Sepsis Biomarkers: Tracing the Evolution, A Historical Perspective

Sepsis Biomarkers: Tracing the Evolution, A Historical Perspective

jameswebb_autor card

Sepsis, a life-threatening condition triggered by the body’s response to infection, has been a challenge for medical professionals throughout history. Over the years, the identification and monitoring of sepsis have been significantly enhanced by the discovery and development of sepsis biomarkers. These biomarkers, which are measurable indicators of the body’s response to infection, have revolutionized early diagnosis and treatment strategies.

Sepsis 5000 years ago

Early Recognition While the first written description of the sepsis syndrome appears in an Egyptian papyrus circa 1600 B.C. discovered in Luxor (Egypt).

This papyrus seems to be the copy of another much older manuscript dated in 3000 BC, and it is considered the oldest known surgery treatise. This work describes symptoms, signs and their follow up, prognosis and treatment of 48 cases of traumatic wounds, fractures and dislocations in different parts of the body.

There are clear references to fever as a secondary phenomenon in the wounds, with special emphasis in its detection during subsequent clinical assessment monitoring the patients’ evolution.

In some cases, the fever modifies both treatment and prognosis. Other signs of infectious complication are described, such as the presence of pus as a secondary and late phenomenon, and is associated with a bad prognosis.

It is clear therefore that Egyptian physicians, without knowing the concept of infection or inflammation, identified some clear signs of what today we know as local suppuration and systemic infection.

The modern word sepsis comes from the Greek word “sepo”, which means “I rot”. Homer (c. 800 BC) used the word in the 24th song of the Iliad where Priam enters into the Greek camp to beg Achilles for the return of Hector`s body that has being lying on the beach for 12 days.

The physician and philosopher Hippocrates (c. 400 BC) uses “sepsis” in his Hippocratic corpus cited in the Epidemics book describes his view of sepsis as dangerous biological decay believed to occur in the colon and release various substances which caused “auto-intoxication”. Hippocrates tried to find a pharmacological response through antisepsis properties in alcohol, wine and vinegar.

Sepsis at the turn of the millenium

Three centuries later, the pioneering Roman pharmacologist Galen (129-199 AD), a respected Roman physician, and philosopher, developed the precursor for the apothecary,  and theorized about sepsis,  wound healing and pus which lasted for 1500 years.

The Romans believed that the syndrome resulted from invisible creatures that gave off fumes, and created the foundation of the thinking behind the effort spent by the Romans on a public health system, emphasizing hygiene practices. However, they never considered transmission by person to person contact, and therefore missed the general theory of infectious disease.

Sepsis forgotten

for 1200 years

However, the use of sepsis as a medical term declined until the Renaissance. One of the first bibliographic references in a medical context appears thanks to Matthaeus Silvaticus (c. 1280- c. 1342) a physician from the famous Salerno School who wrote one of the most famous medical encyclopedias, the Pandactae Medicinae,  in the late Middle Ages.


Printed in at least eleven editions in various countries between the invention of the printing press and 1500, this text provides a description of the terms “sepsis” and “virtus” or “septic property” (“Sepsis: Putredo”; “Séptica Virtus: Putredine inducens”). Thanks to the work of Arab physicians who translated the classic Greek medical works European physicians could appropriate many concepts  that had partially disappeared.the use of sepsis

Sepsis in the 1700s 

In 1750 Sir John Pringle, the father of military healthiness, used for the word sepsis in his work Experiments upon septic and antiseptic substances. Pringle was among the first persons to see the importance of these principles in hospitals and camps.

During the 17th century the first references about the use of the term in several European languages can be found; in a French medical dictionary in 1834, long before the microbiological revolution, it is defined simply as putrefaction, in a German medical dictionary from 1845 uses the term in the context of the disease, and  in 1858 the word sepsis was included in the Oxford English Dictionary

Sepsis in the 1800s 

At the start of the golden age of germ theory, Ignaz Semmelweiss made monumental observations about puerperal sepsis, or sepsis that occurs after childbirth.

He noticed that in his ward, women who had assistance from midwives during delivery developed puerperal sepsis 2% of the time, whereas those who had help from medical students developed it 16% of the time.

As a result of a colleague dying from an infection acquired during an autopsy when he accidentally cut himself, Semmelweiss was able to recognize that the reason medical students had higher rates of puerperal sepsis in their patients was because they would perform autopsies and deliver babies without washing their hands.

He instituted a policy forcing the medical students to wash their hands before seeing a patient and saw the rates of puerperal sepsis reduce to below 3%.

Unfortunately, his pioneering life-saving policy was met with heavy criticism, and he was fired.

Soon after Semmelweiss, Joseph Lister, Louis Pasteur and Robert Koch did their seminal work in furthering our understanding of microbiology and infectious disease. Building upon Pasteur’s experiments disproving the theory that diseases developed spontaneously, Lister formalized his theories on wound sepsis.

Realizing wound sepsis occurred due to pathogens entering the breaks in the skin, he developed dressings with carbolic acid which led to a significant decline in wound sepsis and associated death in his hospital.

However, it wasn’t until the late 19th and early 20th centuries that sepsis was better understood. The introduction of concepts like bacterial infection and inflammation paved the way for the identification of biomarkers associated with sepsis.

The Modern era of sepsis biomarkers


1990s researchers discovered that the levels of procalcitonin (PCT), the precursor of the hormone calcitonin, were elevated in patients with bacterial infections. Before its discovery diagnosing bacterial infections and distinguishing them from viral infections was often a challenging and time-consuming process. Clinicians had to rely on various clinical signs and laboratory tests, which were not always precise. This ambiguity often led to delayed or incorrect treatment decisions, impacting patient outcomes.

PCT measurements allowed for a more accurate and rapid differentiation between these two types of infections. As a result, clinicians gained a valuable tool to aid in diagnosing bacterial infections promptly and initiating appropriate treatments such as antibiotics when necessary.

However, its use a diagnostic biomarker for sepsis is questionable, as there are heterogeneous studies with lack of consensus about the use of PCT, and several medical societies do not recommend its use for sepsis diagnosis. Its use should be restricted to antibiotics withdrawal.

PCT values also lack any prognostic capability regarding the progression of sepsis.

Mid-20th century, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) emerged as potential biomarkers for sepsis. CRP, an acute-phase protein produced by the liver, was noted to increase in response to inflammation. ESR, on the other hand, measures the rate at which red blood cells settle in a tube of blood and can serve as a general indicator of inflammation. While these markers provided valuable information, they lacked specificity for sepsis.

Late 20th century 

Advancements in molecular biology and genetics allowed researchers to delve deeper into the intricacies of the immune response. Cytokines, small signalling proteins produced by immune cells, were found to play a crucial role in the development of sepsis. Their levels in the bloodstream provided insights into the severity of the condition. Additionally, genomic studies helped identify genetic factors that might predispose individuals to sepsis or influence their response to treatment.

In recent decades, the focus has shifted towards utilizing a panel of biomarkers rather than a single marker. This multi-marker approach provides a more comprehensive view of the complex sepsis pathology. Biomarkers like interleukins, chemokines, and cell surface markers have all contributed to a deeper understanding of the condition and improved patient care.

Present & Future 

Epigenetics has emerged as a fascinating area of research in understanding the mechanisms and potential treatments for sepsis. Epigenetics refers to the study of changes in gene expression or cellular traits that do not involve alterations to the DNA sequence itself. In sepsis, epigenetic modifications play a crucial role in both the development of the condition and its potential treatment strategies.

In summary, epigenetics plays a critical role in understanding the underlying molecular mechanisms of sepsis and offers promising avenues for diagnosis and treatment. By unraveling the epigenetic changes associated with sepsis, researchers and clinicians aim to improve early detection, tailor therapies, and ultimately enhance the prognosis and quality of life for septic patients.

Featured Articles

Featured video

Reproducir vídeo


Epigenetics IVD Newsletter

Reciba las últimas noticias sobre EpiDisease, y actualizaciones y análisis de los últimos avances sobre el desarrollo de herramientas IVD con nuestro boletín bimensual EPINEWS