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Serum Amyloid a Protein in Acute Viral Infections

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Serum Amyloid a Protein in Acute Viral Infections 210 Archives ofDisease in Childhood 1993; 68: 210-214 Arch Dis Child: first published as 10.1136/adc.68.2.210 on 1 February 1993. Downloaded from Serum amyloid A protein in acute viral infections Hiroyuki Miwata, Toshiyuki Yamada, Masahiko Okada, Toyoichiro Kudo, Hiroshi Kimura, Tsuneo Morishima Abstract infections have been reported to cause weak Concentrations of serum amyloid A protein C reactive protein responses,'8 9 and increased (SAA) were measured in 254 children with C reactive protein concentrations have been viral diseases, including measles, varicella, used to distinguish bacterial from viral origins. rubella, mumps, echo-30 meningitis, chronic In this study we investigated the clinical signifi- hepatitis B and C, and in eight with Kawasaki cance of SAA in viral diseases based on the disease. following points: (1) kinetics of SAA in acute Latex agglutination nephelometric immuno- viral diseases, (2) comparisons of SAA between asay was used for assaying SAA. In 191 out of the acute and chronic viral diseases, (3) relation 195 patients (98%), SAA concentrations between SAA and C reactive protein, (4) relation became markedly raised in the acute phase of between SAA and other acute phase reactants. the viral disease: measles (97%), varicella We used the latex agglutination nephelometric (100%), mumps (95%), and echo-30 meningitis immunoassay to assay SAA as it is simple, fast, (99%) with mean titres of 82-4, 80-5, 60 2, and precise.20 We also measured SAA in patients 75-2, and 101-1 itg/mI respectively. This with Kawasaki disease, which is classified as a increase in SAA was followed by a rapid collagen vascular disease. return to normal concentrations (<5 ig/ml) during convalescence. Remarkably higher concentrations of SAA (mean 1630 *g/ml) Patients and methods were detected in the acute phase of patients PATIENTS with Kawasaki disease, but in most of the The study group consisted of 254 children with children with chronic hepatitis B or C, the viral infections including measles (n= 34), titres of SAA remained normal. There was no varicella (n= 17), rubella (n= 31), mumps close correlation between SAA and serum (n= 37), enterovirus infections (echo-30 http://adc.bmj.com/ concentrations for a,-acid glycoprotein, 02- meningitis, n=76), chronic hepatitis B (n=29), microglobulin, transferrin, and IgG. and chronic hepatitis C (n=30), and eight There was a clear coffelation between children with Kawasaki disease. The children SAA and C reactive protein concentrations, were between 1 and 14 years old (mean 6-4 although SAA showed a greater incremental years). Measles, varicella, rubella, and mumps change than C reactive protein in the acute were diagnosed according to clinical findings phase. In the acute phase of these viral and serological evaluations. Echo-30 meningitis on September 28, 2021 by guest. Protected copyright. diseases, 56% of the patients had raised SAA was diagnosed based on clinical manifestations concentrations (5 *g/ml) with normal C (fever, headache, vomiting, and stiff neck) and reactive protein concentrations (<5 ,tg/ml). by lymphocytic pleocytosis of >30x 106 cells/l Department of in of the echo- Paediatrics, These results indicate that SAA could be use- the cerebrospinal fluid. Isolation Nagoya University ful as an inflammatory marker in children with 30 virus and/or serological examination by School of Medicine, acute viral infections. neutralising test were also conducted to confirm Nagoya, the diagnosis. Serum samples were collected Japan Hiroyuki Miwata (Arch Dis Child 1993;68:210-4) during an epidemic in the Nagoya area in 1991. Toyoichiro Kudo Chronic hepatitis was defined as a continuous Hiroshi Kimura Serum amyloid A protein (SAA), a putative hepatic inflammatory process lasting one year or Tsuneo Morishima serum precursor of the amyloid A protein that more. Patients with mild increases in serum Department of activities were Laboratory Medicine, constitutes amyloid fibrils in secondary aminotransferase (50-100 IU/1) Niipata University amyloidosis,' has been clinically evaluated as selected for study. Hepatitis C was diagnosed by School of Medicine, one of the sensitive acute phase reactants in detection of the C-100 antibody and by the Niigata, For a decade increased concentrations presence of hepatitis C virus RNA using the Japan serum.2 Toshiyuki Yamada of SAA have been reported in a number of polymerase chain reaction method.2' A diagnosis Masahiko Okada inflammatory diseasesY'4 It has been particu- of hepatitis B was based on positive hepatitis B Correspondence and reprint larly useful in the diagnosis of acute renal or surface antigenaemia and presence of anti- requests to: 16 and in monitor- hepatitis B core antibody. The diagnosis of Dr Hiroyuki Miwata, hepatic allograft rejections'5 Departmnnt of Paediatrics, ing disease activity in rheumatoid arthritis Kawasaki disease was based on clinical mani- Nagoya University School 17 festations and laboratory data.22 of Medicine, patients. 65 Tsuruma-cho, In patients with bacterial infections, C reactive Sera were obtained from patients at designated Showa-ku, been as a useful intervals and stored at -70°C until analysis. Nagoya 466, protein has widely recognised Japan. inflammatory marker, although no such markers Single serum samples were also obtained from Accepted 10 September 1992 have been identified for viral diseases. Viral 51 age matched healthy children. Serum amyloid A protein in acute viral infections 211 SAA ASSAY: LATEX AGGLUTINATION ACUTE PHASE REACTANTS NEPHELOMETRIC IMMUNOASSAY For other acute phase reactants we also measured Arch Dis Child: first published as 10.1136/adc.68.2.210 on 1 February 1993. Downloaded from SAA was measured by latex agglutination C reactive protein, P2-microglobulin (132-M), nephelometric immunoassay as described pre- al-acid glycoprotein (acI-AG), transferrin, and viously.20 SAA was purified from the pooled IgG, in the same samples using the latex sera of patients with rheumatic arthritis.23 agglutination assay. Antiserum to SAA was raised in rabbits accord- ing to standardised procedures. Immunoglobulin G was isolated from the antiserum by diethyla- Results minoethanol cellulose ion exchange chromato- SAA CONCENTRATIONS IN PATIENTS graphy, adjusted to 1 mg/ml, and then Fifty one normal controls aged 1-14 years conjugated to 10% polystyrene latex particles (mean 5-8) had mean (SD) SAA concentrations (mean diameter 0-1 pm) in 0-2 mol/l ammonium of 1-72 (1 11) [ig/ml. From these data an buffer at pH 8-2 for one hour at 37°C. After arbitrary upper limit for the normal SAA washing, latex particles were suspended at 0-1% concentration was set at 5-0 jig/ml (mean+ in the same ammonium buffer containing 05% 3SD). In cases with acute viral diseases, SAA bovine serum albumin.20 For the assay, an concentrations increased in the acute phase and automated immunochemistry analyser, LX-3000 declined thereafter throughout convalescence (Eiken Chemical Co Ltd and AIC, Tokyo, (see table 1). By contrast, however, in children Japan), was used. An aliquot of 20 ml of a test with chronic hepatitis B and C the titre of SAA sample or assay standard, along with 240 ,.d remained within normal at 3-0 (2-3) jig/ml in of 005 mol/l hydroxyethylpiperazine-ethane- hepatitis B and 15 (1 1) pg/ml in hepatitis C sulphonic acid (HEPES) buffer at pH 7-4, and (fig 1). 80 V of a latex solution were mixed and incubated in glass cells at 37°C. Light scattering was recorded at 45 seconds and 305 seconds KINETICS OF SM DURING THE COURSE OF after mixing, and any observed increases in this ILLNESS interval were used to calculate the SAA concen- Changes in the SAA concentration were investi- tration. For the assay standard we used an SAA gated at designated intervals. Figure 2 shows enriched high density lipoprotein.24 the kinetics for SAA in 12 cases of measles, 14 Table I Mean (SD) concentrations of SAA (tsglml) in the acute and convalescent phase of illness Phase ofillness Viral infection Measles Varicella Rubella Mumps Echo-30 meningitis Controls http://adc.bmj.com/ (n=34) (n=17) (n=31) (n=37) (n=76) (n=SI) Acute 82-4(113-3) 80-5(148-9) 60-2(71-9) 75-2 (160-2) 101-1 (157-0) 17(11) Convalescence 4-3 (3 3) 4-3 (2-1) 3-0 (2-1) 3-0 (2-0) 3-4 (1-6) (log 10) on September 28, 2021 by guest. Protected copyright. to so X *S E 0, 0'~ ~ ~ ~ ~ :C, * * * l en 4~~~~ A C A C A C A C A C m I)n Measles Varicella Rubella Mumps Echo-30 ..*- : 0.~ a) I I Figure I SAA concentrations in children with measles, rubella, varicella, mumps, echo-30 meningitis, hepatitis B, and hepatitis when compared with normal controls. SAA concentrations in serum samplesfrom infectedpatients were obtained during the acute (A) and convalescent (C) phases ofacute viral infections. The dotted line indicates the upper limit ofthe normal range. 212 Miwata, Yamada, Okada, Kudo, Kimura, Morishima Measles Echo-30 meningitis Kawasaki disease of echo-30 meningitis, and eight of Kawasaki 10000 10000 10000 disease. Higher than normal SAA was detectable Arch Dis Child: first published as 10.1136/adc.68.2.210 on 1 February 1993. Downloaded from - 10001. = 1000 in all patients with measles on the day the rash E 0) appeared, but SAA titres sharply declined ± 1000 i- 100 z 'E. 100 \~, between days 4 and 7 in seven of these cases and remained above normal in the remaining five () 10. cn 10 un 10 cases. SAA concentrations were raised at the onset of neurological symptoms in 13 of the 14 1' 1 .,, , . _ w 01 2345678 0123456789 2 6101418222630 patients with echo-30 meningitis. In nine of Days after rash Days after onset of Days after fever these cases, the SAA titre decreased dramatically appeared meningitis appeared between days 4 and 8, but in the remaining five Figure 2 Kineticsfor SAA concentrations in 12 children with measles, 14 with echo-30 cases SAA concentrations continued to be high.
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