Clinical Differences between Community-Acquired Mycoplasma pneumoniae Pneumonia and COVID-19 Pneumonia

Mycoplasmapneumoniae is one of the major causative pathogens of community-acquired pneumonia (CAP). M. pneumoniae CAP is clinically and radiologically distinct from bacterial CAPs. One feature of the Japanese Respiratory Society (JRS) guidelines is a trial to be carried out to differentiate between M. pneumoniae pneumonia and bacterial pneumonia for the selection of antibiotics. The purpose of the present study was to clarify the clinical and radiological differences of the M. pneumoniae CAP and coronavirus disease 2019 (COVID-19) CAP. This study was conducted at 5 institutions and assessed a total of 210 patients with M. pneumoniae CAP and 956 patients with COVID-19 CAP. The median age was significantly younger in patients with M. pneumoniae CAP than COVID-19 CAP. Among the clinical symptoms, cough and sputum were observed more frequently in patients with M. pneumoniae CAP than those with COVID-19 CAP. However, the diagnostic specificity of these findings was low. In contrast, loss of taste and anosmia were observed in patients with COVID-19 CAP but not observed in those with M. pneumoniae CAP. Bronchial wall thickening and nodules (tree-in-bud and centrilobular), which are chest computed tomography (CT) features of M. pneumoniae CAP, were rarely observed in patients with COVID-19 CAP. Our results demonstrated that there were two specific differences between M. pneumoniae CAP and COVID-19 CAP: (1) the presence of loss of taste and/or anosmia and (2) chest CT findings.


Introduction
Mycoplasma pneumoniae is one of the major causative pathogens of community-acquired pneumonia (CAP) and the most frequent pathogen in atypical pneumonia [1]. Epidemiological studies in Japan have demonstrated that the incidence of M. pneumoniae pneumonia is the second-to-third leading pathogen of CAP, accounting for as many as 10-30% of all cases of CAP [2][3][4]. Although pneumonia due to M. pneumoniae is usually of mild-to-moderate severity, some cases are known to develop into severe, life-threatening pneumonia [1][2][3][4]. Underlying conditions, clinical symptoms, laboratory data, and radiologic findings of M. pneumoniae pneumonia are different from other bacterial pneumonia [5,6]. Thus, the Japanese Respiratory Society (JRS) pneumonia guidelines proposed a differential diagnosis between other bacterial and M. pneumoniae pneumonia for the selection of an appropriate antibiotic for the management of CAP [2]. In addition, clinical findings of M. pneumoniae pneumonia are clearly different from Legionella CAP [7].
Since 2020, the novel, severe, acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), has become the most important pathogen in CAP [8]. The purpose of the present study was to clarify the clinical and radiological differences of M. pneumoniae CAP and coronavirus disease 2019 (COVID-19) CAP.

Study Population
The present study was conducted at five institutions (Kansai Medical University Hospital, Kansai Medical University Medical Center, Kansai Medical University Kori Hospital, Kansai Medical University Kuzuha Hospital, and Kansai Medical University Temmabashi General Clinic) between January 2017 and December 2021. We enrolled adult patients consecutively diagnosed with CAP, defined in accordance with the JRS guidelines [2]. The diagnosis was based on clinical signs and symptoms (cough, fever, productive sputum, dyspnea, chest pain, or abnormal breath sounds) and radiographic pulmonary abnormalities that were at least segmental and were not as a result of pre-existing or other known causes. Exclusion criteria included the following: immunosuppressive illness (i.e., HIV positive, neutropenia secondary to chemotherapy, use of >20 mg/day prednisone or other immunosuppressive agents, and history of organ transplant); hospitalization in the preceding 90 days; residence in a nursing home or extended care facility; receiving regular endovascular treatment as an outpatient (dialysis, antibiotic therapy, chemotherapy, immunosuppressant therapy); and active tuberculosis. All cases of pneumonia occurring more than three days after hospitalization were considered nosocomial and were excluded.
M. pneumoniae was diagnosed using positive culture and/or real-time polymerase chain reaction (PCR) results from nasopharyngeal swab specimens and/or a four-fold rise in the antibody titer level between paired sera. COVID-19 was diagnosed with positive PCR results from sputum or nasopharyngeal swab specimens in accordance with the protocol recommended by the National Institute of Infectious Diseases, Japan.
The severity of pneumonia was evaluated using predictive rules via the A-DROP system (a 6-point scoring system) proposed by the JRS guidelines: age over 70 years in men and over 75 years in women, dehydration, respiratory failure, orientation disturbance, and low blood pressure [2]. Patients were stratified into four severity classes: 0 point = mild, 1 or 2 points = moderate, 3 points = severe, and 4 or 5 points = extremely severe. The time between the clinical onset of pneumonia (fever and/or other symptoms) and judgement of pneumonia severity ranged from 1 to 14 days (mean, 4.8 days) for COVID-19 pneumonia and from 1 to 10 days (mean, 5.2 days) for M. pneumoniae pneumonia. Pneumonia severity score was judged before any treatment against both M. pneumoniae and COVID-19 pneumonia.
High-resolution computed tomography (CT) was performed in all patients with 1-mm collimation at 10-mm intervals. Informed consent was obtained from all patients, and the study protocol was approved by the Ethics Committee of Kansai Medical University (approval number 2020319).

Statistical Analysis
Discrete variables are expressed as counts (percentages) and continuous variables as medians and interquartile ranges. Frequencies were compared using Fisher's exact test. Between-group comparisons of normally distributed data were performed using Student's t-test. Skewed data were compared using the Mann-Whitney U test.

Analysis Patients
The data of a total of 210 patients with M. pneumoniae CAP and 956 patients with COVID-19 CAP were analyzed. Cases of pneumonia mixed with other microorganisms were excluded from the study. During the study period, other microbiological diagnosis was established in 398 patients. The most common pathogens were Streptococcus pneumoniae, found in 281 cases, followed by Haemophilus influenzae in 93 cases, Moraxella catarrhalis in 21 cases and Staphylococcus aureus in 16 cases. Dual pathogens were detected in 34 cases. Of the 956 patients with COVID-19 CAP, 260 had lineage B.1.1.7, also known as the Alpha variant, and 274 had lineage B.1.617, also known as the Delta variant. Table 1 shows the underlying conditions and clinical findings of patients in the M. pneumoniae CAP and COVID-19 CAP groups at the first examination. The median age was significantly younger in patients with M. pneumoniae CAP than those with COVID-19 CAP. Among comorbid illnesses at baseline, the frequency of diabetes mellitus was significantly higher in patients with COVID-19 CAP than those with M. pneumoniae CAP. Respiratory symptoms such as cough, sputum production, sore throat and chest pain were observed more frequently in patients with M. pneumoniae CAP than those with COVID-19 CAP. Cough is usually stubborn in M. pneumoniae CAP, but not in COVID-19 CAP. In contrast, loss of taste and anosmia were observed in patients with COVID-19 CAP, but not observed in those with M. pneumoniae CAP. Interestingly, the presence of runny nose was low frequency in both M. pneumoniae CAP and COVID-19 CAP.

Clinical Presentation of M. pneumoniae CAP and COVID-19 CAP
With regard to pneumonia severity, approximately 90% of cases were mild-to-moderate severity in both CAP groups. The number of patients admitted to the intensive care unit and patients with in-hospital mortality were higher in patients with COVID-19 CAP than M. pneumoniae CAP. These findings were caused by the lack of a specific antimicrobial agent against COVID-19.
Of the 210 patients with M. pneumoniae CAP, 84 patients received minocycline, 64 patients received macrolides and 62 patients received quinolones. Eighteen severe patients received glucocorticoid in addition to antibiotics. Of the 956 patients with COVID-19 CAP, 648 patients received antiviral therapy, 258 patients received antibiotics and 619 patients received glucocorticoid. Table 2 shows the underlying conditions and clinical findings of patients in the M. pneumoniae CAP and age-and gender-matched patients with COVID-19 CAP at the first examination. Among clinical symptoms, cough and sputum were observed more frequently in patients with M. pneumoniae CAP than those with COVID-19 CAP. In addition, loss of taste and anosmia were observed in one-third of patients with COVID-19 CAP. Although pneumonia severity was identical between the unmatched COVID-19 CAP group and matched COVID-19 CAP group, the number of patients admitted to intensive care units and patients with in-hospital mortality were significantly reduced in patients with the matched COVID-19 CAP group.

Chest CT Findings
At the first CT examination within 10 days after symptom onset, bronchial wall thickening (83.8%) was observed most frequently, followed by nodules (tree-in-bud and centrilobular) (81.4%) in patients with M. pneumoniae CAP. In contrast to M. pneumoniae CAP, bronchial wall thickening and nodules (tree-in-bud and centrilobular) were rarely observed in patients with COVID-19 CAP (Figure 1

Discussion
Patients with M. pneumoniae CAP have several distinct clinical features compared to patients with CAP due to other pathogens. M. pneumoniae infection occurs predominantly in school-aged children and younger adults. Cough is the main symptom, which is usually paroxysmal and often persistent. Peripheral white blood cell (WBC) count is usually normal at less than 10,000/µL. Thus, the JRS extracted six parameters from patients with M. pneumoniae pneumonia using multiple regression analysis [5]. Several studies have supported the usefulness of the JRS scoring system for distinguishing between M. pneumoniae pneumonia and other bacterial pneumonia [9,10]. In the present study, the sensitivity rates for presumptive diagnosis of M. pneumoniae CAP and COVID-19 CAP were 86.2% and 69.9%, respectively, based on four or more parameters of the criteria. The matching rates in two parameters, (1) age <60 years and (2) presence of stubborn cough, were significantly lower in COVID-19 CAP than in M. pneumoniae CAP. When the ageand gender-matched groups, only one parameter, the frequency of stubborn cough, was different between the two groups.
To increase the diagnostic sensitivity, in addition to the JRS scoring system, chest CT findings were a useful tool as an auxiliary diagnostic test to differentiate between M. pneumoniae CAP and bacterial CAP for the selection of antibiotics [11,12]. Typical chest CT findings of M. pneumoniae pneumonia resemble a combination of bronchial wall thickening and tree-in-bud and centrilobular nodules and/or ground-glass opacity with lobular distribution [11,12]. In contrast, bronchial wall thickening and nodules (tree-inbud and centrilobular) were rarely observed in patients with COVID-19 CAP. These findings of chest CT among patients with COVID-19 pneumonia were consistent with previous reports [13][14][15]. Thus, physicians can differentiate M. pneumoniae CAP from COVID-19 CAP using chest CT findings.
A similar investigation was performed in pediatric patients using 80 patients with COVID-19 and 95 patients with M. pneumoniae CAP by Guo et al. [16]. Compared to COVID-19 and M. pneumoniae, fever and cough are observed more common in M. pneumoniae CAP. COVID-19 patients presented remarkably increased alanine

Discussion
Patients with M. pneumoniae CAP have several distinct clinical features compared to patients with CAP due to other pathogens. M. pneumoniae infection occurs predominantly in school-aged children and younger adults. Cough is the main symptom, which is usually paroxysmal and often persistent. Peripheral white blood cell (WBC) count is usually normal at less than 10,000/µL. Thus, the JRS extracted six parameters from patients with M. pneumoniae pneumonia using multiple regression analysis [5]. Several studies have supported the usefulness of the JRS scoring system for distinguishing between M. pneumoniae pneumonia and other bacterial pneumonia [9,10]. In the present study, the sensitivity rates for presumptive diagnosis of M. pneumoniae CAP and COVID-19 CAP were 86.2% and 69.9%, respectively, based on four or more parameters of the criteria. The matching rates in two parameters, (1) age <60 years and (2) presence of stubborn cough, were significantly lower in COVID-19 CAP than in M. pneumoniae CAP. When the ageand gender-matched groups, only one parameter, the frequency of stubborn cough, was different between the two groups.
To increase the diagnostic sensitivity, in addition to the JRS scoring system, chest CT findings were a useful tool as an auxiliary diagnostic test to differentiate between M. pneumoniae CAP and bacterial CAP for the selection of antibiotics [11,12]. Typical chest CT findings of M. pneumoniae pneumonia resemble a combination of bronchial wall thickening and tree-in-bud and centrilobular nodules and/or ground-glass opacity with lobular distribution [11,12]. In contrast, bronchial wall thickening and nodules (tree-in-bud and centrilobular) were rarely observed in patients with COVID-19 CAP. These findings of chest CT among patients with COVID-19 pneumonia were consistent with previous