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\title{A case of anaphylaxis caused by the inhalation of sheep's milk vapors in
a child with severe multi-food allergy.}



\author[1]{Foti Randazzese Simone}%
\author[1]{Toscano Fabio}%
\author[1]{Crisafulli Giuseppe}%
\author[1]{Galletta Francesca}%
\author[1]{Sara Manti}%
\author[1]{Caminiti Lucia}%
\affil[1]{Universita degli Studi di Messina Dipartimento di Patologia Umana dell'Adulto e dell'Eta Evolutiva Gaetano Barresi}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{TITLE PAGE}

\textbf{Full Title of Manuscript} : A case of anaphylaxis caused by the
inhalation of sheep's milk vapors in a child with severe multi-food
allergy.

\textbf{Authors' Full Names} : Foti Randazzese Simone, Toscano Fabio,
Crisafulli Giuseppe, Galletta Francesca, Manti Sara, Caminiti Lucia.

\textbf{Authors' Institutional Affiliations} : Department of Human
Pathology in Adult and Developmental Age ``Gaetano Barresi'', University
of Messina, Messina (Italy).

\textbf{Running Title} : Adverse reactions after inhalation of food
allergens.

\textbf{Corresponding Author} : Foti Randazzese Simone, Pediatric
Resident, Pediatric Unit, Department of Human Pathology in Adult and
Developmental Age ``Gaetano Barresi'', University of Messina, via
Consolare Valeria, 1, 98121, Messina, Italy. Tel. 0902213165.
E-mail:\emph{simone.foti.92@gmail.com}.

\textbf{Word count} : 1055 words (Main Text).

\textbf{Number of Tables and Figures} : 1 table, no figures.

\textbf{MAIN TEXT FILE}

\textbf{I. CONFLICT OF INTEREST}

The authors declare that they have no competing financial interests.

\textbf{II. FINANCIAL SUPPORT}

The authors declare they have not received financial support.

\textbf{III. KEYWORDS}

Milk; Allergy; Inhalation; Case Report.

\textbf{IV. MAIN TEXT}

To the Editor,

Nowadays food allergy represents an important public health problem both
in children and in adults, with an increasing prevalence in the last
years \textsuperscript{1, 2}. The worldwide epidemiology depends on
diagnostic methods, dietary habits and cultural
practices\textsuperscript{2}. The most common foods involved in children
are cow's milk, egg, peanut, tree nut and wheat flour
\textsuperscript{1, 2}. It is well known that adverse reactions commonly
occur after ingestion of food, with a wide range of clinical
manifestations, such as respiratory, cardiovascular, cutaneous and
gastrointestinal symptoms, and anaphylaxis \textsuperscript{3}. In
literature adverse reactions after inhalation of food particles are also
described in highly sensitive patients \textsuperscript{3}, so it is
important to identify and to follow-up them.

Here we describe the case of S., a 4-year-old female child followed up
by the Pediatric Allergology Unit of Messina University Hospital for
severe atopic dermatitis, allergic rhinitis, severe IgE-mediated
multi-food allergy (milk, egg, peanut, nut, legumes, kiwi) and suspected
transient hypogammaglobulinemia of infancy. Family history of allergic
rhinitis asthma and food allergy. Her parents are dairy owners. S.
didn't take milk since she was five months old because of a failure to
thrive, vomiting, bloody diarrhoea and skin rashes after cow's milk
consumption. At the beginning of our follow-up at the age of 2 years
old, Skin Prick Tests (SPT), Prick by Prick (PbP), Component Resolved
Diagnosis (CRD) and cow's milk Challenge were performed. SPT were
positive for alpha-lactalbumin, beta-lactoglobulin and casein, with PbP
positivity for milk. CRD showed high specific IgE levels for Bos
d\_milk, Bos d 4, Bos d 5, Bos d 8, Cap h\_milk and Ovi a\_milk
(\emph{Table 1} ). During the cow's milk Challenge the baby developed a
severe anaphylaxis, characterized by urticaria, wheezing and loss of
consciousness, after the ingestion of 0,2 ml of milk. Intramuscular
injection of adrenaline and intravenous infusion of methylprednisolone
were administered, with the complete resolution of the symptoms in three
hours. Self-injectable adrenaline and strict avoidance of exposure to
cow's milk proteins were prescripted. After some months, S. developed an
adverse reaction following the administration of nasal drops containing
lactoferrin, characterized by mild angioedema of the face and sneezing
attacks. At the age of 3 years old a new adverse reaction occurred in a
very unusual circumstance: the mother reported that the baby was playing
with her sister inside the parents' dairy farm where she inhaled the
milk vapors released by the sheep milk making process. She immediately
developed anaphylaxis characterized by hives, angioedema of the face and
wheezing; the symptoms regressed after the oral administration of
antihistamines and oral corticosteroids.

The real epidemiology of allergic reactions induced by the inhalation of
food vapors and/or particles in children is still
unknown\textsuperscript{3, 4}. There are few data about its frequency in
current scientific literature. Roberts et al. reported that 5\% of
children followed up for food allergy and asthma have respiratory
symptoms after inhaling food particles \textsuperscript{5}. The
inhalation of food allergens depends on its presence in the air: farms
or food industries, restaurants, school or home have been described as
the places where the reaction can most frequently
occur\textsuperscript{4}. In particular, processing of food, such as
boiling, may release a significant quantity of particles in the air. All
of the foods may induce clinical symptoms when inhaled, but the most
commonly reported in children are wheat flour, seafood, soy, legumes,
peanut, tree nut and cow's milk \textsuperscript{4}. According to the
clinical case reported in this manuscript, Leonardi et al. wrote that
allergic reactions to airborne milk proteins have been described in
literature, in particular in children and adolescents with cow's milk
allergy during the administration of inhaled drugs containing milk
proteins\textsuperscript{3}. Barbi et al. described the case of an
8-year-old girl with asthma and cow's milk allergy who developed a fatal
anaphylaxis while she was in a dairy shop \textsuperscript{6}.
Nowak-Wegrzyn et al. reported a case of anaphylaxis in an eight-year-old
boy with cow's milk allergy and persistent asthma occurred after the
administration of Fluticasone/Salmeterol contaminated by
lactose\textsuperscript{7}. The diagnostic workup in these subjects is
complex and it is based on the history and the clinical evaluation of
the patient \textsuperscript{3}. The most frequent clinical
manifestations include respiratory symptoms (asthma, wheezing, coughing,
sneezing attacks and rhinitis), skin reactions (rashes or urticaria),
ocular symptoms (conjunctival hyperemia and lacrimation) and rarely
anaphylaxis\textsuperscript{3, 4}. It is important to establish the
relationship between the inhalation of the foods and the onset of the
symptoms. Skin testing (SPT and PbP) or serum-specific IgE for the foods
suspected are also important for the diagnosis \textsuperscript{3}, but
nowadays CRD, also known as Precision Allergy Molecular Diagnostic
Applications (PAMD@), have an increasing role in improving the
management of allergic diseases, in particular food allergy, because it
may stratify the risk of anaphylaxis during the Challenge
\textsuperscript{3, 8}. However the gold standard actually used to
confirm the diagnosis of food allergy is the Oral Challenge, with the
ingestion of the suspected food by the patient \textsuperscript{3}.
There is no evidence in literature about the use of specific inhalation
Challenge in the field of food allergy, although it is considered the
reference for the diagnosis of Occupational Rhinitis and Occupational
Asthma; however its use is limited in specialized centers
\textsuperscript{9}. Being asthmatic is the main risk factor in these
patients. When an allergic patient has experienced an adverse reaction
after inhalation of food particles, the dietary and environmental
avoidance of the offending food has an essential role
\textsuperscript{9, 10}, as well as the educational interventions on
children and their families and the use of emergency treatment in case
of exposure to the allergen, represented by intramuscular administration
of Adrenaline, Short-Acting Beta Agonists (SABAs), oral corticosteroids
and antihistamines.

Our case report highlights the risk of anaphylaxis caused by inhalation
of milk vapors in children with severe food allergy. It is an event
rarely described and only adverse reactions related to cow's milk vapors
are reported in current literature, hence to date our case represents
the first report describing an adverse reaction caused by the inhalation
of sheep's milk vapors. According to the severe clinical course and the
possible airways involvement it is essential to identify the subjects at
risk, to limit the exposure to aerosolized food with environmental
measures and to practice the allergen avoidance diet and the emergency
treatment when anaphylaxis occurs.

\textbf{V. ACKNOWLEDGMENTS}

We thank our patient's mother for her precious collaboration.

\textbf{VI. INFORMED CONSENT}

Informed consent was obtained.

\textbf{VII. IMPACT STATEMENT}

Adverse reactions after the inhalation of food particles are an emerging
problem among children with food allergy, with an important impact on
their daily life. It's essential to identify and to follow-up these
patients, in order to implement educational and environmental measures,
with the essential role of the avoidance diet and the emergency
treatment in case of anaphylaxis.

\textbf{VIII. REFERENCES}

\begin{enumerate}
\tightlist
\item
  Peters RL, Krawiec M, Koplin JJ, Santos AF. Update on food allergy.
  Pediatr Allergy Immunol. 2021 May; 32(4): 647-657.
\item
  Caimmi D, Caffarelli C, Licari A, Miraglia Del Giudice M, Calvani M,
  Marseglia GL, et al. Food allergy in primary care. Acta Biomed. 2021
  Nov 29; 92(S7).
\item
  Leonardi S, Pecoraro R, Filippelli M, Miraglia del Giudice M,
  Marseglia G, Salpietro C, et al. Allergic reactions to foods by
  inhalation in children. Allergy Asthma Proc. 2014 Jul-Aug; 35(4):
  288-94.
\item
  Ramirez DA Jr, Bahna SL. Food hypersensitivity by inhalation. Clin Mol
  Allergy. 2009 Feb 20; 7: 4.
\item
  Roberts G, Golder N, Lack G. Bronchial challenges with aerosolized
  food in asthmatic, food-allergic children. Allergy. 2002 Aug; 57(8):
  713-7.
\item
  Barbi E, Gerarduzzi T, Longo G, Ventura A. Fatal allergy as a possible
  consequence of long-term elimination diet. Allergy. 2004 Jun; 59(6):
  668-9.
\item
  Nowak-Wegrzyn A, Shapiro GG, Beyer K, Bardina L, Sampson HA.
  Contamination of dry powder inhalers for asthma with milk proteins
  containing lactose. J Allergy Clin Immunol. 2004 Mar; 113(3): 558-60.
\item
  Steering Committee Authors; Review Panel Members. A WAO - ARIA -
  GA2LEN consensus document on molecular-based allergy diagnosis
  (PAMD@): Update 2020. World Allergy Organ J. 2020 Mar 7; 13(2).
\item
  Jeebhay MF, Moscato G, Bang BE, Folletti I, Lipi\selectlanguage{polish}ń\selectlanguage{english}ska-Ojrzanowska A,
  Lopata AL, et al. Food processing and occupational respiratory allergy
  - An EAACI position paper. Allergy. 2019 Oct; 74(10): 1852-1871.
\item
  Muraro A, de Silva D, Halken S, Worm M, Khaleva E, Arasi S, et al;
  GA2LEN Food Allergy Guideline Group; GALEN Food Allergy Guideline
  Group. Managing food allergy: GA2LEN guideline 2022. World Allergy
  Organ J. 2022 Sep 7; 15(9).
\end{enumerate}

\textbf{IX. TABLE}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Total IgE & 340 IU/ml & 0,00-48,00\tabularnewline
\midrule
\endhead
Bos d\_milk & 31,38 kU\textsubscript{A}/L & \textless{}
0,3\tabularnewline
Bos d 4 & 9,07 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Bos d 5 & 21,88 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Bos d 8 & 29,41 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cap h\_milk & 18,22 kU\textsubscript{A}/L & \textless{}
0,3\tabularnewline
Ovi a\_milk & 25,18 kU\textsubscript{A}/L & \textless{}
0,3\tabularnewline
Gal d\_white & 13,44 kU\textsubscript{A}/L & \textless{}
0,3\tabularnewline
Gal d 2 & 10,56 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Gal d 3 & 1,75 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Ara h 1 & 10,43 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cic a & 10,87 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Gly m 6 & 3,88 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Len c & 3,79 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Pis s & 3,48 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Ave s & 4,69 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Act d 1 & 18,66 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Ana o & 10,56 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Ber e & 8,42 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Car i & 2,35 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cor a 9 & 17,67 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cor a 11 & 5,84 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Jug r 1 & 1,27 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Jug r 4 & 11,24 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Pru du & 15,77 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cuc p & 2,01 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Hel a & 2,95 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Pap s & 8,86 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Ses i & 2,37 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cor a\_pollen & 4,79 kU\textsubscript{A}/L & \textless{}
0,3\tabularnewline
Der f 1 & 4,13 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Der p 1 & 10,98 kU\textsubscript{A}/L & \textless{} 0,3\tabularnewline
Cap h-epithelia & 7,12 kU\textsubscript{A}/L & \textless{}
0,3\tabularnewline
\bottomrule
\end{longtable}

Table 1. Component Resolved Diagnosis results.

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