Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2014.00074
Lyme and associated tick-borne diseases: global challenges in the context of a public health threat. Running title: Global challenges of Lyme disease
1Infectious diseases, Hôpitaux Universitaires Paris - Ile de France -Ouest, Assistance Publique - Hôpitaux de Paris, France
Lyme disease, caused by Borrelia burgdorferi and transmitted by ticks, was initially considered a recent, rare and regional occurrence. We now have evidence that very similar bacteria infected humans in Europe during the ice age (1). Evidence-based data are scarce therefore many aspects of the disease remain controversial (2,3,4), but in 2013 the Centers for Disease Control and Prevention (CDC) revised their annual estimates from 30,000 cases to 300,000 cases in the USA alone. Having dramatically increased their numbers, the CDC are now calling Lyme disease “a tremendous public health problem in the United States” (5). The lack of a gold standard for diagnosis makes producing accurate statistics difficult. Some pathogenic strains belonging to the B. burgdorferi sensu lato complex have a worldwide distribution, yet they are rarely considered or tested for (6,7,8,9,10,11,12,13). Borrelia miyamotoi, for instance, phylogenetically close to relapsing fever borreliae, is now recognized as a cause of Lyme-like disease and relapsing fever in Asia, Europe and North America. It usually does not cross react with B. burgdorferi tests (12,13). A novel isolate of Borrelia has been isolated by PCR in a post-treatment serum from a patient with neurologic Lyme disease (13). These recent historical, geographical and microbial data should prompt the medical community to realize that cases of persisting post tick-bite syndromes are probably due to multiple pathogens and that these occult infections will require a new approach if not an actual paradigm shift. Diagnostic pitfalls in routine practice Classical forms of Lyme disease are usually easy to manage, but these medical conditions with pleomorphic non specific symptoms may prove confusing to physicians (14). Lyme disease may mimic chronic inflammatory or degenerative diseases, including a wide range of auto-immune diseases. Although practitioners from every medical specialty are likely to have encountered cases of Lyme disease, they may have failed to recognize it, no matter how skilled they are.
A major obstacle is that only 30% of the patients report a history of tick bite and only 70 to 80% present with a primary erythema migrans, the pathognomonic initial lesion. This lesion may go unrecognized, or be mistaken for an “insect bite” or an “allergic rash”. Mini-erythema migrans are less likely to be diagnosed. Secondary erythema migrans are observed in approximately 50% of cases. Bacteriologic and pathologic analogies have been reported between tertiary neuroborreliosis and tertiary neurosyphilis (15). Syphilis, once well-known as the great imitator, gives us a good historical model for the concept of occult infection. Occult infections and their role in the pathophysiology of some diseases of unclear etiology Charles Nicolle, working at the Institut Pasteur in Tunis and Nobel prize winner in 1928, showed great interest in the concept of occult infections (“les infections inapparentes”) like typhus, syphilis and relapsing fever (Borrelia recurrentis) (16). Relapsing fever due to another species of Borrelia (B. crocidurae) is still a public health concern in some parts of Africa, and the recently discovered B. miyamotoi may also become a similar problem in Asia, Europe and America (12,13,17). Peptic ulcer disease is another example of the hidden link between an occult infection with another spiral-shaped bacterium, Helicobacter pylori, and a chronic disorder. B. burgdorferi may persist in tissues even after antibiotic treatments, as animal models have shown (18,19,20,21,22,23). In fact dormant persister cells of bacteria from different genera can escape the bactericidal effect of antibiotics and be responsible for latent infections (13,24,25,26). Clinicians have no diagnostic tests to check for the persistence of live borreliae. B. burgdorferi, having a complex genetic structure, is a highly adaptable organism capable of evading immune response through different processes. It can survive extracellularly and intracellularly (27,28). The complexity of Lyme disease requires high quality diagnostic methods, yet serology is the only diagnostic tool widely used. Serology, the current main diagnostic method Physicians should be made aware that, in the presence of primary erythema migrans, serology will often be negative therefore diagnosis should be clinical (29). However, many practitioners are still under the misconception that a positive serology is required for early stage diagnosis. For later stages of the disease serology remains the main diagnostic tool. The Infectious Diseases Society of America (IDSA) and the European Concerted Action on Lyme Borreliosis (EUCALB) are recommending a two-tier testing approach, the first step being an ELISA using whole sonicate of the in vitro cultured tick-derived strain B31 of Borrelia burgdorferi (30,31). If positive, confirmation by immunoblot testing IgG and IgM is required. According to these guidelines, immunoblot is not to be performed if the ELISA is negative. However, in 2011, the CDC modified their case definition and included single-tier IgG immunoblot seropositivity as a diagnostic criterion for Lyme disease (32). But most practitioners still use the two-tier system despite the poor sensitivity of ELISA tests, ranging from 34% to 70.5% (33,34,35,36). Calibration of the tests is a crucial issue. Calibration of serology When Lyme serology was developed, no reliable method was available to be used as a gold standard for comparison. As most of the signs and symptoms are non-specific, no reliable clinical diagnostic score could be established. The low yield of culture and the difficulty involved in using the technique routinely were another major obstacle. A pragmatic cut-off level for the serologic tests had to be determined arbitrarily on blood donors (31,37). In the late seventies, when Lyme disease was first discovered, it was understandably thought to be a rare and regional phenomenon. Therefore, a low prevalence was set as experts were afraid the serologies would produce too many false positive diagnoses (31,37). Patients and control populations are ill-defined with a high variability in predictive positive and negative values from one test to another. Culture of B. burgdorferi or detection of its genome by polymerase chain reaction (PCR) may occasionally confirm the clinical diagnosis in seronegative patients, however none of these methods are sensitive enough to be considered reliable diagnostic methods, especially in routine practice (33,37,38,39,40,41,42,43,44,45).
As a result, many patients suffering signs and symptoms compatible with Lyme disease, but whose test is negative, are falling by the wayside. Clinical and epidemiological consequences of negative serology Modern medical practice expects to rely on evidence. Most physicians would not consider diagnosing Lyme disease without serological proof. Yet the failure to diagnose seronegative neuroborreliosis, especially the acute or severe forms, can have dire consequences including chronic neurologic sequelae or even death. A review of the literature shows that a diagnosis of Lyme neuroborreliosis is often difficult to prove (46,47,48,49). The sensitivity of intrathecal antibody index (measuring specific antibodies within the cerebro-spinal fluid) ranges from 55% to 80%. In a Swedish study, antibodies were present in serum of only 23% of children with neuroborreliosis (49). Cognitive tests or SPECT brain imaging may help to provide objective evidence (50,51,52,53). Pragmatic diagnostic criteria including response to empiric antibiotic treatment are used to diagnose neuroborreliosis (46). Should this strategy be recommended in other clinical presentations as well? In fact some clinicians will not hesitate to classify as Lyme disease cases, seronegative patients with a highly compatible clinical picture, provided other diagnoses have been ruled out. In a major clinical trial on Lyme disease, 40% of the enrolled patients were seronegative. These patients had a history of erythema migrans, neurologic or cardiac symptoms, radiculoneuropathy or arthritis (54). Clinicians, often unaware of the difficulties involved in diagnosing Lyme disease, will fall back on “weak” alternative diagnoses (“viral”, “idiopathic”, “auto-immune”, “degenerative”, “inflammatory” or “psychosomatic”) (55). New techniques are needed to accurately assess these patients. This current over-reliance on inaccurate testing procedures not only flaws the diagnosis of individual patients but it also has epidemiological consequences especially as new species and variants continue to be identified on all continents (56,57). Possible causes of seronegativity Several factors leading to seronegativity have been identified in confirmed cases of Lyme disease: (i) the arbitrary cut-off level of tests, (ii) the sequestration of antibodies in immune complexes, (iii) the wide variety of species and subspecies of Borrelia that co-exist in different parts of the world and (iv) coinfections with other pathogens which may be responsible for some or all of the symptoms or which may alter the immune response (38,39,45,58). The complex B. burgdorferi sensu lato includes (Table 1): B. burgdorferi sensu stricto (including genetic diversity), B. afzelii, B. garinii (several serotypes) and additional species isolated in different parts of the world (7,56,59). Some of these species have been isolated in symptomatic patients (6,7,8,9,10,11,12,13). B. spielmanii may cause early skin disease (8). B. bavariensis, B. bisettii, B. valaisiana, B. americana, B. andersonii, B. lonestari and more recently B. kurtenbachii have been isolated from patients with Lyme-like diseases (7,8,9,10,60). The pathogenic role of B. lusitaniae, isolated in a case of vasculitis, remains to be substantiated (7). Despite such diversity in strains, most of the commercially available tests still rely on the original 1982 Massachusetts B31 isolate of B. burgdorferi. No diagnostic tool is available for routine detection of B. miyamotoi (12,13). Coinfections with other microbes add to the complexity of these illnesses (Table 1). Among patients with early Lyme disease in the USA, 2% to 12% were found to also have human granulocytic anaplasmosis, and 2% to 40% babesiosis (30). In Brazil, a Lyme-like syndrome, due to the tick Amblyomma, has been described and mobile non cultivable spirochetes could be visualized in patients’ blood using a dark field microscope (61). A new tick-borne bacterial pathogen, Candidatus Neoehrlichia mikurensis, was reported in Switzerland (62). In recent years other microbial agents, besides protozoans (Babesia sp., Theileria sp.), have been isolated from ticks, such as Bartonella sp. and Chlamydiales (63,64,65,66,67). Whether ticks prove to be competent vectors to transmit these agents to humans has yet to be studied extensively. However, the clinical consequences of such coinfections are being described more and more frequently (68,69,70,71,72,73,74). An illustration of the limits of serology is the Scottish example: the sensitivity of the immunoblot was improved by using local Scottish strains of Borrelia (75,76). In these studies, the authors compared the standard Western blot prepared from the reference strain B31 of B. burgdorferi sensu stricto antigen with a Western blot prepared with a mixed antigen adding two local isolates, E5 (B. afzelii) and G4 (B. burgdorferi sensu stricto), to the reference strain B31. In their first study done on a limited number of sera, of the 15 samples that tested equivocal, 11 (73%) became positive when tested with the mixed antigen. In their second study, done on a higher number of sera, the mixed antigen test was positive for 99 patients versus 85 patients with the reference test. The negative predictive value of the mixed antigen was higher than the reference antigen (96% versus 88%), but the specificity was similar. Conclusion and perspectives The numerous complexities of Lyme disease make it an extremely difficult illness to fully comprehend. It remains a diagnostic challenge even for the best informed of clinicians. The lack of a gold standard for diagnosis renders the management of patients difficult and seriously hinders our ability to produce accurate statistics, especially as very similar syndromes could be due to other species of Borrelia. In some patients suffering from syndromes of unclear origin, following tick bite, other microbial agents could also be playing a role. Lyme disease has now entered the political debate as shown by the amendment (Section 54.1-2963.2) voted in 2013 by the State of Virginia, USA, that compels physicians to inform their patients that the “current laboratory testing for Lyme disease can be problematic”. The fact that politicians are being called upon to rule on these matters should prompt scientists to regain control of the situation. Politicians should instead become aware of the necessity to fund research and facilitate the setting up of independent international working groups. Reliable testing is essential to investigate the many syndromes of unclear origin that may mimic many other medical disorders. Some clinicians and researchers working with “Lyme disease”, have long suspected that other micro-organisms, besides B. burgdorferi probably play an important role in what ails their patients, but progress has been stilted by the focus remaining largely on B. burgdorferi. A tick-associated poly-organic syndrome has been suggested (77). The educated intuition of these clinicians is gradually being validated as research is finding more pathogens for which ticks are competent vectors: viruses, Babesia and Babesia-like organisms, Anaplasma, Bartonella and Bartonella-like organisms and even more recently Chlamydiales (63,64,65,66,67,68,69,70,71,72,73,74). For these complex ill-defined syndromes to be suitably investigated, future research will need to leave behind the Koch-Henle postulate, one microbe-one disease, hence the need for a multidisciplinary paradigm shift so that a broader clinico-biological approach can be taken. Proper fundamental and clinical research is urgently needed as it would be the most cost effective way of ensuring that patients are accurately diagnosed and that the best therapeutic strategies are decided upon (78). Development of new diagnostic methods is badly needed. New PCR methods and new genomic techniques, such as high throughput sequencing, could prove promising in identifying the complex mix of microbial agents that are probably involved (13,79). Next generation sequencing allowed the identification of various bacteria from Ixodes ricinus ticks in Alsace, a region of high incidence of Lyme disease in France: Anaplasma phagocytophilum, Bartonella henselae, B. grahamii, Borrelia afzelii, B. garinii, B. burgdorferi, B. miyamotoi, Candidatus Neoerlichia mikurensis, Ehrlichia canis, Rickettsia canadensis, R. felis and R. helveti
Keywords: Lyme Disease, Borrelia burgdorferi, Borrelia miyamotoi, novel borreliae, diagnosis, coinfections, tick borne disease, occult infection
Citation: Perronne C (2014). Lyme and associated tick-borne diseases: global challenges in the context of a public health threat. Running title: Global challenges of Lyme disease. Front. Cell. Infect. Microbiol. 4:74. doi: 10.3389/fcimb.2014.00074
http://journal.frontiersin.org/Journal/ ... 00074/full
Received: 25 Mar 2014; Accepted: 19 May 2014.
Edited by: Muriel Vayssier-Taussat, INRA, France
Leona Gilbert, University of Jyväskylä, Finland
Josette Raymond, Université paris descartes, France
Copyright: © 2014 Perronne. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Christian Perronne, Hôpitaux Universitaires Paris - Ile de France -Ouest, Assistance Publique - Hôpitaux de Paris, Infectious diseases, Garches (Paris area), 92380, France, firstname.lastname@example.org
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