Unethical Medicine (or Unethical Case Files): Do no harm? The ethical implications of employing one disease to treat another - The Case of Malariotherapy

Welcome to "Unethical Medicine," a new Ethos column dedicated to exploring the darker chapters of medical history. Each story sheds light on some of the dubious experiments and practices that have shaped modern medicine and offers contemporary lessons in ethics. Drawn from past and present events, the column will also consider the potential for future unethical practices and decision-making to occur as medical technologies and artificial intelligence tools evolve. 

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Do no harm? The ethical implications of employing one disease to treat another - The Case of Malariotherapy

In the early 20th century, a groundbreaking but controversial medical practice emerged: the use of malaria to treat syphilis, which became known as malariotherapy. The method, developed by Austrian physician-psychiatrist, Julius Wagner-Jauregg, involved deliberately infecting patients with malaria to induce high fevers, with the intention of killing the syphilis-causing bacteria. Offering a novel solution before the advent of antibiotics, the practice raised significant moral and bioethical questions that continue to resonate in medical history.

The Age-old Problem of Syphilis

A debilitating and often fatal disease, syphilis was a major public health issue in the early 1900s. There are several theories on the origins of the disease, including the popular ‘Columbian exchange hypothesis’ which posits that explorer Christopher Columbus’s crew transported it from the New World to the Old World in the 15th century where it spread through Europe, but evidence from palaeoanthropology points to the disease having evolved and spread millennia earlier. A sexually transmitted infection, the disease has four clinical stages; a short primary it stage that self-resolves, a secondary stage that features generic symptoms such as skin rashes, fever, headaches and fatigue, a latent (third) stage where the patient seems to have recovered and can last for years, and finally the tertiary stage characterised by multi-organ damage including neuromuscular symptoms (neurosyphilis), eye pain and vision impairment (ocular syphilis) and hearing changes (otosyphilis). 

The onset of the tertiary stage can result in disfigurement and rapid death, which is why it became so feared and catalysed a blame game with regional colloquial names emerging, for instance the British called it the ‘French Disease’, the French termed it the ‘Neapolitan Disease’, the Polish used the ‘German Disease’, and the Russians called it the ‘Polish Disease’, among others. In 1905, during the golden age of microbiology, Erich Hoffman and Fritz Schauddin discovered the bacterium that caused syphilis, a spirochaete named Treponema pallidum. The microbe became a new and visible target for ‘rational’ treatment development, not all of them drug-based.  

Discovery and Practice of Malariotherapy

Prior to antibiotics, a lack of effective or safe treatments for syphilis led to the exploration of unconventional methods to cure the disease. Since Hippocrates, physicians had observed that fevers could have a positive effect on insanity and cholera, and in the 15th century fever was reported by Ruy Dias de Isla to improve syphilis. More than three centuries later Wagner-Jauregg observed that fever could have therapeutic effects on neurosyphilis and postulated that fevers could be induced for the purpose. Initially experimenting with tuberculin and typhoid, in 1917 he introduced malaria into the treatment regimen, reasoning that the repeated high fever cycles might combat the bacterial infection.

The procedure involved deliberately infecting syphilis patients with malaria, usually through mosquito bites, or injections of infected blood. The resulting characteristic fevers would last for several days, during which the syphilitic bacteria would be weakened, or preferably, killed. After several rounds of fever spikes, patients were treated with antimalarial drug quinine to eliminate the malaria infection. While not without risks, the method offered hope for patients who, at the time, had few other options.

Malariotherapy was regarded as a life-saving intervention and became widely used in mental institutions and hospitals worldwide to treat an array of mental diseases, from psychoses and schizophrenia to general paralysis of the insane (GPI), a terrible manifestation of neurosyphilis caused by nervous system degeneration. The method proved surprisingly effective, with many GPI patients showing significant improvement - around 27% showed great improvement and another 25% mild improvement, which provided a lifeline for the victims. Wagner-Jauregg's work garnered international recognition, and he was the first psychiatrist to be awarded the Nobel Prize in Physiology or Medicine in 1927, legitimising the approach and spreading the practice. Malariotherapy gradually fell out of favor with the discovery of penicillin in the 1940s, which provided a safer and more effective treatment for syphilis.

Unethical Considerations

Despite its apparent medical success, malariotherapy raised serious ethical concerns:

Informed Consent

One of the most significant ethical issues of malariotherapy was lack of informed consent, a common problem of the time. Many patients undergoing malariotherapy were in mental institutions and may not have been capable of fully understanding the nature of the treatment, its risks, and even potential benefits. Ensuring that patients or their guardians provided informed consent was often overlooked, violating modern ethical standards.

Risk of Harm

Deliberately infecting patients with malaria parasites posed significant health risks. Malaria is a deadly disease that can cause serious complications, or even death. The ethical principle of non-maleficence, or ‘do no harm,’ comes into question when considering the potential dangers of inducing malaria in already health-compromised patients. A review of malariotherapy for GPI patients, for instance found that up to 13% died of malaria complications. Moreover, there were risks of transmitting other diseases via infected blood. 

Exploitation of Vulnerable Populations

The use of institutionalized patients, particularly those with mental illnesses, highlights issues of exploitation. Individuals suffering from neurosyphilis were often marginalized and in the most severe cases of GPI lacked the autonomy or advocacy to refuse participation. This exploitation of vulnerable populations for medical experimentation is a critical ethical concern.

Balancing Risks and Benefits

Although malariotherapy offered potential benefits, the risks involved were substantial. The fundamental ethical principle of beneficence requires that the benefits of treatment outweigh the risks. In the absence of alternative treatments, malariotherapy was considered justifiable at the time, but from a contemporary perspective, the risk-benefit ratio is ethically contentious. The efficacy of malariotherapy has never been proven in clinical trial, largely due to the ethical issues raised and the availability of better drugs and treatments for underlying diseases such as syphilis.

Patient Autonomy

Respecting patient autonomy is a fundamental ethical principle and was clearly compromised in the development and practice of malariotherapy. Many patients, particularly those suffering the most severe forms of neurosyphilis, were unable to make informed decisions about their treatment and were instead taken by their doctors. 

Ethical Oversight

It goes without saying that today the requirement for ethical oversight in medical research and treatment is paramount. The case of malariotherapy is an interesting one because it didn’t represent a one-off or experimental event, here was a treatment that was lauded, practiced widely and its creator given the highest honour in medicine. Institutional Review Boards (IRBs) and ethics committees were non-existent and the threshold for patient welfare and rights was much lower.

Legacy and Lessons

Adoption of malariotherapy as a conventional treatment for neurosyphilis in the early 20th century remains a significant case study in medical ethics, but the practice didn’t disappear entirely. There have been additional and diverse reports of malariotherapy use, attempting to treat Lyme disease in the US in 1990, and HIV in China in 1997 where trials concluded that malarial infection boosted the CD4+ cells that are depleted by HIV infection. However, later studies of natural coinfections of malaria and HIV showed that HIV increased the severity of malaria, while malaria increased the HIV viral load, suggesting that even under controlled conditions further malariotherapy research was not justified. This was reiterated by the Centers for Disease Control in 2003, which declared “the use of induced malaria infection in HIV-infected individuals cannot be justified”.

The use of malaria to treat syphilis was a bold and innovative approach and juxtaposes the potential for medical ingenuity with fundamental ethical considerations. While providing a crucial treatment option in its time, the issues surrounding malariotherapy serve as a reminder of the ethical responsibilities inherent in medical practice. Reflecting on past practices, the medical community can strive to uphold the highest ethical standards while moving forward with valuable biomedical research.