0
Selected Reports |

Asthma Associated With Incontinentia Pigmenti and Fanconi AnemiaAsthma Without Cellular Inflammation: Variable Airflow Limitation Without Cellular Bronchitis FREE TO VIEW

Angira Dasgupta, MD; May S. Sanaee, MD; Carla M. T. Bauer, PhD; Fernando M. Botelho, PhD; Donald M. Arnold, MD; Martin R. Stampfli, PhD; Parameswaran Nair, MD, PhD, FCCP
Author and Funding Information

From the Divisions of Respirology (Drs Dasgupta, Sanaee, Stampfli, and Nair) and Hematology (Dr Arnold), Department of Medicine; and McMaster Immunology Research Centre Department of Pathology and Molecular Medicine (Drs Bauer, Botelho, and Stampfli), McMaster University, Hamilton, ON, Canada.

Correspondence to: Parameswaran Nair, MD, PhD, FCCP, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, 50 Charlton Ave E, Hamilton, ON, L8N 4A6, Canada; e-mail: parames@mcmaster.ca


Funding/Support: Dr Nair is supported by a Canada Research Chair in Airway Inflammometry. Dr Stampfli is supported by an operating grant from the Canadian Institutes of Health Research. Dr Arnold is supported by a New Investigator Award from the Canadian Institutes of Health Research in partnership with F. Hoffmann-La Roche Ltd.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(3):856-858. doi:10.1378/chest.12-0859
Text Size: A A A
Published online

Airway inflammation is considered a central component of asthma and, therefore, international guidelines recommend antiinflammatory medications. We describe the clinical history of a 34-year-old woman with airway hyperresponsiveness and asthma who had a reduced ability to mount an inflammatory response due to two unrelated and rare genetic conditions: Fanconi anemia and incontinentia pigmenti. Absence of eosinophils in blood and sputum led to a successful reduction in the dose of corticosteroids without loss of asthma control demonstrating the clinical utility of monitoring treatment using biomarkers and the importance of recognizing the components of airway diseases that contribute to symptoms.

Asthma is characterized by variable airflow limitation, airway inflammation, and airway hyperresponsiveness (AHR). Although less commonly encountered in clinical practice, AHR and variable airflow limitation in asthma may occur dissociated from airway inflammation. We present a rare association of Fanconi anemia and incontinentia pigmenti with asthma, characterized by AHR without cellular airway inflammation. This is the first case, to our knowledge, of an association of two rare, unrelated genetic conditions with asthma.

A 34-year-old woman with Fanconi anemia and incontinentia pigmenti was seen for a reassessment of asthma, postnasal drip, and cough that were being treated with prednisone, budesonide, and formoterol and montelukast. She had clinical allergies to cat and grass pollen (confirmed on skin-prick testing, but normal total serum IgE) and had never smoked. She had asthma from childhood with symptoms of episodic wheezing, cough, and breathlessness on exertion that were quickly relieved by short-acting bronchodilators, and she had been under the care of two respirologists who had confirmed variable airflow obstruction by demonstrating significant diurnal peak flow variability of >20% over a 2-week observation period. She had a history of several hospitalizations due to febrile neutropenia and recurrent infections, and, therefore, had been started on regular injections of filgrastim, a granulocyte colony-stimulating factor (G-CSF) analog. Recently, she had been diagnosed with oropharyngeal cancer that was treated by local excision. An autofluorescence bronchoscopic evaluation did not show any evidence of in situ cancer of the airway epithelium.

Her physical examination was noncontributory except for the phenotypic findings of her genetic abnormalities such as short stature, facial dysmorphism, dental anomalies, bilateral thenar hypoplasia with distally set and abnormal thumbs, one café au lait spot beneath her right breast, and a halo nevus on her back in the lower left flank. The diagnosis of Fanconi anemia was reconfirmed by identifying chromosomal breakage in response to mitomycin C.1 The genomic rearrangement abnormality of incontinentia pigmenti was confirmed by nuclear factor-κB (NF-κB) essential modulator (NEMO) gene mutation analysis.2 Spirometry showed mild airflow obstruction, and her provocative concentration of methacholine causing a 20% drop in FEV1, measured by the tidal breathing method,3 was 2.08 mg/mL, indicating mild AHR. Exacerbations that were often triggered by chest infections were characterized by increased wheezing, chest tightness, occasionally fever, and decreases in FEV1. In the past, these episodes had been treated by increasing the dose of inhaled corticosteroids and additional bronchodilators and prednisone whenever the FEV1 dropped to below 20% of her baseline measurement. She had also been prescribed antibiotics (macrolides and quinolones) on a number of these occasions.

Multiple attempts to obtain sputum, when her asthma was stable, during an exacerbation and after G-CSF therapy, by hypertonic saline induction4 were unsuccessful, which in our clinical experience of 20 years suggested that she did not have a cellular bronchitis.5 Eosinophil-free granules were also consistently absent in sputum (Table 1). Noneosinophilic exacerbations are common6 and not usually steroid responsive.7 Cough was attributed to her postnasal drip and recurrent respiratory infections with consequent mild parenchymal scarring of the upper lobes confirmed on a high-resolution CT scan of the thorax. Eosinophils were consistently absent in blood, which is an indicator that systemic steroids are probably not necessary to control symptoms in airway diseases.8 Based on all these observations, prednisone, inhaled steroid, and montelukast were tapered and eventually discontinued. Salbutamol as required and formoterol 12 μg bid were recommended for her hyperresponsiveness. She has not had an asthma exacerbation that required prednisone in the past 2 years, confirming that corticosteroid probably was previously unnecessary and perhaps was contributing to her recurrent airway infections and consequent exacerbations that were likely noneosinophilic.

Table Graphic Jump Location
Table 1 —Serial Clinical and Sputum Characteristics

FVC and FEV1 are shown in Liters. Bud = budesonide; Form = formoterol; PC20 = provocative concentration of methacholine causing a 20% drop in FEV1; prn = as required (pro re nata); VC = vital capacity.

Asthma occurring in a patient with a genetic impairment in cellular immunity offers a unique opportunity to study and treat AHR independent of airway inflammation. This patient with asthma had two rare genetic disorders that are associated with an inability to mount an inflammatory response. This report also highlights the utility of monitoring cell counts in sputum and in blood to establish appropriate therapy for asthma.

Fanconi anemia is a rare, inherited hematologic disorder that leads to bone marrow failure.1 Patients have pancytopenia and are prone to recurrent infections. In the present patient, neutropenia was treated with a G-CSF analog, which resulted in an increase in peripheral blood neutrophil counts and a decrease in hospitalizations. However, there were no demonstrable cells in sputum and very low cellularity in bronchial wash, implicating a persistent absence of cellular luminal airway inflammation. Since the patient did not consent for a bronchial mucosal biopsy, it was not possible to compare luminal cells with mucosal inflammatory cell infiltration.

Incontinentia pigmenti is an x-linked genodermatosis associated with skin pigmentation, abnormalities of teeth, skeletal system, eyes, CNS, and immunodeficiency. In women, this disorder has a highly variable presentation. A mutation in the NF-κB essential modulator gene has been identified in 70% to 80% of patients with this disease and was confirmed in the patient. This results in a total or partial loss of NF-κB activity2 which, in turn, is partially responsible for the immune dysfunction. We tested this in the patient. The p65 unit in peripheral blood mononuclear cells translocated easily to the nucleus when stimulated by tumor necrosis factor-α. Integrity of lymphocytes was demonstrated by an exaggerated interferon-γ production when stimulated with phorbal myristate acetate/ionomycin from both CD4 and CD8 T cells. The proportion of major histocompatibility complex class 2 (CD11chiHLA-DR+) cells were, however, reduced (2% of all mononuclear cells) compared with a control experiment (12%).

We speculate that AHR is independently regulated from the eosinophilic and neutrophilic inflammatory response in this patient. Although there was no luminal inflammation, we cannot absolutely rule out tissue inflammation, particularly mononuclear cells. AHR may be mediated by an interaction between T lymphocytes and airway smooth muscle cells or inherent NF-κB activity in muscle or epithelial cells.9 The exaggerated interferon-γ activity probably indicates that the recurrent viral and bacterial infections, as opposed to allergic stimulus, contributed to the observed NF-κB activity in the patient. This is not unexpected given her two associated immunodeficient conditions.

In summary, this case history illustrates the dissociation between AHR and cellular bronchitis, and the importance of recognizing the various components of airway diseases that contribute to symptoms.10 Quantitative cell counts in sputum help to identify the minimum dose of antiinflammatory treatment needed to maintain asthma control. Presently, we do not have any therapeutic strategies specifically to improve AHR.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Nair is listed on a patent for a “sputum filtration device” and has acted as a scientific advisor for a University spin-off company “Cellometrics Inc.” He has received grant support for investigator-initiated studies from GlaxoSmithKline Canada. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

AHR

airway hyperresponsiveness

G-CSF

granulocyte colony-stimulating factor

NF-κB

nuclear factor-κB

German J, Schonberg S, Caskie S, Warburton D, Falk C, Ray JH. A test for Fanconi’s anemia. Blood. 1987;69(6):1637-1641. [PubMed]
 
Smahi A, Courtois G, Vabres P, et al The International Incontinentia Pigmenti (IP) Consortium Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. Nature. 2000;405(6785):466-472. [CrossRef] [PubMed]
 
Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7(3):235-243. [CrossRef] [PubMed]
 
Pizzichini E, Pizzichini MM, Efthimiadis A, Hargreave FE, Dolovich J. Measurement of inflammatory indices in induced sputum: effects of selection of sputum to minimize salivary contamination. Eur Respir J. 1996;9(6):1174-1180. [CrossRef] [PubMed]
 
D’silva L, Hassan N, Wang HY, et al. Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice. Can Respir J. 2011;18(3):144-148. [PubMed]
 
McGrath KW, Icitovic N, Boushey HA, et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612-619. [CrossRef] [PubMed]
 
Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid unresponsive asthma. Lancet. 1999;353(9171):2213-2214. [CrossRef] [PubMed]
 
Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo controlled trial. Am J Respir Crit Care Med. 2012;186(1):48-55. [CrossRef] [PubMed]
 
Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med. 1998;158(5 pt 1):1585-1592. [PubMed]
 
Hargreave FE, Parameswaran K. Asthma, COPD and bronchitis are just components of airway disease. Eur Respir J. 2006;28(2):264-267. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Serial Clinical and Sputum Characteristics

FVC and FEV1 are shown in Liters. Bud = budesonide; Form = formoterol; PC20 = provocative concentration of methacholine causing a 20% drop in FEV1; prn = as required (pro re nata); VC = vital capacity.

References

German J, Schonberg S, Caskie S, Warburton D, Falk C, Ray JH. A test for Fanconi’s anemia. Blood. 1987;69(6):1637-1641. [PubMed]
 
Smahi A, Courtois G, Vabres P, et al The International Incontinentia Pigmenti (IP) Consortium Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. Nature. 2000;405(6785):466-472. [CrossRef] [PubMed]
 
Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7(3):235-243. [CrossRef] [PubMed]
 
Pizzichini E, Pizzichini MM, Efthimiadis A, Hargreave FE, Dolovich J. Measurement of inflammatory indices in induced sputum: effects of selection of sputum to minimize salivary contamination. Eur Respir J. 1996;9(6):1174-1180. [CrossRef] [PubMed]
 
D’silva L, Hassan N, Wang HY, et al. Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice. Can Respir J. 2011;18(3):144-148. [PubMed]
 
McGrath KW, Icitovic N, Boushey HA, et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612-619. [CrossRef] [PubMed]
 
Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid unresponsive asthma. Lancet. 1999;353(9171):2213-2214. [CrossRef] [PubMed]
 
Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo controlled trial. Am J Respir Crit Care Med. 2012;186(1):48-55. [CrossRef] [PubMed]
 
Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med. 1998;158(5 pt 1):1585-1592. [PubMed]
 
Hargreave FE, Parameswaran K. Asthma, COPD and bronchitis are just components of airway disease. Eur Respir J. 2006;28(2):264-267. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
CHEST Collections
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543