Transient Neutropenia in Immunocompetent Infants with Respiratory Syncytial Virus Infection
Abstract
:1. Introduction
2. Methods
2.1. Study Design and Setting
2.2. Study Participants
2.3. Data Collection and Definitions
2.4. Outcome Measures
2.5. Follow-Up Assessment
2.6. Statistical Analysis
3. Results
3.1. Basic Characteristics
3.2. Potential Risk Factors for Neutropenia
3.3. Follow-up Assessment
4. Discussion
4.1. RSV Infection and Neutropenia
4.2. Age-Related Prevalence of Neutropenia
4.3. Inflammatory Effect of Airway Microbiota in RSV Infection
4.4. Potential Role of Airway Microbiota Composition in Neutropenic Phenomenon
4.5. Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ANC | absolute neutrophil count |
GRSS | global respiratory severity score |
RSV | respiratory syncytial virus |
References
- Griffiths, C.; Drews, S.J.; Marchant, D.J. Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment. Clin. Microbiol. Rev. 2017, 30, 277–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shi, T.; McAllister, D.A.; O’Brien, K.L.; Simoes, E.A.F.; Madhi, S.A.; Gessner, B.D.; Polack, F.P.; Balsells, E.; Acacio, S.; Aguayo, C.; et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: A systematic review and modelling study. Lancet 2017, 390, 946–958. [Google Scholar] [CrossRef] [Green Version]
- Xing, Y.; Proesmans, M. New therapies for acute RSV infections: Where are we? Eur. J. Pediatr. 2019, 178, 131–138. [Google Scholar] [CrossRef] [PubMed]
- DeVincenzo, J.P.; McClure, M.W.; Symons, J.A.; Fathi, H.; Westland, C.; Chanda, S.; Lambkin-Williams, R.; Smith, P.; Zhang, Q.; Beigelman, L.; et al. Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study. N. Engl. J. Med. 2015, 373, 2048–2058. [Google Scholar] [CrossRef] [Green Version]
- ClinicalTrials.gov. A Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine (JNJ-64041575) Regimens in Hospitalized Infants and Children Aged 28 Days to 36 Months Infected with Respiratory Syncytial Virus. Available online: https://ClinicalTrials.gov/show/NCT03333317 (accessed on 7 July 2020).
- Alexandropoulou, O.; Kossiva, L.; Haliotis, F.; Giannaki, M.; Tsolia, M.; Panagiotou, I.P.; Karavanaki, K. Transient neutropenia in children with febrile illness and associated infectious agents: 2 years’ follow-up. Eur. J. Pediatr. 2013, 172, 811–819. [Google Scholar] [CrossRef]
- Pascual, C.; Trenchs, V.; Hernandez-Bou, S.; Catala, A.; Valls, A.F.; Luaces, C. Outcomes and infectious etiologies of febrile neutropenia in non-immunocompromised children who present in an emergency department. Eur. J. Clin. Microbiol. Infect Dis. 2016, 35, 1667–1672. [Google Scholar] [CrossRef] [PubMed]
- Segel, G.B.; Halterman, J.S. Neutropenia in pediatric practice. Pediatr. Rev. 2008, 29, 12–23. [Google Scholar] [CrossRef] [PubMed]
- Von Elm, E.; Altman, D.G.; Egger, M.; Pocock, S.J.; Gotzsche, P.C.; Vandenbroucke, J.P.; Initiative, S. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet 2007, 370, 1453–1457. [Google Scholar] [CrossRef]
- Caserta, M.T.; Qiu, X.; Tesini, B.; Wang, L.; Murphy, A.; Corbett, A.; Topham, D.J.; Falsey, A.R.; Holden-Wiltse, J.; Walsh, E.E. Development of a Global Respiratory Severity Score for Respiratory Syncytial Virus Infection in Infants. J. Infect Dis. 2017, 215, 750–756. [Google Scholar] [CrossRef] [Green Version]
- Siefker, D.T.; Vu, L.; You, D.; McBride, A.; Taylor, R.; Jones, T.L.; DeVincenzo, J.; Cormier, S.A. Respiratory Syncytial Virus Disease Severity Is Associated with Distinct CD8(+) T-Cell Profiles. Am. J. Respir. Crit. Care Med. 2020, 201, 325–334. [Google Scholar] [CrossRef]
- World Health Organization. WHO Global Database on Child Growth and Malnutrition. The WHO Anthro Survey Analyser. Available online: https://www.who.int/nutgrowthdb/software/en/ (accessed on 7 July 2020).
- Goldstein, B.; Giroir, B.; Randolph, A.; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr. Crit. Care Med. 2005, 6, 2–8. [Google Scholar]
- Mansbach, J.M.; Hasegawa, K.; Piedra, P.A.; Avadhanula, V.; Petrosino, J.F.; Sullivan, A.F.; Espinola, J.A.; Camargo, C.A. Haemophilus-Dominant Nasopharyngeal Microbiota Is Associated with Delayed Clearance of Respiratory Syncytial Virus in Infants Hospitalized for Bronchiolitis. J. Infect Dis. 2019, 219, 1804–1808. [Google Scholar] [CrossRef]
- Hsieh, M.M.; Everhart, J.E.; Byrd-Holt, D.D.; Tisdale, J.F.; Rodgers, G.P. Prevalence of neutropenia in the U.S. population: Age, sex, smoking status, and ethnic differences. Ann. Intern. Med. 2007, 146, 486–492. [Google Scholar] [CrossRef] [PubMed]
- Mahajan, P.; Browne, L.R.; Levine, D.A.; Cohen, D.M.; Gattu, R.; Linakis, J.G.; Anders, J.; Borgialli, D.; Vitale, M.; Dayan, P.S.; et al. Risk of Bacterial Coinfections in Febrile Infants 60 Days Old and Younger with Documented Viral Infections. J. Pediatr. 2018, 203, 86–91.e2. [Google Scholar] [PubMed]
- Byington, C.L.; Enriquez, F.R.; Hoff, C.; Tuohy, R.; Taggart, E.W.; Hillyard, D.R.; Carroll, K.C.; Christenson, J.C. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics 2004, 113, 1662–1666. [Google Scholar] [CrossRef]
- Barg, A.A.; Kozer, E.; Mordish, Y.; Lazarovitch, T.; Kventsel, I.; Goldman, M. The Risk of Serious Bacterial Infection in Neutropenic Immunocompetent Febrile Children. J. Pediatr. Hematol. Oncol. 2015, 37, e347–e351. [Google Scholar] [CrossRef] [PubMed]
- Titus, M.O.; Wright, S.W. Prevalence of serious bacterial infections in febrile infants with respiratory syncytial virus infection. Pediatrics 2003, 112, 282–284. [Google Scholar]
- Levine, D.A.; Platt, S.L.; Dayan, P.S.; Macias, C.G.; Zorc, J.J.; Krief, W.; Schor, J.; Bank, D.; Fefferman, N.; Shaw, K.N.; et al. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics 2004, 113, 1728–1734. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karavanaki, K.; Polychronopoulou, S.; Giannaki, M.; Haliotis, F.; Sider, B.; Brisimitzi, M.; Dimitriou, C.; Scordias, G.; Marangou, F.; Stamatiadou, A.; et al. Transient and chronic neutropenias detected in children with different viral and bacterial infections. Acta Paediatr. 2006, 95, 565–572. [Google Scholar] [CrossRef] [PubMed]
- Cass, L.; Davis, A.; Murray, A.; Woodward, K.; Ito, K.; Strong, P.; Rapeport, G. 1335. Safety and Pharmacokinetic Profile of PC786, a Novel Inhibitor of Respiratory Syncytial Virus L-protein Polymerase, in a Single and Multiple-Ascending Dose Study in Healthy Volunteer and Mild Asthmatics. Open Forum Infect Dis. 2018, 5 (Suppl. S1), S407–S408. [Google Scholar] [CrossRef] [Green Version]
- Coakley, E.; Ahmad, A.; Larson, K.; McClure, T.; Lin, K.; Lin, K.; Tenhoor, K.; Eze, K.; Noulin, N.; Horvathova, V.; et al. LB6. EDP-938, a Novel RSV N-Inhibitor, Administered Once or Twice Daily Was Safe and Demonstrated Robust Antiviral and Clinical Efficacy in a Healthy Volunteer Challenge Study. Open Forum Infect Dis. 2019, 6 (Suppl. S2), S995. [Google Scholar] [CrossRef] [Green Version]
- De Steenhuijsen Piters, W.A.; Heinonen, S.; Hasrat, R.; Bunsow, E.; Smith, B.; Suarez-Arrabal, M.C.; Chaussabel, D.; Cohen, D.M.; Sanders, E.A.; Ramilo, O.; et al. Nasopharyngeal Microbiota, Host Transcriptome, and Disease Severity in Children with Respiratory Syncytial Virus Infection. Am. J. Respir. Crit. Care Med. 2016, 194, 1104–1115. [Google Scholar] [CrossRef] [PubMed]
- Hasegawa, K.; Mansbach, J.M.; Ajami, N.J.; Espinola, J.A.; Henke, D.M.; Petrosino, J.F.; Piedra, P.A.; Shaw, C.A.; Sullivan, A.F.; Camargo, C.A., Jr.; et al. Association of nasopharyngeal microbiota profiles with bronchiolitis severity in infants hospitalised for bronchiolitis. Eur. Respir. J. 2016, 48, 1329–1339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Folsgaard, N.V.; Schjorring, S.; Chawes, B.L.; Rasmussen, M.A.; Krogfelt, K.A.; Brix, S.; Bisgaard, H. Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release. Am. J. Respir. Crit. Care Med. 2013, 187, 589–595. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Zhang, X.; Zhang, N.; Wang, X.; Sun, L.; Chen, N.; Zhao, S.; He, Q. Airway microbiome, host immune response and recurrent wheezing in infants with severe respiratory syncytial virus bronchiolitis. Pediatr. Allergy Immunol. 2020, 31, 281–289. [Google Scholar] [CrossRef] [PubMed]
- O’Donnell, D.R.; McGarvey, M.J.; Tully, J.M.; Balfour-Lynn, I.M.; Openshaw, P.J. Respiratory syncytial virus RNA in cells from the peripheral blood during acute infection. J. Pediatr. 1998, 133, 272–274. [Google Scholar] [CrossRef]
- Rezaee, F.; Gibson, L.F.; Piktel, D.; Othumpangat, S.; Piedimonte, G. Respiratory syncytial virus infection in human bone marrow stromal cells. Am. J. Respir. Cell Mol. Biol. 2011, 45, 277–286. [Google Scholar] [CrossRef] [Green Version]
- Bennett, B.L.; Garofalo, R.P.; Cron, S.G.; Hosakote, Y.M.; Atmar, R.L.; Macias, C.G.; Piedra, P.A. Immunopathogenesis of respiratory syncytial virus bronchiolitis. J. Infect Dis. 2007, 195, 1532–1540. [Google Scholar]
- Russell, C.D.; Unger, S.A.; Walton, M.; Schwarze, J. The Human Immune Response to Respiratory Syncytial Virus Infection. Clin. Microbiol. Rev. 2017, 30, 481–502. [Google Scholar] [CrossRef] [Green Version]
- McConnochie, K.M.; Hall, C.B.; Walsh, E.E.; Roghmann, K.J. Variation in severity of respiratory syncytial virus infections with subtype. J. Pediatr. 1990, 117, 52–62. [Google Scholar] [CrossRef]
Neutropenic Infants (n = 31) | Non-neutropenic Infants (n = 261) | Relative Risk (95%CI) | p Value | |
---|---|---|---|---|
Basic Characteristics | ||||
Female infant | 18 (58) | 113 (43) | 1.34 (0.96–1.87) | 0.12 |
Age < 3 months at onset | 23 (74) | 90 (34) | 2.15 (1.65–2.81) | <0.0001 * |
Weight-for-length z-score < −2 | 0 (0) | 15 (5.8) | not applicable | 0.38 |
Admission before day 5 of illness | 22 (71) | 156 (60) | 1.19 (0.93–1.52) | 0.23 |
Vital Signs and Oxygen Saturation on Admission | ||||
Axial temperature > 38.5 °C | 2 (6.5) | 39 (15) | 0.43 (0.11–1.70) | 0.28 |
Heart rate > 180 beats/min | 0 (0) | 18 (6.9) | not applicable | 0.23 |
Respiratory rate > 34 breaths/min | 25 (81) | 185 (71) | 1.14 (0.94–1.37) | 0.25 |
Arterial oxygen saturation < 95% | 2 (6.5) | 37 (14) | 0.46 (0.12–1.80) | 0.40 |
Laboratory Findings on Admission | ||||
Absolute lymphocyte count < 1.5 × 109/L | 0 (0) | 2 (0.8) | not applicable | 1.0 |
C-reactive protein < 1.0 mg/L | 17 (55) | 71 (27) | 2.02 (1.38–2.94) | 0.0015 * |
Consolidation on chest radiography | 2 (6.5) | 52 (20) | 0.32 (0.08–1.26) | 0.086 |
Culture of Nasopharyngeal Aspirate | ||||
Moraxella catarrhalis | 1 (3.9) † | 87 (42) ‡ | 0.09 (0.01–0.63) | <0.0001 * |
Streptococcus pneumoniae | 1 (3.9) † | 51 (25) ‡ | 0.16 (0.02–1.09) | 0.013 * |
Haemophilus influenzae | 2 (7.7) † | 45 (22) ‡ | 0.36 (0.09–1.38) | 0.12 |
Any of these 3 bacteria | 4 (15) † | 131 (63) ‡ | 0.24 (0.10–0.61) | <0.0001 * |
Treatments | ||||
Antibiotic use during course of RSV infection | 5 (16) | 57 (22) | 0.74 (0.32–1.70) | 0.64 |
Corticosteroid use during course of RSV infection | 1 (3.2) | 14 (5.4) | 0.60 (0.08–4.42) | 1.0 |
Hospital stay >7 days | 4 (13) | 58 (22) | 0.58 (0.23–1.49) | 0.35 |
Severity of RSV Infectio | ||||
GRSS on admission > 3.5 | 8 (26) | 52 (20) | 1.30 (0.68–2.47) | 0.44 |
Odds Ratio (95%CI) | p Value | |
---|---|---|
Any of the 3 bacteria † identified in cultures of nasopharyngeal aspirate | 0.11 (0.03–0.35) | <0.0001 * |
Age at onset of RSV infection, per 1-month increment | 0.81 (0.65–0.97) | 0.020 * |
GRSS on admission, per 1-point increment | 0.92 (0.67–1.24) | 0.59 |
C-reactive protein, per 1-mg/L increment | 1.02 (0.99–1.05) | 0.10 |
Female infant | 1.49 (0.61–3.70) | 0.38 |
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Korematsu, T.; Koga, H. Transient Neutropenia in Immunocompetent Infants with Respiratory Syncytial Virus Infection. Viruses 2021, 13, 301. https://doi.org/10.3390/v13020301
Korematsu T, Koga H. Transient Neutropenia in Immunocompetent Infants with Respiratory Syncytial Virus Infection. Viruses. 2021; 13(2):301. https://doi.org/10.3390/v13020301
Chicago/Turabian StyleKorematsu, Tatsuya, and Hiroshi Koga. 2021. "Transient Neutropenia in Immunocompetent Infants with Respiratory Syncytial Virus Infection" Viruses 13, no. 2: 301. https://doi.org/10.3390/v13020301