CYTOKINE STORM and the INFLUENZA PANDEMIC

Angela L. Petrosino, MPH, CHES (Northwest Ohio Consortium for Public Health)

A cytokine storm 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 (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.

Treating the Cytokine Storm of Avian Influenza, the Premise of this Website:
1. Bird flu patients die from acute respiratory distress syndrome (ARDS) caused by the cytokine storm, and not directly from the virus. Historic survival in ARDS is 60%-85%; with bird flu-associated ARDS it is 43%.
2. Neuraminidase inhibitors (i.e. Tamiflu, Relenza) are not clinically proven effective for bird flu patients and cannot address the lethal cytokine storm associated with the infection.
3. The treatment to prevent or stop the autoimmune reaction (cytokine storm) is commercially available by prescription, but is not currently being recommended by the World Health Organization to treat these patients.

Acute respiratory viral infection (especially from the H5N1 subtype influenza virus) 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.
H5N1 Virus

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.

Proposed Mechanism of the Cytokine Storm Evoked by Influenza virus.
Osterholm. New England Journal of Medicine, 352 (18): 1839, Figure 3. May 5, 2005
Animation of chart above on NEJM.org

Sepsis 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 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.

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”. Antigenic shift causes an abrupt or sudden, major change in certain proteins on the surface of the influenza A virus (specifically the hemagglutinin or “HA” protein and the neuraminidase or the “NA” 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.

Electron Micrograph of the H5N1 Bird Flu Virus

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.

Tamiflu and Relenza have not been effective in patients with cytokine storm, and have not been tested in patients with bird flu. Prescription Angiotension Blockers may be beneficial in treating Bird Flu, and the cytokine storm which has proven lethal in over half of the patients who have contracted the avian flu to date. This book is a must read for those wanting to be prepared to treat a patient with avian influenza: Prescription Angiotension Blockers and their use in treating Bird Flu.

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.

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.
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.

The Bird Flu
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 earlier this year, 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.

How do physicians rate our preparedness to handle the potential H5N1 pandemic? This MDLinx survey is telling.

SYMPTOMS OF BIRD FLU (H5N1):
Initial Presentaion of Influenza A (H5N1) Avian Influenza:
* Pulmonary: Radiographically confirmed pneumonia, acute respiratory distress syndrome (ARDS), or other severe respiratory illness for which an alternate diagnosis cannot be established
* 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.
* Dyspnea
* Fever (temperature of >38°C or >100.4°F)

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:

* hypotension
* tachycardia
* dyspnea
* fever (temperature of >38°C or >100.4°F)
* Ischemia, or insufficient tissue perfusion (especially involving the major organs)
* uncontrollable hemorrhage
* and multisystem organ failure (caused primarily by hypoxia, tissue acidosis, and severe metabolism dysregulation

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):

* 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.
* ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) have proven to be beneficial in treating the cytokine storm (the major cause of lethality in Bird Flu). PUBMED: The cytomine storm and the renin-angiotensin-aldosterone system. More information is found on ACE inhibitors and the Bird Flu in this e-book.
* 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.
* 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.
* 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%. Tamiflu has been declared "ineffective" against the bird flu by a physician who has personally used the drug to treat 41 bird flu patients (19% of all reported cases to date).
* Prednisone and corticosteroids: Treatment of active disease may involve the use of corticosteroids .
* 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.
*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%.

Drug-resistance may occur in about one-third of patients taking amantadine or rimantadine. Additionally influenza A and B viruses could develop resistance to zanamivir and oseltamivir based on laboratory studies of the drugs.