epidemiological studies, observing civilian populations or military personnel by using

Transcription

1 THE YALE JOURNAL OF BIOLOGY AND MEDICINE 56 (1983), Epidemiologic Aspects of M. pneumoniae Disease Complications: A Review H.M. FOY, M.D., Ph.D.,a C.M. NOLAN, M.D.,b AND I.D. ALLAN, R.N., M.A.a adepartment of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington; bseattle.king County Health Department, Seattle, Washington Received January 4, 1983 As early as the 1940s, erythema multiforme exudativum (Stevens-Johnson syndrome) and hemolytic anemia were associated with outbreaks of atypical pneumonia, a disease later found to be caused by Mycoplasma pneumoniae. Epidemiologic evidence has also associated neurological complications, especially aseptic meningitis and meningoencephalitis, with M. pneumoniae infections. Urticarial and morbilliform skin rashes often appear late in the course of M. pneumoniae pneumonia. A multitude of other complications have been ascribed to M. pneumoniae infections, often reported as case reports diagnosed by serologic antibody titers only. More systematic investigations are needed to assess the frequency of complications to M. pneumoniae infections. Isolation of the agent, not only serologic titer rises, should be required before a syndrome is attributed to M. pneumoniae infection. The incidence of Mycoplasma pneumoniae pneumonia and minor infections has been thoroughly studied in civilian and military populations (1-6]. The infection is endemic in most areas of the world; epidemics occur at four- to seven-year intervals. Infection rates in epidemics can be as high as 35 percent among school children, but pneumonia is diagnosed in only a small proportion of those infected [2]. The large epidemiological studies, observing civilian populations or military personnel by using isolation of M. pneumoniae from respiratory specimens and serologic tests, have rarely reported complications [2-6]. Instead, they described M. pneumoniae infections, including pneumonia, as mild. It is conceivable that patients who present with extrapulmonary symptoms may escape detection in such studies. In contrast, physicians who study patients hospitalized for pneumonia report more cases of severe disease and complications [1,7]. Clearly, a selection for severity has already taken place with hospitalization. In the Seattle field studies of M. pneumoniae pneumonia in a prepaid medical care group, only 2 percent of M. pneumoniae pneumonia patients were hospitalized [5]. Complications were reported as early as the 1940s, when atypical pneumonia was first described and cold agglutinins were used for diagnosis. What is now usually labeled Stevens-Johnson syndrome was first associated with outbreaks of atypical pneumonia among military recruits in Canada in the early 1940s [8]. Finland et al. reported on four cases of erythema multiforme exudativum (Stevens-Johnson syndrome) during an epidemic of atypical pneumonia in Boston, [9]. 469 Address reprint requests to: Dr. Hjordis M. Foy, Dept. of Epidemiology SC-36, University of Washington, Seattle, WA Copyright t 1983 by The Yale Journal of Biology and Medicine, Inc. All rights of reproduction in any form reserved.

2 470 FOY ET AL. Hemolytic anemia was also reported during these epidemics [10]. However, the cause of hemolysis could possibly be attributed to treatment with sulfonamides, drugs commonly used as antimicrobial therapy at the time. In 1956, Yesnick associated "aseptic pneumonia" with neurological complications, but at a very low rate [11]. In 1965, Skoldenberg noticed temporal association between cold agglutinin positive pneumonia and aseptic meningitis in Stockholm [12]. The latter patients usually also had positive chest findings. Since more specific diagnostic tools for diagnosis of M. pneumoniae infection became available in the 1960s, a large number of case reports of severe manifestations and complications have accumulated. These have been extensively reviewed [13-15]. Too often the diagnosis was made in retrospect, from significant antibody titer rise to M. pneumoniae between acute and convalescent serum. Few clinicians have had the foresight to take cultures for M. pneumoniae in such cases; in fact, many medical centers do not have access to a laboratory with competence and experience in mycoplasma isolation. Utilizing serologic diagnosis for a multitude of disease syndromes introduces a risk of making false associations, since non-specific increases in antibody titers to M. pneumoniae may occur. We conducted an epidemiologic study of M. pneumoniae pneumonia in a large health maintenance organization in Seattle, the Group Health Cooperative, between 1963 and The membership averaged 150,000. The study included 947 cultureproven cases of M. pneumoniae pneumonia. Skin rashes were the only noteworthy complications and occurred in 17 percent of cases [5]. These were usually described as either urticarial or morbilliform, and in one case as erythema nodosum. A few patients experienced recurring urticarial rashes for a couple of months before total recovery [5]. However, in the Group Health studies physicians were only asked to submit specimens from patients who presented with pneumonia, not from patients who had neurological or other disease syndromes. Unless such complications were preceded by pneumonia, unusual manifestations would have escaped notice. In Seattle, epidemics occurred in and then again in The School of Public Health has the only laboratory that carries out isolation of M. pneumoniae, and the School serves as a referral center to which physicians not serving the Group Health population also submit specimens. From the first documented epidemic, we reported two cases of Stevens-Johnson syndrome with isolates of M. pneumoniae in the throat [16,17]. During the 1974 epidemic a 12-year-old boy was seen with septic arthritis, primarily of the hip joint, and leukopenia with bone marrow suppression. He also had pneumonia and M. pneumoniae was isolated from his throat (but not from joint fluid) [unpublished case]. None of these three patients were members of the Group Health Cooperative but were referred to us from other community physicians. Other referred patients from whom M. pneumoniae was isolated had no noteworthy complications, although most required hospitalization for pneumonia. Thus evidence of a high rate of severe complications during an epidemic period was lacking, but surveillance for complications was casual at best. In we observed a third epidemic of M. pneumoniae pneumonia in Seattle, seven years after the previous one. At this time the Group Health study had been terminated. Instead, the Seattle-King County Public Health Department, covering a population of 1.25 million, was monitoring respiratory diseases by offering serologic diagnosis (complement fixation test using antigen purchased from Microbiological Associates) to the practicing physicians in the community free of charge (Fig. 1). In 1979, 6 percent of 299 sera submitted to the health department

3 A REVIEW OF M. PNEUMONIAE COMPLICATIONS Serologic Surveillance, Seattle - King County Heolth Dept. 140 L Total number sera 12 0 La C F pos. for M. pn q80 r 607 Z) h 2 Lx L 0 FIG. 1. Number of sera 40 and sera positive for M. pneumoniae (by fourfold or higher titer rise or single 20- titer of >64) submitted to -.- the Seattle-King County f-:-health Department by MONTHS M J J AS ON D:J F MA M J Yeor J AS ON D.J F Ma M J 1981 J ASO N D month-may 1979 through December had significant titer rises or a single titer of > 64 to M. pneumoniae. In 1980, the proportion of positives rose to 16 percent of 687 sera tested and, in 1981, 31 percent of 486 sera tested were positive. The epidemic appeared to have started in March of the highest incidence was shown between December 1980 and March of 1981; thereafter the epidemic dissipated. Community physicians were notified about the epidemic in October of 1980 in a monthly newsletter with a circulation of approximately 2,100. In the same letter sera from cases with complications were solicited in a concerted effort to evaluate the frequency of severe complications to M. pneumoniae infections during the epidemic. A questionnaire was subsequently sent to physicians who could be located and who had patients with significant antibody titer rises or single titers of 2 64 during the epidemic. Unfortunately, names and addresses of physicians who forwarded sera through other laboratories were not available. Information on age, sex, hospitalization, diagnosis, and complications was requested. A total of 114 (77 percent) of 148 questionnaires were returned. An analysis of the information on the questionnaires showed that: Fifty-six patients (49 percent) whose sera had been forwarded had been hospitalized-a much higher proportion than the 2 percent observed in our Group Health studies [2]. Thus, these patients were probably a sub-sample with more severe disease than the average patient seen in the community with M. pneumoniae infection. The majority were adults, whereas children are known to have the highest attack rates in the general population and consistently constituted almost 80 percent of all cases in our population-based studies [2]. This probably indicates that M. pneumoniae disease is more likely to be complicated in adults, as case reports suggest, and/or that pediatricians were less inclined to draw blood samples. Seventy-seven or 67 percent of those with positive sera had been diagnosed as hav-

4 472 FOY ET AL. ing pneumonia. The patients without a diagnosed pneumonia were investigated usually because of signs of a severe respiratory tract infection. Many minor complications such as myalgia, diarrhea, vomiting, poorly described skin rashes, pleurisy (six patients), and pleural effusion (two patients) were reported. The major complications noted were as follows: two cases of acute respiratory distress syndrome (19 and 62 years old), two cases of Stevens-Johnson syndrome (34 and 37 years old), one case of gross hematuria (39 years old), and one case of empyema (40 years old). Cardiac complications were suspected in two patients (62 and 84 years old) with pneumonia. Hepatitis was encountered in three cases, but drug reactions or viral hepatitis could not be ruled out. Anemia was also reported but not described in detail. Although probably not all physicians treating M. pneumoniae pneumonia in the community utilized the free diagnostic services, it does not appear that the epidemic was followed by a marked increase in conditions that are considered complications to M. pneumoniae infections. In the U.S., because of the fragmented structure of the health care system, it would be difficult to arrive 4t reliable estimates of complications to M. pneumoniae infections. In certain European countries and Japan, which have centralized laboratory facilities and comprehensive community health care systems, the opportunities to investigate rates of complications are far better. Thus Lind et al. reported that, at least in the 1972 epidemic of M. pneumoniae infections in Copenhagen, there was an increase in the rate of aseptic meningitis attributed to this organism [18]. Sterner and Biberfeld noticed a high rate of meningitis and meningoencephalitis among patients hospitalized for M. pneumoniae pneumonia in Stockholm [7]. Assaad et al., who compiled data on neurological diseases with viral and M. pneumoniae infections from many countries, under the aegis of WHO, commented on increased numbers of patients with aseptic and viral meningitis with serological evidence of M. pneumoniae infections during an epidemic in Finland [19]. Similar observalions have recently been made in France [20]. Family studies of M. pneumoniae infections offer additional insight into the frequency of complications. In a Seattle family study, the only complications noted among 59 infected members were two cases with typical bullous hemorrhagic myringitis and several cases of skin rashes [21]. Balassanian et al. reported a case of psychosis in an adult woman among 36 family members studied [22]. Biberfeld and Sterner reported two cases of acute psychosis in middle-aged women and one case of myocarditis among 70 family members studied [23]. As far as other complications are concerned, epidemiologic support for significant impacts is lacking [24]. Ponka reported that 4.5 percent of Finnish patients hospitalized with serologic titer rises to M. pneumoniae had myocarditis, but warned in a later publication that the CF test with glycolipid used as an antigen may give false positive results, particularly in heart disease [25,26]. On similar grounds, and because of lack of epidemiological association, Leinikki et al. rejected pancreatitis as a complication of M. pneumoniae infection [27]. In summary, in epidemiologic studies of M. pneumoniae, neurological disease, including acute psychosis, has been associated by several authors. Studies in the early 1940s and the later Seattle experience also suggest that cases of Stevens-Johnson syndrome occur during epidemics. Population-based studies suggest that other complications attributed to M. pneumoniae are rare. Isolation of the organism should be sought, in addition to serologic titer rise, to document that a disease syndrome is due to M. pneumoniae, since false positive serologic rises have been demonstrated [26,27,28].

5 A REVIEW OF M. PNEUMONIAE COMPLICATIONS 473 REFERENCES 1. Foy HM: Pneumonia, Mycoplasma pneumoniae. In Communicable and Infectious Diseases. Edited by PF Wehrle, FH Top. St. Louis, The CV Mosby Company, 1981, pp Foy HM, Kenny GE, Cooney MK, et al: Long-term epidemiology of infections with Mycoplasma pneumoniae. J Infect Dis 139: , Chanock RM, Mufson MA, Bloon HH, et al: Eaton agent pneumonia. JAMA 175: , Mogabgab WJ: Mycoplasmapneumoniae and adenovirus respiratory illnesses in military and university personnel, Am Rev Respir Dis 97: , Foy HM,.Kenny GE, McMahan R, et al: Mycoplasma pneumoniae pneumonia in an urban area. JAMA 214: , Denny FW, Clyde WA Jr, Glezen WP: Mycoplasma pneumoniae disease: clinical spectrum, pathophysiology, epidemiology, and control. J Infect Dis 123:74-92, Sterner G, Biberfeld G: Central nervous system complications of Mycoplasmapneumoniae infection. Scand J Infect Dis 1: , Stanyon JH, Warner WP: Mucosol respiratory syndrome. Can Med Assoc J 53: , Finland M, Jolliffe LS, Parker F Jr: Pneumonia and erythema multiforme exudativum: Report of four cases and three autopsies. Am J Med 4: , Finland M, Peterson OL, Allen HE, et al: Cold agglutinins. II. Cold isohemagglutinins in primary atypical pneumonia of unknown etiology with a note on the occurrence of hemolytic anemia in these cases. J Clin Invest 24: , Yesnick L: Central nervous system complications of primary atypical pneumonia. AMA Arch Intern Med 97:93-98, Skoldenberg B: Aseptic meningitis and meningoencephalitis in cold agglutinin-positive infections. Br Med J i: , Cassell GH, Cole BC: Mycoplasmas as agents of human disease. New Eng J Med 304:80-89, Murray HW, Masur H, Senterfit LB, et al: The protean manifestations of Mycoplasma pneumoniae infection in adults. Am J Med 58: , Ponka A: The occurrence and clinical picture of serologically verified Mycoplasma pneumoniae infections with emphasis on central nervous system, cardiac and joint manifestations. Ann Clin Res 1 l(suppl 24):9-60, Foy HM, Kenny GE, Koler J: Mycoplasma pneumoniae in Stevens-Johnson's syndrome. Lancet ii: , Foy HM, Alexander ER: Mycoplasma pneumoniae infections in childhood. In Advances in Pediatrics. Edited by I Schulman. Chicago, Year Book Medical Publishers, Inc, 1969, pp Lind K, Zoffman H, Larsen SO, et al: Mycoplasma pneumoniae infection associated with affection of the central nervous system. Acta Med Scand 205: , Assaad F, Gispen R, Kleemola M, et al: Neurological diseases associated with viral and Mycoplasma pneumoniae infections. Bull WHO 58: , Michel D, Laurent B, Granouillet R, et al: Infections aigues recentes et parfois persistantes a Mycoplasma pneumoniae, associees a des manifestations neurologiques. Discussion des liens de causalite. Rev Neurol (Paris) 137: , Foy HM, Grayston JT, Kenny GE, et al: Epidemiology of Mycoplasma pneumoniae infection in families. JAMA 197: , Balassanian N, Robbins FC: Mycoplasma pneumoniae infection in families. New Eng J Med 277: , Biberfeld G, Sterner G: A study of Mycoplasma pneumoniae infections in families. Scand J Infect Dis 1:39-46, Clyde WA Jr: Neurological syndromes and mycoplasmal infections. Arch Neurol 37:65-66, Ponka AS: Carditis associated with Mycoplasmapneumoniae infection. Acta Med Scand 206:77-86, Ponka A, Ponka T, Sarna S, et al: Questionable specificity of lipid antigen in the Mycoplasma pneumoniae complement fixation test in patients with extrapulmonary manifestations. J Infect 3: , Leinikki P, Pantzar P, Tykka H: Antibody response in patients with acute pancreatitis to Mycoplasma pneumoniae. Scand J Gastroenterol 8: , Kenny GE: Serology of Mycoplasmic Infections. In Manual of Clinical Immunology. Edited by NR Rose, H Friedman. Washington, DC, American Society for Microbiology, 1980, pp