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\begin{document}

\title{Resolution of Chronic Cough Following Treatment for Iron Deficiency
Anemia}



\author[1]{Eric Mull}%
\author[1]{Swati Jayaram}%
\author[1]{Ethan Bassett}%
\author[1]{Amanda Jacobson-Kelly}%
\author[1]{Rebecca Scherzer}%
\affil[1]{Nationwide Children's Hospital}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
A previously healthy 4-year-old female presented for a cough that was
not responsive to treatment of inhaled corticosteroid (ICS). Pertinent
history included meconium aspiration with no respiratory support
required and a course of confirmed SARS-CoV-2 with fever and mild
respiratory symptoms of a cough, that resolved in 2-3 weeks. Child was
seen in Allergy clinic 2 months before first Pulmonary clinic
appointment with a compliant of cough that redeveloped. Cough was dry,
associated with strenuous activity, and noticeably present at night. She
was started on albuterol 2 puffs every 4 hours, as needed.%
\end{abstract}%



\sloppy


\textbf{Resolution of Chronic Cough Following Treatment for Iron
Deficiency Anemia}

A previously healthy 4-year-old female~presented for a cough that
was~not responsive~to treatment of inhaled
corticosteroid~(ICS).~Pertinent history included~meconium aspiration
with no respiratory support required and~a~course of confirmed
SARS-CoV-2 with~fever and mild respiratory~symptoms of a cough, that
resolved in 2-3 weeks. Child~was seen in~Allergy clinic~2 months before
first Pulmonary clinic appointment with a compliant of cough~that
redeveloped.~~Cough~was dry, associated with strenuous activity,
and~noticeably present~at night. She was started on albuterol 2
puffs~every 4 hours, as needed.

At the one month follow~up in Allergy clinic,~cough remained present
with a mixed response to bronchodilator therapy. Given~her history~of
worsening cough at night and symptoms with~activity, as~well as a~minor
family history of asthma,~the patient~was started on fluticasone 44 mcg,
2 puffs twice a~day (BID).~At that time, she was~also referred
to~pulmonary division~for further workup and evaluation.

History~obtained during pulmonary visit reaffirmed~that obtained
from~the patient's~previous~allergy visits. In addition, there were no
reports of wheezing and whenever evaluated by a medical professional,
the~child always sounded ``clear.'' Vitals were~within~normal limits
with a saturation of peripheral oxygen (SpO2) of 96\%.~A chest x-ray~was
obtained showed nonspecific~findings of reactive~or viral airway disease
(Figure 1). Given that there was no improvement~on the~standard
dose~ICS~and the patient was too young to perform spirometry or fraction
exhaled nitric oxide (FENO) accurately, her therapy~was
altered~to~combination~ICS~with long acting beta2-agonist (LABA).
Mometasone/formoterol 100/5 mcg 1 puff BID.

Four months later, there was~almost complete resolution of nocturnal
cough and activity intolerance.~However, she~continued to have a
frequent dry cough during the daytime. As the patient was scheduled for
a direct laryngoscopy within the week of her pulmonary clinic visit, a
flexible bronchoscopy with bronchoalveolar lavage (BAL) was added
with~blood work under sedation~for a~severe asthma~workup, which
included a complete blood count (CBC) with differential and
immunoglobulin E (IgE).

Flexible bronchoscopy was unremarkable for visual findings other than
pale mucosa (Figure 1). Cultures showed no growth. Cytology showed a
neutrophil predominance of 50\%, followed by macrophages at 33\%, and
lymphocytes at 17\%. Due to the fact lipid-laden macrophage index of 6
out of 200 and~the absence~of findings of cobblestone mucosa,~aspiration
and reflux were~unlikely to be attributing to her symptoms. Her~blood
work~resulted showing IgE of 66 {[}IU{]}/mL (Reference Range {[}RR{]}
0-75). The CBC was concerning for microcytic anemia with a hemoglobin
(Hgb) of 10.4 g/dL (RR 11.5-13.5 g/dL) and a hematocrit (Hct) of 32.6\%
(RR 34.0-40.0\%). The mean corpuscular volume (MCV) was low at 68.5 fL
(RR 75.0-87.0 fL) and she had a basophilia of 1.8\% (RR 0.1-1.1\%).

Ultimately, she was~referred to hematology~and was started on oral
ferrous sulfate at 3 mg/kg daily after~finding her low ferritin~of 4
ng/mL (RR 7-142 ng/mL). After 2 months of~therapy, her~symptoms of
cough~completely resolved~and family weaned her from the
ICS+LABA.~Within 3 months after~that, she had
normalized~blood~work.~This included a Hgb 4.3 g/dL, Hct 43.8\%, MCV
82.8 fL, and a ferritin of 52. She was then transitioned to a
multivitamin. At her follow up in pulmonary clinic~two months after
discontinuing ICS+LABA, there were no respiratory complaints.

Cough is a common presenting symptom in
pediatrics\textsuperscript{{[}1{]}}. This natural process that protects
the airways and occurs~spontaneously or voluntarily.~If lasting longer
than 4 weeks in the pediatric~population, it~is considered
chronic\textsuperscript{{[}2{]}}. Common etiologies in children include:
asthma, protracted bronchitis, tracheomalacia, habit cough, and various
systemic disorders\textsuperscript{{[}2{]}}. This case is unique~due to
reported resolution of cough and ability to tolerate weaning~off
of~ICS+LABA following~the~identification and correction of iron
deficiency anemia (IDA).

Iron deficiency (ID) and IDA are very common~diagnoses worldwide,
impacting 1-2 billion individuals a year.~Occurring predominantly~in
children, especially in low- to middle income
families\textsuperscript{{[}3{]}}. Classically, ID is~characterized~with
fatigue, lethargy, difficulty concentrating, dizziness, tinnitus,
pallor, and headache\textsuperscript{{[}4{]}}. While~a cough~hasn't been
directly associated with ID, there is an association with nitric
oxide~(NO)~production\textsuperscript{{[}5{]}}, which is a modulator of
type 2~inflammation. It is increased~in the exhaled breath of many
asthmatics with its concentrations~widely~recognized~as a~marker of
airway inflammation and measured via fractional concentration of exhaled
nitric oxide (FENO)\textsuperscript{{[}6,7{]}}.~Other than occurring in
patients with~asthma,~NO~is known to be an important pathogenic effector
in pertussis and other respiratory tract diseases that are caused by
inflammation\textsuperscript{{[}8,9{]}}.

There are currently published reports of iron supplementation being
beneficial in the treatment~of a cough associated with angiotensin
converting enzyme inhibitor (ACEI). This is due to decreased ACEI
induced generation of NO in bronchial epithelial~cells. Iron has
the~ability to inhibit the activity of NO synthase (NOS), the
heme-related enzyme involved in NO production\textsuperscript{{[}10{]}}.
Thus, suggesting that iron supplementation~reduces the~generation of NO
and may consequently abolish a dry cough\textsuperscript{{[}6{]}}.

Although other~mechanisms by which ID may favor a lingering cough are
unknown, there have been findings of reduced epithelial airway thickness
in subjects with ID~that suggests~a cough~could be favored by increased
mucosa permeability to irritative stimuli\textsuperscript{{[}10{]}}.~In
addition,~plausible explanation~includes~ID acting to impair the defense
mechanisms of airway mucosa via physiologic
changes\textsuperscript{{[}11{]}}.~It is known that~ID weakens the
defensive response to injuries by impairing immune~function, such~as the
production of interleukin-2, a cytokine, which plays an important role
in maintaining the normal immune response\textsuperscript{{[}12{]}}.

In summary, while ID and IDA direct mechanisms for cough production are
unknown, there are known associations with physiologic changes in the
respiratory tract that~may promote and extend the length~of time for
a~cough to persist. When the targeted~therapy directly~addressed to
the~symptoms is not responding, there may be utility in the~differential
assessment~of standard blood work.

Swati Jayaram, MD\textsuperscript{a}, Ethan Bassett,
MD\textsuperscript{c}, Amanda Jacobson-Kelly, MD\textsuperscript{bd},
MSc\textsuperscript{d}, Rebecca Scherzer, MD\textsuperscript{be}, Eric
S. Mull, DO\textsuperscript{ab}

\textsuperscript{a}Division of Pulmonary
Medicine;\textsuperscript{b}Department~of Pediatrics;
\textsuperscript{c}Division of Otolaryngology;
\textsuperscript{d}Division of
Hematology/Oncology;\textsuperscript{e}Division of Allergy and
Immunology

Columbus, Ohio

Institution: Nationwide Children's Hospital; Columbus, OH

Funding Source: None

Financial Disclosure: None

Conflicts of Interest: None

Reference:

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\end{enumerate}

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\verb`IDA and Cough Figure.docx`  available at \url{https://authorea.com/users/326440/articles/659645-resolution-of-chronic-cough-following-treatment-for-iron-deficiency-anemia}

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