such an ancient and easily recognisable disease was unfamiliar to European doctors until the latter years of the nineteenth century, when the first epidemics began in the cooler climates of industrialised Europe and the United States!
Such has been the dramatic success of vaccination programmes, using live attenuated viral vaccines taken by mouth, that polio has been largely eliminated from developed countries. In 2018, according to the Global Polio Eradication Initiative, the disease is now endemic in just three countries: Afghanistan, Nigeria and Pakistan. But, given the ease and extent of modern travel, we cannot rest assured until this historic and maiming disease is completely eradicated in these remaining pockets of potential contagion.
While poliomyelitis is now approaching global control, it is not the only enterovirus to afflict humanity. Other members of this virus family are still commonly encountered in developed countries, including viruses that can be baffling in their presentations and clinically unpredictable in the course of their illnesses. Perhaps the best known of these are the Coxsackie B viruses, which sometimes present with a condition known to doctors as epidemic pleurodynia. Also known as ‘Bornholm disease’, after the Danish island where it was first recognised, this can present as severe chest pain arising from inflammation in the intercostal muscles of the chest wall. Popularly known as ‘the devil’s grip’, the sudden onset and severity of the pain can mimic a heart attack. Coxsackie B viruses can occasionally cause inflammation of the brain, presenting as the condition known as myalgic encephalomyelitis, or ‘Royal Free disease’, named after the London teaching hospital where it first presented. The same enterovirus may also present with inflammation of the heart muscle, or myocarditis, coupled with inflammation of the membrane surrounding the heart, known as pericarditis, a combination that presents in both children and adults and can very occasionally prove fatal. Other enteroviruses, including the echoviruses and types 70 and 71 enteroviruses, can cause chest infections and various patterns of muscle, meningeal and brain infections, where the diagnosis of the causative virus may be exceedingly difficult to pin down.
Viruses and their associated illnesses can be very puzzling. Ever since we first discovered their enigmatic presence among us, questions have inevitably arisen as to the evolutionary purpose behind their behaviours. When faced with the unpleasant, sometimes life-threatening, effects of virus infections, we are inclined to wonder what possible benefit such behaviour might confer on the virus. In the case of the poliovirus we saw how it appears to be mere happenstance that the virus causes serious illness in a tiny minority of those it infects. But there are other viruses that sweep through the human population and inflict dreadful patterns of illnesses in the majority of those infected, sometimes accompanied by a high mortality. This is all the more baffling since all that matters to the virus is its survival and successful replication. Survival of the virus must surely be threatened by killing its host. When one views the same question from a medical perspective, we are inclined to question: why are some viruses so deadly?
The Four Horsemen of the Apocalypse feature in the biblical Book of Revelation, where, having been released by the opening of seven seals, they ride out on red, white, black and pale horses. Theologians differ in their interpretations of what these riders might signify, but one of the four is commonly interpreted as pestilence, which, in modern terminology, would be interpreted as plague. While the common childhood infections, caused by viruses, are usually self-limiting, some viruses are truly dreadful in their capacity for death and suffering. In the recorded pages of history, two plagues of humanity would justify the term ‘apocalyptic’: these are the bacterial pandemics known as bubonic plague, as seen in the Black Death in the Middle Ages, and its viral counterpart, the plague of smallpox. Both have tormented humanity from ancient times, bequeathing a grim legacy in historical records and grave pits.
The Black Death was named after the festering swellings, or ‘buboes’, where lymph glands in the groin or armpit became swollen with pus and erupted onto the skin of victims. The causative bacterium, Pasturella pestis, is transmitted by the bite of an infected rat flea. Although the public commonly assumes that bubonic plague has gone away, in fact a milder form of the illness is still endemic in rural parts of the United States, South America, Asia and Africa. The viral apocalypse, smallpox, was named after the rash that accompanied the disease, which resulted from pustular blistering in the skin that healed with deep circular scars, or ‘pocks’.
It is comforting to use the past tense here since, mercifully, smallpox has been eradicated as a plague. The clinical term for smallpox was ‘variola’, and the disease followed two very different patterns of virulence, depending on the causative virus. Variola major and Variola minor are species within the family of poxviruses. The poxviruses infect a wide variety of animals, but only three species infect humans: namely the two variola viruses and a related species, Molluscum contagiosum, which causes minor blisters on the skin of children. We shall confine our attentions to the variola viruses, which have a number of unusual features.
Humans are the only hosts for smallpox, so we are the exclusive reservoir of the two variola viruses in nature. The individual ‘brick-shaped’ virions are relatively large, measuring 302 to 350 by 244 to 270 nanometres. Before being displaced by the discovery of the ‘Megaviruses’, poxviruses were the giants among the viruses, being big enough to be seen as tiny cytoplasmic inclusions under high magnification of the light microscope. This feature alone alerts us to the fact that we are dealing with a relatively complex virus. The variola genome is predictably large and DNA-based. Unusually for a virus, it contains the genetic wherewithal for the manufacture of its own virus messenger, RNA, which takes care of the manufacture of viral proteins. This virus also has its own coded enzymes and transcriptional factors which control the manufacture of daughter viruses within the cytoplasm of infected host cells.
Smallpox viruses are extremely contagious, spreading by that most infectious route of all, aerosol inhalation. The viruses are also capable of spread through skin contact with the blistering rash, or through contaminated clothing, bed linen, utensils or dust. Infection usually begins with the arrival of the virus into the air passages of the throat and lungs of a susceptible individual, where they penetrate the superficial lining cells to be ‘discovered’ by the tissue macrophages, the first line of the human immunological defences. The stage of infection within the macrophages is asymptomatic, but accompanied by stealthy advance of the virus towards its ultimate goal. By about the third day after infection, the ‘virus-factories’ within the macrophages journey on to the lymphatic stream and local lymph glands, from where the viruses spread to the other key elements of the ‘reticuloendothelial system’, in particular the bone marrow, spleen and circulating blood. This triggers a massive immune counter-attack on the virus, including cytotoxic T-cells and interferons. But, as the history, and the grave pits, suggests, this counter-attack is unsuccessful in the majority of sufferers. Symptoms begin with a severe sore throat at much the same time that blood-borne spread carries the viruses to the skin, where they produce the blistering and scarring rash, with its predilection for the face and limbs. The blisters are the result of direct viral invasion of the skin and they teem with viruses.
Historically it is thought that smallpox first arrived among humans about 10,000 years ago in the agricultural settlements in northeast Africa, spreading to India through trade with Ancient Egypt. It grieves one to imagine such a disease spreading through such populations of naïve people, and impossible to imagine exactly what they thought was among them. No doubt they had some simple rules for dealing with contagion, and, equally likely, they would have blamed some occult cause. We discover the pathognomonic pocks in the mummified skin of Ancient Egyptian mummies, such as the Pharaoh Rameses V, who died in 1156 BCE.
Smallpox, or the ‘small pocks’, was a clinical term that came into usage in the sixteenth and seventeenth centuries to differentiate it from the inch-or-more-diameter
