Cover story

Cover story

Alternative asthma therapies: An evidence-based review

By Kathi J. Kemper, MD, MPH, and Mitchell R. Lester, MD

From Ma huang to bee pollen, deep breathing to acupuncture,alternative asthma therapy is in vogue. You need to know what your patientsare using, whether it's safe, and how it works. Here's the evidence.

Suppose you agree with the National Heart, Lung, and Blood Institute(NHLBI) asthma guidelines that patient education is essential for good asthmamanagement. You start a class for families of school-age patients, and findyourself barraged by questions about complementary and alternative medical(CAM) therapies.

• Should we start our child on herbs or vitamins to help decrease his need for medications?
• I've heard that the Chinese have used ma huang for thousands of years, and my friend says vitamin C has really helped her asthma. Are these remedies safe?
• Can you refer us to an acupuncturist or homeopathic practitioner for supplementary treatments?

How do you answer questions like these? Should you warn families offthese far-out, "unscientific" approaches, or just go along onthe assumption that since these remedies are "natural," they'reprobably harmless? Is it possible that some of them work? How can you tell?

This article will help you evaluate the claims and the evidence, focusingon biochemical, lifestyle, and biomechanical and bioenergetic alternativesto standard therapies (Table 1). The article is not meant to replace informationon standard medical care, as outlined in Dr. Kemper's article, "A practicalapproach to chronic asthma management," in the August 1997 issue ofContemporary Pediatrics.

Why patients choose alternative therapy

Alternative therapy is not often discussed with physicians, but it iswidely used these days--especially for children with chronic diseases likeasthma. An Australian survey of asthmatic children from 1 to 6 years ofage, for example, showed that 55% used alternative therapy. The CAM therapiesmost commonly used for asthma are dietary changes, herbal remedies, meditation,and homeopathy.¹

Families may seek CAM therapies because they are frustrated with modernmedicine's inability to "cure" asthma or because they fear theadverse effects of steroids and other common asthma medications. Or theymay prefer the traditional practices of their ethnic group, or want therapiesthat seem more "natural" than the medications physicians prescribe,or be unwilling to relinquish control over their children's health to so-calledexperts.

Whatever the reason for choosing CAM, the most commonly used therapiesare herbs and other dietary supplements. Whether they are purified or raw,synthetic or natural, modern or ancient, herbs and supplements work biochemically--justas standard medications do. Their risks and benefits can be evaluated inrandomized, double-blind, placebo-controlled clinical trials, and theremay be more such studies than you are aware of.

Herbal remedies

Herbal remedies are a mainstay of ethnobotanical medicine worldwide (Table2). Cultural remedies that are part of traditional Chinese medicine (TCM),Kanpo (the Japanese indigenous medical system), Ayurvedic medicine (thetraditional medicine in India), and other traditional healing systems relyheavily on herbs. Like medications, herbs are believed to work through avariety of mechanisms. Some decrease inflammation (licorice root), whileothers soothe irritated airways (slippery elm bark and wild cherry bark),reduce anxiety (kava kava), relieve bronchospasm (ephedra), or dry secretions(Jimsonweed,also known as datura). Herbs are used singly and in combination.The Puerto Rican remedy, siete jarabes, is a combination remedy, a honeyedsyrup containing almond oil, castor oil, wild cherry, licorice, and cocillana.²

Many immigrants rely on traditional therapies rather than mainstreammedications. To the extent that herbs are not toxic and are an importantpart of a patient's cultural belief system, they can be safely incorporatedinto a medical plan. The challenge for a mainstream American pediatricianis to know which ones are safe and unlikely to interact negatively withstandard treatments.

Coffee and tea. In the 1800s coffee was the treatment of choice for asthma.Epidemiologic data support a relationship between coffee intake and reducedrespiratory symptoms that may be mediated through coffee's xanthine content.Caffeine is chemically related to theophylline. Like theophylline, it increasesintracellular cyclic adenosine monophosphate (cAMP) and thereby relaxesbronchial smooth muscles. In a large Italian study, adults who drank twoto three cups of coffee daily had about 25% less asthma than adults whoabstained.³American data support a dose-effect association betweencoffee intake and a reduced risk of asthmatic symptoms. There are no recent,randomized controlled trials evaluating the effects of caffeine on childhoodasthma symptoms, nor on the interaction between coffee, tea, colas, andmodern asthma medications.

Shinpi-to and saiboku-to. Clinical trials indicate some steroid-sparingeffects of the ancient Chinese herbal combination remedy, saiboku-to, reducingthe need for anti-inflammatory medications in adult asthmatics taking itover several months. Saiboku-to contains five herbs that slow steroid breakdown,possibly increasing the risk of side effects (or decreasing dosage requirements)in patients dependent on oral steroids. Like the new asthma drug zileuton,saiboku-to and shinpi-to, another Chinese herbal asthma remedy, inhibit5-lipoxygenase and thus the synthesis of the pro-inflammatory leukotrienes.⁴

Ma huang (Ephedra sinica). This herb has been an asthma remedy in Chinafor over 5,000 years. Ephedrine, ma huang's principle active ingredient,was included in mainstream medical therapies for pediatric asthma untilthe mid-1980s when it was replaced by more specific b-agonist medicationsthat had fewer cardiovascular side effects. It continues to be a mainstayof natural herbal asthma remedies when used in combination with anti-inflammatoryherbs such as licorice root. Ephedra gained notoriety in the 1990s as adolescentstried using it as a natural high. The US Food and Drug Administration hasreceived over 600 complaints of adverse effects, including 22 deaths, relatedto ephedra, a situation that has led to tighter state regulations on theavailability and strength of ephedra-containing products as well as a warningfrom the FDA.

Licorice root (Glycyrrhiza glabra radix). Folk medicines around the worlduse licorice root to treat coughs. The herb's active compounds, glycyrrhetinicacid and carbenoxolone, are potent inhibitors of cortisol metabolism, therebyenhancing endogenous and exogenous steroid benefits and side effects. Asrecently as the 1960s, licorice was used successfully by American physiciansto treat Addison's disease. Because of its inhibitory effects on steroidbreakdown, side effects of licorice include fluid retention, peripheraledema, hypertension, headaches, hypokalemia, lethargy, and muscle weakness.Similar effects were seen when troleandomycin (TAO), a macrolide antibiotic,was used in combination with methylprednisolone. TAO delayed steroid breakdownand improved asthma symptoms, but also enhanced steroid side effects; thisled most clinicians to abandon TAO as an adjunct in asthma treatment. Nostudies have yet evaluated the risks and benefits of including licoriceroot in a standard pediatric treatment regimen for asthma. Patients usinglicorice should be closely monitored for steroid-like side effects.

Coleus forskohlii. This herb is used in Ayurvedic medicine to treat asthma.Like theophylline, it increases intracellular cAMP and is an effective bronchodilator.⁵Another Ayurvedic herbal remedy, Tylophora indica, has proven beneficialin controlled, double-blind cross-over studies, but the most effective dosagesand long-term effects on children are unknown.⁶

Gingko biloba. This is one of the most widely used herbal remedies inEurope. Standardized extract of Gingko biloba (EGb), is sold under severaldifferent brand names: Ginkgobil, Rokan, Tanakan, Tebonin, and Kaveri. Ginkgo'sactive ingredient, ginkgolide, antagonizes platelet activating factor (PAF),and may decrease airway inflammation. Ginkgo is also a powerful antioxidant.Although Gingko biloba has a long history and a reasonable biochemical rationale,only one small pilot study has evaluated its effectiveness as an asthmaremedy. That study found it protective against exercise-induced bronchospasm;it also decreased participants' reactivity to house dust mite antigen.⁷Its long-term use is still experimental.

Onions (Allium cepa). Nine different compounds isolated from this commonfolk remedy inhibit leukotriene synthesis in vitro. Crude onion extractsreduce experimentally induced bronchoconstriction in guinea pigs.⁸Onions are extremely safe and well tolerated in normal diets. Hypersensitivityis rare. Additional research is needed to determine the best dose and frequencyof onion supplements for asthmatic children.

Bee pollen. This substance has been widely touted as a natural remedyfor atopic diseases. There are no clinical trials evaluating its effectivenessin treating childhood asthma. Serious allergic reactions and even fatalitieshave been reported. This is not a safe adjunctive therapy for asthmaticpatients.

Herbal products are not regulated by the FDA. Consumers who rely on themmust beware of the potential for variations in purity and potency, and contaminationwith other herbs, insects, pesticides, herbicides, heavy metals, and evenmedications. Consumers need to understand that herbal products are not necessarilysafe (or organic) simply because they are natural. Evidence for the safetyand efficacy of herbal remedies for asthma is summarized in Table 3.

Nutritional supplements

The vitamins and minerals most commonly recommended for asthma includevitamin B₆, vitamin C, magnesium, and selenium. Salt restrictionis also recommended.

Vitamins. In a double-blind, placebo-controlled study of steroid-dependentadult asthmatics, 300 mg of pyridoxine (Vitamin B₆) supplementstaken daily significantly improved morning peak flow rates. There was nobenefit on acute symptoms. In a case series of adult asthmatics who hadlow serum levels of pyridoxine, supplementation led to fewer and less severewheezing episodes. Pyridoxine supplements of 200 mg per day reduced thenumber of asthma attacks, the severity of symptoms, and the need for medicationsin a double-blind study of 76 asthmaticchildren.⁹ Side effectsare rare with these doses. Pyridoxine supplements may be particularly helpfulfor children whose serum levels of pyridoxal phosphate have been depletedby chronic theophylline use.

Antioxidant vitamins are commonly suggested complementary therapies forasthma. Adults whose diets are naturally high in antioxidants such as vitaminC­ and vitamin E­rich foods have the fewest pulmonary problems.Six months of daily vitamin C (1 g per day) failed to reduce asthma symptomsin one study, but did reduce them in another double-blind comparison trial.In some children, 500 mg of oral vitamin C has a protective effect againstexercise-induced asthma.¹⁰ Taking 500 to 1,000 mg per day isprobably safe for most children, although higher doses may lead to diarrhea.Additional studies are necessary to determine the effectiveness and optimaldosing, frequency, and duration of vitamin C supplementation.

Magnesium. Dietary magnesium intake is strongly correlated with asthmasymptoms; the more magnesium, the fewer the symptoms. Intravenous magnesiumhas proven helpful in treating pediatric status asthmaticus. In a randomized,controlled, double-blind cross-over study of oral magnesium supplementation(400 mg daily) in adults, there was a statistically significant improvementin asthma symptoms and a small reduction in bronchodilator requirements,but no significant change in pulmonary function tests during the three weeksof treatment.¹¹ Additional prospective, controlled studies areneeded to evaluate the effectiveness and safety of oral magnesium supplementsin preventing childhood asthma episodes.

Selenium. Plasma and erythrocyte levels of selenium and the activityof the selenium-dependent enzyme glutathione reductase are lower in asthmaticadults than in nonasthmatics. However, no clinical trials document benefitsto pediatric asthma patients from selenium supplements.

Saltrestriction. While bronchial sensitivity to methacholine is increasedby high salt intakes, a pediatric case control study found no associationbetween levels of salt intake and asthma or exercise-induced bronchospasm.Studies are not strong enough to suggest that asthmatic children shouldseverely restrict their salt intake.

Fatty acids. Omega-3 fatty acids (found in fish oils, canola oil, andflax seed oil) have been touted as important anti-inflammatory food supplements.Omega-3 fatty acids limit leukotriene synthesis by blocking arachidonicacid metabolism. Eating fresh oily fish (cod, mullet, orange roughy, salmon,tuna, mackerel, rainbow trout) is associated with a significantly reducedrisk of asthma and improved pulmonary function in large epidemiologic studiesin both adults and children.¹² In a long-term, double-blind trialof supplementation with one g daily of fish oil in adult asthmatics, pulmonaryfunction tests did not improve until the ninth month of treatment.¹³Many asthmatics may consider this too long to wait. Canned fish and saladbar shrimp containing sulfites should be avoided in sensitive asthmatics.However, fresh fish is generally well tolerated and can be reasonably recommendedas part of a life-long healthy diet. Additional research is needed beforerecommending routine supplementation with fish oil capsules for asthma.Evidencefor the safety and efficacy of nutritional supplements is summarized inTable 4.

Lifestyle therapies

Lifestyle therapies that address the asthmatic child's environment arecentral to the control and prevention of asthma symptoms in mainstream medicine.Unfortunately, there is no alternative therapy for housecleaning, althoughmany CAM enthusiasts wish there were. CAM lifestyle recommendations, inaddition to environmental measures, generally involve three areas: diet,exercise, and mind-body therapies.

Diet. Many families blame food allergies for asthmatic symptoms, eventhough only 2% to 3% of patients react to double-blind, placebo-controlledfood challenges. Some CAM enthusiasts routinely advise asthmatics to followelimination diets (restricting major allergenic foods), minimal diets (allowingonly a very small number of foods), vegan diets, or diets excluding putativetriggers (such as dairy products).^14,15 Despite the lack of evidencefrom food challenge tests, recommending dietary changes has a powerful effect.In a study of adult asthmatics, 79% of respondents who had tried a restricteddiet reported improvement in their asthma symptoms. While restricted dietsmay be helpful in a minority of patients, they should be strictly supervisedby a nutritionist and limited to brief trials to prevent deficiencies. Inthe absence of documented food allergies, there is no conclusive evidencethat restricted diets are helpful in reducing asthma symptoms.

Dairy products are often blamed for inducing respiratory symptoms andrestricted in the diet of patients with asthma. However, among adult asthmaticpatients who believed their symptoms were triggered by dairy foods, milkwas not significantly more likely than placebo to trigger symptoms in randomized,blinded challenges.¹⁶Dairy restriction is potentially dangerousfor children with steroid-dependent asthma, who need calcium's protectiveeffects to maintain bone density. No controlled trials indicate significantbenefits to eliminating dairy products from the diets of most children withasthma.

Exercise. Nearly 90% of asthmatics find that exercise, especially incold, dry air, triggers symptoms. Nevertheless, the benefits of cardiovascularfitness are so important that children with asthma should be encouragedto exercise. Asthma is easier to control in patients who are physicallywell conditioned, and asthmatic symptoms triggered by exercise can be readilycontrolled. Many Olympic-caliber athletes have asthma and have set worldrecords for athletic performance.

Despite theoretical concerns about eliciting the diving reflex or chlorine-precipitatedbronchospasm, swimming is commonly recommended as beneficial exercise forasthmatic children. Studies of swimming programs have not demonstrated thatswimming is better than other aerobic conditioning programs, but they generallyindicate longitudinal improvements in overall fitness, swimming ability,and self-esteem. Spa treatments (swimming in hot spring or mineral water)may be even better. In a cohort study of adults with severe, steroid-dependentasthma who received spa therapy, 69% experienced significant clinical improvement;rates of improvement were even higher among older patients (41to 60 yearsof age) and those with more severe disease.¹⁷ Similar studieshave not been done in children, nor are insurance companies likely to raceto reimburse this form of therapy.

Controlled breathing. Yoga, particularly yogic breathing (pranayama),may help reduce the frequency of asthma attacks.¹⁸ Yoga breathingexercises emphasize slow, regular breaths in which the ratio of inhalationto exhalation is 1:2; inhaling hot, moist air can enhance the benefits.¹⁹Long-term (one to four years) follow-up of asthmatic adults indicated sustainedimprovement in pulmonary function and exercise tolerance and decreased relianceon rescue medications following a four-week yoga therapy training program.²⁰A randomized, controlled trial of yoga training in young adult asthmaticsresulted in greater calm, improved attitudes, enhanced exercise tolerance,decreased asthma symptoms, and decreased use of asthma medications, butno changes in pulmonary function tests.²¹ Additional studiesare needed to determine the most effective components, duration, and frequencyof training and practice, but these exercises are safe for patients whoare interested in exploring alternative exercise programs.

Other types of breathing exercises frequently suggested for asthma combineaspects of physical training and mind-body interventions. Training may includevoice lessons to improve breath control and functioning of the diaphragmthrough relaxation and postural changes. In a randomized, controlled trialof German adults with mild asthma, breathing exercises significantly improvedpulmonary function. These long-term improvements were comparable to theshort-term benefits of inhaled b-agonist medications.

A recent breathing exercise fad in the popular press and on the Internetis Buteyko breathing. This technique is named after a Russian physician,Konstantin Buteyko, who believed that "over-breathing" or deepbreaths cause a number of diseases, including asthma, and that to reduceasthma symptoms, patients should be trained to "breathe less."²²This is nonsense. Nevertheless, since your patients are likely to encountermoving testimonials about this technique, you should be familiar with it.Information about Buteyko is available on the web at www.buteyko.com.

Environmental manipulation. While there is plenty of evidence to supportreducing exposure to dust mites, cockroaches, animal danders, and otherallergens and sensitizers in the environment, claims are being made foralternative devices that purport to purify the environment. No studies supportthe use of such devices as ozone or ion generators, vaporizers, aromatherapy,magnets, or radionic devices. On the positive side, there are no known adverseeffects of these therapies, either.

Mind-body therapies. Children with asthma are more likely to have symptomswhen they are stressed. Stress management can take a variety of forms andmay be helpful for both parents and children. Transcendental meditationhas proven helpful in improving pulmonary function among adult asthmaticswho practice it regularly. Progressive relaxation training augments thebenefits of acomprehensive asthma management program for children. Autogenictraining (in which patients silently repeat relaxing affirmations) can alsohelp manage stress and improve pulmonary function when practiced over severalmonths. Just three sessions of systematic relaxation training improved pulmonaryfunctions in asthmatic children more than three sessions of simply sittingquietly.²³

Hypnosis has proven useful in improving symptoms and pulmonary function,enhancing parental confidence in managing their children's asthma, and reducingthe amount of medication and number of physician visits for asthmatic children,even preschoolers.²⁴ Physicians experienced in using clinicalhypnosis may help patients reduce reactivity to allergens, reliance on oralsteroids, and even rates of hospitalization. Most claims are of modest symptomaticrelief, with few complete cures. Additional studies are needed to assesstypes of training, frequency, and duration, and the patients for whom hypnosisis most likely to be helpful.

Asthmatic children can learn to reduce air-flow resistance through biofeedbacktraining. Regularly practicing biofeedback can improve attitudes about asthma,reduce anxiety levels, reduce the frequency and severity of asthma symptoms,and lowermedication use and emergency room visits.²⁵ The types,duration, and frequency of biofeedback training and patients most likelyto benefit remain unknown.

Stress reduction and mind-body treatments work only when practiced regularly,so families must be committed and persistent in following these programs.Tryto find out what kind of therapies appeal to your patients, so that theychoose treatments they are likely to keep up. Additional studies are neededto assess the most effective types of therapy for children of differentages. The pros and cons of these lifestyle therapies are summarized in Table5.

Joints, muscles, and energy fields

Biomechanical and bioenergetic therapies rely on manipulation of thepatient's body and of unseen energy fields believed to influence healthand disease.

Massage. This traditional therapeutic modality not only feels good buthas been shown to reduce stress and anxiety. In a recent randomized, controlledtrial, 20 minutes of massage given by parents at bedtime for a month helpedimprove children's pulmonary function tests, even compared with standardrelaxation exercises.²⁶ The necessary frequency, duration, andlong-term benefits of massage therapy remain unknown. However, when parentsdo the massage, costs and side effects are minimal. You can safely recommendthis complementary therapy for families to try.

Chiropractic. Some chiropractors claim to benefit a variety of clinicalconditions, including asthma. Only one randomized clinical trial has investigatedthis claim; it did not find that real chiropractic therapy offered any benefitbeyond sham chiropractic. There is no scientific basis for recommendingchiropractic therapy for the relief of asthma symptoms in children. It offersno proven clinical benefit, and may--because of frequent visits and X-rays--increaseshealth-care costs and dependence on health professionals.

Acupuncture. All of the bioenergetic therapies rely on a belief in anunseen vital or healing energy that affects patients' health and well-being.Practitioners can affect the flow, amount, or intensity of this healingenergy through a variety of techniques.

In acupuncture, the vital energy, known as qi or chi, flows through channelsand can be balanced by proper placement and stimulation of acupuncture needles.Traditional Chinese medical practitioners claim that asthma is one of theconditions most amenable to acupuncture, but data from controlled trialsoffer conflicting results. Most clinical trials have not been methodologicallyrigorous but do support a modest role for acupuncture for adult asthmatics.²⁷In one case series, acupuncture was effective in aborting acute attacksif the needle sensation was felt strongly and needles were left in placewith frequent stimulation for 15 to 60 minutes. In one controlled trial,true acupuncture performed 20 minutes before exercise was more effectivethan sham needling in reducing exercise-induced asthma.²⁸ Anotherstudy, on the contrary, found no benefits of acupuncture in preventing exercise-inducedbronchospasm.

Adverse effects of acupuncture are exceedingly rare. A MedLine searchfor the years 1981 to 1994 revealed a total of 193 patients with reportedadverse events. These included several pneumothoraces, one of which ledto death, and an additional death from status asthmaticus. Although theseside effects are rare, they underscore the importance of regarding acupunctureas an experimental, adjunctive therapy and cautioning patients against substitutingacupuncture for conventional medical care.

Healing touch and prayer. These are commonly used healing techniquesin nearly every culture. In healing touch, reiki, and noncontact therapeutictouch, healers transmit healing energy through their beneficent intent,focusing the flow of energy through their hands. Prayer does not requirethe use of hands or even the physical presence of the healer to intervenewith spiritual powers or unseen forces. We were able to find only one studythat evaluated the effectiveness of healing touch or prayer on patientswith asthma. In an uncontrolled pilot study performed in Germany, 12 patientsall received treatments from a healer who placed his hand on the patients'chests for one to three minutes of healing; an average of 17 to 18 treatmentswere given over an eight- week period. Most patients felt improved and severalwere able to reduce their use of medication.²⁹ Regardless ofwhether or not one believes in a healing energy, these types of treatmentscertainly appear to be safe as long as patients do not abandon mainstreammedical therapies without consulting their physician.

Homeopathy. This mode of treatment is not based on classical chemicalor physical laws, but on the two principles of "like cures like"and the "law of dilutions." The first principle means that a remedyis chosen because of its tendency to cause the same symptoms patients experienceas part of their illness. The second means that the remedy gains in potencythe more dilutions it undergoes; the most potent remedies are those thatare diluted to the point at which they contain no molecules of the therapeuticcompound. Homeopathy fits into the bioenergetic category because pracitionersbelieve that dilution imparts and amplifies healing energy or informationfrom the original remedy to the diluted medication. That healing energyis then used by the patient's inner self to encourage healing.

A 1994 placebo-controlled trial of homeopathy in the treatment of adultswith allergic asthma concluded that true homeopathy was superior to placeboin reducing asthmatic symptoms. Pulmonary function testsshowed no significantdifferences, however. No studies have evaluated the effectiveness of homeopathyin treating children with asthma. Homeopathic remedies may be assumed tobe quite safe biochemically, and may be a harmless, inexpensive, and usefulplacebo. They cannot be recommended as active therapy or replacement forstandard treatment, however.The evidence for effectiveness and risk of thesebiomechanical and bioenergetic therapies is summarized in Table 6.

Summing up the evidence

Complementary and alternative medical therapies are used frequently bychildren suffering from chronic illnesses such as asthma. Many herbs andnutritional supplements are similar to or have become mainstream medicaltherapies. Combination herbs containing anti-inflammatory compounds mayreduce dosage requirements for standard medications, but could potentiatethe side effects of oral steroids. Herbal adrenergic stimulants run therisk of serious side effects. Nutritional supplements such as vitamin B₆,Vitamin C, magnesium, and fish oil may be helpful but are no substitutefor a healthy diet. More research is needed to ascertain how best to integratenutritional supplements into mainstream care for children with asthma, bothto promote effectiveness and to reduce side effects and costs. Safe recommendationsinclude a diet containing plenty of antioxidant-rich fresh fruits, onionsand other vegetables, and fatty fish.

Exercise, including yoga and breathing exercises, should be encouragedfor children with asthma. Effective environmental therapies stress avoidanceof allergens and other triggers. Stress management is important; a varietyof techniques may be helpful, depending on patient preferences. Massagetherapy appears promising, at minimal cost and little risk of side effects.Acupuncture cannot be routinely recommended without additional researchin children but need not be discouraged. Prayer and healing touch have notundergone rigorous study, but are safe ancillary therapies. Homeopathy mayoffer an inexpensive placebo, but has not been adequately tested in children.

New fads are bound to come along with extravagant claims for effectiveness.While some alternative treatments may offer modest benefit for helping childrenwith chronic asthma, none are recommended as a replacement for standardmedical therapies and none should be the sole treatment for acute symptoms.Asthma management plans should stress prompt medical care if symptoms persistor worsen on existing treatments.

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DR. KEMPER is Director, Center for Holistic Pediatric Education andResearch, Children's Hospital, Boston, MA.

DR. LESTER is Clinical Director, Pediatric Asthma Center, Children'sHospital, and Instructor in Pediatrics, Harvard Medical School, Boston.