- Email: [email protected]
Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia
J Infect Chemother (2011) 17:803–806 DOI 10.1007/s10156-011-0265-7
ORIGINAL ARTICLE
Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia Tomohiro Oishi • Mitsuo Narita • Kou Matsui • Takahiro Shirai Mai Matsuo • Jun Negishi • Takayuki Kaneko • Shinya Tsukano Tetsuo Taguchi • Makoto Uchiyama
• •
Received: 7 February 2011 / Accepted: 30 May 2011 / Published online: 17 June 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract The immunological pathogenesis of Mycoplasma pneumoniae pneumonia is known to involve several cytokines. The serum levels of interleukin-18 (IL-18) were examined using enzyme-linked immunosorbent assay in 23 pediatric patients (median age 6 years; range 4–13 years; 14 girls and 9 boys) with M. pneumoniae pneumonia admitted to our hospital. Serum levels of IL-18 ranged from 22 to 1808 pg/ml with a mean of 543 pg/ml. We started steroid therapy in two cases with IL-18 values greater than 1000 pg/ml without being aware of IL-18 levels. Examination of associations between IL-18 levels determined by enzyme-linked immunosorbent assay and a routine laboratory test showed that levels of lactate dehydrogenase (LDH) and IL-18 were significantly correlated. To determine the appropriateness of steroid administration in M. pneumoniae pneumonia patients, serum LDH should be examined. Patients with elevated levels of LDH are likely to have significantly elevated IL-18 values (C1000 pg/ml) and thus can be candidates for steroid therapy.
Keywords Interleukin-18 (IL-18) Lactate dehydrogenase (LDH) Mycoplasma pneumoniae Child Pneumonia
Introduction Mycoplasma pneumoniae (M. pneumoniae) is an important pathogen causing pediatric pneumonia, particularly in children older than 5 years [1]. Host immune responses play a central role in the development of this type of pneumonia [2]. The role of cytokines in the pathogenesis of M. pneumoniae lung disease has been increasingly examined in clinical, animal, and in vitro studies [3–10]. One study found a significant association between the serum level of IL-18 and the severity of M. pneumoniae pneumonia in adults [9]. This study was undertaken to investigate serum levels of IL-18 in pediatric pneumonia due to M. pneumoniae.
Patients and methods T. Oishi M. Uchiyama Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medicine and Dental Sciences, Asahimachi, Niigata 951-8510, Japan T. Oishi (&) K. Matsui T. Shirai M. Matsuo J. Negishi T. Kaneko S. Tsukano T. Taguchi Department of Pediatrics, Niigata Prefectural Shibata Hospital, 1-2-8 Honcho, Shibata, Niigata 957-8588, Japan e-mail: [email protected] M. Narita Department of Pediatrics, Sapporo Tokushukai Hospital, Sakae-dori 18-4-10, Shiroishi-ku, Sapporo 003-0021, Japan
Study population We enrolled 23 patients (median age 6 years; range 4–13 years; 14 girls and 9 boys) who were admitted to the Niigata Prefectural Shibata Hospital from August 2006 to February 2008 and from whom acute and convalescent serum samples could be obtained. Informed consent was received from the patients or their parents. Past histories, family histories, and histories of atopic diseases or bronchial asthma were found to be unremarkable for the patients in this study. In all cases, the diagnosis of M. pneumoniae pneumonia was confirmed radiographically as well as serologically by
123
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a fourfold or greater rise in the titer of antimycoplasma antibody as measured by a microparticle agglutination test (Serodia Myco II; Fujirebio, Tokyo, Japan).
Results
IL-18 measurements
IL-18 levels ranged from 22 to 1808 pg/ml, with a mean value of 543 pg/ml. Seventeen of the 23 patients had serum IL-18 values[260 pg/ml in acute or convalescent serum samples or both. Thus, IL-18 levels in the majority of the pediatric patients with M. pneumoniae pneumonia were abnormally elevated.
Serum samples were stored at -80°C until they were assayed for IL-18, which was measured with a commercially available ELISA kit (MBL, Nagoya, Japan) according to the supplier’s instructions. The minimum significant concentration of IL-18 that could be detected in the serum (i.e., the test sensitivity) was 12.5 pg/ml, and values [260 pg/ml (the mean plus 3 standard deviations of the IL-18 level in healthy controls) were considered abnormally elevated. These thresholds were also based on the supplier’s instructions. Relationship between IL-18 values and severity as assessed using chest X-ray findings The assessment of the severity of each case based on chest X-ray images was made according to the Japanese Respiratory Society guidelines for the management of community-acquired pneumonia for adults (The Committee for the JRS Guidelines in Management of Respiratory Infections, 2000). Namely, cases in which a shadow was visible in one-third or less of a lung were classified as mild, those in which the shadow was visible in more than one-third but less than two-thirds of a lung were classified as moderate, and those in which the shadow was visible in more than two thirds of a lung were classified as severe. Other clinical laboratory data The following clinical parameters were determined by routine methods: white blood cell count (WBC), neutrophil count (NEU), c-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). We checked for correlations between IL-18 and other clinical parameters. Statistical analysis Patients were classified into groups according to the severity of pneumonia as assessed by chest X-ray findings, and IL-18 values were compared among these groups with Student’s T test. Pearson’s product–moment correlation coefficient was used to evaluate the relationship between IL-18 values and other clinical laboratory data. A p value of \0.05 was considered significant. This study was approved by the ethics committees of the Niigata Prefectural Shibata Hospital.
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IL-18 levels in serum
Relationship between IL-18 values and severity as assessed using chest X-ray findings Of the 23 patients, 10 patients were classified as having mild pneumonia according to the chest X-ray findings, 13 patients as having moderate pneumonia, and none as having severe pneumonia. Figure 2 shows the values of serum IL-18 in the mild and moderate severity categories. The mean value of IL-18 in patients with moderate pneumonia was significantly higher than that in patients with mild pneumonia (721 vs. 317 pg/ml, p \ 0.01) (Fig. 1). Relationship between IL-18 levels and clinical laboratory data The correlations between IL-18 and other clinical parameters, WBC, NEU, CRP, -AST, -ALT and LDH, are shown in Figs. 1 and 2. Only the correlation between IL-18 and LDH was statistically significant, although the degree of correlation was not very strong (Fig. 3). Clinical courses of two patients with highly elevated IL-18 values Two patients had serum IL-18 values that were[1000 pg/ml (Fig. 3). One patient was a 5-year-old girl (Fig. 4) who Serum IL-18 (pg/ml)
P<0.01 2000 1800 1600 1400 1200 1000 800 600 400 200 0
Mild
Intermediate
Degree of severity as assessed by chest X-ray
Fig. 1 Serum IL-18 values classified according to the degree of severity as assessed on the basis of chest X-ray findings. IL-18 values were significantly higher in the intermediate severity group than in the mild severity group. Standard deviations are expressed by the vertical bars
J Infect Chemother (2011) 17:803–806 12000
r2 = 0.12
10000 8000
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mPSL* admission 6.8 8.4 561 X320 1314
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38
Serum IL-18 (pg/ml)
Fig. 2 Correlations between serum values of IL-18 and clinical laboratory data. Significant correlations were not found between serum values of IL-18 and white blood cell counts (WBC), c-reactive protein (CRP) values, aspartate aminotransferase (AST) values, and alanine aminotransferase (ALT) values
37
36 8/23
8/30
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Fig. 5 Clinical course of an 8-year-old girl. MINO minocycline 900 800 700 600 LDH 500 (IU/l) 400 300 200 100 0
r2 = 0.64
0
500
1000 1500 Serum IL-18 (pg/ml)
2000
Fig. 3 Correlation between serum values of IL-18 and lactate dehydrogenase levels. A significant correlation was found between serum values of IL-18 and lactate dehydrogenase (LDH) values AZM CTRX
CLDM
O2 admission 3
WBC(x10 µl) CRP(mg/dl) LDH (IU/l) MPA IL-18(pg/ml) BT( ) 40
mPSL*
8.0 8.0 512 X640 178
6.3 10.2 780
1808
2/17
2/21
*(1mg/kgX3/day)
discharge
8.5 0.7
9.7 2.6 311 X10280
5.2 0.2 232
2/26
2/28
3/5
39 38 37 36 2/15
Fig. 4 Clinical course of a 5-year-old girl. BT body temperature, MPA antimycoplasma particle agglutination titer, AZM azithromycin, CTRX ceftriaxone, mPSL methylprednisolone
developed fever and cough on February 15, 2007, and was taken to a clinic the next day. Antibiotics were not prescribed, and her fever and cough persisted. She returned to the clinic on February 17, and was diagnosed with pneumonia based on a chest X-ray. Later that day, she was admitted to our hospital. On admission, we commenced empiric antimicrobial therapy with azithromycin and ceftriaxone; however, this did not improve her condition. When additional chest X-rays revealed enlargement of
consolidation and she developed respiratory distress on February 21 (the seventh day from onset), we initiated steroid therapy (1 mg/kg of methylprednisolone administered intravenously three times a day) with supplemental oxygen. After the initiation of this treatment, the patient’s fever rapidly resolved and her respiratory status gradually improved. The chest X-ray abnormality had begun to improve by February 28 (14th day from onset). The patient’s serum IL-18 level increased from 178 pg/ml on the day of admission to 1808 pg/ml on the seventh day from onset. The second patient with a highly elevated level of IL-18 was an 8-year-old girl (Fig. 5). She developed fever and cough on August 23, 2007, and her doctors took a wait-andsee approach. Her cough worsened gradually, and she was taken to a nearby clinic on the eighth day from onset. She was diagnosed with pneumonia based on a chest X-ray, and she was admitted to our hospital the same day. Since the consolidation visible on X-ray was widespread and dyspnea was observed on admission, we initiated steroid therapy (1 mg/ kg of methylprednisolone administered intravenously three times a day) with supplemental oxygen, along with empiric antimicrobial therapy including ceftriaxone and minocycline. The patient’s fever rapidly resolved and her respiratory status gradually improved. The chest X-ray abnormality had improved by September 6 (14th day from onset). Her serum IL-18 level was 1314 pg/ml on admission and 1204 pg/ml on the 14th day from onset. Steroids were not used in the remaining 21 patients.
Discussion Considering that the established normal upper limit for serum IL-18 is 260 pg/ml [7], the serum IL-18 values in the present pediatric patients with M. pneumoniae pneumonia
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were significantly elevated, a finding which is consistent with previous reports of similar cases [7, 11]. Narita et al. [7] observed significantly elevated pleural fluid levels of IL-18 in severe cases of M. pneumoniae pneumonia, and Tanaka et al. found a significant positive correlation between circulating IL-18 levels and the number of affected pulmonary lobes detected by computed tomography in adult patients with M. pneumoniae pneumonia. We did not attempt to replicate these results in the present study of pediatric patients with M. pneumoniae pneumonia, because pleural fluid cannot be obtained in all M. pneumoniae pneumonia cases, and computed tomography cannot be performed in all pediatric patients. In this context, our results in serum samples from pediatric patients are consistent with previous reports [7, 9] in that significantly higher levels of IL-18 were found for the intermediate severity group when compared to the mild severity group, and they further confirm that IL-18 plays a significant role in the development of M. pneumoniae pneumonia. We had empirically initiated steroid treatment in the cases with the two highest IL-18 levels without knowing the IL-18 levels when we initiated the steroid therapy. Although we have reported only two cases and it is premature to make firm conclusions based on them, this observation strongly suggests the possibility that serum IL18 levels could be a useful and objective measure to determine which patients can be candidates for steroid therapy. However, IL-18 cannot currently be measured in most hospitals and clinics in a timely fashion. Consequently, the use of steroid hormone would remain empiric. Therefore, we searched for a relationship between IL-18 and other clinical laboratory data that are more easily obtained. We found that levels of LDH were significantly correlated with those of IL-18. Thus, it may be possible to estimate the IL-18 level when the LDH level is known. Given that an IL-18 value of 1000 pg/ml strongly suggests that steroid treatment is necessary, the corresponding LDH value is 480 IU/L (Fig. 3). In fact, the initial LDH levels were 512 and 561 in the two cases for which steroid was given. In contrast, the LDH value was lower than 480 IU/L in all of the remaining 21 patients who did not receive steroid. Steroid therapy has been advocated for the treatment of M. pneumoniae pneumonia [3, 11–13]. One point which must be emphasized is that our findings on the elevated serum levels of IL-18 and LDH in severe cases can be applied to the clinical manifestation of atypical pneumonia in which a definite area of consolidation can be seen on chest roentgenograms, and cannot be applied to other manifestations such as acute respiratory distress syndrome and bronchiolitis obliterans organizing pneumonia, for which a lobar consolidation is not visible and different pathomechanisms from atypical pneumonia must be underlying. In fact, a histologic difference between atypical
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pneumonia and bronchiolitis obliterans organizing pneumonia has been reported: neutrophilic inflammation in the former [14] and lymphocytic inflammation in the latter [15]. However, there has been no consensus on which patients should be considered for steroid therapy. Further studies are needed to confirm the usefulness of serum IL-18 and LDH levels as measures of the severity of pediatric M. pneumoniae pneumonia.
References 1. McIntosh K. Community-acquired pneumonia in children. N Engl J Med. 2002;346:429–37. 2. Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev. 2004;17(4):697–728. 3. Hoek KL, Cassell GH, Duffy LB, Atkinson TP. Mycoplasma pneumoniae-induced activation and cytokine production in rodent mast cells. J Allergy Clin Immunol. 2002;109:470–6. 4. Hsieh CC, Tang RB, Tsai CH, Chen W. Serum interleukin-6 and tumor necrosis factor-alpha concentrations in children with Mycoplasma pneumonia. J Microbiol Immunol Infect. 2001;34:109–12. 5. Lee KY, Lee HS, Hong JH, Lee MH, Lee JS, Burgner D, et al. Role of prednisolone treatment in severe Mycoplasma pneumoniae pneumonia in children. Pediatr Pulmonol. 2006;41(3):263–8. 6. Lieberman D, Livnat S, Schlaeffer F, Porath A, Horowitz S, Levy R. IL-1beta and IL-6 in community-acquired pneumonia: bacteremic pneumococcal pneumonia versus Mycoplasma pneumoniae pneumonia. Infection. 1997;25:90–4. 7. Narita M, Tanaka H, Abe S, Yamada S, Kubota M, Togashi T. Close association between pulmonary disease manifestation in Mycoplasma pneumoniae infection and enhanced local production of interleukin-18 in the lung, independent of gamma interferon. Clin Diagn Lab Immunol. 2000;7(6):909–14. 8. Narita M, Tanaka H, Yamada S, Abe S, Ariga T, Sakiyama Y. Significant role of interleukin-8 in pathogenesis of pulmonary disease due to Mycoplasma pneumoniae infection. Clin Diagn Lab Immunol. 2001;8:1028–30. 9. Tanaka H, Narita M, Teramoto S, Saikai T, Oashi K, Igarashi T, et al. Role of interleukin-18 and T-helper type 1 cytokines in the development of Mycoplasma pneumoniae pneumonia in adults. Chest. 2002;121(5):1493–7. 10. Yang J, Hooper WC, Phillips DJ, Talkington DF. Interleukin-1b responses to Mycoplasma pneumoniae infection are cell type specific. Microb Pathog. 2003;34:17–25. 11. Iwata A, Izumikawa K, Sekita T, Ishimoto H, Sakamoto N, Nakayama S, et al. A case of mycoplasmal pneumonia with bronchiolitis treated with steroids. Kansenshogaku Zasshi. 2007; 81(5):586–91. 12. Tamura A, Matsubara K, Tanaka T, Nigami H, Yura K, Fukaya T. Methylprednisolone pulse therapy for refractory Mycoplasma pneumoniae pneumonia in children. J Infect. 2008;57(3):223–8. 13. Tanaka H, Okada H, Yamagishi M, Honma S, Sugawara H, Abe S, et al. Therapeutic effectiveness of prednisolone in Mycoplasma pulmonis-infected pneumonia in mice. Nihon Kyobu Shikkan Gakkai Zasshi. 1994;32(1):42–7. 14. Rollins S, Colby T, Clayton F. Open lung biopsy in Mycoplasma pneumoniae pneumonia. Arch Pathol Lab Med. 1986;110:34–41. 15. Llibre JM, Urban A, Garcia E, Carrasco MA, Murcia C. Bronchiolitis obliterans organizing pneumonia associated with acute Mycoplasma pneumoniae infection. Clin Infect Dis. 1997;25: 1340–2.
ORIGINAL ARTICLE
Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia Tomohiro Oishi • Mitsuo Narita • Kou Matsui • Takahiro Shirai Mai Matsuo • Jun Negishi • Takayuki Kaneko • Shinya Tsukano Tetsuo Taguchi • Makoto Uchiyama
• •
Received: 7 February 2011 / Accepted: 30 May 2011 / Published online: 17 June 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract The immunological pathogenesis of Mycoplasma pneumoniae pneumonia is known to involve several cytokines. The serum levels of interleukin-18 (IL-18) were examined using enzyme-linked immunosorbent assay in 23 pediatric patients (median age 6 years; range 4–13 years; 14 girls and 9 boys) with M. pneumoniae pneumonia admitted to our hospital. Serum levels of IL-18 ranged from 22 to 1808 pg/ml with a mean of 543 pg/ml. We started steroid therapy in two cases with IL-18 values greater than 1000 pg/ml without being aware of IL-18 levels. Examination of associations between IL-18 levels determined by enzyme-linked immunosorbent assay and a routine laboratory test showed that levels of lactate dehydrogenase (LDH) and IL-18 were significantly correlated. To determine the appropriateness of steroid administration in M. pneumoniae pneumonia patients, serum LDH should be examined. Patients with elevated levels of LDH are likely to have significantly elevated IL-18 values (C1000 pg/ml) and thus can be candidates for steroid therapy.
Keywords Interleukin-18 (IL-18) Lactate dehydrogenase (LDH) Mycoplasma pneumoniae Child Pneumonia
Introduction Mycoplasma pneumoniae (M. pneumoniae) is an important pathogen causing pediatric pneumonia, particularly in children older than 5 years [1]. Host immune responses play a central role in the development of this type of pneumonia [2]. The role of cytokines in the pathogenesis of M. pneumoniae lung disease has been increasingly examined in clinical, animal, and in vitro studies [3–10]. One study found a significant association between the serum level of IL-18 and the severity of M. pneumoniae pneumonia in adults [9]. This study was undertaken to investigate serum levels of IL-18 in pediatric pneumonia due to M. pneumoniae.
Patients and methods T. Oishi M. Uchiyama Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medicine and Dental Sciences, Asahimachi, Niigata 951-8510, Japan T. Oishi (&) K. Matsui T. Shirai M. Matsuo J. Negishi T. Kaneko S. Tsukano T. Taguchi Department of Pediatrics, Niigata Prefectural Shibata Hospital, 1-2-8 Honcho, Shibata, Niigata 957-8588, Japan e-mail: [email protected] M. Narita Department of Pediatrics, Sapporo Tokushukai Hospital, Sakae-dori 18-4-10, Shiroishi-ku, Sapporo 003-0021, Japan
Study population We enrolled 23 patients (median age 6 years; range 4–13 years; 14 girls and 9 boys) who were admitted to the Niigata Prefectural Shibata Hospital from August 2006 to February 2008 and from whom acute and convalescent serum samples could be obtained. Informed consent was received from the patients or their parents. Past histories, family histories, and histories of atopic diseases or bronchial asthma were found to be unremarkable for the patients in this study. In all cases, the diagnosis of M. pneumoniae pneumonia was confirmed radiographically as well as serologically by
123
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J Infect Chemother (2011) 17:803–806
a fourfold or greater rise in the titer of antimycoplasma antibody as measured by a microparticle agglutination test (Serodia Myco II; Fujirebio, Tokyo, Japan).
Results
IL-18 measurements
IL-18 levels ranged from 22 to 1808 pg/ml, with a mean value of 543 pg/ml. Seventeen of the 23 patients had serum IL-18 values[260 pg/ml in acute or convalescent serum samples or both. Thus, IL-18 levels in the majority of the pediatric patients with M. pneumoniae pneumonia were abnormally elevated.
Serum samples were stored at -80°C until they were assayed for IL-18, which was measured with a commercially available ELISA kit (MBL, Nagoya, Japan) according to the supplier’s instructions. The minimum significant concentration of IL-18 that could be detected in the serum (i.e., the test sensitivity) was 12.5 pg/ml, and values [260 pg/ml (the mean plus 3 standard deviations of the IL-18 level in healthy controls) were considered abnormally elevated. These thresholds were also based on the supplier’s instructions. Relationship between IL-18 values and severity as assessed using chest X-ray findings The assessment of the severity of each case based on chest X-ray images was made according to the Japanese Respiratory Society guidelines for the management of community-acquired pneumonia for adults (The Committee for the JRS Guidelines in Management of Respiratory Infections, 2000). Namely, cases in which a shadow was visible in one-third or less of a lung were classified as mild, those in which the shadow was visible in more than one-third but less than two-thirds of a lung were classified as moderate, and those in which the shadow was visible in more than two thirds of a lung were classified as severe. Other clinical laboratory data The following clinical parameters were determined by routine methods: white blood cell count (WBC), neutrophil count (NEU), c-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). We checked for correlations between IL-18 and other clinical parameters. Statistical analysis Patients were classified into groups according to the severity of pneumonia as assessed by chest X-ray findings, and IL-18 values were compared among these groups with Student’s T test. Pearson’s product–moment correlation coefficient was used to evaluate the relationship between IL-18 values and other clinical laboratory data. A p value of \0.05 was considered significant. This study was approved by the ethics committees of the Niigata Prefectural Shibata Hospital.
123
IL-18 levels in serum
Relationship between IL-18 values and severity as assessed using chest X-ray findings Of the 23 patients, 10 patients were classified as having mild pneumonia according to the chest X-ray findings, 13 patients as having moderate pneumonia, and none as having severe pneumonia. Figure 2 shows the values of serum IL-18 in the mild and moderate severity categories. The mean value of IL-18 in patients with moderate pneumonia was significantly higher than that in patients with mild pneumonia (721 vs. 317 pg/ml, p \ 0.01) (Fig. 1). Relationship between IL-18 levels and clinical laboratory data The correlations between IL-18 and other clinical parameters, WBC, NEU, CRP, -AST, -ALT and LDH, are shown in Figs. 1 and 2. Only the correlation between IL-18 and LDH was statistically significant, although the degree of correlation was not very strong (Fig. 3). Clinical courses of two patients with highly elevated IL-18 values Two patients had serum IL-18 values that were[1000 pg/ml (Fig. 3). One patient was a 5-year-old girl (Fig. 4) who Serum IL-18 (pg/ml)
P<0.01 2000 1800 1600 1400 1200 1000 800 600 400 200 0
Mild
Intermediate
Degree of severity as assessed by chest X-ray
Fig. 1 Serum IL-18 values classified according to the degree of severity as assessed on the basis of chest X-ray findings. IL-18 values were significantly higher in the intermediate severity group than in the mild severity group. Standard deviations are expressed by the vertical bars
J Infect Chemother (2011) 17:803–806 12000
r2 = 0.12
10000 8000
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CRP (mg/dl)
4000 2000 0
0
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CRP(mg/dl) LDH(IU / l) MPA IL-18(pg/ml) BT ( ) 40
mPSL* admission 6.8 8.4 561 X320 1314
*(1mg/kgX3/day) 10.2 2.0 361
10.3 0.4 407 X10280
9/3
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discharge 6.6 0.1 268
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0
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CTRX MINO d.i.v.
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1000
1500
2000
38
Serum IL-18 (pg/ml)
Fig. 2 Correlations between serum values of IL-18 and clinical laboratory data. Significant correlations were not found between serum values of IL-18 and white blood cell counts (WBC), c-reactive protein (CRP) values, aspartate aminotransferase (AST) values, and alanine aminotransferase (ALT) values
37
36 8/23
8/30
9/9
Fig. 5 Clinical course of an 8-year-old girl. MINO minocycline 900 800 700 600 LDH 500 (IU/l) 400 300 200 100 0
r2 = 0.64
0
500
1000 1500 Serum IL-18 (pg/ml)
2000
Fig. 3 Correlation between serum values of IL-18 and lactate dehydrogenase levels. A significant correlation was found between serum values of IL-18 and lactate dehydrogenase (LDH) values AZM CTRX
CLDM
O2 admission 3
WBC(x10 µl) CRP(mg/dl) LDH (IU/l) MPA IL-18(pg/ml) BT( ) 40
mPSL*
8.0 8.0 512 X640 178
6.3 10.2 780
1808
2/17
2/21
*(1mg/kgX3/day)
discharge
8.5 0.7
9.7 2.6 311 X10280
5.2 0.2 232
2/26
2/28
3/5
39 38 37 36 2/15
Fig. 4 Clinical course of a 5-year-old girl. BT body temperature, MPA antimycoplasma particle agglutination titer, AZM azithromycin, CTRX ceftriaxone, mPSL methylprednisolone
developed fever and cough on February 15, 2007, and was taken to a clinic the next day. Antibiotics were not prescribed, and her fever and cough persisted. She returned to the clinic on February 17, and was diagnosed with pneumonia based on a chest X-ray. Later that day, she was admitted to our hospital. On admission, we commenced empiric antimicrobial therapy with azithromycin and ceftriaxone; however, this did not improve her condition. When additional chest X-rays revealed enlargement of
consolidation and she developed respiratory distress on February 21 (the seventh day from onset), we initiated steroid therapy (1 mg/kg of methylprednisolone administered intravenously three times a day) with supplemental oxygen. After the initiation of this treatment, the patient’s fever rapidly resolved and her respiratory status gradually improved. The chest X-ray abnormality had begun to improve by February 28 (14th day from onset). The patient’s serum IL-18 level increased from 178 pg/ml on the day of admission to 1808 pg/ml on the seventh day from onset. The second patient with a highly elevated level of IL-18 was an 8-year-old girl (Fig. 5). She developed fever and cough on August 23, 2007, and her doctors took a wait-andsee approach. Her cough worsened gradually, and she was taken to a nearby clinic on the eighth day from onset. She was diagnosed with pneumonia based on a chest X-ray, and she was admitted to our hospital the same day. Since the consolidation visible on X-ray was widespread and dyspnea was observed on admission, we initiated steroid therapy (1 mg/ kg of methylprednisolone administered intravenously three times a day) with supplemental oxygen, along with empiric antimicrobial therapy including ceftriaxone and minocycline. The patient’s fever rapidly resolved and her respiratory status gradually improved. The chest X-ray abnormality had improved by September 6 (14th day from onset). Her serum IL-18 level was 1314 pg/ml on admission and 1204 pg/ml on the 14th day from onset. Steroids were not used in the remaining 21 patients.
Discussion Considering that the established normal upper limit for serum IL-18 is 260 pg/ml [7], the serum IL-18 values in the present pediatric patients with M. pneumoniae pneumonia
123
806
were significantly elevated, a finding which is consistent with previous reports of similar cases [7, 11]. Narita et al. [7] observed significantly elevated pleural fluid levels of IL-18 in severe cases of M. pneumoniae pneumonia, and Tanaka et al. found a significant positive correlation between circulating IL-18 levels and the number of affected pulmonary lobes detected by computed tomography in adult patients with M. pneumoniae pneumonia. We did not attempt to replicate these results in the present study of pediatric patients with M. pneumoniae pneumonia, because pleural fluid cannot be obtained in all M. pneumoniae pneumonia cases, and computed tomography cannot be performed in all pediatric patients. In this context, our results in serum samples from pediatric patients are consistent with previous reports [7, 9] in that significantly higher levels of IL-18 were found for the intermediate severity group when compared to the mild severity group, and they further confirm that IL-18 plays a significant role in the development of M. pneumoniae pneumonia. We had empirically initiated steroid treatment in the cases with the two highest IL-18 levels without knowing the IL-18 levels when we initiated the steroid therapy. Although we have reported only two cases and it is premature to make firm conclusions based on them, this observation strongly suggests the possibility that serum IL18 levels could be a useful and objective measure to determine which patients can be candidates for steroid therapy. However, IL-18 cannot currently be measured in most hospitals and clinics in a timely fashion. Consequently, the use of steroid hormone would remain empiric. Therefore, we searched for a relationship between IL-18 and other clinical laboratory data that are more easily obtained. We found that levels of LDH were significantly correlated with those of IL-18. Thus, it may be possible to estimate the IL-18 level when the LDH level is known. Given that an IL-18 value of 1000 pg/ml strongly suggests that steroid treatment is necessary, the corresponding LDH value is 480 IU/L (Fig. 3). In fact, the initial LDH levels were 512 and 561 in the two cases for which steroid was given. In contrast, the LDH value was lower than 480 IU/L in all of the remaining 21 patients who did not receive steroid. Steroid therapy has been advocated for the treatment of M. pneumoniae pneumonia [3, 11–13]. One point which must be emphasized is that our findings on the elevated serum levels of IL-18 and LDH in severe cases can be applied to the clinical manifestation of atypical pneumonia in which a definite area of consolidation can be seen on chest roentgenograms, and cannot be applied to other manifestations such as acute respiratory distress syndrome and bronchiolitis obliterans organizing pneumonia, for which a lobar consolidation is not visible and different pathomechanisms from atypical pneumonia must be underlying. In fact, a histologic difference between atypical
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pneumonia and bronchiolitis obliterans organizing pneumonia has been reported: neutrophilic inflammation in the former [14] and lymphocytic inflammation in the latter [15]. However, there has been no consensus on which patients should be considered for steroid therapy. Further studies are needed to confirm the usefulness of serum IL-18 and LDH levels as measures of the severity of pediatric M. pneumoniae pneumonia.
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