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\begin{document}

\title{Changing clinical characteristics of pediatric inpatients with pneumonia
during COVID-19 pandamic: a retrospective study}



\author[1]{Mengxue Chen}%
\author[1]{Yabing Zhou}%
\author[2]{Shengjie Jin}%
\author[1]{Shasha Bai}%
\author[1]{Xiaoyu Tang}%
\author[1]{Quanhua Liu}%
\author[1]{Liwei Wang}%
\author[1]{Ruoxu Ji}%
\author[1]{Haipei Liu}%
\author[1]{Wenwei Zhong}%
\author[1]{Yi Chen}%
\author[1]{Dingzhu Fang}%
\author[1]{Jianhua Zhang}%
\author[1]{Li Hua}%
\affil[1]{Shanghai Jiao Tong University School of Medicine}%
\affil[2]{The Hang Seng University of Hong Kong}%


\vspace{-1em}



  
  \date{June 04, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} The COVID-19 pandemic have impacts on the
prevalence of other {[}pathogen{]}(javascript:;)s and people's social
lifestyle. This study aimed to compare the {[}pathogen{]}(javascript:;),
allergen and micronutrient characteristics of pediatric inpatients with
pneumonia prior to and during the COVID-19 pandemic in a large tertiary
hospital in Shanghai, China. \textbf{Methods:} Patients with pneumonia
admitted to the Department of Pediatric Pulmonology of Xinhua Hospital
between March-August 2019 and March-August 2020 were recruited. And
clinical characteristics of the patients in 2019 were compared with
those in 2020. \textbf{Results:} Hospitalizations for pneumonia
decreased by 74\% after the COVID-19 pandemic. For
{[}pathogen{]}(javascript:;)s, virus, mycoplasma pneumoniae (MP) and
mixed infection rates were all much lower in 2020 than those in 2019 (
\emph{P} \textless{} 0.01). Regarding allergens, compared with 2019, the
positive rates of house dust mite, shrimp and crab were significantly
higher in 2020 ( \emph{P} \textless{} 0.01). And for micronutrients, the
levels of vitamin B2, B6, C and 25-hydroxyvitamin D (25(OH)D) in 2020
were observed to be significantly lower than those in 2019 ( \emph{P}
\textless{} 0.05). For all the study participants, longer hospital stay
(OR = 1.521, \emph{P} = 0.000), milk allergy (OR = 6.552, \emph{P} =
0.033) and {[}calcium{]}(javascript:;) (Ca) insufficiency (OR = 12.048,
\emph{P} = 0.019) were identified as high-risk factors for severe
pneumonia by multivariate analysis. \textbf{Conclusions:} The number of
children hospitalized with pneumonia and incidence of common pathogen
infections were both reduced, and that allergy and micronutrient status
in children were also changed after the outbreak of the COVID-19
pandemic.%
\end{abstract}%



\sloppy


\textbf{Full title:} Changing clinical characteristics of pediatric
inpatients with pneumonia during COVID-19 pandamic: a retrospective
study

\textbf{Running head:} Changing characteristics of pneumonia

\textbf{Authors:}Mengxue Chen\textsuperscript{1+}, Yabing
Zhou\textsuperscript{2+}, Shengjie Jin\textsuperscript{3}, Shasha
Bai\textsuperscript{1}, Xiaoyu Tang\textsuperscript{1}, Quanhua
Liu\textsuperscript{1}, Liwei Wang\textsuperscript{1}, Ruoxu
Ji\textsuperscript{1}, Haipei Liu\textsuperscript{1}, Wenwei
Zhong\textsuperscript{1}, Yi Chen\textsuperscript{1}, Dingzhu
Fang\textsuperscript{1}, Jianhua Zhang\textsuperscript{1*}, Li
Hua\textsuperscript{1*}

\textsuperscript{+} \textbf{Mengxue Chen and Yabing Zhou contributed
equally to the article.}

\textbf{Affiliations:}

\textsuperscript{1}Department of Pediatric Pulmonology, Xin Hua
Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai,
China.

\textsuperscript{2} Department of Traditional Chinese Medicine, Xin Hua
Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai,
China.

\textsuperscript{3} Department of Mathematics, Statistics and Insurance,
Hang Seng University of Hong Kong, Hong Kong, China.

\textbf{Correspondence to}

\textbf{Li Hua, MD, PhD}

Department of Pediatric Pulmonology, Xin Hua Hospital, Shanghai Jiao
Tong University School of Medicine, 1665 Kongjiang Road, Shanghai
200092, China.

Tel: +86 18818237316

E-mail: huali991229@163.com

\textbf{Jianhua Zhang, MD, PhD}

Department of Pediatric Pulmonology, Xin Hua Hospital, Shanghai Jiao
Tong University School of Medicine, 1665 Kongjiang Road, Shanghai
200092, China.

Tel: +86 15000572623

E-mail: zjh12195@126.com

\textbf{Author's contributions}

LH, JHZ, MXC and YBZ conceived and designed the study. YBZ, MXC, XYT,
QHL, LWW, RXJ, HPL, WWZ, YC and DZF collected the data. MXC, SJJ, SSB,
LH, YBZ, XYT, QHL and LWW sorted out the data. MXC, SJJ, SSB and LH
conducted the statistical analysis. MXC and LH drafted the manuscript.
LH, MXC, YBZ and JHZ reviewed and edited the manuscript. All authors
read and approved the manuscript.

\textbf{Abstract}

\textbf{Background:}

The COVID-19 pandemic have impacts on the prevalence of other pathogens
and people's social lifestyle. This study aimed to compare the pathogen,
allergen and micronutrient characteristics of pediatric inpatients with
pneumonia prior to and during the COVID-19 pandemic in a large tertiary
hospital in Shanghai, China.

\textbf{Methods:}

Patients with pneumonia admitted to the Department of Pediatric
Pulmonology of Xinhua Hospital between March-August 2019 and
March-August 2020 were recruited. And clinical characteristics of the
patients in 2019 were compared with those in 2020.

\textbf{Results:}

Hospitalizations for pneumonia decreased by 74\% after the COVID-19
pandemic. For pathogens, virus, mycoplasma pneumoniae (MP) and mixed
infection rates were all much lower in 2020 than those in 2019
(\emph{P}\textless{} 0.01). Regarding allergens, compared with 2019, the
positive rates of house dust mite, shrimp and crab were significantly
higher in 2020 (\emph{P} \textless{} 0.01). And for micronutrients, the
levels of vitamin B2, B6, C and 25-hydroxyvitamin D (25(OH)D) in 2020
were observed to be significantly lower than those in 2019
(\emph{P}\textless{} 0.05). For all the study participants, longer
hospital stay (OR = 1.521, \emph{P} = 0.000), milk allergy (OR = 6.552,
\emph{P} = 0.033) and calcium (Ca) insufficiency (OR = 12.048, \emph{P}
= 0.019) were identified as high-risk factors for severe pneumonia by
multivariate analysis.

\textbf{Conclusions:}

The number of children hospitalized with pneumonia and incidence of
common pathogen infections were both reduced, and that allergy and
micronutrient status in children were also changed after the~outbreak
of~the~COVID-19~pandemic.

\textbf{Keywords:}

Characteristics, Children, COVID-19, Pneumonia

\textbf{Introduction}

Pneumonia is the leading infectious cause of death amongst children
worldwide. It accounts for more than 138 million new cases and almost
one million deaths annually, mostly amongst children under 5 years
old\textsuperscript{1, 2}. Numerous pathogens, both viral and bacterial,
are involved in pediatric pneumonia. Research showed a concomitant
decrease in all-cause pneumonia during the COVID-19 pandemic in
China\textsuperscript{3}. These changes might have come from the
competition of severe acute respiratory syndrome coronavirus-2
(SARS-CoV-2) with other respiratory viruses, but they were more likely
to have come from improvements in population hygiene practices to
prevent SARS-CoV-2 transmission, such as wearing facemasks, paying
attention to hand hygiene\textsuperscript{4}.

SARS-CoV-2 is the third zoonotic and highly pathogenic coronavirus to
emerge in the twenty-first century\textsuperscript{5}. And the virus has
underwent frequent mutations and recombinations, yielding new variants
that can cross the species barrier\textsuperscript{6}. The World Health
Organization (WHO) has identified five variants of concern as Alpha,
Beta, Gamma, Delta, and the latest one named Omicron\textsuperscript{7}.
COVID-19 caused by SARS-CoV-2 emerged in December 2019 in Wuhan, Hubei
Province, China\textsuperscript{5}. On 11 March 2020, the WHO declared
the COVID-19 pandemic. Since then, the number of globally confirmed
COVID-19 cases has been increasing exponentially, which has engendered
substantial health and economic burdens worldwide\textsuperscript{8}.
Governmental agencies of different countries worldwide have been widely
promoting several measures to prevent the COVID-19 outbreak. Before the
vaccination programme at the end of 2020, the fight against the COVID-19
epidemic mainly relied on preventive measures, including encouraging
individual-level hygiene (wearing a mask outside, keeping social
distance, disinfecting with alcohol and washing hands frequently) and
community-level prevention measures (promotion of remote work and study,
suspension of mass gathering)\textsuperscript{9-12}. These
non-pharmaceutical interventions (NPIs) not only decrease the spreading
of the SARS-CoV-2, but also have impact on the prevalence of other
pathogens\textsuperscript{13-15}. Moreover, public health measures
during COVID-19 have led to an unprecedented change in social lifestyle
which might have effect on the allergen sensitization and micronutrient
levels in population\textsuperscript{16, 17}.

In this context, our study aimed to compare the pathogen, allergen and
micronutrient characteristics of pediatric inpatients with pneumonia
prior to and during the COVID-19 pandemic in a large tertiary hospital
in Shanghai, China. We present this article in accordance with the
STROBE reporting checklist.

\textbf{Methods}

\textbf{2.1 Study participants}

This was a retrospective study and conducted in Xinhua Hospital, a large
tertiary hospital in Shanghai, China. The inclusion criteria for the
study were: pneumonia patients admitted to the Department of Pediatric
Pulmonology of Xinhua Hospital from March to August 2020 (during the
COVID-19 pandemic when all students studied online at home and
strengthened personal protection) and in the same period of 2019 (prior
to the COVID-19 pandemic when all students studied at school) ; negative
for COVID-19; and aged 3 months to 16 years. Children were diagnosed
with pneumonia or severe pneumonia based on the criteria recommended by
the 2011 pediatric community-acquired pneumonia
guidelines\textsuperscript{18}. Since the COVID-19 pandemic, all
pneumonia patients were screened for COVID-19 using real-time reverse
transcriptase polymerase chain reaction and each recruited child was
confirmed negative for COVID-19. Patients with congenital abnormalities,
immunodeficiency, metabolic disorders, chronic conditions, underlying
lung diseases, airway foreign bodies, tuberculosis or nosocomial
respiratory infections were excluded from this study.

Written informed consent was obtained from parents or legal guardians
for all the subjects who are under 16. The study was approved by the
Ethics Committee of Xinhua Hospital (approval number: Approval No.
XHEC-D-2023-019), and conducted according to the principles in the
Declaration of Helsinki.

\textbf{2.2 Data collection and specimen detection}

The study participants' clinical characteristics, including age, sex,
length of stay, season of hospitalization, pathogen, allergen-specific
IgE (sIgE) and micronutrient levels were collected from the electronic
medical records.

Peripheral blood samples and respiratory specimens were obtained on
admission by trained nurses following standard operating procedures.
Pathogen detections were conducted, including: bacterial cultures
prepared from secretions of lower respiratory tracts; direct
immunofluorescence assay for the virus antibody tests, including
respiratory syncytial virus (RSV), adenovirus (ADV), influenza virus
(IV), parainfluenza virus (PIV) and coxsackie virus; and mycoplasma
pneumonia (Mp) IgM tested with ELISA. Mp infection was defined as
seropositivity of Mp IgM in the acute stage.

Five main allergens, namely house dust mite, milk, egg white, shrimp and
crab were evaluated in this study. Serum sIgE was measured by ImmunoCAP,
and concentration [?] 0.35 IU/ml was considered as positive, otherwise, as
negative\textsuperscript{19}.

The explored micronutrients in our study included vitamin A, B1, B2, B6,
C, serum 25-hydroxyvitamin D (25(OH)D), calcium (Ca)~and zinc (Zn).
Vitamins were analyzed with electrochemical detection, while calcium and
zink were determined with atomic absorption spectrometry.

\textbf{2.3 Statistical Analysis}

Clinical characteristics of the study participants prior to the COVID-19
pandemic were compared with those during the COVID-19 pandemic. All data
were entered into the statistical package SPSS version 25.0 (SPSS Inc.,
Chicago, IL, USA). Continuous variables were expressed as median
(interquartile range, IQR), and compared with Mann-Whitney U test.
Categorical variables were presented as number (\%) and analyzed using
Chi-square~test or Fisher's exact test. Binary logistic regression
analysis was used to examine the related factors of severe pneumonia in
children. Two-sided \emph{P} values [?] 0.05 were considered statistically
significant.

\textbf{Results}

\textbf{3.1 Clinical characteristics of pediatric inpatients with
pneumonia prior to and during the COVID-19 pandemic}

A total of 1038 children with pneumonia admitted to the Department of
Pediatric Pulmonology of Xinhua Hospital were enrolled, including 825
cases occurred from March to August 2019 and 213 cases during the same
period in 2020, which indicated a reduction of 74\% in the number of
pneumonia inpatients after the~outbreak of~the~COVID-19~pandemic. Figure
1 depicts monthly distribution of these inpatients.

Clinical characteristics of the pneumonia inpatients prior to and during
the COVID-19 pandemic were compared, as shown in Table 1. The median age
of the patients in 2020 was much smaller than that in 2019
(\emph{P}\textless{} 0.01), while the median hospital stay in 2020 was
signifcantly longer than that in 2019 (\emph{P} \textless{} 0.01). No
differences were found in gender and season of hospitalization between
the two years (\emph{P} \textgreater{} 0.05).

For pathogens, both virus and MP infection rate were much lower during
the~COVID-19~pandemic than those prior to it (\emph{P} \textless{}
0.01), whereas no significant difference was found in bacterial
infection rate between the two years (\emph{P} \textgreater{} 0.05).
In~virus~infections, coxsackie virus was the most common, followed by
IV, PIV and ADV in 2020, while IV was the most common virus, followed by
PIV, ADV and coxsackie virus in 2019. Compared with 2019, the positive
rates of RSV, ADV, IV and PIV were decreased in 2020. However, the
positive rate of coxsackie virus was higher in 2020 than that in 2019.
Mixed infections were signifcantly less frequent during
the~COVID-19~pandemic than those before the pandemic
(\emph{P}\textless{} 0.01). Co-infections with viruses and MP were the
most common type of mixed infection in both 2019 and 2020.

Regarding allergens, compared with 2019, the positive rates of house
dust mite, shrimp and crab were significantly higher in 2020
(\emph{P}\textless{} 0.01). And for micronutrients, the levels of
vitamin B2, B6, C and 25(OH)D in 2020 were observed to be significantly
lower than those in 2019 (\emph{P} \textless{} 0.05).

\textbf{3.2 Clinical characteristics of pediatric inpatients with severe
pneumonia prior to and during the COVID-19 pandemic}

Among the participants, 5.2\% (43/825) in 2019 and 3.3\% (7/213) in 2020
were diagnosed with severe pneumonia respectively, showing no difference
between the two years (\emph{P} \textgreater{} 0.05). Table 2 showed the
clinical characteristics of the children with severe pneumonia, and
significant differences were found in age and vitamin B6 status between
the two years (\emph{P} [?] 0.05). Severe pneumonia inpatients in 2020
with median age of 6 months were much younger than those in 2019 with
median age of 35 months. The level of vitamin B6 in 2020 was lower than
that in 2019. No differences were found in other characteristics between
the two years (\emph{P} \textgreater{} 0.05).

\textbf{3.3 Related factors of severe pneumonia in pediatric inpatients
prior to and during the COVID-19 pandemic by univariate analysis}

Through univariate analysis, related factors of severe pneumonia were
explored among the patients prior to and during the~COVID-19~pandemic
respectively. As shown in table 3, younger age, longer hospital stay,
hospitalization in spring and insufficiency of Ca~and Zn had significant
correlations with severe pneumonia among the children in 2019 (\emph{P}
\textless{} 0.05). However, in 2020, only younger age and longer
hospital stay were found associated with severe pneumonia (\emph{P}
\textless{} 0.05).

\textbf{3.4 Related factors of severe pneumonia in pediatric inpatients
by multivariate analysis}

Binary logistic regression analysis was used to examine risk factors of
severe pneumonia among all the children. Table 4 showed that longer
hospital stay (OR = 1.521, \emph{P} = 0.000), milk allergy (OR = 6.552,
\emph{P} = 0.033) and Ca insufficiency (OR = 12.048, \emph{P} = 0.019)
were high-risk factors for severe pneumonia in the pediatric inpatients,
after adjusting for other factors.

\textbf{Discussion}

We found that between March-August 2020, the number of children
hospitalized with pneumonia at Xinhua Hospital was decreased by 74\%
compared with the same period of 2019. Recent studies have witnessed a
significant reduction in the numbers of pediatric admissions in 2020 in
many other countries, including France, the United States and
Morocco\textsuperscript{20, 21}. This was due to the recommendations
imposed at the beginning of the pandemic to avoid access to hospital,
except in cases of real need, and also to the public fear of SARS-CoV-2
infection in the hospital \textsuperscript{22}. Additionly, the change
in lifestyle during the COVID-19 pandemic might also have reduced the
onset of respiratory viral diseases by preventing much person-to-person
disease transmission\textsuperscript{23, 24}. In other words, this
reduction could be considered as an unexpected positive consequence of
the NPIs taken during the COVID-19 pandemic, which may have led to a
decrease in morbidity and healthcare costs of the infectious
diseases\textsuperscript{25}.

For pathogens, our results showed that viral, Mp and mixed infection
rate was reduced respectively in 2020 in children with pneumonia, which
was similar to Pengcheng Liu et al's, Ying Zhang et al's and Huang QS et
al's reports, possibly because of the use of stringent NPIs such as
lockdown and border closures in 2020\textsuperscript{25-27}. However, in
our study, the detection of coxsackie virus increased compared with
2019. The result is in line with the study of Andrew Po-Liang Chen et
al's in Taiwan\textsuperscript{28}. Since coxsackie virus is a
non-enveloped virus, it might be inherently less susceptible to
inactivation by ethanol-containing disinfectant\textsuperscript{29}.
This viral property might hamper the preventive effectiveness using
routine hand disinfectants. Furthermore, Leung et al's randomized
control trial suggests that face mask is more effective in filtering out
enveloped viruses than non-enveloped viruses\textsuperscript{30}.
Consequently, chloride- and hydrogen peroxide-based products should be
added for comprehensive infection control. In addition, it is important
that coxsackie virus should continue to be monitored diligently in
children during the COVID-19 pandemic. And the diseases caused by
coxsackie virus should be taken seriously such as hand-foot-mouth
disease (HFMD) or herpangina.

Change in lifestyle could trigger the change of people's susceptibility
to various allergens\textsuperscript{16}. Our study showed that the
positive rates of allergens, including house-dust mite, shrimp and crab
in 2020 were significantly higher than those in 2019 in children with
pneumonia. The increasing positive rate of house dust mite during the
COVID-19 pandemic might be because people stayed at home for a long time
with poor ventilation. Shanghai has a humid subtropical monsoon climate.
The lack of ventilation led to long-term high relative humidity and lack
of sunshine in the house, which were more conducive to the accumulation
and reproduction of dust mites in carpets, pillows, and
mattresses\textsuperscript{31, 32}. Moreover, house dust mite
allergen,\emph{Der p1,} exerts several key activities on the airway
mucosa\textsuperscript{33}. Such molecules have been shown to favor
oxidative stress of the respiratory mucosa and, thus, to exacerbate
inflammatory conditions such as asthma or allergic
rhinitis\textsuperscript{34}. Regarding shrimp and crab allergens, the
reason would be that people's eating habits had been changed during the
pandemic and it also might be related to the co-sensitization with the
increasing positive rate of house dust mite\textsuperscript{35}.
Therefore, during home isolation, our room should be fully ventilated,
and the sheets and blankets should be washed frequently.

Our study found that hospitalized patients with pneumonia in children
presented the lower levels of vitamin B2, B6, C and 25(OH)D in 2020 than
those in 2019. The possible reason would be that the COVID-19 lockdown
has affected the dietary habits and nutritional patterns. It has been
reported that the dietary patterns of Chinese people during the COVID-19
lockdown changed, showing a decrease in the frequency of intake of fresh
vegetables and fruit, rice, poultry, meat, and soybean
products\textsuperscript{36}. However, certain nutrients such as vitamin
A, vitaminB2, vitamin B6, vitamin B12, vitamin D, vitamin C, and the
minerals Ca and Zn, are important for proper immune
function\textsuperscript{37}. Deficiencies and a suboptimal nutritional
status of these micronutrients could potentially favor the spread of
diseases by reducing resistance to infection and
reinfection\textsuperscript{17}. For example, the vitamin D receptor is
expressed in almost all types of cells of the immune system and the
correct immune system function will depend on the correct
bioavailability of vitamin D from these cells\textsuperscript{38}. For
vitamin C, it also has roles in several aspects of immunity, including
supporting leucocytes migration to sites of infection, phagocytosis and
bacterial killing, natural killer cell activity and antibody
production\textsuperscript{39}. To date, despite the existence of
several vaccines in motion to deal with the SARS-CoV-2, the global
population must learn to live for a longer time with the virus among
us\textsuperscript{17}. Therefore, we should keep a healthy and balanced
diet in our daily life to strengthen our natural defense system.

There were some limitations in this retrospective study. First, our
report was a single-center study, and we only enrolled pneumonia
inpatients in our clinical center between March-August 2020 when all
students studied online at home and stringent public health measures
were adopted during the COVID-19 pandemic. From September 2020, students
went back to school. As the control, pneumonia inpatients in the same
period of 2019 were recruited prior to the COVID-19 pandemic. Our
results were based on a small number of pneumonia cases, and thus they
should be interpreted with caution and confirmed in future studies.
Second, the identification of the pathogens responsible for pneumonia
remains challenging, particularly when mixed infections occur. A
proportion of children in this study had no proven causal pathogen. The
low detection rate of bacteria and viruses in our study may be due to
the fact that some inpatients received antibiotic therapy in outpatient
department. The use of next-generation sequencing for pathogen detection
could be a useful additional method. Third, only five main allergens
were analyzed in this study. Finally, the effects of micronutrient
supplementation was not taken into account due to lack of information in
this aspect.

\textbf{Conclusions}

The data in this study suggest that number of children hospitalized with
pneumonia and incidence of common pathogen infections were both reduced,
and that allergy and micronutrient status in children were also changed
after the~outbreak of~the~COVID-19~pandemic and adoption of stringent
public health measures.

\subsection*{ACKNOWLEDGEMENTS}

{\label{acknowledgements}}

We thank all of the study participants and their parents.

\textbf{Funding information}

This study was funded by the Project for Innovation Teams in Local High
Level Universities in Shanghai, and the Medical Innovation Research
Project of ''Scientific~and~Technological~Innovation~Action~Plan'' of
Science and Technology Commission of Shanghai Municipality (No.
20Y21900500).

\textbf{Conflict of interests}

No financial or non-financial benefits have been received or will be
received from any party related directly or indirectly to the subject of
this article.

\textbf{Ethical Statement}

The authors are accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved. The study was conducted in
accordance with the Declaration of Helsinki (as revised in 2013).The
study was approved by the Ethics Committee of Xinhua Hospital (Approval
No. XHEC-D-2023-019).

\textbf{Data availability}

The datasets generated during and/or analysed during the current study
are available from the corresponding author on reasonable request.

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