Inflammatory Profile in Children With Severe Acute Respiratory Syndrome

Pak C. Ng, MD, FRCPCH*; Christopher W.K. Lam, PhD‡; Albert M. Li, MRCP*; Chun K. Wong, PhD‡; Frankie W.T. Cheng, MRCPCH*; Ting F. Leung, MRCP*; Ellis K.L. Hon, FAAP*; Iris H.S. Chan, PhD‡; Chi K. Li, FRCP*; Kitty S.C. Fung, FRCPA§; and Tai F. Fok, MD, FRCPCH*

ABSTRACT. Objective. To study the inflammatory he severe acute respiratory syndrome (SARS) cytokine profile in children with severe acute respiratory is a newly discovered infectious disease caused syndrome (SARS) and to investigate whether monoclo- by a novel coronavirus.1,2 Hong Kong is one of nal antibody to -␣ (TNF-␣) could be T 3,4 the most severely affected cities. The outbreaks of considered for treatment of these patients. SARS at the Prince of Wales Hospital and in a Methods. Plasma concentra- densely populated housing estate, Amoy Gardens, ␤ tions ( [IL]-1 , IL-6, IL-8, IL-10, IL-12p70, and have affected 1755 local residents and claimed 299 ␣ TNF- ) were monitored longitudinally on admission, im- lives (as of July 16, 2003). Similar to the H5N1 “avian mediately before corticosteroids, and 1 to 2 days and 7 to flu” influenza infection, patients with SARS-associ- 10 days after the drug treatment in a cohort of pediatric -ated coronavirus (SARS-CoV) infection develop pri ؍ patients (n 8) with virologic confirmed SARS-associ- mary viral pneumonia and lymphopenia, and severe ated coronavirus infection. None of the patients required cases may involve acute respiratory distress syn- mechanical ventilation or intensive care treatment. All 5,6 children except 1 (patient 3) received corticosteroids. drome (ARDS). The H5N1 influenza virus has Results. Plasma IL-1␤ levels (excluding patient 3) been shown to be a potent inducer of proinflamma- tory .6,7 In particular, there is substantial were substantially elevated immediately before (range: ␣ ␣ 7–721 ng/L) and 7 to 10 days after (range: 7–664 ng/L) upregulation in tumor necrosis factor- (TNF- ) pro- 7 corticosteroid treatment. In contrast, the plasma concen- duction. Whether SARS-CoV may induce a similar trations of other key proinflammatory cytokines, includ- inflammatory cytokine pattern and contribute to the ing IL-6 and TNF-␣, were not overtly increased in any of unusual severity of human disease is not known. the patients throughout the course of illness. In addition, Recently, it was proposed that cytolysis may be as- plasma IL-10 concentration was significantly lower 1 to 2 sociated with viral amplification in the early stage of days and 7 to 10 days after corticosteroid treatment, com- SARS, which is then followed by an adaptive immu- pared with the immediate pretreatment level. Similarly, nologic response with clearance of virus and severe plasma IL-6 and IL-8 concentrations were significantly tissue .8 The use of immunomodulating decreased 7 to 10 days after the drug treatment. drugs, such as corticosteroids or monoclonal anti- Conclusions. Pediatric SARS patients have markedly body to TNF-␣, may be useful in suppressing the elevated circulating IL-1␤ levels, which suggests selec- host immune response. Thus, knowing the cytokine tive activation of the caspase-1–dependent pathway. pattern could assist the clinicians in understanding ␣ Other key proinflammatory cytokines, IL-6 and TNF- , the disease mechanism and in designing a treatment showed only mildly elevated levels at the initial phase of strategy most effective for the management of this the illness. The current evidence does not support the use ␣ condition. We measured prospectively a panel of of TNF- monoclonal antibody in this group of children. proinflammatory and anti-inflammatory cytokines, Pediatrics 2004;113:e7–e14. URL: http://www.pediatrics. using the flow cytometric technique during the acute org/cgi/content/full/113/1/e7; children, cytokines, SARS. phase of illness, to investigate whether monoclonal antibody to TNF-␣ is indicated for treatment of ABBREVIATIONS. SARS, severe acute respiratory syndrome; SARS. This report describes the inflammatory cyto- SARS-CoV, SARS-associated coronavirus; ARDS, acute respira- kine profile in a cohort of children with SARS. tory distress syndrome; TNF-␣, tumor necrosis factor-␣; IL, inter- leukin; RSV, respiratory syncytial virus. METHODS Patients During the SARS outbreak between March 13 and May 17, 2003, 8 children with virologic confirmed SARS-CoV infection were admitted to the pediatric unit of the Prince of Wales Hospi- From the Departments of *Paediatrics, ‡Chemical Pathology, and §Micro- tal. Their clinical characteristics are summarized in Table 1. biology, Prince of Wales Hospital, Chinese University of Hong Kong, Sha- tin, New Territories, Hong Kong. Received for publication Jul 31, 2003; accepted Oct 1, 2003. Drug Regimen Reprint requests to (P.C.N.) Department of Paediatrics, Level 6, Clinical All febrile children with suspected SARS were initially given a Sciences Bldg, Prince of Wales Hospital, Shatin, New Territories, Hong broad-spectrum antibiotic, cefotaxime, and an antimicrobial, Kong. E-mail: [email protected] erythromycin or clarithromycin, for treatment of atypical pneu- PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- monia. Oral ribavirin (40–60 mg/kg/d) was also started when the emy of Pediatrics. child had a definitive contact history of SARS or had high

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TABLE 1. Clinical Features and Treatment Outcomes Among Children With SARS Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Age (y) 0.3 14.9 16.6 17.5 13.1 2.2 7.5 6.2 Sex (M/F) F F M M M M M F Clinical features Downloaded from Fever Yes Yes Yes Yes Yes Yes Yes Yes Dyspnea Yes No No No Yes No No No Runny nose No Yes No No No Yes No No Cough Yes No Yes No Yes Yes Yes No Diarrhea Yes Yes Yes No Yes No No No Chills/rigors No Yes No Yes Yes No No No

www.aappublications.org/news Myalgia No Yes Yes No Yes No No No Others - - - Headache - Febrile convulsion Dizziness - Contact history Parents No contact Father Parents Parents Parents Father Grandmother Radiologic findings Chest radiograph Right upper and Right and left Right upper zone Left upper zone Right and left Right perihilar and Right upper zone Left middle zone left lower zone lower zone consolidation consolidation lower zone left lower zone consolidation consolidation consolidation consolidation consolidation consolidation CT of the thorax Right upper and Right and left Right upper zone Left upper zone Right and left Bilaterial N/A N/A left lower zone lower zone air space air space lower zone multifocal air air space air space consolidation consolidation air space space consolidation consolidation consolidation consolidation Virology byguestonSeptember 25,2021 RT-PCR Pos (throat) Pos (throat, Pos (stool) Neg (throat, Neg (throat, N/A N/A N/A stool) stool and stool and urine) urine) Serology (acute and Ͻ1/40, 1/320 Ͻ1/40, 1/320 Ͻ1/40, 1/640 Ͻ1/40, 1/320 Ͻ1/40, Ͼ1/640 Ͻ1/40, Ͼ1/640 Ͻ1/40, Ͼ1/640 Ͻ1/40, 1/160 convalescent titers) Treatment and outcome Oral ribavirin Prescribed Prescribed Prescribed Prescribed Prescribed Prescribed Prescribed Prescribed (day 1–14) (day 5–17) (day 6–15) (day 6–15) (day 7–16) (day 5–8) (day 1–11) (day 4–13) Intravenous ribavirin - - - - - Prescribed -- (day 9–13) Oral prednisolone Prescribed Prescribed - Prescribed Prescribed Prescribed Prescribed Prescribed (day 8–22) (day 10–24) (day 7–21) (day 8–22) (day 6–20) (day 6–20) (day 6–20) Intravenous pulse - Prescribed - - - Prescribed -- methylpredisolone (day 14–15) (day 10–11) Duration of fever (d) 10 (day 1–10) 8 (day 1–8) 6 (day 1–6) 9 (day 1–9) 9 (day 1–9) 10 (day 1–10) 4 (day 1–4) 6 (day 1–6) Outcome Alive Alive Alive Alive Alive Alive Alive Alive CT indicates computed tomography; RT-PCR, reverse-transcriptase polymerase chain reaction; Neg, negative test; Pos, positive test; N/A, not applicable. (Ͼ38.5°C) and abnormal radiographic changes suggestive of Ethical Approval pneumonia on admission. When the patient remained febrile 48 to The study was approved by the research ethics committee of 72 hours after commencement of antibiotics and antiviral treat- the Chinese University of Hong Kong. Informed consent was ment, oral prednisolone (0.5–1 mg/kg/d) was added. Intravenous ribavirin (20 mg/kg/d) and pulse methylprednisolone (10 mg/ obtained from the parents or guardians for all patients. kg/d, for 2–3 days) were reserved for those who had persistent fever, continuing clinical deterioration, or progressive consolida- tion on chest radiographs or computed tomography scan of the RESULTS thorax. Thereafter, a dose-tapering course of oral prednisolone The clinical features; laboratory, radiology, and was prescribed in the following 2 weeks. This pediatric treatment regimen was extrapolated from the adult experience,3,8 and the virology findings; and treatment outcomes are sum- dose and timing of commencement of these medications were marized in Table 1. All patients had significant in- constantly under review during the outbreak. crease in their convalescent viral titers specific for SARS-CoV. All except 1 child (patient 3) received Laboratory Investigations oral prednisolone. In most cases (except patients 2 In view of the difficulty in diagnosing SARS at the initial stage and 6), subsidence of fever and improvement in chest of clinical presentation, serial blood tests for monitoring lympho- cyte counts, biochemical enzymes, and inflammatory cytokines radiographic appearances occurred within 48 hours were performed in all children with probable SARS.9 Blood sam- of corticosteroid treatment (Table 1). Patient 6 also ples for cytokine measurement were obtained 1) on admission, 2) received intravenous ribavirin because of persistent immediately (ie, within 24 hours) before commencement of corti- high fever and severe pneumonia. Patients 2 and 6 costeroids, 3) 1 to 2 days after the drug treatment, and 4) 7 to 10 days after the drug treatment. All specimens were collected dur- required pulse methylprednisolone for treatment of ing the routine blood sampling procedure to minimize the distur- progressive lung condition, and both patients re- bance to the patients. On each occasion, 0.6 mL of venous blood sponded with substantial clearance of chest radio- was collected in a chilled container. The blood samples were immediately immersed in ice and transported to the laboratory for graph 72 hours after treatment. None of the children processing. required mechanical ventilation, and all patients sur- Plasma was separated by centrifugation (1900 ϫ g for 5 min- vived. ␮ Ϫ utes) at 4°C and stored in 200- L aliquots at 80°C until analysis. Four children (patients 4, 5, 6, and 8) did not have A panel of proinflammatory and anti-inflammatory cytokines— including interleukin (IL)-1␤, IL-6, IL-8, IL-10, IL-12p70, and TNF- blood taken for cytokines on admission. The longi- ␣—were simultaneously quantified by the Human Inflammatory tudinal profile of the inflammatory cytokines are Cytokine Cytometric Bead Array Kit (BD Pharmingen, San Diego, illustrated in Fig 1. Plasma IL-1␤ concentrations (ex- CA) using flow cytometry (FACSCalibur system, Becton Dickin- cluding patient 3) were substantially elevated both son Corp, San Jose, CA). The assay sensitivities for IL-1␤, IL-6, IL-8, IL-10, IL-12p70, and TNF-␣ were 7.2, 2.5, 3.6, 3.3, 1.9, and 3.7 immediately before (range: 7–721 ng/L) and 7 to 10 ng/L, respectively. In cytometric bead array, 6 bead populations days after corticosteroid treatment (range: 7–664 with distinct fluorescence intensities were coated with specific ng/L; Fig 1A). In contrast, the plasma levels of other antibodies for capturing different cytokines in plasma. The cyto- kine-captured beads were then mixed with phycoerythrin-conju- key inflammatory cytokines, including IL-6 (range: gated detection antibodies to form sandwich complexes. After 2.5–99 ng/L) and TNF-␣ (range: 0–18 ng/L), were incubation, washing, and acquisition of sample data, the result not overtly increased in any patient throughout the was generated in a graphic format using the BD cytometric bead course of illness (Fig 1B–F). array analysis software. The coefficients of variation for all cyto- kine assays were Ͻ10%. The cytokine results before and after corticosteroid In addition, microbiologic investigations were performed to treatment are summarized in Table 2. Plasma IL-10 detect common bacterial and viral pathogens associated with com- concentrations were significantly lower 1 to 2 days munity-acquired pneumonia. Throat swab, sputum samples, and and 7 to 10 days after corticosteroid treatment, com- blood samples were taken for routine bacterial cultures. Throat ϭ swab in infants and throat gargle samples from older children pared with the immediate pretreatment level (P were also obtained for 1) antigen detection of influenza A and B; .028, for both time points). Similarly, both plasma respiratory syncytial virus (RSV); adenovirus; and parainfluenza IL-6 and IL-8 concentrations were significantly de- 1, 2, and 3, using the commercial immunofluorescence assay kits; ϭ 2) virus isolation using different culture cell lines to recover com- creased 7 to 10 days after the drug treatment (P mon respiratory viruses and SARS-CoV; and 3) reverse-transcrip- .018 and P ϭ .043, respectively). The overall trend of tase–polymerase chain reaction for detecting influenza A and B, these cytokines suggests elevated levels at the initial 10 RSV, enteroviruses, and SARS-CoV. Tracheal aspirate sample phase of the disease (ie, the first 2 time points), which was not available for virologic or cytokine analysis, as none of the patients required intubation or mechanical ventilation. Paired was then followed by a decline in plasma concentra- acute and convalescent serum samples were tested for Chlamydia tion with time (Fig 1B–D , Table 2). The reductions in pneumoniae, C psittaci, Mycoplasma pneumoniae, and SARS-CoV an- plasma cytokine levels 7 to 10 days after corticoste- tibodies.11 It was estimated that reverse-transcriptase–polymerase chain reaction for all types of clinical specimens identified approx- roid therapy paralleled improvements in the clinical imately 62% of SARS patients, whereas paired viral titers for conditions. Plasma TNF-␣ concentrations, however, SARS-CoV is considered to be the gold standard test for diagnos- were not significantly different before and after cor- ing SARS. More than 90% of patients demonstrate a significant ticosteroid treatment (P ϭ .08, for both time points). increase in titer when the convalescent sample is taken 4 weeks after the onset of illness.11 Patient 6 was the sickest child in our cohort. His cytokine profile indicated that he had the highest Statistical Analysis proinflammatory cytokine levels—IL-1␤ (721 ng/L), Wilcoxon signed rank test was used to assess the difference in IL-6 (88 ng/L), IL-8 (26.7 ng/L), and TNF-␣ (18 ng/ plasma cytokine concentrations immediately before and 1 to 2 L)—immediately before corticosteroid treatment. days or 7 to 10 days after commencement of corticosteroids. All The decline in plasma cytokine concentrations was statistical tests were performed by SPSS for Windows (Release 10; SPSS Inc, Chicago, IL). The level of significance was set at 5% in all also much slower compared with other patients (Fig comparisons. 1).

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/113/1/ by guest on September 25, 2021 e7 e9 Fig 1. A, Change in plasma IL-1␤ concentrations in 4 different time points after the onset of illness—on admission, immediately before corticosteroid treatment, and 1 to 2 days and 7 to 10 days after treatment—in 8 children with mild and moderate SARS. All patients (except patient 3) received corticosteroid treatment. B, Change in plasma IL-6 concentrations in 4 different time points after the onset of illness—on admission, immediately before corticosteroid treatment, and 1 to 2 days and 7 to 10 days after treatment—in 8 children with mild and moderate SARS. All patients (except patient 3) received corticosteroid treatment.

e10 CYTOKINES IN PEDIATRICDownloaded SARSfrom www.aappublications.org/news PATIENTS by guest on September 25, 2021 Fig 1. C, Change in plasma IL-8 concentrations in 4 different time points after the onset of illness—on admission, immediately before corticosteroid treatment, and 1 to 2 days and 7 to 10 days after treatment—in 8 children with mild and moderate SARS. All patients (except patient 3) received corticosteroid treatment. D, Change in plasma IL-10 concentrations in 4 different time points after the onset of illness—on admission, immediately before corticosteroid treatment, and 1 to 2 days and 7 to 10 days after treatment—in 8 children with mild and moderate SARS. All patients (except patient 3) received corticosteroid treatment.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/113/1/ by guest on September 25, 2021 e7 e11 Fig 1. E, Change in plasma IL-12p70 concentrations in 4 different time points after the onset of illness—on admission, immediately before corticosteroid treatment, and 1 to 2 days and 7 to 10 days after treatment—in 8 children with mild and moderate SARS. All patients (except patient 3) received corticosteroid treatment. F, Change in plasma TNF-␣ concentrations in 4 different time points after the onset of illness—on admission, immediately before corticosteroid treatment, and 1 to 2 days and 7 to 10 days after treatment—in 8 children with mild and moderate SARS. All patients (except patient 3) received corticosteroid treatment.

e12 CYTOKINES IN PEDIATRICDownloaded SARSfrom www.aappublications.org/news PATIENTS by guest on September 25, 2021 TABLE 2. Changes in Cytokine Profile of Children With SARS (Excluding Patient 3) Before and After Corticosteroid Treatment Plasma Cytokine Immediately Before 1–2 Days After 7–10 Days After Normal Concentrations Corticosteroid Treatment Corticosteroid Treatment Corticosteroid Treatment Reference (ng/L) (n ϭ 7) (n ϭ 7) (n ϭ 7) Range19–23 IL-1␤ 127 (105–400) 130 (58–390) 100 (39–433) Ͻ1.5 IL-6 29 (24–56) 20 (3–74) 3 (3–27)* Ͻ4.3 IL-8 6.4 (3.6–24.4) 7.5 (3.6–26.7) 3.6 (3.3–11.8)* Ͻ30.4 IL-10 9.2 (6.9–15.9) 5.3 (4.9–6.5)* 3.3 (2.0–3.3)* Ͻ2.0 IL-12p70 12.1 (6.2–125) 13.0 (5.5–121) 10.5 (5.9–126) Ͻ9.0 TNF-␣ 3.7 (3.7–7.2) 3.7 (2.1–5.8) 3.7 (2.4–7.4) Ͻ3.5 Results are median (interquartile range). * P Ͻ .05

DISCUSSION flammatory and antiviral action of normal TNF-␣ This study was designed to investigate prospec- response may even be adversely attenuated by this tively the longitudinal cytokine profile of children treatment. However, we must point out that the cir- with SARS. Similar to H5N1 “avian flu” pneumonia, culating TNF-␣ levels may not necessarily reflect the SARS-CoV–induced atypical pneumonia is also asso- levels produced locally in the lungs, although a sub- ciated with pulmonary epithelial cell proliferation, stantial increase in regional TNF-␣ level is likely to infiltration of alveolar , early hyaline overspill into the circulation. Hence, more research membrane formation, hemophagocytosis, and other into pulmonary cytokine production and in severe histopathologic features suggestive of ARDS.6,12 The cases is required for clinicians to understand better presence of hemophagocytosis supports the notion the immunologic aspect of this new disease. that cytokine dysregulation may be, at least partly, More important, previous studies on cytokines responsible for an exaggerated and persistent inflam- and ARDS suggested that nonsurvivors who re- matory response causing diffuse alveolar damage ceived intensive care treatment had 1) significantly and alveolar fibroproliferation.6,12,13 Marked in- higher circulating TNF-␣, IL-6, and IL-8 levels on crease in TNF-␣ and other proinflammatory cyto- admission; 2) persistent elevation of proinflamma- kines, including IL-6 and -␥, have been tory cytokine levels over time; and that 3) such levels documented in human influenza A H5N1 infec- remained elevated despite corticosteroid treatment, tion.6,7 To date, the cytokine pattern in children with compared with survivors.13,17 Again, our findings SARS has not been reported. Our results revealed a indicate a decreasing trend in most key inflamma- predominant upregulation of IL-1␤ but not TNF-␣ or tory cytokines with time and a significant decrease in IL-6 after SARS-CoV infection in children. In exper- plasma concentrations of IL-6, IL-8, and IL-10 after 7 imental respiratory infection of pig lungs, Van Reeth to 10 days of corticosteroid treatment (Fig 1). The et al14 showed that IL-1 but not TNF-␣ or interfer- reduction in plasma cytokine levels corresponded on-␣ was increased after porcine reproductive-respi- closely with improvement in the clinical condition ratory syndrome virus infection, whereas all 3 proin- and resolution of inflammatory shadows on chest flammatory cytokines were upregulated in response radiographs. It has been suggested that effective con- to swine influenza virus. Similarly, IL-1␤ but not tainment of host inflammatory response, as a result TNF-␣ was secreted from macrophages infected with of either spontaneous improvement or suppression a neurotropic strain of coronavirus in irradiated by anti-inflammatory drugs such as corticosteroids, mice.15 A unique feature of IL-1␤ production is that was associated with a reduction in circulating in- this pyrogenic cytokine is synthesized as an inactive flammatory cytokine levels. The reduction in cyto- precursor (pro-IL-1␤), and virus-induced activation kine levels also correlated with improvement in gen- of caspase-1 (IL-1␤–converting enzyme) is required eral clinical condition, pulmonary function, and for converting this precursor protein into its biolog- survival.13,17 In view of rapid deterioration in lung ically active form (IL-1␤).16 Pirhonen et al16 found function in many adult patients during the acute that influenza A and Sendai virus could infect hu- phase of SARS-CoV infection,3,8 it would be deemed man macrophages, and induced the activation of unethical to withhold corticosteroid treatment in any caspase-1–dependent pathway resulting in enhance- patients who had persistent fever or progressive ra- ment of IL-1␤ production. Hence, one plausible ex- diographic changes at the onset of the outbreak.8 planation of our observation is that there has been a Hence, all except 1 patient in this cohort were treated selective activation of the caspase-1–dependent with corticosteroids. Consequently, we are unable to pathway in SARS-CoV infection. Nonetheless, the conclude with confidence that the reduction in cir- exact mechanism that leads to SARS-CoV–induced culating cytokine levels was associated with cortico- immunomodulation remains to be elucidated. Our steroid usage or just the natural recovery process of results also suggest that other key circulating proin- illness independent of any drug treatment. The ab- flammatory and anti-inflammatory cytokines— sence of overtly elevated plasma IL-6 and TNF-␣ TNF-␣, IL-6, and IL-10—on admission and immedi- levels, together with a progressive reduction in con- ately before corticosteroid treatment were not centrations of other cytokines, IL-8 and IL-10, did overtly elevated as observed in H5N1 infection. predict a favorable outcome for our patients. Such Monoclonal antibody to TNF, therefore, is unlikely to findings concur with our previous clinical observa- be useful in this group of children, and the proin- tion that children tend to have milder disease and a

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/113/1/ by guest on September 25, 2021 e7 e13 less aggressive clinical course than adult SARS pa- outcome of severe acute respiratory syndrome in children. Lancet. 2003; tients.4 The cytokine results, therefore, cast doubt on 561:1701–1703 5. Yuen KY, Chan PKS, Peiris M, et al. Clinical features and rapid viral the liberal use of corticosteroids in pediatric SARS diagnosis of human disease associated with avian influenza A H5N1 patients, as the host immunologic response did not virus. Lancet. 1998;351:467–471 seem to be as severe as initially anticipated. How- 6. To KF, Chan PKS, Chan KF, et al. Pathology of fatal human infection ever, it is important to note that our patients had associated with avian influenza A H5N1 virus. J Med Virol. 2001;63: 242–246 relatively mild symptoms, and none required me- 7. Cheung CY, Poon LLM, Lau AS, et al. Induction of proinflammatory chanical ventilation or intensive care. Thus, the re- cytokines in human macrophages by influenza A (H5N1) viruses: a sults may not be generalizable to cases with severe mechanism for the unusual severity of human disease? Lancet. 2002;360: disease. Nonetheless, it is reassuring that there was 1831–1837 no fatality among the pediatric patients in Hong 8. So LKY, Lau ACW, Yam LYC, Cheung TMT, Poon E, Yung RWH. Development of a standard treatment protocol for severe acute respi- Kong. It is interesting that corticosteroids were not ratory syndrome. Lancet. 2003;361:1615–1617 used in Canada, and all children recovered with 9. WHO case definition of SARS; 2003. Available at: http://www.who. supportive treatment.19 Corticosteroids should prob- int/csr/casedefinition/en ably be reserved for patients with severe disease, in 10. Severe acute respiratory syndrome (SARS): laboratory diagnostic tests. Available at: http://www.who.int/csr/sars/diagnostictests/en particular, those who require oxygen supplementa- 11. Peiris JSM, Chu CM, Cheng VCC, et al. Clinical progression and viral tion and mechanical ventilatory support. load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361:1767–1772 CONCLUSIONS 12. Nicholls JM, Poon LLM, Lee KC, et al. Lung pathology of fatal severe Pediatric SARS patients had markedly elevated acute respiratory syndrome. Lancet. 2003;361:1773–1778 ␤ 13. Meduri U, Headley S, Tolley E, Shelby M, Stentz F, Postlethwaite A. plasma IL-1 levels, which suggested selective Plasma and BAL cytokine response to corticosteroid rescue treatment in caspase-1–dependent pathway activation in infected late ARDS. Chest. 1995;108:1315–1325 macrophages. In contrast to H5N1 influenza infec- 14. Van Reeth K, Labarque G, Nauwynck H, Pensaert M. Differential pro- tion,6,7 other key proinflammatory cytokines, includ- duction of proinflammatory cytokines in the pig lung during different ␣ respiratory virus infections: correlations with pathogenicity. Res Vet Sci. ing IL-6 and TNF- , were only mildly elevated at the 1999;67:47–52 initial phase of the illness. Most of these cytokine 15. Stohlman SA, Yao Q, Bergmann CC, Tahara SM, Kyuwa S, Hinton DR. levels fell with time and coincided with improve- Transcription and translation of proinflammatory cytokines following ment in clinical conditions and radiographic appear- JHMV infection. Adv Exp Med Biol. 1995;380:173–178 16. Pirhonen J, Sareneva T, Kurimoto M, Julkunen I, Matikainen S. Virus ances. Thus, the current evidence does not support ␤ ␣ infection activates IL-1 and IL-18 production in human macrophages the use of monoclonal antibody to TNF- for treat- by a caspase-1-dependent pathway. J Immunol. 1999;162:7322–7329 ment of children with SARS. A randomized, con- 17. 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