The Open Dermatology Journal




ISSN: 1874-3722 ― Volume 13, 2019

Impact of Co-Infections in Lyme Disease



Giuseppe Stinco*, Serena Bergamo
Department of Experimental and Clinical Medicine, Institute of Dermatology, University of Udine, Italy

Abstract

Lyme disease is one of the most frequent tick-borne diseases worldwide, it can be multi-systemic and insidious, in particular when it shows a chronic course.

In recent years co-infections represent an emerging issue in Lyme disease spectrum because in addition to Borrelia burgdorferi sl many other potential pathogens may be transmitted by hard ticks Ixodes species. The main co-infections found in Lyme disease described in this review are represented by Anaplasma phagocytophilum, Babesia species, Bartonella species, Rickettsiae species and tick-borne encephalitis virus. For each single co-infecting micro-organism, clinical features, diagnostic issues and therapeutical approaches are discussed.

Co-infections represent an emerging problem because they might exacerbate Lyme disease clinical features, they can also mimic Lyme borreliosis sharing common manifestations, and eventually they can change the course of the disease itself.

The presence of one or more co-infecting agent during the course of Lyme disease may represent an issue especially in endemic areas for tick-borne diseases and in people occupationally exposed.

The aim of this review is to summarize the more important co-infections in patients with Lyme disease and to discuss their importance in the disease process.

Keywords: Anaplasma phagocytophilum, Babesia species, Bartonella species, Borrelia burgdorferi, Co-infections, Lyme disease, Rickettsiae species, Tick-borne encephalitis virus.


Article Information


Identifiers and Pagination:

Year: 2016
Volume: 10
Issue: Suppl 1: M6
First Page: 55
Last Page: 61
Publisher Id: TODJ-10-55
DOI: 10.2174/1874372201610010055

Article History:

Received Date: 22/10/2015
Revision Received Date: 16/12/2015
Acceptance Date: 16/12/2015
Electronic publication date: 28/03/2016
Collection year: 2016

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 1188
Abstract HTML Views: 1234
PDF Downloads: 269
ePub Downloads: 207
Total Views/Downloads: 2898

Unique Statistics:

Full-Text HTML Views: 614
Abstract HTML Views: 649
PDF Downloads: 182
ePub Downloads: 140
Total Views/Downloads: 1585
Geographical View

© Stinco and Bergamo; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Institute of Dermatology, “Santa Maria della Misericordia” University Hospital, Piazzale Santa Maria della Misericordia, 15, 33100-Udine, Italy; Tel: (+39) 0432559822; Email: giuseppe.stinco@uniud.it





INTRODUCTION

Lyme disease (LD) is one of the commonest vector-borne infections worldwide, caused by a spirochete, Borrelia burgdorferi sensu lato (Bb), and transmitted to humans through hard tick (Ixodes spp.) bite [1Scarpa C, Trevisan G, Stinco G. Lyme borreliosis. Dermatol Clin 1994; 12(4): 669-85.
[PMID: 7805296]
, 2Shapiro ED. Clinical practice. Lyme disease. N Engl J Med 2014; 370(18): 1724-31.
[http://dx.doi.org/10.1056/NEJMcp1314325] [PMID: 24785207]
]. In addition to Bb, other human pathogens may be transmitted by Ixodes ticks [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
]. A concomitant infection of more than one agent is named co-infection. The risk for human co-infections with multiple pathogens after an Ixodes tick bite differs by geographic location and depends on the prevalence of pathogens within the reservoir host and Ixodes ticks [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
-6Reis C, Cote M, Paul RE, Bonnet S. Questing ticks in suburban forest are infected by at least six tick-borne pathogens. Vector Borne Zoonotic Dis 2011; 11(7): 907-16.
[http://dx.doi.org/10.1089/vbz.2010.0103] [PMID: 21158500]
]. The more relevant co-infections in LD are caused by Anaplasma phagocytophilum, Babesia species, Bartonella species, primary Bartonella hensalae and tick-borne encephalitis virus (TBEV) [5Franke J, Hildebrandt A, Dorn W. Exploring gaps in our knowledge on Lyme borreliosis spirochaetes--updates on complex heterogeneity, ecology, and pathogenicity. Ticks Tick Borne Dis 2013; 4(1-2): 11-25.
[http://dx.doi.org/10.1016/j.ttbdis.2012.06.007] [PMID: 23246041]
]. Bartonella henselae is the aetiologic agent of cat scratch disease, which is not transmitted to humans by ticks.

The clinical and pathological impact of co-infections was first recognized in 1990, about ten years after the discovery of LD and they are thought to be the main reason for treatment failures [7Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
].

Co-infections might exacerbate LD as well as they can induce similar clinical manifestations or change the course of the disease [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
, 4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 7Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
, 8Heyman P, Cochez C, Hofhuis A, et al. A clear and present danger: tick-borne diseases in Europe. Expert Rev Anti Infect Ther 2010; 8(1): 33-50.
[http://dx.doi.org/10.1586/eri.09.118] [PMID: 20014900]
]. However the actual burden of co-infections in the natural disease history has not been unravelled yet. When two or more pathogens infect a patient, clarifying which is the major responsible of the clinical pictures can be challenging, since LD can share common clinical features with other conditions transmitted by Ixodes ticks bite especially in early stages [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
, 9Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. JAMA 1996; 275(21): 1657-60.
[http://dx.doi.org/10.1001/jama.1996.03530450047031] [PMID: 8637139]
, 10Krause PJ, McKay K, Thompson CA, et al. Deer-Associated Infection Study Group. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34(9): 1184-91.
[http://dx.doi.org/10.1086/339813] [PMID: 11941544]
]. The difficulties in diagnosis and management of co-infections in LD are more related to late and chronic LD since co-infecting agents might cause chronic forms of diseases too [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
, 7Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
].

In such cases an accurate anamnestic report in early stages may be useful to recognize the chronic course of the co-infection together with LD.

The diagnosis of co-infections is based on patient’s history, the course of the disease, results of medical technical tests, physical examination and the exclusion of differential diagnoses.

Laboratory tests for diagnosis of LD and co-infecting agents are available both for serology, culture and indirect detection by lymphocyte transformation test [11Chan K, Marras SA, Parveen N. Sensitive multiplex PCR assay to differentiate Lyme spirochetes and emerging pathogens Anaplasma phagocytophilum and Babesia microti. BMC Microbiol 2013; 13: 295.
[http://dx.doi.org/10.1186/1471-2180-13-295] [PMID: 24359556]
, 12Belongia EA. Epidemiology and impact of coinfections acquired from Ixodes ticks. Vector Borne Zoonotic Dis 2002; 2(4): 265-73.
[http://dx.doi.org/10.1089/153036602321653851] [PMID: 12804168]
]. The most widely used and reliable test is the two-step serological diagnosis with the confirmation by Western blot in case of positive or doubtful serology. Serological findings, especially in endemic areas, are not always signs of the current infection and a negative serology is not sufficient to exclude the disease [13Aguero-Rosenfeld ME, Donnarumma L, Zentmaier L, et al. Seroprevalence of antibodies that react with Anaplasma phagocytophila, the agent of human granulocytic ehrlichiosis, in different populations in Westchester County, New York. J Clin Microbiol 2002; 40(7): 2612-5.
[http://dx.doi.org/10.1128/JCM.40.7.2612-2615.2002] [PMID: 12089287]
, 14Bakken LL. Role of experience and context in learning to diagnose Lyme disease. J Contin Educ Health Prof 2002; 22(3): 131-41.
[http://dx.doi.org/10.1002/chp.1340220302] [PMID: 12227235]
]. The positive serological result only proofs that infection has taken place, but cannot prove the disease and there may be seronegativity in case of co-infection with long lasting chronic disease.

Since the treatment of the infections caused by various tick-borne pathogens differs from one another, concomitant infections are becoming a serious epidemiological and clinical problem [15Horowitz HW, Aguero-Rosenfeld ME, Holmgren D, et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis 2013; 56(1): 93-9.
[http://dx.doi.org/10.1093/cid/cis852] [PMID: 23042964]
].

The aim of this review is to summarize the most important co-infections in patients with LD and to discuss their importance in the disease process.

ANAPLASMA PHAGOCYTOPHILUM

Tick-borne Rickettsiae in the genera Ehrlichia and Anaplasma are intracellular bacteria that infect wild and domestic mammals and humans. They can cause human granulocitic anaplasmosis (HGA), an acute febrile illness ranging from asymptomatic to severe disease in humans [16Chen SM, Dumler JS, Bakken JS, Walker DH. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 1994; 32(3): 589-95.
[PMID: 8195363]
]. The main features of HGA are fever, headache, joint and muscle pain and laboratory findings such as leukopenia, thrombocytopenia and high liver enzymes levels in peripheral blood. Usually the infection is mild and self-limiting, even if it can be life-threatening with the development of meningitis and other central nervous system disorders. The incubation period is about 7 days from the tick bite and the development of symptoms. Co-infection between LD and HGA ranges from 2% to 11% in three studies [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
, 17Belongia EA, Reed KD, Mitchell PD, et al. Clinical and epidemiological features of early Lyme disease and human granulocytic ehrlichiosis in Wisconsin. Clin Infect Dis 1999; 29(6): 1472-7.
[http://dx.doi.org/10.1086/313532] [PMID: 10585798]
, 18Steere AC, McHugh G, Suarez C, Hoitt J, Damle N, Sikand VK. Prospective study of coinfection in patients with erythema migrans. Clin Infect Dis 2003; 36(8): 1078-81.
[http://dx.doi.org/10.1086/368187] [PMID: 12684924]
]. In a recent study Strle et al. demonstrated that in Slovenia, a country endemic for LD, TBE and HGA, none of 67 patients involved in the survey with typical erythema migrans was found to be co-infected with A. phagocytophilum, even if only serology was performed by the Authors as diagnostic tool [19Strle F, Bogovič P, Cimperman J, et al. Are patients with erythema migrans who have leukopenia and/or thrombocytopenia coinfected with Anaplasma phagocytophilum or tick-borne encephalitis virus? PLoS One 2014; 9(7): e103188.
[http://dx.doi.org/10.1371/journal.pone.0103188] [PMID: 25057802]
].

In 2007, Grab et al. found that the infection of A. phagocytophilum may be responsible of a more severe form of LD with enhanced dissemination and possible long-term complications because co-infection causes reduction in transendothelial electric resistance and increased production of metalloproteinases, cytokines and chemokines [20Moniuszko A, Dunaj J, Swięcicka I, et al. Co-infections with Borrelia species, Anaplasma phagocytophilum and Babesia spp. in patients with tick-borne encephalitis. Eur J Clin Microbiol Infect Dis 2014; 33(10): 1835-41.
[http://dx.doi.org/10.1007/s10096-014-2134-7] [PMID: 24848130]
, 21Grab DJ, Nyarko E, Barat NC, Nikolskaia OV, Dumler JS. Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cells. Clin Vaccine Immunol 2007; 14(11): 1420-4.
[http://dx.doi.org/10.1128/CVI.00308-07] [PMID: 17898182]
].

Recently, Horowitz et al. analysed patients having erythema migrans and a positive blood culture for Anaplasma phagocytophilum living in Valhalla, New York. They found that the total number of symptoms was not significantly different in patients with LD alone and patients with LD and HGA. In addition to that, the Authors interestingly noted that patients having HGA alone experienced a shorter duration of illness compared with those co-infected by Bb and Anaplasma phagocytophilum, maybe because they went sooner to the doctor. In this study leukopenia and thrombocytopenia were reported more frequently in HGA alone than in co-infections, even if this difference was not statistically significant [15Horowitz HW, Aguero-Rosenfeld ME, Holmgren D, et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis 2013; 56(1): 93-9.
[http://dx.doi.org/10.1093/cid/cis852] [PMID: 23042964]
]. In Literature conflicting data about the severity of co-infection compared to LD or HGA alone are available [7Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
, 10Krause PJ, McKay K, Thompson CA, et al. Deer-Associated Infection Study Group. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34(9): 1184-91.
[http://dx.doi.org/10.1086/339813] [PMID: 11941544]
, 17Belongia EA, Reed KD, Mitchell PD, et al. Clinical and epidemiological features of early Lyme disease and human granulocytic ehrlichiosis in Wisconsin. Clin Infect Dis 1999; 29(6): 1472-7.
[http://dx.doi.org/10.1086/313532] [PMID: 10585798]
, 18Steere AC, McHugh G, Suarez C, Hoitt J, Damle N, Sikand VK. Prospective study of coinfection in patients with erythema migrans. Clin Infect Dis 2003; 36(8): 1078-81.
[http://dx.doi.org/10.1086/368187] [PMID: 12684924]
].

The diagnosis of HGA is mostly based on serology findings: specific antibodies can be detected two to three weeks after the onset of the illness. Anaplasma phagocytophilum can also be amplified by means of PCR from the blood or it can be cultured from blood as well. Eventually intragranulocitic morulae can be directly detected from peripheral blood stained with Giemsa and observed under microscope [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 15Horowitz HW, Aguero-Rosenfeld ME, Holmgren D, et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis 2013; 56(1): 93-9.
[http://dx.doi.org/10.1093/cid/cis852] [PMID: 23042964]
, 22Rikihisa Y. Anaplasma phagocytophilum and Ehrlichia chaffeensis: subversive manipulators of host cells. Nat Rev Microbiol 2010; 8(5): 328-39.
[http://dx.doi.org/10.1038/nrmicro2318] [PMID: 20372158]
].

Doxycycline 100 mg twice a day is found to be the most effective therapy, it can be the treatment of choice also in children [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
, 4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
]. Usually it is prescribed orally for 14 days, but no universal data are available [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 15Horowitz HW, Aguero-Rosenfeld ME, Holmgren D, et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis 2013; 56(1): 93-9.
[http://dx.doi.org/10.1093/cid/cis852] [PMID: 23042964]
, 23Nadelman RB, Horowitz HW, Hsieh TC, et al. Simultaneous human granulocytic ehrlichiosis and Lyme borreliosis. N Engl J Med 1997; 337(1): 27-30.
[http://dx.doi.org/10.1056/NEJM199707033370105] [PMID: 9203428]
].

Rifampicin and possibly levofloxacin may be second choice treatments: they showed good antimicrobial activity in vitro, but clinical studies are poor or lacking. Anaplasma phagocytophilum has found to be resistant to several classes of antibiotics such as amoxicillin and other beta-lactams, erythromycin, azithromycin, clarithromycin, clindamycin, trimethoprim-sulfamethoxazole [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
, 24Horowitz HW, Hsieh TC, Aguero-Rosenfeld ME, et al. Antimicrobial susceptibility of Ehrlichia phagocytophila. Antimicrob Agents Chemother 2001; 45(3): 786-8.
[http://dx.doi.org/10.1128/AAC.45.3.786-788.2001] [PMID: 11181361]
, 25Krause PJ, Corrow CL, Bakken JS. Successful treatment of human granulocytic ehrlichiosis in children using rifampin. Pediatrics 2003; 112(3 Pt 1): e252-3.
[http://dx.doi.org/10.1542/peds.112.3.e252] [PMID: 12949322]
].

BABESIA SPECIES

Human babesiosis is a tick-borne disease, caused primarily by the intraerythrocytic protozoan Babesia microti and by other Babesia species. In the United States Babesia microti has found to be more often detected in ticks, whether in Europe Babesia divergens seemed to be prevalent [6Reis C, Cote M, Paul RE, Bonnet S. Questing ticks in suburban forest are infected by at least six tick-borne pathogens. Vector Borne Zoonotic Dis 2011; 11(7): 907-16.
[http://dx.doi.org/10.1089/vbz.2010.0103] [PMID: 21158500]
, 8Heyman P, Cochez C, Hofhuis A, et al. A clear and present danger: tick-borne diseases in Europe. Expert Rev Anti Infect Ther 2010; 8(1): 33-50.
[http://dx.doi.org/10.1586/eri.09.118] [PMID: 20014900]
, 11Chan K, Marras SA, Parveen N. Sensitive multiplex PCR assay to differentiate Lyme spirochetes and emerging pathogens Anaplasma phagocytophilum and Babesia microti. BMC Microbiol 2013; 13: 295.
[http://dx.doi.org/10.1186/1471-2180-13-295] [PMID: 24359556]
, 26Hildebrandt A, Fritzsch J, Franke J, Sachse S, Dorn W, Straube E. Co-circulation of emerging tick-borne pathogens in Middle Germany. Vector Borne Zoonotic Dis 2011; 11(5): 533-7.
[http://dx.doi.org/10.1089/vbz.2010.0048] [PMID: 20846013]
]. It can be transmitted either by Ixodes ticks or less often with blood transfusions and by perinatal infection. The clinical spectrum of the infection ranges from asymptomatic or moderate disease to rapidly progressive and sometimes fatal [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 11Chan K, Marras SA, Parveen N. Sensitive multiplex PCR assay to differentiate Lyme spirochetes and emerging pathogens Anaplasma phagocytophilum and Babesia microti. BMC Microbiol 2013; 13: 295.
[http://dx.doi.org/10.1186/1471-2180-13-295] [PMID: 24359556]
]. Acute Babesiosis usually shows as fever and flu-like symptoms such as myalgia, chills, gastro-intestinal features. Since Babesia causes an intra-erythrocytic infection, haemolysis ranging with different severity can be detected as well. Immunocompromised subjects as oncologic, asplenic and undergoing immunosuppressive therapy patients could develop a more severe disease form which might become chronic and relapsing [27Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am 2008; 22(3): 469-488, viii-ix.
[http://dx.doi.org/10.1016/j.idc.2008.03.010] [PMID: 18755385]
].

Babesia infection can be proved with DNA amplification by means of PCR. It can be detected also with direct confirmation of the protozoan on blood smear, but this technique is not straightforward and usually requires multiple examinations. Serology is not helpful because it is poorly associated with clinical symptoms, especially in endemic areas [28Krause PJ, Ryan R, Telford S III, Persing D, Spielman A. Efficacy of immunoglobulin M serodiagnostic test for rapid diagnosis of acute babesiosis. J Clin Microbiol 1996; 34(8): 2014-6.
[PMID: 8818902]
, 29Krause PJ. Telford SR 3rd, Ryan R. Diagnosis of babesiosis: evaluationof a serologic test for the detection of Babesia microti antibody. J Infect Dis 1994; 169: 923-6.
[http://dx.doi.org/10.1093/infdis/169.4.923] [PMID: 8133112]
].

Studies of clinical outcomes suggest that patients with acute Babesia co-infection have more severe symptoms and a longer duration of illness than patients with LB alone, but the risk of spirochete dissemination seems to be similar [7Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
].

Concomitant infections may be difficult to diagnose since both LD and Babesiosis have overlapping symptoms e.g. flu-like illness with fever and fatigue [20Moniuszko A, Dunaj J, Swięcicka I, et al. Co-infections with Borrelia species, Anaplasma phagocytophilum and Babesia spp. in patients with tick-borne encephalitis. Eur J Clin Microbiol Infect Dis 2014; 33(10): 1835-41.
[http://dx.doi.org/10.1007/s10096-014-2134-7] [PMID: 24848130]
].

In Literature atovaquone, azithromycin, clindamycin with or without quinine are found to be effective [15Horowitz HW, Aguero-Rosenfeld ME, Holmgren D, et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis 2013; 56(1): 93-9.
[http://dx.doi.org/10.1093/cid/cis852] [PMID: 23042964]
]. Clindamycin 600 mg every 8 hours taken orally plus quinine 650 mg orally every 8 hours for 7 to 10 days have efficacy proven in Literature in milder forms of disease [30Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000; 343(20): 1454-8.
[http://dx.doi.org/10.1056/NEJM200011163432004] [PMID: 11078770]
, 31Drugs for parasitic infections. Med Lett Drugs Ther 1998; 40(1017): 1-12. [No authors listed]
[PMID: 9442765]
], while the intravenous use of clindamycin is preferred in more severe disease forms. Alternative and similarly effective treatments are atovaquone 750 mg twice daily taken orally plus azithromycin 250 mg daily except for the fisrt day of treatment (500 mg) for 7 days as well. These therapies have to be associated with an adequate anti-Borrelial drug regimen (e.g. doxycycline) [8Heyman P, Cochez C, Hofhuis A, et al. A clear and present danger: tick-borne diseases in Europe. Expert Rev Anti Infect Ther 2010; 8(1): 33-50.
[http://dx.doi.org/10.1586/eri.09.118] [PMID: 20014900]
].

In immunocompromised patients there are some evidences for a more prolonged anti-Babesia therapy (e.g. more than 10 days) to be prescribed [32Krause PJ, Gewurz BE, Hill D, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 2008; 46(3): 370-6.
[http://dx.doi.org/10.1086/525852] [PMID: 18181735]
]. In patients severely ill with haemolysis and organ failure with high levels of Babesia in blood, transfusions may be sensible [33Bonoan JT, Johnson DH, Cunha BA. Life-threatening babesiosis in an asplenic patient treated with exchange transfusion, azithromycin, and atovaquone. Heart Lung 1998; 27(6): 424-8.
[http://dx.doi.org/10.1016/S0147-9563(98)90089-9] [PMID: 9835673]
, 34Hatcher JC, Greenberg PD, Antique J, Jimenez-Lucho VE. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis 2001; 32(8): 1117-25.
[http://dx.doi.org/10.1086/319742] [PMID: 11283800]
].

According to data available, it seems that babesiosis represents a minor health hazard and can cause little consequence as a co-infection in LD [3Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
].

CONTEMPORARY INFECTION WITH ANAPLASMA PHAGOCITOPHILUM AND BABESIA SPECIES

Bb sensu lato, Anaplasma phagocytophilum and Babesia share very similar epidemiology and trasmission cycles, having hard ticks as vectors and white-footed mice and white-tailed deer as reservoir hosts [11Chan K, Marras SA, Parveen N. Sensitive multiplex PCR assay to differentiate Lyme spirochetes and emerging pathogens Anaplasma phagocytophilum and Babesia microti. BMC Microbiol 2013; 13: 295.
[http://dx.doi.org/10.1186/1471-2180-13-295] [PMID: 24359556]
].

Since Bb, Anaplasma phagocitophilum and Babesia may be co-transmitted by Ixodes ticks bite, the clinical features of acute and chronic disease can be atypical, complex and variable [10Krause PJ, McKay K, Thompson CA, et al. Deer-Associated Infection Study Group. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34(9): 1184-91.
[http://dx.doi.org/10.1086/339813] [PMID: 11941544]
].

In an original study, Krause et al.[10Krause PJ, McKay K, Thompson CA, et al. Deer-Associated Infection Study Group. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34(9): 1184-91.
[http://dx.doi.org/10.1086/339813] [PMID: 11941544]
] analysed clinical and laboratory features as well as short-term complications in 192 people living in New England who experienced infections due to Bb and or Babesia and Ehrlichia. The Authors found that erythema migrans is very peculiar of LD alone, whereas flu-like symptoms are more suggestive of LD concurrent with babesiosis and/or HGA. However, LD itself in small percentage (about 10%) can present with fever, chills and headache. Such an epidemiologic report is confirmed also in Europe: in an Italian study conducted on more than 700 people living in an endemic area for LD, flu-like symptoms as fever, myalgia and headache preceded, accompanied or were the only clinical sign of LD in 16.88% of patients [35Stinco G, Ruscio M, Bergamo S, Trotter D, Patrone P. Clinical features of 705 Borrelia burgdorferi seropositive patients in an endemic area of northern Italy. ScientificWorldJournal 2014; 2014: 414505.].

From the study by Krause et al, it seems that patients having only LD experienced a fewer number of symptoms and a shorter time of illness compared to those with babesiosis, HGA or co-infection between LD and babesiosis or HGA. The Authors suggest performing serological laboratory tests for Babesia and Ehrlichia in suspected LD patients having prolonged flu-like symptoms and poorly responding to an appropriate antiborrelial therapy.

In contrast with other reports [33Bonoan JT, Johnson DH, Cunha BA. Life-threatening babesiosis in an asplenic patient treated with exchange transfusion, azithromycin, and atovaquone. Heart Lung 1998; 27(6): 424-8.
[http://dx.doi.org/10.1016/S0147-9563(98)90089-9] [PMID: 9835673]
, 36Marcus LC, Steere AC, Duray PH, Anderson AE, Mahoney EB. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium. Ann Intern Med 1985; 103(3): 374-6.
[http://dx.doi.org/10.7326/0003-4819-103-3-374] [PMID: 4040723]
, 37Zeidner NS, Dolan MC, Massung R, Piesman J, Fish D. Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis suppresses IL-2 and IFN gamma production and promotes an IL-4 response in C3H/HeJ mice. Parasite Immunol 2000; 22(11): 581-8.
[http://dx.doi.org/10.1046/j.1365-3024.2000.00339.x] [PMID: 11116438]
], Krause et al. found that the presence of a co-infection does not help Bb to spread more rapidly into blood, skin, joint, nervous system and heart [10Krause PJ, McKay K, Thompson CA, et al. Deer-Associated Infection Study Group. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34(9): 1184-91.
[http://dx.doi.org/10.1086/339813] [PMID: 11941544]
].

BARTONELLA SPECIES

Bartonella species are vector-transmitted, blood-borne, intracellular, gram-negative bacteria that can induce prolonged infection in the host. Persistent infections in domestic and wild animals result in a substantial reservoir of Bartonella organisms in nature that can serve as a source for inadvertent human infection. A wide spectrum of disease has been described in immunocompetent individuals, including bacillary angiomatosis, peliosis hepatitis, lymphadenitis, and aseptic meningitis with bacteremia and cat-scratch disease [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 38Bass JW, Vincent JM, Person DA. The expanding spectrum of Bartonella infections: II. Cat-scratch disease. Pediatr Infect Dis J 1997; 16(2): 163-79.
[http://dx.doi.org/10.1097/00006454-199702000-00002] [PMID: 9041596]
]. Human bartonellosis main features are represented by infected skin lesions and lymphadenopathy. It can be a multisystemic disease with involvement of spleen, liver, central nervous system and eye [39Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am 1998; 12(1): 137-55.
[http://dx.doi.org/10.1016/S0891-5520(05)70414-1] [PMID: 9494835]
].

Even if Bartonella henselae has been found in Ixodes ticks in USA, Europe and Russia, there are no proven data in Literature for a tick-born transission of human bartonellosis [40Holden K, Boothby JT, Kasten RW, Chomel BB. Co-detection of Bartonella henselae, Borrelia burgdorferi, and Anaplasma phagocytophilum in Ixodes pacificus ticks from California, USA. Vector Borne Zoonotic Dis 2006; 6(1): 99-102.
[http://dx.doi.org/10.1089/vbz.2006.6.99] [PMID: 16584332]
-42Morozova OV, Cabello FC, Dobrotvorsky AK. Semi-nested PCR detection of Bartonella henselae in Ixodes persulcatus ticks from Western Siberia, Russia. Vector Borne Zoonotic Dis 2004; 4(4): 306-9.
[http://dx.doi.org/10.1089/vbz.2004.4.306] [PMID: 15671737]
].

Bartonella infection can be detected by serologic findings (controversial), PCR amplification (either in blood or in tissue) and culture (difficult) [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
, 43Jensen WA, Fall MZ, Rooney J, Kordick DL, Breitschwerdt EB. Rapid identification and differentiation of Bartonella species using a single-step PCR assay. J Clin Microbiol 2000; 38(5): 1717-22.
[PMID: 10790087]
].

The main treatment suggested is azithromycin 500 mg single dose orally on day one, followed by 250 mg every 6 hours for 4 days [44Centers for Disease Control and Prevention (CDC)-Bartonella Infection. Available from: http://www.cdc.gov/bartonella/clinicians /index.html ].

RICKETTSIA SPECIES

Ixodes tick bites might transmit Rickettsia species as well. Some Rickettsia species are known to cause human diseases, whereas some others are not fully identified as pathogen to humans [45Tijsse-Klasen E, Sprong H, Pandak N. Co-infection of Borrelia burgdorferi sensu lato and Rickettsia species in ticks and in an erythema migrans patient. Parasit Vectors 2013; 6: 347.
[http://dx.doi.org/10.1186/1756-3305-6-347] [PMID: 24326096]
].

Usually the co-infection between Borrelia and Rickettsia does not represent a diagnostic challenge because the acute Rickettsia infection is dominated by a typical generalized exanthema, high fever, abdominal symptoms, prostration and potentially central nervous system impairment.

The main-stray treatment for Rickettsiosis is doxycycline [4Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
].

TICK-BORNE ENCEPHALITIS (TBE)

In endemic areas, TBE and LD are equally transmitted by Ixodes ticks. TBE and neuroborreliosis share common clinical features such as lymphocytic meningitis, meningomyelitis, limb weakness, cranial nerve impairment [46Logina I, Krumina A, Karelis G, et al. Clinical features of double infection with tick-borne encephalitis and Lyme borreliosis transmitted by tick bite. J Neurol Neurosurg Psychiatry 2006; 77(12): 1350-3.
[http://dx.doi.org/10.1136/jnnp.2004.060731] [PMID: 16754695]
]. Differentiating between TBE and LD is important because of the different therapeutic approaches.

TBE is a febrile illness, which develops within 1 month after a tick bite and has typically a biphasic course: a flu-like symptoms prodromic period ranging from 1 to 2 weeks after the tick bite is followed by a 2 to 10 day asymptomatic period. After that, about one out of three patients experience the second phase of the disease with aseptic meningitis. Some of them later will develop a post-encephalitis syndrome [47Dumpis U, Crook D, Oksi J. Tick-borne encephalitis. Clin Infect Dis 1999; 28(4): 882-90.
[http://dx.doi.org/10.1086/515195] [PMID: 10825054]
, 48Randolph SE. The shifting landscape of tick-borne zoonoses: tick-borne encephalitis and Lyme borreliosis in Europe. Philos Trans R Soc Lond B Biol Sci 2001; 356(1411): 1045-56.
[http://dx.doi.org/10.1098/rstb.2001.0893] [PMID: 11516382]
]. In a paper by Logina et al, the Authors focused on common clinical features shared by LD and TBE, suggesting that physician should have a low-threshold for prescribing antibiotics against LD in patients with TBE [44Centers for Disease Control and Prevention (CDC)-Bartonella Infection. Available from: http://www.cdc.gov/bartonella/clinicians /index.html ].

Infection by TBE virus can be detected by specific antibody titre in cerebrospinal fluid (ELISA). Serology in this case is found to be sensitive and specific for the diagnosis [49Hunfeld KP, Oschmann P, Kaiser R, et al. Diagnostics. In: Oschmann P, Kraiczy P, Halperin J, Brade V, Eds. Lyme borreliosis and tick-borne encephalitis. Bremen: UNI-MED Verlag AG 1999; pp. 80-111.].

Any specific antiviral therapy for TBE is not available yet. In endemic areas, vaccination against TBE virus is accessible and strongly recommended.

CONCLUSION

In recent years co-infections in LD spectrum represent an emerging issue, even if they are less frequent compared to the report of micro-organisms found in ticks. Such a problem is more evident in endemic places with significant differences among different geographic areas, according to natural habitat which may foster the vital cycle of pathogen. Humans, as occasional hosts, may be infected, though concomitant infections with more than two organisms are rarely reported.

Only a single paper describing four co-infecting pathogens detected in forestry workers in an endemic area can be found in Literature [50Chmielewska-Badora J, Moniuszko A, Żukiewicz-Sobczak W, Zwoliński J, Piątek J, Pancewicz S. Serological survey in persons occupationally exposed to tick-borne pathogens in cases of co-infections with Borrelia burgdorferi, Anaplasma phagocytophilum, Bartonella spp. and Babesia microti. Ann Agric Environ Med 2012; 19(2): 271-4.
[PMID: 22742800]
]. The actual role of these infections in asymptomatic people is not unravelled yet, as well as the possible effect on clinical history of disease; also the therapeutical approach in such cases is not well defined.

LD is a highly complex condition and still partially controversial as regards late and chronic phases. Possible explanations to clinical features of such phases have been searched in co-infections in LD, even if studies on adequate records did not support this hypothesis. In a convincing review Lantos and colleagues’ main purpose was to answer several questions about the relevance of co-infections in chronic LD; they found that Literature does not sustain the diagnosis of chronic and atypical co-infections in patients with chronic unspecific LD [7Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
].

On the other hand, more and more reports of single clinical cases or case series point out the role of co-infections as worsening or trigger factor in late LD picture. Recently a correlation between cutaneous B-cell lymphomas and Bb has been supposed [51Takino H, Li C, Hu S, et al. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States. Mod Pathol 2008; 21(12): 1517-26.
[http://dx.doi.org/10.1038/modpathol.2008.159] [PMID: 18820662]
-53Bonin S, Stinco G, Patriarca MM, Trevisini S, di Meo N, Trevisan G. Could co-infection with Anaplasma play a role in Borrelia-associated primary cutaneous marginal zone B-cell lymphomas? Indian J Dermatol Venereol Leprol 2016; 82(1): 81-4.
[PMID: 26658390]
]. In our experience, in primitive cutaneous B-cell lymphomas we found that in 100% of cases the presence of Bb and Anaplasma phagocytophilum could be detected by means of PCR (unpublished data).

In front of such controversies, in endemic areas for tick-borne diseases, it is sensible that co-infections are searched and noticed especially in potentially exposed people (either for working or for travelling reasons). Prospective studies on wide records are needed to prove the actual burden of this issue.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGeMENTS

Declared none.

REFERENCES

[1] Scarpa C, Trevisan G, Stinco G. Lyme borreliosis. Dermatol Clin 1994; 12(4): 669-85.
[PMID: 7805296]
[2] Shapiro ED. Clinical practice. Lyme disease. N Engl J Med 2014; 370(18): 1724-31.
[http://dx.doi.org/10.1056/NEJMcp1314325] [PMID: 24785207]
[3] Swanson SJ, Neitzel D, Reed KD, Belongia EA. Coinfections acquired from ixodes ticks. Clin Microbiol Rev 2006; 19(4): 708-27.
[http://dx.doi.org/10.1128/CMR.00011-06] [PMID: 17041141]
[4] Berghoff W. Chronic lyme disease and co-infections: differential diagnosis. Open Neurol J 2012; 6: 158-78.
[http://dx.doi.org/10.2174/1874205X01206010158] [PMID: 23400696]
[5] Franke J, Hildebrandt A, Dorn W. Exploring gaps in our knowledge on Lyme borreliosis spirochaetes--updates on complex heterogeneity, ecology, and pathogenicity. Ticks Tick Borne Dis 2013; 4(1-2): 11-25.
[http://dx.doi.org/10.1016/j.ttbdis.2012.06.007] [PMID: 23246041]
[6] Reis C, Cote M, Paul RE, Bonnet S. Questing ticks in suburban forest are infected by at least six tick-borne pathogens. Vector Borne Zoonotic Dis 2011; 11(7): 907-16.
[http://dx.doi.org/10.1089/vbz.2010.0103] [PMID: 21158500]
[7] Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review. Am J Med 2014; 127(11): 1105-10.
[http://dx.doi.org/10.1016/j.amjmed.2014.05.036] [PMID: 24929022]
[8] Heyman P, Cochez C, Hofhuis A, et al. A clear and present danger: tick-borne diseases in Europe. Expert Rev Anti Infect Ther 2010; 8(1): 33-50.
[http://dx.doi.org/10.1586/eri.09.118] [PMID: 20014900]
[9] Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. JAMA 1996; 275(21): 1657-60.
[http://dx.doi.org/10.1001/jama.1996.03530450047031] [PMID: 8637139]
[10] Krause PJ, McKay K, Thompson CA, et al. Deer-Associated Infection Study Group. Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 2002; 34(9): 1184-91.
[http://dx.doi.org/10.1086/339813] [PMID: 11941544]
[11] Chan K, Marras SA, Parveen N. Sensitive multiplex PCR assay to differentiate Lyme spirochetes and emerging pathogens Anaplasma phagocytophilum and Babesia microti. BMC Microbiol 2013; 13: 295.
[http://dx.doi.org/10.1186/1471-2180-13-295] [PMID: 24359556]
[12] Belongia EA. Epidemiology and impact of coinfections acquired from Ixodes ticks. Vector Borne Zoonotic Dis 2002; 2(4): 265-73.
[http://dx.doi.org/10.1089/153036602321653851] [PMID: 12804168]
[13] Aguero-Rosenfeld ME, Donnarumma L, Zentmaier L, et al. Seroprevalence of antibodies that react with Anaplasma phagocytophila, the agent of human granulocytic ehrlichiosis, in different populations in Westchester County, New York. J Clin Microbiol 2002; 40(7): 2612-5.
[http://dx.doi.org/10.1128/JCM.40.7.2612-2615.2002] [PMID: 12089287]
[14] Bakken LL. Role of experience and context in learning to diagnose Lyme disease. J Contin Educ Health Prof 2002; 22(3): 131-41.
[http://dx.doi.org/10.1002/chp.1340220302] [PMID: 12227235]
[15] Horowitz HW, Aguero-Rosenfeld ME, Holmgren D, et al. Lyme disease and human granulocytic anaplasmosis coinfection: impact of case definition on coinfection rates and illness severity. Clin Infect Dis 2013; 56(1): 93-9.
[http://dx.doi.org/10.1093/cid/cis852] [PMID: 23042964]
[16] Chen SM, Dumler JS, Bakken JS, Walker DH. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 1994; 32(3): 589-95.
[PMID: 8195363]
[17] Belongia EA, Reed KD, Mitchell PD, et al. Clinical and epidemiological features of early Lyme disease and human granulocytic ehrlichiosis in Wisconsin. Clin Infect Dis 1999; 29(6): 1472-7.
[http://dx.doi.org/10.1086/313532] [PMID: 10585798]
[18] Steere AC, McHugh G, Suarez C, Hoitt J, Damle N, Sikand VK. Prospective study of coinfection in patients with erythema migrans. Clin Infect Dis 2003; 36(8): 1078-81.
[http://dx.doi.org/10.1086/368187] [PMID: 12684924]
[19] Strle F, Bogovič P, Cimperman J, et al. Are patients with erythema migrans who have leukopenia and/or thrombocytopenia coinfected with Anaplasma phagocytophilum or tick-borne encephalitis virus? PLoS One 2014; 9(7): e103188.
[http://dx.doi.org/10.1371/journal.pone.0103188] [PMID: 25057802]
[20] Moniuszko A, Dunaj J, Swięcicka I, et al. Co-infections with Borrelia species, Anaplasma phagocytophilum and Babesia spp. in patients with tick-borne encephalitis. Eur J Clin Microbiol Infect Dis 2014; 33(10): 1835-41.
[http://dx.doi.org/10.1007/s10096-014-2134-7] [PMID: 24848130]
[21] Grab DJ, Nyarko E, Barat NC, Nikolskaia OV, Dumler JS. Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cells. Clin Vaccine Immunol 2007; 14(11): 1420-4.
[http://dx.doi.org/10.1128/CVI.00308-07] [PMID: 17898182]
[22] Rikihisa Y. Anaplasma phagocytophilum and Ehrlichia chaffeensis: subversive manipulators of host cells. Nat Rev Microbiol 2010; 8(5): 328-39.
[http://dx.doi.org/10.1038/nrmicro2318] [PMID: 20372158]
[23] Nadelman RB, Horowitz HW, Hsieh TC, et al. Simultaneous human granulocytic ehrlichiosis and Lyme borreliosis. N Engl J Med 1997; 337(1): 27-30.
[http://dx.doi.org/10.1056/NEJM199707033370105] [PMID: 9203428]
[24] Horowitz HW, Hsieh TC, Aguero-Rosenfeld ME, et al. Antimicrobial susceptibility of Ehrlichia phagocytophila. Antimicrob Agents Chemother 2001; 45(3): 786-8.
[http://dx.doi.org/10.1128/AAC.45.3.786-788.2001] [PMID: 11181361]
[25] Krause PJ, Corrow CL, Bakken JS. Successful treatment of human granulocytic ehrlichiosis in children using rifampin. Pediatrics 2003; 112(3 Pt 1): e252-3.
[http://dx.doi.org/10.1542/peds.112.3.e252] [PMID: 12949322]
[26] Hildebrandt A, Fritzsch J, Franke J, Sachse S, Dorn W, Straube E. Co-circulation of emerging tick-borne pathogens in Middle Germany. Vector Borne Zoonotic Dis 2011; 11(5): 533-7.
[http://dx.doi.org/10.1089/vbz.2010.0048] [PMID: 20846013]
[27] Vannier E, Gewurz BE, Krause PJ. Human babesiosis. Infect Dis Clin North Am 2008; 22(3): 469-488, viii-ix.
[http://dx.doi.org/10.1016/j.idc.2008.03.010] [PMID: 18755385]
[28] Krause PJ, Ryan R, Telford S III, Persing D, Spielman A. Efficacy of immunoglobulin M serodiagnostic test for rapid diagnosis of acute babesiosis. J Clin Microbiol 1996; 34(8): 2014-6.
[PMID: 8818902]
[29] Krause PJ. Telford SR 3rd, Ryan R. Diagnosis of babesiosis: evaluationof a serologic test for the detection of Babesia microti antibody. J Infect Dis 1994; 169: 923-6.
[http://dx.doi.org/10.1093/infdis/169.4.923] [PMID: 8133112]
[30] Krause PJ, Lepore T, Sikand VK, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000; 343(20): 1454-8.
[http://dx.doi.org/10.1056/NEJM200011163432004] [PMID: 11078770]
[31] Drugs for parasitic infections. Med Lett Drugs Ther 1998; 40(1017): 1-12. [No authors listed]
[PMID: 9442765]
[32] Krause PJ, Gewurz BE, Hill D, et al. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 2008; 46(3): 370-6.
[http://dx.doi.org/10.1086/525852] [PMID: 18181735]
[33] Bonoan JT, Johnson DH, Cunha BA. Life-threatening babesiosis in an asplenic patient treated with exchange transfusion, azithromycin, and atovaquone. Heart Lung 1998; 27(6): 424-8.
[http://dx.doi.org/10.1016/S0147-9563(98)90089-9] [PMID: 9835673]
[34] Hatcher JC, Greenberg PD, Antique J, Jimenez-Lucho VE. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis 2001; 32(8): 1117-25.
[http://dx.doi.org/10.1086/319742] [PMID: 11283800]
[35] Stinco G, Ruscio M, Bergamo S, Trotter D, Patrone P. Clinical features of 705 Borrelia burgdorferi seropositive patients in an endemic area of northern Italy. ScientificWorldJournal 2014; 2014: 414505.
[36] Marcus LC, Steere AC, Duray PH, Anderson AE, Mahoney EB. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium. Ann Intern Med 1985; 103(3): 374-6.
[http://dx.doi.org/10.7326/0003-4819-103-3-374] [PMID: 4040723]
[37] Zeidner NS, Dolan MC, Massung R, Piesman J, Fish D. Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis suppresses IL-2 and IFN gamma production and promotes an IL-4 response in C3H/HeJ mice. Parasite Immunol 2000; 22(11): 581-8.
[http://dx.doi.org/10.1046/j.1365-3024.2000.00339.x] [PMID: 11116438]
[38] Bass JW, Vincent JM, Person DA. The expanding spectrum of Bartonella infections: II. Cat-scratch disease. Pediatr Infect Dis J 1997; 16(2): 163-79.
[http://dx.doi.org/10.1097/00006454-199702000-00002] [PMID: 9041596]
[39] Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am 1998; 12(1): 137-55.
[http://dx.doi.org/10.1016/S0891-5520(05)70414-1] [PMID: 9494835]
[40] Holden K, Boothby JT, Kasten RW, Chomel BB. Co-detection of Bartonella henselae, Borrelia burgdorferi, and Anaplasma phagocytophilum in Ixodes pacificus ticks from California, USA. Vector Borne Zoonotic Dis 2006; 6(1): 99-102.
[http://dx.doi.org/10.1089/vbz.2006.6.99] [PMID: 16584332]
[41] Hercík K, Hásová V, Janecek J, Branny P. Molecular evidence of Bartonella DNA in ixodid ticks in Czechia. Folia Microbiol (Praha) 2007; 52(5): 503-9.
[http://dx.doi.org/10.1007/BF02932111] [PMID: 18298048]
[42] Morozova OV, Cabello FC, Dobrotvorsky AK. Semi-nested PCR detection of Bartonella henselae in Ixodes persulcatus ticks from Western Siberia, Russia. Vector Borne Zoonotic Dis 2004; 4(4): 306-9.
[http://dx.doi.org/10.1089/vbz.2004.4.306] [PMID: 15671737]
[43] Jensen WA, Fall MZ, Rooney J, Kordick DL, Breitschwerdt EB. Rapid identification and differentiation of Bartonella species using a single-step PCR assay. J Clin Microbiol 2000; 38(5): 1717-22.
[PMID: 10790087]
[44] Centers for Disease Control and Prevention (CDC)-Bartonella Infection. Available from: http://www.cdc.gov/bartonella/clinicians /index.html
[45] Tijsse-Klasen E, Sprong H, Pandak N. Co-infection of Borrelia burgdorferi sensu lato and Rickettsia species in ticks and in an erythema migrans patient. Parasit Vectors 2013; 6: 347.
[http://dx.doi.org/10.1186/1756-3305-6-347] [PMID: 24326096]
[46] Logina I, Krumina A, Karelis G, et al. Clinical features of double infection with tick-borne encephalitis and Lyme borreliosis transmitted by tick bite. J Neurol Neurosurg Psychiatry 2006; 77(12): 1350-3.
[http://dx.doi.org/10.1136/jnnp.2004.060731] [PMID: 16754695]
[47] Dumpis U, Crook D, Oksi J. Tick-borne encephalitis. Clin Infect Dis 1999; 28(4): 882-90.
[http://dx.doi.org/10.1086/515195] [PMID: 10825054]
[48] Randolph SE. The shifting landscape of tick-borne zoonoses: tick-borne encephalitis and Lyme borreliosis in Europe. Philos Trans R Soc Lond B Biol Sci 2001; 356(1411): 1045-56.
[http://dx.doi.org/10.1098/rstb.2001.0893] [PMID: 11516382]
[49] Hunfeld KP, Oschmann P, Kaiser R, et al. Diagnostics. In: Oschmann P, Kraiczy P, Halperin J, Brade V, Eds. Lyme borreliosis and tick-borne encephalitis. Bremen: UNI-MED Verlag AG 1999; pp. 80-111.
[50] Chmielewska-Badora J, Moniuszko A, Żukiewicz-Sobczak W, Zwoliński J, Piątek J, Pancewicz S. Serological survey in persons occupationally exposed to tick-borne pathogens in cases of co-infections with Borrelia burgdorferi, Anaplasma phagocytophilum, Bartonella spp. and Babesia microti. Ann Agric Environ Med 2012; 19(2): 271-4.
[PMID: 22742800]
[51] Takino H, Li C, Hu S, et al. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States. Mod Pathol 2008; 21(12): 1517-26.
[http://dx.doi.org/10.1038/modpathol.2008.159] [PMID: 18820662]
[52] Gatti A, Stinco G, Trevisini S, et al. Electrochemotherapy as a novel treatment for primary cutaneous marginal zone B-cell lymphomas. Dermatol Ther (Heidelb) 2014; 27(4): 244-7.
[http://dx.doi.org/10.1111/dth.12128] [PMID: 24754311]
[53] Bonin S, Stinco G, Patriarca MM, Trevisini S, di Meo N, Trevisan G. Could co-infection with Anaplasma play a role in Borrelia-associated primary cutaneous marginal zone B-cell lymphomas? Indian J Dermatol Venereol Leprol 2016; 82(1): 81-4.
[PMID: 26658390]

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open