COVID-19: Unravelling the Uncertainties

May 5, 2020

Tom Jefferson, Carl Heneghan

The Great German strategist Helmuth Von Moltke encapsulated uncertainty as follows:

“No plan of operations extends with any certainty beyond the first contact with the main hostile force”. 

In the arena of respiratory infectious agents, Moltke’s ‘tactical genius’ could aid our current thinking.

Moltke thought it was only possible to plan the beginning of a military operation.  What he meant is that leaders cannot foresee the future, and therefore need flexibility in their planning, as the uncertain will always happen.

The uncertainties

We have no idea how many respiratory agents there are. Since 1970, 1500 pathogens have been discovered. 70% of these have come from animals. Some authors report that up 40% of respiratory infections have no recognised causes. In our analysis of the RCGP surveillance data  (week 17 of 2020) out of 428 samples, 353 (82.5%) were an unknown agent, and only 75 (17.5%) were positive for COVID 19.

Perhaps, this is because our identification methods are not good, or perhaps because they are not infectious or they are caused by unknown agents like COVID 19 was up until a few months ago. Or perhaps, it is a mixture of these reasons.

By their very nature viruses are non-living objects which require host substrate to reproduce and mutate randomly. Some of them do so at very high rates. This has two major implications. First targeting a set antigenic configuration runs the risk of chasing “yesterday’s virus”, as in the case of influenza. Second that concentrating all our efforts in targeting specific agents may distract us from the appearance of new threats and lull us into a false sense of security.

The latter is the story of our preparedness for COVID 19 or any other agents for which we have no specific preventive interventions of therapies.

What should we do to minimise the risks of the unknown?

We do not really understand the ecology of respiratory viruses, and we cannot know or understand the ecology of unknown ones. To further our understanding and minimise the risks we need to: 

  1. Study zoonoses in detail including contact between humans and wild animals. 
  2. Devote resources to understanding the origins of outbreaks and possible facilitating factors for their diffusion. 
  3. De politicise the solutions. As all of these agents are potential global threats, politicising them and mudslinging matches are likely to impede science by creating barriers where none should be.
  4. Think multi-respiratory pathogen in terms of solutions: As we do not know what is around the corner, we must rely on measures which are aspecific, i.e. not directed to single agents. These are familiar to everyone by now: distancing, barriers, contact tracing and hygiene. The bonus here is that most of the measures also work against other types of agents such as gastrointestinal infections.
  5. We should understand the impact of places of quarantine or isolation. These should be self-standing dedicated facilities where infectious or potentially infectious patients can be treated without risks or displacement of those who need routine care.
  6. Understand the role the urban environment has in facilitating the transmission dynamics of respiratory infections. This includes the role of cities and towns; buildings (e.g., high rise buildings, hospitals, care homes); and modes of transports ( such as aeroplanes, buses and cruise ships).

Our understanding of the properties of respiratory pathogens is incomplete and the evidence gaps are vast – they should be filled as a matter of urgency. We should privilege studies looking at the effects of a mix of interventions and experimenting with different materials to reduce spread, harms (and hence enhance compliance) and contact. 

Furthermore,  studies of specific remedies such as drugs and vaccines should be carried out openly with anonymised data made publicly available. It is possible that altruistic volunteers may waive their right to anonymity as a service to humanity, thereby making the dataset complete and replicable. Compounds developed with state aid or are meant for wide consumption should not be covered by any form of confidentiality. Secrecy breeds plot theories with divisions and politics creeping in.

‘No battle plan ever survives contact with the enemy,’ said Von Moltke. Our so-called ‘plans’ for dealing with the outbreak have not survived contact with COVID-19.


Tom Jefferson is a senior associate tutor and honorary research fellow, Centre for Evidence-Based Medicine, University of Oxford. Disclosure statement is here

Carl Heneghan is Professor of Evidence-Based Medicine, Director of the Centre for Evidence-Based Medicine and Director of Studies for the Evidence-Based Health Care Programme. (Full bio and disclosure statement here)