Disease and aroma have been paired since the birth of medical science.
Olfaction, or smell, is, evolutionarily speaking, our oldest sense. Despite this pedigree, it receives much less attention than the show ponies of the sensory world: vision and hearing.
In fact, one survey conducted in 2011 found that around half of people aged 16 to 30 would rather give up their sense of smell than their smartphone or laptop.
This, perhaps, is not altogether surprising. Humans navigate the world primarily using sight and sound, so the loss of smell, or anosmia, is less of a hindrance than losing sight or hearing.
That being said, olfaction is not to be sniffed at - as we will see.
The whiff of disease
Producing a pungent stench is an essential ability for many creatures. For example, pheromones can be considered an olfactory marketing campaign, advertising a healthy animal to potential mates far and wide.
But in this section, we discuss the opposite side of the fragrance coin; rather than healthy aromas, we take a look at the olfactory cues associated with disease and ask, "What do diseases smell like?"
Since the early days of medical science, people have linked certain diseases to specific smells. For instance, one passage in the Sushruta Samhita - a Sanskrit text written long before the birth of Christ - reads:
"[B]y the sense of smell we can recognize the peculiar perspiration of many diseases, which has an important bearing on their identification."
Over more recent years, doctors have moved away from sniffing their patients and tasting their urine to more socially acceptable (and reliable) methods. However, certain diseases are still thought to have a characteristic smell.
The following descriptions of diseases' aromas come from a paper published in 1998.
- scrofula - stale beer
- typhoid fever - baked bread
- yellow fever - a butcher's shop
- diphtheria - sweet
- diabetic ketosis - a fruity aroma of decomposing apples
- inability to metabolize methionine - boiled cabbage
- hyperaminoaciduria - dried malt or hops
Sniffing out an immune response
From an evolutionary standpoint, being able to sniff out a sick individual would be an advantage. If a mouse could detect the whiff of an immune response and avoid a colleague with an onboard pathogen, their ability to survive would be enhanced.
Humans also appear to be able to sniff out those who are currently embarking on an immune response, and a study published in the journal Psychological Science put it to the test.
First, samples of body odor were taken from a group of healthy volunteers. Then, the scientists triggered an immune response by injecting the participants with endotoxin. Their body odor was once again sampled, and then assessed and rated.
The authors concluded:
"Within just a few hours, endotoxin-exposed individuals had a more aversive body odor relative to when they were exposed to a placebo. Moreover, this effect was statistically mediated by the individuals' level of immune activation."
Therefore, sick people smelled worse - and the sicker they were, the worse their smell was rated.
Interestingly, the differences in odor could be detected within just 4 hours of the immune system being triggered. It is also worth noting that the sick people did not sweat more, and that the smell was not only stronger, but different, as well.
How can immune response alter body odor?
Before we answer this question, it is worth also asking, "What is body odor?" In humans, body odor is primarily due to bacteria and skin gland secretions - particularly the apocrine sweat glands that are found in the armpits, among other locations.
Body odor is, in fact, a complex and variable cocktail of compounds, including exotically named chemicals such as E-3-methyl-2-hexenoic acid, 3-methyl-3-sulfanylhexan-1-ol, and sulfanylalkanols.
There are a number of ways that an infection could modify a person's aroma. Firstly, our bodies are rammed to the rafters with microbes, some of which play a role in the way we smell. Therefore, a pathogen that alters the levels or types of these microbes could also adjust our body odor.
Secondly, genes associated with the major histocompatibility complex that control the body's immune response also influence odor and mating preferences in mice.
Thirdly, an activated immune system changes the excretion of other metabolic byproducts from the endocrine, or hormonal, system. For instance, levels of corticosterone in the blood are elevated during an immune response, and androgens are reduced.
The human nose is nowhere near as refined as the canine's. Over recent years, scientists have investigated whether dogs might be able to use their impressive powers to detect cancer.
Could canines help to improve cancer-detection?
The findings are not without controversy, but some studies have yielded impressive detection rates. For example, in one study, four trained sniffer dogs were able to detect lung cancer in breath samples from 125 people with accuracy rates of 68 to 84 percent.
Another study demonstrated that an 8-year-old female black Labrador Retriever could correctly diagnose more than 90 percent of colorectal cancers from breath and stool samples. She was even able to detect early cancers.
Although training dogs to be ever more accurate might be useful in diagnosing cancers early, it is not a perfect solution; it involves intense, expensive training and the time of an experienced handler.
Also, there is variability in accuracy between dogs, and even in the same dog on different days. Some studies have also produced less impressive, almost random results.
Because of these issues, the current emphasis is on replicating the hound's nose with an artificial olfaction sensor, or an "electronic nose," which detects volatile organic compounds.
Electronic noses have come on leaps and bounds in recent years and are now capable of detecting and recognizing a range of specific flavors and odors. They are already used in some industrial processes.
Most electronic noses use sensor arrays that react to volatile compounds as they make contact; the sensors physically change as they interact. These changes are digitally recorded and pumped through statistical models.
There is hope that electronic noses will, one day, be able to detect bacteria and distinguish MRSA in hospital ventilation systems. Scientists have also tried to use them to detect lung cancer from expelled breath and to identify brain tumors.
Others have tried to use electronic noses to detect kidney disease, bowel disease, and diabetes from urine. Results have varied, but a nonintrusive way to detect medical conditions at an early stage would be of huge benefit.
The impact of a reduced sense of smell
Sadly, anosmia and hyposmia - that is, a partial loss of sense of smell - have received relatively little research. They are not considered critical and have therefore attracted less interest and funding.
Anosmia comes with a host of potential dangers.
However, impaired olfactory function affects an estimated 2.7 million adults in the United States.
A reduced sense of smell can be caused in a number of ways, including head trauma, viral infections, nasal obstruction, some medications, and neurologic disorders. And it is far from a harmless annoyance.
A paper titled "Hazardous events associated with impaired olfactory function" set out to document the dangers linked with a reduced sense of smell.
They found that more than a third of 124 people with a reduced sense of smell had experienced a related hazardous event. These included:
- cooking-related incidents - 45 percent of respondents
- eating spoiled food - 25 percent
- inability to detect a gas leak - 23 percent
- inability to smell fire - 7 percent
At the other end of the scale, some people with hyposmia become obese because salty, deep-fried foods are the only ones that seem appealing. Also, because taste stimulates salivary and pancreatic activity, a reduced sense of smell can interfere with digestion.
Sense of smell and dementia diagnosis
Due in part to the aging population, dementia is an ever-increasing problem. And unfortunately, dementia is difficult to treat and cannot be cured. The emphasis is on treating the symptoms, slowing the disease, and, wherever possible, catching it early.
Early diagnosis can be difficult as there are no biomarkers and early symptoms are often mistaken for normal aging. Here's where olfaction comes in.
An impaired sense of smell is one of the earliest clinical features of both Parkinson's disease and Alzheimer's. There is an overall reduction in the sense of smell, particularly affecting the individual's ability to identify and recognize odors.
A number of studies have investigated whether or not this factor might be useful in diagnosis. In a meta-analysis of 81 studies, the authors conclude:
"[O]lfactory identification and recognition appear as the most interesting candidates to be included in a battery to detect subclinical cases in AD [Alzheimer's disease]."
Another study found that olfaction deficits are more significant in people with Lewy body disease (LBD) than in those with Alzheimer's. Distinguishing between the two is important because drugs used for some dementias are not appropriate for people with LBD.
To conclude, although substantial leaps in olfaction research are few and far between, there is certainly a great deal of potential for the future of medical diagnostic technology. As Alexander Graham Bell noted, "If you are ambitious to find a new science, measure a smell."