Abstract
Febrile children are often given antibiotics empirically and unnecessarily. MxA is a protein induced in peripheral lymphoid cells by type 1 interferons during active viral infection. The ability of a whole blood ELISA assay for MxA to identify children with viral illness was studied in 122 children who presented with acute onset fever and 52 age-matched healthy controls. The febrile children were divided into three groups according to their final diagnoses: etiologically diagnosed viral infection, clinically diagnosed viral infection, and bacterial infection. MxA levels in the bacterial infection group and controls were similar and low (90.9 ± 69.7 and 76.9 ± 63.2 ng/mL, respectively). In contrast, mean MxA levels in the two viral infection groups were higher than in both the bacterial and control groups (719.2 ± 386.4 and 827.0 ± 651.1, respectively). A receiver operating characteristic analysis showed that the area under the curve of the MxA level was greater than under the curves of both the white blood cell count and the C-reactive protein concentration. Whole blood assay of MxA is a clinically useful tool for diagnosing viral illness in febrile children and should help reduce use of unnecessary antibiotics.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- CRP:
-
C-reactive protein
- PBMC:
-
peripheral blood mononuclear cells
- ROC:
-
receiver operating characteristic
- WBC:
-
white blood cell
References
Makela MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimaki M, Blomqvist S, Hyypia T, Arstila P 1998 Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 36: 539–542
Huang N, Morlock L, Lee CH, Chen LS, Chou YJ 2005 Antibiotic prescribing for children with nasopharyngitis (common colds), upper respiratory infections, and bronchitis who have health-professional parents. Pediatrics 116: 826–832
Baker MD, Bell LM, Avner JR 1993 Outpatient management without antibiotics of fever in selected infants. N Engl J Med 329: 1437–1441
Baskin MN, O'Rourke EJ, Fleisher GR 1992 Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. J Pediatr 120: 22–27
Jaskiewicz JA, McCarthy CA, Richardson AC, White KC, Fisher DJ, Dagan R, Powell KR 1994 Febrile infants at low risk for serious bacterial infection–an appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative Study Group. Pediatrics 94: 390–396
Le Bon A, Tough DF 2002 Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14: 432–436
Samuel CE 2001 Antiviral actions of interferons. Clin Microbiol Rev 14: 778–809
Staeheli P, Pitossi F, Pavlovic J 1993 Mx proteins: GTPases with antiviral activity. Trends Cell Biol 3: 268–272
van der Bliek AM 1999 Functional diversity in the dynamin family. Trends Cell Biol 9: 96–102
Staeheli P, Haller O, Boll W, Lindenmann J, Weissmann C 1986 Mx protein: constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus. Cell 44: 147–158
Zhao H, De BP, Das T, Banerjee AK 1996 Inhibition of human parainfluenza virus-3 replication by interferon and human MxA. Virology 220: 330–338
Schnorr JJ, Schneider-Schaulies S, Simon-Jodicke A, Pavlovic J, Horisberger MA, ter Meulen V 1993 MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line. J Virol 67: 4760–4768
Chieux V, Chehadeh W, Harvey J, Haller O, Wattre P, Hober D 2001 Inhibition of coxsackievirus B4 replication in stably transfected cells expressing human MxA protein. Virology 283: 84–92
Ronni T, Matikainen S, Sareneva T, Melen K, Pirhonen J, Keskinen P, Julkunen I 1997 Regulation of IFN-α/beta, MxA, 2′,5′-oligoadenylate synthetase, and HLA gene expression in influenza A-infected human lung epithelial cells. J Immunol 158: 2363–2374
Simon A, Fah J, Haller O, Staeheli P 1991 Interferon-regulated Mx genes are not responsive to interleukin-1, tumor necrosis factor, and other cytokines. J Virol 65: 968–971
Ronni T, Melen K, Malygin A, Julkunen I 1993 Control of IFN-inducible MxA gene expression in human cells. J Immunol 150: 1715–1726
Meier V, Mihm S, Ramadori G 2000 MxA gene expression in peripheral blood mononuclear cells from patients infected chronically with hepatitis C virus treated with interferon-alpha. J Med Virol 62: 318–326
Deisenhammer F, Reindl M, Harvey J, Gasse T, Dilitz E, Berger T 1999 Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies. Neurology 52: 1239–1243
Itazawa T, Adachi Y, Imamura H, Okabe Y, Yamamoto J, Onoue Y, Adachi YS, Miyawaki T, Murakami G 2001 Increased lymphoid MxA expression in acute asthma exacerbation in children. Allergy 56: 895–898
Itazawa T, Adachi Y, Nakabayashi M, Fuchizawa T, Murakami G, Miyawaki T 2006 Theophylline metabolism in acute asthma with MxA-indicated viral infection. Pediatr Int 48: 54–57
Forster J, Schweizer M, Schumacher RF, Kaufmehl K, Lob S 1996 MxA protein in infants and children with respiratory tract infection. Acta Paediatr 85: 163–167
Halminen M, Ilonen J, Julkunen I, Ruuskanen O, Simell O, Makela MJ 1997 Expression of MxA protein in blood lymphocytes discriminates between viral and bacterial infections in febrile children. Pediatr Res 41: 647–650
Chieux V, Hober D, Harvey J, Lion G, Lucidarme D, Forzy G, Duhamel M, Cousin J, Ducoulombier H, Wattre P 1998 The MxA protein levels in whole blood lysates of patients with various viral infections. J Virol Methods 70: 183–191
Chieux V, Hober D, Chehadeh W, Harvey J, Alm G, Cousin J, Ducoulombier H, Wattre P 1999 MxA protein in capillary blood of children with viral infections. J Med Virol 59: 547–551
Esposito S, Blasi F, Arosio C, Fioravanti L, Fagetti L, Droghetti R, Tarsia P, Allegra L, Principi N 2000 Importance of acute Mycoplasma pneumoniae and Chlamydia pneumoniae infections in children with wheezing. Eur Respir J 16: 1142–1146
Bachur RG, Harper MB 2001 Predictive model for serious bacterial infections among infants younger than 3 months of age. Pediatrics 108: 311–316
Towbin H, Schmitz A, Jakschies D, Von Wussow P, Horisberger MA 1992 A whole blood immunoassay for the interferon-inducible human Mx protein. J Interferon Res 12: 67–74
Hanley JA, McNeil BJ 1982 The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143: 29–36
Hanley JA, McNeil BJ 1983 A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 148: 839–843
Roers A, Hochkeppel HK, Horisberger MA, Hovanessian A, Haller O 1994 MxA gene expression after live virus vaccination: a sensitive marker for endogenous type I interferon. J Infect Dis 169: 807–813
Greenes DS, Harper MB 1999 Low risk of bacteremia in febrile children with recognizable viral syndromes. Pediatr Infect Dis J 18: 258–261
Heiskanen-Kosma T, Korppi M, Jokinen C, Kurki S, Heiskanen L, Juvonen H, Kallinen S, Sten M, Tarkiainen A, Ronnberg PR, Kleemola M, Makela PH, Leinonen M 1998 Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis J 17: 986–991
Sakaguchi S, Negishi H, Asagiri M, Nakajima C, Mizutani T, Takaoka A, Honda K, Taniguchi T 2003 Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock. Biochem Biophys Res Commun 306: 860–866
O'Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, Perry AK, Nguyen BO, Lane TF, Taniguchi T, Miller JF, Cheng G 2004 Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med 200: 437–445
Venet C, Zeni F, Viallon A, Ross A, Pain P, Gery P, Page D, Vermesch R, Bertrand M, Rancon F, Bertrand JC 2000 Endotoxaemia in patients with severe sepsis or septic shock. Intensive Care Med 26: 538–544
Cohen J 2000 The detection and interpretation of endotoxaemia. Intensive Care Med 26: S51–S56
Marshall JC, Walker PM, Foster DM, Harris D, Ribeiro M, Paice J, Romaschin AD, Derzko AN 2002 Measurement of endotoxin activity in critically ill patients using whole blood neutrophil dependent chemiluminescence. Crit Care 6: 342–348
Girardin E, Grau GE, Dayer JM, Roux-Lombard P, Lambert PH 1988 Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 319: 397–400
Calandra T, Baumgartner JD, Grau GE, Wu MM, Lambert PH, Schellekens J, Verhoef J, Glauser MP 1990 Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 Immunoglobulin Study Group. J Infect Dis 161: 982–987
Korppi M, Heiskanen-Kosma T, Leinonen M 1997 White blood cells, C-reactive protein and erythrocyte sedimentation rate in pneumococcal pneumonia in children. Eur Respir J 10: 1125–1129
Heiskanen-Kosma T, Korppi M 2000 Serum C-reactive protein cannot differentiate bacterial and viral aetiology of community-acquired pneumonia in children in primary healthcare settings. Scand J Infect Dis 32: 399–402
Virkki R, Juven T, Rikalainen H, Svedstrom E, Mertsola J, Ruuskanen O 2002 Differentiation of bacterial and viral pneumonia in children. Thorax 57: 438–441
Acknowledgements
The authors thank Dr Gyokei Murakami (Department of Pediatrics, Toyama Red Cross Hospital), Dr Masayoshi Miura (Department of Pediatrics, Toyama City Hospital), Dr Hiromichi Kubota (Department of Pediatrics, Kouseiren Takaoka Hospital) and Dr Yoichi Onoue (Department of Pediatrics, Toyama Prefectural Central Hospital) for their recruitment of the subjects. And they thank C Sakai and H Moriuchi for their excellent technical assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by grants from the Ministry of Health, Laboratory and Welfare in Japan, and by Kyowa Medex Co., Ltd., Tokyo, Japan.
Rights and permissions
About this article
Cite this article
Nakabayashi, M., Adachi, Y., Itazawa, T. et al. MxA-Based Recognition of Viral Illness in Febrile Children by a Whole Blood Assay. Pediatr Res 60, 770–774 (2006). https://doi.org/10.1203/01.pdr.0000246098.65888.5b
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.pdr.0000246098.65888.5b
This article is cited by
-
FebriDx®: A Rapid Diagnostic Test for Differentiating Bacterial and Viral Aetiologies in Acute Respiratory Infections
Molecular Diagnosis & Therapy (2019)
