Post-infectious body odor

Every infection has a distinct odor. It could be associated with changes in the gut microbiome. Besides, circulating B-cells from our immune system are also producing chemical odors that appear after viral infection. T-cell and cytokine involvement is also possible. Infections can change body odor for the worse.  PATM or MEBO conditions could begin after an infection and linger thereafter.  

COVID-19 is known to be associated with a specific odor.  Early studies identified volatile compounds that discriminated COVID-19 from other conditions. Some of these compounds - such as fruity smelling ketones - are also associated with diabetes - a risk factor for Severe COVID-19 infection. Another compound, Heptanal, associated with lung cancer, can also predict the severity of the Coronavirus disease.

Dogs (and rats and other animals) can easily detect the smell of COVID-19. They are already helping during this pandemic - Massachusetts schools, for example, are using dogs to sniff out Covid-19. The dogs come to the schools weekly and work to detect cases in empty classrooms, auditoriums, cafeterias and gymnasiums, If Covid is detected, the authorities tell the health nurse who relays the information to the people affected.

Long COVID - when people continue to have symptoms of COVID-19 for months after their initial illness. - has a distinct smell as well. A paper posted today on MedRxiv tells that dogs can easily detect long COVID as well - in at least half of the cases. 

Between May and October 2021, 45 Long COVID patients sent their axillary sweat samples to the National Veterinary School of Alfort. Average age of the patients was 45 (6-71) and 73.3% were female. No patient had been admitted in intensive care unit during the acute phase. Prolonged symptoms had been evolving for an average of 15.2 months (range: 5-22). Main symptoms of prolonged phase were intense fatigue (n=37, 82.2%), neurocognitive disorders such as concentration and attention difficulties, immediate memory loss (n=24, 53.3%), myalgias/arthralgias (n=22, 48.9%), cardiopulmonary symptoms (dyspnea, cough, chest pain, palpitations) (n=21, 46.7%), digestive symptoms (diarrhea, abdominal pain, reflux, gastroparesis...) (n=18, 40.0%), ENT disorders (hyposmia, parosmia, tinnitus, nasal obstruction, inflammatory tongue, dysphonia, sinusitis) (n=18, 40.0%) (table 1). 11 (24.4) patients had at least one positive SARS-CoV-2 serology before any vaccination, 29 (64.4%) had a negative SARS-CoV-2 serology and 5 (11.1%) had no serology results. Snapshot of the table shows some of the cases. Interestingly, patients with odor exhibited symptoms similar to long COVID sufferers in the MEBO community. This includes loss of smell and heart palpitations. 

REFERENCES

Dominique GRANDJEAN, Dorsaf SLAMA, Capucine GALLET, Clothilde JULIEN, Emilie SEYRAT, Marc BLONDOT, Maissa BENAZAZIEZ, Judith ELBAZ, Dominique SALMON Screening for SARS-CoV-2 persistence in Long COVID patients using sniffer dogs and scents from axillary sweats samples  medRxiv 2022.01.11.21268036; doi: https://doi.org/10.1101/2022.01.11.21268036

Worried about body odor?

You are not alone. According to pre-COVID surveys, over one third said the fear of smelling unpleasant left them feeling unhappy and unattractive. Many people who survived COVID-19 worry about their body odor getting worse post-infection.

A team of researchers from Virginia Commonwealth University surveyed 322 individuals with loss of smell or taste as a result of confirmed COVID-19 infection and found that about half of them felt depressed and worried about their body odor [Coelho et al., 2021].  Extrapolating results of other surveys, this translates into about 20% of those who got through COVID-19.  

The most frequently reported phantom smell (likely not actually there) is the odor of smoke or burned food [Frasnelli et al, 2004]. Interestingly, these are also the most frequently reported types of smells that long-COVID sufferers can't perceive, when others detect them. 

Temporary loss of smell is common. About 20% of population experience it sometime before the age of 75. This number increases to ~80% in older age. 

Loss of smell associated with viral infections, especially COVID-19 is much more prevalent. Sometimes it's the only symptom associated with this infection. A meta-analysis of published reports reveals that the overall prevalence of alteration of the sense of smell or taste following COVID-19 infection ranges between 31% and 67% in severe and mild-to-moderate symptomatic patients, respectively. Fortunately, in most (70-80%) cases it comes back in 6 month or longer. A higher recovery rate was highlighted for subjects who underwent influenza vaccination. 

REFERENCES

Coelho DH, Reiter ER, Budd SG, Shin Y, Kons ZA, Costanzo RM. Quality of life and safety impact of COVID-19 associated smell and taste disturbances. American Journal of Otolaryngology. 2021 Jul 1;42(4):103001.

Frasnelli J, Landis BN, Heilmann S, Hauswald B, Hüttenbrink KB, Lacroix JS, Leopold DA, Hummel T. Clinical presentation of qualitative olfactory dysfunction. European Archives of Oto-Rhino-Laryngology and Head & Neck. 2004 Aug;261(7):411-5. 

Maiorano E, Calastri A, Robotti C, Cassaniti I, Baldanti F, Zuccaro V, Stellin E, Ferretti VV, Klersy C, Benazzo M. Clinical, virological and immunological evolution of the olfactory and gustatory dysfunction in COVID-19. American Journal of Otolaryngology. 2022 Jan 1;43(1):103170.

Vaira LA, De Vito A, Lechien JR, Chiesa‐Estomba CM, Mayo‐Yàñez M, Calvo‐Henrìquez C, Saussez S, Madeddu G, Babudieri S, Boscolo‐Rizzo P, Hopkins C. New onset of smell and taste loss are common findings also in patients with symptomatic COVID‐19 after complete vaccination. The Laryngoscope. 2021 Nov 26.

FMO3 and COVID-19

Flavin-containing monooxygenase 3 (FMO3) enzyme is a seemingly insignificant enzyme that normally converts fishy-smelling trimethylamine (TMA) into a neutral trimethylamine-N-oxide (TMAO). The amounts of this highly specialized detoxifying enzyme are highly variable. It depends on the age, sex hormones, infections (estradiol and testosterone, hepatitis virus have been found to reduce FMO3 capacity), obesity traits and diseases such as diabetes. The difference can be up to 20-fold between individuals. Mutations in the FMO3 gene cause low metabolic capacity associated with the disorder trimethylaminuria (TMAU) that attracts little biomedical interest.  This condition, however, might matter more than it seems.

Could there be a link between FMO3 and SARS-CoV-2 infection and vaccination? 

Individuals differ in their susceptibility to viral infections and genes contribute to the risk score. Less than 10% of humans infected with Mycobacterium tuberculosis develop TB, partially because of polymorphism in Tyrosine kinase (TYK2, P1104A) also responsible for severe COVID-19. Early in the pandemic, it was discovered that SARS-CoV-2 infection is dependent on the ACE2 receptor for cell entry and the serine protease TMPRSS2 for spike protein priming. ACE2 expression, indeed, influences COVID-19 risk and a rare variant located close to this gene was found to confer protection against COVID-19, possibly by decreasing ACE2 expression. Interestingly, FMO3 is one of the few genes with expression correlated to ACE2 [Sungnak et al, 2020] along with genes associated with immune functions. 

One of the characteristics of COVID-19 is the appearance of inflammatory processes, which could be leading to increased levels of TMAO. It could contribute to the hypercoagulative state in COVID-19-associated coagulopathy (CAC). SARS-Cov2 was shown to enhance TMAO-induced inflammation.  

Coronavirus disease is associated with increased risk of thrombotic events. According to recent research, low levels of FMO3 protect against thrombosis [Shih et al, 2019] while some FMO3 mutations confer higher risk [Oliveira-Filho et al, 2021]. FMO3 rs1736557 might increase the anti‐platelet efficacy of clopidogrel [Zhu et al, 2021]. Genetic risk can be mediated by gut microbiota [Gabashvili, 2020]. There are also associations with salt tolerance, wound healing, and diseases such as diabetes, renal and cardiovascular conditions increasing risk of severe COVID-19. 

Studying trimethylaminuria-like conditions might help in developing strategies for prevention and therapy of other diseases, including COVID-19.

Our COVID-19 disease and vaccines study [NCT04832932, Gabashvili, 2021] compares side-effects of vaccines and clinical course of infections (including vaccine breakthroughs) in several cohorts including MEBO and TMAU. You can help by enrolling and participating in this online survey in English or Spanish.

REFERENCES

Andreakos E, Abel L, Vinh DC, Kaja E, Drolet BA, Zhang Q, O’Farrelly C, Novelli G, Rodríguez-Gallego C, Haerynck F, Prando C. A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection. Nature immunology. 2021 Oct 18:1-6. 

Gabashvili IS. Cutaneous Bacteria in the Gut Microbiome as Biomarkers of Systemic Malodor and People Are Allergic to Me (PATM) Conditions: Insights from a Virtually Conducted Clinical Trial. JMIR Dermatology. 2020 Nov 4;3(1):e10508.  

Gabashvili IS. Community-Based Phenotypic Study of Safety, Tolerability, Reactogenicity and Immunogenicity of Emergency-Use-Authorized Vaccines Against COVID-19 and Viral Shedding Potential of Post-Vaccination Infections: Protocol for an Ambispective study. medRxiv 2021.06.28.21256779; doi: https://doi.org/10.1101/2021.06.28.21256779

Liu W, Wang C, Xia Y, Xia W, Liu G, Ren C, Gu Y, Li X, Lu P. Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy. Acta Diabetologica. 2021 Feb;58(2):221-9.

Janmohamed A, Dolphin CT, Phillips IR, Shephard EA. Quantification and cellular localization of expression in human skin of genes encoding flavin-containing monooxygenases and cytochromes P450. Biochemical pharmacology. 2001 Sep 15;62(6):777-86.

Oliveira-Filho AF, Medeiros PF, Velloso RN, Lima EC, Aquino IM, Nunes AB. Trimethylaminuria and Vascular Complications. Journal of the Endocrine Society. 2021 Apr;5(Supplement_1):A313-4. 

Zhu KX, Song PY, Li MP, Du YX, Ma QL, Peng LM, Chen XP. Association of FMO3 rs1736557 polymorphism with clopidogrel response in Chinese patients with coronary artery disease. European Journal of Clinical Pharmacology. 2021 Mar;77(3):359-68.

Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, Worlock KB. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature medicine. 2020 May;26(5):681-7.

Shih, D.M., Zhu, W., Schugar, R.C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M. and Allayee, H., 2019. Genetic deficiency of Flavin-containing monooxygenase 3 (Fmo3) protects against thrombosis but has only a minor effect on plasma lipid levels—brief report. Arteriosclerosis, thrombosis, and vascular biology, 39(6), pp.1045-1054. 

The PKU microbiome

Phenylketonuria or PKU is an inborn error of metabolism associated with a "mousy" or "musty" odor. This odor is due to a buildup of phenylalanine substances in the body. Recent study explored gut microbiome in adults with PKU and found high levels of Bifidobacterium, Bacillus, Alistipes, Clostridium, Akkermansia, and Bacteroides, while much lower levels of Lactobacillus, Porphyromonas, Frisingicoccus, Blautia, and Faecalibacterium.

REFERENCES

Mancilla VJ, Mann AE, Zhang Y, Allen MS. The Adult Phenylketonuria (PKU) Gut Microbiome. Microorganisms 2021, 9, 530.