Louse-borne relapsing fever-A systematic review and analysis of the literature: Part 2-Mortality, Jarisch-Herxheimer reaction, impact on pregnancy.

Louse-borne relapsing fever (LBRF) is a classical epidemic disease, which in the past was associated with war, famine, poverty, forced migration, and crowding under poor hygienic conditions around the world. The disease's causative pathogen, the spirochete bacterium Borrelia recurrentis, is confined to humans and transmitted by a single vector, the human body louse Pediculus humanus corporis. Since the disease was at its peak before the days of modern medicine, many of its aspects have never been formally studied and to date remain incompletely understood. In order to shed light on some of these aspects, we have systematically reviewed the accessible literature on LBRF since the recognition of its mode of transmission in 1907, and summarized the existing data on mortality, Jarisch-Herxheimer reaction (JHR), and impact on pregnancy. Publications were identified by using a predefined search strategy of electronic databases and a subsequent review of the reference lists of the obtained publications. All publications reporting patients with a confirmed diagnosis of LBRF published in English, French, German, and Spanish since 1907 were included. Data extraction followed a predefined protocol and included a grading system to judge the certainty of the diagnosis of reported cases. The high mortality rates often found in literature are confined to extreme scenarios. The case fatality rate (CFR) of untreated cases is on average significantly lower than frequently assumed. In recent years, a rise in the overall CFRs is documented, for which reasons remain unknown. Lacking standardized criteria, a clear diagnostic threshold defining antibiotic treatment-induced JHR does not exist. This explains the wide range of occurrence rates found in literature. Pre-antibiotic era data suggest the existence of a JHR-like reaction also in cases treated with arsenicals and even in untreated cases. LBRF-related adverse outcomes are observed in 3 out of 4 pregnancies.

Tick-borne relapsing fever as a potential veterinary medical problem.

Tick-borne relapsing fever (TBRF) caused by the bacteria Borrelia, is poorly documented in veterinary medicine. Given the widespread presence of the soft tick vectors - Ornithodoros and the recently discovered hard tick vectors, as well as their close association with animal hosts, it is highly likely that infection occurs, but is rarely reported to be of veterinary importance. Sporadic reports of canine infection, some being fatal through to probable cause of abortion in horses have been published. Some of these pathogens exist in regions where there are limited diagnostic facilities, hence, they are likely to be missed and their impact on productivity may be unquantified. Here we review available literatures on cases of TBRF in domestic and wild animals in order to show their potential veterinary medical impact. Future efforts using field and laboratory surveys are needed to determine pathogenesis, vector competence and distribution in animals, their impact on animal health and productivity as well as to prevent further spill to the human population, where it is already a public health problem in some parts of the world.

Plasmodium falciparum malaria co-infection with tick-borne relapsing fever in Dakar.

BACKGROUND: West African tick-borne relapsing fever (TBRF) due to Borrelia crocidurae and malaria are co-endemics in Senegal. Although expected to be high, co-infections are rarely reported. A case of falciparum malaria and B. crocidurae co-infection in a patient from Velingara (South of Senegal) is discussed. CASE: A 28 year-old-male patient presented to Aristide Le Dantec Hospital for recurrent fever. He initially presented to a local post health of Pikine (sub-urban of Dakar) and was diagnosed for malaria on the basis of positive malaria rapid diagnostic test (RDT) specific to Plamodium falciparum. The patient was treated as uncomplicated falciparum malaria. Four days after admission the patient was referred to Le Dantec Hospital. He presented with fever (39 °C), soreness, headache and vomiting. The blood pressure was 120/80 mmHg. The rest of the examination was normal. A thick film from peripheral blood was performed and addressed to the parasitology laboratory of the hospital. Thick film was stained with 10% Giemsa. Trophozoite of P. falciparum was identified at parasite density of 47 parasites per microlitre. The presence of Borrelia was also observed, concluding to malaria co-infection with borreliosis. CONCLUSIONS: Signs of malaria can overlap with signs of borreliosis leading to the misdiagnosis of the latter. Thick and thin smear or QBC test or molecular method may be helpful to detect both Plamodium species and Borrelia. In addition, there is a real need to consider co-infections with other endemics pathogens when diagnosing malaria.

Louse-borne relapsing fever in Finland in two asylum seekers from Somalia.

We report two cases of louse-borne relapsing fever (LBRF) in young Somali asylum seekers having recently arrived to Finland. They had sought medical attention for a febrile illness. Blood smears were examined for suspected malaria, but instead, spirochete shaped bacteria were observed. The bacteria were confirmed as Borrelia recurrentis by PCR and sequencing. The patients survived, but their treatment was complicated by Jarisch-Herxheimer reaction. We conclude that LBRF must be considered as a diagnostic option in febrile refugees also in the northernmost parts of Europe.

Insights into Borrelia miyamotoi infection from an untreated case demonstrating relapsing fever, monocytosis and a positive C6 Lyme serology.

We describe a patient from the United States with PCR- and serology-confirmed Borrelia miyamotoi infection who recovered without antibiotics. Our findings suggest that B. miyamotoi infection may cause relapsing fever, blood monocytosis and antibody reactivity to the C6 peptide. Further studies are required to better define the spectrum of clinical and laboratory findings for this emerging tick-transmitted infection.

Louse-borne relapsing fever among East African refugees in Europe.

Louse-borne relapsing fever a neglected and forgotten disease by western physicians has recently re-emerged among East African migrants seeking asylum in Europe. We review here the cases observed so far together with a critical reappraisal of several issues regarding clinical presentation, diagnosis and treatment.

Hypercholesterolemia and ApoE deficiency result in severe infection with Lyme disease and relapsing-fever Borrelia.

The Lyme disease (Borrelia burgdorferi) and relapsing-fever (Borrelia hispanica) agents have distinct infection courses, but both require cholesterol for growth. They acquire cholesterol from the environment and process it to form cholesterol glycolipids that are incorporated onto their membranes. To determine whether higher levels of serum cholesterol could enhance the organ burdens of B. burgdorferi and the spirochetemia of B. hispanica in laboratory mice, apolipoprotein E (apoE)-deficient and low-density lipoprotein receptor (LDLR)-deficient mice that produce large amounts of serum cholesterol were infected with both spirochetes. Both apoE- and LDLR-deficient mice infected with B. burgdorferi had an increased number of spirochetes in the joints and inflamed ankles compared with the infected wild-type (WT) mice, suggesting that mutations in cholesterol transport that result in high serum cholesterol levels can affect the pathogenicity of B. burgdorferi. In contrast, elevated serum cholesterol did not lead to an increase in the spirochetemia of B. hispanica. In the LDLR-deficient mice, the course of infection was indistinguishable from the WT mice. However, infection of apoE-deficient mice with B. hispanica resulted in a longer spirochetemia and increased mortality. Together, these results argue for the apoE deficiency, and not hypercholesterolemia, as the cause for the increased severity with B. hispanica. Serum hyperlipidemias are common human diseases that could be a risk factor for increased severity in Lyme disease.

Borrelia miyamotoi infection in nature and in humans.

Borrelia miyamotoi is a relapsing fever Borrelia group spirochete that is transmitted by the same hard-bodied (ixodid) tick species that transmit the agents of Lyme disease. It was discovered in 1994 in Ixodes persulcatus ticks in Japan. B. miyamotoi species phylogenetically cluster with the relapsing fever group spirochetes, which usually are transmitted by soft-bodied (argasid) ticks or lice. B. miyamotoi infects at least six Ixodes tick species in North America and Eurasia that transmit Lyme disease group spirochetes and may use small rodents and birds as reservoirs. Human cases of B. miyamotoi infection were first reported in 2011 in Russia and subsequently in the United States, Europe and Japan. These reports document the public health importance of B. miyamotoi, as human B. miyamotoi infection appears to be comparable in frequency to babesiosis or human granulocytic anaplasmosis in some areas and may cause severe disease, including meningoencephalitis. The most common clinical manifestations of B. miyamotoi infection are fever, fatigue, headache, chills, myalgia, arthralgia, and nausea. Symptoms of B. miyamotoi infection generally resolve within a week of the start of antibiotic therapy. B. miyamotoi infection should be considered in patients with acute febrile illness who have been exposed to Ixodes ticks in a region where Lyme disease occurs. Because clinical manifestations are nonspecific, etiologic diagnosis requires confirmation by blood smear examination, PCR, antibody assay, in vitro cultivation, and/or isolation by animal inoculation. Antibiotics that have been used effectively include doxycycline for uncomplicated B. miyamotoi infection in adults and ceftriaxone or penicillin G for meningoencephalitis.

Real-time monitoring of disease progression in rhesus macaques infected with Borrelia turicatae by tick bite.

The hallmark of disease caused by tick- and louse-borne relapsing fever due to Borrelia infection is cyclic febrile episodes, which in humans results in severe malaise and may lead to death. To evaluate the pathogenesis of relapsing fever due to spirochetes in an animal model closely related to humans, disease caused by Borrelia turicatae after tick bite was compared in 2 rhesus macaques in which radiotelemetry devices that recorded body temperatures in 24-hour increments were implanted. The radiotelemetry devices enabled real-time acquisition of core body temperatures and changes in heart rates and electrocardiogram intervals for 28 consecutive days without the need to constantly manipulate the animals. Blood specimens were also collected from all animals for 14 days after tick bite, and spirochete densities were assessed by quantitative polymerase chain reaction. The complexity of disease caused by relapsing-fever spirochetes was demonstrated in the nonhuman primates monitored in real time. The animals experienced prolonged episodes of hyperthermia and hypothermia; disruptions in their diurnal patterns and repolarization of the heart were also observed. This is the first report of the characterizing disease progression with continuous monitoring in an animal model of relapsing fever due to Borrelia infection.

Characteristics of Borrelia hermsii infection in human hematopoietic stem cell-engrafted mice mirror those of human relapsing fever.

Rodents are natural reservoirs for a variety of species of Borrelia that cause relapsing fever (RF) in humans. The murine model of this disease recapitulates many of the clinical manifestations of the human disease and has revealed that T cell-independent antibody responses are required to resolve the bacteremic episodes. However, it is not clear whether such protective humoral responses are mounted in humans. We examined Borrelia hermsii infection in human hematopoietic stem cell-engrafted nonobese diabetic/SCID/IL-2Rγ(null) mice: "human immune system mice" (HISmice). Infection of these mice, which are severely deficient in lymphoid and myeloid compartments, with B. hermsii resulted in persistent bacteremia. In contrast, this infection in HISmice resulted in recurrent episodes of bacteremia, the hallmark of RF. The resolution of the primary episode of bacteremia was concurrent with the generation of B. hermsii-specific human IgM. Remarkably, HISmice generated antibody responses to the B. hermsii outer-membrane protein Factor H binding protein A. Sera from humans infected by B. hermsii have a similar reactivity, and studies in mice have shown that this response is generated by the B1b cell subset. HISmice contain several B-cell subsets, including those with the phenotype CD20(+)CD27(+)CD43(+)CD70(-), a proposed human equivalent of mouse B1 cells. Reduction of B cells by administration of anti-human CD20 antibody resulted in diminished anti-B. hermsii responses and persistent bacteremia in HISmice. These data indicate that analysis of B. hermsii infection in HISmice will serve as a model in which to study the cellular and molecular mechanisms involved in controlling human RF.

Toll-like receptor 2 deficiency results in impaired antibody responses and septic shock during Borrelia hermsii infection.

Overwhelming bacteremia is a leading cause of death. To understand the mechanisms involved in protective antibody and pathological inflammatory responses during bacteremia, we have been studying the murine model of Borrelia hermsii infection. Toll-like receptor (TLR) signaling plays an important role in generating the rapid anti-B. hermsii antibody responses required for the resolution of bacteremia. Using NF-κB reporter assays, we found that B. hermsii activates TLR2 and TLR9. However, TLR2(-/-) TLR9(-/-) mice exhibited an impairment in anti-B. hermsii antibody responses similar to that of TLR2(-/-) mice. Moreover, the impairment in the antibody responses of TLR2(-/-) mice or TLR2(-/-) TLR9(-/-) mice coincides with an order-of-magnitude-higher bacteremia, and death results from septic shock, as evidenced by a dysregulated systemic cytokine response and characteristic organ pathology. Since TLR2 appears to be the major extracellular sensor stimulated by B. hermsii, we hypothesized that during elevated bacteremia the activation of intracellular sensors of bacteria triggers dysregulated inflammation in TLR2(-/-) mice. Indeed, blocking the internalization of B. hermsii prevented the induction of inflammatory cytokine responses in TLR2-deficient cells. Furthermore, we found that B. hermsii activates the cytoplasmic sensor nucleotide-binding oligomerization domain 2 (NOD2). Macrophages deficient in both TLR2 and NOD2 have impaired cytokine responses to B. hermsii compared to cells lacking TLR2 alone, and B. hermsii-infected TLR2(-/-) NOD2(-/-) mice exhibited improved survival compared to TLR2(-/-) mice. These data demonstrate that TLR2 is critical for protective immunity and suggest that, during heightened bacteremia, recognition of bacterial components by intracellular sensors can lead to pathological inflammatory responses.

Induction of distinct neurologic disease manifestations during relapsing fever requires T lymphocytes.

Relapsing fever borreliosis is a multisystemic infection characterized primarily by bacteremia but can extend to the CNS. The incidence of CNS disease manifestations in humans depends on the infecting relapsing fever Borrelia species. In the murine model of Borrelia hermsii infection we found high incidence of distinct signs of CNS disease that ranged from a flaccid tail to complete paralysis of hind limbs. Infiltration of large number of T cells into the spinal cord of B. hermsii-infected mice and the upregulation of MHC class II and CD80 on infiltrating macrophages and on microglial cells suggested a role for T cell and Ag-presenting cell interactions in this pathogenesis. Indeed, B. hermsii infection did not induce CNS disease manifestations in T cell-deficient mice (TCR-beta x delta(-/-)), although it resulted in bacteremia comparable to wild-type (Wt) level. Moreover, the infiltration of immune cells into the spinal cord of TCR-beta x delta(-/-) mice was reduced and the resident microglial cells were not activated. Histopathological analysis of lumbar sections of the spinal cord confirmed severe inflammation in Wt but not in TCR-beta x delta(-/-) mice. Induction of CNS disease was dependent on the B. hermsii strain as well as on the ability of the host to control bacteremia. Mice that are impaired in controlling B. hermsii, such as CD14(-/-) mice, exhibited more severe CNS disease than Wt mice. This study demonstrates that distinct neurologic disease manifestations develop during relapsing fever and that T cells play a critical role in the induction of neuropathogenesis.

Concomitant infection decreases the malaria burden but escalates relapsing fever borreliosis.

About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF) Borrelia infection can be misdiagnosed with malaria due to similar manifestations and geographic distributions of the two diseases. More alarmingly, a high prevalence of concomitant infections with malaria and RF Borrelia has been reported. Therefore, we used a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas the numbers of parasitized erythrocytes were reduced 15-fold. This may be explained by polarization of the host immune response toward the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts that succumb to sepsis. Mixed infection also resulted in severe malaria anemia with low hemoglobin levels, even though the parasite counts were low. Overall, coinfected animals had a higher fatality rate and shorter time to death than those with either malaria or RF single infection. Furthermore, secondary malaria infection reactivated a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of RF Borrelia infection. Our study highlights the importance of investigating concomitant infections in vivo to elucidate the immune responses that are involved in the clinical outcome.

Genetic control of the innate immune response to Borrelia hermsii influences the course of relapsing fever in inbred strains of mice.

Host susceptibility to infection is controlled in large measure by the genetic makeup of the host. Spirochetes of the genus Borrelia include nearly 40 species of vector-borne spirochetes that are capable of infecting a wide range of mammalian hosts, causing Lyme disease and relapsing fever. Relapsing fever is associated with high-level bacteremia, as well as hematologic manifestations, such as thrombocytopenia (i.e., low platelet numbers) and anemia. To facilitate studies of genetic control of susceptibility to Borrelia hermsii infection, we performed a systematic analysis of the course of infection using immunocompetent and immunocompromised inbred strains of mice. Our analysis revealed that sensitivity to B. hermsii infections is genetically controlled. In addition, whereas the role of adaptive immunity to relapsing fever-causing spirochetes is well documented, we found that innate immunity contributes significantly to the reduction of bacterial burden. Similar to human infection, the progression of the disease in mice was associated with thrombocytopenia and anemia. Histological and fluorescence in situ hybridization (FISH) analysis of infected tissues indicated that red blood cells (RBCs) were removed by tissue-resident macrophages, a process that could lead to anemia. Spirochetes in the spleen and liver were often visualized associated with RBCs, lending support to the hypothesis that direct interaction of B. hermsii spirochetes with RBCs leads to clearance of bacteria from the bloodstream by tissue phagocytes.

Understanding tropism and immunopathological mechanisms of relapsing fever spirochaetes.

Mice infected with relapsing fever (RF) spirochaetes survive recurrent waves of high-level bacteraemia with little, if any, clinical complications or tissue injury. In the absence of B-cells, peak bacteraemia does not resolve, resulting in multi-organ complications. During peak bacteraemia, large amounts of interleukin-10 (IL-10) are produced in blood and tissues. In mice unable to clear peak bacteraemia, exogenous IL-10 greatly reduced the clinical manifestations, serum levels of CXCL13, cerebral microgliosis, and the pathogen load. In contrast, IL-10 deficiency in mice unable to clear peak bacteraemia resulted in microvascular complications with distinct severities, depending on the serotype: serotype 2 (Bt2), which causes peak bacteraemia of c. 10(8)/mL, resulted in rapid death from subarachnoid and intraparenchymal haemorrhage; in contrast, serotype 1, which causes peak bacteraemia of c. 10(7)/mL, resulted in milder multi-organ haemorrhage and thrombosis. IL-10 deficiency also resulted in multi-organ haemorrhage and thrombosis with infarction in wild-type mice despite lower peak bacteraemia. Two mechanisms for pathogen control have been identified: antibody clearance of peak bacteraemia, and antibody-independent lowering of bacteraemia via phagocytosis in the spleen. IL-10 plays opposite roles in pathogen control, depending on the severity of bacteraemia: during persistent high bacteraemia, IL-10 helps to control it by protecting innate immune cells from apoptosis; in contrast, during transient peak bacteraemia, IL-10 slows down antibody-mediated clearance. A successful outcome from RF depends on a balanced immune response to clear bacteraemia while avoiding microvascular injury, in which production of IL-10, in response to the pathogen load, plays a critical role.

The loss and gain of marginal zone and peritoneal B cells is different in response to relapsing fever and Lyme disease Borrelia.

T cell-independent Abs are protective against Lyme disease and relapsing fever, illnesses caused by Borrelia spirochetes with distinct blood-borne phases of infection. To understand this protective response, we characterized splenic and peritoneal B cell compartments during infection using flow cytometry and immunohistochemistry. In the spleen, early after infection, Borrelia crocidurae, a relapsing fever species, induced a striking loss of marginal zone (MZ) B cells from the MZ, while Borrelia burgdorferi, the agent of Lyme disease, induced the expansion of this subset. At the same time, no significant changes were observed in follicular B cells in response to either species of Borrelia. In the peritoneal cavity, a further loss was demonstrated early in response to B. crocidurae in the B1b, B1c, and B2 cell subsets, but B1a cells were not significantly altered. The loss of B1c and B2 cells was sustained through subsequent peaks of spirochetemia, suggesting these subsets may be important in resolving relapsing episodes. In contrast, an early and significant increase in peritoneal B1a, B1b, and B1c cells, but not B2 cells, occurred in response to B. burgdorferi. Later in the course of infection, both species of Borrelia induced the selective expansion of peritoneal B1b cells, suggesting that B1b cells may participate in long-lasting immunity to Lyme and relapsing fever spirochetes. Our data demonstrate that different Borrelia can activate the same B cell subsets in distinct ways and they each elicit a complex interplay of MZ and multiple peritoneal B cell subsets in the early response to infection.

Relapsing fever borreliosis in interleukin-10-deficient mice.

Relapsing fever (RF) is a spirochetal infection characterized by periods of sickness with fever at time of high bacteremia that alternate with afebrile periods of relative well being during low bacteremia. Patients with epidemic RF who are doing relatively well have extraordinarily high levels of interleukin-10 (IL-10) in the circulation. We investigated the possibility that IL-10 plays an important protective role in this infection using wild-type and IL-10-deficient mice inoculated with virulent serotype 2 of the RF spirochete Borrelia turicatae. During peak bacteremia there was increased systemic production of IL-10 that quickly resolved in the postpeak period; in contrast, IL-6 and CXCL13 production increased during the peak but remained elevated during postpeak bacteremia. IL-10 deficiency resulted in lower bacteremia, increased specific antibody production, higher production of CXCL13 and IL-6, and thrombotic and hemorrhagic complications affecting multiple organs with secondary tissue injury. Our results revealed that production of IL-10 is highly regulated during RF and plays an important protective role in the prevention of hemorrhagic and thrombotic complications at the cost of reduced pathogen control.