Treatment: Medical Professional’s Guidance

These sections are intended for use by medical professionals and are based on the most accurate international medical protocols and information available to us. Use of this information for clinical diagnosis and treatment is subject to our disclaimers of liability. Local protocols and preferred choices of medication may vary, if in doubt consult locally.

  • General Overview
  • Features of Human Infection
  • DIAGNOSIS
  • Treatment
  • Prognosis
  • Prophylaxis

Overview

Human infection by serovars of Leptospira Interrogans can result in a febrile disease with acute and generalised presentations resulting from vasculitis. There are as many different clinical variants as there are serovars of the bacterium (about 180), and patients may present asymptomatically or in acute stages of multisystemic failure. All infections are classified into icteric or anicteric forms. Infections by leptospires tend to be commonly referred to as Weil’s Disease though this description is strictly only applicable to the presentations involving jaundice, as identified by Weil’s original account of the condition.

The infection methods are dealt with elsewhere on the LIC website, where it is shown that the infection is extremely easy to miss in initial stages when the patient may be asymptomatic or present with typical FUO symptoms. The patient often ignores these early stages unless they are made aware of the significance of their symptoms by prior education. Subclinical infections are common where the infectious agents are prevalent indicating that the estimated prevalence of the condition is probably far too low. The infection may progress rapidly to fatal septicemic multisystemic failure or remain as a barely detectable subclinical illness. There is no reliable method to identify the final route of the infection from the initial stages of the disease, and all cases must be treated as potentially life-threatening. The exact route is related to the precise serovar involved, though not reliably. Simultaneous infections from multiple serovars is possible though not as widely reported as expected.

Recovery from an infection, once the serious stages are passed, is usually within 6 to 12 weeks and infers immunity to the serovars involved, though not to any of the multitude of other serovars.

FEATURES OF HUMAN INFECTION

Initial infection and presentation

The recognised incubation period is 5 to 15 days, though cases over 30 days and under 48 hours have been documented.Every infection has identical initial dynamics. Most cases present with the classically difficult to categorise symptoms of sudden headaches, fevers, nausea ( with or without emesis ) and muscle pains and tenderness. The diagnosis based on these symptoms alone is usually influenza, though symptoms of conjunctival suffusion, skin rashes ( a transient rash of the skin and mucous membranes ) and the photophobic presentations of meningitis can cause suspicion of primary bacterial menengitis rather than leptospirosis.

The infection often follows a biphasic course. For the first 3 to 7 days, the Septic phase, the basterium spreads throughout the blood, CSF and most body tissues. This phase results in extensive vasculitis, though the clinical presentations vary dramatically in intensity. From 10 to 30 days the Immune phase sees the removal of the bacterium from the blood and CSF, remaining in the urine and aqueous humor in an intermittent pattern. During this stage many of the body systems show detriment.

The Septic phase is identical in all cases, and follows the symptoms detailed above.
Presented cases then diversify, depending on the serovar causing the infection, the bacterial load and the general state of health of the patient. It is not the intention of this section of the WDIC to classify all of the serovars (there are far too many). There are numerous serovars which are known ONLY to cause mild infection. These are almost NEVER icteric or fatal, though simultaneous infections by other serovars or unrelated infections may tip the balance in a few cases.
The icteric ‘Weils’ route is comparatively rare. Of the infections caused by the known ‘high risk’ serovars such as icterohaemorrhagiae, bataviae, lai and others, only about 5 to 13% of cases progress to severe icteric disease (based on the rather innacurate estimates of the totol infection levels). Even more uncertain is the mortality of these severe cases. Reports of 5% or 45% are common, though our evidence suggests the average average is about 40%.

Anicteric cases

The Immune phase may or may not occur. If it does, there may be:

  • meningitis (aseptic)
  • rashes
  • conjunctival bleeding
  • cough, with blood-stained sputum and pulmonary infiltrates
  • acalculous cholecystitis – more common in paediatric cases

Icteric cases

The Immune phase now presents with major symptoms:

  • Jaundice – though with a red tinge to the skin caused by combination of janundice and vasculitis
  • renal failure: oliguria, or in rare cases anuria. Serum K is normal or low, creatinine and BUN usually high. The oliguria reflects interstitial nephritis.
  • multisystemic manifestations of haemorrhagia : epistaxis, rashes, GI and pulmo tract bleeding.
  • myocarditis and pulmonary involement
  • hepatomegaly
  • splenomegaly is possible but rare in reported cases

If the haemorrhagic and renal symptoms are present with jaundice, then the case can be classified as a true infection of Weil’s Disease.
Fatalities result from renal or myocardial failure, with rare fatal haemoptysis and respiratory failure in recent cases of lai infection. In general, supportive treatment of the clinical effects of infection on these systems will prevent primary fatalities. Death resulting from renal failure is more common in emerging countries where renal ITU support may not be available.

DIAGNOSIS

The initial suspicions should be based on the presentations given above. Definitive diagnosis is the result of either isolation of the bacterium from a clinical specimen (of any form) or by seroconversion or greater rise in antibody titer. You should NOT wait for etiological confirmation before initiating treatment. Once similar conditions such as malaria, Lyme Disease, yellow fever, meningitis (primary) and septecaemia have been excluded treatment should begin immediately.

Etiology

  • During Septic phase – darkfield examination or cultures from blood or CSF
  • During Immune phase – cultures from urine.

Serology

  • ELISA or Dot-ELISA
  • Macroscopic slide agglutination
  • Microscopic agglutination, with an initial titer of 1:100 or a rise of at least four times between levels in two blood specimen tests separated by 14 days.

Haematology and urinalysis

  • Total WBC slightly raised with neutroplilia
  • Erythrocyte sedimentation rate raised to approx 60mm
  • Erythrocyte count and haemoglobin ususally normal unless haemorrhagia develops.
  • Thrombocytopenia, levels of 80 to 150 x 109/l are common, dropping to 5 x 109/l in severe infections.
  • Serum creatinine and BUN raised
  • Serum K normal or reduced
  • Serum bilirubin levels increased (mailny direct)
  • Albuminuria is always present, though transient in mild cases.
  • Proteinuria and haematuria common
  • Hyalinem granular and cellular casts are common. Red cell casts are NOT indicative of infection.
  • There is always anaemia in severe jaundiced cases.
  • Serum amylase can be raised with jaundiced cases ( some reports of up to 300% increases)
  • Blood urea levels of up to 70mmol/l may be found.
  • Nitrogen retention is invariably present in mild forms, though is transient.
  • SGOT, SGPT and alkaline phosphatase levels elevated
  • Serum creatinine phosphokinase(CK) and MB variant markedly raised

DIFFERENTIATION

Given all of the wonderfully nonspecific presentations of leptospirosis, it is not beyond imagination to see why it is commonly misdiagnosed as influenza, aseptic meningitis, hepatitis, or in cases of diagnosis by desparation, ‘viral illness’ or ‘pyrexia of unknown origin’. Seasonal influenza epidemics are suspected in some cases to be actually leptospirosis. If the patient presents with a compatible history then they should be assumed infected until disproven by laboratory analysis. If you are presented with a suitable history but initial suspicion centers on influenza, typhus, Q fever, borreliosis, brucellosis, toxoplasmosis, malaria, pyelonephritis, hepatitis or similar febrile conditions then you should suspect that leptospirosis is lurking in there somewhere until disproven.

Primary bacterial meningitis can be differentiated by granulocytosis and specific antigen agents found in lumbar taps of CSF.
Primary viral meningitis can be differentiated by the lack of haemorrhagia, nitrogen retention and proteinuria and confirmed with specific tests for the meningotides.
Viral hepatitis has much higher serum transaminases, and lacks the rapid onset, conjunctival suffusions, headaches, proteinuria and long duration of fever beyond the onset of icterus.

TREATMENT

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Management of an infection is aimed to provide antibiotic therapy whilst dealing with the multisystemic results of the bacterial presence. In general if these complications can be managed the patient will tend to complete recovery within 6 to 12 weeks. There is no immunotherapy course available for these infections.

Antibiotic therapy

Most agents are of use except chloramphenicol. Effective therapy should be initiated between 7 and 10 days after infection – which may of course be several days after you receive the patient. After that time, the bacteria have been removed naturally. Agents used and their regimes include:

 

  • Penicillin G – 2.4 to 3.6 megaunits/day IV
  • Crystalline penicillin, 6 to 8 megaunits/day divided IV and IM
  • Procaine penicillin and crystalline penicillin at 2 to 2.5 megaunits/day each IM, reducing to 1 to 1.2 megaunits/day each IM when fever reduces, totalling a 5 to 7 days course, then 1.5 megaunits/day of procaine penicillin until 2 days after cessation of albuminuria.
  • Erythromycin – 250mg / 6-hourly for 5 days.
  • Doxycycline – 100mg orally twice daily.

 

Some sources recommend tetracycline. The regime should be:

  • Initial dose of 500mg
  • 250mg every 8 hours, PO,IV or IM for 24 hours
  • 250 to 500mg 6 every 6 hours for 6 days

However, many reports now bring this into question. Tetracycline is nephrotoxic and in patients with renal insufficiency the antagonistic effects are hardly advisable. Pregnant women and children should also not be treated with these agents as they affect calcification processes.

If treating with penicillin groups, theere may be a Jarisch-Herxheimer reaction after 4 to 5 hours of therapy, where temperatures rise to 37.8 – 38.4 oC with severe rigors and hypotension. The reaction is temporary, not fully understood, and should NOT be cause to remove the therapy. Management of the JH reaction is simply supportive.

General therapy

For mild infections treatment should be symptomatic. The early phases should aim to manage the fever and nausea by rest and rehydration as required. Analgesics to relieve the muscular pain can be used though Aspirin relatives that may aggravate haemorrhagia must be avoided. Delerium may be present, and relatives should be prompted to react appropriately. Rest for 7 to 14 days is required. Early ambulation can exacerbate symptoms. Patients used to dealing with colds and influenza must be prevented from insisting they will “feel better once they’re up and about again”.

Severe icteric cases require multisystemic intensive management. ICU renal care is required, and perotoneal dialysis should be available. Initial care should monitor TBC, creatininine, urea and electrolytes, urinary output, volume anbd fluid balance hourly. Temp, BP and HR should also be monitored hourly. Usual monitoring of liver function, serum transaminases, clotting and PT times should be performed, plus ECG and chest X-rays and blood grouping. Hypovolaemia should be treated with standard infusion methods. If renal insufficiency is present the dietrary fluids must be restricted and a high carbohydrate, protein-free regime employed.

Oliguria, if resulting from dehydration or hypotension, may be corrected directly by fluid replacement. Furosemide can assist to re-establish diruesis. If oliguria is the result of acute renal failure then peritoneal dialysis should be initiated immediately, before blood urea reaches 35 mmol/l. Dialysis should continue until normal function returns, which is expected without direct therapy unless other complications arise.

Renal failure is managed conventionally, by removing protein from the diet, eliminating gut nitrogen, electrolytic balancing and neomycin 1000mg PO every 4 hours.

Haemorrhagia is managed symptomatically with transfusions and intervention if required. Steroid therapy has been used to control thrombocytopenia.

Myocardial management should follow standard cardiological protocols. There is no alteration to the agents or regimes employed except where existing complications demand.

Prognosis

If not jaundiced, recovery is usual in 2 to 6 weeks, plus 4 weeks of residential convalescence. In jaundiced patients, the fatalities are due to renal, hepatic or myocardial failure. Rates are low, reported between zero and 6%. If these complications are survived, recovery is also complete. Psychological manifestations may persist in a few patients for up to three years after infection, requiring support. 10% of patients report recurrent headaches and uveitis, lasting a few years. Infection conveys specific immunity to the serovars exposed, though NOT to the others from the known list of 180+.

Prophylaxis

Specific agents should only be provided to those who are expecting to enter high risk areas (Doxycycline 200mg per week) or those reporting known exposure but are as yet asymptomatic (Doxycycline 100mg per day for 7 days). Prevention of infection is the only reliable method of control, and relies on physical barriers and environmental controls to prevent exposure to the organisms.