Oroya Fever Research Articles

Bartonellosis (Oroya Fever, Peruvian Wart): A Case Report

Bartonellosis (also called Carrión's Disease, Oroya Fever or Peruvian Wart) is caused by the bite of mosquitoes of the Lutzomyia genus belonging to the Psychoid family. They are nocturnal blood-sucking insects, with complete metamorphosis. About 450 species are known, distributed throughout the American continent, mostly in tropical and subtropical areas. In Ecuador, sporadic cases have been reported, with certain characteristics such as, for example, not presenting the blood phase and, in the eruptive phase, not being aggressive. Here, we present a unique case of a 13-year-old boy with a history of congenital heart disease, who presented a clinical picture of one year of evolution suggestive of dermatosis, characterized by papules and nodules that occasionally bleed. The mother reports living in an area of lush vegetation and being in contact with bites. The results of blood count, peripheral blood smear, liver function and coagulation: normal. Blood sample: Negative Bartonella spp. PCR biopsy ribC gene: Positive B. bacilliformis. This case demonstrates the importance of maintaining an entomo-epidemiological surveillance system in patients exposed to arthropod bites that allows for timely detection of cases in order to make a diagnosis and provide timely treatment.

JMM Profile: Bartonella bacilliformis: a forgotten killer.

Bartonella bacilliformis causes Carrión's disease, an infectious disease present in rural Andean areas of Peru and Ecuador. The disease has an acute and a chronic phase called Oroya fever and Peruvian wart, respectively. Oroya fever is potentially fatal if treated inadequately. Female Lutzomyia verrucarum, a phlebotomine sand fly endemic to South America, is the major vector. B. bacilliformis exhibits high susceptibility levels to a variety of antibacterial agents. B. bacilliformis is difficult to culture. Most endemic areas are remote with fragile health systems and poor communication. Thus, the true burden of the disease is difficult to ascertain.

About Carrion street and bartonellosis

Daniel Alcides Carrión (1857-1885) was a Peruvian medical student who established the relationship between the clinical entities called Oroya fever and Peruvian wart, until then independent diseases. By autoinoculation of Peruvian wart extracts from a patient, he contracted the Oroya fever. This fact showed that both clinical entities occurred due to the same cause. Subsequent investigation showed that the agent involved was the bacteria Bartonella bacilliformis. On the other hand, a street called Carrion is located in front of the Faculty of Medicine of the University of Chile. It is a legend or medical tradition in this Faculty that this street is named in honor of this Peruvian martyred student. This work shows that this medical story has no historical basis and analyzes its true origin.

Bartonella spp. Bloodstream Infection in a Canadian Family.

Historically, Bartonella spp. have been associated with febrile illness (Oroya fever, trench fever, and cat scratch disease), endocarditis (numerous Bartonella spp.), and vasoproliferative lesions (Bartonella bacilliformis, Bartonella quintana, Bartonella henselae, and Bartonella vinsonii subsp. berkhoffii), occurring most often but not exclusively in immunocompromised patients. Recently, bloodstream infections with various Bartonella spp. have been documented in nonimmunocompromised individuals in association with a spectrum of cardiovascular, neurologic, and rheumatologic symptoms. As documented in this family, symptoms for which the medical implications remain unclear can occur in multiple family members infected with one or more Bartonella spp. Serial serologic and molecular microbiological findings supported exposure to or infection with Bartonella spp. in all seven family members. Either antibiotics failed to eliminate bacteremic infection, resulted in partial resolution of symptoms, or potentially reinfection occurred during the 19-month study period. There is a substantial need for clinical research to clarify the extent to which Bartonella spp. bacteremia induces nonspecific cardiovascular, neurologic, or rheumatologic symptoms, for ongoing improvement in the sensitivity and specificity of diagnostic testing, and clarification as to if, when, and how to treat patients with documented Bartonella spp. bacteremia.

Oroya Fever, Verruga Peruana, and Other Bartonelloses Incidence Rates in Colombia (2009-2013).

BackgroundBartonella bacilliformis, the etiological agent of Carrion's disease and presumed to be transmitted by phlebotomine sandflies, is endemic to the high-altitude valleys of the South American Andes, including Colombia.MethodsThis observational, retrospective study in which the incidence of bartonelloses (International Classification of Diseases, 10th revision (ICD-10) codes A44.0-A44.9) in Colombia, from 2009-2013, was estimated based on data extracted from the personal health records system (Registro Individual Prestación Servicios, RIPS). Using the official population estimates of the National Statistics Department (Departamento Administrativo Nacional de Estadísticas, DANE), crude and adjusted incidence rates were estimated (cases/100,000 population).ResultsA total of 1,389 cases were reported (median 289/year), for a cumulative national rate of 3.02 cases/100,000 population; 91.2% were female; 66.8% were <40-year-old (3.8% <9.9-year-old). The cases were 2.9% Oroya fever (A44.0), 13.1% verruga peruana (A44.1), and the rest (85.3%) were other forms of bartonelloses (A44.8-A44.9). The highest rates of Oroya fever were reported in Bolivar (2.5 cases/1,000,000 population). For verruga peruana highest number of cases were reported in Antioquia (32; 17.8%; 5.21 cases/1,000,000 population) and the highest rate at Magdalena (11.54 cases/1,000,000 population) (Risaralda, 6.45; Caldas, 5.1). For other forms of bartonelloses, the highest rates were reported at Magdalena (48.65 cases/1,000,000 population), followed by Huila (32.8) and La Guajira (18.9). At Nariño, Putumayo, Amazonas, Cauca, and Valle del Cauca, 11.7% of the cases of the country were reported.ConclusionsLutzomyia columbiana, the potential vector of Bartonella bacilliformis in Colombia, is distributed not only in Nariño, Cauca, and Valle del Cauca but also in the Antioquia, Caldas, Huila, La Guajira, Risaralda, Cordoba, and Caribbean areas. Given this distribution, the transmission would be occurring, as seen in reported cases, in more areas than previously described by classic reports of these diseases in the country.

Máxime "Max" Kuczyński: Father of Peruvian Public Health and of the 66th President of Peru.

Máxime Kuczyński (1890-1967), a medical pioneer born in Poland, was renowned for his work in tropical medicine in the Peruvian jungle, especially on Bartonella baciliformis, the cutaneous form known as verruga peruana of deadly Oroya fever. His unique university training in anthropology, philosophy, and parasitology lead to a participatory observational method of practicing medicine. At the request of the Peruvian President, he ventured into the Peruvian Amazon in 1936 to establish a public health service in partnership with indigenous populations. In June 2016, his son Pedro Pablo Kuczyński, a former Prime Minister of Peru, was elected the 66th President of Peru.

Carrion's Disease: the Sound of Silence.

Carrion's disease (CD) is a neglected biphasic vector-borne illness related to Bartonella bacilliformis. It is found in the Andean valleys and is transmitted mainly by members of the Lutzomyia genus but also by blood transfusions and from mother to child. The acute phase, Oroya fever, presents severe anemia and fever. The lethality is high in the absence of adequate treatment, despite the organism being susceptible to most antibiotics. Partial immunity is developed after infection by B. bacilliformis, resulting in high numbers of asymptomatic carriers. Following infection there is the chronic phase, Peruvian warts, involving abnormal proliferation of the endothelial cells. Despite potentially being eradicable, CD has been expanded due to human migration and geographical expansion of the vector. Moreover, in vitro studies have demonstrated the risk of the development of antimicrobial resistance. These findings, together with the description of new Bartonella species producing CD-like infections, the presence of undescribed potential vectors in new areas, the lack of adequate diagnostic tools and knowledge of the immunology and bacterial pathogenesis of CD, and poor international visibility, have led to the risk of increasing the potential expansion of resistant strains which will challenge current treatment schemes as well as the possible appearance of CD in areas where it is not endemic.

One hundred years after the expedition by Harvard University to Peru to investigate Carrion’s disease. Lessons for science

In 1913, around 100 years ago, the Harvard University sent an expedition to Peru, led by Richard Strong, to investigate Carrion’s disease. This paper provides a critical review of the scientific research carried out in this expedition.Richard Strong was a physician who performed unethical human experimentation in the Philippines and China. In Peru, Strong conducted experiments on humans to inoculate wart secretions to a psychiatric patient, which led him to replicate the Peruvian wart in this individual, although he could not replicate Oroya fever. Based on this experiment, and without taking into account epidemiological and clinical evidence, the Harvard expedition erroneously concluded that Oroya fever and Peruvian wart were two different diseases.A retrospective review of the scientific work conducted by the expedition in Peru allows drawing the following lessons for science: a) disapproving unethical human experimentation conducted by the expedition; b) to determine the cause of infectious diseases, it is necessary to obtain the best scientific, experimental and observational evidence, and c) to acknowledge that, despite the poor infrastructure, researchers in developing countries are able to produce high-quality scientific knowledge that may surpass the knowledge generated by researchers in developed countries.

Infectious agents, Leptospira spp. and Bartonella spp., in blood donors from Cajamarca, Peru.

The implementation of molecular and serological tests has led a great decline in transfusion-transmitted infections. Unfortunately, however, this has only occurred in high-income countries, whereas the scenario is different in low-income countries and in rural areas of middle-income countries, in which access to serological tests is sometimes not feasible or limited by economic factors1,2. Furthermore, in middle and low-income countries, the burden of infectious diseases tends to be higher and subjects are often weakened by various factors, including malnutrition. These factors result in a population that is more vulnerable and at increased risk of infections. Although the search for relevant pathogens that can be transmitted by blood transfusion is implemented worldwide, various pathogens that can be present in blood bank donations remain under studied, as in the case of some bacteria such as Leptospira spp. and Bartonella spp. Bartonella species are re-emerging blood-borne organisms, capable of causing prolonged infections in animals and humans3, while leptospirosis is recognised as an emerging public health problem worldwide4. Both infections are considered to be neglected tropical diseases. In humans, Bartonella spp. cause infections of varying severity, ranging from asymptomatic bacteraemia to severe cases with chronic manifestations responsible for persistent disease and death3. So far, various members of the Bartonella genus have been associated with human disease, the most relevant being Bartonella henselae, causing cat scratch disease, Bartonella quintana, causing trench fever, and Bartonella bacilliformis, the causal agent of Carrion’s disease2. This last micro-organism is endemic in Latin America, and specifically in the Andean valleys. B. bacilliformis infects red blood cells and endothelial cells and, as mentioned above, is the aetiological agent of Carrion’s disease, a biphasic disease with two different clinical presentations: an initial febrile phase with haemolytic anaemia, known as Oroya fever, which has a mortality rate ranging from 44–88% in untreated patients, and a second phase characterised by the development of dermal eruptions, known as “Peruvian wart”5. It is important to highlight the presence of asymptomatic people, who account for about 45% of the population in some endemic areas6; consequently, the risk of transfusion transmission is of note, especially because of the ability of B. bacilliformis to survive in blood stored at 4 oC for up to 1 year7. Leptospirosis is one of the most common bacterial zoonotic diseases worldwide. Various mammals such as rodents, livestock and domestic pets can act as reservoir hosts8. Traditionally, infection in humans is due to contact with Leptospira-contaminated sites in different environments: at work (veterinarians, farmers, sewer cleaners), in alleys and slums with poor drainage, and in recent years, during international travel and recreational activities9. Infection by Leptospira may be asymptomatic or may cause a mild influenza-like illness that can resolve spontaneously. Symptomatic infection may present as non-specific symptoms such as fever, chills, headache, myalgia and jaundice8. As mentioned above, the presence of asymptomatic carriers may favour the risk of transfusion-related transmission. The distribution of Carrion’s disease is limited to the Andean valleys, while leptospirosis occurs worldwide, being more common in tropical and subtropical regions due to the wet weather. Rainfall, flooding and climatic phenomena, such as “El Nino”, increase the risk of these bacterial infections4. There is no information about the prevalence of these bacteria in blood donors in Peru. Moreover, analyses to detect the presence of Leptospira spp. are not routine in this country and the presence of B. bacilliformis is only tested for in blood banks in endemic areas, but not in the remaining ones, irrespectively of whether there are inhabitants arriving from or travelling to endemic areas10,11. This represents a health problem, since subjects receiving a blood transfusion are usually immunocompromised and more vulnerable to the development of severe infectious diseases from potentially transfusion-transmitted micro-organisms. The aim of the present study was to examine the prevalence of Bartonella spp. and Leptospira spp. in blood donors in Cajamarca, in northern Peru, and describe the associated epidemiological factors.

Complete Genome Sequence of Bartonella ancashensis Strain 20.00, Isolated from the Blood of a Patient with Verruga Peruana.

Here we present the complete genome sequence of Bartonella ancashensis strain 20.00, isolated from the blood of a Peruvian patient with verruga peruana, known as Carrion’s disease. Bartonella ancashensis is a Gram-negative bacillus, phylogenetically most similar to Bartonella bacilliformis, the causative agent of Oroya fever and verruga peruana.

Proteins of Bartonella bacilliformis: Candidates for Vaccine Development.

Bartonella bacilliformis is the etiologic agent of Carrión's disease or Oroya fever. B. bacilliformis infection represents an interesting model of human host specificity. The notable differences in clinical presentations of Carrión's disease suggest complex adaptations by the bacterium to the human host, with the overall objectives of persistence, maintenance of a reservoir state for vectorial transmission, and immune evasion. These events include a multitude of biochemical and genetic mechanisms involving both bacterial and host proteins. This review focuses on proteins involved in interactions between B. bacilliformis and the human host. Some of them (e.g., flagellin, Brps, IalB, FtsZ, Hbp/Pap31, and other outer membrane proteins) are potential protein antigen candidates for a synthetic vaccine.

Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection.

Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterized by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defense mechanisms, including macrophage dysfunction, neutrophil dysfunction, and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.

La enfermedad y la muerte de Carrión

La demostración de la unidad etiológica de la Verruga eruptiva del Perú y la llamada Fiebre de La Oroya, se hizo el día que Carrión se inoculó el botón verrucoso y reprodujo la forma maligna de la enfermedad (Fiebre de La Oroya), pagando con su muerte su devoción científica.

La glucemia en la enfermedad de Carrión y en la Bartonellosis del perro

Se ha estudiado la glucemia en ayunas en sujetos normales, enfermos carriónicos y perros infestados con Bartonella canis. En estos últimos se ha realizado además dosajes de glucógeno hepático y pruebas de tolerancia a la glucosa. Los resultados obtenidos permiten las siguientes conclusiones: 1.Una hiperglucemia de grado moderado puede ser constatada, con alguna frecuencia, en la fase hemática de la Enfermedad de Carrión. 2. Esta alteración de la glucemia se presenta también en la Bartonellosis experimental del perro, durante la fase de anemia intensa. 3. Una hipoglucemia, a veces de grado severo y responsable probablemente de la muerte del animal, acompaña con frecuencia a la etapa terminal de la Bartonellosis grave del perro, sucediendo a la hiperglucemia cuando ambos trastornos se presentan en el mismo caso. 4. La hiperglucemia constatada tanto en el enfermo carriónico como en el perro bartonellósico, puede ser explicada por una exagerada glucogenolisis hepática, estimulada por el estado infeccioso y quizás también por la anoxia anémica. 5. Un agotamiento de las reservas de glucógeno en el hígado - producido principalmente por un mayor consumo de glucosa y una disminución de la capacidad del mismo para fijar aquella sustancia - y una probable inhibición de la neoglucogenia, serían los factores responsables del estado hipoglucémico que se presenta en la etapa terminal de la Bartonellosis grave del perro.

Oroya fever and verruga peruana: bartonelloses unique to South America.

Bartonella bacilliformis is the bacterial agent of Carrión's disease and is presumed to be transmitted between humans by phlebotomine sand flies. Carrión's disease is endemic to high-altitude valleys of the South American Andes, and the first reported outbreak (1871) resulted in over 4,000 casualties. Since then, numerous outbreaks have been documented in endemic regions, and over the last two decades, outbreaks have occurred at atypical elevations, strongly suggesting that the area of endemicity is expanding. Approximately 1.7 million South Americans are estimated to be at risk in an area covering roughly 145,000 km2 of Ecuador, Colombia, and Peru. Although disease manifestations vary, two disparate syndromes can occur independently or sequentially. The first, Oroya fever, occurs approximately 60 days following the bite of an infected sand fly, in which infection of nearly all erythrocytes results in an acute hemolytic anemia with attendant symptoms of fever, jaundice, and myalgia. This phase of Carrión's disease often includes secondary infections and is fatal in up to 88% of patients without antimicrobial intervention. The second syndrome, referred to as verruga peruana, describes the endothelialcell-derived, blood-filled tumors that develop on the surface of the skin. Verrugae are rarely fatal, but can bleed and scar the patient. Moreover, these persistently infected humans provide a reservoir for infecting sand flies and thus maintaining B. bacilliformis in nature. Here, we discuss the current state of knowledge regarding this life-threatening, neglected bacterial pathogen and review its host-cell parasitism, molecular pathogenesis, phylogeny, sand fly vectors, diagnostics, and prospects for control.

Diagnosis of Carrion’s Disease by Direct Blood PCR in Thin Blood Smear Negative Samples

Bartonella bacilliformis is the etiologic agent of Carrion's disease. This disease has two well established phases, the most relevant being the so called Oroya Fever, in which B. bacilliformis infect the erythrocytes resulting in severe anemia and transient immunosuppression, with a high lethality in the absence of adequate antibiotic treatment. The presence of B. bacilliformis was studied in 113 blood samples suspected of Carrion’s disease based on clinical criteria, despite the absence of a positive thin blood smear, by two different PCR techniques (using Bartonella-specific and universal 16S rRNA gene primers), and by bacterial culture. The specific 16S rRNA gene primers revealed the presence of 21 B. bacilliformis and 1 Bartonella elizabethae, while universal primers showed both the presence of 3 coinfections in which a concomitant pathogen was detected plus Bartonella, in addition to the presence of infections by other microorganisms such as Agrobacterium or Bacillus firmus. These data support the need to implement molecular tools to diagnose Carrion’s disease.

Daniel Alcides Carrion (1857–1885) and a history of medical martyrdom

Daniel Carrion, a sixth-year medical student, died while investigating the effects of self-inoculation of the causative organism of Oroya Fever and Bartonellosis and thereby contributed to understanding of the disease before the organisms had been identified.

Bartonella bacilliformis: A Systematic Review of the Literature to Guide the Research Agenda for Elimination

BackgroundCarrion's disease affects small Andean communities in Peru, Colombia and Ecuador and is characterized by two distinct disease manifestations: an abrupt acute bacteraemic illness (Oroya fever) and an indolent cutaneous eruptive condition (verruga Peruana). Case fatality rates of untreated acute disease can exceed 80% during outbreaks. Despite being an ancient disease that has affected populations since pre-Inca times, research in this area has been limited and diagnostic and treatment guidelines are based on very low evidence reports. The apparently limited geographical distribution and ecology of Bartonella bacilliformis may present an opportunity for disease elimination if a clear understanding of the epidemiology and optimal case and outbreak management can be gained.MethodsAll available databases were searched for English and Spanish language articles on Carrion's disease. In addition, experts in the field were consulted for recent un-published work and conference papers. The highest level evidence studies in the fields of diagnostics, treatment, vector control and epidemiology were critically reviewed and allocated a level of evidence, using the Oxford Centre for Evidence-Based Medicine (CEBM) guidelines.ResultsA total of 44 studies were considered to be of sufficient quality to be included in the analysis. The majority of these were level 4 or 5 (low quality) evidence and based on small sample sizes. Few studies had been carried out in endemic areas.ConclusionsCurrent approaches to the diagnosis and management of Carrion's disease are based on small retrospective or observational studies and expert opinion. Few studies take a public health perspective or examine vector control and prevention. High quality studies performed in endemic areas are required to define optimal diagnostic and treatment strategies.

Daniel Carrion’s experiment: the use of self-infection in the advance of medicine

In 1885, Daniel Carrion (1857-1885), a young Peruvian medical student, was trying to establish the prodromal symptoms of 'verruga disease', an infectious disease rare outside South America but endemic in parts of Peru. As part of this investigation he was inoculated with fluid from a verruga lesion from a patient with the chronic form of the disease. He recorded the clinical features which developed, including fever, malaise, arthralgia, vomiting and anaemia, and it became apparent that he had developed the anaemic, febrile, acute phase of the illness (known as Oroya fever). This did not however progress in his case to the chronic form of the disease, and he died a few weeks later on 5 October 1885. His sacrifice served to establish, supposedly, that Oroya fever and verruga disease had a common aetiology and his death stimulated further research into the cause, now established as the bacterium Bartonella bacilliformis. Carrion is considered a martyr of Peruvian medicine and 5 October has been designated Peruvian Medicine Day in his honour.

Bartonella spp.: Throwing light on uncommon human infections

After 2 decades of Bartonella research, knowledge on transmission and pathology of these bacteria is still limited. Bartonella spp. have emerged to be important pathogens in human and veterinary medicine. For humans, B. henselae is considered to represent the most relevant zoonotic Bartonella species and is responsible for cat scratch disease, bacillary angiomatosis, and other disorders. Over the years, many Bartonella species have been isolated from humans, cats, dogs, and other mammals, and infections range from an asymptomatic state (e.g., animal-specific species) to even life-threatening diseases (e.g., Oroya fever). It is obvious that the analysis of pathogenicity mechanisms underlying Bartonella infections is needed to increase our understanding of how these pathogens adapt to their mammalian hosts resulting in acute or chronic diseases.