Zhang Xiaohong Department of Infectious Diseases Sun Yat-Sen university Leptospirosis

A NEWS REPORT

The news report From the Yangcheng evening news paper 25 SEP 2000 In Fujian province A 27 year old young man Xu, went to the hospital because of chills and fever The doctor made a diagnosis as leptospirosis After the patient had been injected PG and Virazole, the doctor let him back home.

General Review General Review Etiology Etiology Epidemiology Epidemiology Pathogenesis and Pathology Pathogenesis and Pathology Clinical Manifestations Clinical Manifestations Diagnosis Diagnosis Treatment and Prevention Treatment and Prevention Leptospirosis

A z of worldwide distribution caused by pathogenic leptospira species A zoonoses of worldwide distribution caused by pathogenic leptospira speciesz oonoses Source of infection: Rats, Swine Source of infection: Rats, Swine Basic clinical Features: high fever, conjunctival suffusion and myalgia Basic clinical Features: high fever, conjunctival suffusion and myalgia Severe cases: jaundice,renal failure, pulmonary hemorrhage and Severe cases: jaundice,renal failure, pulmonary hemorrhage and meningeal signs Effective with treatment of penicillin G Effective with treatment of penicillin G General

Thin, flexible, finely coiled with a hook at the ends Thin, flexible, finely coiled with a hook at the ends Gram-Negative, Gram-Negative, Giemsa stain: Light red 0.1μm in diameter 0.1μm in diameter 6-20μm in length 6-20μm in length Etiology: Morphology

Etiology: Picture Etiology: Picture (dark-field microscope) Motility can be seen Motility can be seen It is characterized by very active motility, by roating and bending It is characterized by very active motility, by roating and bending

Obligate aerobic, slow growing Obligate aerobic, slow growing Cultured in Korthol media enriched with rabbit serum or albumin, at 30 ℃ and an optimal PH 7.2 to 7.6 ， their generation time varies from 7 to 12 hours It can be isolated by intraperitoneally inoculating of young guinea-pig It can be isolated by intraperitoneally inoculating of young guinea-pig Etiology: Culture

It is sensitive to dry, suds, ethanol and bleaching powder It is sensitive to dry, suds, ethanol and bleaching powder Survive in damp soil and water for Survive in damp soil and water for 4wks- 3mths Etiology: Resistance

Serogroups, >200 serotypes Serogroups and 74 serotypes in China The most common serogroups: The most common serogroups: L. icterohemorrhagic( 黄疸出血群 ) L. icterohemorrhagic( 黄疸出血群 ) L. pomona( 波摩那群 ) L. pomona( 波摩那群 ) L. canicola( 犬群 ) L. canicola( 犬群 ) L. hebdomadis( 七日热群 ) L. hebdomadis( 七日热群 ) Widest distribution in China : L.pomona L. icterohemorrhagic causes the most severe illness L. icterohemorrhagic causes the most severe illness Etiology: Classfication

In 1886, Weil, a German doctor observed 4 cases of leptospirosis with jaundice, than this disease is called as Weil disease In China: in 1937, Professor Tang zeguang ( 汤泽光 )discovered leptospirosis in Guangzhou 汤泽光 Epidemiology

Reservoirs of infection: rodents, domestic livestock (swine and cattle), dogs and foxes Reservoirs of infection: rodents, domestic livestock (swine and cattle), dogs and foxes Source of infection Source of infection – Livestock ： swine,dogs, cattle,sheep,horses – Wild animals ： rats(Apodemus agarius, 黑线姬鼠 ), rabbits,wolfs,snakes and frogs Epidemiology ： Source of Infection

The main source of Infection ： The main source of Infection ： – Apodemus agariu: L.icterohemorrhagic. F – Apodemus agariu: L.icterohemorrhagic. Field style in south of China Apodemus agariu Apodemus agariu – Swine: L. pomona. F – Swine: L. pomona. Flood style and raining style in north of China Epidemiology ： Source of Infection

Epidemiologic styles ： f field styleraining style f flood style Source of infection Apodemus agarius Swine and dog Swine serogroupL.icterohemorrhagic L. pomona factors of transmission contaminated rat urine raining water flood overflowing arearice fieldvillagethe area where flooded clinical typeInfluenza-typhoid fever Pulmonary hemorrhageieterohemorrhage Influenza-typhoid fever meningoencephaliti s

Infected animals excrete leptospiras in the urine Exposure to the water, soil or plants contaminated by urine of Infected animals Exposure to the water, soil or plants contaminated by urine of Infected animals Direct contact with infected animal tissues and organs Direct contact with infected animal tissues and organs Ingest the drink or food contaminated by the urine of the reservoir animal Ingest the drink or food contaminated by the urine of the reservoir animal Epidemiology ： Routes of transmission

Leptospires can gain entry through cuts and abrasions in the skin or through mucous membranes of the eyes, nose and mouth Human-to-human transmission is rare – Short time for human to excrete leptospira – Acidic urine of human Epidemiology ： Routes of transmission

Human are susceptible to leptospira Universal: Human are susceptible to leptospira Get life long post- infection immunity to the same serotype Type-specific immunity: Get life long post- infection immunity to the same serotype Epidemiology Susceptibility

Geographic distribution: Worldwide Distribution, in both rural and urban areas and in temperate and tropical climates Seasonal distribution: Summer and early fall. Peak occurrence from June to October in our country Age, sex : Young adult men. Males comprise 80% of cases Epidemiology ： Epidemiologic feature

Occupation (a significant risk factor ) – It originally was thought of as being an occupational disease, and approximately 30-50% of human cases are occupation-related – It is an occupational hazard for people who work outdoors or with animals, such as rice and sugar-cane field workers, farmers, sewer workers, veterinarians, dairy workers and military personnel... – It is also a recreational hazard to those who swim or wade in contaminated waters Epidemiology ： Epidemiologic feature

Epidemic style ： field style, flood style and raining style Epidemics also follow natural disasters, such as floods and earthquakes, which drive rats out of sewers Epidemiology ： Epidemiologic feature

Pathogenesis: leptospira Skin,mucous membranes Blood stream Type of Influenza- typhoid fever Pulmonary Hemorrhage ieterohemorrhage Renal failure Meningoencephalitis Interstitial nephritis Hemorrhagic pneumonitis Hepatitis Meningitis and Encephalitis Organs leptospiramia

The basic pathological finding is infectious-toxic lesion of the systemic capillary The basic pathological finding is infectious-toxic lesion of the systemic capillary In some cases severe damage can be seen in the organs and tissues In some cases severe damage can be seen in the organs and tissues – Liver: cellular inflitration around the portal area – Kidney: – Kidney: Interstitial nephritis – Lung: pulmonary congestion and hemorrhage – Brain: perivascular cuffing Pathology ：

Diseased kidney affected by Leptospirosis

Pathological finding type of severe hemorrhage

Complicated clinical manifestations One serotype can result in many kinds of clinical manifestations One clinical type can be caused by many serotypes Clinical manifestations vary greatly in different patients Incubation period: 7-13 days(2-28d) Clinical Manifestations

3 phases (according to the course of disease) : Early phase: 1st~3rd days after illness. common manifestations of all clinical types Second phase: 3rd ~10th days after illness Late phase complications: 7th ~10th days after illness Clinical Manifestations

Early phase (leptospiramia) Last 4-7days Begin with abrupt fever to 39 ℃ -40 ℃ Sometimes has a persistent high fever Non-specific symptoms caused by leptospiramia and its toxins Such as: chills, headache, myalgia, back pain, anorexia, nausea and vomiting A sore throat is common and herpes simplex labialis may occur Clinical Manifestations

Second phase (organs damage) With prominent clinical presentation Patients can be classified into the following clinical types: 1). Type of Influenza-typhoid fever (Ordinary leptospiremia) 2). Pulmonary hemorrhage Type of ieterohemorrhage 3). Type of ieterohemorrhage (Weil disease) 4). Renal function failure 5). Meningoencephalitis Clinical Manifestations

Clinical Manifestations Type of Influenza-typhoid fever 3 Symptoms: Chills and Fever MyalgiaFatigue 3 signs: Conjunctival suffusion Calf muscle tenderness Enlargement of lymph nodes 寒热身痛一身乏， 眼红腿痛淋巴大。

Clinical Manifestations Type of pulmonary hemorrhage  Pulmonary hemorrhage Pulmonary hemorrhage Clinical feature of the early phase (3-4 days)

Clinical Manifestations Type of pulmonary hemorrhage 1 ． Type of mild hemorrhage  Cough and hemoptysis  A little bit of moist rale can be heard  Dot-like or small nodular densities in chest X-ray  Prognosis is fine if treatment is given in time

Clinical Manifestations Type of pulmonary hemorrhage

2 、 Type of severe hemorrhage  Fever and other toxicemia symptoms get worse  Breath and pulse get faster and faster; Pallor or cyanosed ; With more hemoptysis or even bleeding from mouth and nose; With more moist rale; Patchy or confluent densities can be seen on chest X-ray  Confusion,fear or even coma ! ! 神色惧变心发慌, 脉速气紧罗音现

Clinical Manifestations Type of pulmonary hemorrhage cyanosed coma

Causes of severe hemorrhage ① High virulence of the leptospira L.icterohemorrhagic ② No immunity to leptospira ③ Delayed treatment and no rest ④ Herxheimer reaction after penicillin therapy

Clinical Manifestations Type of ieterohemorrhage Hepatic function impairment Jaundice Hepatomegaly Hemorrhage: Nose bleeding skin petechiae, purpura Hemoptysis, hematemesis, hematuria Kidney damage Proteinurin, Renal failure

Leptospirosis can cause jaundice

Clinical Manifestations Type of meningoencephalitis headachevomiting neck stiffness mental confusion Twitch,paralysis, brain edema, brain hernia, respiration failure CSF ： pressure ↑, protein ↑ WBC ↑,Glu ↓, chloride is normal 2-3days Clinical feature in the early phase

Clinical Manifestations Type of renal failure 1. Renal impairment can be found in all types of leptospirosis 2. However the type of renal failure is definitely uncommon 2. However the type of renal failure is definitely uncommon

Clinical Manifestations Complication in period of recovery Late phase complications  Late fever: recurrence of fever in the phase of convalescence  Reactive meningitis:  Reactive meningitis: Meningeal symptoms, aseptic meningitis. Leptospiras not detected in CSF, good prognosis  Ocular late complication: Iritis, Cyclitis, Optic neuritis, Uveitis

 Occlusive cerebroarteritis Appears mths after initial illness caused by L.pomona Abnormal CSF, basal multiple arteritis The symptoms are hemiparalysis and aphasia Clinical Manifestations Complication in period of recovery

Diagnosis Based on : Based on :  Information of epidemiology  Clinical features  Data of laboratory

 Epidemic area  Epidemic season （ June-Oct ）  Contact history Diagnosis Information of epidemiology

Diagnosis Clinical Features  3 Symptoms  3 Signs  Specific organ dysfunction

3 Symptoms  3 Signs  Specific organ dysfunction 3 Symptoms Chills and fever MyalgiaFatigue 3 signs Conjunctival suffusion Calf muscle tenderness Enlargement of Lymph nodes Diagnosis Clinical Features

Conjunctival suffusion

3 Symptoms, 3 Signs, Specific organ dysfunction Organs Pulmonaryhemorrhage hepatitis Interstitialnephritis Meningitis and encephalitis Pulmonaryhemorrhage Icterohemorrhage Renal failure Renal failure Meningoencephalitis Diagnosis Clinical Features

Diagnosis Data of laboratory  Peripheral blood: WBC↑N↑ Urine: proteinuria, hematuria, cylindruria Urine: proteinuria, hematuria, cylindruria  Blood culture  Microscopic agglutination test (MAT) ： Positive result appears in about 7 to 8 days after onset of illness, and  Microscopic agglutination test (MAT) ： live antigen, determination of titer and identification of serotype. Positive result appears in about 7 to 8 days after onset of illness, and persist for many years period of recovery leptospirosis The titer ≥1:400 or fourfold increased in period of recovery supports a diagnosis of leptospirosis

 Type of influenza and typhoid fever ： Influenza Influenza Typhoid fever Typhoid fever S Septicemia  Type of pulmonary hemorrhage ： Bacterial pneumonia Bacterial pneumonia Pulmonary tuberculosis Pulmonary tuberculosis  Type of icterohemorrhage ： Viral hepatitis Viral hepatitis Differential diagnosis

 Type of meningoencephalitis ： Viral encephalitis Viral encephalitis Tuberculotic meningitis Tuberculotic meningitis  Type of renal failure ： Acute nephritis Acute nephritis Hemorrhagic fever with renal syndrome Hemorrhagic fever with renal syndrome Differential diagnosis

Early finding ， early diagnosis, early treatment and treat in near hospital ( 三早一就地 ) Early diagnosis and effective treatment are very important Antibiotic treatment will shorten the duration of fever and reduce the incidence of complications Treatment principle of treatment

Treatment Etiologic treatment  Penicillin G is the first choice. The first dose of penicillin should be small, 50’000U as the first one, then increase later, 4~6 times/day, the duration is about 7 days  For the patients who are allergic to penicillin, gentamycin can be used, the dose is 80’000U/time, 3 times daily for 7 days  Tetracycline 500 mg/time 4 times/day 5~7 days

Clinical Manifestations Herxheimer Reaction ( 赫氏反应 )  The illness gets worse after the initiation of penicillin G therapy  In 0.5 to 4 hours after the first dose, it begins abruptly with chills, high fever and myalgia which persists for 0.5 to 1 hours, which persists for 0.5 to 1 hours, hypotension or shock, tachycardia  Caused by the lysis of massive leptospira and the release of toxin after PG therapy

1. General supportive measures 2. For the severe cases Tranquilizer: valium, luminal, Tranquilizer: valium, luminal, wintermine and phenergan 3. Treatment of Herxheimer reaction ： Tranquilizer, Corticosteroid intravenous drip Treatment Symptomatic treatment

Treatment Treatment of pulmonary hemorrhage Tranquilizer Tranquilizer Hydrocortisones Hydrocortisones Cedilanid Cedilanid for cardiac failure Haemostatic for bleeding

Treatment Treatment of type of icterohemorrhage It is similar to the treatment of icteric hepatitis Bed rest Bed rest Liver protection Liver protection Supportive measure and nutrition Supportive measure and nutrition The treatment of renal failure

treatment is given in time, the prognosis is fine For mild type, if the treatment is given in time, the prognosis is fine ieterohemorrhage, severe meningitis and encephalitis, the mortality rate is high For the type of severe hemorrhage, severe ieterohemorrhage, severe meningitis and encephalitis, the mortality rate is high Prognosis

A NEWS REPORT

Did the physician make any mistakes? What should the physician do after the first dose of PG therapy? What was the diagnosis of the patient when he came to the hospital again? What was the patient died from? disscution

Control the source of infection ： Control the source of infection ： Maintain swine, dogs, cows Maintain swine, dogs, cows Eradicate rats Eradicate rats Interrupt the routes of transmission Interrupt the routes of transmission – wearing protective clothing – refrain from contact with infected animals and from swimming in contaminated water Prevention

Protect susceptible people: Protect susceptible people: – Immunization with leptospira vaccines Peoples who live in the severe epidemic area Peoples who live in the severe epidemic area Peoples who have more chances to contact Peoples who have more chances to contact with the contaminated water or soil with the contaminated water or soil Peoples who just enter the epidemic area Peoples who just enter the epidemic area One month before epidemic season(April~May) One month before epidemic season(April~May) Hypodermic, 1ml/time, after a week,repeat it Hypodermic, 1ml/time, after a week,repeat it Prevention

Protect susceptible people: Protect susceptible people: – Chemoprophylaxis When people who enter the epidemic area, take doxycycline, 200mg orally once weekly during the risk of exposure When people who enter the epidemic area, take doxycycline, 200mg orally once weekly during the risk of exposure Prevention

zoonotic disease caused by pathogenic leptospira Leptospirosis is a zoonotic disease caused by pathogenic leptospira Apodemus agarius and swine are the chief sources of infection Apodemus agarius and swine are the chief sources of infection The main route of transmission is exposure to the contaminated water or soil The main route of transmission is exposure to the contaminated water or soil The basic clinical features are 3 symptoms and 3 signs The basic clinical features are 3 symptoms and 3 signs summy (1)

There are 3 phases and 5 clinical types MAT is a important test for diagnosis etiologic treatment,the first dose should be small PG is the first choice of etiologic treatment,the first dose should be small Pay attention to the Herxheimer reaction Pay attention to the Herxheimer reaction Chemoprophylaxis are useful methods of prevention Prophylactic inoculation and Chemoprophylaxis are useful methods of prevention summy (2)

Zoonoses are defined by the WHO as "Diseases and infections which are naturally transmitted between vertebrate animals and man" A zoonotic agent may be a bacterium, virus, fungus, parasite, or other communicable agent Zoonoses cover a broad range of diseases with different clinical and epidemiological features and control measures zoonoses

Japanese encephalitis Yellow fever West Nile fever Haemorragic fevers Rabies SARS Hepatitis E Avian influenza zoonoses

Apodemus agarius