A cold virus in the blood…

Sometimes, viruses jump – or leak – from where we think they belong, turning up in an unexpected body compartment. We saw it with Ebola virus – it’s now known to have an unquantified but non-zero risk of sexual transmission via the semen [1]; we saw it with Zika virus – it is now known to cross into maternal and foetal tissues and sometimes cause congenital Zika syndrome and other neurological issues.[2,3]

Xiaoyan Lu and colleagues present a new study where this issue is once again highlighted but with a different virus: Rhinovirus Viremia in Patients Hospitalized with Community Acquired Pneumonia.[4] The study doesn’t bring entirely new information to the table because we’ve known about rhinoviruses (RVs) in the blood for a while [7] and I’ve written about it here [5]. We call detection of a virus in blood, viraemia (UK spelling) by the way.

This very nice study is a good reminder for those new to the concept. Even common cold viruses can trade in their “respiratory virus” tag for the more gruesome “blood-borne virus” badge if conditions and host permit. Nobody puts rhino in a corner!

Details: patients, tools and screening…

This is a report from the Etiology of Pneumonia in the Community (EPIC; cool name!) study from which:

  • Of 2,638 children with community acquired pneumonia (CAP; X-Ray evidence of pneumonia) were enrolled…
    • 723 (27%) had an RV detected in a nasopharyngeal/oropharyngeal swab
    • 416 of those also had an blood sample to test (mostly taken within 3 days of their swab)
  • Of 2,488 adults enrolled…
    • 209 (8%) were RV positive
    • 154 had blood sample to test.
  • these CAP cases came from 8 hospitals, between January 2010 to June 2012.

Previous testing had excluded other respiratory virus infections in these cases – although it isn’t clear if previous testing was conducted on these respiratory samples and sera. The nucleic acid extracts were tested using a very good RV real-time RT-PCR that I’ve also used a lot (see ref 18 in this paper and our past and some future RV papers). RV positives were genotyped.

What’s in the nose versus what’s in the blood..

Among the upper respiratory tract swabs that tested positive for an RV

  • 278 (48%) turned out to be an RV that belongs to the species RV-A;
  • 253 were RV-Cs (44%) and
  • 39 were RV-Bs (7%).

RV-Bs also had the lowest viral loads, with RV-As and RV-Cs having similar but higher amounts of virus in the respiratory swabs. RV-Bs were also found in older CAP cases (median age 16 years) than the RV-Cs (median age of 3 years) or RV-As (median age of 8 years).

ASIDE: Despite there being 32 known and distinct RV-B genotypes – comprising 19% of all the known 167 RV genotypes – they are usually under-represented among respiratory illnesses.[6] Here RV-Bs represented just 7% of those genotyped. I’ve frequently seen the same pattern among mixed respiratory samples in Queensland and in the wider international literture as well. The RV-Bs are considered the wimps of the RV world.[12]

But the story of RV in the blood – rhinoviraemia – has other twists.

One RV species rules the bloodways…

From 57 (10%) rhinoviraemic cases – 56 (98%) were represented by 25 different RV-C genotypes! That’s an over-representation of one RV species. RV-B was nowhere to be seen and only 1 instance of RV-A was to be found.

RVs disappeared from the blood between 14 to 51 days later in 29 (52%) of the 56 viraemic cases.

Most of the cases of viraemia occurred among children aged 1-2 years (a quarter of all viraemic people) and those with RV-C viraemia also had a significantly higher swab viral load. 15% of the 375 cases <10 years old were RV viraemic. A concurrent but non-RV virus detection was less frequent among those with, than those without, viraemia. I’d suggest they had a strong non-specific (innate) immune response happening which kept the “shields up” – preventing other viruses from getting a foothold.

Those with rhinoviraemia were also significantly more likely to have chest retractions, wheezing or pre-existing asthma. RVs flourish among those with asthma and are the most frequent virus to cause of asthma attacks.

The authors discussed some interesting points…

  • previous studies that looked, found rhinoviraemia in a similar 11-12% of children with a range of symptomatic respiratory illnesses and found RV-C to be the most common species, supporting Lu’s findings
  • rhinoviraemia probably was unable to be detected in the past because RV-Cs don’t grow in commonly used cell lines. When a lot of RV discovery was going on decades ago, the definitions of their importance were laid down using diagnostic culture methods with this massive limitation.[13] RV-Cs – >30% of all RVs – would not have been detected
  • there’s no evidence of infectious virus in the blood – just viral RNA. My personal bet: virus is there but we’ll need a very sensitive method to detect it
  • the recently discovered receptor for RV-C viruses (cadherin-related family member 3; CDHR3) is quite different from that used by RV-As and RV-Bs and is also associated with asthma susceptibility [10]

NOTE: while writing this post a new rhinoviraemia paper came out.[9] In it, a team from The Netherlands found RV in the blood of 4 of 27 adult patients. All 4 died from respiratory problems (only a fifth of the viraemia-negative patients died). These 27 were patients who:

  • had a bronchoalveolar lavage (BAL) sample collected between January 2008 and June 2014 (n=638 adults)
  • had returned a RV positive RT-PCR result from testing of their BAL (n=84)
  • had a suitably high level of RV RNA in the RT-PCR data (CT<25; n=43)
  • had an accompanying blood sample available (n=27)

None the RV were genotyped from blood samples as the viral loads were considered to be too low [at CT<25?? should have been fine for 5’UTR sequencing but if not, then the more informative VP4/VP2 nested RT-PCR – as used in the Lu study above – is great] Instead, the authors genotyped the RV from the BAL samples. Unfortunately, we’ve just seen that we can’t be sure of the vale in extrapolating the genotype from a respiratory site to that in a different anatomic compartment. Despite that issue, there were no RV-C sequences found among the 4 rhinoviraemia cases. Is there an age-related difference in severe RV-A and RV-C disease?

Lu’s findings should, once again, really hammer home why RVs should never be discounted as just “common cold” viruses – even if that is their most frequent appearance in the community.

ASIDE: Just because a virus does a thing many consider a minor inconvenience, does not discount the times it does another thing that is associated with serious illness.

Poliovirus, an easily transmitted virus, very often causes no noticeable disease or only mild illness – but on occasion it causes more severe disease (Polio). Meningitis, muscle paralysis (from which you may recover, have residual effects) affecting limbs, diaphragm (breathing is made difficult or impossible), head, face and neck muscles, permanent paralysis and death (up to 10% of those paralysed). Even though it’s a rare event, that rarity is relative to your personal perspective. If 0.5% or 1:200 susceptible people infected became, that means you may be unlikely to see someone in the room with you affected (if everyone in the room was to be infected). In Brisbane, a city of 2 million people, that equates to about 10,000 paralysed people if they all got infected. My personal perspective on that is – holy crap! Look at that over multiple seasons and multiple years and it seems so very clear to me why we would accept a safe vaccine where one exsits.IT also colours my perception of “poliovirus”

Poliovirus is not known for its subclinical or mild infections – it’s known for paralysis and rendering people unable to breath properly – even though that is only in a small percentage of the outcomes. We should really learn to think of RVs in terms of the massive health impact (and national economic burden) they place on the very young, the elderly and those with asthma, pneumonia, chronic obstructive pulmonary disease and other comorbidities.

References…

  1. Ebola RNA Persistence in Semen of Ebola Virus Disease Survivors — Final Report
    http://www.nejm.org/doi/full/10.1056/NEJMoa1511410#t=article
  2. Congenital Zika Syndrome
    https://www.cdc.gov/zika/hc-providers/infants-children/zika-syndrome-birth-defects.html
  3. Neurologic Complications Associated With the Zika Virus in Brazilian Adults
    https://jamanetwork.com/journals/jamaneurology/article-abstract/2647256
  4. Rhinovirus Viremia in Patients Hospitalized with Community Acquired Pneumonia
    https://academic.oup.com/jid/article-abstract/doi/10.1093/infdis/jix455/4096795/Rhinovirus-Viremia-in-Patients-Hospitalized-with?redirectedFrom=fulltext
  5. Rhinoviruses (HRVs) in the blood reflect more HRV in the nasopharynx and worse disease…
    https://virologydownunder.blogspot.com.au/2013/08/rhinoviruses-in-blood-reflect-more.html
  6. Community-Wide, Contemporaneous Circulation of a Broad Spectrum of Human Rhinoviruses in Healthy Australian Preschool-Aged Children During a 12-Month Period
    https://www.ncbi.nlm.nih.gov/pubmed/22829638
  7. Disseminated Rhinovirus C8 Infection with Infectious Virus in Blood and Fatal Outcome in a Child with Repeated Episodes of Bronchiolitis
    http://jcm.asm.org/content/53/5/1775.long
  8. Detection of Human Rhinovirus C Viral Genome in Blood among Children with Severe Respiratory Infections in the Philippines
    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027247
  9. Rhinovirus viremia in adult patients with high viral load in bronchoalveolar lavages
    https://www.ncbi.nlm.nih.gov/pubmed/29049949
  10. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations
    https://www.nature.com/articles/ng.2830
  11. Brisbane population
    https://www.google.com.au/search?q=brisbane+population&ie=utf-8&oe=utf-8&client=firefox-b-ab&gfe_rd=cr&dcr=0&ei=9rjvWf-EOqnr8Af6t6WgAg
  12. Happy Birthday rhinoviruses (RVs) – 60 years old today!
    https://virologydownunder.blogspot.com.au/2013/09/happy-birthday-rhinoviruses-rvs-60.html
  13. Human rhinoviruses: the cold wars resume.
    https://www.ncbi.nlm.nih.gov/pubmed/18502684

 

2 thoughts on “A cold virus in the blood…”

  1. Referring to the recent studies about H7N9 airborne transmission in small animal models (mice, ferrets), I wonder whether I could ask you an opinion, if I can. The question is this: since the H7N9 subtypes seem to be able to pass from infected ferrets to uninfected through air droplets, is it possible that many other mammals (domestic, peri-domestic and wild) are falling ill with these viruses all around? How can we exclude that cats, dogs, rats are infecting themselves in China through direct contact, bodily fluids, air, or birds scraps? And, by this way, infecting also humans? Are there biological constraints that block the virus passage from birds to other mammals (other than ferrets)? Since the H7N9 had not functioned well in sustaining human-to-human transmission so far, what was the trouble (since the ferrets and mice work better)? And pigs! Are pigs totally immune to H7N9… (and ferrets not)!?

    1. *I* certainly can’t exclude that. But are these animals *susceptible* to infection? That would need to be determined and then the animals tested.
      But there are very few notable (symptomatic) human cases reported.

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