Clinical features and outcomes of adult COVID-19 patients co-infected with Mycoplasma pneumoniae

A recent review published by the Journal of Infection raised concerns towards co-infection with Mycoplasma pneumoniae (MP) in coronavirus disease 2019 (COVID-19) patients.1Lansbury L. Lim B. Baskaran V. Lim W.S. Co-infections in people with COVID-19: a systematic review and meta-analysis.J Infect. 2020; Abstract Full Text Full Text PDF PubMed Scopus (904) Google Scholar It is difficult to distinguish between COVID-19 with or without MP co-infection because of the overlapping manifestations and image features. Similar clinical characteristics, complications, and outcomes were reported for patients infected with either MP alone or with viral co-infection.2Chiu C.Y. Chen C.J. Wong K.S. Tsai M.H. Chiu C.H. Huang Y.C. Impact of bacterial and viral coinfection on mycoplasmal pneumonia in childhood community-acquired pneumonia.J Microbiol Immunol Infect. 2015; 48: 51-56Crossref PubMed Scopus (48) Google Scholar Until now, the morbidity of co-infection with MP in COVID-19 patients and whether co-infection with MP has worse clinical outcomes have not been reported yet and thus remain uncertain. To answer these questions, we conducted a retrospective observational study in The Central Hospital of Wuhan from January 15, 2020, to March 15, 2020. For diagnosing COVID-19, a real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was performed with sputum or throat swab samples. To establish MP infection, IgM chemiluminescence immunoassay was used (MP IgM positive and antibody titer ≥ 1:1603Wang L. Feng Z. Zhao M. Yang S. Yan X. Guo W. Shi Z. Li G. A comparison study between GeXP-based multiplex-PCR and serology assay for Mycoplasma pneumoniae detection in children with community acquired pneumonia.BMC Infect Dis. 2017; 17: 518Crossref PubMed Scopus (31) Google Scholar) or positive results for MP RT-PCR tests of throat swabs.3Wang L. Feng Z. Zhao M. Yang S. Yan X. Guo W. Shi Z. Li G. A comparison study between GeXP-based multiplex-PCR and serology assay for Mycoplasma pneumoniae detection in children with community acquired pneumonia.BMC Infect Dis. 2017; 17: 518Crossref PubMed Scopus (31) Google Scholar Comorbidity, clinical manifestation, laboratory findings, and outcomes were collected from all patients. The study was approved by the ethics committee of The Central Hospital of Wuhan (Ethics 2020-34). Among a total of 874 patients with laboratory-confirmed COVID-19, the overall rate of M. pneumoniae co-infection was 2.5% (22 of the 874 patients). In this study, 88 patients with COVID-19 mono-infection were matched as the control group using the propensity score. Patients co-infected with influenza or other bacteria besides MP were excluded from both groups. The characteristics, treatment, and clinical outcomes are summarized in Tables 1 and 2.Table 1Baseline characteristics of coronavirus disease 2019 (COVID-19) and M. pneumoniae co-infection patients.CharacteristicsCOVID-19 mono-infection patients (n = 88)COVID-19 patients co-infection with M. pneumoniae (n = 22)pBaselineAge (years)57.00 (46.50–65.00)56.50 (52.50–66.50)0.726Male45 (51.1)11 (50.0)1.000Time from illness onset to hospital admission (days)10.50 (7.00–20.00)14.50 (5.50–20.00)0.666ComorbiditiesDiabetes20 (22.7)5 (22.7)1.000Hyperlipemia3 (3.4)1 (4.5)1.000Hypertension16 (18.2)4 (18.2)1.000Chronic heart failure2 (2.3)1 (4.5)1.000Liver cirrhosis2 (2.3)2 (9.1)0.373Anemia6 (6.8)2 (9.1)1.000Chronic kidney diseases1 (1.1)1 (4.5)0.858Rheumatoid arthritis0 (0.0)2 (9.1)0.05Cerebrovascular disease1 (1.1)1 (4.5)0.858Myasthenia Gravis1 (1.1)1 (4.5)0.858Deep venous thrombosis0 (0.0)1 (4.5)0.451COPD6 (6.8)1 (4.5)1.000SymptomsFever55 (62.5)10 (45.5)0.226Cough27 (30.7)4 (18.2)0.368Dyspnea7 (8.0)2 (9.1)1.000Fatigue6 (6.8)4 (18.2)0.214Diarrhea2 (2.3)2 (9.1)0.373Chestpain1 (1.1)0 (0.0)1.000Dizzy0 (0.0)1 (4.5)0.451other11 (12.5)4 (18.2)0.728SignsRespiratory rate36.70 (36.50–37.02)36.50 (36.30–36.98)0.096Heart rate86.00 (79.75–97.25)94.00 (79.25–98.50)0.437Systolic pressure (mmHg)20.00 (18.00–20.00)19.50 (18.00–20.00)0.273Diastolic pressure (mmHg)130.00 (120.00–139.25)127.00 (116.00–143.25)0.672Peripheral oxygen saturation (%)80.00 (73.50–87.00)82.50 (72.75–88.50)0.624Laboratory testsWhite blood cell count (× 109/L)5.63 (4.90–7.08)5.81 (5.13–6.84)0.627Neutrophil count (× 109/L)3.55 (2.91–5.19)3.35 (2.64–5.43)0.725Lymphocyte count (× 109/L)1.35 (0.91–1.73)1.63 (1.20–2.04)0.167Monocyte count (× 109/L)0.39 (0.31–0.51)0.38 (0.33–0.56)0.257Hemoglobin (g/L)131.00 (119.00–142.00)123.00 (118.50–130.50)0.087Platelet count (× 109/L)204.00 (165.75–258.25)187.50 (144.00–250.25)0.269Albumin (g/L)39.90 (36.90–43.85)41.65 (36.12–43.05)0.858Alanine aminotransferase (ALT) (U/L)22.70 (15.10–33.15)23.15 (13.98–33.23)0.949Aspartate aminotransferase (AST) (U/L)19.60 (15.00–26.25)19.30 (14.53–23.70)0.834Direct Bilirubin (μmol/L)3.28 ± 2.1519.19 ± 72.260.039Indirect Bilirubin (μmol/L)8.03 ± 4.0714.67 ± 28.720.037Creatine (μmol/L)68.15 (55.82–88.95)56.70 (50.48–72.72)0.057Urea (mmol/L)4.50 (3.83–5.60)4.21 (3.34–4.54)0.151Creatine kinase (U/L)70.50 (49.75–115.75)66.00 (48.75–78.75)0.279Creatine kinase -MB (U/L)6.00 (5.00–9.00)7.15 (5.00–11.40)0.324Troponin (ng/mL)0.00 (0.00–0.01)0.01 (0.00–0.03)0.12Brain Natriuretic Peptid (pg/mL)32.50 (14.88–85.75)58.50 (20.75–126.85)0.245Lactate dehydrogenase (U/L)156.00 (138.00–194.75)177.00 (141.00–208.25)0.52Blood glucose (mmol/L)5.29 (4.70–6.99)5.55 (5.12–7.25)0.358Sodium (mmol/L)140.00 (137.57–142.00)139.50 (138.00–140.90)0.386Potassium (mmol/L)4.21 (3.97–4.50)4.16 (4.01–4.39)0.572Calcium (mmol/L)2.29 (2.19–2.45)2.38 (2.28–2.45)0.188Chloride (mmol/L)103.30 (102.02–106.40)104.20 (101.17–106.48)0.934Phosphorus (mmol/L)1.09 (0.93–1.22)1.11 (0.98–1.22)0.731Prothrombin Time (s)13.34 ± 5.4011.60 ± 0.840.004International Normalized Ratio1.16 ± 0.501.00 ± 0.080.005Prothrombin Activity (%)89.78 ± 30.65104.90 ± 20.140.006Activated Partial Thromboplastin Time (s)31.07 ± 8.8828.53 ± 5.150.082Thrombin Time (s)16.95 ± 1.7916.88 ± 1.540.86Fibrinogen (g/L)2.52 (2.17–3.05)2.37 (2.09–2.60)0.121D-dimer (ug/mL)0.45 (0.25–1.02)0.72 (0.44–1.61)0.062Interleukin-6 (pg/mL)4.49 (2.26–12.34)2.90 (2.08–5.89)0.138Procalcitonin (ng/ml)0.05 (0.04–0.08)0.05 (0.03–0.07)0.382C Reactive Protein (mg/dl)0.36 (0.12–2.63)0.24 (0.10–2.08)0.452 Open table in a new tab Table 2Treatments and clinical outcomes in COVID-19 and M. pneumoniae co-infection patients.Treatments and outcomesCOVID-19 mono-infection patients (n = 88)COVID-19 patients co-infection with M. pneumoniae (n = 22)pTreatmentsAntiviralsUmifenovir74 (84.1)16 (72.7)0.354Ribavirin58 (65.9)18 (81.8)0.235Interferon alpha inhalation1 (1.1)0 (0.0)1.000Lopinaviritonavir2 (2.3)1 (4.5)1.000Oseltamivir11 (12.5)4 (18.2)0.728Antibiotics24 (85.7%)47 (87%)Fluoroquinolones31 (35.2)18 (81.8)<0.001Cephalosporins23 (26.1)11 (50.0)0.056Amoxicillin and Clavulanate Potassium0 (0.0)3 (13.6)0.005Corticosteroids25 (28.4)14 (63.6)0.005OutcomesDischarge86 (97.7)21 (95.5)1.000Death2 (2.3)1 (4.5)..Length of cough16.25 (12.25–22.50)20.00 (12.00–25.75)0.043Length of hospital stay (days)16.00 (10.00–22.25)14.00 (7.25–18.25)0.145Severity of diseaseMild84 (95.5)21 (95.5)1.000Moderate4 (4.5)1 (4.5).. Open table in a new tab The median age of COVID-19 mono-infection patients was 57.00 (46.50–65.00) years, which was similar to that of MP co-infection patients who were 56.50 (52.50–66.50) years. There were no significant differences in the major complaints on admission between the two groups. The major complaints on admission were fever (59.1%), cough (28.2%), dyspnoea (8.2%), fatigue (9.1%), and diarrhoea (3.6%) in all the patients. However, one patient (1.1%) in the mono-infection group reported chest pain and one patient in the co-infection group mentioned dizziness (4.5%). Likewise, most of the comorbidities were similar in both groups, except for rheumatoid arthritis (RA) that was reported in the MP co-infection group (9.1% vs 0.0%, p = 0.05). Wakabayashi et al.4Wakabayashi A. Ishiguro T. Takaku Y. Miyahara Y. Kagiyama N. Takayanagi N. Clinical characteristics and prognostic factors of pneumonia in patients with and without rheumatoid arthritis.PLOS ONE. 2018; 13e201799Crossref Scopus (11) Google Scholar reported that MP was one of the most frequent causative microbial agents of pneumonia in RA patients and the mortality was statistically higher in those patients than in non-RA patients suffering from pneumonia. Patients coinfected with MP were more likely to have higher bilirubin levels compared with patients infected with COVID-19 alone (14.67 ± 28.72 vs 8.03 ± 4.07, p = 0.037). Pooled analysis of six studies show that bilirubin concentration was significantly higher in patients with severe COVID-19 (SMD: 0.48 μmol/L; 95% CI, 0.11-0.85 μmol/L, p = 0.012).5Paliogiannis P. Zinellu A. Bilirubin levels in patients with mild and severe Covid-19: a pooled analysis.Liver Int. 2020; 40: 1787-1788Crossref PubMed Scopus (54) Google Scholar In sepsis, a higher serum bilirubin level at ICU admission is associated with subsequent ARDS development and mortality.6Zhai R. Sheu C.C. Su L. Gong M.N. Tejera P. Chen F. Wang Z. Convery M.P. Thompson B.T. Christiani D.C. Serum bilirubin levels on ICU admission are associated with ARDS development and mortality in sepsis.Thorax. 2009; 64: 784-790Crossref PubMed Scopus (68) Google Scholar However, there was no similar trend of ARDS development and mortality observed in this study. Previous studies reported that COVID-19 with liver injury is associated with poorer clinical outcomes. Alanine aminotransferase (AST) abnormality was associated with the highest mortality risk compared to other indicators. However, in our study, AST was almost at a normal level, hence there was no evidence to support co-infection with MP could lead to liver injury and increase mortality in COVID-19 patients. Both M. pneumoniae pneumonia (MMP) and COVID-19 have been reported to induce hypercoagulability[7], Moreover, in children with MPP, complications as acute cerebral infarction and pulmonary embolism have been reported.8Garcia A.V. Fingeret A.L. Thirumoorthi A.S. Kadenhe-Chiweshe A. Kandel J.J. Severe Mycoplasma pneumoniae infection requiring extracorporeal membrane oxygenation with concomitant ischemic stroke in a child.Pediatr Pulmonol. 2013; 48: 98-101Crossref PubMed Scopus (14) Google Scholar In patients with COVID-19, Zhang L. et al7Zhang L. Yan X. Fan Q. Liu H. Liu X. Liu Z. Zhang Z. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19.J Thromb Haemost. 2020; 18: 1324-1329Crossref PubMed Scopus (807) Google Scholar reported that D-dimer on admission more than 2.0 µg/mL could effectively predict in-hospital mortality. In our study, Prothrombin Time (11.60 ± 0.84 s vs 13.34 ± 5.4 s, p = 0.004) was shorter and Prothrombin Activity (104.90 ± 20.14 s vs 89.78 ± 30.65 s, p = 0.006) was higher in the co-infection group. Therefore, COVID-19 co-infection with MP has an even higher risk of blood coagulation, and thrombosis than the mono-infected patients and routine anticoagulation prophylactics is strongly recommended. Quinolone antibiotics were more frequently administered to the patients with MP co-infection (81.8% vs. 35.2%, p < 0.001), and corticosteroids were more frequently administered to patients with MP co-infection (63.6% vs. 28.4%, p = 0.005). However, different antibiotics and corticosteroids strategy showed no associations with a better outcome. Previous studies reported that children with MMP co-infected with human bocavirus, human rhinovirus, or respiratory syncytial virus had a longer fever process, higher leukocyte count, higher C-reactive protein, higher percentage of pneumothorax and diffuse large area of inflammation in chest X-ray compared with mono-infection.9Zhang X. Chen Z. Gu W. Ji W. Wang Y. Hao C. He Y. Huang L. Wang M. Shao X. et al.Viral and bacterial co-infection in hospitalised children with refractory Mycoplasma pneumoniae pneumonia.Epidemiol Infect. 2018; 146: 1384-1388Crossref PubMed Scopus (27) Google Scholar However, in our study the severity of disease was comparable in the two groups, and most patients were categorized as having moderate pneumonia (95.5% vs. 95.5%) in both groups. The overall clinical outcome was good in this study; only one fatal case in co-infection group and two fatal case in mono-infection group were reported (4.5% vs. 2.3%, p = 1.00). The length of cough was longer in the MP co-infection group [20.00 (12.00–25.75) vs 16.25 (12.25–22.50), p = 0.043], while the length of hospital stay was slightly longer [16.00 (10.00–22.25) vs 14.00 (7.25–18.25), p = 0.145], but without statistical significance. In previous study,2Chiu C.Y. Chen C.J. Wong K.S. Tsai M.H. Chiu C.H. Huang Y.C. Impact of bacterial and viral coinfection on mycoplasmal pneumonia in childhood community-acquired pneumonia.J Microbiol Immunol Infect. 2015; 48: 51-56Crossref PubMed Scopus (48) Google Scholar a similar association of length of hospital stay and length of cough was found in MMP children co-infected with viruses like adenovirus, influenza A, respiratory syncytial virus and bacteria like Streptococcus pneumoniae There are some limitations in our study. First, using IgM to diagnose MP co-infection may lead to false negative, the sensitivity of IgM serology was 81.82%.10Medjo B. Atanaskovic-Markovic M. Radic S. Nikolic D. Lukac M. Djukic S. Mycoplasma pneumoniae as a causative agent of community-acquired pneumonia in children: clinical features and laboratory diagnosis.Ital J Pediatr. 2014; 40: 104Crossref PubMed Scopus (78) Google Scholar Second, our study may have the selective bias because children were not included in our study. In conclusion, our study is the first to describe the clinical features and outcomes of COVID-19 patients co-infected with MP. There were no significant associations between MP co-infection and major complaints on admission, but an approximate of 4 days increasement in the length of cough was reported. Importantly, the already elevated risk of thrombosis in COVID-19 patients is significantly increased by the co-infection with MP. Lu, Wang and Xu, the corresponding author, were responsible for the conceptualization of the study, the revision and approval of this manuscript. Lei and Shen participated in the design and drafted the manuscript, collected data and were responsible for its accuracy. Tefsen helped to revise the manuscript. All authors contributed to the data analysis and interpretation. All authors read and approved the final manuscript. None. Not applicable. This work was supported, in part, by the Anhui Provincial Special Project of Central Government Guiding Local Science and Technology Development of China (201907d07050001) and the special fund for coronavirus disease 2019 of Wuhu (no. 2020dx2-1).