ASPERGILLUS AND OTHER FUNGAL INFECTIONS

At the time of writing Aspergillus (sensitivity and infection) was becoming an increasingly frequent problem and appeared to be one of the consequences of vigorous eradication of early Pseudomonas infection - observed both in Leeds and Copenhagen. By 2010 there were some 350 references to CF and Aspergillus.

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 et al, 1967).(also see Brueton et al, 1980 below for typical chest X-ray).

Winifred Young (1909-1969) (figure 8) was appointed as a research clinician at the Queen Elizabeth Hospital for Children Hackney Road London in 1943 and established a cystic fibrosis clinic there in 1950. Winifred Young and Margaret Mearns (figure 21) were treating children with CF at the Queen Elizabeth Hospital for Children, Hackney, London – at the time one of the few CF clinics in the UK. Children who survived were referred from there (along with those from Archie Norman's clinic at Great Ormond Street) to Dr John Batten’s adult CF clinic at the Royal Brompton Hospital, London. As early as 1972, Drs Margaret Mearns and Winifred Young published encouraging results of their meticulous clinical and microbiological follow-up and treatment reflecting their care in the Sixties (Mearns, 1972 below). These were further indications that vigorous meticulous treatment of the secondary effects of the basic defect at an early stage could significantly improve prognosis. From the 1950s their young patients had received prophylactic erythromycin and nebulised neomycin and intensive physiotherapy – before 1957 they had 50 infants who, at a year, had no significant trouble and who, at 5 years, were still considered to be free of bronchitis (Mearns, 1969). It is a reflection of the much inferior medical communication systems in those times, or perhaps the attitudes of the general paediatricians, that the effective treatment regimens at the few large UK CF clinics, such as this, were not more widely adopted throughout the UK. 1969 McCarthy DS, Pepys J, Batten J. Hypersensitivity to fungi in Cystic fibrosis. Proceedings of the 5th International Cystic Fibrosis Conference, Cambridge. P194. Ed. Lawson D. Cystic Fibrosis Trust, London. [Conference] Positive skin test reactions to common allergens were present in 50% of 37 patients with cystic fibrosis. Many subsequent papers reported an increase in atopy in people with CF although clinical manifestations of allergy have not proved a major problem with the exception of allergic bronchopulmonary aspergillosis and more recently allergic reactions to intravenous antibiotics – which are now both major problems.(also Price et al, 1979 below).

1969 McCarthy DS, Pepys J, Batten J. Hypersensitivity to fungi in Cystic fibrosis. Proceedings of the 5th International Cystic Fibrosis Conference, Cambridge. P194. Ed. Lawson D. Cystic Fibrosis Trust, London. [Conference]
Positive skin test reactions to common allergens were present in 50% of 37 patients with cystic fibrosis. Many subsequent papers reported an increase in atopy in people with CF although clinical manifestations of allergy have not proved a major problem with the exception of allergic bronchopulmonary aspergillosis and more recently allergic reactions to intravenous antibiotics – which are now both major problems.(also Price et al, 1979 below).

1976 Warner JO, Taylor BW, Norman AP, Soothill JF. Association of cystic fibrosis and allergy. Arch Dis Child 1976; 51:507-11. [PubMed]
A number of previous studies had shown an increased prevalence of atopy in people with cystic fibrosis. In this study from London this association was confirmed. Immediate skin hypersensitivity was present in 59% of 123 children with CF – a much higher incidence than normal. Also atopy was more frequent in the obligate heterozygotes. Allergic children with CF tended to have a worse respiratory state. The authors suggested that the increase in allergy possibly was related to impaired handling of antigen at mucosal surfaces. One of many studies on allergy and cystic fibrosis which never seemed to have a great influence on clinical management - other than the reactions to Aspergillus fumigatus.

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]
The report in the 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 the complication of allergic bronchopulmonary aspergillosis (ABPA) in children with CF, even although 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 11) associated with eosinophilia, positive skin tests and positive serum precipitins for Aspergillus. 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.

1986 Ferguson A, Merrett TG, Littlewood JM, Bolderson I. IgE antibodies to foods are not a feature of cystic fibrosis. Human Nutrition - Clinical Nutrition 1986; 40:255-258.
It had been suggested that patients with cystic fibrosis have abnormal immune responses to foods. In collaboration with Dr Anne Ferguson of Edinburgh, we measured IgE antibodies to inhalants and foods (by RAST) in 105 patients with cystic fibrosis aged between eight months and 28 years. Serum IgE was elevated (greater than 180 kU/l) in 21 (20%) patients. In 43, (41%) IgE antibodies were detected in serum. The majority of positive results were with house-dust mite, grass pollen or Aspergillus. Only four of the patients had a positive RAST to a food - one to milk, one to wheat and two to egg. On the basis of high serum IgE or positive RAST results, 44.8 per cent of the patients were atopic and the frequency of atopy was age-related, being higher in patients aged four years or more. However, the presence of food antibodies was unrelated to age. This study confirms the high prevalence of atopy in patients with cystic fibrosis but unequivocally demonstrates that the presence of IgE antibodies to foods in their serum is rare. Of course, we had previously observed that many children with quite obvious clinical food intolerance (proved by withdrawal and challenge) have neither positive skin tests nor raised IgE levels nor positive RAST to foods (Minford AMB et al. Food intolerance and food allergy in children: a review of 68 cases. Arch Dis Child 1982; 57:742747).

2005 Hilliard T. Edwards S. Buchdahl R. Francis J. Rosenthal M. Balfour-Lynn I. Bush A. Davies J. Voriconazole therapy in children with cystic fibrosis. J Cyst Fibros 2005; 4:215-220. [PubMed]
There is increasing evidence for the efficacy of the antifungal voriconazole, particularly in immunosuppression. We describe our experience of using voriconazole in children with CF.We performed a retrospective case note review of children with CF treated with voriconazole in a single centre over an 18 month period. A total of 21 children aged 5 to 16 years (median 11.3) received voriconazole for between 1 and 50 (22) weeks. Voriconazole was used as monotherapy in 2 children with recurrent allergic bronchopulmonary aspergillosis (ABPA); significant and sustained improvements in clinical and serological parameters for up to 13 months were observed, without recourse to oral steroids. Voriconazole was used in combination with an immunomodulatory agent in a further 11 children with ABPA, with significant improvement in pulmonary function and serology. 8 children without ABPA but who had recurrent Aspergillus fumigatus isolates and increased symptoms also received voriconazole; this group did not improve with treatment. Adverse effects occurred in 7 children (33%: photosensitivity reaction 3, nausea 2, rise in hepatic enzymes 1, hair loss 1). The authors concluded that voriconazole may be a useful adjunctive therapy for ABPA in CF. Voriconazole monotherapy appears to be an alternative treatment strategy when oral corticosteroids may not be suitable. ABPA and even Aspergillus bronchitis were definitely more common and this is valuable experience in the use of an effective antifungal agent.

2006 Shoseyov D, Brownlee KG, Conway SP, Kerem E. Aspergillus bronchitis in cystic fibrosis. Chest 2006; 130:222-226.
A report of six patients with CF with respiratory deterioration that did not respond to appropriate antibiotic treatment. All had had A. fumigatus in their sputum cultures but did not fulfil the accepted criteria of allergic bronchopulmonary aspergillosis (ABPA). Treatment with antifungal agents was followed by improvement in their clinical condition. The authors suggest that in patients with CF, A. fumigatus should be considered as a pathogen that may directly cause respiratory exacerbations (rather than by only causing an allergic reaction as in ABPA). Antifungal therapy should be considered when deteriorating respiratory function is not responding to antibacterial therapy and A. fumigatus is growing in sputum cultures. Problems with Aspergillus were becoming increasingly common and it is experience in both Leeds and Copenhagen that as the prevalence of chronic Pseudomonas falls, as a result of early eradication therapy, the number of patients growing Aspergillus increases. There is also increasing evidence that, although, at times manifest as typical ABPA, the presence of the fungus in the airways can also cause a subtle deterioration in respiratory function or, as in the present report, even cause an acute bronchial infection which should be treated with appropriate anti-fungal drugs.

2006 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. We present the clinical course of four children with CF and severe ABPA, in whom pulse methyprednisolone 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. See also Cohen-CymberKnoh et al. 2009. [PubMed]

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.
Oral corticosteroids are standard therapy for ABPA and are associated with severe side effects. Monthly pulses of high-dose intravenous methylprednisolone (HDIVPM) are an effective therapy for autoimmune diseases with fewer side effects compared to oral prednisone. 9 patients with CF and ABPA (4 male, 5 female, ages 7-36 years) received HDIVPM (10-15 mg/kg/d), for 3 days per month, and itraconazole, until clinical and laboratory resolution of 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. High-dose IV-pulse methylprednisolone appears to be an effective treatment for ABPA in CF with minor side effects. The side effects associated with oral prednisolone in patient having prolonged problems with ABPA are very distressing and this method of giving steroids is welcome.