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Role of Pulmonary Inflammation in CLL

Date: November 23, 2003

by Chaya Venkat

Neglect that Chest Cold and/or Sinus Congestion at Your Peril

Related Articles:
CLL, Chronic Inflammation and What You Can Do About It

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Just reading the posts of CLL patients on the various Internet chat groups has left me with the impression that pulmonary complications are a major cause of hospitalizations and death in CLL patients. That "anecdotal" impression is now backed by very strong statistical evidence, published by Dr. Kanti Rai et. al. in the November issue of the journal Cancer. The statistics are rather impressive, based on 110 CLL patients who were admitted to a hospital with a respiratory disease between 1993 and 2001. There were 142 admissions over that period of time. Pneumonia was the cause of the hospitalization in a whopping 75% of the cases; and 18% of the remaining 25% of the cases were related problems such as lung infiltration, pleural effusion, lung cancer and upper airway blockage. Forty four of these 110 patients died, because of pneumonia and related chest inflammation causes. The abstract below gives a few more of the details of this very important study, but the take home message is very clear: as a CLL patient, neglecting chest and sinus inflammation problems is really dumb, it carries with it a stiff penalty.


Cancer. 2003 Nov 1;98(9):1912-7.

Pulmonary complications in chronic lymphocytic leukemia.

Ahmed S, Siddiqui AK, Rossoff L, Sison CP, Rai KR.

Divisions of Hematology and Oncology, Long Island Jewish Medical Center, New Hyde Park, New York 11040

BACKGROUND: Although pulmonary complications account for significant morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), to the authors' knowledge there are sparse data available in published literature. The authors evaluated pulmonary complications in patients with CLL and identified prognostic variables that predict hospital mortality in these patients.
METHODS: Clinical data were analyzed retrospectively from patients with CLL who required hospitalization for a respiratory illness at a tertiary care institution from January 1993 to December 2001. A logistic regression analysis with a backward elimination procedure was carried out to determine prognostic variables that predict hospital mortality.
RESULTS: There were 110 patients who were admitted on 142 occasions with a pulmonary complication. The median age was 75 years (range, 43-97 years), and the male:female ratio was 1.7:1.0. Among 142 admissions, 68% were high risk according to the Rai criteria, 68% of patients admitted had received prior therapy for CLL, and 35% had received treatment within 3 months of admission. The most common pulmonary complications were pneumonias (75%), malignant pleural effusion/and or lung infiltrate due to CLL (9%), pulmonary leukostasis (4%), Richter transformation or nonsmall cell lung carcinoma (3%), and upper airway obstruction (2%). Forty-four of 110 patients (40%) died. In multivariate analysis, admission absolute neutrophil counts </= 0.5 x 10(9)/L (odds ratio, 4.6; 95% confidence interval [95% CI], 1.3-16.6) and blood urea nitrogen (BUN) levels >/= 20 mg/dL (odds ratio, 3.0; 95% CI, 1.1-8.3) were correlated significantly with mortality.
CONCLUSIONS: Pneumonia was the major pulmonary complication in hospitalized patients with CLL. Severe neutropenia and high BUN levels were correlated significantly with increased mortality.

Copyright 2003 American Cancer Society.

PMID: 14584074

I am concerned that many of the patients seem to look for help with these "sniffles" in terms of home-made remedies such as nasal sprays and flushing out the mucus with saline solutions of various sorts. Nothing wrong with clearing out your sinuses, provided you make absolutely sure you are not making the problem worse by using less than sterile sprays and solutions. But these approaches do little more than palliative help with the symptoms, make you feel a little less stuffed up temporarily. Given the huge risk factor of pulmonary inflammation in CLL patients, it is very important for you to discuss ways and means of dealing with this problem a little more aggressively. By that I mean attempting to see if the root cause chronic inflammation can be brought under control.

Chronic inflammation and CLL are closely inter-related.  Some researchers believe that chronic inflammation is often responsible for allowing the odd cancer cell to flourish.  In the absence of this clear malfunctioning of the immune system, the first few cancer cells may not have been able to establish a foot hold in your body and grow up to be a full fledged CLL.  The interesting thing is that as CLL grows, it in turn feeds the inflammation.  Several cytokines, especially TNF-alpha (tumor necrosis factor alpha) are involved in fanning the flames of inflammation, and this particular cytokine is also at very high levels in CLL patients, considered to be the produced by subverted immune system cells.  Chronic inflammation helps CLL, and in turn, CLL helps create the cytokine mix that sustains the inflammatory state.  As I said, CLL and chronic inflammation are very good friends of each other.

One of the overt symptoms of inflammation of the airways and lungs is creation of copious amounts of mucus.  This thick secretion is what gives you that stuffed up feeling, as well as making you feel out of breath.  Lungs and airways filled with mucus makes it harder for the vital oxygen exchange, and in the case of patients with anemia to begin with, the reduced oxygen exchange just makes things that much worse.  Mucus accumulation can also provide a nice hospitable place for bacteria to grow.  In CLL patients with reduced ability to fight infections, you can see how a simple inflammation of the airways, sinuses or lungs can quickly snowball out of control, become full fledged pneumonia.  I wonder how many CLL patients are cases of "walking pneumonia", shrugging off the out of breath and stuffy feelings as par for the course, just grin and bear it.  If you are one of them, please stop being so macho, you really need to get some good medical help with that chest and sinus congestion before it becomes a real problem.

Here are some practical suggestions:

The second abstract below from well known researchers at M. D. Anderson leaves little room for doubt, TNF-alpha plays a major role in CLL progression and survival, it is a clear risk factor. Since this powerful cytokine that controls the progression and outcome of CLL is also implicated in initiating and nurturing chronic inflammation (and in fact this cytokine snowballs into higher gear as the underlying inflammation is allowed to persist unchecked) it seems reasonable to consider control of chronic inflammation as one of our top priorities.

Chronic inflammation is not just a problem in CLL, it is implicated in just about every cancer you can think of. In fact, asthma drugs such as Singulair and Accolate are now considered potent chemopreventive drugs, from the perspective of their ability to control this particular aspect of chronic inflammation. ("Chemopreventive" comes from the word "chemo" meaning "cancer". Chemopreventive therefore means cancer-preventive).


J Am Acad Dermatol. 1998 Jul;39(1):27-35.

Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: a clinical, histopathologic, and immunopathologic study of eight patients.

Davis MD, Perniciaro C, Dahl PR, Randle HW, McEvoy MT, Leiferman KM.

Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

BACKGROUND: Unusual papulovesicular lesions resembling arthropod bites have been described in patients with chronic lymphocytic leukemia (CLL).
OBJECTIVE: Our purpose was to describe and characterize further the clinical, histopathologic, and immunopathologic features of these lesions.
METHODS: Eight patients were identified retrospectively who had CLL and characteristic skin lesions. Clinical and histologic features were recorded. Skin biopsy specimens were analyzed immunohistochemically for eosinophil granule major basic protein, eosinophil-derived neurotoxin, neutrophil elastase, and mast cell tryptase.
RESULTS: The clinical features, including the lesional distribution, suggested arthropod bites, although most patients could not recall having been bitten. Mixed T- and B-cell lymphoid cell infiltrates were present within lesions, along with prominent eosinophil infiltration and eosinophil granule protein deposition.
CONCLUSION: Exuberant papulovesicular lesions develop in patients with CLL apparently as an exaggerated response to arthropod bites. Prominent eosinophil infiltration and degranulation within these lesions likely contribute to the severity of symptoms.

PMID: 9674394

Blood. 2002 Aug 15;100(4):1215-9.

The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia.

Ferrajoli A, Keating MJ, Manshouri T, Giles FJ, Dey A, Estrov Z, Koller CA, Kurzrock R, Thomas DA, Faderl S, Lerner S, O'Brien S, Albitar M.

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston 77030

Tumor necrosis factor-alpha (TNF-alpha), a cytokine possessing pleiotropic biological activities, is produced by leukemic lymphocytes in patients with chronic lymphocytic leukemia (CLL) and acts as an autocrine and paracrine growth factor in this disease. In this study, TNF-alpha levels were determined in 150 patients with CLL and correlated with disease characteristics, prognostic factors, and survival. The mean TNF-alpha plasma concentration in the patients with CLL was significantly higher than in the healthy control population (16.4 versus 8.7 pg/mL; P <.0001). Patients having an elevated TNF-alpha level had more advanced Rai and Binet stage disease, higher serum beta(2)-microglobulin (beta(2)M) levels, a greater percentage of cells expressing CD38, and lower hemoglobin and platelet levels. Patients having chromosomal abnormalities such as 11q deletion, trisomy 12, and chromosome 17 aberrations had a higher mean TNF-alpha level (27.5 pg/mL) than patients having a diploid karyotype or other miscellaneous cytogenetic abnormalities (14.2 pg/mL; P <.001). The TNF-alpha level was a predictor of survival when the Cox proportional hazards model was used with TNF-alpha entered as a continuous variable (P =.0001). Also, patients having a TNF-alpha level above the mean value of 14 pg/mL had significantly shorter survival duration (P =.00001). The TNF-alpha level remained predictive of survival in Cox multivariate analysis independent of Rai staging and beta(2)M, hemoglobin, prior therapy, white cell count, and platelet level (P =.005). We conclude that the TNF-alpha level serves as a prognostic factor in patients with CLL and that inhibition of TNF-alpha in these patients could have therapeutic importance.

PMID: 1214920

I have just waded through a long and very detailed review paper titled "Lipoxygenase Inhibitors as Potential Cancer Chemopreventives" by the researchers of the National Cancer Institute (see the abstract below). If any of you wish to read the full article, all you have to do is click on the live link provided at the top of the abstract, you can read the full article for free. Among the compounds discussed are our favorites, the  cysteinyl leukotriene receptor antagonists, Singulair and Accolate (generic names are montelukast and zafirlukast, respectively).  A third one in the same family of drugs, generic name pranlukast, is on its way to FDA approval.

The picture is getting a little clearer as we go along. Chronic inflammation is at the root of many of these linked diseases, and keeping it under control should be one of the primary goals of all CLL patients and their healthcare professionals. In addition to keeping away dangerous stuff like pneumonia, a proactive approach to controlling chronic inflammation may translate into slower growth of the CLL and reducing its propensity to accumulate in bone marrow and lymph nodes. This is no small thing, a concerted push in this direction may be what is needed to move us in the direction of making CLL a "managed disease", much like diabetes or high blood pressure.


Article in AACR Journals

Cancer Epidemiol Biomarkers Prev. 1999 May;8(5):467-83.

Lipoxygenase inhibitors as potential cancer chemopreventives.

Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ.

Chemoprevention Branch, Division of Cancer prevention, National Cancer Institute, Bethesda, MD 20892-7322

Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO metabolites have been found in lung, prostate, breast, colon, and skin cancer cells, as well as in cells from patients with both acute and chronic leukemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumor cell adhesion, and regulation of apoptotic cell death. Agents that block LO-catalyzed activity may be effective in preventing cancer by interfering with signaling events needed for tumor growth. In fact, in a few studies, LO inhibitors have prevented carcinogen-induced lung adenomas and rat mammary gland cancers. During the past 10 years, pharmacological agents that specifically inhibit the LO-mediated signaling pathways are now commercially available to treat inflammatory diseases such as asthma, arthritis, and psoriasis. These well-characterized agents, representing two general drug effect mechanisms, are considered good candidates for clinical chemoprevention studies. One mechanism is inhibition of LO activity (5-LO and associated enzymes, or 12-LO); the second is leukotriene receptor antagonism. Although the receptor antagonists have high potential in treating asthma and other diseases where drug effects are clearly mediated by the leukotriene receptors, enzyme activity inhibitors may be better candidates for chemopreventive intervention, because inhibition of these enzymes directly reduces fatty acid metabolite production, with concomitant damping of the associated inflammatory, proliferative, and metastatic activities that contribute to carcinogenesis. However, because receptor antagonists have aerosol formulations and possible antiproliferative activity, they may also have potential, particularly in the lung, where topical application of such formulations is feasible.

PMID: 10350444




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