While investigating the role of inflammation and its associations with stroke and delayed damage, I came across a couple of interesting articles that connect stroke and traumatic brain injury (TBI). By now we are all very familiar with the inflammatory response and various cytokines and cells associated with ischemic stroke. What may not be as clear, however, are the similarities between inflammation-mediated stroke reperfusion injury and other common causes of brain trauma.
TBI is commonly associated with high mortality and permanent neural deficits. In both the United States and Europe, TBI is the leading cause of death for individuals under the age of 45 and stroke is the second most common cause of death worldwide. Although traumatic tissue damage and ischemia have different causes, it has been shown that they are connected through the inflammatory pathway. Both TBI and stroke patients commonly suffer from delayed damage, mediated by the inflammatory response. Interestingly, in both cases, delayed damage often results in greater damage than that caused by the primary injury.
Besides direct mechanical injury, TBI leads to swelling of the brain due to local cellular edema. This increases the pressure on the cerebral microcirculatory vessels, which can cause ischemia (as seen with stroke). Often the blood-brain barrier is also broken down, which can lead to further swelling, hypoxia, and exacerbation of the problem. As with stroke, TBI causes up-regulation of cytokines, such as TNF, accumulation of leukocytes and macrophages, and increased expression of adhesion molecules.
This information clearly points out the need for further research regarding the inflammatory response in the brain. Whether it caused by transient ischemia or traumatic, mechanical force, the extent of many brain injuries has the potential to be greatly decreased through furthering our understanding of the delayed damage mechanism.
Finally, I think it is important to realize that post-insult inflammatory damage is not exclusive to stroke. The same inflammatory cells and mediators present in the ischemic brain can also be activated by other means and facilitate further tissue damage. I’m wondering if the connection between minor concussion (often seen in football) and any resulting inflammation related damage has been given much scrutiny. It would be interesting to determine exactly what portion of damage, resulting from minor concussion, is the result of delayed onset mechanisms.
References:
Andrews, Peter, and Rhodes, Jonathan. "The brain as a site of inflammation after acute injury". Blackwell, 2006. Pg: 275-276.
Feuerstein, Giora. “Inflammation and Stroke". Birkhauser, 2001. Pg: 181-186.
09 October 2008
08 October 2008
Overview of medical therapy in IBD
Hi Everyone!
Pat will be providing an overview of Inflammatory Bowel Disease, mainly focusing on Crohn's Disease (CD) and Ulcerative Colitis (UC). To go along with this, I wanted to provide an overview of the current treatments used in IBD, as this is not something we will directly review in our articles.
The overall goal of treatment in IBD is to stop the abnormal inflammatory response that is responsible for the symptoms, and aid in the induction and maintenance of remission. There is debate as to the approach taken in medical therapy. Some feel it better to start with less aggressive medications and work up the line to achieve the optimal medication for the individual patient. Others feel that starting with more aggressive medications at onset of disease may help to prevent irreversible bowel injury and lead to a better long-term outcome. However, I simply would like to give you an overview of the available medications. As we learn more about this disease over the next few weeks, the door is obviously wide open for debates on treatment approaches.
Aminosalicylates
Aminosalicylates are aspirin-like medications that contain 5-aminosalicylic acid (5-ASA), a potent anti-inflammatory agent. 5-ASA agents likely have multiple anti-inflammatory effects including inhibition of cyclooxygenase, lipoxygenase, B-cells and multiple inflammatory cytokines. These agents are usually used to treat mild to moderate symptoms, and are availiable in both oral and topical forms. More solid data exists for the use of 5-ASA agents in the effective treatment of UC than in CD. Their efficacy of treatment for CD is much less clear, and often is determined by the location of the disease in the GIT.
Antibiotics
Antibiotics such as Metronidazole and Ciprofloxacin are sometimes used to treat mild to moderate symptoms of CD; however, the evidence to support their mechanism of action is limited. Antibiotics are deemed more appropriate for treatment of perianal disease and fistulas in CD because of the risk for septic complications. In contrast, antibiotics are rarely used in the treatment of active UC.
Corticosteroids
These steroids act in our body by binding to glucocorticoid receptors in many of our different cell types and activating glucocorticoid-responsive elements (GREs). This leads to a wide array of effects on the immune system including inhibition of the recruitment and proliferation of lymphocytes and monocytes and a decreased production of inflammatory mediators (cytokines, prostaglandins, etc). Corticosteroids are effective for inducing remission in CD and UC; however, long term use to maintain remission is not recommended due to their numerous side effects. One particular steroid, budesonide, is a non-systemic acting glucocorticoid that may be used for the maintenance of remission. However, proper dosing schedules or amounts have yet to be determined.
Immunomodulators
Two immunomodulators currently used in the treatment of CD and UC are 6-Mercaptopurine and Azathioprine. The metabolites of these medications interfere with nucleic acid synthesis, and they have anti-proliferative effects on activated lymphocytes. Often immunomodulators are used when the disease is moderate to severe or when a patient is unresponsive to other drug treatments (5-ASAs or steroids). These medications are effective in both induction and maintenance of remission; however, their onset of action is typically 3-4 months, so other medications must be coupled with these initially.
Methotrexate (MTX) is another immunomodulator primarily used in treatment for CD. It acts as a competitive inhibitor or dihydrofolate reductase, one of the key enzymes necessary for folate production. As a result, MTX interferes with DNA synthesis and has multiple anti-inflammatory effects as it works as an immunosuppresant.
Since all of these immunomodulators interfere with the immune system, patients are at an increased risk of infection and must have their white blood cell counts monitored.
Biologic Agents
These agents are a group of medications that act in a variety of ways to inhibit TNF-alpha. TNF-alpha is a cytokine that mediates multiple pro-inflammatory processes central to the pathogenesis of IBD. Two common biologic agents used in treatment of IBD are infliximab and adalimumab. Infliximab is an intravenous infusion whereas adalimumab is administered subcutaneously. Indications for the usage of these therapies include both the induction and maintenance of remission for patients with moderate to severe disease. These biologic agents have also proved very useful in the treatment of fistulas and extra intestinal manifestations in CD.
Ok, well I figure this will at least give everyone some good introductory information on medical therapy in IBD. I by no means presented everything about the medical treatment, and just like in many other situations, treatment must be individualized to the patient.
References
Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: A review of medical therapy. World J Gastroenterol 2008; 14(3):354-377.
Cummings JR, Keshav S, Travis SP. Medical management of Crohn's disease. BMJ 2008; 336:1062-6.
Pat will be providing an overview of Inflammatory Bowel Disease, mainly focusing on Crohn's Disease (CD) and Ulcerative Colitis (UC). To go along with this, I wanted to provide an overview of the current treatments used in IBD, as this is not something we will directly review in our articles.
The overall goal of treatment in IBD is to stop the abnormal inflammatory response that is responsible for the symptoms, and aid in the induction and maintenance of remission. There is debate as to the approach taken in medical therapy. Some feel it better to start with less aggressive medications and work up the line to achieve the optimal medication for the individual patient. Others feel that starting with more aggressive medications at onset of disease may help to prevent irreversible bowel injury and lead to a better long-term outcome. However, I simply would like to give you an overview of the available medications. As we learn more about this disease over the next few weeks, the door is obviously wide open for debates on treatment approaches.
Aminosalicylates
Aminosalicylates are aspirin-like medications that contain 5-aminosalicylic acid (5-ASA), a potent anti-inflammatory agent. 5-ASA agents likely have multiple anti-inflammatory effects including inhibition of cyclooxygenase, lipoxygenase, B-cells and multiple inflammatory cytokines. These agents are usually used to treat mild to moderate symptoms, and are availiable in both oral and topical forms. More solid data exists for the use of 5-ASA agents in the effective treatment of UC than in CD. Their efficacy of treatment for CD is much less clear, and often is determined by the location of the disease in the GIT.
Antibiotics
Antibiotics such as Metronidazole and Ciprofloxacin are sometimes used to treat mild to moderate symptoms of CD; however, the evidence to support their mechanism of action is limited. Antibiotics are deemed more appropriate for treatment of perianal disease and fistulas in CD because of the risk for septic complications. In contrast, antibiotics are rarely used in the treatment of active UC.
Corticosteroids
These steroids act in our body by binding to glucocorticoid receptors in many of our different cell types and activating glucocorticoid-responsive elements (GREs). This leads to a wide array of effects on the immune system including inhibition of the recruitment and proliferation of lymphocytes and monocytes and a decreased production of inflammatory mediators (cytokines, prostaglandins, etc). Corticosteroids are effective for inducing remission in CD and UC; however, long term use to maintain remission is not recommended due to their numerous side effects. One particular steroid, budesonide, is a non-systemic acting glucocorticoid that may be used for the maintenance of remission. However, proper dosing schedules or amounts have yet to be determined.
Immunomodulators
Two immunomodulators currently used in the treatment of CD and UC are 6-Mercaptopurine and Azathioprine. The metabolites of these medications interfere with nucleic acid synthesis, and they have anti-proliferative effects on activated lymphocytes. Often immunomodulators are used when the disease is moderate to severe or when a patient is unresponsive to other drug treatments (5-ASAs or steroids). These medications are effective in both induction and maintenance of remission; however, their onset of action is typically 3-4 months, so other medications must be coupled with these initially.
Methotrexate (MTX) is another immunomodulator primarily used in treatment for CD. It acts as a competitive inhibitor or dihydrofolate reductase, one of the key enzymes necessary for folate production. As a result, MTX interferes with DNA synthesis and has multiple anti-inflammatory effects as it works as an immunosuppresant.
Since all of these immunomodulators interfere with the immune system, patients are at an increased risk of infection and must have their white blood cell counts monitored.
Biologic Agents
These agents are a group of medications that act in a variety of ways to inhibit TNF-alpha. TNF-alpha is a cytokine that mediates multiple pro-inflammatory processes central to the pathogenesis of IBD. Two common biologic agents used in treatment of IBD are infliximab and adalimumab. Infliximab is an intravenous infusion whereas adalimumab is administered subcutaneously. Indications for the usage of these therapies include both the induction and maintenance of remission for patients with moderate to severe disease. These biologic agents have also proved very useful in the treatment of fistulas and extra intestinal manifestations in CD.
Ok, well I figure this will at least give everyone some good introductory information on medical therapy in IBD. I by no means presented everything about the medical treatment, and just like in many other situations, treatment must be individualized to the patient.
References
Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: A review of medical therapy. World J Gastroenterol 2008; 14(3):354-377.
Cummings JR, Keshav S, Travis SP. Medical management of Crohn's disease. BMJ 2008; 336:1062-6.
07 October 2008
World Stroke Day 2008 and More
I found out that world stroke day is on Oct. 29 and the theme is "Little Strokes, Big Trouble" and the 6th World Congress of Stroke was held in Vienna on September 24 to 27, 2008.
Here is the Website:
http://stroke.ahajournals.org/cgi/content/full/39/9/2407
In class the other day someone asked about ischemic vs. hemorrhagic stroke and their occurrence, the American Stroke Association says that ischemic accounts for 83% of all strokes and hemorrhagic the other 17%.
Also we discussed possible treatments for hemorrhagic strokes and i looked on the Mayo Clinic Website and found out that the treatment depends on the cause and severity of the hemorrage. Medication treatments can range from blood pressure lowering meds to coagulants to just pain releivers to releive the symptoms. Also they talk about medications to prevent possible seizures. They also discuss different surgeries to treat the different types of hemorrhagic strokes such as for aneurysm, arteriovenous malformations, and general. These range from clamping the vessel to removal of hematoma to catheters through the vessel. One of the treatments for AVM really was interesting it was called coil embolization and invloved inserting a catheter through the leg and threading through the body to the brain. Then it coils around the affected AVM and a glue is injected to block the vessel. I found this article very helpful:
http://www.mayoclinic.org/stroke/hemorrhagic-stroke.html
Still while looking for treatments for hemorrhaic stroke i didn't find much on how to immediatily reduce damage except by having the person be monitored for damage just from the symptoms or having them lie down to reduce blood flow to the area. I would really like to know if anyone found anything else or it that all one can do?
We also discussed fucoidin and i found this post from last semester on it posted by dan k that i though was interesting thanks dan k. He talks about where fucoidin is found and a study that was done by Japanese scientists that showed it caused apoptosis is lymphoma cells.
http://inflammablog.blogspot.com/search?q=fucoidin
Here is the Website:
http://stroke.ahajournals.org/cgi/content/full/39/9/2407
In class the other day someone asked about ischemic vs. hemorrhagic stroke and their occurrence, the American Stroke Association says that ischemic accounts for 83% of all strokes and hemorrhagic the other 17%.
Also we discussed possible treatments for hemorrhagic strokes and i looked on the Mayo Clinic Website and found out that the treatment depends on the cause and severity of the hemorrage. Medication treatments can range from blood pressure lowering meds to coagulants to just pain releivers to releive the symptoms. Also they talk about medications to prevent possible seizures. They also discuss different surgeries to treat the different types of hemorrhagic strokes such as for aneurysm, arteriovenous malformations, and general. These range from clamping the vessel to removal of hematoma to catheters through the vessel. One of the treatments for AVM really was interesting it was called coil embolization and invloved inserting a catheter through the leg and threading through the body to the brain. Then it coils around the affected AVM and a glue is injected to block the vessel. I found this article very helpful:
http://www.mayoclinic.org/stroke/hemorrhagic-stroke.html
Still while looking for treatments for hemorrhaic stroke i didn't find much on how to immediatily reduce damage except by having the person be monitored for damage just from the symptoms or having them lie down to reduce blood flow to the area. I would really like to know if anyone found anything else or it that all one can do?
We also discussed fucoidin and i found this post from last semester on it posted by dan k that i though was interesting thanks dan k. He talks about where fucoidin is found and a study that was done by Japanese scientists that showed it caused apoptosis is lymphoma cells.
http://inflammablog.blogspot.com/search?q=fucoidin
New and On-going Targeted Therapies for Breast Cancer.
With breast cancer awareness month going on, I thought it would be appropriate to blog about the newest and on-going targeted therapies (mainly monoclonal antibody therapy) happening, as breast cancer is the most commonly diagnosed malignancy among women.
One of the biggest developments in breast cancer therapy to date is the use of the drug trastuzumab (Herceptin), which directly attacks the protein HER2 (human epidermal growth factor receptor). HER2 is the protein that aggressively promotes tumor growth in malignant breast cancer. Herceptin is a human monoclonal antibody which binds extracellularly to the HER2 protein to promote cell death (apoptosis). This will subsequently inhibit the proliferation of HER2 dependent tumors. This is extremely helpful, as more than 20 percent of breast cancer tumors overproduce this certain protein.
This is not the only type of therapy being done today to target this certain type of protein. Other monoclonal antibody-based therapies include another drug called pertuzumab. This certain type of antibody will bind to different sites of the cancer cells preventing proliferation of the tumor. This drug has been shown to be quite effective when used with trastuzumab to fight against the cancer cell lines that are resistant to trastuzumab. It has shown much success with the over-production of the HER2 protein.
Another type of targeted therapy, not using an antibody, is the use of a tyrosine kinase inhibitor. For the HER2 protein to activate tumor cell proliferation it has to be acted upon by a certain enzyme; this case being tyrosine kinase. This certain type of enzyme will act as a growth stimulating factor subsequently activating proliferation of the tumor cells. So by inhibiting the tyrosine kinase enzyme, you can stop the tumor from proliferating. A drug called Lapatinib is currently being clinically tested. It has shown much success in inhibiting the tyrosine kinase enzyme and causing growth arrest as well as cell suicide. Again, certain cell lines of breast cancer can become resistant to the drug trastuzumab, and combining the drug with Lapatinib will increase the effectiveness of trastuzumab.
The last type of therapy that I wanted to talk about is actually one of the newest therapies being worked on. It has been shown that high levels of IGF-1 (insulin-like growth factor) can increase the risk for breast cancer. The IGF-1 receptor is responsible for numerous cellular processes including proliferation and protection from apoptosis. Basically it keeps tumor cells alive and metastasizing. Current research is showing that using an antibody that could potentially block the IGF-1 receptor could help the effectiveness of trastuzumab, and stop tumor growth.
The importance of advancing these therapies becomes evident as more breast cancer cell lines are developing resistance to the drug trastuzumab, which has been around for a couple of decades. As more and more research is being done, and more targeted therapies are being developed, the survival rates for breast cancer patients are rising; yet this is just the beginning for breast cancer therapy.
One of the biggest developments in breast cancer therapy to date is the use of the drug trastuzumab (Herceptin), which directly attacks the protein HER2 (human epidermal growth factor receptor). HER2 is the protein that aggressively promotes tumor growth in malignant breast cancer. Herceptin is a human monoclonal antibody which binds extracellularly to the HER2 protein to promote cell death (apoptosis). This will subsequently inhibit the proliferation of HER2 dependent tumors. This is extremely helpful, as more than 20 percent of breast cancer tumors overproduce this certain protein.
This is not the only type of therapy being done today to target this certain type of protein. Other monoclonal antibody-based therapies include another drug called pertuzumab. This certain type of antibody will bind to different sites of the cancer cells preventing proliferation of the tumor. This drug has been shown to be quite effective when used with trastuzumab to fight against the cancer cell lines that are resistant to trastuzumab. It has shown much success with the over-production of the HER2 protein.
Another type of targeted therapy, not using an antibody, is the use of a tyrosine kinase inhibitor. For the HER2 protein to activate tumor cell proliferation it has to be acted upon by a certain enzyme; this case being tyrosine kinase. This certain type of enzyme will act as a growth stimulating factor subsequently activating proliferation of the tumor cells. So by inhibiting the tyrosine kinase enzyme, you can stop the tumor from proliferating. A drug called Lapatinib is currently being clinically tested. It has shown much success in inhibiting the tyrosine kinase enzyme and causing growth arrest as well as cell suicide. Again, certain cell lines of breast cancer can become resistant to the drug trastuzumab, and combining the drug with Lapatinib will increase the effectiveness of trastuzumab.
The last type of therapy that I wanted to talk about is actually one of the newest therapies being worked on. It has been shown that high levels of IGF-1 (insulin-like growth factor) can increase the risk for breast cancer. The IGF-1 receptor is responsible for numerous cellular processes including proliferation and protection from apoptosis. Basically it keeps tumor cells alive and metastasizing. Current research is showing that using an antibody that could potentially block the IGF-1 receptor could help the effectiveness of trastuzumab, and stop tumor growth.
The importance of advancing these therapies becomes evident as more breast cancer cell lines are developing resistance to the drug trastuzumab, which has been around for a couple of decades. As more and more research is being done, and more targeted therapies are being developed, the survival rates for breast cancer patients are rising; yet this is just the beginning for breast cancer therapy.
05 October 2008
Difference in Global Mortality in the Influenza Pandemic of 1968-1969
This week in IMMU 7630, we’ll be talking about flu pandemics. To preview/review, influenza viral particles have surface proteins called neuraminidases and hemagglutinins. There are 9 known neuraminidases (called N1, N2, etc.) and 16 known hemagglutinins (H1, H2, etc.). Viruses are named for the neuraminidases and hemagglutinins on their surface (H1N1, H3N2, H5N1, etc.). Pandemics occur when a known flu virus, such as the H1N1 virus, reasserts with an unknown flu virus (often a wild bird flu), such as H2N2. The new virus is an H2N2 and not related to the H1N1 strain. Humans have no pre-existing immunity to this new virus, and this can cause a pandemic or epidemic.
One example of this was the 1957/58 Asian flu virus which originated in China. It occurred when 3 genes from wild duck flu virus reasserted with five genes for circulating human strain (it was an H2N2 viruThe death rate was highest in the elderly (those 65 or older).
In 1968/69, there was a new pandemic, caused by the “Hong Kong Flu”. It was an H3N2, occurring when two genes from a wild duck flu virus reasserted with the six genes from the circulating H2N2 virus. Although there were ~1-4 million deaths worldwide, there were substantially less deaths in the US than in 1957/58 pandemic (~34,000).
The impact of this pandemic in different countries, by different age groups was looked at by C. Viboud et al (http://www.journals.uchicago.edu/doi/pdf/10.1086/431150?cookieSet=1). This pandemic had two seasons – 1969/68 and 1969/70. Interestingly, the mortality rates by country differed for these two seasons. The authors examined excess deaths from influenza and also looked at the proportion of excess pneumonia and influenza mortality (P&I mortality) in The United States, Canada, Japan, England, Australia, and France.
For each country, the authors examined the proportion of excess pneumonia and influenza mortality (P&I mortality) in persons <65 years of age. They found that this P&I mortality increased 2.2-4.6 fold during the first H3N2 pandemic season, as compared to the last H2N2 season. This “age-shift” is often characteristic of pandemics, indicating that a new virus form is circulating that a large proportion of the population has not been exposed to.
It has actually been speculated that during the 1968/69 pandemic, older people might have actually had some pre-existing immunity to the H3N2 virus from the 1957/58 virus. There was only a shift in the hemagglutinin; the neuraminidase remained the same. Many people might have had antibodies and memory T-cells to the H2N2, and they might have cross-reacted with the H3N2 virus. Unfortunately, this paper did not look at smaller age groups to try to discern this.
The remainder of the paper was spent focusing on the geographic differences in the pandemic. In the United States and Canada, the majority of the excess deaths from influenza occurred in the first year of the pandemic (70% and 54%, respectively), while in Japan, England, Australia, and France, the percentage of total excess deaths in the first year were much smaller (32%, 23%, 22%, and 15% respectively). The pandemic seemed to affect the North American continent quickly in the first year, while Europe, Asia, and Australia had more deaths from the flu the second year. This phenomenon is referred to as a “smoldering” pandemic.
This difference in pandemic is probably caused because in North America and Canada, people had very little pre-existing immunity to either the neuraminidase or hemagglutinin gene; thus, many of them got sick the first year. In contrast, people in Europe, Asia, and Australia would have had high pre-existing immunity. Phylogenetic analyses of the neuraminidase gene did show that there was genetic drift during this time period; that is, there are two genetically distinct gene clusters for the N2 gene, one in 1968/69 and the other in 69/70.
This led the authors to hypothesize that people in Europe, Asia, and Australia had high exposure to the H2N2 virus during its last pandemic season, and that the emergent H3N2 virus was fairly similar to the H2N2 virus. In contrast, people in North America did have as much exposure to the late H2N2 virus and thus less pre-existing immunity to the new H3N2 virus.
The severe second pandemic season in Europe, Asia, and Australia was still puzzling. To analyze this, the authors looked at phylogenetic relationships of the hemagglutinin H3 gene and the neuraminidase N2 gene. For the neuraminidase N2 gene, they found two distinct gene clusters, with different antigenic sites. The first cluster was present in the first pandemic season 1968/69, while the second, with a new antigenic site, was found in 1969/70. This genetic drift might explain why the pandemic was more severe in Europe, Asia, and Australia the second season. People now needed to make new antibodies to the new antigen. Interestingly, since the hemagglutinin gene did not drift much during this time, a substantial proportion of the North American population would have already made antibodies to it and would still be protected.
The “smoldering” response suggests that if a vaccine could have been made after year 1 in Europe, Asia, and Australia, a good percentage of the deaths could have been prevented. This is an interesting idea, although it unfortunately does not help us to predict new future pandemics.
After thinking about this paper and what we have learned in class, I was trying to think about how vaccine repsonses to infectious agents like influenza might be improved on a yearly basis. In the case of the 1968/1969 pandemic, the mortality varied around the world because the virus drifted differently. There have also been instances in the United States where the yearly vaccine is very different than that year's virus and is thus ineffective. Do we need to have a more global effort when it comes to vaccine production? Or, each year, do we need to make a vaccine that is a combination of vaccines in order to catch more variation in virus? Obviously, both of the ideas might be complicated and cost-prohibitive. It would be hard to justify either during non-pandemic years.
One example of this was the 1957/58 Asian flu virus which originated in China. It occurred when 3 genes from wild duck flu virus reasserted with five genes for circulating human strain (it was an H2N2 viruThe death rate was highest in the elderly (those 65 or older).
In 1968/69, there was a new pandemic, caused by the “Hong Kong Flu”. It was an H3N2, occurring when two genes from a wild duck flu virus reasserted with the six genes from the circulating H2N2 virus. Although there were ~1-4 million deaths worldwide, there were substantially less deaths in the US than in 1957/58 pandemic (~34,000).
The impact of this pandemic in different countries, by different age groups was looked at by C. Viboud et al (http://www.journals.uchicago.edu/doi/pdf/10.1086/431150?cookieSet=1). This pandemic had two seasons – 1969/68 and 1969/70. Interestingly, the mortality rates by country differed for these two seasons. The authors examined excess deaths from influenza and also looked at the proportion of excess pneumonia and influenza mortality (P&I mortality) in The United States, Canada, Japan, England, Australia, and France.
For each country, the authors examined the proportion of excess pneumonia and influenza mortality (P&I mortality) in persons <65 years of age. They found that this P&I mortality increased 2.2-4.6 fold during the first H3N2 pandemic season, as compared to the last H2N2 season. This “age-shift” is often characteristic of pandemics, indicating that a new virus form is circulating that a large proportion of the population has not been exposed to.
It has actually been speculated that during the 1968/69 pandemic, older people might have actually had some pre-existing immunity to the H3N2 virus from the 1957/58 virus. There was only a shift in the hemagglutinin; the neuraminidase remained the same. Many people might have had antibodies and memory T-cells to the H2N2, and they might have cross-reacted with the H3N2 virus. Unfortunately, this paper did not look at smaller age groups to try to discern this.
The remainder of the paper was spent focusing on the geographic differences in the pandemic. In the United States and Canada, the majority of the excess deaths from influenza occurred in the first year of the pandemic (70% and 54%, respectively), while in Japan, England, Australia, and France, the percentage of total excess deaths in the first year were much smaller (32%, 23%, 22%, and 15% respectively). The pandemic seemed to affect the North American continent quickly in the first year, while Europe, Asia, and Australia had more deaths from the flu the second year. This phenomenon is referred to as a “smoldering” pandemic.
This difference in pandemic is probably caused because in North America and Canada, people had very little pre-existing immunity to either the neuraminidase or hemagglutinin gene; thus, many of them got sick the first year. In contrast, people in Europe, Asia, and Australia would have had high pre-existing immunity. Phylogenetic analyses of the neuraminidase gene did show that there was genetic drift during this time period; that is, there are two genetically distinct gene clusters for the N2 gene, one in 1968/69 and the other in 69/70.
This led the authors to hypothesize that people in Europe, Asia, and Australia had high exposure to the H2N2 virus during its last pandemic season, and that the emergent H3N2 virus was fairly similar to the H2N2 virus. In contrast, people in North America did have as much exposure to the late H2N2 virus and thus less pre-existing immunity to the new H3N2 virus.
The severe second pandemic season in Europe, Asia, and Australia was still puzzling. To analyze this, the authors looked at phylogenetic relationships of the hemagglutinin H3 gene and the neuraminidase N2 gene. For the neuraminidase N2 gene, they found two distinct gene clusters, with different antigenic sites. The first cluster was present in the first pandemic season 1968/69, while the second, with a new antigenic site, was found in 1969/70. This genetic drift might explain why the pandemic was more severe in Europe, Asia, and Australia the second season. People now needed to make new antibodies to the new antigen. Interestingly, since the hemagglutinin gene did not drift much during this time, a substantial proportion of the North American population would have already made antibodies to it and would still be protected.
The “smoldering” response suggests that if a vaccine could have been made after year 1 in Europe, Asia, and Australia, a good percentage of the deaths could have been prevented. This is an interesting idea, although it unfortunately does not help us to predict new future pandemics.
After thinking about this paper and what we have learned in class, I was trying to think about how vaccine repsonses to infectious agents like influenza might be improved on a yearly basis. In the case of the 1968/1969 pandemic, the mortality varied around the world because the virus drifted differently. There have also been instances in the United States where the yearly vaccine is very different than that year's virus and is thus ineffective. Do we need to have a more global effort when it comes to vaccine production? Or, each year, do we need to make a vaccine that is a combination of vaccines in order to catch more variation in virus? Obviously, both of the ideas might be complicated and cost-prohibitive. It would be hard to justify either during non-pandemic years.
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