Bacterial Infections
Borreliosis / Lyme disease
Background
Borreliosis [bore-El-ee-Oh-sis] (Lyme disease) is caused by a spirochaetal bacterium of the Borrelia species. Borreliae are spiral shaped with a flexible cell wall. They are pleomorphic, which means that they can change their physical form, including to that of a cell-wall deficient form. This aids the bacteria to evade the immune system of their host.
Borreliae
are related to Treponema spirochaetes (the causative agent of syphilis)
but they have far more capabilities. There are hundreds of strains and
sub-types of Borrelia bacteria. Borrelia burgdorferi sensu stricto (Bb.ss.)
is the strain of bacterium which caused an outbreak of infection in Old
Lyme, Connecticut, in the US. This is where Lyme disease acquired its
name from. This particular strain of Borrelia produces predominantly rheumatologic
complications. In the UK and the rest of Europe, other strains exist and
come under the collective term of Borrelia burgdorferi sensu lato (Bb.sl.).
They include B. garinii, B. afzelii, and B. valaisiana. These strains
result in predominately neurological complications. The differing strains
may respond differently to antibiotics.
Signs & Symptoms
The incubation period of Borreliosis is generally from 3-32 days after tick exposure. As with other spirochaetal infections, Borreliosis generally occurs in stages, with remissions and exacerbations, and different clinical manifestations at each stage. The early stages may be asymptomatic but the patient may present later with more systemic manifestations of the illness.
The early stages of disease classically presents with a single, expanding Erythema Migrans (EM or "bull's-eye") rash, which may last for weeks. However, the EM rash may be absent in over 50% of Borreliosis cases.
There can be a significant range of rashes beyond the classic EM, including multiple, flat, raised, or blistering rashes. The rash may vary in colour and lack the central clearing that is associated with the classic "Bull's-eye". Rashes may also resemble other common presentations, including allergic reaction, ringworm and cellulitis. This can result in misdiagnosis.
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Acrodermatitis chronica atrophicans
Acrodermatitis chronica atrophicans (ACA) is another dermatological manifestation of Borreliosis which can take a chronically progressive course and finally leads to a widespread atrophy of the skin. Involvement of the peripheral nervous system (predominantly sensory polyneuropathy) is frequently observed.
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Other symptoms of Borreliosis can be diverse and none of them are unique to the disease, making diagnosis difficult. Early symptoms are generally flu-like, including fever, persistent swollen glands, sore throat and general aches and pains. If left untreated, infection can lead to more serious complications. These affect the nervous system, joints, heart and other tissues. Symptoms can include "viral-like" meningitis, encephalopathy, joint inflammation, facial palsy, peripheral neuropathy and other nerve inflammation which can lead to pain, altered or loss of sensation, and loss of co-ordination. In severe cases paralysis may occur. It is therefore extremely important to initiate treatment in the early stages of infection to avoid permanent tissue damage.
Fewer than 50% of all Borreliosis patients recall a tick bite, and patients do not necessarily need to be involved in rural activities for a bite to occur. City parks and gardens can harbour Borrelia-infected ticks. It is therefore useful to consider early Borreliosis in an evaluation when flu-like symptoms occur during spring, summer and autumn.
Because of its varied symptoms, Borreliosis is known to mimic many conditions and is often overlooked as a differential diagnosis. A proportion of patients that are diagnosed with Borreliosis have previously been misdiagnosed with conditions such as ME/CFS, Fibromyalgia, Viral Meningitis, Parkinson's Disease, Motor Neurone Disease (ALS), Carpal Tunnel Syndrome and Rheumatoid Arthritis. Some patients have been classed as suffering from mental illness and some children have received a diagnosis of ADHD.
Treatment
There is a great deal of controversy regarding the treatment of Borreliosis. Although most doctors would agree that treatment of a Borrelial infection (in its early, localised phase) is clinically successful in most cases, there is far less agreement regarding the treatment of neuroborreliosis and disseminated infection.
Two opposing groups of doctors have released treatment guidelines for Borreliosis and co-infections. One publication of evidence-based guidelines is from the Infectious Disease Society of America (IDSA). These guidelines recommend oral therapy, usually with tetracyclines or amoxicillin, for a period of up to 4 weeks. IV treatment for 2-4 weeks with a broad-spectrum cephalosporin- or penicillin-antibiotic is advised for neuroborreliosis, with the exception of cases of facial palsy or peripheral neuropathy alone. The authors maintain that there is no convincing biological evidence for the existence of symptomatic chronic B. burgdorferi infection amongst patients that have received the recommended treatment. A continuation of symptoms post-treatment is considered to be "Post Lyme Syndrome", which appears to arise via immunologic mechanisms which are triggered by the infection.
These treatment guidelines are available from the 
National
Guideline Clearinghouse.
The other evidence-based guidelines, from the International Lyme and Associated Diseases Society (ILADS), advise differently. They recommend that the duration of therapy should be guided by clinical response. Post-treatment relapses could be the result of persistent infection, or re-infection, and further treatment may be necessary. In cases of persistent infection, the practice of stopping antibiotics to allow for a delayed recovery is not recommended. In such cases, it is reasonable to continue treatment until clinical abnormalities have resolved and all symptoms have disappeared. ILADS supports published studies that report persistent or long-term chronic infection with B. burgdorferi.
These treatment guidelines are available from the National
Guideline Clearinghouse.
Unfortunately, there is a lack of evidence either for or against the use of long-term antibiotic treatment for chronic Borreliosis. Only three double-blind, placebo-controlled clinical trials have been funded in the US, and all had conflicting results. It is clear that much more study needs to be done to determine a definite and successful treatment regime.
The Jarisch-Herxheimer reaction
The Jarisch-Herxheimer reaction (also referred to as a J-H reaction, Jarisch-Herxheimer, or a herx) can occur during the treatment of Borreliosis. It is believed to result from large quantities of endotoxin-like substances (toxic structural components of bacteria) being released into the body as bacteria are lysed (killed) by the antibiotic therapy. It is thought that the release of endotoxins occurs faster than the body can remove them with the natural detoxification process performed by the liver and kidneys.
The J-H reaction is most commonly associated with the treatment of syphilis (another spirochetal infection), and was named after two dermatologists (Adolf Jarisch and Karl Herxheimer) who first observed the reaction in syphilis patients during treatment. The reaction also occurs in the treatment of tick-borne relapsing fever, Q-fever and certain other diseases.
The J-H reaction typically manifests between 1 and 12 hours after the initiation of antibiotic therapy. Symptoms can include fever (generally low grade), chills, headache, myalgias, rigors, hyperventilation, tachycardia, hypertension followed by hypotension (due to vasodilation and declining peripheral resistance), and an exacerbation of cutaneous lesions (which can be mistaken for an alergic reaction to treatment). Careful management (supportive therapy and the use of certain medications such as Diphenhydramine hydrochloride) can help avoid premature cessation of antibiotic treatment.
There is some disagreement regarding the duration of the J-H reaction in the treatment of Borreliosis, with reports varing from a few hours to repeated reactions during the course of treatment.
Testing
The debate between doctors also extends to testing. It is very difficult
to culture Borrelia bacteria directly from patients, therefore tests rely
on indirect methods of detection, e.g. from the patient's immune response
to infection. Current blood testing techniques follow a two-tier protocol
set out by the Centres
for Disease Control and Prevention (CDC) in the US. The first step
is an ELISA which is followed, if positive or equivocal, by a confirmatory
western blot. However, the CDC states explicitly that "This surveillance
case definition was developed for national reporting of Lyme disease;
it is not intended to be used in clinical diagnosis".
Furthermore, a number of studies have revealed that as many as 50% of
Borreliosis cases, confirmed by Borrelial DNA or Borrelial culture, were
reported as negative when tested using the CDC's recommendations. In an
interlaboratory comparison study of tests for the detection of B. Burgdorferi,
by the College of
American Pathologists, it was concluded that "these tests will
not be useful as a screening test until their sensitivities are improved".
It should be noted that a few patients may have infection without the presence of antibodies (seronegative), and this is often because of early antibiotic treatment or other medications, such as steroids. The serodiagnosis of late disease requires good specific clinical histories, and with some patients there may need to be a trial of treatment.
Western blot ( immunoblot), ELISA (Enzyme-Linked ImmunoSorbent Assay) and PCR (polymerase chain reaction) can be performed on blood or cerebrospinal fluid (CSF), which is obtained via a lumbar puncture. However, in addition to the limitations of testing described above, antigen capture in CSF can be extremely elusive; reportedly CSF yields positive results in only 10-30% of patients cultured. Therefore, the diagnosis of neurologic borrelial infection should not be excluded solely on the basis of a negative CSF antibody analysis.
More recent techniques for clinical testing, such as LTT-MELISA (Memory Lymphocyte Immunostimulation Assay), have been developed. Other methods, such as the use of Focus Floating Microscopy (FFM), are under investigation . One study found FFM to be more specific than PCR (96.0% vs 45.2%) and nearly equally specific (99.4% vs 100%). It demonstrates that FFM could potentially be a quick, and inexpensive method to reliably detect Borrelia in cutaneous tissue sections. Other research has indicated that chemokine CXCL13 could also be a possible marker for neuroborreliosis.
As the debate over diagnostic and treatment methods rages on, infected patients may be left without a definitive diagnosis, they may be denied treatment, or be inadequately treated. In many cases, while physicians disagree over a patient's cause of symptoms, need for treatment, or the type and duration of treatment required, the patient remains without an acceptable quality of life.
Transmission
Other than being a tick-borne disease, Borreliosis may be passed from an infected mother to her foetus. It can also be passed through transfusion of infected blood. Borrelia bacteria can survive for up to 48 days at 4 degrees centigrade in human blood processed for transfusion. Animal studies document viable Borrelia in stored semen, in milk, urine, other body fluids and faecal matter. Transmission to offspring through milk has also been documented, as has isolation of Borrelia from aborted or still-born foetuses. Much more study needs to be done to determine other modes of transmission in humans.
Bartonellosis
Background
Bartonellosis [bar-ton-el-lo-sis] is an infection that is caused by bacteria of the Bartonella species. These are faculative intracellular bacteria which are associated with a number of emerging anthropozoonoses. They have been detected in, or isolated from, diverse vertebrate hosts, including humans, various domestic animals, and a wide range of wildlife which serve as natural hosts.
Bartonellosis.
Of the ten Bartonella species that are believed to produce infection in humans, the most commonly encountered are Bartonella henselae, B. quintana, and B. bacilliformis. The latter causes Oroya fever and Verruga peruana. Outbreaks are limited to the Andes and cases elsewhere have been found in travellers. B. quintana is the cause of Trench fever, which is found world-wide and causes febrile outbreaks. Poor sanitation and lack of personal hygiene strongly correlates with transmission by the body louse, Pediculis humanus. B. quintana is emerging as a recognised cause of disease amongst homeless people and AIDS sufferers. B. henselae is the cause of Cat Scratch Disease and is found throughout the world in association with domestic and feral cats. In the UK, B. henselae is considered to be endemic to the cat and dog population. Both the cat flea Ctenocephalides felis and Ixodid ticks are arthropod vectors.
Signs & Symptoms
Bartonella infections can cause varying degrees of illness, from benign lymphadenopathy to life-threatening systemic disease. In cases of B. henselae infections, lymph nodes (especially around the head, neck, and upper limbs) may become inflamed. Fever, headache, and loss of appetite may occur. Rare complications are bacillary angiomatosis and Parinaud's oculoglandular syndrome.
A number of studies demonstrate the roll of B. henselae as a concurrent infection in cases of Borreliosis. In one study, elevated levels of B. henselae-specific antibodies were detected by immuneflorescent assay in a number of patients, and B. henselae-specific DNA was detected in their blood and cerebrospinal fluid. B. henselae-specific DNA was also detected in live ticks obtained from the households of two of these patients.
The incubation of B. henselae is generally 3-12 days. A lesion may appear at the site of inocculation, but this may be difficult to identify in cases of Borreliosis when it could be combined with an Erythema Migrans rash. After 1-3 weeks, lymphadenopathy generally appears and is combined with a low-grade fever. Atypical presentations include encephalopathy, joint inflammation, vision loss and respiratory dysfunction. More acute disease may precede, or occur without, lymphadenopathy.
Testing
An indirect Immunofluorescence Assay (IFA) is the principle test used.
Treatment
Bartonella infections are generally treated with macrolides, tertracyclines, aminoglycosides, or chloramphenicol. The latter is not usually used to treat either B. henselae or B. quintana infections, although it has been used to treat B. bacilliformis.
Duration of therapy is commonly at least three weeks, but longer courses may be required for disseminated disease. Because these infections often fail to respond to therapy, or patients experience relapse later, switching to antibiotics from other classes may be needed.
