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\begin{document}

\title{Neither iatrogenic nor hereditary cause; A rare case of anaphylaxis to
low sorb tubing used for infusions}



\author[1]{Amber Gibson}%
\author[2]{Muhammad Baig}%
\author[2]{Sana Mohiuddin}%
\author[3]{Wafik Zaky}%
\affil[1]{University of Texas MD Anderson Cancer Center Children's Cancer Hospital}%
\affil[2]{University of Texas MD Anderson Cancer Center}%
\affil[3]{MD Anderson Cancer Center}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\selectlanguage{english}
\begin{abstract}
Presented is an interesting case of a patient with diagnosis of central
nervous system (CNS) malignancy and Hashimoto thyroiditis, who developed
anaphylaxis to low sorb tubing which was used for chemotherapy and
supportive care medication. The patient had no known drug allergies and
an unremarkable work up for hereditary angioedema, rheumatological and
immunodeficiency disorders. This hypersensitivity reaction (HSR) has not
been previously reported in literature and delayed the patient's cancer
related treatment, which has the potential of impacting patient
outcomes. We report this rare case, discuss differential diagnosis for
HSR in patients with negative allergy history, and provide management
guidelines.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Hypersensitivity reaction to mediations is not an uncommon phenomenon in
cancer patients, but anaphylaxis to commonly used infusion lines,
particularly low sorb tubing has not been previously reported in the
literature. The possibility of adverse effects from interaction between
blood and plastic tubing created some concern in the early days of
medical care. The mechanisms responsible for most of these reactions are
unknown, and these reactions may be immunologic or non-immunologic. The
clinical presentation of these reactions can vary from mild cutaneous
reactions to severe life-threatening reactions. These life-threatening
anaphylactic reactions can limit the use of front-line chemotherapeutic
agents making it imperative to accurately find the inciting factor so
that appropriate chemotherapy can continue. Here we present a unique
case of a child with brain cancer and Hashimoto thyroiditis, who
developed an allergic reaction to the IV tubing system.

\textbf{Case Description}

A previously healthy four-year-old female with a new diagnosis of grade
IV primitive neuroectodermal (PNET) brain tumor underwent surgical
resection and came to our institution for chemo-radiation as standard of
care. The patient was scheduled to receive vincristine during radiation
therapy. During her initial infusion of vincristine she developed an
anaphylactic reaction with facial flushing, cough, lip swelling and
oxygen desaturation to 87\% at room air within 3 minutes of starting the
infusion. The infusion was stopped and the patient was given a dose of
diphenhydramine and hydrocortisone, which abated her symptoms.

An extensive root cause analysis was done to determine the cause of the
allergic reaction, since anaphylaxis to vincristine is rare. In the
following 2 weeks the patient had similar anaphylactic reactions while
receiving IV pentamidine and premedication with IV hydrocortisone,
proving that anaphylaxis was not due to vincristine. The patient did not
experience any reaction to saline flushes, chlorhexidine or alcohol
wipes.

Our work up for multiple allergic reactions included complement levels,
antibodies for rheumatologic and autoimmune diseases and thyroid
function tests. Thyroid stimulating hormone (TSH) was elevated at 7.3
mcunit/mL (normal reference 0.27 - 4.20). No eosinophilia or
immunodeficiency was detected in the work up and immunoglobulin levels
were unremarkable. The patient was referred to endocrinology and a
complete work up showed elevated prolactin 50.1 ng/mL (4.8 - 23.3 ng/mL)
which was secondary to TSH elevation. The patient also had clear
rhinorrhea for which an upper respiratory viral panel was sent and this
was negative. She was diagnosed as having allergic rhinitis, a common
co-exiting condition with Hashimotos thyroiditis, for which cetirizine
was started with moderate improvement of her symptoms.

Further work up by endocrine team revealed elevated thyroid peroxidase
antibodies at 29.8 IU/mL (reference range: 0.2 - 8.9 IU/mL) with
subsequent normalization of TSH and Free T4 which was consistent with
the diagnosis of Hashimoto thyroiditis.

The consistency found between all the allergic reactions was the IV
tubing set used. When we changed from low sorb tubing to regular tubing,
the patient did not experience any further allergic reactions to
chemotherapeutic and non-chemotherapeutic agents, without the use of
premedication. She was able to successfully receive additional doses of
vincristine and proceed with maintenance chemotherapy as standard of
care for PNET. The patient was referred to allergy and immunology for
further work up but there were no significant findings.

\textbf{Discussion}

Hypersensitivity Reaction (HSR) is common in cancer patients. Although
this can potentially happen with any therapeutic agent, such reactions
are common with platinum compounds, L-asparaginase, epipodophyllotoxins,
methotrexate, procarbazine and taxanes at a rate of approximately 6\% of
infusions. (1,2) HSR to plasticizing agents like phthalates and
triphenyl phosphite that are used in combination with polyvinyl chloride
(PVC) have also been well studied in the past. Phtahalates specifically
have been found to be a triggering factor for asthma and contact
dermatitis. (3) Additionally, triphenyl phosphite has been reported to
cause HSR in a case series involving 5 patients with reactions varying
from urticarial, angioedema to anaphylaxis. (4) Direct allergic
reactions to PVC are rare but several studies have suggested allergic
reactions to different components of PVC. (5-6) Because of this reported
hypersensitivity to PVC, many hospitals have now switched to PVC free
tubing systems. As in our case, the low sorb tubing system was used,
which is PVC free and has a polyethylene lining which provides an inert
surface to most chemicals and helps prevent absorption of drugs into the
matrix of the tubing material. Polyethylene compounds such as
Polyethylene glycol has been reported previously to cause HSR as part of
the PEGylated L-asparaginase or oral agents used for bowel regimen.
(7-9)

The HSR rate and severity depends on the administration route of
allergen. For example, pooled HSR rates using PEG-asparaginase in
children with acute lymphoblastic leukemia were between 23.5\% and 8.7\%
for IV and intramuscular (IM) administration, respectively (10).
However, Burke et al reported higher rates of PEG asparaginase
associated HSR with IM route (11).

Although HSR in pediatric cancer patients is not rare, for patients with
negative allergy history, the HSR differential diagnosis should include
autoimmune/rheumatologic disorders, hereditary angioedema, some
immunodeficiency disorders and mast cell disorders. As in our patient,
she was diagnosed with Hashimoto Thyroiditis during her work up. High
concordance of allergic disorders with Hashimoto disease (up to 23\%)
has previously been reported, which could be an added factor for the
severe reaction in our patient. (12) HSR management options include use
of an alternative drug, giving the same drug with premedication, or
performing desensitization. Switching agents, especially chemotherapy
can have a negative impact on patients' outcome when the culprit agent
is essential or is the best treatment option.

Skin tests can be used in the evaluation of IgE-mediated drug reactions,
but standardized testing dose for testing is only available for a few
drugs. The unclear mechanisms responsible for reactions to certain
drugs, and possible toxicity of testing reagents restrict the use of
this testing approach.

Furthermore, referral to allergist/immunologist is warranted for
patients with negative allergy history and multiple and/or severe HSR.

Up to date, no HSR to low sorb tubing has been reported in the published
literature. This case highlights the importance of targeted work up and
referral to an allergist in cancer patients with negative allergy
history, as switching cancer specific management may affect patient
outcomes.

\textbf{Authorship Contributions:} Amber Gibson has contributed to the
manuscript by leading the project and writing of the manuscript; Usman
Baig and contributed to the manuscript by revising the manuscript and
providing the table; Sana Mohiuddin has contributed to the manuscript by
editing the manuscript and providing the figure, Wafik Zaky has
contributed to the manuscript by serving as a senior author and final
revision of the manuscript.

\textbf{Disclosure of Conflicts of Interest:} There are no conflicts of
interest to disclose by any author.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
  Gillian M Shephard; Hypersionsitivity reactions to chemotherapeutic
  drugs; Clin Rev Allergy Immunol. 2003 Jun;24(3):253-62
\item
  Yagmur IT, Guzelkucuk Z, Yarali N, Ozyoruk D, Toyran M, Civelek E,
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\item
  Hwang YH, Paik MJ, Yee ST. Diisononyl phthalate induces asthma via
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\item
  Suuronen K, Pesonen M, Henriks-Eckerman ML, Aalto-Korte K. Triphenyl
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  dermatitis. 2013 Jan;68(1):42-9.
\item
  Aalto-Korte K, Alanko K, Henriks-Eckerman M L, Estlander T, Jolanki R.
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\item
  Sowa J, Kobayashi H, Tsuruta D,Sugawara K, Ishii M. Allergic contact
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\item
  Savitz JA, Durning SJ. A rare case of anaphylaxis to bowel prep: A
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\item
  Lee SH, Cha JM, Lee JI, et al. Anaphylactic shock caused by ingestion
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  David Gachoka. Polyethylene Glycol (PEG)-Induced Anaphylactic Reaction
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\item
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\item
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\item
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\end{enumerate}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/TABLE-1/TABLE-1}

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\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

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