Other Borrelia infections

D. A. WARRELL

The borreliae are large, loosely coiled, motile spirochaetes. Borrelia recurrentis is the cause of louse-borne relapsing fever, while tick-borne relapsing fever is caused by B. duttoni and a number of other species or groups of Borrelia. The recently discovered B. burgdorferi is the cause of Lyme disease. B. vincenti, now renamed Treponema vincentii, has, with Fusobacterium (Bacteroides) fusiforme, been implicated in acute necrotizing ulcerative gingivitis and Vincent's angina but it is now regarded as part of the normal flora of the mouth.

Relapsing fevers
The borreliae that cause relapsing fevers are spirochaetes 8 to 20 &mgr;m long and 0.2 to 0.6 &mgr;m thick, with 3 to 15 coils and 15 to 30 axial filaments or flagella in some strains. These motile organisms divide by transverse binary fission. They can be stained in blood films (Fig. 1) 455 by a wide variety of routine methods including Giemsa, Leishman, and Romanovsky stains; Wright's stain is rapid and convenient. Dark-ground examination and the acridine orange fluorescent (QBC®) method can also be used. Several species of Borrelia including B. recurrentis have now been cultured in Kelly's BSKII artificial media. Borrelia can also be cultured on chick chorioallantoic membrane and perpetuated in rodents and ticks. Plasmid DNA has been detected in at least three Borrelia species.

EPIDEMIOLOGY
Louse-borne (epidemic) relapsing fever
The human body louse, Pedunculus humanus corporis, and to a lesser extent the head louse (P.h. capitis) are the sole vectors, which become infected while feeding on blood from a human patient. The louse's infected haemolymph may be inoculated through the skin when it is crushed by scratching, but spirochaetes can also penetrate intact skin: in this way a new infection can arise. Lice move from person to person when there is crowding and poor hygiene. When the host's surface body temperature deviates far from 37°C, as a result of death, fever, or exposure, or if infested clothing is discarded, the louse is forced to find a new host. The chaos of war, famine, and other disasters favours the spread of lice and epidemic louse-borne infections such as relapsing fever and typhus. The yellow plague in Europe in AD 550 and the famine fevers of the seventeenth and eighteenth centuries were probably relapsing fever. During the first half of the twentieth century it is estimated that there were at least 50 million cases, with a 10 per cent mortality. Epidemics occurred in Europe, the Middle East, and the northern third of Africa, starting in 1903, 1923, and 1943. The major endemic focus of the disease persists in the highlands of Ethiopia, where there is an annual epidemic coinciding with the cool, rainy season when people are forced to wear lice-infested clothes and crowd together into shelters. An annual incidence of 10 000 cases in Ethiopia seems likely. Recent outbreaks have occurred in the Sudan, Somalia, West Africa, and Vietnam. Other endemic foci may exist in the Balkans, the Peruvian and Bolivian Andes, and China. There is no known animal reservoir. Between epidemics, the infection persists in man in mild or asymptomatic form.

Tick-borne (endemic) relapsing fever
There is a close, but not exclusive, relationship between the species of Borrelia, their soft (argasid) tick vectors and reservoirs (genus Ornithodoros), and mammal reservoir species. For example, in East and Central Africa, the domestic tick O. moubata transmits B. duttoni between humans; there is no known animal reservoir. In western North Africa and the Middle East, however, various small rodents have burrows in or near human dwellings, and borreliae of the Crocidurae group may be transmitted to man by the rodent tick Alectrobius sonrai (formerly O. erraticus sonrai). In the western United States, O. hermsi, a parasite of chipmunks and other tree squirrels, transmits B. hermsii to man, especially to individuals who sleep in tick-infested log cabins near the Grand Canyon, Arizona. Other important borreliae causing tick-borne relapsing fever (and their tick vectors) include: B. hispanica (A. sonrai) in Africa; B. persica (O. tholozani) in the Middle East; B. venezuelensis (O. venezuelensis) in Central and South America; and B. turicatae (O. turicatae), B. parkeri (O. parkeri), and B. mazzotti (O. mazzotti) in North America. When night-feeding ticks have access to man, tick-borne relapsing fever may result.

Tick-borne relapsing fever has occurred in most continents except Australasia and the Pacific region. It is particularly common in West Africa, where a recent survey revealed a prevalence of 1 per cent among children (in western Senegal). At one health centre in Rwanda, 1650 proven cases are treated each year (6 per cent of all patients). In North America, cases are usually isolated and sporadic but in 1968, 11 out of a group of 42 boy scouts were infected on Browne Mountain, Washington, while camping in rodent-infested cabins, and in 1973 there were 62 cases among people staying in the log cabins along the north rim of the Grand Canyon. Two hundred and eighty cases of tick-borne relapsing fever have been identified in the United States during the past 25 years. In Colorado the incidence is increasing (23 confirmed cases since 1977). In Jordan, from 1959 to 1969, there were 723 cases of tick-borne relapsing fever, with four deaths.

Spirochaetes enter the tick in its blood meal from infected humans or animals. Unlike B. recurrentis, they invade the tick's salivary and coccal glands, and genital apparatus, and so can be transmitted when the tick feeds on a new host and transovarially to the tick's progeny. Thus ticks are reservoirs of borreliae while lice are not. Ticks infest the burrows, caves, tree stumps, and roughly built shacks that shelter their mammal hosts—rodents, insectivores, lagomorphs, bats, and small carnivores. In Western countries, tick-borne relapsing fever may occasionally be diagnosed in travellers, in intravenous drug abusers, and in recipients of blood transfusions.

PATHOPHYSIOLOGY
The physiological changes during the spontaneous crisis and the Jarisch-Herxheimer reaction induced by antimicrobial treatment in louse-borne relapsing fever are typical of an ‘endotoxin reaction’. Although endotoxin or endotoxin-like activity has been described for other spiro- chaetes: B. burgdorferi, Treponema hyodysenteriae, B. vincenti and B. buccalis, and Leptospira canicola, it has not been detected consistently in patients nor found by gas-liquid chromatography or Limulus assay in sonicates of B. recurrentis, B. hispanica or T. pallidum. In patients with louse-borne relapsing fever who were treated with procaine penicillin, symptoms of the severe Jarisch-Herxheimer reaction were associated with a transient marked elevation in plasma concentrations of tumour necrosis factor, interleukin 6, and interleukin 8. The stimulus for cytokine release seems to be phagocytosis of spirochaetes made susceptible by the action of penicillin. Benzylpenicillin attaches to penicillin-binding protein I in B. hermsii spirochaetes. Large surface blebs are produced and the damaged 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 complement system is not essential for elimination of spirochaetes, whether or not specific immunoglobulins are present. In vitro, surface contact with spirochaetes induces mononuclear leucocytes to produce pyrogen and thromboplastin, which could be responsible for the fever and disseminated intravascular coagulation in louse-borne relapsing fever. There is some evidence to suggest that kinins are released during the Jarisch-Herxheimer reaction of syphilis and louse-borne relapsing fever. The marked peripheral leucopenia that develops during the reaction is more likely to be the result of sequestration, perhaps in the pulmonary blood vessels, than to destruction of leucocytes. Spirochaetes may be found in the organs that bear the brunt of the infection (liver, spleen, myocardium, and brain), but it is not clear how their pathological effects are produced. The petechial rash results simply from thrombocytopenia and is not a vasculitis. The cardiorespiratory and metabolic disturbances in relapsing fever are principally the result of persistent high fever, dramatically accentuated by the Jarisch-Herxheimer reaction or spontaneous crisis.

IMMUNITY AND THE RELAPSE PHENOMENON
Studies of the relapse phenomenon in mice infected with B. hermsii have demonstrated spontaneous variation of protein antigens resulting in a mixed population of up to 26 new serotypes. The mechanism that alters the expression of variable major protein (VMP) antigens has been partly elucidated. Extrachromasomal DNA on linear plasmids recombines to activate the genes controlling VMP synthesis. Between attacks, spirochaetaemia may persist, even though it is undetectable by microscopy and is insufficient to produce symptoms. Spirochaetes may retreat to immunologically compromised sites such as the brain and eye. Antibody destroys the population of spirochaetes to which it is specific and selects out antigenic variants, but does not affect the rate of antigenic variation.

PATHOLOGY
Spirochaetes are usually confined to the lumen of blood vessels but tangled masses are also found in the characteristic splenic miliary abscesses (Fig. 2) 456,457,458,459 and infarcts, and within the central nervous system adjacent to haemorrhages. A perivascular, histiocytic, interstitial myocarditis is found in the majority of cases and may be responsible for conduction defects, arrhythmias, and myocardial failure resulting in sudden death. Splenic rupture with massive haemorrhage, cerebral haemorrhage, and hepatic failure are other causes of death. The liver shows hepatitis with patchy mid-zonal haemorrhages and necrosis (Fig. 3) 460. There is meningitis and perisplenitis; most serosal cavities and surfaces of viscera are studded with petechial haemorrhages (Fig. 4) 461. Thrombi are occasionally found occluding small vessels, but the peripheral gangrene sometimes found in patients recovering from louse-borne typhus is not seen.

CLINICAL FEATURES
The illness starts suddenly with rigors and a fever that mounts to nearly 40°C in a few days. Early symptoms are headache, dizziness, nightmares, generalized aches and pains often focused in the lower back, knees and elbows, anorexia, nausea, vomiting, and diarrhoea. Later there is upper abdominal pain, cough, and epistaxis. Patients are usually prostrated; most are confused. Hepatic tenderness is the most common sign (about 60 per cent). The liver is palpably enlarged in about half of cases. Splenic tenderness and enlargement are slightly less common. Jaundice has been reported in between 10 and 80 per cent of patients. A petechial or ecchymotic rash is seen in between 10 and 60 per cent; the lesions occur particularly on the trunk (Fig. 5) 462. Other sites of spontaneous bleeding include the nose in 25 per cent, and less commonly the lungs, gastrointestinal tract, conjunctivae (Fig. 6) 463, and retinae. Many patients have tender muscles. Meningism occurs in about 40 per cent of cases; other neurological features include cranial-nerve lesions, monoplegias, flaccid paraplegia, and focal convulsions attributable, perhaps, to cerebral haemorrhages.

Time course and relapses
The incubation period is 4 to 18 (average 7) days. In untreated cases of the louse-borne disease, the first attack of fever resolves by crisis in 4 to 10 (average 5) days whereas in tick-borne disease initial fever lasts only about 3 days. There follows an afebrile remission of 5 to 9 days and then a series of up to five relapses in louse-borne disease and up to 13 in tick-borne disease (Fig. 7) 464. No petechial rash occurs during the relapses, which are generally less severe than the initial attack, but may be associated with iritis or iridocyclitis and severe epistaxis.

Differences between louse-borne and tick-borne relapsing fever
The tick-borne disease is generally milder and less drawn out. The incidence of some symptoms and signs in the two diseases appears strikingly different. For example, in some series of cases, only 7 per cent of patients with tick-borne relapsing fever were jaundiced and neurological signs were more common than in the louse-borne disease.

Severe manifestations
These include myocarditis, which presents as acute pulmonary oedema, liver failure and severe bleeding attributable to thrombocytopenia, liver damage, and disseminated intravascular coagulation. Dysentery, salmonellosis, typhoid, typhus, malaria, and tuberculosis have been described in association with relapsing fever.

The spontaneous crisis and Jarisch-Herxheimer reaction
Whether or not treatment is given, an attack of relapsing fever usually ends dramatically. About 1 h after intravenous tetracycline, or on about the fifth day of the untreated illness, the patient becomes restless and apprehensive, and suddenly begins to have distressingly intense rigors, which last 10 to 30 min. The ensuing phenomena have features of a classical endotoxin reaction. During the 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 several hours, is characterized by profuse sweating, a fall in blood pressure, and slow decline in temperature. Deaths during this phase follow intractable hypotension or the development of acute pulmonary oedema and are attributable to myocarditis. The classical Jarisch-Herxheimer reaction is in syphilis (Chapter 7.11.34) 146. Similar reactions have been described in Lyme disease and leptospirosis (treated with penicillin), sodoku (arsenicals), Brucella melitensis (tetracycline), and even in meningococcal infections.

DIAGNOSIS
In the febrile patient, spirochaetes can usually be demonstrated in thin or thick blood films stained with Giemsa or Wright's stain and counterstained for 10 to 30 min with 1 per cent crystal violet, or by dark-field examination (see Fig. 1 455). Towards the end of the attack, during remissions, and particularly in children with tick-borne disease, spirochaetaemia may not be detectable. In these cases, blood or cerebrospinal fluid can be injected intraperitoneally into young mice, which will develop spirochaetaemia within 14 days. Serological methods are not generally used. The serum of patients with relapsing fever may give positive reactions with Proteus OXK, OX19, and OX2, and false-positive serological responses for syphilis in 5 to 10 per cent of cases.

DIFFERENTIAL DIAGNOSIS
In a febrile patient with jaundice, petechial rash, bleeding, and hepatosplenomegaly, the differential diagnosis will include falciparum malaria, yellow fever, viral hepatitis, rickettsial infections, especially louse-borne typhus, and leptospirosis. The diagnosis can be quickly confirmed by examining a blood smear, but the possibility of a complicating infection, particularly typhoid, should not be forgotten.

PROGNOSIS
The mortality in treated cases is less than 5 per cent. During major epidemics of louse-borne relapsing fever, mortalities of 40 per cent or higher have been reported. Deaths during relapses are most unusual; they occur only in the tick-borne disease.

TREATMENT
Antimicrobials
Although tick-borne relapsing fever is usually milder than the louse-borne variety, it is more difficult to treat because spirochaetes persist in tissues such as the central nervous system and eye, and produce relapses. Oral tetracycline, 500 mg 6-hourly for 10 days, is, however, effective. Oral erythromycin can be given to pregnant women (500 mg 6-hourly for 10 days) and children (125-250 mg 6-hourly for 10 days). In patients unable to swallow tablets, treatment can be initiated with intravenous tetracycline hydrochloride, 250 mg, or erythromycin lactobionate, 300 mg.

Louse-borne relapsing fever is readily cured with a single oral dose of 500 mg of tetracycline or 500 mg of erythromycin stearate. Few patients with severe louse-borne relapsing fever are able to swallow the tablets without vomiting them up: a more reliable treatment is a single intravenous dose of tetracycline hydrochloride, 250 mg, or, for pregnant women and children, a single intravenous dose of erythromycin lactobionate, 300 mg (children, 10 mg/kg body weight). In mixed epidemics of louse-borne relapsing fever and louse-borne typhus a single oral dose of 100 mg of doxycycline has been effective.

Benzylpenicillin (300 000 u), procaine penicillin with benzylpenicillin (600 000 u), and procaine penicillin with aluminium monostearate (600 000 u), all by intramuscular injection, have been used but they may fail to prevent relapses, and the long-acting preparations produce only slow clearance of spirochaetaemia. Chloramphenicol is effective in tick-borne relapsing fever in a dose of 500 mg 6-hourly for 10 days in adults and 250 mg 6-hourly for 10 days in older children; and in louse-borne relapsing fever in a single dose of 500 mg by mouth or intravenous injection in adults.

Jarisch-Herxheimer reaction
Antimicrobials have reduced the mortality of relapsing fevers from 30 to 70 per cent to less than 5 per cent, but drugs such as tetracycline, which usually eliminate spirochaetes rapidly from the blood and prevent relapses, often induce a severe Jarisch-Herxheimer type of reaction that may occasionally prove fatal. Clearly, in a disease with such a high natural mortality, treatment cannot be withheld, especially as severe spontaneous crises, which may also prove fatal, occur in a large proportion of louse-borne 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. Hydrocortisone, in doses up to 20 mg/kg, and paracetamol do not prevent the reaction but 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 Jarisch-Herxheimer reaction of early syphilis, but in louse-borne relapsing fever, an oral dose of prednisolone, 3 mg/kg, given 18 h before tetracycline treatment and infusion of betamethasone, 3.75 mg/kg, do not prevent the reaction. However, meptazinol, an opioid antagonist with agonist properties, diminishes the reaction when given in a dose of 100 mg by intravenous injection. The discovery of an explosive release of tumour necrosis factor, interleukin 6 and interleukin 8 just before the start of the Jarisch-Herxheimer reaction prompted the testing of a polyclonal, ovine, Fab, antitumour necrosis factor antibody. Infused for 30 min before treatment with intramuscular penicillin this antibody suppressed the reaction.

Supportive treatment
Patients must be nursed 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 antipyretics and vigorous fanning with tepid sponging. Although patients with acute louse-borne relapsing fever have an expanded plasma volume, most are dehydrated and relatively hypovolaemic. Adults may need four or more litres of isotonic saline intravenously during the first 24 h. Infusion should be controlled by monitoring of jugular venous, central venous, or pulmonary artery-wedge pressures. Particularly during the flush phase of the Jarisch-Herxheimer reaction or spontaneous crisis, acute myocardial failure may develop. This is signalled by a rise in central venous pressure above 15 cmH&sub2;O; 1 mg digoxin should be given intravenously over 5 to 10 min. 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 in all cases with prolonged prothrombin times. Heparin is not effective in controlling coagulopathy and should not be used. Complicating infections—typhoid, salmonellosis, bacillary dysentery, tuberculosis, typhus and malaria—must be treated appropriately.

Delousing
Patients with louse-borne relapsing fever are infectious until they have been thoroughly deloused by shaving off infested hair (Fig. 8) 465, washing with soap or 1 per cent lysol solution, and dusting with 10 per cent DDT, 1 per cent malathion or 0.5 per cent permethrin. Their clothes, instinct with infected lice, are disinfected by heat. Ticks should be searched for and removed but they usually feed for a short time and then detach and so are rarely found by the time the patient presents with tick-borne relapsing fever. A recent study in Ethiopia demonstrated that treatment of cases of louse-borne relapsing fever with antimicrobials was not effective in controlling an epidemic without the addition of vigorous delousing measures.

PREVENTION
Tick control can be attempted by spraying buildings with insecticides such as 2 per cent benzene hexachloride or 0.5 per cent malathion, and by reducing the number of rodent vectors. Lousiness is prevented by improved hygiene and use of DDT or other insecticide powders.

REFERENCES
Anderson, T.R. and Zimmerman, L.E. (1955). Relapsing fever in Korea. A clinicopathologic study of eleven fatal cases with special attention to association with salmonella infections. American Journal of Pathology, 31, 1083-109.
Barbour, A.G. (1987). Immunobiology of relapsing fever. Contributions to Microbiological Immunology, 8, 125-37.
Bryceson, A.D.M., Parry, E.H.O., Perine, P.L., Warrell, D.A., Vucotich, D., and Leithead, C.S. (1970). Louse-borne relapsing fever. A clinical and laboratory study of 62 cases in Ethiopia and a reconsideration of the literature. Quarterly Journal of Medicine, 39, 129-70.
Butler, T., Aikawa, M., Habte-Michael, A., and Wallace, C. (1980). Phagocytosis of Borrelia recurrentis by blood polymorphonuclear leukocytes is enhanced by antibiotic treatment. Infection and Immunity, 28, 1009-13.
Felsenfeld, O. (1965). Borrelia, human relapsing fever and parasite-vector-host relationships. Bacteriology Reviews, 29, 46-74.
Felsendfeld, O. (1971). Borrelia: strains, vectors, human and animal borreliosis. Green, St Louis.
Goubau, P.F. (1984). Relapsing fevers. A review. Annales de la Societé Belge de Médicine Tropicale, 40, 335-64.
Horton, J.M. and Blaser, M.J. (1985). The spectrum of relapsing fever in the Rocky Mountains. Archives of Internal Medicine, 145, 871-5.
Negussie, Y. et al. (1992). Detection of plasma tumor necrosis factor, interleukins-6 and -8 during the Jarisch-Herxheimer reaction of relapsing fever. Journal of Experimental Medicine, 175, 1207-12.
Plasterk, R.H.A., Simon, M.I., and Barbour, A.G. (1985). Transposition of structural genes to an expression sequence on a linear plasmid causes antigenic variation in the bacterium Borrelia hermsii. Nature, 318, 257-63.
Sundnes, K.O. and Teklehaimanot, A. (1993). Epidemic of louse-borne relapsing fever in Ethiopia. Lancet, 342, 1213-15.
Teklu, B., Habte-Michael, A., Warrell, D.A., White, N.J., and Wright, D.J.M. (1983). Meptazinol diminishes the Jarisch-Herxheimer reaction of relapsing fever. Lancet, i, 835-9.
Trape, J.F. et al. (1991). Tick-borne borreliosis in West Africa. Lancet, 337, 473-5.
Warrell, D.A., Perine, P.L., Krause, D.W., Bing, D.H., and MacDougal, S.J. (1983). Pathophysiology and immunology of the Jarisch-Herxheimer like reaction in louse-borne relapsing fever: comparison of tetracycline and slow-release penicillin. Journal of Infectious Diseases, 147, 898-909.
Warrell, D.A., Pope, H.M., Parry, E.H.O., Perine, P.L., and Bryceson, A.D.M. (1970). Cardiorespiratory disturbance associated with infective fever in man: studies of Ethiopian louse-borne relapsing fever. Clinical Science, 39, 123-45.