Clinical Challenge Series: Managing the

Complex Patient With Adult-Onset Asthma

Authors: Michael E. Wechsler, MDFaculty and Disclosures

CME Released: 2/13/2020

Valid for credit through: 2/13/2021

The following cases are modeled on the interactive grand rounds approach. The questions
within the activity are designed to test your current knowledge. After each question, you will
be able to see whether you answered correctly and read evidence-based information that
supports the most appropriate answer choice. The questions are designed to challenge you;
you will not be penalized for answering the questions incorrectly. At the end of the activity,
there will be a short post-test assessment based on the material presented.

Case 1:  David, a 52-Year-Old Man With a History of

Respiratory Tract and Sinus Infections
David, a 52-year-old man presents to the emergency
department (ED) with shortness of breath and sinus
symptoms that have not improved with home treatment
over the past 3 weeks. He was referred by his primary
care physician (PCP) when he presented with oxygen
desaturation during his visit.

His relevant medical history (Table 1) and physical

examination findings (Table 2) are summarized below.

Table 1. David's Medical History

History Findings
Present illness Cough, wheeze, shortness of breath, and mucous production for the past 3
weeks

He reports 5 upper respiratory tract infections and sinus infections in the last
2 years. His symptoms improved with oral antibiotics for the first 2 or 3
episodes, but he was given courses of prednisone for the past few episodes
when his symptoms did not respond to antibiotic therapy. Each time, he felt
better, but his symptoms returned 3 or 4 weeks after completing the course of
prednisone
Medical Hypertension
Family Father alive; age 81 with hypertension, type 2 diabetes, hyperlipidemia

Mother alive; age 78 with asthma, rheumatoid arthritis

Psychosocial PHQ-2 screening negative for depression
 Drinks alcohol socially; does not take illicit drugs; former smoker, quit 18
years ago
Current Losartan, 50 mg once daily
medications
Immunizations Influenza vaccination 3 months ago

PHQ = Patient Health Questionnaire.

Table 2. David's Physical Examination

Physical Examination Findings

Vital signs BP = 130/81 mm Hg

HR = 106 bpm

Respirations 28/min

T = 99.6 F

O2 saturation = 88% at rest on room air; 81% with ambulation

BMI 24 kg/m2
General Well-nourished, appears fit
Skin Raised macular rash on both legs (resolved with corticosteroids in the
past)
Head and neck Mild sinus tenderness
Chest and lungs Wheezing, bilateral rales
Heart Tachycardia; no auscultation of S3, S4, or murmurs

ECG shows T-wave inversion

Abdomen Normal
Upper/lower Mild bilateral leg edema
extremities

BMI = body mass index; BP = blood pressure; HR = heart rate; ECG = electrocardiogram; T
= temperature

Case 1 Continues
After reviewing David's medical history and physical examination findings, the ED physician
orders laboratory tests (Table 3) and a chest x-ray.

Table 3. Laboratory Tests

CBC Results
WBC 12,000 cells/µL
Neutrophils 4,200 cells/µL
Lymphocytes 2,700 cells/µL
Monocytes 130 cells/µL
Eosinophils 1680 cells/µL
Basophils 75 cells/µL
HGB/HCT 14.1 g/dL, 47%
ESR 40 mm/hr
CRP 15 mg/L
Platelet 250,000 cells/µL
Metabolic Panel Results
Sodium 135 mEq/L
Potassium 3.5 mEq/L
Chloride 98 mEq/L
CO2 27 mEq/L
Glucose, HbA1c 100 mg/dL, 5.1%
Urinalysis Results
Urine dipstick Trace protein, no casts, no cells

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HbA1c = glycated

hemoglobin; HCT = hematocrit; HGB = hemoglobin; WBC = white blood cell.

Case 1 Continues
The chest x-ray shows bilateral pulmonary infiltrates (Figure 1). Sputum returns negative for
bacteria. David is diagnosed with possible bacterial pneumonia and is discharged with a
course of azithromycin and levofloxacin.

Figure 1. David's chest x-ray showing bilateral pulmonary infiltrates.

Two days later, he returns to the ED because he is still feeling short of breath. Repeat chest x-
ray shows persistent infiltrates. A chest computed tomography (CT) scan is done and is
negative for pulmonary embolism (PE) but shows ground glass opacities bilaterally. A
transthoracic echocardiogram revealed an ejection of 35% with some apical hypokinesis.
David receives a bolus injection of furosemide and is referred to a cardiologist for further
evaluation.

At the visit with the cardiologist, laboratory tests show that David's troponin level is 0.8
ng/mL (normal range: 0 to 0.4 ng/mL). The cardiologist recommends cardiac catheterization.
Results show no coronary artery disease but there is at least one area of hypokinesis. The
cardiologist orders an endomyocardial biopsy (Figure 2A), gives David another bolus
injection of furosemide, and admits David to the hospital.

David continues to experience shortness of breath while in the hospital. Chest x-rays show
that the pneumonia has not resolved. He receives an intravenous infusion of vancomycin. The
next day, the biopsy results come back and show that David has eosinophilic myocarditis.

A repeat complete blood count (CBC) shows an increased eosinophil count of 2600 cells/µL.
A bone marrow biopsy and anti-neutrophil cytoplasmic antibody (ANCA) testing were also
ordered. Both the bone marrow biopsy and peripheral blood smear showed eosinophilia.
The ANCA testing results return as positive with specificity for myeloperoxidase 1:640, so
the attending physician treats David with methylprednisolone 1 g/d. Within 24 hours, David
feels significantly better. He is no longer short of breath and a follow-up chest x-ray shows
clearing up of the pulmonary infiltrates. David says that he is feeling better than he has felt in
the last couple of months. A day later, David's eosinophil count is down to 100 cells/µL.

One month later, a follow up endomyocardial biopsy shows that the eosinophilic myocarditis
has resolved (Figure 2B).

Figure 2. David's endomyocardial biopsy at admission (A) and 1 month following

discharge (B).

Based on David's history, laboratory results, and symptoms, what is his diagnosis?

Antibiotic-related hypersensitivity myocarditis

Eosinophilic granulomatosis with polyangiitis

Eosinophilic pneumonia

Hypereosinophilic syndrome

Based on David's history, laboratory results, and symptoms, what is his diagnosis?
Your Peers Chose:

Antibiotic-related hypersensitivity myocarditis

18%

Eosinophilic granulomatosis with polyangiitis

42%

Eosinophilic pneumonia

25%

Hypereosinophilic syndrome

15%

An acute or chronic history of sinusitis and the presence of asthma symptoms, pulmonary
infiltrates, eosinophilia, and extravascular eosinophils are suggestive of eosinophilic
granulomatosis with polyangiitis (EGPA). In the early stages of the disease, patients often
present with non-specific symptoms including asthma and weight loss, frequently mistaken
for other vasculitides or eosinophilic diseases. Among the eosinophilic disorders, asthma,
granulomas, and vasculitis are notably absent in patients with hypereosinophilic syndrome.
Eosinophilic pneumonia is commonly associated with asthma but can be distinguished from
EGPA by the absence of necrotizing granulomas and less pronounced eosinophil infiltration
into the walls of the vasculature. Cardiac involvement, including myocarditis, is observed in
approximately 27% to 47% of patients with EGPA. Unlike EGPA-associated eosinophilic
myocarditis, antibiotic-related hypersensitivity myocarditis quickly resolves after
discontinuing treatment with antibiotic therapy.

Discussion
EGPA, formerly called Churg-Strauss syndrome, is a rare small and medium vessel ANCA-
associated vasculitis that is characterized by peripheral eosinophilia, asthma (typically adult-
onset), pulmonary infiltrates, sinusitis, neuropathy, and vasculitis of 1 or more end-organs.[1]
The prevalence of EGPA is estimated to be 10 to 15 cases per million individuals and
primarily affects adults between age 40 and 60 years.[2] Diagnosing EGPA is challenging and
patients are often seen by several physicians before a definitive diagnosis is made. The
median duration of asthma onset to diagnosis is 5 to 9 years.[2] Patients with EGPA are
frequently misdiagnosed because it is a rare disease and its symptoms frequently mimic more
common ailments, particularly in the earlier stages of the disease. Late-onset asthma
presenting in adulthood may be a clue to distinguish EGPA from more common asthma or
allergy disorders. Clinical manifestations involving the lungs, skin, sinuses, cardiovascular
system, peripheral and central nervous systems, joints, and gastrointestinal tract are most
common, though EGPA can affect any organ system (Figure 3).[2] Furthermore, many
patients with undiagnosed EGPA take steroids to control their asthma or sinusitis so key
diagnostic features such as necrotizing granulomas and vasculitis are not unmasked until
steroid therapy is discontinued.

Patients typically present in 3 distinct phases, which can occur in any order.[3] In the
prodromal or allergy phase, the patient develops asthma, allergic rhinitis, and sinusitis.[3]
During the eosinophilic phase, there is a substantial rise in peripheral eosinophil count and
end-organ infiltration, particularly in the lungs, heart, and gastrointestinal system.[3] Clinical
manifestations of necrotizing vasculitis (eg, peripheral neuropathy and purpura) are observed
in the vasculitic phase and the patient often presents with constitutional symptoms such as
fever, weight loss, and malaise.[3]

Cardiac involvement, occurring in as many as 27% to 47% of cases, is a major cause of death
and results in poor prognosis in EGPA.[4] Patients with cardiac involvement may present with
myocarditis, acute myocardial infarction, acute heart failure, eosinophilic vasculitis,
pericarditis, pericardial effusion, valvular heart disease, or cardiomyopathy.[4] Idiopathic HES,
viral and parasitic infections, drug hypersensitivities, hematologic malignancies, and other
vasculitides must be ruled out before a diagnosis of EGPA with cardiac involvement can be
made.[5]

Differential diagnoses include other ANCA-associated vasculitides and eosinophilic diseases.

[6]
EGPA is usually distinguishable because of the presence of asthma and eosinophilia, but
clinicians often overlook eosinophil counts provided in routine blood tests and consequently
do not include eosinophilic disorders in the differential diagnosis.[7] EGPA belongs to the
family of ANCA-associated vasculitides which also include granulomatosis with polyangiitis
and microscopic polyangiitis.[8] ANCAs are autoantibodies against the cytoplasmic granules
of neutrophils and monocytes. ANCA is present in approximately 30% to 40% of patients
with EGPA, so the absence of ANCA in the blood does not exclude a diagnosis of EGPA.[3,6]
Clinical manifestations of EGPA vary with ANCA status: ANCA-positive patients manifest
more renal or peripheral nerve involvement, as well as a predisposition to relapse, and
ANCA-negative EGPA patients more frequently have cardiac manifestations and higher
mortality. [9-11] The ANCA autoantibodies that are known to be associated with vasculitis
target myeloperoxidase (MPO) or proteinase 3 (PR3). In ANCA-positive patients with
EGPA, approximately 70% will have positive results for anti-MPO, whereas anti-PR3 is less
commonly seen.[9] In clinical practice anti-MPO antibodies are used to differentiate EGPA
from other diseases, particularly idiopathic HES, since biopsy proof of vasculitis to
distinguish EGPA from HES is not always possible.

Hypereosinophilic syndromes (HES) are rare conditions characterized by persistent blood and

bone marrow eosinophilia lasting longer than 6 months.[12] Eosinophil infiltrates are most
commonly found in the heart, skin, nervous system, lungs, gastrointestinal tract, liver and
spleen. HES can be distinguished from EGPA based on the absence of asthma, vasculitis, and
necrotizing granulomas.[12,13]

Eosinophilic pneumonia is characterized by pulmonary infiltrates and peripheral eosinophilia.

It is often associated with patients with asthma, but differs from EGPA in that
extrapulmonary manifestations are rare. Histological evidence of eosinophil infiltration in the
walls of blood vessels may be present but it is not a prominent feature.[12] Necrotizing
granulomas are not a feature of eosinophilic pneumonia and while eosinophilic abscesses
may be found within the air spaces, the necrosis does not extend into the adjacent lung
parenchyma.[12,13]

Figure 3. Clinical manifestations of EGPA[2]

What initial treatment would you recommend for David?

Cyclophosphamide 90 mg/d infusion and prednisone 60 mg/d

Intravenous gammaglobulin

Azathioprine 150 mg/d

Methotrexate 15 mg/wk

What initial treatment would you recommend for David?

Your Peers Chose:

Cyclophosphamide 90 mg/d infusion and prednisone 60 mg/d

59%

Intravenous gammaglobulin

17%

Azathioprine 150 mg/d

13%

Methotrexate 15 mg/wk

11%

Patients with severe EGPA and myocardial involvement have a worse prognosis. It is
important to treat these patients aggressively with high-dose corticosteroids and
cyclophosphamide to aggressively address inflammation and prevent sequelae. Azathioprine,
methotrexate, and IV gammaglobulin may be appropriate choices for maintenance therapy.

Discussion
Glucocorticoids, immunomodulators, and monoclonal antibodies are used in the treatment of
EGPA.[6] Treatment plans may vary depending on the patient's presentation.[6] Symptoms of
asthma and sinus disease are managed with bronchodilators, nasal steroids, and anti-
immunoglobulin E (IgE) therapy. Historically, standard therapy has been systemic
corticosteroids. For initial therapy, patients with milder disease may be started on prednisone
at 1 mg/kg/day for 2 to 3 weeks, and then titrate down (0.3 mg/kg/day after 3 months and
0.15 mg/kg/day after 6 months) to a minimal effective dose or complete withdrawal.[6]
Intensive therapy with glucocorticoids (1 mg/kg/d) and cyclophosphamide are recommended
for patients with life- and/or organ-threatening disease manifestations (ie, cardiovascular
involvement, severe ocular disease, alveolar hemorrhage, and/or glomerulonephritis).[6]
Maintenance therapy with an immunosuppressant can be started 2 to 3 weeks after the last
dose of cyclophosphamide pulse or a few days after oral cyclophosphamide. Either
azathioprine, methotrexate (with folic acid replacement) or rituximab can be given.
Mepolizumab, a newer biologic approved for EGPA is another option to choose from.[6]

Case 1 Continues
David is given an infusion of cyclophosphamide and is discharged on prednisone (60 mg/d).
He receives instructions to return in a month for a second infusion. At his follow-up visit, he
has gained 16 lbs. He is no longer experiencing shortness of breath, but he is very irritable
and having trouble sleeping because of the prednisone. After his second infusion of
cyclophosphamide, he develops nausea and vomiting. When he returns a few days later, he is
a slightly dehydrated and his white blood cell count is down to 3,000 cells/µL. His eosinophil
count is normal and he is not short of breath, but he says that he is not feeling well.

What next steps do you recommend for David?

Continue current therapy, return in 1 month for a third cyclophosphamide infusion

Remain on current dosage of prednisone, switch to azathioprine

Taper off the dosage of prednisone, return in 1 month for a third cyclophosphamide infusion

Taper off dosage of prednisone and re-evaluate WBC for possible third cyclophosphamide
infusion

What next steps do you recommend for David?

Your Peers Chose:

Continue current therapy, return in 1 month for a third cyclophosphamide infusion

19%
Remain on current dosage of prednisone, switch to azathioprine

17%

Taper off the dosage of prednisone, return in 1 month for a third cyclophosphamide infusion

21%

Taper off dosage of prednisone and re-evaluate WBC for possible third cyclophosphamide
infusion

43%

Cyclophosphamide can cause myelosuppression, bone marrow failure, and severe

immunosuppression which can lead to serious and potentially fatal infections. A CBC should
be ordered during each cyclophosphamide treatment to determine whether dose adjustments
are necessary and to ensure that neutrophil counts are ≥ 1500 cells/µL and platelets are >
50,000 cells/µL.

Discussion

Corticosteroids are synthetic analogues of the natural steroids produced by the adrenal cortex.
These synthetic compounds have anti-inflammatory, anti-proliferative, immunosuppressive,
and vasoconstrictive effects.[14] Long-term effects of steroid use include adrenal suppression
(Box 1),[14] decreased bone density, weight gain, insulin resistance, increased cardiovascular
risk, as well as depression and mood disturbances.[14] These adverse effects can be minimized
by using the lowest steroid dose possible while maintaining symptom remission.[6]

At low doses, cyclophosphamide selectively targets regulatory T cell which leads to

immunosuppression. The most commonly reported adverse effects are neutropenia, febrile
neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.[15] Cyclophosphamide is also
associated with urinary tract and renal toxicity, cardiotoxicity, hepatotoxicity, pulmonary
toxicity, embryo-fetal toxicity, and secondary malignancies.[15] Patients taking
cyclophosphamide are also at risk of myelosuppression, immunosuppression, bone marrow
failure, and infections.[15] Thus, physicians should frequently monitor patients for adverse
effects and tolerability.

Box 1. Signs and symptoms of adrenal suppression[14]

Weakness/fatigue
Malaise
Nausea
Vomiting
Diarrhea
Abdominal pain
Headache (usually in the morning)
Fever
Anorexia/weight loss
Myalgia
Arthralgia
Psychiatric symptoms (eg, depression, irritability)

Case 1 Continues
You recommend to taper to lower the dose of prednisone for better tolerability. When David
returns a month later, his WBC is 4000 cells/µL, so you recommend a switch to azathioprine
(150 mg/d). David does well on his new therapies and he is able to get down to 10 mg/d
prednisone with no symptom flares. His ejection fraction improves to 52%.

A few months later, he returns with a sinus infection and more asthma symptoms. You
determine that he is having another flare and increase his dose of prednisone to 40 mg/d for 3
days and his symptoms improve. After his symptoms resolve you decrease his dose of
prednisone back to 10 mg/d but he has another flare.

Of the following, which would you recommend regarding David's steroid therapy?

Remain at the 10 mg dose until the flare subsides, then taper off

Increase to 40 mg and taper as tolerated while continuing azathioprine

Switch to another oral glucocorticoid

Increase to 15 mg until he has another flare

Of the following, which would you recommend regarding David's steroid therapy?

Your Peers Chose:

Remain at the 10 mg dose until the flare subsides, then taper off

23%
Increase to 40 mg and taper as tolerated while continuing azathioprine

51%

Switch to another oral glucocorticoid

14%

Increase to 15 mg until he has another flare

12%

Glucocorticoid therapy, with or without immunosuppressants, is effective in inducing

symptom remission in most patients with EGPA. However, patients can experience frequent
relapses during steroid tapering. In addition to preventing relapses, long-term maintenance
therapies are used to improve steroid tolerability through their steroid-sparing effects.

Discussion

Patients can still have flares while on maintenance therapy with steroids and an
immunosuppressive agent. As a result, they require higher doses of steroids to prevent flares.
Approximately 85% of patients with EGPA require long-term prednisone at a mean dose of
12.9 ± 12.5 mg/d to control asthma, sinusitis, and/or arthralgias.[6] This is well above the
minimal target dose of ≤ 7.5 mg/d.[6] When administered in conjunction with prednisone
therapy, long-term maintenance treatments such as methotrexate, azathioprine,
mycophenolate, and mepolizumab can improve steroid tolerability through their steroid-
sparing effects.[6]

Case 1 Conclusion
At a follow-up visit 6 months later, David is symptom-free and has not had a flare while on
prednisone (12 mg/d) and azathioprine. He continues to follow up with his PCP for his
hypertension and to ensure he is current with his recommended vaccinations. He also states
that he is working with a trainer at the gym and a nutritionist to help keep his weight gain
from the steroids under control.

Case 2: A 40-Year-Old Woman With Adult-Onset Asthma

and Sinus Disease
Chelsea is a 40-year-old woman with a history of asthma
and sinus disease. Prior to developing adult-onset asthma,
she was otherwise healthy. She has been prednisone-
dependent for 5 years. As a result, she has developed
early-onset osteoporosis. Her symptoms were being
controlled on prednisone (8 mg/d) but the dose was tapered down to 5 mg/d because the side
effects became intolerable for her.

Two weeks later she experienced numbness in her foot and weakness with a foot drop. When
her symptoms did not improve, she visited her PCP, who immediately ordered a CT scan of
her head. The scan was negative for stroke, but showed evidence of chronic sinusitis with
nasal polyps. The PCP then reviewed Chelsea's medical history (Table 4), performed a
comprehensive physical exam (Table 5), and ordered laboratory tests (Table 6). Chelsea's
PCP recommends that she be admitted to the hospital for further evaluation of the
neuropathy.

Table 4. Chelsea's medical history

History Findings
Medical Adult-onset asthma, nasal polyps, and chronic rhinosinusitis at age 33

Early-onset osteoporosis at age 39

Family Father died at age 52 in a car accident

Mother alive; age 67 with type 2 diabetes

Psychosocial Does not drink alcohol, take illicit drugs, or smoke

PHQ-2 screening positive for depression; patient reports that she is

frustrated by her weight gain, poor health, and her inability to endure the
outdoor activities she used to enjoy before her asthma diagnosis
Current Prednisone, 5 mg/d
medications
Alendronate, 40 mg/d
Immunizations Influenza vaccination 1 week ago

Table 5. Chelsea's physical examination findings

Physical Examination Findings

Vital signs BP = 130/80 mm Hg

HR = 84 bpm

Respirations 27/min

T = 98.9 F

O2 saturation = 93% at rest on room air

BMI 31 kg/m2
General Well-nourished, obese
Skin Normal
Head and neck Normal
Chest and lungs Normal; faint wheeze on auscultation
Heart Normal
Abdomen Normal
Upper/lower extremities Patient reports numbness in her left foot; weakness with a foot drop

Table 6. Laboratory Tests

CBC Results
WBC 13,600 cells/µL
Neutrophils 4,200 cells/µL
Lymphocyte 2,800 cells/µL
Monocytes 590 cells/µL
Eosinophils 3,500 cells/µL
Basophils 89 cells/µL
HGB/HCT 13.7 g/dL, 50%
ESR 36 mm/hr
CRP 22 mg/L
Platelet 287,000 cells/µL
ANCA Negative
Metabolic Panel Results
Sodium 136 mEq/L
Potassium 3.7 mEq/L
Chloride 96 mEq/L
CO2 28 mEq/L
Glucose, HbA1c 112 mg/dL, 5.5%
Urinalysis Results
Urine dipstick Negative, no casts, no cells

Case 2 Continues
Upon admission, the attending physician orders a chest x-ray and CT scan, an EMG, and
nerve conduction studies. There is no evidence of pulmonary infiltrates on the chest x-ray.
There are some small nodular densities on the CT scan but no significant infiltrates or pleural
effusions. The EMG and nerve conduction studies indicate that she has evidence of
mononeuropathy multiplex. During her stay, she also develops a rash in the form of palpable
purpura (Figure 4), prompting the attending dermatologist to order a skin biopsy. The skin
biopsy showed evidence of leukocytoclastic vasculitis.

Figure 4. Palpable purpura on Chelsea's lower legs.

 

What is the cause of leukocytoclastic vasculitis in this patient?

Lupus

EGPA

Rheumatoid arthritis

Chronic eosinophilic pneumonia

What is the cause of leukocytoclastic vasculitis in this patient?

Your Peers Chose:

Lupus
28%

EGPA

43%

Rheumatoid arthritis

11%

Chronic eosinophilic pneumonia

18%

Chelsea's medical history (adult-onset asthma, steroid dependence) and laboratory findings
(eosinophilia, elevated ESR, CRP) suggest that EGPA is the cause of leukocytoclastic
vasculitis in this patient. Skin biopsy specimens in patients with EGPA typically will show
leukocytoclastic vasculitis surrounded by an infiltrate of eosinophils and neutrophils.

Discussion

The most common clinical manifestations of EGPA include asthma, allergic rhinosinusitis
(with or without nasal polyps), and multiple mononeuropathy.[16] Approximately half of
patients with EGPA will also present with cutaneous manifestations such hemorrhagic lesions
(eg, palpable purpuras, petechiae, ecchymosis, and hemorrhagic bullae) or dermal nodule
frequently located on the scalp or distributed bilaterally over the extensor surfaces of the
extremities.[16]

What next steps do you recommend for Chelsea?

Continue prednisone at current dose

Increase the prednisone dose

Plasmapheresis
Methotrexate

What next steps do you recommend for Chelsea?

Your Peers Chose:

Continue prednisone at current dose

19%

Increase the prednisone dose

52%

Plasmapheresis

14%

Methotrexate

15%

In patients with severe peripheral neuropathy, EGPA treatment should begin with
methylprednisolone pulses followed by induction therapy with a high-dose course of
prednisone.

Discussion

Methylprednisolone pulses (7.5 to 15 mg/kg/d for 2 days) are recommended in patients with
EGPA presenting with heart, gastrointestinal, central nervous system, severe peripheral
neuropathy, severe ocular disease, alveolar hemorrhage, and/or glomerulonephritis.[6] For the
induction of remission, patients should start with prednisone 1 mg/kg/d for 2 to 3 weeks
followed by gradual tapering down to 0.3 mg/kg/d after 3 months and 0.15 mg/kg/d after 6
months.[6] The maintenance steroid dose should optimally be < 7.5 mg/d to limit
glucocorticoid adverse effects.[6] In patients with life-threatening disease manifestations, or
severe organ involvement, a remission-induction regimen of glucocorticoids and another
immunosuppressant (ie, cyclophosphamide) should be prescribed.[6]

Plasmapheresis is not routinely used for the treatment of EGPA because of its low efficacy
but it can be considered in ANCA-positive patients with rapidly progressive
glomerulonephritis or pulmonary-renal syndrome. According to data from the recent
PEXIVAS study, plasmapheresis does not reduce the risk for end stage renal disease or
mortality in patients with ANCA-associated vasculitis.[17] Methotrexate or other long-term
maintenance therapies can be used in conjunction with a tapered-down steroid dose once
symptom remission has been achieved.

Case 2 Continues
Based on her history and lab findings, Chelsea is diagnosed with EGPA and is given
methylprednisolone (80 mg, TID) for 2 days. After 2 days of treatment, she still has persistent
neuropathy but her eosinophil counts normalize. Her rash has also improved at this time, only
appearing faintly. She is discharged on prednisone (50 mg/d) and is referred to a
rheumatologist for further evaluation.

She begins seeing a rheumatologist who tapers the prednisone dose to 15 mg/d. Chelsea
begins to feel better and her rash has resolved but she has persistent neuropathy. Her
symptoms are controlled with 15 mg/d and she cannot go to a lower dose without
experiencing a flare. Chelsea says that the side effects are intolerable and that she is feeling
very depressed. She asks if there are any other treatment options for EGPA.

Question 1 of 2
In addition to tapering the steroid, which of the following would you recommend for Chelsea
at this time?

Initiate treatment with cyclophosphamide

Initiate treatment with mepolizumab

Initiate treatment with omalizumab

Initiate treatment with tacrolimus

Question 2 of 2
How confident are you right now in your ability to select treatments for patients with a
diagnosis of EGPA? (Select ranking from 1 [Not confident] to 5 [Very confident])
1 - Not confident

2 - Slightly confident

3 - Moderately confident

4 - Mostly confident

5 - Very confident

Question 1 of 2
In addition to tapering the steroid, which of the following would you recommend for Chelsea
at this time?

Your Peers Chose:

Initiate treatment with cyclophosphamide

45%

Initiate treatment with mepolizumab

29%

Initiate treatment with omalizumab

17%
Initiate treatment with tacrolimus

9%

Glucocorticoid monotherapy is not effective in reducing symptoms and maintaining

remission in all patients with EGPA. Cyclophosphamide is mostly used for remission
induction but has significant toxicity. At this time, mepolizumab, a monoclonal antibody, is
the only drug indicated for the treatment of EGPA. It is approved for the treatment of adults
with eosinophilic asthma and EGPA treatment and should be considered for symptom
remission and to reduce glucocorticoid use, and by extension, steroid-induced side effects. It
is generally a safe and well-tolerated therapy.

Discussion

Most patients with EGPA achieve remission with glucocorticoid monotherapy but additional
immunosuppression with immunomodulators or biologic therapy can be considered in
patients like Chelsea who have persistent symptoms and whose prednisone dose cannot be
tapered to the minimal target dose of 7.5 mg/d after 3 to 4 months of therapy.[6] In December
2017, the FDA approved the first agent available for treatment of EGPA in adults,
mepolizumab, which is a monoclonal antibody that prevents the cytokine IL-5 from binding
to receptors on the surface of eosinophils, which prevents their maturation, differentiation,
and proliferation.[18,19] Results from a multicenter, double-blind, parallel group, phase 3 trial
demonstrated that patients receiving 300 mg mepolizumab had ≥ 24 weeks of accrued
remission compared to placebo (28% vs 3%; OR, 5.91%; 95% CI, 2.68 to 13.03; P < .001).[20]
The annualized relapse rate was 1.14 in patients receiving mepolizumab, compared with 2.27
in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P < .0001).[20] In addition, 44% of
patients receiving mepolizumab vs 7% of patients in the placebo group had an average daily
dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 of
the study (OR, 0.20; 95% CI, 0.09 to 0.41; P < .0001).[20]

Case 2 Continues
Chelsea asks about side effects of mepolizumab. She is worried that it will have the same
effects as the prednisone.

Which of the following adverse events was associated with mepolizumab in >5% of patients
in the large clinical trial in EGPA?

Injection site reaction

Serious infectious events (requiring hospitalization)

Herpes zoster

Risk of malignancy

Which of the following adverse events was associated with mepolizumab in >5% of patients
in the large clinical trial in EGPA?

Your Peers Chose:

Injection site reaction

44%

Serious infectious events (requiring hospitalization)

31%

Herpes zoster

19%

Risk of malignancy

6%

A commonly reported adverse effect with mepolizumab therapy is injection site reaction.
Increased risk of herpes zoster is rare and there is no risk of infection or malignancy.

Discussion

The recommended dosage of mepolizumab in patients with EGPA is 300 mg, administered
once every 4 weeks by subcutaneous injection as 3 separate 100 mg injections into the upper
arm, thigh, or abdomen.[19] Mepolizumab is generally a safe and well-tolerated therapy. The
most common adverse reactions include injection site reaction, headache, back pain, and
fatigue.[19,21] Herpes zoster reactions have been reported in older patients taking mepolizumab
for asthma; if clinically appropriate, patients should be encouraged to be vaccinated.[19]
Mepolizumab may cause hypersensitivity reactions (anaphylaxis, angioedema,
bronchospasm, hypotension, urticaria, rash) in some patients, which may occur after dose
administration.[19]
Case 2 Conclusion
Chelsea starts treatment with mepolizumab and over the course of 3 months she is able to
taper-down the prednisone dose to 4 mg/d. She begins losing weight, her depression has
significantly improved, and her bone mineral density has increased.

Educational Impact Challenge

What did you learn from this activity? Please click on the "Next" button to proceed to a brief
survey to see how your knowledge improved after the education. You can also see how your
answers compare with those of your peers.

Educational Impact Challenge

Question 1 of 5
David, a 52-year-old man presents to the ED with a 3 week history of shortness of breath and sinus
symptoms. He was referred by his PCP when he presented with oxygen desaturation during his visit.
David reports 5 upper respiratory tract infections and sinus infections in the past 2 years. He often
had to take prednisone when his symptoms did not respond to antibiotic therapy. Each time, he felt
better, but his symptoms returned 3 or 4 weeks after completing the course of prednisone. Further
tests in the ED show T wave inversion on his ECG and bilateral pulmonary infiltrates on CXR. A
number of other tests were ordered:

 Troponin level: 0.8 ng/mL

 Endomyocardial biopsy showing eosinophilic myocarditis
 Blood eosinophil count: 2600 cells/ µL
 Bone marrow biopsy and peripheral blood smear showed eosinophilia
 Positive ANCA test with specificity for myeloperoxidase 1:640

Based on David's history, laboratory results, and symptoms, what is his diagnosis?

Antibiotic-related hypersensitivity myocarditis

Eosinophilic granulomatosis with polyangiitis

Eosinophilic pneumonia
Hypereosinophilic syndrome

Question 2 of 5
What initial treatment would you recommend for David?

Cyclophosphamide 90 mg/d infusion and prednisone 60 mg/d

Intravenous gammaglobulin

Azathioprine 150 mg/d

Methotrexate 15 mg/wk

Question 3 of 5
Chelsea is a 40-year-old woman who was recently diagnosed with EGPA. She is currently taking
prednisone 15 mg/d to control her symptoms. Past attempts to lower the dose of the prednisone led
to flares. Chelsea says that the side effects of the prednisone are intolerable and that she is feeling
very depressed. She asks if there are any other treatment options for EGPA.

In addition to tapering the steroid, which of the following would you recommend for Chelsea
at this time?

Initiate treatment with cyclophosphamide

Initiate treatment with mepolizumab

Initiate treatment with omalizumab

Initiate treatment with tacrolimus

Question 4 of 5
How confident are you right now in your ability to select treatments for patients with a
diagnosis of EGPA? (Select ranking from 1 [Not confident] to 5 [Very confident])

1 - Not confident

2 - Slightly confident

3 - Moderately confident

4 - Mostly confident

5 - Very confident

Question 5 of 5
Please indicate your prior familiarity with the subject matter. What percentage of this
program's content was new to you?

0%; none of the content was new to me

1% to 24%

25% to 49%
50% to 74%

75% to 99%

100%; all of the content was new to me

Question 1 of 5
Based on David's history, laboratory results, and symptoms, what is his diagnosis?

Your Peers Chose:

Antibiotic-related hypersensitivity myocarditis

17%

Eosinophilic granulomatosis with polyangiitis

68%

Eosinophilic pneumonia

11%

Hypereosinophilic syndrome

4%

An acute or chronic history of sinusitis and the presence of asthma symptoms, pulmonary
infiltrates, eosinophilia, and extravascular eosinophils are suggestive of eosinophilic
granulomatosis with polyangiitis (EGPA). In the early stages of the disease, patients often
present with non-specific symptoms including asthma and weight loss, frequently mistaken
for other vasculitides or eosinophilic diseases. Among the eosinophilic disorders, asthma,
granulomas, and vasculitis are notably absent in patients with hypereosinophilic syndrome.
Eosinophilic pneumonia is commonly associated with asthma but can be distinguished from
EGPA by the absence of necrotizing granulomas and less pronounced eosinophil infiltration
into the walls of the vasculature. Cardiac involvement, including myocarditis, is observed in
approximately 27% to 47% of patients with EGPA. Unlike EGPA-associated eosinophilic
myocarditis, antibiotic-related hypersensitivity myocarditis quickly resolves after
discontinuing treatment with antibiotic therapy.

Question 2 of 5
What initial treatment would you recommend for David?

Your Peers Chose:

Cyclophosphamide 90 mg/d infusion and prednisone 60 mg/d

72%

Intravenous gammaglobulin

15%

Azathioprine 150 mg/d

9%

Methotrexate 15 mg/wk

4%

Patients with severe EGPA and myocardial involvement have a worse prognosis. It is
important to treat these patients aggressively with high-dose corticosteroids and
cyclophosphamide to aggressively address inflammation and prevent sequelae. Azathioprine,
methotrexate, and IV gammaglobulin may be appropriate choices for maintenance therapy.

Question 3 of 5
In addition to tapering the steroid, which of the following would you recommend for Chelsea
at this time?

Your Peers Chose:

Initiate treatment with cyclophosphamide

27%

Initiate treatment with mepolizumab

59%

Initiate treatment with omalizumab

11%

Initiate treatment with tacrolimus

3%

Glucocorticoid monotherapy is not effective in reducing symptoms and maintaining

remission in all patients with EGPA. Cyclophosphamide is mostly used for remission
induction but has significant toxicity. At this time, mepolizumab, a monoclonal antibody, is
the only drug indicated for the treatment of EGPA. It is approved for the treatment of adults
with eosinophilic asthma and EGPA treatment and should be considered for symptom
remission and to reduce glucocorticoid use, and by extension, steroid-induced side effects. It
is generally a safe and well-tolerated therapy.