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\title{COVID-19 infection in two children with cystic fibrosis in two prevalent
regions of the globe}



\author[1]{Hossein Sadeghi}%
\author[2]{Amin Saeidinia}%
\author[1]{Nooralam  Rai}%
\author[3]{HamidReza  KianiFar }%
\author[2]{Abdolkarim Hamedi}%
\author[2]{seyed javad seyedi}%
\affil[1]{Columbia University Medical Center}%
\affil[2]{Mashhad University of Medical Sciences}%
\affil[3]{3.	Allergy Research Center, Mashhad University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 07, 2024}


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\begin{abstract}
Cystic fibrosis (CF) is a disease with chronic lung disease that is
exacerbated by viral infection. COVID-19 has caused a worldwide pandemic
with high death rates. As science suggests, patients with CF would be
severely affected with a high rate of morbidity, hospitalization and
mortality. Our aim was to present two cases with CF in highly prevalent
COVID-19 regions of the world.%
\end{abstract}%



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\textbf{Introduction:}

CF is a chronic genetic disease with progressive lung disease,
malnutrition, liver disease and CF-related diabetes (1). Viral
infections are a major factor causing pulmonary exacerbations in CF (2).
In a recent study published by Cosgriff et. al. (3) people with cystic
fibrosis (CF) who were 15 years and older, infected with COVID-19 appear
to have better outcomes than initially anticipated. We report the only
two cases of CF in literature less than 15 years of age with better than
expected outcomes post COVID-19 infection and discuss the possible
effects of hypertonic Saline as a plausible explanation.

\textbf{Clinical Data:}

Two cases with CF affected by COVID-19 are presented; one a COVID-19
positive and the only hospitalized case of patient with CF in Iran, a
country of 82 million with an estimated CF carrier rate of 1 in 8,000
and an epicenter of COVID-19 in the Middle-East, and a second case in
New York City, an epicenter of COVID-19 in the United States, of a
patients with CF with past history of frequent exacerbations due to
viral infections who required no hospitalization despite two positive
COVID-19 parents.

Case 1 is a 3-month old male, the second child of a family with
consanguineous marriage, with pancreatic insufficient CF, who was born
at full term gestation with birth weight of 3.25 kg status post two
operations for intestinal obstruction at 3 and 46 days of life. Sweat
test were 98 mmol/L and 90 mmol/L. He was admitted because of fever,
tachypnea and hypoxia, with oxygen saturation of 78\% in room that
increased to 97\% on 4 L/min of oxygen via oxyhood. He weighed 3.5 kg.
Lungs were remarkable for bilateral crackles and presence of bilateral
lower limb edema. On admission, WBC was (16.9 x 109 )/L (21\%
neutrophil, 62\% lymphocyte and 10\% monocyte), Hb 9.4 g/L, platelet of
(412 x 109 )/L. Electrolytes and liver function tests were normal. Chest
radiograph and chest CT showed patchy infiltrates and increased
interstitial markings bilaterally. EKG was normal with QT interval of
0.37. G6PD level was normal. He was treated with Meropenem and
Vancomycin until the deep throat culture results showed Klebsiella
pneumonia that was sensitive to Meropenem. Vancomycin was discontinued.
Hydroxychloroquine was started at 3mg/kg/dose, twice a day for 10 days.
On the third day of admission, he was started on aerosolized albuterol
and hypertonic saline (5\%) three times daily with improvement in oxygen
requirement and respiratory symptoms. After five days of inhalation
therapy, his clinical status improved with resolution of respiratory
distress and oxygen requirement. His bilateral lower limb edema was
attributed to hypoalbuminemia and treated with nutritional
supplementation and appropriate pancreatic enzyme dosing.

Case 2 is a 10 years old girl with pancreatic insufficient cystic
fibrosis (delta F508/W1282X) with moderate bronchiectasis, G-tube for
nutritional support, and port for frequent IV antibiotics. In March of
2020, her BMI was 50\textsuperscript{th} percentile, FVC 1.35 L (72\% of
predicted value), FEV1 0.89 L (53\% of predicted value) , FEV1/FVC ratio
79\% and FEF25-75\% of 0.46 L/s (20\% of predicted value). Her family's
apartment is located in an urban neighborhood of New York City that is
among the most affected geographical location by COVID-19. Her parents
both developed symptoms including fever, chest congestion and cough and
tested positive for SARS-CoV-2 by nasopharyngeal RT-PCR. Although
isolation precautions were recommended, because of space limitations, it
was essentially impossible to keep the child with CF isolated while her
parents recovered. Additionally, because of delays in reporting of test
results, her parents did not learn they were positive until about 1 week
after symptoms started. This individual with CF requires frequent
courses of oral and IV antibiotics for CF pulmonary exacerbations, and
often they are triggered by common viral infections, based on PCR viral
respiratory panels tested on admission. With this in mind, our team
anticipated that she would be at risk for respiratory complications with
COVID-19. Remarkably, she developed a mild pulmonary exacerbation
characterized by cough and increased sputum production without hypoxemia
or associated weight loss that was managed at home with oral
sulfamethoxazole/trimethoprim, frequent chest vest therapy, nebulized
albuterol, 7\% hypertonic saline, and alfa dornase. She recovered
clinically about a week after starting these therapies.

\textbf{Discussion:}

Based upon our findings, COVID-19 does not significantly affected
individuals with CF. This can be due to infection control measures and
minimizing contact that hold true in many regions of the world but does
not apply to these two cases. One explanation for this observation can
be the CF medical therapy regimen that includes hypertonic saline.
Previous studies have shown that salt can affect viruses. In a study by
Zhang et. al. (4), high salt was identified as a crucial regulator of
signaling. In another study by Siber and Podgornik (5) the influence of
salt was shown on encapsidation of single- stranded viral RNA molecules.
This influence was also shown on double stranded RNA at 250 mM sodium
chloride. 5\% hypertonic saline is equivalent to 0.85 mM NaCl. More
studies are needed to answer the therapeutic role of hypertonic saline
in treatment of COVID-19.

There can be additional protective factors in CF such as genetics or
immunological factors that remain to be identified. It appears that
patients with CF need an additional risk factor such as malnutrition or
severe airway obstruction that puts them at risk from COVID-19
infection. There is still significant unknowns in dealing with the
COVID-19 infection and there is no place for complacency. Until there is
more scientific data, social distancing and infection control measures
should be continued.

\textbf{References:}

1.Elborn JS. Cystic fibrosis. Lancet. 2016; 388:2519-2531.

2.Frickmann H, Jungblut S, Hirche TO, Grob U, Zautner AE. Spectrum of
viral infections in patients with cystic fibrosis. Eur J Microbiol
Immunol. 2012; 2(3):161-175.

3.Cosgriff R, Ahern S, Bell SC, Brownlee K, Burgel PR, Byrnes C, Corvol
H, Cheng SY, Elbert A, Faro A, et al. A multinational report to
characterise SARS-CoV-2 infection in people with cystic fibrosis. J Cyst
Fibros. 2020. https://doi.org/10.1016/j.jcf.2020.04.012

4.Zhang WC, Du LJ, Zheng XJ, Chen XQ, Shi C, Chen BY, Sun XN, Li C,
Zhang YY, Liu Y, Xiao H, et al. Elevated sodium chloride drives type I
interferon signaling in macrophages and increases antiviral resistance.
J Biol Chem. 2018; 293:1030-9.

5.Siber A, Podgornik R. Influence of salt and viral protein charge
distribution on encapsidation of single-stranded viral RNA molecules. J
Org Chem. 2008;29(1). Doi:10.102/jo01024a700.

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