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Relation of Mycoplasma pneumoniae seroreactivity, immunosuppression, and chronic disease to Legionnaires' disease. A twelve-month prospective study of sporadic cases in Massachusetts.

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.

Adolescent

[Legionnaires' disease (author's transl)].

The epidemic of respiratory disease (Legionnaires' disease) occurred after the American Legion convention between 21-24 July 1976 in Philadelphia, USA, similar epidemics occurred previously with unknown etiology in the USA and in England with similar clinical symptoms and pathological findings of the disease, the isolated etiological agent, its morphology culture, pathological findings in laboratory animals, serological and immunofluorescent test, the proposed term for the causative organism (Legionella pneumophila) at the International Symposium on Legionnaires Disease held at the Center for Disease Control in Atlanta, Georgia, USA, on November 13th-15th, 1978 are reviewed.

Disease Outbreaks

Indirect immunofluorescence test for serodiagnosis of Legionnaires disease: evidence for serogroup diversity of Legionnaires disease bacterial antigens and for multiple specificity of human antibodies.

Evidence obtained by others who used direct immunofluorescence staining to demonstrate serological differences among strains of Legionnaires disease bacterium prompted this study of parameters influencing the ability of the indirect immunofluorescence test to detect human antibodies to Legionnaires disease bacterium. A total of 25 Legionnaires disease bacterium strains, representing four serogroups, were used as immunofluorescence antigens to test selected human sera. The use of diethyl ether in preparing the antigens was discontinued when it was found that titers against ether-killed group 2 (Togus 1-like) antigens were impossible to determine. Instead, heat-killed suspensions of Legionnaires disease bacterium in 0.5% buffered normal chicken yolk sac were used to show the serogroup diversity of the strains and the serogroup specificity of the antibody response of some, but not all, patients with serological evidence of Legionnaires disease. These studies suggest that multiple antigens should be used in serological tests for Legionnaires disease. Furthermore, the fact that some sera contain antibodies that bind equally well to strains of all four serogroups implies that demonstration of a fourfold increase in titer of paired sera when tested with a single antigen should not be interpreted as evidence of infection with a strain of the same serogroup.

Antibodies, Bacterial

Legionnaires' disease in non-Legionnaires. A report of five cases.

Seventeen patients with illness resembling Legionnaires' disease were evaluated for antibodies to the Legionnaires' bacillus. Three patients were Legionnaires who developed pneumonia after attending the July 1976 convention. All three were seropositive (titers greater than or equal to 1:128) to the Legionnaires' bacillus. None of the remaining 14 patients were Legionnaires. Five were seropositive and nine, seronegative (titers less than or equal to 1:32). The seropositive patients had illnesses best explained by Legionnaires' disease, whereas the seronegative patients had illnesses better explained by other diagnoses. This correlation between serology and clinical findings supports the specificity of the antibody test for Legionnaires' disease. Of the five non-Legionnaire seropositive cases, two occurred before, and one 3 months after, the convention. The case histories of these five patients are presented. Disease generally involved the lungs, kidneys, and the central nervous system. Although the pathogenesis of this multiple organ involvement is unclear, a possible explanation is the production of a toxin by the Legionnaires' bacillus.

Adolescent

Microbiology of Legionnaires' disease bacterium.

Legionnaires' disease bacterium in tissue does not readily react with the Gram stain but can be seen by other stains and direct immunofluorescence. It is a slow-growing, aerobic, gram-negative rod that can be cultivated over a narrow temperature range on Mueller-Hinton agar supplemented either with complex biological mixtures or certain ferric salts and cysteine. The bacterium produces unique, branched-chain fatty acids, catalase, oxidase (weakly), and gelatinase and uses starch while ignoring other carbohydrates. Pigment production is related to tyrosine in the medium. In-vitro studies suggest susceptibility to all antibiotics except vancomycin, but a class 1 beta-lactamase has been demonstrated. Analysis of DNA confirmed the unrelatedness of this bacterium to previously recognized prokaryotes. Diagnosis of the disease has depended largely on serologic test findings and the demonstration of the bacterium in tissue and, occasionally, on isolation. Additional, simpler, and more rapid diagnostic tests should soon be available.

Bacteria

The compromised host and Legionnaires' disease.

Pneumonia caused by Legionnaires' disease bacterium was recognized in eight patients during a 7-month period. The patients were immunosuppressed by their underlying illness, corticosteroid therapy, and other exogenous immunosuppressive agents. Five of the patients had received immunosuppressive therapy for less than 16 days. Clinical presentation was similar to that of other bacterial pneumonias in compromised patients. Legionnaires' disease progressed to necrotizing pneumonia with abscess formation and respiratory failure in two patients. Diagnosis was made by [1] culture of lung tissue and bronchial washings; [2] direct fluorescent antibody staining of lung tissue, sputum, and bronchial washings; and [3] serologic evidence of infection. Therapy with oral erythromycin was ineffective. Intravenous erythromycin was given to six patients, with a good response. However, two patients showed further clinical improvement after rifampin was added. Because this illness may be more severe in compromised hosts, open lung biopsy and special microbiologic tests should be done when Legionnaires' disease is suspected.

Adrenal Cortex Hormones

Growth, survival, and resistance of the Legionnaires' disease bacterium.

The Legionnaires' disease (LD) bacterium can now be readily cultured on artificial media. Studies were done to define the growth and survival of the LD bacterium in these media and ascertain its susceptibility to disinfecting agents. Growth-curve studies of the Philadelphia 1 strain using Mueller-Hinton broth with ferric pyrophosphate and L-cysteine (Feeley-Gorman broth) showed a lag phase of less than 24 h, a generation time of 3.8 h during the logarithmic phase, a plateau of 2 x 10(7) organisms per millilitre, and continued viability for as long as 110 d. Viability on chocolate agar with 1% hemoglobin and 2% IsoVitaleX added reached 150 d. This strain was susceptible to a variety of commonly recommended hospital and laboratory disinfectants, often in low concentrations. These investigations suggest that prolonged survival may occur in natural as well as artificial milieus and that low concentrations of phenolics, quaternary ammonium compounds, glutaraldehyde, formaldehyde, and hypochlorite could eradicate potential reservoirs for human infection.

Bacteria

"Endotoxicity" of the Legionnaires' disease bacterium.

The Legionnaires' disease (LD) bacterium is a gram-negative organism whose "endotoxicity" appears to differ in several respects from the classic endotoxicity generally associated with gram-negative bacteria. Discrepancies were noted between the high activity of LD bacteria in gelating limulus lysate in vitro and their low pyrogenicity in rabbits. Further in-vivo biologic tests indicated that LD bacteria were relatively weak in "endotoxicity". Analysis of LD bacterial cells and in their cellular fractions by gas-liquid chromatography indicated that LD bacteria did not contain hydroxy fatty acids commonly associated with lipid A of endotoxin. The branched-chain fatty acids that were characteristic of LD bacteria were associated with the cell envelope, and were readily extracted into organic solvents without prior saponification. The presence of 2-keto-3-deoxyoctonate in LD bacteria and cell extracts was detected by a microassay method but remains to be confirmed with gas-liquid chromatography and mass spectrometry. The active principle "endotoxicity" in LD bacteria may be a new type of bacterial lipopolysaccharide.

Animals

The "missing" investigation of Legionnaires' disease.

The investigation of Legionnaires' disease was riddled with problems, and as a result, was largely ineffective. But the lesions it taught can be extremely valuable to future public-health efforts if they are heeded. This chapter has attempted to highlight those problems and offer some possible solutions. It is now up to the public-health hierarchy to use what is offered in these pages to spark the building of programs and systems that provide the level of effectiveness the American people have a right to expect from public-health departments. Finally, it was my intent to raise questions about the Center for Disease Control's new organism. The Center may, indeed, have found the responsible agent. We must not, however, allow ourselves to have tunnel vision in the continuing investigation--switching to other possibilities only if the microorganism theory is exhausted. The evidence and remaining questions demand a broader scope of investigation. How tragic it will be if we have not learned from the inflexibility and narrowness of the 1976 investigation of Legionnaires' disease.

Centers for Disease Control and Prevention, U.S.

Severe cerebral disturbance in legionnaires' disease.

In two cases of legionnaires' disease pneumonia was associated with severe cerebral disturbance. In one case legionnaires' disease was diagnosed retrospectively by serological methods, and in the other the development of similar cerebral symptoms in the course of pneumonia prompted a clinical diagnosis of legionnaires' disease and the institution of effective treatment.

Aphasia

Legionnaires' disease in patients with associated serious disease.

Of nine patients with Legionnaires' disease, seven were receiving corticosteroids, and all nine had serious underlying diseases. Direct immunofluorescent examination of respiratory secretions, including sputum and transtracheal aspirates, showed the Legionnaires' disease (LD) bacterium in five of seven patients who seroconverted and in a sixth patient with a single elevated titer to the LD bacterium. All nine patients received erythromycin therapy, and five survived. Two patients showed persistence of their infection after receiving 2 weeks of erythromycin therapy, and two patients developed pulmonary abscesses. These cases of Legionnaires' disease show the occurrence of pulmonary abscesses, the possibility of relapse after giving only 2 weeks of erythromycin therapy, and the utility of direct immunofluorescence for early diagnosis.

Adrenal Cortex Hormones

Pathology of Legionnaires' disease.

The acute lesion in Legionnaires' disease pneumonia is an acute fibrinopurulent bronchopneumonia in which the alveoli are filled with many neutrophils and macrophages and abundant fibrin. There is only slight necrosis. Although characteristic, the lesion is not specific for this agent. However, the association with this lesion of myriad small pleomorphic rods, which stain well with Dieterle's silver-impregnation method but poorly or not at all with Gram-type stains, is uncommon except in Legionnaires' disease pneumonia. Final diagnosis requires isolation of the organism or immunofluorescent studies of the tissue, sera or both. The full spectrum of the pneumonia is not known, but organization has been reported once. No definite anatomic correlate for the extrathoracic manifestations of Legionnaires' disease has been identified nor has the organism been found at extrathoracic sites.

Bacteria

Epidemiology of Legionnaires' disease.

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.

Air Conditioning

Immunology and immunopathology of Legionnaires' disease.

The immune response to the Legionnaires' disease (LD) bacterium has been shown serologically. Recent evidence suggests significant differences in seroreactivity depending on the source of antigen; these data now unequivocally show strain variation for the LD bacterium. Nothing is known about the cellular immune reactivity in patients with Legionnaires' disease. There is little evidence that the lesions and manifestations of the disease are due to immunopathologic mechanisms. Possible explanations for the pathogenesis of pulmonary lesions in Legionnaires' disease include toxic factors, bacterial chemotactic factors, neutral proteases (with complement cleaving activity), lipopolysaccharides, and products of lymphocytes.

Antibodies, Bacterial

Legionnaires' disease in Nottingham, England.

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.

Antibodies, Bacterial

[Legionnaires' disease (author's transl)].

Since Legionnaires' disease was diagnosed in Spain for the first time, we have considered it of interest to review the subject and to bring it up to date as much as possible. Legionnaires' disease is an infectious illness which principally affects people in the fifth decade of life and which has been diagnosed in different countries in the world, including Spain. The etiologic agent is a Gram-negative bacteria, which does not grow in the normal culture media and which requires special stains for its identification. Clinically the disease presents as an atypical pneumonia accompanied by gastrointestinal symptoms and hyponatremia as a characteristic laboratory finding. It appears with greater frequency during the summer season in an epidemic form, although isolated cases have been reported during the entire year. It is potentially a very severe condition, and the mortality rate has been calculated at 15--20 percent. A definite diagnosis requires the isolation of the etiologic agent: directly, by stain (direct immunofluorescence, Dieterle's silver stain), isolation and culture in an enriched media (Mueller-Hinton agar supplemented with Iso-Vitalex and hemoglobin), or indirectly by serologic methods (indirect immunofluorescence). Eryhtromycin is the antibiotic of choice with or without the association of another antibiotic of wider spectrum.

Bacteriological Techniques

Sporadic Legionnaires' disease.

The first case of Legionnaires' disease recognized in Pennsylvania since the Philadelphia epidemic of 1976 was that of a 53-year-old emphysematous man who had extensive unilateral pneumonia accompanied by high fever, hypoxemia, and disorientation. His illness progressed despite treatment with cephalothin, but he recovered coincident with the administration of gentamicin and erythromycin. The diagnosis was established serologically by a 32-fold rise in antibody titer to the agent of Legionnaires' disease. Similar illness did not affect others in his community, and infection in four family members was excluded clinically and serologically.

Antibodies, Bacterial

Legionnaires' disease in pneumonia patients in Iowa. A retrospective seroepidemiologic study, 1972-1977.

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.

Adolescent