Leptospirosis

Chapter 1 – Leptospirosis

v History

o  (+) plausible expos’: (direct) to body fluid or organs of infec’ animal, or (indirect) to contaminat’ water or soil.

o  Incub period 3-20 days (typic’ 5-14 days), then, clinical ill’ sets on sudden’.

o  Expert consensus: 2 recognizable clinical syndr’

§ Anicteric: self-limit’ mild flu-like ill’. Extremely rare death.

§ Icteric (Weil Disease): severe ill’ w/ multiorgan involv’ or fail’; Weil syndr’ primari’ manifests as: profound jaundice, renal dysfunc’, liver necrosis, pulmon’ dysfunc’, & hemorrhag’ diathesis. Pulmon’ manifest’: cough, dyspnea, bloody sputum, hemoptysis, respirato’ fail’.

() 2 phase (distinct @ anicteric syndr’, oft’ continuous & undistinguishable @ Icteric syndr’):

Septicemic: acute, 5-7 days, then 1-3 days in which Px’s ↓ed temperature & ~ afebrile à regress to relative’ asympt’ ill’, or progress to more severe ill’.

Immune (delayed): Øspecific sympt’ (s.as: fever & myalgia) ~ less +++ than @ acute stage. (77% cases) (+) intense & analgesic-unrespons’ headache, oft’ heralds onset of meningit’.

Fever recur’ indicates immune phase.

o  Can’t predict clinical severity’s level @ onset.

o  Acute ill’ after infec’ by any Leptospira serovar. Most sympt’ can (+) @ varying degrees: headache, fever (38-40^OC), rigors, myalg’ (typic’ focal @ calf & lumbar), nausea & emesis, anorexia, diarrhea, cough, pharyngit’, conjunctivit’, Øpruritic skin rash.

o  @ serolo’ confirmed cases: 5% w/o fever history, 55% w/ afebrile presentat’, 100% myalg’ & headache presentat’

o  Aseptic meningit’, important syndr’ @ immune anicteric stage. (50% cases) (+) meningeal sympt’. Meningit’ usu lasts few days (occasional’ 1-2 weeks). (Less common) Cranial nerve palsies, peripher’ facial palsies, encephalit’, & changes in conscious’. Mild delirium ~ seen.

o  Abdominalgia w/ diarrhea or constipation (30% cases), hepatomega’, nausea, emesis, anorexia. (~ Rare, clinical’ signific) (+) Acalculous cholecystit’.

o  (2-10% cases) Uveitis (+) @ early or late ill’ (also, report: 1 year post-initial ill’). Iridocyclit’ & chorioretinit’, late complic’ which ~ persist for years.

(+) @ 3 weeks – 1 month post-expos’.

o  (Most common (92% cases), ocular complic’) (+) Subconjunctiva hemorrhage.

o  Renal manifestat’: hematuria; oliguric & anuric acute tubular necrosis ~ (+) @ week 2 due to hypovolem’ & ↓ed renal perfus’.

v Physic’ Exam

o  Depends on severity & time from onset of sympt’. Px ~ appear mild’ ill or toxic.

o  (Common @ early @ ill’) fever ≤ 40^OC & tachy♥. Fever (typic’ ↓ed post- 7 days)

o  Hypotension, oliguria, chest auscult’ find’ @ presentat’ ~ presage severe ill’.

o  If (+) +++ & prolong’ fever à ~ (+) hypovolemic shock & hypotension.

o  Warm & flushed skin (early @ ill’), ~ + transient petechial erupt’ that can involve palate.

o  @ late @ disease, jaundice & purpura can (+).

o  (Classic ocular find’) (+) Conjunctival suffusion regardless of severity of ill’, characteris: conjunctivit’-like conjunctival redness w/o inflammato’ exudat’.

o  (Common) uveit’ followi’ acute leptospirosis (~ only mild’ if acute stage Px + antibiotic).

o  Muscle tender’ can + early infec’ myositis (can affect any muscle and +++ if @ paraspinal & calf muscles)

o  Neurol’ exam’ can reveal sign of meningit’: neck stiffn’ (early @ ill’,(~ represent early meningismus) can be confused as muscle in origin) & rigidity, & photophobia.

o  Lung exam’ results: (@ early or mild ill’) ~ normal; (@ severe ill’) ~ (+) consolidation due to alveol’ hemorrhage; (if (+) ♥-related pulmon’ edema) ~ (+) rales & wheezing.

o  (Main pulmon’ manifest’, ~ +++, can (+) w/o typical Weil syndr’ presentat’) dyspnea & hemoptysis due to alveol’ hemorrhage.

o  (if +++) ~ (+) myocarditis. All physic’ find’ of biventricul’ ♥ fail’ can be (+): ↑ed JVein pulsations; a new S3 gallop; & dysrhythm’ (includ’: atrial fibrillation, varyi’ severity ♥ blocks, & ventricul’ ectopy).

o  Abdomin’ exam’ ~ reveal enlarged & tender liver due to hepatitis. Acalculous cholecystit’ which ~ suggested by (+) Murphy sign (a find’ @ profound ill’). Reported: (+) Pancreatitis @ severe case.

o  Heme-positive stool & gross blood can be (+) on rectal exam’ @ Px w/ DIC & bleed’.

o  (@ severe ill’, ~ early find’) ~ (+) delirium (can be due to shock). Late in ill’ @ into convalescent, prolong’ mental sympt’ ~ persist: depression, anxiety, irritability, psychosis, & dementia.

o  ~ (+) Rash as macul’ or maculopapul’ erupt’ w/ erythemat’ urticarial, petechial, or desquamat’ lesions. Adenopathy ~ noted.

v DDx

o  Flu-like ill’ @ mild ill’ ~ resemble benign viral syndr’; more +++ ill’  ~ resemble meningit’ or sepsis.

o  Don’t miss critical DDx (serious, each’s Tx is different): other bacterial meningit’, acute toxin-induced hepatit’, pancreatit’, cholangit’, or Goodpasture disease.

o  Possible key to correct Dx’s via history (if (+) case cluster, it ~ suggest a common expos’).

o  Brucellosis

o  Dengue

o  Enteroviral Infections

o  Hantavirus Pulmonary Syndrome

o  Hepatitis A

o  Malaria

o  Meningitis

o  Q Fever

o  Rickettsial Infection

o  Viral Hemorrhagic Fevers

o  Enteric Fever

o  Infantile polyarteritis nodosa

o  Kawasaki disease

o  Primary HIV infection

o  Typhoid fever

o  Yellow fever

o  Mononucleosis

o  Cholecystitis

o  Pancreatitis and pancreatic pseudocyst

v Workup

o  Leptospires grow slow’ in culture, w/ slow recovery rate. Acute serolo’ test’s low acute sensitivity à shouldn’t be Tx’s initiation’s basis (ill’-consistent history & sympt’ as basis, instead).

o  Leptospira isolated from human as criterion standard. Lab tests also to find extent of organ involvem’ (routinely (+) @ suspected Px after acute infec’). Complete Blood Count’s necessary. Find’ @ general lab studies:

§ In Px w/ mild ill’, ↑ed Erythrocyte Sedimentation Rate (ESR) & peripher’ leukocytosis (3,000 - 26,000 x10⁹/L) w/ left shift.

§ Can (+) +++ anemia due to pulmon’ and GI hemorhage.

§ Platelet Count ~ ↓ed as component of DIC (diseeminated intravascul’ coagulation).

§ BUN & serum creatinine ~ ↑↑↑ed @ anuric & oliguric phase.

§ Serum creatinine kinase (MM fraction) is oft’ ↑ed @ muscul’ involvem’.

§ ~ (+) Prolong coagulation time @ liver dysfunc’ & or DIC.

§ On liver function test: serum bilirubin ~ ↑ed as part of obstructi’ ill’ due to liver capillarit’; (Less oft’ & less significant’) ↑ed Hepatocellu’ transaminases (usu’ < 200U/L); (Common) Jaundice & bilirubinem’ (disproportion’ to Hepatocyte damage); ALP ~ ↑ed 10x.

o  1 MAT-titer 1:800 or (+) spirochete on Dark-field microscop’, + appropriate clinical scenario à strongly suggesti’.

o  Urinalysis: ~ (+) proteinuria. WBCs, RBCs, hyaline casts, & granular casts ~ (+) in urinary sediment.

o  CSF’s analysis for exluding other etio’ of bacterial meningit’. If Leptospirosis involve CSF à  (initial’) PMN WBCs predomin’ @ CSF, then monocytes do, instead. CSF protein level ~ ≥ normal; CSF’s normogluco, & normotensive but lumbar puncture can relieve headache. Routine Leptospira CSF isolate Ø change Tx.

o  (Common @ leptospiremic phase of Weil syndr’) ECG abnormali’.

o  @ severe ill’: ~ (+) CHFailure & cardiogenic shock.

o  Culture

§ For definitive diagn’. Can isolate infecting serovar. Leptospire’s viable in anticoagulat’ blood for 11 days à mailable specimen.

§ Blood culture ~ negative: if drawn too early or late, or once immune syst’ gets activated. Leptospires ~ Ø detectable in blood till 4 days after onset of sympt’ (7-14 days post-expos’). Leptospire’s isolatable from: CSFluid w/in first 10 days; urine w/in several weeks post-initial infec’.

§ Urine culture ~ positive (~ take 8 weeks to grow) for months or years after onset of ill’.

o  Microscop’ Agglutination Testing (MAT)

§ Uses antigens from common (frequent’ locally endemic) leptospire serovars à serovars selection affect accuracy.

§ In clinical’ disease-consistent Px: 1 titer > 1:200 or serial titers > 1:100 suggest leptospirosis (Ø diagn’). 4x ↑ in titer between acute & convalescent specimen à positive result. Antibody response’s Ø detectable until week 2 of ill’ & can be affected by Tx.

§ False-negative ~ due to testing 1 specimen pre- immune phase of ill’.

§ False-positive ~ @ Legionellosis, Lyme disease, & syphilis.

o  Other Test

§ Screening tests for Leptospirosis (easy, rapid): macroscop’ slide agglutination test, Patoc-slide agglutination test, microcapsule agglutination test, latex agglutination test, dipstick test, & indirect hemagglutination test à (advisable) to be confirmed (positive or negative) ((prefered) via MAT)).

§ If IgM ELISA (uses broadly reactive antigen) positive à do confirma’ tests.

§ Nucleic Acid Amplification (PCR-based) is for leptospirosis diagn’. PCR confirms diagnosis rapidly @ early stage when leptospires ~ (+) and pre- (+) detectable antibody titer; can’t identify infecting serovar.

§ Dark-field exam of blood or urine frequently misdiagn’ Leptospirosis.

o  Chest Radiography

§ (Most common) Bilateral diffuse airspace disease.

§ ~ reveal ♥mega’ & pulmon’ edema due to myocarditis.

§ In Px w/ alveolar hemorrhage due to pulmon’ cappilarit’: lung parenchyma ~ (+) multiple patchy infilrtrat’.

o  Histolo’ Find’

§ A bit post-inocul’ & @ incub’ period, Leptospires replicat’ in liver acitve’ à disseminate throughout body & infec’ many tissues.

§ Silver stain & immunofluorescence can identify leptospire in liver, spleen, ren, CNS, muscles, & ♥.

§ @ Acute phase: histolo’ reveals leptospires w/o much inflammato’ infiltrate.

§ Leptospirosis ~ seen as infective system’ vasculit’. Leptospiral toxins degrade capillary’s endotheliocyte’s membranes à (1) blood & leptospires extravasat’ to nearby tissues; (2) ischemia & cell death ~ (+) ((later in ill’) MN WBC predominate in these infarcts).

§ Leptospires can be found @ immunolo’-privileged sites (eg @: renal tubules, CNS, eye’s anterior chamber) for weeks - months post-initial infec’.

(Figure right below) Silver stain, liver, fatal human leptospirosis. Courtesy of the Centers for Disease Control/Dr. Martin Hicklin

Reference:

1. http://emedicine.medscape.com/article/220563-workup

2. http://emedicine.medscape.com/article/220563-presentation

3. http://emedicine.medscape.com/article/220563-differential