Respiratory infection induced episode of alveolar hemorrhage (RIIEAH) in the pediatric diffuse alveolar hemorrhage: a retrospective single-center study

Abstract

Background

Respiratory infections are recognized as common triggers of alveolar hemorrhage episodes in pediatric diffuse alveolar hemorrhage (DAH). However, comprehensive studies investigating this association in detail remain limited. The aim of this study was to explore the etiological spectrum, clinical features, treatment strategies and outcomes of the respiratory infection induced episode of alveolar hemorrhage (RIIEAH) in the pediatric DAH.

Methods

The children of DAH who had RIIEAH and a definite etiological diagnosis were included. All the subjects had been hospitalized in the Department of Pediatrics at the First Affiliated Hospital of Guangxi Medical University from January 2023 to February 2024. A retrospective, single-center study was conducted.

Results

1. A total of 21 RIIEAHs were included, in which 12 RIIEAHs occurred at the unstable stage, 6 RIIEAHs occurred at the stable stage and 3 RIIEAHs occurred at the end stage. 2. Various pathogens could result in RIIEAHs including mycoplasma pneumoniae (n = 7), coronavirus (n = 3), haemophilus influenzae (n = 3), chlamydia pneumoniae (n = 2), human metapneumovirus (n = 2), acinetobacter baumannii (n = 1), pueumocystis carinii (n = 1) and mixed pathogens (n = 2). 3. The majority of the RIIEAHs (n = 19) presented with prodromal symptoms. Clinical manifestations of RIIEAHs included worsening anemia (n = 13), hemoptysis (n = 13), bleeding on bronchoscopy (n = 12) and dyspnea (n = 9). 4. An intensive glucocorticoid therapy was administrated in the 19 RIIEAHs, in which 18 RIIEAHs resolved.

Conclusions

RIIEAH can be caused by various pathogens at any disease stage of pediatric DAH and an intensive glucocorticoid therapy seems to be effective for this condition.

Background

Diffuse alveolar hemorrhage (DAH) is a severe life-threatening clinical syndrome in children and can be caused by a wide variety of disorders [1]. It is considered as a chronic disease with a relapsing course [2, 3]. Recurrent episode of alveolar hemorrhage can result in pulmonary interstitial fibrosis and restrictive lung function [1, 4]. What’s more, severe episode of alveolar hemorrhage is the common cause of death in DAH [2]. Therefore, preventing and managing of the episode of alveolar hemorrhage is crucial to improve the prognosis of pediatric DAH. Respiratory infections are recognized as common triggers of alveolar hemorrhage episodes in pediatric DAH [5–7]. However, only the individual cases reports have been published and comprehensive studies investigating this association in detail remain limited. This might be mainly due to the rarity of the diseases and the limitations of the conventional detection techniques for the pathogens. In view of this, we conducted this study with the aim to explore the etiological spectrum, clinical features, treatment strategies and outcomes of the respiratory infection induced episode of alveolar hemorrhage (RIIEAH) in the pediatric DAH.

Subjects and methods

Subjects

The children of DAH aged less than 16-year-old, who had RIIEAH and a definite etiological diagnosis were included. All the subjects had been hospitalized in the Department of Pediatrics at the First Affiliated Hospital of Guangxi Medical University from January 2023 to February 2024. The cases caused by the definite non-immune disorders such as congenital heart disease, coagulation disorders, acute respiratory distress syndrome, inhalation injury and those with incomplete data were excluded in this study.

Study design

A retrospective study was conducted. Clinical data were collected by reviewing the medical records including the etiology of DAH, age, gender, disease stage, disease severity, etiological diagnosis and prodromal symptoms, clinical features, treatment strategies and outcomes of RIIEAH.

Diagnostic criteria for DAH

DAH was diagnosed when the subjects fulfilled all the following conditions: (1) presence of respiratory symptoms (dyspnea, hemoptysis or cough) or anemia; (2) diffuse pulmonary infiltrates (ground-glass opacities or consolidations) on the chest CT; (3) presence of hemosiderin laden macrophages in the bronchoalveolar lavage fluid (BALF) or lung tissue specimen [1].

Diagnostic criteria for episode of alveolar hemorrhage

Episode of alveolar hemorrhage was defined when the subjects fulfilled all the following conditions: (1) presence of hemoptysis or anemia or bleeding on bronchoscopy (bloody secretions or progressively hemorrhagic BALF); (2) an increase of the pulmonary infiltrates (ground-glass opacities or consolidations) on the chest CT; (3) exclusion of the bleeding caused by the other diseases or conditions rather than alveolar hemorrhage [8–10].

Definition of the disease stage for DAH

Unstable stage was defined as presence of anemia or persistent pulmonary infiltrates (ground-glass opacities or consolidations) on the chest CT [8–10]. Stable stage was defined as absence of hemoptysis, dyspnea, anemia or obvious pulmonary infiltrates (ground-glass opacities or consolidations) on the chest CT [8–10]. End stage was defined as presence of persistent dyspnea and extensive interstitial fibrosis or emphysema on the chest CT [4, 8–10] (Fig. 1).

Fig. 1.

CT findings of RIIEAHs in the pediatric DAH. A revealed nearly normal appearance in the case at the stable stage; B revealed an increase of the pulmonary infiltrates in the same case to B in RIIEAH; C revealed persistent pulmonary infiltrates in the case at the unstable stage; D revealed an increase of the pulmonary infiltrates in the same case to C in RIIEAH; E revealed extensive interstitial fibrosis with emphysema in the case at the end stage; F revealed an increase of the pulmonary infiltrates in the same case to E in RIIEAH

Etiological diagnosis of infection

The infectious etiology was confirmed when the subjects fulfilled any of the following conditions: (1) identificaiton of the pathogens from the qualified specimens of BALF, deep sputum, nasopharyngeal aspirate (NPA) or pharyngeal swabs using the method of metagenomics next-generation sequencing (mNGS), targeted next-generation sequencing (tNGS) or polymerase chain reaction (PCR); (2) seroconversion of mycoplasma pneumoniae (Mp)-specific IgM from negative titer to positive titer of ≥ 1:160 or fourfold increase of Mp-specific IgM titer during the acute stage of Mp infection [11].

Definition for RIIEAH

RIIEAH was diagnosed if the case of pediatric DAH developed episode of alveolar hemorrhage due to the respiratory infection when other causes were excluded. Resolved of RIIEAH was defined as absence of hemoptysis, relief of dyspnea and improvement of anemia with an increase in Hb level by greater than 10.0 g/L without red blood cells transfusion.

Statistical analysis

Statistical analysis was performed using SPSS 20.0 software. Measurement data were expressed as medians (25th-75th percentile). Counting data were expressed as count (percentage). For the categorical variables, comparisons between groups were performed by the χ² test or the fisher exact test. A two-sided P value < 0.05 was considered to be statistically significant.

Results

General information

A total of 16 cases with 21 RIIEAHs were included. The median age was 135.0 (104.0, 167.5) months and the median disease duration were 84.0 (36.0, 125.5) months. Twelve RIIEAHs occurred at the unstable stage, 6 RIIEAHs occurred at the stable stage and 3 RIIEAHs occurred at the end stage. Respiratory failure developed in 5 RIIEAHs, all of which occurred at the unstable or end stage of DAH. The majority of the RIIEAHs (n = 19) occurred at a low-dose of glucocorticoid treament (prednisone ≦0.5 mg.kg.d) period (Table 1).

Table 1.

Clinical data of RIIEAHs in pediatric DAH

No	Agee	Gender	Etiology of DAH	Disease stage	Disease duratione	RF	IMV	Worsening anemia	Hemoptysis	Dyspnea	Etiologic diagnosis	Detection method	Specimen	Prodromal symptoms	Duration from prodromal symptom to RIIEAH	Treatment before RIIEAH	Treatment of RIIEAH	Outcome
1a	155	M	AAV	unstable	132	Y	Y	Y	N	Y	Hi	tNGS	deep sputum	fever, cough	1d	PRED 0.5 mg/kg.d, MMF	MIT, TAIT, HAh	resolvedg
2a	148	M	AAV	unstable	125	N	N	Y	N	N	hMPV	tNGS	BALF	cough, rhinorrhea	3d	PRED 0.3 mg/kg.d, MMF	IGT	resolved
3	85	F	idiopathic	unstable	24	N	N	Y	Y	N	CoV	PCR	pharyngeal swabs	fever, cough, rhinorrhea	3d	PRED 0.3 mg/kg.d, MTX, CTX	IGT	resolved
4b	167	M	idiopathic	unstable	84	N	N	Y	N	N	Mp	serology	serum	fever, cough	1d	PRED 0.5 mg/kg.d, HCQ	TAIT	unimproved
5b	168	M	idiopathic	unstable	85	Y	Y	Y	Y	Y	Ab	mNGS	BALF	cough, sputum	2d	PRED 0.5 mg/kg.d, HCQ, MTX	MIT, TAIT, HAh	death
6	138	M	idiopathic	stable	84	N	N	Y	N	Y	Mp	tNGS	BALF	fever, cough	2d	PRED 0.2 mg/kg.d, HCQ	IGT	resolved
7	121	F	idiopathic	stable	36	N	N	Y	N	N	Mp	tNGS	BALF	cough	7d	HCQ	IGT	resolved
8	54	F	idiopathic	unstable	12	N	N	N	N	N	Cp	tNGS	BALF	no	-	PRED 0.2 mg/kg.d, MTX	TAIT	resolved
9c	180	F	idiopathic	unstable	132	Y	N	N	Y	Y	Hi	tNGS	deep sputum	nasal congestion, cough, sore throat	7d	PRED 0.4 mg/kg.d, AZA	IGT, TAIT	resolved
10c	177	F	idiopathic	unstable	129	N	N	N	Y	N	hMPV	tNGS	pharyngeal swabs	sore throat, cough	1d	PRED 0.5 mg/kg.d, AZA	IGT	resolved
11c	174	F	idiopathic	unstable	126	Y	Y	Y	Y	Y	Mp	tNGS	BALF	fever, cough	2d	PRED 0.1 mg/kg.d, AZA	MIT, HAh	resolved
12	90	M	idiopathic	unstable	36	N	N	Y	N	N	Mp	tNGS	BALF	no	-	MTX	IGT	resolved
13	145	F	AAV	end	72	N	N	N	Y	Y	Hi	tNGS	BALF	fever,cough	3d	PRED 0.2 mg/kg.d, HCQ	IGT, TAIT	resolved
14	191	F	idiopathic	stable	144	N	N	Y	Y	N	Cp	mNGS	BALF	fever, cough	2d	PRED 0.2 mg/kg.d, AZA	IGT	resolved
15d	135	F	idiopathic	end	84	N	N	-f	Y	Y	Mp	serology	serum	fever, cough	2d	PRED 0.3 mg/kg.d, HCQ	IGT	resolved
16d	133	F	idiopathic	end	82	Y	N	-f	Y	Y	CoV	PCR	pharyngeal swabs	fever, nasal congestion	2d	PRED 0.3 mg/kg.d, HCQ	IGT, TAIT	resolved
17	125	M	idiopathic	stable	96	N	N	Y	N	N	CoV, RV	tNGS	BALF	fever, cough	16d	PRED 0.2 mg/kg.d, HCQ	IGT	resolved
18	41	F	idiopathic	stable	10	N	N	N	Y	N	Mp	tNGS	BALF	cough	6d	PRED 0.2 mg/kg.d	IGT, TAIT	resolved
19	132	F	idiopathic	stable	60	N	N	N	Y	N	Kp, Sp	tNGS	NPA	cough	1d	PRED 1.0 mg/kg.d	IGT, TAIT	resolved
20	118	F	idiopathic	unstable	96	N	N	Y	Y	N	CoV	PCR	pharyngeal swabs	fever, nasal congestion, rhinorrhea	1d	PRED 0.2 mg/kg.d, MTX	IGT, TAIT	resolved
21	67	M	idiopathic	unstable	36	N	N	Y	Y	Y	P.carinii	tNGS	BALF	cough	2d	PRED 0.9 mg/kg.d, HCQ	MIT, TAIT	resolved

M male, F female, AAV ANCA-associated vasculitis, Hi Haemophilus influenzae, tNGS targeted next-generation sequencing, mNGS metagenomics next-generation sequencing, MIT methylprednisolon impact therapy, TAIT targeted anti-infection treatment, MMF mycophenolate mofetil, IMV invasive mechanical ventilation, RF respiratory failure, Hb hemoglobin, hMPV human metapneumovirus, BALF bronchoalveolar lavage fluid, AZA azathioprine, IGT intensive glucocorticoid therapy, PRED prednison, CoV coronavirus, MTX methotrexate, CTX cyclophosphamide, Mp mycoplasma pneumoniae, HCQ hydroxychloroquine, Ab acinetobacter baumannii, Cp chlamydia pneumoniae, RV rhinovirus, Kp klebsiella pneumoniae, Sp streptococcus pneumoniae, NPA nasopharyngeal aspirate, P.carinii pueumocystis carinii, HA hemostatic agent

^{a, b, c, d} It was the same case

^e It was calculated in months

^f These 2 RIIEAHs occurring at the end stage presented with a decrease in Hb level by greater than 20.0 g/L, but no anemia

^g Resolved was defined as absence of hemoptysis, relief of dyspnea and improvement of anemia with an increase in Hb level by greater than 10.0 g/L without red blood cells transfusion

^h Short-term treatment with ethamsylate, haemocoagulase and/or vitamin K₁ were administrated in the 3 RIIEAHs

Compared to the RIIEAHs occurred at the stable stage of DAH, the RIIEAHs occurred at the unstable stage or end stage had a higher incidence of developing respiratory failure and requirement of invasive mechanical ventilation, but the difference was not statistically significant (Table 2).

Table 2.

Comparation of the RIIEAHs between different disease stage of pediatric DAH

	Unstable and end stage (n = 15)	Stable stage (n = 6)	P value
Dyspnea	8 (53.3%)	1 (16.7%)	0.178
Hemoptysis	10 (66.7%)	3 (50.0%)	0.631
Respiratory failure	5 (33.3%)	0 (0.0%)	0.262
Invasive mechanical ventilation	3 (20.0%)	0 (0.0%)	0.532
Worsening anemiaa	11 (73.3%)	4 (66.7%)	1.000
Death	1 (0.7%)	0 (0.0%)	1.000

^a These 2 RIIEAHs occurring at the end stage which presented with a decrease in hemoglobin level by greater than 20.0 g/L, but no anemia were also considered as worsening anemia here

Etiological diagnosis of infections in RIIEAHs

Various pathogens could result in RIIEAHs including mycoplasma pneumoniae (n = 7), coronavirus (n = 3), haemophilus influenzae (n = 3), chlamydia pneumoniae (n = 2), human metapneumovirus (n = 2), acinetobacter baumannii (n = 1), pueumocystis carinii (n = 1) and mixed pathogens (n = 2). Of these pathogens, nonviral pathogens (n = 16) were more common. Notably, the majority of the pathogens (n = 20) belonged to the common pathogens of community-acquired respiratory infection, whereas 2 pathogens (Ab and Kp) belonged to the typical pathogens of hospital-acquired respiratory infection and 1 pathogen (pueumocystis carinii) belonged to the opportunistic respiratory infection (Table 1).

Prodromal symptoms and clinical features of RIIEAHs

The majority of the RIIEAHs (n = 19) presented with prodromal symptoms and most of them (n = 15) occurred within 3 days from the prodromal symptoms. Prodromal symptoms included fever, cough, nasal congestion, rhinorrhea and sore throat, in which cough was most common and found in 17 RIIEAHs (Table 1).

Thirteen RIIEAHs presented with worsening anemia which was defined as presence of anemia and a decrease in hemoglobin (Hb) level by greater than 10.0 g/L. Of these RIIEAHs with worsening anemia, the median Hb level at the time of occurring RIIEAH was 103.2 (74.0, 108.7) g/L and the median decrease in Hb level was 23.0 (16.0, 37.0) g/L. Notably, the 2 RIIEAHs occurring at the end stage presented with a decrease in Hb level by greater than 20.0 g/L, but no anemia. Hemoptysis and dyspnea developed in 13 and 9 RIIEAHs respectively. All the 12 RIIEAHs in which bronchosopy had been performed presented with bleeding on bronchoscopy (Table 1). Compared to the RIIEAHs occurred at the stable stage of DAH, the RIIEAHs occurred at the unstable stage or end stage had a higher incidence of worsening anemia, dyspnea and hemoptysis, but the difference was not statistically significant (Table 2).

Treatments and outcomes

An intensive glucocorticoid therapy with methylprednisolone ≥ 2 mg/kg.d intravenously was administrated in the 19 RIIEAHs, in which a glucocorticoid pulse therapy with methylprednisolone 10 ~ 30 mg/kg.d with the maximum 1 g intravenously was administrated in the 4 RIIEAHs. A targeted anti-infection treatment was administrated in the 11 RIIEAHs and hemostatic agents were only administrated in 3 RIIEAHs (Table 1).

The majority of the RIIEAHs (n = 19) resolved, whereas there was 1 case death due to the RIIEAH. Of these cases with intensive glucocorticoid therapy (n = 19), 18 RIIEAHs resolved (Table 1).

Discussion

DAH is a relatively rare but life-threatening disease in children. It can be caused by a wide variety of etiologies including the immune disorders and non-immune disorders [12, 13]. The cases caused by the immune disorders such as ANCA-associated vasculitis (AAV), systemic lupus erthematosus (SLE), juvenile idiopathic arthritis (JIA) are definite immune-mediated DAH [2, 12]. Recently, idiopathic pulmonary hemosiderosis (IPH) has also been considered as immune-mediated DAH as numerous studies have demonstrated that IPH presented a good response to immunosuppressive therapy [3, 14]. In this study, the etiological diagnosis included idiopathic in 18 cases, AAV in 3 cases and the cases caused by the definite non-immune disorders were excluded. Therefore, all of which were considered as immune mediated DAH.

Previous studies have reported that the prognosis of pediatric DAH was poor and the cases survived only 3 ~ 5 years on average after onset of disease [15, 16]. With the application of immunosuppressive therapy, the prognosis of pediatric DAH has been improved significantly [2, 3, 14–16]. At present, the majority of the cases can survive long-term [2]. Still, it can result in death in some cases [2]. Also, a substantial proportion of the cases with long-term survival had persistent abnormal radiology and a limited improvement in lung function [2]. Episode of alveolar hemorrhage is the predominant cause of death in the pediatric DAH [2]. And, recurrent episode of alveolar hemorrhage can result in end stage lung disease with extensive pulmonary interstitial lung fibrosis. So, reducing the episode of alveolar hemorrhage is an essential way to improve the prognosis of pediatric DAH. Respiratory infection is related to the episode of alveolar hemorrhage in the pediatric DAH [5–7]. The mechanism is still unknown. It is possible that respiratory infection activates the inflammation or immune response in the lungs [17, 18]. In this study, RIIEAH was referred as the episode of alveolar hemorrhage induced by the respiratory infection in pediatric DAH. To our knowledge, this was the first study to explore the etiological spectrum, clinical features, treatment strategies and outcomes of RIIEAH in the pediatric DAH systematically.

In clinic, pediatric DAH was classified as acute stage, unstable stage, stable stage and end stage [8–10]. The cases at the acute stage typically present as episode of alveolar hemorrhage, those at the unstable stage present a similar clinical manifestations to the episode of alveolar hemorrhage due to the recurrent, dormant alveolar hemorrhage and those at the stable stage nearly perform as normal person [2, 8–10]. In addition, some cases develop to the end-stage lung disease with extensive pulmonary interstitial lung fibrosis and alveolar structural damage [1, 4]. In this study, RIIEAH occurred at any disease stage of pediatric DAH and seemed to be more severe in the cases at the unstable or end stage. This might be due to the damaged integrity of the pulmonary vascular in the cases at the unstable and end stage.

In this study, the predominant method to identify the pathogen is NGS. Compared to the routine pathogen tests, it has the advantages of high throughput, high sensitivity and quantification [19] and brought innovation to the etiological diagnosis. BALF is the appropriate specimen for NGS due to the little bacterial colonization [20]. In this study, BALF was the most commonly used specimen for NGS. Also, Mp infection was identified using the serological method in this study. In some studies, Mp infection was identified by an Mp-specific IgM of ≥ 1:160 [21]. Whereas, Mp-specific IgM may exist for several months after Mp infection [22], detection of Mp-specific IgM in a single serum for diagnosis of current MP infection has limited values, as it may be a reaction to the Mp infection several months before. Therefore, we identified the current MP infection by seroconversion or fourfold increase of Mp-specific IgM titer in this study.

Our findings demonstrated that various pathogens including bacteria, virus, even fungi could result in the RIIEAH. Of these pathogens, nonviral pathogens, especially Mp seemed to be more common. Of note, the majority of the pathogens found in this study were the common pathogens of community-acquired respiratory infection [23]. In view of this, the strategies for RIIEAH prevention in pediatric DAH should focus more on the community-acquired infection. Still, several pathogens of the typical hospital-acquired respiratory infection [24] were also found in this study, even resulted in death in 1 case. Therefore, hospital-acquired respiratory infection could not be ignored in RIIEAH prevention. Besides, there was one RIIEAH which was caused by the pueumocystis carinii. Pueumocystis carinii was an opportunistic pathogen and usually resulted in the pneumonia in the patients with immunodeficiency [25]. The cases of pediatric DAH are at high risk of pueumocystis carinii pneumonia due to the immunosuppressive therapy.

In this study, the majority of RIIEAHs presented with prodromal symptoms and occurred at the early stage of respiratory infection. Further more, RIIEAHs seemed to be able to be screened out by the clinical manifestations or blood routine test, as hemoptysis or worsening anemia was relatively common in RIIEAHs in this study. Whereas, differentiation between RIIEAH and pneumonia is challenging sometimes. To the cases which are difficult to make the differential diagnosis, bronchoscopy may help clarify the diagnosis. In this study, there was 1 RIIEAH without worsening anemia or hemoptysis. In this case, the diagnosis of RIIEAH was confirmed by bronchoscopy. Moreover, the recent literature from Villeneuve T et al. had showed that bronchoscopy was an informative procedure at the onset of AAV disease in patients with respiratory manifestations, in which BAL could be used to confirm DAH [26]. Besides, the RIIEAHs in which bronchosopy had been performed all presented with bleeding on bronchoscopy in this study. Consequently, bronchoscopy had good diagnostic value in the diagnosis of RIIEAH.

Until now, there has been no standard and uniform treatment protocol for RIIEAH. Glucocorticoid has been referred as the cornerstone of treatment for pediatric DAH [2, 3, 14]. In terms of the mechanism, glucocorticoid can reduce the acute inflammatory responses such as lung alveolar epithelial swelling, thrombotic microangiopathy and the increased inflammatory and the cytokines [27]. In clinic, glucocorticoid has been found to be able to significantly improve the prognosis of pediatric DAH [3, 14–16]. Notably, a substantial proportion of the cases of pediatric DAH could relapse during the period of glucocorticoid tapering without any other triggers [3, 14]. In this study, the majority of the RIIEAHs occurred at a low-dose of glucocorticoid treatment period. Given this, an intensive glucocorticoid therapy may be required in RIIEAH. In this study, an intensive glucocorticoid therapy was administrated in the majority of the RIIEAHs. Also, a targeted anti-infection treatment has been included in the treatment of RIIEAH. In this study, a targeted anti-infection treatment was administrated in the 11 RIIEAHs. In fact, some pathogens especially the virus like hMPV, RV still lack an effective anti-infection treatment. Notably, the RIIEAHs caused by the virus mentioned above could resolve with an intensive glucocorticoid therapy only in our study. Therefore, the role of a targeted anti-infection treatment in the treatment of RIIEAH especially those caused by the virus need further evaluate. Hemostasis treatment seems to be less effective in RIIEAH due to the pathogenesis and is not commonly used. In this study, hemostatic agents were administrated only in 3 RIIEAHs. Recently, activated recombinant factor VII (FVIIa) has been found to be able to induce rapid local hemostasis with administration either systemically or intrapulmonary for the treatment of DAH [27]. Regrettably, no cases used FVIIa in this study. The experience with application of FVIIa needs to be accumulated in practice.

Nevertheless, there were some limitations in this study. Since this was a single center study and pediatric DAH was a relatively rare disease, the sample size in this study was restricted, which might result in the selection bias. Also, this was a retrospective clinical study, which might result in the recall or diagnostic bias. In the future, a multiple centers, large sample size and prospective clinical study should be performed.

Conclusions

RIIEAH can be caused by various pathogens at any disease stage of pediatric DAH and an intensive glucocorticoid therapy seems to be effective for this condition.

Abbreviations

DAH

Diffuse alveolar hemorrhage

RIIEAH

Respiratory infection induced episode of alveolar hemorrhage

Mp

Mycoplasma pneumoniae

CoV

Coronavirus

Hi

Haemophilus influenza

BALF

Bronchoalveolar lavage fluid

NPA

Nasopharyngeal aspirate

mNGS

Metagenomics next-generation sequencing

tNGS

Targeted next-generation sequencing

PCR

Polymerase chain reaction

Cp

Chlamydia pneumoniae

hMPV

Human metapneumovirus

Ab

Acinetobacter baumannii

Kp

Klebsiella pneumoniae

RV

Rhinovirus

Hb

Hemoglobin

AAV

ANCA-associated vasculitis

SLE

Systemic lupus erythematosus

JIA

Juvenile idiopathic arthritis

IPH

Idiopathic pulmonary hemosiderosis

FVIIa

Activated recombinant factor VII

Authors’ contributions

Qing Wei and Xun Chen took part in designing the study, analysis as well as the interpretation of the data and drafting the manuscript. Qing Wei and Xun Chen contributed equally to the study. Qing Wei is the first author and Xun Chen is a co-first author. Jing Liu and Guangmin Nong conceptualized and designed the whole study, supervised and instructed data collection and analysis, critically reviewed and revised the manuscript. Jing Liu and Guangmin Nong contributed equally to the study. Jing Liu is the corresponding author and Guangmin Nong is a co-corresponding author. Yan Li and Xiaobo Zhang provided the clinical data, took part in collecting the data and reviewed the manuscript. Chunyan Li reviewed the CT scan and provided the imaging data. All authors have read and approved the final manuscript.

Funding

This study was supported by Guangxi Clinical Research Center for Pediatric disease (NO: AD22035219) and the grant (principal investigator: Guangmin Nong) from the Fund of Clinical Climbing Program of the First Affiliated Hospital of Guangxi Medical University (YYZS2020014).

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

The present study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (2024-E216-01). Informed consent was obtained from all subjects and/or their legal guardian(s) in case of minors (below 16 years of age). All the methods and procedures carried out in this study were in accordance with relevant guidelines and regulation.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.