2 MATERIALS AND METHODS
2.1 Setting and patients
The clinical data of SMA children in the division of respiratory and
sleep disorders of the Children’s Hospital Affiliated with the Capital
Institute of Pediatrics in Beijing, China, from March 2016 to December
2021 were analyzed retrospectively. RRTIs and ARF were considered severe
conditions requiring intervention, and clinical characteristics were
analyzed to determine the risk factors for RRTIs and/or ARF in children
with SMA who had not started treatment with disease-modifying
medications or mechanical ventilation. This study was reviewed and
approved by the ethics committee of the Capital Institute of Pediatrics
(Identifier, SHERLL2019014). The study was exempt from informed consent.
2.2 Diagnostic criteria
SMA was diagnosed by a defect in the SMN1 gene localized to 5q11.2-q13.3
and classified into clinical groups on the basis of age of onset and
maximum motor function achieved: very weak infants unable to sit
unsupported (type 1), non-ambulatory patients able to sit independently
(type 2), and ambulant pediatric patients (type 3).1
RRTIs were diagnosed by the following criteria: for children under two,
upper respiratory infection ≥ 7 episodes/year, bronchitis ≥ 3
episodes/year, or pneumonia ≥ 2 episodes/year; two to five years old,
upper respiratory infection ≥ 6 episodes/year, bronchitis ≥ 2
episodes/year, or pneumonia ≥ 2 episodes/year; over five years old,
upper respiratory infection ≥ 5 episodes/year, bronchitis ≥ 2
episodes/year, or pneumonia ≥ 2 episodes/year. The number of lower
respiratory infections could replace the number of upper respiratory
infections, but not vice versa. The interval between onsets of
respiratory infection was at least seven days.5
The diagnostic criterion of ARF caused by infectious pneumonia was
severe dysfunction of ventilation with arterial partial pressure of
oxygen < 8.0 kPa (60 mmHg) while breathing room air,
with/without arterial partial pressure of carbon dioxide
(PCO2) > 6.7 kPa (50
mmHg).6
2.3 Inclusion and exclusion criteria
At enrollment, children were under eighteen years old and genetically
confirmed to have homozygous SMN1 gene alterations; all completed PSG
without signs of respiratory tract infection. Exclusion criteria
included the initiation of treatment with disease-modifying medications
or mechanical ventilation, alone or combined with the presence of other
congenital diseases or other neuromuscular disorders. All children were
divided into a disease group and a control group according to whether
RRTIs and/or ARF occurred within one year.
2.4 Data collection
The electronic and handwritten medical records created by doctors in the
division of respiratory and sleep disorders were reviewed to collect the
clinical data, including sex, age, height, weight, type of SMA, genetic
results, regular use of mechanical insufflation-exsufflation (MI-E),
number of occurrences of respiratory tract infection and ARF in one
year, past history and medication history. Spirometry was performed in
children over five years old who could complete the flow-volume loop
test using MasterScreen (Jaeger, Germany) equipment. The percent
predicted scores of spirometry were reported. PSG was attended by
trained pediatric sleep nurse using Alice 6 LDx (Philips, USA) equipment
and was scored using the American Academy of Sleep Medicine Version 2.3
pediatric criteria7 (see further details in
E-appendice 1). The age-specific body mass index z score (BMIz) was
obtained according to the WHO child growth standard and the 2000
American CDC growth curve standard.8,9
2.5 Statistical analysis
Continuous data conforming to a normal distribution are represented by
(x ± s), and the differences between two groups were evaluated by the t
test. Data not conforming to a normal distribution are represented by M
(Q1, Q3), and the differences between two groups were evaluated by the
Mann–Whitney U test. Categorical variables are expressed as cases (%),
and comparisons between groups were performed with the chi-square test
and Fisher’s exact test. The differences in clinical indices between the
two groups were compared, and the variables with statistically
significant differences were included in the binary multivariate
logistic regression. The results showed the risk of each covariate in
the model and 95% confidence interval to obtain the independent risk
factors for RRTIs and/or ARF in children with SMA. Receiver operating
characteristic (ROC) curves were constructed to determine the best
cutoff point for positive indicators that could best predict the
occurrence of RRTIs and/or ARF. The statistical significance of all
verifications was based on a bilateral P value < 0.05. SPSS
25.0 software was used for statistical processing, and GraphPad Prism
9.3.1 was used to draw ROC curves.
The clinical data were screened before logistic regression on the basis
of the clinical characteristics. The parameters of the spirometry were
not included because the test was not performed in children under five.
Because sleep stages vary greatly among children of different ages, for
instance, the sleep structure of infants is very different from that of
older children, such indicators with age differences were not
considered. In addition, in order to minimize the possible effects of
multicollinearity, the representative
apnea hypopnea index (AHI) was
chosen because there is overlap among the parameters of respiratory
events in PSG; moreover, the AHI is the sum of apneas and hypopneas
occurring per hour. In addition, the
mean pulse oxygen saturation
(MSpO2) with small individual differences was selected
because the standard deviation of MSpO2 was less than
the lowest pulse oxygen saturation (LSpO2).