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Profiles and predictive value of cytokines in children with human metapneumovirus pneumonia



Human metapneumovirus (HMPV) is an important cause of respiratory tract infections in young children. Early innate immune response to HMPV is focused on induction of antiviral interferons (IFNs) and other pro-inflammatory cytokines that are critical for the formation of adaptive immune responses. To evaluate the predictive value of Th1/Th2 cytokines which include IL-2, IL-4, IL-6, IL-10, INF-γ and TNF-α in pneumonia caused by HMPV.


A retrospective study was performed among 59 pneumonia pediatric patients with HMPV infection and 33 healthy children as the control cohort, which was detected by the immunofluorescence assay, and the Th1/Th2 cytokines were measured by flow cytometry. 131 children infected with Influenza virus A (IVA) and 41 children infected with influenza virus B (IVB) were detected by RT-PCR assay in throat swabs.


When compared with the healthy children, children who were infected with HMPV pneumonia had a significantly lower level of IL-2 (p < 0.001) and higher levels of IL-4 (p < 0.001), IL-6 (p = 0.001), IL-10 (p < 0.001), and IFN-γ (p < 0.001). Compared with patients diagnosed with IVA or IVB infection, HMPV-positive patients had significantly higher levels of IL-4 (p < 0.001 and < 0.001), IFN-γ (p < 0.001 and < 0.001), and TNF-α (p < 0.001 and 0.016). Moreover, compared with IVA patients, HMPV-positive patients had a significantly lower level of IL-6 (p = 0.033). Finally, when comparing cytokine levels among the patients with HMPV pneumonia, IL-6 and TNF-α levels were found to be significantly higher in the severe group than the mild group (p = 0.027 and 0.049). The IL-6 and TNF-α were used to differentiate between mild symptoms and severe symptoms in children diagnosed with HMPV pneumonia with an AUC of 0.678 (95% CI 0.526–0.829) and 0.658 (95% CI 0.506–0.809), respectively.


Our study indicated that difference in cytokine trends depending on the virus species. The levels of IL-4, TNF-α and IFN-γ were significantly distinguished in children infected with HMPV versus IVA and IVB. IL-6 and TNF-α may be helpful in assessing the severity and prognosis of HMPV infection.


Human metapneumovirus (HMPV) is a negative-sense, single-stranded RNA virus that belongs to Metapneumovirus genus within the family Pneumovirinae. It was first isolated from a pediatric patient in the Netherlands in 2001 [1]. It is also one of the most common viruses causing acute upper and lower respiratory tract infections in children, immunocompromised individuals, and elderly [2,3,4,5]. HMPV infection most commonly occurs in children below 2 years old [6]. The virus usually causes a series of severe diseases, such as pneumonia and bronchiolitis, and is associated with poor prognosis [7,8,9,10]. HMPV is mainly divided into two major groups, A and B, which are further subdivided into four sub-groups, namely A1, A2, B1, and B2 [11, 12]. Recently, more HMPV subtypes were identified (A2c, A2b1, and A2b2) [13].

HMPV infection is one of the major causes of pneumonia in children that is associated with high morbidity and mortality [4, 14]. A rapid and correct diagnosis is crucial for the treatment of HMPV pneumonia. In clinical practice, real-time polymerase chain reaction (RT-PCR) is used to directly detect HMPV DNA in children with pneumonia due to high specificity and sensitivity of the test [15, 16]. However, previous studies have shown that pneumonia caused by HMPV is often combined with other respiratory viruses, such as respiratory syncytial virus (RSV), influenza virus, etc. So the detection of HMPV alone is not sensible to establish the relationship between HMPV and pneumonia in case of co-infection [16, 17]. HMPV preferentially targets ciliated epithelial cells of the human respiratory tract and causes a broad spectrum of respiratory illnesses [18]. The previous study showed that inflammasomes play an important role in hMPV-mediated lung disease and antiviral responses in severely infected children. Level of the pro-inflammatory cytokine IL-18 was significantly upregulated in hMPV-infected children [19]. It is well-known that Th1/Th2 cytokines were crucial in anti-infection immunity after virus infection [20], and our previous study suggested that serum Th1/Th2 cytokines were effective biomarkers to diagnose whether patients afflicted by Gram-negative bacteria [21, 22]. Since serum Th1/Th2 profiles and levels are altered in infected patients, they can be used to quickly identify infectious diseases exist in the early stage and determine the severity of the disease. In this article, we studied the clinical application value of Th1/Th2 cytokines as a reference of auxiliary diagnostic and assessment of disease severity and prognosis of HMPV infection in children with pneumonia.

Materials and methods

Study design and patients

We conducted a retrospective study among the children who were diagnosed with pneumonia from May 2012 to June 2019. The study included 59 children with HMPV pneumonia and 33 healthy children as the control cohort. At the same time, 131 children infected with IVA and 41 children infected with IVB were also enrolled in this study. This study has been approved by the medical ethics committee of Children’s Hospital of Zhejiang University School of Medicine. Written informed consents were obtained from parents or guardians of the patients involved in the study. Patients who met the following criteria were enrolled: (1) children under the age of 5 years; (2) primarily diagnosed with pneumonia [23]; (3) children ruled out other respiratory pathogen infections. At the onset of pneumonia, throat swab specimens and blood samples were taken for microbiological analyses and serum Th1/Th2 cytokines determination. According to guidelines for the management of community-acquired pneumonia in children of the People’s Republic of China (2013 Edition) [24], the HMPV-positive patients were divided into 2 groups: mild and severe group.

Detection of HMPV

HMPV was detected by immunofluorescence assay (Diagnostic Hybrids INC, Ohio, USA) in throat swabs. All operations were conducted according to the manufacturer’s instructions.

Detection of IVA and IVB

Influenza virus A (IVA) and influenza virus B (IVB) were detected by RT-PCR assay (liferiver, China) in throat swabs. All operations were conducted according to the manufacturer’s instructions.

Measurement of serum cytokines

1 mL blood sample was collected from every child, and the blood samples were centrifuged at 1000 g for 20 min. The serum was carefully harvested, the Th1/Th2 cytokines were then measured by FACScaliburTM flow cytometer (Becton Dickinson, San Jose, CA, USA). Concentrations of IL-2, IL-4, IL-6, IL-10, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ) were quantitatively determined by the CBA kit-BDTM CBA Human Th1/Th2 Cytokine Kit II (BD Biosciences, San Jose, CA). The minimal and maximum limits of detection for all six cytokines were 1.0 and 5000 pg/mL, respectively.

Statistical analysis

The measurement data were selected to test normality using the Shapiro–Wilk test or the Kolmogorov–Smirnov test depending on the sample size. The t-test or the Wilcoxon rank-sum test was used to test for differences in cytokines across influenza populations according to their normality. Non-parametric multiple group component differences were tested using the Kruskal–Wallis test and further adjusted for p values for two-by-two comparisons using Holm’s method. The receiver operating characteristic curve (ROC) was used to analyze the results of mild and severe groups, and the sensitivity and specificity were calculated. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic effect. The closer the AUC is to 1.0, the better the prediction. The AUC between 0.7 and 0.9 shows moderate accuracy of prediction. When the AUC is above 0.9, the accuracy is relatively high. Statistical analyses were completed using R 4.1.2. We reported 2-sided p values, and p < 0.05 was considered statistically significant.


From May 2012 to June 2019, a total of 59 patients tested positive for HMPV, about 75% of the patients were below 6 months old, and 92.4% of the patients were below 2 years old.

The Th1/Th2 cytokines used in this study are cytokine profile inspection projects in our hospital and the reference ranges for normal values of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ were 1.1-9.8pg/ml, 0.1-3.0pg/ml, 1.7-16.6pg/ml, 2.6-4.9pg/ml, 0.1-5.2pg/ml, 1.6-17.3pg/ml respectively. The levels of six cytokines in the HMPV pneumonia group and normal control group are shown in Fig. 1 and Additional file 1: Table S1. HMPV pneumonia group had lower IL-2 (median levels, pg/ml: 3.40 vs. 5.80, p < 0.001), higher IL-4 (median levels, pg/ml: 3.00 vs. 1.40, p < 0.001), IL-6 (median levels, pg/ml: 8.10 vs. 4.10, p = 0.001), IL-10 (median levels, pg/ml: 9.20 vs. 2.40, p < 0.001) and IFN-γ (median levels, pg/ml: 8.70 vs. 4.60, p < 0.001), whereas no significant difference of TNF-α levels was found between the two groups (median levels, pg/ml, 2.40 vs. 2.30, p = 0.160).

Fig. 1
figure 1

Serum cytokine levels in the control group (N = 33) and HMPV pneumonia group (N = 59). AF represent IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ levels, respectively. *Control: healthy children group (HC), HMPV Human metapneumovirus

In order to confirm the differences of cytokines profiles between HMPV and influenza virus, 131 IVA-positive and 41 IVB-positive patients were enrolled in this study, and six cytokines were identified in IVA-positive or IVB-positive children. The cytokine levels in the HMPV, IVA, and IVB groups were shown in Fig. 2 and Additional file 1: Table S1. Compared with IVA and IVB patients, HMPV-positive patients had significantly higher levels of IL-4, TNF-α, and IFN-γ (median levels, pg/ml, IL-4: HMPV = 3.00, IVA = 1.90 (p < 0.001), and IVB = 2.00 (p < 0.001); TNF-α: HMPV = 2.40, IVA = 1.90 (p < 0.001), and IVB = 2.10 (p = 0.016); IFN-γ: HMPV = 8.70, IVA = 5.55 (p < 0.001), and IVB = 5.20 (p < 0.001)). Compared with IVA patients, patients with HMPV had a significantly lower level of IL-6 (median levels, pg/ml, 8.10 vs. 17.40, p = 0.033). In addition, compared with IVA patients, IVB-positive patients had significantly lower levels of IL-6 (median levels, pg/ml, 7.90 vs. 17.40, p = 0.033) and IL-10 (median levels, pg/ml, 6.60 vs. 11.00, p = 0.017). No difference was found in IL-2 among the three groups (median levels, pg/ml, HMPV = 3.40, IVA = 3.00, IVB = 3.00, p = 0.449).

Fig. 2
figure 2

Serum cytokine levels in children with IVA (N = 131), IVB (N = 41), or HMPV (N = 59) infection. A, B, C, D, E and F represent IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ levels, respectively. *IVA: Influenza virus A, IVB: Influenza virus B, HMPV: Human metapneumovirus

Among the HMPV-positive patients, 39 patients comprised the mild group, and 20 patients comprised the severe group. As shown in Fig. 3 and Additional file 1: Table S1, IL-6 and TNF-α were found to be significantly higher in the severe group than mild group (median levels, pg/mL IL-6:15.35 vs. 5.30, p = 0.027; TNF-α: 2.90 vs. 5.30, p = 0.049). No significant differences of other inflammatory cytokines (IL-2, IL-4, IL-10, and IFN-γ) levels were found between these two groups (median levels, pg/mL, IL-2: severe = 3.25, mild = 3.70, p = 0.400; IL-4: severe = 3.10, mild = 2.90, p = 0.126; IL-10: severe = 9.95, mild = 7.90, p = 0.511; IFN-γ: severe = 10.25, mild = 8.10, p = 0.164).

Fig. 3
figure 3

Serum cytokine levels in HMPV-positive children with mild symptom (MS, N = 39) and severe symptom (SS, N = 20). AF represent IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ levels, respectively

To confirm the differential diagnostic value of inflammatory cytokine levels in the severity of HMPV pneumonia in children, we used ROC-analysis to compare the six cytokines (Fig. 4). The analysis results indicated IL-6 and TNF-α were effective biomarkers to differentiate between mild and severe symptoms in children diagnosed with HMPV pneumonia with an AUC of 0.678 (95% CI 0.526–0.829) and 0.658 (95% CI 0.506–0.809), respectively. The cut-off points are calculated through the corresponding points of the ROC curve, and the points at which (sensitivity + specificity − 1) take the maximum value are calculated as the cut-off points. Hence, IL-6 ≥ 7.20 pg/mL had a sensitivity of 85.0% and a specificity of 59.0% for severe HMPV pneumonia. TNF-α ≥ 2.50 pg/mL had a sensitivity of 70.0% and a specificity of 64.1% in differentiating between severe and mild HMPV pneumonia.

Fig. 4
figure 4

ROC curve of multiple cytokines prediction model for differentiating between mild symptom (MS, N = 39) and severe symptom (SS, N = 20) HMPV pneumonia. AF represent the ROC curve of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, respectively


We grouped 59 children tested HMPV-positive by age and found that 75% were younger than 6 months and 92.4% were younger than 2 years. Therefore, the target of HMPV attack is mainly children under the age of two, which further narrows the scope of previous studies showing that children under the age of five are the main HMPV infections [25]. Children under the age of two are the major population for prevention and control of metapneumovirus pneumonia.

To confirm the immune status of children with HMPV infection and predictive ability of Th1/Th2 cytokines in children with HMPV pneumonia, 59 children with a single infection of HMPV were enrolled in this study. Compared with the HMPV pneumonia group and healthy control group, the former had a significantly lower level of IL-2 and higher levels of IL-4, IL-6, IL-10, and IFN-γ. In addition, IL-6 and TNF-α showed increased expression with severe group. Unlike previous studies, our results showed that the level of IL-2 was significantly lower in the HMPV-infected group, which may because IL-2 is not only very important for maintaining and generating regulatory T cells but also promotes the general proliferation of T lymphocytes, augmenting natural killer cells activity, and inhibiting the formation of granulocyte-macrophage colony. Hence, after infection, the level of IL-2 often decreases [21, 22]. IL-10 can deactivate the macrophage cells. The function and proliferation of T cells and natural killer cells can directly be inhibited by IL-10. Furthermore, the growth and differentiation of B cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells can be regulated by IL-10 [26, 27]. Alvarez et al. reported that up-regulation of IL-10 was found in mice with HMPV infection [28]. IL-6 is a major pro-inflammatory mediator that induces acute-phase responses and contributes to host defense against infection and tissue damage. Respiratory syncytial virus (RSV), which is closely related to HMPV, had demonstrated a positive correlation between high IL-6 level and the severity of RSV [29]. In addition, there was a research showed HMPV induced a more severe disease in mice than that of RSV [30]. These results were, to some extent, associated with higher level of IL-6. Consistent with our findings, IL-6 plays an important role in HMPV pathogenicity, which may account for the level of IL-6 was significantly increased in the severe group [31]. The relationship between TNF-α and HMPV has rarely been mentioned in previous studies, but some studies have shown that the expression of TNF-α is increased in RSV-infected patients [32]. In our research, the expression level of TNF-α was significantly increased in the severe group, the mechanism may be similar to RSV, but needs to be further explored. TNF-α may be helpful to distinguish MS and SS group of HMPV. The previous research showed that excessive expression of TNF-α can activate the signal transducer and activator of transcription 3 (STAT3) pathway through NF-κB-mediated IL-6. Unconstrained TNF-α production leads to the excessive activation of inflammatory cytokines, forming a cytokine storm [33]. This may be the reason for the high expression of TNF-α in the SS group than that of MS group. Consistent with previous studies, our results indicated that IL-4 levels were elevated in HMPV-infected group. IL-4 is a potent inflammatory response activator. Previous studies have shown that IL-6 may increase IL-4 and TNF-α production to induce inflammatory responses during the Th2 differentiation process [34]. However, IL-4 secreted by Th2 helper cells may be inhibited when pro-inflammatory cytokine levels are elevated. On the other hand, increased IL-4 level may induce suppression of pro-inflammatory cytokines during the late immune response phase [31, 32]. This may lead to various sensitivities among cytokines that may be helpful to differentiate multiple respiratory viruses. Interestingly, it is speculated that a balanced Th1 type immunity may lead to the clearance of HMPV through activation of IFN-γ secreted by T cells [35].

The hospitalization rate of HMPV infection was similar to that of influenza, using cytokines as biomarkers may be able to differentiate between HMPV and IV. In the early period of influenza-virus infection, NK cells produce IFN-γ. In the subsequent immune response, T cells are the major producer of IFN-γ. Influenza-specific effector CD8+ T cells produce a series of cytokines, including IFN-γ and TNF-α through a variety of antigen-dependent pathways [36]. Due to less studies on the differences of cytokine profiles between HMPV and IV, our findings suggested that the levels of IFN-γ and TNF-α are higher than those of influenza virus may be the two viruses have different inflammatory mechanisms, which require further research. Apart from of IL-6, IL-1β, IFN-γ, TNF-α and IL-8, few studies reported increased levels of IL-4 after influenza virus infection [36, 37]. This rule consists with our findings that HMPV-positive patients had a significantly higher level of IL-4. According to a study on influenza virus A, the levels of IL-6 in the site of initial virus infection were increased persistently for 6 days, this may be related the level of IL-6 in HMPV-positive patients was lower than that of IVA-positive patients [37].

Our study also has a little limitation. The sample size is not large enough and data collection time span is too long may affect the consistency of results. In further studies, we plan to increase the detection range and number of samples. In addition, the detection capacity of antigen assay we used in diagnosing HMPV is slightly lower than the gold standard PCR test.


In conclusion, the majority of children diagnosed with HMPV were below 6 months old. Our study suggested that difference in cytokine trends depending on different virus species. The children with HMPV infection have significantly lower level of IL-2 and higher levels of IL-4, IL-6, IL-10, and IFN-γ when compared with health children. The levels of IL-4, TNF-α and IFN-γ were significantly different in children infected with HMPV versus IVA and IVB. The level of IL-6 was significantly higher in IVA patients than in HMPV patients, which may be able to distinguish HMPV and IVA. IL-6 and TNF-α may be helpful in assessing the severity and prognosis of HMPV infection.

Availability of data and materials

All datasets generated in this study are included in the manuscript and/or supplementary files.


  1. van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, Osterhaus AD. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7(6):719–24.

    Article  Google Scholar 

  2. Panda S, Mohakud NK, Pena L, Kumar S. Human metapneumovirus: review of an important respiratory pathogen. Int J Infect Dis. 2014;25:45–52.

    Article  Google Scholar 

  3. de Zwart AES, Riezebos-Brilman A, Alffenaar JC, van den Heuvel ER, Gan CT, van der Bij W, Kerstjens HAM, Verschuuren EAM. Evaluation of 10 years of parainfluenza virus, human metapneumovirus, and respiratory syncytial virus infections in lung transplant recipients. Am J Transplant. 2020;20(12):3529–37.

    Article  Google Scholar 

  4. Broor S, Bharaj P, Chahar HS. Human metapneumovirus: a new respiratory pathogen. J Biosci. 2008;33(4):483–93.

    Article  CAS  Google Scholar 

  5. Holzemer NF, Hasvold JJ, Pohl KJ, Ashbrook MJ, Meert KL, Quasney MW. Human metapneumovirus infection in hospitalized children. Respir Care. 2020;65(5):650–7.

    Article  Google Scholar 

  6. van den Hoogen BG, Osterhaus DM, Fouchier RA. Clinical impact and diagnosis of human metapneumovirus infection. Pediatr Infect Dis J. 2004;23(Suppl 1):25–32.

    Article  Google Scholar 

  7. Wang X, Li Y, Deloria-Knoll M, Madhi SA, Cohen C, Ali A, Basnet S, Bassat Q, Brooks WA, Chittaganpitch M, et al. Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study. Lancet Glob Health. 2021;9(1):e33–43.

    Article  Google Scholar 

  8. Døllner H, Risnes K, Radtke A, Nordbø SA. Outbreak of human metapneumovirus infection in norwegian children. Pediatr Infect Dis J. 2004;23(5):436–40.

    Article  Google Scholar 

  9. Singleton RJ, Bulkow LR, Miernyk K, DeByle C, Pruitt L, Hummel KB, Bruden D, Englund JA, Anderson LJ, Lucher L, et al. Viral respiratory infections in hospitalized and community control children in Alaska. J Med Virol. 2010;82(7):1282–90.

    Article  Google Scholar 

  10. Moe N, Krokstad S, Stenseng IH, Christensen A, Skanke LH, Risnes KR, Nordbø SA, Døllner H. Comparing human metapneumovirus and RSV: viral co-detections, genotypes and risk factors for severe disease. PLoS ONE. 2017;12(1):e0170200.

    Article  Google Scholar 

  11. Biacchesi S, Skiadopoulos MH, Boivin G, Hanson CT, Murphy BR, Collins PL, Buchholz UJ. Genetic diversity between human metapneumovirus subgroups. Virology. 2003;315(1):1–9.

    Article  CAS  Google Scholar 

  12. Huck B, Scharf G, Neumann-Haefelin D, Puppe W, Weigl J, Falcone V. Novel human metapneumovirus sublineage. Emerg Infect Dis. 2006;12(1):147–50.

    Article  CAS  Google Scholar 

  13. Nao N, Saikusa M, Sato K, Sekizuka T, Usuku S, Tanaka N, Nishimura H, Takeda M. Recent molecular evolution of human Metapneumovirus HMPV: subdivision of HMPV A2b strains. Microorganisms. 2020;8(9):1280.

    Article  CAS  Google Scholar 

  14. Principi N, Bosis S, Esposito S. Human metapneumovirus in paediatric patients. Clin Microbiol Infect. 2006;12(4):301–8.

    Article  CAS  Google Scholar 

  15. Butt SA, Maceira VP, McCallen ME, Stellrecht KA. Comparison of three commercial RT-PCR systems for the detection of respiratory viruses. J Clin Virol. 2014;61(3):406–10.

    Article  CAS  Google Scholar 

  16. Lin CY, Hwang D, Chiu NC, Weng LC, Liu HF, Mu JJ, Liu CP, Chi H. Increased detection of viruses in children with respiratory tract infection using PCR. Int J Environ Res Public Health. 2020;17(2):564.

    Article  CAS  Google Scholar 

  17. Emanuels A, Hawes SE, Newman KL, Martin ET, Englund JA, Tielsch JM, Kuypers J, Khatry SK, LeClerq SC, Katz J, Chu HY. Respiratory viral coinfection in a birth cohort of infants in rural Nepal. Influenza Other Respir Viruses. 2020;14(6):739–46.

    Article  CAS  Google Scholar 

  18. Rodriguez PE, Frutos MC, Adamo MP, Cuffini C, Cámara JA, Paglini MG, Moreno L, Cámara A. Human metapneumovirus: epidemiology and genotype diversity in children and adult patients with respiratory infection in Córdoba, Argentina. PLoS ONE. 2020;15(12):e0244093.

    Article  CAS  Google Scholar 

  19. Malmo J, Moe N, Krokstad S, Ryan L, Loevenich S, Johnsen IB, Espevik T, Nordbø SA, Døllner H, Anthonsen MW. Cytokine profiles in human metapneumovirus infected children: identification of genes involved in the antiviral response and pathogenesis. PLoS ONE. 2016;11(5):e0155484.

    Article  Google Scholar 

  20. Ye Q, Shao WX, Shang SQ, Pan YX, Shen HQ, Chen XJ. Epidemiological characteristics and immune status of children with RSV. J Med Virol. 2015;2:323–9.

    Article  Google Scholar 

  21. Xu XJ, Tang YM, Liao C, Song H, Yang SL, Xu WQ, Shi SW, Zhao N. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med. 2013;39(2):319–26.

    Article  CAS  Google Scholar 

  22. Ye Q, Shao WX, Xu XJ, Yang YZ. The clinical application value of cytokines in treating infectious diseases. PLoS ONE. 2014;9(6):e98745.

    Article  Google Scholar 

  23. Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, Thomson A, British Thoracic Society Standards of Care Committee. British thoracic society guidelines for the management of community acquiredpneumonia in children: Update 2011. Thorax. 2011;66:ii1–23.

    Article  Google Scholar 

  24. Respiratory Group Pediatrics Society of Chinese Medical Association. Editorial Board of Chinese Journal of Pediatrics. Guidelines for the management of community-acquired pneumonia in children 2013 revision. Chin J Pediatr. 2013;5110:856–62.

    Google Scholar 

  25. Geiser J, Boivin G, Huang S, Constant S, Kaiser L, Tapparel C, Essaidi-Laziosi M. RSV and HMPV infections in 3D tissue cultures: mechanisms involved in virus-host and virus-virus interactions. Viruses. 2021;13(1):139.

    Article  CAS  Google Scholar 

  26. Yu H, Hu W, Song X, Zhao Y. Immune modulation of platelet-derived mitochondria on memory CD4 + T cells in humans. Int J Mol Sci. 2020;21(17):6295.

    Article  CAS  Google Scholar 

  27. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9.

    Article  CAS  Google Scholar 

  28. Alvarez R, Tripp RA. The immune response to human metapneumovirus is associated with aberrant immunity and impaired virus clearance in BALB/c mice. J Virol. 2005;79(10):5971–8.

    Article  CAS  Google Scholar 

  29. Welliver RC Sr. The immune response to respiratory syncytial virus infection: friend or foe? Clin Rev Allergy Immunol. 2008;34(2):163–73.

    Article  CAS  Google Scholar 

  30. Huck B, Neumann-Haefelin D, Schmitt-Graeff A, Weckmann M, Mattes J, Ehl S, Falcone V. Human metapneumovirus induces more severe disease and stronger innate immune response in BALB/c mice as compared with respiratory syncytial virus. Respir Res. 2007;8(1):6.

    Article  Google Scholar 

  31. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123–30.

    Article  CAS  Google Scholar 

  32. Nguyen TH, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, Foster PS, Yang M. TNF-α and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease. J Immunol. 2016;196(9):3547–58.

    Article  CAS  Google Scholar 

  33. Pandey P, Karupiah G. Targeting tumour necrosis factor to ameliorate viral pneumonia. FEBS J. 2022;289(4):883–900.

    Article  CAS  Google Scholar 

  34. Cui AH, Zhao J, Liu SX, Hao YS. Associations of IL-4, IL-6, and IL-12 levels in peripheral blood with lung function, cellular immune function, and quality of life in children with moderate-to-severe asthma. Med Baltim. 2017;96(12):e6265.

    Article  CAS  Google Scholar 

  35. Palavecino CE, Céspedes PF, Gómez RS, Kalergis AM, Bueno SM. Immunization with a recombinant bacillus Calmette–Guerin strain confers protective Th1 immunity against the human metapneumovirus. J Immunol. 2014;192(1):214–23.

    Article  CAS  Google Scholar 

  36. Gu Y, Zuo X, Zhang S, Ouyang Z, Jiang S, Wang F, Wang G. The mechanism behind influenza virus cytokine storm. Viruses. 2021;13(7):1362.

    Article  CAS  Google Scholar 

  37. Wang S, Le TQ, Kurihara N, Chida J, Cisse Y, Yano M, Kido H. Influenza virus- cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J Infect Dis. 2010;202(7):991–1001.

    Article  CAS  Google Scholar 

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We thank all parents and children for their consent and cooperation.


This work was supported by the National Nature Science Foundation of China (81701535), the science and technology projects in Zhejiang Province (LGC21H200004 and 2019C03037) and the Medical Scientific Projects from the Health Department of Zhejiang Province (2018KY455).

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WL conceived the idea and supervised this work. WX wrote the manuscript. LL and BW performed data processing and analysis. WX and AFA collected data. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Wei Li.

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The study was approved by the Committee on Ethics in the Children’s Hospital, Zhejiang University School of medicine (2021-IRB-182).

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1. Table S1.

Serum cytokine levels in each group (Median, pg/ml).

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Xiang, Wq., Li, L., Wang, Bh. et al. Profiles and predictive value of cytokines in children with human metapneumovirus pneumonia. Virol J 19, 214 (2022).

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