| What is a Cytokine Storm? | | | | viruses containing a combination of genes from a |
| | | | human influenza virus and an avian influenza virus. The |
| A cytokine storm, also called "systemic inflammatory | | | | origin of the 1918-19 pandemic virus is not clear, but if |
| response syndrome" (SIRS) is the systemic | | | | its origin was in China as suspected, it could have |
| expression of a healthy and vigorous immune system | | | | similarly been caused by a genetic recombination of |
| resulting in the release of more than 150 | | | | human and avian influenza viruses. This can more |
| inflammatory mediators (cytokines, oxygen free | | | | easily occur if humans are in close proximity to both |
| radicals, and coagulation factors). Both | | | | live birds and pigs, as can occur in public markets in |
| pro-inflammatory cytokines (such as Tumor Necrosis | | | | Asia. Osterholm reports the last influenza pandemic |
| Factor-alpha, InterLeukin-1, and InterLeukin-6) and | | | | (1968) occurred 37 years ago, emerging in China. At |
| anti-inflammatory cytokines (such as interleukin 10, | | | | that time China's human population was 790 million, its |
| and interleukin 1 receptor antagonist) are elevated in | | | | pig population was 5.2 million, and its poultry |
| the serum, and the fierce and often lethal interplay | | | | population was 12.3 million. Today, these populations |
| of these cytokines is referred to as a "Cytokine | | | | number 1.3 billion, 508 million, and 13 billion, |
| Storm". The primary contributors to the cytokine | | | | respectively. The human and animal populations of |
| storm are TNF-a (Tumor Necrosis Factor-alpha) and | | | | other Asian countries have similarly increased |
| IL-6 (Interleukin-6). The cytokine storm is an | | | | exponentially, which has increased the chances for |
| inappropriate (greatly exaggerated) immune response | | | | close contact between birds, pigs and humans in |
| that is caused by rapidly proliferating and highly | | | | these countries, creating optimal conditions for the |
| activated T-cells or natural killer (NK) cells. These cells | | | | emergence of new viruses, such as the H5N1 |
| are themselves activated by infected macrophages. | | | | subtype. On August 12, 2004, the Vietnamese |
| The cytokine storm must be treated and suppressed | | | | Ministry of Health reported three confirmed human |
| or lethality can result. | | | | deaths to the World Health Organization (WHO) from |
| Acute respiratory viral infection results in a cytokine | | | | confirmed avian influenza H5 infection. If the virus is |
| storm effecting the lungs, and subsequent damage | | | | confirmed to belong to the same H5N1 strain that |
| to alveoli and lung tissue results in the lethality seen in | | | | caused 22 cases (15 deaths) in Vietnam and 12 cases |
| more severe flu viral infections, especially those | | | | (8 deaths) in Thailand in 2005, and human-to-human |
| fatalities among young healthy adults. | | | | contact versus human to bird or human-to-swine |
| In the absence of prompt medical intervention to | | | | contact is suspected, this may indicate that H5N1 has |
| stop the "cytokine storm", the lung will suffer | | | | adapted to the point that it is transmissible and has |
| permanent damage. Many of these patients will | | | | the potential to cause the next pandemic. In May |
| develop acute respiratory distress syndrome (ARDS), | | | | 2006, it was reported that a family of 7 died of the |
| i.e. will present with pulmonary edema that is not | | | | bird flu after having no detectible contact with an |
| caused by volume overload, or a depressed left | | | | infected bird. If this is the case, the virus may have |
| ventricular function. Deaths will usually result from | | | | undergone a final mutation giving it the potential to |
| multisystem organ failure, and not from lung failure. | | | | cause a pandemic. What Are the Symptoms of the |
| Sepsis, Viral Infections, and Cytokine Storm | | | | Bird Flu: Initial Presentaion of Influenza A (H5N1) Avian |
| Sepsis is a severe systemic inflammatory response | | | | Influenza: |
| and is one example of a pathologic condition | | | | - Pulmonary: Radiographically confirmed pneumonia, |
| associated with "cytokine storm". Sepsis is an often | | | | acute respiratory distress syndrome (ARDS), or |
| lethal hemodynamic collapse which is usually the result | | | | other severe respiratory illness for which an alternate |
| of a super infection by gram-negative bacterial | | | | diagnosis cannot be established |
| endotoxins. Sepsis is also classified as septic shock | | | | - One or more of the following: cough and/or sore |
| syndrome (SSS). | | | | throat and/or shortness of breath, AND a history of |
| Cytokine storm can also result from viral infections | | | | contact with poultry (e.g., visited a poultry farm, a |
| such as influenza, and an exaggerated systemic | | | | household raising poultry, or a bird market) or contact |
| immune response to that particular viral infection | | | | with a known or suspected human case of influenza |
| (designated a type A, subtype "H1N1" virus) may | | | | A (H5N1) in an H5N1-affected country within 10 days |
| have been the cause of high lethality seen in the | | | | of symptom onset. |
| influenza pandemic of 1918 to 1919. The great | | | | - Dyspnea |
| influenza pandemic was the most destructive | | | | - Fever (temperature of >38°C or |
| pandemic in recorded world history, and killed more | | | | >100.4°F) |
| people (estimated between 20 to 50 million) than all | | | | Symptoms Of The Cytokine Storm: |
| casualties resulting from the first World War. | | | | The end stage, or final result, of cytokine storm |
| Although the Spanish Flu pandemic affected an | | | | (SIRS) or sepsis is multiple organ dysfunction |
| enormous percentage of the world wide population | | | | syndrome (MODS). The end-stage symptoms of the |
| (up to 20% of the world population according to | | | | bird flu, or other infection precipitating the cytokine |
| some sources), and killed between 20 and 50 million | | | | storm may include: |
| persons, no more than 5% of the people who | | | | - hypotension |
| contracted the Spanish Flu died (Brown et. al | | | | - tachycardia |
| reported the highest death rate in India at 50 deaths | | | | - dyspnea |
| per 1000 persons contracting the disease, or a five | | | | - fever (temperature of >38°C or |
| percent fatality rate). After 218 human cases of | | | | >100.4°F) |
| avian influenza (bird flu) have been confirmed | | | | - Ischemia, or insufficient tissue perfusion (especially |
| world-wide (as of May, 2006), the lethality rate | | | | involving the major organs) |
| stands at 57%. Should this strain develop into a | | | | - uncontrollable hemorrhage |
| pandemic, and should it keep its current mortality | | | | - and multisystem organ failure (caused primarily by |
| rate, it has the potential to be 10 times more lethal | | | | hypoxia, tissue acidosis, and severe metabolism |
| than the 1918 pandemic. | | | | dysregulation |
| Is the World Health Organization Adequately | | | | Oxygen free radicals, histamine, complement factor |
| Defending against a Potential Pandemic of Avian | | | | C5a, Beta-endorphin, thromboxane B2, and platelet |
| Influenza | | | | activating factor are implicated in SSS. The major |
| Avian Influenza (also called the "Bird flu") currently is | | | | pro-inflammatory cytokines which are implicated in |
| 10 times more lethal than the strain of Spanish Flu | | | | SSS are TNF-alpha, IL1, IL6 and IL8. Serum TNF alpha |
| that caused the great influenza pandemic of 1918 and | | | | concentrations in excess of 1 ng/mL are frequently |
| killed up to 50 million people world-wide, and it could | | | | predictive of a lethal outcome, however serum |
| become the most lethal flu pandemic of all history if | | | | concentrations of other inflammatory cytokines |
| the virus mutates allowing it to be more easily | | | | involved in the pathophysiology of Septic shock are |
| passed from person to person. Bird Flu patients die | | | | usually not reliable predictors of the severity of the |
| from acute respiratory distress syndrome (ARDS) | | | | shock state or clinical outcome. These cytokines are |
| caused by the "cytokine storm", and NOT directly | | | | released by macrophages following activation by |
| from the virus. Neuraminidase inhibitors (i.e. Tamiflu, | | | | bacterial endotoxins. |
| Relenza) are not proven effective for bird flu | | | | Preventing and/or treating the cytokine storm |
| patients, although they have been recommended by | | | | associated with influenza with antiviral medications, |
| the World Health Organization for this use, are | | | | prescription medications and vaccines that are |
| currently used to treat almost all bird flu patients, and | | | | approved (or may soon be approved) by the U.S. |
| are being stockpiled by governments world-wide | | | | Food and Drug Administration (FDA): |
| (including the United States) to treat a potential | | | | - Acambis Biotechnology Vaccine: Acambis announced |
| pandemic should the avian influenza virus undergo a | | | | on August 4, 2005 that it has entered into |
| final mutation which would allow it to be more easily | | | | collaboration with a Belgian research centre to |
| passed from person to person. A treatment to | | | | develop a single-dose flu vaccine that could offer |
| prevent or reduce the autoimmune reaction (cytokine | | | | permanent protection against all strains of both |
| storm) associated with the bird flu is commercially | | | | influenza A and influenza B, potentially offering |
| available by prescription, but is not currently being | | | | protection against future influenza pandemics. |
| recommended by the World Health Organization to | | | | - ACE inhibitors and Angiotensin II Receptor Blockers |
| treat these patients. | | | | (ARBs) make sense in the treatment of, and have |
| Influenza A, The most lethal influenza and the | | | | proven to be beneficial in treating the cytokine storm |
| precursor of all Pandemic Viruses | | | | (the major cause of lethality in Bird Flu) of SARS. See |
| Influenza viruses responsible for causing pandemics | | | | also: PUBMED, The cytokine storm and the |
| are influenza type A viruses which emerge as a result | | | | renin-angiotensin-aldosterone system. |
| of a process called "antigenic shift". Antigenic shift | | | | - Amantadine (Brand name Symmetrel: Treatment of |
| causes an abrupt or sudden, major change in certain | | | | influenza type A-2, but not type B). This drug cannot |
| proteins on the surface of the influenza A virus | | | | treat the cytokine storm associated with avian |
| (specifically the hemagglutinin or "HA" protein and the | | | | influenza, and has not been tested in patients with |
| neuraminidase or the "NA" protein).Certain antigenic | | | | the bird flu. |
| shifts may allow the virus to become more easily | | | | - Aventis Vaccine: Preliminary research suggests the |
| transmissible, more "contagious". Once this type of | | | | influenza A vaccine developed by Sanofi-Aventis is |
| shift occurs, wide-spread infection usually follows | | | | effective against H5N1 avian flu virus. The NIH (US |
| quickly. Antigenic shift is most dangerous when it | | | | National Institutes of Health) reported on August 5, |
| occurs in a virus that has demonstrated high lethality, | | | | 2005 (New York Times) that preliminary tests have |
| such as the H5N1 bird flu. | | | | confirmed that an experimental vaccine in |
| History has recorded 10 pandemics of influenza A in | | | | development by Sanofi-Aventis Pharmaceutical |
| the past 300 years. The sudden appearance of new | | | | Company appears to be effective in preventing |
| influenza A virus subtypes during the 20th century | | | | infection with the bird flu (avian influenza virus). |
| has caused three pandemics, all of which spread | | | | Researchers believe that the avian influenza virus, an |
| world-wide within 1 year of first being detected. | | | | influenza type-A, subtype H5N1, could trigger the |
| Influenza Pandemics of the 20th Century | | | | next worldwide flu pandemic. |
| - 1918-19, "Spanish flu," [Type A, subtype (H1N1)], | | | | - Oseltamivir (Brand name Tamiflu: a neuraminidase |
| caused the highest number of known influenza | | | | inhibitor for treatment or prevention of both influenza |
| deaths: more than one-half million people died within | | | | type A and B, indicated for use within 2 days of |
| the United States (nearly half of the deaths were | | | | symptoms). This drug cannot treat the cytokine |
| young healthy adults aged 20-40), and between 50 | | | | storm associated with avian influenza, and has not |
| and 100 million people may have died worldwide. Most | | | | been tested in patients with the bird flu. Most of the |
| deaths occurred within the first few days after | | | | avian flu victims in SE Asia and Turkey received |
| infection, some deaths within hours of symptom | | | | Tamiflu, and still suffered mortality rates exceeding |
| onset, and other deaths occurred later as a result of | | | | 50%. Tamiflu has been declared "ineffective" against |
| complications. Influenza A (H1N1) viruses still circulate | | | | the bird flu by a physician who has personally used |
| today after having been reintroduced in the 1970s. | | | | the drug to treat 41 bird flu patients (19% of all |
| Although called the "Spanish Flu" because the first | | | | reported cases to date). |
| widely reported deaths were in Spain, it probably | | | | - Prednisone and corticosteroids: Treatment of active |
| originated in China. | | | | disease may involve the use of corticosteroids. |
| - 1957-58, "Asian flu," [Type A, subtype (H2N2)], | | | | - Rimantadine (Brand name Flumadine: Treatment of |
| caused about 70,000 deaths in the United States. | | | | influenza type A, but not B). This drug cannot treat |
| The "asian flu" was initially identified in China in late | | | | the cytokine storm associated with avian influenza, |
| February 1957. Three months later, it spread to the | | | | and has not been tested in patients with the bird flu. |
| United States with early reports of infection as early | | | | - Zanamivir (Brand name Relenza: a neuraminidase |
| as June 1957. | | | | inhibitor for treatment of both influenza type A and |
| - 1968-69, " Hong Kong flu," [Type A subtype | | | | type B, indicated for use within 2 days of |
| (H3N2)], was responsible for about 34,000 deaths in | | | | symptoms). This drug cannot treat the cytokine |
| the United States. The "Hong Kong flu" virus was | | | | storm associated with avian influenza, and has not |
| first detected in Hong Kong in early 1968 and spread | | | | been tested in patients with the bird flu. Most of the |
| to the United States within a few months. Influenza | | | | avian flu victims in SE Asia and Turkey received |
| A (H3N2) viruses still circulate today. Both the | | | | Tamiflu (a drug similar to Relenza), and still suffered |
| 1957-58 and 1968-69 pandemics were caused by | | | | mortality rates exceeding 50%. |