- Email: [email protected]
Mycoplasma pneumoniae community-acquired pneumonia (CAP) in the elderly: Diagnostic significance of acute thrombocytosis
ISSUES IN INFECTIOUS DISEASE
Mycoplasma pneumoniae community-acquired pneumonia (CAP) in the elderly: Diagnostic significance of acute thrombocytosis Burke A. Cunha, MD, and Francisco M. Pherez, MD
The most common cause of nonzoonotic atypical community-acquired pneumonia (CAP) is Mycoplasma pneumoniae. M. pneumoniae CAP is most common in young adults but may occur at any age. Like other atypical CAPs, M. pneumoniae is associated with a characteristic pattern of extrapulmonary organ involvement and nonspecific laboratory tests. M. pneumoniae CAP is frequently accompanied by gastrointestinal manifestations (eg, loose stools/diarrhea), nonexudative pharyngitis, or skin involvement (ie, erythema multiforme). Central nervous system involvement with M. pneumoniae is rare and accompanied by highly elevated cold agglutinin titers. Cardiac, hepatic, and renal involvement are not features of M. pneumoniae CAP. Because M. pneumoniae CAP is most frequent in ambulatory young adults, it is an easily overlooked diagnosis in elderly patients hospitalized with CAP. The hallmark clinical finding of M. pneumoniae CAP is protracted nonproductive cough. The characteristic nonspecific laboratory test finding uniquely associated with M. pneumoniae CAP is elevated cold agglutinin titers. Seventy-five percent of patients with M. pneumoniae infection have elevated cold agglutinin titers. However, the absence of elevated cold agglutinin titers does not argue against the diagnosis of M. pneumoniae. If cold agglutinins are present in a patient with CAP, the higher the cold agglutinin titer is (⬎1:64), the more likely the cold agglutinins are due to M. pneumoniae. Q fever is the only other atypical CAP that is rarely associated with cold agglutinins. We present a hospitalized patient with CAP in whom all microbiologic and serologic diagnostic test results were negative during the first week of her hospitalization. M. pneumoniae CAP was not suspected because of her age. Her initial M. pneumoniae immunoglobulin-M and cold agglutinin titers were negative. During the second week of hospitalization, an increased platelet count was noted. It is a common misconception that acute thrombocytosis is an acute phase reactant. Her acute thrombocytosis increased and persisted. The diagnostic clue to the cause of this hospitalized patient with CAP was acute thrombocytosis. In a patient with CAP, acute thrombocytosis is usually associated with Q fever pneumonia and less commonly with M. pneumoniae. If Q fever can be excluded on the basis of a recent/proximate zoonotic vector contact history, then acute thrombocytosis is an important clue to M. pneumoniae CAP. Acute thrombocytosis due to M. pneumoniae and Q fever occurs during weeks 1 and 2 of the infection. In patients with CAP, acute thrombocytosis that occurs during weeks 1 and 2 of the illness should suggest M. pneumoniae in patients without recent zoonotic vector contact history. (Heart Lung® 2009; 38:444 – 449.)
M
ycoplasma pneumoniae is one of the most common causes of nonzoonotic atypical community-acquired pneumonias (CAPs). M. pneumoniae CAP is most common in children and From the Infectious Disease Division, Winthrop-University Hospital, Mineola, New York; and State University of New York School of Medicine, Stony Brook, New York. Reprint requests: Burke A. Cunha, MD, Chief, Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501. 0147-9563/$ – see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.hrtlng.2008.10.005
444
www.heartandlung.org
young adults but may occur in any age group, including the elderly.1–3 Atypical CAPs may be differentiated from typical CAPs by the presence or absence of extrapulmonary involvement. Each zoonotic and nonzoonotic atypical pathogen (ie, M. pneumoniae, C. pneumoniae, and Legionnaire’s disease) is accompanied by its own characteristic set of signs and laboratory abnormalities. The characteristic pattern of organ involvement with M. pneumoniae permits its differentiation from other atypical and typical CAP pathogens in addition to CAP. The characteristic pattern of
SEPTEMBER/OCTOBER 2009
HEART & LUNG
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
extrapulmonary organ involvement with M. pneumoniae includes head, eyes, ears, nose and throat involvement (ie, nonexudative pharyngitis or otitis/bullous myringitis), gastrointestinal involvement (ie, loose stools/diarrhea), or skin involvement, (ie, erythema multiforme). Ordinarily, central nervous system, cardiac, hepatic, and renal involvement are rare.4 –11 M. pneumoniae rarely may present with central nervous system manifestations (ie, meningoencephalitis). Patients with M. pneumoniae CAP and meningoencephalitis have high titers of cold agglutinins (ie, ⱖ1:256). Cardiac manifestations are rare but include mycoplasma myocarditis.8,9 Relative bradycardia is not a feature of M. pneumoniae CAP.2,11 Clinically, C. pneumoniae CAP pattern of extrapulmonary involvement resembles mycoplasma but differs in 2 important respects. Loose stools and diarrhea are less common in C. pneumoniae than in M. pneumoniae CAP. Laryngitis is the unique clinical sign of C. pneumoniae CAP among the atypical CAP pathogens. Ear findings are less common with C. pneumoniae than M. pneumoniae CAP. E. multiforme is not a feature of C. pneumoniae CAP. Like M. pneumoniae CAP, C. pneumoniae is not infrequently associated with nonexudative pharyngitis. Both M. pneumoniae and C. pneumoniae CAP may exacerbate existing asthma or result in permanent asthma.2,6,7 Nonspecific laboratory tests are helpful in differentiating among the various causes of atypical CAP. For example, hepatic involvement, manifested by mildly increased serum transaminases, is a regular feature of Legionnaire’s disease but is not a feature of M. pneumoniae or C. pneumoniae CAP. Hyponatremia is common with Legionnaire’s disease but may also occur with M. pneumoniae or C. pneumoniae CAP. Otherwise unexplained hypophosphatemia in a patient with CAP is uniquely associated with Legionnaire’s disease.6,7,10 The hallmark nonspecific laboratory finding associated with M. pneumoniae is an elevation of cold agglutinins. Elevations of cold agglutinins occur in 75% of patients with M. pneumoniae and increase most commonly during or after weeks 1 and 2 of the patient’s CAP.12–16 There are a variety of infectious and noninfectious causes of elevated cold agglutinin titers, but in patients with CAP, M. pneumoniae is the only atypical pathogen associated with high cold agglutinin titers (⬎1:64).15 The absence of an elevation of cold agglutinins does not rule out M. pneumoniae CAP. Cold agglutinin titers with M. pneumoniae CAP may be slightly or highly elevated. However, the higher the cold agglutinin titer is in a patient with CAP without an other explanation, the more likely the patient has M. pneumoniae CAP.6,15 In a patient with presumed mycoplasma CAP, the presence of hepatic or renal involvement argues
HEART & LUNG
VOL. 38, NO. 5
Figure 1 Chest x-ray of patient with M. pneumoniae CAP.
Figure 2 Serial platelet counts during hospitalization in an elderly female with M. pneumoniae CAP.
against the diagnosis.6,7,10 The diagnosis of M. pneumoniae may be confirmed by demonstrating an elevated M. pneumoniae immunoglobulin (Ig)M titer. Increased M. pneumoniae IgG titers without increased IgM titers indicates prior exposure and not active infection. The presence of an elevated IgM and IgG titer indicates recent M. pneumoniae infection.8,9 M. pneumoniae is a common cause of ambulatory CAP in young adults. In elderly patients, M. pneumoniae CAP is often not considered in the differential diagnosis because of the patient’s age. M. pneumoniae is an uncommon cause of CAP in elderly, hospitalized patients.4 – 6 We present a case of M. pneumoniae CAP in an elderly hospitalized patient with emphysema.
CASE REPORT A 73-year-old woman transferred from a nursing home was admitted with progressive shortness of
www.heartandlung.org
445
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
Table I Clinical features of Mycoplasma pneumoniae community-acquired pneumonia Key characteristics
Symptoms Mental confusion Prominent headache Hoarseness Myalgias Ear pain Pleuritic pain Abdominal pain Diarrhea Signs Rash Nonexudative pharyngitis Lobar consolidation Cardiac involvement Relative bradycardia Chest x-ray Infiltrates Pleural effusion Laboratory abnormalities WBC count Relative lymphopenia Thrombocytosis (acute) 2 Serum phosphorus 1 Serum ferritin 1 Cold agglutinins (ⱖ1:64) Diagnostic tests Direct isolation (culture) 1 IgM titers Legionella DFA Legionella urinary antigen
C. pneumoniae
Legionella species
Mycoplasma pneumoniae
— — ⫹ ⫾ ⫾ — — ⫾
⫹ ⫾ — ⫾ — ⫾ ⫾ ⫾
—† —ⴱ ⫹ ⫾ ⫾ — — ⫾
— ⫾ — ⫾ —
— — ⫾ ⫹ ⫹
⫹a ⫹ — ⫾b —
Patchy, lower lobe Focal/segmental/lobar — ⫾ 1/N — — — — — ⫾ C. pneumoniae — —
Patchy, lower lobe ⫾ N — ⫹ — — ⫹
1 ⫹ — ⫹ ⫹ — ⫾ Legionella sp. ⫹ ⫹**
⫾ M. pneumoniae — —
DFA, Direct fluorescent antibody test; N, normal; WBC, white blood cell; Ig, immunoglobulin. ⫹ ⫽ usually present; ⫾ ⫽ sometimes present; — ⫽ usually absent; 1 ⫽ increased; 2 ⫽ decreased; a⫽ erythema multiforme; b⫽ myocarditis, heart block, or pericarditis; † ⫽ mental confusion only if meningoencephalitis present; * ⫽ present if meningitis/meningoencephalitis; ** ⫽ only with Legionella pneumophila (serotype 01). Adapted from Cunha BA, ed. Pneumonia essentials (3rd ed.). Jones & Bartlett, Sadbury, MA: 2008.
breath, productive cough, and wheezing. She had no fever or chills, gastrointestinal symptoms, or headaches. Her medical history included congestive heart failure, chronic obstructive pulmonary disease (COPD) (eg, chronic bronchitis), diabetes mellitus, coronary artery disease, pulmonary hypertension, and mild dementia. On admission she was thought to have an acute exacerbation of chronic bronchitis, and moxifloxacin 400 mg (intravenously) every 24 hours, oxygen, and prednisone were administered. On hospital day 9, ill-defined infiltrates on chest x-ray and a temperature of 101.6°F developed in the patient.
446
www.heartandlung.org
Her pertinent physical examination on hospital day 9 showed a noninjected pharynx, no conjunctival injection, and a negative cardiac examination. Auscultation of the lungs revealed bilateral hypoventilation with rales and dullness to percussion over the right lower lobe and parahilar area. Her abdomen was soft and nontender, with no organomegaly. Her lower extremities were edematous but otherwise unremarkable. Laboratory workup on hospital day 9 revealed a white blood cell count of 20 K/mm3 (polymorphonuclear cells ⫽ 96%, lymphocytes ⫽ 4%) and a platelet count of 322 K/mm3. Her erythrocyte sedi-
SEPTEMBER/OCTOBER 2009
HEART & LUNG
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
Table II Differential diagnosis of thrombocytosis Acute thrombocytosis
Infectious causes Q fever Mycoplasma pneumoniae
Noninfectious causes Hemorrhage Hemolytic anemias Iron-deficiency anemia Kawasaki’s disease Drugs Ceftriaxone Miconazole -lactam/-lactamase inhibitors combinations Carbapenems Oral cephalosporins Recovery from thrombocytopenia
Chronic thrombocytosis
Chronic osteomyelitis Subacute bacterial endocarditis Secondary syphilis Abscesses Lung Renal Splenic Empyema Rheumatoid arthritis Ulcerative colitis Regional enteritis Cystic fibrosis Celiac disease Splenectomy Sickle cell disease Essential thrombocythemia Carcinomas Lymphomas MDS CML Wegener’s granulomatosis
Adapted from Cunha BA. The differential diagnostic approach to thrombocytosis. Infect Dis Pract 2008;32: 740-744. MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia.
mentation rate was 46 mm/h (n⫽ 1–16 mm/h) and C-reactive protein was 208.33 mg /L (n ⫽ ⬍3 mg /L). Serum transaminases were normal. Blood cultures were negative. M. pneumoniae IgM titer was 1 (n ⫽ ⬍0.90), and the IgG titer was 1.31(n ⫽ ⬍1.10). C. pneumoniae, Q fever, adenovirus and Legionella titers were negative. Legionella urinary antigen testing was also negative. Cold agglutinin titers were present at 1:8. Chest x-ray showed worsening infiltrates in the right lower and middle lobes, but she remained unchanged clinically (Fig 1). Her white blood cell count and relative lymphopenia normalized, but her platelet count increased during hospitalization, peaking to 500 K/mm3 on hospital day 18 (Fig 2). Repeat M. pneumoniae IgM titer peaked at 1.79 (n ⫽ ⬍0.90) on hospital day 15 with an IgG titer at 1.60 (n ⫽ ⬍1.10). On hospital day 17, repeat chest x-ray showed worsening right lower lobe pneumonia. Moxifloxacin was discontinued, and doxycycline 100 mg every 12 hours by mouth was given for an additional 2 weeks of therapy.
HEART & LUNG
VOL. 38, NO. 5
DISCUSSION M. pneumoniae CAP is a common cause of ambulatory pneumonia in adults. In elderly patients, M. pneumoniae is frequently not considered in the differential diagnosis of CAP on the basis of age alone. Elderly patients with CAP may have a dry, nonproductive cough with a variety of causes. Underlying lung disease in many elderly patients makes the relative contribution of mycoplasma’s characteristic nonproductive cough sometimes difficult to appreciate. Furthermore, mycoplasma CAP is usually associated with fevers of less than 102°F, which is lower than with typical bacterial pneumonias or Legionella. The low-grade fevers are another reason that clinicians often assume that the patient has some sort of mild typical bacterial cause of CAP, and tests for M. pneumoniae are not ordered. As with other infectious disease problems, the clinician needs historical, physical findings or non specific laboratory test to prompt specific testing to rule in or out various diagnostic possibilities.1,6 Myco-
www.heartandlung.org
447
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
plasma CAP may resemble the typical bacterial CAP if there is a paucity of extrapulmonary findings characteristic of mycoplasma. M. pneumoniae CAP is associated with upper respiratory tract involvement, that is, nonexudative pharyngitis and otitis or bullous myringitis. If these and E. multiforme are not present, there are virtually no physical findings that would suggest M. pneumoniae CAP. Importantly, in contrast with Legionnaire’s disease, Q fever, or psittacosis, relative bradycardia is not a feature of M. pneumoniae CAP.2,6 UC nonspecific laboratory tests, i.e., the white count, differential count, and serum transaminases will not help the clinician to consider testing for M. pneumoniae1,2,6 (Table I). The only test uniquely associated with M. pneumoniae is an elevation of cold agglutinins. Cold agglutinin titers may not increase until weeks 1 and 2 of the illness and are only elevated in 75% of cases. A negative cold agglutinin titer ordered too early or even during the clinical illness does not argue against or rule out M. pneumoniae CAP. However, the presence of elevated cold agglutinin titers argues in favor of mycoplasma CAP in the appropriate clinical setting. A high cold agglutinin titer (ie, ⱖ1:64) is highly indicative of M. pneumoniae in a patient with CAP.12–16 In the case presented, an elderly woman with underlying COPD (ie, emphysema) presented with a cough not much different than when she an exacerbation of her COPD, low-grade fevers (ie, ⬍102°F), and a slightly elevated white blood cell count. Serum transaminases were normal, and cold agglutinin titers were not initially present. The chest x-ray also was unhelpful in determining the cause of her CAP. Patients with M. pneumoniae usually present with an ill-defined lower lobe infiltrate without pleural effusion or consolidation.2 In this case, her minimal ill-defined infiltrates were explained on the basis of her COPD. During the patient’s hospitalization, the only nonspecific laboratory clue to the presence of M. pneumoniae was acute thrombocytosis.17–19 This occurred during weeks 1 and 2 of her hospitalization. Her platelet count reached 502 k/mm3 and slowly decreased over several days during her hospitalization. Her cold agglutinin titer was minimally elevated at 1:8, but her elevated M. pneumoniae IgM titer confirmed the diagnosis of M. pneumoniae. The only infectious causes of acute thrombocytosis are Q fever and M. pneumoniae (Table II). She was initially treated with a respiratory quinolone and later switched to doxycycline, completing a 3-week course of oral therapy.
448
www.heartandlung.org
Cunha, BA
CONCLUSIONS This case has several important clinical points for clinicians to keep in mind. First, M. pneumoniae CAP should be suspected in all age groups, and age, per se, should not exclude M. pneumoniae from diagnostic consideration.1,2,6,7 Second, M. pneumoniae should be considered in patients with ill-defined pulmonary infiltrates without relative bradycardia and with unelevated serum transaminases.2,10,11 In such patients, cold agglutinin titers should be obtained every 3 days, particularly during weeks 1 and 2 of the infection. If present, the findings of nonexudative pharyngitis, otitis/bullous myringitis, or E. multiforme in a patient with CAP should suggest the possibility of M. pneumoniae CAP.6 –9 In the absence of such findings, the presence of otherwise unexplained acute thrombocytosis may be the only nonspecific laboratory clue to M. pneumoniae CAP.17–20 The finding of thrombocytosis should prompt testing for cold agglutinins, if not already ordered, and M. pneumoniae IgM and IgG titers.
REFERENCES 1. Cunha BA, Quintiliani R. The atypical pneumonias, a diagnostic and therapeutic approach. Postgrad Med 1979;66:95-102. 2. Cunha BA, ed. Pneumonia essentials (3rd ed.). Jones & Bartlett, Sudbury, MA 2009;46-78. 3. Johnson DH, Cunha BA. Mycoplasma pneumonia. Infect Dis Pract 1996;20:67-8. 4. Sanches-Vargas FM, Gomez-Duarte OG. Mycoplasma pneumoniae—an emerging extra-pulmonary pathogen. Eur J Clin Microbiol Infect Dis 2007;14:105-15. 5. Sillis ANJ, Andrews BE, Jenkins PF, et al. The clinical spectrum and diagnosis of Mycoplasma pneumoniae infection. Q J Med 1986;58:241-51. 6. Cunha BA. The atypical pneumonias: clinical diagnosis and importance. Clin Microbiol Infect 2006;12(Suppl 3):12-24. 7. Cunha BA. Viral & mycoplasma pneumonias. In: Rackel ER, Bope ED, eds.Conn’s current therapy—2008 (60th ed.). Philadelphia, PA: WB Saunders; 2008; 261-265. 8. Murray HW, Masur H, Senterfit LB, et al. The protean manifestations of mycoplasma pneumoniae infections in adults. Am J Med 1975;58:229-42. 9. Mansel JK, Rosenow EC, Martin JW. Mycoplasma pneumoniae. Chest 1989;95:639-46. 10. Cunha BA. Hepatic involvement in mycoplasma pneumoniae community acquired pneumonia. J Clin Microbiol 2003;41: 3456-7. 11. Cunha BA. Diagnostic significance of relative bradycardia. Clin Microbiol Infect Dis 2000;6:633-4. 12. Jansson E. Wagner O. Cold agglutinins in pneumonia. Acta Med Scand 1964;175:747-50. 13. Griffin JP. Cold agglutinins in pneumonia. Ann Intern Med 1969;71:667-8. 14. Smith GN, Weir WRC. Cold agglutinins accompanying Mycoplasma pneumoniae infection. Br Med J 1980;281: 1391-2. 15. Cunha BA. Mycoplasma pneumoniae pneumonia: diagnostic significance of elevated cold agglutinin titers. Eur J Clin Microbiol Infect Dis 2008;27:1017-1019.
SEPTEMBER/OCTOBER 2009
HEART & LUNG
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
16. Parchuri S, Cunha BA. Mycoplasma pneumoniae community acquired pneumonia: Diagnostic usefulness of the agglutination- dissociation test. Infect Dis Pract 2006;30:550-1. 17. Othman N, Isaacs D, Kesson A. Mycoplasma pneumoniae infections in Australian Children. J Paediatr Child Health 2005;41:671-6. 18. Kottayam R, Rozenberg G, Cohn RJ. Unusual haematologic
HEART & LUNG
VOL. 38, NO. 5
manifestations of Mycoplasma pneumoniae infection. J Paediatr Child Health 2007;43:80-2. 19. Marrie TJ. Mycoplasma pneumoniae pneumonia requiring hospitalization. With emphasis on infection in the elderly. Arch Intern Med 1993;153:488-94. 20. Cunha BA. The differential diagnostic approach to thrombocytosis infectious disease practice.2008;32:740-744.
www.heartandlung.org
449
Mycoplasma pneumoniae community-acquired pneumonia (CAP) in the elderly: Diagnostic significance of acute thrombocytosis Burke A. Cunha, MD, and Francisco M. Pherez, MD
The most common cause of nonzoonotic atypical community-acquired pneumonia (CAP) is Mycoplasma pneumoniae. M. pneumoniae CAP is most common in young adults but may occur at any age. Like other atypical CAPs, M. pneumoniae is associated with a characteristic pattern of extrapulmonary organ involvement and nonspecific laboratory tests. M. pneumoniae CAP is frequently accompanied by gastrointestinal manifestations (eg, loose stools/diarrhea), nonexudative pharyngitis, or skin involvement (ie, erythema multiforme). Central nervous system involvement with M. pneumoniae is rare and accompanied by highly elevated cold agglutinin titers. Cardiac, hepatic, and renal involvement are not features of M. pneumoniae CAP. Because M. pneumoniae CAP is most frequent in ambulatory young adults, it is an easily overlooked diagnosis in elderly patients hospitalized with CAP. The hallmark clinical finding of M. pneumoniae CAP is protracted nonproductive cough. The characteristic nonspecific laboratory test finding uniquely associated with M. pneumoniae CAP is elevated cold agglutinin titers. Seventy-five percent of patients with M. pneumoniae infection have elevated cold agglutinin titers. However, the absence of elevated cold agglutinin titers does not argue against the diagnosis of M. pneumoniae. If cold agglutinins are present in a patient with CAP, the higher the cold agglutinin titer is (⬎1:64), the more likely the cold agglutinins are due to M. pneumoniae. Q fever is the only other atypical CAP that is rarely associated with cold agglutinins. We present a hospitalized patient with CAP in whom all microbiologic and serologic diagnostic test results were negative during the first week of her hospitalization. M. pneumoniae CAP was not suspected because of her age. Her initial M. pneumoniae immunoglobulin-M and cold agglutinin titers were negative. During the second week of hospitalization, an increased platelet count was noted. It is a common misconception that acute thrombocytosis is an acute phase reactant. Her acute thrombocytosis increased and persisted. The diagnostic clue to the cause of this hospitalized patient with CAP was acute thrombocytosis. In a patient with CAP, acute thrombocytosis is usually associated with Q fever pneumonia and less commonly with M. pneumoniae. If Q fever can be excluded on the basis of a recent/proximate zoonotic vector contact history, then acute thrombocytosis is an important clue to M. pneumoniae CAP. Acute thrombocytosis due to M. pneumoniae and Q fever occurs during weeks 1 and 2 of the infection. In patients with CAP, acute thrombocytosis that occurs during weeks 1 and 2 of the illness should suggest M. pneumoniae in patients without recent zoonotic vector contact history. (Heart Lung® 2009; 38:444 – 449.)
M
ycoplasma pneumoniae is one of the most common causes of nonzoonotic atypical community-acquired pneumonias (CAPs). M. pneumoniae CAP is most common in children and From the Infectious Disease Division, Winthrop-University Hospital, Mineola, New York; and State University of New York School of Medicine, Stony Brook, New York. Reprint requests: Burke A. Cunha, MD, Chief, Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501. 0147-9563/$ – see front matter © 2009 Published by Mosby, Inc. doi:10.1016/j.hrtlng.2008.10.005
444
www.heartandlung.org
young adults but may occur in any age group, including the elderly.1–3 Atypical CAPs may be differentiated from typical CAPs by the presence or absence of extrapulmonary involvement. Each zoonotic and nonzoonotic atypical pathogen (ie, M. pneumoniae, C. pneumoniae, and Legionnaire’s disease) is accompanied by its own characteristic set of signs and laboratory abnormalities. The characteristic pattern of organ involvement with M. pneumoniae permits its differentiation from other atypical and typical CAP pathogens in addition to CAP. The characteristic pattern of
SEPTEMBER/OCTOBER 2009
HEART & LUNG
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
extrapulmonary organ involvement with M. pneumoniae includes head, eyes, ears, nose and throat involvement (ie, nonexudative pharyngitis or otitis/bullous myringitis), gastrointestinal involvement (ie, loose stools/diarrhea), or skin involvement, (ie, erythema multiforme). Ordinarily, central nervous system, cardiac, hepatic, and renal involvement are rare.4 –11 M. pneumoniae rarely may present with central nervous system manifestations (ie, meningoencephalitis). Patients with M. pneumoniae CAP and meningoencephalitis have high titers of cold agglutinins (ie, ⱖ1:256). Cardiac manifestations are rare but include mycoplasma myocarditis.8,9 Relative bradycardia is not a feature of M. pneumoniae CAP.2,11 Clinically, C. pneumoniae CAP pattern of extrapulmonary involvement resembles mycoplasma but differs in 2 important respects. Loose stools and diarrhea are less common in C. pneumoniae than in M. pneumoniae CAP. Laryngitis is the unique clinical sign of C. pneumoniae CAP among the atypical CAP pathogens. Ear findings are less common with C. pneumoniae than M. pneumoniae CAP. E. multiforme is not a feature of C. pneumoniae CAP. Like M. pneumoniae CAP, C. pneumoniae is not infrequently associated with nonexudative pharyngitis. Both M. pneumoniae and C. pneumoniae CAP may exacerbate existing asthma or result in permanent asthma.2,6,7 Nonspecific laboratory tests are helpful in differentiating among the various causes of atypical CAP. For example, hepatic involvement, manifested by mildly increased serum transaminases, is a regular feature of Legionnaire’s disease but is not a feature of M. pneumoniae or C. pneumoniae CAP. Hyponatremia is common with Legionnaire’s disease but may also occur with M. pneumoniae or C. pneumoniae CAP. Otherwise unexplained hypophosphatemia in a patient with CAP is uniquely associated with Legionnaire’s disease.6,7,10 The hallmark nonspecific laboratory finding associated with M. pneumoniae is an elevation of cold agglutinins. Elevations of cold agglutinins occur in 75% of patients with M. pneumoniae and increase most commonly during or after weeks 1 and 2 of the patient’s CAP.12–16 There are a variety of infectious and noninfectious causes of elevated cold agglutinin titers, but in patients with CAP, M. pneumoniae is the only atypical pathogen associated with high cold agglutinin titers (⬎1:64).15 The absence of an elevation of cold agglutinins does not rule out M. pneumoniae CAP. Cold agglutinin titers with M. pneumoniae CAP may be slightly or highly elevated. However, the higher the cold agglutinin titer is in a patient with CAP without an other explanation, the more likely the patient has M. pneumoniae CAP.6,15 In a patient with presumed mycoplasma CAP, the presence of hepatic or renal involvement argues
HEART & LUNG
VOL. 38, NO. 5
Figure 1 Chest x-ray of patient with M. pneumoniae CAP.
Figure 2 Serial platelet counts during hospitalization in an elderly female with M. pneumoniae CAP.
against the diagnosis.6,7,10 The diagnosis of M. pneumoniae may be confirmed by demonstrating an elevated M. pneumoniae immunoglobulin (Ig)M titer. Increased M. pneumoniae IgG titers without increased IgM titers indicates prior exposure and not active infection. The presence of an elevated IgM and IgG titer indicates recent M. pneumoniae infection.8,9 M. pneumoniae is a common cause of ambulatory CAP in young adults. In elderly patients, M. pneumoniae CAP is often not considered in the differential diagnosis because of the patient’s age. M. pneumoniae is an uncommon cause of CAP in elderly, hospitalized patients.4 – 6 We present a case of M. pneumoniae CAP in an elderly hospitalized patient with emphysema.
CASE REPORT A 73-year-old woman transferred from a nursing home was admitted with progressive shortness of
www.heartandlung.org
445
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
Table I Clinical features of Mycoplasma pneumoniae community-acquired pneumonia Key characteristics
Symptoms Mental confusion Prominent headache Hoarseness Myalgias Ear pain Pleuritic pain Abdominal pain Diarrhea Signs Rash Nonexudative pharyngitis Lobar consolidation Cardiac involvement Relative bradycardia Chest x-ray Infiltrates Pleural effusion Laboratory abnormalities WBC count Relative lymphopenia Thrombocytosis (acute) 2 Serum phosphorus 1 Serum ferritin 1 Cold agglutinins (ⱖ1:64) Diagnostic tests Direct isolation (culture) 1 IgM titers Legionella DFA Legionella urinary antigen
C. pneumoniae
Legionella species
Mycoplasma pneumoniae
— — ⫹ ⫾ ⫾ — — ⫾
⫹ ⫾ — ⫾ — ⫾ ⫾ ⫾
—† —ⴱ ⫹ ⫾ ⫾ — — ⫾
— ⫾ — ⫾ —
— — ⫾ ⫹ ⫹
⫹a ⫹ — ⫾b —
Patchy, lower lobe Focal/segmental/lobar — ⫾ 1/N — — — — — ⫾ C. pneumoniae — —
Patchy, lower lobe ⫾ N — ⫹ — — ⫹
1 ⫹ — ⫹ ⫹ — ⫾ Legionella sp. ⫹ ⫹**
⫾ M. pneumoniae — —
DFA, Direct fluorescent antibody test; N, normal; WBC, white blood cell; Ig, immunoglobulin. ⫹ ⫽ usually present; ⫾ ⫽ sometimes present; — ⫽ usually absent; 1 ⫽ increased; 2 ⫽ decreased; a⫽ erythema multiforme; b⫽ myocarditis, heart block, or pericarditis; † ⫽ mental confusion only if meningoencephalitis present; * ⫽ present if meningitis/meningoencephalitis; ** ⫽ only with Legionella pneumophila (serotype 01). Adapted from Cunha BA, ed. Pneumonia essentials (3rd ed.). Jones & Bartlett, Sadbury, MA: 2008.
breath, productive cough, and wheezing. She had no fever or chills, gastrointestinal symptoms, or headaches. Her medical history included congestive heart failure, chronic obstructive pulmonary disease (COPD) (eg, chronic bronchitis), diabetes mellitus, coronary artery disease, pulmonary hypertension, and mild dementia. On admission she was thought to have an acute exacerbation of chronic bronchitis, and moxifloxacin 400 mg (intravenously) every 24 hours, oxygen, and prednisone were administered. On hospital day 9, ill-defined infiltrates on chest x-ray and a temperature of 101.6°F developed in the patient.
446
www.heartandlung.org
Her pertinent physical examination on hospital day 9 showed a noninjected pharynx, no conjunctival injection, and a negative cardiac examination. Auscultation of the lungs revealed bilateral hypoventilation with rales and dullness to percussion over the right lower lobe and parahilar area. Her abdomen was soft and nontender, with no organomegaly. Her lower extremities were edematous but otherwise unremarkable. Laboratory workup on hospital day 9 revealed a white blood cell count of 20 K/mm3 (polymorphonuclear cells ⫽ 96%, lymphocytes ⫽ 4%) and a platelet count of 322 K/mm3. Her erythrocyte sedi-
SEPTEMBER/OCTOBER 2009
HEART & LUNG
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
Table II Differential diagnosis of thrombocytosis Acute thrombocytosis
Infectious causes Q fever Mycoplasma pneumoniae
Noninfectious causes Hemorrhage Hemolytic anemias Iron-deficiency anemia Kawasaki’s disease Drugs Ceftriaxone Miconazole -lactam/-lactamase inhibitors combinations Carbapenems Oral cephalosporins Recovery from thrombocytopenia
Chronic thrombocytosis
Chronic osteomyelitis Subacute bacterial endocarditis Secondary syphilis Abscesses Lung Renal Splenic Empyema Rheumatoid arthritis Ulcerative colitis Regional enteritis Cystic fibrosis Celiac disease Splenectomy Sickle cell disease Essential thrombocythemia Carcinomas Lymphomas MDS CML Wegener’s granulomatosis
Adapted from Cunha BA. The differential diagnostic approach to thrombocytosis. Infect Dis Pract 2008;32: 740-744. MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia.
mentation rate was 46 mm/h (n⫽ 1–16 mm/h) and C-reactive protein was 208.33 mg /L (n ⫽ ⬍3 mg /L). Serum transaminases were normal. Blood cultures were negative. M. pneumoniae IgM titer was 1 (n ⫽ ⬍0.90), and the IgG titer was 1.31(n ⫽ ⬍1.10). C. pneumoniae, Q fever, adenovirus and Legionella titers were negative. Legionella urinary antigen testing was also negative. Cold agglutinin titers were present at 1:8. Chest x-ray showed worsening infiltrates in the right lower and middle lobes, but she remained unchanged clinically (Fig 1). Her white blood cell count and relative lymphopenia normalized, but her platelet count increased during hospitalization, peaking to 500 K/mm3 on hospital day 18 (Fig 2). Repeat M. pneumoniae IgM titer peaked at 1.79 (n ⫽ ⬍0.90) on hospital day 15 with an IgG titer at 1.60 (n ⫽ ⬍1.10). On hospital day 17, repeat chest x-ray showed worsening right lower lobe pneumonia. Moxifloxacin was discontinued, and doxycycline 100 mg every 12 hours by mouth was given for an additional 2 weeks of therapy.
HEART & LUNG
VOL. 38, NO. 5
DISCUSSION M. pneumoniae CAP is a common cause of ambulatory pneumonia in adults. In elderly patients, M. pneumoniae is frequently not considered in the differential diagnosis of CAP on the basis of age alone. Elderly patients with CAP may have a dry, nonproductive cough with a variety of causes. Underlying lung disease in many elderly patients makes the relative contribution of mycoplasma’s characteristic nonproductive cough sometimes difficult to appreciate. Furthermore, mycoplasma CAP is usually associated with fevers of less than 102°F, which is lower than with typical bacterial pneumonias or Legionella. The low-grade fevers are another reason that clinicians often assume that the patient has some sort of mild typical bacterial cause of CAP, and tests for M. pneumoniae are not ordered. As with other infectious disease problems, the clinician needs historical, physical findings or non specific laboratory test to prompt specific testing to rule in or out various diagnostic possibilities.1,6 Myco-
www.heartandlung.org
447
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
plasma CAP may resemble the typical bacterial CAP if there is a paucity of extrapulmonary findings characteristic of mycoplasma. M. pneumoniae CAP is associated with upper respiratory tract involvement, that is, nonexudative pharyngitis and otitis or bullous myringitis. If these and E. multiforme are not present, there are virtually no physical findings that would suggest M. pneumoniae CAP. Importantly, in contrast with Legionnaire’s disease, Q fever, or psittacosis, relative bradycardia is not a feature of M. pneumoniae CAP.2,6 UC nonspecific laboratory tests, i.e., the white count, differential count, and serum transaminases will not help the clinician to consider testing for M. pneumoniae1,2,6 (Table I). The only test uniquely associated with M. pneumoniae is an elevation of cold agglutinins. Cold agglutinin titers may not increase until weeks 1 and 2 of the illness and are only elevated in 75% of cases. A negative cold agglutinin titer ordered too early or even during the clinical illness does not argue against or rule out M. pneumoniae CAP. However, the presence of elevated cold agglutinin titers argues in favor of mycoplasma CAP in the appropriate clinical setting. A high cold agglutinin titer (ie, ⱖ1:64) is highly indicative of M. pneumoniae in a patient with CAP.12–16 In the case presented, an elderly woman with underlying COPD (ie, emphysema) presented with a cough not much different than when she an exacerbation of her COPD, low-grade fevers (ie, ⬍102°F), and a slightly elevated white blood cell count. Serum transaminases were normal, and cold agglutinin titers were not initially present. The chest x-ray also was unhelpful in determining the cause of her CAP. Patients with M. pneumoniae usually present with an ill-defined lower lobe infiltrate without pleural effusion or consolidation.2 In this case, her minimal ill-defined infiltrates were explained on the basis of her COPD. During the patient’s hospitalization, the only nonspecific laboratory clue to the presence of M. pneumoniae was acute thrombocytosis.17–19 This occurred during weeks 1 and 2 of her hospitalization. Her platelet count reached 502 k/mm3 and slowly decreased over several days during her hospitalization. Her cold agglutinin titer was minimally elevated at 1:8, but her elevated M. pneumoniae IgM titer confirmed the diagnosis of M. pneumoniae. The only infectious causes of acute thrombocytosis are Q fever and M. pneumoniae (Table II). She was initially treated with a respiratory quinolone and later switched to doxycycline, completing a 3-week course of oral therapy.
448
www.heartandlung.org
Cunha, BA
CONCLUSIONS This case has several important clinical points for clinicians to keep in mind. First, M. pneumoniae CAP should be suspected in all age groups, and age, per se, should not exclude M. pneumoniae from diagnostic consideration.1,2,6,7 Second, M. pneumoniae should be considered in patients with ill-defined pulmonary infiltrates without relative bradycardia and with unelevated serum transaminases.2,10,11 In such patients, cold agglutinin titers should be obtained every 3 days, particularly during weeks 1 and 2 of the infection. If present, the findings of nonexudative pharyngitis, otitis/bullous myringitis, or E. multiforme in a patient with CAP should suggest the possibility of M. pneumoniae CAP.6 –9 In the absence of such findings, the presence of otherwise unexplained acute thrombocytosis may be the only nonspecific laboratory clue to M. pneumoniae CAP.17–20 The finding of thrombocytosis should prompt testing for cold agglutinins, if not already ordered, and M. pneumoniae IgM and IgG titers.
REFERENCES 1. Cunha BA, Quintiliani R. The atypical pneumonias, a diagnostic and therapeutic approach. Postgrad Med 1979;66:95-102. 2. Cunha BA, ed. Pneumonia essentials (3rd ed.). Jones & Bartlett, Sudbury, MA 2009;46-78. 3. Johnson DH, Cunha BA. Mycoplasma pneumonia. Infect Dis Pract 1996;20:67-8. 4. Sanches-Vargas FM, Gomez-Duarte OG. Mycoplasma pneumoniae—an emerging extra-pulmonary pathogen. Eur J Clin Microbiol Infect Dis 2007;14:105-15. 5. Sillis ANJ, Andrews BE, Jenkins PF, et al. The clinical spectrum and diagnosis of Mycoplasma pneumoniae infection. Q J Med 1986;58:241-51. 6. Cunha BA. The atypical pneumonias: clinical diagnosis and importance. Clin Microbiol Infect 2006;12(Suppl 3):12-24. 7. Cunha BA. Viral & mycoplasma pneumonias. In: Rackel ER, Bope ED, eds.Conn’s current therapy—2008 (60th ed.). Philadelphia, PA: WB Saunders; 2008; 261-265. 8. Murray HW, Masur H, Senterfit LB, et al. The protean manifestations of mycoplasma pneumoniae infections in adults. Am J Med 1975;58:229-42. 9. Mansel JK, Rosenow EC, Martin JW. Mycoplasma pneumoniae. Chest 1989;95:639-46. 10. Cunha BA. Hepatic involvement in mycoplasma pneumoniae community acquired pneumonia. J Clin Microbiol 2003;41: 3456-7. 11. Cunha BA. Diagnostic significance of relative bradycardia. Clin Microbiol Infect Dis 2000;6:633-4. 12. Jansson E. Wagner O. Cold agglutinins in pneumonia. Acta Med Scand 1964;175:747-50. 13. Griffin JP. Cold agglutinins in pneumonia. Ann Intern Med 1969;71:667-8. 14. Smith GN, Weir WRC. Cold agglutinins accompanying Mycoplasma pneumoniae infection. Br Med J 1980;281: 1391-2. 15. Cunha BA. Mycoplasma pneumoniae pneumonia: diagnostic significance of elevated cold agglutinin titers. Eur J Clin Microbiol Infect Dis 2008;27:1017-1019.
SEPTEMBER/OCTOBER 2009
HEART & LUNG
Mycoplasma pneumoniae community-acquired pneumonia in the elderly
Cunha, BA
16. Parchuri S, Cunha BA. Mycoplasma pneumoniae community acquired pneumonia: Diagnostic usefulness of the agglutination- dissociation test. Infect Dis Pract 2006;30:550-1. 17. Othman N, Isaacs D, Kesson A. Mycoplasma pneumoniae infections in Australian Children. J Paediatr Child Health 2005;41:671-6. 18. Kottayam R, Rozenberg G, Cohn RJ. Unusual haematologic
HEART & LUNG
VOL. 38, NO. 5
manifestations of Mycoplasma pneumoniae infection. J Paediatr Child Health 2007;43:80-2. 19. Marrie TJ. Mycoplasma pneumoniae pneumonia requiring hospitalization. With emphasis on infection in the elderly. Arch Intern Med 1993;153:488-94. 20. Cunha BA. The differential diagnostic approach to thrombocytosis infectious disease practice.2008;32:740-744.
www.heartandlung.org
449