8.6.34 Relapsing fevers 1188

8.6.34 Relapsing fevers 1188

section 8  Infectious diseases 1188 8.6.34  Relapsing fevers David A. Warrell ESSENTIALS Louse-​borne relapsing fever and tick-​borne relapsing fever are char- acterized by repeated episodes of high fever separated by afebrile periods. They are caused by Borrelia spirochaetes distinct from those responsible for Lyme borrelioses. Untreated patients may suffer as many as five (louse-​borne relapsing fever) or ten (tick-​borne re- lapsing fever) febrile relapses of decreasing severity. B. myamotoi is much less likely to relapse. Humans are the sole reservoir of epidemic louse-​borne relapsing fever caused by B. recurrentis and transmitted by body lice (Pediculus humanus corporis). Endemic tick-​borne relapsing fevers are caused by at least 17 different Borrelia species and have their own par- ticular species of soft Ornithodoros, or, in the case of B. myamotoi and B. lonestari, hard Ixodes or Ablyomma tick vectors that also act as res- ervoirs. Transmission transplacentally, or by needlestick, blood trans- fusion, or laboratory accident is also possible. Louse-​borne relapsing fever is a classic historical epidemic disease of war, famine, and refugees, now largely confined to mountainous areas of the Horn of Africa and possibly Peru but still retaining its pandemic potential. Imported cases are increasingly recognized in refugees from the Horn of Africa. Tick-​borne relapsing fever has expanding endemicity in sub-​Sahelian West Africa and is common in Rwanda and Tanzania. It occurs sporadically in parts of North America, Europe, the Middle East, and central Asia. The most distinctive feature of these infections, the relapse phe- nomenon, is explained by antigenic variation of borrelial outer-​ membrane lipoprotein (vmp). Starting 2–​18  days after infection, there is acute fever, chills, headache, pain, and prostration. Petechial rash (thrombocytopenia), bleeding, jaundice, hepatosplenomegaly, and liver dysfunction are common. In some forms of tick-​borne re- lapsing fever, there are neurological manifestations:  lymphocytic meningitis, VII and other cranial nerve lesions, myelitis, radiculitis, and uveitis during relapses. Dangerous complications are hyperpyrexia, shock, myocar- ditis causing acute pulmonary oedema, acute respiratory distress syndrome, cerebral or massive external bleeding, ruptured spleen, hepatic failure, Jarisch–​Herxheimer reactions, and typhoid or other complicating bacterial infections. Pregnant women are at high risk of aborting and perinatal mortality is high. Diagnosis by microscopy of blood films is more difficult in tick-​ borne relapsing fever than louse-​borne relapsing fever. Serology and polymerase chain reaction are used increasingly. The most important differential diagnosis in residents and travellers from tropical en- demic areas is falciparum malaria. Untreated mortality, exceeding 40% in some epidemics, can be re- duced to less than 5% by treatment with antibiotics such as penicillin, tetracycline, erythromycin, and chloramphenicol, but elimination of spirochaetaemia is often accompanied by a potentially fatal Jarisch–​ Herxheimer reactions. Prevention of louse-​borne relapsing fever is by eliminating lousiness by sterilizing clothing, using insecticides and repellents, and improving hygiene. Improved house construction, control of peridomestic rodents, use of residual insecticides, protection of sleepers with impregnated bed nets, and a postexposure course of doxycyline can reduce the risk of tick-​borne relapsing fever. Historical background A disease characterized by repeated episodes of several days of high fever separated by afebrile periods of about a week was first described by Rutty in Dublin in 1770, but Craigie in Edinburgh coined the name ‘relapsing fever’ and distinguished it from ty- phus in 1843. Obermeier saw spirochaetes, now recognized as Borrelia recurrentis (Fig. 8.6.34.1), in the blood of febrile pa- tients in Berlin in 1866. Transmission by human body lice was proved by Mackie in 1907. David Livingstone described fatal tick-​borne fever in Angola in 1857. Its cause was discovered by Ross and Milne in 1904 in Uganda and, independently, by Dutton and Todd in 1905 in Eastern Congo. Both of them were infected while carrying out autopsies and Dutton died of pneu- monia while debilitated after relapses of B. duttonii infection (Fig. 8.6.34.2). Aetiology The bacteria that cause relapsing fevers are large, loosely coiled, motile spirochaetes (genus Borrelia, family Spirochaetaceae), 8–​20 µm long and 0.2–​0.6 µm thick, with between 3 and 15 coils and, in some strains, 15–​30 axial filaments or flagella. They divide by transverse binary fission. Borrelia can be cultured on chick chorioallantoic membrane and maintained in rodents and Fig. 8.6.34.1  Borrelia recurrentis spirochaetes in a Giemsa-​stained thin blood film. Copyright D. A. Warrell.

8.6.34  Relapsing fevers 1189 ticks. In vitro culture of Borrelia species, including B. recurrentis, B. duttonii, and B. crocidurae, is now possible using Barbour–​ Stoenner–​Kelly medium and Kelly-​Pettenkofer medium for B. myamotoi sensu lato. Rapidly increasing amounts of genomic data are available. Sequencing of flagellin and rrs genes suggests that there are three phylogenetic clusters of Borrelia: (1) Lyme borreliae (B. burg- dorferi sensu stricto, B. garinii, and B. afzelii (see Chapter 8.6.33 on Lyme disease); (2)  New World tick-​borne relapsing fever borreliae (B. parkeri, B. turicatae, B. hermsii, and so on); and (3)  Old World tick-​borne relapsing fever and louse-​borne re- lapsing fever borreliae (B. crocidurae, B. duttonii, B. hispanica, B. recurrentis, and so on). Molecular phylogenetic studies have shown close identity of B. recurrentis and B. duttonii suggesting only clonal difference and that B. recurrentis adapted rapidly to louse-​transmission with genome reduction and low genetic vari- ability. The three clades of B. myamotoi from Asia, Europe, and North America produce identical clinical effects. Epidemiology Louse-​borne (epidemic) relapsing fever (LBRF) The vector of B. recurrentis is the human body louse Pediculus humanus corporis and, perhaps, the head louse P. humanus capi- tis. Body lice, unlike head lice, retreat from the skin after feeding and hide and lay their eggs in clothing seams. More than 20 000 lice have been recovered from the clothes of one person. Lice are obligate blood-​sucking human ectoparasites that ingest borreliae while feeding. Under conditions of crowding and poor hygiene they can move from person to person. When the host’s body sur- face temperature deviates far from 37°C as a result of fever, cli- matic exposure, or death, or when infested clothing is discarded, the louse is forced to find a new host who can then be infected. Transmission of B. recurrentis is by scratching, which crushes lice so that their coelomic fluid is inoculated through broken skin or intact mucous membranes such as the conjunctiva, or inoculates infected louse faeces. Blood transfusion, needlestick injuries, and contamination of broken skin by a patient’s blood can also result in infection. Unlike ticks, lice cannot infect their progeny and are therefore not reservoirs and, since there is no known animal res- ervoir, the infection must persist in humans between epidemics in mild or asymptomatic forms. Wars, famines, and other disasters that generate large numbers of refugees and prisoners favour the spread of lice and epidemic louse-​ borne infections such as relapsing fever and typhus. The yellow plague in Europe in ad 550, which halved the world’s population, and the famine fevers of the 17th and 18th centuries in Ireland and elsewhere were probably LBRF. In the 20th century, a pandemic raged in North Africa, the Middle East, and Africa from 1903 to 1936, causing an estimated 50  million cases with 10% mortality. A second epidemic in 1943–​1946 created 10 million cases. An en- demic focus persists in the Horn of Africa. In cold, wet weather, im- poverished people with louse-​infested clothes crowd together for shelter. In the Ethiopian highlands there are annual epidemics of thousands of cases coinciding with the small (belg) and big (kiremt) rains, but in the south the disease was perennial before its recent de- cline. Outbreaks have also occurred in Somalia. In Rumbek County, South Sudan in 1999–​2000, there were 20 000 cases with some 2000 deaths, 580 in January 1999 alone. In Ancash in the Peruvian Andes at altitudes above 3800 m, a cluster of 60 clinical cases was reported in 1983; 36 of the patients had B. recurrentis in their blood films. Serological evidence of B. recurrentis infection has been found in homeless people in Marseille. Recently, many cases have been iden- tified in refugees to Europe from Ethiopia, Eritrea, and Somalia, and non-endemic countries such as Mali, arriving in Germany (45 cases in 2017 alone), Italy, Switzerland, and the Netherlands. Tick-​borne (endemic) relapsing fever (TBRF) Spirochaetes have been identified in a larval Amblyomma tick in fossilized amber from the Dominican Republic, dated at 15–​20 Fig. 8.6.34.2  Temperature chart of J. Everett Dutton who, with J L Todd, discovered the transmission of TBRF in the Congo. Dutton contracted TBRF at the beginning of November 1904. He had relapses of fever and spirochaetaemia on 7 and 16 December 1904 and 8 January 1905. His death on 27 February 1905 is attributable to pneumonia while he was debilitated by relapsing fever. From Dutton JE, Todd JL (1905). The nature of human tick-​fever in the eastern part of the Congo Free State with notes on the distribution and bionomics of the tick. Liverpool School of Tropical Medicine Memoir XVII.

section 8  Infectious diseases 1190 mya, and today, TBRF is endemic in most temperate and trop- ical countries except in South and Far East Asia, Australasia, the Pacific, Arctic, and Antarctic regions. In different parts of the world, particular species of borreliae and soft ticks (genus Ornithodoros, family Argasidae) are ecologically intimate, forming Borrelia–​tick complexes (Table 8.6.34.1). At least two borreliae associated with human disease are transmitted by hard ticks (Ixodidae): B. lonestari by Amblyomma americanum (United States) and B. miyamotoi sensu lato by Ixodes spp. (Japan, Europe, Russia, United States). At least 17 Borrelia species are now known to cause human TBRF. Ornithodoros tick vectors occur in dry savannah areas and scrub, caves, piles of timber and dead trees, or in holes in walls, roof spaces, and beneath the floors of log cabins, anywhere in- habited by small rodents. Unlike LBRF, TBRFs are zoonoses, ex- cept B. duttonii infection that is transmitted exclusively between humans. Vertebrate reservoir species include rodents (rats, mice, gerbils, squirrels, and chipmunks), insectivores, lagomorphs, bats, small carnivores, dogs, and birds. Soft ticks attack at night, remaining attached for less than 30 min before retreating to their hiding places. Spirochaetes ingested while the tick sucks blood from an infected animal or human invade the tick’s salivary and coxal glands and genital apparatus. Infection is transmitted to a new host either by a bite, introducing infected saliva, or by contaminating mucosal membranes with infected coxal fluid. Borreliae are not excreted in tick faeces. Ticks remain infected for life, even after being starved of blood for as long as 7 years. Spirochaetes can be transmitted venereally from male to female ticks and by females (but perhaps not those of the O. moubata complex) transovarially to their progeny. Borreliae may also be transmitted by hard ticks (Ixodidae). Borrelia miyamotoi sensu lato was first found in I. persulcatus ticks in Hokkaido, Japan in the early 1990s and, since 2011 has been recog- nized as a human pathogen in the relapsing fever group of Borrelia. It is prevalent in I. persulcatus in Russia, I. ricinus in Western Europe, and I. scapularis, I. pacificus and I. dammini in the United States. These ticks are also vectors of Lyme disease group Borrelia. B. lone- stari is transmitted by Amblyomma americanum in the United States and may be a human pathogen. TBRF, like LBRF, may be transmitted by blood transfusion, needlestick injuries, laboratory accidents, and transplacentally. In Europe, TBRF is caused by B. hispanica, especially in Spain, Portugal, and Greece, while B. crocidurae and at least three other Borrelia spp. are present in Turkey and adjacent territories. In Israel, the incidence of B. persica infection among military personnel is 6.4/​100 000 per year. In the West African savannah region, B. cro- cidurae is the most prevalent bacterial infection, creating a medical problem second only to malaria. Its prevalence is 1% among chil- dren in western Senegal and it is increasing and spreading during the persisting drought (1970–​2009). It is a common infection in Rwanda where, in one health centre alone, 1650 proven cases are treated each year (6% of all patients). In parts of East Africa, es- pecially in Tanzania, B. duttonii is an important cause of abortion, perinatal mortality, and childhood infection. In North America, isolated sporadic outbreaks of B. hermsii, B. turicatae, and B. park- eri infection occur in mountainous areas of British Columbia, Arizona (especially along the North Rim of the Grand Canyon), California (south of Lake Tahoe), Colorado, Montana, New Mexico, and Washington (Browne Mountain). Since the mid-​1980s, more than 300 cases of TBRF have been identified in the United States of Table 8.6.34.1  Borrelia–​tick complexes causing tick-​borne relapsing fevers

1. New World Borrelia spp. with Argasid (soft) ticks genus Ornithodoros B. hermsii O. hermsii Canada, central and western USA, Mexico B. turicatae O. turicata South-​western USA, Mexico B. parkeri O. parkeri Western USA, Baja California B. mazzotti O. talaje Mexico, Central America B. venezuelensis O. (venezuelensis) rudis Central America, Colombia, Venezuela, Argentina, Bolivia, Paraguay
2. Old World Borrelia spp. with Argasid (soft) ticks genus Ornithodoros B. duttonii O. moubata Sub-​Saharan Africa, Madagascar B. crocidurae O. (erraticus) sonrai North, West, and East Africa, Middle East B. graingeri O. graingeri East Africa B. sp. nov. O. porcinus East Africa B. tillae O. zumpti South Africa B. persica O. tholozani Middle East, central Asia from Uzbekistan to western China B. hispanica O. erraticus Iberian Peninsula, Greece, Cyprus, North Africa B. sp. nov. O. erraticus Southern Spain B. latyschevii O. tartakowskyi Eastern Europe, Iran, Iraq, Afghanistan, central Asia B. caucasica O. (verrucosus) asperus Eastern Europe, Iraq
3. Borrelia spp. with Ixodid (hard) ticks general Ixodes and Amblyomma B. myamotoi sensu lato Ixodes persulcatus, I. ricinus, I. scapularis, I. pacificus, I. dammini Japan, Russia, Europe, NE United States B. lonestari Amblyomma americanum South and Southeastern United States

8.6.34  Relapsing fevers 1191 America. In Western countries, TBRF has been reported more than 20 times in returned travellers, usually from West Africa. A new species of TBRF spirochaete, B. kalaharica, has been described in a traveller from South Africa. This species may also be transmitted by Ornithodoros savingyi in Nigeria. Immunopathology and the relapse phenomenon Symptomatic attacks of relapsing fever are terminated when specific bactericidal IgM antibodies generated by the B1b cell subset lyse spirochaetes in the blood, independently of complement and T cells. However, some spirochaetes persist between the relapses, extracellu- larly in various organs including spleen, liver, kidneys, eye, and espe- cially in the brain and cerebrospinal fluid. Relapse of spirochaetaemia and symptoms is explained by antigenic variation, which has been investigated in the greatest detail in B. hermsii. Silent gene sequences from an archive stored in extra chromosomal plasmids are trans- posed to one end of an expression linear plasmid where their recom- bination leads to synthesis of a new variable major outer membrane lipoprotein (vmp). This new coat allows the borreliae to escape from the host’s humoural immune response until antibodies are gener- ated against the new serotypic vmp antigen; this explains the relapse phenomenon and the successive appearance of borreliae expressing different vmps during the course of an untreated infection. Borreliae also possess defences against the host’s innate immunity. B. herm- sii surface protein BhCRASP-​1 binds factor H (FH), an inhibitor of the alternative pathway of complement activation, so protecting the pathogen against opsonophagocytosis by inhibiting C3b binding. Plasminogen is also bound and activated to plasmin by BhCRASP-​1, stimulating fibrinolysis that frees spirochaetes to spread in the blood stream. Another protective mechanism is rosetting of erythrocytes around spirochaetes. This shields them, by masking or steric hin- drance, from host antibody and may cause microcirculatory ob- struction that is damaging to the host and reminiscent of cerebral malaria. Antigenic variation might also generate isogenic serotypes with properties that promote the spirochaete’s survival in vector and reservoir species (e.g. invasiveness for vertebrates’ cerebral vascular endothelium). These same vmps are the principal tumour necrosis factor-​α (TNFα)-​inducing factors in LBRF. Pathophysiology Physiological disturbances during the spontaneous crisis and the Jarisch–​Herxheimer reaction (JHR) induced by antimicrobial treat- ment in LBRF are typical of an endotoxin reaction. Outer mem- brane vmps of B. recurrentis stimulate monocytes to produce TNFα through NF-​κB. In patients treated with antibiotics, symptoms of the severe JHR are associated with a transient marked elevation in plasma concentrations of TNFα, interleukin (IL)-​6, IL-​8, and IL-​1β (Fig. 8.6.34.3). The stimulus for cytokine release is the phagocyt- osis of spirochaetes made susceptible by the action of penicillin. Benzyl penicillin attaches to penicillin-​binding protein I in B. herm- sii spirochaetes. Large surface blebs are produced and the dam- aged spirochaetes are phagocytosed rapidly by neutrophils in the blood and by the spleen. Complement may enhance phagocytosis of spirochaetes, especially in the non​immune host, but the com- plement system is not essential for elimination of spirochaetes whether or not specific immunoglobulins are present. In vitro, sur- face contact with spirochaetes induces mononuclear leucocytes to produce inflammatory cytokines and thromboplastin, which could be responsible for the fever and disseminated intravascular coagu- lation in LBRF. Kinins may be released during the JHR of syphilis and LBRF. The marked peripheral leucopenia that develops during the reaction reflects sequestration, perhaps in the pulmonary blood vessels, rather than leucocyte destruction. Spirochaetes may be found in those organs that bear the brunt of the infection such as liver, spleen (Fig. 8.6.34.4), myocardium (Fig. 8.6.34.5), and brain (Fig. 8.6.34.6), but it is unclear how their pathological effects are produced. The petechial rash results from thrombocytopenia not vasculitis. The cardiorespiratory and metabolic disturbances in relapsing fever are principally the result of persistent high fever, accentuated by the JHR or spontaneous crisis. Pathology Most spirochaetes are confined to the lumen of blood vessels, but tangled masses are also found in the characteristic splenic miliary abscesses (Fig. 8.6.34.4) and infarcts as well as within the central nervous system adjacent to haemorrhages. Some strains of TBRF borreliae can invade the central nervous system, aqueous humour, and other tissues. In LBRF, a perivascular histiocytic interstitial Rigors Penicillin Plasma cytokine 100 000 10 000 1000 ng/l 100 10 5–1.00124824 0 300 600 Spirochaete count/mm3 blood Spirochaetes IL-1 IL-8 TNF IL-6 Fig. 8.6.34.3  Typical Jarisch–​Herxheimer reactions in a patient with LBRF treated with intravenous penicillin. Following penicillin, the number of spirochaetes (dashed red line referring to right hand axis) fell abruptly and circulating levels of TNFα, IL-​6, IL-​8, and IL-​1β started to rise after about 1 h, peaking at 4 h. As cytokine levels were increasing, this patient experienced sustained rigors which subsided before peak levels were achieved.

section 8  Infectious diseases 1192 myocarditis, found in most cases, may be responsible for conduction defects, arrhythmias, and myocardial failure resulting in sudden death (Fig. 8.6.34.5). Splenic rupture with massive haemorrhage, cerebral haemorrhage (Fig. 8.6.34.6), and hepatic failure are other causes of death. The liver shows hepatitis with patchy midzonal haemorrhages and necrosis. There is meningitis and perisplenitis. Most serosal cavities and surfaces of viscera are studded with pe- techial haemorrhages (Figs. 8.6.34.5, 8.6.34.6) and there may be Fig. 8.6.34.6  Cerebral haemorrhage. Copyright D. A. Warrell. Fig. 8.6.34.5  Epicardial and endocardial haemorrhages. Copyright D. A. Warrell. (a) (b) Fig. 8.6.34.4  Spleen in LBRF: (a) Section of spleen at autopsy; (b) Warthin Starry stain showing Borrelia recurrentis (arrows). (a) Copyright D. A. Warrell; (b), courtesy of Dr Ken Fleming.

8.6.34  Relapsing fevers 1193 massive pulmonary haemorrhage (Fig. 8.6.34.7). Thrombi are occa- sionally found occluding small vessels, but the peripheral gangrene sometimes found in patients recovering from louse-​borne typhus (see Chapter 8.6.40) does not occur in LBRF. Clinical features Louse-​borne relapsing fever Adults Prisoners and poor, malnourished street-​dwellers are the most likely to become infected, especially young men. After an incubation period of 4–​18 (average 7) days, the illness starts sud- denly with rigors and a fever that mounts to nearly 40°C in a few days. Early symptoms are headache, dizziness, nightmares, gener- alized aches and pains (especially affecting the lower back, knees, and elbows), anorexia, nausea, vomiting, and diarrhoea. Later there is upper abdominal pain, cough, and epistaxis. Patients are usually prostrated (Fig. 8.6.34.8) and most are confused. Hepatic tenderness is the commonest sign (about 60%). The liver is en- larged in approximately 50% of patients. Splenic tenderness and enlargement are slightly less common. Jaundice has been reported in 10–​80% of patients. A petechial or ecchymotic rash is seen in 10–​60% of patients (Figs. 8.6.34.9, 8.6.34.10); the lesions occur par- ticularly on the trunk. Other sites of spontaneous bleeding include Fig. 8.6.34.8  Patients presenting with relapsing fever at a clinic in Addis Ababa. Most are febrile, confused, and prostrated. Copyright D. A. Warrell. Fig. 8.6.34.7  Pulmonary haemorrhage. Copyright D. A. Warrell.

section 8  Infectious diseases 1194 the conjunctivae (Fig. 8.6.34.11), nose in 25% (Fig. 8.6.34.9), and less commonly the lungs (Fig. 8.6.34.7), gastrointestinal tract, and retina. Many patients have tender muscles. Meningism oc- curs in about 40% of patients; other neurological features include cranial nerve lesions, monoplegias, flaccid paraplegia, and focal convulsions attributable, perhaps, to cerebral haemorrhages. In untreated people, the first attack of fever resolves by crisis in 4–​10 (average 5) days, followed by an afebrile remission of 5 to 9 days, and then a series of up to five relapses of diminishing severity, occasionally complicated by epistaxis. Petechial rashes are absent during relapses. Pregnant women are especially susceptible to severe disease and abortions are frequent. Children In children older than 5 years, clinical features resemble those in adults but are generally less severe and the case fatality is lower. Fever, chills, headache, abdominal pain and tenderness, vomiting, cough, musculoskeletal pains, tachycardia, and petechial rash are common. In younger children, hepatosplenomegaly, cough, and signs of consolidation may be more common. Reported case fatal- ities in children range from 1.9 to 5.5%. Tick-​borne relapsing fever Adults After an incubation period of 2–​18  days, the illness starts with sudden fever, chills, headache, muscle and joint pains, extreme fatigue, prostration, and drenching sweats. These symptoms are similar to those in LBRF but the initial fever usually lasts about 3 days only to recur about 7–​15 days later. Epistaxis, abdominal pain, diarrhoea, cough, and erythematous or petechial rashes may follow. Jaundice is less common than in LBRF. Several cases of acute respiratory distress syndrome (ARDS) have been described in the United States of America. Neurological disturbances are more common than in LBRF, varying in incidence with the borrelia spe- cies involved, from less than 5% in patients with B. hispanica and B. persica infections to as high as 40% in patients with B. duttonii. However, one careful study in northern Tanzania found no focal neurological abnormalities in patients with B. duttonii TBRF. The neurological features that have been described are reminiscent of Lyme neuroborreliosis and include paraesthesias, visual symptoms, lymphocytic meningitis, cranial nerve palsies (especially VII, VII, V and VI), encephalitis, radiculomyelitis, sciatica, delirium, and hallucinations. Untreated patients may have up to 13 relapses (Fig. 8.6.34.2), becoming sequentially less severe. Ocular complications usually occur during the third and fourth relapses. They include conjunctival injection, eye pain, photophobia, eyelid oedema, kera- titis, various degrees of anterior and posterior uveitis, optic neuritis, and blindness. Spirochaetaemia is higher in pregnant than in non​pregnant women and abortion and perinatal mortality are common. In Fig. 8.6.34.9  Ethiopian patient with LBRF showing petechiae on the shoulder and epistaxis. Copyright D. A. Warrell. Fig. 8.6.34.10  Ethiopian patient with severe LBRF complicated by typhoid, showing jaundice, petechial haemorrhages, and emaciation. Copyright D. A. Warrell. Fig. 8.6.34.11  Subconjunctival haemorrhage in a patient with LBRF. Copyright D. A. Warrell.

8.6.34  Relapsing fevers 1195 Tabora, Tanzania, parturition was precipitated in 58% of infected pregnant women. Perinatal mortality was 436/​1000 births, its risk related to low birthweight and gestational age. Total fetal wastage was 475/​1000. Children In endemic areas of B. duttonii TBRF in East Africa, most cases are in children, many of them under 5 years old, and pregnant women, implying that older non​pregnant people may acquire some im- munity. Fever, splenomegaly, convulsions sometimes recurrent, meningism, petechiae, and jaundice are described. Neonates with congenital infection have fever, inability to suck, jaundice, and fea- tures of septicaemia. Reported case fatalities in children less than 1 year old are 2.3 to 73%, compared to 1.6 to 19% in older children. Hard-​tick-​transmitted Borrelia The index cases of B. myamotoi sensu latu infection in the United States and Europe were elderly immunosuppressed patients who presented with meningoencephalitis associated with spirochaetes in the cerebrospinal fluid (CSF) that resolved with antibiotic treat- ment. However, immunocompetent patients rarely develop menin- gitis but present, after an incubation period of 12–​16 days, with fever that recurred in only 10% of them, chills, headache, myalgia, arth- ralgia, nausea, and fatigue. Fewer than 10% of cases have erythema migrans-​like rashes. Their systemic symptoms were more severe than in patients with Lyme disease. Unlike patients with classic re- lapsing fevers, there is no dramatic febrile crisis, either spontaneous or induced by treatment and there is no evidence that B. myamotoi sensu lato possesses evasive antigenic variation that would allow re- lapsing attacks. In south-​eastern and eastern United States, patients have been de- scribed with a disease termed Southern tick-​associated rash illness or Masters’ disease. Atypical erythema migrans is associated with systemic symptoms after bites by A. americanum hard ticks. B. lone- stari has been implicated but causation is not yet proven. Severe disease Severe manifestations include hyperpyrexia, myocarditis with acute pulmonary oedema, ARDS, hepatic failure, ruptured spleen, and haemostatic failure attributable to thrombocytopenia, liver damage, and disseminated intravascular coagulation leading to cerebral, massive gastrointestinal, pulmonary, or peripartum haemorrhage. Dysentery, salmonellosis, typhoid, typhus, tuberculosis, bacterial pneumonia, and malaria are infections that can complicate relapsing fever, increasing the risk of death. The spontaneous crisis and Jarisch–​Herxheimer reaction Whether or not treatment is given, attacks of relapsing fever usually end dramatically. On about the fifth day of the untreated illness, or about 1 to 2 h after antibiotic treatment, the patient becomes restless and apprehensive and suddenly begins to have distressingly intense rigors that last between 10 and 30 min. The ensuing phenomena have features of a classic endotoxin reaction. During the initial chill phase, temperature, respiratory and pulse rates, and blood pressure rise sharply. Delirium, gastrointestinal symptoms, cough, and limb pains are associated. Some patients die of hyperpyrexia at the peak of fever. The flush phase, which lasts many hours, is characterized by profuse sweating, a fall in blood pressure, and a slow decline in temperature. Deaths during this phase follow intractable hypo- tension, sudden postural hypotension prompted by the patient’s standing up, or the development of acute pulmonary oedema attrib- utable to myocarditis. The incidence of JHRs is highest in adults with LBRF treated with intravenous tetracycline (approaching 100% in some studies). It is lower when low-​dose or slow-​release penicillin is used and in children. JHR is less commonly observed in TBRF but can be severe and even fatal. The classic JHR occurs in secondary syphilis in which the spirochaetes are in the tissues and the reaction is less frequent, more insidious, and much less severe than in relapsing fevers. Milder reac- tions have been described in Lyme disease and leptospirosis (treated with penicillin), sodoku (treated with arsenicals), Brucella melitensis (treated with tetracycline), and even in typhoid and meningococcal infections. Laboratory findings Spirochaete densities may exceed 500 000/​mm3 of blood. There is a moderate normochromic anaemia and a neutrophil leucocyt- osis with marked leucopenia during the spontaneous crisis and JHR. Thrombocytopenia is usual and there is a mild coagulopathy with evidence of increased fibrinolysis. Biochemical evidence of hepatocellular damage (raised levels of aminotransferases, alkaline phosphatase, direct and total bilirubin, low albumin) and mild renal impairment are common. The cerebrospinal fluid shows a lympho- cyte or neutrophil pleocytosis without visible spirochaetes. There is electrocardiogram (ECG) evidence of myocarditis with prolongation of the QTc interval, T-​wave abnormalities, and ST-​ segment depression with transient acute right heart strain after the JHR. Chest radiographs may show pulmonary oedema or pneu- monic consolidation. Patients with B. myamotoi sensu lato infections may have leuco- penia, thrombocytopenia, and elevated transaminase levels. Diagnosis Thick and thin blood films should be taken while patients are fe- brile. Spirochaetes are demonstrated by Giemsa’s, Wright’s, Field’s, or Diff-​Quick staining (Fig. 8.6.34.1), dark-​field examination, or a quantitative buffy coat technique (acridine orange). The sensitivity of thick films is 20 times greater than thin films. Misidentification of Plasmodium vivax microgametes as spirochaetes has led to the diagnosis of ‘pseudoborreliosis’. In TBRF, spirochaetes may be difficult or impossible to find even at the height of a relapse and, increasingly, polymerase chain reaction (PCR) and serology are being used. Lyme disease Borreliae may produce cross-​reacting antibodies due to expression of conserved antigenic epitopes, but an ELISA using the glycerophosphodiester phosphodiesterase (GlpQ) gene product can distinguish relapsing fevers from Lyme disease. In LBRF, the higher and more persistent spirochaetaemia is more easily detected. Borreliae can be isolated in mice and cul- tured in vitro. The serum of patients with relapsing fever may give positive re- actions with proteus OXK, OX19, and OX2 and false-​positive sero- logical responses for syphilis in 5 to 10% of cases.

section 8  Infectious diseases 1196 B. myamotoi sensu lato is best detected by PCR in a pretreatment blood sample, complemented by enzyme immunoassay (EIA) using a recombinant GlpQ protein. Spirochaetes may sometimes be seen in Giemsa-​stained thick blood films and in CSF and in infected se- vere combined immunodeficient mice. Differential diagnosis In a febrile patient with jaundice, petechial rash, bleeding, hepatosplenomegaly, thrombocytopenia, coagulopathy, and ele- vated serum aminotransferases, the most frequent and urgent dif- ferential diagnosis is falciparum malaria. Yellow fever and other viral haemorrhagic fevers such as Rift Valley Fever in the Horn of Africa, viral hepatitis, rickettsial infections (especially louse-​borne typhus which shares LBRF’s epidemiological predispositions), and leptospirosis might also cause confusion. Trench fever (Bartonella quintana) transmitted by lice, and sodoku (Spirillum minus) fol- lowing a rat bite can also cause episodic recurrent fever. Although the diagnosis of relapsing fever can often be confirmed quickly by examining a blood smear, the possibility of complicating bacterial infection, particularly typhoid, or coinfection with malaria should never be forgotten. In the north-​eastern United States, B. myamotoi sensu lato in- fection is sympatric with Lyme disease and must be distinguished from other deer-​tick-​transmitted infections such as Babesia microti, Anaplasma phagocytophyllum and Powassan/​deer tick fever virus diseases. Prognosis During major LBRF epidemics, overall case fatalities of 40% or higher have been reported, but in treated cases they are less than 5%. TBRF is less dangerous and deaths during relapses are most unusual but have been reported. In both LBRF and TBRF, pregnant women and infants are at greatest risk of dying. Treatment Antibiotics LBRF LBRF is readily cured without relapses by a single oral dose of 500 mg tetracycline or 500 mg erythromycin stearate. However, since few pa- tients with severe LBRF are able to swallow tablets without vomiting them up, a more reliable treatment is a single intravenous dose of 250 mg tetracycline hydrochloride or, for pregnant women and chil- dren, a single intravenous dose of 300 mg erythromycin lactobionate (children 10 mg/​kg body weight). In mixed epidemics of LBRF and louse-​borne typhus, a single oral dose of 100 mg doxycycline proved effective. Benzyl penicillin (300 000 units), procaine penicillin with benzyl penicillin (600 000 units), and procaine penicillin with aluminium monostearate (600 000 units), all by intramuscular injection, are often effective but might fail to prevent relapses. Long-​acting pre- parations clear spirochaetaemia slowly and the JHR is protracted. Some experienced clinicians prefer to use a low initial dose of peni- cillin (adult dose, 100 000–​400 000 units by intramuscular injec- tion) in severe cases and pregnant women because they believe that the incidence and severity of the JHRs will be less. Chloramphenicol is effective in a single dose of 500 mg by mouth or intravenous injection in adults. A meta-​analysis of trials of chemotherapy of LBRF concluded that no clear superiority of any drug had been confirmed and that azithromycin should be tried in future. TBRF, including B. myamotoi sensu lato infection Although TBRF is usually milder than LBRF, it is more difficult to treat because spirochaetes persist in tissues, such as the central ner- vous system and eye, and produce relapses. Oral tetracycline, 500 mg every 6 h for 10 days is, however, effective. Oral erythromycin can be given to pregnant women (500 mg every 6 h for 10 days) and children (125–​250 mg every 6 h for 10 days). In patients unable to swallow tablets, treatment can be initiated with 250 mg intravenous tetra- cycline hydrochloride or with 300 mg erythromycin lactobionate. Chloramphenicol is effective in a dose of 500 mg every 6 h for 10 days in adults, and 250 mg every 6 h for 10 days in older children. JHR Antimicrobials have reduced the mortality of relapsing fevers from 30 to 70% to less than 5%. However, drugs such as tetracycline, which rapidly eliminate spirochaetes from the blood and prevent relapses, usually induce a severe JHR that may occasionally prove fatal. Clearly, in a disease with such a high natural mortality, treat- ment cannot be withheld, especially as severe spontaneous crises, which might also prove fatal, occur in a large proportion of LBRF cases after the fifth day of fever. There is no evidence, however, that the shorter and more intense reaction following tetracycline is more dangerous than the more prolonged but apparently milder reaction following slow-​release penicillin. Neither hydrocortisone in doses up to 20 mg/​kg nor paracetamol prevent the JHR but they reduce peak temperatures, hasten the fall in temperature, and lessen the fall in blood pressure during the flush phase. Pretreatment with oral prednisolone can prevent the JHR of early syphilis, but in LBRF nei- ther an oral dose of 3 mg/​kg prednisolone given 18 h beforehand nor an infusion of 3.75 mg/​kg β-methasone prevented the reaction to tetracycline treatment. However, meptazinol, an opioid antagonist/​ agonist, diminishes the reaction when given in a dose of 100 mg by intravenous injection. The discovery of an explosive release of TNFα, IL-​6, and IL-​8 just before the start of the JHR prompted the testing of a polyclonal ovine Fab anti-​TNFα antibody. When infused for 30 min before treatment with intramuscular penicillin, this anti- body suppressed the JHR. Supportive treatment Patients must be nursed flat in bed for at least 24 h after treatment to prevent postural hypotensive collapse and the precipitation of fatal cardiac arrhythmias. Hyperpyrexia should be prevented with anti- pyretics, vigorous fanning, and tepid sponging. Although patients with acute LBRF have an expanded plasma volume, most are dehy- drated and relatively hypovolaemic. Adults may need 4 litres or more of isotonic saline intravenously during the first 24 h. Infusion should be controlled by monitoring jugular venous or central venous pres- sures. Acute myocardial failure may develop, particularly during the

8.6.34  Relapsing fevers 1197 flush phase of the JHR or spontaneous crisis. This is signalled by a rise in central venous pressure above 15 cmH2O; 1 mg digoxin given intravenously over 5–​10 min has proved effective in this emergency. Because of the intense vasodilatation, diuretics may accentuate the circulatory failure by causing relative hypovolaemia. Oxygen should be given during the reaction, particularly in severe cases. Vitamin K should be given to all patients with prolonged prothrombin times. Heparin is not effective in controlling coagulopathy and should not be used. Complicating infections (typhoid, salmonellosis, bacillary dys- entery, tuberculosis, typhus, malaria) must be treated appropriately. Prevention and control No vaccines are available. LBRF: delousing Infested clothing should be deloused using heat (>60°C), chlorine bleach, or insecticide (10% dichlorodiphenyltrichloroethane (DDT), 1% malathion, 2% temephos, 1% propoxur, or 0.5% permethrin), and patients should be bathed with soap and 1% Lysol (cresol). Lice are abundant in hair, which should be washed or shaved off. Breaking transmission from lice to the susceptible population is es- sential for the control of an epidemic. Eugenol and β-​caryophyllene from clove essential oil repel Pediculus humanus corporis. TBRF: tick control Tick infestation of dwellings can be reduced by improved house construction (e.g. rodent-​proofing of cabins on the North Rim of the Grand Canyon), control of peridomestic rodent hosts, and use of residual insecticides (pyrethroids, benzene hexachloride, λ-​ cyhalothrin, malathion, or DDT). Travellers should avoid sleeping in places where ticks and rodents are abundant, such as poorly maintained log cabins, should apply repellents to their skin (di- ethyl toluamide (DEET)), and should sleep under insecticide-​ impregnated bed nets. Postexposure prophylaxis with doxycycline (200 mg followed by 100 mg on the next 4 days) proved effective against B. persica in Israel. FURTHER READING Antinori S, et al. (2016). Louse-​borne relapsing fever among East African refugees in Europe. Travel Med Infect Dis, pii: S1477-​8939(16)00006-​5. Barbour AG (2014). Phylogeny of a relapsing fever Borrelia species trans- mitted by the hard tick Ixodes scapularis. Infect Genet Evol, 27, 551–​8. Barbour AG, Hayes SF (1986). Biology of Borrelia species. Microbiol Rev, 50, 381–​400. Boutellis A, Abi-​Rached L, Raoult D (2014). The origin and distribu- tion of human lice in the world. Infect Genet Evol, 23, 209–​17. Bryceson ADM, et al. (1970). Louse-​borne relapsing fever: a clinical and laboratory study of 62 cases in Ethiopia and a reconsideration of the literature. QJM, 39, 129–​70. Cadavid D, Barbour AG (1998). Neuroborreliosis during relapsing fever: review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals. Clin Infect Dis, 26, 151–​64. Cutler SJ, et al. (2017). Diagnosing Borreliosis. Vector Borne Zoonotic Dis, 17, 2–11. Fekade D, et al. (1996). Prevention of Jarisch–​Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med, 335, 311–​5. Felsenfeld O (1971). Borrelia: strains, vectors, human and animal bor- reliosis. Green, St Louis, . Guerrier G, Doherty T (2011) Comparison of antibiotic regimens for treating louse-​borne relapsing fever: a meta-​analysis. Trans R Soc Trop Med Hyg, 105, 483–​90. Hasin T, et al. (2006). Postexposure treatment with doxycycline for the prevention of tick-​borne relapsing fever. N Engl J Med, 355, 148–​55. Krause PJ, et al. (2015). Borrelia miyamotoi infection in nature and in humans. Clin Microbiol Infect, 21, 631–​9. LaRocca TJ, Benach JL (2008). The important and diverse roles of anti- bodies in the host response to borrelia infections. Curr Top Microbiol Immunol, 319, 63–​103. Lescot M, et al. (2008). The genome of Borrelia recurrentis, the agent of deadly louse-​borne relapsing fever, is a degraded subset of tick-​ borne Borrelia duttonii. PLoS Genet, 4, e1000185. Marosevic D, et al. (2017). First insights in the variability of Borrelia recurrentis genomes. PLoS Negl Trop Dis, 11, e0005865. Moran-​Gilad J, et al. (2013). Postexposure prophylaxis of tick-​borne relapsing fever:  lessons learned from recent outbreaks in Israel. Vector Borne Zoonotic Dis, 13, 791–​7. Negussie Y, et al. (1992). Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch–​Herxheimer reaction of re- lapsing fever. J Exp Med, 175, 1207–​12. Parry EH, et al. (1970). Some effects of louse-​borne relapsing fever on the function of the heart. Am J Med, 49, 472–​9. Perine PL, Teklu B (1983). Antibiotic treatment of louse-​borne re- lapsing fever in Ethiopia: a report of 377 cases. Am J Trop Med Hyg, 32, 1096–​100. Platonov AE, et al. (2011). Humans infected with relapsing fever spiro- chete Borrelia miyamotoi, Russia. Emerg Infect Dis, 17, 1816–​23. Schwan TG, et al. (2012). Endemic foci of the tick-​borne relapsing fever spirochete Borrelia crocidurae in Mali, West Africa, and the potential for human infection. PLoS Negl Trop Dis, 6, e1924. Talagrand-Reboul E, et al. (2018). Relapsing Fevers: Neglected Tick- Borne Diseases. Front Cell Infect Microbiol, 8, 98. Telford SR 3rd, et al. (2015). Borrelia miyamotoi disease: neither Lyme disease nor relapsing fever. Clin Lab Med. 35(4):867–​82. Trape JF et al. (2013). The epidemiology and geographic distribution of relapsing fever borreliosis in West and North Africa, with a review of the Ornithodoros erraticus complex (Acari: Ixodida). PLoS One, 8, e78473. Vidal V, et al. (1998). Variable major lipoprotein is a principal TNF-​ inducing factor of louse-​borne relapsing fever. Nat Med, 4, 1416–​20. Vuyyuru R, et al. (2011). Characteristics of Borrelia hermsii infection in human hematopoietic stem cell-​engrafted mice mirror those of human relapsing fever. Proc Natl Acad Sci U S A, 108, 20707–​12. Warrell DA, et al. (1970). Cardiorespiratory disturbances associated with infective fever in man: studies of Ethiopian louse-​borne re- lapsing fever. Clin Sci, 39, 123–​45. Warrell DA, et  al. (1971). Physiologic changes during the Jarisch–​ Herxheimer reaction in early syphilis. A comparison with louse-​ borne relapsing fever. Am J Med, 51, 176–​85. Warrell DA, et  al. (1983). Pathophysiology and immunology of the Jarisch–​Herxheimer-​like reaction in louse-​borne relapsing fever: comparison of tetracycline and slow-​release penicillin. J Infect Dis, 147, 898–​909. Wright DJ1, Maria B (2011). Ich bin ein Berliner. The contributions of early British colonial and German scientists to the elucidation of the nature of spirochaetes. Clin Microbiol Infect, 17, 484–​6.