https://orcid.org/0000-0003-4638-3820
Figures
Abstract
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.
Author summary
Louse-borne relapsing fever (LBRF) is an ancient epidemic disease, with descriptions dating back to Hippocrates’ times. Linked to war, famine, poverty, forced migration, and crowding under poor hygienic conditions, the disease has accompanied humankind throughout history and, until 100 years ago, the disease was well known among physicians in Europe and North America. Since then, the disease has fallen into oblivion, and reports of the disease are largely confined to Ethiopia. However, the disease has recently resurfaced when it was recognized as a cause of fever in East African migrants (originating from Somalia, Eritrea, and Ethiopia) arriving to Europe. Since the disease was at its peak before the days of modern medicine, many aspects of the disease have never been formally studied and, to date, remain incompletely understood. In order to shed light on some of these aspects, we have reviewed and analysed the accessible literature on LBRF since the recognition of its mode of transmission in 1907, and compiled this two-part review focusing on epidemiology and diagnostic aspects (part 1) and mortality, JHR, and impact on pregnancy (part 2). We deliberately did not include an analysis on the antimicrobial treatment of LBRF, since Guerrier and Doherty have published a comprehensive meta-analysis on this aspect in 2011.
Citation: Kahlig P, Neumayr A, Paris DH (2021) Louse-borne relapsing fever—A systematic review and analysis of the literature: Part 2—Mortality, Jarisch–Herxheimer reaction, impact on pregnancy. PLoS Negl Trop Dis 15(3): e0008656. https://doi.org/10.1371/journal.pntd.0008656
Editor: Aparna Krishnavajhala, Baylor College of Medicine, UNITED STATES
Published: March 11, 2021
Copyright: © 2021 Kahlig et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Relapsing fevers are potentially fatal ectoparasite-borne diseases which are caused by spirochetes of the genus Borrelia and characterized by recurring episodes of fever [1].
Relapsing fevers are classified according to their transmitting vector which include tick-borne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF). While several Borrelia spp. have been identified to cause TBRF, Borrelia recurrentis is the only species known to cause LBRF [2]. The incubation period of LBRF ranges from 4 to 18 (average 7) days. The attack starts abruptly with a fever that increases to nearly 40°C in a few days, accompanied by rigors. Early symptoms include headache, dizziness, generalized aches and pains (affecting especially the lower back, knees, and elbows), anorexia, nausea, vomiting, and diarrhea. Upper abdominal pain, cough, and epistaxis develop later [3]. A petechial or ecchymotic rash, particularly involving the trunk, is seen in 2% to 8% of patients, and 7% to >70% of patients develop jaundice [4]. Subconjunctival hemorrhages and epistaxis are common (25%), hemoptysis, gastrointestinal bleeding, and retinal hemorrhages less so [3]. In severe cases, neurological involvement, myocarditis, acute respiratory distress syndrome, hepatic failure, spleen rupture, disseminated intravascular coagulation leading to intracranial, massive gastrointestinal, pulmonary or peripartum hemorrhage may occur [3]. Case fatalities between 30% and 80% [4–12] have been reported in untreated patients during major epidemics, but with antibiotic treatment mortality is reduced to 2% to 5% [13]. Untreated attacks resolve by crisis after 4 to 10 (average 5) days. This is followed by an afebrile remission of 5 to 9 days and succeeded by up to 5 relapses of diminishing severity, during which there may be epistaxis, but no petechial rashes [3]. The crisis which abruptly terminates untreated attacks is a consequence of specific bactericidal antibodies lysing spirochetes in the blood. The relapse phenomenon can be attributed to the antigenic variation of the bacterium’s outer membrane lipoproteins (vmp) [14]. Once antibodies have been generated against a specific vmp variant, a new vmp variant is expressed by the Borrelia. After the removal of the majority population through antibodies, the minority variant population expands until antibodies are also generated against the new vmp variant. Also linked to vmp is the phenomenon of Jarisch–Herxheimer reaction (JHR) [15]. Named after the researchers who first described the reaction in patients with syphilis [16–18], the JHR has been described to occur after the elimination of spirochetes in patients with syphilis, leptospirosis, Lyme disease, and relapsing fever [18]. Around 1970, several authors had studied this reaction in LBRF patients after treatment with antibiotics [4,18–21]. The observations resembled the 4 phases described for fever induced by endotoxin [22]. JHR occurs about 45 minutes to 2 hours after administration of antibiotic treatment and is characterized by restlessness followed by a chill phase of acute and intense rigors lasting 10 to 30 minutes. During this chill phase, body temperature, pulse, and respiratory rates rise steeply, and associated delirium (sometimes leading to dangerous behavior) as well as potentially fatal hyperpyrexia may occur. The flush phase following the chill phase is characterized by a systemic vasodilatation with a fall in blood pressure (possibly leading to collapse and intractable hypotension). This is accompanied by profuse sweating and a slowly declining body temperature, threatening the patient for several hours. The prodromal phase, the chill phase, the flush phase, and the phase of defervescence have been described in detail by several authors [4,20]. Both the spontaneous crisis that terminates untreated attacks and the JHR induced by antibiotic treatment show pathophysiological features of a classic endotoxin reaction mediated by proinflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 6 (IL-6), IL-8) [18]. A recent review has addressed the current understanding of the pathogenesis of JHR, which seems to be of multifactorial genesis and is not fully understood yet [18]. A JHR occurs in up to 80% to 90% of treated patients [13], and symptoms usually resolve in a few hours. Even though JHR is rarely fatal, it does enhance the risk for complications and a fatal outcome (liver and renal function impairment, acute respiratory distress syndrome, myocardial injury, hypotensive shock, seizures, strokes, induction of uterine contractions in pregnancy) [13,18]. Besides supportive treatment, administration of antibodies against TNF-α have been proven effective in the management of the JHR [23–25].
A variety of antibiotic drugs, including tetracyclines, erythromycin, chloramphenicol, and penicillin, are effective as single-dose treatment (given orally or parenterally) in LBRF [13]. A meta-analysis of antibiotic treatment of LBRF published by Guerrier and Doherty in 2011 found no significant difference between tetracycline and penicillin with regard to mortality rate. Tetracycline use was found to be associated with faster resolution of fever and a lower risk of relapse compared to penicillin treatment. However, tetracycline use appears to be associated with a higher risk for JHR compared to penicillin treatment [26].
In a study on TBRF in pregnant women conducted in Rwanda, the risk of pregnancy loss was 33% and that of perinatal mortality 15% [27]. In another study on TBRF in pregnant women in Tanzania, the risk of pregnancy loss was 30% and that of perinatal mortality 15% [28]. In contrast to TBRF, data on the impact of LBRF on pregnancy is scarce. A publication on LBRF published in 1970 states: "Abortion or miscarriage is the usual fate of pregnancy. That we had one live premature birth and three uninterrupted pregnancies is probably due to a standard of care not normally available in an epidemic. That congenital infection and abortion are the rule is clear from El Ramly’s post-mortem studies (1946)" [4].
With this systematic review, we aim to summarize the available data and address the following main review questions: What is the mortality of untreated and treated LBRF? What are the reported frequencies of the JHR in LBRF? What is the impact of LBRF on pregnancy?
Methods
A systematic review protocol established for this review is available in the Supporting information section (S1 Text). The electronic databases Biosis, CINAHL, Cochrane Library, Current Contents Connect, Elsevier, EMBASE ovid, Ovid MEDLINE, PMC, PUBMED, SCOPUS, and Web of Science were searched on 04/Oct/2017 using the search term: ((Relapsing AND fever AND (Louse OR Lice OR (Pediculus AND humanus))) OR (Borrelia AND recurrentis) OR LBRF). A second and third search, using the same search term on the same databases, was conducted on 07/Aug/2018 and 17/Jun/2019, respectively. After checking for and removing duplicates (using Endnote software and manually [29]), publications were prescreened by checking titles and abstracts if they concerned patient(s) with the diagnosis of LBRF. Publications not reporting patient(s) with the diagnosis of LBRF were excluded. The remaining publications were then assessed in full text for eligibility according to the inclusion criteria: reporting conclusively diagnosed case(s) of LBRF and published after 1907 (the year of the discovery of the disease’s transmission) and published in English, French, German, or Spanish. Publications not fulfilling these inclusion criteria were excluded. Publications that could neither be retrieved through their respective journals, nor by contacting libraries, or after contacting the authors, were classified as “not retrievable” and excluded. Additional relevant publications identified when reading the full-text articles or checking their reference lists were reviewed and included if they fulfilled the inclusion criteria (“snowball” search strategy). Finally, a subsearch was conducted on (i) outcome, (ii) JHR, and (iii) impact on pregnancies. Inclusion criteria for (i) outcome were: available conclusive data on number of patients treated/untreated plus treatment plus mortality. Inclusion criteria for (ii) JHR were: available conclusive data on number of patients treated/untreated plus number of patients with a JHR/JHR rate plus reaction after treatment described as JHR. In order to investigate a potential influence of the study objectives/endpoints on the reported incidence rates of JHR, we conducted a subgroup analysis. Thus, the 42 included studies were divided into 2 groups, one primarily focusing on JHR and the other primarily focusing on other aspects of LBRF. Inclusion criteria for (iii) impact on pregnancies were: available conclusive data on the number of cases plus pregnancy outcome.
A data extraction sheet for screening and selecting eligible publications was developed and is available in the Supporting information section (S2 Text). The following data were extracted from eligible publications using a standardized excel spreadsheet: patient characteristics (number of patients, age, gender, origin, occupation, social status, and way and duration of migration), diagnostic method (microscopy and molecular method), symptoms and signs (fever, chills, myalgia, headache, hepatomegaly, splenomegaly, signs of hemorrhage, and others), treatment (number of treated and untreated patients, drug, dosage, and duration and route of administration), and outcome (JHR, abortion/stillbirth, premature delivery, and mortality).
To minimize bias, the same reviewer conducted a second full data extraction ≥1 month after the first extraction. Discrepant results and unclear cases were resolved by consulting a second reviewer. In order to consider the probability of a correct diagnosis of LBRF, all reviewed cases were graded according to the used diagnostic method and respectively classified (Table 1).
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (S1 Checklist).
Results
Our search strategy identified 4,943 publications of which 184 proved eligible for being included and analysed (Fig 1; S1 Fig; S1 Data). Lists of included and excluded publications are available in the Supporting information section (S3–S6 Text).
Mortality
After full-text assessment of the eligible 184 publications, 102 proved eligible after applying subsearch inclusion criteria for "outcome."
The identified treated cases (n = 5,969) were divided into 2 groups according to the treatments used: treated with arsenicals (n = 2,338) and treated with antibiotics (n = 3,631). The group treated with antibiotics was not divided further, since a recent systematic review has already compared the antibiotic treatments of LBRF [26]. Identified studies with data on untreated cases are listed in Table 2.
An overview on all identified LBRF cases with the according case fatality rates (CFRs) is shown (Table 3).
Fig 2 depicts the CFR of LBRF cases from the reviewed studies according to treatment modality over time.
The dots correspond to the CFR of the respective group. The columns represent the absolute number of cases. The table gives detailed information on the data for each segment of time. Note: Since the data set is compiled from published literature reporting on cases, outbreaks and clinical studies from different regions, different populations as well as different seasons, no trend in annual incidence of LBRF can be inferred.
Between 2010 and 2019, 127 patients were treated with an overall CFR of 6.3%. Of these, 53 were treated in the frame of a study conducted in Ethiopia which reported a CFR of 13.21%. The other patients were treated in Europe (n = 72), Saudi Arabia (n = 1), and Israel (n = 1). Among these, 1 fatal case occurred in Europe, which corresponds to a CFR of 1.35%. An overview on CFR in relation to treatment and geographical region is shown in Fig 3. Reported signs, symptoms, and factors associated with mortality and poor prognosis are summarized in Table 4.
Jarisch–Herxheimer reaction (JHR)
After full-text assessment, 184 publications were eligible. After applying subsearch inclusion criteria for "JHR," 42 publications were included and are summarized in Table 5.
We identified 3 studies [24,59,86] in which already previously published patient data were republished [4,23,50]. Data from these 3 studies were compiled (data of identical patients/cases).
Overall, JHR was observed in 1,452 of the 2,618 reported cases, corresponding to an incidence rate of 55.8%. Of note, the incidence rate of JHR rate in studies focusing on JHR (ncases = 603) versus studies not focusing on JHR (ncases = 2015) was 71.78% and 50.62%, respectively.
Pregnancies
After full-text assessment of the eligible 184 publications, 14 proved eligible after applying subsearch inclusion criteria for "pregnancies." The characteristics of these 14 included studies are summarized in Table 6.
In total, 206 pregnancies and their outcome were reported in the 14 included studies (Table 6): The overall incidence of an adverse pregnancy outcome was 70.9% (n = 146). When considering only cases reported by studies graded at least “B” (n = 122 pregnancies), adverse pregnancy outcomes were reported in 76.2% of the cases (n = 93) (Fig 4).
(A) Microscopically diagnosed cases. (B) Microscopically and clinically diagnosed cases. One study reported adverse pregnancy outcomes without specifying them (gray color) [89].
Discussion
Mortality
Observational factors potentially related to high case fatality.
High mortality rates in untreated cases (30% to 80%) [4–12] were mostly traced back to reports of epidemics based either on observations by the authors or on renditions of observational reports by colleagues. In both cases, these are rough estimations without any diagnostic evidence [5,8,90]. In other instances, high rates trace back to coinfections with other diseases [38,90–93]. Additionally, some authors attribute the striking differences in reported mortality rates to the general poor health and nutritional condition of the affected population, the lack of medical and sanitary measures, and sociopolitical factors like war [10–12,35,49,92]. Exemplarily, observations from China noted the difference between an outbreak among “robust” soldiers and among poor villagers, where mortality had been near 0% and 50%, respectively [35]. CFRs and the course of the disease depend on the general condition and health of the population [94,95]. Additionally, a study found the disease to be more common and have an atypical course during famine years, compared to other years [94]. However, some authors noted that the disease is relatively benign, given appropriate treatment within a short time after the manifestation of symptoms [49], as Gaud and Morgan’s quote of Charles Nicolle shows: “No one need to die of relapsing fever provided that it is diagnosed in time” [49].
Untreated cases and analysis of CFR.
Anecdotal CFR of up to 80% are described in literature [4–12]; however, evidence-based data only show CFR up to 47.1% (Table 2). One study stands out with a CFR of 47.1%, which is the only data reaching the reported high CFRs (Table 2). The study investigated relapsing fever in Nigeria, including 52 of the untreated cases which originated from a prison in Kano, among whom 30 died resulting in a mortality rate of 57.69%. The reasons for the strikingly high CFR remain unknown. The only information available is that the author conducted weekly inspections only on the inmates. Coinfections or poor nutritional, medical, and health conditions cannot be excluded. Only 2 patients died out of the remaining 16 reported untreated patients, accounting for a mortality rate of 12.5% [38]. The prison series may be regarded as an extreme scenario. Interestingly, CFR drops roughly by half, when the extreme scenario is excluded (Table 3). The overall CFR for untreated cases was only slightly higher than the overall CFR for patients treated with arsenicals. When excluding the prison series, the overall CFR in untreated patients is 3.1%, which is lower than the overall CFR for patients treated with antibiotics. This demonstrates the impact of an insufficiently investigated extraordinary scenario on reported CFRs. Still, the overall results strikingly contrast with the rates of 40% to 80% that have been reported earlier, and published available data suggest that untreated LBRF may not be as deadly as reported earlier. Since the mortality rate is influenced by many factors, the numbers given may not reflect every situation. However, they reflect the overall rates and tendencies from all confirmed LBRF cases that were identified through published literature research.
Benefit of therapy.
Since antibiotic treatment of LBRF may trigger a strong and possibly even lethal JHR, the benefit of specific therapy has been questioned in certain situations. However, there is also no evidence to support a beneficial outcome when treatment is withheld. As suggested by Wolff and agreed to by Bryceson and colleagues, patients in a critical condition should primarily be treated symptomatically. Only after the attack should specific treatment be given [4,95]. Today, this approach of “resuscitate first—but then treat” appears to be the most widely accepted consensus regarding the management of LBRF patients.
Rise of CFR in treated cases.
Figs 2 and 3 demonstrate that antibiotic treatment reduced the CFR of LBFR compared to untreated cases and treatment using arsenicals in mid-20th century. However, the figures also show that over the past few decades, the CFR reported in the literature seems to have increased in patients treated with antibiotics. Fig 3 demonstrates both the geographic distribution and the increased number of studies publishing cases from the African continent, primarily East Africa. The patients treated in Europe were immigrants and refugees that were taken care of in European hospital centers. The patients in Ethiopia were mostly men from poor socioeconomic status, who could not afford costs for diagnosis and treatment. The poverty and the lack of awareness of LBRF prevented or delayed admission to medical care [54]. Two factors may have been responsible for this striking difference in CFR: on the one hand, the difference in the general condition and nutritional status of the 2 populations; on the other hand, the availability of medical care to the people affected. Unknown factors such as additional coinfections in the population from Arsi (Ethiopia) may have contributed. The rise over the past few decades may indicate a decline in health status of the affected population in Ethiopia. Further studies investigating the reasons for these high CFR in Ethiopia are needed.
The Jarisch–Herxheimer reaction
“Resolvement by crisis” in untreated cases.
In LBRF, a JHR-like reaction, often called crisis, has been observed after treatment since the beginning of the last century [34,41,47, 88,95–98]. Even untreated cases have been reported to exhibit a spontaneous resolvement of fever through crisis, which has been recognized by researchers to resemble the features and severity of the JHR in certain cases [50,63,99]. A study comparing the effects of different antibiotic treatments followed 6 untreated cases that had been admitted during this spontaneous crisis. These observations showed that the JHR was indistinguishable from the spontaneous crisis [45]. Unfortunately, there are no published studies which have investigated the process in detail during the natural course of the disease. It would be of great academic interest to compare the clinical and laboratory changes during the spontaneous reaction and the reaction after antibiotic treatment.
Detection bias.
Lack of standardized defining criteria: The observed incidence rate of JHR reported in studies range from 0% to 100% (Table 5). A reason for the discrepancies may be that there was neither a uniform protocol or guidelines for the classification of severity, nor a standardized definition or threshold from which point on the observations may be regarded as a JHR. Only 3 studies noted a predefined grading system [7,23,24,55]. A study stated that comparison is hampered due to this issue and noted further that some studies include critically ill patients, while others exclude this group of patients [7]. Another study reflected on its own results of a JHR rate of only 7.4% and states that these low results may have been caused by the lack of defining criteria for the occurrence of a JHR [54].
Influence of monitoring: Our data suggest that studies investigating JHR report higher incidence rates than studies which primarily focus on other aspects (Table 5). A review suggested that JHRs are often not recognized, thus underreported and easily overlooked [18]. Most studies investigating the pathophysiology after treatment included close monitoring of patients, often observing most of the parameters that are likely to change during JHR, hence increasing the likelihood of the reaction being detected. Mild reactions, on the other hand, may be easily overlooked without close monitoring, considering that they already peak 4 hours after treatment [18]. The issue may be demonstrated in the 37 cases studied by Brown and colleagues, who reported no JHR in the series. However, there was no information available about a threshold or definition used to identify a potential JHR. Intriguingly, rigors were observed in 30% of patients. The aims of the study were to survey a refugee camp and identify clinical criteria for diagnosing LBRF in the absence of laboratory facilities. As the resources in the given situation were not suitable for proper monitoring, the question may retrospectively be raised as to whether a certain number of JHRs could have been missed [65]. Another issue may be the degree of experience of the involved personnel and scientific researchers with diagnosing JHR. Perine, an author focusing on JHR [20,55,63,100], published JHR rates of 100% when studying the treatment of LBRF both in 1974 and 1983 (Table 5). Salih reported a JHR rate of 14.4% when researching treatment of LBRF in 1977. It seems likely that experience in detection influenced the striking difference. The pathophysiology of the reaction after treatment suggests a chance of missing the diagnosis when vital signs are monitored only 3 to 4 times a day, which may be assumed standard procedure in hospitalized stable patients.
Developing a grading system: There is a need to develop and widely apply a clear definition as to what should be regarded as a JHR. Until then, published data can hardly be compared to one another, since most studies do not report the process of monitoring and the threshold from which they consider a reaction as a JHR. Seboxa and Rahlenbeck defined a JHR as an increase in body temperature (>1°C), tachycardia, and a drop in systolic and diastolic blood pressure greater than 10 mmHg during 4 hours after treatment [7]. If further factors were to be added, the JHR might be objectified more precisely. An initial rise in body temperature, a rise in heart rate, rigors, an initial rise in blood pressure, tachypnoea, a late drop in arterial blood pressure, and a decline of body temperature could be easily measured and added to a protocol. If some of these changes were to be detected after treatment, a JHR might be diagnosed.
Redefining the reaction after treatment: The data suggest that defining the JHR as a reaction after antibiotic treatment should be reconsidered. It seems likely that there is always a reaction, which is altered by administering antimicrobial drugs, and thus more likely to be detected. Detection is favored by the circumstance of patients being monitored to various degrees in a medical facility.
Pregnancies
Lack of data.
To the best of our knowledge, this is the first review regarding the question of the influence of the B. recurrentis infection on pregnancy outcomes. Finding an explanation for these high rates is difficult due to scarce data. Most cases are simply noted in the reports without any further information [37,38,44,65,67,71].
Descriptions of cases and the question of congenital infection.
However, there are a few cases of LBRF described in detail. In one case, a mother was admitted on the third day of fever with the pregnancy intact. On the fifth day of fever, labor began just as her body temperature began to fall, and she gave birth to a stillborn child. The second case was of a woman admitted in labor on the seventh day of fever, when birth was given to a premature infant. This infant developed a fever with spirochetemia on the sixth day and died on the seventh day after birth. The postmortem examination found jaundiced conjunctivae, a collapsed left lung, and a congested right lung. Spirochetes were found in sections of the spleen, kidney, liver, lung and, as noted, “suprarenal.” Additional direct films were taken from the umbilical cord, lungs, liver, kidneys, and spleen, which all revealed positive results. Regarding the route of transmission, the author found the evidence to be inconclusive. When examining the placenta, the maternal surface contained a large number of spirochetes in the maternal blood sinuses. However, no positive results were yielded from the fetal vili. Nevertheless, all possible sources of infection other than intra-utero were found to be unlikely, suggesting an intrauterine infection as a probable source of infection in this case [88]. A similar scenario was described by Chung and Chang, in which a premature infant died within a week after birth. This was supposed to be a case of congenital infection. The mother was admitted with relapsing fever during parturition [41]. Another study gave a detailed account on the adverse pregnancy outcomes. The report concludes that both age of the mother and age of gestation had no influence on adverse events. Adverse events were observed at any gestation week during pregnancy. Further, the study reported spirochetes in a stillborn infant’s blood, obtained from its heart, and intrauterine infection was suspected in 2 new born infants [48]. Bryceson and colleagues stated that abortion and miscarriage seem to be usual outcomes of pregnancies where the mother is infected with B. recurrentis. The authors further referenced a colleague, El Ramley A., who found congenital infection and abortion to be a standard in his studies [4].
Association between gestational progress and adverse outcome?
In one publication, all adverse events took place before the 20th week of gestation, and no stillbirths had been observed past that point [6]. By contrast, several studies reported adverse pregnancy outcomes past that time: 2 stillbirths in the ninth month of pregnancy [65], a premature delivery in the seventh month of gestation [41], a premature delivery at 7.5 months of gestation [44], a stillbirth in the fifth month, and in the case of a further 2 women, a stillbirth and a premature delivery in the seventh month of gestation [88]. The evidence suggests that adverse pregnancy outcomes may occur at any time, as another study has observed [89].
Need for further studies.
Results of the analysis demonstrated an enormous rate of adverse pregnancy outcomes for pregnant women infected with B. recurrentis (Fig 4). While most aspects of LBRF were extensively researched, the effect on pregnant women and the unborn child has not been investigated yet. Factors that influence the risk of adverse pregnancy outcome during LBRF are currently unknown or not retrievable in published literature. The findings suggest a need for studies specifically looking at LBRF during pregnancy. Regarding adverse pregnancy outcomes during TBRF infection, rates between 30% and 44% were reported [27,28,101–103]. Larsson and colleagues recently demonstrated the effects of Borrelia duttonii infection in a mouse model, where spirochetes frequently caused congenital infection [102]. A treatable, neglected disease with a probability of up to 75% of adverse pregnancy outcomes should receive close attention, especially when dealing with women in, or from, endemic countries. Parallels can be drawn to similar neglected diseases, such as scrub typhus and murine typhus, in which a poor neonatal outcome (stillborn, premature, and/or small for gestation age) has been reported in 43.6% and 33.3%, respectively [104]. There is a need for further studies and increased awareness, especially among women in endemic countries.
Key learning points
- Reported CFRs in Africa have been rising throughout the past few decades.
- There is no standardized protocol on diagnosing JHR and reported JHR rates depend on the focus of the study, monitoring of patients, and awareness.
- Three out of 4 pregnancies are negatively affected by LBRF.
Top five papers
- Warrell DA. Louse-borne relapsing fever (Borrelia recurrentis infection). Epidemiol Infect. 2019;147:e106. doi: 10.1017/S0950268819000116
- Bryceson ADM, Parry EHO, Perine PL, Warrell DA, Vukotich D, Leithead CS. A clinical and laboratory study of 62 cases in ethiopia and a reconsideration of the literature1. QJM. 1970;39(1):129–70. doi: 10.1093/oxfordjournals.qjmed.a067198
- Felsenfeld O. Borrelia; Strains, Vectors, Human and Animal Borreliosis. St. Louis: Warren H. Green; 1971.
- Butler T. The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. Am J Trop Med Hyg. 2017;96(1):46–52. PubMed PMID: CCC:000397822900010.
- Guerrier G, Doherty T. Comparison of antibiotic regimens for treating louse-borne relapsing fever: A meta-analysis. Trans R Soc Trop Med Hyg. 2011;105(9):483–90. doi: http://dx.doi.org/10.1016/j.trstmh.2011.04.004. PubMed PMID: 51548792.
Supporting information
S1 Checklist. PRISMA checklist.
27-item checklist for systematic reviews.
https://doi.org/10.1371/journal.pntd.0008656.s001
(DOC)
S1 Text. Review Protocol.
Established to conduct this systematic review.
https://doi.org/10.1371/journal.pntd.0008656.s002
(DOCX)
S2 Text. Data Extraction Sheet.
Used for screening and selecting eligible publications.
https://doi.org/10.1371/journal.pntd.0008656.s003
(DOCX)
S3 Text. References before sub-search.
Included and excluded references for qualitative synthesis, before a subsearch was conducted on (i) outcome, (ii) JHR, and (iii) impact on pregnancies.
https://doi.org/10.1371/journal.pntd.0008656.s004
(DOCX)
S4 Text. References–mortality.
Included and excluded references in mortality section.
https://doi.org/10.1371/journal.pntd.0008656.s005
(DOCX)
S5 Text. References–JHR.
Included and excluded references in JHR section.
https://doi.org/10.1371/journal.pntd.0008656.s006
(DOCX)
S6 Text. References–pregnancies.
Included and excluded references in pregnancies section.
https://doi.org/10.1371/journal.pntd.0008656.s007
(DOCX)
S1 Data. Data extracted from included studies.
Excel spreadsheet containing, in separate sheets, the underlying numerical data.
https://doi.org/10.1371/journal.pntd.0008656.s009
(XLSX)
References
- 1.
Felsenfeld O. Borrelia; Strains, Vectors, Human and Animal Borreliosis. St. Louis: Warren H. Green; 1971.
- 2. Cutler SJ. Relapsing Fever Borreliae: A Global Review. Clin Lab Med. 2015;35(4):847–65. http://dx.doi.org/10.1016/j.cll.2015.07.001. pmid:26593261.
- 3. Warrell DA. Louse-borne relapsing fever (Borrelia recurrentis infection). Epidemiol Infect. 2019;147:e106. pmid:30869050
- 4. Bryceson ADM, Parry EHO, Perine PL, Warrell DA, Vukotich D, Leithead CS. A clinical and laboratory study of 62 cases in ethiopia and a reconsideration of the literature. QJM. 1970;39(1):129–70.
- 5. Beveridge GEG. The Louse-Borne Type of Relapsing Fever as Prevalent in the Anglo-Egyptian Sudan, 1926-and 1927. Med J Aust. 1928;1(4):110–2.
- 6. Borgnolo G, Hailu B, Ciancarelli A, Almaviva M, Woldemariam T. Louse-borne relapsing fever. A clinical and an epidemiological study of 389 patients in Asella Hospital, Ethiopia. Trop Geogr Med. 1993;45(2):66–9. pmid:8511813.
- 7. Seboxa T, Rahlenbeck S. Treatment of louse-borne relapsing fever with low dose penicillin or tetracycline: a clinical trial. Scand J Infect Dis [Internet]. 1995;27(1):29–31. Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/105/CN-00115105/frame.html. pmid:7784810
- 8. Steen R, Townsend RS. Relapsing Fever in Bulandshahr District. Ind Med Gaz. 1913;48(9):338–41. PubMed Central PMCID: PMC5177298. pmid:29005896
- 9. Antinori S, Mediannikov O, Corbellino M, Grande R, Parravicini C, Bestetti G, et al. Louse-Borne Relapsing Fever (Borrelia recurrentis) in a Somali Refugee Arriving in Italy: A Re-emerging Infection in Europe? PLoS Negl Trop Dis. 2016;10(5):e0004522. http://dx.doi.org/10.1371/journal.pntd.0004522. pmid:27149282.
- 10. Oliver MR, Liles WC, Spach DW. Relapsing fever. Wilderness Environ Med. 1996;7(1):46–55. pmid:26116126.
- 11. Kirk R. The Epidemiology of Relapsing Fever in the Anglo-Egyptian Sudan. Ann Trop Med Parasitol. 1939;33(2):125–40.
- 12. Garnham PC, Davies CW. An epidemic of louse-borne relapsing fever in Kenya. Trans R Soc Trop Med Hyg. 1947;41(1):141–70. pmid:20270461.
- 13.
Barbour AG. Relapsing Fever and other Borrelia Diseases. Tropical Infectious Diseases: Elsevier Inc.; 2011: p.295–302.
- 14. Barbour AG, Hayes SF. Biology of Borrelia species. Microbiol Rev. 1986;50(4):381–400. pmid:3540570; PubMed Central PMCID: PMC373079.
- 15. Vidal V, Scragg IG, Cutler SJ, Rockett KA, Fekade D, Warrell DA, et al. Variable major lipoprotein is a principal TNF-inducing factor of louse- borne relapsing fever. Nat Med. 1998;4(12):1416–20. http://dx.doi.org/10.1038/4007. pmid:9846580.
- 16. Herxheimer K. Ueber eine bei Syphilitischen vorkommende Quecksilberreaktion. Dtsch Med Wochenschr. 1902;28:895–7.
- 17. Jarisch A. Therapeutische Versuche bei Syphilis. Wien Med Wochenschr. 1895;45:721–4.
- 18. Butler T. The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. Am J Trop Med Hyg. 2017;96(1):46–52. CCC:000397822900010. pmid:28077740
- 19. Schofield TP, Talbot JM, Bryceson AD, Parry EH. Leucopenia and fever in the "Jarisch-Herxheimer" reaction of louse-borne relapsing fever. Lancet. 1968;1(7533):58–62. pmid:4169111.
- 20. Warrell DA, Pope HM, Parry EH, Perine PL, Bryceson AD. Cardiorespiratory disturbances associated with infective fever in man: studies of Ethiopian louse-borne relapsing fever. Clin Sci. 1970;39(1):123–45. pmid:5448162.
- 21. Parry EH, Bryceson AD, Leithead CS. Acute hemodynamic changes during treatment of louse-borne relapsing fever. Lancet. 1967;1(7481):81–3. pmid:4163060.
- 22. Altschule MD, Freedberg AS, McManus MJ. Circulation and respiration during an episode of chill and fever in man. J Clin Investig. 1945;24(6):878–89. PMC435527. pmid:16695285
- 23. Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, et al. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor α. N Engl J Med. 1996;335(5):311–5. FULL TEXT LINK http://dx.doi.org/10.1056/NEJM199608013350503. PubMed Central PMCID: PMC8663853. pmid:8663853
- 24. Coxon R, Fekade D, Knox K, Hussein K, Melka A, Daniel A, et al. The effect of antibody against TNF alpha on cytokine response in Jarisch-Herxheimer reactions of louse-borne relapsing fever. QJM: monthly journal of the association of physicians [Internet]. 1997;90(3):213–21. Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/331/CN-00138331/frame.html. pmid:9093599
- 25. Knox K, Fekade D, Hussein K, Melka A, Coxon R, Smith D, et al. Ovine polyclonal anti-TNF fab antibody suppresses Jarische-Herxheimer reaction of Louse-Borne relapsing fever. Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy. 1994;34(0):143. BIOSIS:PREV199598025505.
- 26. Guerrier G, Doherty T. Comparison of antibiotic regimens for treating louse-borne relapsing fever: A meta-analysis. Trans R Soc Trop Med Hyg. 2011;105(9):483–90. http://dx.doi.org/10.1016/j.trstmh.2011.04.004. pmid:21803390.
- 27. Goubau PF. Relapsing fevers—a review. Annales De La Societe Belge De Medecine Tropicale. 1984;64(4):335–64. WOS:A1984ABX2000002. pmid:6397148
- 28. Melkert PW. Relapsing fever in pregnancy: analysis of high-risk factors. Br J Obstet Gynaecol. 1988;95(10):1070–2. Epub 1988/10/01. pmid:3191046.
- 29. Qi X, Yang M, Ren W, Jia J, Wang J, Han G, et al. Find Duplicates among the PubMed, EMBASE, and Cochrane Library Databases in Systematic Review. PLoS ONE. 2013;8(8):e71838. PMC3748039. pmid:23977157
- 30. Duchamp JC. La fievre recurrente chez les Serbes. Le progrès médical, Paris. 1917:10–3.
- 31. Porot A. Délire et réactions psychomotrices dans la fièvre récurrente de l’indigène. Bulletin de la Société de Pathologie Exotique. 1917;10(7):532–6.
- 32. Margolis A. Beobachtungen über Rückfallfieber. Beitr Klin Infektkrk. 1919;7:254.
- 33. Ed Prado. Estudio del tifus recurrente en el Perú. Ann Fac Med Lima. 1920;3:26–45 and 134–52.
- 34. Fry AS. An Epidemic of Fifty-Four Cases of Relapsing Fever Observed in Birjand, East Persia Ind Med Gaz. 1920;55(1):2–8. PubMed Central PMCID: PMC5180769. pmid:29008260
- 35. Jouveau-Dubreuil H. Etude clinique sur la fièvre récurrente du Setchouen (Chine occidentale). Bull Soc Pathol Exot. 1920;13:38.
- 36. Sinton JA. Relapsing Fever at Meshed, North-East Persia Ind Med Gaz. 1921;56(7):241–50. PubMed Central PMCID: PMC5166278. pmid:29007220
- 37. Sergent E, Foley H. L’épidémiologie de la fiévre récurrente dans l’afrique du nord. Trans R Soc Trop Med Hyg. 1922;16(3):170–87. https://doi.org/10.1016/S0035-9203(22)90496-1.
- 38. McCuLloch WE. Relapsing Fever in Northern Nigeria-A Study of 300 Cases. J Trop Med Hyg. 1925;28(18):332–41.
- 39. Chu F-Ta, Deitrick S, Chung S-F. Relapsing Fever in Children. A Study of Twenty-Six Epidemic Cases. National Medical Journal of China. 1931;17(2):224–32.
- 40. Chung H-L. Studies on the Transmission of Relapsing Fever in North China. Preliminary Observations Chinese Medical Journal. 1936;50(12):1723–34.
- 41. Chung H-L, Chang FC. Relapsing Fever. Clinical and Statistical Study of 337 Cases. Chin Med J (Engl). 1939;55(1):6–33.
- 42. Wolman M. Observations on the Value of Treatment in Louse-borne Relapsing Fever. East Afr Med J. 1944;21(11):336–40.
- 43. Wolman M. Louse-borne relapsing fever treated with calcium gold keratinate. Lancet (London, England). 1945;2(6381):775–7. pmid:21007364.
- 44. Ingraham HS, Lapenta RG, Author A, Correspondence A, Ingraham HS. Penicillin in the treatment of louse-borne relapsing fever. US Nav Med Bull. 1946;46(11):1719–23. PubMed Central PMCID: PMC21002713. pmid:21002713
- 45. Perine PL, Teklu B. Antibiotic treatment of louse-borne relapsing fever in Ethiopia: A report of 377 cases. Am J Trop Med Hyg. 1983;32(5):1096–100. pmid:6625065.
- 46. Russell H. Human and Experimental Relapsing Fever, Accra, Gold Coast, 1929–1930. West Afr Med J. 1931;4(3):59–66.
- 47. Chang SL. Relapsing fever in Changsha. A report of 41 cases. Chin Med J. 1938;54:163–72.
- 48. El Ramley AH. Relapsing fever. J Egypt Public Health Assoc. 1946;21:1–48.
- 49. Gaud M, Morgan MT. Epidemiological Study on Relapsing Fever in North Africa (1943–1945). Bull World Health Organ. 1948;1(1):69–92. pmid:20603922; PubMed Central PMCID: PMC2556137.
- 50. Salih SY, Mustafa D, Abdel Wahab SM, Ahmed MA, Omer A. Louse-borne relapsing fever: I. A clinical and laboratory study of 363 cases in the Sudan. Trans R Soc Trop Med Hyg. 1977;71(1):43–8. pmid:871032.
- 51. Borgnolo G, Denku B, Chiabrera F, Hailu B. Louse-borne relapsing fever in Ethiopian children: A clinical study. Ann Trop Paediatr. 1993;13(2):165–71. pmid:7687113.
- 52. Mitiku K, Mengistu G. Relapsing fever in Gondar, Ethiopia. East Afr Med J. 2002;79(2):85–7. pmid:12380884
- 53. Ramos JM, Malmierca E, Reyes F, Wolde W, Galata A, Tesfamariam A, et al. Characteristics of louse-borne relapsing fever in Ethiopian children and adults. Ann Trop Med Parasitol. 2004;98(2):191–6. http://dx.doi.org/10.1179/000349804225003136. pmid:15035729.
- 54. Nordmann T, Feldt T, Bosselmann M, Tufa TB, Lemma G, Holtfreter M, et al. Outbreak of Louse-Borne Relapsing Fever among Urban Dwellers in Arsi Zone, Central Ethiopia, from July to November 2016. Am J Trop Med Hyg. 2018;98(6):1599–602. BIOSIS:PREV201800626499. pmid:29692298
- 55. Bryceson AD, Cooper KE, Warrell DA, Perine PL, Parry EH. Studies of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating Borrelia endotoxin. Clin Sci. 1972;43(3):343–54. pmid:5077513.
- 56. Knaack RH, Wright LJ, Leithead CS, Kidan TG, Plorde JJ. Penicillin vs. tetracycline in the treatment of louse borne relapsing fever. A preliminary report. Ethiop Med J. 1972;10(1):15–22. pmid:4669835.
- 57. Perine PL, Krause DW, Awoke S, McDade JE. Single dose doxycycline treatment of louse borne relapsing fever and epidemic typhus. Lancet. 1974;2(7883):742–4. pmid:4143011.
- 58. Galloway RE, Levin J, Butler T, Naff GB, Goldsmith GH, Saito H, et al. Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrentis infection. Am J Med. 1977;63(6):933–8. pmid:605915.
- 59. Salih SY, Mustafa D. Louse-borne relapsing fever: II. Combined penicillin and tetracycline therapy in 160 Sudanese patients. Trans R Soc Trop Med Hyg. 1977;71(1):49–51. pmid:871033.
- 60. Butler T, Hazen P, Wallace CK. Infection with Borrelia recurrentis: Pathogenesis of fever and petechiae. J Infect Dis. 1979;140(5):665–75. pmid:528787.
- 61. Butler T, Aikawa M, Habte-Michael A, Wallace C. Phagocytosis of Borrelia recurrentis by blood polymorphonuclear leukocytes is enhanced by antibiotic treatment. Infect Immun. 1980;28(3):1009–13. pmid:7399684.
- 62. Teklu B, Habte-Michael A, Warrell DA, White NJ, Wright DJM. Meptazinol diminishes the jarisch herxheimer reaction of relapsing fever. Lancet. 1983;1(8329):836–9. BIOSIS:PREV198376081118. pmid:6132178
- 63. Warrell DA, Perine PL, Krause DW, Bing DH, MacDougal SJ. Pathophysiology and immunology of the Jarisch-Herxheimer-like reaction in louse-borne relapsing fever: Comparison of tetracycline and slow-release penicillin. J Infect Dis. 1983;147(5):898–909. pmid:6842024.
- 64. Zein ZA. Louse borne relapsing fever (LBRF): Mortality and frequency of Jarisch-Herxheimer reaction. J R Soc Health. 1987;107(4):146–7. pmid:3116249.
- 65. Brown V, Larouze B, Desve G, Rousset JJ, Thibon M, Fourrier A, et al. Clinical presentation of louse-borne relapsing fever among Ethiopian refugees in northern Somalia. Ann Trop Med Parasitol. 1988;82(5):499–502. pmid:3257078.
- 66. Daniel E, Beyene H, Tessema T. Relapsing fever in children—demographic, social and clinical features. Ethiop Med J. 1992;30(4):207–14. pmid:1459120.
- 67. Gebrehiwot T, Fiseha A. Tetracycline versus penicillin in the treatment of louse-borne relapsing fever. Ethiop Med J [Internet]. 1992;30(3):175–81. Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/444/CN-00087444/frame.html. pmid:1396621
- 68. Mekasha A. Louse-borne relapsing fever in children. J Trop Med Hyg. 1992;95(3):206–9. pmid:1597878.
- 69. Negussie Y, Remick DG, DeForge LE, Kunkel SL, Eynon A, Griffin GE. Detection of plasma tumor necrosis factor, interleuklns 6, and 8 during the jarisch-herxheimer reaction of relapsing fever. J Exp Med. 1992;175(5):1207–12. pmid:1569394
- 70. Cuevas LE, Borgnolo G, Hailu B, Smith G, Almaviva M, Hart CA. Tumour necrosis factor, interleukin-6 and C-reactive protein in patients with louse-borne relapsing fever in Ethiopia. Ann Trop Med Parasitol. 1995;89(1):49–54. pmid:7741594.
- 71. De Jong J, Wilkinson RJ, Schaeffers P, Sondorp HE, Davidson RN. Louse-borne relapsing fever in southern Sudan. Trans R Soc Trop Med Hyg. 1995;89(6):621. pmid:8594674.
- 72. Remick DG, Negussie Y, Fekade D, Griffin G. Pentoxifylline fails to prevent the Jarisch-Herxheimer reaction or associated cytokine release. J Infect Dis. 1996;174(3):627–30. pmid:8769625.
- 73. Cooper PJ, Fekade D, Remick DG, Grint P, Wherry J, Griffin GE. Recombinant human interleukin-10 fails to alter proinflammatory cytokine production or physiologic changes associated with the Jarisch-Herxheimer reaction. J Infect Dis. 2000;181(1):203–9. http://dx.doi.org/10.1086/315183. pmid:10608768.
- 74. Eguale Tewdros, Abate Getahun, Balcha F. Relapsing Fever in Hossana, Ethiopia: A Clinical and Epidemiological Study. Ethiop J Health Sci. 2002;12(2):103–8.
- 75. Alfaifi AA, Masoodi I, Alzaidi O, Hussain S, Khurshid S, Sirwal IA. Spirocheatal shock syndrome. Indian J Med Microbiol. 2014;32(2):183–5. http://dx.doi.org/10.4103/0255-0857.129822. pmid:24713911.
- 76. Hoch M, Wieser A, Loscher T, Margos G, Purner F, Zuhl J, et al. Louse-borne relapsing fever (Borrelia recurrentis) diagnosed in 15 refugees from northeast Africa: Epidemiology and preventive control measures, Bavaria, Germany, July to October 2015. Eurosurveillance. 2015;20(42). http://dx.doi.org/10.2807/1560-7917.ES.2015.20.42.30046. pmid:26538532.
- 77. Wilting KR, Stienstra Y, Sinha B, Braks M, Cornish D, Grundmann H. Louse-borne relapsing fever (Borrelia recurrentis) in asylum seekers from Eritrea, The Netherlands, July 2015. Eurosurveillance. 2015;20(30):3. pmid:26250069.
- 78. Ciervo A, Mancini F, Di Bernardo F, Giammanco A, Vitale G, Dones P, et al. Louseborne relapsing fever in young migrants, sicily, Italy, july-september 2015. Emerg Infect Dis. 2016;22(1):152–3. http://dx.doi.org/10.3201/eid2201.151580. pmid:26690334.
- 79. Costescu Strachinaru DI, Cambier J, Kandet-Yattara H, Konopnicki D. Relapsing fever in asylum seekers from Somalia arriving in Belgium in August 2015. Acta Clinica Belgica: International Journal of Clinical and Laboratory Medicine. 2016;71(5):353–5. http://dx.doi.org/10.1080/17843286.2016.1157942. pmid:612314718.
- 80. Lucchini A, Lipani F, Costa C, Scarvaglieri M, Balbiano R, Carosella S, et al. Louseborne relapsing fever among East African refugees, Italy, 2015. Emerg Infect Dis. 2016;22(2):298–301. http://dx.doi.org/10.3201/eid2202.151768. pmid:26812354.
- 81. Osthoff M, Schibli A, Fadini D, Lardelli P, Goldenberger D. Louse-borne relapsing fever—report of four cases in Switzerland, June-December 2015. BMC Infect Dis. 2016;16(1:210. http://dx.doi.org/10.1186/s12879-016-1541-z. pmid:27188655.
- 82. Seilmaier M, Guggemos W, Wieser A, Fingerle V, Balzer L, Fenzl T, et al. 25 Cases of Louse-borne Relapsing Fever in Refugees from East Africa. Dtsch Med Wochenschr. 2016;141(14):E133–E42. CCC:000381007800002. pmid:27404939
- 83. Von Both U, Alberer M. Borrelia recurrentis infection. N Engl J Med. 2016;375(5):e5. http://dx.doi.org/10.1056/NEJMicm1513366. pmid:27518689.
- 84. Zammarchi L, Antonelli A, Bartolini L, Pecile P, Trotta M, Rogasi PG, et al. Louse-Borne Relapsing Fever with Meningeal Involvement in an Immigrant from Somalia to Italy, October 2015. Vector-Borne and Zoonotic Diseases. 2016;16(5):352–5. http://dx.doi.org/10.1089/vbz.2015.1928. pmid:26938933.
- 85. Hytonen J, Khawaja T, Gronroos JO, Jalava A, Meri S, Oksi J. Louse-borne relapsing fever in Finland in two asylum seekers from Somalia. Apmis. 2017;125(1):59–62. http://dx.doi.org/10.1111/apm.12635. pmid:27859692.
- 86. Parry EH, Warrell DA, Perine PL, Vukotich D, Bryceson AD. Some effects of louse-borne relapsing fever on the function of the heart. Am J Med. 1970;49(4):472–9. pmid:4249048.
- 87. Jukes AM. Preliminary note on some cases of Spirillar Fever in the Darjeeling district. Ind Med Gaz. 1912;47:476–7. pmid:29005496
- 88. Robertson RC. Relapsing Fever in Shanghai (First Report). Chin Med J (Engl). 1932;46(9):853–85.
- 89. Benhamou E. Aspects actuels de la fièvre recurrente épidémique en Afrique du Nord. Bulletin de l’Academie de medecine. 1945;129(25–29):530–2. Epub 1945/01/01. pmid:21008569.
- 90. Greaves FC, Gezon HM, Alston WF, Author A, Correspondence A, Greaves FC. Studies on louse-borne relapsing fever in Tunisia. US Nav Med Bull. 1945;45:1029–48. PubMed Central PMCID: PMC21004211. pmid:21004211
- 91. Zimmerman LE. Some Experiences with Enteric Diseases in Korea *†: Perforation of Paratyphoid Ulcers and Salmonella Septicemia Complicating Relapsing Fever. Am J Public Health Nations Health. 1953;43(3):279–84. pmid:13030878; PubMed Central PMCID: PMC1620059.
- 92. Kulescha GS, Titowa NA. The pathological anatomy and aetiology of complications of relapsing fever. Virchows Arch Pathol Anat Physiol Klin Med. 1923;241:319–551.
- 93. McCowen WT. Bilious Typhus Relapsing Fever. Ind Med Gaz. 1906;41(10):387–96. Epub 1906/10/01. pmid:29006131; PubMed Central PMCID: PMC5181027.
- 94. Levy GS. Typhus recurrens im Kindesalter. Zeitschr Kinderh. 1926;42:627.
- 95. Wolff BP. Asiatic relapsing fever; report of 134 cases treated with mapharsen*. Ann Intern Med. 1946;24(2):203–16. pmid:21012794
- 96. Kostoff KH. Arsal treatment in cases of relapsing fever. Dtsch Med Wochenschr. 1917;43(27–52):1168–9. WOS:000201475900124.
- 97. Loewy R. The clinical picture and therapy of relapsing fever. Med Klin. 1918;14(3):62–3.
- 98. Willcox WH. Typhus and Relapsing Fever in Mesopotamia and Northern Persia 1. Proc R Soc Med. 1920;13(Med Sect):59–81. pmid:19981140; PubMed Central PMCID: PMC2152263.
- 99. Bryceson AD. Clinical pathology of the Jarisch-Herxheimer reaction. J Infect Dis. 1976;133(6):696–704. pmid:932495.
- 100. Warrell DA, Perine PL, Bryceson AD, Parry EH, Pope HM. Physiologic changes during the Jarisch-Herxheimer reaction in early syphilis. A comparison with louse-borne relapsing fever. Am J Med. 1971;51(2):176–85. pmid:5095525.
- 101. Melkert PW, Stel HV. Neonatal Borrelia infections (relapsing fever): report of 5 cases and review of the literature. East Afr Med J. 1991;68(12):999–1005. Epub 1991/12/01. pmid:1800101.
- 102. Larsson C, Andersson M, Guo BP, Nordstrand A, Hägerstrand I, Carlsson S, et al. Complications of Pregnancy and Transplacental Transmission of Relapsing-Fever Borreliosis. J Infect Dis. 2006;194(10):1367–74. pmid:17054065
- 103. McConnell J. Tick-borne relapsing fever under-reported. Lancet Infect Dis. 2003;3(10):604. pmid:14558501
- 104. McGready R, Prakash JA, Benjamin SJ, Watthanaworawit W, Anantatat T, Tanganuchitcharnchai A, et al. Pregnancy outcome in relation to treatment of murine typhus and scrub typhus infection: a fever cohort and a case series analysis. PLoS Negl Trop Dis. 2014;8(11):e3327. Epub 2014/11/21. pmid:25412503; PubMed Central PMCID: PMC4238995.