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 year
symptoms improved with oral antibiotics for the first 2 or 3 episodes, but he was gi
courses of prednisone for the past few episodes when his symptoms did not respond
antibiotic therapy. Each time, he felt better, but his symptoms returned 3 or 4 weeks
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 ag

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 extremities Mild bilateral leg edema

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

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
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

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

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.