Bartonellosis are diseases caused by any Bartonella species.1 They are neglected, re-emergent, and distributed worldwide, affecting mainly populations suffering from poverty, with precarious sanitation, and that are in direct contact with arthropods and domestic animals.2,3 Most species cause zoonotic diseases.1,3

Bartonella spp. are fastidious Gram-negative bacilli, well adapted to a variety of animal reservoirs, particularly mammals. These bacteria are capable of infecting and surviving inside erythrocytes. The intraerythrocytic phase allows for a protection niche for the agent, resulting in a prolonged and recurrent infection.4 The bacteria can also infect endothelial cells.5

The main route of transmission of Bartonella spp. is from infected humans or animals to new hosts through blood-sucking arthropod vectors. Transmission through animal scratches has been reported but it is not certain, since fleas are needed for transmission among cats.1,6 Recent studies reinforce the hypothesis that these bacteria can be transmitted through blood transfusion, which is a concern for people all over the world since currently there is no preventive action against this possibility.3,7–9 In addition, asymptomatic infection by Bartonella sp. has already been detected in blood donors.3,8–18

Bartonella spp. are responsible for a broad clinical spectrum, from asymptomatic bacteremia to potentially fatal presentations. Although the manifestations associated with bartonellosis have increased considerably over the past decades, physicians usually do not consider the possibility of infection with these bacteria among differential diagnoses, except in cases with localized lymph node enlargement or endocarditis with negative culture,19,20 which suggests that bartonellosis has been neglected by the medical community, leaving many cases undiagnosed.

Among the 16 species of Bartonella that are pathogenic to humans, three are responsible for the majority of clinical symptoms: Bartonella bacilliformis, Bartonella quintana, and Bartonella henselae.5,21

Until 1993, B. bacilliformis was considered the only species of this genus. It is the etiologic agent of Carrion's disease, previously known as the only bartonellosis. B. bacilliformis is transmitted by the female Lutzomyia verrucarum, endemic in the Peruvian Andes and regions of Ecuador and Colombia.

Reports in recent decades of outbreaks in regions of atypical altitude strongly suggest epidemiological areas as potential for expansion. Current climate changes associated with human activities have contributed to the resurgence of infection and its expansion into new areas. Climate changes affect vector distribution and, additionally, phenomena such as El Niño have caused an increase in humidity levels, which favors the reproduction of vectors and the occurrence of outbreaks.22,23 Some studies envolving animals to search for potential new hosts have shown that some species of apes in the jungles of South America, such as the Feline Night Monkey (Aotus infulatus), are susceptible to B. bacilliformis infection. These data warn of the risk of expansion of Carrion's disease due to the possible adaptation of vectors in areas inhabited by these animals, which may serve as disease dispersal facilitators in neighboring endemic regions, including Brazil.24

The disease is biphasic, with an acute phase (Oroya fever) characterized by fever, hemolytic anemia, and transient immunodeficiency and a chronic phase (Peruvian wart) marked by cutaneous vasoproliferative lesions.1,25

The acute phase of the disease lasts from one to four weeks and severity can range from mild to fatal. Absence of antibiotic treatment can lead to a mortality rate of up to 88%. This is caused by the massive invasion of erythrocytes and initially leads to non-specific symptoms such as malaise, drowsiness, headache, chills, fever, anorexia and myalgia, which make the patient increasingly more jaundiced and confused. As the disease progresses, a severe hemolytic condition, accompanied by lymphadenopathy and hepatosplenomegaly, is established. Disease worsening can lead to acute respiratory distress, pericardial effusion, myocarditis, endocarditis, delirium, seizures, coma and multiple organ failure.1,9,25

After an average of two months in the acute febrile phase (which may not occur, particularly in natives of the endemic region) the Peruvian wart appears, an eruptive cutaneous manifestation formed by angiomatous lesions, which is often clinically and histologically similar to lesions of bacillary angiomatosis (BA). These lesions may present as angiomatous lesions, papules, papule-tumors, or nodules. They appear in patches, predominantly on the face and extremities, and measure 0.2–4cm in diameter. They may persist for months or even years, and can be accompanied by fever, bone, and/or joint pains. The severity of the eruption is variable and it appears not to be related to previous antibiotic treatment. This is the tissue phase of Carrion's disease and is self-limiting.26 Although not fatal, if left untreated, these lesions persist as pathogen reservoirs and a source of contagion through the vector. This infection is usually treated with rifampicin, although streptomycin is also effective and was the drug of choice before 1975. Peruvian wart does not respond to treatment with chloramphenicol or penicillin. Treatment alternatives include ciprofloxacin and azithromycin associated with deflazacort.27 It does not lead to scarring, except when there is secondary infection.28,29

Histologically, Peruvian wart lesions show a proliferation of endothelial cells of the terminal vasculature in the dermis and subcutis. The acute and chronic inflammatory infiltrate that accompanies the presence of B. bacilliformis in the interstice and inside the endothelial cells is an important finding, even in non-ulcerated lesions. The lesions can have more differentiated and ectatic vessels that are clinically and histologically similar to pyogenic granuloma. Cellular atypia can be seen, particularly in more solid lesions, with imperceptible lumens and spindle cells that resemble Kaposi sarcoma.30

B. quintana was initially associated with trench fever (TF), characterized by recurrent febrile episodes. Currently reported in hikers, alcoholics, and AIDS patients in the United States and Europe, the disease has been considered as re-emergent and is the agent implicated in cases of chronic bacteremia, endocarditis, and BA. Humans are the only known reservoirs and the transmission among them is through body lice, the reason why this pathogen is strongly associated to unsanitary conditions and poor personal hygiene.31 The disease is also known as quintana fever or five-day fever, and it has an incubation period of 15–25 days. TF can be asymptomatic or severe. Approximately half of those affected experience a sudden onset of flu-like symptoms with no respiratory symptoms and short duration. High and prolonged fever can occur over several weeks. Symptoms remit for many days and after an asymptomatic period there can be paroxysmal clinical exacerbation three to five times or more within a year.30 Eighty to 90% of patients present with erythematous, maculopapular lesions of up to 1cm on the trunk.32 Furred tongue, conjunctival congestion, and musculoskeletal pain are frequently associated.33

B. henselae is a zoonotic agent whose main reservoir is domestic cats. Transmission between cats does not occur in the absence of fleas, although transmission to humans is often associated with cat scratches. Fig. 1 shows the cat scratch observed in a 28-year-old man with Type I diabetes, presenting with nausea and vomiting for three days and lowering of consciousness for one day. He had Glasgow 3 level of consciousness and sepsis of unknown origin. There were two injuries that suggested scratching lesions. Infection by Bartonella sp. was detected through conventional polymerase chain reaction (PCR) for the internal transcribed spacer (ITS) region from a blood sample.

Figure 1.

Lesions caused by cat scratches presented by a 28-year-old man with Bartonella sp. infection detected by polymerase chain reaction.

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Contact with cats is a risk factor for B. henselae infection.34 Cats living in warm and humid geographical areas have a higher number of potential vectors and higher levels of bacteremia (7–%–43%) and anti-B. henselae seroprevalence (4%–81%).25,35 This suggests that Bartonella sp. infection could be more prevalent in developing tropical countries. In Campinas, SP, Brazil, 90.2% of the cats involved in the study were positive for the test detecting the presence of B. henselae DNA in their blood.36

Besides cats, other pets already described as reservoirs include guinea pigs, rabbits, and dogs.37

Ticks have been proven to be vectors37 and contact with these arthropods has been associated with Bartonella sp. infection in blood donors from Hemocentro at Unicamp (Campinas, SP).34

Immunocompetent patients infected with B. henselae can develop cat scratch disease (CSD), characterized by a self-limited regional lymphadenitis associated with fever.

For Bass et al.38 in their review, CSD incidence is proportional to the density of the cat population, their ages, and human exposure to these animals. The authors also related the incidence of the disease to the prevalence and degree of infestation by fleas, Ctenocephalides felis, to warm and humid climates, related to geographical location and seasonality, reinforcing that the disease is more prevalent in tropical regions.

Lymphadenitis follows the primary lesion, from a few days to many weeks after the cat scratch or bite, apparently by the exposure of the dermis to bacteria found in the feces of feline fleas. It is characterized by an erythematous, non-pruritic papule on the area of the trauma or on its extremity, in case of a scratch. In 2–3 days it becomes vesicular and crusty, remaining for a few days and evolving to a patch that can last for up to 2–3 months. The lesion persists for 7–21 days or is sometimes present with lymph node enlargement. Rarely, the cutaneous lesion is the only clinical manifestation, even when there is history of a scratch or bite. The presence of the inoculation lesion should be thoroughly sought in the history and physical examination, since it can be found in over 90% of cases.25 After this period there can be superficial scarring similar to that of varicella. It may measure from a few millimeters to 1cm in diameter.30

The histopathology of cutaneous lesions mimics that of lymph nodes, with the formation of granulomas with a central necrotic area, surrounded by lymphocytes and histiocytes and with a neutrophilic infiltrate. The pus can be loculed, which is important during aspiration. It differs from other granulomatous diseases with the presence of concurrent microabscesses and granulomas.39 Histopathological findings in lymph nodes can be mistaken for those seen in Hodgkin's disease, including cells similar to Reed–Stenberg cells.40 Microabscesses with bacterial clusters identified with the Warthin–Starry staining may be observed, mainly on newer lesions.26

Although rare, purpura can be serious.41 Maculopapular exanthem, erythema multiforme, and erythema nodosum are the cutaneous manifestations that, for Warwick,42 accompany CSD. For that author, erythema nodosum is the most frequent, to which Carithers,43 who does not see this association as a surprise, agrees, since erythema nodosum appears in the course of other granulomatous diseases such as tuberculosis and sarcoidosis. Erythema nodosum can occur in association with typical cases but usually appears associated with diffuse and non-regional lymph node enlargement.44

B. henselae also causes a wide variety of clinical conditions, such as fever of unknown origin, splenic and hepatic manifestations, encephalopathies, ocular diseases, endocarditis, etc.1

Patients infected by B. quintana or B. henselae, particularly those who are immunodeficient, can develop BA, which is characterized by angioproliferative lesions.21 Specifically in cases of B. henselae infection, these injuries may also be associated with peliosis, a rare condition characterized by small blood-filled cystic spaces found in the liver, often diagnosed only through biopsy, which may cause liver failure or rupture and may even be fatal.21,45 Bacillary peliosis can also affect other organs.46

Cutaneous lesions are the main manifestations of BA but the disease may not affect the skin in up to 45% of cases.47 They may be solitary lesions, but, more frequently, are multiple and widespread. They may be papules, plaques, angiomatous tumors, rarely hyperkeratotic, or nodules with skin-colored surface. A scaling collarette on the base of the lesion is a typical feature. They resemble pyogenic granuloma. They are friable and can bleed easily and profusely. The presentation of hardened and hyperpigmented plaques is the least frequent. There are reports of involvement in the oral, anal, conjunctival, gastrointestinal, and female genital mucous membranes, as well as airways. BA can be accompanied by disseminated visceral disease both in immunodeficient and immunocompetent individuals.38,48,49Fig. 2 shows the case of a single angiomatous lesion in the third interdigit of the right hand of a 26-year-old woman presenting with fever, oral candidiasis, and weight loss for 2 months. Anti-HIV serology was reagent. Anatomopathological examination was compatible with bacillary angiomatosis and Warthin–Starry staining showed bacterial clumps. Gram-negative bacilli were observed through the analysis of a skin fragment using transmission electron microscopy.

Figure 2.

Bacillary angiomatosis: (A) single angiomatous lesion on the third interdigit of the right hand of a woman; (B) electron microscopy of cutaneous fragment transmission with innumerable Gram-negative bacilli featuring intra- and extracellular distribution (1200×, inset 16,000×).

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Differential diagnosis with Kaposi sarcoma can be clinically impossible, particularly with early sarcomatous lesions. Both diseases can occur at the same time. Any other angiomatous lesions will be part of the differential diagnosis.26,30

Regarding histology, there are three main features: (1) angioproliferation in lobules, with vessels formed by prominent endothelial cells, with atypia and mitoses being seen in areas with dense cellularity; (2) predominance of neutrophils in the inflammatory infiltrate and occasional leukocytoclasia; (3) presence of interstitial or intracellular bacterial clumps found with Warthin–Starry staining, immunohistochemistry, transmission electron microscopy, or confocal microscopy.26,30,50

It has been suggested that the difference between the angiogenic and granulomatous response triggered by the organism observed in BA and CSD, respectively, appears to be determined by the degree of the host's immunocompetence.51,52 The concurrence of lesions with clinical and pathological features of CSD and BA, also reported after the use of corticosteroids, with the demonstration of the same agent, supports the above interpretation.53

Bartonella spp. can cause asymptomatic cyclic bacteremia in humans and animals. This chronic infection can potentially result in endocarditis and be fatal.1 Nearly 31% of endocarditis cases have negative cultures and of those, up to 30% are caused by Bartonella spp.20 Six species of Bartonella have been associated with endocarditis, but 95% of endocarditis cases from these agents are caused by B. quintana or B. henselae.54 Vasculitis can occur and even simulate systemic vasculitis with antineutrophil cytoplasmic antibodies (ANCA) positivity (Fig. 3).55Fig. 3 shows a case of skin vasculitis seen in a 42-year-old white male with a history of cat scratches and fever for 2 months. Skin lesions had appeared on his legs two weeks earlier. The diagnosis of endocarditis caused by B. henselae was confirmed by serology, PCR and culture.

Figure 3.

Cutaneous vasculitis on the leg of a 42-year-old man with a history of cat scratches and fever, with a diagnosis of B. henselae endocarditis confirmed by polymerase chain reaction, serology, and culture.

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B. henselae can cause chronic non-specific hepatic inflammation in adults and children. It can also be responsible for hepatic angiomatosis and bacillary peliosis, besides granulomatous hepatitis, with or without necrosis. Bartonella spp. are not included in guidelines for the screening of cryptogenic hepatitis and it is possible that part of the 40% of de novo hepatitis cases that occur after liver transplants are related to infection by these bacteria.56

Often identified as the clinical expression of atypical CSD, non-classic forms of the disease should be considered separately, sch asmorbilliform exanthem, urticaria, erythema marginatum, granuloma annulare, leukocytoclastic vasculitis.32,41Fig. 4 shows a case of annular granuloma in a 52-year-old woman who reported a lesion similar to the image at the site of a cat scratch on her left forearm seven years earlier. The lesions spread. She had intense myalgia and arthralgia that made walking difficult. Chest and abdominal tomography showed mediastinal and retroperitoneal multiple lymph node enlargement. She had been treated with deflazacort 7.5mg/d, methotrexate 15mg/week and hydroxychloroquine 400mg/d for 2 years, with a diagnosis of sarcoidosis. The anatomopathological examination of the skin was compatible with annular granuloma. B. henselae DNA was amplified in a fragment of a mediastinal lymph node and in the patient's blood.

Figure 4.

Annular granuloma presented by a 52-year-old woman. B. henselae DNA was amplified in a fragment of the mediastinal lymph node and in the patient's blood.

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Pyogranulomatous panniculitis was described in a dog whose owner had similar lesions. Both improved with treatment for Bartonella sp. infection.57 The authors followed a 32-year-old woman with sclerosing panniculitis, with a granulomatous reaction on her right leg detected during histological analysis and history of recurrent anemia of unknown origin, dependent on corticosteroids for 4 years. Electron microscopy showed Gram-negative bacteria inside an erythrocyte. Her case improved with erythromycin treatment. With the discontinuation of the antibiotic therapy after six weeks, the lesions recurred and no longer responded to antibiotic therapy. A blood sample from the patient was subsequently screened for B. henselae DNA, which showed to be positive (Fig. 5).

Figure 5.

Sclerosing panniculitis with recurrent anemia. Sclerosing panniculitis in the right leg of a 32-year-old woman with a history of recurrent anemia of unknown origin. The patient subsequently tested for positive B. henselae DNA in blood samples.

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Cutaneous manifestations can appear whether or not associated with granulomatous manifestation on the liver, spleen, heart, bones, and mesenteric and/or mediastinal lymph nodes.30

A growing number of possible immune parainfectious or post-infectious manifestations have been described in association with Bartonella spp. infection.41 Considering the broad spectrum of the infection and the potential complications associated to Bartonella spp., the infection should be considered by physicians more frequently among the differential diagnoses of idiopathic conditions. The conditions that should include Bartonella sp. infection in the differential diagnosis are listed in Table 1.

Bartonellosis are associated with a broad spectrum of symptoms, debilitating conditions, and potentially fatal outcomes. Ectoparasites are involved in the transmission of Bartonella sp. These diseases are frequently neglected by health care professionals and researchers. The infection can be asymptomatic and have a great impact on the morbidity of, for example, patients with Hansen's disease (as triggers for Type 2 leprosy reaction), or patients with sickle cell anemia (associated with painful crisis due to vaso-occlusion), and cryptogenic hepatitis or cirrhosis. Diagnosis is challenging because physicians do not consider the possibility of bartonellosis and, even when this occurs, there are technical and laboratory difficulties for a conclusive diagnosis. There should be incentives for more research related to Bartonella spp. infection. There are limited resources for the investigation of these agents since Bartonellosis are not even in the list of neglected diseases of the World Health Organization.83 However, these diseases are amenable to being controlled, prevented, and even eradicated with plausible and effective measures.

Doctoral Scholarship from CNPq159717/2013-2 (Drummond, MR); Productivity Grant from CNPq 301900/2015-9 (Velho, PENF).

Karina de Almeida Lins: Approval of final version of the manuscript; conceptualization and planning of the study; composition of the manuscript; critical review of the literature; critical review of the manuscript.

Marina Rovani Drummond: Approval of final version of the manuscript; composition of the manuscript; critical review of the literature; critical review of the manuscript.

Paulo Eduardo Neves Ferreira Velho: Approval of final version of the manuscript; conceptualization and planning of the study; composition of the manuscript; critical review of the literature; critical review of the manuscript.

None declared.