Part 5: Inflammation

“People need to have things trumpeted into their ears several times and from all directions. The first sound pricks up the ear, the second shakes it, and with the third, it goes in.”
– Rene Theophile Hyacinthe Laennec –

This vast group of disorders can be recognised by their well-known cardinal signs: rubor (redness), calor (heat), tumour (swelling), dolor (pain), and loss of function.

John Hunter was one of the first to stress that inflammation was in fact a beneficial reaction designed to rid the body of infection or repair injury, rather than a disease in itself as was widely believed before his time. We now know that this paradigm shift of Hunter’s is unfortunately not always correct.

Acute and Chronic Inflammation

Let us suppose that you come across a young lady complaining of a painful red hot and swollen right knee. You examine the knee and decide an inflammatory cause is a possibility. What next?

The inflammation section of the sieve guides us through more levels of thinking to help us make a logical diagnosis of what might be wrong. The first decision is whether the problem is acute inflammation (developing rapidly) or chronic inflammation (developing slowly). A useful next question might therefore determine how long the knee has been a problem. You will remember that acute inflammation is generally a furious and mostly non-specific reaction, with the hallmark on a cellular level of exudation. Chronic inflammation, by contrast, is a more refined, complicated and generally more specific reaction, with the hallmark of proliferation.

Obvious as it may seem now, explaining differences such as this posed a great challenge to scientific inquiry. Each critical insight along the way had to be carefully teased out and proven – take for example the work of Ilya Mechnikov.Mechnikov and the Science of Inflammation

Mechnikov was studying the larvae of starfish and had noticed the existence of some small mobile cells under the microscope. He hypothesised that these cells may play some role in the defence of the organism against germs.

To test his theory, Mechnikov plucked some small thorns from a tangerine plant that he had prepared as a Christmas tree for his children (he was very poor). He then jabbed these thorns into the larvae and left them overnight to test how they might react.

To Mechnikov’s delight, the next morning he found the small mobile cells he had seen had migrated to surround and apparently isolate the thorn.

It next occurred to Mechnikov that these cells might be actively taking up and digesting bacteria that had been introduced with the thorn. People already knew that when inflammation occurs in humans, leucocytes escaped from the blood. Mechnikov put these pieces of knowledge together, and for the first time described phagocytosis.Starfish LarvaeIlya Ilyich Mechnikov (1845-1916). Mechnikov was the son of an officer of the Imperial Guard in the Ukraine region. Even as a boy he was so passionate about natural history that he would give lectures to other children. He worked so hard at university that he completed the prescribed four-year natural history course in two.

Mechnikov’s wife had tuberculosis and was so weak at their wedding that she had to be carried to the church. Mechnikov struggled for five years more to save her life. After her death he plunged into a deep depression and attempted to take his own life by overdosing on opium. Happily the attempt failed.Mechnikov remarried, but in 1880, his second wife had a severe attack of typhoid and Mechnikov again became depressed. In order to save his family from embarrassment, he decided this time to take his life by means of a scientific experiment, and so inoculated himself with relapsing fever to test whether it was transmissible by blood. It was, and made him very sick, though again he thankfully failed to kill himself.

After his successful work on inflammation, Mechnikov regained a sense of purpose in life. He received many distinctions and honours from around the world including the Nobel Prize in 1908. He had long hair and an unkempt beard and it is said that he wore overshoes and carried an umbrella in all weathers, that his pockets were always overfull with scientific papers, and that he always wore the same hat – and often, when he was excited, sat on it. In later life he suffered heart attacks and after again becoming deeply distressed about World War I, died in 1916.After we have decided whether an inflammation is acute or chronic we must decide what might be causing it. As shown in the sieve, there are really only three possibilities. First the immune system may be activated by an infection. Secondly the immune system may have remained activated, perhaps inappropriately, after an infection has passed. Finally, the immune system may be activated by something altogether non-infectious, or even inappropriately activated by parts of the patient’s own body.
Infectious Inflammations

Little need be said about the importance of the infectious group of diseases. They are perhaps the most common of all ailments worldwide and account for much suffering (and for much of the work of doctors). When thinking of infections in the sieve, we must go a level deeper yet. We must next decide what the infective agent actually is likely to be, so that we might aim our treatment appropriately. In our sieve we arrange the possible inciting agents from small to large in size so that we continue to think through them logically.
One of the first to clearly enunciate the contagious nature of some diseases was Fracastorius, who published a short treatise in 1541 called De Contagione. Some suggest that an unsavoury professional interest might have aided his insights. It took many more years before the great scientist Koch exactly defined infection with his famous postulates, which we still rely on today.
Edward Jenner (1749-1823) and the Defeat of Smallpox

One of the great stories in the history of infectious disease involves the work of Edward Jenner. It is Jenner we must thank for the eradication of the Smallpox virus – a disease which claimed many hundreds of millions of deaths and left many more victims disfigured for life.
Jenner was the son of a clergyman and his great love was the English countryside where he grew up. After an initial interest in classics he decided to become a doctor and at age 13 became apprenticed to the surgeon of Sodbury, near Bristol. He trained under his great friend and mentor John Hunter.
Jenner’s interest in smallpox came from overhearing a rural dairymaid state ‘I shall never have smallpox for I have had cowpox. I shall never have an ugly pockmarked face’. Interested, Jenner began visiting farms around his village and studying all the various brands of pox that affected the cow’s teat. To his excitement, Jenner indeed found a strain of cowpox that seemed to be associated with a protection from the smallpox plague. This was the vaccinia virus, later employed by Pasteur as the basis for his new word ‘vaccine’.
Jenner then confirmed the dairymaid’s theory in a dramatic experiment. First he collected cowpox virus from an infected maid. Then he scratched the arms of a young boy named James Phipps and inoculated the wound with the virus (after first obtaining consent from the boy’s parents). As expected, Phipps developed cowpox, which quickly cleared. Next Jenner daringly began to inoculate Phipps with pus from smallpox patients. This act received wide condemnation by fellow doctors but to their amazement Phipps remained well. Jenner had achieved the first vaccination.
Jenner presented his results to the Royal Society but they were rejected as ‘incredible’ and he was warned ‘not to promulgate such a wild idea lest it should injure his established credit’. However he persisted, and soon proved the claim beyond doubt. Despite the ability to make a vast fortune from his discovery, Jenner was determined to freely share the secret. He spent much time refining the technique and sending vaccines all around the world. Among the first beneficiaries were Jenner’s own son, the governor general of India, Thomas Jefferson and the last of the Mohicans. Two centuries later, thanks to the legacy of Jenner, smallpox was completely eradicated from the natural world. The last sufferer, Ali Maow Maalin of Somalia, survived.
Besides research, Jenner was a successful, skilful and popular doctor. He was also a kind man and subsequent to his experiments on the boy had a cottage built for James Phipps with his own money. He planted the rose garden himself. The night before he died of a stroke he walked to a neighbouring village and provided fuel for poor families.
Jenner published many naturalist essays on such topics as the nesting of cuckoos and the migration of birds. He wrote good poetry and loved to play the violin.
Post – Infectious & Non-Infectious Inflammations
“A disease, however much its cause may be adverse to the human body, is nothing more than an effort of Nature, who strives with might and main to restore the health of the patient by the elimination of the morbidic humor.”
– Thomas Sydenham -Let us again consider the case of the young lady with a painful red swollen knee. We decided above that the cause was likely to be some sort of inflammation – either acute or chronic. We now know to consider infection as a possible cause of inflammation. Now let us meet examples of the other two types of inflammation.

Post-infectious inflammations develop aberrantly after an infection has cleared. A classic example is rheumatic fever. In this condition an initial bacterial throat infection, gives rise to a delayed immune reaction that causes a new disease. It is thought that somehow the bacteria induce the immune system’s antibodies to react against targets in normal body tissues such as the heart, brain and skin. Larger joint involvement, including knees, is also typical.

Non-infectious inflammations are often also ‘auto-immune’, but often it is not known why the immune system has become activated. Genetic factors and viruses have been implicated in some conditions. Many such non-infectious inflammations may affect knees, for example rheumatoid arthritis, which causes painful inflammations acutely, and chronically can totally destroy the normal architecture of the joints.

Non-infectious inflammations may also arise from other parts of the sieve, such as trauma, as part of the healing response. Do not worry about such overlap – just remember the point of this system – a practical means to diagnose disease.Thomas Sydenham (1624-1689). Sydenham briefly served time in the army (on the side of Cromwell), before gaining his medical degree at Oxford University. Sydenham was an ardent follower of the tradition of Hippocrates and perhaps his greatest achievement was to revive the methods of clinical observation, examination and rational experience.
Sydenham was also one of the first to study the epidemiology of diseases and his clinical reputation rests upon his firsthand accounts of malarial fever, scarlet fever, measles, dysentery, hysteria, and numerous other conditions. He made particularly fine accounts of renal stones and gout, which he suffered from himself. He also introduced Cinchona bark (which is used to make quinine) into England, and praised opium. Sydenham was heavily disparaged by his critics, yet benefited immensely from this by being allowed to work in total detachment from the speculative theories of his time.
Sydenham was the first to define the chorea that we now recognise as one of the major criterion for diagnosing rheumatic fever. “This is a kind of convulsion which attacks boys and girls…” he stated. “The hand cannot be steady for a moment. It passes from one position to another by a convulsive movement, however much the patient may strive to the contrary.” ‘Sydenham’s Chorea’, as we now know it is the only eponym to bear Thomas Sydenham’s name despite a huge contribution to medicine.
For his great legacy of work, Sydenham has been labelled the ‘English Hippocrates – Father of English Medicine’.