Louse-Borne Relapsing Fever with Meningeal Involvement in an Immigrant from Somalia to Italy,October 2015

Introduction

Borrelial relapsing fever is a vector-borne infection caused by spirochetes belonging to the genus Borrelia, clinically characterized by recurrent febrile episodes (Cutler 2010). There are two major forms of this disease that have similar clinical features, but different etiologic agents, vectors, and epidemiology: louse-borne relapsing fever (LBRF) and tick-borne relapsing fever (TBRF) (Cutler 2010). Borrelia recurrentis, transmitted by Pediculus humanus humanus, is the etiological agent of LBRF, whereas several Borrelia spp (at least 15) transmitted by soft tick belonging to the genus Ornithodoros are the agents of TBRF (Dworkin et al. 2008). Humans are the only known vertebrate host of B. recurrentis and LBRF outbreak often occurs in the setting of famine or overcrowding. B. recurrentis was found in the past in many parts of the world (Dworkin et al. 2008), but currently the main focus of endemicity is localized in East African countries, namely in Ethiopia, and neighbor countries such as Eritrea, Somalia, and Sudan. Ethiopia is the country with the highest burden of LBRF with 4754 suspected cases reported in 2013–2014 all over the country according to the Ethiopian Health Ministry (Ethiopian Ministry of Health 2013/2014) and account for up to 27% of all admissions in some areas, ranking fifth among all the mortality causes in the highlands (Eguale et al. 2002).

With the exception of Borrelia duttoni, for which humans are the main reservoir, Borrelia spp causing TBRF are zoonotic pathogens (Dworkin et al. 2008) and each species has a particular epidemiological distribution. The principal endemic regions for TBRF are East Africa (B. duttoni), West and North Africa (Borrelia crocidurae), Eurasia (Borrelia persica. Borrelia caucasica, Borrelia latyschewii, Borrelia microtii, and Borrelia baltazardi), Iberian Peninsula and Morocco (Borrelia hispanica), the United States (Borrelia hermsii and Borrelia turicatae), and Mexico (Borrelia dugesi and B. turicatae) (Dworkin et al. 2008, Cutler 2010, Elbir et al. 2013). The majority of TBRF cases are diagnosed in local population living in endemic areas in intimate contact with animal reservoirs or in travelers who have spent time in caves, abandoned huts, or who have slept outdoors in tick-infested areas (Larsson et al. 2009).

From the clinical point of view, recurrent febrile episodes (usually 1 or 2) accompanied by constitutional symptoms such as headache and myalgias, with asymptomatic interval in between, are common features of all relapsing fevers (Elbir et al. 2013); however, there are subtle clinical differences between TBRF and LBRF and even between the species causing TBRF.

The incubation periods are similar for both forms: 4–8 days for LBRF (range 2–15 days) and 7 days (range 4 to >18 days) for TBRF (Bryceson et al. 1970, Dworkin et al. 2008). In TBRF, the average length of each episode of TBRF is 3 days, in contrast LBRF is characterized by episodes during 5.5 days in average (Dworkin et al. 2008). In TBFR, febrile episodes are similar in severity, whereas in LBRF, subsequent episodes are milder (Estanislao and Pachner 1999). The average time between the first episode and the first relapse is 7 days for TBRF and 9 days for LBRF (Dworkin et al. 2008). Borrelia recurrentis infections have a high mortality rate exceeding 30% in untreated cases, which decreases to 2–6% with an appropriate treatment (Cutler et al. 2009). B. duttonii has an overall fatality rate of 2.3% and results in a particularly poor prognosis if acquired during pregnancy because it leads to a perinatal mortality of 436/1000 (Elbir et al. 2013). B. crocidurae and B. hispanica account for low mortality rates if compared with B. duttonii and B. recurrentis (Cutler et al. 2009). Neurological manifestations are more common in TBRF than in LBRF. Among these manifestations, the more frequently observed are meningismus and facial palsy, whereas encephalitis, myelitis, radiculitis, and neuropsychiatric disturbances are less frequent (Cadavid and Barbour 1998). Nine to 48% of patients infected with B. duttoni have meningismus and in 50–100% of these patients cerebrospinal fluid (CSF) is altered, with mononuclear pleocytosis being the most common finding (Cadavid and Barbour 1998). In patients with B. recurrentis infection, manifestations suggesting meningeal involvement are reported in 41% of cases, whereras alteration of CSF has not been reported before (Cadavid and Barbour 1998).

In Europe, very few cases of relapsing fever have been recently reported. Concerning TBRF, the Iberian Peninsula and Asia Minor are known areas of endemicity, where cases due to B. hispanica, B. persica, B. caucasica, and B. crocidurae may occur (Rebaudet and Parola 2006). Moreover, sporadic cases of imported TBRF have been diagnosed in travelers returning from different non-European destinations including Senegal, Mauritania, Mali, Morocco (Wyplosz et al. 2005), Rocky Mountain cabin of Colorado, the United States (Wyplosz et al. 2005), and Cyprus (Simon 1985). Concerning LBRF, last cases diagnosed up to July 2015 were those in French and British colonial soldiers returning to their countries who acquired the infection in Africa after World Wars I and II (Cutler et al. 2009), even if an increase of B. recurrentis antibodies was detected in homeless populations in Marseille, France, in 2002, suggesting that this disease has occurred as a small epidemic that was not detected before (Brouqui et al. 2005).

From July to October 2015, 36 cases of LBRF have been diagnosed in Europe (the Netherlands, Switzerland, Germany, Finland, and Italy) in immigrants from the Horn of Africa (European Centre for Disease Prevention and Control 2015, Goldenberger et al. 2015, Hoch et al. 2015, Nicolai et al. 2015, Wilting et al. 2015, Ciervo et al. 2016, Cutler 2016, Lucchini et al. 2016), representing a relevant increase in the number of relapsing fever cases observed in Europe if compared with published available data. Most of them are likely to have been exposed to body lice infestations during their journey to Europe. Two subjects diagnosed in Turin (Italy) were permanently residing in Italy since 2011, suggesting a transmission in a refugee reception center (European Centre for Disease Prevention and Control 2015.). Louse vectors were recovered from clothes in some cases (European Centre for Disease Prevention and Control 2015.).

Here we report on a case of LBRF presenting as a meningitis-like syndrome and CSF pleocytosis diagnosed in Florence, Italy, in an immigrant arrived from Somalia.

Case Study

In October 2015, a 19-year-old Somali male presented to the emergency department of Florence, Careggi University Hospital, Florence, Italy, with a 3-day history of high fever, abdominal pain, dysuria, and painful urination associated with constipation.

The patient had disembarked in Sicily 10 days before admission after a migration trip from his country of origin through Kenya, South Sudan, Sudan, and Libya and reached Florence, through Bologna. His past clinical history was unremarkable and no previous episodes of fever were reported.

Physical examination revealed fever (39.1°C), blood pressure 120/70 mmHg, heart rate 106 bpm, normal oxygen saturation, abdominal tenderness on epigastrium, and right-upper quadrant and neck stiffness. The patient underwent chest X-ray, abdominal ultrasonography, head CT scan (all normal), lumbar puncture, and blood tests including tests for malaria. Blood test revealed a normal white blood cell count (9440 WBC/μL; normal: 4000–10,000/μL) with neutrophilia (87%; normal: 37–75%), thrombocytopenia (82,000/μL; normal: 140,000–440,000/μL), elevated procalcitonin (25.67 ng/mL; normal: <0.5 ng/mL), normal hepatic and renal function, and increased fibrinogen (1139 mg/dL; normal: 200–450). CSF was clear, leucocytes were slightly increased (25/μL, 86% polymorphonucleates, 14% mononucleates; normal: <5/μL), whereas protein and glucose were normal and CSF Gram stain was negative.

While malaria tests were still ongoing, the patient was empirically treated with ceftriaxone 2g iv suspecting a possible meningitis and then transferred to the local Infectious and Tropical Diseases Unit. Two hours after antimicrobial therapy, the patient developed hypotension (blood pressure 70/30 mmHg) and tachypnea (30 breaths/min) that was treated with normal saline 0.9% 2000 cc ev and hydrocortisone 250 mg iv.

In the meanwhile, hemoscopy for malaria revealed presence of spirochetes and no malaria parasites (Fig. 1). Immunochromatographic test for malaria was negative.

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FIG. 1.

Blood smear showing Borrelia recurrentis spirochetes.

Doxycycline 100 mg twice a day for 7 days was added. In the following days, the conditions of the patient improved, hypotension resolved 1 day after admission, and fever subsided 3 days after admission. He was discharged on day 7 and continued with ceftriaxone 2 g ev once a day for further 4 days at the outpatient service, then was lost to follow-up despite several telephone recalls. No louse was observed in the patient's clothes. Clothes had been changed twice, after his arrival to Sicily and in Bologna.

The case was reported to the competent Public Health Department. An attempt to control the abandoned building occupied by immigrants where the subject slept for few days in Florence was done. However, the inspection was very difficult because of the little cooperation of people living in the structure. In the following 2 months, no other case with LBRF was diagnosed in Florence.

Nested polymerase chain reaction (PCR) for Borrelia spp. (Borrelia spp. oligomix Alert kit; ELITechGroup, Trezzano sul Naviglio, Italy) was positive on both blood and CSF specimens. Amplification and sequencing with universal 16S rDNA primers D88 and E94 (Paster et al. 2001) revealed a 100% identity with B. recurrentis A1 (accession no. NR_074866.1).

Discussion

The case highlights the challenging management of LBRF in a setting where this infection is extremely rare to be observed. An increasing number of cases have been reported in Europe starting from July 2015, as a consequence of the new migration wave from African countries (Iniziative e Studi sulla Multietnicità 2015). The case was particularly difficult to manage because the patient presented to the emergency department with a meningitis-like syndrome and was treated accordingly with iv ceftriaxone. A sudden development of Jarisch-Herxheimer reaction (JHR), with profound hypotension requiring vigorous fluid resuscitation, was observed. Central nervous system involvement (meningoencephalitis, meningitis, neuropathies, and cranial-nerve palsy, and even central nervous system hemorrhage) is one of the several known clinical features of LBRF, which may accompany febrile episodes (European Centre for Disease Prevention and Control Updated 2015).

In the absence of antibiotic treatment, the reported mortality rate of LBRF is up to 40%, which decreases to 2–6% in treated cases (Cutler et al. 2009). A major challenge associated with the antibiotic treatment is the JHR, occurring shortly after the first dose (usually 2–4 h) in about 76% of cases (Eguale et al. 2002), with a 5% mortality rate (Warrell et al. 1970).

Among the recently reported cases in Europe, 1 of 36 immigrants (European Centre for Disease Prevention and Control 2015, Cutler 2016) died of multiorgan failure after initiation of antibiotic therapy, despite intensive care treatment (Hoch et al. 2015). Among the proposed strategies to prevent JHR are pretreatment with anti-TNF (Fekade et al. 1996), starting of treatment during afebrile periods when spirochetemia is lower, or alternatively avoiding commencing antibiotic treatment during the peak of the febrile period (Cadavid 2014). According to a recent meta-analysis, a significant benefit in favor of penicillin, compared with tetracycline, emerged from three of five trials comparing the rate of JHR (Guerrier and Doherty 2011). However, no clear options to prevent JHR are available (Pound and May 2005) and a close monitoring after the initiation of antibiotic treatment is recommended to intervene promptly with supportive care and fluid balance monitoring in case of JHR (Dworkin et al. 2008).

To the best of our knowledge, this is the first case of B. recurrentis infection presented with CSF pleocytosis, and this report highlights hemoscopy as an indispensable diagnostic tool in the workup of febrile immigrant because it is the only test (together with PCR) that may allow the detection of spirochetes in the blood, unlike the malaria rapid diagnostic test.

In conclusion, LBRF is a rare but emerging infectious disease among vulnerable displaced immigrants from the Horn of Africa. Since immigrants from endemic areas can carry with them the vector and some cases have been acquired in Europe, the infection should be suspected even in subjects with compatible clinical features living in the same place where new arrival immigrants are hosted. Healthcare providers should be aware of this condition to implement adequate diagnostic, therapeutic, and public health measures.