Smallpox: causes, symptoms, diagnosis, treatment, and prognosis

Smallpox is a strong infectious disease caused by variola virus, which is highly contagious and with a high mortality. The clinical manifestations are extensive rashes developing into maculae, papules, blisters, and pustules, accompanied by severe viremia. After incrustation and decrustation, lifelong depressed scars are left.


The variola virus is a member of the orthopoxvirus family. Virues in the orthopoxvirus family are very similar in shape, size, structure, resistance to the outside world, and immunological characteristics. The pustule caused by variola virus and alastrim virus is small and with intact and protruding edge, whereas the pustule caused by vaccinia virus is large and with irregular margin. The variola virus is more pathogenic, but the cytopathic effect is slightly slower than the vaccinia virus. The variola virus, alastrim virus, and vaccinia virus can proliferate in various cell tissue cultures. The variola virus causes typical smallpox.

Figure 1, some variola viruses in microscopy

Figure 2, a variola virus in microscopy

The variola virus is brick-shaped, about 200 micrometers × 300 micrometers. It has strong resistance and can resist dryness and low temperature. It can survive for several months to one and a half years in crusts, dust, and clothing. Variola virus is highly contagious. People who have not had smallpox or have not been vaccinated with antismallpox vaccine can suffer from smallpox regardless of gender and ages, including neonates. Smallpox is mainly transmitted by inhalation or direct contact with droplets.


Inhalation through the respiratory tract is the main route of transmission of smallpox. Variola viruses are adsorbed on the surface of the epithelial cells of the upper respiratory tract of the susceptible individuals, invade, and quickly reach lymphatic tissues such as regional lymph nodes and tonsils. After mass replication, variola viruses enter the blood, forming the first transient viremia. Variola viruses infect mononuclear macrophages through the bloodstream, and replicate in the cells and are released in the blood, leading to the second viremia. Through blood circulation, the viruses disseminate more widely to the skin, mucous membranes, and internal organs. At this time, the patient has high fever and general malaise. In 2 to 3 days of prodromal symptoms, smallpox eruption occurs. Because variola virus is not heat-resistant, viremia only lasts for a short period of time after fever. On the second day after fever, it is generally difficult to detect the variola virus in the blood. The viruses are mainly present in tissues with low temperature such as skin. After variola viruses invade the skin tissue cells, they proliferate in the dermis, causing telangiectasia in the dermal layer, cytoplasmic vacuoles. pyknosis, and hypochromatosis. Maculae occur clinically. Subsequently, the viruses invade the epidermal cells and proliferate, causing local swelling, skin thickening, and papules, cell degeneration, necrosis, fluid exudation between cells, and blisters. Incompletely destructed cells are separated in blisters, forming many small rooms. Deep cell wall traction results in umbilication of blisters. In microscopy, sharply demarcated, round, 1 - 4μm in diameter inclusions are present in the cytoplasm of the epithelial cells around the blisters. Various inflammatory cells infiltrated into the blister lead to pustules. The fluid in the pustules is absorbed and the crust is formed. Due to rupture and scratching, secondary bacterial infections are common in the pustules, aggravating the deep lesions of local skin and systemic toxic symptoms. During pustules, hepatolienomegaly may be present. Secondary infection in the mouth or nasopharynx can cause cervical lymphadenopathy. If the pustule only involves the epidermis, the scar after decrustation is not obvious. The pustule involving the dermis or secondary infection results in a lifelong depressed scar. Due to the lack of the stratum corneum, the mucosal lesions are ruptured faster than the skin lesions. Mucosal lesions are easy to form different depths of ulcers but not blisters, and the viruses are easily shed from the ulcers. Therefore, mucosal lesions play an important role in the early transmission. Mucosa in the respiratory tract, digestive tract, urinary tract, and vagina can be involved. Significant inflammatory reaction around the ulcers can cause serious symptoms, if involvement in the cornea, can cause corneal opacity, ulcers, or secondary bacterial infections, resulting in blindness.

Signs and Symptoms

The incubation period is generally 8 to 12 days. Sudden onset, high fever, headache, emesis, and other systemic symptoms are present. On the 1st to 2nd day after onset, transient morbilliform or scarlatiniform lesions may occur in the lower extremities, inner thighs, armpits, and both sides of the waist. On the 3rd to 4th day, the body temperature drops rapidly, subjective symptoms are relieved, and the centrifugal rashes occur in the head, face, extremities, and trunk, initially dark red maculae, developing into papules after few hours. On the 6th to 7th day, blisters occur, with umbilication, with red halos surrounding the blister, and rashes occur in the mouth, throat, canthi, and conjunctiva. On the 8th to 9th day, blisters develop into pustules, the body temperature rise again, and poisoning symptoms are increased. On the 11th to 12th day, the pustules gradually dry up, forming yellow-green thick crusts, severe subjective itching is present, the body temperature gradually drops, and systemic condition improves. In 2 to 4 weeks, decrustation occurs, leaving scars.

In addition to ordinary smallpox occurring in individuals who have never been vaccinated, variola minor and variola major can also be seen in clinical practices. The former is caused by weak alastrim virus or occurs in individuals vaccinated but with reduced antibodies, which is characterized by mild systemic symptoms, less rash, generally without blisters or pustules, with short course of disease, without scars after healing. The latter is characterized by severe systemic symptoms, with hemorrhagic or pustular rashes fused, with many complications, mainly skin and mucous membrane secondary bacterial infections. Severe patients may have sepsis, meningitis, laryngitis, otitis media, bronchitis or pneumonia, and corneal opacity, leading to blindness.

Ordinary smallpox

Patients have typical symptoms, and about 90% of patients who have not been vaccinated are with ordinary smallpox.

Variola minor includes the following types.

  • Variola sine eruptione, also known as pharyngeal smallpox or transient smallpox, is common in patients who have some immunity to smallpox, and is characterized by transient fever, headache, myalgia, lumbago, and precursor eruption, without typical smallpox rashes. It is contagious and difficult to diagnose in clinical practices, mainly based on serological examination.
  • Modified smallpox is characterized by mild symptoms, low body temperature, less rash, generally without pustules, without scars, short course, and incrustation in about 10 days.
  • Alastrim is caused by alastrim virus. Due to weak virulence, the incubation period can be as long as 20 days. It is characterized by mild symptoms, short course, low mortality, less rash, without scars. Its blisters are soft and easy to rupture, sometimes can be unilocular, so alastrim is easily misdiagnosed as chickenpox.

Variola major with high mortality up to 20% to 50% can be divided into confluent and hemorrhagic smallpox.

  • Confluent smallpox is characterized by more rash, wide distribution, rapid development, fused pustules, significantly swollen skin, mainly in the face, back of the hands, and back of the feet, mucosal ulcers, redness and swelling, abnormal pain, severe symptoms of toxemia, high fever, and failure.
  • Hemorrhagic smallpox, also known as black smallpox, is mostly caused by coagulopathy, is characterized by petechiae and ecchymosis on the skin and mucosa, with severe splanchnic hemorrhage, and is easily misdiagnosed as hemorrhagic disease. Due to high fever, irritability, and collapse, most patients may die before the rashes develop into blisters.


In the papular stage, dermal papillary telangiectasia, dermal papillary edema, perivascular lymphocytes and tissue cell infiltration are visible. In the vesicular stage, epidermal thickening, intracellular and intercellular edema, spinous cell ballooning degeneration, spinous cell separation to form blisters in the lower stratum spinosum can be seen. In the pustular stage, peripheral dermal neutrophils infiltration into the epidermis and blister fluid, and the epidermal regeneration when healing can be seen. In the vesicular and pustular stage, typical eosinophilic inclusion bodies (Guarnieri's bodies) can be seen in the cytoplasm of spinous cells. In severe cases, extravasation of red blood cells can be seen.


On the basis of typical lesions, distribution, development of rashes, and epidemiology, the diagnosis is not difficult.


Symptomatic and supportive treatment is proposed. Antibiotics can be applied to prevent secondary infections. Whole blood or plasma transfusion and intramuscular gammaglobulin are appropriate in the treatment for severe patients.


It depends on the patient's age, constitution, immunity, virulence of virus strains, clinical types, and immediate and appropriate treatment. The mortality of variola major can reach 50%, while the mortality of alastrim is less than 1%.