Brucellosis is an infectious disease caused by micro-organisms of the genus Brucella, transmitted to man from lower animals. The disease may be subclinical, subacute, acute, chronic, or relapsing, and infection may localize in various viscera and tissues, including the endocardium, bone marrow, biliary tract, liver, spleen, meninges, and eye.
Etiology.
Brucellae are small, gram-negative, aerobic, non motile and non-spore-forming coccobacilli. Three’ species, characterized by their affinity for a particular animal host, account for most human infections: Brucella abortus (cattle), Brucella melitensis (sheep and goats), and Brucella suis (pigs). A newly described species, Brucella canis, causes abortion in beagles and has, on infrequent occasions, been transmitted to humans in contact with infected dogs.
History.
Brucellae were first isolated by Bruce in 1887 from the spleens of British soldiers dying on the island of Malta. This disease, now known to have been caused by infection with B. melitensis, was contracted by drinking raw goat’s milk. Bang, in 1897 in Denmark, isolated a strain of the. species now designated B. abortus from cattle with infectious abortion. Traum ir. 1914 isolated the third species, B. suis, from an infected sow
Epidemiology.
Human brucellosis in the United States most commonly results from ingestion of raw milk or unpasteurized milk products from infected cattle. Infection also occurs in slaughterhouse workers, farmers, and veterinarians as a result of contact with infected meat or infected placentas of cattle, pigs, goats, and sheep. Although species affinities of brucellae are usually maintained, pigs may be infected with and spread B. melitensis, as well as B. suis.
Up to 5 per cent of cattle and 1 to 2 per cent of swine in this country are infected. In countries that utilize sheep and goats more extensively, these animals constitute the predominant sources of infection. In the case of ingested dairy products, the organism penetrates the gastrointestinal mucosa; with direct contact the organism enters through breaks in the skin or the conjunctiva. It presumably may also be inhaled, because brucellae have been isolated from the air of a slaughterhouse where infected animals were killed, and infection is readily transmitted to laboratory animals by aerosol. Many persons have become infected with the organism in the laboratory, and one laboratory accident involving apparent airborne spread has been described. Brucellae are destroyed in milk and milk products by pasteurization; otherwise, they may remain viable in refrigerated milk for 10 days and in cheese up to 90 days. They may persist in meat for several weeks.
Pathogenesis and Pathology
After penetration of skin or mucous membranes, the organisms spread via lymphatics to regional nodes and thence to thoracic duct and the blood stream. Hematogenous dissemination leads to localization in spleen, bone marrow, liver, kidneys, endocardium, and elsewhere. In cattle, swine, sheep, and goats, organisms also localize in mammary glands, male and female genital organs, and in the pregnant uterus, fetal fluids, and membranes, causing abortion. Correlated with genital, uterine, and fetal infection is the finding, in these tissues, of a 4-carbon, polyhydric alcohol, erythritol, which promotes the growth of brucellae. Although erythritol is apparently not present in the human testicle, orchitis is, paradoxically, a complication of human brucella ’infection. Erythritol is not present in human placentas, and brucellosis is not associated with abortions in humans.
Characteristically, Brucella infections are granulomas consisting of foci of lymphocytes, epithelioid cells, plasma cells, and multinucleated giant cells. In severe cases, caseation necrosis and abscess formation may occur, a finding most characteristic of infection with B. suis. The brucellae are found within monocytes. In this location they are apparently protected, to a degree, against bactericidal antibodies and are altered in their susceptibility to some antimicrobial drugs. This property may be related to the phenomenon of chronicity, yet monocytes in animals previously infected with Brucella have an increased capacity to destroy the organisms, presumably as an expression of “cellular” immunity.
Clinical Manifestations.
The incubation period varies from a few days to a few weeks or even months. Onset may be insidious with nonspecific findings such as low-grade fever, headache, weakness, joint pains, insomnia, sweats, and low back pain. Less commonly, onset may be abrupt with high fever, chills, and prostration, but with few localizing signs. It is probable that fever and some of the other acute manifestations of infection are an effect, at least in part, of Brucella endotoxin, which resembles endotoxin from other gram-negative bacteria. Some lymphadenopathy occurs in about one half of cases, and splenomegaly occurs in about one third, usually in the more severely ill. Some exposed persons develop no detectable illness or mild symptoms not distinguishable from other common illnesses. Such patients usually develop agglutinins and, rarely, patients with few symptoms have been found to have positive blood cultures.
Brucellosis has been diagnosed occasionally in patients with Hodgkin’s disease and other forms of reticuloendothelial neoplasia. Apparently, when such neoplastic processes affect patients with Brucella infection, the neoplasia may interfere with immunity and lead to dissemination of the organism from localized foci of infection.
Infrequent but severe complications of brucellosis include meningoencephalitis, spondylitis, endocarditis, orchitis, pancytopenia, nephritis, hepatic and splenic suppuration, cholecystitis, arthritis, and uveitis. When the complication is the presenting complaint, as is sometimes the case, the diagnosis of brucellosis may not be suggested. For that reason the varied involvement possible with this disease should be kept in mind. Careful questioning will usually elicit a history consistent with exposure to infection with this organism.
The initial illness may persist a few days or a few weeks, and improvement may be followed by one or more relapses. Renewed physical activity may provoke relapse. The accompanying figure illustrates the course of a patient with acute B. melitensis infection who responded to treatment with oxytetracycline. Her disease relapsed a few weeks later but was successfully re-treated with the same drug. In untreated cases, disability for a year or more is not unusual. A few patients may have low fever, weakness, joint pains, mental depression, and other vague complaints for up to several years, in association with serologic evidence of infection. Such patients, usually designated as having chronic brucellosis, may show little response to antimicrobial treatment, and the mechanism of their illness is unclear.
Instances of chronic, recurrent, suppurative disease of liver or spleen of many years’ duration have also been described. The lesions often calcify with the passage of time, and calcific densities in roentgenograms of liver or spleen may be a clue to diagnosis. Such cases usually respond to treatment, although recovery is slow, and relapses may occur.
Diagnosis.
Definitive diagnosis will depend upon isolation of the organism from blood, bone marrow, or local sites of involvement. Cultures should be examined for growth every four to five days, and not be discarded before six weeks of incubation.
The organisms may be isolated in trypticase soy or tryptose phosphate broth; the primary isolation of B. abortus requires the presence of 10 per cent carbon dioxide. Virulent organisms possess a capsule and grow as small, glistening translucent colonies on agar. This property is gradually lost by cultivation on artificial media (smooth —*rough mutation). B. abortus is inhibited by methionine, whereas B. suis and 8. melitensis are inhibited by basic fuchsin and crystal violet. B. suis may be distinguished from the other species by production of H2S. Within species, patterns of metabolic activity and other characteristics permit the definition of several “biotypes,” which may be of value in epidemiologic work.Cross-reacting agglutinating antibodies are formed in response to two principal antigenic determinants common to virulent strains of the three major species.
Studies suggest that the antigens are specific, surface polysaccharides. They are designated M and A (M for melitensis, which predominates in this species, and A for abortus. which predominates in B. abortus and B. suis). These characteristics permit serologic differentiation of B. melitensis from the other two species.
Agglutinating antibody is usually present by the time the patients are first seen. Titers of 1:80 or greater are indicative of past or present infection. There is considerable variation in the titer of agglutinating antibody in both acute and chronic brucellosis; in addition, in some cases, lower dilutions of serologic tests will not show agglutination when higher dilutions are positive (prozone reaction). This reaction is caused by incomplete or blocking antibodies, and can be avoided by using 5 per cent sodium chloride or albumin solution as a diluent instead of physiologic, saline.
An intradermal skin test is available utilizing several preparations of Brucella antigen. It is of the delayed hypersensitivity type, and has about the same significance as the tuberculin test. As positive skin tests are frequent in endemic areas, the test is of little value in diagnosis of individual cases; moreover, the test may elicit a low titer of circulating Brucella agglutinins.
Differential Diagnosis.
Acute febrile brucellosis must be differentiated from diseases whose onset is associated with fever but without localizing signs. These include influenza, other viral respiratory infections, infectious mononucleosis, early stages of infectious hepatitis, malaria, typhoid, primary histoplasmosis, disseminated tuberculosis, and lymphoma.
Chronic brucellosis may simulate psychoneurosis, anxiety states, and mental depression. Except in infrequent cases when serum agglutinins are not detected because of prozone reactions and blood cultures are negative, it is usually possible to discover laboratory evidence of Brucella infection, and the diagnosis should not be made without such evidence. The skin test should not be depended upon for
diagnosis of brucellosis.
Treatment
Tetracycline and its derivatives are usually effective in relieving the acute manifestations of the infection Tetracycline 0.5 gram four times daily for a period of 21 days, is recommended for uncomplicated Brucella infection in adults. Some patients in the first few hours of treatment will have a Herxheimer-like reaction characterized by increased fever, weakness, hypotension, and generalized discomfort. These clear spontaneously and, in the author’s experience, have not been a serious problem. In more severe cases streptomycin, 0.5 gram twice daily, may be given during the first two weeks of tetracycline treatment. Relapses can be re-treated on the same regimen as was used initially. In patients with the rare but serious complication of pancytopenia, steroids, such as prednisone, 40 to 50 mg. per day, should be given for the first seven to ten days of antimicrobial treatment. Steroids may also be beneficial in relieving the prostration of more severely ill patients.
Prognosis.
Most acute cases of brucellosis respond to a course of antimicrobial therapy with a prompt and lasting recovery. Relapse may occur one or more times in about 5 per cent of cases treated 21 days or longer, but responds to retreatment. There is some evidence that there may be residual damage in patients with Brucella nephritis. In untreated brucellosis, the mortality is less than 2 per cent, and the majority of the patients make a complete recovery within three to six months. There remains a group, however, approximately one fifth of those infected, in whom .relapsing disease is present for a year or more.
As the individual episodes are usually acute, although milder than the original attacks, this protracted course of acute brucellosis is not easily confused with so-called “chronic brucellosis.” Chronic brucellosis is a syndrome that is not well understood, and its variable and relatively mild symptomatology may not respond to antimicrobial therapy. When a basis for treatment exists, i.e., history of possible exposure, symptomatology consistent with the infection, and serologic (or cultural) evidence of infection, it is reasonable to give antimicrobial treatment. If relapse occurs, re-treatment may be given once or twice. Thereafter, barring the presence of localized foci of infection, the illness is probably not related to brucellosis infection, and no more antimicrobial treatment should be given.
Prevention.
There is a continuing and successful effort to reduce brucellosis in cattle and swine populations. The ultimate eradication of the disease in man depends upon the success of this effort. As the disease is spread principally through milk and milk products, it is essential that all milk be pasteurized not only for use in fluid form, but in cheese, creams, and other dairy products. At present there is no acceptable vaccine or other method to prevent infection in slaughterhouse workers, farmers, veterinarians, and laboratory workers dealing with this agent.
