Treatment

4  Allergic Bronchopulmonary Aspergillosis

47

Medication

Study design

Outcomes

Reference

Inhaled corticosteroids

Beclomethasone 400 μg QD vs. placebo

Double-blind trial of 32

No beneft over placebo

Br J Dis Chest

for 6 mo

asthma patients

1979 [87]

Budesonide/formoterol 1600/24 μg QD

Retrospective case series of

Control of asthma symptoms but continued rise

Agarwal 2011

21 oral corticosteroid naïve

in total IgE levels

[88]

asthmatic ABPA-S patients

Systemic corticosteroids

Prednisone 0.5 mg/kg QD × 1 wk then

Case series of 20 asthma

“Complete remission” in all patients

Rosenberg

QOD

patients

1977 [64]

Prednisone 0.5 mg/kg QD × 2 wk then

Case series of 84 asthma

16 (19%) “remission without recurrent

Patterson 1986

QOD × 3 mo

patients

exacerbation,” 38 (45%) corticosteroid dependent

[65]

Prednisolone 0.75 mg/kg QD × 6 wk,

Case series of 126 asthma

All had “remission” at 6 wk, 25 (20%) “relapsed”

Agarwal 2006

0.5 mg/kg QD × 6 wk, then taper 5 mg

patients

during course of treatment, 17 (13.5%)

[48]

every 6 wk

corticosteroid dependent

Methylprednisolone IV 10–15 mg/kg

Case series of 14 CF

All with clinical improvement, increased FEV1,

Cohen-

QD × 3 days every 4 wk until remission

patients (9 IV vs 5 PO)

reduced serum IgE levels, IV less medication

Cymberknoh

vs. prednisone 0.5–2 mg/kg QD for

adverse events than PO

2009 [85]

2–4 wk with taper over 1–3 mo; all

itraconazole 200–400 mg QD

High: prednisolone 0.75 mg/kg

Prospective open label RCT

No difference in time to frst exacerbation (H:

Agarwal 2016

QD × 6 wk, 0.5 mg/kg QD × 6 wk, then

of 92 asthma patients with

132 vs M: 100 days) and number of exacerbations

[84]

taper 5 mg every 6 wk vs. Medium:

acute ABPA

(H: 18/44, 42%, M: 24/48, 50%). Similar

prednisolone 0.5 mg/kg QD × 2 wk then

improvement in lung function between both

QOD × 8 wk, then taper 5 mg every

groups, less cumulative corticosteroid dose, and

2 wk

corticosteroid related adverse reactions in

medium-dose group

Antifungal therapy

Itraconazole 200 mg BID vs.

Randomized double-blind

Decreased prednisone dose and decreased serum

Stevens 2000

placebo × 16 wk; all prednisone >10 mg

trial of 55 asthma patients

total IgE levels in itraconazole (13/28, 45%) vs.

[90]

QD

placebo (5/27, 19%)

Itraconazole and prednisolone vs

Retrospective study of 21

Improved FEV1 and decreased precipitins in all,

Skov 2002

itraconazole 200–600 mg QD

CF patients (9 both, 12

total IgE levels decreased 42% itraconazole vs.

[96]

itraconazole monotherapy)

56% itraconazole/prednisolone

Itraconazole 400 mg QD vs.

Randomized double-blind

Decreased serum total IgE and Aspergillus-

Wark 2003

placebo × 16 wk

trial of 29 asthma patients

specifc IgG levels as well as fewer exacerbations

[92]

with itraconazole vs placebo

Voriconazole 300–600 mg QD or

Retrospective study of 20

“Clinical response” at 6 mo in 73% with

Chishimbra

posaconazole 800 mg QD

asthma patients

voriconazole and 78% with posaconazole

2012 [97]

Isavuconazole 200 mg TID × 2 days

Case report of 1 patient

Symptomatic improvement, decreased inhaled

Jacobs 2017

then 200 mg QD

with asthma

steroid dosing, and normalization of FEV1

[98]

Itraconazole 200 mg BID × 4 mo vs.

Prospective open label RCT

Higher rate of composite response at 6 wk in

Agarwal 2018

prednisolone 0.5 mg/kg QD × 4 wk,

of 131 asthma patients with

prednisolone (63/63, 100%) vs itraconazole

[99]

0.25 mg/kg QD × 4 wk, 0.125 mg/

acute ABPA

(60/68, 88%), similar time to frst exacerbation,

kg × 4 wk, then taper 5 mg every 2 wk

number of exacerbations, and change in lung

function. Higher rate of adverse events in

prednisolone group

Voriconazole 200 mg BID × 4 mo vs.

Open label RCT of 50

No difference in rates of composite response,

Agarwal 2018

prednisolone 0.5 mg/kg QD × 4 wk,

asthma patients with acute

time to frst exacerbation, number of

[100]

0.25 mg/kg QD × 4 wk, 0.125 mg/

ABPA

exacerbations, and change in lung function.

kg × 4 wk, then taper 5 mg every 2 wk

Higher rate of adverse events in prednisolone

group

Monoclonal antibodies

Omalizumab 375 mg SQ every

Open label RCT of 13

Decrease in exacerbations compared to placebo

Voskamp 2015

2 wk × 4 mo vs placebo then 3 mo

asthma patients with

(2 vs 12 events), decrease in FeNO

[103]

washout followed by cross-over

chronic ABPA

Omalizumab 300–600 mg SQ every

Retrospective study of 18

Stabilization of lung function decline, decrease in

Perisson 2017

15 days

pediatric CF patients

corticosteroid daily dose, improvement in

[104]

nutritional status, no adverse events

(continued)

4  Allergic Bronchopulmonary Aspergillosis

49

[89]. Inhaled corticosteroids should not be used as mono-

nosis and treatment of Aspergillosis, the Infectious Diseases

therapy to treat ABPA but may be useful if additional con-

Society of America (IDSA) recommends treating symptom-

trol of the underlying asthma is required.

atic asthmatic patients with known bronchiectasis or mucoid

impaction despite oral or inhaled corticosteroids with oral

Antifungal Therapy

itraconazole with therapeutic drug monitoring [91].

Similar to the treatment of ABPA associated with asthma,

adjunctive therapy with itraconazole in ABPA complicating

Antifungal therapy is generally used as adjunctive therapy

CF has also been reported to be benefcial. In a retrospective

along with corticosteroids to reduce the dose of corticoste-

study of 21 patients, Skov et al. found an improvement in

roids or if corticosteroids alone are insuffcient to induce

FEV1 to pre-exacerbation levels and decreased precipitins in

remission [90–92]. In patients with recurrent exacerbations

all patients as well as decreased total serum IgE levels in

of ABPA, it is recommended to treat with a combination of

56% of patients on combination therapy with itraconazole

glucocorticoids and itraconazole [90–92]. If antifungal ther-

and prednisone [96]. The Cystic Fibrosis Foundation recom-

apy is used, then the selected drug should exhibit activity

mends the addition of itraconazole in cases of ABPA in

against the Aspergillus species. Of the triazoles exhibiting

which there is a poor response to corticosteroids, relapse, or

Aspergillus activity, itraconazole has the most clinical expe-

corticosteroid toxicity or dependence [20]. The IDSA also

rience and data demonstrating its effectiveness in the treat-

recommends treating CF patients with ABPA, who have fre-

ment of ABPA. Itraconazole is administered at a dose of

quent exacerbations and/or declining lung function with oral

200 mg twice a day for 4–6 months and then tapered off over

itraconazole with therapeutic drug monitoring [91].

4–6 months. Itraconazole is a strong inhibitor of the cyto-

There are emerging data regarding the use of newer tri-

chrome P450 3A4, so it is important to consider drug–drug

azoles for the treatment of ABPA. In a study by Chishimba

interactions prior to initiation of therapy. Of particular note

et al., treatment of ABPA complicating asthma with voricon-

in this patient population, coadministration of itraconazole

azole led to a clinical response in 73% of patients and treat-

increases levels of budesonide, uticasone propionate, dexa-

ment with posaconazole led to a clinical response in 78% of

methasone, and methylprednisolone, which may lead to

patients [97]. In a case study of one patient with diffcult-to-­

inadvertent toxicity from higher-than-intended doses of cor-

control ABPA complicating asthma with repeated relapses

ticosteroids [89, 93, 94]. Drug levels should be monitored to

and who was unable to tolerate itraconazole or voriconazole,

ensure adequate bioavailability in patients with severe dis-

isavuconazole was used with symptomatic improvement and

ease, patients not responding to therapy, or in those taking

increasing FEV1 as well as subsequent weaning of the

medications that may interact with itraconazole [95]. The

inhaled corticosteroid dose [98]. In an attempt to minimize

suspension formulation has higher bioavailability than that

corticosteroid use, the IDSA recommends consideration of

of the capsule formulation. Absorption is improved in an

alternative mold-active azole therapy in patients requiring

acidic environment, so the medication should not be taken

antifungal therapy if unable to achieve therapeutic levels of

with antacids [95]. The most common side effects of azole

itraconazole [91]. Further research is needed on the potential

therapy include elevated hepatic transaminases, gastrointes-

role of voriconazole, posaconazole, or isavuconazole in the

tinal intolerance, peripheral neuropathy, rash, and headache

treatment of ABPA.

as well as the risk of multiple drug–drug interactions.

Use of mold-active azoles as monotherapy for treatment

Data from two randomized, double-blind placebo-­

of ABPA has been proposed. In an open-label randomized

controlled trials demonstrated the effectiveness of itracon-

controlled trial in India of 131 patients with acute-stage

azole in the treatment of ABPA complicating asthma. In a

ABPA complicating asthma randomized to monotherapy

multicenter study of 55 patients in the United States, Stevens

with prednisolone versus itraconazole, prednisolone was

et al. found a higher rate of treatment response in the group

more effective than itraconazole (100% vs. 88%) in causing

randomized to receive itraconazole compared to placebo

a treatment response, but there was no difference in timing to

with a response defned as a ≥50% reduction in corticoste-

frst exacerbation or number of exacerbations [99]. There

roid dosing, a ≥25% decrease in total serum IgE levels, and

were also signifcantly higher rates of adverse events in the

at least one of the following: resolution or absence of pulmo-

prednisolone group such as weight gain, cushingoid habitus,

nary infltrates, improvement of pulmonary function tests,

and acne. In patients taking itraconazole monotherapy, 9/60

and/or improvement in exercise tolerance by at least 25%

(15%) developed liver function test abnormalities. The same

[90]. In a single center study in the UK, Wark et al. found a

research group in India conducted a similar open-label ran-

decrease in total serum IgE and Aspergillus-specifc IgG lev-

domized control trial comparing monotherapy with prednis-

els, normalization of sputum eosinophilia, and fewer ABPA

olone versus voriconazole in 50 asthmatic patients with

exacerbations in patients treated with itraconazole compared

acute-stage ABPA [100]. The proportion of patients demon-

to placebo [92]. In the 2016 practice guidelines for the diag-

strating a positive treatment response was similar between