LITERATURE MONITOR:
A REVIEW OF RECENTLY
PUBLISHED CLINICAL ARTICLES

PROBIOTIC MILK CONSUMPTION
REDUCES INFECTION

Probiotic milk consumption may reduce the number of respiratory and gastrointestinal (GI) infections in children.

Hatakka et al observed 282 children (ages 1 to 6 years) who drank an average 260 mL/d of milk laced with Lactobacillus rhamnosus during a seven-month period. The investigators compared the rates of digestive and upper respiratory tract infections and absence from school of these children with those of 289 similar children who drank the same amount of noninfected milk and served as controls.

The children in the L rhamnosus group had a mean 4.9 days of absence from day care or school due to illness compared with the controls’ 5.8 days. In addition, the relative risk of upper respiratory tract infections with complications and lower respiratory tract infections was reduced by 17% in the children given probiotic milk. These children also showed a 19% relative reduction in the number of antibiotic treatments required for respiratory infection. Probiotic milk consumption also appeared to lower the risk of diarrhea.

These differences were reduced somewhat when the analysis was controlled for the children’s ages. The investigators theorized that the differences between the experimental and control groups would have been greater had not about 15% of the children in the control group also consumed L rhamnosus during the trial.

L rhamnosus may lower infection rates either by improving humoral and cellular immunity or by otherwise stimulating nonspecific immunity. No matter which pathway is actually used, the investigators believe that because of the significant societal cost of respiratory tract infections in children, administration of probiotic milk would be an advisable, side-effect–free means of addressing the problem.

Hatakka K, Savilahti E, Pönkä A, et al. Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial. BMJ. 2001;322:1327-1329.

DOES SMOKING CAUSE LUNG
METASTASIS FROM BREAST CANCER?

Patients with breast cancer who smoke appear to be at an increased risk for developing pulmonary metastatic disease, according to a recent case-control study. This association may help explain why so many smokers are included in breast cancer fatalities.

The authors studied 87 case patients diagnosed with breast cancer and pulmonary metastasis and 174 control patients diagnosed with breast cancer alone. Cases and controls were matched according to year of diagnosis, age at diagnosis, size of primary tumor, and nodal status. Roughly 38% of the case patients and 29% of the controls had ever smoked; rates of current smoking were 24% and 15%, respectively.

The unadjusted odds ratio for active cigarette smoking at the time of breast cancer diagnosis was 1.76 for women with pulmonary metastasis, as compared with women without. In the final multivariate model, which included adjustments for use of hormone replacement therapy and presence of other sites of metastatic disease, the odds ratio increased to 1.96 for women with pulmonary metastasis versus those without.

Smoking may make the lungs a more susceptible environment for metastasis, the authors suggested. But whether smoking causes the metastasis, and through what mechanism, has not yet been clearly defined.

Murin SM, Inciardi J. Cigarette smoking and the risk of pulmonary metastasis from breast cancer. Chest. 2001;119:1635-1640.

MUCOLYTIC THERAPY REDUCES
COPD EXACERBATIONS

Mucolytic drugs do reduce the number and severity of chronic obstructive pulmonary disease (COPD) exacerbations. But, long-term therapy is required to achieve this effect, and the extent of the reduction is described as “modest.”

A review of 23 randomized trials produced evidence that mucolytic drug therapy reduced the number of COPD exacerbations by 0.07 per patient per month; it also lowered the number of days ill and days on antibiotic therapy by 0.56 and 0.53 per patient per month, respectively. Differences in adverse effects and lung function for the 2,097 experimental subjects and 2,046 controls were not significant.

Two of the 23 studies examined patients with severe COPD (those with a forced expiratory volume less than 50% of predicted). In these patients, the reduction in the number of COPD exacerbations was much higher: 0.13 per patient per month.

The researchers concluded that long-term administration of mucolytics would benefit patients with repeated, prolonged, or severe exacerbations of chronic COPD that result in hospitalization. However, they excluded isobutyrylcysteine from this recommendation, because the only study of this agent found that it had no impact on COPD exacerbations.

Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. BMJ. 2001;322:1271-1274.

PRESENTATION TIME HAS
NO EFFECT ON ASTHMA SEVERITY

How important to treatment and outcome is the time of an emergency department (ED) visit for asthma exacerbation? Not very, finds a multicenter, prospective cohort study conducted by Brenner et al.

The researchers evaluated data from six studies that enrolled 4,096 consecutive asthma patients (ages 2 to 54 years) who had presented to emergency departments; of these, 807 sought treatment between midnight and 7:59 am; the other 3,289 came in during the day or evening. Except for an increased likelihood of intubation in adults presenting at night, the investigators found that circadian differences had little effect on treatment, hospital admission, or relapse after ED discharge.

There were some differences in presentation between the patients arriving at night and those presenting at other times, the authors acknowledged. Patients presenting at night experienced a shorter duration of symptoms than did the other patients. They also appeared to have somewhat more severe disease, although the differences in severity measurements did not always reach significance. However, hospital admission and relapse rates were similar in the two groups.

The researchers did note one apparent contradiction in their findings. Despite objective evidence to the contrary, patients seeking treatment at night were less likely than those presenting at other times to label their symptoms as severe. Yet, adult patients seeking treatment at night were 10 times more likely to be intubated than were those arriving at other times. There may exist a subset of patients, Brenner et al explained, who have a “blunted perception” of bronchospasm, hypoxia, and hypercapnia and whose exacerbations are characterized by rapid symptom onset and respiratory failure. These patients may not believe that their symptoms are severe until they are in extremis, the researchers wrote, noting that two thirds of these patients had experienced daytime symptoms but did not seek treatment until night.

Further examination of patients presenting at night is needed, the researchers said, to develop differential therapeutic strategies. For those who display insensitivity to respiratory stimuli, educational interventions emphasizing the importance of home peak flow monitoring during nighttime exacerbations could reduce morbidity and mortality because of acute asthma.

Brenner BE, Chavda KK, Karakurum MB, et al. Circadian differences among 4,096 emergency department patients with acute asthma. Crit Care Med. 2001;29:1124-1129.

GENDER BIAS AND COPD;
SPIROMETRY AIDS DIAGNOSIS

Gender bias appears to be a significant factor in the diagnosis of chronic obstructive pulmonary disease (COPD). Primary care physicians are not only underdiagnosing COPD—especially in women—but they are not utilizing the available tools, such as spirometry, to better test for the disease.

A recent survey presented six hypothetical cases to 192 North American physicians. All of the cases were identical except for the age and gender of the patient. In each case, the patient was a middle-aged former smoker who presented with chronic cough, dyspnea, and expiratory wheezing. The researchers found that women were significantly less likely to be given an initial diagnosis of COPD than were men (42% vs 58%, respectively); the gender bias decreased, however, after the physicians received spirometric findings and results from a corticosteroid trial.

Spirometry led to a diagnosis of COPD in 65% of the women and 76% of the men. After the corticosteroid trial, 78% of women and 85% of men were given a COPD diagnosis. But only 22% of the physicians would have requested spirometry after initially reviewing the cases.

The study also reveals considerable confusion in differentiating COPD from asthma, which was the most common alternative diagnosis to COPD. This misdiagnosis is particularly worrisome in postmenopausal women because of the effect of corticosteroids on bone mineral density.

Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691-1695.

AN ALTERNATIVE TO OZONE-DEPLETING MDIs

Albuterol delivered by means of a metered-dose inhaler (MDI) that contains chlorofluorocarbon (CFC) propellants is the most commonly prescribed treatment for asthma; however, CFC propellants have been associated with depletion of the ozone layer.

Albuterol, delivered via an MDI formulated with the propellant hydrofluoroalkane (HFA) 134a, is as safe and effective as the drug delivered through a CFC-propelled MDI, report the authors of a multicenter, double-blind, placebo-controlled, randomized trial.

Lumry and associates compared the effectiveness of 12 weeks of treatment with CFC-propelled albuterol, HFA-propelled albuterol, or placebo in 313 asthma patients. After a three-week run-in period during which all subjects received the CFC-propelled drug (180 µg four times daily), 108 patients were randomized to continue this regimen, 101 were assigned to treatment with HFA-propelled albuterol at the same dosage, and 104 were given placebo.

After the first dose of medication on day 1 and at weeks 6 and 12, both actively treated groups had comparable mean values for forced expiratory volume in one second (FEV1); in addition, these groups experienced significantly greater improvement in FEV1 from baseline than did the placebo controls.

Both actively treated groups were also similar in the percentage of patients who responded to treatment, the maximum response to treatment, and time-to-onset and duration of response.

Patient-completed diaries showed a similar frequency of adverse events (ie, upper and viral respiratory infection, throat irritation, and upper respiratory inflammations) in all groups: 59% for CFC-propelled albuterol, 66% for HFA-propelled albuterol, and 69% for placebo.

Asthma exacerbations occurred in 5%, 4%, and 8% of patients, respectively. There were no clinically significant changes in electrocardiographic or Holter findings, vital signs, or laboratory test results among patients.

Lumry W, Noveck R, Weinstein S, et al. Switching from Ventolin CFC to Ventolin HFA is well tolerated and effective in patients with asthma. Ann Allergy Asthma Immunol. 2001;86:297-303.

GENDER, FAT, AND LUNG FUNCTION

Researchers from the Johns Hopkins School of Medicine have compared the effect of abdominal obesity on pulmonary function in men and women. They found that while comparisons of waist and hip circumferences, expressed by the waist-to-hip ratio (WHR), correlated negatively with pulmonary function in men, this was not the case in women.

Harik-Khan et al examined 1,094 men and 540 women from the Baltimore Longitudinal Study of Aging. In addition to WHR, they measured body mass index (BMI) and took other anthropometric measurements. On average, the men had higher BMI and WHR measurements than did the women.

The researchers evaluated the correlations between both WHR and BMI and the subjects’ forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). They found that WHR was more reliable than was BMI as an indicator of the negative effects of obesity on lung function. But their findings were gender-specific: WHR was a better predictor of FVC in men than in women, and it was significant as a predictor of FEV1 in men alone. Neither FVC nor FEV1 appeared to be influenced by BMI.

The researchers concluded that WHR is a reliable predictor of male pulmonary function because it strongly describes the abdominal obesity prevalent in men. This distribution, they suggested, would be more likely to reduce vital capacity than would the more generalized distributions of fat found in women.

Harik-Khan R, Wise R, Fleg J. The effect of gender on the relationship between body fat distribution and lung function. J Clin Epidemiol. 2001;54:399-406.

MANAGING COEXISTING ASTHMA AND ANXIETY

Clinicians should watch for patients presenting to the emergency department with asthma who may be dealing with anxiety-related dysfunctional breathing as well, according to a recent editorial from BMJ.

Keeley and Osman outline three approaches to the potential overlap between hyperventilation associated with anxiety and asthma symptoms:
• First, clinicians should take a detailed history, conduct a thorough examination, and assess physiological measurements, including peak flow diaries, as first steps in avoiding misdiagnosis.
• Second, they should determine whether the cause of the dysfunctional breathing is nonasthmatic—anxiety or laryngeal dysfunction, for example. Allaying anxiety may avoid increased use of bronchodilators and other medications. Research has shown that corticosteroids are more likely to be prescribed when panic and fear levels are high, regardless of lung function.
• Third, make sure patients know the difference between symptoms of an asthma attack and those of hyperventilation associated with hypocapnia, a common experience for some patients with asthma.

Also, teach patients to recognize the side effects associated with increased bronchodilator use. When in doubt, however, the authors added, patients should treat themselves for asthma while making an effort to slow down their breathing to avoid hypocapnia.

Keeley D, Osman L. Dysfunctional breathing and asthma. BMJ. 2001;322:1075-1076.