Symptom resolution in patients with Mycoplasma pneumoniae pneumonia

1Department of Medicine, University of Alberta, Edmonton, Alberta; 2Bayer Inc, Toronto, Ontario Correspondence and reprints: Dr Thomas J Marrie, 2F1.30 Walter C Mackenzie Health Sciences Center, 8440 112 Street, Edmonton, Alberta T6G 2B7. Telephone 780-407-2634, fax 780-407-3132, e-mail tom.marrie@ualberta.ca TJ Marrie, M Beecroft, Z Herman-Gnjidic, M Poulin-Costello. Symptom resolution in patients with Mycoplasma pneumoniae pneumonia. Can Respir J 2004;11(8):573-577.

M ycoplasma pneumoniae causes 17% to 34% of cases of community-acquired pneumonia (CAP) treated in an ambulatory setting (1)(2)(3)(4) and accounts for 1% to 32% of patients who are hospitalized for the treatment of CAP (5)(6)(7)(8)(9)(10)(11)(12)(13)(14).M pneumoniae pneumonia is generally mild to moderate in severity.However, the range of extrapulmonary manifestations of this infection are wide.Mansel et al (15) reported on 148 patients in a retrospective review of all cases of M pneumoniae pneumonia at the Mayo Clinic over a 14-year period.Cough was the most common symptom, occurring in 97% of patients, followed by fever in 85%; 52% had a sore throat; 22% had rhinorrhea; 25% had chest pain; and 17% complained of dyspnea.Other symptoms included nausea, vomiting, diarrhea and anorexia in 42% of patients; headache in 33%, chills in 32%, myalgia and arthralgia in 24%, night sweats 13% and 7% had one or more symptom of neurological disease including diplopia, syncope, confusion or tinnitus.However, the natural history of the resolution of symptoms of M pneumoniae pneumonia in adults has not been well described.A prospective study of the treatment of CAP on an outpatient basis gave us the opportunity to describe the resolution of symptoms in these patients.

Study design and patient population
This was a prospective, randomized, double-blind, multicentre study to compare the efficacy and safety of moxifloxacin hydrochloride 400 mg (orally, once daily) for 10 days with clarithromycin 500 mg (orally, twice daily) for 10 days in the treatment of nonhospitalized patients with CAP.
Patients 18 years of age or older, with signs and symptoms consistent with bacterial pneumonia of mild to moderate severity, not requiring hospitalization (Fine risk class I to III) participated in the study (16).To be classified as having CAP, patients had to have both radiological evidence (as determined by a radiologist) of a new or progressive infiltrate(s) consistent with pneumonia, and two or more of the following symptoms/physical findings: productive cough, purulent sputum, dyspnea or tachypnea (respiratory rate greater than 20 breaths/min), rigors or chills, or pleuritic chest pain.
Patients were excluded from the trial if they met any of the following criteria: a history of allergy to carboxyquinolone or macrolide derivatives; pregnant or nursing women; severe hepatic impairment (baseline serum glutamic-oxaloacetic transaminase or ©2004 Pulsus Group Inc.All rights reserved ORIGINAL ARTICLE serum glutamic-pyruvic transaminase and/or total bilirubin three times the upper limit of normal or higher); coexistent disease considered likely to affect the outcome of the study (eg, lung cancer, lung abscess, collagen vascular disease affecting the lungs, empyema, cystic fibrosis, known or suspected active tuberculosis, or alcoholism); or use of systemic corticosteroids greater than 15 mg/day oral prednisone (or its equivalent).

Clinical evaluation
The primary efficacy variable was clinical improvement measured by a change in the sum of five pneumonia symptom scores (fatigue, cough, dyspnea, sputum and pleuritic chest pain) from baseline to day 14.The severity scale for each of the five symptoms was a six-point scale from 0 (no symptom) to 5 (very severe symptom) (Table 1).The sum of the five severity scales had a range of 0 to 25, and was transformed into a 0 to 100 scale through direct multiplication by four.Untransformed scores were used for the analysis of resolution of individual symptoms.
These individual symptoms were assessed by a clinician (site assessment) at baseline (0 h to 48 h pretherapy office visit), on day 7 of treatment (phone call), at the end of therapy (day 14 office visit), on day 30 (phone call) and at the follow-up visit (day 42 after onset of treatment; office visit).Individual patient diaries (self-assessment) were also used to record symptom resolution data (days 0 through 14, 30 and 42).
Symptom resolution was defined as a total symptom score of 20 or less at day 14.A score of 20 or less was chosen because it indicated very mild individual symptoms (eg, an untransformed score of 1 for each symptom).For individual symptoms, a score of less than 1 at day 14 was termed resolution.

Etiological diagnosis
Serum samples (acute phase, day 14 and day 42) were received frozen on dry ice.Before testing, samples were thawed and centrifuged at 3000 g for 10 min.

M pneumoniae immunoglobulin G and immunoglobulin M
Serum samples were tested using a semiquantitative enzymelinked immunosorbent assay (Savyon Diagnostics Ltd, Israel) according to the manufacturer's instructions.A standard curve was generated for each assay using the calibrators provided by the manufacturer.The absorbance values of the patient samples were then plotted on the standard curve and the concentration of antibodies interpolated and expressed as binding units/mL (BU/mL).Patient samples with BU/mL values of greater than 15% BU/mL were considered positive.Results of prestudy, day 14 and six-week follow-up serum were interpreted based on both the immunoglobulin (Ig) G and IgM results (Table 2).Patients with negative serology at prestudy but whose IgG and/or IgM became positive at day 14 or the six-week follow-up were considered as having recent/current infection.

Statistical methods
The two-sample unpaired Student's t test was used to test significant differences between the two groups.The significance level was 0.05.

RESULTS
Five hundred eighteen patients were enrolled in the present study, of whom 76 (14.6%) were diagnosed as having M pneumoniae pneumonia.Because these patients were a small subset of the original study, the influence of antibiotic choice on the outcome for patients with M pneumoniae was not analyzed.Sixty-four of the patients with M pneumoniae had blood cultures done at the time of enrollment and all were negative for a pathogen -one patient had yeast isolated but this was felt to be a contaminant.Thirty-eight of the 64 patients had a sputum specimen processed for culture at the time of enrollment.Twelve (31.5%) were positive for a respiratory pathogen.These Sixty per cent of the patients were female (Table 3) and most had mild pneumonia.The symptoms reported by these patients are given in Table 4. Cough and fatigue were the most frequent and most severe symptoms.At 14 days, the symptoms had almost completely resolved.Figure 1 shows the time course of the resolution of symptoms for the entire patient group.Note that the symptom score decreased by 50% within six days.Sixty patients could be divided into two populations based on a total symptom score of 20 or less, or greater than 20 at day 14.The majority (97.3%) had a total symptom score of greater than 20 at the time of enrollment while 19 of these 60 patients (31.6%) had a score greater than 20 on day 14.Those with a score of greater than 20 on day 14 had a higher mean total score at the time of presentation than those with a day 14 score of 20 or less (70 versus 52, respectively; P<0.001).Figure 2 shows the time course of symptom resolution for patients with a total symptom score of greater than 20 at day 14 compared with those with a score of 20 or less at day 14.At all time points, those patients with a score greater   Figure 1) Mean self-assessed daily total symptom scores for than 20 had a significantly higher score (P<0.001).At day 42, 12.6% of these patients still had a score greater than 20.
The M pneumoniae patients who had a symptom score of 20 or less at day 14 were compared with those who had a symptom score of greater than 20 (Table 5).There were no statistically significant differences between the two groups.
Patients with M pneumoniae were compared with the 442 patients who had pneumonia due to agents other than M pneumoniae (Table 6).The M pneumoniae patients were more likely to be female and younger, and less likely to have comorbid illnesses.
The mean symptom scores at presentation were essentially identical for the M pneumoniae patients and patients with pneumonia caused by other agents (Table 6 and Figure 3).However, after day 8, symptom resolution was slower among the M pneumoniae patients (P<0.01).
One of the most important findings in the present study was that 22 of 64 (34.3%) patients with M pneumoniae who were employed at the time of onset of pneumonia did not take time off work.

DISCUSSION
There have been few studies examining the time required to recover from M pneumoniae pneumonia.Marrie et al (2) studied 31 patients with pneumonia of unknown etiology and 38 patients with atypical pneumonia (the majority of whom had M pneumoniae pneumonia).Both groups of patients completed the short form-36 health survey at presentation and again 30 days after presentation.Both groups of patients suffered a severe deterioration of physical function at the time of presentation with marked but incomplete recovery at 30 days.It is noteworthy that the group with atypical pneumonia had higher physical functioning and mental health scores at 30 days than those with pneumonia of unknown etiology.Benusiglio       from atypical pneumonia during the acute illness and during convalescence (two to 18 months).Seven of the patients had M pneumoniae pneumonia.At the time of admission, 75% of the patients had abnormalities of gas exchange, 52% had a restrictive pattern and 52% had an obstructive pattern.The frequency of abnormalities in the pulmonary function tests decreased dramatically after two to four weeks, and nearly disappeared in all patients during convalescence.However, the mid-maximum expiratory flow rate was abnormal for all patients except those who had M pneumoniae infection.The authors concluded that small airway involvement could not be demonstrated during convalescence in patients with M pneumoniae infection.Macfarlane and Morris (18) studied 10 patients with M pneumoniae pneumonia and found that the diffusion capacity was reduced for a mean of 21 weeks.Our study indicates that the time course for symptom resolution in adults with M pneumoniae pneumonia was related to the severity of the symptoms at the time of presentation.Patients with a mean total symptom score of 70 at the time of presentation had a mean total symptom score of 32 at day 14 compared with a mean score of 8 for patients who had a mean total symptom score of 52 at the time of presentation.We also noted that 12.6% of patients still had a score of greater than 20 at 42 days.
Increasing age is associated with a decrease in the number and severity of symptoms reported by patients with CAP (19).Metlay et al (20) had patients rate the severity of cough, fatigue, dyspnea, myalgia and fever on a scale from 0 (absent) to 5 (severe) on days 0 to 7, 14, 21 and 28 from the time of presentation.They studied 126 ambulatory patients and defined cure as the time to resolution for all five symptoms.The median time to symptomatic cure was 21 days (interquartile range 21 to 28 days).Thirty-five per cent had unresolved symptoms at the end of the study period.However, all of our patients were relatively young, and based on Metlay's data (20) might be expected to have more severe symptoms.
One of the noteworthy findings from the present study was that 34.3% of patients who were employed at the time of diagnosis of the pneumonia did not take time off work.
Eight of our patients had a respiratory pathogen isolated from a sputum specimen and, hence, may have had a dual infection.We did not exclude these patients from the analysis because in any population of patients with M pneumoniae pneumonia there may be some patients with polymicrobial infection.
When the speed of symptom resolution for M pneumoniae pneumonia patients was compared with the other 442 patients in our study (Figure 3), we noted that the mean total symptom scores were identical for the first eight days, after day 8, the patients with M pneumoniae showed slower resolution.

CONCLUSION
The majority of patients with M pneumoniae pneumonia have resolution of symptoms within two weeks; however, most (65%) do take some time off work.
were: three Staphylococcus aureus isolates; two Haemophilus influenzae; two Streptococcus pneumoniae; two Streptococcus species; and one each of Moraxella catarrhalis, group G streptococcus and Acinetobacter species.
Symptoms inMycoplasma pneumoniae pneumonia Can Respir J Vol 11 No 8 November/December 2004 575 Marrie et al Can Respir J Vol 11 No 8 November/December 2004 576

Figure 2 )
Figure 2) Time course of symptom resolution when patient were divided into two groups according to a symptom score of 20 or less at day 14 (n=41) versus a score of greater than 20 on day 14 (n=19)

Figure 3 )
Figure 3) Time course of resolution of total symptom score for patients with Mycoplasma pneumoniae pneumonia (•) compared with 442 patients with pneumonia due to other etiological agents (× ×)

TABLE 4
Symptoms and mean severity score of five symptoms at time of presentation and at 14 days

TABLE 5
Comparison of the Mycoplasma pneumoniae patients at day 14 who had a symptom score of 20 or less versus those patients with a symptom score of greater than 20

TABLE 6
Comparison of Mycoplasma pneumoniae patients with patients with pneumonia due to agents other than M pneumoniae