Leptospirosis, brucellosis, plague and Q fever

• Leptospirosis, brucellosis, plague and Q fever are four zoonoses caused by unrelated bacteria. They share a pattern: an animal reservoir, an environmental or occupational exposure, an acute febrile illness, and a need for specific antibiotics and public health action.
• Leptospirosis is spread in animal urine, often through contaminated water or soil. It is the most common zoonotic infection worldwide and can range from a self-limiting fever to Weil disease with multiorgan failure. ^[1][7]
• Brucellosis is acquired from infected animals or unpasteurised milk products. It causes undulant fever, sweats, arthralgia and focal disease, and it needs weeks of combined antibiotics. ^[3][2]
• Plague is a flea-borne disease of rodents, usually presenting as painful bubonic lymphadenitis; pneumonic plague spreads from person to person and can kill within 24 hours. ^[4][9]
• Q fever is an airborne infection from birth products and excreta of infected livestock; most people recover without antibiotics, but chronic Q fever endocarditis requires months of treatment. ^[6][10]
• In every suspected case the exposure history tells you which disease to test for and treat, and local public health authorities should be notified. ^[5]

By the end of this page you should be able to:

1. Take an exposure history that points to one of these four infections.
2. Recognise the typical presentation, course and complications of each.
3. Choose the right test for the stage of illness and the organism.
4. Give the correct antibiotic, dose, route and duration for each infection, including the adjustments for children and pregnancy.
5. Know when to notify public health, and how to protect staff and contacts.

These four infections are not a natural group by organism, but they are commonly taught together because they are zoonoses: infections of animals that reach humans accidentally. ^{[7][8][9][10]}

• Leptospirosis is acute infection with pathogenic Leptospira spirochaetes. Mild disease is an influenza-like illness; severe disease is called Weil disease when it includes jaundice and renal impairment, and it can include pulmonary haemorrhage. ^[1][7]
• Brucellosis is infection with Brucella species. The four species of greatest human importance are B. melitensis (from sheep and goats), B. suis (from pigs), B. abortus (from cattle) and B. canis (from dogs). B. melitensis and B. suis are the most pathogenic. ^[3][8]
• Plague is infection with Yersinia pestis. The main clinical forms are bubonic, septicaemic and pneumonic plague. ^[4][9]
• Q fever is infection with Coxiella burnetii. It presents as an acute self-limited febrile illness, pneumonia or hepatitis, and in some patients it becomes chronic, especially endocarditis. ^[6][10]

All four are underdiagnosed and underreported, and the true burden is larger than recorded case numbers suggest. ^[1][2]

• Leptospirosis occurs worldwide and is most common in tropical and subtropical climates. An estimated 1 million cases occur globally each year, with nearly 60,000 deaths. ^[1]
• Brucellosis is found globally, is reportable in most countries and is one of the most widespread zoonoses. Human-to-human transmission is very rare. ^[2][3]
• Plague persists in natural foci on every continent except Oceania, with human cases in recent years mainly in Africa, particularly Madagascar and the Democratic Republic of the Congo. ^[4]
• Q fever has a worldwide distribution except New Zealand, and it is reportable in the United States. ^[6][10]

Incubation periods differ and help with diagnosis:

Leptospirosis: 5 to 14 days (range 2 to 30 days) per CDC; the Merck Manual gives 2 to 20 days (usually 7 to 13). ^[1]

• Brucellosis: highly variable, from 1 week to 2 months, usually 2 to 4 weeks (WHO); the Merck Manual gives an average of 2 weeks (range 5 days to several months). ^[2]
• Plague: 1 to 7 days. ^[4]
• Q fever: usually 2 to 3 weeks (not given in the sources used here; the acute illness is most often recognised by exposure and serology).

The exposure history is the single most useful diagnostic step for these four diseases. ^[1][3][4][6]

Ask every patient with an unexplained acute febrile illness:

1. Water and soil. Did you swim, wade or work in fresh water or wet soil after heavy rain or flooding? Did you drink untreated water? (Leptospirosis.) ^[1]
2. Raw animal products. Did you drink unpasteurised milk or eat fresh (unpasteurised) cheese, especially from sheep or goats? Have you handled raw meat or offal? (Brucellosis and, less often, plague.) ^[2][3]
3. Animals and birth products. Do you work with livestock, especially sheep, goats and cattle, particularly around parturition? (Q fever and brucellosis.) ^[2][6]
4. Rodents and fleas. Have you been in rural, rodent-infested or plague-endemic areas, or do you have a sick or dead rodent nearby? Have you been bitten by fleas? (Plague.) ^[5][4]
5. Occupation and travel. Are you a veterinarian, abattoir worker, butcher, hunter, farmer, laboratory worker or wildlife worker? Have you travelled to a region where these diseases are common? (All four.) ^[2][3][6]

People at particular risk are those who work with animals and are in contact with blood, placenta, fetuses and uterine secretions, as well as hunters and laboratory workers. ^[2][3]

• Leptospira are long, thin, motile spirochaetes, classified into more than 300 pathogenic serovars. They survive for weeks to months in fresh water and wet soil in warm areas. ^[1]
• Brucella are small, aerobic, intracellular coccobacilli shed in urine, milk, placental fluid and other fluids. ^[8]
• Yersinia pestis is a Gram-negative coccobacillus. Humans are accidental hosts in a cycle shared with rodents and fleas. ^[5][9]
• Coxiella burnetii is a strictly intracellular Gram-negative bacterium. It is excreted in birth products, urine, faeces and milk, and it survives in dust. ^[6][10]

Pathogenic leptospires colonise the renal tubules of reservoir animals and are shed in urine. Humans are infected when contaminated water or soil contacts mucous membranes or broken skin, and through ingestion. Most infections are mild and self-limited, but in some patients the organism spreads to involve the kidneys, liver, lungs and meninges. ^[1][7]

Brucella are intracellular pathogens of the reticuloendothelial system. They enter through mucous membranes, skin breaks, the conjunctivae or the gut, then persist in macrophages. Relapses are common when treatment is too short, and the illness can become chronic or focal. ^[2][3][8]

Infected fleas deposit Y. pestis into the skin. The organism travels to the draining lymph node, which becomes an inflamed, painful bubo. From there it can enter the bloodstream (septicaemic plague) or the lungs (secondary pneumonic plague). Primary pneumonic plague follows inhalation of respiratory droplets from an infected person or animal. ^[4][5][9]

C. burnetii is most often acquired by inhaling aerosols from contaminated dust, especially around parturient animals. Many infections are asymptomatic; symptomatic patients develop a self-limited febrile illness, pneumonia or hepatitis, and a minority progress to chronic infection, most importantly endocarditis. ^[6][10]

The disease has a wide spectrum. Many patients are asymptomatic. Others have an influenza-like illness with fever, headache, myalgia, chills, nausea, vomiting, diarrhoea and abdominal pain. Conjunctival suffusion (redness of the conjunctiva without purulent discharge) is a useful sign. ^[1]

Untreated disease can progress to kidney failure, jaundice, respiratory distress or failure, liver failure and meningitis. In 5 to 10% of cases (CDC) or 5 to 15% in patients with jaundice (Merck Manual; can exceed 50% in severe disease) multiorgan failure and death can occur. Severe Weil disease combines jaundice with renal impairment and bleeding. ^[1]

Leptospirosis is often confused with other acute febrile illnesses, malaria, viral hepatitis, dengue and meningitis, which is why the exposure history matters so much. ^[1]

Brucellosis is usually a subacute or chronic febrile illness with fever, fatigue, night sweats, headache, myalgia, anorexia or weight loss and arthralgia. The fever can be undulant, rising and falling over weeks. Hepatomegaly and splenomegaly are common, and focal disease includes endocarditis and meningitis. ^[3][2]

Brucellosis very rarely kills: no more than 2% of all people with brucellosis die from the infection. ^[3]

Bubonic plague is the most common form. It begins suddenly with fever, chills, headache and body aches, followed within days by a painful, swollen lymph node (bubo), often in the groin, armpit or neck. ^[4]

Pneumonic plague presents with severe respiratory symptoms: shortness of breath and cough, often with blood-stained sputum. It is the most contagious form and can be fatal within 18 to 24 hours if untreated. ^[4][5]

Septicaemic plague occurs when Y. pestis multiplies in the blood. It can develop from either other form and can cause bleeding under the skin, cyanosis, tissue necrosis of the extremities, multi-organ failure and death. ^[4]

Many people with Q fever never become ill. Those who do usually develop a flu-like illness with fever, chills, fatigue and muscle pain; some develop pneumonia or hepatitis. Q fever is reportable in the United States, and C. burnetii is classed as a potential bioterrorism agent. ^[6][10]

A minority develop chronic Q fever, most often endocarditis on a damaged valve or in an immunocompromised host. Chronic Q fever is life-threatening and needs prolonged combination therapy. ^[6]

Acute febrile zoonoses overlap with common infections such as influenza, malaria, dengue, typhoid, typhus and viral hepatitis. The table lists features that point toward each of the four.

Diagnosis depends on how long the patient has been ill. Leptospiral DNA can be detected in blood, serum, urine or cerebrospinal fluid (if there are neurological signs) early in illness; later, an antibody response can be detected. CDC does not recommend testing asymptomatic people for leptospirosis. ^[1]

Brucellosis cannot be diagnosed from symptoms alone because they are non-specific. Laboratory confirmation is required. Most hospital laboratories run serological tests that detect antibodies to B. abortus, B. melitensis and B. suis; infection with B. canis or the B. abortus RB51 vaccine strain cannot be detected by serology and must be confirmed by culture. Two serum samples taken a few weeks apart may be needed; if this is not possible, a single sample can support a probable diagnosis. ^[3]

Because culture and isolation are hazardous, the laboratory must be told that brucellosis is suspected. ^[3]

Confirmation requires laboratory testing. The preferred specimen is pus from a bubo, blood or sputum, with antigen detection, microscopy and culture. ^[4]

The diagnosis is usually clinical and epidemiological at first, because the symptoms mimic many other illnesses. Blood tests confirm infection; laboratory confirmation can take weeks, so treatment for high-risk or symptomatic patients is started before results are available. ^[6]

All four infections produce non-specific inflammatory changes. Tests such as full blood count, liver function, renal function, blood cultures and inflammatory markers support assessment but are not diagnostic in any single patient.

There is no formal scoring system for any of these four infections in the sources used. Classification is clinical:

• Leptospirosis: mild influenza-like illness versus severe disease (multiorgan failure, pulmonary haemorrhage, or Weil disease). ^[1][7]
• Brucellosis: uncomplicated versus focal or chronic disease (endocarditis, neurobrucellosis, spondylitis, hepatic or renal involvement). ^[3][2]
• Plague: by site (bubonic, septicaemic, pneumonic) and by severity. ^[4][9]
• Q fever: acute versus chronic; chronic disease is defined by persistence of organisms and serological evidence of chronic infection, most often endocarditis. ^[6]

For a patient with high clinical suspicion, start antibiotics as soon as possible without waiting for laboratory results. ^[1]

Mild disease (oral): doxycycline is the drug of choice, 100 mg orally twice daily for 7 days in adults (CDC; the Merck Manual gives 5 to 7 days); children 2 mg/kg per day in two equally divided doses, not exceeding 200 mg per day, for 7 days. Alternatives are azithromycin 500 mg orally once daily for 3 days, ampicillin 500 to 750 mg orally every 6 hours for 7 days, or amoxicillin 500 mg orally every 6 hours for 7 days. ^[1]

Severe disease (intravenous): IV penicillin is the drug of choice, 1.5 million units IV every 6 hours, or ceftriaxone 1 g IV every 24 hours. ^[1]

There are no standard CDC post-exposure prophylaxis recommendations for asymptomatic contacts of leptospirosis; any decision is made case by case. ^[1]

Start treatment once the diagnosis is confirmed by laboratory testing, to help prevent chronic arthritis, endocarditis, chronic fatigue, depression and swelling of the liver or spleen. ^[3]

Standard regimens differ between guidelines, and both are in current use:

• WHO: doxycycline 100 mg twice daily for 45 days plus streptomycin 1 g daily for 15 days (WHO fact sheet) or 14 days (Merck Manual); or doxycycline 100 mg twice daily for 45 days plus rifampicin 15 mg/kg/day (600 to 900 mg) for 45 days. Streptomycin may be substituted with gentamicin 5 mg/kg daily for 7 to 10 days. ^[2]
• CDC: doxycycline and rifampin for at least 6 weeks for infections with B. melitensis, B. abortus, B. suis and B. canis. Rifampin must not be used for B. abortus RB51 infection because that strain is resistant to it; use trimethoprim-sulfamethoxazole instead. Other options such as trimethoprim-sulfamethoxazole can also be used when there are contraindications such as drug allergy or pregnancy. ^[3]

Treatment of brucellosis in children under 8 years is not settled, and WHO lists trimethoprim-sulfamethoxazole combined with an aminoglycoside (streptomycin or gentamicin) or rifampicin as an option. ^[2]

Start antibiotics as soon as plague is suspected; do not wait for diagnostic test results. ^[5]

Gentamicin and the fluoroquinolones are first-line in the United States, and the following agents are recommended: ^[5]

• Pneumonic or septicaemic plague in adults: ciprofloxacin 400 mg every 8 hours IV, or 750 mg every 12 hours by mouth; levofloxacin 750 mg every 24 hours; moxifloxacin 400 mg every 24 hours; gentamicin 5 mg/kg every 24 hours; streptomycin 1 g every 12 hours; doxycycline 200 mg loading dose then 100 mg every 12 hours. ^[5]
• Bubonic or pharyngeal plague: the same agents with adjusted routes, plus doxycycline as above. ^[5]
• Duration of treatment is 10 to 14 days, longer if fever persists. ^[5]

Children receive weight-based doses of the same agents, and agents such as streptomycin and gentamicin are dosed by weight. ^[5]

Post-exposure prophylaxis is given for 7 days to people with known exposure: close, sustained contact (CDC: less than 6 feet, about 1.8 m) with a patient with pneumonic plague, or direct contact with infected body fluids or tissues. Recommended prophylaxis is ciprofloxacin, levofloxacin, moxifloxacin or doxycycline at the doses listed by CDC. ^[5]

Healthcare workers in direct contact with pneumonic plague patients should receive chemoprophylaxis for 7 days, or for as long as they are exposed. ^[4]

Most asymptomatic patients and those who have recovered do not need treatment. ^[6]

Acute Q fever: doxycycline 100 mg every 12 hours for 14 days in adults; children 8 years or older 2.2 mg/kg (up to 100 mg) every 12 hours for 14 days. The same 14-day doxycycline course is recommended by CDC for children under 8 years at high risk (hospitalised, severe illness, pre-existing heart valve disease, immunocompromised, or illness already present for more than 2 weeks); the Merck Manual gives 10 days for high-risk children. For children under 8 years with mild, uncomplicated illness, doxycycline 2.2 mg/kg (up to 100 mg) every 12 hours for 5 days is recommended, with a switch to trimethoprim-sulfamethoxazole if fever persists beyond 5 days. ^[6]

Pregnant women with acute Q fever should receive trimethoprim-sulfamethoxazole 160 mg/800 mg every 12 hours throughout pregnancy, not beyond 32 weeks gestation; specialist advice is needed after 32 weeks. ^[6]

Doxycycline works best if started within the first 3 days of symptoms. ^[6]

Chronic Q fever (for example, endocarditis or vascular infection) requires doxycycline 100 mg every 12 hours plus hydroxychloroquine 200 mg every 8 hours: at least 18 months for endocarditis or vascular infection, and an individualized duration for other organ disease, guided by serology and symptoms. ^[6]

• Leptospirosis: renal failure, hepatic failure, pulmonary haemorrhage, meningitis and multiorgan failure. ^[1][7]
• Brucellosis: endocarditis, meningitis, chronic fatigue, arthritis, hepatosplenomegaly and abscess formation. ^[2][3]
• Plague: post-mortem tissue necrosis and cyanosis in septicaemic disease, pneumonia and shock. ^[4][9]
• Q fever: chronic endocarditis or vascular infection, especially on damaged valves or in immunocompromised patients and after pregnancy. ^[6]

Untreated leptospirosis causes multiorgan failure in 5 to 10% of cases (CDC) or 5 to 15% in patients with jaundice (Merck Manual; can exceed 50% in severe disease). ^[1] Untreated brucellosis has a mortality of 2% or less, but illness can be prolonged. ^[3] Plague is fatal in 30 to 60% of untreated bubonic cases and in all untreated pneumonic or septicaemic cases. ^[4] Acute Q fever is usually self-limited, but chronic Q fever is serious and prolonged. ^[6]

Prevention is different for each, but some measures apply to all: avoid unpasteurised milk and products, protect against flea bites and rodent exposure, use protective equipment when handling livestock birth products, and pasteurise milk. ^[2][4][6]

• Leptospirosis: avoid wading or swimming in potentially contaminated water, especially after flooding; protect skin and wounds; control rodents. ^[1]
• Brucellosis: elimination of infection in animals; vaccination of cattle, goats and sheep in enzootic areas; pasteurisation of milk and cheese; protective barriers for agricultural and slaughterhouse workers. ^[2]
• Plague: avoid handling animal carcasses; flea and rodent control; inform communities when zoonotic plague is present. WHO does not recommend vaccination except for high-risk groups such as laboratory staff and healthcare workers. ^[4]
• Q fever: reduce contact with livestock during parturition, avoid raw milk, and note that no Q fever vaccine is available in the United States. ^[6]

Notification: brucellosis is a reportable and nationally notifiable condition in the United States. ^[3] Q fever is reportable in the United States. ^[10] Plague should be notified to local and state health departments immediately, and patients with pneumonic plague must be isolated to prevent spread. ^{[5] [4]}

• Pregnancy. For Q fever, acute disease in pregnancy is treated with trimethoprim-sulfamethoxazole as above; chronic Q fever in pregnancy should be managed by an infectious diseases and obstetric specialist. ^[6] For brucellosis, the optimal treatment of pregnant women is not yet determined. ^[2] For plague, specialist advice is needed. For leptospirosis, standard regimens are generally used but specialist advice is prudent.
• Children. Doses for all four are weight-based, and doxycycline is recommended by CDC for even young children with Q fever because short courses do not stain permanent teeth. ^{[6] [5] [1]}
• Immunocompromised and valvular disease. These patients are the ones who develop chronic Q fever endocarditis. ^[6]

• A careful history and examination, rather than tests, make the diagnosis in most settings. ^[4]
• Oral doxycycline covers leptospirosis and brucellosis (with rifampin) and can be started presumptively when the clinical picture fits and tests are unavailable. ^[1][2][3]
• Keep basic infection-control measures: standard precautions, droplet precautions for pneumonic plague, and prompt reporting of suspected cases. ^[4][5]
• Pasteurisation of milk and simple rodent and flea control are the most effective community measures. ^[2][4]

• These four infections are zoonoses; the exposure history is the diagnostic key. ^[1][3][4][6]
• Leptospirosis is the most common zoonotic infection worldwide and ranges from a mild fever to multiorgan failure (5 to 10% of cases (CDC) or 5 to 15% in patients with jaundice (Merck Manual; can exceed 50% in severe disease)). Treat mild disease with oral doxycycline for 7 days (CDC; 5 to 7 days in other references); severe disease with IV penicillin or ceftriaxone. ^[1][7]
• Brucellosis is a chronic febrile illness spread by unpasteurised milk and animal contact. It needs combined therapy for at least 6 weeks (CDC) or 45 days (WHO regimen). ^[2][3]
• Plague is flea-borne, presents as bubonic or pneumonic disease, and must be treated immediately with gentamicin or a fluoroquinolone; pneumonic plague is rapidly fatal and contagious. ^[4][5]
• Q fever is airborne from livestock. Acute disease is treated with doxycycline for 14 days; chronic endocarditis needs doxycycline plus hydroxychloroquine for at least 18 months. ^[6]
• Notify public health for suspected cases; protect contacts with chemoprophylaxis where indicated. ^[5][4]
• WHO does not recommend plague vaccination except for high-risk groups; no Q fever vaccine is available in the United States. ^[4][6]

• Sepsis and septic shock
• Fever of unknown origin
• Community-acquired pneumonia
• Infective endocarditis
• Acute kidney injury
• Travel medicine and immunisation
• Meningitis