The Leptospirosis Information Center

Persistent human leptospirosis - professional guide

A great number of the email queries received by the LIC concern the symptoms of persistent human leptospirosis (PHL) - the condition is more common than generally accepted and we are receiving reports each year of new manifestations.

When the acute phase of infection has run its course, patients continue to report physical and psychological symptoms in at least 20% of all infections. These long-term effects can run for several years and are often not correctly identified and treated by medical professionals. Indeed, if the acute phase has been missed, physicians can encounter the patient within the PHL phase and correct diagnosis is bordering on the miraculous. In general the timescale is around two to six years, with a gradual improvement over that time but in a non-linear form. Some patients report almost permanent symptoms but these are often caused by sequelae from the acute infection, combined with age-related effects.

Care should be taken to differentiate between PHL as detailed here, which is a long-term but essentially transient condition, and persistent carrier-phase leptospirosis where the subject has little or no symptoms but remains infected with the bacterium and in some cases remains infectious. Carrier-phase infection is almost unheard of in humans though is prevalent in many animals. PHL, in contrast, is possible in all species.

Rate of occurrence

It is generally thought that around 10% of patients report symptoms of PHL [ref 1], however very little research has been performed on PHL in humans and reporting is known to be a tiny fraction of true incidence, so we believe that the true figures are around 30% to 40%. Often, patients and their physicians fail to associate the symptomology with PHL and thus cases are not reported to the research community. We stongly believe that a protocol of medium-term supervisory management should be standard for confirmed cases of acute leptospirosis with a view to identifying the instances of PHL. At present attending physicians do not in general keep in contact with past cases so the prevalence data is based on proactive patient requests for help.

PHL: Symptoms

Reports from patients and published studies show a defined trend in symptoms following infection:-

• HEADACHES: Patients report recurrent headaches, sometimes with nausea, akin to migraine.
• EYE PAIN: A significant number of patients report pain in the eyes and the upper sinuses. There are limited reports of visual disturbances associated with this aspect.
• UVEITIS: Several recent reports show that a characteristic form of uveitis can be found in post-acute leptospiral patients.[ref 5]
• FATIGUE: In almost all cases patients report chronic fatigue, often relapsing. For many years after infection patients report periods where acute fatigue confines them to bed for a few days. Many state that their general levels of energy are significantly lower than pre-infection, leading to difficulties with work, sports and suchlike.
• DEPRESSION: Significant numbers report depression as a psychological effect, again recurrent and fluctuating in intensity over several years. Patients often report feeling generally 'unwell' and are depressed and angry at their inability to 'shake off' the symptoms.
• PSYCHOLOGICAL CHANGES: Patients and their families often report changes in psychological character, mood swings, shortness of temper and alterations in the relationships with others.
• PARAINFECTIOUS ENCEPHALOMYELITIS: This has been reported with significant frequency in patients with a history of acute leptospiral infection.[ref 2]
• OCD: It may be the case in selected patients that via a process analogous to Sydenham's chorea, infections with certain bacteria (reported [ref 3] for group A beta-hemolytic streptococci, among others), may trigger autoimmune responses that cause or exacerbate some cases of childhood-onset obsessive-compulsive disorder (OCD) or tic disorders (including Tourette's syndrome). This is the early stages of a hypothesis and should not be taken as a clinical opinion. The reference given does not specifically isolate leptospira. A very small number of patient reports suggests a possible link though this is unvalidated.

PHL: Proposed causes

There is no single reason for this continuation of symptoms - some of the effects are sequelae (lasting damage to the body that takes time to heal) left after the bacteria have been removed, though some are not. The accepted view of the research community is that PHL is the result of bacterial residency in immunoligically privileged (IP) sites [these are areas of body tissue where, due to design, the immune system is not as active as elsewhere]. In these sites, bacteria can form strongholds where they are effectively trapped, though able to cause some health effects. Areas include the brain, spinal cord and the ocular fluids [ref 5], plus renal tubules. The sypmtomology of PHL as reported coincides well with these locations. The physical presence of the bacteria can lead to some pathogenic responses, the result of limited immune system reaction, but there are also issues of intracellular toxicity caused by compounds released from the bacteria. These toxin-related effects can explain why systemic pathogeneses can be observed from what should be a highly localised colony of bacteria.

Isolating leptospira from IP sites in humans is rare, simply because testing is uncommon. An important study in India isolated leptospira from the eyes of living patients [ref 5] and in veterinary science, where PHL is also commonly found, there have been clinical reports confirming residency. For example active leptospira have been isolated from vitreous samples taken from the eyes of horses with chronic uveitis [ref 4]. It is likely that CSF taps from patients with PHL will test positive, especially when using sensitive modern testing equipment such as PCR.

PHL: Diagnosis

Definitive diagnosis of PHL requires isolation of active leptospira from serological samples. Due to the diffuse nature of the symptoms this can be the only reliable clinical diagnosis - the issue arises as to obtaining such samples, and certainly in most cases a blood or urine test will be negative (although is likely to show a positive antibody reaction for a year or two following the acute infection, which will prove the patient was infected at some point in the past). Drawing samples from IP sites is clinically complex and unpleasant for the patient, and may not always give a positive result even when taken with care, as the bacterial colonies in question are small. however if the patient presents with PHL-based uveitis then there is a possible subdefinitive diagnosis based on the characteristics of the uveitis [ref 5]. Leptospiral uveitis is statisically more likely to present with six factors:

1. Anterior chamber cells
2. Vitreous opacities
3. Papillitis
4. Vasculitis
5. Panuveitis (bilateral or unilateral)
6. Lack of visual deficit

Where the patient reports psychological changes, headaches, lethargy, fatigue and other non-localised symptoms, diagnosis can be almost impossible unless the acute infection was noted in the past, and a diagnostic timescale of symptoms can be constructed. It may not be helpful to the patient, but one of the obvious differentials of PHL is that it fails to respond to the sort of treatments the symptoms should be expected to!

Treatment

Treatment of PHL is still an unexplored area - the LIC has been working in this field for several years and has been collecting data from patients and medical staff across the world, but no agreed effective protocol has been found. In general the protocol is for a repeat course (or more) of antibiotic therapy. Several points should be made about treatment of associated pathologies - often patients reporting PHL are treated for the symptoms in isolation and in some cases the standard treatment can interfere with therapy for PHL itself. Also, the general health of the patient has an impact, so diet and nutrition are important. Patients who suffer from fatigue will often find that rest helps, so the "get up and fight it off" approach can be unhelpful in the least. The main issue in treating PHL is recognising that it is present when the patient has no idea that that were infected to begin with (PHL is equally common in patients with subclinical infections, and seems to be unaffected by the treatment regime used at the time or lack of it). There is an undercurrent of ignorance about the long-term effects of leptospirosis amongst non-specialist medical staff and so often the patient must often prompt the attending doctors into a diagnosis. Patients having a history of leptospirosis should not hesitate to suggest PHL to their doctors, but may find blank looks facing back at them.

Adrenal cortex hormones (ACH)

There is relatively little published work on the use of ACH during treatment though what is available is not encouraging. Rodent studies showed that combining ACH and antibiotic therapy (using penicillin) in the acute treatment of infection can have negative effects - the ACH seemingly has no effect at all and can even reduce the potency of the antibiotic leading to decreased patient outcomes.
One human case reported was a gravely ill patient with leptospirosis and severe hypoxaemia. There was diffuse alveolar haemorrhage and myositis thus a bolus of corticosteroids was used over the first 24 hours complementary to the traditional treatment. Outcome was good though the paper does not indicate the effect ACH therapy may have had on the antibiotic agents and there was only one patient so no comparisons can be drawn.
ACH therapy for chronic infection is a difficult area to draw conclusions on - for a patient with a significant leptospiral residency who is still receiving antibiotic therapy the addition of ACH could reduce the existing treatment effectiveness as described above. For patients suffering from post-infection pathologies there is an argument for ACH treatment. As an example, some patients can develop parainfectious encephalomyelitis after an infection of leptospira. In one reported case the progressive course of this condition was reversed rapidly with eventual full recovery after corticosteroid therapy. In cases such as this the leptospiral cause of the condition can need to be ignored when treating the pathologies.

PHL: Prognosis

In general two conclusions can be drawn, based on patient data alone:

1. RESIDENCY of leptospires presents no direct risk to life during PHL that can be clinically identified. The recurrence of full-stage infection is possible in the very long term if the antibody levels in the blood diminish, however the mere presence of the bacteria in IP sites does not directly compromise body systems in a signifiacnt way. The by-products of PHL can manifest as clinical symptoms in IP sites though as yet the presentations are of chronic but non-critical pathologies. Quality of life can be significantly diminished, but the patient is not at risk from deterioration or death.
2. SEQUELAE resulting from acute infection may present a wide range of long term risks and depend on the precise course of the initial infection. These sequelae are clinically isolated from the initial cause and can be treated using normal methods, should they be available.

In summary, patients suffering acute leptosiral infection should be monitored medically for a period of up to five years post-recovery by a local medical practitioner with a view to identifying symptoms of PHL and offering clinical support for associated pathologies. Treatment is not simple, but often the patient is most in need of information and advice as to why they feel like they do, and will accept that the condition has to run its course provided they have access to advice and support.

1. Zentralbl Bakteriol Mikrobiol Hyg [A] 1984 Sep;257(4):531-4
   May human leptospirosis develop as a chronic infection?
   Nicolescu M, Andreescu N
2. Neurology 1980 May;30(5):481-6
   Steroid-responsive encephalomyelitis in childhood.
   Pasternak JF, De Vivo DC, Prensky AL.
3. J Am Acad Child Adolesc Psychiatry 1995 Mar;34(3):307-11
   Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome.
   Allen AJ, Leonard HL, Swedo SE
   Section on Behavioral Pediatrics, NIMH, Bethesda, MD 20892-1600.
4. Berl Munch Tierarztl Wochenschr 1998 Nov-Dec;111(11-12):415-7
   [Demonstration of intraocular leptospira in 4 horses suffering from equine recurrent uveitis].
   [Article in German]
   Brem S, Gerhards H, Wollanke B, Meyer P, Kopp H
   Landesuntersuchungsamt fur das Gesundheitswesen Sudbayern, Oberschleissheim.
5. J. Infect. Diseases 1998;177:1314-21
   Identification of Leptospira species in the pathogenesis of uveitis and determination of clinical ocular characteristics in south India
   Chu KM, Rathinam R, Namperumalsamy P & Dean D.

See also

Prognoses for human leptospirosis - professional guide