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\begin{document}

\title{Allergic bronchopulmonary aspergillosis in children}



\author[1]{Sara Manti}%
\author[2]{Giuseppe Fabio Parisi}%
\author[3]{Maria Papale}%
\author[4]{Amelia Licari}%
\author[5]{Elena Chiappini}%
\author[3]{Enza Mulè}%
\author[6]{Novella Rotolo}%
\author[3]{salvatore leonardi}%
\affil[1]{UOC Genetics and Immunology Paediatrics}%
\affil[2]{University of Catania}%
\affil[3]{University of Catania School of Medicine}%
\affil[4]{Fondazione IRCCS Policlinico San Matteo}%
\affil[5]{University of Florence, Meyer Children's Hospital}%
\affil[6]{University}%


\vspace{-1em}



  
  \date{May 07, 2024}


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\selectlanguage{english}
\begin{abstract}
Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease
caused by Aspergillus induced hypersensitivity that occurs in
immunocompetent but susceptible patients with asthma and/or cystic
fibrosis (CF). In children, ABPA remains mostly undiagnosed, resulting
in one of the most common causes of poorly controlled asthma and highly
significant morbidity in children with CF. Currently, no specific
diagnostic criteria of ABPA for children are available. Corticosteroids
and itraconazole are the mainstays of therapy, althoughthere is a lack
of randomized clinical trials regarding their usefulness for ABPA in
children. Several monoclonal antibodies, such asomalizumab and
mepolizumab, may be potential therapies for refractory ABPA in pediatric
patients; however, further data are required to clarify the optimal dose
and duration of therapy as a routine treatment approach.%
\end{abstract}%



\sloppy


\textbf{Key messages}

In children, allergic bronchopulmonary aspergillosis remains largely
undiagnosed resulting in one of the most common causes of poorly
controlled asthma and significant morbidity in children with cystic
fibrosis.

An early diagnosis allows us to start an earlier treatment of allergic
bronchopulmonary aspergillosis that is crucial for preventing the severe
sequelae such as impairment in lung function, pulmonary fibrosis, and
bronchiectasis.

New, targeted therapies for allergic bronchopulmonary aspergillosis have
emerged as effective options complementing the understanding of
host-\emph{Aspergillus} interaction.

Firstly described in the United Kingdom in 1952, Allergic
bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused
by\emph{Aspergillus,} principally \emph{Aspergillus fumigatus} , induced
hypersensitivity that occurs in immunocompetent but susceptible patients
with asthma and/or cystic fibrosis (CF) {[}1{]}. The prevalence of ABPA
in the pediatric population is not known. The first pediatric case of
ABPA was reported in 1970, since then only rare case reports and small
case series have been described. ABPA may be found in up to 6\% of all
asthmatic patients, and from 2\% to 15\% in CF patients {[}1{]}. Age
more than 12 years, low-CF index, presence of immunoglobulin (Ig)E and
eosinophilia, bronchial colonization with \emph{Stenotrophomonas
maltophilia} and \emph{Pseudomonas aeruginosa} , long-term azithromycin
therapy, and higher cumulative doses of inhaled corticosteroids (CS)
have been reported as risk factors for ABPA in CF children {[}2{]}.

At present, the underlying pathophysiology of ABPA is not clearly
understood. Repeated inhalation of \emph{Aspergillus} spores causes
airway colonization, the release of proteolytic enzymes and
pro-inflammatory cytokines, and, lastly, evokes a T-helper (Th) cell -2
type immune response as well as a polyclonal antibody response leading
to increased serum IgE-, IgG- and IgA antibodies levels {[}3{]}. An
impaired balance between human leukocyte antigen (HLA)-antigen D-related
molecules associated with susceptibility and resistance to ABPA has been
hypothesized to be also involved in the pathogenesis of ABPA {[}3{]}.

Clinically, children with ABPA may present both systemic symptoms such
as fever and weight loss, and respiratory symptoms, including poorly
controlled asthma, wheezing, increased productive cough,
tachypnea/dyspnea, chest pain, hemoptysis, and exacerbations responding
poorly to antibiotics. The reported mean age on clinical presentation is
12.9\selectlanguage{ngerman}±4 years as a latent period up to 10 years before diagnosis had been
described and male preponderance has been also reported {[}2{]}. At
physical examination crackles and rhonchi are usually reported. Patients
with ABPA show a severe progression in all lung function parameters,
and, FEF at 50\% VC (FEF\textsubscript{50}), the volume of trapped gas,
and specific airway resistance as the best predictors have been reported
{[}1, 2, 4{]}. Recently, exhaled nitric oxide (FE\textsubscript{NO}) has
been proposed as biomarker for the diagnosis of ABPA in CF {[}5, 6{]}.
It has been assessed that an early disease recognition may prevent the
progression of ABPA, and, accordingly, clinical and radiographic stages
of ABPA progression have been proposed {[}7, 8{]}. The radiographic
findings of ABPA on chest-X-ray are not specific, but pulmonary
infiltrates, consolidation, and macronodular densities are commonly
reported at the early-stage disease, whereas, central bronchiectasis,
ring shadows, and pulmonary fibrosis are reported at the end-stage.
Chest computed tomography (CT) demonstrates high attenuation mucus plugs
and different patterns of central, cylindrical, varicose, and cystic
bronchiectasis, that, involving multiple bronchi, appear described as
``a string of pearls'' or ``signet ring sign'' {[}7, 8{]}. Recently,
magnetic resonance imaging (MRI) has also been proposed as a diagnostic
tool in ABPA since it appears highly specific (100\%) and sensitive
(94\%) for the diagnosis of ABPA in CF, detecting the inverted mucoid
impaction signal, defined by the presence of mucus with both high T1 and
low T2 signal intensities {[}7, 8{]}. The diagnostic criteria for ABPA
in children are the same used in the adult population. In addition to
the presence of a predisposing condition such as asthma or CF, patient
must show increased IgE against \emph{Aspergillus
fumigatus}(\textgreater{}0.35 kUA/L), and total serum
IgE\textgreater{}1000 IU/ml (2400 ng/mL), and, at least two out of three
secondary criteria must be satisfied including radiographic transient or
fixed findings consistent with ABPA; serum IgG \textgreater{}27 mg/L
against \emph{Aspergillus fumigatus} ; and elevated serum eosinophils
levels (\textgreater{}500 mmc) {[}7{]}. Because of the clinical
(pulmonary infiltrate, bronchiectasis, exacerbations) and radiographic
(central bronchiectasis) findings are similar between ABPA and CF, the
diagnosis of ABPA may be difficult in this cluster of patients.
Therefore, the CF Foundation Consensus has suggested the diagnostic
criteria and criteria for screening for ABPA in CF patients {[}3{]}.
Detection of acute/subacute clinical deterioration not related to other
etiologies, serum total IgE concentration major than 1000 IU/mL (or 2400
ng/mL), cutaneous reactivity to \emph{Aspergillus fumigatus,} or
presence of specific IgE to \emph{Aspergillus fumigatus} , precipitating
antibodies to\emph{Aspergillus fumigatus,} and new or recent
abnormalities on imaging investigations are defining a patient with CF
affected by ABPA {[}3{]}. The goals of the treatment of ABPA are to
eradicate colonization and/or proliferation of \emph{Aspergillus
fumigatus} ; suppress inflammatory response; reduce pulmonary
exacerbation and prevent fibrotic end-stage disease. The most effective
treatment for the acute phase of ABPA is prednisolone at the recommended
dosage is 0.5 mg/kg/day for the first 2 weeks, followed by a progressive
tapering over the next 12--16 weeks in patients with asthma {[}7{]};
0.5--2.0 mg/kg/day (maximum 60 mg) for 1--2 weeks, then 0.5--2.0
mg/kg/day every other day for 1--2 weeks, and then taper in next 2--3
months in patients with CF {[}3, 7{]}. There are several doubts on the
efficacy of itraconazole in children with ABPA, since the available
literature data are mainly based on data generated in adults. Thus, it
is not currently recommended as first\selectlanguage{english}-line treatment. The recommended
dose of itraconazole is 5 mg/kg/day, a maximum 400 mg/day (in two
divided doses if the total daily dose exceeds 200 mg) and 3--6 months of
a total duration of therapy is suggested {[}7{]}. The evidence of a slow
or poor response to CS, relapse of the disease in CS\selectlanguage{english}-dependent ABPA, and
CS\selectlanguage{english}-induced toxicity suggest the use of itraconazole in treating of ABPA
in patients with CF {[}3, 7{]}. The rationale for the use of omalizumab,
a humanized monoclonal anti-IgE, in the ABPA, is due to its ability to
prevent allergen-induced IgE-mediated. This therapy is recommended to be
administered as a subcutaneous injection. The dose and frequency of
dosing are guided by a nomogram derived from total serum IgE level and
body weight in kilograms. Patients with ABPA and treated with omalizumab
reported a significant reduction in exacerbation rates, oral CS
exposure, and CS toxicity {[}1-3, 9{]}. Recently, mepolizumab, a
monoclonal antibody against interleukin (IL)-5 has been proposed as an
alternative treatment in ABPA {[}10{]}. Other adjuvant therapies such as
amphotericin B, voriconazole, isavuconazole, and vitamin D have been
proposed in treating ABPA, but further studies are required to assess
their efficacy {[}3{]}. The monitoring treatment response in ABPA should
include the determination of total serum IgE levels every 3 to 6
months/year since it has been suggested that a decrease in total IgE
levels, at least 25\% from baseline, is associated with a clinical
improvement, on the contrary, an increase by \textgreater{}50\% is
associated with pulmonary exacerbations {[}3{]}. Spirometry should be
performed every 3 to 6 months because of a decline of 15\% in functional
vital capacity (FVC), which may be a warning signal of ABPA exacerbation
{[}3{]}. The re-evaluation of environmental exposure and chest-X-ray for
patients with IgE level double, even if asymptomatic, should also be
performed. A synacthen test is suggested when adrenal insufficiency is
suspected {[}3{]}.

In summary, many advances in the understanding of pathophysiology have
been made and several treatment options for ABPA are currently
available. However, whereas in the adult population ABPA is a
well\selectlanguage{english}-recognized entity, in children, it remains mostly undiagnosed,
resulting in one of the most common causes of poorly controlled asthma
and highly significant morbidity in children with CF. An early diagnosis
allows us to start an earlier treatment of ABPA that is crucial for
preventing the severe sequelae such as impairment in lung function,
pulmonary fibrosis, and bronchiectasis.

\textbf{References}

\begin{enumerate}
\tightlist
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