A family of four owns and operates a sheep ranch near Ennis, Montana. They also keep a few goats, which serve primarily to help mow the lawn around their house because the family doesn't drink goat's milk. However, their 16-year-old son learns something about how cheeses are made in his high school biology course, finds this interesting, and looks for additional information on the internet. He finds detailed instructions for making a soft cheese (like cottage cheese) from goat's milk, so the family decides to try this, using their own readily available source of raw goat's milk. (NOTE: Throughout human history, in many places it has been traditional to milk goats from the rear, not from the side as with cows, so that there are potentially some additional issues for this case.) The cheese is ready to eat after about two weeks, and everyone in the family tries it. They decide that the cheese is basically "OK" (and they eventually eat all of it) but not worth the trouble to make it on a regular basis.

About two months after the cheese-making incident, everyone in the family begins to experience malaise, chills, sweats, fatigue, weakness, myalgias, slight weight loss, arthralgias, and a non-productive cough. They also develop fever, which seems to come and go almost on a daily cycle, rising in the afternoon and falling during the night. These symptoms persist for three weeks without diminishing, so the family decides to visit their physician. By then, the father (who is 42 years old) and the daughter (who is 14) are experiencing lower back pain in addition to the other symptoms. Their vital signs are normal except for fever. On physical examination, all of the family members are found to have extensive tender lymphadenopathy. The mother (who is 40 years old) and the son also have splenomegaly, while the father and son have testicular tenderness that might be indicative of epididymo-orchitis. There are no other remarkable findings. The physician knows that the family has a sheep ranch, but she doesn't know about the goats. The family doesn't mention them when the physician takes a detailed history because they don't connect the cheese-making incident with their disease.

Question 2.1: What is your preliminary diagnosis?

The symptoms are not particularly helpful with respect to making a specific diagnosis. The family basically appears to have a "fever of unknown origin," in which case the differential includes many febrile conditions without localizing manifestations (e.g., tuberculosis, endocarditis, autoimmune disease, brucellosis, malaria, typhoid fever, and several others).

Question 2.2: What tests should you perform?

Cultures of blood, bone marrow, and/or lymph nodes should be ordered, in hopes of identifying a causative agent. A CO2 detection system (such as BACTEC) is recommended for blood cultures, as it may yield results more rapidly than some other culture methods. However, one must tell the lab what unusual agents to look for. Biopsies of bone marrow and/or lymph nodes might be examined to look for granulomas. The usual CBC with differential might also be helpful.

Test Results:

The CBC indicates that the WBC count is a little low, although not markedly so. The other CBC results are unremarkable. A biopsy sample of bone marrow reveals the presence of noncaseating granulomas.

After about three weeks, the lab reports that the blood and bone marrow cultures are positive for Brucella melitensis.

Question 2.3: What is your final diagnosis and how is it confirmed?

Considering the identity of the bacterium cultured from blood and marrow samples, this family's "fever of unknown origin" is clearly a case of brucellosis. Further confirmation of this diagnosis probably isn't necessary, but a serum agglutination test (SAT) to detect antibodies to B. melitensis is available for this purpose.

Question 2.4: How does this causative agent produce disease?

Brucella is an intracellular parasite of the mononuclear phagocyte (reticuloendothelial) system. The organism is phagocytosed by macrophages and monocytes shortly after entering the human body. It is then carried to the spleen, liver, bone marrow, lymph nodes, kidneys, and other organs. Brucella can survive intracellularly because it inhibits polymorphonuclear leukocyte degranulation. Granulomas might form in all of the invaded organs, and destructive changes in these and other tissues occur in patients with advanced cases of brucellosis. Infection with Brucella often causes osteomyelitis of the lumbar vertebrae, starting at the superior end plate (a region with a rich blood supply) and occasionally progressing to involve the entire vertebra, disk space, and adjacent vertebrae.

The various species of Brucella that cause brucellosis vary in virulence. B. abortis and B. canis tend to produce a mild disease with rare suppurative complications, while B. suis causes the formation of destructive lesions and has a prolonged course. B. melitensis (the causative agent in this case) typically causes relatively severe cases. Its relatively high virulence might be due to the fact that it is more able to resist the bactericidal effects of serum and phagocytic killing than are other species of Brucella.

Question 2.5: What is the epidemiology of this disease?

Brucellosis occurs worldwide (>500,000 documented cases/year), but is relatively are in the U.S. (usually <100 cases/year). The disease results primarily from consumption of contaminated unpasteurized milk and other dairy products (such as homemade goat cheese in this case). Laboratory personnel are also at significant risk for infection through direct contact or inhalation of the bacterium. (Samples sent to the lab should carry a clear warning if the physician has any reason to suspect brucellosis.) The animal reservoir from which the disease is acquired depends on the Brucella species, as they infect different animals. B. abortus infects cattle; B. suis infects swine; B. canis infects dogs, foxes, and coyotes; and B. melitensis infects goats and sheep.

Question 2.6: How is this disease treated?

Single-antibiotic treatment and relatively short courses of treatment (i.e., less than 8 weeks) have been associated with relapses. As a result, it is now recommended that a combination of doxycycline and an aminoglycoside (gentamicin, streptomycin, or netilmicin) be given for 4 weeks, followed by a combination of doxycycline and rifampin for 4 to 8 additional weeks.

Question 2.7: How is this disease prevented?

Control of human brucellosis is accomplished primarily through control of the disease in domestic animals, which requires identification by serological testing and elimination of infected herds, and vaccination of healthy animals. (This is why the incidence rate in the U.S. is relatively low.) Avoidance of unpasteurized dairy products also helps to prevent cases in humans.