In Tyrrell’s Rule of Three, we reminded people of the reality of the epidemiology of influenza-like illness (ILI) or acute respiratory infections (ARI). Call it what you want, but do not use the F word. 

 The rule was first muttered to Tom at the end of the 90s and is still valid today, as those following our Week in Numbers series know. It goes like this:

“In any given year, a third of upper respiratory infections will have no known cause. A third will be caused by a mixture of agents: this third consists of all known agents, with the exception of rhinoviridae, which cause the remaining third”.

As guessing is not in our arsenal, let us concentrate on the “missing third” for a minute. Of course, it is impossible to know what is going on. Some cases may be due to hitherto unknown agents (think of SARS-CoV-2), which are identified from time to time. Others may be due to diagnostic mistakes and laboratory errors, and some may not be infectious at all. 

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In this post, we lay out the evidence that stress can cause or precipitate ILI. 

Towards the end of its “life,” with closure looming on the horizon, the MRC Common Cold Unit examined the role of stress in the genesis. Tyrrell and Gwaltney, in turn, collaborated with Sheldon Cohen of Carnegie Mellon University in two studies of similar design.

In the first study, 276 volunteers aged 18 to 55 underwent screening, isolation and several rounds of life stressor and social network assessment before and after nasal challenge with rhinovirus, which was carried out in the middle of a quarantine period to avoid cross-infections. Forty percent of the volunteers developed ILI (or “colds”). To cut to the chase, those who smoked and had chronic stressors in their lives (lasting 3 months or more), especially work and family, had significantly more colds, nearly three times the odds. The role of other factors, such as level of education and personality traits, was less clear. Overall, the longer the stress period (follow-up was 2 years), the higher the risk of developing ILI.

This study tells us little about those who did not develop illness despite nasal bombardment with rhinovirus.

In the subsequent study, 394 health volunteers underwent a similar procedure but this time with three types of rhinovirus, one type of RSV, and Coronavirus 229E. 

Twenty-six controls were given saline nasal squirts. The findings are intriguing. Infection (confirmed by laboratory testing) and symptoms (confirmed by questionnaires and interviews) showed a clear dose-response with a degree of psychological stress. There was no difference by the respiratory agent. Analysis of other variables (smoking, diet, sleep, alcohol consumption and so on) did not explain the dose-response, which was aspecific. 

Perhaps the key finding is encapsulated in this sentence: 

“The stress index was associated with host resistance and not with differential exposure to the virus”  and “...the consistency of the stress-illness relation among three very different viruses….was impressive. This observation suggests that stress is associated with a suppression of a general resistance process in the host, leaving persons susceptible to to multiple infectious agents”  

The follow-up is unspecified but presumed to be 28 days as per standard Common Cold Unit procedures for follow-up serological testing.

So what? We hear you ask.

Acute stress can simulate ILI. 

Chronic stress is even worse and can open the door to everything that infects, whether it is A or B. A more recent prospective Spanish study carried out in the community (i.e., with naturally occurring ILI) supported these findings. The first study shows that even three months of stress have a significant impact; the second study suggests that the degree of stress is also important.

So, to what extent can this evidence explain recent events?

This post was written by two chronically stressed old geezers who are still alive (we think).

Readings

Cohen S, Frank E, Doyle WJ, Skoner DP, Rabin BS, Gwaltney JM Jr. Types of stressors that increase susceptibility to the common cold in healthy adults. Health Psychol. 1998 May;17(3):214-23. doi: 10.1037//0278-6133.17.3.214. PMID: 9619470.

Cohen S, Tyrrell DA, Smith AP. Psychological stress and susceptibility to the common cold. N Engl J Med. 1991 Aug 29;325(9):606-12. doi: 10.1056/NEJM199108293250903. PMID: 1713648.

Takkouche B, Regueira C, Gestal-Otero JJ. A cohort study of stress and the common cold. Epidemiology. 2001 May;12(3):345-9. doi: 10.1097/00001648-200105000-00015. PMID: 11338315.