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Mayo Clin Proc. 2010 February; 85(2): e5–e8.
PMCID: PMC2813828

28-Year-Old Woman With Rapidly Progressive Shortness of Breath

A 28-year-old female nurse at a skilled nursing facility with a medical history remarkable only for depression presented to an outside emergency department (ED) in October 2007 with maxillary sinus tenderness, tinnitus, and otalgia of 3 weeks' duration. She had been married for 5 years and had no history of foreign travel. Her family history was only remarkable for a maternal uncle with sarcoidosis. At the time of her evaluation, a physician noted that the patient had cervical lymphadenopathy and made a diagnosis of acute sinusitis and otitis media. The patient was prescribed amoxicillin-clavulanate and discharged home. After 1 week of antibiotic therapy, all of the symptoms had improved.

In the following month, she developed intermittent flu-like symptoms of cough, sore throat, fatigue, and night sweats. During the following 2 months, she unintentionally lost more than 30 lbs (13.6 kg). For these reasons, she was admitted to her local hospital.

On admission, she was afebrile with marked cervical, supraclavicular, and axillary lymphadenopathy. Laboratory testing disclosed marked peripheral eosinophilia of 2300/μL, which was 15% of the white blood cell differential. Computed tomography (CT) of the chest showed normal lung parenchyma but demonstrated substantial bilateral hilar adenopathy. A cervical lymph node biopsy revealed reactive hyperplasia but was negative for malignancy and granulomas. A week after hospitalization and supportive therapy, the patient was discharged without a diagnosis; her fever and sore throat spontaneously resolved.

Two months after her hospitalization, the patient began experiencing a painful, asymmetrical, multifocal weakness that was worse in the lower extremities and more prominent on the right. According to the patient, her weakness was persistent and neither worsened with exercise nor improved with rest. Her initial neurologic examination was remarkable for a right foot drop and considerable right lower extremity weakness, but after 2 weeks she developed bilateral foot drop and symmetrical bilateral lower extremities weakness.

In the next 2 months, she experienced symmetrical weakness in her lower extremities and became wheelchair-bound. She was readmitted to the hospital. Findings on CT of the head were negative. Electromyography (EMG) and nerve conduction studies (NCSs) showed reductions in both conduction velocity and the amplitude of sensory and motor action potentials. Additional laboratory tests showed a fasting serum glucose level of 90 mg/dL (reference ranges provided parenthetically) (70-100 mg/dL) and were negative for Epstein-Barr virus IgM and IgG; cytomegalovirus IgG and IgM; extractable nuclear antigen panel (Sjögren syndrome antigen A, Sjögren syndrome antigen B, scleroderma-70 antigen, antihistidyl—transfer RNA synthetase, Smith antibodies, ribonucleoprotein); Lyme IgM and IgG; human immunodeficiency virus; hepatitis A, B, and C; perinuclear antineutrophil cytoplasmic antibody (ANCA); and cytoplasmic ANCA. However, she continued to have elevated levels of peripheral eosinophils (15%) and a mildly elevated antinuclear antibody level (5.1 U [≥3 U is positive]). A muscle biopsy was unremarkable for myositis. A lumbar puncture with cerebrospinal fluid (CSF) studies yielded the following results: erythrocyte count, 1/mm3 (0/mm3); leukocyte count, 1/mm3 (0-3/mm3); glucose, 48 mg/dL (40-85 mg/dL); total protein, 95 mg/dL (15-50 mg/dL); and a normal level of angiotensin-converting enzyme.

  1. On the basis of the available clinical information, which one of the following conditions best explains our patient's neurologic abnormalities?
    1. Bacterial meningitis
    2. Viral meningitis
    3. Mononeuritis multiplex
    4. Diabetic neuropathy
    5. Myasthenia gravis
    In patients with meningitis, clinical manifestations typically include fever, headache, stiff neck, and photosensitivity. Our patient's CSF study showed a normal leukocyte count, and the patient had no clinical features that would be suggestive of bacterial or viral meningitis. Mononeuritis multiplex is a painful asymmetrical sensorimotor peripheral polyneuropathy, involving at least 2 different nerves. As the condition continues to progress over the course of days to weeks, it becomes less multifocal and more symmetrical, as in the case of our patient. Mononeuritis multiplex is often associated with vasculitic diseases, hypereosinophilic diseases, and infectious diseases such as human immunodeficiency virus infection and hepatitis. Electromyography and NCSs often show reduced sensory and motor action potential amplitudes and nerve conduction velocity. Additionally, CSF studies may show an elevated level of protein, but with a normal cell count and glucose. Our patient had no history of diabetes, and her fasting glucose level was normal, making diabetic neuropathy an unlikely explanation for her paralysis. Myasthenia gravis is an autoimmune disease that involves antibody directed against the postsynaptic acetylcholine receptors at the neuromuscular junction. Patients often present with ptosis, diplopia, dysarthria, fatigability, respiratory difficulty, and improving weakness with rest. Our patient did not report clinical symptoms that would be consistent with myasthenia gravis.
    The patient was diagnosed as having mononeuritis multiplex. A short course of intravenous immunoglobulin was initiated, followed by a short 5-day burst of 60 mg/d of prednisone, with mild improvement. She received outpatient rehabilitation that included intensive physical and occupational therapy. After 3 months of extensive therapy, her weakness completely resolved, and she was able to ambulate without assistance.
    With the resolving weakness, the patient began developing a new nocturnal cough and shortness of breath on mild exertion. She returned to her local ED, was diagnosed as having an asthma exacerbation, and was sent home with albuterol inhalers and a short 8-day prednisone taper, with an initial dose of 40 mg/d and a dose reduction of 10 mg every 2 days. Her symptoms improved, but as her prednisone was tapered below 20 mg/d, she began having increased shortness of breath. She made subsequent visits to her local ED, and CT of the chest was performed. In contrast to the CT findings 5 months earlier, CT of the chest revealed patchy ground-glass opacities, consistent with alveolitis. A presumptive diagnosis of asthma exacerbation was made in her local ED.
  2. Which one of the following findings would be most supportive of a diagnosis of asthma?
    1. Increased forced expiratory volume in the first second of expiration (FEV1)
    2. Reduced diffusing capacity of lung for carbon monoxide
    3. Increased FEV1/forced vital capacity (FVC) ratio
    4. Increased FEV1 of 12% or higher after administration of bronchodilator
    5. Increased FEV1 of 12% or higher after methacholine challenge
    Pulmonary function tests (PFTs) play a vital role in the diagnosis and management of asthma. In patients with asthma, PFTs often show an obstructive pattern, with reduction in FEV1 and forced expiratory flow rates. The diffusing capacity of lung for carbon monoxide is usually normal or increased. The FEV1 is typically reduced more than FVC, resulting in an overall decreased FEV1/FVC ratio. Clinical diagnosis of asthma is further supported by an increase in FEV1 of 12% or more after the administration of 2 to 3 puffs of a short-acting bronchodilator. However, the lack of confirmatory airway obstruction on PFTs does not rule out the diagnosis of asthma. In cases in which PFT results are normal, the diagnosis of asthma can be made by documenting a decrease in FEV1 of 20% or greater after methacholine challenge, which is highly suggestive of asthma.1
    The patient was referred to a local pulmonologist because of the abnormal CT findings. She underwent a PFT, which showed an increase in FEV1 of 15% after administration of a bronchodilator, confirming the clinical diagnosis of asthma. She began taking another short 8-day prednisone taper and inhaled corticosteroids, with a short-acting bronchodilator for rescue therapy. However, as her prednisone dose was reduced below 20 mg, she became increasingly short of breath. A bronchoscopy with bronchoalveolar lavage was performed, which was remarkable for 60% eosinophils but was otherwise negative for fungi, Pneumocystis jirovecii (formerly, Pneumocystis carinii), and malignancy.
  3. Which one of the following is the least likely diagnosis?
    1. Allergic bronchopulmonary aspergillosis (ABPA)
    2. Churg-Strauss syndrome (CSS)
    3. Löffler syndrome
    4. Hypereosinophilic syndrome (HES)
    5. Chronic obstructive pulmonary disease (COPD)
    Eosinophilic lung disease is characterized by the following 3 features: peripheral blood eosinophilia with concurrent radiographic abnormality, lung tissue eosinophilia on lung biopsy, and increased eosinophils in bronchoalveolar lavage.2 Differential diagnoses to consider for eosinophilic lung disease include: ABPA, CSS, Löffler syndrome, HES, and eosinophilic pneumonia. Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction that occurs when the airway is colonized by Aspergillus species. Churg-Strauss syndrome is a vasculitic disorder that is often characterized by adult-onset asthma, mononeuropathy or polyneuropathy, sinusitis, and prominent peripheral eosinophilia. Löffler syndrome occurs when the larvae of helminths penetrate into alveoli from the bloodstream, causing a localized hypersensitivity reaction. Hypereosinophilic syndrome is an idiopathic disease that is often associated with marked peripheral eosinophilia and can involve multiple organs, including the lungs, heart, kidneys, and brain. In contrast to eosinophilic lung disease, COPD is characterized by inflammation and imbalances between proteinases and antiproteinases in the lung, resulting in destruction of the airway and inflammation of the lung. Chronic obstructive pulmonary disease is the least likely cause of this patient's illness because it is typically not associated with eosinophilia.
    By the middle of summer, 9 months after her episode of acute sinusitis, the patient was brought back to her ED, with tachypnea and in moderate respiratory distress. Despite placement of a closed face mask with 9 L of oxygen bleed-in, her oxygen saturation remained at 80%. She was treated with high doses of intravenous methylprednisolone along with continuous albuterol nebulizer treatment and was transferred to Mayo Clinic in Rochester, MN for further evaluation and management.
    On arrival at our institution, the patient's vital signs were as follows: temperature, 36.5oC; blood pressure, 105/62 mm Hg; pulse, 62 beats/min; and respiratory rate, 24 breaths/min. Her oxygen saturation was greater than 90% while receiving 4 L of oxygen by nasal cannula. Physical examination revealed tachypnea, with diffuse, bilateral expiratory wheezes. Additional laboratory studies were negative for peripheral eosinophilia, perinuclear ANCA, cytoplasmic ANCA, and Aspergillus IgM and IgG. Bronchoscopy with transbronchial biopsy of the lower lobe showed few eosinophils, and bronchoalveolar lavage was negative for fungi, P jirovecii, Legionella species, bacteria, and influenza. A second EMG/NCS was performed, showing an axonal length—dependent peripheral neuropathy with substantial involvement of the peroneal nerve, consistent with a history of mononeuritis multiplex. A second CT of the chest showed scattered ground-glass opacities in both lungs that were most prominent in the mid-lungs.
  4. Given what is known about this patient's neurologic and pulmonary history, which one of the following is the most likely diagnosis?
    1. HES
    2. CSS
    3. Löffler syndrome
    4. ABPA
    5. COPD
    In a patient with eosinophilic lung disease with concomitant neurologic symptoms, HES and CSS should be among the top differential diagnoses. Hypereosinophilic syndrome is often difficult to differentiate from CSS because it is also associated with marked peripheral eosinophilia and involvement of multiple organ systems, such as the heart, gastrointestinal tract, lungs, brain, and kidneys. However, asthma is an uncommon feature of HES.3,4 Churg-Strauss syndrome typically presents with chronic sinusitis, adult-onset asthma, prominent peripheral blood eosinophilia, and mononeuropathy or polyneuropathy. Given our patient's history of adult-onset asthma as confirmed by PFTs, CSS appeared to be a more likely diagnosis than HES. Löffler syndrome is unlikely in a patient without a history of foreign travel. Allergic bronchopulmonary aspergillosis is also unlikely because her serologic testing was negative for Aspergillus spp on 3 different occasions and typically would not be associated with neurologic abnormalities. Given the patient's young age and bronchoalveolar lavage findings that are diagnostic for eosinophilic lung disease, COPD is an unlikely diagnosis.
    The American College of Rheumatology established 6 criteria to aid clinicians in establishing the diagnosis of CSS: asthma, peripheral eosinophil level greater than 10%, mononeuropathy or polyneuropathy, migratory or transient pulmonary opacities on radiographic imaging, paranasal sinus abnormalities, and a tissue biopsy specimen showing extravascular eosinophils.5 In retrospect, if all the various stages of her illness are considered, our patient met all 6 classification criteria for CSS. Interestingly, on arrival at our institution, the patient no longer had peripheral eosinophilia, most likely because of the multiple high doses of corticosteroids that were administered before her transfer. Although she was not found to have an elevated peripheral eosinophil level while at Mayo Clinic, a retrospective review of her medical history and laboratory findings led our pulmonologists to conclude that she clearly met all of the clinical criteria for the diagnosis of CSS. After the diagnosis was made, the patient immediately began to undergo medical treatment.
  5. Which one of the following would be considered the first-line treatment for our patient?
    1. Prolonged, high-dose oral corticosteroids
    2. Cyclophosphamide
    3. Low-dose intravenous immunoglobulin
    4. Plasma exchange
    5. Omalizumab (anti-IgE therapy)
    The mainstay therapy for CSS is high-dose systemic corticosteroid therapy, with doses between 0.5 and 1.5 mg/kg per day administered for 6 to 12 weeks until the disease is completely resolved. In patients who have demonstrable vasculitis, a higher dose of corticosteroids would be preferred. Inhaled corticosteroids may be added to manage the underlying asthma. In a few small-scale clinical trials, cyclophosphamide and high-dose intravenous immunoglobulin have been shown to benefit patients with severe disease that was nonresponsive to corticosteroids, but plasma exchange does not provide a superior benefit to the mainstay treatment of corticosteroids.6,7 In one case study, a patient with severe asthma that was secondary to CSS and refractory to inhaled and oral corticosteroids began receiving anti-IgE therapy; at 3-month follow-up, PFT results had improved.8
    The patient began taking high-dose prednisone (60 mg/d), with a slow taper over the course of 16 weeks. At 4-month follow-up, the patient's PFT results had normalized and her shortness of breath had completely resolved. She was contemplating the possibility of returning to work in the near future.

DISCUSSION

Churg-Strauss syndrome is a small-vessel vasculitic disease that is characterized by sinusitis, asthma, marked peripheral eosinophilia, and peripheral neuropathy. The mean age at diagnosis of CSS is 50 years, but nonspecific constitutional symptoms of malaise, fevers, and weight loss can appear in those aged 30 to 40 years. Adult-onset asthma is the most common feature of CSS and is estimated to occur in 95% of patients with CSS.9 Asthma can precede other symptoms by up to 10 years.

The American College of Rheumatology established 6 criteria to aid clinicians in making the diagnosis of CSS.5 Meeting 4 of these 6 criteria would yield a sensitivity of 85.0% and a specificity of 99.7% for the diagnosis of CSS. Interestingly, the testing of ANCA is not helpful in the diagnosis of CSS because less than 40% of patients with CSS are ANCA-positive.10

Surgical biopsy of affected lung tissue is considered the criterion standard in the diagnosis of CSS, whereas transbronchial lung biopsy is rarely useful. Typical histological features of CSS include extensive eosinophilic infiltrates, vasculitis, and granulomatous inflammation. Lanham et al11 make the point that CSS is typically underdiagnosed because of the emphasis on histological demonstration of eosinophilic infiltrates, extravascular granulomas, and vasculitis, the last of which is found only in a minority of cases. Lanham et al suggest that CSS can be identified solely on clinical findings.

The mainstay therapy for CSS is high-dose corticosteroids tapered slowly over the course of 12 weeks or until symptoms have resolved. Early withdrawal of corticosteroids can cause CSS relapse. Patients' symptoms, serum eosinophil level, and erythrocyte sedimentation rate should be routinely monitored for responsiveness to therapy. For patients who are nonresponsive to corticosteroids, other novel treatment options should be considered, including cyclosporine, intravenous immunoglobulin, and anti-IgE therapy.6-8

Correct answers: 1. c, 2. d, 3. e, 4. b, 5. a

REFERENCES

1. US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute Guidelines for the Diagnosis and Management of Asthma, expert panel report 2 Bethesda, MD: National Asthma Education and Prevention Program, National Institutes of Health, National Heart, Lung, and Blood Institute; 2002. http://www.nhlbi.nih.gov/guidelines/archives/epr-2_upd/index.htm Accessed December 8, 2009
2. Allen JN, Davis WB. Eosinophilic lung diseases. J Respir Crit Care Med. 1994;150(5, pt 1):1423-1438 [PubMed]
3. Fauci AS, Harley JB, Roberts WC, Ferrabs VJ, Gralnick HR, Bjornson BH. The idiopathic hypereosinophilic syndrome: clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. 1982;97(1):78-92 [PubMed]
4. Katzenstein AL. Diagnostic features and differential diagnosis of Churg-Strauss syndrome in the lung: a review. Am J Clin Pathol. 2000;114(5):767-772 [PubMed]
5. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33(8):1094-1100 [PubMed]
6. Guillevin L, Jarrousse B, Lok C, et al. The Cooperative Study Group for Polyarteritis Nodosa Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange: a prospective randomized trial of 71 patients. J Rheumatol. 1991;18(4):567-574 [PubMed]
7. Danieli MG, Cappellie M, Logullo F, Salvi A, Danieli G. Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome. Ann Rheum Dis. 2004;63(12):1649-1654 [PMC free article] [PubMed]
8. Giavina-Bianchi P, Giavina-Bianchi M, Agondi R, Kalil J. Three months'administration of anti-IgE to a patient with Churg-Strauss syndrome [letter]. J Allergy Clin Immunol. 2007;119(5):1279 [PubMed]
9. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 1999;78(1):26-37 [PubMed]
10. Sablé-Fourtassou R, Cohen P, Mahar A, et al. French Vasculitis Study Group Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med. 2005;143(9):632-638 [PubMed]
11. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984;63(2):65-81 [PubMed]

Articles from Mayo Clinic Proceedings are provided here courtesy of The Mayo Foundation for Medical Education and Research