Does H5N1 cause systemic infection?

AlaskaDenise · Apr 13, 2006

Yes.

see (among many sources):
(this article discusses primarily WSN H1N1, but some comments are relevent)
http://jvi.asm.org/cgi/content/full/75/19/9297?pmid=11533192

.....Although the virulence of influenza A viruses is controlled polygenically, the HA plays a pivotal role in determining the severity of infection in avian strains (8, 11, 26). The HA cleavage site sequences in virulent and avirulent avian influenza viruses differ; the former possess a series of basic amino acids at this site, while the latter do not (10, 13). The ubiquitous host proteases furin and PC6, which specifically recognize these multiple basic residues, cleave the HAs of virulent viruses, leading to systemic infection (12, 27). By contrast, the HAs of avirulent viruses are not cleaved by these proteases because they lack the requisite series of basic residues at their cleavage sites. Instead, they are susceptible to proteases that are presumably localized in the respiratory and/or intestinal tract, thus leading to localized viral infection.
All mammalian influenza viruses, excluding equine H7N7 viruses, have a single Arg residue at the HA cleavage site. Thus, the HAs cannot be cleaved by ubiquitous furin or PC6 protease, resulting in a localized infection. However, a mouse-adapted human isolate, A/WSN/33 (WSN; H1N1), which is recognized as a neurovirulent strain, causes systemic infection when inoculated intranasally into mice (3). Studies with WSN-A/Hong Kong/68 (H3N2) reassortant viruses indicated that the NA gene determines WSN neurovirulence in mice by facilitating HA cleavage (24). Only a single Arg is present at the HA cleavage site of WSN virus, suggesting that the mechanism of HA cleavage mediated by the WSN NA differs from that in pathogenic avian viruses. ......

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The NA of the WSN33 H1N1 had systemic infection and neurovirulence due to the plasminogen-binding capabiltiy of a muation at postion 130. H5N! doesn't have this (to my knowledge).

However H5N1 DOES have the multi-basic amino acids, meaning that the above explanation about umbiqutous host proteases causing cleavage and systemic infections.

I've been reading like crazy trying to chase down all these items, and just read this article today. You can go back and find all the references to multi-basic amino acids and neurovirulence and you'll get the details on how and why H5N1 MAY produce systemic infections.

I hope some the the professionals here will correct any of my misunderstandings.
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I found another one...
See also:
http://www.sciencemag.org/cgi/content/full/279/5349/393

...In addition to its role as a determinant of host range, the HA gene is important in determining the virulence of avian influenza A viruses for poultry (16). All human influenza virus HA genes characterized to date, including the 1918 viruses (17), have a single, basic Arg residue at the cleavage site between HA1 and HA2. An insertion similar to the basic amino acid insertion adjacent to the cleavage site in the HA gene of the A/Hong Kong/156/97 virus has been found in several highly pathogenic avian H5 viruses. Basic amino acids adjacent to the cleavage site allow proteases other than trypsin-like proteases to cleave the HA into HA1 and HA2 domains. This event would enable the virus to spread systemically by altering the tissue range of these viruses from the respiratory and alimentary tract to other sites, such as the brain, heart, and blood vessels (18). It has been suggested that the acquisition of a ubiquitously cleavable avian HA by a human influenza A virus could make a virus lethal (16). It remains to be shown whether gene segments other than the HA may also have contributed to the ability of the virus to infect a human....
.

emmysue · Apr 14, 2006

Re: Does H5N1 cause systemic infection?

Here's another article about systemic infection:

Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts

http://depts.washington.edu/einet/?a=printArticle&print=1348
Am J Pathol. 2006 Jan;168(1):176-83
Researchers at the Erasmus Medical Center have demonstrated systemic spread of avian influenza virus in cats infected by respiratory, digestive, and cat-to-cat contact. The paper by Rimmelzwaan et al., appears in the Jan 2006 issue of The American Journal of Pathology. The paper is accompanied by a Commentary by C. Brown, ?Avian influenza: Virchow's reminder?. Avian influenza (H5N1) is highly contagious in birds and spreads easily due to the agricultural and migratory nature of the bird species infected. While spread of avian influenza from bird to man is known to occur, human-to-human spread is extremely rare. Thus, the disease events that take place during mammal-to-mammal spread are not well characterized. To assess the spread of H5N1 influenza virus in mammalian hosts, Rimmelzwaan et al. examined cats infected via the respiratory tract, via the digestive tract (by feeding on infected chicks), or by close contact with respiratory-infected cats. The researchers then examined mucous membranes (throat, nasal, and rectal swabs) and organ systems (respiratory, digestive, nervous, cardiovascular, urinary, lymphoid, and endocrine) for the presence of virus and viral protein. As expected, all cats were infected with H5N1 virus and exhibited clinical signs of disease, and virus was detected in throat, nasal, and rectal swabs, regardless of the original site of infection. Most interesting, virus spread throughout the organ systems with virus being found in respiratory and digestive tracts, liver, kidney, heart, brain, and lymph nodes. Furthermore, examination of infected tissues revealed cellular damage at sites containing viral proteins.
These data underscore the potential for influenza virus to spread not only from the respiratory tract but also from the digestive and urinary tracts, greatly increasing the possible routes of mammalian transmission. Systemic disease has long been known to occur in birds, with the fecal-oral route of transmission being most important. However, this is the first demonstration of systemic replication in cats, providing a cautionary tale for humans regarding how influenza is spread and how the disease presents itself. Rimmelzwaan and colleagues caution that because of the systemic nature of avian influenza, "H5N1 virus infection needs to be included in the differential diagnosis of a broader range of clinical presentations than is currently done." In addition better understanding of the mechanisms of spread, including possible fecal-oral route in humans, "may limit the risk of H5N1 virus developing into a pandemic influenza virus."
The susceptibility of carnivores to avian influenza A virus was first recorded in a paper published in the China Journal of Veterinary Science in 2003, demonstrating that tigers had died of influenza A virus infection in China in 2002. Subsequently in 2004 during the H5N1 avian influenza outbreak in Thailand considerable mortality occurred among zoo tigers and leopards probably as a result of ingestion of diseased poultry. More recently, deaths of chickens and dogs were reported in Turkey, although the cause was not determined. (Promed 1/14/06)

GaudiaRay · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

Don't mind my being slightly off topic, but the answer was, is and will be, "Don't Get Sick". This disease takes no prisoners by choice. The wish that the pandemic be less virulent is just a hash smoker's dream. Everything that can be done to isolate and remain safe is a right choice. That 10th plague story, with the hiding behind closed doors as the angel of death swept through sounds uncomfortable by awfully inviting when, once sick, one can have only prepped for pnumonia and meningial diseases. Pantropic is pantropic. Don't get sick.

HenryN · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

Jason Gale said:
Is anyone aware of published researching showing active H5N1 virus outside the respiratory system? I understand H5N1 RNA and antigen have been found separately, but not together. The presence of active virus outside the respiratory system would suggest systemic infection and cast doubt about the effectiveness of Relenza as a treatment for human H5N1 cases. Jason

H5N1 is able to easily move into new regions by virtue of its HA cleavage site, which allows the virus to attack many cell types because it can be cleaved by many cell specific proteases (1st step required for entry into a cell).

H5N1 know how to get around and all HPAI H5N1 have a polybasic cleavage site, which is one of the 1st tests done to diagnose HPAI.

gsgs · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

I assume H5N1 moves by the blood.
But apparantly it doesn't attack blood-cells.
In the respiratory system it preferrably binds to these a2-3 cells
are these cells also in the other organs which become infected
or is this a different process ? And why can't normal flu do the same ?

AlaskaDenise · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

gsgs said:
I assume H5N1 moves by the blood.
But apparantly it doesn't attack blood-cells.
In the respiratory system it preferrably binds to these a2-3 cells
are these cells also in the other organs which become infected
or is this a different process ? And why can't normal flu do the same ?

I do know that normal flu is only cleaved by the enzymes in the upper respiratory area.

.

emmysue · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

Jason - This is from the WHO website:
http://www.who.int/csr/disease/avian_influenza/avianinfluenza_factsheetJan2006/en/index.html#humans

Clinical features 1. In many patients, the disease caused by the H5N1 virus follows an unusually aggressive clinical course, with rapid deterioration and high fatality. Like most emerging disease, H5N1 influenza in humans is poorly understood. Clinical data from cases in 1997 and the current outbreak are beginning to provide a picture of the clinical features of disease, but much remains to be learned. Moreover, the current picture could change given the propensity of this virus to mutate rapidly and unpredictably.
The incubation period for H5N1 avian influenza may be longer than that for normal seasonal influenza, which is around 2 to 3 days. Current data for H5N1 infection indicate an incubation period ranging from 2 to 8 days and possibly as long as 17 days. However, the possibility of multiple exposure to the virus makes it difficult to define the incubation period precisely. WHO currently recommends that an incubation period of 7 days be used for field investigations and the monitoring of patient contacts.
Initial symptoms include a high fever, usually with a temperature higher than 38oC, and influenza-like symptoms. Diarrhoea, vomiting, abdominal pain, chest pain, and bleeding from the nose and gums have also been reported as early symptoms in some patients.
Watery diarrhoea without blood appears to be more common in H5N1 avian influenza than in normal seasonal influenza. The spectrum of clinical symptoms may, however, be broader, and not all confirmed patients have presented with respiratory symptoms. In two patients from southern Viet Nam, the clinical diagnosis was acute encephalitis; neither patient had respiratory symptoms at presentation. In another case, from Thailand, the patient presented with fever and diarrhoea, but no respiratory symptoms. All three patients had a recent history of direct exposure to infected poultry.
One feature seen in many patients is the development of manifestations in the lower respiratory tract early in the illness. Many patients have symptoms in the lower respiratory tract when they first seek treatment. On present evidence, difficulty in breathing develops around 5 days following the first symptoms. Respiratory distress, a hoarse voice, and a crackling sound when inhaling are commonly seen. Sputum production is variable and sometimes bloody. Most recently, blood-tinted respiratory secretions have been observed in Turkey. Almost all patients develop pneumonia. During the Hong Kong outbreak, all severely ill patients had primary viral pneumonia, which did not respond to antibiotics. Limited data on patients in the current outbreak indicate the presence of a primary viral pneumonia in H5N1, usually without microbiological evidence of bacterial supra-infection at presentation. Turkish clinicians have also reported pneumonia as a consistent feature in severe cases; as elsewhere, these patients did not respond to treatment with antibiotics.
In patients infected with the H5N1 virus, clinical deterioration is rapid. In Thailand, the time between onset of illness to the development of acute respiratory distress was around 6 days, with a range of 4 to 13 days. In severe cases in Turkey, clinicians have observed respiratory failure 3 to 5 days after symptom onset. Another common feature is multiorgan dysfunction, notably involving the kidney and heart. Common laboratory abnormalities include lymphopenia, leukopenia, elevated aminotransferases, and mild-to-moderate thrombocytopenia with some instances of disseminated intravascular coagulation.
Limited evidence suggests that some antiviral drugs, notably oseltamivir (commercially known as Tamiflu), can reduce the duration of viral replication and improve prospects of survival, provided they are administered within 48 hours following symptom onset. However, prior to the outbreak in Turkey, most patients have been detected and treated late in the course of illness. For this reason, clinical data on the effectiveness of oseltamivir are limited. Moreover, oseltamivir and other antiviral drugs were developed for the treatment and prophylaxis of seasonal influenza, which is a less severe disease associated with less prolonged viral replication. Recommendations on the optimum dose and duration of treatment for H5N1 avian influenza, also in children, need to undergo urgent review, and this is being undertaken by WHO.
In suspected cases, oseltamivir should be prescribed as soon as possible (ideally, within 48 hours following symptom onset) to maximize its therapeutic benefits. However, given the significant mortality currently associated with H5N1 infection and evidence of prolonged viral replication in this disease, administration of the drug should also be considered in patients presenting later in the course of illness.
Currently recommended doses of oseltamivir for the treatment of influenza are contained in the product information at the manufacturer?s web site. The recommended dose of oseltamivir for the treatment of influenza, in adults and adolescents 13 years of age and older, is 150 mg per day, given as 75 mg twice a day for 5 days. Oseltamivir is not indicated for the treatment of children younger than 1 year of age.
As the duration of viral replication may be prolonged in cases of H5N1 infection, clinicians should consider increasing the duration of treatment to 7 to 10 days in patients who are not showing a clinical response. In cases of severe infection with the H5N1 virus, clinicians may need to consider increasing the recommended daily dose or the duration of treatment, keeping in mind that doses above 300 mg per day are associated with increased side effects. For all treated patients, consideration should be given to taking serial clinical samples for later assay to monitor changes in viral load, to assess drug susceptibility, and to assess drug levels. These samples should be taken only in the presence of appropriate measures for infection control.
In severely ill H5N1 patients or in H5N1 patients with severe gastrointestinal symptoms, drug absorption may be impaired. This possibility should be considered when managing these patients.

Goju · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

Snowy - even the hash smokers don't have that dream! LOL

GaudiaRay said:
Don't mind my being slightly off topic, but the answer was, is and will be, "Don't Get Sick". This disease takes no prisoners by choice. The wish that the pandemic be less virulent is just a hash smoker's dream. Everything that can be done to isolate and remain safe is a right choice. That 10th plague story, with the hiding behind closed doors as the angel of death swept through sounds uncomfortable by awfully inviting when, once sick, one can have only prepped for pnumonia and meningial diseases. Pantropic is pantropic. Don't get sick.

Snowy Owl · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

For me, prepare for the worst and hope for the best is a concept that Ihave enshrined in my mind and therefore drive my actions and my research.

As for the Haschish smokers, well I would not recommend that when one's is contemplating the perspectives of a pandemic, it would certainly leads to intense paranoia.

Mellie · Apr 15, 2006

Re: Does H5N1 cause systemic infection?

Thanks Alaska Denise and emmysue and all. Interesting thread.

It's good to see more info on the web, including clinical symptoms.

Does H5N1 cause systemic infection?

AlaskaDenise

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