Case15 - 2007.pdf

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case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 356;20 www.nejm.org may 17, 2007 2083

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate EditorJo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters, Assistant Editor

From the Division of Pulmonary andCritical Care, Department of Medicine,Brigham and Womens Hospital (M.E.W.);the Departments of Radiology (J.O.S.) andPathology (E.J.M.), Massachusetts GeneralHospital; and the Departments of Medi-cine (M.E.W.), Radiology ( J.O.S.), and Pa-thology (E.J.M.), Harvard Medical School all in Boston.

N Engl J Med 2007;356:2083-91.Copyright 2007 Massachusetts Medical Society.

Presentation of Case

A 20-year-old woman with asthma was taken to the emergency room of another hos-pital because of cardiorespiratory arrest. The patient had had severe asthma sincechildhood. She was born after a normal pregnancy and delivery to a teenaged, singlemother, who smoked three packs of cigarettes per day during pregnancy and duringthe patients childhood. Asthma developed at the age of 4 years, and exacerbationsoccurred frequently thereafter, triggered by cold air, hot humid air, physical activity,respiratory infections, anxiety, and exposures to paint and to cats and birds that werekept in her home or the homes of relatives. Attacks often occurred at night or in theearly morning. A timeline of medical therapy for asthma is shown in Table 1, and theresults of pulmonary-function tests are shown in Table 2. During testing, the resultsimproved after bronchodilator therapy. She was followed by pediatricians and spe-cialists in pulmonary medicine; however, she repeatedly missed outpatient follow-upappointments and visited emergency rooms on many occasions because of exacer-bations. She was inconsistent in her use of inhalers and oral medications; she usedinhaled bronchodilators up to 10 times per day when she had symptoms. At the ageof 15 years, she told hospital staff that she rarely took her medications regularly.

Involvement by the Department of Social Services was requested because of non-compliance with treatment, and the patients mother was counseled to stop smok-ing, but these interventions were unsuccessful. Visiting-nurse assessments of the pa-tients residence for possible allergens were scheduled, but despite multiple attempts,the assessments were not performed because of the familys absence from the home.

Oxygen desaturation occurred during some asthma episodes, including an episodeof status asthmaticus at the age of 8 years, with an oxygen saturation of 80% whilethe patient was breathing ambient air and had a respiratory rate of more than 50breaths per minute. She was admitted to this hospital every few months because ofasthma and pneumonia, occasionally to the pediatric intensive care unit. Trachealintubation was never required. Peripheral-blood eosinophilia was never documented.Immunoglobulin E levels were not measured.

Five months before this admission, 1 day after receiving treatment in an emer-gency room for an asthma flare, the patient was seen at an urgent care facility be-cause of shortness of breath, cough productive of white sputum, chills, and wheez-

Case 15-2007: A 20-Year-Old Womanwith Asthma and Cardiorespiratory Arrest

Michael E. Wechsler, M.D., M.M.Sc., Jo-Anne O. Shepard, M.D.,and Eugene J. Mark, M.D.

reserved.Downloaded from www.nejm.org on May 19, 2007 . Copyright 2007 Massachusetts Medical Society. All rights

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n engl j med 356;20 www.nejm.org may 17, 20072084

ing of 2 days duration, despite around-the-clockinhalational treatments with nebulized albuterol(2.5 mg) and nebulized ipratropium (0.5 mg). Herother asthma medications were salmeterol (onepuff twice daily), fluticasone propionate deliveredas an aerosol (220 g per puff, at a dose of twopuffs with a spacer adaptor, twice daily), predni-sone (5 mg every other day), and albuterol with theuse of a metered-dose inhaler (two puffs four timesdaily as needed).

The patient had a history of obesity, gastro-esophageal reflux for which she took esomepra-zole, depression, wrist fractures after a fall, a pari-etal skull fracture after an assault, chickenpox, andpinworms. Childhood vaccinations had been givenbut had been delayed because of missed appoint-ments. She had no allergies to medications. Shewas of South Asian, Scottish, and Dutch ancestry.

She had missed many months of school becauseof asthma and had left school after the eighthgrade at the age of 15 years. She gave birth to achild at the age of 19 years and lived with thechild, her mother, and her half-siblings. She toldsome caregivers that she smoked cigarettes butalso told many others that she did not smoke. Thepatients mother and other maternal relatives hadasthma and eczema, and there was a family his-tory of diabetes mellitus. Her two half-siblings

were healthy; her fathers medical history was notknown.

On physical examination at the urgent care fa-cility, the patient was in moderate respiratory dis-tress. The blood pressure was 152/62 mm Hg, thepulse 120 beats per minute, and the temperature37.4C; the respirations were 28 per minute, andthe oxygen saturation was 90 to 91% while thepatient was breathing ambient air. At her request,a peak-flow measurement was not performed. Thebody habitus was cushingoid, and there were dif-fuse wheezes in both lungs, without rales or rhon-chi. There was no digital clubbing or cyanosis. Theremainder of the examination was normal. A chestradiograph revealed consolidation in the rightmiddle lobe and patchy opacity in the left upperlobe. A combination solution of albuterol and ip-ratropium was administered by nebulizer twice,

and she was discharged home while receivingprednisone (60 mg daily, with instructions to ta-per the dose), her other medications, and a 5-daycourse of azithromycin.

Approximately 8 weeks before admission, thepatient was seen in the emergency room of a localhospital because of respiratory symptoms. Cla-rithromycin was prescribed, but the symptomsworsened; several days later, a chest radiographrevealed a left-upper-lobe and perihilar infiltrate

Table 1. Timeline of Asthma Therapies.

Age Range Medications Taken at Home

Medications Administeredon Admission (to Emergency

Department or Hospital)

410 yr MetaproterenolAlbuterol by nebulizer and metered-dose inhalerTheophylline

Isoetharine by nebulizerCromolyn sodium inhalerBeclomethasone inhalerTapered prednisone (514 days)

Epinephrine (subcutaneous)Aminophylline (intravenous)Methylprednisolone (intravenous)

1015 yr Albuterol by nebulizer and metered-dose inhalerIpratropium bromide by nebulizerSalmeterol xinafoate inhalerFluticasone propionate metered-dose inhalerBudesonide inhalerTapered prednisone (514 days)Montelukast sodium tabletsBeclomethasone inhaler

Epinephrine (subcutaneous)Terbutaline sulfate (subcutaneous

or intravenous)

1520 yr Albuterol metered-dose inhalerAlbuterol and ipratropium bromide by nebulizerTheophyllineSalmeterol xinafoate inhalerFluticasone propionate metered-dose inhalerMontelukast sodium tabletsPrednisone (560 mg daily)

Epinephrine (subcutaneous or in-travenous)

DexamethasoneTerbutaline (subcutaneous or intra-

venous)Magnesium sulfate (intravenous)


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case records of the massachusetts general hospital


suggestive of pneumonia. Ceftriaxone was pre-scribed and admission to the hospital was recom-mended, but she left against medical advice to carefor her child. One week later, she saw her primarycare physician, who prescribed levofloxacin. Threedays later, she was seen at an urgent care facilitybecause of persistent symptoms. At that time, she

was taking prednisone (30 mg) daily and albuterolas needed. Prednisone (30 mg) was administeredorally, and a combination of albuterol and ipratro-pium was given by nebulizer. She was instructedto take prednisone (60 mg) daily, tapering to afinal dose of 10 mg every other day. A follow-upvisit and an appointment with a pulmonary spe-cialist were scheduled, but the patient did not keepthe appointments.

During the next weeks, the patient visited emer-gency departments four or five times because ofacute symptoms of asthma, and she made numer-

ous phone calls to her primary care physician, re-questing refills of her medications. The physicianbecame aware that the patient was receiving asth-ma medications from several different providers.

In the early hours of the morning of admission,the patients mother noted that the patient wasawake and using a nebulizer, as she did frequently.When her mother next saw her, approximately2 hours later, the patient was lying on the floor,unresponsive, without spontaneous respirationsor pulse. The patients mother called emergencymedical services (EMS).

On examination by EMS providers, the patientwas cold, cyanotic, and in asystole. The tracheawas intubated, and cardiopulmonary resuscitationwas initiated. Epinephrine (1 mg) and atropine(1 mg) were administered intravenously; this wasrepeated twice without response. The patient wastaken to the emergency room of another hospital,arriving 25 minutes later while cardiopulmonaryresuscitation was in progress. She remained inasystolic cardiac arrest, despite aggressive resus-citation attempts. She was pronounced dead 10

minutes after arrival. The body was transferred tothis hospital, and an autopsy was performed.

Differential Diagnosis

Dr. Michael E. Wechsler: May we review the imagingstudies?

Dr. Jo-Anne O. Shepard: Chest radiographs (Fig. 1Aand 1B) obtained 17 months before her death, onone of the patients multiple visits for asthma ex-acerbations, show pneumomediastinum, with air

tracking into the neck. On the lateral view (Fig. 1B)there is a tiny anterior pneumothorax. The pneu-

mothorax results from the Macklin effect, inwhich a peripheral alveolus ruptures and the airtracks centrally along the interstitium into themediastinum and soft tissues. These features aretypical of asthma. Bilateral focal consolidationsare present, representing pneumonia.

Dr. Wechsler: This case highlights the problemof asthma-associated morbidity and mortality,with more than 4000 deaths from asthma occur-ring annually in the United States.1 This patientsmultiple hospitalizations and emergency roomvisits exemplify the annual 500,000 asthma-relatedhospitalizations and 2 million emergency roomvisits that account for $16 billion per year spentfor asthma treatment2 and the millions of asthma-related lost work and school days. This patientdropped out of school because of the hold thatasthma had on her life.

There are many possible causes of death in apatient with asthma in whom respiratory failuredevelops. Patients with corticosteroid-inducedchronic immunosuppression are predisposed tolife-threatening infections, anaphylaxis, and acute

hypersensitivity reactions; however, this patient didnot have a history or laboratory evidence to suggestany of these diagnoses, nor did she have any un-derlying cardiac disease. She did not have a historyof eosinophilia or other major clinical manifes-tations of eosinophilic pneumonia or the ChurgStrauss syndrome. She had nearly all the risk fac-tors for life-threatening asthma and death fromasthma (Table 3), except for aspirin sensitivity andolder age. Although not a consistent cigarettesmoker, she had some history of smoking and

Table 2. Results of Pulmonary-Function Tests.*

Measure Age

7 Yr 11 Yr 18 Yr

actual value (% of predicted value)

FVC (liters) Normal 2.79 (125)

FEV1 (liters) Normal 2.00 (100) 2.49 (96)FEF25 of FVC (liters/sec) 3.29 (73)

FEF75 of FVC (liters/sec) (44) 0.62 (46)

FEF2575 of FVC (liters/sec) 1.45 (56) 1.71 (58)

* FVC denotes forced vital capacity in liters, FEV1forced expiratory volume inthe first second, FEF25 maximum forced expiratory flow rate when 25% of theFVC has been exhaled, FEF75 maximum forced expiratory flow rate when 75%of the FVC has been exhaled, and FEF2575 maximum forced expiratory flowrate between 25% and 75% of the FVC exhaled.


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exposure to secondhand smoke both in utero andduring childhood. She had not required mechani-cal ventilation, but she had been hospitalized manytimes. Therefore, I believe that this patient hadstatus asthmaticus with resultant fatal asthma.

Why did this patient die from asthma? Theanswer may lie with the treatment plan, the com-pliance of the patient with the plan, and the inher-ent severity of her disease (so severe that no mea-sure taken could have saved her). Each of thesefactors must be addressed in this case.

Discussion of Management

To address growing concern about increased asth-ma-related morbidity and mortality, in the late1990s the National Institutes of Health (NIH) for-mulated the National Asthma Education and Pre-vention Program, establishing guidelines for themanagement of asthma.3 The NIH recommendedstratification of patients according to the severityof asthma (mild intermittent, mild persistent, mod-erate persistent, and severe persistent disease) andimplementation of treatment algorithms. At differ-ent times, this patients condition fell into the cat-

egories of both moderate and severe persistentdisease. Whereas all patients with asthma shouldavoid or control factors that trigger attacks, patientswith persistent asthma should also use controllermedication daily to control airway inf lammation(e.g., inhaled corticosteroids) and, as the severityincreases, escalate therapy appropriately. Asthmaguidelines from 2006 focus on maintenance ofcontrol, reflecting an understanding that asthmaseverity involves not only the severity of the un-derlying disease but also its responsiveness to treat-ment, and that severity is not an unvarying fea-ture of an individual patients asthma but maychange over months or years.4

Inhaled corticosteroids, which had been in-cluded in this patients regimen early in her care,are the cornerstone of these recommendations.There is evidence that inhaled corticosteroids notonly improve lung function and symptoms but alsomay prevent deaths from asthma.5 Short-actingbeta-agonists may be used in the short term torelieve symptoms; however, if there is poor asth-ma control despite the use of inhaled corticoste-roids, as in this case, other controller therapies,such as long-acting beta-agonists, leukotriene

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l

A B

Figure 1. Radiographic Images.

Posterior anterior (Panel A) and lateral (Panel B) chest radiographs obtained 17 months before the patients deathshow pneumomediastinum (Panel A, large arrows) and an anterior pneumothorax (Panel B, large arrow). Bilateral

focal consolidations (Panels A and B, small arrows) are consistent with pneumonia.


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modifiers, cromolyn, theophylline, or even sys-temic corticosteroids should be added to the regi-men. All these medications were prescribed atvarious times for this patient, but not on a con-sistent basis. When the disease is controlled, thedoses or number of controller medications may bereduced. This patients asthma rarely, if ever, ap-

peared to be sufficiently controlled to allow thetapering of medications.

Patient education is essential at every step ofasthma management, and patients should con-tinue to monitor their disease subjectively (i.e.,assessing symptoms) and objectively (using peak-flow meters or spirometry). Although such ap-proaches were attempted in this case, they wereunsuccessful.

Managing Severe Asthma

Both the patient and the physician have responsi-

bilities in the management of severe asthma. How-ever, a major problem in the control of asthma isthat much of the responsibility lies with the pa-tient.

Adherence to Controller Therapy and Appropriate

Technique

Even if a medication is shown to be effective inideal circumstances, as in a clinical trial, its effec-tiveness in practice requires adherence to a pre-scribed regimen; for medication to be effective,patients must take it regularly as it is meant to betaken. Like this patient, nearly 70% of patients withsevere asthma do not refill prescriptions for in-haled corticosteroids,6,7 and many use inhalers in-correctly. Poor adherence to asthma medicationsmay be due to lack of an immediate benefit, thepatients preference for pills rather than inhalers,suboptimal results because the patients techniqueof use is suboptimal, cost, inconvenience, and lackof education by health care providers. Many pa-tients, like this one, are children or adolescentswho may have problems accepting the facts of their

illness and the necessity for adhering to an oner-ous treatment regimen. The cost of the medica-tions may be an issue, since asthma is increasinglyprevalent among economically disadvantaged, in-ner-city children for whom access to medicationsis often a difficulty. Physicians clearly worked withthis patient to maximize adherence and to explainthe importance of taking medications daily.

Adverse effects of medications can also lead topoor adherence. For example, inhaled corticoste-roids can cause dysphonia, oral thrush, osteoporo-

sis, cataracts, glaucoma, and adrenal suppression.

None of these complications were apparent inthis case.

Consistent Physician Care

Consistency of health care providers was a problemin this case, because no single physician could ap-preciate the full scope of this patients multiplepresentations for worsening asthma. During thelast 5 years of her life, she saw many different pri-mary care doctors, pulmonologists, and allergists.She went to different clinics and emergency roomsmany times, each time seeing different physicians.This fragmentation of care could have resulted ina missed opportunity for one physician to detecther clinical deterioration during a period of weeksor months and to provide support.

Education and Warning Signs

Education of patients about triggers and warningsigns of severe attacks is critical to the manage-ment of severe asthma. This patient knew whatprovoked her asthma (e.g., cold air and hot, humidair), and she avoided going outside in winter. We

do not know whether she had a peak-flow meterwith which to assess the degree of airflow obstruc-tion or whether she was aware of the severity of herdisease. There was no record of allergy testing.

Other Medical Options

This patients physicians had tried virtually allavailable therapies to control her disease (Table 1),including new treatments such as leukotriene-receptor antagonists. Novel therapies are now avail-able that might have helped control this patients

Table 3. Risk Factors for Life-Threatening Asthma and Death from Asthma.

Long duration of asthma

Poor control of asthma

Systemic dependence on corticosteroids

Noncompliance with medication regimen

Psychosocial factorsPoor socioeconomic conditions

Inconsistent medical follow-up

Delayed medical care

Older age

Cigarette smoking

Aspirin sensitivity

Prior hospitalization for asthma

Prior use of mechanical ventilation


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asthma. For instance, omalizumab, a monoclonalantibody against IgE, prevents IgE from bindingto mast cells and other inflammatory cells, therebypreventing the release of inflammatory mediators.Its use may permit a lower dose of corticosteroidsand may reduce the frequency of exacerbations,which, in turn, could reduce the number of outpa-

tient and emergency room visits and hospitaliza-tions among patients with moderate-to-severe asth-ma.8,9 Tumor-necrosis-factor (TNF) inhibitors havealso been investigated in asthma. TNF is a proin-flammatory cytokine affecting adhesion, migra-tion, activation, and proliferation of many types ofcells. It is increased in the bronchoalveolar-lavagefluid of patients with asthma, and preliminary datasuggest that TNF inhibitors may significantly im-prove lung function and symptoms in patients withsevere asthma.10

Factors Contributing to Poor Outcomes

Despite Optimal Medication Regimens

Several factors can result in poor outcomes despiteoptimized medication regimens. Exposure to en-vironmental exacerbating factors such as dust,smoke, or cockroaches may impair responsivenessto specific therapies. Caregivers made attempts tomodify the home environment of this patient whenshe was a child, but they were unsuccessful. Wedo not know whether the issue of environmentalfactors had been raised with the patient during re-cent years or whether she would have been morecompliant as a young adult than her mother hadbeen during the patients childhood.

Coexisting diseases can also impair asthmaoutcomes despite optimal medication regimens.This patient had evidence of gastroesophagealreflux disease, a condition that may provoke orworsen symptoms of asthma. She used a proton-pump inhibitor, but it would have been importantto ascertain that the ref lux was adequately con-trolled and was not contributing to asthma exac-erbations. Chronic sinusitis and postnasal drip

may also exacerbate asthma. This patient had ahistory of multiple episodes of pneumonia, whichresulted in the exacerbation of symptoms, and in-fection certainly could have contributed to her re-spiratory failure and death.

Some conditions mimic severe asthma. Thispatients fleeting pulmonary infiltrates and air-flow obstruction could suggest diagnoses such ascystic fibrosis, allergic bronchopulmonary asper-gillosis, bronchocentric granulomatosis, or theChurgStrauss syndrome. She had no history of

eosinophilia or vasculitis, which are characteristicof the last three disorders. Although IgE levels maybe elevated in these conditions, IgE testing was notperformed.

Pharmacogenetics and the Efficacy

of Asthma Therapies

This patient may be one of the many patients whoseasthma is unresponsive to current standard ther-apies. As many as 40% of patients do not have aresponse to inhaled corticosteroids,11-13 and per-haps even a higher proportion do not have a re-sponse to leukotriene modifiers. Heterogeneity ofthe underlying biology may affect responsivenessto specific therapies. Symptoms may be driven byperturbations in corticosteroid, leukotriene, IgE, orbeta-adrenergic pathways or even in other pathwaysyet to be identified; each of these pathways may bemodulated by different medications, so therapies

should ideally be tailored to the underlying patho-genesis. Similarly, asthma may be mediated by eo-sinophils or, in the case of severe asthma, by neu-trophils. TNF may have a role, and natural killercells may be principal effector cells.14 Since it iscurrently not possible to identify the specific path-way involved in a given patients asthma, we pre-scribe on the basis of trial and error an approachthat, as this case shows, is not always successful.

Pharmacogenetics, the study of how geneticdifferences influence variability in therapeutic andadverse responses to drugs, may predict some ofthe heterogeneity of responses to asthma treat-ments. A mutation in a specific pathway may causeor prevent a response to a medication aimed at thatpathway or cause an adverse reaction. In asthma,genetic factors may affect responses to beta-ago-nists, leukotriene modifiers, and inhaled cortico-steroids.15 In particular, a common variant in thegene coding for the 16th amino acid of the beta-adrenergic receptor is associated with a decline inlung function and asthma exacerbations in pa-tients receiving either short- or long-acting beta-

agonists.16-19

Among patients with asthma, thispolymorphism occurs in one sixth of white pa-tients and up to one quarter of black patients.

Although genetic testing is not routinely avail-able, caregivers should be aware of the potentialgenotype-specific effects of long-acting beta-ago-nists and their potential association with badoutcomes, including death, in patients with asth-ma.20 Although these therapies are helpful for themajority of patients with asthma, those taking thelong-acting beta-agonists salmeterol or formoterol


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have an increased risk of both exacerbations andasthma-related death, as compared with those notreceiving these medications.21 Although we do nothave any genotypic information for this patient,we know she took salmeterol, and a pharmacoge-netically mediated deleterious effect of this long-acting beta-agonist could have played a role in her

deteriorating condition and death. A large, pro-spective, genotype-stratified trial investigatingwhether long-acting beta-agonists cause such ad-verse effects, which is currently being conductedby the Asthma Clinical Research Network of theNIH, may answer this question.

Use of Biomarkers in Asthma Control

This patient had a normal forced expiratory vol-ume in 1 second, but she clearly had severe asth-ma, as shown by the long duration and frequencyof her symptoms, frequent use of quick-relief in-

halers, and missed work and school. An importantarea of asthma research is the use of biomarkersto assess airway inf lammation and guide therapyfor patients with asthma. Adjustment of asthmamedications on the basis of assessment of sputumeosinophils, exhaled nitric oxide, and airway hy-perreactivity can reduce asthma exacerbations22-25and also potentially minimize treatment-relatedside effects.

DR. MICHAEL E. WECHSLERS

DIAGNOSIS

Fatal asthma.

Pathological Discussion

Dr. Eugene J. Mark: The diagnosis of fatal asthmafalls within the purview of both the hospital pa-thologist and the forensic pathologist, the latterbecause of the possibility that asthma may explainsudden unexpected death. Factors for the forensicpathologist to consider in determining whether

asthma was the cause of sudden, unwitnesseddeath include a history of severe attacks, the exis-tence and location of therapeutic drugs and inhal-ers that could have been used by the patient, andgross and microscopical evidence of acute andchronic asthma. At autopsy, the common differen-tial diagnosis of the cause of death includes as-phyxia from other causes, anaphylactic reaction,coexistent pulmonary emboli, and coronary arterydisease.

In this case, the autopsy findings were charac-

teristic of fatal asthma.26-31 The gross pathologicalfeatures of fatal asthma may be more dramaticthan the microscopical findings. Pneumothoraxmay occur as a complication of the disease and isa potential cause of death; its documentation atautopsy requires opening the chest under a waterseal. No pneumothorax was found in this patient.

The lungs were hyperinflated, with rounded con-tours when removed from the body (Fig. 2A). Ex-

l

A

C

B

D

E

Figure 2. Autopsy Findings.

The right lung is hyperinflated in this gross photograph taken before the

lung was removed from the body (Panel A); a depressed polygonal lobule(arrow) contrasts with the hyperinflated adjacent lung. Mediastinal emphy-

sema is present (Panel B), with bubbles of air in the pericardial fat (arrows).

A small bronchus is filled with mucus and sloughed epithelial cells (PanelC, hematoxylin and eosin). A terminal bronchiole (Panel D, hematoxylin

and eosin) contains hypertrophic smooth muscle (arrow). Numerous eosin-ophils are present in the pulmonary interstitium (Panel E, hematoxylin and

eosin). (Photographs in Panels A and B courtesy of Dr. Pavan Auluck, De-partment of Pathology, Massachusetts General Hospital.)


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amination of a cut section showed that the pa-renchyma protruded above the cut edge of thevisceral pleura. When left lying on a dissect ingtable, the lungs deflated only slowly. In some casesit may be difficult to inflate the lungs with forma-lin through the bronchial tree because of bron-chiolar obstruction, which was the case with this

patients lungs. Pneumomediastinum was present,with interstitial emphysema in fibroadipose tissue(Fig. 2B). Mucus plugs in bronchi are a frequentfinding; the mucus may protrude from the cut endof a bronchus.

Microscopically, bronchi and bronchioles weredistended by mucus (Fig. 2C), and lymphocytes,neutrophils, and mast cells were present in thebronchiolar mucosa. The bronchial basement mem-brane was thickened, and airway smooth-musclehypertrophy caused bronchiolar narrowing or sub-total occlusion (Fig. 2D).32 Signs of chronic scar-

ring, resulting in constrictive bronchiolitis, werepresent, with small focal scars representing oblit-erated bronchioles. Eosinophils are an inconsis-tent finding in fatal asthma33,34; they may bepresent in the bronchial lumen, in alveoli, or inthe pulmonary interstitium, as in this case (Fig.2E).35,36 There were no pulmonary emboli, and

the remainder of the autopsy disclosed no evidenceof coronary artery disease or other abnormalities.

A Physician: The patients mother noted that thepatient was using a nebulizer shortly before shedied. Could that have contributed to her death?

Dr. Wechsler: Frequent use of albuterol was un-likely to have caused her death unless there was

an underlying cardiac abnormality. The frequentuse of nebulized beta-agonists was an indicator ofthe poor control of her asthma, which ultimatelycaused her death. We attempted a postmortemanalysis of tissue from this patient for evidenceof the deleterious mutation in the beta-adrener-gic receptor, but we were unable to extract DNAof suff icient quality.

Anatomical Diagnosis

Status asthmaticus with hyperinflated lungs, pleu-

ral and pericardial interstitial emphysema, mucusplugging, bronchiolar scarring, and eosinophilicpneumonitis.

Dr. Wechsler reports receiving consulting fees or advisory-board fees from Genentech, Merck, Pfizer, Tanox, and CriticalTherapeutics and lecture fees from Novartis, Genentech, andMerck, and serving as an investigator in a trial of a bronchialthermoplasty system sponsored by Asthmatx. No other potentialconflict of interest relevant to this article was reported.

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Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or referencematerial is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of theimages from the CPC, not only those published in theJournal. Radiographic, neurologic, and cardiac studies, gross specimens,and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of theCase Record.

The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the currentsubscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected].

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