Descending the Magic Mountain: how early clinical trials transformed the treatment of tuberculosis.
This essay was written by Jo Colston and was first published in the 1998 Mill Hill Essays.
In 1924 the Nobel Prize-winning German novelist Thomas Mann wrote his masterpiece, The Magic Mountain. The novel is set in a tuberculosis sanatorium high in the Swiss Alps. The sanatorium, The Berghof, is a cross between a hospital, a luxury health farm and a winter sports centre. The hero of The Magic Mountain, Hans Castorp visits The Berghof to spend a couple of weeks with his cousin Joachim who has recently been admitted to “take the cure” for his tuberculosis. Joachim is anxious to leave The Berghof and take-up his recently acquired and much prized military commission — unfortunately his military career was to be short-lived. He is soon back at The Berghof and, like many other residents of the sanatorium, dies of his tuberculosis before he has chance to leave again. Hans, initially intending to stay for no more than a three week vacation to perk him up after the rigors of completing his engineering exams, is diagnosed as having tuberculosis during his visit and ends up staying there for seven years. The Magic Mountain explores the relationship between love and life in an atmosphere of sickness and death; it is also part of twentieth century social history, describing the everyday life within an institution which was commonplace in its day, the tuberculosis sanatorium. As Mann himself described life within such an institution:-
“You will have got from my book an idea of the narrowness of this charmed circle of isolation and invalidism. It is a sort of substitute existence, and it can, in a relatively short time, wholly wean a young person from actual and active life. Everything there, including the conception of time, is thought of on a luxurious scale. The cure is always a matter of several months, often of several years. But after the first six months the young person has not a single idea left save flirtation and the thermometer under his tongue. After the second six months in many cases he has even lost the capacity of any other ideas. He will become completely incapable of life in the flatland.
Such institutions as the Berghof were a typical pre-war phenomenon. They were only possible in a capitalistic economy that was still functioning well and normally. Only under such a system was it possible for patients to remain there year after year at the family’s expense. The Magic Mountain became a swan song of that form of existence. Perhaps it is a general rule that epics descriptive of some particular phase of life tend to appear as it nears its end. The treatment of tuberculosis has entered upon a different phase today; and most of the Swiss sanatoria have become sports hotels.”
Of course not all sanatoria were like The Berghof. For many people a short stay in the tuberculosis ward in the local hospital was followed by many months in a much more prosaic institution — unsuitable ever to become a sports hotel! Nevertheless, the philosophy was similar; tuberculosis was treated with a combination of bed-rest, exercise, fresh-air and good nutrition. Many improved and returned to “life in the flatland”; many did not.
The events which were to presage the end of the tuberculosis sanatorium began in 1943, at Rutgers University in New Jersey. The discovery of penicillin had stimulated interest in screening for other antibiotics which might be useful in treating bacterial infections. The discovery of streptomycin by Schatz and Waksman, and the demonstration of its activity against tuberculosis in guinea pigs led to an amazing world-wide demand for the drug. More than twenty thousand people were dying every year from tuberculosis in Britain alone, no wonder they were desperate to get hold of this new “miracle cure”. This clamour for the drug, and the black market which was created made a rational assessment of its usefulness very difficult. In 1946 The Medical Research Council set up the Streptomycin Clinical Trials (Tuberculosis) Committee; the objective was to design a trial which would unequivocally demonstrate whether streptomycin would be of any value in treating tuberculosis.
Many of the issues addressed by the Streptomycin Trial Committee are still of relevance in the design of clinical trials today, and the Streptomycin Trial of 1948 is seen as something of a watershed in clinical trial design. Firstly, there was the ethically difficult question of a control group. For a number of years it had been accepted that when a new treatment was being tested, it was important to include a group of patients who were not given the treatment; this control group could then be used to compare with the group that had received treatment. However, there was no other widely effective treatment available for tuberculosis at that time and it could be a fatal condition; streptomycin had been shown to be effective in animal experiments and in a number of anecdotal reports. Was it ethically acceptable to withhold treatment from the control group? The decision of the Committee was that it was essential to “effectively reveal the value of the treatment” and in order to do this a control group, untreated with streptomycin, was indispensable.
The second issue to be addressed was that of “randomisation” and “blindness” of the trial. If there was to be a Control Group it was essential that it was as similar as possible to the group that was to be treated with streptomycin. It was also essential that no-one involved with the management of the trial knew which patients were in the Control Group and which were in the Streptomycin Group, that is that they were “blind” to that information. This was achieved by allocating at random a sealed envelope to each patient who was admitted to the trial. Each envelope contained a number. After a patient was accepted into the trial his or her envelope was opened at the co-ordinating centre and the number determined whether he or she was allocated to the Control Group, and therefore treated with bed-rest alone, or the Streptomycin Group, treated with bed-rest plus streptomycin. This method effectively prevented introduction of bias into the results, which would have happened if doctors had been allowed to select the of patients who would receive the drug.
There was one important element of the Streptomycin Trial which did differ from the current concept of the clinical trial. In most trials conducted today, it is standard practice to obtain the “informed consent” of the patients involved; the general objectives and structure of the trial is explained and the subjects formally agree to participate. In the Streptomycin Trial the patients were unaware that they were participating in a trial.
An independent panel was appointed to evaluate the results of the trial; they concluded that there was a clear difference between the Streptomycin Group and the Control Group. Half of the Streptomycin Group showed “considerable improvement” compared to one in twenty five of the Control Group; less than one in ten of the patients treated with streptomycin died compared to more than a quarter of the group treated with bed-rest alone. Unfortunately these promising early results were soon overshadowed by the emergence of streptomycin-resistant strains of tuberculosis. It is ironic that the recent discovery that the treatment of HIV-patients with a single drug results in the rapid emergence of drug-resistance which can be avoided by treating with a cocktail of anti-HIV agents, has been hailed as a major breakthrough; this was a lesson which was learned almost fifty years ago by those treating tuberculosis.
Following the streptomycin trial, in 1948 the MRC set up a new research unit, the Tuberculosis Research Unit, under the Directorship of Dr Philip D’Arcy Hart, who was also Secretary of the Streptomycin Trial Committee. The study of tuberculosis was changing rapidly; the discovery of streptomycin was just a start. Other drugs quickly followed and the tuberculosis Research Unit became the focus of research on these new drugs. Some of these drugs were highly active against tuberculosis and (unlike streptomycin) are still widely used. One of the major issues addressed by the MRC Tuberculosis Research Unit was how these drugs could be applied in the most operationally effective way. Some of the most radical findings emerged from trials carried out by the Tuberculosis Unit in South India. These showed that it was not necessary to hospitalise people during their treatment for tuberculosis; patients could be effectively treated and cured in their homes. This finding was to have enormous medical, social and, not least, economic impact. Sanatoria were no longer required, enabling them to be closed down or reborn as “sports hotels”.
The results of the MRC trials, demonstrating that patients could be effectively treated at home and generally making the treatment of tuberculosis shorter and operationally simpler, still form the cornerstone of tuberculosis treatment and control. The most important, and often the most difficult, issue is to ensure that patients take their drugs regularly and for the full course, to ensure that a complete cure is achieved. The current strategy is referred to as DOTS – Directly Observed Treatment, Short course – in which patients are treated at home but a system of supervision, to ensure that the drugs are taken regularly, is incorporated.
The introduction of specific drugs which were highly effective against tuberculosis, and the work such as that of the MRC Tuberculosis Unit showing how these drugs could be used effectively in field conditions, had a profound effect. It has been estimated that the closure of tuberculosis sanatoria resulted in an annual saving of thirty million pounds in Britain alone. Unfortunately the association with HIV infection, the emergence of multiple-drug resistant strains, the failure of both patients and doctors to adhere to proven treatment schedules, and the inability of health-care systems to provide the necessary drugs and treatment infrastructure, have all contributed to tuberculosis once more becoming an international threat. As Thomas Mann said of his hero of The Magic Mountain:-
Hans Castorp is a searcher after the Holy Grail…..It is the idea of the human being, the conception of a future humanity that has passed through and survived the profoundest knowledge of disease and death. The Grail is a mystery, but humanity is a mystery too. For man himself is a mystery, and all humanity rests upon reverence before the mystery that is man.