UPDATE ON SINUSITIS, NSAIDS, AND MYELODYSPLASTIC SYNDROME
From Update in Family Medicine, presented October 27-28, 2005, by the University of Michigan Medical School and
the Michigan Academy of Family Physicians
| UPDATE ON ACUTE SINUSITIS —James F. Peggs, MD, Professor and Associate Chair, Department of Family Medicine,
University of Michigan Medical School, Ann Arbor
|
| General: definition—inflammation of paranasal sinuses and nasal cavity lasting <4 wk; epidemiology—common problem;
not always understood by patients; adults have 2 to 3 upper respiratory infections (URIs) per year; children have
twice that per year; 1 billion viral URIs (1% to 2% of these complicated by bacterial infection); 20 million cases of acute
bacterial rhinosinusitis; 5% of visits to primary care doctor; most common diagnosis for which antibiotics prescribed
|
| Role of sinuses: provide shape to skull; decrease weight of skull; moisturize inspired air; provide defense mechanisms
(mucus production; mucociliary function helps to clean debris in air we breathe); make 0.75 to 1 qt of mucus in nasal passages
and sinuses daily (normal healthy adult); insults to patency and diminishing function of osteomeatal complex lead
to lack of ventilation and lack of drainage of mucus
|
| Causes of acute sinusitis: infectious (majority viral); allergic disease (occasionally); trauma (rarely); organisms—
streptococcal species and Haemophilus influenzae account for 80% to 90% of organisms in acute bacterial sinus infections;
most viral URIs cause symptoms (significant mucus production, intermittent facial pain and pressure, and nasal congestion;
no difference between viral and bacterial) lasting 2 wk
|
| Diagnosing acute bacterial sinusitis: study (mid 1990s) comparing clinical findings and history with computed tomography
(CT) evidence of sinusitis showed best predictors of bacterial sinusitis are maxillary toothache, purulent secretion by examination,
history of discolored nasal discharge, poor response to decongestant, and abnormal transillumination (in dark
room, place flashlight just inside infraorbital ridge, and have patient open mouth, look to see if light transmitted to bony palate,
and compare sides); length of illness (not evidence-based, but expert opinion); theoretic framework for decision
making—severity of symptoms and number of risk factors; left alone, bacterial sinusitis improves after several weeks; extra
15% get better with antibiotics (shorten course of disease, but do not necessarily prevent significant infectious complications)
|
| Antibiotics: first-line—amoxicillin, trimethoprim–sulfamethoxazole (Bactrim, Septra); length of treatment at least 10
days (14 days recommended); alternatives to first-line therapy—doxycycline; azithromycin (3-day course); second-
line alternatives—for treatment failure, increase dose for another 14 days; fluoroquinolones; amoxicillin and potassium
clavulanate (Augmentin); telithromycin
|
| Symptom control: efficacious—topical decongestant sprays (3-day maximum use); oral decongestants; topical anticholinergic
sprays (ipratropium bromide [Atrovent]; antihistamines (decrease secretions; traditional sedating forms); possible
efficacy—nasal steroids; suggested, but efficacy not proven—zinc; vitamin C; echinacea (E angustifolia); saline
irrigation (neti pots); steam
|
| X-rays: not very helpful, especially plain films; limited sinus CT possibly indicated if symptoms persist >3 wk despite therapy
or patient has >3 recurrent episodes in 1 yr; referral—when condition not responding
|
| THE COX-2 CONUNDRUM: TRADE-OFFS AND EFFECTIVENESS OF NSAIDS —A. Mark Fendrick, MD, Professor,
Division of General Medicine, Department of Internal Medicine University of Michigan Medical School; Professor, Health
Management and Policy, School of Public Health, University of Michigan, Ann Arbor
|
| General: nonsteroidal anti-inflammatory drugs (NSAIDs) most widely used drugs by patients; unmet need (patients need
analgesic and anti-inflammatory); variability in how physicians treat chronic pain and inflammatory conditions since cyclooxygenase
(COX)-2 inhibitors pulled from market because of cardiovascular adverse events
|
| Aspirin: beneficial (heart attack; pain; prevention of colonic polyps); better alternatives to high-dose aspirin for pain relief;
patients with angina, coronary disease, diabetes, or anginal equivalents should take aspirin; aspirin for primary prevention
involves trade-off (helps heart but hurts stomach and rarely, may cause hemorrhagic stroke); controversy as to who
should take it for primary prevention; web-based cardiac risk calculator calculates 10-yr risk (downloadable to personal
digital assistant [PDA]; use to determine whether patient needs cholesterol reduction and aspirin for primary prevention);
<50% of high-risk women and just over 50% of high-risk men taking aspirin; study shows overuse of aspirin in some
populations
|
| COX-2 inhibitors: rofecoxib (Vioxx) pulled from market (September 2004) after placebo-controlled study looking at
whether COX-2 inhibitors could prevent colonic polyps and colonic polyp progression showed doubling of cardiac adverse
events; studies showed valdecoxib (Bextra) also increased likelihood of cardiovascular adverse events; study
showed same story with high doses (200 mg or 400 mg bid) of celecoxib (Celebrex); study (not published) showed high
dose once daily did not appear to have same effect (definitive data not available)
|
| Naproxen: 11 observational trials suggest naproxen slightly cardioprotective (not as much as aspirin)
|
| Ibuprofen: not implicated in cardiac problems; blocks site on platelet where aspirin works to prevent cardiovascular
events (keep in mind when patients taking aspirin for heart)
|
| Gastrointestinal (GI) effects: COX-2 inhibitors developed in attempt to find safer NSAID (fewer GI side effects); thousands
of people die annually because of NSAID-related adverse events (100,000 hospitalizations each year); hospitalization
rates due to NSAIDs did not change with safer NSAIDs because they were given to higher-risk patients; physicians
returning to prescribing more traditional NSAIDs since data on COX-2 inhibitors became available; multiple NSAID use
most common risk factor for GI adverse events; aspirin causes GI side effects even at 81-mg dose (doubles risk); enteric-
coated aspirin provides no real risk reduction for bad GI outcomes; studies show risk for GI adverse events substantially
increases when aspirin combined with NSAID; study of patients >55 yr of age showed that 50% taking COX-2 inhibitors
on long-term basis also taking aspirin; another 10% took breakthrough over-the-counter (OTC) NSAID for problem not
thought related to why they took COX-2 inhibitor; strategy for decreasing GI adverse events—acetaminophen, tramadol,
or glucosamine possible alternatives to NSAID; lowest effective dose of NSAID; COX-2 inhibitors for those with GI
risk factors (no benefit of using COX-2 and aspirin vs NSAID and aspirin; risk for complications 4 times higher with
celecoxib plus aspirin than with celecoxib alone); prostaglandin analogue therapy or misoprostol works in preventing
gastric and duodenal ulcers, but qid dosing and side effects reason for infrequent use; H2 blockers and proton pump inhibitors
(PPIs); primary prevention trial looking at COX-2 inhibitors and traditional NSAIDs with or without PPIs in patients
at high risk (>60 yr of age and/or past ulcer 6 mo to 5 yr ago) shows impact of PPI in preventing ulcer formation
equally in those who took traditional NSAID or COX-2 inhibitor; patients requiring aspirin for heart should get it, but
study showed dramatic impact of PPI on patients at high risk
|
| Summary: weigh cardiovascular and GI risk factors; in patients with neither, use traditional NSAIDs; patients with high
GI risk and no cardiac risk candidates for COX-2 inhibitor; patient on aspirin who needs NSAID needs gastroprotective
therapy; may use acetaminophen (up to 4 g/day)
|
| DIAGNOSIS AND MANAGEMENT OF MYELODYSPLASTIC SYNDROME —Harry P. Erba, MD, Assistant Professor,
Division of Hematology/Oncology, Department of Medicine, University of Michigan Medical School, Ann Arbor
|
| General: heterogeneous group of acquired bone marrow failure syndromes characterized by peripheral blood cytopenia
and ineffective hematopoiesis; bone marrow examination shows dysplastic-looking cells; diagnosis made by careful morphologic
review of peripheral blood and bone marrow; patients present with cytopenia detected at time of complete blood
count (CBC) done for some other reason or with symptoms or signs related to cytopenia (eg, anemia, neutropenic infections,
thrombocytopenic hemorrhage)
|
| Diagnosis: differential diagnosis for pancytopenia—hypersplenism; active viral infection; nutritional deficiencies; alcohol;
chemotherapy; radiation therapy; bone marrow aspirate and biopsy required for diagnosis after ruling out other possibilities;
peripheral blood findings—dysplastic neutrophils; peripheral smear with cells of variety of sizes and shapes;
hemogram with elevated red cell distribution width (RDW; nonspecific); dysplastic platelets; bone marrow—abnormal
granulocyte precursors; megaloblastic erythroid maturation; dysplastic megakaryocytes; karyotypic analysis—light micrograph
showing spread of metaphase chromosomes from one cell (chromosomes differ in length, position of centromere,
and banding patterns); cytogeneticist puts into karyotype (where chromosomes paired up) and looks for
chromosomal changes; cytogenetic abnormalities can help make diagnosis (acquired changes; not in germ line)
|
| History: referred to as myelodysplastic syndrome (MDS) in last 25 yr; previously referred to by variety of names (eg,
preleukemia, oligoblastic leukemia, smoldering acute leukemia); true incidence difficult to quantify—multiple names;
bone marrow biopsy not done on patients who have peripheral smear highly suggestive of MDS with no good therapeutic
options; not considered true malignancy, therefore not captured in cancer registries; incidence increases with age
|
| Natural history: patients with MDS either die of unrelated causes, progress to acute leukemia, or die from complications
of neutropenic infections, thrombocytopenic hemorrhage, and complications of long-term red blood cell (RBC) transfusion
(iron overload)
|
| Prognostic factors: patients treated for other malignancies with curative intent develop complication of that therapy
(treatment-related MDS); alkylating agents produce chromosomal changes (incidence up to 20%); MDS shows up about
4 to 5 yr after exposure to drug; poor prognosis; French-American-British (FAB) classification system—5 subtypes
include refractory anemia (RA), RA with ringed sideroblasts (RAS), RA with excess blasts (RAEB), RA with excess
blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML); from RA to CMML, more blasts accumulate
until 30% blasts which, by definition, is acute leukemia; RA and RAS have good prognosis; more advanced
stages have very poor prognosis; World Health Organization classification—acute myelogenous leukemia (AML) defined
as >20% blasts; classification recognizes subtype of MDS characterized by abnormality on long arm of chromosome
5 (5q- syndrome); clinically, patients with 5q- syndrome (women in middle to older age) present with macrocytic
anemia, normal platelets, and bone marrow with characteristic morphology; patients with isolated deletion of long arm of
chromosome 5 have median survival of 10 yr; International Prognostic Scoring System—number of blasts, types of
chromosomal changes, and number of cytopenias taken into account; system developed from clinical outcomes of 5000
patients who received only supportive care; patients get score for each characteristic and divided into low- to high-risk
groups; clinical advances come from careful observation of patients along with bone marrow and blood samples from
these patients
|
| Therapy: allogeneic stem cell transplantation—potentially curative; data from 250 patients showed 40% cure rate after
allogeneic stem cell transplants (well selected population; young and healthy enough to undergo stem cell transplantation);
of patients >50 yr of age (majority of patients with MDS), very few alive 4 yr after transplant; patients with poor-
risk karyotypic changes have high risk for relapse (80%); supportive care—erythropoietin to treat anemia of patients
with MDS; meta-analysis of 205 transfusion-dependent patients given erythropoietin (Procrit) injections showed 16% of
patients became infusion-independent or had significant rise in hemoglobin; data show 30% response rate when
filgrastim (Neupogen) added as synergistic agent to erythropoietin (better in patients with RAS; correlated with low
erythropoietin level and lower need for transfusion); prognostic scoring system developed to predict how likely person
will benefit from erythropoietin based on erythropoietin levels and number of transfusions person getting per month;
azacitidine—Food and Drug Administration (FDA)-approved for treatment of MDS; DNA methyl-transferase inhibitor
(theory that overmethylation of DNA leads to recruitment of protein that blocks transcription of genes important to hematopoiesis
and tumor-suppressor genes, causing MDS); cells of patient with MDS can differentiate (in laboratory) when
exposed to azacitidine; clinical trial of azacitidine vs supportive care showed 20% to 25% had complete or partial remission
in azacitidine group, while another one third had improvement in blood counts (improvement lasts to median of 15
mo); prolongation in time to AML transformation or death; overall survival not different (not curative); side effects include
myelosuppression and cutaneous reactions; quality of life improvement in those on azacitidine arm; decitabine—
in development; DNA methyltransferase inhibitor; clinical trial showed 17% response rate; drugs given by subcutaneous
injection or intravenously, requiring office visits for administration; lenalidamide—congener of thalidomide without
neuropathy and teratogenic activity associated with thalidomide; phase 2 trials (patients with low-grade MDS) showed
56% had improvement in RBC transfusion requirements; erythroid response seen most in patients with 5q- syndrome;
choosing therapy—disease characteristics used to determine which therapy appropriate (international prognostic score);
patient factors important; goal must be determined (palliation or cure)
|
| Summary: MDS heterogeneous group of clonal stem cell disorders characterized by cytopenias and risk for progression to
AML; diagnosis based on morphology and cytogenetic analysis; development of effective therapies requires clinical trials
|
Educational Objectives
| The goal of this program is to provide the listener with information on acute sinusitis, use of nonsteroidal antiinflammatory
drugs (NSAIDs), and myelodysplastic syndrome (MDS). After hearing and assimilating this program, the clinician will be
better able to:
|
 | 1. Diagnose and treat acute sinusitis.
|
| 2. Discuss the role of COX-2 inhibitors.
|
| 3. Discuss concerns about NSAIDs and gastrointestinal adverse events.
|
| 4. Define MDS and how it is diagnosed.
|
| 5. Explain therapeutic options for patients with MDS.
|
Discussed on This Program
Acetaminophen [several trade names]
Amoxicillin [Amoxil, Trimox]
Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600, Augmentin XR]
Aspirin (acetylsalicylic acid; ASA) [several trade names]
Azacitidine [Vidaza]
Azithromycin [Zithromax, Zmax]
Celecoxib [Celebrex]
Decitabine (orphan drug)
Doxycycline [several trade names]
Echinacea (E angustifolia)
Epoetin alfa (erythropoietin; EPO) [Epogen, Procrit]
Filgrastim (granulocyte colony stimulating factor; G-CSF) [Neupogen}
Glucosamine
Ibuprofen [several trade names]
Ipratropium bromide [Atrovent]
Lenalidomide [Revlimid]
Misoprostol [Cytotec]
Naproxen [several trade names]
Telithromycin [Ketek]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [several trade names]
Vitamin C
Rofecoxib [Vioxx] (withdrawn from market 09/30/04)
Thalidomide [Synovir, Thalomid]
Tramadol HCl [Ultram]
Valdecoxib [Bextra]
Zinc sulfate [several trade names]
Suggested Reading
Abraham NS, Graham DY: NSAIDs and gastrointestinal complications: new clinical challenges. Expert Opin Pharmacother
6:2681, 2005; Bannwarth BG: Risk of gastrointestinal effects with COX-2 inhibitors and NSAIDs: how strong is
the evidence? BMJ 17:1474, 2005; Bennett JM, Komrokji RS: The myelodysplastic syndromes: diagnosis, molecular
biology and risk assessment. Hematology 10:258, 2005; Brook I, Hausfeld JN: Recovery of interfering bacteria in the
nasopharynx following antimicrobial therapy of acute maxillary sinusitis with telithromycin or amoxicillin-clavulanate. Antimicrob
Agents Chemother 49:4793, 2005; Brook I, et al: Eradication of pathogens from the nasopharynx after acute
maxillary sinusitis with low- or high-dose amoxicillin/clavulanic acid. Int J Antimicrob Agents 26:416,2005; Lewis MR,
Kay D: Risk of gastrointestinal effects with COX-2 inhibitors and NSAIDs: COX-2 inhibitors were thought of as a safe option.
BMJ 331:1474, 2005; Look AT: Molecular Pathogenesis of MDS. Hematology (Am Soc Hematol Educ Program)
156, 2005; Lovegrove C: Most hospital deaths from gastrointestinal events occur in the elderly: the role of NSAIDs. Nat
Clin Pract Gastroenterol Hepatol 2:501, 2005; Lovegrove C: Long-term use of aspirin and NSAIDs reduces the risk of
colorectal cancer. Nat Clin Pract Gastroenterol Hepatol 2:498, 2005; Malcovati L, et al: Prognostic factors and life
expectancy in myelodysplastic syndromes classified to WHO criteria: a basis for clinical decision making. J clin Oncol
23:7594, 2005; Panani AD, Pappa V: Hidden chromosome 8 abnormalities detected by FISH in adult primary myelodysplastic
syndromes. In Vivo 19:919, 2005; Pinheiro RF, et al: The 5q-syndrome and autoimmune phenomena: Report of
three cases. Leuk Res Oct, 2005; Pitako JA, et al: Quantification of outpatient management and hospitalization of patients
with high-risk myelodysplastic syndrome treated with low-dose decitabine. Ann Hematol 84, 25, 2005; Puccetti L:
risk of gastrointestinal effects with COX-2 inhibitors and NSAIDs: why were patients at major risk excluded? BMJ
331:1474, 2005; Scheiman JM: Nonsteroidal anti-inflammatory drugs, aspirin, and gastrointestinal prophylaxis: an ounce
of prevention. Rev Gastroenterol Disord 5:39, 2005; Underhill JL: Risk of gastrointestinal effects with COX-2 inhibitors
and NSAIDs: what does evidence form randomized trials show about celecoxib? BMJ 331:1474, 2005; Wright ED,
Frenkiel S: Infectious adult rhinosinusitis: etiology, diagnosis, and management principles. J Otolaryngol 34 S7, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Fendrick is a consultant for the following companies: Merck, AstraZeneca Pharmaceuticals, Merck-Medco,
Procter & Gamble, GlaxoSmithKline, Pfizer, Eli Lilly and Co., TAP Pharmaceuticals, Aventis Pharmaceuticals, and Amgen.
Drs. Peggs, Fendrick, and Erba were recorded at Update in Family Medicine, held October 27-28, 2005, in Ann Arbor,
Michigan, and sponsored by the University of Michigan Medical School, Department of Family Medicine and
Michigan Academy of Family Physicians. The Audio-Digest Foundation thanks the speakers and the sponsors for
their cooperation in the production of this program.
|
