- Email: [email protected]
A 41-Year-Old Woman With Shortness of Breath and History of Rash and Recurrent Laryngeal Edema
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Pulmonary, Critical Care, and Sleep Pearls
]
A 41-Year-Old Woman With Shortness of Breath and History of Rash and Recurrent Laryngeal Edema Ali Ataya, MD; Ibrahim Faruqi, MD, MPH; and Juan C. Salgado, MD
A 41-year-old Hispanic woman with a 20 pack-year smoking history presented with worsening shortness of breath on exertion that gradually started 2 years ago, then significantly deteriorated over the last 4 months. She was diagnosed with COPD 2 months prior to her presentation and started on treatment with fluticasone propionate and albuterol. Her medical history was relevant for undifferentiated connective tissue disorder diagnosed 5 years prior due to a positive antinuclear antibody test, arthralgia, recurrent urticarial skin rash, peripheral neuropathy, abdominal pain, and diffuse body swelling. She was started on treatment with prednisone and azathioprine at the time and had substantial improvement in the occurrence of her urticaria. She also had a history of recurrent laryngeal edema of unclear etiology. She had no history of IV drug abuse, no exposure to animals, was not sexually active, and had no recent travel outside of Florida. There was no significant family history of lung diseases. CHEST 2015; 147(2):e44-e47
Physical Examination Findings On presentation, the patient was afebrile with a heart rate of 78 beats/min, BP of 132/92 mm Hg, and respiratory rate of 20 breaths/min and saturating 93% on 3 L oxygen. Her BMI was 22.6 kg/m2. Her physical examination was remarkable for decreased air entry bilaterally and expiratory wheezing in all lung fields. There was no evidence of clubbing, her heart rate was regular with no added sounds, and there was no evidence of any active skin lesions.
Diagnostic Studies Her CBC count and complete metabolic panel findings were normal except for a mild leukocytosis level of 14,000/mL. Her chest radiograph (Fig 1) and CT chest scan (Fig 2) are shown. Her erythrocyte sedimentation rate, C-reactive protein level, and autoimmune panel (antinuclear antibody [ANA], antineutrophil cytoplasmic antibody, double-stranded DNA [dsDNA],
Manuscript received May 16, 2014; revision accepted June 30, 2014. AFFILIATIONS: From the Division of Pulmonary and Critical Care Medicine, The University of Florida, Gainesville, FL. CORRESPONDENCE TO: Ali Ataya, MD, 1600 SW Archer Rd, Division of Pulmonary and Critical Care, The University of Florida, PO Box 100225, Gainesville, FL, 32608; e-mail: [email protected]
e44 Pulmonary, Critical Care, and Sleep Pearls
Figure 1 – Lung volumes are hyperexpanded with attenuation of vascular markings in both lungs. There is evidence of pleural thickening or scar in the right minor fissure.
antitopoisomerase, Sjögren antibodies, rheumatoid factor, cyclic citrullinated peptide, smooth muscle,
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1193 © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.
[
147#2 CHEST FEBRUARY 2015
]
Figure 2 – A, B, Hyperexpanded lungs with diffuse centrilobular emphysematous changes at the apices (A) that are more predominant and extensive at the bases (B).
ribonucleoprotein, and histidyl tRNA synthetase) results were all normal. She tested negative for hepatitis and HIV. C1 esterase-inhibitor level was normal. Her a1-antitrypsin genotype was normal. Her complement levels were low, with a C3 level of 42 mg/dL (normal, 90-180 mg/dL), C4 level of 9 mg/dL (normal, 15-46 mg/dL), and C1q level , 3.6 mg/dL (normal, 5.0-8.6 mg/dL). Pulmonary function tests (PFTs) showed a very severe obstructive pattern (FEV1, 29%) with significant reduction in diffusion capacity of lung for carbon monoxide (6% corrected for hemoglobin). Echocardiogram findings were unremarkable except for mildly elevated right ventricular systolic pressure (35-40 mm Hg).
What is the diagnosis?
journal.publications.chestnet.org
e45
Diagnosis: Hypocomplementemic urticarial vasculitis syndrome Discussion Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare immune-complex-mediated or type 3 hypersensitivity reaction that usually occurs in the third or fourth decade of life and predominately affects women in an 8:1 ratio. As the name suggests, the disease is characterized by low complement levels, urticarial skin lesions, and systemic multiorgan involvement. Angioedema may be the presenting symptoms in 50% of patients. Other organs involved include the joints, kidneys, GI tract, lungs, nervous system, eyes, and heart. Obstructive pulmonary disease with physiologic abnormalities on PFTs and basilar emphysematous radiologic changes occur in 50% of patients with HUVS. Most patients are already established smokers, but the degree of emphysema that occurs in this population is clearly out of proportion to the degree of tobacco abuse. The pulmonary findings are believed to occur as a result of vasculitis involvement of the lung, resulting in elastase release. Smoking plays a synergistic role through recruitment of neutrophils, thus accelerating the rate of lung damage. A panacinar emphysema with basilar hyperlucency, similar to a1-antitrypsin deficiency, occurs and it is the major cause of morbidity and mortality in this population. Other than emphysema, HUVS has been reported to involve the lungs in various other ways as well, such as asthma, chronic cough, dyspnea, pleuritis, pleural effusions, and tracheal stenosis. Once it occurs, the rate of decline in lung function can be quick and dramatic. HUVS is a clinical diagnosis based on the presence of urticaria and typical systemic features of the disease. Patients will have decreased levels of all complement lines and will also have a positive C1q precipitin antibody level. Almost 50% of patients will also test positive for ANA, with high titers in some cases. A skin biopsy specimen of the urticarial lesions will reveal an underlying leukocytoclastic vasculitis and direct immunofluorescence will show an immunoglobulin and complement deposition in a granular pattern at the dermal-epidermal junction with involvement of the vessels in the superficial dermis. HUVS can be misdiagnosed as systemic lupus erythematosis (SLE). Indeed, . 50% of patients do meet American e46 Pulmonary, Critical Care, and Sleep Pearls
College of Rheumatology criteria for SLE, but it is important to note that patients with HUVS will not be positive for dsDNA and emphysema is not a feature in SLE. Once diagnosed, patients are usually treated with steroids and even dapsone for the urticarial skin manifestations. In refractory cases, more potent immunosuppressant agents can be used, such as mycophenolate mofetil, methotrexate, azathioprine, and cyclosporine. There have also been reports of rituximab and anakinra being used with success. Patients with deteriorating pulmonary disease have also been successfully transplanted. Clinical Course
The constellation of symptoms, the degree of emphysema out of proportion to the tobacco abuse, and low complement levels led to the diagnosis of HUVS. Given that the patient was already on treatment that suppressed her urticarial, we were unable to obtain a skin biopsy specimen to demonstrate leukocytoclastic vasculitis. She was continued on the prednisone and azathioprine regimen, since it helped ameliorate her skin and systemic symptoms, and was referred to rheumatology. Given the severity of her obstructive lung disease, she was referred to the transplant team and is undergoing evaluation for lung transplantation at this time.
Clinical Pearls 1. HUVS is a rare type 3 hypersensitivity disorder characterized by urticaria, along with other systemic symptoms such as angioedema and arthralgia. 2. More than 50% of patients with HUVS may have obstructive lung disease seen on PFTs as well as radiologic evidence of basilar predominant emphysema mimicking A1AT deficiency. 3. The pulmonologist should always consider this diagnosis in young patients with basilar emphysema who have a normal A1AT genotype. This should prompt the pulmonologist to ask for a history of urticaria and angioedema as well as check for low complement levels. 4. Most patients with HUVS meet American College of Rheumatology criteria for SLE, since there is an overlap in symptoms and they may have a positive ANA test. Emphysema is not a feature of SLE and dsDNA should be negative in HUVS. 5. Treatment with high-dose steroids and dapsone is aimed to ameliorate the extrapulmonary manifestations of HUVS. Their role in the pulmonary manifestations remains unclear, but patients should
[
147#2 CHEST FEBRUARY 2015
]
be advised to quit smoking and be referred early for lung transplant evaluation.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Readings McDuffie FC, Sams WM Jr, Maldonado JE, Andreini PH, Conn DL, Samayoa EA. Hypocomplementemia with cutaneous vasculitis and
journal.publications.chestnet.org
arthritis. Possible immune complex syndrome. Mayo Clin Proc. 1973; 48(5):340-348. Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL. Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease. Mayo Clin Proc. 1982;57(4):231-238. Wisnieski JJ, Baer AN, Christensen J, et al. Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine (Baltimore). 1995;74(1):24-41. Lee P, Gildea TR , Stoller JK. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes. Cleve Clin J Med. 2002; 69(12):928-929. Pujara AC, Mohammed TL. Hypocomplementemic urticarial vasculitis syndrome: a rare cause of basilar panacinar emphysema. J Thorac Imaging. 2012;27(3):W50-W51.
e47
Pulmonary, Critical Care, and Sleep Pearls
]
A 41-Year-Old Woman With Shortness of Breath and History of Rash and Recurrent Laryngeal Edema Ali Ataya, MD; Ibrahim Faruqi, MD, MPH; and Juan C. Salgado, MD
A 41-year-old Hispanic woman with a 20 pack-year smoking history presented with worsening shortness of breath on exertion that gradually started 2 years ago, then significantly deteriorated over the last 4 months. She was diagnosed with COPD 2 months prior to her presentation and started on treatment with fluticasone propionate and albuterol. Her medical history was relevant for undifferentiated connective tissue disorder diagnosed 5 years prior due to a positive antinuclear antibody test, arthralgia, recurrent urticarial skin rash, peripheral neuropathy, abdominal pain, and diffuse body swelling. She was started on treatment with prednisone and azathioprine at the time and had substantial improvement in the occurrence of her urticaria. She also had a history of recurrent laryngeal edema of unclear etiology. She had no history of IV drug abuse, no exposure to animals, was not sexually active, and had no recent travel outside of Florida. There was no significant family history of lung diseases. CHEST 2015; 147(2):e44-e47
Physical Examination Findings On presentation, the patient was afebrile with a heart rate of 78 beats/min, BP of 132/92 mm Hg, and respiratory rate of 20 breaths/min and saturating 93% on 3 L oxygen. Her BMI was 22.6 kg/m2. Her physical examination was remarkable for decreased air entry bilaterally and expiratory wheezing in all lung fields. There was no evidence of clubbing, her heart rate was regular with no added sounds, and there was no evidence of any active skin lesions.
Diagnostic Studies Her CBC count and complete metabolic panel findings were normal except for a mild leukocytosis level of 14,000/mL. Her chest radiograph (Fig 1) and CT chest scan (Fig 2) are shown. Her erythrocyte sedimentation rate, C-reactive protein level, and autoimmune panel (antinuclear antibody [ANA], antineutrophil cytoplasmic antibody, double-stranded DNA [dsDNA],
Manuscript received May 16, 2014; revision accepted June 30, 2014. AFFILIATIONS: From the Division of Pulmonary and Critical Care Medicine, The University of Florida, Gainesville, FL. CORRESPONDENCE TO: Ali Ataya, MD, 1600 SW Archer Rd, Division of Pulmonary and Critical Care, The University of Florida, PO Box 100225, Gainesville, FL, 32608; e-mail: [email protected]
e44 Pulmonary, Critical Care, and Sleep Pearls
Figure 1 – Lung volumes are hyperexpanded with attenuation of vascular markings in both lungs. There is evidence of pleural thickening or scar in the right minor fissure.
antitopoisomerase, Sjögren antibodies, rheumatoid factor, cyclic citrullinated peptide, smooth muscle,
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-1193 © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.
[
147#2 CHEST FEBRUARY 2015
]
Figure 2 – A, B, Hyperexpanded lungs with diffuse centrilobular emphysematous changes at the apices (A) that are more predominant and extensive at the bases (B).
ribonucleoprotein, and histidyl tRNA synthetase) results were all normal. She tested negative for hepatitis and HIV. C1 esterase-inhibitor level was normal. Her a1-antitrypsin genotype was normal. Her complement levels were low, with a C3 level of 42 mg/dL (normal, 90-180 mg/dL), C4 level of 9 mg/dL (normal, 15-46 mg/dL), and C1q level , 3.6 mg/dL (normal, 5.0-8.6 mg/dL). Pulmonary function tests (PFTs) showed a very severe obstructive pattern (FEV1, 29%) with significant reduction in diffusion capacity of lung for carbon monoxide (6% corrected for hemoglobin). Echocardiogram findings were unremarkable except for mildly elevated right ventricular systolic pressure (35-40 mm Hg).
What is the diagnosis?
journal.publications.chestnet.org
e45
Diagnosis: Hypocomplementemic urticarial vasculitis syndrome Discussion Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare immune-complex-mediated or type 3 hypersensitivity reaction that usually occurs in the third or fourth decade of life and predominately affects women in an 8:1 ratio. As the name suggests, the disease is characterized by low complement levels, urticarial skin lesions, and systemic multiorgan involvement. Angioedema may be the presenting symptoms in 50% of patients. Other organs involved include the joints, kidneys, GI tract, lungs, nervous system, eyes, and heart. Obstructive pulmonary disease with physiologic abnormalities on PFTs and basilar emphysematous radiologic changes occur in 50% of patients with HUVS. Most patients are already established smokers, but the degree of emphysema that occurs in this population is clearly out of proportion to the degree of tobacco abuse. The pulmonary findings are believed to occur as a result of vasculitis involvement of the lung, resulting in elastase release. Smoking plays a synergistic role through recruitment of neutrophils, thus accelerating the rate of lung damage. A panacinar emphysema with basilar hyperlucency, similar to a1-antitrypsin deficiency, occurs and it is the major cause of morbidity and mortality in this population. Other than emphysema, HUVS has been reported to involve the lungs in various other ways as well, such as asthma, chronic cough, dyspnea, pleuritis, pleural effusions, and tracheal stenosis. Once it occurs, the rate of decline in lung function can be quick and dramatic. HUVS is a clinical diagnosis based on the presence of urticaria and typical systemic features of the disease. Patients will have decreased levels of all complement lines and will also have a positive C1q precipitin antibody level. Almost 50% of patients will also test positive for ANA, with high titers in some cases. A skin biopsy specimen of the urticarial lesions will reveal an underlying leukocytoclastic vasculitis and direct immunofluorescence will show an immunoglobulin and complement deposition in a granular pattern at the dermal-epidermal junction with involvement of the vessels in the superficial dermis. HUVS can be misdiagnosed as systemic lupus erythematosis (SLE). Indeed, . 50% of patients do meet American e46 Pulmonary, Critical Care, and Sleep Pearls
College of Rheumatology criteria for SLE, but it is important to note that patients with HUVS will not be positive for dsDNA and emphysema is not a feature in SLE. Once diagnosed, patients are usually treated with steroids and even dapsone for the urticarial skin manifestations. In refractory cases, more potent immunosuppressant agents can be used, such as mycophenolate mofetil, methotrexate, azathioprine, and cyclosporine. There have also been reports of rituximab and anakinra being used with success. Patients with deteriorating pulmonary disease have also been successfully transplanted. Clinical Course
The constellation of symptoms, the degree of emphysema out of proportion to the tobacco abuse, and low complement levels led to the diagnosis of HUVS. Given that the patient was already on treatment that suppressed her urticarial, we were unable to obtain a skin biopsy specimen to demonstrate leukocytoclastic vasculitis. She was continued on the prednisone and azathioprine regimen, since it helped ameliorate her skin and systemic symptoms, and was referred to rheumatology. Given the severity of her obstructive lung disease, she was referred to the transplant team and is undergoing evaluation for lung transplantation at this time.
Clinical Pearls 1. HUVS is a rare type 3 hypersensitivity disorder characterized by urticaria, along with other systemic symptoms such as angioedema and arthralgia. 2. More than 50% of patients with HUVS may have obstructive lung disease seen on PFTs as well as radiologic evidence of basilar predominant emphysema mimicking A1AT deficiency. 3. The pulmonologist should always consider this diagnosis in young patients with basilar emphysema who have a normal A1AT genotype. This should prompt the pulmonologist to ask for a history of urticaria and angioedema as well as check for low complement levels. 4. Most patients with HUVS meet American College of Rheumatology criteria for SLE, since there is an overlap in symptoms and they may have a positive ANA test. Emphysema is not a feature of SLE and dsDNA should be negative in HUVS. 5. Treatment with high-dose steroids and dapsone is aimed to ameliorate the extrapulmonary manifestations of HUVS. Their role in the pulmonary manifestations remains unclear, but patients should
[
147#2 CHEST FEBRUARY 2015
]
be advised to quit smoking and be referred early for lung transplant evaluation.
Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
Suggested Readings McDuffie FC, Sams WM Jr, Maldonado JE, Andreini PH, Conn DL, Samayoa EA. Hypocomplementemia with cutaneous vasculitis and
journal.publications.chestnet.org
arthritis. Possible immune complex syndrome. Mayo Clin Proc. 1973; 48(5):340-348. Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL. Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease. Mayo Clin Proc. 1982;57(4):231-238. Wisnieski JJ, Baer AN, Christensen J, et al. Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine (Baltimore). 1995;74(1):24-41. Lee P, Gildea TR , Stoller JK. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes. Cleve Clin J Med. 2002; 69(12):928-929. Pujara AC, Mohammed TL. Hypocomplementemic urticarial vasculitis syndrome: a rare cause of basilar panacinar emphysema. J Thorac Imaging. 2012;27(3):W50-W51.
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