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Coxsackievirus infection

Category: Illness or disabilities

Type

Involuntary

Introduction and description

Coxsackievirus belongs to a family of linear, positive-sense single-stranded RNA viruses.  It is a member of the Picornaviridae family and belongs to the genus Enterovirus. Human enteroviruses have originally consisted of

  • ·       polioviruses (PVs),
  • ·       coxsackie A viruses (CVAs),
  • ·       coxsackie B viruses (CVBs),
  • ·       echoviruses, and
  • ·       the numbered enteroviruses

Enterovirus-71 (EV71), for example, is considered to be a ‘serious emerging CNS pathogen’ as is Enterovirus 68 (EV68, EV-D68, HEV68).  The numbered enteroviruses appear to be very new.  An analysis of strains isolated in Europe (Austria, France and Germany) showed that the clades C1b and C2b originated in 1994 and 2002.  The common ancestor of human EV-71 likely emerged around 1941 subsequently diverging into three genogroups: B, C, and the now extinct genogroup A [PMID: 20089660].

Coxsackievirus exhibits virus latency –the ability to persist for extended periods of time within certain host tissues.   They are also cytolytic [they are able to kill the host cell], yet can persist for extended periods of time within certain host tissues, not damaging the cell, at a greatly reduced rate of replication.  The relationship between host and virus at times appears almost symbiotic – and this we will explore.

The Coxsackievirus family is a very common group of paediatric and adult viruses, and is found world-wide.

The remarkable distribution of Coxsackievirus infections can be appreciated by the high seroprevalence in many countries around the world. In one study, IgG antibodies against CV were detected in 21.6% of individuals throughout various regions of Greece. An analysis of a French-Canadian population in Montreal showed a seroprevalence as high as 60-80% for some strains of CV In a region of China, the seroprevalence for a single serotype of CV was shown to be greater than 50% in groups aged 15 years or more. The wide distribution of CV, their genetic variability, and ability to persist in the human host make it challenging for epidemiologists to link previous viral infection and subsequent pathology, suggesting a potential role for these viruses in chronic human idiopathies in addition to recognized illnesses.  PMID: 26142496 

Background

The Coxsackieviruses were discovered in 1948–49 by Dr. Gilbert Dalldorf.  Dalldorf had been searching for a cure for poliomyelitis.  In carrying out his experiments, he discovered viruses that often mimicked polio in mice. The virus family he discovered was eventually given the name Coxsackie, from Coxsackie, New York.  He found that

·       Group A coxsackieviruses caused a flaccid paralysis, a shared symptom with polio.   Coxsackie A virus caused paralysis and death of the mice in Dalldorf’s experiments, with extensive skeletal muscle necrosis

·       Group B coxsackieviruses caused a spastic paralysis (due to focal muscle injury and degeneration of neuronal tissue).  Coxsackie B caused less severe infection in the mice in Dalldorf’s experiments, but with damage to more organ systems, such as heart, brain, liver, pancreas, and skeletal muscles.

Note that the virus does not act the same way in mice as in human beings , but the general separation between the virus types remains valid. “Although CVB can readily infect via the intraperitoneal route in mice, the gastrointestinal route acts as a barrier to infection. These findings illuminate clear differences between the natural human host, and the murine model of infection.”

Symptoms

Main symptoms

Both group A and group B Coxsackieviruses can cause fever, headache, backache and general aches and pains.  The difference between Group A and Group B is so marked, however, it may be better to think of them as two separate virus families :

Coxsackie A

Picornaviruses (Coxsackie A and enterovirus [EV] 71) are responsible for most hand, foot and mouth disease (HFMD). Coxsackie (usually A16; rarely, A5 or 10) virus infections are often subclinical.

Coxsackie A tends to infect the skin and mucous membranes, causing rash, painful blistering, herpangina [also called mouth blisters, a painful mouth infection], acute haemorrhagic conjunctivitis, as well as hand, foot, and mouth (HFM) disease.

Skin peeling on hands and feet and nail dystrophies can occur after coxsackievirus infections, especially coxsackievirus A6. The nail dystrophy ranges from developing Beau's lines (deep, horizontal grooves in nails), nail breakage, to actually losing one or more nails and occurs one to two months after the primary infection.

At least 23 serotypes (1–22, 24) of group A are recognized.  Having an infection with one coxsackievirus serotype doesn't give you immunity to any of the others.

  • Coxsackievirus A1 - The most frequent symptoms among people infected with only CVA1 are nausea and diarrhoea, patients with CVA1 infection can sometimes be  asymptomatic.
  • Coxsackieviruses A2, A3, and A4 - are associated mainly with herpangina.  They may only present with fever and pharyngeal inflammation or sore throat.  There may be a cough and runny nose. 
  • Coxsackievirus A5 - Human enterovirus species A (HEV-A) consists of at least 16 members of different serotypes that are known to be the causative agents of hand, foot, and mouth disease (HFMD), ….. CVA5, CVA6, CVA10, and CVA12 mainly cause herpangina or are occasionally involved with sporadic cases of HFMD.[ PMID: 22438546]
  • Coxsackievirus A6 - broke out in Finland in 2008, and was identified as one of the responsible pathogens for a series of very severe hand, foot, and mouth disease [HFMD] outbreaks in Europe, North America and Asia. [PMID:  26112307].  However, patients infected with CA6 alone, had a shorter hospital stay and a lower incidence of neurologic system complications when compared to patients co-infected with EV71 [PMID: 26398767]
  • Coxsackievirus A7 -  in addition to HFND, this serotype infrequently causes polio-like permanent paralysis.  EV71 and CVA7 are occasionally associated with neurological diseases, indicating that A7 may be somewhat different from the other serotypes or again it may be the presence of EV71 that is key.
  • Coxsackievirus A8 - associated mainly with herpangina
  • Coxsackievirus A9 – is especially associated with “petechial and purpuric rashes”. Petechiae are tiny purple, red, or brown spots on the skin. They usually appear on your arms, legs, stomach, and buttocks. ... Though petechiae look like a rash, they're actually caused by bleeding under the skin.  Bleeding into the skin or mucosa from small vessels produces a purpuric rash.
  •  Coxsackievirus A10 – again, co-infection with EV71 has been associated with neurologic system complications such as encephalitis, meningoencephalitis or meningitis, even though the serotype normally only causes hand, foot, and mouth disease (HFMD).
  • Coxsackievirus A12 - a causative agent of herpangina , occasionally involved with sporadic cases of HFMD.[PMID: 22438546]
  • Coxsackievirus A16 - is one of the major pathogens associated with hand, foot, and mouth disease (HFMD) in infants and young children. HFMD caused by CA16 infection is generally thought to be mild and self-limiting. However, recently several severe and fatal cases involving CA16 have been reported. Again, studies have shown that co-infection with CA16 and EV71 can cause serious complications PMID:  24231751
  • Coxsackie 21 - mild cough, runny nose, and sore throat can be caused by coxsackievirus A21
  • Coxsackie 24 – in addition to HFMD, this serotype has caused acute haemorrhagic conjunctivitis

As you can see from the list, EV71 appears to be a far more dangerous and virulent pathogen than the Coxsackie A group of viruses.  Enterovirus 71 (EV71) is notable for its etiological role in epidemics of severe neurological diseases in children. It was first isolated and characterized from cases of neurological disease in California in 1969. Enterovirus 71 infrequently causes polio-like permanent paralysis.  The two viruses that seem to share some similarity to EV71 are A7 and A14.
The World Health Organization reported an outbreak in 2008 in China, involving enterovirus EV-71 which caused a total of 1884 cases, including 20 deaths. 

Enterovirus 68 (EV68, EV-D68, HEV68) is another member of the Picornaviridae family, and a numbered enterovirus. First isolated in California in 1962 and once considered rare, it has been on a worldwide upswing in the 21st century. “With some uncertainty, it has been implicated in cases of the polio-like disorder called acute flaccid myelitis”.

In other words, there is every reason to think that Coxsackie virus A remains the cause of hand, foot and mouth disease (HFMD), which will be unpleasant causing rash, painful blistering, and herpangina.  In contrast, the numbered Enteroviruses are extremely dangerous recently emerging pathogens.

Coxsackie B

Group B coxsackieviruses – cause sore throat, gastrointestinal distress, extreme fatigue as well as chest and muscle pain, which can also lead to spasms in arms and legs .  BUT, in addition this group of viruses can affect other organs.  Coxsackie B virus has been found during studies of numerous diseases of the eye, heart, brain, back and spine, skin, lungs [including epidemic pleurodynia (Bornholm disease)], liver, muscles, pancreas, and so on.  Please note that it has been found - this does not necessarily mean it is the causative agent.

So long is the list of diseases associated with this virus, that we have decided to put the evidence in the section labelled ‘observations’ under the heading ‘other’.  Even then the papers listed are but a very small subset of all the papers on PubMed.  Coxsackie B viruses are divided into six recognized serotypes (1–6):

Muscle diseases

Coxsackie-B-virus-specific probes prepared by reverse transcription of purified virus genomic RNA and molecular cloning techniques were used … to test for the presence of virus RNA in skeletal muscle biopsy samples. ….. Of the nine patients with inflammatory muscle disease, five were positive for Coxsackie-B-virus RNA  PMID:  2883345

Encephalitis lethargica

The epidemic of encephalitis lethargica (EL), called classical EL, was rampant throughout the world during 1917-1926, affecting half a million persons. The acute phase was lethal for many victims. Post-encephalitic parkinsonism (PEP) affected patients for decades. Our purpose was to investigate the cause of classical EL by studying the few available brain specimens. Cases of PEP and modern EL were also studied. Transmission electron microscopy (TEM) and immunohistochemistry were employed to examine brain from four classical EL cases, two modern EL cases and one PEP case.
27 nm virus-like particles (VLP) were observed in the cytoplasm and nuclei of midbrain neurons in all classical EL cases studied. Large (50 nm) VLP and 27 nm intranuclear VLP were observed in the modern EL cases and the PEP case. Influenza virus particles were not found. … Immunohistochemistry of classical EL cases using anti-poliovirus and anti-coxsackievirus B polyclonal antibodies showed significant staining of cytoplasm and nuclei of neurons as well as microglia and neuropil. … Sequence analysis revealed up to 95% identity to multiple human Enteroviruses.  PMID: 22715890

Heart disease

Infection by viruses in the Enterovirus family as a whole may progress to myocarditis [inflammation of the heart muscle ] or pericarditis [Inflammation of the lining around the heart], which can result in permanent heart damage or death.

Up to 30% of dilated cardiomyopathy (DCM)  patients exhibit evidence of an infection with enteroviruses (EV) such as for example Coxsackievirus B3. Moreover, EVs have been detected in 20% to 40% of patients who died suddenly after acute myocardial infarction, suggesting that EV infection increases the susceptibility of the heart to injury and catastrophic dysfunction. PMID: 27867991

Aseptic meningitis

Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord. Aseptic meningitis is caused by viruses, mycobacteria, spirochetes, fungi, & medications, as opposed to bacteria.  Coxsackieviruses and Enteroviruses are believed to be among the leading causes of aseptic meningitis .

Sjögren's syndrome

Coxsackievirus is the cause of a number of so called ‘auto-immune disorders’, which when properly investigated were found not to be a case of the immune system attacking the body, but the immune system attacking a virus.  Sjögren's syndrome is but one of numerous diseases associated with this virus.
The hypothesis that a persistent viral infection may drive the autoimmune response has been held for some time, however, the identity of the viruses has remained elusive. Only recently have identifications been made using newer testing methods and equipment.

Parkinson’s disease

Coxsackie virus-like particles (VLP) and enterovirus antigen have been found in Parkinson's disease (PD) brainstem neurons.[ PMID:  29899977]

 

Cause

The picture looks quite bleak when you list the number of organs and types of tissue that Coxsackie appears to infect, but there is one aspect of this virus that is oddly positive. 

Viruses can sometimes interfere with each other's growth and replication within a host animal.  In other words they compete and actually attack one another.  Researchers have found this interference can be mediated by a substance produced by the host animal, a protein known as interferon.

Certain symptoms of infections, such as fever, muscle pain and "flu-like symptoms", are caused by the production of IFNs and other cytokines.

It appears that in the world of viruses and bacteria it is whole-scale war. They fight against each other, virus against virus, bacteriophage against virus, bacteria against virus and so on. Our bodies are a battle ground of pathogens - every day WWIII is enacted in our bodies.

An oncolytic virus is theoretically defined as a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses.  But are they killing the cancerous cell or another virus or pathogen – undetected but there anyway – that is in that cell? 

Cavatak, a wild-type Coxsackievirus A21, is being used in human clinical trials as an oncolytic virus.  But what is it killing – cells or an invisible virus or other pathogen?

The oncolytic aspect as defined above is thus not entirely right. An oncolytic virus is a virus that kills WHATEVER IS CAUSING THE CANCER in the cells.

So let us assume for the sake of argument that an organ is cancerous because of virus A. It may be that Coxsackievirus is at war with A and will thus attack it with a will - in doing so it destroys the cancerous cells and appears to be oncolytic. It may or may not win, but if it wins you destroy the virus causing it.  And if it wins it will appear to be the only virus left - accused of being a pathogen but not guilty.

Coxsackievirus, viewed in this way, is not a harmful organism.  It appears to be a virus that causes fever, headache, backache and general aches and pains when it infects you, then it sits quietly in people’s organs, having worked its way round the body, waiting for infections that are more harmful. 

….. CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection …... CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells.  PMID: 26142496 

Following stimulation of quiescent cells by injury or infection, infectious virus is produced, suggesting that latent CVB may be reactivated directly in response to cellular infection.  It may even be a virus the body can recruit in its defences against other pathogens.  But to be triggered it needs interferon and this is produced by our immune systems.

As such – and here this is an hypothesis – whenever the host’s immune system has in some way been compromised by stress or immunosuppression via pharmaceuticals, then interferon won’t be produced and the presence of Virus A will result in very serious illness, ……..because Coxsackievirus will lie dormant unable to get up and fight! 

Two cell receptors have been identified which contribute to CVB entry into target cells. CVB utilizes a transmembrane protein found within the tight junctions of polarized cells called the Coxsackievirus and adenovirus receptor (CAR) . Also, human decay accelerating factor (DAF) has been shown to function as a co-receptor for CVB entry for some viral isolates.  It almost looks like the body has been adapted to be able to recruit this particular virus.

The medical profession have been somewhat over-active in using immunosuppressants to treat a whole host of diseases, including practically all the diseases now classified as auto-immune.  Immunosuppressant drugs are a class of drugs that suppress, or reduce, the strength of the body's immune system.

Recent studies have shown the clinical dangers of suppressing the humoral immune response …... Treatment with rituximab [an immunosuppressant]  is routinely given to patients suffering from lymphomas, leukemias, transplant rejection and some autoimmune disorders. However, case reports describing EV meningoencephalitis following treatment with rituximab have been increasing in number (Servais, Caers et al., 2010;Schilthuizen, Berenschot et al., 2010). …

Perhaps the increase in the severity of the diseases associated with Coxsackie virus is principally caused by the use of immunosuppressants.

Diagnosis, Prevention and Treatment

Diagnosis

Never was the need to know the TRUE cause of an illness more important, as the cure is in knowing who your enemies are. 

METAGENOMIC TESTING is the key to success.  It enables you to identify pathogens

Prevention

Enteroviruses are shed in human stool.  People have caught these viruses, for example by swimming in natural waters when visiting areas where there is limited sewage treatment.  EV infection can be acquired through ingestion of infectious faecal material and oral or respiratory secretions. Transmission is more frequent in places where routine hygiene is limited e.g., where there is no running water for hand washing), because EV is shed in stool for weeks after infection. Transmission is markedly seasonal in temperate regions, but incidence in tropical and subtropical areas is high throughout the year.

Coxsackieviruses can also be acquired via respiratory transmission (someone coughs or sneezes on you). They can also get these infections by touching a contaminated object.  For example, the CDC states that "you might get infected by kissing someone who has hand, foot, and mouth disease or by touching a doorknob that has viruses on it, then touching your eyes, mouth, or nose."

Still, because kids can shed the coxsackievirus in their stool and respiratory tract secretions (saliva and nasal secretions) for weeks after their symptoms have gone away or even without any symptoms, outbreaks can be hard to control or avoid.

Thus although basic hygiene practises should be encouraged, Coxsackieviruses are very difficult to prevent.

And maybe that is what was intended, if their role is indeed as a symbiotic partner.  They were meant to be caught.

Treatment


There are no vaccines and no antivirals that treat Coxsackieviruses.  Many healers are thus turning to plants as a helpful palliative medicine and, in the case of the numbered Enteroviruses, curative medicine.

 

 

 

References and further reading

  • [On a case of Coxsackie virus infection with pneumonia, with late recurrence and pleuro-pericarditis].  Pesce M, et al. G Mal Infett Parassit. 1967.  PMID  5601366 [Indexed for MEDLINE]
  • Indian J Ophthalmol. 2000 Jun;48(2):159.  An outbreak of acute conjunctivitis caused by Coxsackie virus A 24.  Madhavan HN, Malathy J, Priya K.  PMID:  11116516
  • Ann Transl Med. 2016 Oct; 4(Suppl 1): S23.  doi:  10.21037/atm.2016.10.06 PMCID: PMC5104620 PMID: 27867991 - Connecting enterovirus infection to dystrophin dysfunction in dilated cardiomyopathy - Qiongling Wang and Xander H. T. Wehrens
  • Dalldorf G, Gifford R (June 1951). Clinical and epidemiologic observations of Coxsackie-virus infection. N. Engl. J. Med. 244 (23): 868–73. doi:10.1056/NEJM195106072442302. PMID 14843332.
  • Phytother Res. 2018 May;32(5):811-822. doi: 10.1002/ptr.6024. Epub 2018 Jan 22.  Antiviral potential of medicinal plants against HIV, HSV, influenza, hepatitis, and coxsackievirus: A systematic review.  Akram M1, Tahir IM2, Shah SMA1, Mahmood Z3, Altaf A2, Ahmad K4, Munir N3, Daniyal M5, Nasir S6, Mehboob H7.
  • Lancet. 1987 May 2;1(8540):1004-7.  Dermatomyositis, polymyositis, and Coxsackie-B-virus infection.  Bowles NE, Dubowitz V, Sewry CA, Archard LC.
  • J Exp Med. 1951 Feb 28; 93(3): 247–266. Pmcid: Pmc2136090 Pmid: 14824399; Pathogenesis Of Coxsackie Virus Infection ; Multiplication Of Virus And Evolution Of The Muscle Lesion In Mice - Joseph L. Melnick And Gabriel C. Godman
  • Virology. Author manuscript; available in PMC 2016 Oct 1.  Published in final edited form as:Virology. 2015 Oct; 484: 288–304. Published online 2015 Jul 1. doi:  10.1016/j.virol.2015.06.006 PMCID: PMC4567421 NIHMSID: NIHMS704976 PMID: 26142496  Recent Progress in Understanding Coxsackievirus Replication, Dissemination, and Pathogenesis - Jon Sin,1 Vrushali Mangale,2 Wdee Thienphrapa,2 Roberta A. Gottlieb,1 and Ralph Feuer2,*
  • PLoS One. 2015 Sep 23;10(9):e0138514. doi: 10.1371/journal.pone.0138514. eCollection 2015.  Genotypes of the Enterovirus Causing Hand Foot and Mouth Disease in Shanghai, China, 2012-2013.   Xu M1, Su L1, Cao L1, Zhong H1, Dong N1, Dong Z1, Xu J1.   Department of Clinical Laboratory, Children's Hospital of Fudan University, Shanghai, 201102, China.
  • An Outbreak of Concurrent Echovirus 30 and Coxsackievirus A1 Infections Associated with Sea Swimming among a Group of Travelers to Mexico   Elizabeth M. Begier M. Steven Oberste Marie L. Landry Timothy Brennan Diana Mlynarski Patricia A. Mshar Kasia Frenette Terry Rabatsky-Ehr Katherine Purviance Ava Nepaul ... Clinical Infectious Diseases, Volume 47, Issue 5, 1 September 2008, Pages 616–623, https://doi.org/10.1086/590562 Published: 01 September 2008
  • J Clin Microbiol. 2011 Jul; 49(7): 2426–2434.  doi:  10.1128/JCM.00007-11 PMCID: PMC3147834 PMID: 21543560 Complete Genome Analysis of Coxsackievirus A2, A4, A5, and A10 Strains Isolated from Hand, Foot, and Mouth Disease Patients in China Revealing Frequent Recombination of Human Enterovirus A▿†Y. F. Hu,‡ Fan Yang,‡ J. Du,‡ J. Dong,‡ T. Zhang, Z. Q. Wu, Y. Xue, and Qi Jin*
  • BMC Infect Dis. 2012 Jun 20;12:136.  Evidence for an enterovirus as the cause of encephalitis lethargica.  Dourmashkin RR1, Dunn G, Castano V, McCall SA.  Faculty of Life Sciences, London Metropolitan University, London, UK. dourmashkin@blueyonder.co.uk
  • Virol J. 2015; 12: 92. Published online 2015 Jun 18. doi:  10.1186/s12985-015-0325-1 PMCID: PMC4495935 PMID: 26084565 Outbreak of febrile illness caused by coxsackievirus A4 in a nursery school in Beijing, China   Jin-Song Li,# Xiao-Gen Dong,# Meng Qin, Zhi-Ping Xie, Han-Chun Gao, Jun-Yong Yang, Xiao-Xin Yang, Dan-Di Li, Jie Li, and Zhao-Jun Duan

 

 

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