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A closer look at Bartonellosis
The term “fever of unknown origin” (FUO), coined in 1961, was initially defined as an illness of more than three weeks, during which fever higher than 38.3°C (101°F) was recorded on several occasions, remaining undiagnosed after one week of investigations in hospital. This definition has undergone some slight modifications throughout the years to reflect evolutionary changes in clinical practice.
According to data available from several industrialized countries, the prevalence of FUO in hospitalized patients is in the range of 2.5 to 3.0%. Reported causes of FUO exceed 200 and fall into diverse sub-specialty categories. Literature surveys show the distribution of FUO by diagnostic category to typically be the following: infections (28%), inflammatory diseases (21%), malignancies (17%), undiagnosed (19%) and miscellaneous (34%). In recent years, the share of malignancies seems to be increasing.
According to data retrieved from the Gideon diagnostic and reference web application, 55 zoonotic disease entities have been recorded - so far - as involved, worldwide, in FUO events. The leading zoonoses on the list, in ascending order of their recorded probability, are Campylobacteriosis, Brucellosis, Salmonellosis, Bartonellosis (Cat Scratch Disease and other Bartonella henselae infections), Toxoplasmosis, Relapsing fever, Leptospirosis, Lyme disease, Mycobacteriosis (miscellaneous nontuberculous) and Q-fever. The eventual diagnosis of such diseases, following their clinical and epidemiological investigations, is highly dependable upon laboratory involvement.
Bartonellosis, one of the most probable FUO causes among the zoonoses, is the subject of this month’s review. This bacterium causes cat scratch disease (CSD), also called Lymphoreticulosis benigna, Regional Granulomatous Lymphadenitis and Parinaud’s Oculoglandular Syndrome. The same disease agent causes Bacillary Angiomatosis.
Etiology
Cat scratch disease is, in most cases, caused by Bartonella henselae, a gram-negative rod which belongs to the family Bartonellaceae. There are two major serotypes/genotypes of B. henselae: type I (Houston I) and type II (BA-TF/Marseille). Strain variations are thought to exist within these serotypes.
Other human diseases caused by B. henselae include bacillary angiomatosis and peliosis hepatis, mainly in immunocompromised patients. Bacillary angiomatosis is also caused by B. quintana, a nonzoonotic pathogen carried by humans. B. henselae can cause endocarditis in people with pre-existing valve disease and is one of the prominent causes of FUO in humans.
Bartonella spp. found in animals and implicated in human disease include:
- B. vinsonii subsp. berkhoffii has been isolated from healthy dogs and coyotes. This species may cause endocarditis in people with pre-existing valve disease.
- B. vinsonii subsp. arupensis has been isolated from the blood of a cattle rancher with fever and heart valve disease. This organism can also be found in rodents.
- B. elizabethae, found in rodents, may cause endocarditis in humans.
- B. washoensis has been implicated in human cardiac disease. Rodents are probably the reservoir host.
- B. grahamii, found in rodents, may cause human uveitis.
All Bartonella species are very closely related and may cross-react in serologic assays.
In terms of geographic distribution, B. henselae occurs worldwide. B. henselae type 1 is more common in the eastern United States, where it represents approximately half of all isolates, than in the western states. Type 2 is the dominant serotype in Europe, and type 1 in Asia.
Transmission
B. henselae is probably transmitted between cats by cat fleas (Ctenocephalides felis). Experimental studies have shown that fleas, or the intradermal inoculation of flea feces, can spread the infection between cats. Transmission is reduced or absent when fleas are controlled. B. henselae has also been isolated from ticks but the role of this organism is unknown. Whether B. henselae can be spread among cats by other routes is unknown. Oral inoculation of infectious flea feces did not transmit the infection.
Transmission to humans is not completely understood. Cases of CSD are usually reported in people who have been scratched, bitten or licked by cats. It is possible that the source of infection is cat claws or teeth contaminated by flea feces. It has also been suggested, but not proven, that fleas may be able to transmit B. henselae directly to humans. In Parinaud’s oculoglandular syndrome, a form of CSD that affects the eye, the site of inoculation is thought to be the eyelid or conjunctiva, which may occur when patients rub their eyes after contact with a cat.
In up to 10% of cases there is no recognized cat contact.
Bartonella is a successful parasite of a wide range of mammals in that it usually causes no ill effects to its host. It is only when they get into the wrong host (eg humans) that disease is seen. Cats and other felids are thought to be the only reservoir hosts for B. henselae; naturally-infected bacteremic cats are asymptomatic. However, there have been suggestions that B. henselae may be involved in some chronic feline diseases.
Serologic studies suggest that 14%-70% of cats may carry B. henselae at some point in their lives. Kittens are more likely to be infected than adults. Bacteremia can last for months and, in some cats, up to several years. Relapsing bacteremia has been observed in some cats.
B. henselae has not been isolated from dogs. In some studies, experimentally-infected rodents have remained asymptomatic. When inoculated with large numbers of bacteria, the only lesion was granulomatous hepatitis.
Clinical signs
In humans, the incubation period in humans is usually three to 10 days, but may be as long as 20 days.
In immunocompetent people, B. henselae causes CSD, a mild to severe, self-limiting infection. The initial skin rash, seen in 25%-90% of patients, consists of one or more small erythematous papules, pustules, macules, vesicles or ulcers at the site of inoculation. One to four weeks later, one or more lymph nodes become enlarged; soon afterward, the skin lesions disappear. The affected lymph nodes are usually painful or tender and the skin over the nodes is warm, reddened and indurated. Occasionally, the nodes may suppurate. The lymphadenopathy usually lasts for a few weeks to a few months, but in some patients the lymph nodes have remained enlarged for up to two years.
Other common symptoms are a fever, malaise and fatigue. The fever usually disappears within two weeks but fatigue may persist for weeks or months. Less often, there may be headaches, anorexia, vomiting, nausea, weight loss, splenomegaly, generalized pain or a sore throat.
Complications and atypical presentations are reported to occur in 5% to 16% of patients:
- Parinaud’s oculoglandular syndrome occurs in 2%-6% of patients. This syndrome is characterized by nonpurulent unilateral conjunctivitis, conjunctival granuloma and periauricular lymphadenopathy. It usually resolves without permanent damage.
- Encephalitis has been reported in 1%-7% of patients with CSD. It usually occurs two to six weeks after the classic symptoms. Patients with CNS disease may take up to a year to recover.
- Cranial or peripheral nerve involvement may include myelitis, optic neuritis with transient unilateral blindness, facial nerve paresis or transient peripheral neuropathies. Patients with myelitis can be extremely weak, with abnormal reflexes, sensory loss and sphincter dysfunction.
- In people with existing heart valve abnormalities, B. henselae bacteremia can result in endocarditis.
- Disseminated disease occurs in fewer than 1% of patients. The usual signs are a persistent spiking fever, hepatosplenomegaly and abdominal pain.
- Other reported complications include transient nonspecific maculopapular or nodular rashes, thrombocytopenic purpura, osteolytic lesions, arthritis, synovitis and pneumonia.
B. henselae can also cause bacillary angiomatosis (epithelioid angiomatosis), a vascular proliferative disease of the skin and/or internal organs. This can occur in immunocompetent people, but is most often an AIDS-related disease. The most apparent symptoms are one to hundreds of cutaneous papules and nodules, varying in size from pinhead-sized to 10 cm in diameter. These should be differentiated from granulomas, Kaposi’s sarcoma (violaceous nodules) or lichenoid violaceous plaques. Bacillary angiomatosis can involve the internal organs, including the heart, brain, liver, spleen, larynx, lymph nodes and gastrointestinal tract.
As mentioned, B. henselae has been found in patients with FUO. It also causes Peliosis hepatis, a rare condition that may also be caused by other pathogens, drugs and toxins and is characterized by multiple blood-filled cysts and sinusoidal dilatation in the liver. Peliosis hepatis can be seen in some patients with bacillary angiomatosis.
B. henselae infections do not seem to be transmitted person-to-person by casual contact.
Diagnostic tests and treatment
B. henselae infections can be confirmed by culture of the organism, PCR or serology.
Isolation of B. henselae is difficult, but may be accomplished using specialized media. PCR can differentiate B. henselae from B. quintana, the other cause of bacillary angiomatosis.
Serologic assays include an indirect immunofluorescence assay and enzyme-linked immunosorbent assay (ELISA).
Cross-reactions occur with other species of Bartonella. Cross-reactions have also been reported with other organisms including Chlamydia spp. and Coxiella burnetti.
Although B. henselae is sensitive to a number of antimicrobials in vitro, antibiotics are not consistently effective for cat scratch disease.
In contrast, bacillary angiomatosis caused by B. henselae usually responds well to antibiotics.
Arnon Shimshony, DVM, is Associate Professor at the Koret School of Veterinary Medicine Hebrew University of Jerusalem, Rehovot, and is the ProMED-mail Animal Diseases Zoonoses Moderator. Dr. Shimshony was Chief Veterinary Officer, State of Israel, from 1974 to 1999.