4. Discussion
In recent 10 years, an increasing number of studies about PB in children
associated with respiratory infections are being reported3-7. However, many literatures on PB and BCs are
composed of case reports or small case series, and accurate
epidemiological data of PB and BCs are still lacking. Lu S et al.6reported 22 cases of BCs among 161 MPP children with
FOB and BAL treatment from November 2015 to December 2016. Wei F et
al13 analyzed a study of 63 PB children associated
with influenza virus from May 2014 to April 2020. In the study, we
identified 269 children with PB from 4958 cases of pneumonia with FOB
and BAL treatment, and we estimated that PB accounted for 5.4% in
children with pneumonia requiring FOB.
We identified that MP, bacteria, influenza virus, ADV and Candida
albicans can trigger PB. In rencent years, PB associated with MP has
been reported in various studies. In a investigation enrolled 15
children with PB, MP infection accounted for 86.7% of the
cases4. Guo et al. also identified that in a study of
73 subjects with type I PB, MP infection was detected in 90.4% of the
children14. In the present study which is the largest
research to date of PB, MP was positive in 257 ( 95.5%) patients,
including single MP infecton in 202 (75.1%) cases and coinfection of MP
with bacteria and/ or virus in 55( 20.4%) subjects. Moreover, the
seasonal distribution of PB from 2016 to 2019 indicated that the peak
incidence of PB was observed in winter, especially in 2019 winter. Yan X
also 15demonstrated that MPP had a higher prevalence
rate in winter and peaks occurred in November 2019 in a 3-year
retrospective analysis from Bei Jing. The considerable detection rate of
MP in PB and epidemic consistency of PB and MPP indicated that MP is a
prominent pathogen of PB. MPP is usually considered to be self-limited
and benign16, however it may proceed to severe or
fulminant pneumonia, endanger the lives 17,18.
Previous studies 6,19,20 also showed that MP infection
can lead to varying degrees of respiratory mucus plug, even BCs,
resulting in PB. The mechanism of its role in PB maybe that MP infection
not only directly cause damage to the airway, including epithelial
necrosis to block the respiratory tract and cilia shedding to cause
cilia removal dysfunction, but also promote airway hypersecretion by the
excessive inflammation21,22. Compared with bacterial
and viral infections, MP infection is more likely to induce excessive
inflammatory response in the body23 which can induce
continuous formation of mucus plug in the airway and cause damage to the
whole body.
The mean age of our patients was 6.7 ± 2.8 years (range, 9 months-14
years) which was similar to the 6.1 ± 2.8 years reported in previous
study14. The clinical manifestations of PB are
diverse, including fever, cough, dyspnea or respiratory distress and
damage to extrapulmonary system, among which rapid progression to
hypoxemia can be applied as a strong indicator of PB. However, when
patients with mild symptoms have no or mild signs of hypoxemia, many
clinicians cannot recognize it. In our study, 62 (23.0%) cases suffered
from hypoxemia. Li W et al. [18] revealed that in their study all
the 15 children with PB showed no signs of hypoxemia, and Lu S et al.6 reported that only 9 out of 22 children with MPP BCs
received oxygen therapy. All the above suggested that hypoxemia was not
sensitive enough to discover PB. Therefore, we should comprehensively
evaluate the clinical manifestations in order to recognize PB timely.
The incidence of ICU treatment in our study was 17.8% ( 48/269 cases) ,
which was lower than that of 58.3% ( 14/24 cases) in Lu et al’s
study24, and no death cases were observed in our
study. The rate of critically ill and mortality was significantly lower
than previous descriptions8,25 . The possible
explanation may be attributed to the following two aspects. On one hand,
the clinical manifestation of PB depends on the location and degree of
bronchial obstruction, ranging from fragmented partial BCs to a large
and complete cast that fills the entire airway6. On
the other hand, rapid FOB treatment contributed to early effective
intervention and prevented the development of respiratory failure.
We found that patients in the multiple group exhibited severe clinical
manifestations, including higher peak body temperature, longer duration
of fever and hospitalization, higher incidence of intra and
extra-pulmonary complications, higher levels of inflammation indicators
and D-dimer. Furthermore, multiple logistic regression identified that
N% >75.5%, LDH >598.5U/L and
D-dimer>0.45mg/l were the independent risk factors for
multiple FOB therapy. It was reported that higher neutrophil(63.1%) was
positively correlated with excessive inflammation and disease
severity26 in children with MPP. LDH is a nonspecific
inflammatory biomarker and exists within the cytoplasm. Xu et
al.27 identified LDH as independent risk factor for
mucus plug formation in children with RMPP and our results showed that
LDH >598.5U/L is a predictor of multiple FOB therapy.
Although the pathogenesis of PB was not completely clear, at present it
is commonly believed that PB triggered by infection result from
inappropriate immune reponse to infection and direct damage of pathogen
to the airway3,28.The higher level of inflammation
biomarkers indicate the excessive inflammation, which can lead to
continuous formation of mucus plug, resulting in multiple FOB to clear
the subsequent BCs.
The increase of D-dimer is an important indicator of high fibrinolysis,
representing blood hypercoagulability and the presence of thrombi29. It was reported 30that the
D-dimer level in the severe MPP group was higher than that in the mild
group in children(0.61 vs.0.30mg/L), and the level of D-dimer was
positively correlated with the severity of MPP. In the study, we found
an elevated D-dimer level in PB children and D-dimer
>0.45mg/l was a risk factor for multiple FOB and BAL
treatments, which was consistent with the view of Zhang et
al31. Their study showed that children receiving
multiple FOB treatments for RMPP had higher D-dimmer levels (1.808 mg/L)
compared with the monotherapy group (0.567mg/L). However, the median
level of D-dimer in our study was lower than that of Zhang et al and we
speculated that there are two possible explanations. On one hand, the
enrolled subjects in the two study were different. RMPP children may
exhibit higher D-dimmer level duo to intensive body reponse to MP
infection. On the other hand, in the present study, D-dimer level of a
significant number of children may not be measured at the peak of
disease process. In summary, we speculated that hypercoagulability play
an important role in inducing subsequent mucus plugs formation of PB and
higher D-dimer level is an important risk factor for patients requiring
multiple FOB treatments.
The imaging features of children with PB were diverse, including
pulmonary consolidation, atelectasis, pleural effusion, emphysema and
pneumothorax14,32. Recent literature [18] found
that 13 out of 15 PB children had lung consolidation involved unilateral
or bilateral infiltration, and 5 cases developed pleural effusion. Lu S
et al.6 also observed that all 22 children with BCs
had lobar consolidation and 6 cases developed atelectasis. Our results
showed that the imaging manifestations of PB were not specific, and PB
patients were more likely to be associated with lung consolidation
(97.4%), which was consistent with the 98.6% of PB children with lung
consolidation or atelectasis reported previously14.
Therefore, we concluded that PB should be considered when patients with
persistent fever and large chest imaging infiltration.
Although PB presented with severe clinical manifestations and the
critical form in children has a mortality rate as high as 7-10% due to
failing to extract BCs in time8,9,25, the prognosis of
PB is generally favorable if the disease can be treated promptly. Most
reports 4,6 of effective therapy were based on
standard antibiotic treatment, glucocorticoids, IVIG and clearance of
BCs with FOB. In agreement with this notion, all patients in the present
study received appropriate antibiotic treatment, up to 95.5% subjects
received glucocorticoid therapy, and 20.4% received IVIG to modulate
immunity. FOB procedure is of prominent efficacy in treatment of PB,
including direct clearance of BCs to improve lung ventilation, the
clearance of various inflammatory factors and easy access to the lower
airway for the pathogenic detection. Recent studies33,34 found that compared with late FOB therapy, FOB
therapy during the early disease process in RMPP patients with large
pulmonary lesions resulted in faster recovery of clinical and
inflammation characters and shorter hospital stay. Furthermore, there
are a considerable number of children with PB requiring multiple FOB
therapy. In our study, the proportion of patients in mutiple group was
46.5% (125/269) which was consistent with the result of Cai
L35. Their study showed that more than 50% children
with PB received multiple FOB treatment and all achieved favorable
prognosis. In summary, we believed that in patients with persistent
fever, higher level of inflammation indicators and large infiltration in
chest imaging, FOB is of great significance in timely diagnosis and
effective treatment.
There were several limitations to this study. Firstly, it was a
retrospective study and there may have been some selection bias.
Secondly the patients were enrolled from a single center and the results
may not easily extrapolate to patients admitted to other regions.
Thirdly, to timely identify PB and avoid improper application of FOB, a
RCT study should be designed between PB and such diseases.