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

Dear Editor,

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. 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. 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 ≥ 1:160) or positive results for MP RT-PCR tests of throat swabs. 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 1

Baseline characteristics of coronavirus disease 2019 (COVID-19) and M. pneumoniae co-infection patients.

Characteristics	COVID-19 mono-infection patients (n = 88)	COVID-19 patients co-infection with M. pneumoniae (n = 22)	p
Baseline
Age (years)	57.00 (46.50–65.00)	56.50 (52.50–66.50)	0.726
Male	45 (51.1)	11 (50.0)	1.000
Time from illness onset to hospital admission (days)	10.50 (7.00–20.00)	14.50 (5.50–20.00)	0.666
Comorbidities
Diabetes	20 (22.7)	5 (22.7)	1.000
Hyperlipemia	3 (3.4)	1 (4.5)	1.000
Hypertension	16 (18.2)	4 (18.2)	1.000
Chronic heart failure	2 (2.3)	1 (4.5)	1.000
Liver cirrhosis	2 (2.3)	2 (9.1)	0.373
Anemia	6 (6.8)	2 (9.1)	1.000
Chronic kidney diseases	1 (1.1)	1 (4.5)	0.858
Rheumatoid arthritis	0 (0.0)	2 (9.1)	0.05
Cerebrovascular disease	1 (1.1)	1 (4.5)	0.858
Myasthenia Gravis	1 (1.1)	1 (4.5)	0.858
Deep venous thrombosis	0 (0.0)	1 (4.5)	0.451
COPD	6 (6.8)	1 (4.5)	1.000
Symptoms
Fever	55 (62.5)	10 (45.5)	0.226
Cough	27 (30.7)	4 (18.2)	0.368
Dyspnea	7 (8.0)	2 (9.1)	1.000
Fatigue	6 (6.8)	4 (18.2)	0.214
Diarrhea	2 (2.3)	2 (9.1)	0.373
Chestpain	1 (1.1)	0 (0.0)	1.000
Dizzy	0 (0.0)	1 (4.5)	0.451
other	11 (12.5)	4 (18.2)	0.728
Signs
Respiratory rate	36.70 (36.50–37.02)	36.50 (36.30–36.98)	0.096
Heart rate	86.00 (79.75–97.25)	94.00 (79.25–98.50)	0.437
Systolic pressure (mmHg)	20.00 (18.00–20.00)	19.50 (18.00–20.00)	0.273
Diastolic pressure (mmHg)	130.00 (120.00–139.25)	127.00 (116.00–143.25)	0.672
Peripheral oxygen saturation (%)	80.00 (73.50–87.00)	82.50 (72.75–88.50)	0.624
Laboratory tests
White blood cell count (× 109/L)	5.63 (4.90–7.08)	5.81 (5.13–6.84)	0.627
Neutrophil count (× 109/L)	3.55 (2.91–5.19)	3.35 (2.64–5.43)	0.725
Lymphocyte count (× 109/L)	1.35 (0.91–1.73)	1.63 (1.20–2.04)	0.167
Monocyte count (× 109/L)	0.39 (0.31–0.51)	0.38 (0.33–0.56)	0.257
Hemoglobin (g/L)	131.00 (119.00–142.00)	123.00 (118.50–130.50)	0.087
Platelet count (× 109/L)	204.00 (165.75–258.25)	187.50 (144.00–250.25)	0.269
Albumin (g/L)	39.90 (36.90–43.85)	41.65 (36.12–43.05)	0.858
Alanine aminotransferase (ALT) (U/L)	22.70 (15.10–33.15)	23.15 (13.98–33.23)	0.949
Aspartate aminotransferase (AST) (U/L)	19.60 (15.00–26.25)	19.30 (14.53–23.70)	0.834
Direct Bilirubin (μmol/L)	3.28 ± 2.15	19.19 ± 72.26	0.039
Indirect Bilirubin (μmol/L)	8.03 ± 4.07	14.67 ± 28.72	0.037
Creatine (μmol/L)	68.15 (55.82–88.95)	56.70 (50.48–72.72)	0.057
Urea (mmol/L)	4.50 (3.83–5.60)	4.21 (3.34–4.54)	0.151
Creatine kinase (U/L)	70.50 (49.75–115.75)	66.00 (48.75–78.75)	0.279
Creatine kinase -MB (U/L)	6.00 (5.00–9.00)	7.15 (5.00–11.40)	0.324
Troponin (ng/mL)	0.00 (0.00–0.01)	0.01 (0.00–0.03)	0.12
Brain Natriuretic Peptid (pg/mL)	32.50 (14.88–85.75)	58.50 (20.75–126.85)	0.245
Lactate dehydrogenase (U/L)	156.00 (138.00–194.75)	177.00 (141.00–208.25)	0.52
Blood glucose (mmol/L)	5.29 (4.70–6.99)	5.55 (5.12–7.25)	0.358
Sodium (mmol/L)	140.00 (137.57–142.00)	139.50 (138.00–140.90)	0.386
Potassium (mmol/L)	4.21 (3.97–4.50)	4.16 (4.01–4.39)	0.572
Calcium (mmol/L)	2.29 (2.19–2.45)	2.38 (2.28–2.45)	0.188
Chloride (mmol/L)	103.30 (102.02–106.40)	104.20 (101.17–106.48)	0.934
Phosphorus (mmol/L)	1.09 (0.93–1.22)	1.11 (0.98–1.22)	0.731
Prothrombin Time (s)	13.34 ± 5.40	11.60 ± 0.84	0.004
International Normalized Ratio	1.16 ± 0.50	1.00 ± 0.08	0.005
Prothrombin Activity (%)	89.78 ± 30.65	104.90 ± 20.14	0.006
Activated Partial Thromboplastin Time (s)	31.07 ± 8.88	28.53 ± 5.15	0.082
Thrombin Time (s)	16.95 ± 1.79	16.88 ± 1.54	0.86
Fibrinogen (g/L)	2.52 (2.17–3.05)	2.37 (2.09–2.60)	0.121
D-dimer (ug/mL)	0.45 (0.25–1.02)	0.72 (0.44–1.61)	0.062
Interleukin-6 (pg/mL)	4.49 (2.26–12.34)	2.90 (2.08–5.89)	0.138
Procalcitonin (ng/ml)	0.05 (0.04–0.08)	0.05 (0.03–0.07)	0.382
C Reactive Protein (mg/dl)	0.36 (0.12–2.63)	0.24 (0.10–2.08)	0.452

Table 2

Treatments and clinical outcomes in COVID-19 and M. pneumoniae co-infection patients.

Treatments and outcomes	COVID-19 mono-infection patients (n = 88)	COVID-19 patients co-infection with M. pneumoniae (n = 22)	p
Treatments
Antivirals
Umifenovir	74 (84.1)	16 (72.7)	0.354
Ribavirin	58 (65.9)	18 (81.8)	0.235
Interferon alpha inhalation	1 (1.1)	0 (0.0)	1.000
Lopinaviritonavir	2 (2.3)	1 (4.5)	1.000
Oseltamivir	11 (12.5)	4 (18.2)	0.728
Antibiotics	24 (85.7%)	47 (87%)
Fluoroquinolones	31 (35.2)	18 (81.8)	<0.001
Cephalosporins	23 (26.1)	11 (50.0)	0.056
Amoxicillin and Clavulanate Potassium	0 (0.0)	3 (13.6)	0.005
Corticosteroids	25 (28.4)	14 (63.6)	0.005
Outcomes
Discharge	86 (97.7)	21 (95.5)	1.000
Death	2 (2.3)	1 (4.5)	..
Length of cough	16.25 (12.25–22.50)	20.00 (12.00–25.75)	0.043
Length of hospital stay (days)	16.00 (10.00–22.25)	14.00 (7.25–18.25)	0.145
Severity of disease
Mild	84 (95.5)	21 (95.5)	1.000
Moderate	4 (4.5)	1 (4.5)	..

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. 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). In sepsis, a higher serum bilirubin level at ICU admission is associated with subsequent ARDS development and mortality. 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. In patients with COVID-19, Zhang L. et al 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. 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, 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%. 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.

Authors’ contributions

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.

Declaration of Competing Interest

None.