Brucellosis (Brucella): The Intracellular Cause of Undulant Fever, and How It Is Diagnosed

A farmer in a rural area develops a fever that rises and falls in waves over several weeks, along with drenching night sweats, joint pains, and fatigue. He has been treated for malaria more than once with no improvement. He drinks fresh, unpasteurized milk from his own goats. The pattern of a relapsing fever that does not respond to antimalarials, in someone with animal or raw-dairy exposure, points to brucellosis.

Brucellosis is one of the most common infections passed from animals to humans worldwide, yet it is easily missed because its wavering fever mimics malaria and many other illnesses. The organism behind it, Brucella, has a defining trick: it survives inside the body's own immune cells. This page is about how that intracellular life explains the whole disease, and how brucellosis is diagnosed.

Introduction

Brucella is a small Gram-negative coccobacillus and the cause of brucellosis, one of the world's most widespread zoonoses (diseases passed from animals to humans). Humans are an accidental host: the organism's natural home is livestock, and people are infected by contact with infected animals or their products, above all unpasteurized dairy.

Brucellosis is known by many names that hint at its features and history: undulant fever (for the fever that rises and falls in waves), Malta fever and Mediterranean fever (for where it was first studied), and Bang's disease. It was first isolated by the British army doctor David Bruce, after whom the organism is named.

Two facts make brucellosis important and easy to miss. Its wavering fever closely mimics malaria and other febrile illnesses, so it is frequently misdiagnosed, especially in tropical regions. And the organism is a serious laboratory biohazard, one of the most common causes of laboratory-acquired infection, so a suspicion of brucellosis changes how the specimen must be handled (below).

What Brucella looks like

Figure 1: Brucella appearing as faintly staining gram-negative coccobacilli

Brucella is a small, non-motile, non-capsulated Gram-negative coccobacillus that often stains faintly (a weak, sometimes hard-to-see Gram-negative). It is:

• Strictly aerobic (some species need added CO₂ to grow), catalase-positive, and oxidase-positive.
• Slow-growing and fastidious, which is why culture takes weeks (below).
• An intracellular organism, able to survive and multiply inside the host's macrophages.

The species and their animal hosts

Brucella species are named by the animal they mainly infect, and the animal reservoir predicts the human risk. The four main human pathogens:

• Brucella melitensis (goats and sheep): the most pathogenic and the commonest cause of human brucellosis.
• Brucella abortus (cattle): causes abortion in cattle, hence the name.
• Brucella suis (pigs).
• Brucella canis (dogs).

The severity roughly follows the species: B. melitensis causes the most serious human disease, B. abortus generally milder.

How people get brucellosis

Humans are infected in three main ways, each with a portal of entry:

• Ingestion: eating undercooked meat or, most importantly, consuming unpasteurized dairy (milk, soft cheese). Entry is through the digestive tract. This is the commonest route in most settings.
• Direct contact: the organism enters through skin cuts or mucous membranes during contact with infected animals or their tissues, an occupational risk for farmers, veterinarians, and slaughterhouse workers.
• Inhalation: breathing in aerosols containing the organism, a risk in farms, slaughterhouses, and, notably, laboratories.

Person-to-person spread is rare. The occupational and dietary pattern, farmers, abattoir and veterinary workers, and raw-dairy consumers, is the epidemiological signature of brucellosis.

Virulence factors and how Brucella causes disease

Brucella has no exotoxins and a poorly understood set of virulence factors. Its power comes almost entirely from one strategy: surviving inside the host's own cells.

Survival inside macrophages (the key factor). When Brucella is engulfed by macrophages, most bacteria would be destroyed. Brucella instead survives and multiplies inside them. This intracellular life is the master fact of the disease, and almost everything clinical follows from it:

• Because the organism hides inside cells, antibodies (which act outside cells) cannot easily reach it. This is why the infection persists and relapses, and why antibody tests confirm exposure but the organism is hard to clear.
• Because macrophages carry it through the body, Brucella is delivered to the organs rich in these cells, the lymph nodes, liver, spleen, and bone marrow (the reticuloendothelial system).
• Because it lives inside cells, treatment needs antibiotics that penetrate cells and must be given for a long time and in combination, or the infection relapses.

Endotoxin (LPS). Its lipopolysaccharide is considered the main virulence factor in the classic sense, driving the fever and inflammation. There are no exotoxins.

Granuloma formation. In the organs it seeds, the immune response to the intracellular organism forms granulomas (collections of immune cells, including epithelioid and giant cells), which can progress to abscesses. This granulomatous response is why brucellosis can cause chronic, localized disease in bone, liver, or spleen.

Putting it together

The sequence explains the undulant fever. Brucella enters (usually via raw dairy), is taken up by macrophages, and survives inside them instead of being killed. The macrophages carry it into the blood (bacteremia, causing a fever spike) and seed the liver, spleen, lymph nodes, and bone marrow. The immune system brings the bacteremia down (fever falls), but organisms sheltering inside cells and granulomas survive and later re-enter the blood (fever rises again), producing the classic wavering, relapsing "undulant" fever. The same intracellular hiding is why the disease becomes chronic and why it is so hard to cure without prolonged, cell-penetrating combination therapy.

Laboratory diagnosis

First, a safety warning

Brucella is a Hazard Group 3 organism and one of the most common causes of laboratory-acquired infection, usually from inhaling aerosols or from accidental inoculation.

If brucellosis is suspected, the laboratory must be informed, and cultures must be handled in a biosafety cabinet with aerosol-generating steps minimized.

The diagnostic challenge

Because the organism hides inside cells and grows slowly, catching it is difficult, so diagnosis usually combines culture, serology, and sometimes PCR.

Figure 2: Brucella colonies in Blood Agar

Culture (definitive, but slow). Brucella can be grown from blood, bone marrow, or tissue. Two features matter:

• It is very slow-growing, so blood cultures must be held for up to 6 to 8 weeks before being called negative, far longer than routine cultures. The laboratory must be told to hold them.
• Bone marrow culture is more sensitive than blood, because that is where the organism concentrates. The classic Castañeda biphasic medium (solid and liquid in one bottle) was designed for it. Brucella grows on blood agar and chocolate agar but not MacConkey, as small, white, non-hemolytic colonies.

Figure: Brucella identification flow chart (Image source: Laboratory Response Network (LRN)

Serology (the practical mainstay). Because culture is slow and hazardous, most diagnosis is serological. The Rose Bengal test is the most widely used screening test, a rapid slide agglutination that is quick and simple; its procedure and limitations are on its own page. A positive screen is followed by a quantitative agglutination test, complement fixation, or ELISA. The antibody pattern helps stage the illness:

• IgM rises first (within 1 to 2 weeks), then IgG rises as the disease continues.
• In chronic brucellosis, IgG persists while IgM has disappeared, so a high IgG with absent IgM suggests long-standing infection.

PCR detects Brucella DNA in blood or tissue and is faster and safer than culture where available.

Treatment

Treatment of brucellosis follows directly from the organism's intracellular life, and the principle is the high-yield part. Because Brucella hides inside cells, treatment must use antibiotics that penetrate cells, must combine two drugs (single drugs relapse), and must be given for a prolonged course (weeks, not days). The classic combination uses doxycycline plus an aminoglycoside (or rifampicin). Using one drug, or too short a course, leads to relapse, which is the commonest treatment failure. Specific doses and durations are clinical decisions and are not covered here.

Prevention

Preventing human brucellosis rests on food hygiene and occupational hygiene, because those are the two routes in:

• Pasteurize dairy. The single most effective measure. All milk should be heat-treated, and raw milk and products made from it (soft cheese, ice cream) avoided.
• Cook meat thoroughly.
• Occupational protection for farmers, veterinarians, slaughterhouse workers, and laboratory staff (protective equipment, safe handling, informing the laboratory of suspected cases).
• Animal control: vaccinating and testing livestock reduces the reservoir at source. There is no routine human vaccine.

Controlling brucellosis in animals is ultimately how human disease is reduced, since humans are only an accidental host.

How to remember

It lives inside your cells, and that explains everything. Brucella survives inside macrophages. Hold that one fact and the whole disease follows: hiding from antibodies (so it relapses), riding macrophages to the liver, spleen, and marrow (where it seeds), needing cell-penetrating drugs in combination for weeks (or it relapses), and forming granulomas.

Undulant = up and down. The fever of brucellosis rises and falls in waves ("undulant"). Each wave is a burst of organisms leaving their cellular hideouts into the blood; each fall is the immune system beating the wave back before the next escape. The name describes the mechanism.

Think dairy and animals, and malaria that won't respond. A relapsing fever in someone with raw-milk or animal exposure, especially if "malaria" treatment has failed, should raise brucellosis. That clinical trigger is the exam and bench cue.

Tell the lab, and wait weeks. Two lab facts: warn the laboratory (it's a Hazard Group 3 biohazard and a classic lab-acquired infection), and hold blood cultures for 6 to 8 weeks because it grows so slowly. Slow to grow, dangerous to handle.

Species by animal, melitensis worst. The species are named by their animal host (melitensis goats/sheep, abortus cattle, suis pigs, canis dogs), and B. melitensis causes the most severe human disease.

Key exam facts in one table

Where students get confused

Why brucellosis relapses and is hard to cure. Because Brucella hides inside macrophages, where antibodies cannot reach it and where many antibiotics do not penetrate. This is why it needs cell-penetrating drugs, in combination, for weeks, and why single or short courses fail.

It mimics malaria. The wavering fever leads to repeated misdiagnosis as drug-resistant malaria, especially in the tropics. A relapsing fever with animal or raw-dairy exposure that does not respond to antimalarials should prompt thinking of brucellosis.

Cultures must be held for weeks. Brucella grows so slowly that a routine culture discarded at the usual time will be falsely negative. The laboratory must be told to hold blood cultures for 6 to 8 weeks.

Tell the laboratory, it is a biohazard. Brucella is one of the most common laboratory-acquired infections, from aerosols. A suspicion of brucellosis must be communicated so the lab handles it in a safety cabinet. Students often overlook that the diagnosis changes lab safety.

The species are named by animal host. melitensis (goats/sheep), abortus (cattle), suis (pigs), canis (dogs). B. melitensis is the most virulent in humans.

Serology stages the illness. IgM appears first; persistent IgG with absent IgM points to chronic disease. A single positive titer is interpreted with the clinical picture and exposure history.

References

1. Corbel, M. J. (1997). Brucellosis: an overview. Emerging Infectious Diseases, 3(2), 213–221. https://doi.org/10.3201/eid0302.970219
2. Głowacka, P., Żakowska, D., Naylor, K., Niemcewicz, M., & Bielawska-Drózd, A. (2018). Brucella: virulence factors, pathogenesis and treatment. Polish Journal of Microbiology, 67(2), 151–161. https://doi.org/10.21307/pjm-2018-029
3. Hayoun, M. A., Muco, E., & Shorman, M. (2023). Brucellosis. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK441831/
4. Tille, P. M. (2022). Bailey & Scott's Diagnostic Microbiology (15th ed.). Elsevier.