Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, refers to a combination of immune complex-mediated (type III) and cell-mediated/delayed (type IV) hypersensitivity reactions to inhaled antigens (1). HP is a rare disease that can occur in people of all ages, with an average diagnosis age of 50–60 years (2). However, the number of HP diagnoses in children is far fewer than in adults. Due to the different causes and intensity of exposures, differences in geographical area, and differences in local climate and customs, there are no accurate epidemiological data of HP in the world (3). In children beyond the age of 2 years, more than half of all new cases of interstitial lung diseases (ILDs) in Germany were due to HP (4). Studies reviewing lung biopsies of pediatric patients with ILD have shown that HP can be present even in children younger than 2 years of age. Generally, the most common ILD entity diagnosed in children who have positive environmental exposure history is HP. HP is also one of most common diagnoses in children with ILD who are immunocompetent without systemic disorders (5). The latest HP guidelines divide HP into acute HP and chronic HP according to the course of the disease, and non-fibrotic HP and fibrotic HP according to histological characteristics, which have different clinical, imaging, and histological features (6). The clinical manifestations of HP patients are heterogeneous and are affected by various factors, such as the type of antigens, exposure time, timing of treatment, and genetics. The diagnosis and treatment guidelines for HP have been improved with the efforts of researchers and tend to be comprehensive (7).

Herein, we analyzed clinical characteristics, treatment, and outcome of HP children in our center for the purpose of improving clinicians' understanding of this disease.

In summary, we retrospectively reviewed and analyzed the clinical data of 6 children with HP admitted to our center. The 6 children received the acute diagnosis and treatment plan, and the prognosis was satisfactory.

It was previously reported that as of 2005, 95 children with HP had been reported worldwide (10). However, due to the narrow age range, limited environmental exposure, and non-specific clinical and imaging features, these may be related to a variety of other infections. Furthermore, immune-mediated diffuse lung diseases overlap, so HP is likely to be underreported and underdiagnosed in the pediatric population (11). Due to lack of prior knowledge, we believe that the number of children with HP in China is far underestimated. Most HP are sporadic; however, recent studies have found the existence of familial HP, which mainly occurs in Japan (12). Among our 6 children, two of the children's patients also suffered from HP at the same time, but due to economic factors, genetic testing was not performed. Studies have found that gene mutations related to telomere shortening, such as TERT, TERC, RTEL1, and PARN, are related to the pathogenesis of HP (13). In addition, further studies surface that MHC class II regions, proteins involved in antigen processing and presentation, and immune proteasome components will increase the risk of HP (14), and the increased risk of chronic HP is related to the MUC5B promoter polymorphism rs35705950 (15). This reminds researchers that research on genome-wide associations to assess genetic susceptibility is necessary. The specific pathogenesis of HP in children needs further study by multiple medical centers.

HP is an immune-mediated ILD that occurs in genetically susceptible individuals after repeated inhalation of organic antigens (such as fungi, bacteria, and animal and insect proteins), which may lead to an immune response to acute lung inflammation (16). It is characterized by recruitment of granulocytes as well as T cells and B cells (17). This immune response can become chronic, leading to the activation of myofibroblasts and the deposition of extracellular matrix (18). In certain individuals with progressive factors (such as aging, further exposure, or genetic susceptibility), key pathogenic changes occur, leading to the expansion and activation of fibroblasts and myofibroblast populations, and excessive extracellular matrix accumulate and destroy the lung structure, eventually leading to lung fibrosis (19). However, for children, once HP is diagnosed, most will return to normal soon after leaving the sensitized environment and rarely progress to fibrotic HP. This also suggests that lung biopsy is unnecessary (20). Children with HP in our center have been traced back to a clear history of sensitization. It is worth noting that in addition to pet dogs, pigeons, and moldy houses, more and more children are now showing interest in musical instruments, so before using wind instruments, thorough cleaning and disinfection are necessary to attract the attention of parents and children. This is similar to previously reported potential causes for musicians playing contaminated wind instruments as HP (21).

Patients with acute and subacute HP may have non-specific manifestations, such as fever, cough, shortness of breath, wheezing, and even dyspnea. In patients with chronic HP, the main manifestations are weight loss, decreased activity endurance, and small blisters on lung auscultation (22). Surprisingly, most of the children diagnosed in our center start with chest tightness, except for other system abnormalities. Combined with the history of exposure to the antigenic environment, it is necessary to be highly vigilant against the occurrence of HP.

For the diagnosis of HP, in addition to the medical history and specific pathogen IgG detection to identify antigens, other related tests, such as HRCT, BALF cytology analysis, and lung biopsy histology, mainly play a diagnostic role, while respiratory pathogen testing, parasite screening, special pathogen testing, etc. mainly play a role in differential diagnosis. The detection of specific antigen IgG is suspicious because it cannot be determined whether the increase in IgG is caused by contact with the antigen or by the body's immune response after exposure. In addition to testing for respiratory viruses, we also tested for fungi, cryptococcus, Aspergillus fumigatus, and parasites, and the results were all negative. Therefore, we believe that it is difficult to identify specific pathogens in children. In addition, the significant increase in eosinophil counts in the peripheral blood of 3 children aroused our attention. Except for parasitic infections, the significance of the increase in eosinophil counts in children with HP needs to be explored. In the past decade, circulating biomarkers related to HP, such as lung epithelial-derived proteins (KL-6 (23), YKL-40 (24) and CCL17 (25)) and ANA (26), have been well-studied. Six children with HP were tested for anti-nuclear antibodies in our center, and the results were all negative, and the conditions for testing other markers are temporarily unavailable.

Six children received HRCT after admission. Compared with HP chest HRCT features in the 2020 HP guidelines, interstitial changes in small airways with nodules or masses, rather than large-scale consolidations, were observed in HP children. However, HP children's chest HRCT in our center has some different characteristics. There were 3 cases of children with HRCT that showed increased mass shadows before treatment, a center density that was much higher than the periphery, and the periphery showing a halo sign or faint cloudiness. The lesion is close to the outer band of both lungs and close to the pleura. When it is treated, it appears that the peripheral lesions are absorbed before the central lesions and are finally completely absorbed without leaving any traces of the lesions. The HRCT signs of children with HP in our center are different from ILDs, such as Aspergillus infection, pulmonary hemorrhage, and pulmonary alveolar proteinosis. This should arouse the attention of imaging physicians to strengthen cooperation with clinicians and to provide an extra layer of insurance for the diagnosis of children with HP. Recently, one case report referred that lung FDG uptake, or its combination with CT findings, may be a biomarker for predicting disease severity or progression from subacute to chronic HP (27).

Since its introduction in the 1970s, bronchoalveolar lavage (BAL) has become increasingly recognized as a low-risk research tool that can provide potential prognostic value (28). When combining BALF cell analysis with HRCT and experienced multidisciplinary discussions, it may help narrow the differential diagnosis and help avoid surgical lung biopsy (29). In the characteristic BALF of HP, lymphocytosis (usually >50%) is less pronounced in chronic fibrotic HP, but is usually at a higher level than other ILDs. Some researchers maintain that BALF lymphocytosis >30% can distinguish chronic fibrosis HP from idiopathic pulmonary fibrosis. BALF cell morphology, such as T-cell activation and foamy macrophages, can also be used to support the diagnosis of HP (30). The clinical utility of a reduced CD4/CD8 ratio (usually between 0.5 and 1.5 in HP) is controversial because it varies greatly and often does not decrease or even increase in chronic HP (31). To our surprise, there was no significant increase in lymphocyte counts in the BALF of 3 children who underwent bronchoscopy. Due to insufficient knowledge, CD4/CD8 was not tested in our center. For children with HP, chronic fibrotic HP is relatively rare, and whether it progresses to pulmonary fibrosis needs to be carefully considered. In addition, whether the guardian is willing to accept the bronchoscopy of the child to obtain the results of the examination also needs to be considered, and the proficiency of BAL also has a certain influence on the results.

All 6 children completed the pulmonary function examinations with a high degree of cooperation, suggesting restrictive ventilation dysfunction, which is consistent with the changes in pulmonary function caused by small airway disease, but it is of no diagnostic value because many other ILDs can also cause the same changes. However, as a non-invasive test, lung function plays a certain role in evaluating the recovery process of children with HP.

The treatment principle of HP is to remove the exposure source, oral systemic corticosteroids, and immunosuppressive therapy (32). For chronic fibrotic HP, anti-fibrotic therapy is necessary (33). If children's HP is not effectively treated in the acute phase, it may become chronic HP. Among the 6 cases, 2 cases improved rapidly after breaking away from the exposure source, and 4 cases received glucocorticoid therapy, and the treatment effect was satisfactory. Other treatment options, such as the application of immunosuppressants, biological inhibitors, and anti-fibrosis drugs, have been reported; however, the center has no relevant clinical experience yet.

This study is the first national center in China to conduct a study on HP in children. First, it emphasizes the importance of finding a clear history of exposure and at the same time getting rid of pathogenic factors as early as possible is the first measure of treatment. Second, multi-disciplinary discussions facilitate the diagnosis of HP in children, such as the wisdom of the imaging department, the strategizing of the respiratory department, and the full assistance of the laboratory department. Finally, after more than 20 years of development, BAL has played an increasingly important role in the diagnosis and treatment of ILD in children. We will carry out more comprehensive and meaningful research on BALF in the near future for children with HP to provide more clues.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Ethics Committee of the children's hospital affiliated to Zhejiang university school of medicine and informed consent was obtained from the child's parents. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

FZ completed the first draft. TY, ZL, XJ, LY, and LW have participated in the data collection and improved the later revision of the article. LT revised the article to ensure the authenticity and practicability. All authors approved the final article as submitted and agree to be accountable for all aspects of the work.

This work was supported by National Natural Science Foundation of China (81170016, 81470214, and 82070028) and Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents (2016).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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