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The occurrence, clinical, and epidemiologic characteristics of fatal nosocomial Legionnaires' disease were ascertained by examining a sample of autopsy specimens submitted by hospitals participating in the National Nosocomial Infections Study. Sections of lung tissue from 263 patients were submitted by 40 hospitals in 24 states. Legionnaires' disease was identified in 10 patients (3.8%) from six hospitals in five states. The clinical and epidemiologic characteristics of sporadic fatal nosocomial Legionnaires' disease were similar to those from cases that occurred during epidemics of Legionnaires' diseases. A case-control study showed that cases of Legionnaires' disease were associated with an increased occurrence of Legionnaires' disease during the period June through November, temperatures greater than 39.2 degrees C, and administration of corticosteroids before onset of pneumonia. Legionnaires' disease can occur as a fatal nosocomial pneumonia and has clinical and epidemiologic features that may be helpful in differentiating it from nosocomial pneumonia of other causes.

The indirect fluorescent antibody test and a microhemagglutination technique detected antibodies in human sera to Legionnaires' disease antigen about equally. Since the hemagglutination technique was simpler, more rapid, and less expensive, we used it to ascertain the prevalence of antibody in 1200 sera from apparently healthy, nonhospitalized Michigan residents. Prevalence was analyzed by age, sex, geographic location (county or residence), and season of the year. There was a significant difference in prevalence between seasons: 91 of 600 sera (15.2%) from February to March 1978 had a titer equal to or greater than 1.16, contrasted with 179 of 600 sera (29.8%) from August to September 1978. This difference was independent of age and sex. There was no significant difference by geographic location, sex, or age except for decreased prevalence for persons 60 years or older.

Legionnaires' disease bacterium was identified as the cause of severe pneumonia in some Nottingham, England, patients in 1977. Laboratory studies were not restricted to Nottingham but included several other areas in England. The 41 cases identified were evenly divided between areas; they also accounted for about one half of all cases for the entire country. No source of infection has been identified in these sporadic cases. There was no contact between patients, and only a few had travelled abroad before their illnesses. Serologic sampling of populations in Nottingham did not reveal a large background of infection. Only 31 of 2023 sera tested had low titer antibody to the Pontiac antigen used. Guinea-pig antisera to two positive lung extracts showed an antigenic relation to the Pontiac but not to the Togus strain,suggesting strain variation.

Respiratory illness occurred in members of a "package tour" to Benidorm, Spain, in 1973. Three of the tourists died with similar pneumonic illnesses, and 86 other travellers who had stayed at the same hotel also had respiratory illnesses. After the organism associated with the epidemic of Legionnaires' disease in Philadelphia 3 years later was identified, sera from patients involved with the "Benidorm episode" were tested. Evidence of infection with the Legionnaires' disease bacterium was obtained from sera from three of the patients who had died and from sera of two of the surviving tourists. Six of 16 members of the staff of the hotel involved had elevated titres to the LD bacterium, suggesting that there may be persistent or recurrent activity in a particular building or locality over a period of years. Surveys of travellers returning to Scotland have shown a large amount of illness, and studies are being conducted to determine the proportion caused by Legionnaires' disease.

The frequency of Legionnaires' disease among 586 cases of pneumonia that occurred in Iowa between fiscal years 1972 and 1977 was studied retrospectively on the basis of paired sera. The frequency of confirmed Legionnaires' disease was 4.1% and of presumptive Legionnaires' disease was 11.4%. Infections with the Legionnaires' disease (LD) bacterium were most frequent in the summer. Of the 22% of pneumonias for which a cause could be defined, Legionnaires' disease was third in frequency behind Mycoplasma pneumoniae and influenza A virus infections. Infections with the LD bacterium occurred in association with pneumonias in most age groups. The youngest patient with LD infection was a 5-year-old boy with pneumonia. The disease occurred 3.2 times more often in males than in females. In males, the frequency of confirmed and presumptive Legionnaires' disease increased steadily to plateau after the fourth decade at about 12% and 28%, respectively. In females the frequency of presumptive Legionnaires' disease was 7% to 16%, relatively evenly distributed over all age groups. Pneumonias associated with LD bacterium infection should be considered in the differential diagnosis of community-acquired pneumonias in most age groups.

As of 30 September 1979, 1005 confirmed cases of sporadic legionellosis caused by Legionella pneumophila serogroups 1 to 4 in U.S. residents had been reported to the Centers for Disease Control; 19% were fatal. All but 2% of the 1005 cases were associated with pneumonia documented by chest radiograph. About 75% of the cases occurred in June through October. The risk of acquiring sporadic legionellosis was increased among males and persons 50 years or older; persons with renal disease necessitating dialysis or transplantation, with chronic bronchitis or emphysema, with diabetes mellitus, and with cancer (10 selected sites or types); persons who smoke; and persons being treated with immunosuppressive drugs. Increasing age and chronic bronchitis or emphysema were associated with increased risk of death. The sensitivity of culturing L. pneumophila from specimens positive by direct immunofluorescence was estimated to be 45%. The distribution of serogroups 1, 2, 3, and 4 of L. pneumophila in 57 fresh, not previously examined direct fluorescent antibody-positive specimens was 84%, 11%, 4%, and 2%, respectively; all 26 strains isolated from these specimens were of one of these four serogroups.

Three patients with severe pneumonia at a community hospital in Columbus, Ohio, were found to have Legionnaires' disease in late August 1977. A subsequent serologic survey of patients with pneumonia at this hospital identified three additional cases. Among patients with pneumonia, hospital exposure in the 2 weeks before onset of illness was significantly associated with Legionnaires' disease (P = 0.003). Serosurveys of hospital employees with a recent history of upper respiratory illness, healthy employees, and workers at the hospital construction site showed that one of 101, one of 107, and none of 114, respectively, has a single reciprocal titer of greater than or equal to 256 to the Legionnaires' disease (LD) bacterium. Serosurveys of patients with pneumonia at three control hospitals identified five additional patients with Legionnaires' disease, three of them with pneumonia that was apparently hospital acquired in a single renal transplant unit. A fourth patient from that unit without clinical illness had a fourfold rise in titer to LD bacterium.

Data on sporadic cases of Legionnaires' disease in Great Britain reported to the Communicable Disease Surveillance Centre, London, and the Communicable Diseases (Scotland) Unit, Glasgow, were analysed. Eighty-four cases, including 18 patients who died, were identified with dates of onset between 1 January 1976 and 30 September 1978. The age and sex distribution showed a predominance of middle-aged men. The incidence trends suggest that true seasonal variation may occur. Eighteen patients developed illness during or shortly after a holiday abroad. All patients had pneumonia, but many also had features suggesting involvement of the central nervous system and gastrointestinal tract. Person-to-person spread was not observed.

In July 1976 a pneumonialike epidemic from a previously unrecognized microorganism erupted among Legionnaires who had attended a meeting in Philadelphia. There were an estimated 182 cases, in which 29 patients died. Among other things the episodes shows that even in a medically sophisticated industrialized nation, a bacterical pathogen can produce a small epidemic and defy identification for almost 6 months. One historical implication of the event is the need to consider the possibility of a return of large-scale epidemic disease rivaling the sweeps of bubonic plague in fourteenth-century Europe. Such epidemics could occur through any of a variety of microorganismic mechanisms recognized as operating at the present time. It is suggested that humans would react to such a disaster much as their progenitors did centuries ago.

Forty-nine cases of Legionnaires' disease were identified from May 1977 through July 1978 in patients and employees at Wadsworth Medical Center. Cases clustered in October and November 1977. Fifteen patients died. All Legionnaires' disease (LD) patients were in the hospital before onset of illness (median time from admission to onset, 17 days; range, 3 to 276 days). Twenty patients were immunosuppressed or compromised by malignancy. In 1977, six of 12 renal-homograft recipients acquired LD pneumonia in contrast to three of 22 during the preceding 3 years (P = 0.031, Fisher's exact test). In a prospective survey of 1658 consecutive hospital admissions, seven cases of Legionnaires' diseases occurred (0.4%), including six among 14 patients who seroconverted to the LD bacterium. Prevalence of a reciprocal titer of 128 or above in Wadsworth employees was significantly greater than in a nearby control population (P = 0.044, Fisher's exact test). Exposure to the external hospital environment may be an important factor, and soil may be a reservoir for the LD bacterium. Legionnaires' disease at Wadsworth may be a nosocomial pneumonia affecting a small group of patients with particular risk factors.

Thirty-nine cases of Legionnaires' disease in a 16-month period were identified in visitors to and residents of Bloomington, Indiana. Thirty-five patients had spent at least one night at the Indiana Memorial Union in the 2 weeks before becoming ill. Five of 32 sporadic cases nationwide between 1 January and 31 March 1978 were retrospectively shown to be in persons who had recently visited the Union. The risk of acquiring Legionnaires' disease as a Union visitor was at least 17 times greater than that for Bloomington residents 20 years or older. Employees who had worked at the Union 5 years or longer were more likely to be seropositive than workers in other Bloomington hotels. Legionnaires' disease bacterium was isolated from five environmental sites in Bloomington. A cooling tower may have been involved in disease spread, but it was not the only source. Hypochlorite solution was added to cooling tower water as a precautionary measure; however, one case was confirmed in a man with Union exposure 9 days after hypochlorite treatment had begun.

Since July 1976 when an outbreak of severe, acute respiratory disease of unknown origin occurred among attendees at the 58th Annual Convention of the American Legion in Philadelphia, great progress has been made, including identification of the causative organism, Legionella pneumophila. Clinical features include not only respiratory involvement but often abdominal complaints, encephalopathy, renal disease, and rhabdomyolysis. Erythromycin appears to be an effective antimicrobial agent. Epidemiologic studies have defined epidemics as well as sporadic cases. Legionella pneumophila has appeared as an opportunistic pathogen. Organisms have been isolated from air-handling equipment and evaporative condensers in four instances. At present diagnosis usually is based on the demonstration of a fourfold rise in antibody titer between serum specimens obtained 3 to 6 weeks apart. Recent data suggest that organisms may be shown in tracheal secretions using a direct flluorescent antibody procedure and that antigen may be shown in urine using the microenzyme-linked immunosorbent assay (ELISA) technique.

Sixty-nine laboratory-documented cases of Legionnaires' disease occurred in Vermont between 1 May and 31 December 1977. Clinical manifestations were similar to those in the 1976 Philadelphia epidemic. Case-control studies suggested that Legionnaires' disease patients were more likely to present with headache or diarrhea than were patients with pneumonia of presumed nonbacterial cause. The case-fatality ratio for patients treated with erythromycin was 4%, compared with 17% in patients not treated with erythromycin. Thirteen patients had been hospitalized throughout the 10 days preceding onset of illness, equaling the maximal known incubation period. This suggests either acquisition or reactivation of infection in the hospital. However, even during the week of peak disease activity, cases occurred in patients with no recent hospital contact. The only community factor possibly associated with acquisition was home air conditioning. This prevalence of seroreactivity to the Legionnaires' disease bacterium in various community populations was as high as 26%, suggesting a possible endemic area.

Open lung biopsies from three patients with Legionnaires' disease were examined by light and transmission electron microscopy. The patients had serious underlying disease. All developed a rapidly progressive pneumonia unresponsive to penicillin, oxacillin, and gentamicin. One patient, who received erythromycin, survived. Light microscopy in all three showed severe acute bronchopneumonia. The Legionnaires' disease bacterium was seen in tissue sections and confirmed by direct immunofluorescence. Transmission electron microscopy showed numerous rod-shaped intracellular organisms that were morphologically similar to other gram-negative bacteria and the Rickettsieae. They were within phagolysosomes, free in the cytoplasm, and rarely within structures resembling dilated rough endoplasmic reticulum. Lung tissue changes included marked detachment and necrosis of alveolar pneumocytes, septal and alveolar exudate with lysis, and prominent endothelial cell swelling and degeneration. Capillary and epithelial basement membranes were consistently intact, suggesting that the tissue changes are potentially capable of reverting to normal structure and function.

Ten recorded epidemics of Legionnaires' disease are reviewed to gain a working perspective on the epidemiology of the disease. Salient features have included a summer-fall seasonality, a male predominance that may largely reflect increased exposure risk among men, and a striking absence of person-to-person spread. That the disease is spread primarily via the airborne route is well established; air-treatment and air-conditioning equipment has been implicated as the amplification and delivery system in four epidemics. Soils and excavation sites have been suggested as sources of the organism in at least one recorded epidemic. Evidence to date suggests that the Legionnaires' disease bacterium may be widespread in nature. More complete epidemiologic understanding must await development of improved microbiologic and immunologic tests.

In August and September 1977 a discrete cluster of 27 serologically or pathologically confirmed cases of Legionnaires' disease, plus six highly presumptive cases were identified in the area of Kingsport, Tennessee. Three patients died. Most patients manifested severe pneumonia and fever; no mild or asymptomatic disease forms were recognized despite intensive case-finding efforts. Illness was epidemiologically associated with residing, visiting, or working in one geographic area of Kingsport, residence there being the factor most strongly associated. Although the attack rate for area residents was 0.64%, the randomly determined prevalence of serologic reactors was 5.2%, which is not significantly different from that in a nonimplicated control neighborhood. The epidemic did not correlate temporally with any identified environmental or demographic event. No source of the bacterium was found either by a detailed case-control study of area associations or by bacterial isolation from sentinel guinea pigs or environmental specimens. There was no evidence of person-to-person spread.

One hundred patients with sporadic, community-acquired, serologically confirmed Legionnaires' disease were matched with control subjects known by the patients (acquaintance controls) and control subjects chosen from among patients with negative serodiagnostic tests for Legionnaires' disease (clinical controls). Each clinical control subject was also matched with an acquaintance control of his own. Legionnaires' disease patients had smoked more cigarettes, consumed more alcohol, and were more likely to have resided near excavation sites than acquaintance or clinical control subjects. Parallel differences between clinical controls and their acquaintances were not seen. Legionnaires' disease patients had traveled away from home for more time during the 2 weeks before onset of illness than had their acquaintances. The difference was of greater magnitude than that between clinical control subjects and their acquaintances. Legionnaires' disease patients were more likely to have resided near construction sites than clinical controls, and there were more construction workers among patients than among clinical control subjects.

From April 1977 through March 1978, 28 presumptive cases of Legionnaires' disease were identified among 432 consecutive candidates having paired sera or tissue samples submitted to the Massachusetts Public Health Laboratories. Among the subgroup of 209 candidates with documented diffuse pneumonia and temperature of 39 degrees C or above, 24 (11.5%) had Legionnaires' disease whereas the diagnostic yield was only four of 223 (1.8%) among the remainder. The case-fatality rate was two of 28 (7%). Patients with Legionnaires' disease when compared to the entire group of candidates were similar in mean age (49 versus 48 years) and frequency of immunosuppressant therapy (15% versus 12%) but were more often male (64% versus 47%) with underlying chronic illness (46% versus 22%). Complement fixation tests against Mycoplasma pneumoniae (whole organisms) showed seroreactivity in 81% of Legionnaires' disease (LD) cases (22 to 27) compared to 13% of non-LD cases; conversely, 29% of all cases seropositive for M. pneumoniae (22 of 75) were seropositive for the LD bacterium compared to only 1% (five of 357) of the remainder. The coincidence of seroreactivity for M. pneumoniae and the LD bacterium is unexplained but suggests that M. pneumoniae seropositive cases should be evaluated for the possibility of Legionnaires' disease.

Summertime pneumonias in Philadelphia during 1976 were studied epidemiologically, and the epidemiologic, clinical, and laboratory features of pneumonia cases serologically positive for Legionnaires' disease were compared with features of serologically negative cases. Both groups were similar in many respects, but in patients with Legionnaires' disease diarrhea and neurologic findings were significantly more frequent (P = 0.01 and P = 0.05 respectively). A diagnosis of Legionnaires' disease was also suggested by an elevated serum creatinine phosphokinase level (P = 0.02) and the presence of occult blood in the urine with fewer than six erythrocytes per highpower field. Abnormalities in renal function tests or liver function tests were commoner in patients with Legionnaires' disease (P = 0.05). Radiographic features, however, could not be used to separate pneumonia cases. The high frequency of extrapulmonary manifestations involving the gastrointestinal tract, the central nervous system, kidneys, and liver suggests that Legionnaires' disease is a multisystemic disorder possibly caused by a toxin-producing organism.

Sera of 24 patients with an unexplained pneumonia were tested for the presence of antibodies against the Legionnaires' disease bacterium. Fifteen patients had positive serology. The series comprised 12 male and three female patients ranging in age from 17 to 66 years (mean, 51.1 years). All of the patients had a high fever, little or no sputum production, and radiographic evidence of pneumonia. The radiographic abnormalities ranged from a patchy infiltrate to extensive consolidation. In eight patients with confirmed Legionnaires' disease, severe confusion was one of the most striking signs. A variety of antibiotics had no clear effect on the duration of the illness in these cases, although the severity seemed to be influenced. Two of the patients died, and in three the course was protracted. All cases were sporadic. Eight patients had been infected abroad and seven in the Netherlands, two of whom were on immunosuppressive therapy and were infected in a hospital.

Clinical, pulmonary, and serologic findings in Legionnaires who attended the 1976 American Legion Convention in Philadelphia were studied 2 years after the Legionnaires' disease epidemic there. All 31 survivors of Legionnaires' disease studied became ill within 2 weeks after the convention, and 18 had not fully recovered 2 years after the epidemic. Twenty-five (28%) of 90 additional Legionnaires exposed at the convention but not diagnosed as having Legionnaires' disease became ill during the same time interval; five of these had symptoms during the next 2 years. Survivors had decreased diffusion capacities measured by the carbon monoxide single-breath method. These differences could not be accounted for by ventilation abnormalities or concurrent illness. Significant levels of IgG or IgM antibodies persisted in 94% of survivors of Legionnaires' disease and in 53% of Legionnaires exposed at the convention, which suggests a high prevalence of subclinical infection. Persistence of IgM antibody raises the question of latency or subclinical infection as part of the natural history of Legionnaires' disease.

A review of the medical records of 123 persons with Legionnaires' disease hospitalized in the 1976 Philadelphia epidemic showed that the manifestations of infection ranged from mild grippe to a severe pneumonia that also involved other organ systems. Early in the illness, constitutional symptoms predominated. Fever, malaise, myalgia, rigors, confusion, headache, and diarrhea were usually followed by nonproductive cough and dyspnea. Physical examination showed few abnormalities other than rales. Moderate leukocytosis with left shift, elevated erythrocyte sedimentation rate, elevation of serum levels of liver enzymes, and hematuria and proteinuria were characteristic. Chest radiograph showed patchy, often nodular, areas of consolidation. Progression of pneumonia led to respiratory failure and the need for mechanical ventilatory assistance for 19 patients; renal failure, primarily after shock, occurred in 18 persons. Twenty-six patients died. Treatment with erythromycin or tetracycline resulted in the lowest case-fatality ratios, but the associations were not statistically significant.