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<h1>Bird Flu (Avian Influenza) Pandemic, the Cytokine Storm: What Drugs Work and Don't Work</h1>

What is a Cytokine Storm?
 
 by Steven P. Petrosino, Ph.D. and Angela L. Petrosino, MPH
 
 A cytokine storm, also called "systemic inflammatory response
syndrome" (SIRS) is the systemic expression of a healthy and
vigorous immune system resulting in the release of more than 150
inflammatory mediators (cytokines, oxygen free radicals, and
coagulation factors). Both pro-inflammatory cytokines (such as
Tumor Necrosis Factor-alpha, InterLeukin-1, and InterLeukin-6) and
anti-inflammatory cytokines (such as interleukin 10, and
interleukin 1 receptor antagonist) are elevated in the serum, and
the fierce and often lethal interplay of these cytokines is
referred to as a "Cytokine Storm". The primary contributors to the
cytokine storm are TNF-a (Tumor Necrosis Factor-alpha) and IL-6
(Interleukin-6). The cytokine storm is an inappropriate (greatly
exaggerated) immune response that is caused by rapidly
proliferating and highly activated T-cells or natural killer (NK)
cells. These cells are themselves activated by infected
macrophages. The cytokine storm must be treated and suppressed or
lethality can result.
 
 Acute respiratory viral infection results in a cytokine storm
effecting the lungs, and subsequent damage to alveoli and lung
tissue results in the lethality seen in more severe flu viral
infections, especially those fatalities among young healthy adults.
 
 In the absence of prompt medical intervention to stop the
"cytokine storm", the lung will suffer permanent damage. Many of
these patients will develop acute respiratory distress syndrome
(ARDS), i.e. will present with pulmonary edema that is not caused
by volume overload, or a depressed left ventricular function.
Deaths will usually result from multisystem organ failure, and not
from lung failure.
 
 

Sepsis, Viral Infections, and Cytokine Storm
 
 

Sepsis is a severe systemic inflammatory response and is one
example of a pathologic condition associated with "cytokine storm".
Sepsis is an often lethal hemodynamic collapse which is usually the
result of a super infection by gram-negative bacterial endotoxins.
Sepsis is also classified as septic shock syndrome (SSS).
 
 
Cytokine storm can also result from viral infections such as
influenza, and an exaggerated systemic immune response to that
particular viral infection (designated a type A, subtype "H1N1"
virus) may have been the cause of high lethality seen in the
influenza pandemic of 1918 to 1919. The great influenza pandemic
was the most destructive pandemic in recorded world history, and
killed more people (estimated between 20 to 50 million) than all
casualties resulting from the first World War. Although the Spanish
Flu pandemic affected an enormous percentage of the world wide
population (up to 20% of the world population according to some
sources), and killed between 20 and 50 million persons, no more
than 5% of the people who contracted the Spanish Flu died (Brown
et. al reported the highest death rate in India at 50 deaths per
1000 persons contracting the disease, or a five percent fatality
rate). After 218 human cases of avian influenza (bird flu) have
been confirmed world-wide (as of May, 2006), the lethality rate
stands at 57%. Should this strain develop into a pandemic, and
should it keep its current mortality rate, it has the potential to
be 
10 times more lethal than the 1918 pandemic.
 
 

Is the World Health Organization Adequately Defending against a
Potential Pandemic of Avian Influenza
 
 Avian Influenza (also called the "Bird flu") currently is 10
times more lethal than the strain of Spanish Flu that caused the
great influenza pandemic of 1918 and killed up to 50 million people
world-wide, and it could become the most lethal flu pandemic of all
history if the virus mutates allowing it to be more easily passed
from person to person. Bird Flu patients die from acute respiratory
distress syndrome (ARDS) caused by the "cytokine storm", and NOT
directly from the virus. Neuraminidase inhibitors (i.e. Tamiflu,
Relenza) are not proven effective for bird flu patients, although
they have been recommended by the World Health Organization for
this use, are currently used to treat almost all bird flu patients,
and are being stockpiled by governments world-wide (including the
United States) to treat a potential pandemic should the avian
influenza virus undergo a final mutation which would allow it to be
more easily passed from person to person. A treatment to prevent or
reduce the autoimmune reaction (cytokine storm) associated with the
bird flu is commercially available by prescription, but is not
currently being recommended by the World Health Organization to
treat these patients.
 
 
Influenza A, The most lethal influenza and the precursor of all
Pandemic Viruses
 
 Influenza viruses responsible for causing pandemics are
influenza type A viruses which emerge as a result of a process
called "antigenic shift&#8221;. Antigenic shift causes an abrupt or
sudden, major change in certain proteins on the surface of the
influenza A virus (specifically the hemagglutinin or
&#8220;HA&#8221; protein and the neuraminidase or the
&#8220;NA&#8221; protein).Certain antigenic shifts may allow the
virus to become more easily transmissible, more "contagious". Once
this type of shift occurs, wide-spread infection usually follows
quickly. Antigenic shift is most dangerous when it occurs in a
virus that has demonstrated high lethality, such as the H5N1 bird
flu.
 
 History has recorded 10 pandemics of influenza A in the past
300 years. The sudden appearance of new influenza A virus subtypes
during the 20th century has caused three pandemics, all of which
spread world-wide within 1 year of first being detected.
 
 
Influenza Pandemics of the 20th Century
 
 
<ul>
<li>1918-19, "Spanish flu," [Type A, subtype (H1N1)], caused the
highest number of known influenza deaths: more than one-half
million people died within the United States (nearly half of the
deaths were young healthy adults aged 20-40), and between 50 and
100 million people may have died worldwide. Most deaths occurred
within the first few days after infection, some deaths within hours
of symptom onset, and other deaths occurred later as a result of
complications. Influenza A (H1N1) viruses still circulate today
after having been reintroduced in the 1970s. Although called the
"Spanish Flu" because the first widely reported deaths were in
Spain, it probably originated in China.</li>
<li>1957-58, "Asian flu," [Type A, subtype (H2N2)], caused about
70,000 deaths in the United States. The "asian flu" was initially
identified in China in late February 1957. Three months later, it
spread to the United States with early reports of infection as
early as June 1957.</li>
<li>1968-69, " Hong Kong flu," [Type A subtype (H3N2)], was
responsible for about 34,000 deaths in the United States. The "Hong
Kong flu" virus was first detected in Hong Kong in early 1968 and
spread to the United States within a few months. Influenza A (H3N2)
viruses still circulate today.
 
 Both the 1957-58 and 1968-69 pandemics were caused by viruses
containing a combination of genes from a human influenza virus and
an avian influenza virus. The origin of the 1918-19 pandemic virus
is not clear, but if its origin was in China as suspected, it could
have similarly been caused by a genetic recombination of human and
avian influenza viruses. This can more easily occur if humans are
in close proximity to both live birds and pigs, as can occur in
public markets in Asia. Osterholm reports the last influenza
pandemic (1968) occurred 37 years ago, emerging in China. At that
time China's human population was 790 million, its pig population
was 5.2 million, and its poultry population was 12.3 million.
Today, these populations number 1.3 billion, 508 million, and 13
billion, respectively. The human and animal populations of other
Asian countries have similarly increased exponentially, which has
increased the chances for close contact between birds, pigs and
humans in these countries, creating optimal conditions for the
emergence of new viruses, such as the H5N1 subtype.
 
 On August 12, 2004, the Vietnamese Ministry of Health
reported three confirmed human deaths to the World Health
Organization (WHO) from confirmed avian influenza H5 infection. If
the virus is confirmed to belong to the same H5N1 strain that
caused 22 cases (15 deaths) in Vietnam and 12 cases (8 deaths) in
Thailand in 2005, and human-to-human contact versus human to bird
or human-to-swine contact is suspected, this may indicate that H5N1
has adapted to the point that it is transmissible and has the
potential to cause the next pandemic. In May 2006, it was reported
that a family of 7 died of the bird flu after having no detectible
contact with an infected bird. If this is the case, the virus may
have undergone a final mutation giving it the potential to cause a
pandemic.
 
 
What Are the Symptoms of the Bird Flu:
 
 Initial Presentaion of Influenza A (H5N1) Avian Influenza:
 
 
<ul>
<li>Pulmonary: Radiographically confirmed pneumonia, acute
respiratory distress syndrome (ARDS), or other severe respiratory
illness for which an alternate diagnosis cannot be established</li>
<li>One or more of the following: cough and/or sore throat and/or
shortness of breath, AND a history of contact with poultry (e.g.,
visited a poultry farm, a household raising poultry, or a bird
market) or contact with a known or suspected human case of
influenza A (H5N1) in an H5N1-affected country within 10 days of
symptom onset.</li>
<li>Dyspnea</li>
<li>Fever (temperature of &gt;38&#176;C or &gt;100.4&#176;F)</li>
</ul>
Symptoms Of The Cytokine Storm:
 
 The end stage, or final result, of cytokine storm (SIRS) or
sepsis is multiple organ dysfunction syndrome (MODS). The end-stage
symptoms of the bird flu, or other infection precipitating the
cytokine storm may include:
 
 
<ul>
<li>hypotension</li>
<li>tachycardia</li>
<li>dyspnea</li>
<li>fever (temperature of &gt;38&#176;C or &gt;100.4&#176;F)</li>
<li>Ischemia, or insufficient tissue perfusion (especially
involving the major organs)</li>
<li>uncontrollable hemorrhage</li>
<li>and multisystem organ failure (caused primarily by hypoxia,
tissue acidosis, and severe metabolism dysregulation</li>
</ul>
 
 Oxygen free radicals, histamine, complement factor C5a,
Beta-endorphin, thromboxane B2, and platelet activating factor are
implicated in SSS. The major pro-inflammatory cytokines which are
implicated in SSS are TNF-alpha, IL1, IL6 and IL8. Serum TNF alpha
concentrations in excess of 1 ng/mL are frequently predictive of a
lethal outcome, however serum concentrations of other inflammatory
cytokines involved in the pathophysiology of Septic shock are
usually not reliable predictors of the severity of the shock state
or clinical outcome. These cytokines are released by macrophages
following activation by bacterial endotoxins.
 
 
Preventing and/or treating the cytokine storm associated with
influenza with antiviral medications, prescription medications and
vaccines that are approved (or may soon be approved) by the U.S.
Food and Drug Administration (FDA):
 
 
<ul>
<li>Acambis Biotechnology Vaccine: Acambis announced on August 4,
2005 that it has entered into collaboration with a Belgian research
centre to develop a single-dose flu vaccine that could offer
permanent protection against all strains of both influenza A and
influenza B, potentially offering protection against future
influenza pandemics.</li>
<li>ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) 
<a href="http://www.genomed.com/pdf/AT1RSARS.pdf" target="_blank">make sense in the treatment of</a>, and have proven
to be 
<a href="http://www.genomed.com/pdf/ACE_vertebrate_pathophysiology.pdf" target="_blank">beneficial</a> in treating the cytokine storm (the
major cause of lethality in Bird Flu) of SARS. See also: PUBMED, 
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&amp;cmd=Display&amp;dopt=pubmed_pubmed&amp;from_uid=9547740" target="_blank">The cytokine storm and the
renin-angiotensin-aldosterone system</a>.</li>
<li>Amantadine (Brand name Symmetrel: Treatment of influenza type
A-2, but not type B). This drug cannot treat the cytokine storm
associated with avian influenza, and has not been tested in
patients with the bird flu.</li>
<li>Aventis Vaccine: Preliminary research suggests the influenza A
vaccine developed by Sanofi-Aventis is effective against H5N1 avian
flu virus. The NIH (US National Institutes of Health) reported on
August 5, 2005 (New York Times) that preliminary tests have
confirmed that an experimental vaccine in development by
Sanofi-Aventis Pharmaceutical Company appears to be effective in
preventing infection with the bird flu (avian influenza virus).
Researchers believe that the avian influenza virus, an influenza
type-A, subtype H5N1, could trigger the next worldwide flu
pandemic.</li>
<li>Oseltamivir (Brand name Tamiflu: a neuraminidase inhibitor for
treatment or prevention of both influenza type A and B, indicated
for use within 2 days of symptoms). This drug cannot treat the
cytokine storm associated with avian influenza, and has not been
tested in patients with the bird flu. Most of the avian flu victims
in SE Asia and Turkey received Tamiflu, and still suffered
mortality rates exceeding 50%. 
<a target="_new" href="http://www.cytokinestorm.com/tamiflu.html">Tamiflu has been
declared "ineffective" against the bird flu</a> by a physician who
has personally used the drug to treat 41 bird flu patients (19% of
all reported cases to date).</li>
<li>Prednisone and corticosteroids: Treatment of active disease may
involve the use of corticosteroids.</li>
<li>Rimantadine (Brand name Flumadine: Treatment of influenza type
A, but not B). This drug cannot treat the cytokine storm associated
with avian influenza, and has not been tested in patients with the
bird flu.</li>
<li>Zanamivir (Brand name Relenza: a neuraminidase inhibitor for
treatment of both influenza type A and type B, indicated for use
within 2 days of symptoms). This drug cannot treat the cytokine
storm associated with avian influenza, and has not been tested in
patients with the bird flu. Most of the avian flu victims in SE
Asia and Turkey received Tamiflu (a drug similar to Relenza), and
still suffered mortality rates exceeding 50%.</li>
</ul></li>
</ul>

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