Version May 2024
INTRODUCTION — South American bartonellosis, or Carrion's disease, is an infection caused by Bartonella bacilliformis, a pleomorphic gram-negative bacterium. This organism is transmitted to humans predominantly by female phlebotomine sand flies [1,2]. The disease typically manifests as a biphasic illness, with an initial febrile phase, known as Oroya fever, followed by a secondary phase, characterized by the development of nodular skin lesions, known as verruga peruana. Variable clinical patterns associated with this infection have been observed, ranging from asymptomatic bacteremia to fulminant illness [1,2].
Issues related to B. bacilliformis will be reviewed here; issues related to infection caused by other Bartonella species are discussed separately. (See related topics.)
HISTORY — There is evidence from pre-Columbian artifacts that the verrucous cutaneous form of the disease was present in South America at least 1000 years prior to the arrival of Europeans [3]. During the Inca era, the disease was called "Sirki," which means "warts in blood." Subsequent descriptions of similar verrucous skin lesions emerged in the 16th century among Spanish conquistadors, and these lesions became known as verruga peruana [2,4]. In 1871, a major outbreak of febrile hemolytic anemia occurred among workers constructing a railway line to the mining town of La Oroya near Lima, Peru; this outbreak resulted in the death of more than 4000 workers and was referred to as Oroya fever [2]. Less than 15 years later, in 1885, Daniel Alcides Carrión, a Peruvian medical student, demonstrated that verruga peruana and Oroya fever are caused by the same organism; this discovery resulted from a heroic experiment in which when he injected himself with infectious skin lesion material from a patient with verruga peruana and soon thereafter developed a fatal infection with fever and severe hemolytic anemia [2,4]. As a tribute to him, both manifestations of this disease were thereafter known as Carrion's disease [5].
EPIDEMIOLOGY — Carrion's disease is endemic to the "verruga zone," a region in the Andes Mountains of Peru, Colombia, and Ecuador, but new emerging areas have been described in these countries [2,6,7]. Sporadic cases have been reported in Bolivia, Chile, and Guatemala [8].
B. bacilliformis is transmitted by the bite of the female sand fly of the genus Lutzomyia spp. The vector typically lives 500 to 3200 meters (1600 to 10,500 feet) above sea level and feeds during the night, particularly at dusk [1,9]. Lutzomyia verrucarum is the most effective vector in Peru [10]. Some outbreaks in nonendemic areas have been associated with other Lutzomyia species, such as L. maranonensis, L. robusta, and L. peruensis, denoting the potential of the vector to adapt to other climates and spread the disease to other regions [11-13]. Lutzomyia columbiana has been proposed as a new potential vector for Carrion's disease in Colombia [7].
Other possible vectors have been described in areas where Lutzomyia spp are not commonly found. B. bacilliformis has been isolated by polymerase chain reaction in ticks (Amblyomma spp and Rhipicephalus spp) collected from tapirs and collared peccaries captured in the Peruvian Amazon [14]. Humans are the principal hosts; no reservoir of B. bacilliformis has been identified in any domestic or wild animal.
Oroya fever occurs most frequently among tourists and transient workers who are immunologically naïve to B. bacilliformis, whereas verruga peruana occurs most frequently among individuals living in the verruga zone. In one cohort study in an endemic region of Peru, the incidence in the general population was 12 cases per 100 person-years, with a breakdown of clinical manifestations as follows [9]:
●Oroya fever (11 percent)
●Verruga peruana and a recent febrile illness suggestive of Oroya fever (37 percent)
●Verruga peruana without a recent febrile illness (32 percent)
●Asymptomatic infection (21 percent)
Infection occurred most frequently among children <5 years of age (38 cases per 100 person-years), and there was a linear decrease in incidence with increasing age. Clustering of cases was also observed; 70 percent of cases occurred in 18 percent of households.
Underreporting can occur in the setting of mild infection. One series of 11 patients with chronic verrucous skin lesions was described in a coastal, lowland region of Ecuador [15]. A serologic study of more than 200 individuals in the surrounding region noted 21 percent seropositivity among contacts of index cases. Likewise, a study done among healthy children in six rural communities in the highlands of Ecuador showed a seroprevalence of 28 percent [6].
Vertical transmission of B. bacilliformis to a newborn whose mother had a febrile illness in the third trimester of pregnancy has been described [16].
Climate change has been associated with increases in the incidence of Carrion's disease in Peru, as occurred during the El Niño events of 1986 to 1988 and 1997 to 1998 [17,18].
MICROBIOLOGY — B. bacilliformis was the first Bartonella organism identified as a human pathogen. It is an intracellular, pleomorphic, gram-negative bacterium that is the recognized causative organism of Oroya fever and verruga peruana.
It is possible that some illnesses previously attributed to B. bacilliformis are due to a subsequently recognized Bartonella species, Bartonella rochalimae; this organism was isolated from an American tourist who presented with fever, splenomegaly, anemia, and a history of insect bites after a trip to Peru that included travel to a region in which B. bacilliformis is endemic [19]. Studies performed in endemic and nonendemic areas for B. bacilliformis have demonstrated B. rochalimae infection in asymptomatic dogs as well as in fleas from cats and guinea pigs; these findings support the potential zoonotic transmission of this pathogen [20,21].
Another Bartonella species, Bartonella ancashensis, was identified in 2003 during an antibiotic treatment trial of patients with verruga peruana; two patients were infected with a Bartonella species distinct from any known Bartonella species, and molecular analysis identified a new species that is phylogenetically similar to B. bacilliformis [22-24].
PATHOGENESIS — B. bacilliformis produces virulence factors, including adhesin, flagellin, and hemin, that alter the immune system and allow the organism to evade the host immune response [25]. In addition, these virulence factors facilitate the organism's invasion of erythrocytes (causing intraerythrocytic replication and hemolysis) and replication within endothelial cells (promoting proliferation and angiogenesis) [25]. In the acute phase, the organism causes a substantial increase in interleukin-10 secretion by erythrocytes, which attenuates cytokine production and suppresses the function of certain immune cells, including T helper cells, macrophages, and dendritic cells [26,27]. This perturbation in host immune function favors persistent B. bacilliformis infection and creates an immune state that is more vulnerable to secondary infection with bacterial pathogens. During the chronic form, there are high levels of interferon-gamma and interleukin-4 [28].
It was previously believed that B. bacilliformis was the only Bartonella with multiple unipolar flagella; this characteristic provides a unique mechanism to enter erythrocytes. Subsequently, multiple unipolar flagella have been observed in other Bartonella species, including B. rochalimae, B. schoenbuchii, and B. clarridgeiae [19,29,30]. Other organisms lacking these flagella are capable of entering red blood cells via other mechanisms.
In the chronic form of the disease, the bacterium invades endothelial cells, forms Rocha-Lima inclusion bodies, and causes overproduction of epidermal growth factor (EGF); the abundant production of EGF stimulates endothelial proliferation and angiogenesis, producing hypervascular nodules. Similar events have been described in the setting of infection due to other Bartonella species that cause bacillary angiomatosis [31,32]. (See "Bartonella infections in people with HIV", section on 'Bacillary angiomatosis'.)
CLINICAL MANIFESTATIONS — Infection with B. bacilliformis causes an acute febrile illness, Oroya fever, and a secondary phase with chronic cutaneous manifestations, verruga peruana [33,34]. Other clinical presentations may also occur, including asymptomatic or chronic bacteremia, verruga peruana without Oroya fever, or recurrent verrucous illness; serologic surveys indicate that as many as 56 percent of seropositive individuals have asymptomatic infection [35]. In addition, many patients who develop verruga peruana lesions do not recall a history of febrile illness in the preceding three months [9,34]. The incubation period of South American bartonellosis is 1 to 30 weeks (mean 8 weeks) [1].
Acute phase (Oroya fever) — The acute, or hematic, phase generally begins with an insidious onset of mild fever, headache, anorexia, and malaise [33]. In one review that included 145 patients with bartonellosis, the most common clinical features were fever, pallor, malaise, painless hepatomegaly, and lymphadenopathy [34]. Anemia develops due to parasitic infection of red blood cells and cells of the reticuloendothelial system, with subsequent clearance of parasitized cells from circulation [36]. The acute phase lasts two to four weeks, and the majority of patients who receive treatment recover; progression to the eruptive phase occurs after weeks or months in less than 5 percent of cases.
In the absence of antimicrobial therapy, mortality can reach 90 percent; when treatment is started early, mortality is generally less than 10 percent [34]. Factors associated with poor prognosis include the presence of anasarca, petechiae, and altered mental status [34]. Other risk factors associated with increased mortality include age >45 years, history of alcohol use, and presentation with shock, pulmonary edema, pericarditis, seizures, or coma [37].
Acute phase secondary complications are common, as discussed in the following section.
Complications — Infectious and/or noninfectious complications occur in up to 70 percent of patients with Oroya fever.
Infectious complications include secondary infection with Salmonella (typhi and non-typhi), Shigella dysenteriae, Staphylococcus aureus, Klebsiella spp, Enterobacter spp, Candida spp, toxoplasmosis reactivation, disseminated histoplasmosis, Pneumocystis jirovecii pneumonia, leptospirosis, and malaria due to Plasmodium vivax [34,38-40]. Apart from hemolytic anemia associated with Bartonella described earlier, other hematological syndromes include disseminated intravascular coagulation, autoimmune hemolytic anemia, hemophagocytic syndrome, and thrombocytic purpura [41].
Noninfectious complications include anasarca, neurologic manifestations, ocular compromise, and cardiovascular complications [34]. In one study that included 68 patients with Oroya fever in Peru, cardiovascular complications were observed in 53 percent of cases; the investigators reported a range of cardiovascular complications [42]:
●Heart failure – 91 percent
●Pericardial effusion – 44 percent
●Pulmonary edema – 36 percent
●Cardiogenic shock – 17 percent
●Cardiac tamponade – 11 percent
●Myocarditis – 11 percent
In addition, B. bacilliformis has been reported as the etiology of acute endocarditis in a child with congenital coronary artery-to-right ventricular fistula and in an adult whose clinical course was complicated by the development of systemic vasculitis [38,43].
Eruptive phase (verruga peruana) — The eruptive, or verruga, phase occurs after organisms invade capillary endothelial cells and induce cellular proliferation, producing hemangioma-like nodules in the skin and mucous membranes [33]. Verruga peruana can appear two to eight weeks after the patient has apparently recovered from Oroya fever [3,44]. However, most patients with verruga peruana do not have an antecedent history of febrile illness.
There are three major types of skin lesions: miliary, nodular, and mular [34].
●Miliary lesions are small (less than 3 mm), round, soft, reddish pinpoint papules clustered in crops that are confined to the papillary dermis (picture 1) [36,44]. Untreated, these lesions can progress to the nodular phase.
●Mular lesions are nodular lesions that evolve into larger (>5 mm) lesions (picture 2). These lesions are highly vascular, bulbous, tend to bleed easily, and can ulcerate.
●Nodular lesions are nontender wart-like lesions that may become pedunculated (picture 3). Some subcutaneous lesions become apparent with a purplish color on the skin surface as they push upward, thinning the overlying skin.
Lesions usually develop on the skin but can also involve mucous membranes. Lesions of more than one type may occur simultaneously in a given patient [44]. In the absence of antimicrobial therapy, lesions may persist for months or years. Patients with verruga peruana often have concomitant systemic symptoms like fever, malaise, or osteoarticular pain [34].
As lesions regress, they become more pale because of diminished vascularization. There may be some residual hyperpigmentation, but scarring does not usually occur. Recurrence of verrucous lesions has also been described. Mortality in the eruptive phase is very low [45].
The verruga lesions are formed by proliferation of capillaries and endothelial cell hyperplasia and are similar to those seen in cutaneous bacillary angiomatosis and Kaposi's sarcoma. (See "Bartonella infections in people with HIV" and "AIDS-related Kaposi sarcoma: Staging and treatment".)
DIAGNOSIS — The diagnosis of Oroya fever is established by blood culture or by identification of B. bacilliformis organisms on a Giemsa-stained blood smear (picture 4) [44]. More than 70 percent of patients with acute Oroya fever have a positive blood culture for B. bacilliformis; there may be a delay of more than 14 days for the organism to grow in culture. B. bacilliformis is fastidious and requires Columbia agar, an enriched blood medium, for growth, which occurs most readily at 25 to 28°C; other Bartonella spp grow readily at 37°C [46]. Routine blood cultures are useful to evaluate for the presence of secondary bacteremia. The reliability of microscopy depends on the skill of the laboratory technician and may be associated with misdiagnosis [47].
The diagnosis of verruga peruana is generally based on characteristic clinical features, with or without skin biopsy [34]. Studies have reported positive blood cultures for B. bacilliformis in 13 to 47 percent of patients with verruga peruana, but the clinical significance of bacteremia at this stage is unknown since many of these represent asymptomatic or transient bacteremia [34,48].
The histologic findings consist of a highly dense proliferation of small- and large-sized blood vessels [49]. Neutrophils and endothelial cells predominate in the dermis; histiocytes, plasma cells, lymphocytes, and mast cells are also variably present. Hyperkeratosis, parakeratosis, and mild acanthosis are observed in the epidermis. In some cases, Giemsa staining of a biopsy sample demonstrates characteristic cytoplasmic inclusions, referred to as Rocha-Lima inclusions [49]. In addition, electron microscopy allows visualization of the B. bacilliformis organism [49]. Phagocytized B. bacilliformis may be observed within neutrophils, histiocytes, and/or endothelial cells [49,50].
Serologic tests for B. bacilliformis infection have been developed [51], including an immunoblot test that uses a sonicate of whole B. bacilliformis as an antigen [52], and an indirect fluorescence antibody test [48]. These tests have been useful in epidemiologic studies [51].
Excellent results with polymerase chain reaction (PCR) techniques for diagnosing B. bacilliformis on blood samples from patients with clinically diagnosed Oroya fever have been described [53]. Among the different approaches, Bartonella-specific 16S rRNA PCR presents the lowest detection limit (5 colony-forming units/mcL) in blood samples and dried blood spots, improving the detection of patients with low-level bacteremia [54]. However, its high cost and the lack of molecular laboratories in endemic areas limits its use [53,55]. Loop-mediated isothermal amplification, a nucleic acid amplification method, demonstrates similar sensitivity to PCR but requires less specialized equipment, enabling use in some endemic areas [56].
DIFFERENTIAL DIAGNOSIS — South American bartonellosis may be confused with other illnesses that cause fever or cutaneous lesions. Oroya fever can mimic other infectious and tropical diseases (table 1):
●Zika and Chikungunya fever are arboviruses in South America that cause acute febrile illness in areas where Oroya fever has been described. (See "Zika virus infection: An overview" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
●Malaria and dengue share some common clinical features and similar endemic patterns with Oroya fever. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Dengue virus infection: Clinical manifestations and diagnosis".)
●Oroya fever may mimic infection with Salmonella typhi in areas of the tropics where typhoid fever is common, particularly in patients with prominent gastrointestinal complaints. In addition, typhi and non-typhi Salmonella may cause secondary infection in patients with Oroya fever. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
●Viral hepatitis constitutes an important differential diagnosis in the highlands and the Amazon basin, where prevalence of both conditions is high.
●Some clinical features of Oroya fever overlap with those of leptospirosis. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
●Bartonellosis may have features that overlap with hematologic malignancy such as acute leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)
Verruga peruana may need to be differentiated from other skin conditions, including (table 1):
●Bacillary angiomatosis – Bacillary angiomatosis occurs most often in patients with HIV infection or other form of immunosuppression. (See "Bartonella infections in people with HIV", section on 'Bacillary angiomatosis'.)
●Yaws – Yaws causes papules with subsequent ulceration. Clinical diagnosis is generally straightforward in endemic areas; confirmation requires serology.
●Pyogenic granuloma – Pyogenic granuloma is a benign vascular tumor of the skin or mucous membrane. (See "Pyogenic granuloma (lobular capillary hemangioma)".)
●Angioma – An angioma is a capillary proliferation on the skin. (See "Overview of benign lesions of the skin", section on 'Cherry angioma'.)
●Cutaneous lymphoma – Cutaneous lymphomas are a heterogeneous group of T cell and B cell neoplasms that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. (See "Classification of primary cutaneous lymphomas".)
●Capillary malformation – Capillary malformation is a vascular malformation with nodular features that is present at birth. (See "Capillary malformations (port wine birthmarks) and associated syndromes".)
●Kaposi sarcoma – Kaposi sarcoma is an angioproliferative disorder due to infection with human herpesvirus 8. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment".)
●Tuberculosis and atypical mycobacterial infection – Rapidly growing mycobacteria can cause cutaneous infection. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
●Mpox – Mpox is an emerging disease caused by monkeypox virus; it can manifest as a painful rash involving the face and extremities, similar to verruga peruana. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)".)
TREATMENT — Prompt initiation of appropriate antimicrobial therapy is essential for patients with known or suspected Bartonellosis infection (table 2). The optimal approach to treatment is uncertain; clinical practice is based on small case series.
In vitro susceptibility testing for Bartonella species is difficult because the organism is fastidious; primary isolation requires up to four weeks of incubation on blood agar plates [57]. Multiple antimicrobial agents are active against B. bacilliformis in vitro, including chloramphenicol, fluoroquinolones, penicillins, cephalosporins, doxycycline, rifampin, and trimethoprim-sulfamethoxazole. Vancomycin, clindamycin, aminoglycosides, and imipenem are not considered good treatment options for this organism since relatively high doses are required to inhibit bacterial growth [1,57].
Oroya fever — For treatment of uncomplicated Oroya fever in nonpregnant adults, we favor ciprofloxacin; data for this approach are limited and largely based on observational data and clinical experience [57]. There are no well-designed clinical trials that have evaluated the possible resistance of B. bacilliformis to ciprofloxacin, but limited in vitro data has suggested intrinsic resistance and reduced susceptibility to nalidixic acid and ciprofloxacin among some isolates [58-60]. An antimicrobial susceptibility assessment of 100 strains isolated from endemic areas in Peru demonstrated a 26 percent resistance to ciprofloxacin [61]; therefore, for treatment of severe or persistent disease, we favor administering the combination regimen of ceftriaxone and ciprofloxacin [62].
Previously, chloramphenicol was a preferred agent for treating Oroya fever [34,63,64]; we favor it as an alternative treatment choice [65]. It has activity against B. bacilliformis as well as Salmonella, a common secondary infection [63,66]. However, treatment failure with persistent Bartonella bacteremia and relapse after treatment has been described among patients treated with chloramphenicol [34,67]. In addition, successful treatment of Oroya fever with chloramphenicol does not eliminate the risk for development of verruga peruana [57]. If chloramphenicol is used, coadministration of another antibiotic (such as a beta-lactam agent) is warranted.
For the treatment of uncomplicated Oroya fever in children and pregnant women, we favor amoxicillin-clavulanic acid; in severe cases, we favor treatment with ceftriaxone [62]. Ciprofloxacin and chloramphenicol should be avoided in pregnancy [68].
Dexamethasone may be administered for patients with severe neurologic complications to reduce cerebral edema. Blood transfusion may be warranted in cases of severe anemia [69].
Dosing is summarized in the table (table 2).
With successful therapy, clinical response is generally observed promptly, including defervescence and resolution of hemolysis.
Verruga peruana — We favor azithromycin for the treatment of verruga peruana in adults, children, and pregnant women [46,62]. Azithromycin has been shown to have clinical efficacy comparable to rifampin [8].
Rifampin is an acceptable alternative agent for treating verruga peruana [34,64], although its use as monotherapy may lead to rapid development of resistance, and treatment failures with rifampin have been described [70]. In addition, the verruga zone contains regions with a high incidence of tuberculosis, and rifampin monotherapy may lead to mycobacterial resistance. Intramuscular streptomycin and oral rifampin have comparable efficacy; rifampin is favored over streptomycin, given the difficulty with adherence to intramuscular therapy [34].
Ciprofloxacin is also an acceptable alternative agent for treating verruga peruana [46,57]. Its efficacy appears to be similar to that of azithromycin, although there is less clinical experience with this agent, and it is not appropriate for the treatment of pregnant women.
Chloramphenicol is not effective for the treatment of verruga peruana.
Dosing is summarized in the table (table 2).
With successful therapy, the skin lesions typically resolve within one month with no residual scarring.
There is no available vaccine against B. bacilliformis. In vitro studies and whole-genomic sequencing of different strains have led to the synthesis of proteins that can serve as a potential target for vaccine development [71-74]. A vaccine candidate that used an external membrane protein was evaluated in a murine model and shown to stimulate an immunogenic response with production of antibodies that inhibited the invasion of B. bacilliformis in human erythrocytes [75]. Further studies are needed to characterize its immunogenic properties and elucidate the potential role of vaccines in preventing Carrion's disease.
SUMMARY AND RECOMMENDATIONS
●South American bartonellosis, or Carrion's disease, is an infection caused by Bartonella bacilliformis and transmitted by phlebotomine sand flies. The classic biphasic illness is characterized by an initial febrile phase, known as Oroya fever, followed by a secondary phase characterized by the development of skin lesions, known as verruga peruana. (See 'Introduction' above.)
●South American bartonellosis is endemic to the "verruga zone," a region in the Andes Mountains of Peru, Columbia, and Ecuador. New endemic areas have been described in these countries and can be related with new potential vectors. Oroya fever occurs most frequently among tourists and transient workers who are immunologically naïve to B. bacilliformis, while verruga peruana occurs most frequently among individuals native to the verruga zone. (See 'Epidemiology' above.)
●The acute, or hematic, phase generally begins on average two months after inoculation, usually with insidious onset of mild fever, headache, anorexia, and malaise. This stage lasts between two to four weeks; mortality is low in patients who receive appropriate antimicrobial therapy. Anemia develops due to parasitic infection of red blood cells and cells of the reticuloendothelial system, with subsequent clearance of parasitized cells from the circulation. (See 'Acute phase (Oroya fever)' above.)
●The eruptive, or verruga, phase occurs after organisms invade capillary endothelial cells and induce cellular proliferation, producing hemangioma-like nodules in the skin and mucous membranes. Verruga peruana can appear weeks or months after the patient has apparently recovered from Oroya fever. However, most patients with verruga peruana do not have a clear antecedent history of febrile illness. (See 'Eruptive phase (verruga peruana)' above.)
●The diagnosis of Oroya fever is made by blood culture or by identification of B. bacilliformis organisms on a Giemsa-stained blood smear. The diagnosis of verruga peruana is generally based on characteristic clinical features and serology and confirmed by histopathologic analysis. (See 'Diagnosis' above.)
●We suggest ciprofloxacin for treating uncomplicated Oroya fever in nonpregnant adults (Grade 2C); for the treatment of severe or persistent disease, we favor the administration of ciprofloxacin in combination with ceftriaxone. For the treatment of uncomplicated Oroya fever in children and pregnant women, we favor treatment with amoxicillin-clavulanic acid; in severe cases, we favor treatment with ceftriaxone. Dosing is summarized in the table (table 2). (See 'Oroya fever' above.)
●We suggest azithromycin for treating verruga peruana in adults, pregnant women, and children (Grade 2C); rifampin and ciprofloxacin are alternative choices. Dosing is summarized in the table (table 2). (See 'Verruga peruana' above.)
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