Malaria, Schistosomiasis, Tetanus MUDr. Roman Stebel Department of Infectious Diseases University Hospital Brno Obsah obrázku obloha Popis vygenerován s vysokou mírou spolehlivosti Leading causes of death in Sub-Saharan Africa, South Asia, and Southeast Asia for persons age 0-44 (World Health Organization, 2015) Picture 1 As you know, in the developing world treatable infectious diseases remain big killers... causesdeath Picture 1 Now it’s time to look at number 3: Malaria! causesdeath Leading causes of death in Sub-Saharan Africa, South Asia, and Southeast Asia for persons age 0-44 (World Health Organization, 2015) Picture 1 That’s right: 300 million new cases per year making it the most prevalent serious infectious disease! causesdeath Leading causes of death in Sub-Saharan Africa, South Asia, and Southeast Asia for persons age 0-44 (World Health Organization, 2015) > Obsah obrázku zvíře Popis vygenerován s vysokou mírou spolehlivosti > Obsah obrázku osoba, muž, budova, stojící Popis vygenerován s velmi vysokou mírou spolehlivosti > Alphonse-laveran Malaria - History uFebrile illness known already in ancient Greece and Sumeria. The name mall'aria - "bad air," as the cause of the disease was considered bad air around the standing waters. uSir Patrick Manson - the second half of the 18th century, was obsessed with the idea that malaria was carrying mosquitoes, he was not taken seriously - "Mosquito (crazy) Manson". uTo confirm his theory, he brought mosquitoes from an Italian hospital to London, where he had the mosquitoes suck on his eldest son. The young Manson really got sick (survived but treated for 1 year). uFrench physician Charles Laveran in 1880 observed in the blood of a sick soldier a protozoan Plasmodium. uLater, the presence of Plasmodium was demonstrated in the bowels of the Anopheles mosquito. In 1907 he received the Nobel Prize. Etiology of Malaria uMalaria is caused by a parasite of the genus Plasmodium – a single celled organism that cannot survive outside of their host uThe vectors of the infection are female mosquitoes of the genus Anopheles Agent Form Incubation period Period of burst Severity Possibility of relapses P. vivax Tertian 8-28 d. 48 h. Benign Yes P. ovale Tertian 8-28 d. 48 h. Benign Yes P. malariae Quartan 18-42 d. 72 h. Benign No P. falciparum Tropica 8-28 d. 24-48 h. Malignant No P. knowlesi Quotidian 12 d. 24 h. Malignant (sometimes) No Obsah obrázku snímek obrazovky Popis vygenerován s velmi vysokou mírou spolehlivosti Mosquitoes of the genus Anopheles - Transmitters of Malaria „Breeding grounds“ for mosquitoes: •rural areas •standing waters •occurrence outside urban agglomerations •malaria does not occur in large cities, exception Mumbai (A. stephansi) Pathogenesis of Malaria - Plasmodium has a wildly complex life cycle! Obsah obrázku text, mapa Popis vygenerován s velmi vysokou mírou spolehlivosti lifecycle_diag Distribution of Malaria Obsah obrázku text, mapa Popis vygenerován s velmi vysokou mírou spolehlivosti 2.1 billion people live in MALARIOUS areas! World Malaria Map by CDC (https://www.cdc.gov/malaria/travelers/about_maps.html) Obsah obrázku text, mapa Popis vygenerován s velmi vysokou mírou spolehlivosti Like HIV and TB, malaria is unequally distributed, even in the tropics… In areas of Africa with high transmission there are 2700 deaths per day = 2 per minute. It’s especially hard on kids... 75% of the deaths are among African children! www.uhhg.org/mcrh/resources/video/malariappt.pdf Geographic Occurrence of Malaria uMalaria is found in tropical and subtropical regions, where Plasmodia may reproduce sexually uMalaria does not occur in the mountains at altitudes above 1500 m, in equatorial areas over 2,500 m Historical Malaria Extension - the last case in Czechoslovakia in 1958 Malaria Symptoms uInitial non-specific symptoms: fever with headache, nausea, joint and muscle pain ("flu-like") uMalaria attack - begins with a fever, chills, rapid rise of temperature to 40 ° C, fever lasts 2 to 12 hours, rapidly decreases, with markedly sweating uBetween attack of fever - growing fatigue, nausea, vomiting, diarrhea, dry cough... uObjectively typically subikterus, hepatosplenomegaly uMalaria is not accompanied by lymphadenopathy or exanthema Severe Tropical Malaria (malignant) uP. vivax et ovale → attac only the young erythrocytes (reticulocytes) uP. malariae → attac only older erythrocytes, parasitemia remains low uP. falciparum (+ knowlesi) → attacks erythrocytes of various ages → high parasitemia On the surface of cells infected with P. falciparum occurs specifics adhesive molecules, lead to adhesion to capillary endothelium, infected cells accumulate in microcirculation of the CNS, kidney, liver, lung, myocardium → microtrombies, ischemia, DIC uThe lethality of the tropics imported is around 1%, in malignant forms up to 20% u uComplications of tropical malaria: uCerebral malaria uRenal failure uPulmonary edema uBleeding symptoms uHepatic failure uGastrointestinal complications uCirculation failure - algal malaria uHypoglycemia, ionic dysbalance... Clinical and Biological Criteria for Severe Malaria Obsah obrázku snímek obrazovky Popis vygenerován s velmi vysokou mírou spolehlivosti Diagnostic Tests for Malaria uThick and thin blood smears are gold standard uidentify species and quantify density uDNA probe, immunoassay u Obsah obrázku snímek obrazovky Popis vygenerován s velmi vysokou mírou spolehlivosti Differential Diagnosis of Malaria uDengue fever and others arbovirosis (rash) uTyphoid fever uReturnable typhus uRickettsiosis (rash) uLeptospirosis (Southeast Asia) uSeptic states such as meningococcal sepsis (Africa) uAfrican trypanosomosis uSchistosomiasis, filariasis (eosinophilia) uEnteroviral infections uInfectious mononucleosis – EBV, CMV (tonsilitis) uBabesiosis uAnaplasmosis uViral gastroenteritis (children, diarrhea) Malaria Treatment 1) Targeted antimalarial therapy Choice of antimalarial - depending on the type of plasmodium, the amount of parasitemia, the area of infection (incidence of antimalarial resistance) and the clinical condition of the patient 2) Supportive therapy •for imported malaria always hospitalization, outpatient treatment - for semi-immune persons only •for malignant malaria - complex intensive care (ICU), for cerebral malaria anti-edema therapy, corticosteroid effect controversial, currently not recommended The success of treatment is monitored daily examination of blood smears until the disappearance of asexual stages. Side effects Contraindication Availability Chlorochin GI SE Alergy, epilepsy, porfyria, myastenia gravis Plaquenil Artemeter /lumefantrin GI SE Alergy, first trimester of pregnancy Riamet Atovachon /proguanil GI SE Alergy, renal failure, pregnancy Malarone Meflochin Cardiotoxicity – arytmia sleeping disorders, nightmares Alergy, epilepsy, depresiv disorders, schizophrenia, first trimester of pregnancy Lariam Chinin per os Cardiotoxicity – arytmia Intervalu, cinchonism only magistraliter Chinin i.v. Cardiotoxicity – arytmia Intervalu, cinchonism only magistraliter Primachin Alergy, deficiency of G6-PDH, pregnancy Primaqiune Doxycyklin GI SE, photosensitivity Alergy, liver disorders, pregnency, children under 6 years ATB Prevention of Malaria u1) Personal Protection: •protective clothing, insect repellants, household insecticide products •window and door screens, bed nets u2) Antimalarial Chemoprophylaxis: u u Obsah obrázku text, mapa Popis vygenerován s velmi vysokou mírou spolehlivosti Schistosomiasis uParasitic disease caused by several species of flatworm uAffects many in developing countries (it’s estimated that 207M have the disease and that of those, 120M are symptomatic) uCan contract it by wading or swimming in lakes, ponds and other bodies of water infested with the parasite’s snail host. Distribution Map A Brief History... uFirst described by German pathologist uTheodore Maximilian Bilharz uBilharz performed autopsies on Egyptian patients who had died from the disease: ufound male & female parasite eggs in the liver portal system, bladder. uLater seen in Japan, called Katayama fever uSymptoms: rash on legs, fever, diarrhoea, bloody stools à emaciation, edema à death. Life Cycle Life Cycle (eggs à larvae à snail) u1. Parasite eggs released into freshwater (from human urine, feces, blood) u2. Eggs hatch à ciliated miracidia, free swimming u3. Miracidia find & infect snail host (different species prefer different snail species) u4. Each miracidia transforms into many fork-tailed, free swimming forms called cercariae within 4-6 weeks of entering snail. u5. Cercariae leave snail and move into water at a rate of 1500/day for up to 18 days. 1. 1. mira Miracidia larva with cilia u6. Cercariae find a human host, upenetrate skin, and differentiate into ularval forms called schistosomulae. u u7. Migrate through the host’s skin, gain uaccess to the lymphatic system. u u u8. Travel to the lungs (stay 3-8 days, 70% are eliminated) u9. Migrate to liver portal system, mature into male & female adults u u cer Cercariae with forked tail Life Cycle (into human à lymphatics à lungs à liver) Circariae need to find a human host within a day, or they die. Circariae find a human host and lose their tail as they’re penetrating the skin. u10. In liver m & f pair up à female inserts uherself into the gynecophoral canal of male u u11. Migrate to favoured sites: u S. mansoni – mesenteric venules of large bowel & rectum u S. japonicum – mesenteric veins of the small intestine S. haematobium – perivesical venous plexus surrounding the bladder Life Cycle (maturation à movement to target organs à egg production) Paired male & female u12. Females release eggs uEgg characteristics: u- covered in microbarbs à cling to vascular endothelium u- pores, which allow the release of: u 1) Antigens 2) Enzymes (aid in passage of eggs through host tissues) u13. Eggs enter lumen of excretory organs u 50% à passed out of body (urine, stool, blood) 50% à trapped in tissues u u Life Cycle (eggs release) Japonicum can release up to 2000 eggs/day!! uCercariae penetrate skin à rash (schistosome or swimmer’s itch) uEggs laid in target organs release antigens uCause Katayama fever: - fever - eosinophilia - urticaria - malaise - diarrhea Acute Infection (early stage) Uticaria: itchy, raised, swollen bumps uSymptoms of chronic infection caused by eggs that travel to various parts of body uEggs remain trapped in host tissues à secrete Ags à granulomatous inflammatory immune response uFibroblast cells are also at site of Infection. During late stage of chronic infection, they replace the granulomas. Their prolif. is stim. by factors produced by the schistosome egg and by cytokines from macrophages and CD4 T-cells. uFibroblasts mediate collagen deposition in the granuloma, leading to fibrosis (= fibrous connective tissues development). Chronic Infection (late stage) Uticaria: itchy, raised, swollen bumps Granuloma uIn Schistosoma mansoni infections: uWall of colon is damaged as eggs pass through inflamm. response à ulcers, inflammatory polyps, lead to fibrosis u uClinically: diarrhea, abdominal pain uEggs can also accumulate in the appendix ucan lead to appendicitis Chronic Infection (when eggs meet the GI tract) uHepatosplenic schistosomiasis uEggs carried by portal circulation à liver uGranulomatous response uGranulomas are walled off with fibrous tissue à fibrosis obstructs portal veins à portal hypertension, liver cirrhosis u esophageal varices (dilated esophageal veins, which drain the liverà bursting can cause bleeding to death. Caused directly by portal hypertension.) u splenomegaly (enlarged spleen, due to fibrosis)… Chronic Infection (when eggs meet the liver/spleen) gradient greater than 10 mmHg is considered portal hypertension. At gradients greater than 10 mmHg, blood flow though the hepatic portal system is redirected from the liver into areas with lower venous pressures  eg. The esophageal vein, which usually drains blood from the esophagus. uIn those with severe hepatosplenic schistosomiasis uBlood gets shunted directly back to the heart (doesn’t pass through liver). uEggs accumulate in heart, sometimes lodged in pulmonary arterioles. uForm granulomas à block pulmonary circulation à pulmonary hypertension. ucan lead to right ventricular failure, and eventually cardiovascular collapse. Chronic Infection (when eggs meet the heart) uGenitourinary complications uEggs lodge themselves in wall of bladder & can develop into polyps uPolyps can erode, ulcerate & cause hematuria (blood cells in urine) uEggs lodge in ureters and urethra, cause lumps and lesions à kidney failure uEggs lodge into ovaries, the uterus, cervix, fallopian tubes à lumps à complications incl. infertility u(For the men: eggs can also lodge into the testes and the prostate) u uCNS complications uS. haematobium and S. mansoni can migrate to the spine uS. japonicum found in the brain and causes encephalopathy (general brain dysfunction) u u u Chronic Infection (when eggs meet the genitourinary areas or CNS) Diagnosis uMicroscopic Detection uTake stool or urine sample to detect eggs uS. haematobium eggs are oval and have a spike at the tip uS. japonicum eggs small and almost spherical with tiny spine uS. mansoni eggs have a spike on the side (spine) u u S. mansoni S. japonicum S. haematobium uAntibody tests uAn earlier and more sensitive form of detection uSome complications uCross-reactivity with other helminthic infections (other flatworm parasites) uCan’t tell the difference between current and old infections as antibodies stay long after infection is over. uCan’t tell you anything about overall worm burden so we can’t tell how serious the infection is Diagnosis uAntigen tests: uDetect antigens in blood with immunoelectrophoresis u2 types are detected though share similar complications with antibody tests uMolecular detection: u20-25% of schistosomiasis genome has been sequenced à can use 2 probes to detect S. mansoni DNA in human blood uGenome sequencing has the potential to yield DNA vaccines u Diagnosis Prevention —For travelers it’s easy - don’t swim in fresh, stagnant water (running water is better, still not safe). — —Harder in endemic areas à people are dependent on nearby freshwater. —Focused on education, eliminating snail nesting grounds —„Molluscicides“ can be used to eliminate snails. —Proper irrigation systems and engineering are key —There are ways to build irrigation and canalization systems that don’t allow snails to inhabit the surrounding area uHowever, many irrigation/canalization projects since the 50s have ignored UN instructions, may have contributed to spread of the parasite! — Treatment uSwimmer’s itch and Katayama Fever are usually treated symptomatically. u uChemotherapy is treatment of choice - Praziquantel is most widely used drug. u uPraziquantel uExtremely well tolerated, few side effects uBroad-spectrum antihelminthic drug (antihelminthic= drugs that expel parasitic worms) uCures schistosomiasis in 80 – 90% of patients, 90% reduction in egg excretion in those not cured uCauses worm muscles contract – cannot hold onto human tissues uResistance has been reported in Egypt and Senegal u Tetanus uClostridium tetani •relatively large, Gram-positive, rod-shaped bacteria •spore-forming, anaerobic •found in soil, especially heavily-manured soils, and in the intestinal tracts and feces of human and animals clostridium tetani Left. Stained pus from a mixed anaerobic infection. At least three different clostridia are apparent. Right. Electron micrograph of vegetative Clostridium tetani cells. clostridium tetani Brief History of Disease u5th century BC: Hippocrates first described the disease u u1884: Carle and Rattone discovered the etiology (cause/origin of disease) uProduced tetanus by injecting pus from a fatal human case uNicolaier was able to do the same by injecting soil samples into animals u u1889: Kitasato isolated the organism from human victim, showed that it could produce disease when injected into animals. Reported that toxin could be neutralized by specific antibodies. u u1897: Nocard demonstrated the protective effect of passively transferred antitoxin à used in WWI u u1924: Descombey developed tetanus toxoid for active immunization à used in WWII Distribution Worldmap In developing countries, neonatal tetanus is a leading cause of neonatal mortality, accounting for over 250,000 deaths annually. It’s often called the silent killer, since infants often die before their birth is recorded. Virulence & Pathogenicity u uNot pathogenic to humans and animals by invasive infection but by the production of a potent protein toxin! u 1.Tetanus toxin or tetanospasmin 2.The second exotoxin produced is tetanolysin (function not known) u u tetToxic Hc Tetanus toxin uProduced when spores germinate and vegetative cells grow after gaining access to wounds. The organism multiplies locally and symptoms appear remote from the infection site. u uOne of the three most poisonous substances known on a weight basis, the other two being the toxins of botulism and diphtheria. uTetanus toxin is produced in vitro in amounts up to 5 to 10% of the bacterial weight. uEstimated lethal human dose of Tetanospamin = 2.5 nanograms/kg body u uBecause the toxin has a specific affinity for nervous tissue, it is referred to as a neurotoxin. The toxin has no known useful function to C. tetani. u u 1.Initially binds to peripheral nerve terminals 2. 2.Transported within the axon and across synaptic junctions until it reaches the central nervous system u TetToxinTransport Blocks the release of inhibitory neurotransmitters (glycine and gamma-amino butyric acid, GABA) across the synaptic cleft, which is required to check the nervous impulse. If nervous impulses cannot be checked by normal inhibitory mechanisms, it leads to unopposed muscular contraction and spasms that are characteristic of tetanus. Tetanospasmin initially binds to peripheral nerve terminals. It is transported within the axon and across synaptic junctions until it reaches the central nervous system. There it becomes rapidly fixed to gangliosides at the presynaptic inhibitory motor nerve endings, and is taken up into the axon by endocytosis. The effect of the toxin is to block the release of inhibitory neurotransmitters (glycine and gamma-amino butyric acid) across the synaptic cleft, which is required to check the nervous impulse. If nervous impulses cannot be checked by normal inhibitory mechanisms, it produces the generalized muscular spasms characteristic of tetanus. Tetanospasmin appears to act by selective cleavage of a protein component of synaptic vesicles, synaptobrevin II, and this prevents the release of neurotransmitters by the cells. Methods of Transmission uC. tetani can live for years as spores in feces and soil. As soon as it enters the human body through a major or minor wound and the conditions are anaerobic, the spores germinate and release the toxins. u uTetanus may follow burns, deep puncture wounds, ear or dental infections, animal bites, abortion. u uOnly the growing bacteria can produce the toxin. uIt is the only vaccine-preventable disease that is infectious but not contagious from person to person. Symptoms uTetanic seizures (painful, powerful bursts of muscle contraction) uif the muscle spasms affect the larynx or chest wall, they may cause asphyxiation ustiffness of jaw (also called lockjaw) ustiffness of abdominal and back muscles (opisthotonus) ucontraction of facial muscles (risus sardonicus) The back muscles are more powerful, thus creating the arc backward “Oposthotonus” by Sir Charles Bell, 1809. tetanus tetaiac002 Baby has neonatal tetanus with complete rigidity Obsah obrázku osoba, muž, interiér, postel Popis vygenerován s velmi vysokou mírou spolehlivosti Obsah obrázku interiér, ležící Popis vygenerován s velmi vysokou mírou spolehlivosti Obsah obrázku osoba, interiér, zeď, hledání Popis vygenerován s velmi vysokou mírou spolehlivosti Obsah obrázku osoba, muž, tvář, ústa Popis vygenerován s velmi vysokou mírou spolehlivosti Obsah obrázku osoba, držení, ruka Popis vygenerován s velmi vysokou mírou spolehlivosti Most Common Types of Tetanus uGeneralized tetanus -descending pattern: lockjaw à stiffness of neck à difficulty swallowing à rigidity of abdominal and back muscles. -spasms continue for 3-4 weeks, and recovery can last for months -death occurs when spasms interfere with respiration. - uNeonatal tetanus -form of generalized tetanus that occurs in newborn infants born without protective passive immunity because the mother is not immune. -usually occurs through infection of the unhealed umbilical stump, particularly when the stump is cut with an unsterile instrument. Methods of Diagnosis •based on the patient’s account and physical findings that are characteristic of the disease • •diagnostic studies generally are of little value, as cultures of the wound site are negative for C. tetani two-thirds of the time u •Tests that may be performed include the following: •culture of the wound site (may be negative even if tetanus is present) •tetanus antibody test •other tests may be used to rule out meningitis, rabies, strychnine poisoning, or other diseases with similar symptoms Clinical Treatment uif treatment is not sought early, the disease is often fatal u uthe bacteria are killed with antibiotics, such as penicillin or metronidazol; further toxin production is thus prevented u uthe toxin is neutralized with shots of tetanus immune globulin, TIG u uother drugs may be given to provide sedation, relax the muscles and relieve pain u udue to the extreme potency of the toxin, immunity does not result after the disease u Method of Prevention (immunization) uA person recovering from tetanus should begin active immunization with tetanus toxoid (Td) during reconvalescence. uThe vaccine includes tetanus toxoids is routinely given in the EU during childhood. Because the antitoxin levels decrease over time, booster immunization shots are needed every 15 - 20 years. u uPostexposure Prophylaxis: u Previous doses of tetanus toxoid* Clean and minor wound All other wounds Tetanus toxoid-containing vaccineΔ Human tetanus immune globulin Tetanus toxoid-containing vaccineΔ Human tetanus immune globulin◊ <3 doses or unknown Yes§ No Yes Yes ≥3 doses Only if last dose given ≥10 years ago No Only if last dose given ≥5 years ago¥ No Obsah obrázku text Popis vygenerován s velmi vysokou mírou spolehlivosti stebel.roman@fnbrno.cz