The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

The gradual introduction of more aggressive antibiotic therapy during the Eighties and the resulting increase in survival have been associated with a marked increase in these publications on aspergillus, both on allergic bronchopulmonary aspergillosis (ABPA) and aspergillus colonisation and infection.  Although many of these publications are repetitive, it is clear that just as P. aeruginosa followed the reduction in S. aureus infections so Aspergillus infection and ABPA have followed the more aggressive  and successful treatment of P. aeruginosa. Also the use of immunosuppression following transplantations has given added importance to the presence of and potential problems from fungal infections and ABPA (Iversen M et al. Eur J Clin Microbiol Infect Dis 2007; 26:879-886.[PubMed]).

 

Although both corticosteroids and antifungal drugs have a role in the management of these problems, it is disappointing that after so many publications on the subject of Aspergillus and cystic fibrosis, a Cochrane review recently concluded "there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis" (Elphick HE, Southern KW Cochrane Database Syst Rev 2012 Jun 13;6:CD002204. [PubMed]).

 

Initially most attention was paid to ABPA but it is now realised that infection both local within the airways and invasive can be a serious problem. Some of the following studies mentioned relate to ABPA and others to the presence of chronic A. fumigatus infection in the airways.

 

1965 Mearns MB, Young W, Batten JC. Transient pulmonary infiltrations in cystic fibrosis due to allergic aspergillosis. Thorax 1965; 20:385-392.
This was the first description of allergic bronchopulmonary aspergillosis (ABPA) occurring in two children with cystic fibrosis. A subsequent study from this group showed precipitating antibody to Aspergillus to be present in 31% of 122 children with CF compared with in only 7% in 60 asthmatic children (Mearns M et al. Lancet 1967;i:538-539.below )(also see Brueton et al, 1980 below for typical chest X-ray).

 

1967 Mearns M, Longbottom J, Batten J. Precipitating antibodies to aspergillus fumigatus in cystic fibrosis. Lancet 1967;1(7489):538-539. [PubMed]

 

1975 Warren CP, Tai E, Batten JC, Hutchcroft BJ, Pepys J. Cystic fibrosis - immunological reactions to A. fumigatus and common allergens.  Clin Allergy. 1975; 5:1-12. [PubMed]

 

1980 Brueton MJ, Omerod LP, Shah KJ, Anderson CM. Allergic bronchopulmonary aspergillosis complicating cystic fibrosis in childhood. Arch Dis Child 1980; 55:348-353. [PubMed] Full free article available.
This report in the leading, widely read UK paediatric journal, by Martin Brueton when working in Prof. Charlotte Anderson’s unit in Birmingham, was important as it brought to the attention of general paediatricians (most of whom still cared for a few children with CF) the complication of allergic bronchopulmonary aspergillosis (ABPA) in children with CF. The problem had been described previously in older patients with CF (Mearns et al, 1965 above).


This paper certainly made us more aware of ABPA - the condition for which steroids and a not antibiotics were required. The complication came to be suspected in the presence of increasing asthmatic symptoms accompanied by major chest X-ray changes ranging from total or lobar lung collapse to extensive but changing areas of consolidation (figure 1) associated with eosinophilia, positive skin tests and positive serum precipitins for Aspergillus; also there was not the expected clinical response to intravenous antibiotics. Sometimes the extent of the often major segmental x-ray changes was greater than and quite out of keeping with the outward clinical disturbance.

Large doses of oral steroids were recommended and are still used but few would now agree with the authors of the present article that there was no place for anti-fungal agents, for these now have an increasing place in treatment to reduce the load of Aspergillus antigen present. As more intravenous antibiotics were used during the Eighties the incidence of ABPA increased – this was the experience both in Copenhagen and Leeds.

 

 

Fig. 1: Typical X-ray appearance of allergic bronchopulmonary pulmonary aspergillosis (ABPA)

1990 Simmonds EJ, Littlewood JM, Evans EG. Cystic fibrosis and allergic bronchopulmonary aspergillosis. Arch Dis Child 1990; 65:507-511.  [PubMed] Free PMC article

Over a three year period eight patients were identified, an incidence of 5.8%. Patients were clinically well at the time of diagnosis (Shwachman scores 70-90, Chrispin-Norman chest x ray scores 2-15) and they responded rapidly to treatment with oral prednisolone. There had been little deterioration in their respiratory function and nutrition over the study period.

We concluded that allergic bronchopulmonary aspergillosis is not uncommon in patients with cystic fibrosis. It is a potential cause of lung damage and prospective screening could lead to earlier detection and treatment.

 

 

1994 Simmonds EJ, Littlewood JM, Hopwood V, Evans EG. Aspergillus fumigatus colonisation and population density of place of residence. Arch Dis Child 1994; 70:139-140. [PubMed]

The relation between antibody titres of aspergillus in patients with cystic fibrosis and the population density of their place of residence was investigated by Dr Eddie Simmonds - then our CF Research Fellow. Patients with high titres of antibodies to Aspergillus fumigatus were significantly more likely to live in an area of low population density.

So living in a rural environment may predispose to A. fumigatus colonisation. "Mucking out" stables seems to markedly increase exposure to airborne fungal spores.

 

1996 Egan JJ, Yonan N, Carroll KB, Deiraniya AK, Webb AK, Woodcock AA.  Allergic bronchopulmonary aspergillosis in lung allograft recipients. Eur Respir J 1996; 9:169-171. [PubMed]

Following lung transplantation for end-stage cystic fibrosis, two male patients presented with shortness of breath, peripheral blood eosinophilia and segmental lung collapse. At bronchoscopy, each had bronchial mucous plugging containing Aspergillus fumigatus. This finding was associated with a systemic eosinophilia and skin test positivity to Aspergillus. Augmented steroid therapy resulted in the successful resolution of the symptoms.

The authors consider these to be the first reported cases of allergic bronchopulmonary aspergillosis in lung allograft recipients.

 

 

 

2001 Clifton IJ, Whitaker P, Metcalfe R, Phillip M, Shaw N, Conway SP, Peckham DG. Pharmacokinetics of oral voriconazole in patients with cystic fibrosis. J Antimicrob Chemother 2011; 66:2438-40. [PubMed]

 

 

 

2001 Mastella G, Rainisio M, Harms HK, Hodson ME, Koch C, Navarro J, Strandvik B, McKenzie SG. Allergic bronchopulmonary aspergillosis in cystic fibrosis. Eur Respir J 2001 May;17(5):1052-3.[PubMed] Free full text available

Because of the difficulties of recognizing allergic bronchopulmonary aspergillosis (ABPA) in the context of cystic fibrosis (because of overlapping clinical, radiographic, microbiologic, and immunologic features), advances in our understanding of the pathogenesis of allergic aspergillosis, new possibilities in therapy, and the need for agreed-upon definitions, an international consensus conference was convened. Areas addressed included fungal biology, immunopathogenesis, insights from animal models, diagnostic criteria, epidemiology, the use of new immunologic and genetic techniques in diagnosis, imaging modalities, pharmacology, and treatment approaches. Evidence from the existing literature was graded, and the consensus views were synthesized into this document and recirculated for affirmation. Virulence factors in Aspergillus that could aggravate these diseases, and particularly immunogenetic factors that could predispose persons to ABPA, were identified. New information has come from transgenic animals and recombinant fungal and host molecules. Diagnostic criteria that could provide a framework for monitoring were adopted, and helpful imaging features were identified. New possibilities in therapy produced plans for managing diverse clinical presentations.

 

 

 

2002  Skov M, Hoiby N, Koch C. Itraconazole treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Allergy 2002; 57:723-728.[PubMed]

In a retrospective follow-up of 21 CF patients from a total of 250 treated once or twice within a five-year study period (1994-98), 9 patients were treated with systemic glucocorticosteroids in combination with itraconazole and 12 patients were treated with itraconazole (200-600 mg/day) as monotherapy. During treatment the percentage of Aspergillus fumigatus (AF)-positive sputum cultures significantly reduced (P < 0.05); precipitating antibodies to AF decreased significantly in all patients (P < 0.05); forced expiratory volume (FEV1) increased to pre-exacerbation level; total IgE levels decreased in 42% of patients on monotherapy and in 56% on combination therapy. Specific IgE (radioallergosorbant; RAST) level decreased in 6 of 21 patients. Eleven patients had transient increased levels of alanine transaminase (ALAT). One patient had isolated increase in alkaline phosphatase and another in aspartate transaminase (ASAT).

The authors concluded that high dose itraconazole as monotherapy or in combination with systemic glucocorticosteroids seems effective in CF patients with ABPA. No hepatotoxicity was observed during long-term therapy.

 

 

Thomson JM, Wesley A, Byrnes CA, Nixon GM. Pulse intravenous methylprednisolone for resistant allergic bronchopulmonary aspergillosis in cystic fibrosis. Pediatr Pulmonol 2006; 41:164-170.[PubMed]
This is the first reported use of pulse intravenous methylprednisolone in the treatment of ABPA in CF. The authors present the clinical course of four children with CF and severe ABPA, in whom pulse methylprednisolone was used to manage the disease because of relapses or marked side effects on high-dose oral corticosteroids. Methylprednisolone pulses achieved disease control in 3 of the 4 children. However, troublesome side effects were experienced, in some cases necessitating discontinuation of therapy.

 

Pulse methylprednisolone may represent a treatment option for children with CF and ABPA, where ABPA fails to respond adequately to routine therapy.

 

 

2006 Shoseyov D, Brownlee KG, Conway SP, Kerem E. Aspergillus bronchitis in cystic fibrosis. Chest. 2006 ;130:222-226. [PubMed]

Aspergillus fumigatus, a widely distributed spore-bearing fungus, is commonly grown in sputum cultures of patients with cystic fibrosis (CF). A fumigatus may cause allergic bronchopulmonary aspergillosis (ABPA), a complex condition that leads to worsening of airway inflammation and progressive damage and is diagnosed by specific criteria.

In this report, the authors present six CF patients with respiratory deterioration that did not respond to appropriate antibiotic treatment. All had had A. fumigatus in sputum cultures but did not fulfill the criteria of ABPA. Treatment with antifungal agents was followed by improvement in clinical condition.

The authors suggest that in patients with CF, A. fumigatus should be considered as a pathogen that may directly cause respiratory exacerbations. Antifungal therapy should be considered when deteriorating respiratory function is not responding to antibacterial therapy and A. fumigatus is growing in sputum cultures. Thsi was an important new concept - of Aspergillus as a primary pathogen.

 

 

2008 Barton RC, Hobson RP, Denton M, Peckham D, Brownlee K, Conway S, Kerr MA. Serologic diagnosis of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis through the detection of immunoglobulin G to Aspergillus fumigatus. Diag Microbiol Infect Dis 2008; 62:287-291.[PubMed]

Allergic bronchopulmonary aspergillosis (ABPA) is seen in approximately 10% of patients with cystic fibrosis (CF) and can be difficult to diagnose. Consensus criteria require the presence of multiple elevated immunologic markers such as total immunoglobulin E (IgE), Aspergillus IgE and Aspergillus IgG, or precipitins for a robust diagnosis. There is some degree of standardization of total IgE and Aspergillus IgE levels, but there is no standardization in the measurement of IgG antibodies or precipitins to Aspergillus. The interpretation of results may, therefore, be confusing.

Eighty-seven patients with CF were categorized as having ABPA or as controls, using the consensus criteria and an in-house enzyme immunoassay to measure IgG levels to Aspergillus. All sera from patients were then analyzed by commercial fluorescent immunoassay (FEIA) for the quantitative detection of anti-Aspergillus IgG. FEIA results were analyzed against the consensus conference minimum diagnostic criteria to ascertain a cutoff point, which could predict a diagnosis of ABPA in CF. Eighty patients with CF and with no or incomplete evidence of ABPA had a mean FEIA score of 51.1 mg/L, whereas 7 CF patients with ABPA had a mean FEIA score of 132.5 mg/L. Using receiver operator characteristic curve analysis of the ImmunoCAP (Phadia) IgG score on ABPA versus all other patients gave an area under the curve of 0.933 (estimated SE, 0.027).

This analysis provisionally suggested that a score of 90 mg/L may be used as a cutoff point, which would give a sensitivity of 91% and specificity of 88.0% for the diagnosis of ABPA, though this requires further validation. This quantitative approach to Aspergillus IgG measurement in patients with CF along with the results of other tests will hopefully provide a more accurate approach to the diagnosis of ABPA.

 

 

2009 Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, Armoni S, Kerem E. Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros 2009; 8:253-257. [PubMed]
Nine patients with CF and allergic bronchopulmonary aspergillosis (ABPA) (4 male, 5 female, ages 7-36 years) received high dose intravenous methyl prednisolone (HDIVPM) (10-15 mg/kg/d), for 3 days per month, and itraconazole, until clinical and laboratory resolution of their ABPA.
All patients showed clinical and laboratory improvement, (FEV(1) increase, serum IgE levels and total eosinophil counts decrease) and treatment was discontinued after 6-10 pulses. Adverse effects were minor and disappeared shortly after each IV pulse therapy. The authors suggest that high-dose IV-pulse methylprednisolone is an effective treatment for ABPA in CF with minor side effects.

 

This appears to be an effective way of avoiding unwelcome side effects of prolonged courses of oral corticosteroids (prednisolone) which are often severe during treatment of ABPA - particularly the altered facial features distress patients when repeat or prolonged courses are required.

 

 

2009 Roux AL, Catherinot E, Ripoll F, Soismier N, Macheras E, Ravilly S, Bellis G, Vibet MA, Le Roux E, Lemonnier L, Gutierrez C, Vincent V, Fauroux B, Rottman M, Guillemot D, Gaillard JL, Jean-Louis Herrmann for the OMA Group. Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis in France. J Clin Microbiol 2009; 47:4124-4128. [PubMed]
A multicenter prevalence study of nontuberculous mycobacteria (NTM) involving 1,582 patients (mean age, 18.9 years; male/female ratio, 1.06) with cystic fibrosis in France. The overall NTM prevalence (percentage of patients with at least one positive culture) was 6.6% (104/1,582 patients), with prevalences ranging from 3.7% (in the east of France) to 9.6% (in the greater Paris area). Mycobacterium abscessus complex (MABSC; 50 patients) and Mycobacterium avium complex (MAC; 23 patients) species were the most common NTM, and the only ones associated with fulfillment of the American Thoracic Society bacteriological criteria for NTM lung disease. The "new" species, Mycobacterium bolletii and Mycobacterium massiliense, accounted for 40% of MABSC isolates. MABSC species were isolated at all ages, with a prevalence peak between 11 and 15 years of age (5.8%), while MAC species reached their highest prevalence value among patients over 25 years of age (2.2%).
A large survey of NTM in France showing an overall prevalence of 6.6%.


 

2010 Amin R, Dupuis A, Aaron SD, Ratjen F. The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis. Chest 2010 ;137:171-176. [PubMed]

This was a retrospective cohort study of patients with CF followed at The Hospital for Sick Children Toronto from 1999 to 2006. Persistent A. fumigatus infection was defined as the presence of two or more positive sputum or bronchoalveolar cultures for A. fumigatus in a given year. The primary outcome measure was the annual number of hospitalizations for pulmonary exacerbations. Two hundred thirty patients with CF were included in the analysis. The FEV(1) of patients persistently infected with A. fumigatus was 3.61% (P< or =.0001) lower during the study period compared with uninfected patients. There was a significant interaction between A. fumigatus and Pseudomonas aeruginosa on lung function (P=.0006). Patients not infected with either organism had the highest pulmonary function. Persistent A. fumigatus infection (relative risk [RR]=1.94, P=.0002) and CF-related diabetes (RR=1.64, P=.028) were associated with an increased risk of pulmonary exacerbations requiring hospitalization, whereas there was no increased risk of pulmonary exacerbations among patients with allergic bronchopulmonary aspergillosis (RR=1.02, P=.94). When adjusted for baseline pulmonary function, none of these variables were associated with a significantly increased risk of pulmonary exacerbations, with only chronic A fumigatus infection trending toward significance (RR=1.40, P=.065). 

So this study showed that persistent A. fumigatus infection is an independent risk factor for hospital admissions in patients with CF.

 

 

2010 Moss RB. Allergic bronchopulmonary aspergillosis and Aspergillus infection in cystic fibrosis. [Review] Current Opinion in Pulmonary Medicine 2010; 16:598-603. [PubMed]

Recent literature on Aspergillus fumigatus infection and allergy in cystic fibrosis have expanded our understanding of many aspects of allergic bronchopulmonary aspergillosis, and bring new attention to A. fumigatus airways infection and A. fumigatus allergy without allergic bronchopulmonary aspergillosis (ABPA).

RECENT FINDINGS: ABPA, A. fumigatus infection and A. fumigatus allergy without ABPA all likely worsen cystic fibrosis (CF) lung disease. Studies examining utility of new serologic assays for diagnosing ABPA include evaluations of standardized measurement of A. fumigatus-specific IgG, serum chemokine TARC levels, and recombinant A. fumigatus allergens; as yet, none appear ideal. Although oral glucocorticoids remain primary therapy, toxicity and incomplete control have led to an ongoing search for further safe and effective agents including itraconazole and voriconazole, intravenous pulse methylprednisolone, nebulized amphotericin B and omalizumab. Little controlled treatment data is available.

SUMMARY: Diagnosis of CF-ABPA remains difficult, but improvements in serologic assays are occurring. Treatment remains in many cases unsatisfactory, and new agents offer promise but await proper controlled trials of safety and efficacy. A. fumigatus airway infection and A. fumigatus allergy without ABPA are emerging as further complications of A. fumigatus respiratory colonization in patients with CF, but prospective studies are needed to corroborate largely retrospective findings.

 

Fig. 10: Richard Moss.           Author's photo 2013

 

Dr Richard Moss (1949- )(figure 10) of Stanford University is one of N. America's leading CF clinicians and researchers. He has a major interest in the pathogenesis of chronic airways diseases of childhood particularly immunoregulation of inflammation in cystic fibrosis. In the arena of clinical research, as a member of the CFF Therapeutics Development Network his research group conducts many trials. His wide interests include aerosol therapy, gene vectors and corrrection of CFTR-dependent cell biology defects and new treatments for CF complications such as diabetes and osteoporosis, internet-based disease management, and trials of asthma drugs.

 

 

2010 Proesmans M, Vermeulen F, Vreys M, De Boeck K. Use of nebulized amphotericin B in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis. Int J Pediatr 2010; 37:62-87.

Allergic bronchopulmonary aspergillosis (ABPA) often recurs when the corticosteroid treatment is reduced. These authors report successful steroid withdrawl without relapse over 12 months in 6 of 7 patients with difficult ABPA treated with nebulised amphotericin B.

Just as corticosteroids, antibiotics, rhDNase are effective via the nebulised route it is not surprising that so is nebulised amphotericin. We have found this treatment to be useful in a child with a mixed fungal infection of the airways and its use seems logical in troublesome Aspergillus infection to eradicate the antigen from the airways. Also Aspergillus causing bronchitis, as distinct from allergic bronchopulmonary aspergillosis, is now well described (Shoseyov D et al. Chest 2006; 130:222-226.

 

 

2011 Zalar P, Novak M, de Hoog GS, Gunde-Cimerman N. Dishwashers - a man-made ecological niche accommodating human opportunistic fungal pathogens. Fungal Biology 2011; 115:997-1007. [PubMed]
Enrichment of fungi that may require specific environmental conditions was observed in dishwashers, 189 of which were sampled in private homes of 101 towns or communities. One-hundred-two were sampled from various localities in Slovenia; 42 from other European countries; 13 and 3 from North and South America, respectively; 5 from Israel; 10 from South Africa; 7 from Far East Asia; and 7 from Australia. Isolation was performed on samples incubated at 37C. Species belonging to genera Aspergillus, Candida, Magnusiomyces, Fusarium, Penicillium and Rhodotorula were found occasionally, while the black yeasts Exophiala dermatitidis and Exophiala phaeomuriformis (Chaetothyriales) were persistently and most frequently isolated. Sixty-two percent of the dishwashers were positive for fungi, and 56% of these accommodated Exophiala. Both Exophiala species are known to be able to cause systemic disease in humans and frequently colonize the lungs of patients with cystic fibrosis. The authors conclude that high temperature, high moisture and alkaline pH values typically occurring in dishwashers can provide an alternative habitat for species also known to be pathogenic to humans.

This is a very detailed paper the full version of which is available without cost on the internet. In view of the increasing importance of fungal infections such as Aspergillus in people with CF, this is useful information although the presence of these organisms seem to represent a potential more than definite threat at this stage.

 

 

 

2011 Massam J, Bitnun A, Solomon M, Somers GR, Guerguerian AM, van Wylick R, Waters V.  Invasive aspergillosis in cystic fibrosis: a fatal case in an adolescent and review of the literature. Infect Dis J 2011; 30:178-180. [PubMed]

Invasive aspergillosis is a rare complication of cystic fibrosis. In this article, the authors describe a case of an adolescent with cystic fibrosis, which was well-controlled previously, colonized with Aspergillus fumigatus. The patient developed fatal disseminated aspergillosis in the absence of any preexisting risk factors after a short course of intravenous corticosteroid treatment.

 

 

2012 Aaron SD, Vandemheen KL, Freitag A, Pedder L, Cameron W, Lavoie A, Paterson N, Wilcox P, Rabin H, Tullis E, Morrison N, Ratjen F. Treatment of Aspergillus fumigatus in patients with cystic fibrosis: a randomized, placebo-controlled pilot study. PLos One 2012;7:e36077.[PubMed]

The objective of this study was to determine whether treatment directed against Aspergillus fumigatus improves pulmonary function and clinical outcomes in patients with cystic fibrosis (CF).  A double-blind randomized placebo-controlled pilot clinical trial involving 35 patients with CF whose sputum cultures were chronically positive for A. fumigatus. Participants were centrally randomized to receive either oral itraconazole 5 mg/kg/d (N=18) or placebo (N=17) for 24 weeks. The primary outcome was the proportion of patients who experienced a respiratory exacerbation requiring intravenous antibiotics over the 24 week treatment period. Secondary outcomes included changes in FEV(1) and quality of life.   

Four of 18 (22%) patients randomized to itraconazole experienced a respiratory exacerbation requiring intravenous antibiotics, compared to 5 of 16 (31%) placebo treated patients, P=0.70. FEV(1) declined by 4.62% over 24 weeks in the patients randomized to itraconazole, compared to a 0.32% improvement in the placebo group (between group difference=-4.94%, 95% CI: -15.33 to 5.45, P=0.34). Quality of life did not differ between the 2 treatment groups throughout the study. Therapeutic itraconazole blood levels were not achieved in 43% of patients randomized to itraconazole. 

So the authors did not identify clinical benefit from itraconazole treatment for CF patients whose sputum was chronically colonized/infected with A. fumigatus. The obvious limitations of this pilot study were its small sample size, and failure to achieve therapeutic levels of itraconazole in many patients. Also the decline of FEV1% (4.62% over 24 weeks) in the itraconazole group seems to be excessive.

 

 

2013 Baxter CG, Moore CB, Jones AM, Webb AK, Denning DW. E-mediated immune responses and airway detection of Aspergillus and Candida in adult cystic fibrosis. Chest 2013; 143:1351-7. [PubMed]

The recovery of Aspergillus and Candida from the respiratory secretions of patients with cystic fibrosis (CF) is common. Their relationship to the development of allergic sensitization and effect on lung function has not been established. Improved techniques to detect these organisms are needed to increase knowledge of these effects.

A 2-year prospective observational cohort study was performed. Fifty-five adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profile (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years.

Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus. There was no association between the recovery of either organism and the presence of specific IgE responses. There was no difference in lung function decline for patients with Aspergillus or Candida colonization compared with those without (FEV1 percent predicted, P = .41 and P = .90, respectively; FVC % predicted, P = .87 and P = .37, respectively). However, there was a significantly greater decline in FEV1 and increase in IV antibiotic days for those sensitized to Aspergillus (FEV1 decline, P = .03; IV antibiotics days, P = .03).

 

The authors concluded alllergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations.

 

 

2013 Rundfeldt C. Steckel H. Scherliess H. Wyska E. Wlaz P. Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis.  Eur J Pharm Biopharm 2013; 83:44-53.[PubMed]

57% of CF patients are colonized by Aspergillus species and 10-20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA).

The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8degreeC for 3 months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulisers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7 days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4mug/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h.

The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily.

 

 

Lehmann S. Pfannenstiel C. Frmiedrichs F. Kroger K. Wagner N. Tenbrock K. Omalizu aspergillosis in patients with cystic fibrosis. Ther Adv Respir Dis 2014; 8:141-9. [PubMed]
A retrospective study of six patients (four female, two male, age 4-33 years old) with CF and ABPA treated with omalizumab within an observation period of 7.5 years. All patients showed clinical and laboratory stability or even an improvement within the treatment and post-treatment observation period, although omalizumab therapy was less effective in patients with progressed lung disease and long-term ABPA. Side effects of systemic steroids were reduced.

Omalizumab has the potential to be an additional and solitary treatment option in patients with CF and ABPA. Early onset treatment may be beneficial and patients with early stage of lung disease seem to benefit more. mab: a new treatment option for allergic bronchopulmonary

 

Zicari AM. Celani C. De Castro G. Valerio De Biase R. Duse M. Anti IgE antibody as treatment of allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis. Eur Rev Med Pharmaco 2014; 18(13):1839-41. [PubMed]
A girl with CF who experienced clinical and functional improvement over 12-months treatment with omalizumab. At 12 years, she presented with a worsening respiratory condition, asthma symptoms and reduced lung function (FEV1 of 78%). Blood tests showed an increased concentration of plasma total IgE and positive specific IgE antibodies to Aspergillus fumigatus; allergic skin tests were also positive for A. fumigatus. The patient started steroid therapy but had impaired glucose tolerance due to long-term steroid use. Subcutaneous omalizumab 300 mg every two weeks was initiated and after 14 weeks she had improved respiratory symptoms (FEV1 99%) and a marked reduction in the use of systemic antibiotic and corticosteroid therapies. No side effects were reported. This case shows that therapy with omalizumab for a prolonged period can resolve symptoms of asthma.
 
Omalizumab certainly appears to be a useful addition to the treatment available for variety of conditions including asthma and chronic urticaria. There are now reports of success in treatment ABPA in people with cystic fibrosis. A previous report suggests early treatment may be more effective.

 

 

Beam KT, Coop CA. Steroid sparing effect of omalizumab in seropositive allergic bronchopulmonary aspergillosis. Allergy Rhinol (Providence). 2015 Jan;6(2):143-5. doi: 10.2500/ar.2015.6.0128.
  Free PMC Article [PubMed]

A patient with CF with serologic ABPA who did not tolerate therapy with antifungals, was able to significantly reduce (by nearly 80%) her average daily steroid use while receiving anti-IgE therapy with omalizumab added to her other respiratory medications
Omalizumab may reduce corticosteroid dependence in patients with allergic bronchopulmonary aspergillosis for patients unable to tolerate antifungals, though the authors warn the use may be limited by cost.

 

- Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that specifically binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid and to membrane-bound form of IgE (mIgE) on the surface of mIgE-expressing B lymphocytes (Schulman ES. Am J Respir Crit Care Med 2001; 164(8 Pt 2):s6-11)

 

 

Casciaro R, Naselli A, Cresta F, Ros M, Castagnola E, Minicucci L. Role of nebulized amphotericin B in the management of allergic bronchopulmonary aspergillosis in cystic fibrosis: Case report and review of literature.  J Chemother. 2015 Oct;27(5):307-11. doi: 10.1179/1973947814Y.0000000194. Epub 2014 May 14.
[PubMed]

The authors used nebulized liposomal amphotericin B (L-AMB) in a patient affected by CF, complicated by ABPA. The previous combined treatment with oral steroids and azoles had no respiratory benefit and caused relevant side effects. Amphotericin B has always been well tolerated and permitted a slight steroid tapering. They also observed benefits in pulmonary function and laboratory tests.
Few data are available in literature about the use of nebulized AMB in CF and there are no RCTs evaluating antifungals in CF-ABPA. In the authors’ opinion, the reported case suggests that nebulized L-AMB could represent a possible strategy in ABPA management in CF patients.

- There is a later RCT of nebulised budesonide +/- amphotericin in 21 asthmatic patients with ABPA. Over a year 66.7% of the controls but only 8.3% of the treated patients had exacerbations of their ABPA (Ram et al.2016)