Dr. Alberto Barton discovered the organism that became named Bartonella bacilliformis in 1909. Diseases caused by Bartonella spp. occur throughout the US and in all major regions of the world. Higher prevalence of the bacteria occur in areas that harbor higher numbers of insect carriers (arthropod vectors). Bartonella is a Gram-negative bacteria which currently comprises approximately two dozen identified species, about half of which are known to infect humans. They are intracellular parasites that generally infect the red blood cells and blood vessel linings (erythrocytes and endothelial cells) in humans. 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. The bacteria Bartonella represent an important area of medical research in emerging and reemerging infectious disease.
Previously, only three human diseases were recognized as clearly attributable to Bartonella organisms: cat scratch disease, caused by B. henselae was first discovered and documented in the 1990’s as the key agent in Cat Scratch disease (sometimes referred to as Cat Scratch fever); Carrion’s disease, caused by B. bacilliformus (in South America); and trench fever, caused by B. quintana.
More recently, additional pathogenic Bartonella species have been discovered and it is considered a re-immerging stealth pathogen. The full clinical manifestation of all Bartonella infections is unknown, but it has been shown to infect the heart, brain, skin, appendix and blood. It includes conditions as diverse as hepatitis, endocarditis, encephalopathy and meningoencephalitis. Patients can present with psychological and rheumatological issues.
Among 296 patients examined by a rheumatologist, prevalence of antibodies against Bartonella henselae, B. koehlerae, or B. vinsonii subsp. Berkhoffii (185 [62%]) and Bartonella spp. bacteremia (122 [41.1%]) was high. Conditions that were diagnosed prior to the rheumatologic referral included: Lyme disease (46.6%), arthralgia/arthritis (20.6%), chronic fatigue (19.6%), and fibromyalgia (6.1%).
Bartonella organisms are found in a wide range of both wild and domestic mammals including rodents, rabbits, bats, coyotes, cattle, horses, dogs, and cats. The various Bartonella species appear to be adapted to specific hosts.
Cats are the main reservoir for B. henselae, which causes approximately 20,000 reported cases of Cat Scratch Disease (CSD) per year in the United States. However, as with many reportable diseases, the true incidence of CSD is likely underreported and believed to be considerably higher. A study in Brazil showed B. henselae in 90% of feral cats and 50% of domestic cats. Cats become infected with Bartonella (the bacteria that cause cat scratch disease) through flea bites (possibly tick bites) or, potentially fights with other infected cats. While some cats become ill, most simply carry the bacteria in their blood without getting sick. Some studies have found the Bartonella bacteria in the blood of up to 1/3 of healthy cats, particularly kittens. Bartonella are found in numerous arthropods, including fleas (a known vector of CSD), biting flies, lice and ticks.
The evidence for ticks as vectors of Bartonella organisms is fairly strong. Recent studies in both the United States and Europe have found that Ixodes ticks harbor B. henselae in addition to Borrelia, Babesia and Anaplasma organisms. A 2004 PCR analysis of I. Scapularis ticks in New Jersey discovered that a higher percentage of ticks were infected with B. henselae than any of these other pathogens. In addition, B. henselae has been detected in the spinal fluid of patients co-infected with Borrelia burgdorferi, the agent of Lyme disease, though the ability of Ixodes ticks to actually transmit B. henselae to humans has not been specifically demonstrated.
Individuals at high-risk of acquiring Bartonella infection include those who work or live with animals, or those with high exposure to fleas, ticks, lice, and biting flies.
Case report shows evidence that Bartonella bacteria may be transmitted from mother to unborn child in utero.
Bartonella spp. are found worldwide in both wild and domestic animal populations, as well as fleas, biting flies, lice and ticks. It is still unclear to what extent ticks may contribute to the transmission of this disease to humans in Colorado and Nationwide.
Symptoms associated with human disease are varied and include, but are not limited to include:
- Rash (striae)
- Vascular tumors
- Light sensitivity
- Sound sensitivity
- Joint pain
- Short-term memory loss
- Suicidal tendencies
- Neurocognitive dysfunction
Unusual striae formations, caused by bacterial adhesion to structural dermal element may induce collagen malformation which may look like stretch marks or “cat scratch” like rashes. Patients with psychiatric complications from B. henselae have shown more abundance in striae. Bacillary angiomatosis (red/purple raised lesions) are often present in immune compromised patients such as those with HIV/AIDS infections. Patients with thrombotic thrombocytopenic purpura, bleeding under the skin that can cause tiny red or purple dots (petechiae) on the skin that may appear as a rash.
Bartonellosis is a stealth infection that has been increasingly implicated in complex chronic disease syndromes, yet is extremely difficult to diagnose accurately. A Bartonella bacterial infection must be suspected to get the proper diagnostic testing done. History of contact with animals or possible vectors (fleas, ticks, sand flies or lice) is an important consideration. Blood tests and possibly a CT scan can be helpful. CT scans may show swollen lymph nodes or granulomas in body organs. Tissue or skin biopsies may also show the infection. Depending on the Bartonella spp. involved, clinical diagnosis may be variable in difficulty. The three most commonly recognized diseases of Bartonella infections include:
- Cat scratch disease: Also known as cat scratch fever, this disease usually begins with an enlarged lymph node near the scratch that may spread to other lymph nodes as the illness progresses. A fluid or pus filled bump in the skin typically develops. Other symptoms include fever, fatigue, and malaise.
- Trench fever: Fever is the first symptom to develop, which is soon accompanied by alternating chills and sweats. Other symptoms include achy muscles, headache, and eye inflammation with pain. Immunocompromised individuals are particularly at risk as persistence of bacteria can infect heart valves, a condition known as endocarditis.
- Carrión’s disease: Also known as Oroya fever, causes fever, chills, sweats, body aches, and shortness of breath. Neurological problems such as headache, mental status changes, and seizures may also occur. Verruga peruana is a skin disease that occurs in people who have had Oroya fever but were not effectively treated. Skin lesions in verruga peruana contain many blood vessels causing patients to bleed easily. They tend to leave scars if they break. This disease was originally identified in Peru, Ecuador, and Colombia.
Columbia University Medical Center states “Tick-transmitted Bartonella may be a more complex disease, since the possibility of co-infection is always present. The clinical manifestations of tick-transmitted bartonellosis are essentially unknown. They may resemble cat scratch disease, take other clinical forms, or be benign. It is also unclear if co-infection with other tick-transmitted organisms can result in more serious illness; some of the few reported cases of concurrent B. burgdorferi and B. henselae infection in the medical literature appear to suggest this could be the case”.
PCR may be the most reliable and useful test for Bartonellosis infection, given the cross-reactivity of the Bartonella antibody tests. DNA of various Bartonella species can be amplified by PCR in blood, spinal fluid and tissue.
Over 10 species of Bartonella spp. have been implicated in human illness, yet standard PCR assays target one species at a time and are only available for two of the most common species of infection. Importantly, Bartonella spp. infect at very low levels, cycling in and out of the blood, leading to limited detection by PCR.
Several specialty labs concentrate in tick-borne disease testing offer offer PCR testing for multiple species of Bartonella not currently available at many commercial labs.
Though serological testing using immunofluorescent fluorescent antibody (IFA) assays for both IgM and IgG antibodies are available, cross reactions may occur with antibodies to Q fever, Chlamydia, and certain Rickettsial infections. Western blot tests may have greater specificity.
IFA serology is also limited because Bartonella are immune evasive, resulting in the absence of detectable antibodies in patient samples, and because IFA serology test can only be performed on one species at a time.
False negative serological results can also occur in immunocompromised patients. A negative test does not mean not necessarily mean no infection.
Immunohistochemical staining may be used to sometimes microscopically visualize the Bartonella spp., although this method of diagnosis is usually reserved for patients with angiomatosis.
Culture of Bartonella organisms is possible, but the bacteria are extremely slow-growing in the laboratory. This method is of limited usefulness, and has been performed primarily in patients with serious and otherwise unexplained disease presentations, such as endocarditis.
Studies are currently underway to determine the optimal culture media and methods for Bartonella.
According to the CDC, most cases of cat scratch disease (CSD) resolve without treatment, although some patients may develop complications from disseminated disease. The use of antibiotics to shorten the course of CSD disease is debated. Azithromycin has been shown to decrease lymph node volume more rapidly compared to no treatment.
Trench fever, Carrión’s disease, and endocarditis due to Bartonella spp. are serious infections that require antibiotic treatment. Health care providers should consult with an expert regarding treatment options.
A number of other antibiotics are effective against Bartonella infections, including penicillins, tetracyclines, cephalosporins, and aminoglycosides. Since aminoglycosides are bactericidal, they are typically used as first-line treatment for Bartonellosis other than CSD.
Often, with serious infections, more than one antibiotic is used. The presence of B. henselae in cerebrospinal fluid, whatever its origin, is generally agreed to warrant treatment. For central nervous system infection, antibiotics that cross the blood brain barrier are necessary, and combination therapy is usually recommended. Azithromycin or doxycycline in combination with rifampin, clarithromycin or a fluoroquinolone as one of the recommended regimes, however the optimal length of therapy has yet to be determined.
In a recent study, investigators evaluated 14 antibiotics and 25 antibiotic combinations for activity against stationary phase B. henselae. Findings showed drug combinations azithromycin/ciprofloxacin, azithromycin/methylene blue, rifampin/ciprofloxacin, and rifampin/methylene blue could rapidly kill stationary phase B. henselae with no detectable CFU after 1-day exposure. Methylene blue and rifampin were the most active agents against the biofilm B. henselae after 6 days of drug exposure. Antibiotic combinations (azithromycin/ciprofloxacin, azithromycin/methylene blue, rifampin/ciprofloxacin, rifampin/methylene blue) completely eradicated the biofilm B. henselae after treatment for 6 days.
Persistent infection is a hallmark of bacteria growing in biofilms. Bartonella spp. biofilms can form in humans in vivo and under culture conditions in the laboratory. Biofilms are sessile communities of interacting unicellular organisms that adhere to one another and to a surface; forming a complex structure encased in an extracellular polymeric substances (EPS). These EPS confer resistance to antimicrobial agents and can serve as a reservoir niche for bacteria. Up to 80% of human bacterial infections involve biofilm-associated microorganisms. Biofilm-related infections are extremely refractory to antimicrobial treatment and can require 10–1,000 times more antibiotics than bacteria in their planktonic form.
Bartonella spp. can induce long-lasting bacteremia and unfortunately the mechanism(s) of persistent Bartonellosis are poorly understood. For patients that have been additionally infected with Lyme disease (also shown to develop biofilms) and/or other co-infections, treatment and prognosis is more complex. The possibility of Bartonella co-infection in cases of poorly resolving or apparent relapsing of Lyme disease is a warranted consideration. As with Lyme disease, consultation with a physician trained in tick-borne disease diagnostics and treatment is recommended.
Physician referral services are available to patients for help in locating medical care providers trained in diagnosing and treating tick-borne infections.
LDA/Columbia 17th Annual Conference material, presented by Dr. Marna Ericson, 2016