Allergic
Bronchopulmonary
Aspergillosis
European CF Society
Symposium 25
Treating Fungal Disease in CF
June 9, 2012
Richard B. Moss MD
Department of Pediatrics
Stanford University
Disclosures
• Advisory Board/Consultant: Novartis,
Genentech, Gilead, Vertex, Rempex, Rho,
Locus Development
• Sponsored Trial Investigator: Vertex, PTC
• Research Grants: CFFTI, Genentech
Diagnostic Criteria for ABPA in CF
1.
Acute or subacute clinical deterioration not attributable
to another etiology
2. Total serum IgE >500 IU/mL
3. Positive immediate skin test or in vitro demonstration of
IgE antibody to A. fumigatus
4. One or both of the following:
a. Serum precipitins or IgG antibodies to A. fumigatus.
b. New or recent abnormalities on chest x-ray (e.g.,
infiltrates) or chest HRCT (e.g., bronchiectasis, mucus
impaction) that have not cleared with standard therapy
Stevens, Clin Infect Dis 2003;37:S225-64
Therapeutic Approaches for ABPA
• Oral glucocorticosteroid (prednisone)
– Toxicity
• Pulse intravenous glucocorticosteroid
(methylprednisolone)
– Potential for reduced steroid toxicity
• Azoles
– Validated by placebo-controlled trials
– Frequent toxicities (vori>itra). Absorption, metabolism,
drug interactions mandate drug level monitoring;
resistance
• Inhaled amphotericin B
– Multiple formulations, doses, delivery systems
• Anti-IgE (omalizumab)
Pharmacotherapy: Systemic
Glucocorticoids
Indications: All except those with steroid toxicity
Initial dose: 0.5-2.0 mg/kg/d oral prednisone for 1-2 weeks
Begin taper: 0.5-2.0 mg/kg QOD for 1-2 weeks
Taper off: Attempt to taper off within 2-3 months
Relapse: Increase dose, add itraconazole;
taper steroids when clinically improved
Stevens, CID 2003;37:S225-64
Failure of High-Dose ICS-LABA to
Control ABPA
n = 21 adults with ABPA-S
ICS: budesonide 1600 µg/day
Agarwal, Intern Med 2011;50:855-60
Therapeutic Approaches for ABPA
• Oral glucocorticosteroid (prednisone)
– Toxicity
• Pulse intravenous glucocorticosteroid
(methylprednisolone)
– Potential for reduced steroid toxicity
• Azoles
– Validated by placebo-controlled trials
– Frequent toxicities (vori>itra). Absorption, metabolism,
drug interactions mandate drug level monitoring;
resistance
• Inhaled amphotericin B
– Multiple formulations, doses, delivery systems
• Anti-IgE (omalizumab)
Pulse IV Steroids for ABPA
• 4 children with CF and ABPA (3.5-12 yrs), relapses despite daily oral
steroids and itraconazole, toxicity
• IV methylprednisolone 15-20 mg/kg/day x 3, then every 4-9 wks
• Improvements in ABPA in 2 with less toxicity
• Side effects in 2 (hypertension, lethargy/malaise) led to
stopping; no improvement in 1
Thomson, Pediatr Pulmonol 2006;41:164-70
8 patients (9-48 yrs) with relapsing ABPA despite po steroid &
azoles, 15 mg/kg/day x 3, monthly (x1-11). Improved PFT,
serologies, CXR/CT
Skov & Pressler, Ped Pulmonol 2006;S29:345
9 patients (7-36 yr), 10-15 mg/kg/day x 3 every month for 6-12
months. Better tolerated than prednisone. Equal responses,
shorter duration
Cohen-Cymberknoh, JCF 2009;8:253-7
Therapeutic Approaches for ABPA
• Oral glucocorticosteroid (prednisone)
– Toxicity
• Pulse intravenous glucocorticosteroid
(methylprednisolone)
– Potential for reduced steroid toxicity
• Azoles
– Validated by placebo-controlled trials
– Frequent toxicities (vori>itra). Absorption, metabolism,
drug interactions mandate drug level monitoring;
resistance 4-8%
• Inhaled amphotericin B
– Multiple formulations, doses, delivery systems
• Anti-IgE (omalizumab)
Aspergillus in ABPA is More
Prevalent by DNA-based
Detection than Culture, and May
be Azole Resistant
Culture sources:
ABPA, chronic pulmonary aspergillosis – sputum
Invasive pulmonary aspergillosis, normals – bronchial lavage
Denning, CID 2011;52;1123-9
Pharmacotherapy for ABPA
Azoles
• Indications: Slow/poor response to steroids,
relapse, steroid-dependent, steroid toxicity
• Dosing: Itraconazole 5 mg/kg/day po unless
levels obtained. BID dosing when daily dose
>200 mg
• Duration: 3-6 months or longer
• Monitor: LFT. Itraconazole levels if concerns
with absorption, lack of response, or drug-drug
interactions. TDM target trough 0.5-2.5 µg/mL
by HPLC
Stevens, CID 2003;37:S225-64
Hope, Curr Opin Infect Dis 2008;21:580-6
Itraconazole PK and Drug-Drug
Interactions in CF
• Variable absorption and peak levels
– Often <100 ng/mL. Take with acidic liquid (cola). Cyclodextrin
suspension bioavailability 2X > capsule
• Plasma peak 3-6 hr, sputum 2-6 hr. CYP3A4 metabolism.
• Af susceptibility 70% @ 100 ng/mL, >99% @ ≥1 µg/mL
• Inhibits CYP3A4: will level of methylprednisolone, budesonide,
fluticasone, midazolam, cyclosporin, tacrolimus
• Absorption by gastric acid suppression
– To optimize, take 1 hr before acid suppressor
• Metabolism by CYP3A4 inducers (e.g. phenytoin, rifampin, INH)
• PK modeling suggests adult CF dose of 500 mg bid optimal
Hennig, Br J Clin Pharmacol 2006;63:438-50
Voriconazole for ABPA
Much better bioavailability than itra, but much more complex
metabolism (CYP2C9, CYP2C19, CYP3A4, CYP3A5).
• 21 children with CF (5-16 yrs)
• 13 with ABPA; 8 with sputum Af+ but no ABPA
• Voriconazole for 1-50 weeks, monotherapy in 2
• Improvements in ABPA but not Af+ patients
• Side effects in 7 (33%)
Hilliard, JCF 2005;4:215-20
Interpatient variability to 100-fold (vs ~15-fold for itra)
Pediatric doses 4 mg/kg vs 3 mg/kg in adults
Usual maintenance dose 200 mg bid
Suspension preferred to tablet
TDM: target plasma steady-state trough 1-5.5 µg/mL
Pasqualotto, Arch Dis Child 2008;93:578-81
100% AE rate (photosensitivity 5/6; 6/6 visual disturbances)
? Inhibits hepatic metabolism of retinols
Cheng, Pediatri Pulmonol 2010;45:661-6
Voriconazole for ABPA in CF
11 episodes in 9 patients
Glackin, Irish Med J 2009;102:29
6/8 children had sub-therapeutic
steady-state levels
Markantonis, JCF 2012;11:246
Azole Side Effects
• Itraconazole
– GI intolerance, edema 20%; sleep disturbance
10%; rash 7%; peripheral neuropathy 5%, tremor
4%, LFT 2%
• Voriconazole
– LFT 20%; visual changes 18%; rash 17%;
photosensitivity up to 58%*; retinol accumulation;
cardiac, CNS events rare but serious
• Posaconazole
– Not a CYP3A4 substrate but inhibits CYP3A4;
TDM target >0.5 µg/mL; nausea, headache 6%
*Rondeau et al, ERJ 2012
Effect of Posaconazole on Stage 5 ABPA
(Cavitary Chronic Pulmonary Aspergillosis)
24 months posaconazole treatment in patient with
itraconazole and voriconazole-resistant Aspergillus
Chishimba, J Asthma 2012 Mar 2 Epub
Therapeutic Approaches for ABPA
• Oral glucocorticosteroid (prednisone)
– Toxicity
• Pulse intravenous glucocorticosteroid
(methylprednisolone)
– Potential for reduced steroid toxicity
• Azoles
– Validated by placebo-controlled trials
– Frequent toxicities (vori>itra). Absorption, metabolism,
drug interactions mandate drug level monitoring;
resistance
• Inhaled amphotericin B
– Multiple formulations, doses, delivery systems
• Anti-IgE (omalizumab)
Amphotericin B Aerosol Therapy
First clinical neb use 1959; most experience in transplant/oncology
Amphotericin deoxycholate (AMB-d)
3 lipid formulations:
L-AMB (AmBisome) - true liposome
ABLC (Abelcet) - ribbon-like lipid complex
ABCD (Amphocil/Amphotec) - disc-like colloid dispersion
AMB-d may foam; lipids may nebulize better
Effective drug-delivery systems tested include
AMB-d
Respigard II (Marquest); Pari Turbo, Aeroneb
ABLC
AeroEclipse
L-AMB
Halolite
Dosing: 5-50 mg nominal neb dose
lung dose 1.5 ≥ 3 mg
Serum concentration: usu <0.5 - 2 µg/mL (steady-state iv rx level)
Dosing regimes: BID – BIW
Kuper, J Aerosol Med Pulm Drug Deliv 2009;22:1-15
Response to Inhaled Amphotericin
50 mg BIW
Proesmans, Int J Ped 2010; Epub 2010 Dec 23.
Effect of Liposomal Amphotericin
Inhalation in an Adult Patient with ABPA
1 month
LAmB
25 mg BIW
Godet, ERJ 2012;39:1261-3
Therapeutic Approaches for ABPA
• Oral glucocorticosteroid (prednisone)
– Toxicity
• Pulse intravenous glucocorticosteroid
(methylprednisolone)
– Potential for reduced steroid toxicity
• Azoles
– Validated by placebo-controlled trials
– Frequent toxicities (vori>itra). Absorption, metabolism,
drug interactions mandate drug level monitoring;
resistance
• Inhaled amphotericin B
– Multiple formulations, doses, delivery systems
• Anti-IgE (omalizumab)
IgE Binds to Mast Cells at the High
Affinity Receptor (FcRI)
IgE molecule
FcRI binding site
FcRI receptor
IgE molecule bound
to mast cell
Mast cell
Omalizumab Blocks IgE
Binding to Mast Cells
IgE molecule
Omalizumab
FcRI receptor
Omalizumab binds
to CH3 on IgE at
FcRI interaction
site
Mast cell
Omalizumab Prevents the Triggering of
Allergic Inflammation
Removal of IgE and Down-Regulation of FcRI by Omalizumab
IgE must be reduced >99% for FcRI
to become unoccupied and down-regulated
Doses Are Determined by
IgE Level and Body Weight
 Fixed target range for free-IgE suppression requires doses determined by
individual’s pretreatment IgE
High
pre-rx
IgE
IgEIgEIgE
IgE IgE
IgE IgEIgE
IgEIgE IgE
IgE
IgE IgE
IgE
+ Omalizumab
IgE
IgE
Low
pre-rx
IgE
IgE
IgE
IgE IgE
IgE
IgE
+ Omalizumab
Graphical representation assumes patients of equal body weight.
IgE
IgE
Target IgE

<10 IU/mL
Modifying Omalizumab Dosing for ABPA
Maximal “On Label” Dosing for Asthma = 375 mg q 2 wk
Omalizumab in ABPA – Spanish Series
2 of 18 patients in this series had CF
Treatment ≥16 weeks. Follow-up median 36 wks (IQR 28-42)
Dose ~600 mg/week
Perez-de-Llano LA et al. Thorax 2011; 66:539-40
Omalizumab in ABPA – French Series
16 adults, no CF
Tillie-Lebond I et al. Allergy 2011;66:1254-6
Anti-IgE Ablates Aspergillus-Specific Early Asthmatic
Bronchoprovocation Reaction
6 yr old CF-ABPA, BPT pre- & 4 weeks post-omalizumab
Schulze J et al, Respir Med CME 2011;4:33-4
Anti-IgE Treatment Ablates Basophil CD203c
Upregulation in CF-ABPA
Peanut allergy
CF-ABPA
.004
4
Gernez et al, Int Arch Allergy Immunol 2011;154:318-27
Courtesy Y Gernez
Conclusions
•Oral glucocorticosteroids remain the mainstay of
ABPA treatment, but optimal dose, regime & duration
are empirical. Toxicity is limiting factor. Pulse IV
therapy is an attractive option.
•Azoles are validated second tier therapy, but issues
of metabolism, toxicity, drug interactions and
resistance are concerns. Monitoring levels is
advisable. Inhaled amphotericin is an option but
optimal formulation, dose and regime are empirical.
•Immunomodulation with anti-IgE appears effective
and safe but dose and duration are empirical.
•Controlled trials remain a major goal.