Int J Clin Exp Med 2019;12(12):13643-13650 www.ijcem.com /ISSN:1940-5901/IJCEM0101256

Original Article The effects of reduning injection as an adjuvant of azithromycin-based therapy for mycoplasma pneumoniae and asthma in children

Yu Cui1*, Dexiang Liu2*, Zhigang Sun3, Lei Gao1, Hongmin Wang1, Yingjie Hua4, Feng’ai Liu5

Departments of 1Pediatrics, 4Emergency Pediatrics, Zibo City Linzi District People’s Hospital, Zibo, Shandong Province, China; 2Department of Pediatrics, Laoling People’s Hospital, Laoling, Shandong Province, China; 3Department of Pediatrics, The Second People’s Hospital of Liaocheng, Liaocheng, Shandong Province, China; 5Department of Pediatrics, Haiyang People’s Hospital, Haiyang, Shandong Province, China. *Equal contributors and co-first authors. Received August 21, 2019; Accepted October 10, 2019; Epub December 15, 2019; Published December 30, 2019

Abstract: Objective: To explore the efficacy of reduning injection (RDN) combined with azithromycin for the treatment of mycoplasma pneumoniae infection and asthma in children, and its effects on pulmonary function and inflamma- tory cytokine expression. Methods: Eighty-four children with mycoplasma pneumoniae infection and asthma were randomly divided into an observation and a control group, with 42 cases in each group. The patients in the control group were given azithromycin enteric-coated tablets (10 mg PO QD) plus routine treatment, while the patients in the observation group were treated with an adjunctive RDN injection (10 mL of RDN in 100 mL of 5% dextrose in- jection, intravenous infusion) besides azithromycin and routine treatment. The main outcome measures, including the time to defervescence, the time to the disappearance of shortness of breath, cough and lung rales, the length of the hospital stay, the overall response rate, the incidence of adverse events, as well as the eosinophil count (EOS), eosinophil cationic protein (ECP), and interleukin-8 (IL-8) in the peripheral blood were compared. Pulmonary function, parameters including forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF), were also compared between the groups. Results: The patients in the observation group had significantly shorter times for the disappearance of symptoms such as fever, shortness of breath, cough, and lung rales, and shorter hospital stays than those in the control group (all P<0.05). The observation group also had a significantly higher rate of effective treatment than the control group (P<0.05). The levels of EOS, ECP, and serum IL-8 were significantly lower than they were before treatment for both groups (all P<0.05), and the decrease was more noticeable in the observation group (P<0.05). Both groups showed increases in FVC, FEV1, and PEF after treatment (all P<0.05), and the observation group had significantly higher FVC, FEV1, and PEF than the control group (all P<0.05). There was no statistically significant difference in the incidence of adverse events between the two groups (P>0.05). Conclusion: RDN combined with azithromycin is effective in treating children with mycoplasma pneumoniae infection and asthma, which can significantly improve their clinical symptoms and pulmonary function, and shorten their hospital stays. The combination also has a lower incidence of adverse events and a favorable safety profile. Therefore, it is worthy of popularization in clinical practice.

Keywords: Pediatric patients, reduning injection, azithromycin, mycoplasma pneumoniae infection and asthma, pulmonary function, inflammatory cytokines

Introduction accounts for about 7% of community-acquired pneumonia in children, and its incidence is ris- Mycoplasma pneumoniae is one of the most ing [2, 3]. Mycoplasma pneumoniae can cause common types of community-acquired pneu- shortness of breath, fever, cough, and lung monia in children. Children are prone to myco- rales, and it can result in reduced lung and air- plasma pneumoniae infection due to their way function. It can also induce chronic allergic immature and weak immune systems. Recent airway inflammation, enhance eosinophil accu- studies have shown that 20%-60% of hospital- mulation and activation, and contribute to ele- ized children are infected with mycoplasma vated levels of airway inflammatory mediators pneumoniae in China [1]. In fact, mycoplasma such as the eosinophil count (EOS) and eosino- pneumoniae in children under the age of 5 phil cationic protein (ECP). In addition, it can Reduning injection and azithromycin stimulate monocytes to release large amounts Department of Pediatrics at Haiyang People’s of inflammatory cytokines like interleukin-8 (IL- Hospital from June 2017 to January 2018 were 8), further damaging lung tissues, leading to selected as subjects. They were divided into airway hyperresponsiveness, and accelerating two groups (the observation group and the con- the progression of disease [4]. The above path- trol group, 42 patients in each group) according ological changes are similar to the basic patho- to random number tables. There were 50 males logical characteristics of typical asthma [5]. and 34 females. All patients were between 2.0 Therefore, scholars at home and abroad be- and 6.6 years old (weight range, 17.84-40.88 lieve that mycoplasma pneumoniae can trigger kg) and received 6.18 to 8.83 days of treat- acute asthma attacks and exacerbate asthma ment. This study was approved by the Ethics symptoms [6, 7]. Research shows that asthma Committee of Haiyang People’s Hospital, and caused by mycoplasma pneumoniae accounts the caregivers of all the patients signed an for about 47% of asthma in children [8]. Active treatment is essential to relieve symptoms and informed consent. improve prognosis for children with mycoplas- Inclusion criteria ma pneumoniae and asthma. At present, medi- cations are used to fight bacterial infections, Patients who met the diagnostic criteria for relieve cough and reduce sputum, ease muscle mycoplasma pneumoniae and asthma formu- spasms, and prevent asthma attacks. Ma- lated by the Chinese Medical Association (CMA) crolide antibiotics, such as azithromycin injec- Society of Pediatrics in 2008 [12] and patients tion for intravenous infusion, are mostly used who tested positive for mycoplasma pneumoni- to treat mycoplasma pneumonia infection, which can achieve a desirable efficacy. How- ae IgM antibodies, or throat swab polymerase ever, newly found azithromycin-resistant bacte- chain reaction for mycoplasma pneumoniae. rial strains and a high incidence of adverse Exclusion criteria events associated with azithromycin therapy makes it necessary to find a new treatment. Patients with severe asthma and systemic Reduning injection (RDN) is a traditional organic diseases; patients with infectious dis- Chinese medicine (TCM) formula extracted eases, asthma complications, immune system from three Chinese herbal medicines, namely diseases and congenital cardiopulmonary dys- Artemisia annua, Gardenia jasminoides, and plasia or patients who were given macrolide Lonicera japonica. It can inhibit bacterial and antibiotics before admission. viral replication, and is effective in treating respiratory diseases such as pneumonia and Medications acute upper respiratory tract infection [9]. Both groups were given routine treatment. The Research by Ou Yanjuan et al. showed that RDN can significantly alleviate the clinical symptoms patients in the control group were given azi- of elderly patients with acute lung injuries, thromycin enteric-coated tablets (CSPC Ph- improve the results of blood gas analysis, and armaceutical Group Limited, 10 mg PO QD) reduce inflammation [10]. Research by Huang plus routine treatment, while the patients in the Hui et al. revealed that RDN combined with observation group were treated with 10 mL of cefoperazone sodium and sulbactam sodium RDN (Jiangsu Kanion Pharmaceutical Co., Ltd.) injection are effective and safe in treating and 100 mL of 5% Dextrose injection via IV drip chronic obstructive pulmonary disease and pul- once a day, plus azithromycin and routine treat- monary infection [11]. ment. All the patients received 7 days of treatment. Our study aimed to explore the efficacy and safety of RDN plus azithromycin for the treat- Outcome measures ment of mycoplasma pneumonia and asthma in children. Time for symptoms to disappear and length of hospital stays: The time for the recovery of body Materials and methods temperature and the disappearance of symp- Patients toms including shortness of breath, cough, and lung rales, as well as the length of stay in the A total of 84 pediatric patients with mycoplas- hospital, were recorded and compared between ma pneumoniae and asthma treated in the the two groups.

13644 Int J Clin Exp Med 2019;12(12):13643-13650 Reduning injection and azithromycin

_ Table 1. Comparison of the clinical data between the two groups ( x ± sd) Group Observation group (n=42) Control group (n=42) χ2/t P Sex (male/female) 26/16 24/18 0.198 0.657 Age (years) 4.3 ± 2.3 4.5 ± 2.1 0.416 0.678 Course of disease (days) 7.51 ± 1.32 7.32 ± 1.14 0.706 0.482 Weight (kg) 29.36 ± 11.52 28.51 ± 10.14 0.359 0.721

Table 2. _ Comparison of the clinical symptoms and lengths of hospital stays between the two groups ( x ± sd) Observation Group Control group Group t P (n=42) (n=42) Time for recovery of body temperature 1.85 ± 0.77 2.79 ± 0.92 5.078 0.000 Time for disappearance of shortness of breath 3.08 ± 1.32 4.25 ± 1.26 4.155 0.000 Time for disappearance of cough 2.64 ± 1.02 3.58 ± 1.14 3.982 0.000 Time for disappearance of rales 2.46 ± 1.13 3.95 ± 1.26 5.705 0.000 Length of hospital stays 7.46 ± 0.37 8.58 ± 0.45 12.459 0.000

Clinical efficacy: The efficacy of the treatments capacity (FVC), forced expiratory volume in one was assessed after 7 days of treatment ac- second (FEV1), and peak expiratory flow (PEF), cording to the “Routine prevention and treat- were measured. The JAEGER® MasterScreen ment of bronchial asthma in children (trial ver- pediatric (PAED) respiratory system was used sion)” established by the Subspecialty Group to test patients’ pulmonary functions before of Respiratory Diseases in the Chinese Medi- and after treatment. cal Association (CMA) Society of Pediatrics in 2003, and divided into 3 categories. Marked Safety of treatments: The incidence of adverse effect: clinical symptoms disappeared or abat- events was recorded to evaluate the safety pro- ed significantly with only occasional mild at- file of the treatments. tacks which relieved on their own and required Statistical methods no medications; effective: clinical symptoms improved, but medications were still needed; SPSS 23.0 statistical software was used to ineffective: symptoms remained basically un- analyze the data. The measurement data were changed, or even worsened. Overall response expressed as the mean ± standard deviation _ rate = the number of patients who had effec- ( x ± sd). A paired t-test was used for compari- tive treatment or for whom treatment effect sons within groups before and after treatment. was marked/total number of patients * 100%. An independent t-test was used for compari- sons between groups after treatment. The enu- Cytokines detection: Venous blood (5 mL) was meration data were expresses as n (%). The drawn from patients on an empty stomach in incidence of adverse events was compared the morning before and after treatment. The with Yates’ correction and Fisher’s exact prob- EOS in the peripheral blood was measured by ability test. P<0.05 means the difference is sta- the wi101600 automatic blood cell analyzer tistically significant. (Beijing Winstrument Science and Technology Co., Ltd.). The ECP levels were determined using Results an immunofluorescence assay kit (Pharmacia Biotech, Sweden), and the IL-8 levels were Baseline clinical data detected using an enzyme linked immunosor- bent assay kit (R&D Systems, USA). There were no statistically significant differenc- es in sex, age, course of the disease, or weight Pulmonary function parameters: The pulmo- between the two groups (all P>0.05). See Table nary function parameters, including forced vital 1.

13645 Int J Clin Exp Med 2019;12(12):13643-13650 Reduning injection and azithromycin

Figure 1. Comparison of the clinical symptoms and lengths of hospital stays between the two groups. A. Time to recovery of body tempera- ture; B. Time for the disappearance of shortness of breath; C. Time for the disappearance of cough; D. Time for the disappearance of rales; E. Length of hospital stays. Com- pared with the observation group, ▲▲▲P<0.001.

Table 3. Comparison of the treatment efficacy between the two groups (n, %) Group Marked effect Effective Ineffective Total rate of effective treatment Observation group (n=42) 22 (52.38) 18 (42.86) 2 (4.76) 40 (95.24) Control group (n=42) 18 (42.86) 16 (38.09) 8 (19.05) 34 (80.95) χ2 4.086 P 0.043

Table 4. Comparison of the cytokine levels between the two The time to disappearance groups of clinical symptoms and the Observation Control group length of hospital stay Group t P group (n=42) (n=42) 9 The observation group had a EOS (×10 /L) significantly shorter time for the Before treatment 0.91 ± 0.54 0.95 ± 0.56 0.333 0.740 disappearance of symptoms After treatment 0.30 ± 0.16*** 0.46 ± 0.22*** 3.812 0.000 including fever, shortness of ECP (μg/L) breath, cough, and lung rales, Before treatment 12.42 ± 6.97 12.55 ± 7.03 0.085 0.932 and shorter hospital stays than After treatment 5.36 ± 1.14*** 8.31 ± 2.78*** 6.363 0.000 the control group (all P<0.05). IL-8 (ng/L) See Table 2 and Figure 1. Before treatment 52.26 ± 9.98 51.65 ± 9.21 0.291 0.772 Efficacy of treatment After treatment 40.92 ± 5.62*** 45.86 ± 6.85*** 3.613 0.001 Note: Compared with before treatment, ***P<0.001. EOS, eosinophil count; ECP, The observation group had a eosinophil cationic protein; IL-8, interleukin-8. significantly higher rate of effec-

13646 Int J Clin Exp Med 2019;12(12):13643-13650 Reduning injection and azithromycin

Figure 2. Comparison of the cytokine levels between the two groups. A. EOS levels; B. ECP levels; C. IL-8 levels. Compared with before treatment, ***P<0.001; compared with the observation group, ▲▲P<0.01, ▲▲▲P<0.001. EOS, eosinophil count; ECP, eosinophil cationic protein; IL-8, interleukin-8.

Table 5. FEV1, and PEF than the control Comparison of the_ pulmonary function parameters between the two groups ( x ± sd) group (all P<0.05). See Table 5 Observation group Control group and Figure 3. Group t P (n=42) (n=42) The incidence of adverse events FVC (L) Before treatment 3.08 ± 0.58 3.11 ± 0.64 0.225 0.822 There was no statistically signifi- After treatment 3.74 ± 0.65* 3.42 ± 0.69* 2.188 0.032 cant difference in the incidence FEV1 (L) of adverse events between the Before treatment 1.70 ± 0.35 1.68 ± 0.38 0.251 0.803 two groups (P>0.05). See Table After treatment 2.20 ± 0.49** 1.84 ± 0.45** 3.507 0.001 6. PEF (L/s) Discussion Before treatment 4.38 ± 1.48 4.30 ± 1.50 0.246 0.806 *** ** After treatment 6.56 ± 1.57 5.35 ± 1.52 3.588 0.001 Macrolides are commonly used * ** *** Note: Compared with before treatment, P<0.05, P<0.01, P<0.001. FVC, to treat mycoplasma pneumoni- forced vital capacity; FEV1, forced expiratory volume in one second; PEF, peak expiratory flow. ae infection and asthma. Azi- thromycin is a broad-spectr- um second-generation macro- tive treatment than the control group (95.24% lide antibiotic with a long half-life, desirable sta- vs. 80.95%, P<0.05). See Table 3. bility, and excellent tissue penetration. It is widely used for the treatment of mycoplasma Cytokines levels pneumonia and tonsillitis in children due to its favorable efficacy [13]. RDN is a TCM formu- The levels of EOS, ECP, and serum IL-8 were sig- la, which contains the effective components nificantly lower than they were before treat- extracted from three herbs Artemisia annua, ment for both groups (all P<0.05), and the and Lonicera japonica. Its components have decrease was more noticeable in the observa- been proven to have multiple functions such tion group (P<0.05). See Table 4 and Figure 2. as clearing heat, dispelling wind, and detoxifi- cation. Pulmonary function parameters In recent years, RDN has been widely used for Both groups showed increases in FVC, FEV1, its outstanding and long-lasting therapeutic ef- and PEF after treatment (all P<0.05), and the fects on fever, cough and headache. Research observation group had significantly higher FVC, by Panbo et al. found that RDN combined with

13647 Int J Clin Exp Med 2019;12(12):13643-13650 Reduning injection and azithromycin

Figure 3. Comparison of the pulmonary function pa- rameters between the two groups. A. FVC; B. FEV1; C. PEF. Compared with before treatment, *P<0.05, **P<0.01, ***P<0.001; compared with the observation group, ▲P<0.05, ▲▲P<0.01. FVC, forced vital capacity; FEV1, forced expiratory volume in one second; PEF, peak expiratory flow.

Table 6. Comparison of the incidence of adverse events between Studies also showed elevated the two groups (n, %) expression levels of inflamma- Observation Group Control group tory cytokines in children with Group χ2 P (n=42) (n=42) mycoplasma pneumoniae and Skin rash 4 (9.52) 1 (2.38) 0.851 0.356 asthma, which can cause dis- Nausea/vomiting 2 (4.76) 3 (7.14) 0.000 1.000 ease to progress [16, 17]. Local pain from IV drip 2 (4.76) 0 (0.00) 0.494 Therefore, inhibiting inflamma- tory responses is of great Total incidence rate 19.05 (8/42) 9.52 (4/42) 1.556 0.212 importance to their recovery. Research by Wan Yajuan et al. ceftazidime sodium can significantly improve showed that RDN can significantly improve the clinical symptoms and vital signs of adult symptoms such as cough, shortness of breath, patients with mycoplasma pneumonia, and it and wheezing in patients with bronchiolitis, and was superior to ceftazidime sodium monother- shorten their course of disease [18]. The me- apy in terms of efficacy and safety [14]. Studies chanism of RDN may be that it can reduce the by Tian Lili et al. showed that RDN combined levels of inflammatory cytokines, and inhibit with vidarabine in the treatment of children inflammatory responses in lung tissues [19]. with herpes stomatitis had a total rate of effec- tive treatment of 96.55%, much higher than The results of our study showed that the le- that of vidarabine alone, suggesting that RDN vels of EOS, ECP and IL-8 in the peripheral was a potent anti-infective and anti-viral agent blood of patients in the observation group de- [15]. creased significantly after treatment. These results were similar to the findings of other However, there are few studies on its use in the studies, proving that RDN combined with azi- treatment of mycoplasma pneumoniae in chil- thromycin is effective in inhibiting the produc- dren. Our study showed that the addition of tion of pro-inflammatory mediators and allevi- RDN to azithromycin therapy could improve effi- ating inflammatory responses in children with cacy and promote the recovery of children with mycoplasma pneumoniae and asthma [20, 21]. mycoplasma pneumoniae and asthma. Children treated with RDN and azithromycin are more In addition, our study found that there was no likely to experience a faster disappearance of statistically significant difference in the inci- symptoms including fever, shortness of breath, dence of adverse events between the two cough and lung rales, and have significantly groups, demonstrating the favorable safety increased FVC, FEV1, and PEF. profile of the combination therapy of RDN and

13648 Int J Clin Exp Med 2019;12(12):13643-13650 Reduning injection and azithromycin azithromycin. This result was consistent with H, Andriamihaja R, Benhaddou N, Randrianiri- the findings of previous studies [22]. na F, Ratsima E, Imbert P and Raymond J. Prevalence of mycoplasma pneumoniae infec- In conclusion, RDN combined with azithromycin tion in Malagasy children. Pediatr Infect Dis J is effective in treating children with mycoplas- 2017; 36: 467-471. ma pneumoniae infection and asthma, and it [7] Wang L, Zhao MB, Yin Z, Tan L and Zhang Q. can significantly improve their clinical symp- Correlation between mycoplasma pneumoniae infection and acute attack of bronchial asthma toms and pulmonary function, shorten their in children. Shandong Medical Journal 2017; hospital stays, and have a lower incidence of 57: 91-93. adverse events. It also has a favorable safety [8] Smith-Norowitz TA, Weaver D, Chorny V, Norow- profile and is worth being popularized in clinical itz YM, Lent D, Hammerschlag MR, Joks R and practice. Kohlhoff S. Chlamydia pneumoniae induces interferon gamma responses in peripheral However, only three inflammatory cytokines blood mononuclear cells in children with aller- (EOS, ECP, and IL-8) were studied in our attempt gic asthma. Scand J Immunol 2017; 86: 59- to explain the mechanism of RDN on inflamma- 64. tion-related pulmonary injuries. So, further [9] Jujaray D, Juan LZ, Shrestha S and Ballgobin A. research is needed to elucidate the specific Pattern and significance of asymptomatic ele- inflammatory response pathways for the man- vation of liver enzymes in mycoplasma pneu- agement of mycoplasma pneumoniae infection monia in children. Clin Pediatr (Phila) 2018; 57: 57-61. and asthma. [10] Ou YJ, Zhang JJ and G YY. Effects of reduning injection and yanhuning injection on the levels Disclosure of conflict of interest of TNF-alpha and IL-1 in elderly patients with acute lung injury. J Gerontol 2015; 35: 3948- None. 3950. [11] Huang H, Zhang JJ, Yan D and Peng CX. Clinical Address correspondence to: Feng’ai Liu, Depart- trial of reduning injection combined with cefo- ment of Pediatrics, Haiyang People’s Hospital, No. perazone sodium and sulbactam sodium injec- 73 Haiyang Road, Haiyang 265100, Shandong tion in the treatment of pulmonary infection in Province, China. Tel: +86-15866493606; Fax: +86- patients with chronic obstructive pulmonary 0535-3226395; E-mail: [email protected] disease. J Clin Pharmacol 2017; 33: 1391- 1393. References [12] Subspecialty Group of Respiratory Diseases in the Chinese Medical Association (CMA) Society [1] Wood PR, Kampschmidt JC, Dube PH, Cagle of Pediatrics. Guidelines for diagnosis and MP, Chaparro P, Ketchum NS, Kannan TR, treatment of bronchial asthma in children. Singh H, Peters JI, Baseman JB and Brooks EG. Zhonghua Er Ke Za Zhi 2008; 46: 745-753. Mycoplasma pneumoniae and health out- [13] El Boustany P, Epaud R, Grosse C, Barriere F, comes in children with asthma. Ann Allergy Grimont-Rolland E, Carsin A and Dubus JC. Un- Asthma Immunol 2017; 119: 146-152. usual long survival despite severe lung dis- [2] Yin SS, Ma FL and Gao X. Association of myco- ease of a child with biallelic loss of function plasma pneumoniae infection with increased mutations in ABCA-3. Respir Med Case Rep risk of asthma in children. Exp Ther Med 2017; 2018; 23: 173-175. 13: 1813-1819. [14] Pan B and Gao JY. Analysis on clinical safety [3] Li W, Ban C, Zhang J, Hu Y, Han B and Han B. and efficacy of reduning injection combined Correlation study of cough variant asthma and with ceftazidime sodium in treatment for pa- mycoplasma pneumonia infection in children. tients with mycoplasma pneumoniae pneumo- Pak J Pharm Sci 2017; 30: 1099-1102. nia. China Medical Herald 2018; 15: 139-142. [4] Xu MH, Yuan FL, Wang SJ, Xu HY, Li CW and [15] Tian LL. Clinical effects of reduning injection Tong X. Association of interleukin-18 and asth- combined with vidarabine on herpetic stomati- ma. Inflammation 2017; 40: 324-327. tis in children. China Practical Medicine 2018; [5] Kassisse E, Garcia H, Prada L, Salazar I and 13: 139-140. Kassisse J. Prevalence of mycoplasma pneu- [16] Huang H, Liang LH, Lu HX, Wu LL, Xu LP, Zhi YL, moniae infection in pediatric patients with Tong RF, Shen ZB and Wang R. Investigation of acute asthma exacerbation. Arch Argent Pedi- mycoplasma pneumoniae and chlamydia atr 2018; 116: 179-185. pneumoniae infections in children with asth- [6] Ravelomanana L, Bouazza N, Rakotomahefa ma. Chinese Journal of Nosocomiology 2018; M, Andrianirina AZ, Robinson AL, Raobidjaona 28: 598-601.

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13650 Int J Clin Exp Med 2019;12(12):13643-13650