Bartonellosis is a group of gram-negative intracellular facultative bacterium emerging infectious diseases caused by bacteria belonging to the Bartonella genus. Bartonella includes at least 22 named species of bacteria that are mainly transmitted by carriers (vectors), including fleas, lice, or sandflies. Both domestic and wild animals can be infected with Bartonella species (Bartonella spp) by these vectors. Among the Bartonella spp, at least 14 have been implicated in diseases that can be transmitted from animals to people (zoonotic disease). Of these zoonotic species, several may be transmitted to humans by companion animals (dogs and cats), typically through a bite or scratch.
Human diseases that have been identified to be caused by one of the Bartonella spp bacteria include cat scratch disease (Bartonella henselae), Carrion’s disease (Bartonella bacilliformis), and trench fever (Bartonella Quintana). Bartonella spp has also been associated with diseases of the skin (bacillary angiomatosis), liver (peliosis hepatis), heart (endocarditis), eyes (neuroretinal), blood (bacteremia), and brain (encephalitis). Bartonella infection does not always cause overt illness. Several studies have detected clinically healthy people that have tested positive (seropositive) for Bartonella but have no known history of typical Bartonella symptoms. Those who do become ill usually develop a mild disease that tends to end without treatment (self-limiting). However, Bartonella can cause severe infection in some people. Immunocompromised patients, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and people with HIV/AIDS, are more likely to develop severe, life-threatening diseases.
Types
Bartonella quintana – People can get Bartonella quintana from the bite of the human body louse. Body lice spread by close physical contact or by repeatedly using the same clothes or bedding. B. quintana infection is most commonly associated with body louse infestations in areas of high population density and poor sanitation. People experiencing homelessness are at increased risk of developing infection with B. quintana because of limited access to shower and laundry facilities. B. quintana infection occurs worldwide. During the first World War, infection with B. quintana was referred to as “trench fever” due to the many cases among soldiers who lived in crowded trenches in poor hygienic conditions.
Bartonella bacilliformis – formerly known as South American bartonellosis, is transmitted by bites from infected sand flies (genus Lutzomyia). B. bacilliformis only occurs in the Andes Mountains at 3,000 to 10,000 ft. in elevation in western South America, including Peru, Colombia, and Ecuador. Most cases are reported in Peru.
Symptoms
Diseases in humans that have been identified to be caused by one of the Bartonella spp include cat scratch disease, Carrion’s disease, and trench fever.
A rare infection spread by sand flies in some regions of South America, B. bacilliformis has two distinct phases:
- Oroya fever: During this phase, fever, headache, muscle aches, abdominal pain, and severe anemia may occur. Complications may occur in up to 70 percent of patients with Oroya fever, including secondary infections and cardiopulmonary complications such as heart failure, pericardial effusion, pulmonary edema, and cardiogenic shock.
- Verruga peruana (Peruvian warts): During this later phase, growths form under the skin and develop into red-to-purple vascular sores that can become raw or bleed.
Cat scratch disease (CSD):
CSD, caused by Bartonella henselae (B. henselae), is an infectious disease with symptoms that can vary from mild to severe. Although in most patients the disease resolves spontaneously within 2-4 months without treatment, in people with severe cases and/or patients with a suppressed immune system, such as HIV/AIDS, antibiotic treatment is recommended.
The major symptoms of cat scratch disease may not appear for several days or weeks after exposure. A red spot (macule) may appear on the skin at the site of infection and may become raised (papule) 3 to 10 days after exposure. The papule is painless and does not itch. It may become filled with fluid (vesicle), then crust over and heal with a scar similar to those left by chicken pox. The papule persists for 1 to 3 weeks but may go unnoticed or be attributed to an injury.
Within 1-3 weeks, swelling of lymph nodes (lymphadenopathy) develops in a single node or group of regional nodes near the site of the bite or scratch. Swollen lymph nodes frequently occur under the arms, on the neck, or in the groin regions. These nodes usually become very tender and the surface of the skin may appear red and feel hot to the touch. Pus may develop in the involved lymph nodes (suppuration) and become fluctuant. Lymphadenopathy remains regional and typically resolves within 2-4 months but may last up to 6-12 months.
Other symptoms of the cat-scratch disease may include achiness and overall discomfort (malaise), fatigue, headache, and in some patients, fever. Less common symptoms include loss of appetite, sore throat, and weight loss. In some cases, chills, backache, and/or abdominal pain have been reported.
Rare complications of Bartonella henselae infection more typically occur in people with immunocompromised conditions, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and people with HIV/AIDS, although they are being increasingly reported in immunocompetent people, too. Increasingly these atypical manifestations have been reported in patients without the typical symptoms of CSD. Children, in particular, appear to develop inflammation in the liver (granulomatous hepatitis) or spleen (splenitis) and bone infection (osteomyelitis). Other atypical manifestations of CSD include bacillary angiomatosis, encephalopathy (inflammation of the brain), neuroretinitis (inflammation of the retina and optic nerve of the eye), Parinaud’s oculolandular syndrome (conjunctivitis), and endocarditis (infection of the heart valve), Bacillary angiomatosis, caused by B. Quintana or B. henselae, is a skin disorder that is characterized by reddish, elevated lesions that are often surrounded by a scaly ring and bleed easily. The condition may spread to produce a more widespread systemic disorder that can involve the bone, liver, spleen, lymph nodes, gastrointestinal and respiratory tracts, and bone marrow. Bacillary angiomatosis has occasionally been reported in immunocompetent patients.
Bacillary peliosis, a form of peliosis hepatis, is a vascular condition caused by B. henselae. It is characterized by the presence of blood-filled cavities in the liver.
Parinaud’s oculoglandular syndrome, which affects the eye, presents in approximately 5% of patients with CSD. Symptoms include red, irritated, and painful eye (similar to conjunctivitis or “pink eye”), fever, general ill-feeling, and swelling of nearby lymph glands, often in front of the ear (preauricular lymphadenopathy).
Neurologic complications occur in approximately 2% of infected patients, with encephalopathy being the most common presentation. Symptoms generally occur 2 to 3 weeks after the onset of lymphadenopathy, although some patients have been known to present with neurological symptoms without a CSD history. Greater than 90% of these patients have complete, spontaneous recovery with no negative after-effects.
Other rare symptoms of bartonellosis may include swelling of the largest salivary gland (parotid gland), cardiac manifestation with inflammation of the lining of the heart and its valves (endocarditis), renal inflammation (glomerulonephritis), granulomatous inflammation of the liver (hepatitis), splenitis, and/or abscesses of the spleen. In very rare cases, bartonellosis has been associated with atypical pneumonia, an inflammatory reaction to infection characterized by bumps on the lower legs (erythema nodosum), and/or a skin discoloration associated with a decreased blood platelet count (thrombocytopenia purpura).
Carrion’s disease:
Carrion’s disease, caused by Bartonella bacilliformis (B. bacilliformis), is a rare infectious disease that was originally thought to occur only in the Peruvian Andes. Other South American countries have more recently been included. New cases of the disease have been found in individuals who have traveled to other parts of the world.
In most affected individuals, Carrion’s disease is characterized by two well-defined stages: a sudden, acute phase known as Oroya fever and a chronic, benign skin (cutaneous) eruption consisting of raised, reddish-purple nodules known as verruga peruana (Peruvian warts). The first stage usually develops about three to 12 weeks following exposure to the B. bacilliformis bacterium.
Oroya fever may be characterized by a sudden onset of high fever, profuse sweating, severe headache, chills, weakness, and paleness of the skin. In addition, in many affected individuals, mental changes may develop, including confusion and disorientation or a coma. Such abnormalities occur in association with rapidly developing reduced levels of red blood cells (erythrocytes) due to bacterial invasion and destruction of these cells (hemolytic anemia). The first phase of the disease is very similar to malaria.
Additional associated findings may include abdominal pain, severe muscle aches (myalgia) and arthralgia, lymphadenopathy, inflammation of the brain and its protective membranes (meningoencephalitis), seizures, and/or other abnormalities. In addition, some affected individuals may develop chest pain due to insufficient oxygen supply to the heart muscle (angina), thrombocytopenia, labored breathing (dyspnea), impaired digestive and liver function, and/or other abnormalities. Such findings are thought to result from severe hemolytic anemia and the abnormal formation of blood clots within small blood vessels (microvascular thrombosis), leading to an insufficient supply of oxygen to tissues (ischemia), and impaired functioning of organs, and potentially life-threatening complications.
In addition, in some patients, the acute stage of Carrion’s disease may be complicated by an increase in severity due to the presence of other infections, such as salmonellosis or malaria (i.e., intercurrent infections). (For more on salmonellosis, see below. For further information on malaria, please choose “malaria” as your search term in the Rare Disease Database.)
In its mildest form, Carrion’s disease may not be noted until the development of characteristic skin lesions (verruga peruana). In such instances, it may have a gradual onset and initially be characterized by a fever that may be present for less than a week and be unrecognized as a manifestation of Carrion’s disease.
In those affected by Oroya fever, the period of recovery is typically associated with gradually reduced fever and disappearance of the bacterium as seen on microscopic examination of small blood specimens. However, some individuals remain persistently infected for years; blood smear examination, although the historical standard diagnostic test in Peru, is a very insensitive test. Furthermore, some affected individuals may temporarily have an increased susceptibility to certain, subsequent infections, such as Salmonella bacteria (salmonellosis). Infection with certain strains of Salmonella bacteria may cause high fever, abdominal pain, bloody diarrhea, nausea, vomiting, rash, and/or other symptoms and findings. In addition, in some cases, without appropriate antibacterial therapy, B. bacilliformis may remain present in the blood (bacteremia) for months to years without apparent symptoms (asymptomatic), potentially resulting in the continued spread of the disease to others (i.e., as a “reservoir” or an ongoing source of infectious disease). Reports suggest that relapses or recurrences of Oroya fever are rare. According to experts, recurrence of fever after initial improvement of symptoms is considered suggestive of a secondary infection.
Following the resolution of the acute stage of infection (Oroya fever), untreated individuals typically develop distinctive skin lesions within weeks or months. This second stage is known as verruga peruana. As noted above, verruga peruana may develop in individuals who have or have not had previous symptoms of Oroya fever.
Verruga peruana is typically characterized by reddish, purple skin lesions occurring in a series of outbreaks that may develop in one area as they heal in another and recur in certain sites. The lesions may initially be minute, eventually, become nodular and range from about 0.2 to 4 centimeters in diameter, and potentially bleed, ulcerate, or become pus-containing blisters (pustules). Although they typically erupt on exposed skin, such as on the face, arms, and legs, they may also sometimes develop within mucous membranes and internal organs. In untreated individuals, verruga peruana may persist over months to years.
Trench fever:
Trench fever, caused by Bartonella Quintana (B. Quintana), shows symptoms within a few days or up to five weeks following exposure to the bacterium. Affected individuals may develop sudden fever, chills, weakness, headache, dizziness, leg and back pain, and/or other abnormalities. Initial fever may last about four to five days and may recur one or several times, with each episode lasting about five days. Additional findings may include a temporary skin rash consisting of flat (macular) or raised (papular) lesions, and/or enlargement of the liver or spleen (hepatomegaly or splenomegaly). Trench fever is usually a self-limiting disease, although relapses and chronic bacteremic states are well known. A severe form of B. Quintana infection has also been reported in immunocompromised individuals, such as in association with AIDS.
Causes
Bartonella bacteria invade red blood cells (erythrocytes) and the lining of the blood vessels (endothelial cells), where the organism proliferates. Inside the erythrocytes, it is protected from the host’s primary and secondary immune response, thus explaining bacterial persistence that can occur in some cases.
Cat scratch disease
Cat scratch disease is caused by the B. henselae bacterium. Most cases follow a lick, scratch, or bite from a cat or kitten when the bacterium is present on the cat’s claws or oral cavity. Fleas transmit the bacteria among cats. Some case reports have suggested transmission may occur from cat fleas directly to humans, but this has not yet been proven. Cat-to-cat and person-to-person transmission have not been documented. There have also been reports of the disease following the scratch or bite of dogs in 5% of cases.
A feline infected with B. henselae is a common occurrence. Up to half of the domestic cats have antibodies to B. henselae, which indicates that they have been previously exposed to these bacteria. Because cats are infected with B. henselae by fleas, preventing flea exposure will reduce B. henselae infection in cats and kittens and thereby prevent human infection. Kittens under 12 months of age are much more likely to transmit the disease than adult cats. Outdoor cats and cats infested with fleas are also more likely to show antibodies (test seropositive) to B. henselae. Animals that are carrying the disease are not ill, and will not exhibit any symptoms. Not every person exposed to the carrier animal will develop cat scratch disease, and in most cases, the symptoms are temporary (transient) and mild.
Carrion’s disease
B. bacilliformis is the etiologic agent of Carrion’s disease or Oroya fever (acute phase of infection) and verruga peruana or Peruvian warts (chronic phase of infection). The bacterium is primarily carried and transmitted by the night-biting sand fly known as Lutzomyia (formerly Phlebotomus).
The B. bacilliformis bacterium enters the bloodstream via the bite of the sand fly, enabling the bacterium to attach to the surface of erythrocytes. Bacterial invasion and reproduction lead to abnormal fragility and premature destruction of many erythrocytes in the bloodstream (hemolysis). This results in abnormally decreased red blood cell levels and reduced concentrations of hemoglobin, the oxygen-carrying component of the blood (hemolytic anemia). In addition, the bacterium may invade cells lining small blood vessels (capillary endothelial cells), potentially leading to blockage of normal blood flow (vascular occlusion). Severe hemolytic anemia and the abnormal formation of blood clots within small blood vessels may potentially lead to life-threatening complications without prompt appropriate treatment.
With developing immunity, levels of the bacterium markedly decrease in the blood. However, without appropriate antibiotic therapy, asymptomatic low-grade bacteremia may persist for months or years in some cases.
Following the symptom-free (latent) period, most untreated individuals develop distinctive skin lesions characteristic of verruga peruana. The nodular lesions consist of newly formed blood vessels (neovascular proliferation) infiltrated by certain white blood cells that play an important role in fighting and destroying invading microorganisms (e.g., lymphocytes, macrophages).
Trench fever:
Trench fever is caused by infection with B. Quintana most likely transmitted by the human body louse (Pediculus humanus) and is commonly found in homeless, alcoholic, and poverty-stricken populations where poor sanitation and poor hygiene often occur. Other diseases that have been identified to be caused by B. Quintana include bacillary angiomatosis (antiproliferative lesions), bacteremia, and endocarditis. Human endocarditis has now been associated with at least nine different Bartonella spp.
Bartonella vinsonii subsp. berkhoffii has been isolated from immunocompetent patients with endocarditis, arthritis, neurological disease, and vasoproliferative neoplasia. Dogs and wild canines (foxes, coyotes, wolves), which are the primary reservoir hosts, are the suspected reservoir hosts for this bacterium, and ticks are the suspected vectors, but this has not been scientifically proven.
Most infections in immunocompromised patients are caused by B. henselae and B. Quintana. Unlike immunocompetent individuals who usually develop milder diseases such as cat-scratch disease and trench fever, immunocompromised patients, including HIV/AIDS and posttransplant patients, are more likely to develop more severe, potentially life-threatening diseases.
Diagnosis
Most cases of CSD can be diagnosed by the individual’s symptoms and histories, such as the development of papules or pustules after vector exposure or a cat scratch or bite. The development of swollen lymph nodes and fever further reinforces a clinical diagnosis. Blood (serological) testing is available to confirm the diagnosis. PCR and culture tests may also be used in certain cases.
Carrion’s disease may be diagnosed based on a thorough clinical evaluation, detection of characteristic symptoms and physical findings, a complete patient history, including information concerning recent travel to regions where Carrion’s disease is known to occur; and specialized laboratory tests. For example, during the acute stage, the bacterium may easily be seen within red blood cells on blood smears. With this diagnostic test, a drop of blood is smeared on a slide, stained with special dyes to make blood cells more visible, and examined under a microscope. During the chronic, cutaneous stage, the bacterium may be isolated from skin lesions. Blood smears are typically negative during this second stage. However, the bacterium may be cultured from the blood and grown under controlled conditions in the laboratory, enabling the identification of the causative microorganism. In some cases, other laboratory studies may be used to help diagnose Carrion’s disease.
Serological testing is used to diagnose trench fever. However, it is difficult to diagnose in the laboratory, especially with blood cultures, since results are often negative even when the infection is present and growth often takes 20-40 days.
- B. quintana is a fastidious, slow-growing bacterium. Cultures should be held for a minimum of 21 days. It is often helpful for providers to alert the microbiology laboratory that B. quintana is suspected to optimize conditions for growth.
- Serology can aid the diagnosis of B. quintana, although cross-reactivity with other Bartonella species may limit interpretation. Providers should be aware that serological tests do not reliably differentiate among Bartonella species and positive results may persist for years even after effective treatment.
- Molecular detection (including PCR) can be particularly useful in cases of culture-negative endocarditis. Patients with infectious endocarditis sometimes have damaged heart valves that need to be surgically replaced. Molecular detection of Bartonella spp. should be performed on excised heart valve tissue if a patient with endocarditis requires surgical valvular replacement. For patients with suspected B. quintana bacteremia, PCR testing can also be performed on blood.
Direct Detection Methods
- Isolation in culture.
- Detection of antigens of the pathogen.
- PCR- detection of the nucleic acid (DNA).
- Visualization by special stains.
Indirect Detection Methods
- Serology – detection of antibodies against the pathogen.
- Detection of an immune cellular response against the pathogen- Bartonella skin tests. No longer used
- The culture of the bacterium gives a definitive diagnosis, but it is a very time-consuming and expensive process with incubation periods as long as 21 days. Bartonella bacteria are very slow-growing, fastidious, and primary isolation is difficult, with the detection of colonies only after 1 to 4 weeks of incubation on blood agar plates. As Bartonella species are difficult to culture, culture is not routinely recommended. Serology is the best initial test and can be performed by indirect fluorescent assay or enzyme-linked immunosorbent assay.
- Serological testing such as indirect fluorescence assay for B. henselae antibodies was the first microbiological test available but has a variable positive predictive value. It is an indirect diagnostic method that can be negative in the early stage of the disease. In some studies, the positive predictive value of the indirect immunofluorescence assay for B. henselae was reported to be high (=91.4%). Conversely, some studies found a lack of sensitivity of the serological test among patients with CSD. While there is variability in multiple studies of B henselae IgG and IgM indirect fluorescent antibody and ELISA serology, typical sensitivity values are approximately 50% to 80%, [rx]whereas specificity is 90% to 100%. Sensitivity increases when there is a higher clinical index of suspicion for CSD. An IgM titer of 1:16 or higher shows acute disease, with a 3-month duration of detection in 50% of patients. An IgG titer higher than 1:256 is considered evidence of current or past Bartonella infection. Unlike culture and PCR of blood, serology does not rely on Bartonella being present in the blood. It can be used to evaluate response to therapy.
Histopathological examination of the tissue infected by Bartonella species usually shows neutrophils, lymphocytes, and debris scattered throughout the lesions. Warthin-Starry silver staining will show small dark staining bacteria and electron microscopic findings include pleomorphic bacilli with a trilaminar wall. Histopathological examination for Bartonella bacilliformis is performed using Giemsa stain, and it shows cytoplasmic inclusions known as Rocha-Lima inclusions.[rx]
Advanced diagnostic techniques such as PCR on lymph nodes or other material have been applied to the detection of Bartonella. PCR provides the advantages of high specificity and rapid identification, however lacking in sensitivity, ranging from 43% to 76%. The sensitivity of PCR with samples of lymph node tissue or aspirates is 30-60% for CSD. A polymerase chain reaction can detect different Bartonella species; specificity is high, but the sensitivity is lower than with serology.
Clinical Testing and Work-Up
Bartonella infection can be difficult to diagnose. Serological testing is the most cost-effective diagnostic tool in laboratory detection of bartonellosis when positive results are found. However, as previously discussed, false negatives can occur, leading to undiagnosed, untreated patients when further testing is not performed. Detection of IgG and IgM antibodies in blood serum to Bartonella henselae by Indirect Immunofluorescence Assays (IFA) is an accurate way to identify CSD. Microscopic examination of Giemsa-stained blood smears is used to detect B. bacilliformis in patients who may have Carrion’s disease. Other Bartonella species are visible only with silver stains (Warthin-Starry, Steiner, Dieterle), although they sometimes resist staining or are present in such low numbers as to not be detectable.
A polymerase chain reaction (PCR) test is a molecular technique used to detect specific genetic material in blood. Because of the serological cross-reactivity between Bartonella species and other bacteria, PCR analysis of tissue and body fluid is the most specific diagnostic test, especially in identifying distinct genotypes among Bartonella species.
Intradermal skin testing, using hypersensitivity reaction to B. henselae antigen, is a test that is no longer used as more accurate testing is now available. Stains of biopsied tissue from lymph nodes examined microscopically may show small curved Gram-negative rods characteristic of B. henselae, but this staining method is not a definitive diagnosis of CSD. PCR of lymph nodes and other tissues, when used in conjunction with DNA sequencing, allows for diagnostic confirmation of Bartonella spp. and strains.
Complications involving the liver and/or spleen are now identified more frequently with the use of improved serologic, PCR, and diagnostic imaging tests. Abdominal imaging is an important diagnostic tool for patients with the suspected hepatosplenic disease and who present with prolonged fever.
Treatment
Cat scratch disease typically subsides without any treatment, usually within 2 to 4 months. Therapy is symptomatic and supportive. Antipyretics (fever reducers) and analgesics may be administered as needed. Local heat may be applied to the involved lymph nodes.
Cat scratch disease usually has a very good prognosis, with no long-term health effects.
If the affected lymph node produces pus (suppurates) and becomes large and/or painful, it may be necessary to drain the node. Draining the pus through a needle (aspiration) is preferred over making an incision. Usually,, one aspiration is sufficient to relieve discomfort.
Antibiotics may be considered for severe or systemic diseases. Faster reduction of lymph node size has been demonstrated with a 5-day course of azithromycin. Other antibiotics that have been considered effective include rifampin, ciprofloxacin, gentamicin, and trimethoprim/sulfamethoxazole. Bartonella henselae is generally resistant to penicillin, amoxicillin, and nafcillin. Doxycycline and rifampin in combination are the preferred medications for treating neuroretinitis. Effective antibiotic therapy for the complication of endocarditis should include an aminoglycoside prescribed for a minimum of 2 weeks followed by doxycycline or ceftriaxone for 6 weeks.
The treatment of choice for Oroya fever is the administration of the antibiotic chloramphenicol (due to frequent, intercurrent infection with Salmonella). Ciprofloxacin has also been recommended. Antibiotic therapy may rapidly treat acute febrile illness associated with Oroya fever. Blood transfusions may be required to treat severe anemia. For antibiotic treatment of verruga peruana, rifampin and streptomycin are typically recommended. Another treatment for this disorder is symptomatic and supportive.
Carrion’s disease may be prevented by avoiding the sandflies that transmit the bacterium to humans. Insect repellents, bed nets, and long-acting insecticides can help prevent exposure to these insects.
Tetracycline-group antibiotics (doxycycline, tetracycline) are commonly used to treat trench fever. The uncomplicated disease responds to doxycycline and gentamicin. Chloramphenicol is an alternative medication recommended when tetracycline usage is undesirable, such as in severe liver malfunction, and kidney deficiency, in children under nine years and pregnant women. Macrolides and ceftriaxone have also been effective.
A longer duration of treatment is recommended for immunocompromised patients and when the liver or other organs are involved. In patients with AIDS and bacillary angiomatosis, the primary choices of antibiotics are erythromycin or doxycycline. Doxycycline combined with rifampin is effective in patients with severe disease. Extended treatment is often required in these cases.
Though the course of the disease can be far more severe and potentially life-threatening for immunocompromised patients, these patients typically experience full resolution of disease with appropriate antibiotic use and management of complications. The response of immunocompromised patients to antibiotics is significantly more dramatic than immunocompetent patients. Some researchers believe that less virulent strains tend to infect immunocompromised patients and are perhaps more antibiotic responsive.
References
Barth Syndrome
