Clinical characteristics of 50 children with azygos lobe: a retrospective study

An azygos lobe is a rare anatomic variant of the lung which may be misdiagnosed as other pathological conditions. There is a dearth of information on the clinical characteristics of children with azygos lobe. This study aims to summarize the clinical features of children with azygos lobe, which may be helpful to improve recognition and clinical care of those patients. Clinical findings of the children with imaging findings of azygos lobe were collected and analyzed. In this study, 50 children with azygos lobe were included. A total of 28% cases were found to have azygos lobe incidentally. The remaining 72% cases were diagnosed when they presented with respiratory symptoms including cough (36%), fever (34%), wheezing (18%), dyspnea (14%), and cyanosis (8%). Congenital heart disease, Down syndrome, and other respiratory malformations were also found in a small proportion of these patients. Only 7 (14%) patients suffered from azygos lobe infection and were clinically cured after reasonable anti-infective treatment. Compared with the non-infected group, no valuable risk factors were found to be related to azygos lobe infection. All children who had azygos lobe infections responded to appropriate antibiotics therapy. There was no evidence that an azygos lobe was associated with recurrent infections. Conclusion: The clinical characteristics of children with azygos lobe are nonspecific and diagnosis relies on chest imaging. Some congenital abnormalities may be complicated with azygos lobe. It is reasonable to keep watch over those patients without symptoms. What is Known: • An azygos lobe is a congenital variation of the lung. • Azygos lobe can mimic various pathological conditions leading to misdiagnosis and inappropriate treatment in adults, which presents challenges during thoracic surgical interventions. What is New: • Azygos lobe in children may be complicated with other congenital abnormalities. • There is no evidence that azygos lobe is associated with recurrent infections. • After appropriate anti-infective treatment, those children with azygos lobe infections could be clinically cured. What is Known: • An azygos lobe is a congenital variation of the lung. • Azygos lobe can mimic various pathological conditions leading to misdiagnosis and inappropriate treatment in adults, which presents challenges during thoracic surgical interventions. What is New: • Azygos lobe in children may be complicated with other congenital abnormalities. • There is no evidence that azygos lobe is associated with recurrent infections. • After appropriate anti-infective treatment, those children with azygos lobe infections could be clinically cured.


Introduction
An azygos lobe is a congenital variation of the lung, present in about 0.2-1.2% of the population [1]. It forms during embryogenesis when the azygos vein penetrates through the upper lobe of the lung and drags the parietal and visceral pleura with it [2]. Since azygos lobe is a rare anatomic variant, its clinical features are not documented comprehensively; evidence is derived mainly from adult case reports. It is reported azygos lobe can mimic various pathological conditions leading to misdiagnosis and inappropriate treatment in adults, which presents challenges during thoracic surgical interventions. For instance, an azygos lobe may be confused with a pathological air space such as a bulla, abscess, or localized pneumothorax. A consolidated azygos lobe may be confused with a neoplasm, and the abnormally located azygos vein may be mistaken for a pulmonary nodule [2][3][4].
Compared to adults, the clinical characteristics of children with azygos lobe are even more obscure lacking structured analysis. Systematic evaluations are needed to improve timely recognition, and prevent misdiagnosis and unnecessary interventions. Here, we describe pediatric patients with azygos lobe by presenting demographics, clinical, and radiological characteristics.

Subjects and ethics statement
This study was conducted retrospectively at West China Second University Hospital, Sichuan University, a tertiary medical center in Sichuan province. Children with imaging findings of azygos lobe between November 2008 and February 2019 were enrolled in the study. Azygos lobe manifested as the "inverted comma or teardrop shape" on chest Xray, and a fine, convex line in the para mediastinal portion of the upper lobe on CT scan [5][6][7]. The Institutional Review Board/Ethics Committee affiliated with West China Second University Hospital, Sichuan University, approved this study, which was performed in accordance with the ethical standards of the Declaration of Helsinki.

Data collection and statistical analysis
The data of children's age, sex, manifestations, diagnosis, radiological characteristics, and other clinical information were collected. Data were analyzed using the Statistical Package for Social Sciences (SPSS), version 25.0 software (IBM, Armonk, NY). Continuous variables were compared using the Student t test or the nonparametric Mann-Whitney U test; categorical variables were compared using the chi-squared (χ 2 ) or Fisher's exact test. Two-sided P values of <0.05 were considered statistically significant.

Results
A total of 50 children diagnosed as azygos lobe by chest imaging were enrolled in the study. The age of these children varied from 64 days old to 15 years old. The male to female ratio was 27:23. Fourteen (28%) cases were diagnosed as azygos lobe incidentally, without any respiratory symptoms. Among those 14 patients, the radiological examinations were performed for assessment of nephroblastoma metastasis in 2 children and for routine screening of tuberculosis in the other 12 children before administration of systemic corticosteroid treating original diseases (Table 1). Thirty-six (72%) cases were found to have azygos lobe by chest radiology when they presented with respiratory symptoms, including cough (18/50, 36%), fever (17/50, 34%), wheezing (9/50, 18%), dyspnea (7/50, 14%), and cyanosis (4/50, 8%). What is more, 8 (16%) children had a history of recurrent respiratory infections (RRTIs). It is worth noting that RRTIs in those patients did not result from azygos lobe infection.
Moreover, some patients also suffered from other congenital abnormalities. Six (12%) patients were found to have either tracheal bronchus or tracheal stenosis, or both, which were diagnosed by bronchoscopy. One (2%) patient suffered from cystic adenomatoid malformation. Three (6%) patients had complications of congenital heart disease, and 2 (4%) with Down syndrome. Two (4%) patients had a history of preterm birth (Table 1). Notably, 20 (40%) cases with azygos lobes were not diagnosed by the first imaging examination; in other words, the rate of missed diagnosis was high.
In this study, 40 children with azygos lobe were diagnosed by CT alone, 9 children were diagnosed by chest X-ray alone, and 1 child was diagnosed by both methods. The azygos lobes of all cases were located in the right side. On the occasion of diagnosis, 29 (58%) patients had imaging manifestations compatible with pneumonia such as increased markings and infiltrates in the lung fields. Local emphysema, lung consolidation, and atelectasis were seen in 6 (12%), 5 (10%), and 2 (4%) patients, respectively. Furthermore, a small portion of patients manifested with pleural effusion (2/50, 4%) and pleuritis (2/50, 4%) by chest radiology. Among them, one patient (2%) presented with emphysema in azygos lobe, and 7 children (14%) diagnosed with azygos lobe infection, which manifested as patchy opacity (7/50, 14%). The infection was confined to the azygos lobe in 3 patients and involved other lung lobes besides the azygos lobe in 4 other patients ( Fig. 1, Table 2).
We analyzed the clinical characteristics of children with or without azygos lobe infection, and no significant differences between those two groups were found as for sex, age, and complications including other respiratory malformations, recurrent respiratory infections, and congenital heart disease ( Table 3). In this study, all children with azygos lobe infections were clinically cured (their clinical symptoms, abnormal signs disappeared) after reasonable anti-infective treatment.

Discussion
Since an azygos lobe is rare, it is poorly characterized. The lack of understanding leads to missed diagnosis and inappropriate interventions. In this study, we represent the largest case series of pediatric patients with azygos lobe and provide a picture of their clinical characteristics.
To date, clinical features of azygos lobe are mainly described in case reports in adults. Some studies report that an azygos lobe is not susceptible to disease. Because of the mesoazygos, the azygos lobe may be isolated from pathological processes developing in the rest of the lung tissue, such as the dissemination of pulmonary tuberculosis and other pathogen infection [8,9].
However, there are still other reports about pathological conditions associated within the azygos lobe. Ndiaye reported that the azygos lobe could lead to atelectasis or bronchiectasis if the fissure was too deep to compress the underlying bronchus draining the azygos lobe [10]. Cases of spontaneous pneumothorax [11,12], recurrent hemoptysis [6], and cancer [13,14] associated with an azygous lobe have been reported as well. Pathological processes originating from the azygos lobe, such as carcinoma, may be confined to it [3,15].
To the best of our knowledge, the clinical characteristics of children with azygos lobe have not been summarized so far. In this study, 14 (28%) children were found to have azygos lobe incidentally without respiratory symptoms, while the other 36 cases were diagnosed when they suffered from respiratory infections. The symptoms of all 36 patients were generally nonspecific including cough, wheezing, dyspnea, and cyanosis, which were very common in children with respiratory infections. Furthermore, there were no cases of bronchiectasis, pneumothorax, and neoplasm associated with azygos lobe in this case series in children. And the infection of azygos lobe, manifested as patchy opacity (14%), was found in 7 cases, which was different from most previous literature reports. Among them, 3 patients only had azygos lobe infection, while 4 patients also had infections of other lung lobes besides azygos lobe. So, it indicates that the azygos lobe also undergoes pathological changes in children, which should not be ignored. To explore risk factors related to the azygos lobe infection, characteristics of those cases with and without azygos lobe infections were compared. However, no significant risk factors were found.
Interestingly, we found that some cases with azygos lobe were also complicated with other abnormalities including tracheal bronchus, tracheal stenosis, cystic adenomatoid malformation, congenital heart disease, and Down syndrome. Since this is a retrospective study, it is difficult for us to further explore the association of azygos lobe with other abnormalities. For example, whether formation of azygos lobe is related to genetic variation is a question worthy of further exploration.
RRTIs in children remain a great challenge to pediatricians. China defines RRTIs through not only considering numbers   [16]. The causes of RRTIs vary a lot in children. Malnutrition, tobacco exposure, low social economic status, and immunodeficiency are reported to be contributors to the occurrence of RRTIs [17]. Other than that, many respiratory malformations affecting the airway and lung are also reported to be implicated with childhood RRTIs [17]. For example, bronchopulmonary sequestration and cystic adenomatoid malformation are common causes resulting in RRTIs. For those children suffering from sequestration or cystic adenomatoid malformation-related RRTIs, surgical excision of the affected lung may be considered [18,19]. In this study, although 8 patients reported a history of RRTIs, the infections did not result from azygos lobe, which was quite different from other respiratory malformations. Azygos lobe does not require special treatment unless it causes significant diseases, such as spontaneous pneumothorax, recurrent infection, and cancer. Thoracotomy and video-assisted thoracoscopic surgery lobectomy to treat lung cancer originating from azygos lobe were reported [14]. In addition, lobectomy was also recommended in patients with recurrent infection of azygos lobe and spontaneous pneumothorax associated with azygos lobe [12]. In this study, all the children with azygos lobe infection were clinically cured after reasonable anti-infective treatment. Almost one-third of children had no symptoms when they were diagnosed as azygos lobe. It seems azygos lobe is a somewhat benign variant of lung, but long-term follow-up is warranted since azygos lobe in patients may be complicated with spontaneous pneumothorax [12], cancer [14], and other congenital abnormalities.
There were some potential limitations of our study. First, it was a single-center study with a moderate sample size, which may not be generalizable. Second, because of the retrospective design, selection and observational bias may have affected the results. A more elaborate, match-controlled study may be conducted in the future to further confirm our results.  The clinical characteristics of children with azygos lobe are nonspecific and diagnosis relies on chest imaging. There is no evidence that azygos lobe is associated with recurrent infections. So, it is rational to wait and watch when children with azygos lobe are asymptomatic. After appropriate antiinfective treatment, those children with azygos lobe infections could be clinically cured. It is worth noting that azygos lobe in children may be complicated with other congenital abnormalities.
Abbreviations RRTIs, Recurrent respiratory infections; SPSS, Statistical Package for Social Sciences