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Serum Tumor Necrosis Factor-a Concentrations in Children Hospitalized for Acute Lower Respiratory Tract Infection Hanna Nohynek, Anna-Maija Teppo, Eija Laine, Maija Leinonen, and Jnhani Eskola

National Public Health Institute; IV Department of Medicine, Helsinki University Central Hospital; Aurora Hospital, Helsinki, Finland

The production of tumor necrosis factor-a (TNFa) can be induced by the bacterial lipopolysaccharide (LPS) [1-3] but also by some viruses [4] and the malaria parasite [5]. TNFa has antiviral activity: It inhibits the development of the virusinduced cytopathic effect and reduces the viral yield [6]. In viral infections it has been suggestedto induce resistance in uninfected cells and to prevent viral spread by selective killing of virus-infected cells [4]. High concentrations of TNFa have been reported in the serum or cerebrospinal fluid of patients with bacterial [7-10] or parasitic infections [11, 12]. In contrast, elevated TNFa concentrations have not been reported in viral infections [9, 11], except for the end stages of human immunodeficiency virus infection [13, 14]. The importance of TNFa in the physiologicantiviralresponse suggests, however, that TNFa would play a role in other viral infections. Previous reports on TNFa in children have mainly concentratedon severebacterial or parasitic diseasessuch as bacterial meningitis and sepsis with or without a specific focus, infectiouspurpura, and malaria [7, 12, 15, 16]. Toour knowledge only one study has determined TNFa concentrations during respiratory infections [10]. We measured TNFa concentrations in sera of 118children hospitalizedfor acute lowerrespiratory tract infection(ALRI) caused by bacteria or viruses. We wantedto find out whether serum TNFa concentrations were elevated in ALRI and, if so, whether these concentrations could be used to differenti-

Received 26 March 1990; revised 17 December 1990. Presented inpart: 29th Interscience Conference onAntimicrobial Agents andChemotherapy, Houston, September 1989 (abstract 964). Informed consent was obtained from parents. Financial support: Academy of Finland (R.N., M.L., J.E.). Reprints or correspondence: Dr. Juhani Eskola, National Public Health Institute, Mannerheimintie 166, SF-00300 Helsinki, Finland. The Journal of Infectious Diseases 1991;163:1029-1032 © 1991 by The University of Chicago. All rights reserved. 0022-1899/91/6305-0014$01.00

ate ALRI of bacterial and viral origin, whether differences could be foundin TNFa concentrationsof gram-negative and gram-positiveinfection, and whether the "initial" TNFa concentration had prognostic value for clinical outcome.

Materials and Methods Patients. Children admitted to Aurora Hospital with clinically diagnosed ALRI (n = 106)or admittedfor other reasonsbut found to have fever (~38°C) and a pneumonic infiltrate on chest radiography (n = 12)wereenrolled. The original series of 135consecutive patientswiththesecriteria has beendescribed[17]; the presentsubset was selected on the basis of the availability of paired sera for both serologicand TNFa measurements. ALRI was defined on the basis of modified case management guidelinesof the WorldHealth Organization [18] as a community-acquired febrile (~38°C) acute respiratory infection with symptoms lasting ~7 days and difficulty in breathing (chest indrawing or breathing frequency >40/min for infants or >30/min for those ~1 year old. The medianageofthe patientswas 1.7 years (range, 2 months-If years); 58 % were male and 42 % female. Most presented with a moderateor severe but uncomplicated clinical pictureof ALRI. The mean (standard deviation) duration of fever beforehospitalization was2.5 (2) days (range, 40 ng/l

114 87 96 125

60 85 30 70

169 77 114 131

5-900 5-320 5-355 5-450

57 64 43 58

200 150 100 50

NOTE. Initial concentrations were not available for 7 patients.

0 Diagnosis.

The diagnosis of bacterial ALRI was based on blood culture (l positive finding), antigen detection in serum or urine or detection of nucleic acid (Mycoplasma pneumoniae) in nasopharyngeal aspirate (13), or a significant rise in antibodies in paired sera (35). Diagnosis of viral ALRI was based on antigen detection in nasopharyngeal aspirates (30) or a significant rise in antibodies in paired sera (57). The bacteria implicated were Streptococcus pneu-

moniae, Haemophilus influenzae, Branhamella catarrhalis, M. pneumoniae, Chlamydia trachomatis, and Chlamydia pneumoniae, and the viruses implicated were respiratory syncytial virus (RSV), adenovirus, influenza virus types A and B, and parainfluenza types 1,2, and 3 [17].Bacterial involvement was found in 52 patients (44 %), either alone (n = 29) or together with viral involvement(i.e., mixed infection, n = 23). Evidence for viral involvement alone was found in 30 patients (25%). In 36 (31%) the etiology remained unknown [17].

RIA ofTNFa. A solid-phase double-antibody RIA [8] was used to measure serum TNFa concentrations. The detection limit of the assay was 7 ng/l; in calculating the means of the TNFa concentrations, values below the detection limit of the assay were given the arbitrary value of 5 ng/I. The upper limit of normal serum TNFa concentrations, defined as the mean + 2 SD observed in 71 healthy children, was 40 ng!l (mean, 8; SD, 16) (unpublished data). Dataanalysis. Between groups of patients, continuous measures were compared using the Wilcoxon rank sum test. X2 test was used to analyze the independence of categorical variables. Pearson correlation coefficients were calculated to analyze the relation of TNFa concentrations to other continuous variables.

Results Serum TNFa concentrations were elevated in 77 (65 %) of the 118 patients. Mean values for initial and maximal TNFa

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Pnc

H.infl

M.pne





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RSV

Adena

Figure 1. Maximal concentrationof tumor necrosis factor-a (TNF) in serum of patients with acute lower respiratory tract infection due to a single agent. Bars indicate means. Pnc = Streptococcus pneumoniae, H.inft = Haemophilus influenzae, M.pne = Mycoplasma pneumoniae, RSV = respiratory syncytial virus, Adeno = adenovirus.

concentrations for each group are shown in tables 1 and 2. In those 111 children from whom both initial and third- or fifth-day TNFa concentrations were available, the initial concentrations correlated strongly with the maximal concentrations (r = .98, P< .001). The maximal TNFa concentrations were somewhat higher in bacterial (mean, 131 ± 32 ng/l) than in viral (107 ± 20 ng/l) andmixedALRI (93 ± 15 ng/l) , but these differences were not statistically significant. The proportion of patients with elevated (>40 ng/l) TNFa concentrations was somewhat higher in the bacterial and mixed ALRI groups (64%) than in the viral group (50%). The difference, however, was not statistically significant. Of the patients with ALRI of unknown origin, 64 % had elevated TNFa concentrations. The maximal TNFa concentrations in .patients in whom a single agent was implicated are shown in figure 1. In patients with H. injiuenzae infections alone (n = 7), the mean maximal concentration of TNFa was 141 ng/l, and with S. pneumoniae(n = 6),97 ng/l; this difference was not significant. RSV alone (n = 15) was found with the least elevation of TNFa (mean, 42 ng/l) , whereas adenovirus infection (n = 7) was associated with the highest TNFa concentrations (mean, 162 ng/l).

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Table 2. Concentrations of serum tumor necrosis factor-a (TNFa) on admission in patients with acute lower respiratory tract infection.

1ID 1991;163 (May)

TNFa in Children with ALRI

Table 3. Relation of maximal concentration of serum tumor necrosis factor-a (TNFa) to age, etiology of infection, clinical signs and symptoms, and clinical laboratory parameters in 118 children with acute lower respiratory tract infection. TNFa ng/l

~40

(n =

1.6 32 37 32

(n = 77)

p

1.8 51 20 29

NS*

1.9

2.8

Serum tumor necrosis factor-alpha concentrations in children hospitalized for acute lower respiratory tract infection.

Tumor necrosis factor-alpha (TNF alpha) concentrations were measured by radioimmunoassay in sera of 118 children (median age, 1.7 years; range, 2 mont...
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