FIG 4. Activation of interconnected neurites by FceRI stimulation of a single

neuronal cell body. A, Bright field image of neuron network showing rela-

tion of Ag-containing spritzer to neuronal cell body sensitized with IgE

anti-DNP. B, At time 0, beginning of 500-millisecond spritz with Ag (DNP-

HSA). Shown are 0.5 seconds (C) and 1.8 seconds after onset of spritz (D).

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760 LETTERS TO THE EDITOR

along the nerve fiber in sensitized (2/2) but not in nonsensitizedmice (0/3). Repeated spritzes of nonconjugated HSA at this con-centration elicited no responses (0/2; data not shown). To excludepossible mast cell involvement in the transmission of these robustsignals, we conducted similar experiments in mast cell–deficientW/Wv mice and in their wild type control WBB6F1. In W/Wv mice(3/3), detectable intracellular calcium increases were observed onAg challenge (Fig 5, A-C). No calcium signal was seen when thesame ganglion was first challenged with HSA alone (Fig 5, D-F).The wild-type littermates (WBB6F1) responded positively (3/3)on challenge with specific Ag (Fig 5, G-I) but gave no responseto HSA alone. These findings confirm that the observed signaltransmission by FceRI was not likely caused by mast cells anddemonstrate the in vivo presence of functional FceRI on jejunalneurons, because sham sensitization in vivo before an ex vivo chal-lenge yielded no response to Ag challenge.

FIG 5. Myenteric ganglion calcium imaging. Spritzer (internal bore, 40 mm)

is indicated by dotted lines and myenteric plexus by solid lines. A-C, Anti-

DNP IgE sensitized myenteric neurons were imaged in mast cell–deficient

W/Wv mice. A, Resting condition. B, Fluorescent image captured 0.16 sec-

onds after 20-millisecond spritz. C, Four seconds after spritz. D-F, No in-

crease in calcium fluorescence was observed in non-haptenated HSA

spritz. G-I, Positive calcium increases in WBB6F1 control littermates. Time

sequence same as previous.

It is well known that sensory nerves may participate inhypersensitivity reactions, a process known as neurogenic in-flammation, and several lines of evidence support the notionthat sensory nerves may play an important role in cutaneous,lung, gastrointestinal, and joint inflammatory diseases. Herewe now demonstrate that functionally active FceRI is expressedon SCG and myenteric plexus neurons. The discovery of func-tional Fce and Fcg receptors on nerves clearly shows that thisbiological compartment is able to respond to the direct stimulusof antibody-antigen interactions. Our findings define an inde-pendent neuronal (non–mast cell/non-basophil) compartmentwith probable involvement in allergic and possibly otherdiseases.

Hanneke van der Kleij, PhDa

Nicolas Charles, PhDb

Khalil Karimi, PhDa

Yu-Kang Mao, MDa

Jane Foster, PhDa

Luke Janssen, PhDa

Ping Chang Yang, MDa

Wolfgang Kunze, PhDa

Juan Rivera, PhDb

John Bienenstock, MDa

From athe Brain-Body Institute, St Joseph’s Healthcare, Hamilton and Department of

Pathology and Molecular Medicine, McMaster University, Ontario, Canada; andbthe Laboratory of Immune Cell Signaling, National Institute of Arthritis and Muscu-

loskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md. E-mail:

bienens@mcmaster.ca.

The work performed in this study was supported by a grant from the McMaster Brain-

Body Institute, St Joseph’s Healthcare, Hamilton. The work of N.C. and J.R. was

supported by the intramural research program of NIAMS, NIH.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Andoh T, Kuraishi Y. Expression of Fc epsilon receptor I on primary sensory neu-

rons in mice. Neuroreport 2004;15:2029-31.

2. Andoh T, Kuraishi Y. Direct action of immunoglobulin G on primary sensory neu-

rons through Fc gamma receptor I. FASEB J 2004;18:182-4.

3. Rijnierse A, Kroese AB, Redegeld FA, Blokhuis BR, van der Heijden MW, Koster AS,

et al. Immunoglobulin-free light chains mediate antigen-specific responses of murine

dorsal root ganglion neurons. J Neuroimmunol 2009;208:80-6.

4. Furuno T, Ma D, van der Kleij HP, Nakanishi M, Bienenstock J. Bone marrow-

derived mast cells in mice respond in co-culture to scorpion venom activation of su-

perior cervical ganglion neurites according to level of expression of NK-1 receptors.

Neurosci Lett 2004;372:185-9.

5. Bieber T. Fc epsilon RI on antigen-presenting cells. Curr Opin Immunol 1996;8:

773-7.

6. Lin S, Cicala C, Scharenberg AM, Kinet JP. The Fc(epsilon)RIbeta subunit func-

tions as an amplifier of Fc(epsilon)RIgamma-mediated cell activation signals. Cell

1996;85:985-95.

7. Hirano M, Davis RS, Fine WD, Nakamura S, Shimizu K, Yagi H, et al. IgEb im-

mune complexes activate macrophages through FcgammaRIV binding. Nat Immu-

nol 2007;8:762-71.

8. Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with

distinct IgG subclass specificity. Immunity 2005;23:41-51.

9. Mao Y, Wang B, Kunze W. Characterization of myenteric sensory neurons in the

mouse small intestine. J Neurophysiol 2006;96:998-1010.

Available online February 4, 2010.

doi:10.1016/j.jaci.2009.10.054

Ethnic differences in asthma–panic disordercomorbidity

To the Editor:Adults with asthma are at substantially higher risk for panic

disorder (PD) than individuals without asthma.1 There is evidencethat asthma and PD may interact with each other and produce

TABLE I. Participants’ characteristics

Characteristic Mean 6 SD (%)

Age (y) 44.6 6 15.8

Sex (% female) 67.8

Education (y) 11.8 6 2.9

Recruitment site (%)

Emergency department 54.5

Asthma clinic 45.5

Race/ethnicity (%)

Puerto Rican (n 5 142) 47.2

African American (n 5

75)

24.9

White/non-Latino (n 5

22)

7.3

Dominican (n 5 19) 6.3

Afro-Caribbean (n 5

20)

6.6

Other Latino (n 5 15) 5.0

Other (n 5 8) 2.7

Asthma severity� (%)

Mild (n 5 57) 22.3

Moderate/severe (n 5

199)

77.7

�Only 8 participants were rated as severe persistent, and thus, this category

predominantly represents patients with asthma with moderate persistent severity.FIG 1. Rates of panic disorder 6SEM in Puerto Rican and African American

participants with asthma.

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LETTERS TO THE EDITOR 761

greater morbidity for each disease.1,2 Respiratory-related symp-toms, such as dyspnea, chest tightness, and sensations of smoth-ering are common in both disorders. The overlap in symptomsmay lead an individual to mistake a panic attack as an asthma at-tack. This confusion may trigger a maladaptive cycle of usingshort-acting b2-agonists to treat respiratory anxiety symptoms,mistaken as asthma, and thus further increasing feared bodilysensations and panic.3

The study of ethnic differences may help identify patients whoare at greater risk for the deleterious effects of asthma-PDcomorbidity, and may aid the development of culturally relevantinterventions. Puerto Rican adults may be at greater risk fordeveloping PD,4 and non-Latino black adults may be at lower riskfor PD than other racial/ethnic groups.5 Puerto Ricans also havethe highest asthma prevalence rates, followed by non-Latinoblack, non-Latino white, and Mexican Americans.6 The primaryaim of the present study was to examine ethnic differences inasthma-PD comorbidity in a primarily Puerto Rican andAfrican American sample.

Consecutive patients with asthma were recruited from anasthma clinic and the emergency department of an inner-cityhospital in the Bronx, NY. English-speaking and Spanish-speak-ing adults 18 years or older were eligible for participation if theyself-reported an asthma diagnosis. A pulmonary physician whowas blind to diagnosis of PD later conducted a chart review ofparticipants to confirm asthma diagnosis, rate asthma severity,and exclude participants with conditions that could be confusedwith asthma.

Clinical psychology graduate students administered the PDsection of the Primary Care Evaluation of Mental Disorders PatientHealth Questionnaire. This brief psychiatric interview was con-ducted in the clinics immediately after recruitment in either Englishor Spanish, according to the participant’s preference. Both theEnglish and Spanish versions of the Patient Health Questionnaire

have high sensitivity and specificity for diagnosis of PD and goodconstruct validity.7,8 The Primary Care Evaluation of Mental Disor-ders Patient Health Questionnaire uses diagnostic algorithms basedon the Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition. Graduate students were trained using guidelines3

to supplement the psychiatric interview with additional questionsto tease apart asthma attacks and anxiety specifically related toasthma versus full PD criteria. A licensed clinical psychologist pro-vided supervision for all interviews. Participants self-reported theirprimary ethnicity, age, highest level of education completed, andthe number of days of rescue inhaler use during the past week.

Logistic regression models were used to examine between-group differences on diagnosis of PD and use of rescue inhalers,which was split into daily versus not daily use. Given thedistribution of severity ratings, we created a dichotomous variableof intermittent-mild persistent (mild) versus moderate-severepersistent. Comparisons between English and Spanish-speakingparticipants only focused on Puerto Rican and Dominicanparticipants.

A total of 318 patients with asthma (range, 18-89 years)were approached for participation, and 306 (96.2% completionrate) patients agreed to participate. Five participants wereexcluded because of chronic obstructive pulmonary disease,which yielded a final sample of 301 participants (see Table Ifor demographics). Interviews were conducted in Spanish for13.6% of participants. No differences were found between PuertoRican and African American participants on asthma severity oremergency department recruitment. Thirty percent of partici-pants reported experiencing a panic attack during the pastweek, and 16.6% met criteria for PD. Patients with PD were older(51.1 6 12.0 years) than patients without PD (43.3 6 16.2 years;P 5 .001). Patients with PD were more likely to have moderate-severe than mild asthma (odds ratio [OR], 2.00; 95% CI, 1.09-3.67). This finding was not significant after controlling for age

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762 LETTERS TO THE EDITOR

and sex (OR, 1.79; 95% CI, 0.96-3.34). Educational level, sex,and recruitment site were not associated with PD.

Fig 1 shows that Puerto Rican patients with asthma (21.1%;n 5 30 of 142) were more likely to have PD than African Amer-ican patients with asthma (6.7%; n 5 5 of 75; OR, 3.75; 95% CI,1.39-10.12; P < .01). This effect size was even larger after con-trolling for age, sex, and asthma severity (OR, 8.35; 95% CI,1.89-37.00; P < .01). Spanish-speaking Puerto Rican and Domin-ican patients had even higher rates of PD (40%) than English-speaking Puerto Rican and Dominican patients (15.9%; OR,3.53; 95% CI, 1.54-8.09; P <. 01). This finding remained signif-icant after controlling for age and sex. Patients with asthma andPD were more likely to report daily use of quick-relief medication(69.4%) versus patients with asthma without PD (48.2%; OR,2.45; 95% CI, 1.14-5.25; P < .05). This finding did not changeafter controlling for age and sex.

The high rate of PD in Puerto Rican patients may be related tothe culture-bound syndrome of ataques de nervios (nervousattacks), which is an emotional reaction to a stressful event thatincludes multiple behavioral and physical symptoms, and feelingout of control. There is some overlap between PD and ataques denervios.9 The common experience of ataques de nervios in PuertoRican culture may lead to anxiety attacks in response to the stressof asthma attacks. Asthma may produce threatening bodily sensa-tions and feelings of being out of control, and then lead to thedevelopment of chronic anxiety among susceptible individuals.The very high rate of PD in Spanish-speaking patients suggeststhat lower levels of acculturation may be a risk factor forasthma-PD comorbidity. Language barriers with providers mayprevent detection and treatment of PD.

The findings from the current study have clinical implications forasthma management. The high level of daily rescue inhaler useamong patients with PD may reflect poor asthma control orconfusion between panic and asthma symptoms. It may be bene-ficial for patients with asthma and PD to use a peak flow meter tohelp differentiate between asthma and panic symptoms. This studyis limited by the use of a convenience sample of treatment-seekingpatients, and community-based studies are needed. The currentstudy also used a brief psychiatric interview to assess PD and did notassess other psychiatric disorders or ataques de nervios.

In conclusion, it is important for medical providers to be awareof the high rates of PD that may exist in Puerto Rican patients withasthma. Multidisciplinary approaches are needed to devise cul-turally relevant interventions to reduce asthma and PD morbidity.

Jonathan M. Feldman, PhDa,b

Lauren Mayefsky, MAa

Lacey Beckmann, BSa

Paul M. Lehrer, PhDc

Denise Serebrisky, MDd

Chang Shim, MDe

From athe Ferkauf Graduate School of Psychology/Yeshiva University, Bronx; bthe

Department of Epidemiology and Population Health, Albert Einstein College of Med-

icine, Bronx, NY; cthe Department of Psychiatry, UMDNJ—Robert Wood Johnson

Medical School, Piscataway, NJ; and dthe Department of Pediatrics and ethe Depart-

ment of Medicine/Division of Pulmonary Medicine, Albert Einstein College of Med-

icine/Jacobi Medical Center, Bronx, NY. E-mail: jonathan.feldman@einstein.yu.edu.

Disclosure of potential conflict of interest: P. M. Lehrer receives research support from

the NIH. The rest of the authors have declared that they have no conflict of interest.

REFERENCES

1. Hasler G, Gergen PJ, Kleinbaum DG, Ajdacic V, Gamma A, Eich D, et al. Asthma

and panic in young adults: a 20-year prospective community study. Am J Respir Crit

Care Med 2005;171:1224-30.

2. Feldman JM, Lehrer PM, Borson S, Hallstrand TS, Siddique MI. Health care use and

quality of life among patients with asthma and panic disorder. J Asthma 2005;42:

179-84.

3. Feldman JM, Giardino ND, Lehrer PM. Asthma and panic disorder. In: Mostofsky

DI, Barlow DH, editors. The management of stress and anxiety in medical disorders.

Needham Heights (MA): Allyn & Bacon; 2000. p. 220-39.

4. Alegria M, Canino G, Stinson FS, Grant BF. Nativity and DSM-IV psychiatric dis-

orders among Puerto Ricans, Cuban Americans, and non-Latino Whites in the

United States: results from the National Epidemiologic Survey on Alcohol and

Related Conditions. J Clin Psychiatry 2006;67:56-65.

5. Breslau J, Aguilar-Gaxiola S, Kendler KS, Su M, Williams D, Kessler RC. Specify-

ing race-ethnic differences in risk for psychiatric disorder in a USA national sample.

Psychol Med 2006;36:57-68.

6. Rose D, Mannino DM, Leaderer BP. Asthma prevalence among US adults,

1998-2000: role of Puerto Rican ethnicity and behavioral and geographic factors.

Am J Public Health 2006;96:880-8.

7. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version

of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental

Disorders. Patient Health Questionnaire. JAMA 1999;282:1737-44.

8. Diez-Quevedo C, Rangil T, Sanchez-Planell L, Kroenke K, Spitzer RL. Validation

and utility of the patient health questionnaire in diagnosing mental disorders in

1003 general hospital Spanish inpatients. Psychosom Med 2001;63:679-86.

9. Lewis-Fernandez R, Guarnaccia PJ, Martinez IE, Salman E, Schmidt A, Liebowitz

M. Comparative phenomenology of ataques de nervios, panic attacks, and panic

disorder. Cult Med Psychiatry 2002;26:199-223.

Available online February 4, 2010.

doi:10.1016/j.jaci.2009.11.002

Serum ferritin and transferrin levels are notserologic markers of toluene diisocyanate–induced occupational asthma

To the Editor:In a recent article, Hur et al1 reported that by using a proteo-

mic approach, ferritin expression was downregulated whereastransferrin expression was upregulated in bronchoalveolarlavage fluid in subjects with methylene diphenyl diisocya-nate–induced occupational asthma (MDI-OA) or eosinophilicbronchitis compared with exposed asymptomatic controlworkers (AECs) to methylene diphenyl diisocyanate (MDI).The authors also measured these compounds by ELISA usingsera from the MDI-OA/eosinophilic bronchitis and AECgroups. The results showed that serum ferritin and transferrincan be serologic markers in diagnosing MDI-OA. To identifysubjects with MDI-OA, the optimal serum cut-off levels were69.84 ng/mL for ferritin and 2.48 mg/mL for transferrin.When these 2 parameters were combined, the sensitivity was71.43%, and the specificity was 85.71%. These authors specu-late that some susceptible subjects with defects in iron metab-olism and lower serum ferritin levels may develop MDI-OAafter MDI exposure, whereas some subjects with lower serumtransferrin levels may be resistant to MDI exposure. The au-thors then argue that ferritin might act defensively againstMDI, and some subjects with an impaired ferritin level maybe more susceptible to MDI-OA than those who have a normaliron metabolism and are exposed to MDI.

This study was performed to confirm whether these serologicmarkers are associated with the phenotype of toluene diisocya-nate occupational asthma (TDI-OA) and may therefore be used asserologic markers for the diagnosis of TDI-OA.

We enrolled in this study 17 subjects with TDI-OA, a mean age6 SD of 37.2 6 11.6 years, and a median exposure to diisocya-nates of 72 (range, 10-432) months; 12 asymptomatic exposedcontrols (AECs) with a mean age of 42.6 6 14 years and a median