Neurological Manifestations as marker of H1N1 virulence?

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

* Neorological Manifestations are associated with Cytokine Storm.

#4 - probably not

Post #12 seems to indicate that Neurological Manifestations may be associated with Cytokine Storm.

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

Post #12 seems to indicate that Neurological Manifestations may be associated with Cytokine Storm.

Notice that IL-6, TNF, and caspase are repeatedly discussed in Dr. Fedson's paper:

Development of therapy and prophylactics against influenza encephalopathy. Sequential observation of cytochrome c and TNF-alpha concentration in blood serum and cerebrospinal fluid.

Journal Code:N20050399
ISSN:
VOL.;NO.;PAGE.62-65(2004)

Pub. Country;Japan

Abstract;At the time of the onset of influenza encephalopathy, the blood serum and cerebrospinal fluid were obtained at the advanced stage and convalescence, and cytochrome c (I) concentration as a marker of apoptosis and TNF-alpha (II) concentration as a marker of inflammation were measured in order to examine involvement of the apoptosis in the pathology of influenza encephalopathy, and inflammation. We sampled blood serum and cerebrospinal fluid of patients with influenza encephalopathy at its onset, exacerbation, and convalescence, and measured the concentrations of cytochrome c and TNF-alpha for analysis of apoptosis and inflammation, respectively. Both showed high concentrations in blood at the onset, and the concentration of cytochrome c in cerebrospinal fluid increased in convalescence. The results indicate the involvement of inflammation and apoptosis in blood vessels in the onset of encephalopathy, and participation of apoptosis in central nervous system in cerebral atrophy at convalescence stage.

Neurology 2001;57:295-299
© 2001 American Academy of Neurology
Articles
Predictive value of serum interleukin-6 level in influenza virus–associated encephalopathy
Hideo Aiba, MD, Mika Mochizuki, MD, Mitsuaki Kimura, MD and Hiroatsu Hojo, MD

From the Departments of Pediatric Neurology (Drs. Aiba, Mochizuki, and Hojo) and Allergy and Clinical Immunology (Dr. Kimura), Shizuoka Children’s Hospital, Shizuoka, Japan.

OBJECTIVE: In Japan, >200 children with influenza virus–associated encephalopathy were reported in 1999 and the mortality rate was high. The levels of tumor necrosis factor-{alpha} (TNF{alpha}) and interleukin-6 (IL-6) in both CSF and serum were significantly increased in severe cases. The authors found a correlation between elevated serum cytokine levels and mortality and neurologic morbidity.

METHODS: TNF{alpha}, IL-6, soluble tumor necrosis factor receptor 1 (sTNF-R1), interferon-{gamma} (IFN{gamma}), and IL-2 were measured by the ELISA method in sera from six children with encephalopathy before and during therapy, and in six age-matched controls with influenza type A virus infection.

RESULTS: The increases in the serum TNF{alpha}, IL-6, and sTNF-R1 levels were statistically significant at the onset of symptoms before therapy, but the IL-6 level was most useful for diagnosis. The serum IL-6 levels were >6,000 pg/mL in children with brain stem dysfunction, about 150 pg/mL in children without brain stem dysfunction, and <80 pg/mL in controls. The time course of the serum IL-6 level also reflected the clinical condition. Once the serum IL-6 level was increased to >15,000 pg/mL, none of the children survived. The lower the maximal serum IL-6 level, the milder the CNS sequelae.

CONCLUSION: The serum IL-6 level may be the most useful indicator for the diagnosis and the clinical severity of influenza virus–associated encephalopathy.

Apoptosis and microglial activation in influenza encephalopathy
Acta Neuropathologica
Issue Volume 105, Number 3 / March, 2003

Abstract

During influenza epidemics in Japan, the number of children with acute encephalopathies and encephalitis has recently increased. Although the pathophysiologies remain unclear, there is usually brain edema with evidence of damage to the blood-brain-barrier (BBB). We investigated the glial reaction and apoptosis in brains of eight such cases comprising two of acute necrotizing encephalopathy and six of influenza encephalopathy, and compared the results with those in five control brains. Apoptosis, evidenced by chromatin condensation and fragmentation in hematoxylin sections, in situ end labeling of fragmented DNA (TUNEL) and DNA laddering, was observed in neurons and glial cells in four brains with influenza encephalopathy. In the TUNEL-positive brains, the increase in microglia was greater than in the TUNEL-negative brains. Immunoreactivity for active-caspase 3, demonstrated by immunohistochemistry, and the overexpression of a caspase-cleaved fragment of poly(ADP-ribose) polymerase, demonstrated by Western blotting, indicated that activation of caspase 3 is involved in the apoptotic pathway in the brains of influenza encephalopathy cases. Apoptosis or specific pathological processes that cause apoptosis may give rise to aggravated encephalopathy.

I hate to sound like a broken record, but the answer to any pandemic influenza characterized by cytokine storm is not cataloging the genes and mutations or creating vaccines or antivirals, but mitigating cytokine storm.

Even these neurological manifestations are simply one more facet of the cytokine storm brewing in the bloodstream. Damp down the cytokine storm in the bloodstream, and you'll eliminate most of the neurological manifestations. (IMHO.)

 

[AlaskaDenise]

Re: Neurological Manifestations as marker of H1N1 virulence?

Thanks for clarifying my oversight.

So your point about the cytokine storm is that if we mitigate that cytokine excess, normal immune systems will function similar to seasonal flu?

So ideally we need an antiinflammatory source as available and affordable as soap?

.

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

Thanks for clarifying my oversight.

So your point about the cytokine storm is that if we mitigate that cytokine excess, normal immune systems will function similar to seasonal flu?

So ideally we need an antiinflammatory source as available and affordable as soap?

.

Yes, which was one of Dr. Fedson's points: we need drugs which dampen the immune response but don't obliterate it, and are affordable:

What is overwhelmingly important about the anti-inflammatory and immunomodulatory agents discussed here ? statins, fibrates, glitazones, and several others ? is that they are now being produced as inexpensive generic medications and are widely available in 'have not' countries. For example, in the US a 5-day course of treatment with a generic statin would cost $3?20 and a course of resveratrol would cost $1?80 (DS Fedson, unpublished data). In developing countries they would cost even less. They could be stockpiled and made available in each country on the first pandemic day. It is unlikely that this will ever be said for pandemic vaccines and antiviral agents.

More research is needed to determine whether agents that modify the host response will be useful for the treatment and prophylaxis of H5N1 and pandemic influenza.

 

[AlaskaDenise]

Re: Neurological Manifestations as marker of H1N1 virulence?

Yes, which was one of Dr. Fedson's points: we need drugs which dampen the immune response but don't obliterate it, and are affordable:

I wish they'd do more research in this area. My personal choice, based on experience, is curcumin - a strong natural anti-inflammatory.

See:

http://www.grouppekurosawa.com/blog/2005/10/tamiflu-curcumin-egcg-and-influenza.htm (blog with good references)

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=16219905


It would be informative to know outcomes for people having a high curry diet. Does anyone know areas where there is widespread cucurmin (Turmeric) in the everyday foods?

.

 

[Lizw]

Re: Neurological Manifestations as marker of H1N1 virulence?

It would be informative to know outcomes for people having a high curry diet. Does anyone know areas where there is widespread cucurmin (Turmeric) in the everyday foods?

India and Pakistan are obvious choices. I don't know about anti-inflammatory responses as such, but I've read that India has one of the lowest rates of Alzheimers in the world, which Indians attribute to their high consumption of turmeric. Isn't inflammation implicated in Alzheimers?

 

[tropical]

Re: Neurological Manifestations as marker of H1N1 virulence?

Yes, which was one of Dr. Fedson's points: we need drugs which dampen the immune response but don't obliterate it, and are affordable:

But in the above logic, what happens with the primary agent, the flu virus?

The main reason this cytokine storm were raised from the body is the overwhelming presence of masses of cells infected by the virus already in a short time, so if there were no anti-virus medications, oseltamivir, relenza, or whatsoever compound, which is able to neutralize first the virus proliferation in time everywhere, how it will be stoped the subsequent continuation of the viral infection from the already present viruses in the body cells;
by which way than the virus will be extint and beaten when it will be in already enormous quantities?

The "dampen" logic in that case must imply that the most of the serious cases will convert itself as light or mild if it remains the viral component only, instead both the viral and the cytokine immune reaction;
that an only normal body immune reaction through more time could destroy all the big quantities of already acquired infected cells previously(?)

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

But in the above logic, what happens with the primary agent, the flu virus?

The main reason this cytokine storm were raised from the body is the overwhelming presence of masses of cells infected by the virus already in a short time, so if there were no anti-virus medications, oseltamivir, relenza, or whatsoever compound, which is able to neutralize first the virus proliferation in time everywhere, how it will be stoped the subsequent continuation of the viral infection from the already present viruses in the body cells;
by which way than the virus will be extint and beaten when it will be in already enormous quantities?

The "dampen" logic in that case must imply that the most of the serious cases will convert itself as light or mild if it remains the viral component only, instead both the viral and the cytokine immune reaction;
that an only normal body immune reaction through more time could destroy all the big quantities of already acquired infected cells previously(?)

From Dr. Fedson's study:

In a study of mice massively infected with H5N1 influenza virus (1000 LD50), treatment with zanamivir begun 48 hours after infection reduced lung virus titers but led to little improvement in survival.32 However, when two immunomodulatory agents (celecoxib and mesalazine) were added, virus titers remained much the same but survival improved significantly. Unfortunately, the investigators failed to include a group of mice that were treated with celecoxib and mesalazine alone. If they had measured survival rates and virus titers in the two groups (two immunomodulators with and without an antiviral agent), they could have determined whether the antiviral agent was necessary for improving survival.

...the same degree of acute lung injury and the same cell signaling cascade was observed following intra-tracheal instillation of inactivated (not live) H5N1 virus.42 The same pattern was seen in human peripheral blood mononuclear cells when they were exposed to inactivated H5N1 virus. The pulmonary lesions in mice were histologically identical to those seen in fatal cases of H5N1 influenza. None of these changes was seen with inactivated H1N1 virus.

...In cell cultures of human blood macrophages, the onset of apoptosis induced by H5N1 viruses is delayed compared with that for H1N1 viruses,90 suggesting that intracellular persistence of the H5N1 virus might have something to do with its pathologic effects. In other studies, H5N1 virus (but not H5N2 or H5N3 viruses) was shown to induce caspase-dependent apoptosis in porcine alveolar epithelial cells, although levels of virus replication for all three viruses were the same.91 The H5N1 NS1 protein has also been shown to cause caspase-dependent apoptosis in human lung epithelial cells.92

In a splendid study of murine influenza, the PB1-F2 protein of the 1918 influenza virus was shown to cause severe viral and secondary pneumococcal pneumonia.93 PBI-F2 is known to have no major effect on virus replication. Instead, by localizing to the inner and outer mitochondrial membranes, it disrupts mitochondrial morphology and dissipates mitochondrial energy potential, causing apoptosis and cell death. It is thought that apoptosis of immune cells prevents efficient maturation of the adaptive immune response, and that this explains its pathologic effects. Remarkably, the effects of the 1918 PB1-F2 protein can be produced by intranasal administration of only the C-terminal portion of the protein.93

At least with H5N1, cytokine storm can occur without active viral replication, simply by exposure to certain proteins from the virus.

So theoretically, cytokine storm can be treated without any anti-viral. If you can control the cytokine storm, it might not matter how much the virus replicates.

 

[tropical]

Re: Neurological Manifestations as marker of H1N1 virulence?

From Dr. Fedson's study:
...
At least with H5N1, cytokine storm can occur without active viral replication, simply by exposure to certain proteins from the virus.

So theoretically, cytokine storm can be treated without any anti-viral. If you can control the cytokine storm, it might not matter how much the virus replicates.

So the practical use of this theory will be that the illness decourse will be light/mild/surviving if the storm were blocked, no matter how many live viruses remains into the body?

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

So the practical use of this theory will be that the illness decourse will be light/mild/surviving if the storm were blocked, no matter how many live viruses remains into the body?

We just don't know the answer to that question yet.

However, I suspect that will be the case. There is a difference in immune response between the very young and adolescents. If we can roll back the exuberant immune response of the adolescent to the level of the very young, using immunomodulatory drugs, then the answer seems to be yes.

Again, from Fedson:

secondary acute lung injury is less common and less severe in children than it is in young adults, and that it also has a lower mortality rate.115 The cytokine profiles of children and adults with severe burns differ greatly.116 Surgeons have also shown that the inflammatory responses of peritoneal macrophages harvested from children and young adults differ. When challenged in vitro with LPS117 or IL-1β,118 macrophages from children showed a greater predominance of anti-inflammatory activity compared with those from adults.

A model of severe acute inflammation in mice has provided a clue to how anti-inflammatory and immunomodulatory treatment might improve outcomes in severe influenza. Shin and his surgical colleagues showed that following ischemia/reperfusion injury in mice, inflammation was much more severe in 'young adults' (10?12 week old mice) than it was in 'children' (4- to 5-weeks old) (Table 2).119 The liver cells of 'children' showed up-regulation of PPARγ that was more pronounced and lasted longer that what was seen in 'young adults.' In 'children,' PPARγ activity was retained in the nucleus, whereas in 'young adults' it leaked into the cytoplasm. The liver cells of 'children' also showed greater evidence of autophagy than did those of 'young adults.' Importantly, when 'young adults' were treated with a PPARγ agonist (rosiglitazone), PPARγ activity was up-regulated in liver cells to levels similar to that seen in untreated 'children'.

Knowledge such as this could help us prepare for the next influenza pandemic. If PPARγ agonists are able to control acute lung injury, as has been suggested,120 the results of the study by Shin et al. suggest that treatment of young adults might, in effect, 'roll back' the host response of someone who is sexually mature and a poor PPARγ responder (and who might die) to that of a sexually immature child who is a better PPARγ responder (and more likely to live). Whether treatment with fibrates or statins would have a similar effect is unknown and should be studied.

If effective agents can be found, treatment in a pandemic might need to be given only to patients who are on the verge of developing severe, life-threatening illness and continued only until they had recovered. Since most patients infected with a pandemic influenza virus might be expected to have a balanced host response and recover uneventfully (perhaps H5N1 excepted), it would not be necessary to make treatment available for entire populations. Instead, smaller supplies could be stockpiled and reserved for treating only those individuals (perhaps only 2?10% of a population) who might truly benefit.

 

[tropical]

Re: Neurological Manifestations as marker of H1N1 virulence?

Thank You St Michael.


From the below Dr. Fedson text, one sentence seems to be tricky to locate and achieve:

"treatment in a pandemic might need to be given only to patients who are on the verge of developing severe, life-threatening illness and continued only until they had recovered"

With mass infection cases how it will be possible to verify and asses in time (prior an already storm damage) this "verge of severe development", when this time schedule could be only a few days.
Seems as an problem which would jeopardize the storm damping efforts, if the damping compounds could not be used preventively.

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

[/B][/I]With mass infection cases how it will be possible to verify and asses in time (prior an already storm damage) this "verge of severe development", when this time schedule could be only a few days.
Seems as an problem which would jeopardize the storm damping efforts, if the damping compounds could not be used preventively.

I don't know the answer to that.

Resveratrol and Vitamin D could be used throughout any pandemic period,

Statins, fibrates, glitizones and Cox 2 inhibitors all have pediatric indications and dosages, and would be relatively safe for short term prophylaxis.

The global medical community needs to figure out what to actually recommend if this thing hits before the basic research Fedson recommends is completed.

Unfortunately, its not likely that the global medical community will become aware of these possibilities nor is it likely that the research Fedson recommends will be undertaken prior to a high CFR influenza going global (be it H1N1 or other.)

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

Apoptosis under hypercytokinemia is a possible pathogenesis in influenza-associated encephalopathy

Hiroyuki Nunoi
Pediatrics International
Volume 47 Issue 2, Pages 175 - 179

Published Online: 16 Mar 2005
ABSTRACT

Abstract Background : Influenza-associated encephalopathy is reported to be frequent in Japan and East Asia. No evaluating markers except interleukin (IL)-6 and tumor necrosis factor (TNF)-α and no likely pathological mechanism for the disease have yet been elucidated.

Methods : In this study, influenza-associated encephalopathy was defined by clinical symptoms, and the use of an anti-influenza antibody test and/or influenza antigen detection kits, as well as computed tomography and/or magnetic resonance imaging. The levels of proinflammatory cytokines, acute phase proteins, endothelial markers and cytochrome c were compared in sera from 11 patients with and 42 without encephalopathy.

Results : Cytochrome c concentration in sera from patients with encephalopathy was markedly increased compared with that from patients without encephalopathy and normal controls. Although levels of several other proinflammatory cytokines and acute phase proteins such as TNF-α and IL-8 were also elevated in patients with influenza virus infection, the difference between those with and without encephalopathy, though significant, was less dramatic. The mean serum concentration of cytochrome c in 11 patients with encephalopathy, consisting of four deceased, four with and three without residual central nervous system sequelae, was 26.7 ? 19.5 ng/mL on admission. In contrast, cytochrome c levels in 42 patients without encephalopathy were 0.3 ? 0.7 ng/mL.

Conclusion : The present results indicate that cytochrome c is a useful marker to follow patients with influenza-associated encephalopathy and suggest that an apoptosis of cells in several organs including the cerebrum and liver under the influence of hypercytokinemia is a possible mechanism of the disease.

Received 6 January 2004; revised 5 July 2004; accepted 29 September 2004.

 

[St Michael]

Re: Neurological Manifestations as marker of H1N1 virulence?

The Pediatric Infectious Disease Journal?
Prognostic Factors in Influenza-Associated Encephalopathy

Takashi Nagao

Published: 08/21/2008

...

Discussion

An outbreak of encephalopathy suspected to have been caused by influenza infection prompted a national survey of influenza-associated encephalopathy at all hospitals and pediatric clinics in Japan, as well as this analysis of 442 cases. To our knowledge, this is the first study on the prognostic factors of influenza-associated encephalopathy. The mortality rate was as high as 30% without treatment.[1] Therefore, for the administration of intensive care, it is important to identify the factors that affect its prognosis. Using multivariate analysis, we identified several factors that were related to the poor prognosis of this disease.

A severely elevated transaminase level, thrombocytopenia, and hematuria or proteinuria were associated with an unfavorable outcome in influenza-associated encephalopathy. Although the pathogenesis of this disease is still unclear, several reports[8-10] have suggested that it involves cytokines, such as soluble tumor necrosis factor receptor-1, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), IL-8, and IL-10. Nerve and liver cells may be induced to undergo apoptosis in influenza-associated encephalopathy patients as a consequence of hypercytokinemia, resulting in disseminated intravascular coagulopathy and multiple organ failure.[8,10-13] Studies have reported hemophagocytosis in influenza-associated encephalopathy patients, suggesting the activation of macrophages and microglia cells by hypercytokinemia.[14] A severely elevated transaminase level, thrombocytopenia, and hematuria or proteinuria may be associated with disseminated intravascular coagulopathy, multiple organ failure, and hemophagocytosis resulting from hypercytokinemia induced by this disease.[8,10,11]

We also showed that hyperglycemia is a factor leading to poor prognosis. IL-6 may lead to increased cortisol levels, followed by a pronounced dose-dependent increase in blood
glucose.[15,16] Therefore, we postulated that the systemic hypercytokinemia in influenza-associated encephalopathy causes hyperglycemia and that the glucose levels reflect the degree of pathogenicity.

Hypoglycemia provided a significant P value of <0.05 in univariate analysis. However, this did not result in a significant difference in the multivariate analysis, which was probably because the number of patients with hypoglycemia in multivariate analysis was reduced from 8 to only 2 cases, or 1.1% of patients, because of missing data. Hypoglycemia is a symptom of Reye syndrome with a very poor prognosis.[5,17,18] Medium-chain acyl-CoA dehydrogenase deficiency is the most common disorder of fatty acid β-oxidation, and occurs acutely in Reye's-like syndrome, which is often provoked by infection.[19] Reye's-like syndrome is similar to influenza-associated encephalopathy in several of its symptoms, such as loss of consciousness, seizures, and increased aminotransferase levels.[1,20] Therefore, we postulated that influenza-associated encephalopathy may include a metabolic disorder, such as medium-chain acyl-CoA dehydrogenase deficiency.

High-grade fever, particularly ≥41?C, showed a tendency toward being a prognostic factor in the multivariate analysis. Some patients with a poor outcome exhibit a mitochondrial β-oxidation disorder evoked by inactivated carnitine palmitoyltransferase II during high-grade fever in influenza-associated encephalopathy.[21] Analysis of the genotypes and allele compositions of carnitine palmitoyltransferase II have revealed a thermolabile phenotype that occurs more frequently in influenza-associated encephalopathy patients than in healthy subjects.[21] In addition, the use of the nonsalicylate antipyretic drug diclofenac to alleviate fever affected the prognosis of the disease, and the use of mefenamic acid tended to also influence the prognosis, whereas the use of acetaminophen was considered to have little effect. In May 2001, the Japanese Ministry of Health, Labor, and Welfare banned the use of these antipyretic drugs to alleviate fever in influenza infection based on the data of the Collaborative Study Group on Influenza-Associated Encephalopathy.[1] However, it is still unclear whether these drugs are related to the pathogenesis of influenza-associated encephalopathy. Shiga-like toxin II or Shiga-like toxin II-stimulated cytokines may change the brain penetration of diclofenac sodium and mefenamic acid, and consequently increase the risk of the drugs having central nervous system side effects.[22]

We did not find a significant correlation between the prognosis of influenza-associated encephalopathy and flu vaccination record. A more extensive study is required to reveal whether flu vaccination can improve the prognosis after developing the disease because only 13 patients, or 3.1% of the 442 cases, had been immunized against flu.

The survey of influenza-associated encephalopathy is continuing. However, some parts of the questionnaires have been changed and fewer sites are now included in the survey. These changes were made mainly because the Private Information Protection Law came into effect in Japan in 2003, making it very difficult to obtain individual information. We did not obtain information regarding the therapy for influenza-associated encephalopathy because there were no standardized therapeutic protocols between 1998 and 2002. Recently, it has been reported that certain therapeutic regimens can improve the prognosis of influenza-associated encephalopathy.[6,7] In 2005, therapies such as methylprednisolone pulse, plasma exchange, and hypothermia therapy were proposed by the Collaborative Study Group on Influenza-Associated Encephalopathy, and further studies to improve influenza-associated encephalopathy prognosis via therapy are currently underway.

In conclusion, we identified several factors related to the poor prognosis of influenza-associated encephalopathy. Use of diclofenac sodium was the causal factor of poor prognosis. The other factors seem to reflect systemic hypercytokinemia, which is thought to play a role in the pathogenesis of the disease. However, all of these factors (with the exception of the use of diclofenac sodium) may be secondary to the disease process because they are seen in subjects who are moribund from a number of causes. Although these factors cannot be used to make an early diagnosis, our results have 2 major implications: the prognostic factors that we identified are easy to examine clinically, and these factors are important for the administration of intensive care in cases of influenza-associated encephalopathy.