I was recently asked how many common cold viruses are among us at a given time? The short answer is – dozens! 

In the past, I’ve written a few reviews (for example these in 2008, 2009, 2013 and this book chapter) featuring the main common cold viruses, the rhinoviruses. In some of those, I’d summarised a few papers that made note of how many distinct rhinoviruses (RV) of the three known species (Rhinovirus A [RV-A; n=80), Rhinovirus B [RV-B; n=32] and Rhinovirus C [RV-C; n=56] co-circulate at a single site in a defined period of time.

A Brisbane birth cohort study gave us a frame of reference for all of this. It found that during the first two years of life – our most active period of “meeting” all the new respiratory viruses – healthy advantaged Australian children had 13 discrete and obvious short-term episodes of illness which manifest with respiratory tract signs and symptoms; so-called acute respiratory infections (ARIs).

We become infected from birth and, with decreasing rates of illness, continue to be infected throughout our lives.

Family, Genus, Species and all the genotypes that follow

The RVs sit in a taxonomic hierarchy that, from the top down, reads like this… 

• Family: Picornaviridae
• Genus: Enterovirus
• Species: Rhinovirus A, Rhinovirus B, Rhinovirus C
• Virus name: rhinovirus A1, rhinovirus B3 and rhinovirus C1 (respectively)

Anything below this level of naming has traditionally been called a serotype – because that’s how they were defined at the time, with antibody-based tools.

But today we define them with genetic sequence criteria, so I’m just calling all of these distinct viruses, genotypes. I think this makes more sense than types (oh the discussion this paper generated behind the scenes!).

There can also be strains of each genotype (think…differently number-plated cars of the same model which belong to one particular make (=species)).

Studies with details from the old days

In the 1960s, when cell culture methods were used to diagnose virus infections – not the more sensitive PCR methods – one 1964 study still managed to identify 46 different serotypes over 3 successive seasons (1959/60, 1960/61 and 1961/62). This study sampled from ill children and adults from Pennsylvania and New Jersey, United States. 

Between 1998 and 2000, 289 children were enrolled in the Childhood Origins of ASThma (COAST) cohort study.  During the first year of life, a virus was identified in 962 of 1,445 samples with 93 genotypes being identified from among 519 solitary RV infections.

Studies from the naughties

Fast forward to a 2009 study, there were 30 distinct RV-C genotypes alone, identified among children under 5 years of age (yoa) who were in a hospital for acute respiratory symptoms or fever over a 24-month period from October 2001 to September 2003 in Nashville and Rochester, United States. 

A 2007 study did genotype the RVs it found in 75% of samples during a 3-year study of children hospitalised because of acute respiratory illnesses in Bad Kreuznach, Germany. Unfortunately, they didn’t analyse the number of genotypes but did find multiple distinct viruses.

Among 21 neonates (those aged from 0 to 4 months of age) with an RV-positive infection between September 2010 to October 2012, there were 31 positive nasal swabs of which 18 could be typed, revealing 17 different genotypes including viruses from the first week of life. 

In a 2010 studyof 58 children aged 6-8-yoa, samples were collected weekly during April and September 2006, and 2007 and April 2008 in Wisconson, Madison, United States. They found 6-19 genotypes in each period. 

A 2011 study used quite stringent cut-offs to define their genotypes, finding 27 genotypes among 18 0-7yoa children sampled every 2-weeks over a 6-month winter period in The Netherlands. They’d probably have identified more genotypes had they loosened their criteria a bit.

A similar problem seems to have resulted in even fewer genotypes detected across a 24-month period in a 2002 study that selected from samples collected from children under 2-yoa in Finland. Another study from 2011 from Western Australia, Australia, identified 56 genotypes (22 RV-As, 2 RV-Bs and 32 RV-Cs) among asthmatic children, 2-16-yoa. The time period wasn’t clarified in this study so it doesn’t tell us about how many concurrently circulating genotypes. 

In 2012, we published a study that found 74 distinct RVs among healthy preschool-aged children, over a 12-month period in Melbourne Australia. In a study between November 2013 and February 2014, 88 healthy children in Milan, Italy were swabbed weekly, in their homes, identifying 326 RV infections representing at least 29 genotypes of all three RV species. 

We also wrote up our retrospective data from 2001, in 2020, which described 70 genotypes among an unselected sample of mostly young patients at a hospital or clinic.

In a 2018 report, RV circulation among 225 children followed for 2 years after enrollment, or up to age 40 months, was examined in a childcare environment from in Washington, United States. 41 genotypes were identified among children aged between 5 weeks and 30 months from 455 swabbed illnesses in which RVs featured.

So it’s clear that the answer to “how many common cold viruses circulate among us?” is something like 50-100 at a given site when we use sensitive detection methods based on PCR.

Still an underestimate of the impact outside of a hospital

Generally speaking, RV studies that target people out in the community have noted problems with being able to get a genotype from an RV-positive infection. This seems to be because viral loads are lower and the near the limit of some tests and protocols that seek genetic sequence information. That makes it harder to know how many common cold viruses are there.

Perhaps not surprisingly, when we go to a hospital for an RV infection, we’re pretty sick and we can often have more virus replicating. More virus makes it easier to obtain genetic sequences. 

The long and the short of this is that we probably still miss a little of the RV genetic diversity that creates a mild to a moderate day-to-day burden on our lives.

Why does knowing how many viruses are present, matter?

There are a few interesting and important reasons to understand virus diversity over time. 

1. Knowing which genotypes are present can be used to look at whether some genotypes cause more severe disease than others. The RV-Cs for example, seem to be better at triggering asthma attacks than the As or Bs. That knowledge may help target vaccines to the most serious of this diverse spectrum of viruses.
2. The same respiratory virus doesn’t usually make up most of the noticeable (the kind that makes you sick) infections at the same site, year after year. This is because the people at that site who were infected, develop immunity making it harder for that virus to get a foothold. They still tick over, but not at the same high levels so it looks like new viruses replace old ones each year. This gets missed without genotyping.  You can see quite nicely in the Wisconsin study that species and genotype actively exchange.
3. In the past, there was a belief that RVs could cause persistent or chronic (>4 weeks of a cold) infections. With genotyping, we now know this is a rare event. What we usually see is RV exchange sometimes accompanying an imperceptible change in illness. What’s happening is more than one episode of illness, but because they are due to back-to-back infections by different RV genotypes, we may not notice the changeover.
4. It’s important to know how many common cold viruses are causing infections for future vaccine developments. How many different viruses need to be covered by a vaccine for it to have a decent impact on preventing the illness?
5. Surveillance of viruses is important to be sure a new genotype hasn’t emerged to cause unexpected pathology. If such a new genotype had changes in its proteins, those might escape our immune system’s memory of former infections, and we might find we have an epidemic of even a little old common cold virus on our hands. And faces. And surfaces. I don’t think this would be anywhere like as inconsequential as it sounds.
6. Down the list but still important is genetic surveillance to ensure our genetic sequence-based diagnostic methods are working to expectations. Are they capturing all of the expected members of a species or genus? We can only be sure of our PCR assays if we keep checking new genotype genomes against the PCR primers we use.

So how many common cold viruses in one place?

To answer the original question – over a 1 to 2 year period, it isn’t unusual to see up to 93 distinct RVs in a particular region. Not surprising we get a few colds each year is it? What might be surprising to some is how many times we get infected but don’t get very ill at all.

The human immune system is an amazing and nimble system for keeping viral illnesses under control. Keep feeding it with healthy food, some sunlight, decent amounts of sleep and some exercise and it will keep you safe from a lot of things. But sometimes those viruses get away from us like when we’re very young, old, already sick or meeting a new genotype. Then we get sick.

References…

1. Human rhinoviruses: The cold wars resume https://www.journalofclinicalvirology.com/article/S1386-6532(08)00130-3/fulltext
2. Human rhinoviruses: coming in from the cold https://genomemedicine.biomedcentral.com/articles/10.1186/gm44
3. From sneeze to wheeze: What we know about rhinovirus Cs https://www.ncbi.nlm.nih.gov/pubmed/23714395
4. Cough Formation in Viral Infections in Children https://eprints.qut.edu.au/64724/
5. Proposals for the classification of human rhinovirus species C into genotypically assigned types https://www.ncbi.nlm.nih.gov/pubmed/20610666
6. The burden of community‐managed acute respiratory infections in the first 2‐years of life https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.23480
7. EPIDEMIOLOGIC INVESTIGATIONS OF RHINOVIRUS INFECTIONS. https://www.ncbi.nlm.nih.gov/pubmed/14233470
8. Highly frequent infections with human rhinovirus in healthy young children: A longitudinal cohort study https://www.ncbi.nlm.nih.gov/pubmed/21982210
9. A Recently Identified Rhinovirus Genotype Is Associated with Severe Respiratory-Tract Infection in Children in Germany https://www.ncbi.nlm.nih.gov/pubmed/18190255
10. Weekly monitoring of children with asthma for infections and illness during common cold seasons https://www.ncbi.nlm.nih.gov/pubmed/20392488
11. Respiratory Viruses in Neonates: A Prospective, Community-based Birth Cohort Study. https://www.ncbi.nlm.nih.gov/pubmed/27580059
12. The Childhood Origins of Asthma (COAST) study https://www.ncbi.nlm.nih.gov/pubmed/12688623
13. Phylogenetic analysis of rhinovirus isolates collected during successive epidemic seasons https://www.sciencedirect.com/science/article/pii/S0168170202000163
14. A novel group of rhinoviruses is associated with asthma hospitalizations https://www.ncbi.nlm.nih.gov/pubmed/19027147
15. Community-wide, contemporaneous circulation of a broad spectrum of human rhinoviruses in healthy Australian preschool-aged children during a 12-month period https://academic.oup.com/jid/article/207/9/1433/927248
16. Human rhinovirus C: age, season, and lower respiratory illness over the past 3 decades. https://www.ncbi.nlm.nih.gov/pubmed/23146382
17. Prospective evaluation of rhinovirus infection in healthy young children. https://www.ncbi.nlm.nih.gov/pubmed/25866344
18. Heterotypic Infection and Spread of Rhinovirus A, B, and C among Childcare Attendees https://www.ncbi.nlm.nih.gov/pubmed/29684211
19. Genotypic diversity, circulation patterns and co-detections among rhinoviruses in Queensland, 2001
    https://www.microbiologyresearch.org/content/journal/acmi/10.1099/acmi.0.000075

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