Inflammation

Flu Preparedness

Date: September 21, 2005

by Chaya Venkat

Pneumonia Is the Single Biggest Killer of CLL Patients

Articles on Best Practices

In previous articles on Topics we have discussed in detail the role of pneumonia in CLL patients (Role of Pulmonary Inflammation in CLL; CLL, Chronic Inflammation and What You Can Do About It). Pneumonia is the single biggest reason for hospitalization and death in CLL patients.

The flu season will be upon us very shortly. One school of thought is that this year is going to be no different than prior years. Then we are warned of a more scary possibility by pretty reputable scientists and epidemiologists. It could be a whole new ball game this time around - or in the next few years - because of a strain of avian flu that can infect humans. The WHO (World Health Organization) says the avian-flu virus H5N1 is poised to mutate so that it can be easily transmitted from human-to-human. This event will have profound implications. Even the best-case mortality rates are in the millions, and the worst-case scenarios are too horrible to contemplate.

This article is about how you can protect yourself through the regular annual flu season and deal with the flu if you or a family member do get it. Remember, pneumonia is often a subsequent collateral problem associated with influenza, especially for CLL patients. If you are interested in the avian flu, of course, the Internet can serve up lots of detail. The problem is to sort out the credible information. There are few links and pdfs provided at the bottom of this article, each of them from a credible source. They are well worth your reading. You can make up your own mind about the seriousness of this possibility.

CLL Patients Are Particularly at Risk of Catching the Flu

Whether or not you believe the next big flu pandemic is going to happen in the near future, there is little doubt that the annual flu season starts around this time of the year. Did you know roughly 40,000 Americans die of the flu each year? That is a whole lot more of people dying of just the garden variety of flu than patients dying of CLL. By the way, as a CLL patient, you have a nice bulls-eye painted on your forehead when viral infections are a threat. You are more susceptible - and the consequences are more severe.

There are two major components of the immune system that are responsible for protecting us from nasty viral infections. If our bodies have been exposed to a particular strain of flu virus, the next time around there are antibodies present in our blood to jump start the immune response to fight off the invading hordes - but only if they belong to the same strain. "Antibody" is another word for a specific immunoglobulin targeted to the particular pathogen. Antibodies are made by memory B-cells. Guess what, as B-CLL patients, we have heavily corrupted B-cell function. The majority of CLL patients also have sub-par immunoglobulin levels, which is the reason why so many of us require IVIG (intravenous immunoglobulin) therapy, to top up our own waning levels of Ig.

Another extremely important part of our immune system in fighting viruses is the T-cell compartment. In healthy folks T-cells are very efficient serial killers, good at stalking and killing infected cells (Killer T-Cells). Unfortunately, the T-cell compartment in B-CLL patients is also compromised, either as a result of the disease itself or by the therapies we undergo to control the CLL. The exact nature of the T-cell defect is still being debated by experts. But there is general agreement that CLL patients are immune compromised (duh!!), with defective T-cell, NK-cell and dendritic cell function, in addition to the obvious defects in B-cell function.

Abstracts:

http://www.jci.org/cgi/content/full/115/7/1797

J Clin Invest. 2005 Jul;115(7):1797-805. Epub 2005 Jun 16.

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells.

Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In co-culture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity.

PMID: 15965501
______________

Leuk Lymphoma. 2003 Mar;44(3):383-9.

Abnormal T-cell function in B-cell chronic lymphocytic leukaemia.

Scrivener S, Goddard RV, Kaminski ER, Prentice AG.

Plymouth Post-graduate Medical School, Derriford Combined Laboratories, Derriford Hospital, Plymouth PL6 8DH, UK.

There is increasing evidence of T cell dysfunction in B cell chronic lymphocytic leukaemia (B-CLL) which may contribute to the aetiology and progress of the disease. An absolute CD8+ lymphocytosis correlates with disease progression and low expression of CD4 and CD8 (as found in autoimmune disease) is seen with abnormal expression of other surface molecules. Although the expression of T cell surface activation markers, CD25 and CD152, may be increased on culture in B-CLL serum, response to the common mitogens, PHA and PWM, is reduced. This and the excess of CD8 cells may explain partly the variable cooperation of T cells with B cell production of immunoglobulin in B-CLL. In the context of T cell cross-talk with antigen presenting cells, B-CLL B cells are poor antigen presenters. But the T cells themselves have significant abnormalities of expression of the many antigens and ligands necessary for this process. In particular, they exhibit variable expression of the low affinity and non-specific adhesion molecules LFA-1 and ICAM-1, variable, clonally restricted and skewed expression of the TCR repertoire (implying repeated antigenic stimulation possibly by CLL antigens), reduced CD28 and CD152 expression (implying impairment of ability to start or stop an immune response) and reduced IL2 and CD25 (IL2 R) expression (critical for positive feed-back in maintenance and expansion of the T cell response to antigen presentation). Although the production of IL2 and other cytokines by the T cell in B-CLL may be impaired, production of the anti-apoptotic cytokine IL4 is not and there may be a unique and expanded subset of CD8/CD30 cells capable of releasing IL4. The relationship of this T cell subset to the malignant B cell in vivo is unknown. However, T cells which are CD4+/CD152+/CCR4+ migrate selectively in vitro in response to the chemokine CCL22 (specific for the receptor CCR4) produced by the malignant B cells and are always seen amongst the malignant cells in bone marrow and lymph nodes from B-CLL patients. Other abnormalities of cytokine secretion are described. These findings suggest that the T cell in B-CLL may be unable to start, maintain and complete an immune response to the malignant B cell and other antigens and may be involved directly in sustaining the tumour. However, autologous tumour specific cytotoxicity has been shown in vitro and T cells which recognize tumour-derived heavy chain fragments circulate in vivo. If adoptive immunotherapy of any nature is to succeed in B-CLL, manipulation to optimize these CTL responses is needed to overcome the profound and variable T cell dysfunction in this disease.

PMID: 12688308
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Cancer Res. 2003 Aug 1;63(15):4497-506

The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response.

Orsini E, Guarini A, Chiaretti S, Mauro FR, Foa R.

Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza, Via Benevento 6, 00161 Rome, Italy.

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by a profound dysregulation of the host immune system that has a marked impact on the clinical course of the disease. To date, the competence of the circulating dendritic cell (DC) compartment in CLL patients has not been investigated. To address this issue, we sorted DC precursors from the peripheral blood of CLL patients and found a profoundly altered compartment as compared with normal donors. CLL DCs proved a morphologically and phenotypically immature population, lacking the maturation antigen CD83 and the costimulatory molecule CD80, unable to induce a significant proliferative response in allo-mixed lymphocyte reaction, with a reduced ability to release interleukin 12 and to drive a type 1 T-cell response. To investigate whether these defects could be ascribed to inhibiting soluble factors released by the leukemic clone, DCs were generated in vitro from normal monocytes in the presence of allogeneic CLL cells. The addition of CLL cells induced similar markers of abnormal maturation and functional impairment with an inhibition in the expression of costimulatory molecules and a reduction of their allo-stimulatory ability. The blocking of interleukin 6 activity was able to revert the inhibition in a proportion of patients. Taken together, these findings indicate that mechanisms of tumor-induced DC inhibition are operational in CLL patients, resulting in both maturative and functional defects in the circulating DC compartment, with a potential functional impact in the regulation of in vivo T-cell immune responses.

PMID: 12907623
______________

We have discussed in many prior articles the immune suppressive role of various drugs used to treat CLL patients. Don't get me wrong. Immune suppression or not, there are times when we have no choice but to go with the therapy options that are available to us at that point. But some drugs are more extreme than others in terms of their immune suppressive nature, and there is documented increase in opportunistic infections as a result of their use. Among the major culprits are purine analogs such as fludarabine, alkylating agents such as cyclophosphamide, the monoclonal antibody Campath, steroidal drugs such as prednisone. The level of immune suppression and the extent of risk of opportunistic infections depend on a lot of things, such as dose of the drug used, whether several immune suppressive drugs were used in combination, the length of time of the therapy, and the level of vulnerability of the patient going into therapy. If you have advanced CLL, or you have been a valiant warrior of the chemotherapy wars for many years, chances are good you have holes in your immune defenses. We have discussed shingles caused by herpes virus, CMV (cytomegalovirus) reactivation, HPV (human papilloma virus), hepatitis and EBV as a short list of viruses that may be detrimental to your health. Please add the flu virus to that list.

Annual Flu and Quintennial Pneumonia Vaccinations Are Essential

CLL patients are strongly advised to get annual flu and once-in-five-years pneumonia vaccinations. Easy enough to do, a quick visit to the doctor's office, a quick couple of jabs in the arm. Right? I wish it was that simple. Here is the problem. Vaccinations are supposed to work by giving your immune system something to chew on, a sneak pre-view of the antigens that are likely to come by, think of it as a way of priming your defenses and giving the good guys a heads-up. But as we know, CLL patients do not have normal immune systems. It goes with the territory that we do not have "normal" response to vaccinations. In fact, our immune systems may decide to snooze right through the wake-up call of a vaccination, and be caught unprepared when the real bugs arrive on the scene.

Abstract:

Vaccine. 2001 Feb 8;19(13-14):1671-7.

Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia.

Hartkamp A, Mulder AH, Rijkers GT, van Velzen-Blad H, Biesma DH.

Department of Internal Medicine, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.

Although vaccination against Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae type b (Hib) is recommended for immunocompromised patients, such as patients with B-cell chronic lymphocytic leukaemia (B-CLL), its protective effect is questionable. We studied antibody responses to pneumococcal polysaccharide vaccine (Pneumovax-23) and to conjugated H. influenzae type b-vaccine (Act-Hib) in 25 patients with B-CLL. After vaccination, the number of patients with antibody levels in the protective range against pneumococcal serotypes and H. influenzae b increased from 9 (38%) to 12 (50%) of 24 patients and from 8 (35%) to 11 (48%) of 23 patients, respectively. The patients with adequate antibody response to Pneumovax-23 and Act-Hib had significantly less advanced stages of B-CLL, higher gammaglobulin levels, total IgG-levels and IgG-subclasses 2 and 4 levels, and lower levels of soluble CD23. Consequently, vaccination with these vaccines should be given as soon as the diagnosis of B-CLL is made, early in the course of the disease with determination of post-vaccination antibody levels.

PMID: 11166890
______________

Does this mean you can skip getting the flu and pneumonia vaccinations? Not on your life. Less than effective vaccination does not mean there is zero benefit to be had from getting the shots. I strongly urge each of you to get these shots, and this is the right time of the year to get them. By the way, if you do not have CLL yourself, but you are the significant other and caregiver, you should get the shots as well. You may be tough as nails, willing to soldier on with or without the flu. But remember, if you get the flu, chances are much higher that your partner with CLL is that much more at risk of getting the flu from you and in his/her case the resulting infection may be a lot more dangerous. If your family has small children, please discuss with your pediatrician about getting them shots as well. When my daughter was a toddler going to nursery school, she had this concept that a grubby child meant a happy child. Cleanliness and hygiene were the equivalent of not having any fun. Talk about your cute virus magnet. There was not a bug out there that she did not bring home.

Improving the Efficiency of Vaccinations

Are there things we can do improve the efficiency of vaccinations in CLL patients? This is still an open subject, but there are good leads that you might want to explore. Some experts (including our own Dr. Terry Hamblin) think vaccination efficiency in CLL patients may be improved by taking cimetidine at the same time. Cimetidine (brand name Tagamet) is a histamine receptor blocker. It has been around for ages, one of the early drugs that came on the scene for controlling heartburn and hyperacidity in the stomach. In addition to reducing stomach acid, cimetidine also works on blocking histamine-2 receptors. Another drug similar to cimetidine is ranitidine (Zantac), named in the second abstract below.

The first abstract below (from Dr. Neil Kay of Mayo and Project Alpha fame) suggests that the effect of cimetidine is to increase the activity of NK cells (Natural Killer cells). NK cells are frontline troops in defending against invading viruses. This may be mechanism for the improved vaccination efficiency noted by practicing physicians in the field. I wish I could point to larger scale studies with all the appropriate bells and whistles, but I am afraid such studies have not been done. As things stand, since cimetidine has a well-deserved reputation for low adverse effects, you may want to discuss taking this vaccination booster with your doctor. Be aware that you may need to take the cimetidine before, during and after vaccination, for a period of time. You may also need more than the dosage of cimetidine in the over-the-counter version for dealing with acid stomach. Since it is not my intention to practice medicine without a license, I am not going to tell you the dose of cimetidine you should take, or the length of time you should be on it. That is a topic of discussion between you and your doctor.

Abstracts

J Lab Clin Med. 1987 Apr;109(4):396-401.

Cimetidine modulates natural killer cell function of patients with chronic lymphocytic leukemia.

Allen JI, Syropoulos HJ, Grant B, Eagon JC, Kay NE.

Peripheral blood natural killer (NK) activity in patients with B-cell chronic lymphocytic leukemia (B-CLL) is frequently low or absent. Because cimetidine (a histamine-2 antagonist) has been shown to alter human lymphocyte function in vitro, we decided to study cimetidine's effect on peripheral blood NK activity of patients with B-CLL and controls. We administered cimetidine orally (1.2 gm per day) to seven patients with B-CLL and 12 controls for up to 28 days. Peripheral blood NK activity of patients with B-CLL rose from a pretreatment level of 0.7 +/- 0.5 (mean +/- SEM) lytic units/10(6) cells (LU) to 8.7 +/- 2.4 LU (P less than 0.05) at day 28. Peripheral blood NK activity of controls decreased after 14 days of cimetidine treatment but returned to pretreatment levels by day 28. When peripheral blood cells from controls were exposed to cimetidine during in vitro incubation (10 micrograms/ml), mean NK activity was increased at 48 hours (54% +/- 22% increase over controls, n = 5, P less than 0.05). Single cell cytotoxicity assays revealed increased killing of target cells (but not effector-target conjugation) with cimetidine-exposed effector cells. These data suggest that cimetidine may be useful to augment peripheral blood NK activity for patients with B-CLL.

PMID: 3493314
_____________

Leukemia. 1995 Nov;9(11):1902-9.

Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia.

Jurlander J, de Nully Brown P, Skov PS, Henrichsen J, Heron I, Obel N, Mortensen BT, Hansen MM, Geisler CH, Nielsen HJ.

Department of Hematology, University Hospital Rigshospitalet, Copenhagen, Denmark.

Patients with B cell chronic lymphocytic leukemia (B-CLL) have decreased capacity to mount relevant antibody responses upon immunization, and development of hypogammaglobulinemia is part of the natural history of the disease. We investigated the influence of histamine type-2 (H2) receptor blockade by ranitidine on the in vivo antibody production in B-CLL patients following vaccination. Anti-polysaccharide antibodies in B-CLL patients, vaccinated with a tetanus-toxoid conjugated vaccine against Haemophilus influenzae type-B (Hib), reached long-term protective levels in more than 90% of B-CLL patients randomized to ranitidine treatment, as compared to 43% of the untreated patients (P = 0.024). No difference in the response to vaccination against influenza virus types A and B protein could be detected between the two groups. Plasma histamine levels were 2-fold to 20-fold higher in 23 out of 31 B-CLL patients, compared to normal controls, and these levels showed a significant positive correlation to disease duration. These findings indicate the possibility of improving in vivo antibody production against a highly relevant pathogen in B-CLL patients by histamine type-2 receptor blockade, and the combined finding of an immune-stimulatory effect of ranitidine and increased plasma histamine levels, strongly suggests the involvement of histamine in the pathogenesis of B-CLL immunodeficiency.

PMID: 7475282
_____________

Digestion. 1999 Sep-Oct;60(5):415-21.

Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date.

Siegers CP, Andresen S, Keogh JP.

Department of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lubeck, Germany.

BACKGROUND: Evidence first appeared in 1988 that cimetidine as an adjuvant may improve the survival of severely ill gastro-intestinal cancer patients when given peri- or postoperatively. Since then, several studies have appeared which suggest an anticancer activity for cimetidine, although few attempts have been made to corroborate their findings in large, placebo-controlled, double-blind studies.
METHOD: We reviewed the literature concerning cimetidine's potential anticancer activity, particularly with regard to gastro-intestinal cancers.
RESULTS: Most studies suggest that cimetidine may improve the outcome in cancer patients by a three-pronged mechanism involving (1) inhibition of cancer cell proliferation; (2) stimulation of the lymphocyte activity by inhibition of T cell suppressor function, and (3) inhibition of histamine's activity as a growth factor in tumours.
CONCLUSION: Bearing in mind the experimental evidence, as well as the potential and excellent safety profile of cimetidine, more studies are required and justified to clarify cimetidine's protherapeutic activity.

PMID: 10473965
______________

J Thorac Cardiovasc Surg. 1998 Aug;116(2):312-8.

Cimetidine reduces impairment of cellular immunity after cardiac operations with cardiopulmonary bypass.

Katoh J, Tsuchiya K, Osawa H, Sato W, Matsumura G, Iida Y, Suzuki S, Hosaka S, Yoshii S, Tada Y.

Second Department of Surgery, Yamanashi Medical University, Japan.

OBJECTIVE: Depressive effects of cardiopulmonary bypass on cell-mediated immune responses may lead to postoperative infectious complications. We previously reported that cimetidine reduced postbypass depression of the cytotoxic activity of natural killer cells. This study evaluated cimetidine as an agent to preserve cellular immunity after cardiac operations.
METHODS: In a prospective randomized study, 20 patients were divided into two groups of equal size. Cimetidine-group patients received 400 mg of cimetidine intravenously before bypass and a 33 mg/hr intravenous infusion of cimetidine after the operation, continuing until the fifth postoperative day. Control-group patients received conventional perioperative therapy. Lymphocyte subsets, natural killer cell activity, percentage of CD56+CD16+ (percentage of natural killer cells), and percentage of CD11b+CD8+ (percentage of suppressor T lymphocytes) were measured perioperatively.
RESULTS: Although temporary postoperative reductions in percentages of CD3+, CD4+, and CD56+CD16+ cells were observed in both groups, CD8+ percentages on postoperative day 1 and CD11b+CD8+ percentages on postoperative days 1 and 3 in the cimetidine group were significantly lower compared with those in the control group (p = 0.01,p = 0.004, andp = 0.02, respectively). Temporary postoperative reduction of natural killer cell activity was also observed in both groups, but the natural killer cell activity on postoperative day 1 in the cimetidine group (17.1%) was significantly higher (p = 0.02) than that in the control group (8.20%).
CONCLUSIONS: Cimetidine counteracts depressive effects of cardiopulmonary bypass on cell-mediated immunity and may possibly reduce postoperative susceptibility to infection.

PMID: 9699585
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Do's and Don'ts for the Flu Season

1. Don't skip getting the flu and pneumonia shots, both for yourself as the CLL patient as well as your family members and care givers.
2. Discuss with your doctor the advisability of adding cimetidine as a vaccination booster.
3. Remember, the best way of avoiding getting sick is to avoid contact with sick people. Try to stay away from enclosed and crowded places, and do try to eat out less often. With the holiday season coming up, this is hard to do, but how much fun are the holidays going to be if you are hospitalized with pneumonia? Remember, the majority of CLL patients die of some form of pneumonia. This is the single biggest reason for hospitalization for our patient group. Since we are an immune compromised group to begin with, and vaccinations do not work very well for us, some level of "self quarantine" is both appropriate and prudent. How far you want to take the self quarantine concept depends on your analysis of the risks involved. The regular flu season is almost as regular as clockwork. As an additional risk, there are a lot of very serious and credible researchers and organizations that are on record that the risk to humans from avian flu is real, that it is no longer a question of if but when humans will be infected in large numbers.
4. Wash your hands! Do this often, and take your time to wash thoroughly with soap and warm water. Make a habit of not touching your face, mouth, nose, eyes, etc. Get and use frequently the alcohol-based anti-septic hand sanitizers available in supermarkets and drug stores.
5. Ask your doctor for a prescription for "Tamiflu". The generic name for this drug is "oseltamivir" and it is an anti-viral drug that has reasonable efficacy against several strains of flu, including the latest bird-flu version that is scaring everyone. I suggest you try getting the prescription filled right away, this stuff is flying off of the shelves and you may have trouble getting hold of it later on. Many countries including the U.S are stockpiling this drug as part of national preparedness, and supplies are low. Be sure to check the expiration date on the package, you don't want to get something that is going to be past expiration shortly. I also urge you to use caution before you buy it from on-line stores, there are a lot of scams going on capitalizing on the shortage of this drug. The best place to get it is from your local pharmacy.
6. Tamiflu is generally prescribed for 5 days, at 2 capsules per day, 75 milligrams per capsule. The idea is that you take it as soon as you feel any symptoms. It will not do much good if given more than 48 hours after onset of infection. Depending on your powers of negotiation or resourcefulness, see if you can get it for more than a 5 day course. As a CLL patient you may need a longer stint, the present 5 day regimen reflects the shortages. In prior years the standard was for 7 or even 10 days. If possible, each member of your family should have a minimum 5 day (10 capsules) stash of Tamiflu as insurance. Unfortunately, this is not a cheap drug by any means, and insurance companies may balk at paying for more than the bare minimum 10 capsules. But please do resist the temptation to buy it from the guy at the street corner, no matter how deep the discount he offers. Buyer beware!
   
   The abstract below from the prestigious New England Journal of Medicine reports on a very robust placebo controlled and double blinded study with 1,559 patients, to judge the efficacy of Tamiflu . Unfortunately, the drug was administered for a whopping six weeks, something we cannot afford in today's real world constraints of its availability. But the study (and many others that I have not had time to review) makes it clear that Tamiflu may help in preventing and controlling the seriousness of flu infections. It may not be a totally effective safety net, but I would not sneeze at its potential benefits, if I were you.

Abstract

http://content.nejm.org/cgi/content/abstract/341/18/1336

N Engl J Med. 1999 Oct 28;341(18):1336-43.

Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.

Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, Huson L, Ward P, Mills RG.

Department of Medicine, University of Virginia, Charlottesville 22908, USA.

BACKGROUND: Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998.
METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom).
RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent).
CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.

PMID: 10536125
_____________

7. The major complication of flu, especially the bird-flu variety that may come around this year or next year, is deep-seated pneumonia. It is thought that the virus causes a "cytokine storm", an excessive but ineffective response of the body to the virus. Think of this as a Keystone-cops response of the immune system. The bad guys are unscathed but all the cops running around shooting off their side arms cause grave damage to the innocent bystanders. In this case, the inappropriate over-the-top response of the immune system causes massive damage to lung tissue, hence the pneumonia. You are well advised not to take magic potions or herbal remedies that are supposed to "build up your immune system". More often than not, these herbs may make matters worse. Remember, pneumonia is the major killer here, and it is caused by an excessive and inappropriate inflammatory response.
8. In fact, damping down overactive inflammatory response may be of help in pneumonia patients gasping to take breath. The abstract below discusses the use of EPA and DHA from fish oil in controlling respiratory distress, and the results are quite impressive. This is another item for discussion with your doctor, should you be on a daily regimen of fish oil capsules as you get ready for the flu season? You can also read more about inflammation and beneficial effects if omega-3 fish oils by reading Omega 3 PUFA's.

Abstract

Crit Care Med. 1999 Aug;27(8):1409-20.

Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome.

Enteral Nutrition in ARDS Study Group.

Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, Albertson TE, Van Hoozen C, Wennberg AK, Nelson JL, Noursalehi M.

Pulmonary and Critical Care Division, Ohio State University Medical Center, Columbus, OH

OBJECTIVES: Recent studies in animal models of sepsis-induced acute respiratory distress syndrome (ARDS) have shown that a low-carbohydrate, high-fat diet combining the anti-inflammatory and vasodilatory properties of eicosapentaenoic acid (EPA; fish oil), gamma-linolenic acid (GLA; borage oil) (EPA+GLA), and antioxidants improves lung microvascular permeability, oxygenation, and cardiopulmonary function and reduces proinflammatory eicosanoid synthesis and lung inflammation. These findings suggest that enteral nutrition with EPA+GLA and antioxidants may reduce pulmonary inflammation and may improve oxygenation and clinical outcomes in patients with ARDS.
DESIGN: Prospective, multicentered, double-blind, randomized controlled trial.
SETTING: Intensive care units of five academic and teaching hospitals in the United States.
PATIENTS: We enrolled 146 patients with ARDS (as defined by the American-European Consensus Conference) caused by sepsis/pneumonia, trauma, or aspiration injury in the study.
INTERVENTIONS: Patients meeting entry criteria were randomized and continuously tube-fed either EPA+GLA or an isonitrogenous, isocaloric standard diet at a minimum caloric delivery of 75% of basal energy expenditure x 1.3 for at least 4-7 days.
MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were measured, and ventilator settings were recorded at baseline and study days 4 and 7 to enable calculation of PaO2/FIO2, a measure of gas exchange. Pulmonary neutrophil recruitment was assessed by measuring the number of neutrophils and the total cell count in bronchoalveolar lavage fluid at the same time points. Clinical outcomes were recorded. Baseline characteristics of 98 evaluable patients revealed that key demographic, physiologic, and ventilatory variables were similar at entry between both groups. Multiple bronchoalveolar lavages revealed significant decreases (approximately 2.5-fold) in the number of total cells and neutrophils per mL of recovered lavage fluid during the study with EPA+GLA compared with patients fed the control diet. Significant improvements in oxygenation (PaO2/FIO2) from baseline to study days 4 and 7 with lower ventilation variables (FIO2, positive end-expiratory pressure, and minute ventilation) occurred in patients fed EPA+GLA compared with controls. Patients fed EPA+GLA required significantly fewer days of ventilatory support (11 vs. 16.3 days; p = .011), and had a decreased length of stay in the intensive care unit (12.8 vs. 17.5 days; p = .016) compared with controls. Only four of 51 (8%) patients fed EPA+GLA vs. 13 of 47 (28%) control patients developed a new organ failure during the study (p = .015).
CONCLUSIONS: The beneficial effects of the EPA+GLA diet on pulmonary neutrophil recruitment, gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggest that this enteral nutrition formula would be a useful adjuvant therapy in the clinical management of patients with or at risk of developing ARDS.

PMID: 10470743
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9. Dehydration is the single biggest complication of patients sick with flu. If you are not able to dodge the bullet this flu season, and you do come down with a bad case of it, you really need to learn all about managing dehydration. The second PDF below is written by a physician. It gives very practical and easy to follow guidelines on how much fluid is necessary, how to make a good hydration formula based on pure water, sugar and a little bit of salt. The PDF is long, but do take the time to browse through it. Skip the bit about flu pandemic statistics if that is not your bag, the guidelines for home care of sick patients is towards the later sections of the article.
10. Kidding aside, this is not a bad time to stock up on a few essentials such as supply of clean water, easy to prepare and easy to eat food items. You don't have to get into a whole survivalist mode if that is not your gig. But if you are sick, you may not feel like going grocery shopping for essentials and you may not want to make chicken soup from scratch. Canned soups are easy to heat and eat. You can make up your own list of essentials, comfort foods that work well for you. It is simple enough to have some Jello handy, as well as liquids such as ginger ale, Gatorade, basic medications such as Tylenol, etc. You would do no less if there was a weather advisory for your location, with an ice storm or Katrina look-alike on the way, right?

I usually sign off my Alerts with, "Stay healthy". That phrase takes on more urgency and significance during this season. Don't let flu sneak in under the radar. Please take sensible and prudent precautions to protect yourself and your family. Remember, you are more at risk because of your immune compromised status.

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Editor's Note: The following are suggested further reading, listening and viewing for those who are interested in learning more about the H5N1 influenza virus.

Influenza Virus Change and Pandemic Potential - a PowerPoint presentation from Dr. Michael T. Osterholm of the Center for Infectious Disease Research and Policy at the University of Minnesota. An audio and video webcast of the Osterholm presentation may be found at the website for the Woodrow Wilson International Center for Scholars: Emerging Pandemic - Costs and Consequences of an Avian Influenza Outbreak. 

Preparing for the Coming Influenza Pandemic - a monograph authored by Dr. Grattan Woodson, a Georgia based physician to prepare his patients for an avian flu pandemic. There is a section on home care of patients.

Avian Influenza: Assessing the Pandemic Threat. An authoritative 66 page report from the World Health Organization, still in its pre-publication version. You can find other official WHO documents and updates on their Avian Influenza web page.

H5N1 - Killer Flu, is the web link for a PBS documentary broadcast on the program Wide Angle on September 20, 2005. Watch for re-broadcast of this important show.