virology blog
About viruses and viral disease
In early June it was widely reported that the first case of poliomyelitis in 30 years had been identified in Venezuela (see this Tech Times report as an example). Fortunately these reports were incorrect, and Venezuela remains free of polio. Let’s unpack exactly what happened.
On episode #331 of the science show This Week in Virology, the TWiVÂ team discusses the possible association of the respiratory pathogen enterovirus D68 with neurological disease.
You can find TWiV #331 at www.microbe.tv/twiv.
In February 2014 I wrote about children in California who developed a poliomyelitis-like paralysis, also called acute flaccid paralysis or AFP. However, the cause of this paralysis was not known. The CDC has released its study of these cases and concludes “The etiology of AFP with anterior myelitis in the cases described in this report remains undetermined.”
A total of 23 cases of AFP* in California were reported to CDC during the period June 2012 through June 2014. These cases were from diverse geographic regions of the state. Specimens from 19 of the patients were available and tested for poliovirus, aroboviruses, herpesviruses, parechoviruses, adenoviruses, rabies virus, influenza virus, metapneumovirus, respiratory syncytial virus, parainfluenza viruses, Mycoplasma pneumoniae, Rickettsia, and amoebas. Rhinovirus was detected in one patient, and enterovirus D68 in two patients; all others were negative for potential etiologic agents.
All 23 patients with AFP also had anterior myelitis, inflammation of the grey matter of the spinal cord, which is characteristic of poliomyelitis. While the rate of AFP in California betweeen 1992-1998 was 1.4 cases per 100,000 children per year,  anterior myelitis was not described in any of 245 cases reviewed by CDC. However, poliovirus was ruled out as a cause in the 19 individuals who could be tested.
The cause of AFP is often difficult to determine because there infectious and non-infectious etiologies. Only 2 of the 19 clinical specimens met CDC guidelines for poliovirus detection (two stool specimens collected ≥24 hours apart and <14 days after symptom onset) and the others were likely taken too late to detect the presence of virus. The finding of enterovirus D68 in two of the samples is difficult to interpret, as the virus was detected in respiratory specimens and could have been a coincidental infection.
This investigation began with a request from a San Francisco area physician to the California State Department of Public Health to determine whether poliovirus was present in a 29 year old male with AFP and anterior myelitis. Subsequently this department posted alerts for AFP with anterior myelitis to  local health departments, and it is from the cases submitted that the 23 were drawn. Therefore the number of cases of AFP with anterior myelitis might be a consequence of this surveillance.
We are left with the unsatisfying conclusion that these 23 cases of AFP with anterior myelitis were either caused by an undetected infectious agent, or by something else.
*Defined by CDC as “at least one limb consistent with anterior myelitis, as indicated by neuroimaging of the spine or electrodiagnostic studies (e.g., nerve conduction studies and electromyography), and with no known alternative etiology”.
On episode #274 of the science show This Week in Virology, the TWiV team discusses recent cases of polio-like paralysis in California, and the virome of 14th century paleofeces.
You can find TWiV #274 at www.microbe.tv/twiv.
Recently a number of children in California have developed a poliomyelitis-like paralysis. The cause of this paralysis is not yet known, and information about the outbreak is scarce. Here is what we know so far:
I do not have any more information on this outbreak other than what I’ve obtained from ProMedMail. I have worked on enteroviruses, including poliovirus, for over 30 years, so I thought I might speculate on what might be transpiring.
What is a polio-like illness? Acute flaccid paralysis (AFP) is the term used to describe the sudden onset of weakness in limbs. AFP can have many etiologies, including viruses, bacteria, toxins, and systemic disease. It is used by the World Health Organization to maximize the ability to detect all cases of poliovirus. Confirmation that AFP is caused by poliovirus requires demonstration that the virus is present in the infected individual.
Is poliovirus the cause? I do not believe that poliovirus is causing the paralysis of children in California. I understand that they have all been immunized against poliovirus. In addition, should immunization have failed in any of these children, it seems unlikely that wild type polioviruses would be circulating in this area. Vaccine-derived polioviruses can cause paralysis but the US has not used this type of vaccine since 2000.
What might be causing the paralysis? AFP has both infectious and non-infectious etiologies. One possibility is that  a non-polio enterovirus is involved. Poliovirus is classified within the genus Enterovirus in the family Picornaviridae. Other enteroviruses besides poliovirus are known to cause paralytic disease, such as Coxsackieviruses, echoviruses, and many enteroviruses including types 70, 71, 89, 90, 91,96, 99, 102, and 114.
Most enterovirus infections can be associated with different clinical syndromes besides paralysis (such as respiratory disease), and therefore diagnosis is difficult. Stool is generally the most sensitive specimen for establishing an enterovirus infection. However, the virus may no longer be present at onset of symptoms. Polio is much easier to diagnose in individuals with AFP from whom virus can be identified: paralysis is the main serious symptom caused by infection. However note that 99 out of 100 poliovirus infections are asymptomatic or present with undifferentiated viral illness. The incidence of paralytic disease caused by other enteroviruses is even lower – for example 1 in 10,000 EV71 infections are paralytic. If all of the 20 California cases are caused by enteroviruses, this means that there have been many more infections without symptoms.
In one study of non-polio AFP in India, no virus could be isolated in 70% of the cases. Enterovirus 71 was the single most prevalent serotype associated with non-polio AFP. This virus currently causes large outbreaks of hand, foot, and mouth disease throughout Asia, with many fatalities and cases of acute flaccid paralysis. EV71 is known to circulate within the United States.
What about enterovirus 68? It has been reported that EV68 has been isolated from some of the paralyzed children. This isolation does not mean that the virus has caused the paralysis. Enterovirus infections of the respiratory and gastrointestinal tracts are very common and often do not result in any signs of disease. Random samplings of healthy individuals frequently demonstrate substantial rates of enterovirus infections.
Enterovirus type 68 was first isolated in California from an individual with respiratory illness. The virus is known to cause clusters of acute respiratory disease, and there is at least one report of its association with central nervous system disease. I believe it is an unlikely cause of the paralytic cases in California based solely on the past history of the virus and the fact that other enteroviruses are more likely to cause paralysis. It is not clear to me why enterovirus 68 would evolve to become substantially more neurotropic: entering the central nervous system is a dead end because the infection cannot be transmitted to a new host.
All of the above is pure speculation based on very little data. The paralysis might not even be caused by an infection. At this point a great deal of basic epidemiology needs to be done to solve the problem – if indeed it can be solved at all. Based on its population, California would be expected to have about 75 cases of acute flaccid paralysis each year of various etiologies, suggesting that the current number of cases is not unusual or unexpected.
Update: N. Gopal Raj wrote a story last year about acute flaccid paralysis in India, which has the highest rate of non-polio AFP in the world, with 60,000 cases reported in 2011.
The WHO strategy to eradicate poliomyelitis depends upon immunization of every child under 5 years of age, and nationwide AFP (acute flaccid paralysis) surveillance to identify cases of poliomyelitis. A laboratory network then determines whether AFP is caused by poliovirus. Recently a new member of the picornavirus family was identified in children with non-poliovirus AFP. This virus has been named cosavirus (common stool-associated picornavirus).
In one study, a combination of mass sequencing, RT-PCR, and RACE was used to obtain the viral sequence from a stool sample from an Australian child with acute diarrhea. In the second study, stool samples from South Asian children with AFP were partially purified to obtain particle-protected RNA, which was then amplified by randomized oligonucleotides. In both cases a novel picornavirus was identified which is most closely related to cardioviruses and Senecaviruses. However, the viral genome sequences are sufficiently diverged to warrant placing them in a new genus, Cosavirus.
Perhaps the most interesting aspect of this work is the observation that in Pakistan and Afghanistan, cosavirus sequences were detected in over 40% of stool samples from healthy children as well as from children with AFP. In contrast, only 1 of 1000 stool samples from Edinburgh, UK was positive for the virus.
An important question which must be resolved is whether cosavirus can cause AFP. It is possible that many cosavirus infections are asymptomatic, as is the case with poliovirus infection, where only 1 infection in 100 leads to paralysis. Does replication of cosavirus in the intestine interfere with the poliovirus vaccine strains, possibly explaining immunization failures in India? It will also be interesting to study the replication of this virus in cell cultures and in laboratory animals. The viral genome has some unusual features, including two 2A proteins, one of which is not related to any other picornavirus 2A, and a long 5′-noncoding region. Such studies are so far hindered by the fact that no laboratory has yet reported propagation of cosavirus in cultured cells.
Holtz, L., Finkbeiner, S., Kirkwood, C., & Wang, D. (2008). Identification of a novel picornavirus related to cosaviruses in a child with acute diarrhea Virology Journal, 5 (1) DOI: 10.1186/1743-422X-5-159
Kapoor A, Victoria J, Simmonds P, Slikas E, Chieochansin T, Naeem A, Shaukat S, Sharif S, Alam MM, Angez M, Wang C, Shafer RW, Zaidi S, & Delwart E (2008). A highly prevalent and genetically diversified Picornaviridae genus in South Asian children. Proceedings of the National Academy of Sciences of the United States of America, 105 (51), 20482-7 PMID: 19033469