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Tropical Infection Diseases Gatot Sugiharto, MD, Internist Internal Medicine Department Faculty of Medicine, Wijaya Kusuma University Surabaya GSH - Tropmed - 2010 1 LEPTOSPIROSIS Gatot Sugiharto, MD, Internist Internal Medicine Department Faculty of Medicine, Wijaya Kusuma University Surabaya GSH - Tropmed - 2010 2 Introduction • Leptospirosis suatu infeksi anthropo-zoonosis akut • Sering terjadi pada daerah tropis dan subtropis • Nama lain : Weil Disease, Hemorrhagic Jaundice, Mud Fever, Swineherd Disease, Canicola Fever, seven-day fever (commonly in Japan), Cane cutter’s disease (in Australia), Rice field Leptospirosis (in Indonesia) , Fort Bragg fever in U.S.Andaman haemorrhagic fever (AHF) GSH - Tropmed - 2010 3 Leptospirosis • Penyakit ini disebabkan oleh bakteri leptospira, • suatu organisme berbentuk spriral dan tipis yang memiliki daya motilitas yang aktif. • >250 serovars – L. Interrogans – L. canicola – L. hardjo – L. pomona – L. icterohaemorrhagiae GSH - Tropmed - 2010 4 Pekerjaan yang beresiko terkena: Petani Penambang Pekerja kanal nelayan GSH - Tropmed - 2010 5 Route of Transmission • Main resevoir : rodents, livestock (cattle, horses, sheep, goats, swine), canines, and wild mammals • Replicates in renal tubules, excreted in urine • Human infection occurs with direct contact with infected urine, or indirect exposure to organisms in wet soil & water, rarely by droplet inhalation • Often results from occupational exposure to ratinfected water GSH - Tropmed - 2010 6 GSH - Tropmed - 2010 7 GSH - Tropmed - 2010 8 GSH - Tropmed - 2010 9 Mechanism of Disease • Systemic vasculitis occurs, facilitating migration of spirochetes into organs – Hepatocellular damage with jaundice, inc INR – Acute tubular necrosis of kidney – Increased capillary fragility hemorrhage can occur in any internal organ (pulmonary hemorrhage) GSH - Tropmed - 2010 10 Scanning electron microscopy of a renal tubule from an experimentally infected rat GSH - Tropmed - 2010 11 Clinical Presentation(1) • Incubation period: 2-20 days (median 11 days) • Two types of leptospirosis: – Anicteric leptospirosis or self-limited illness (85 - 90% ) – Icteric leptospirosis (5 - 10% ) GSH - Tropmed - 2010 12 Clinical Presentation : early phase (4-7 days) • Symptoms: – HA, myalgia, chills, back pain, anorexia, sore throat nausea/vomiting – Hemoptysis, cough, SOB • Signs: – Acute febrile illness (40oC) – Conjunctival suffusion – Nontender transient pretibial raised erythematous patches – Hepatomegaly – Meningitis Labs: thrombocytopenia, elevated WBC GSHproteinuria, - Tropmed - 2010 13 Clinical Presentation: Late Phase • Second (Immune) phase: day 7+ • Patient develops antibodies to the organism • Meningitis or hepatorenal manifestations more prominent • Fevers may subside, becomes more jaundiced, can bleed into skin, mucous membranes, lungs • Oligouric renal failure, shock, myocarditis, arrythmias can follow GSH - Tropmed - 2010 14 Weil’s Disease • Severe form of leptospirosis • Described by Weil in 1886 as a clinical syndrome in 4 men with severe jaundice, fever, hemorrhage, and renal involvement • Inada et al identified the causal agent in Japan in 1916 • Most severe cases, with hepatorenal involvement and jaundice, can have a mortality rate of 20-40% GSH - Tropmed - 2010 15 Diagnosis • Direct visualization of leptospires in blood (early phase) or urine (late phase) by darkfield microscopic examination – Low sensitivity (40.2%) and specificity (61.5%) – Need special media (Fletcher's, Ellinghausen's, polysorbate ) – Takes 2-3 weeks to be positive • IgM antibodies appear in late phase (5-7 days) – Microscopic agglutination test (MAT), ELISA – Titer >1:100 helps, but fourfold rise in titer is diagnostic (need convalescent sample) GSH - Tropmed - 2010 16 Diagnostic Tests for Leptospirosis GSH - Tropmed - 2010 17 Differential diagnosis • • • • • • • • • Influenza Meningitis (encephalitis) Viral hepatitis Rickettsiosis Typhoid fever Septicemia Toxoplasmosis Legionnaire’s disease Malaria GSH - Tropmed - 2010 18 Treatment • IV penicillin for severe disease • Oral amoxycillin, erythromycin, doxycycline for mild illness (10-14 d) • Jarisch-Herxheimer reactions have been reported in patients treated with penicillin • Prognose • Humans with leptospirosis usually excrete the organism in the urine for 4-6 weeks and occasionally for as long as 18 weeks. GSH - Tropmed - 2010 19 Prevention • Rodent control measures • Immunization of animals with killed vaccines short-lived, requires boosters • Protective clothing, footwear • Burning canefield prior to harvest (young shoots can cut hands) • Drink boiled water • Doxycycline prophylaxis for high-risk workers GSH - Tropmed - 2010 20 COMPLICATIONS • • • • • • • Azotemia Oliguria Hemorrhage Purpura Hemolysis Gastrointestinal bleeding Hypoprothrombinemia & thrombocytopenia GSH - Tropmed - 2010 21 Fort Bragg Fever • August 1942, an unusual acute febrile illness (99.8° to 105.6°F) occurred in a group of soldiers at Fort Bragg, N.C. • Soldiers quartered near a small stream and its tributaries • 40 patients with sudden onset malaise, mild aches, lumbar pain, severe headaches • Bilaterally symmetrical rash limited in to the pretibial areas on the fourth day • Similar outbreaks 1946 and 1947 among soldiers quartered in the same area of the post GSH - Tropmed - 2010 22 MALARIA Gatot Sugiharto, MD, Internist Internal Medicine Department Faculty of Medicine, Wijaya Kusuma University Surabaya GSH - Tropmed - 2010 23 Introduction • The protozoan genus Plasmodium is responsible for malaria • Four important species: Plasmodium falciparum, P. vivax, P. malariae and P. ovale • Rapidly fatal and is responsible for most malaria related deaths : P. Falciparum • Mosquito-transmitted malaria is the greatest public health problem in large parts of the world with more than 500 million clinical cases and over 3 million deaths every year GSH - Tropmed - 2010 24 Epidemiology • Occurs in most of the tropics of the world • Prevalence of falciparum and vivax malarias being about the same in Asia, Oceania and South America • Malaria can be a traveler’s disease and imported into any country. • A rural disease due to the presence of the female Anopheles mosquito vector. GSH - Tropmed - 2010 25 Tranmission • Transmision : by an infected female Anopheles biting • Others : blood transfusion or congenitally fetomaternal • Malaria-carrying Anopheles bite only near dusk and dawn. GSH - Tropmed - 2010 26 GSH - Tropmed - 2010 27 GSH - Tropmed - 2010 28 Clinical manifestation on life cycle. • Plasmodia replicate inside the RBC hemoliysis release of toxic metabolic by products into the bloodstream. • These symptoms include chills, headache, myalgias and malaise, occurring in cycles. • Also may cause splenomegaly, jaundice and anemia • P falciparum may induce kidney failure, coma and death. GSH - Tropmed - 2010 29 Chronic & relapse • All infected liver cells parasitized with P. falciparum and P. malariae rupture and release merozoites at about the same time. • In contrast, P. vivax and P. ovale have two exoerythrocytic forms. The primary type develops, causes liver cell rupture, and releases merozoites. The other form, which develops concurrently, is known as the hypnozoite. • Sporozoites that enter liver cells differentiate into nonsexual hypnozoites that remain dormant for weeks, or even years. • The hypnozoites activate and undergo exoerythrocytic schizogony, forming a wave of merozoites that cause a relapse. GSH - Tropmed - 2010 30 Clinical symptoms(1) • Cough, fatigue, malaise, arthralgia, myalgia, and paroxysm of shaking chills and sweats • The classic paroxysm : begins with shivering and chills, (1-2 hours) followed by high fever • Paroxyms of varying 48 hours belong to vivax, ovale and falciparum malaria, whereas 72 hours belongs to malariae infections. • The 48 hour fever is called tertian (occurs every 3rd day) day 1 : fever, day 2 : no fever, day 3 : fever & so on. The 72 hour fever is called quartan (returns on every 4th day) GSH - Tropmed - 2010 31 • 30% of non-immune adults infected with P falciparum suffer acute renal failure, some with seizures. • Blackwater fever : hemoglobinuria with the passage of dark-colored urine • Non-cardiogenic pulmonary edema :common in pregnant women and results in death in 80% of patients • Profound hypoglycemia : young children and pregnant women. • The most prominent symptoms all relate to loss of RBCs: a) tachycardia, b) anemia, c) fever, d) hypotension and e) splenomegaly. GSH - Tropmed - 2010 32 Severe malaria • 1. Cerebral malaria 2. Acute renal failure 3. ARDS 4. Severe anaemia (Hb < 5g%) 5. DIC 6. Haemoglobinuria 7. Hypotension, Shock 8. Hyperparasitemia 9. Repeated seizures 10. Hyperpyrexia 11. Haemolysis (Sr bil. >3 mg%) GSH - Tropmed - 2010 33 Cerebral malaria • The principal signs : seizures and unconsciousness, preceded by a severe headache. • Neurologic examination : contracted or unequal pupils, a Babinski sign, and absent or exaggerated deep tendon reflexes • Cerebrospinal fluid examination : increased pressure, increased protein, and minimal or no pleocytosis. • High fever, 41° to 42°C, with hot, dry skin may occur. GSH - Tropmed - 2010 34 ARDS • Often fatal, develop rapidly, associated with excessive intravenous fluid therapy. • Fast, labored respiration, SOB, a nonproductive cough, rales and rhonchi • Chest X-rays : increased bronchovascular markings. GSH - Tropmed - 2010 35 Confirmed Diagnosis of Malaria • All clinically suspected malaria cases require laboratory examination and confirmation. • Only in case where laboratory confirmation is not possible start treatment immediately. • Parasitological confirmation is done by thin-thick blood smear microscopy examination or by dipstick (Rapid Diagnostic Test [RDT]) or by serologic test (ICT) GSH - Tropmed - 2010 36 GSH - Tropmed - 2010 37 GSH - Tropmed - 2010 38 Figure 1. Morphology of Plasmodium knowlesi in a Giemsa-stained thin blood smear. Infected erythrocytes were not enlarged, lacked Schuffner stippling, and contained much pigment. Shown are examples of trophozoites (A–F), a schizont (G), and a gametocyte (H). Scale bars = 5 μm. GSH - Tropmed - 2010 39 Malaria Therapy Plasmo dium Un known Falci parum Condition 1st reg Formula 2nd reg Formula Non pregnant Chloroquin Primaquin 4-4-2 3 Kina Primaquin 3x2 (7) 2-3 Pregnant Chloroquin 4-4-2 Kina 3x2 (7) Sensitive Chloroquin Chloroquin Primaquin 4-4-2 3 SP Primaquin 3 2-3 Resisten Chloroquin < 25% Chloroquin SP Primaquin 4-4-2 3 3 Resisten Chloroquin >25% Kina Primaquin 3x2 (7) 3 SP Tetra/doxy Primaquin 3 4x2/2x1 (7) 3 Resisten SP >25% Chloroquin Tetra/doxy Primaquin 4-4-2 4x2/2x1 (7) 3 Chloroquin Kina Primaquin 4-4-2 3x2 (7) 3 Resinten both SP+C Kina Tetra/doxy Primaquin 3x2 (7) 4x2/2x1 (7) 3 3rd reg/ relaps Formula Kina Primaquin 3x2 (7days) 2-3 CI for pregnancy, infant : Primaquin, SP GSH - Tropmed - 2010 40 Plasmo dium Condi tion Vivax/ ovale 1st reg Formula 2nd reg Chloroquin Primaquin 4-4-2 1 (14) Resisten Chloroqui n < 25% Chloroquin Tetra/doxy Primaquin 4-4-2 4x2/2x1 (7) 1 (14) Resisten Chloroqui n >25% Kina Tetra/doxy Primaquin 3x2 (7) 4x2/2x1 (7) 1 (14) Aim Prophylaxis Regimen Chloroquin Doxycycline Kina Primaquin Dose Formula 3rd reg/ relaps Formula 3x2 (7) 1 Chloroquin Primaquin 4 (8-12 week) 3 (8-12 week) Condition 2 tabs/week 1.5 mg/kg/day Duration Temporary visitation 1 week before – 4 week after visitation Permanent visitation Max for 3 months Only for Chloroquin resistan Falciparum Max for 3 months GSH - Tropmed - 2010 41 Monitoring Malaria Treatment Early Tx failure Late Tx failure • H1-3 show sign of severe malaria • H2 parasite count > H0 • H3 parasite count > 25% H0 • H3 sexual parasite still (+) or temp >37.5 • Late clinical failure – In 4th-28th shows sign of severe malaria – Sexual parasite still (+) or temp >37.5 • Late parasitologic failure – Sexual parasite still (+) in 7th, 14th, 21st, 28th day or temp > 37.5 GSH - Tropmed - 2010 42 Artemicin based combined therapy (ACTs) for uncomplicated falciparum malaria • The following ACTs are recommended: –artemether-lumefantrine –artesunate - amodiaquine –artesunate + mefloquine –artesunate + sulfadoxine-pyrimethamine –dihydroartemisinin – piperaquine • The artemisinin derivatives (oral formulations) and partner medicines of ACTs should not be used as monotherapy in the treatment of uncomplicated malaria *Update in 2009 WHO Revised Guidelines GSH - Tropmed - 2010 43 Uncomplicated malaria treatment P. falciparum malaria • The treatment of uncomplicated P. falciparum malaria is undertaken after diagnosis of malaria by light microscopy or Dipstick. • Patients with positive think-thick blood smears or dipstick for P. falciparum malaria is treated by blisters of Coartem® (artemether 20mg/lumefantrine 120mg). See Table 1 for details of prescription. GSH - Tropmed - 2010 44 Coartem® Dosage Schedule Source: WHO, 2007 GSH - Tropmed - 2010 45 TOXOPLASMOSIS Gatot Sugiharto, MD, Internist Internal Medicine Department Faculty of Medicine, Wijaya Kusuma University Surabaya GSH - Tropmed - 2010 46 Definition • Toxoplasmosis is a zoonotic infection caused by a microscopic parasite Toxoplasma gondi. • These microscopic parasites live inside the cells of humans and animals • Domestic cat and other Felidae are the definitive host • Vertebrates are the intermediate host – Amphibians, fish, reptiles, All warm-blooded animals including man GSH - Tropmed - 2010 47 Toxoplasma - organelles GSH - Tropmed - 2010 48 Epidemiology • Toxoplasmosis is one of the most common infections in the world. • About 60 million people in the United States get it. • 400 to 4000 babies are born with congenital toxoplasmosis each year. • 90% of the babies born with it have no symptoms in infancy. • 1 in 10 babies show symptoms when born • 85% of babies show symptoms months to years later. GSH - Tropmed - 2010 49 Transmision • By touching or coming into contact with infected cat feces. • By eating contaminated raw or undercooked meat. • By eating contaminated unwashed fruits or vegetables. • By passing it to your unborn baby. • By organ transplant or blood transfusion GSH - Tropmed - 2010 50 Human/Congenital Transfer GSH - Tropmed - 2010 51 Toxoplasma gondii – Life cycle Oocyst Bradyzoite Tachyzoite GSH - Tropmed - 2010 52 T. gondii – life cycle (cont.) GSH - Tropmed - 2010 53 Toxoplasmosis Cycle GSH - Tropmed - 2010 54 GSH - Tropmed - 2010 55 Toxoplasmosis in Humans • Majority of cases are asymptomatic • Mild fever, sore muscles swollen glands and lymph nodes, similar to mononucleosis • Immunocompromized individuals are at greater risk. HIV patients, Organ transplant patients, people on chemotherapy • Pregnant women’s fetus are at risk if the mother acquires the infection during gestation. • CDC estimates 400-4000 cases of congenital toxoplasmosis per year. • Blindness, Hydrocephalus, seizures and mental retardation are common • 750 human deaths per year make it the 3rd most common lethal food poisoning. GSH - Tropmed - 2010 56 • • • • SYMPTOMS OF TOXMOPLASMOSIS IN CHILDREN Toxoplasmosis can cause premature birth or stillbirth. In most cases newborns do no show any noticeable symptoms. Babies born with severe toxoplasmosis usually have: eye infections, enlarged liver and spleen, jaundice, and pneumonia, some may die after birth. Babies who survive having severe toxoplasmosis can develop: mental retardation, impaired eyesight, cerebral palsy, seizures, and hearing loss. GSH - Tropmed - 2010 57 Toxoplasmosis Diseases GSH - Tropmed - 2010 58 CONGENTIAL TOXOPLASMOSIS • When a pregnant woman gets the infection during pregnancy and passes it on to her fetus. • Women who get toxoplasmosis before conception hardly ever pass the infection during pregnancy. • Babies that get infected during the first trimester show to have the most severe symptoms. GSH - Tropmed - 2010 59 DURATION • Toxoplasmosis can multiply and spread within a week as soon as the person gets infected, but it can take weeks or months before the person gets the symptoms. • Toxoplasmosis is not curable, it stays in the person’s body for life, but will remain inactive causing no harm. (life long immune protection) • If the person’s immune system is not working correctly due to HIV or cancer therapy, toxoplasmosis can be reactivated and cause serious harm. (nervous system) GSH - Tropmed - 2010 60 Diagnosing Toxoplasmosis • Detecting oocysts in the stool • Serological Testing—ELISA tests • IGg and IGm • Titers of IgG can last for years • Titers of IgM usually persist for only 12 weeks GSH - Tropmed - 2010 61 Toxoplasmosis - Diagnosis Antibody testing may be Followed by prenatal PCR or by CT or MRI scans Antibody testing GSH - Tropmed - 2010 62 DIAGNOSIS DURING PREGNANCY • Ultra sounds can be done to diagnose congenital toxoplasmosis (but are not always 100% accurate) • Get blood samples to measure the level of antibodies, which are the bodies defenses in the immune system. • They have been new tests that can detect the DNA of the genes that have toxoplasmosis parasites. (these help detect congenital toxoplasmosis in the fetus) GSH - Tropmed - 2010 63 TREATMENT DURING PREGNANCY • Early diagnosis and prevention can greatly decrease the chances of the baby getting the infection badly, but will not reduce the chances of transmitting the infection from mother to child. • If the pregnant woman is believed to have the infection active and she is in her first trimester of pregnancy : spiramycin. (Studies show that using spiramycin can reduce the chance of the fetus getting infected by 60%) • If the fetus is infected, and the mother is 18 weeks gestation or more : pyrimethamine and sulfadiazine. (to reduce the newborn’s symptoms) GSH - Tropmed - 2010 64 Toxoplasmosis - Treatment • Sulfadiazine and Pyrimethamine (Fansidar) usually given • AIDS patients on antiretrovirals may modify depending on CD4 counts • Patients allergic to sulfa drugs may take Clindamycin, Atovaquone, Clarithromycin, Azithromycin or Dapsone • Leucovorin (Folinic acid) may be given with Pyrimethamine if blood counts are lowered GSH - Tropmed - 2010 65 TREATMENT FOR INFECTED NEWBORNS • Babies that are born with toxoplasmosis are also giving pyrimethamine and sulfadiazine. (first year of life or sometimes longer) • 72% of infected babies had normal intelligence and motor function in their adolescence, but showed that eye infections reappeared • Some babies still developed disabilities even after using the two medications, because of damages done before birth. • In most cases babies are born without symptoms and therefore do not receive early treatment and developing severe disorders GSH - Tropmed - 2010 66 PREVENTION OF TOXOPLASMOSIS • Do not eat raw or undercooked meat • Wash hands after handling raw meat • Clean utensils, cutting boards, or other things that have come in contact with raw meats. • Wash and peel fruits and vegetables • Do not empty or clean cat’s litter boxes (if you do use gloves and wash hands after cleaning it) • Try to keep your cats indoors to stop them from eating any animal that has been infected with parasites. • Use gloves when gardening (soil may have parasites from cats. GSH - Tropmed - 2010 67