been legendary. It took 181 years after discovery of vaccine to eradicate smallpox [1].

It needed many years of research and technology for mass production and distribution of rich quality freeze dried vaccine, containment strategy, international cooperation, political commitment, professional management and dedication of public health workers [2].

Smallpox strictly occurs only in humans who are sole reservoirs of this infection. Antiviral therapy is normally advocated but does not have that promising results. Features contributing to the success of eradication are of universal interest in eliminating the disease; the infection’s long incubation period and low level of communicability, ease of diagnosis, humans being the sole reservoirs of infection, absence of carrier state and availability of an effective live virus vaccine.

Patient Information

Smallpox is a viral disease caused by variola virus. It is a contagious disease and is a highly feared disease. It presents with severe rash all over the body which ultimately leaves ugly scars on the body. Smallpox has been completely eradicated as stated by the World Health Organisation in 1979. No new cases have been reported so far.

This infection typically starts with an acute episode of fever, tiredness and headache. As the infection progresses the rash begins to appear on the body, the rash first appears inside the oral cavity and later to other parts of the body. The rash then spreads to other parts of the body. There will be blister formation which can get secondarily infected. As the blister gets dried, it results in scab formation and will leave scars on the body. The entire duration of this sickness is about two weeks. This can be confused with other viral infections.

Contact with infected individuals should be strictly avoided and immediate medical treatment should be started. Mainly, supportive care in the form of fluids and nutrition is all that is needed. Skin should be kept clean and should not be scratched. Antiviral therapy may be started.

Smallpox has good recovery with people who were previously immmunised. Pregnant women and small children have a poor outlook if infected. Vaccination is the only way of prevention.
As this disease is completely eradicated across the globe the vaccine is no longer given in the immunisation schedule.



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  2. Reinhardt BH. The Global Great Society and the US commitment to smallpox eradication. Endeavour. 2010 Dec;34(4):164-72.
  3. Weiss MM, Weiss PD, Mathisen G, Guze P. Rethinking smallpox. Clin Infect Dis. 2004 Dec 1;39(11):1668-73.
  4. Wiser I, Balicer RD, Cohen D. An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies. Vaccine. 2007 Jan 22;25(6):976-84.
  5. Fields BN. Poxviruses. In: Fields Virology. 3rd ed. Lippincott Williams & Wilkins; 1996:2679-89.
  6. Parrino J, Graham BS. Smallpox vaccines: Past, present, and future. J Allergy Clin Immunol. 2006 Dec;118(6):1320-6.
  7. Christopher GW, Cieslak TJ, Pavlin JA, Eitzen EM Jr. Biological warfare. A historical perspective. JAMA. 1997 Aug 6;278(5):412-7.
  8. McGovern TW, Christopher GW, Eitzen EM. Cutaneous manifestations of biological warfare and related threat agents. Arch Dermatol. 1999 Mar;135(3):311-22.
  9. McCurdy LH, Larkin BD, Martin JE, Graham BS. Modified vaccinia Ankara: potential as an alternative smallpox vaccine. Clin Infect Dis. 2004 Jun 15;38(12):1749-53
  10. Abramowicz M, ed. Drugs and vaccines against biological weapons. Med Lett Drugs Ther. 1999 Feb 12;41(1046):15-6.

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Last updated: 2019-07-11 22:46