Clinical Analysis of Atelectasis Caused by Inuenza A in Xiamen Children’s Hospital Between 2017 and 2019

Background: We aimed to analyze the clinical characteristics of pediatric patients with atelectasis caused by inuenza A to provide a reference for reasonable clinical diagnosis and treatment. Methods: We included 79 pediatric patients with atelectasis caused by inuenza A diagnosed at Xiamen Children’s Hospital between January 1, 2017 and December 31, 2019. We analyzed their epidemiological characteristics, clinical manifestations, imaging changes, diagnosis, treatment process, and outcomes. Results: Among the 79 included patients (males: 52; females: 27), 70 (88.61%) were > 6 years-old and 54 (68.35%) had atelectasis onset during winter. A majority experienced fever and cough. Among them, 44, 16, 21, 14, and 12 had normal/decreased white blood cells, elevated procalcitonin, abnormal hepatic function, abnormal myocardial enzyme spectrum, Mycoplasma pneumoniae infection, and Streptococcus pneumoniae infection, respectively. Seventy-nine patients presented different atelectasis degrees, including 16 and 29 with atelectasis in the right and left lung, respectively, while 34 had multiple consolidations and atelectasis lesions in both lungs. Fiberoptic bronchoscopy examination of 57 cases revealed mucus plug blockage in 6 cases; among them, 2 cases underwent bronchial cast removal. All patients received oseltamivir or peramivir for antiviral treatment and antibacterial treatment for complicated bacterial infection. All the patients recovered and were eventually discharged. Post-discharge follow-up showed that 77 cases were cured while 2 experienced recurrent respiratory tract infections and post-activity shortness of breath with chest computer tomography showing mosaic perfusion.

revealed mucus plug blockage in 6 cases; among them, 2 cases underwent bronchial cast removal. All patients received oseltamivir or peramivir for antiviral treatment and antibacterial treatment for complicated bacterial infection. All the patients recovered and were eventually discharged. Post-discharge follow-up showed that 77 cases were cured while 2 experienced recurrent respiratory tract infections and post-activity shortness of breath with chest computer tomography showing mosaic perfusion. Conclusion There is a high incidence of atelectasis caused by in uenza A during winter among children aged < 6 years. The main manifestations are fever (mostly hyperpyrexia) and cough. Chest imaging shows consolidation and atelectasis occurring in any lung lobe. Some patients present multiple consolidations and atelectasis lesions complicated by mucus plugs or bronchial casts. Timely beroptic bronchoscopy and alveolar lavage could shorten the disease course and improve the prognosis.

Background
In uenza is an acute respiratory tract infectious disease that is caused by in uenza viruses. Based on the antigenicity of the viral matrix protein and nucleoprotein, in uenza viruses are classi ed into type A, B, and C (or in uenza A, B, and C). In uenza A has high antigenic variability and strong infectivity, which causes a sudden start and rapid disease progression with subsequent adverse effects on human health. Children, who are at a high risk of in uenza A, should receive particular attention. Atelectasis refers to a condition characterized by reduced capacity/air content in one or more lung segments/lobes. It is not an independent disease; rather, it often occurs as a complication of various chest diseases. Infective atelectasis is most prevalent among children. It may cause recurrent infections if not promptly diagnosed and treated. Moreover, if long-term treatment is not effective, the pulmonary function may be affected and respiratory failure may occur. Therefore, given the high possibility of in uenza A causing atelectasis, pediatricians should be highly vigilant. However, there have been few clinical studies on atelectasis caused by in uenza A. Consequently, we aimed to analyze the clinical data from pediatric patients with atelectasis caused by in uenza A. We believe that this study could improve doctors' understanding of this disease.

Participants
In this retrospective study, we included 79 pediatric patients with atelectasis caused by in uenza A who were hospitalized in Xiamen Children's Hospital from January 1, 2017 to December 31, 2019. This study was approved by the Ethics Committee of Xiamen Children's Hospital. We obtained informed consent from the families of all the pediatric patients.

Diagnostic basis
According to the Diagnosis and Treatment Plan for In uenza (2018 Edition) [1] issued by the National Health Commission, respiratory tract specimens (including nasopharyngeal swabs and sputum) were collected from the pediatric patients upon hospital admission. Alveolar lavage uid was collected from some pediatric patients and a de nitive in uenza A diagnosis was made via immuno uorescence detection. Atelectasis was con rmed using pulmonary imaging (chest X-ray and/or chest computed tomography [CT]) for all patients.

Data collection
Epidemiological survey: We analyzed 79 pediatric patients with atelectasis caused by in uenza A with respect to the onset season, sex, age, etc.
Clinical analysis: We analyzed the clinical manifestations, laboratory examinations, imaging data, treatment plans, e cacy, outcomes, and other characteristics of the included patients.

Statistical analysis
We used SPSS 22.0 statistical software for data processing. We expressed normally and non-normally distributed measurement data as mean ± standard deviation (x ± s) and median (quartile distance), respectively. Enumeration data were expressed as a percentage.

Epidemiological Characteristics
Between January 1, 2017 and December 31, 2019, 79 pediatric cases of atelectasis caused by in uenza A were de nitively diagnosed in the Xiamen Children's Hospital. These patients included 52 males and 27 females with a male-to-female ratio of 1.94:1.00. The mean age at onset was 4.4 (1.1,5.8) years (0.6-12.5 years). Speci cally, 43.04% (34/79), 45.57% (36/79), and 11.39% (9/79) of the patients had an age at onset of < 3 years, 4-6 years, and > 6 years, respectively. Table 1 presents the speci c age distribution of the included patients. During the three years between 2017 and 2019, the disease onset mainly occurred between November and February, which corresponded to the winter season. Figure 1 shows the speci c time (seasonal) distribution of the onset of atelectasis caused by in uenza A. Bronchoscopic examination and treatment: A total of 57 (72.15%) cases were treated via beroptic bronchoscopic examination and alveolar lavage.
The main manifestations of bronchoscopic examination were mucosal hyperemia and edema; moreover, in ammatory secretions and various sputum volumes were visible. There was signi cant mucus plug blockage in 6 patients (see Fig. 4) who subsequently underwent beroptic bronchoscopic lavage 2-3 times. Among them, 2 patients underwent bronchial cast removal via the bronchoscope (see Fig. 5).
Treatment and outcome: All the pediatric patients received antiviral (oseltamivir/peramivir) treatment after de nitive diagnosis.
Patients with bacterial or Mycoplasma pneumoniae infections received anti-infective treatment. Among them, 9 and 13 patients received gamma globulin for immunity regulation and short-term methylprednisolone for anti-in ammatory treatment, respectively. Moreover, 2 patients were under mechanical ventilation during treatment. Patients with hepatic dysfunction and abnormal myocardial enzyme spectrum underwent liver protective and myocardial nutritional treatments, respectively. The length of hospital stay ranged from 7 to 21 days. All the included pediatric patients fully recovered and were discharged. During the 6-month post-discharge follow-up period, 2 pediatric patients presented with recurrent respiratory tract infections and post-activity shortness of breath. Chest CT showed mosaic perfusion and small airway lesions.

Discussion
In uenza A virus is among the important viral pathogens that cause respiratory tract infections among children. Moreover, atelectasis caused by in uenza A is clinically common. In uenza A is highly prevalent during winter and spring with children being at high risk. Atelectasis caused by in uenza A has similar epidemiological characteristics to those of in uenza A. We observed a 68.35% (54/79) incidence rate of atelectasis caused by in uenza during winter (December to February) in our hospital between 2017 and 2019; moreover, 88.61% (70/79) of the con rmed cases were aged < 6 years. This is consistent with previous epidemiological studies on pediatric in uenza in China and other countries [2,3]. Young children are at a high risk of in uenza A and subsequent atelectasis, which could be attributed to the immature immune function, decreased anti-infection ability, and insu cient ability of the body to inhibit postinfection virus replication. Our ndings indicated that the incidence of atelectasis caused by in uenza A was higher in males than in females (with a male-to-female ratio of 1.94:1). However, this study has a relatively small sample size; moreover, related previous studies in China and other countries lacked a large sample size. Therefore, the exact gender characteristics of atelectasis caused by in uenza A remain unclear.
Atelectasis is characterized by absent or reduced lung gas volume resulting from various causes, which is accompanied by collapsed lung tissue and reduced lung volume. Infections are an important cause of pediatric atelectasis. After a child is infected with in uenza A virus, a strong in ammatory response could cause accumulation and release of many in ammatory cells, sputum congestion, reduced airway mucociliary clearance ability, and other pathophysiological changes, leading to atelectasis. The clinical atelectasis symptoms caused by in uenza A range in severity. They are mostly characterized by acute onset with similar typical symptoms as to those of atelectasis caused by infections with other pathogens [4,5]. Fever and cough with expectoration of different degrees are the main manifestations with fever being the initial symptom in most cases. Children with persistent hyperpyrexia could present with complicated febrile convulsion. Laboratory examinations may present with increased D-dimer, FDP, creatine kinase isoenzyme, and transaminase levels, as well as electrolyte disturbance. Notably, the proportion of patients with maximum temperature > 40℃ was high (65.82%) with the longest duration being 12 days. Therefore, persistent hyperpyrexia could be an important indicator of pediatric in uenza A progressing to atelectasis. Prolonged hyperpyrexia indicates ineffectively controlled in ammation, which causes congestion, edema, necrosis, and shedding of the bronchial mucosa, as well as lumen blocking and compression, which results in atelectasis.
We found that 42 (53.16%) cases with atelectasis caused by in uenza A that presented with mixed infections. The main pathogens include Mycoplasma pneumoniae, Streptococcus pneumoniae, Haemophilus in uenzae, Moraxella catarrhalis, etc. A prospective observational study on in uenza virus by Casalino et al. [6] reported that only 5.6% and 28.6% of in uenza-negative and in uenza-positive patients, respectively, had complicated bacterial infections. This indicates a similar incidence as that observed in this study. In uenza A virus can destroy host epithelial cells, which reduces the host's resistance to external pathogens and contributes toward secondary mixed infections. In uenza virus has been shown to remove sialic acid residues of glycoproteins on the surface of the host cell membrane through neuraminidase. This exposes receptors that bind bacteria bind to cells, which facilitates bacterial colonization and subsequent infections [7]. Wu et al. [8] reported that in uenza A virus signi cantly reduced the response-ability of host macrophages and neutrophils to Streptococcus pneumoniae, as well as the levels of in uenza virus-speci c antibody. This results in an increased probability of mixed infections among patients with in uenza A. There is currently no de nite conclusion regarding the pathogen most likely to cause concurrent infection with in uenza. Although we observed a high mixed infection rate in atelectasis caused by in uenza A, there were different proportions of patients infected with Mycoplasma pneumoniae and different bacteria (Streptococcus pneumoniae, Haemophilus in uenzae, and Moraxella catarrhalis). Therefore, we could not determine the pathogen most likely to cause complicated infections. Moreover, we employed a limited sample size; therefore, there is a need for future studies with larger studies to perform more detailed assessments.
Regarding in uenza A treatment, various guidelines in China and other countries have indicated that antiviral treatment application at the early disease stage (within 48 hours of onset) could reduce in uenza complications, minimize mortality, and shorten hospital stay [1,9]. It remains di cult to clinically diagnose in uenza within 48 hours. We found that most pediatric patients with atelectasis caused by in uenza A did not have an early-stage diagnosis. However, a majority of the patients showed relatively good responses to treatment with neuraminidase inhibitors oseltamivir or peramivir at 48 hours after disease onset. For those who did not, glucocorticoid and/or gamma globulin treatment had a good response. During the follow-up period, two pediatric patients presented recurrent respiratory tract infections and post-activity shortness of breath; further, mosaic perfusion images were observed on lung CT. Occlusive bronchiolitis should be carefully considered and doctors should pay attention to the longterm complications of in uenza virus infection.
The effect and status of bronchoscopic lavage in the treatment of infectious atelectasis remain unclear in China and other countries. Previous studies have suggested that infection-induced atelectasis could subside spontaneously after anti-infective treatment and that bronchoscopic treatment could be excessive [10]. We believe that the advantages of bronchoscopy outweigh its disadvantages. Bronchoscopic alveolar lavage removes pathogens adhered to the airway surface by in ammatory media, effectively reduces direct and indirect pathogen-induced damages to bronchial mucosa, improves lung expansion ability, facilitates lung in ation and pulmonary circulation restructuring, effectively improves clinical pediatric atelectasis symptoms, shortens the disease course, and reduces complications. Among our included patients, 57 were treated with bronchoscopy, which showed su cient e cacy in all of them. Bronchoscopic examination can also be used for differential diagnosis and identifying other complications. In our study, bronchoscopy revealed signi cant mucus plug blockage in 6 pediatric patients; among them, 2 underwent bronchial cast removal through the bronchoscope. This blockage could be attributed to increased airway mucus secretion and decreased clearance ability after cilia damage caused by post-infection continuous in ammatory stimulation. Pulmonary atelectasis complicated by mucus plugs or bronchial casts is a serious complication of in uenza A virus infection. In these cases, tracheoscopy is indicated and bronchial cast removal via bronchoscopy is the most direct and effective diagnosis and treatment method [11,12].

Conclusions
In conclusion, atelectasis caused by in uenza A mainly occurs during winter and among children aged < 6 years. Its main manifestations are recurrent hyperpyrexia and cough with chest imaging showing consolidation and atelectasis. Moreover, mixed infections may occur. Based on conventional antiviral treatment, timely beroptic bronchoscopic examination and alveolar lavage could shorten the disease course, as well as improve clinical symptoms and prognosis.

Declarations
Ethics approval and consent to participate