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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 368;12 nejm.org march 21, 2013 1141

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

Case 9-2013: A 9-Year-Old Boy with Fever,Cough, Respiratory Distress, and Chest Pain

Mary Shannon Fracchia, M.D., Chadi M. El Saleeby, M.D.,Mandakolathur R. Murali, M.D., Pallavi Sagar, M.D., and Mari Mino-Kenudson, M.D.

From the Departments of Pediatrics(M.S.F., C.M.E.S.), Medicine (M.R.M.),Radiology (P.S.), and Pathology (M.M.-K.),Massachusetts General Hospital, andthe Departments of Pediatrics (M.S.F.,C.M.E.S.), Medicine (M.R.M.), Radiology(P.S.), and Pathology (M.M.-K.), HarvardMedical School both in Boston.

N Engl J Med 2013;368:1141-50.

DOI: 10.1056/NEJMcpc1208144

Copyright 2013 Massachusetts Medical Society.

PRESENTATION OF CASE

Dr. Sarita U. Patil (Allergy and Immunology): A 9-year-old boy was admitted to thishospital because of fever, cough, respiratory distress, and chest pain.

The patient had been well until 8 days before admission, when cough, red andwatery eyes, and a temperature of 37.2C developed. Two days later, on a winterholiday, he vomited and did not want to open his presents. The temperature rose to38.9C, and he became increasingly lethargic. The next day, he saw his pediatrician.On examination, the temperature was reportedly 39.4C, the right periorbital re-gion and cheek were erythematous, and a cervical lymph node on the left side wasenlarged. A rapid screening test for streptococcal pharyngitis was negative; sup-portive care was advised, and the patient returned home.

The next day, 4 days before admission, shortness of breath and tachypnea devel-oped. The patient was seen in the emergency department at another hospital, wherea chest radiograph was reportedly normal. A diagnosis of acute otitis media wasmade, and a 5-day course of azithromycin was prescribed. During the next 3 days,cough and occasional vomiting persisted. On the morning of admission, he returnedto his pediatrician. The patient and his family reported that he had worseningcough, midsternal chest pain with deep inspiration, and weight loss of 1.8 kg in1 week. On examination, the temperature was 40.3C, and he appeared to be inrespiratory distress. Acetaminophen was administered, and he was sent to thishospital.

The patients family reported decreased cervical lymphadenopathy in the patient

as compared with earlier in the week; however, cough and shortness of breath hadworsened. He did not have diarrhea, jaundice, rash, tongue or lip swelling, orabdominal or joint pain.

The patient had been delivered by cesarean section because of failure to pro-gress after 42 weeks of uncomplicated gestation; umbilical-cord separation oc-curred in a normal time frame. Between the ages of 6 and 9 years, he had had fiveepisodes of streptococcal pharyngitis, three episodes of otitis media, and fourepisodes of cellulitis (most recently, caused by methicillin-resistant Staphylococcusaureus, sensitive to trimethoprimsulfamethoxazole). One year earlier, he had beenevaluated in the pulmonary clinic at this hospital because of a cough of 3 monthsduration, which occurred during the day but not during sleep. At that time, the

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n engl j med 368;12 nejm.org march 21, 20131142

physical examination was normal. T-cell subsetswere normal; other test results are shown inTable 1. Specific IgE antibodies to environmen-tal allergens were not detected by immunoassays.Antibody titers to the 23-valent pneumococcalpolysaccharide vaccine were not at protectivelevels. Pneumococcal vaccine was administered,

with improvement in the antibody titers to pro-

tective levels. Spirometry was normal. Nasalfluticasone was administered for 1 month, with-out improvement, but the cough gradually re-solved spontaneously.

The patient had attention deficithyperactivi-ty disorder, had had molluscum contagiosum inthe past, and approximately 5 years earlier, had

lymphopenia that had resolved spontaneously,

Table 1. Laboratory Data.*

VariableReference Range,

Age-Adjusted1 Yr beforeAdmission

OnAdmission

2ndHospital Day

3rdHospital Day

Hematocrit (%) 35.045.0 36.9 37.2 30.3 28.2

Hemoglobin (g/dl) 11.515.5 13.1 12.6 10.1 9.2

White-cell count (per mm3) 450013,500 3700 18,000 13,100 13,300

Differential count (%)

Neutrophils 3359 42 92 92 93

Lymphocytes 3350 49 4 3 3

Monocytes 411 7 3 3 2

Eosinophils 08 1 1 2 2

Basophils 03 1

Erythrocyte sedimentation rate (mm/hr) 011 46 53 57

Protein (g/dl)

Total 6.08.3 6.8 5.8 5.7

Albumin 3.35.0 3.2 2.6 2.7

Globulin 2.64.1 3.6 3.2 3.0

Bilirubin (mg/dl)

Total 0.01.0 2.3 1.6 1.3Direct 0.00.4 1.2 0.7 0.8

Phosphorus (mg/dl) 4.55.5 3.3 2.4 3.3

Alkaline phosphatase (U/liter) 15350 458 344 350

Aspartate aminotransferase (U/liter) 1040 69 51 45

Alanine aminotransferase (U/liter) 1055 91 72 64

C-reactive protein (mg/liter)

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case records of the massachusetts general hospital


with no clinical sequelae. He did not have a his-tory of failure to thrive, night sweats, recurrentlower respiratory tract disease, or severe or un-usual infections. Medications on admission in-cluded ibuprofen, acetaminophen, and azithro-mycin. Immunizations, including the influenzaA (H1N1) vaccine, were current, but he had notreceived the seasonal influenza vaccine. He hadno known allergies.

The patient lived with his parents, a sibling,two dogs (one with a newly diagnosed round-worm infection), a cat (less than 1 year of age),and a snake. His home was heated with forcedhot water, and his parents had recently noted

mold in the basement. The home had recentlybeen sprayed with permethrin for eradication oflice. Moles had been seen in the backyard wherethe patient played. He had been exposed to rela-tives with pneumonia 1 month earlier. He hadnot traveled internationally or to the midwesternor southwestern United States. His father workedin construction, smoked in the home, and hadrecurrent skin abscesses. The patients motherand sister were carriers of cystic fibrosis, a ma-

ternal aunt had environmental allergies, and apaternal aunt had rheumatoid arthritis. His par-ents were of western European ancestry, with nohistory of consanguinity.

On examination, the patient was alert andoriented. He appeared ill. The temperature was38.6C, the blood pressure 110/64 mm Hg, thepulse 109 beats per minute, the respiratory rate30 breaths per minute, and the oxygen satura-tion 95% while he was breathing ambient air.The weight was 32.3 kg. Conjunctival injectionwith edema (chemosis), mild erythema of theright upper cheek and the left tympanic mem-brane, dry mucous membranes, and a mildly

enlarged and mobile nontender anterior cervicallymph node were present, and the trachea wasmidline. There was no nasal flaring or supra-sternal retraction on inspiration, there weremild intercostal and subcostal retractions, andthe abdomen protruded on inspiration. Air entrywas good (with poor inspiratory effort becauseof chest pain), and there were coarse breathsounds, without crackles or wheezes; the re-mainder of the examination was normal.

Table 1. (Continued.)

VariableReference Range,

Age-Adjusted1 Yr beforeAdmission

OnAdmission

2ndHospital Day

3rdHospital Day

Serum protein electrophoresis Normal pattern

Complement

Total (U/ml) 63145 169

C3 (mg/dl) 93202 143

C4 (mg/dl) 1351 30

Blood gases

Specimen Venous Venous Arterial

Inspired oxygen (liter/min by nasal cannula) 1 1 1

Partial pressure of oxygen (mm/Hg) 3550 (venous), 80100(arterial)

74 47 109

Partial pressure of carbon dioxide (mm/Hg) 3850 (venous), 3542(arterial)

43 35 29

pH 7.307.40 (venous),7.357.45 (arterial)

7.38 7.44 7.48

Base excess (mmol/liter) 1.0 0.5 2.0

Bicarbonate (mmol/liter) 2430 24 23 21

* To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for phosphorus to millimoles per liter,multiply by 0.3229. To convert the values for IgE to micrograms per liter, multiply by 2.40.

Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used atMassachusetts General Hospital are age-adjusted and are for patients who are not pregnant and do not have medical conditions that couldaffect the results. They may therefore not be appropriate for all patients.




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The platelet count and blood levels of electro-lytes, calcium, magnesium, glucose, total protein,globulin, amylase, and lipase were normal, aswere the results of renal-function tests; other testresults are shown in Table 1. Rapid screening ofa nasal swab for influenza viruses A and B, para-influenza, adenovirus, and respiratory syncytial

virus was negative, as was testing for inf luenzaA (seasonal and H1N1) nucleic acid. Urinalysisrevealed clear amber fluid with 2+ albumin, 1+urobilinogen, and 2+ bilirubin; 3 to 5 red cells,5 to 10 white cells, and many bacteria per high-power field; 3 to 5 hyaline casts per low-powerfield; and mucin. An electrocardiogram revealedsinus tachycardia and nonspecific T-wave changesin the inferior leads. A chest radiograph showedhilar lymphadenopathy and multiple nodularopacities throughout both lungs, more promi-nent in the middle and lower zones. Normal

saline (a total of 1500 ml) was infused in threeboluses. Cultures of the blood and urine wereobtained and remained sterile. Vancomycin wasadministered intravenously.

The patient was admitted to the pediatric in-tensive care unit, and the administration of mer-openem (intravenously) and azithromycin andtrimethoprimsulfamethoxazole (orally) was add-ed. Ten hours after presentation, computed to-mography (CT) of the chest, performed after theadministration of intravenous contrast material,revealed multifocal ill-defined nodular opacitiesthroughout all lung lobes, superimposed areas ofconsolidation, scattered ground-glass opacities,and mediastinal and hilar lymphadenopathy.

On the second day, ultrasonography of theabdomen revealed a small pleural effusion onthe right side and was otherwise normal. Ultra-sound examination of the neck showed bilateralcervical lymphadenopathy, more prominent onthe right side; there was no evidence of deepvenous thrombosis in the neck. During the sec-ond night, while the patient was sleeping, oxy-

gen saturation decreased to 58%, with cyanosison examination; saturation improved with arous-al and rose to 93 to 95% with the administrationof oxygen (1 liter per minute by nasal cannula).The maximal temperature was 38.4C. A chestradiograph was unchanged. A skin test for tu-berculosis was negative at 48 hours. Other testresults were pending.

On the third day, a diagnostic test was per-formed.

DIFFERENTIAL DIAGNOSIS

Dr. MaryShannon Fracchia: All the discussants areaware of the diagnosis in this case. Dr. Sagar,may we see the imaging studies?

Dr. Pallavi Sagar: The chest radiograph (Fig. 1)shows multiple nodular and fluffy opacities dis-

tributed throughout the lungs. The hilar promi-nence is suggestive of lymphadenopathy. A CTscan obtained after the administration of intra-venous contrast material (Fig. 2) shows multifo-cal patchy nodular opacities bilaterally, withoutinternal cavitations. There are areas of more focalconsolidation with adjacent ground-glass opaci-ties. There is both hilar and mediastinal lymph-adenopathy. There is no pleural effusion, pneu-mothorax, pulmonary cysts, or areas of airtrapping. In this clinical context, the findingssuggest infectious causes, including multifocal

pneumonia or septic emboli. Noninfectious con-siderations include pulmonary edema, vasculitiswith pulmonary hemorrhage, and metastatic dis-ease; however, these are less likely in this clini-cal context.

Dr. Fracchia: This child was acutely ill with arespiratory process. Infectious diseases wereprimary considerations, and Dr. El Saleeby willdiscuss the differential diagnosis from the in-fectious diseases perspective.

Differential Diagnosis of Infectious Diseases

Dr. Chadi M. El Saleeby: The diagnosis of pediatricpneumonias is best approached by a multifacto-rial evaluation, which involves the characteristicsof the host (e.g., age and immune status), poten-tial exposures including epidemiologic consider-ations, and the radiographic appearance of thepulmonary process.

The panoply of microbes associated withcommunity-acquired pediatric pneumonias isclosely related to the age of the patient, which isnot the case in adults.1 Viruses are most com-

mon in infants and young children, but in thispatients age group, atypical bacteria predomi-nate. Pneumococcal pneumonia is a possibility,despite the patients immunization; one studyshowed the incidence of uncomplicated infec-tion to be essentially unaffected by vaccinationin the group 5 to 17 years of age.2 Primary oracquired immunologic impairments are gener-ally associated with specific microorganisms,depending on which component of the immune




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system is affected. A detailed immunologic in-vestigation of this patient was not available tous at the time of presentation, but the relativerarity of primary immunodeficiencies arguesagainst them in this case, as do the absence ofrecurrent, persistent, or serious infections; sino-pulmonary disease; failure to thrive; and a sug-gestive family history. The patients history oflymphopenia might indicate infection with the

human immunodeficiency virus, but the lym-phopenia had resolved spontaneously and he hasno history of opportunistic infections.

We also considered the endemic mycoses(histoplasmosis, coccidioidomycosis, and blasto-mycosis), which may have a nodular appearance

on radiographs and can affect persons regard-less of their immune status. However, this pa-tient had not traveled to areas where thesepathogens are endemic, and person-to-persontransmission does not occur. The family had ayoung cat; exposure to kittens is a risk factor forinfection with Bartonella henselae, the causativeagent of cat scratch disease. Pneumonia due toB. henselae is exceedingly rare. It is usually pre-ceded by regional lymphadenopathy draining the

A

B

Figure 1. Chest Radiographs.

The frontal (Panel A) and lateral (Panel B) chest radio-graphs show multiple nodular opacities throughout

both lungs and hilar prominence, features suggestiveof hilar lymphadenopathy.

A

B

Figure 2. CT Images of the Chest.

CT images of the chest viewed in lung windows (Panel A)

and soft-tissue windows (Panel B) after the administra-

tion of intravenous contrast material show multifocalpatchy nodular opacities and areas of consolidationthroughout all lung lobes, with mediastinal and hilar

lymphadenopathy (arrow).




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site of the scratch and is commonly associatedwith extrapulmonary manifestations,3 whichwere not documented in this patient. Exposureto a contaminated water supply may cause le-gionellosis, but clinically significant disease israre in immunocompetent children.4 This pa-tient had no known risk factors for tuberculo-

sis, and a tuberculin skin test was negative at48 hours.

Cognizance of the time of year at presenta-tion is also important, since many respiratorypathogens, particularly viruses, show a predict-able epidemiology.5 A nasal swab for rapidscreening for influenza virus, parainfluenza vi-rus, adenovirus, and respiratory syncytial virusantigens was negative in this case, as was test-ing for influenza A (seasonal and H1N1) virusnucleic acid.

Finally, the radiographic appearance of the

pulmonary process can narrow the differentialdiagnosis. Nodular infiltrates indicate endobron-chial and bronchiolar spread of infection, whichis commonly seen in bacterial pneumonias, es-pecially those associated with aspiration, respi-ratory viruses, tuberculous and nontuberculousmycobacteria, endemic mycoses, Pneumocystis jir-ovecii pneumonia, aspergillosis, and nocardiosis.Angioinvasive aspergillosis is seen exclusively inimmunocompromised hosts. Although nocardi-osis is uncommon in children, it can occur inpersons with a competent immune system, man-ifesting as a subacute respiratory illness. It re-quires no specific exposures and may causenodular infiltrates on imaging. Septic embolimay also be nodular in appearance. In this case,multiple blood cultures and echocardiography toevaluate for infectious endocarditis were nega-tive. An ultrasound examination of the neckshowed no evidence of deep venous thrombosis,ruling out Lemierres syndrome.

Most puzzling illnesses are atypical presenta-tions of common diseases. After initial evaluation

of the patient, our leading diagnoses were aninfection with an atypical bacteria, a viral infec-tion (recognizing the limitations of diagnosticmethods for the upper airways), or a bacterialsuperinfection of a viral pneumonia. Less likelypossibilities included abscesses or septic emboli,perhaps from an endovascular focus, or infec-tion with nocardia species. The administrationof broad-spectrum antimicrobial agents to coverthese potential pathogens was begun. We ad-

vised the primary care team to consider nonin-fectious causes. Pediatric pulmonary consultationwas requested.

Differential Diagnosis from the Pulmonary

Medicine Perspective

Dr. Fracchia: What aspects of this patients presen-

tation are of importance to a pediatric pulmon-ologist? Cough, weight loss, and fever were clini-cally significant, as was tachypnea. A normalrespiratory rate for a 9-year-old boy is similar tothe adult rate of approximately 15 breaths perminute, whereas this patients rate was doublethat. The chest pain on inspiration was also aconcern. Why was he having pleuritic chest pain?Two layers of pleura are separated by a thin layerof fluid to prevent friction during breathing. Whenthe pleura is inflamed or irritated, the fluid isadsorbed, resulting in pain with inspiration. The

differential diagnosis of pleuritic chest pain in-cludes infection, emboli, malignant tumors, andautoimmune inf lammatory processes.

Emboli

Tachypnea, tachycardia, and chest pain would beconsistent with embolic disease, as are the radio-graphic findings. Septic emboli from Lemierressyndrome were considered in light of the cervicallymphadenopathy, but cervical ultrasonographydid not reveal thrombi. Pulmonary emboli froma deep venous thrombosis or fat emboli were lesslikely in view of the absence of trauma, immobil-ity, and a coagulation disorder and in view of theconstitutional symptoms.

Malignant tumors

Lung tumors in children are typically metastasesfrom a primary tumor outside the lung, and wehad not found evidence of a primary tumor inthis patient. The weight loss and radiographicfindings were consistent with cancer, but thepatients presentation was more dramatic and

acute than is typical for cancers. Langerhans-cellhistiocytosis of the lungs can be associated withdyspnea, tachypnea, and weight loss, as seen inthis patient, as well as pulmonary nodules andlymphadenopathy, which were seen on imaging.Pulmonary Langerhans-cell histiocytosis istypically seen in adults with a history of smok-ing, whereas bone and pituitary lesions are morecommon in Langerhans-cell histiocytosis inchildren.6




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Autoimmune and inflammatory processes

After infection, autoimmune and inflammatoryprocesses were at the top of my differential diag-nosis. Patients with vasculitides, particularly theChurgStrauss syndrome and granulomatosis withpolyangiitis (formerly known as Wegeners gran-ulomatosis), may have clinical features that are

similar to those of this patient, and nodules andlymphadenopathy may be apparent on imaging.Patients with ChurgStrauss syndrome, however,typically have wheezing and eosinophilia.7 Thispatient had neither the upper-airway involvementnor the renal involvement typically seen in gran-ulomatosis with polyangiitis. Another consider-ation was sarcoidosis; in patients who are between10 and 40 years of age, it tends to manifest asbilateral infiltrates and hilar lymphadenopathy,as seen in this patient. Children with sarcoidosis,however, are usually asymptomatic or present

with eye or skin findings.8 Aspiration pneumoni-tis was unlikely, since the patient was neurologi-cally intact and did not have a history of ref lux orchoking on liquids. We also considered hyper-sensitivity pneumonitis, but the patient had notbeen exposed to birds or farm animals.

Cystic fibrosis

As a pediatric pulmonologist, I always considercystic fibrosis in a child with lung disease. Thepatients mother and sister were carriers of themost common mutated form of the cystic fibrosistransmembrane conductance regulator (CFTR)gene, F508-CFTR. Although the patients fatherwas negative for this mutation, it is still possiblethat he was a carrier of 1 of the 1800 mutationsnot tested for on the basic genetic panel, so thatthis patient could have inherited the F508-CFTRmutation from his mother and another mutationfrom his father. However, his newborn screeningtest was negative, and cystic fibrosis tends not topresent in such an acute manner. A sweat test wasnegative, which made cystic fibrosis unlikely.

A bronchoscopy was initially deferred, becausethe patient was becoming hypoxemic, and I wasconcerned about impending respiratory failure.A hypersensitivity panel was sent for analysis.Dr. Murali will discuss the case from an immu-nologic perspective.

Hypersensitivity pneumonitis

Dr. Mandakolathur R. Murali: Hypersensitivity pneu-monitis (also known as extrinsic allergic alveoli-

tis) is a noninfectious, immune, inflammatoryinterstitial lung disease with a broad clinicalspectrum that must be in the differential diagno-sis in this case. Many infectious and other causesof pulmonary infiltrates in this case appear tohave been ruled out. Because of the heterogeneityof hypersensitivity pneumonitis and the lack of asingle diagnostic test, many diagnostic criteriahave been proposed for the disease. Schuyler andCormier developed criteria that integrate the var-ious aspects of the disease9; the presence of anyfour major criteria and at least two minor criteriaestablishes a definitive diagnosis of hypersensi-tivity pneumonitis (Table 2). This patient hassymptoms and radiographic findings compatiblewith this diagnosis, including hypoxemia.

The detection of precipitin antibodies in the

serum (on the hypersensitivity panel) is a usefulnoninvasive diagnostic test.10 Examination ofthe gel (see Fig. 1 in the Supplementary Appen-dix, available with the full text of this article atNEJM.org) reveals that this patient has precipi-tins to both Aspergillus fumigatus and A. f lavus.This suggests that he has circulating antibodiesthat can form immune complexes in the alveoliand interstitium when the fungal antigens arepresent in the alveoli. The ensuing antigenanti-

Table 2. Diagnostic Criteria for Hypersensitivity Pneumonitis.*

Major criteria

A history of symptoms compatible with hypersensitivity pneumonitis (e.g.,weight loss, cough, breathlessness, febrile episodes, and fatigue)

Evidence of exposure to the offending antigen in patients history or throughdetection of precipitins (IgG and IgM antibodies) in serum or bronchoal-

veolar-lavage fluidRadiographic changes consistent with hypersensitivity pneumonitis (fleeting,

micronodular, and interstitial infiltrates, in the middle and lower lung zones)

Lymphocytosis in bronchoalveolar-lavage fluid (CD4:CD8 T-cell ratio,

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body complexes are instrumental in initiatingthe vascular and cellular phase of inflammationresulting in the spectrum of hypersensitivitypneumonitis.11 The immune complexes lead tothe production of kinins,12,13 activation of theclassical complement cascade, and generation ofanaphylatoxins and chemotactic peptides, which

contribute to the vascular phase of inflamma-tion and recruit neutrophils and macrophages.Both CD4+ and CD8+ T cells contribute to theimmunopathogenesis of hypersensitivity pneu-monitis,14 with CD4+ cells and immune com-plexes predominating in acute forms of the dis-ease and CD8+ cells in subacute and chronicforms of the disease. Although neutrophils arethe predominant cells in bronchoalveolar lavagein the acute phase, CD8+ cells predominate inthe subacute and chronic phases of the disease.This is reflected in bronchoalveolar lavage by

lymphocytosis with an altered ratio of CD4+T cells to CD8+ T cells, which is a major diag-nostic criterion.9

It is important to know which of three recog-nized phases of hypersensitivity pneumonitisthe patient is in so that his response to therapyand overall prognosis can be predicted. The acutephase is an immune-complex alveolitis that ismanifested on chest imaging as a ground-glassinfiltrate; patients present with fever, chills,cough, and hypoxemia 4 to 48 hours after expo-sure to the antigen. The subacute phase is seenafter weeks or several months of exposure to theantigen and is characterized by peribronchiolarinflammation and granulomas; imaging revealsmicronodules and air trapping. The clinicalmanifestations are cough, dyspnea, and bibasi-lar rales. This patient has fever, cough, dyspnea,bibasilar rales, and hypoxemia, and both nodu-lar and ground-glass opacities are evident onimaging. Therefore, the clinical criteria for adiagnosis of an acute exacerbation of subacutehypersensitivity pneumonitis are met.

In patients with either acute or subacute hy-persensitivity pneumonitis, elimination of theantigen results in a good outcome. Persistentexposure to the antigen for months or years re-sults in the chronic phase, with progressivedyspnea, cough, fatigue, and weight loss, as wellas radiologic features of interstitial fibrosis,honeycombing, and emphysema. In patients inthe chronic phase, inflammation is less amena-ble to therapy and the prognosis is poor. In this

patient, bronchoscopy with bronchoalveolar la-vage was performed, as was transbronchial lungbiopsy, to confirm the diagnosis and determinethe phase of the disease.

CLINICAL DI AGNOSIS

Acute exacerbation of subacute hypersensitivitypneumonitis caused by exposure to AspergillusfumigatusandA. flavus.

PATHOLOGICAL DISCUSSION

Dr. Mari Mino-Kenudson: The transbronchial-biopsyspecimen from this patient shows bronchiolo-centric inflammation that obscures pulmonaryarteries and respiratory bronchioles (Fig. 3Athrough 3D). There are histiocytic aggregates inthe alveolar spaces, along with activated pneu-

mocytes and scattered lymphocytes and eosino-phils. In addition, a few multinucleated giantcells are present in the alveolar walls. Peripheralalveolar walls are well visualized, and there is nonotable fibrosis. This constellation of findings(bronchiolocentric inflammation, histiocytic col-lections, and giant cells without interstitial fibro-sis) is consistent with subacute hypersensitivitypneumonitis. The other possible diagnosis is as-piration pneumonitis, which can be ruled out onthe basis of the patients clinical course.

In this case, there is also prominent acute in-flammation consisting of scattered neutrophilsin the alveolar walls, which is not a feature ofsubacute hypersensitivity pneumonitis (Fig. 3E).The presence of an interstitial neutrophilic infil-trate in this context indicates acute exacerbationof hypersensitivity pneumonitis.15

Bronchoalveolar lavage revealed most of thecells to be granulocytes (including neutrophils),corresponding to the biopsy findings; the ratioof CD4+ T cells to CD8+ T cells was low, at 0.7.These findings, together with the results of se-

rologic testing, are consistent with acute exacer-bation of subacute hypersensitivity pneumonitiscaused by exposure to A. fumigatusand A. f lavus.

MANAGEMENT AND FOLLOW-UP

Dr. Sarita U. Patil (Allergy and Immunology): Westrongly suspected that the patients exposurewas in his home. During the patients hospital-ization, investigation of the residence by state of-




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ficials and a company specializing in indoor-mold remediation revealed that there was amalfunction of the venting system in the base-ment, with visible mold. The venting system mis-directed warm air into the patients room, result-ing in a warm and humid environment, and ahigh density of aspergillus was found in the pa-tients bedroom carpet.

As the first-line therapy for hypersensitivitypneumonitis is removal or minimization of an-tigen exposure, the patient was discharged to analternate residence, where he has continued toreside. Pharmacologic management of hypersen-sitivity pneumonitis with glucocorticoid therapy

is directed at the inf lammatory component of thedisease. Acute hypersensitivity pneumonitis canbe treated with a 2-to-4-week regimen of gluco-corticoids, whereas subacute to chronic casescan require weeks or months of treatment withvariable doses and responses. The use of steroid-sparing therapies (e.g., azathioprine and macro-lide antibiotics) has also been described.16,17

After a 3-month course of treatment withglucocorticoids, the patient regained normal

pulmonary function. He is an avid soccer playertoday and has had no further episodes of hyper-sensitivity pneumonitis.

A Physician: Since fungi such as aspergillus areubiquitous, do we know the risk factors and whythe disease develops in only a few persons?

Dr. Murali: Hypersensitivity pneumonitis, likemany immune disorders, is an outcome of envi-ronmental stimuli interacting with the humanhost genes. Most fungal spores are eliminatedby alveolar macrophages. Genetic predilection tohypersensitivity pneumonitis has been mapped topolymorphisms of tumor necrosis factor , thegenes that modulate the structure of HLA class I

(e.g., the TAP[transporter associated with antigenprocessing] genes), proteasome genes involvedin antigen processing, and polymorphisms ofthe tissue inhibitors of metalloproteinase.18,19

ANATOMICAL DI AGNOSIS

Hypersensitivity pneumonitis, subacute, with fea-tures suggestive of acute exacerbation, caused byAspergillus fumigatusandA. flavusexposure.

A B C

ED

Figure 3. Transbronchial-Biopsy Specimen (Hematoxylin and Eosin).

The transbronchial-biopsy specimen (Panel A) shows bronchiolocentric inflammation that obscures pulmonary arter-ies (arrow) and respiratory bronchioles with a lining of low-columnar epithelial cells (arrowheads). A view at high

magnification (Panel B) shows histiocytic aggregates in the alveolar spaces (encircled areas), along with activatedpneumocytes and scattered lymphocytes and eosinophils (arrows), resulting in a cellular appearance. A few multi-

nucleated giant cells (Panel C, arrows) are present in the alveolar walls. Peripheral alveolar walls are well visualized(Panel D, encircled area), and there is no notable fibrosis. There is also prominent acute inflammation consisting of

scattered neutrophils in the alveolar walls (Panel E, circles). This acute inflammation is not a feature of subacute hy-

persensitivity pneumonitis and therefore, in this context, indicates acute exacerbation of hypersensitivity pneumonitis.




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This case was discussed at the postgraduate course, PrimaryCare Pediatrics; course directors: Ronni L. Goldsmith, M.D., PeterT. Greenspan, M.D., Ronald E. Kleinman, M.D., Janice A. Lowe,M.D., and John Patrick T. Co, M.D., M.P.H., sponsored by theDepartment of Continuing Education, Harvard Medical School.

No potential conflict of interest relevant to this article was re-ported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

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].

References

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4. Greenberg D, Chiou CC, FamigilletiR, Lee TC, Yu V. Problem pathogens: pae-diatric legionellosis implications forimproved diagnosis. Lancet Infect Dis2006;6:529-35.5. Monto AS. Epidemiology of viral re-spiratory infections. Am J Med 2002;112:Suppl 6A:4S-12S.6. Sundar KM, Gosselin MV, Chung HL,Cahill BC. Pulmonary Langerhans cell his-tiocytosis: emerging concepts in pathobi-ology, radiology, and clinical evolution ofdisease. Chest 2003;123:1673-83.7. Sinico RA, Bottero P. Churg-Strauss

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ity pneumonitis. Eur Respir J 2007;29:706-12.11. Gell PGH, Coombs RRA, eds. Clinicalaspects of immunology. Oxford, UnitedKingdom: Blackwell, 1963.12. Kaplan AP, Ghebrehiwet B. The plas-ma bradykinin-forming pathways and itsinterrelationships with complement. MolImmunol 2010;47:2161-9.13. Tesfamariam B, DeFelice AF. Endo-thelial injury in the initiation and pro-gression of vascular disorders. VasculPharmacol 2007;46:229-37.14. Abdelsamed HA, Desai M, Nance SC,

Fitzpatrick EA. T-bet controls severity of

hypersensitivity pneumonitis. J Inflamm(Lond) 2011;8(1):15.15. Hariri LP, Mino-Kenudson M, Shea B,et al. Distinct histopathology of acute on-set or abrupt exacerbation of hypersensi-tivity pneumonitis. Hum Pathol 2012;43:660-8.16. Bogaert P, Tournoy KG, Naessens T,Grooten J. Where asthma and hypersensi-tivity pneumonitis meet and differ: non-eosinophilic severe asthma. Am J Pathol2009;174:3-13.17. Patel AM, Ryu JH, Reed CE. Hyper-sensitivity pneumonitis: current conceptsand future questions. J Allergy Clin Im-munol 2001;108:661-70.

18. Aquino-Galvez A, Camarena A, Mon-tao M, et al. Transporter associated withantigen processing (TAP) 1 gene poly-morphism in patients with hypersensitiv-ity pneumonitis. Exp Mol Pathol 2008;84:173-7.19. Schaaf BM, Seitzer U, Pravica V, AriesSP, Zabel P. Tumor necrosis factor- 308promoter gene polymorphism and in-creased tumor necrosis factor serum bio-activity in farmers lung patients. Am JRespir Crit Care Med 2001;163:379-82.Copyright 2013 Massachusetts Medical Society.



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