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Sudden Fulminant Infection-caused Deaths:
A Biological Dark Matter Universe

Amesh A. Adalja, MD, FACP, FACEP, FIDSA | May 9, 2019

When death from infection is fulminant, it is an impressive pathophysiological process. The interplay between the immune system and the infecting microorganism causes a relentless and damaging derangement of physiology for which all interventions are futile. Understanding the etiology of these fulminant infections is an important task, but, in many cases, a systematic search for a specific etiologic agent of death is not performed. A study from the province of Ontario, Canada, recently published in Open Forum Infectious Diseases, provides important information on this phenomenon.

Infectious Causes Accounted for 6% of Unexpected Deaths

Sehgal and colleagues performed a retrospective cohort study of all unexpected deaths in Ontario that occurred between January 2016 and December 2017. An unexpected death was defined as an individual who was pronounced dead at a residence, en route to the hospital, or after recent hospital admission. Those deaths determined by a pathologist to be infectious in nature were included in the study. Culture, diagnostics, and histopathological specimens – antemortem and postmortem – were reviewed. These studies were sent at the pathologist’s discretion.

Of the 7,506 deaths classified as unexpected, 6% were determined to be due to an infectious etiology. The mean ages of unexpected deaths from infectious and noninfectious causes were not different. Unexpected infectious deaths were more likely to be of respiratory or intra-abdominal origin compared to noninfectious deaths, which were more often cardiac in nature. The median prodrome length of infection-caused deaths was 1 day, with 30% having had some healthcare contact in the days before death.

Pneumonia, Staph, Pneumococcus Predominated;
50% with No Pathogen Identified

Bacterial pneumonia was the most common cause identified (43%), followed by disseminated infection without an identified focus (12%). Pneumonia causes were most frequently caused by pneumococcus and Staphylococcus aureus. Viral pneumonias were overrepresented in the 0- to 20-year-old age group.

In only 50% of cases, however, was a pathogen identified. The most common pathogens isolated were the gram-positive bacterial species S. aureus, followed by pneumococcus and Group A streptococcus. Among the gram negatives, Klebsiella was most common. In fatal viral pneumonia cases, influenza predominated, with other deaths being due to parainfluenza, rhinovirus, and metapneumovirus.

Reducing Biological Dark Matter

Studies like this highlight an important issue: the lack of ability in the modern era to specifically identify the etiologic agent of severe infectious syndromes. That 50% of fulminant rapid deaths – with just a median of 1 day of prodromal symptoms – are not amenable to diagnosis is a major deficiency. Among the unexplained deaths will likely be found more of the common identified pathogens, but also some important pathogens that may be new to the geographic area or novel may occur. Potential pandemic pathogens may be among this cohort. This “biological dark matter,” capable of causing severe disease and death in a resource-rich nation, is an important space to explore and is, in many ways, akin to a disease “hot spot.” With the development of more sophisticated and sensitive diagnostic tests, as well as next-generation sequencing, it is important that these technologies be harnessed to increase the situational awareness of the pathogen landscape the world faces.


Sehgal P, Pollanen M, Daneman N. A retrospective forensic review of unexpected infectious deaths. Open Forum Infectious Diseases 2019;6(4). Accessed May 9, 2019.