The Breathprint of COVID-19

Bad breath in those infected with COVID-19 might be the least of their problems. But studying it helps in understanding the mechanisms of this deadly respiratory disease and developing diagnostic tests. 

Dozens of confirmed cases of halitosis owing to active infection by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) have been reported in the literature (Patel & Woolley, 2020; Riad et al, 2020)

Possible explanations were decreased salivatory flow due to angiotensin‐converting enzyme 2 receptor-mediated alterations in the tongue, a greater risk of bad breath for mouth breathers who are also more prone to halitosis and increased attention to odor when wearing face masks. Another likely explanation is bacterial co‐infections arising from the novel coronavirus.

DNA analyses of microbial communities in the respiratory tract of those infected with SARS‐CoV‐2 frequently detect abnormally high bacterial reads of Prevotella, Streptococci, Treponema, Veillonella and Fusobacteria, known to emit malodorous volatile sulfur compounds and volatile fatty acids (VFAs). In addition to odor, VFAs could impair T- and B-cell proliferation responses and cytokine production.

What molecules could we expect to find in a person infected with the novel coronavirus? Lamote and colleagues review dozens of (often overlapping) molecules detected in other infections. Among those are aliphatic alcohols, branched hydrocarbons, alkane derivatives, terpenes, dimethyl sulfide and other sulfur and nitrogen-containing compounds. Three aldehydes (octanal, nonanal, and heptanal) drew special attention as candidate biomarkers in pediatric SARS-Cov-2 infection (Berna et al., 2020). These three biomarkers demonstrated 100% sensitivity and 66.6% specificity. Analysis of breath in two groups of adults with median ages 40 and 60 identified aldehydes (ethanal, octanal), ketones (acetone, butanone), and methanol that discriminated COVID-19 from other conditions. Aldehyde Heptanal had significant predictive power for severity of the disease.

It has been shown that properly trained dogs  are able to detect an olfactory signature of SARS-CoV-2 infection with a specificity greater than 90%. Several clinical trials have been initiated to study biomarkers of COVID-19 in breath by e-nose and other technologies. Two studies have been already completed and one paper reported successful detection using Aeronose (Wintjens et al, 2020) with 86% sensitivity and negative predictive value of 92%. Gas Chromatography-Ion Mobility Spectrometry allowed differentiation of patients with definite diagnosis of Covid-19 from non-Covid-19 with about 80% accuracy and 82.4%/75% to 90%/80% sensitivity/specificity. 

REFERENCES

Patel J, Woolley J. Necrotizing periodontal disease: Oral manifestation of COVID‐19. Oral diseases. 2020 Jun 7.

Riad A, Kassem I, Hockova B, Badrah M, Klugar M. Halitosis in COVID-19 patients. Special care in dentistry: official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2020 Nov.29

Lamote K, Janssens E, Schillebeeckx E, Lapperre TS, De Winter BY, Van Meerbeeck JP. The scent of COVID-19: viral (semi-) volatiles as fast diagnostic biomarkers?. Journal of breath research. 2020 Jun 29.

Berna AZ, Akaho EH, Harris RM, Congdon M, Korn E, Neher S, Farrej MM, Burns J, John AO. Breath biomarkers of pediatric SARS-CoV-2 infection: a pilot study. medRxiv. 2020 Dec. 7

Ruszkiewicz DM, Sanders D, O'Brien R, Hempel F, Reed MJ, Riepe AC, Bailie K, Brodrick E, Darnley K, Ellerkmann R, Mueller O. Diagnosis of COVID-19 by analysis of breath with gas chromatography-ion mobility spectrometry-a feasibility study. EClinicalMedicine. 2020 Oct 24:100609.

Wintjens AG, Hintzen KF, Engelen SM, Lubbers T, Savelkoul PH, Wesseling G, van der Palen JA, Bouvy ND. Applying the electronic nose for pre-operative SARS-CoV-2 screening. Surgical endoscopy. 2020 Dec 2:1-8.

What's that fatty odor?

Body odor is closely associated with diet. Deciphering the chemistry of human odor is not an easy task - only about 5% of odorous molecules are usually recovered from collection containers, and not all of the molecules are identified in complex spectra. Volatile fatty acids, alcohols, and aromatic ring compounds comprise a substantial fraction of smelly molecules, yet very little is known about the origin and factors controlling their production in humans. Fortunately for some (and not so fortunately for others), the human nose can capture and discriminate many smell signatures. Could this discrimination be used to connect the dots between diet and body odor? MEBO Research has just started an anonymous study using the Aurametrix health analysis tool to find out.

Aurametrix's knowledge base provides a wide selection of foods and symptoms, including different types of odors recognizable by the human nose. Participants in the study have been recording some of their food intake and activities on days when their symptoms are better or worse than average, entering items they suspect might be contributing to or alleviating their body odor on those days. The tool's analysis engine then lets them explore all the possible cause-effect relationships. In addition, Aurametrix performs automated analyses across the entire user community and displays cumulative results as "aggregate correlations." The figure on the right is an excerpt from these results.

Although the study has only just begun, the preliminary results already look very interesting. One example is fatty odor. Aurametrix linked several dietary chemicals to unpleasant "fatty odor" emanating from skin based on Aura entries of several participants. The top chemicals so far are:  Vitamin K1 (phylloquinone), Octadecanoic acid, FODMAPs, Beta-carotene,  Carbohydrates and Monosaccharides. Another interesting result (although there were fewer observations) is that Vitamin B12 obtained from diet seemed to help prevent fatty body odor.

• Could Vitamin K1 really contribute to "fatty" odor?  Could 6 observations derived from different users' Auras be just a coincidence? Vitamin K is proposed to increase production of alkaline phosphatase in intestines. This enzyme produces a number of different substances, some of which have a peculiar sweetish smell.  Chlorophyll, usually recommended to combat body odor and supposedly makes odor "sweeter," is an excellent source of vitamin K1. And so is Asparagus that gives urine a disagreeable odor.
• Octadecanoic (Stearic) acid was also linked to fatty odor in 6 observations. This saturated fatty acid is most abundant in animal fats and cocoa butter, and also in nuts and seeds (peanuts, flax), cheese, cookies and candies. Its smell is fairly mild, yet can be detected by the human nose (Bolton and Halpern, 2010). Besides, it slowly converts in the liver to heart-healthy oleic acid which has a faintly fatty odor with a hint of dead insects. It could also metabolize into other compounds and incorporate into liver lipids or follow alternative routes.
• FODMAPs, highly fermentable but poorly absorbed short-chain carbohydrates and polyols, were found to be an important dietary factor contributing to gastrointestinal symptoms. Perhaps FODMAPs, carbohydrates and monosacharides in particular could also contribute to odor in the absence of GI discomfort?
• Beta-carotene is another heart-healthy chemical with anticancerous properties important in human nutrition as a source of Vitamin A. Tobacco, tea, many spices and flowers owe their flavors to chemicals metabolized from beta-carotene. One of such chemicals is warm and woody beta-Ionone that smells of blackberry at lower concentrations and fatty-cheesy at higher concentrations.

The chemistry of odors and their origins is undoubtedly very complex. Yet, these preliminary results show that together we may find the answers to many health-related questions. With more participants, we'll soon connect the dots between diet and body odor. Want to participate? Write to:

References

Bolton B, & Halpern BP (2010). Orthonasal and retronasal but not oral-cavity-only discrimination of vapor-phase fatty acids. Chemical senses, 35 (3), 229-38 PMID: 20100787

Dunkel M, Schmidt U, Struck S, Berger L, Gruening B, Hossbach J, Jaeger IS, Effmert U, Piechulla B, Eriksson R, Knudsen J, & Preissner R (2009). SuperScent--a database of flavors and scents. Nucleic acids research, 37 (Database issue) PMID: 18931377