History
South American-bartonellosis, (Carrión’s disease, Oroya fever, verruga peruana, verruga peruviana) results from infection with the bacterium Bartonella bacilliformis and is transmitted by sandflies. The infection manifests itself in two very different clinical forms with the causal connection being recognised by the young Peruvian doctor Daniel Alcides Carrión.
Pre-Columbian mummies with histologically confirmed verruga lesions have been discovered in Peru and bartonellosis occurred in Francisco Pizarro’s army (1471-1541). During the Inca era, the disease was called “Sirki,” which means “warts in blood.” In Peru between 1869 and 1873 more than 7000 workers building the Lima-La Oroya railway died from the disease at Cocachacra, 65 kilometers from Lima, 1600 meters above sea level. The name “Oroya fever” refers to this, although in the mining town of La Oroya (altitude 3800 m), strangely enough there was no transmission of Oroya fever. In 1936 a large epidemic was seen in the Guaitara valley on the border between Colombia and Ecuador. An epidemic occurred in 1980 in Ecuador and another in 1987 in Peru with a death rate of 88% in the untreated patients. Now and then there have been isolated cases or small outbreaks. In 1997 there was an outbreak in the area of Cuzco, Peru. In an outbreak in Zumba, Ecuador (1995-96), large numbers of dead rodents were found around the places where the cases had occurred. This finding led to the hypothesis that bartonellosis could have an animal reservoir.
Daniel Alcides Carrión
Daniel Alcides Carrión (1858-1885) was a medical student in Lima, Peru. He was required to prepare an original thesis and choose to study the epidemiology and clinical manifestations of verruga peruviana. His home was in Cerro de Pasco, a mining town high in the Andes where he had seen many cases. These left a deep impression on the young man. He told a classmate that he hoped “to make an important contribution to aching humanity”. He became concerned with the difficulty in diagnosing verruga peruviana before the typical eruption started. The appearance of the skin lesions was preceded by fever and anaemia, but there was a lot of confusion between the prodromal phase of verruga and other febrile disorders such as malaria. Carrión wanted to determine the incubation period and early symptoms of verruga, so he decided to inoculate himself with some fluid from a chronic skin lesion of a verruga patient. Many friends and professors tried to dissuade him. On the morning of August 27, 1885, Carrión was in the Nuestra Senora de las Mercedes ward of the Dos de Mayo Hospital in Lima. A 14-year-old boy named Carmen Paredes was admitted with verruga on his right eyebrow. Assisted by Dr Chavez, a young ward physician, Carrión used a lancet to inoculate his own arm with blood taken from that verruga. He kept a diary afterwards. The first symptoms started after 21 days, with discomfort and pain in his left ankle. Two days later he developed fever, chills, abdominal pain and generalised pain in bones and joints. He had anorexia and noted severe thirst. His urine became dark red and scanty. He developed jaundice. A week later, he became too ill to continue his diary. His classmates took over this task and were surprised at how quickly anaemia developed. A systolic heart murmur developed and grew in intensity. A few days later, muscle fasciculations appeared in his arm muscles. He said to his friends: “Up to today, I thought I was only in the invasive stage of the verruga as a consequence of my inoculation, that is, in the period of anaemia that precedes the eruption. But now I am deeply convinced that I am suffering from the fever that killed our friend, Orihuela. Therefore, this is the evident proof that Oroya fever and the verruga have the same origin, as Dr Alarco once said.” This insight was the essence of Carrión’s experiment. He had not set out to prove the single cause of verruga peruviana and Oroya fever. He only intended to study the incubation period and prodrome of verruga. When a completely different disease developed, he was lucid enough to understand the full meaning of his experiment. On October 3, he became delirious and two days later he fell into a coma and died at midday. He became a hero of Peruvian medicine and is remembered to this day. The day of his death, October 5, is celebrated yearly as the “Dia de la Medicina Peruana”. His burial vault – where doctors pay tribute – is in the Hospital Nacional Dos de Mayo in Lima. The Peruvian National University in Cerro de Pasco carries his name.
Aetiology
Barton described the pathogen in 1909, but he thought that it was a protozoon. The Japanese bacteriologist Hideyo Noguchi demonstrated the bacterial nature of the pathogen. Bartonella bacilliformis is a small Gram-negative coccobacillus (0.6-1 µm), which takes Giemsa and Warthin-Starry stain. The pathogen has one or more polar flagella. It replicates within the vascular endothelium and erythrocytes. The bacterium is related to rickettsiae. The bacillus grows quickly (extracellularly) on non-living culture media with blood or on chicken embryos at 25-28°C. Numerous related organisms are animal pathogens.
Distribution
The disease caused by Bartonella bacilliformis only occurs in certain narrow high valleys of the western-most slopes of the Andes at altitudes between 500 and 3200 meters in Peru, Ecuador and Colombia, between 2° N and 13° S. Whether endemic cases occurred in Chili, Bolivia, Guatemala and Honduras is very doubtful. Sporadic cases of so-called “bartonelloses” have been reported in Africa, (Niger, Sudan), in Asia (Pakistan) and in the USA, but it is still not clear whether there is a connection with Carrión’s disease. Our knowledge about Bartonella and related bacteria has largely increased in recent years but is still very incomplete.
Transmission
A sandfly, Lutzomyia verrucarum, and perhaps a few related species, is responsible for transmission. Transmission only occurs at night and is seasonal, particularly during the rains. It was formerly assumed that the reservoir was purely human, but this was recently cast into doubt (there may be a rodent reservoir). In some of the inhabitants in the endemic valleys bacteria can be found in the blood, but these carriers are usually without any symptoms. These latent infections which are likely to have been contracted in childhood probably give stable immunity. It is only if non-immune populations enter the endemic area that epidemics occur, sometimes on a large scale, such as in wars or when large public works are being carried out. Tourists may be at risk for the disease.
Clinical aspects
The clinical range is wide, going from asymptomatic infections via serious febrile forms with acute haemolytic anaemia, to the angiomatous skin lesions which can be present from the onset or can be preceded by the febrile stage. The mortality of untreated cases varies between epidemics and ranges from 10-40% after 2-3 weeks. The disease is less severe in children and the mortality is far lower. If the course of the disease is favourable, the fever can last for 3 to 4 months. In 40-50% of cases of Oroya fever, concurrent salmonellosis (generally Salmonella typhimurium) complicates the illness and makes the prognosis less favourable. The superinfection causes fever with gastrointestinal symptoms and a deterioration of the patient’s general condition.
Oroya fever or Acute Carrion”s Disease
Key clinical aspects
1. Incubation takes approximately 3 to 8 weeks (range 10-210 days). It begins insidiously with:
2. Irregular intermittent febrile attacks with shivering
3. Rapidly worsening anaemia with tachycardia, pallor and (sub)icterus
4. Severe headache with bone and joint pain. This may persist after the fever has ended
5. Enlargement of the liver and spleen, slightly painful on palpation
6. Generalised painful swollen lymph nodes
7. Myocarditis, pulmonary oedema and anasarca (generalised oedema)
8. Haemorrhagic diathesis as a result of the endothelial lesions: petechiae and tendency to
thrombosis. Necrotic foci are found in the liver, spleen and bone marrow.
9. Neutrophilia
10. Spontaneous abortion, foetal death or transplacental transmission can occur.
11. Neurobartonellosis due to involvement of the CNS takes the form of meningo-encephalitis with or without convulsions and with high mortality. Myelitis also occurs with spastic or flaccid paraplegia with sequelae which can be permanent. There is pleiocytosis of the CSF. More focal and transient lesions of the spinal cord or of the cranial nerves are seen at the verruga stage.
Verruga peruana or Chronic Carrion’s Disease
This is the chronic eruptive stage of infection with Bartonella bacilliformis. The painless wart-like skin eruption results from the abnormal growth of blood vessels with the appearance of haemangiomas and the formation of angioblastic nodules. At this stage Bartonella can still be found in the endothelial cells, but they are only very rarely found in the erythrocytes.
The skin eruption usually appears 6 to 14 weeks after the acute stage. Both pathological conditions can be present at the same time. The skin eruption may initially be accompanied by a mild fever and arthralgia. The eruption is polymorphic. Some lesions disappear quickly, others persist or grow for some time only to shrivel and disappear, generally without leaving scars. There are three forms:
Miliary form: the lesions are small (< 0.5 cm), very numerous and mainly found on the face, on the extensor surface of the limbs and on the trunk. They are initially macular and grow to small vascular, sometimes pedunculated and protruding nodules. Lesions are also present on the digestive and genito-urinary mucosa. Dysphagia, haematemesis, melaena, haematuria and metrorrhagia can occur.
Nodular form: the nodules are larger, less numerous, deeper, chronic and mainly found around the elbows and knees. The mucous membranes are spared. The lesions appear in cycles for 2 to 3 months.
Mular form: there are isolated pseudotumoural haemorrhagic nodules which macroscopically resemble granuloma pyogenicum.
Immunity
Immunity is gradually acquired during the acute stage, so that the disease becomes limited to the wart-like lesions of the skin and mucous membranes which subsequently heal completely and permanently. In experimentally infected monkeys the disease can be reversed from the verruga stage to the febrile haemolytic stage by splenectomy. The same probably occurs in humans. The prognosis of verruga is good. They evolve in spurts and the lesions generally heal spontaneously in less than 6 months.
Diagnosis
The diagnosis is based on the endemicity, the clinical characteristics, full blood count, the presence of Bartonella in blood smears (Giemsa stain), blood cultures or tissue cultures from skin lesions or even the histological examination of the latter. More than 70 percent of patients with acute Oroya fever have a positive blood culture for B. bacilliformis, although 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.
In the differential diagnosis, consideration is given to malaria, dengue, viral hepatitis, babesiosis, bacillary angiomatosis in AIDS patients, typhus, typhoid fever, Yaws, Kaposi’s sarcoma, haemangiomas, pyogenic granuloma and various skin tumours. In mild forms, the number of Bartonella in the blood smear can fall below the detection limit. The degree of haemolysis is then very limited, and the infection is extremely difficult to diagnose if no serology is available. PCR, Immunofluorescence, ELISA and Western Blot among others are used for diagnosis.
Treatment
Until recently chloramphenicol was the drug of choice but ciprofloxacin has now been shown to give better results. Both are also effective in Salmonella infections (in absence of resistance).
Chloramphenicol is administered at doses of 4 g/day for 5 days. Ciprofloxacin is given as 500 mg BD.
The fever disappears in less than 48 hours. The mortality rate of Oroya fever can be largely reduced with antibiotic therapy. Late development of the verruga stage is possible despite correct treatment.
Ciprofloxacin or rifampicin for 2 to 3 weeks can be used in the verruga stage.
Disease control
Spraying with insecticides, especially those which retain their activity for long periods interrupts transmission. However, control measures are not essential in endemic areas because of the immunity of the adult population. Individual protection consists of avoiding spending the night in exposed biotopes and the use of insect repellents or mosquito nets treated with permethrin/deltamethrin.
Although theoretically possible vaccination is not used.
