LITERATURE MONITOR
A REVIEW OF RECENTLY PUBLISHED CLINICAL ARTICLES


RESULTS OF IMMUNOTHERAPY FOR ASTHMA AND ALLERGIC RHINITIS

How frequently is immunotherapy prescribed for asthma and allergic rhinitis? How does it compare with other modalities in terms of patient adherence and cost? Those questions were the focus of a recent study reported in the Annals of Allergy, Asthma, and Immunology. While just 2% of 122,000 health maintenance organization (HMO) diagnoses of asthma and allergic rhinitis were treated with immunotherapy, only a third of those patients completed the intended course of treatment, the researchers found. Moreover, the cost of nonimmunotherapy care was higher for patients who had completed immunotherapy, though that "is consistent with more severe disease in this group."

Analysis of medical records obtained from the Harvard Pilgrim Health Care HMO found 2,667 HMO members who had received at least one immunotherapy injection; 603 of those patients met study criteria (ie, minimum of 4 years' continuous membership, automated medical records, and pharmacy co-payment benefits).

Following first immunization, 23% of the study group had no injections after three months, but more than half continued immunotherapy into the third year. The researchers found that women, patients between the ages of 10 and 20 years, and patients with an unknown allergen had the shortest duration of immunotherapy.

Of the 384 patients who were members of the HMO long enough to have completed the intended course of 61 immunotherapy treatments (followed by 1 year's continuous membership without injection), 128 were found to have successfully completed therapy. A significantly greater proportion of patients with both rhinitis and asthma completed therapy (43%) than did patients with rhinitis only (28%) or asthma only (13%). Patients with asthma only were also three times more likely to have had just 1 immunotherapy visit (35%) than were patients with rhinitis or rhinitis and asthma (12% and 8%, respectively), though the reason for that difference remains unclear, the researchers noted. Patients treated for a ragweed allergy were also significantly more likely to have completed immunotherapy treatment than were patients treated for other allergens (P<.01).

A random review of 115 patient records found the most common reasons for discontinuation of therapy to be the patient's decision (54%) and physician's order to discontinue (30%). Though the medical records did not specify the bases of patients' reasons for discontinuation, the researchers postulated such "likely explanations" as inconvenience, ineffectiveness, cost, and decreased severity of symptoms. Physicians' reasons for ordering the discontinuation of immunotherapy include symptoms resolution, completion of intended course of therapy, lack of efficacy, adverse reaction, and the occurrence of medical contraindications.

Immunotherapy's cost per person-year was $698 for those completing the course; $247 for those who discontinued therapy. The researchers also found that nonimmunotherapy costs (ie, hospitalizations, emergency department visits, and prescription drugs) per person-year for asthma and rhinitis care were 20% greater for the immunotherapy-compliant patients ($508 versus $421). Perhaps those who completed immunotherapy had more severe disease or longer persistence of symptoms, the researchers suggested, and thus had a greater incentive to continue treatment. Compliance to pharmacotherapy also contributed to the higher cost. Drug expenditures were 50% greater for patients who completed therapy than for those who discontinued.

On the other hand, hospitalization costs per person-year averaged $102 for patients who discontinued immunotherapy but only $49 for patients who completed immunotherapy--"which may be evidence supporting the clinical effectiveness of immunotherapy," the researchers wrote.

Donahue JG, Greineder DK, Connor-Lacke L, et al. Utilization and cost of immunotherapy for allergic asthma and rhinitis. Ann Allergy Asthma Immunol. 1999;82:339-347.

MODIFIABLE RISK FACTORS FOR PNEUMONIA

Strategies aimed at reducing the risk for aspiration may be useful in preventing pneumonia in nursing home residents, according to the latest research findings. A study published in a recent Archives of Internal Medicine found that difficulty in swallowing and inability to take oral medication were important risk factors for pneumonia. Interestingly, pneumonia and lower respiratory tract infections were not associated with sustained functional decline in this population, the study's authors concluded.

A total of 475 residents age 59 to 109 years (mean age, 85 years) from five nursing homes were enrolled in the study. Of these subjects, 53.5% were followed for at least 1 year, 37.9% were followed for at least 2 years, and 16.6% were followed for 3 years.

A total of 272 episodes of pneumonia and other lower respiratory tract infections occurred in 170 patients during the entire study period. The mean annual influenza and pneumococcal vaccination rates were 83% and 21%, respectively.

Multivariate analysis showed that the following factors were independently and significantly associated with an increased risk for pneumonia: older age (odds ratio [OR], 1.7), male sex (OR, 1.9), swallowing difficulty (OR, 2.0), and inability to take oral medications (OR, 8.3). In contrast, influenza vaccination was associated with a decreased risk for pneumonia (OR, 0.4).

In terms of other lower respiratory tract infections, older age (OR, 1.6) and immobility (OR, 2.6) were significant and independent risk factors. Here, too, vaccination against influenza was associated with a decreased risk for pneumonia (OR, 0.3).

Those findings "confirm the importance of annual influenza vaccination for residents of long-term care facilities" and suggest that improvements in pneumococcal vaccination rates need to be made in this population.

The researchers also found that residents with pneumonia and other lower respiratory tract infections were not at increased risk for deterioration in functional status (ORs, 0.7 and 0.5, respectively) compared with residents who did not develop infections.

Loeb M, McGreer A, McArthur M, et al. Risk factors for pneumonia and other lower respiratory tract infections in elderly residents of long-term care facilities. Arch Intern Med. 1999;159:2058-2064.


IPRATROPIUM IS EFFECTIVE IN ACUTE ASTHMA EXACERBATION

Inhaled ipratropium bromide in combination with ß-agonist therapy is an appropriate treatment for acute exacerbations of asthma in adults, according to a meta-analysis published in a recent issue of Annals of Emergency Medicine. The study findings demonstrated that treatment is associated with modest statistical improvement in airflow obstruction with no evidence of adverse effects.

The researchers analyzed data from 10 placebo-controlled studies involving a total of 1,377 adults presenting with an acute asthma exacerbation to a hospital emergency department or similar acute care setting.

The addition of ipratropium to inhaled ß-agonist therapy was associated with a 7.3% (100 mL) greater improvement in forced expiratory volume in 1 second (FEV₁) and a 22.1% (32 L/ min) increase in the absolute peak expiratory flow rate. The summary effect size of the addition of ipratropium was 0.38 (95% CI, 0.27-0.48). "Effect sizes," the authors reported, "were negatively correlated with baseline mean expiratory flow rates, suggesting that studies enrolling patients with more severe airflow obstruction showed greater absolute benefits of combination bronchodilator therapy."

In addition, hospitalization rates were lower among patients taking ipratropium (relative risk of hospitalization, 0.73; 95% CI, 0.53-0.99), according to an analysis of data from three of the studies. None of the 10 trials reported any serious treatment-related adverse effects or found any "adverse effects to be of clinical or statistical significance with respect to the single-therapy regimen versus the combination-therapy regimen," according to the report.

The clinical significance of the improvement in airflow obstruction remains unclear, the authors acknowledged. Nevertheless, "it would seem reasonable to recommend the use of combination ipratropium/ß₂-agonist therapy in acute asthma exacerbations in adults, because the addition of ipratropium seemed to provide physiologic evidence of benefit without risk of adverse effects."

Related findings from a literature review published in the same issue of the Annals of Emergency Medicine suggested that multiple doses of nebulized ipratropium bromide are safe and effective for asthmatic children when administered during the first hour of an emergency department visit for acute asthma.

In a meta-analysis of data from 10 trials, the odds ratio for hospitalization in children treated with multiple-dose ipratropium in addition to a regimen of ß₂-agonists and corticosteroids was 0.62 (95% CI, 0.39-0.98), while the number of children needed to be treated (NNT) with ipratropium to prevent one hospitalization was 11. Ipratropium was also associated with a 10% increase in percent predicted FEV₁. The clinical relevance of those data, the authors indicated, were strengthened by their agreement with data from a large clinical trial. Findings from that large trial also suggested that ipratropium's effects are greatest among children with the most severe cases of asthma, since NNT in that subgroup was 6. No clinically significant adverse effects of ipratropium were reported in either the meta-analysis or the large trial.

Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a meta-analysis of randomized clinical trials. Ann Emerg Med. 1999;34:8-18.

Rowe BH, Travers AH, Holroyd BR, et al. Nebulized ipratropium bromide in acute pediatric asthma: does it reduce hospital admissions among children presenting to the emergency department? Ann Emerg Med. 1999;34:75-85.


ORAL NEURAMINIDASE INHIBITOR FOR TREATMENT OF INFLUENZA

The oral neuraminidase inhibitor oseltamivir shows promise in the prevention and treatment of influenza A infection, according to a pair of recent randomized trials reported in JAMA. Oseltamivir, which has just received approval for the treatment of human influenza from the FDA, was associated with "significant antiviral and clinical effects" comparable to those of intranasal zanamivir and superior to those of amantadine and rimantadine, the study's authors explained.

Neuraminidase--one of the two major surface glycoproteins of influenza A and B--is thought to be essential for sustained replication of influenza A and B viruses in humans. The other currently available neuraminidase inhibitor--zanamivir--can only be delivered intranasally or by inhalation, because of its low oral bioavailability, small volume of distribution, and rapid renal elimination, the researchers explained. The present study was designed to determine the safety, tolerability, and antiviral activity of oral oseltamivir for the prevention and early treatment of influenza A.

The study consisted of two randomized trials conducted in healthy volunteers between the ages of 18 and 40 years. In the prophylactic trial, 37 subjects were randomized to placebo or to oseltamivir at 100 mg once daily or twice daily. In the treatment trial, 80 subjects were randomized to placebo or oseltamivir at 20, 100, or 200 mg twice daily or 200 mg once daily. Administration began at 26 and 28 hours after intranasal influenza A virus inoculation in the prophylactic and treatment trials, respectively, and continued for 5 days.

Oseltamivir was 100% effective in protecting against viral recovery in the upper respiratory tract and infection-associated upper respiratory tract illness. It also had an efficacy of 61% in the prevention of laboratory-confirmed infection, which was found in 67% of the placebo recipients but in only 38% of the oseltamivir recipients (four patients in each dose group).

Oseltamivir also significantly reduced the median viral titers by 2.1 log10 at 24 hours after administration and by 3.5 log10 at 36 hours after administration, compared with placebo (P=.02). The median time to cessation of viral shedding was significantly lower in the combined oseltamivir group (58 hours) compared with the placebo group (107 hours; P=.003). "This antiviral effect was associated with significant reductions in illness burden and biochemical markers of host inflammatory responses in the respiratory tract," the researchers noted.

Other findings: Median time to resolution of illness was significantly lower in the oseltamivir group (53 hours) than in the placebo group (95 hours; P=.03), and nasal mucus weights were about 50% lower in the combined oseltamivir group compared with the placebo group (P=.02). In addition, the combined oseltamivir group had a lower frequency of upper respiratory tract illness (18% vs 54%), middle ear pressure abnormalities (28% vs 54%), and fever (14% vs 31%) compared with the placebo group. While no dose-related effects were detected in this study, the researchers acknowledged that the "small sample sizes were insufficient to make firm conclusions."

The overall frequency of adverse events during dosing did not differ across groups. However, the oseltamivir group had a higher incidence of gastrointestinal tract complaints (18% vs 7% in the placebo group), mainly mild to moderate transient nausea.

Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999;282:1240-1246.


IS REFLUX A CAUSE OR EFFECT OF ASTHMA?

Is gastroesophageal reflux (GER) a cause or a result of asthma? A review article published in the Journal of Asthma suggested that GER is a cause of bronchial asthma--but indicates that the reverse may also be true. Forced inspiration, which is commonly observed during an acute asthma attack, can cause incontinence of the lower esophageal sphincter, which may trigger GER, the researchers noted. Also, many of the drugs used to treat bronchial asthma may actually promote or enhance GER, and thus indirectly worsen the asthma symptoms they are designed to alleviate. But determining whether GER causes asthma or asthma GER is not as important from a patient care perspective as remaining alert to clinical or subclinical GER in asthmatic patients, particularly if they fail to respond to normally efficacious asthma pharmacotherapies.

Symptoms of GER include heartburn, epigastric pain, and regurgitation--alone or in any combination. These symptoms may worsen after exercise, along with respiratory symptoms in asthma patients. However, GER may be actively contributing to bronchial asthma, researchers believe, even in the absence of overt symptoms.

Gastroesophageal reflux is typically diagnosed by esophageal manometry and intraesophageal 24-hour pH monitoring, which are "reliable, sensitive, and can be used together with endoscopy," according to the researchers. "When necessary, the vagal-mediated mechanism should be demonstrated by esophageal acidification or distension of the lower tract." Scintigraphic techniques are not considered useful because benefits do not outweigh the cost. The researchers suggested that a modified form of Bernstein's acidification test "could represent an effective, reproducible, and useful approach when the gastric picture is silent or slightly symptomatic."

By first diagnosing and then treating GER, the researchers contended, it may be possible to eliminate symptoms related to esophagitis and bronchoconstriction, results that may also mitigate symptoms and improve the prognosis of bronchial asthma.

An editorial accompanying the review article observed that "as many as 80% of adults and 75% of children with asthma have GER," hence the importance of monitoring for and treating the condition in asthmatics. A common treatment modality is an acid-suppressive dose of omeprazole; however, some patients will not have adequate acid suppression even with "maximal medical therapy." Consequently, surgery should be considered. In fact, surgery "has been demonstrated to be the most effective form of therapy for GER" and can be essential for patients with serious respiratory complications, such as the presence of a hiatal hernia or a shortened esophagus.

Bruno G, Graf U, Andreozzi P. Gastric asthma: an unrecognized disease with an unsuspected frequency. J Asthma. 1999;36:315-325.

Stein MR. Advances in the approach to gastroesophageal reflux (GER) and asthma. J Asthma. 1999;36:309-314.