Bartonellosis

Bartonellosis

Bartonellosis comprises infections caused by the emerging pathogens in the genus Bartonella. In 1909, A. L. Barton described organisms that adhered to RBCs. The name Bartonia, later Bartonella bacilliformis, was used for the only member of the group identified before 1993. Rochalimaea (named for Rocha-Lima), a similar group, were recently combined with Bartonella. Although these organisms were originally thought to be rickettsiae, Bartonella bacteria can be grown on artificial media, unlike rickettsiae.

At least a dozen species belong to the genus Bartonella. Three Bartonella species are currently considered important causes of human disease, but other significant human pathogens in this genus were found to causes disease in humans occasionally. In one study, serum specimens from 114 patients hospitalized with a febrile illness were tested with an indirect immunofluorescence assay (IFA) using rodent and human Bartonella pathogens; 5 patients had high-titer seroconversion to rodent-associated Bartonella. 

B bacilliformis causes Oroya fever and verruga peruana. Bartonella henselaecauses catscratch disease (CSD) and peliosis of the liver (often called bacillary peliosis). Bartonella quintana causes trench fever. Both B henselae and B quintana may cause bacillary angiomatosis, infections in homeless populations, and infections in patients with HIV.

Pathophysiology

The transmission of Bartonella species occurs by traumatic contact with infected animals or by vectors like cat fleas or other blood-sucking arthropods (eg, sand fly, Phlebotomus for B bacilliformis).

B bacilliformis, which uses a polar flagellum for motility, adheres to and invades RBCs. After entry, the organism replicates in vacuoles. This species also makes an endothelial cell–stimulating factor that causes proliferation of both endothelial cells and blood vessels.

B henselae and B quintana do not bind to intact human erythrocytes in the same way that B bacilliformis does; however, these organisms make a protein binder that adheres to feline RBC membranes, and they penetrate into endothelial cells. Both species also initiate production of an endothelial cell–stimulating factor. Because lysis-centrifugation blood cultures show enhanced isolation of B henselae and B quintana, intracellular forms are most likely present in humans. Erythrocytes may serve as a reservoir for Bartonella species.

B quintana also invades endothelial cells and forms bacterial aggregates that are taken internally by the invasome, a unique phagosomal structure.  These proliferate and make intracellular blebs.

Clinical presentation

Currently, Bartonella species cause several clinical syndromes, including catscratch disease (with enlarged nodes and other organ involvement), bacteremia, endocarditis, bacillary angiomatosis, peliosis hepatis, Oroya fever, and verruga peruana. The inability to mount an immune response contributes to manifestations observed in immunosuppressed individuals with advanced AIDS and other diseases.

Catscratch disease

Most affected individuals have typical catscratch disease symptoms and present with an enlarged lymph node.

A primary inoculation lesion often develops at the site of a bite or scratch.

A papule or pustule develops 5-10 days after exposure. This lesion may persist for a few weeks.

B henselae DNA may be chronically shed into peripheral blood during the natural course of catscratch disease. 

Bacteremia and systemic illnesses

Trench fever was described in military personnel during World War I. Urban trench fever is now observed in homeless persons in the United States and Europe.

Symptoms of trench fever begin with chills and fever after an incubation period of a few days to a month. Occasionally, the patient experiences only a single febrile episode that lasts 4 or 5 days. More commonly, several episodes of fever occur. Each episode lasts about 5 days, which is the origin of the designation quintana. The patient cycles between severe chills and profuse sweating. In other patients, continuous fever lasts 2-6 weeks.

Associated symptoms include joint and muscle aches, injected conjunctivae, headache, dizziness, and pain behind the eyes. Some patients have diffuse symptoms without fever.

Some cases of trench fever become chronic with debility, with or without fever or aching, and occasionally with hyperexcitability.

In patients with HIV, infection with either B henselae or B quintana causes gradual onset of aching, headache, fatigue, and weight loss. Fever begins later. Persistent bacteremia with B henselae may develop in people with AIDS.

Encephalopathy has been associated mostly with B henselae. Guillain-Barré syndrome, hydrocephalus, and encephalopathy were associated with B quintanaacute infection in one case report. 

Meningitis due to a "Bartonella washoensis"-like human pathogen was isolated from the blood of a patient with meningitis in California, the patient owned cats, dogs and had contact with squirrels. 

Bacillary angiomatosis and peliosis hepatitis

Bacillary angiomatosis was initially described in persons infected with HIV. Typically, it involved the skin and was believed to resemble Kaposi sarcoma but can affect other organs such as the respiratory tract, bone, lymph nodes, gastrointestinal tract, and brain. When the liver or spleen was involved, bacillary peliosis or peliosis hepatis was diagnosed before Bartonella infection was discovered to be the cause.

Symptoms depend on the anatomic site involved and may include fever, tender lymphadenopathy, and skin lesions.

Oroya fever and verruga peruana

Over a century ago, a medical student named Daniel Carrión injected himself with blood from the skin lesion of a patient who had verruga peruana. He developed Oroya fever. Today, Oroya fever and verruga peruana are called Carrión disease. Prior to that time, the relationship between the diseases was unknown.

Bacteremia of Oroya fever begins 3-12 weeks after a bite from an infected sand fly. The illness may range from mild to very severe. In severe cases, fever, chills, headache, sweating, aches, dyspnea, mental status changes, and seizure may occur. Severe disease has an abrupt onset.

Causes

Catscratch disease

In the United States, catscratch disease is the most common type of bartonellosis.

The clinical syndrome has been recognized for more than a century, but the etiology of this condition was confirmed only in the past decade. Confirmation involved isolating Bartonella species from cats and their fleas, showing an antibody titer rise in patients with the disease, and demonstrating the presence of organisms in biopsy samples through culture and PCR.

Occasional cases are negative for B henselae antibodies. In these instances, rare causes of catscratch disease such as B clarridgeiae or Afipia felis should be considered.

Bacteremia 

Bacteremia may occur with either B henselae or B quintana infection and may result in disseminated diseases. Other species of Bartonella have occasionally been associated with bacteremia.

Oroya fever and verruga peruana

Oroya fever and verruga peruana are manifestations of B bacilliformis infection. These diseases are not found in the United States, but they are common in the Peruvian Andes. Verruga peruana is characterized by subcutaneous nodules consisting of neovascularization, somewhat similar to bacillary angiomatosis.

Diagnose

Microscopic examination of Giemsa-stained blood smears is used to detect B bacilliformis in patients who may have Oroya fever.

Organisms are rod-shaped and slightly curved, similar to Campylobacter or Helicobacter species.

B bacilliformis organisms often appear to be adherent to erythrocytes, but they may actually be inside erythrocytes.

Other Bartonella species are visible only with silver stains (eg, Warthin-Starry, Steiner, Dieterle), if they stain at all. Bacillary forms also exist. These stains are not specific.

Immunostaining can also aid in the diagnosis of early lesions or atypical manifestations of catscratch disease. Capnetti at al  found that immunohistochemical analysis was positive in 25% of cases, PCR in 38% of cases, and Steiner silver stain in 46% of cases of 22 patients with lymphadenopathy and histopathological findings compatible with catscratch disease.

Late in the course of B henselae infection, organisms may not be found in areas of necrotizing granulomas.

Cultures

Culture for Bartonella bacteria is not recommended for routine cases of patients with catscratch disease lymphadenopathy.

Cultures may be useful in patients who have other manifestations of either B henselae or B quintana infection, including fever of unknown origin, neuroretinitis, encephalitis, culture-negative endocarditis, and peliosis or bacillary angiomatosis. Fresh media is required to increase the chance of isolation.

A recent study suggests a novel chemically modified liquid medium that supports the growth of 7 Bartonella species. 

The lysis-centrifugation system (Isolator) is recommended for blood cultures.

Minced tissues may be cultured on chocolate agar plates in a humid atmosphere with carbon dioxide to facilitate growth.

Antibiotic susceptibility is not routinely tested in patients with bartonellosis because susceptibility studies may fail to predict response to therapy.

Treatment

Several therapies have been successful. Whether therapy should be provided at all is unclear because catscratch disease is ordinarily a self-limited condition that lasts weeks to months. Therapy is typically provided because of patient concerns about tender nodes and because early treatment is believed to reduce the possibility of disseminated complications.

Cost-effective pharmaceutical choices include erythromycin or doxycycline. Azithromycin has been shown to be more effective than placebo in resolving lymphadenopathy; some consider azithromycin to be the drug of choice.

If the initial therapeutic choice appears unsuccessful after 2-3 weeks, consider switching to azithromycin, co-trimoxazole, or a quinolone antibiotic. Rifampin in combination with another drug, or the use of gentamicin, may be considered in some situations.

The usual duration of therapy is 3-6 weeks. Patients who are bacteremic require at least 4 weeks of therapy. Patients with HIV and other immunocompromising diseases require more prolonged therapy. Patients who have vegetations due to bartonellosis often require valve replacement. At least initially, an aminoglycoside should be included in the treatment of endocarditis. 

No definitive therapeutic study of CNS bartonellosis or neuroretinitis has been performed, but treating these patients seems prudent. Agents that penetrate the CNS or eye are favored, including doxycycline or azithromycin possibly with rifampin, clarithromycin, or a newer fluoroquinolone antibiotic. A combination of 2 drugs is favored because this may speed healing and because no single agent has been found to cure all cases in which it was used. Data from the literature do not support the use of corticosteroids.

A meta-analysis found 2 studies; one was a randomized controlled study and the other was an observational study. No antibiotic regimen was shown to be beneficial in improving the cure rate or time to achieve cure. 

Surgical Care

In an editorial entitled "Bartonellosis: light and shadows in diagnostic and therapeutic issues" in Clinical Microbiology and Infection (2005), Manfredi et al wrote, "The role of surgical debridement and the unpredictable activity of antimicrobial agents warrant further investigation." The authors go on to point out that "The need for, selection and duration of antimicrobial therapy for CSD remain contentious. Suppurative nodes that become tense and painful should be drained, but incision of non-suppurative lesions should be avoided, as chronic draining fistulae or compromised healing may result."

Prevention

B bacilliformis and B quintana infections: Prevention is best achieved by avoiding the circumstances in which exposure to their arthropod vectors occurs. B bacilliformis transmission is limited to the Andes Mountains at elevations of 1000-3000 meters because of the habitat of the sand fly Phlebotomus, now called Lutzomyia. Outbreaks occur only in the Andes. B quintana is found worldwide and causes febrile outbreaks. Poor sanitation and lack of personal hygiene strongly correlate with transmission by the body louse Pediculus humanus.

B henselae infection: B henselae is found throughout the world in association with both domestic and feral cats. Prevention is achieved by avoiding interactions with cats that might result in scratches, bites, or licks, especially kittens, cats with fleas, and cats that are allowed outdoors.

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