8.0 INFECTIOUS Dxs- Specific Infections FOR STUDENTS.pptx

This presentation provides an overview of infectious diseases, their causes, modes of transmission, prevention, and clinical significance. It highlights key pathogens—including bacteria, viruses, fungi, and parasites—and explains how they spread, the impact they have on human health, and the strategies used for control and treatment. Designed for medical students, healthcare professionals, and anyone interested in global health, the slides combine concise explanations with real-world examples to make complex concepts easy to understand.

1. PATHOLOGY OF INFECTIOUS DISEASES SOME SPECIFIC INFECTIONS MBBS & BDS 400L LECTURE NOTES.

2. MALARIA (15) Malaria, caused by the intracellular parasite Plasmodium , is a worldwide infection that affects 500 million. There are about 170million new cases of malaria annually with about 1-2m death occurring annually due to falciparum malaria. According to the World Health Organization, 90% of deaths from malaria occur in sub-Saharan Africa, where malaria is the leading cause of death in children younger than 5 years old.

3. Plasmodium falciparum , which causes severe malaria, and the three other malaria parasites that infect humans ( P. vivax , P. ovale , and P. malariae ) are transmitted by female Anopheles mosquitoes that are widely distributed throughout Africa, Asia, and Latin America. Nearly all of the approximately 1500 new cases of malaria each year in the United States occur in travelers or immigrants, although rare cases transmitted by Anopheles mosquitoes or blood transfusion do occur. Worldwide public health efforts to control malaria in the 1950s through 1980s failed, leaving mosquitoes resistant to DDT and malathion and Plasmodium resistant to chloroquine and pyrimethamine.

4. The manifestation of malaria varies with endemicity of the disease. Endemicity is the indication of the amount and severity of malaria in a place. An endemic area is a place where there is a constant measurable incidence of cases via natural transmission over succession of years. While a non-endemic area, is a place where transmission can not be proven in 3 successive years. The endemicity of malaria is measured by spleen rates in children <5years of age, parasite rate and environmental features, thus categorizing it as follows: 

5. Stable or holoendemic zones: these are areas where there is persistent year-round transmission. The spleen rate is >75% and parasite rate > 75%. The environmental characteristics include high humidity and thick vegetation. There is a very high mortality in children under 5years of age Hyperendemic / highly endemic zones: the spleen and parasite rates are between 50 and 74%. Malarial transmission is seasonal; mainly during the raining season which decreases during the dry season. Nigeria is a hyperendemic zone for malaria with pockets of holoendemic and mesoendemic zones. Mesoendemic zone: the spleen and parasite rates range between 11 and 49 % with a short transmission period an average annual rainfall of about 2months. These areas (desert) the development of immunity is usually delayed and adult can develop severe malaria. Hypoendemic zone: the spleen and parasite rates are 10%. The transmission of malaria is known to occur but may be absent.

6. Susceptibility to infection Congenital malaria affects about 1% of babies born in holoendemic areas Children <6years of age in endemic zones. All ages in hypoendemic zones and people of non – endemic zones traveling to endemic areas. Pregnant women especially during the 1 st pregnancy. Sickle cell disease patient Elderly patients Patients on cytotoxic chemotherapy  

7. Clinical features The major clinical presentations of malaria are divided into two: Simple malaria and Severe or complicated malaria. Simple Malaria: this is characterized by an incubation period of 8-16 days and sudden onset of an acute febrile illness that is paroxysmal in nature with headaches, diarrhea and other constitutional symptoms following the bursting of RBC releasing merozoites, toxic and other pro-inflammatory substances. These symptoms may last for up to 8hours. Severe Malaria: this is mainly caused by P. falciparum affecting predominantly children and non-immune adults. This form of malaria has a high case fatality rate depending upon the type of severe malaria. Severe malaria can take the form of any of the following: Cerebral malaria Hypotension/Algid malaria Black water fever Acute renal failure

8. Life Cycle and Pathogenesis. The life cycles of the Plasmodium species are similar, although P. falciparum differs in ways that contribute to its greater virulence. The infectious stage of malaria, the sporozoite , is found in the salivary glands of female mosquitoes. When the mosquito takes a blood meal, sporozoites are released into the human's blood and within minutes attach to and invade liver cells by binding to the hepatocyte receptor for the serum proteins thrombospondin and properdin . Within liver cells, malaria parasites multiply rapidly, releasing as many as 30,000 merozoites (asexual, haploid forms) when each infected hepatocyte ruptures.

9. Once released from the liver, Plasmodium merozoites bind by a parasite lectin-like molecule to sialic acid residues on glycophorin molecules on the surface of red cells. Within the red cells the parasites grow in a membrane-bound digestive vacuole, hydrolyzing hemoglobin through secreted enzymes. The trophozoite is the first stage of the parasite in the red cell and is defined by the presence of a single chromatin mass. The next stage, the schizont , has multiple chromatin masses, each of which develops into a merozoite. On lysis of the red cell, the new merozoites infect additional red cells. Although most malaria parasites within the red cells develop into merozoites, some parasites develop into sexual forms called gametocytes that infect the mosquito when it takes its blood meal.

10. GAMETOCYTES Are COMMON And SAUSAGE shaped

11. Pathology of Malaria. The general effects of malaria arise from two main pathogenetic sequences The destruction of RBCs and the release of their contents, including parasites, leading to generation and release of cytokines into circulation. The sequestration of P. falciparum parasitized red cells interfering with blood flow through microvasculature of organs

12. Pathology of Malaria (contd.) 1. Within 24hrs P. falciparum parasitized red cells start to express an antigene known as P. falciparum erythrocyte membrane protein-1 (PfEMP-1). This mediates the adhesion of infected red cells to the endothelium of post capillary venules in the heart, lungs, small intestines, and brain white matter. Ligands include CD36, ICAM-1, thrombospondin . Parasitized red cells also attach to unparasitized ones ( rosetting ), causing microcirculatory impairment. Ischemia due to poor perfusion causes the manifestations of cerebral malaria, which is the main cause of death due to malaria in children .

13. Pathology of Malaria (contd.) 2. Merozoites infect red cells and break down the hemoglobin to release amino acids for metabolism. The iron in the heam is oxidized and the molecule is coverted to haemozoin pigment. The rbcs once filled, ruptures to release more merozoites which induce the release of TNF α , and IL-1, followed by other cytokines. These cytokines cause fever with chills and rigors, suppress production of red blood cells, stimulate nitric oxide production (tissue damage), and induce expression of endothelial receptors for PfEMP1

14. Plasmodium falciparum causes more severe disease than other species. Some features account for its greater pathogenicity: It is able to infect red blood cells of any age, leading to high parasite burdens and profound anemia. The other species infect only young or old cells, a smaller fraction of the red cell pool. It causes infected red cells to clump together (rosette) and to stick to endothelial cells lining small blood vessels (sequestration), which blocks blood flow. It stimulates production of high levels of cytokines, It causes high levels of parasitemia , severe anemia, cerebral symptoms, renal failure, pulmonary edema, and death. Plasmodium vivax , P. ovale , and P. malariae cause low levels of parasitemia , mild anemia, and, in rare instances, splenic rupture and nephrotic syndrome

15. host resistance to Plasmodium . There are two general mechanisms First, inherited alterations in red cells make people resistant to Plasmodium . Second, repeated or prolonged exposure to Plasmodium species stimulates an immune response that reduces the severity of the illness caused by malaria. Several common mutations in hemoglobin genes confer resistance to malaria. People who are heterozygous for the sickle cell trait ( HbS ) become infected with P. falciparum , but they are less likely to die from infection. The HbS trait causes the parasites to grow poorly or die because of the low oxygen concentrations. The geographic distribution of the HbS trait is similar to that of P. falciparum , suggesting evolutionary selection of the HbS trait in people by the parasite. HbC , another common hemoglobin mutation, also protects against severe malaria by reducing parasite proliferation. People can also be resistant to malaria due to the absence of proteins to which the parasites bind. P. vivax enters red cells by binding to the Duffy blood group antigen. Many Africans, particularly most Gambians, are not susceptible to infection by P. vivax because they do not have the Duffy antigen.

16. Individuals living where Plasmodium is endemic often gain partial immune-mediated resistance to malaria, evidenced by reduced illness despite infection. Antibodies and T lymphocytes specific for Plasmodium reduce disease manifestations, although the parasite has developed strategies to evade the host immune response. CTLs may also be important in resistance to P. falciparum . P. falciparum uses antigenic variation to escape from antibody responses to PfEMP1. Each haploid P. falciparum genome has about 50 var genes, each encoding a variant of PfEMP1. At least 2% of the parasites switch PfEMP1 genes each generation. Despite enormous efforts, there has been little progress in developing a vaccine for malaria

17. Organ and systemic pathology in malaria Malaria is a multi-organ and multi-system disorder. With the exception of P. malariae induced membranous nephropathy and chronic renal failure, most organ changes produced by malaria are due to P. falciparum. Most deaths are also due to P. falciparum and occasionally P. vivax. Organ pathology of stable malaria is very different from what is seen in sporadic cases. Severe organ malfunction and death in the non-immune is due to any or a combination of the following: shock (Algid malaria); Acute renal failure ± hemoglobinuria ; severe diarrhea( choleraic malaria); cerebral malaria; acute pulmonary oedema ; and occasionally, hepatic failure and malignant hyperpyrexia. In areas of stable malaria on the other hand, morbidity is mainly due to cerebral malaria and anemia.

18. Cerebral malaria Cerebral malaria is the most life threatening malarial manifestation. It is strictly defined as unarousable coma plus heavy parasitaemia on blood film examination. Clinical features: fever headaches irritability followed by convulsions and coma; with no signs of meningeal irritation or papilloedema ; and no focal neurological signs or deficits. Pathogenesis: up-regulation of ICAM-1 and Thrombospondin receptors on the endothelium of cerebral blood vessels ( TNFα effect ?) and consequent binding to PfEMP-1 on rbcs in heavy parasitaemia leads to sequestration of pRBCs (Immune adults usually able to counter due to anti-PfEMP-1). Consequently there’s endothelial cell damage, intravascular coagulation and ischemia

19. Cerebral malaria Morphology Macroscopy : congested meninges, ; slightly swollen brain, numerous petechial hemorrhages especially in white matter. Dull hue on white matter. Microscopy : Ring hemorrhages an essential diagnostic feature of malaria- central arteriole obliterated by parasitized red blood cells surrounded by a sleeve of brain tissue then a ring of extravasated rbcs . Older lesions the sleeve of brain tissue undergoes necrosis with reparative glial proliferation, giving rise to a coin shaped lesion called malarial or durck’s granuloma. Heamozoin pigment is seen within and outside rbcs . Prognosis: 15% of childhood cases, 20% of adult cases and 50% of affected pregnant women will die even with prompt treatment.

20. Haematologic and reticuloendothelial changes Anaemia Major cause of mortality in malaria endemic areas, especially in children aged 6months to 3years. Pathogenesis: there’s overall reduction in red cell life span in plasmodial infection. Red cells rupture following each cycle of erythrocytic schizogony ; there’s phagocytosis and destruction of parasitized and unparasitized red cells in the spleen and; Erythrocyte destruction through complement mediated cytotoxicity. Morphology: The bone marrow is hyperaemic and expanded Microscopy: Anemia is usually normocytic and normochromic. Bone marrow blood vessels contain parasites. Hemozion is seen within macrophages. There is normoblastic hyperplasia with myelocytic proliferation. There may be temporary marrow suppression in heavy parasitaemia or megaloblastic erythropoiesis if folic acid is deficienct . Peripheral blood film shows, many parasites, polychromasia , anisocytosis , poikilocytosis , target cells, howel jolly bodies and reticulocytes.

21. Other hematological changes in malaria Unconjugated hyperbilirubinemia , and increased urobilinogen in urine. Left shift in leucocyte maturation with initial leukocytosis then leucopenia and monocytosis . ±relative thrombocytopenia and DIC.

22. Splenic changes in Malaria The spleen is the major site of extravascular hemolysis and immunoglobulin production in malaria. This is the basis of the splenomegaly associated with the disease. Splenic rate is the incidence of malaria related splenomagaly in under fives and is used as an index of endemicity in a given community. In areas of stable malaria, the degree of enlargement in this age group is proportionate to the average level of parasitaemia in each case.

23. Splenic changes in Malaria ( contd ) The spleen is enlarged and weighs about 500g. During acute attacks it is soft and diffusely pigmented. Upon repeated attacks the spleen is much larger and may exceed 1000g. In Hyperimmune Malarial Splenomegaly (HIMS), also known as Tropical Splenomegaly Syndrome (TSS); splenomagaly is massive (>1000g sometimes approaching 5kg) in association with moderate anaemia , thrombocytopenia, high IgM level and presence of liver sinusoidal lymphocytosis No other identifiable cause in the presence of chronic low-grade malarial infection in an endemic area. Sustained reversal of clinical and laboratory features with prolonged/ lifelong anti malarial therapy.

24. Splenic changes in Malaria ( contd ) Morphology :Macro; acute malaria causes congestion and enlargement of the spleen in children. capsule is tense and slaty grey, cut surface is red and firm. In chronic malaria infection, the spleen becomes increasingly fibrotic and brittle, with a thick capsule and fibrous trabeculae . The parenchyma is gray or black, Capsule is pitch black. In adulthood capsule is slaty -grey and wrinkled with pulp fibrosis. Splenic size also reduces because of splenic pulp atrophy. Micro; acutely, splenic sinuses and vessels are filled with parasitized red cells. In addition, macrophages with engulfed parasites, red blood cells, and debris are numerous. Hemozoin pigment is found in macrophages, and sinusoidal lining cells. Haemorrhages and infarcts may be present. Spleens from patients with chronic malaria are fibrotic with foci of mineralization (Gandy- Gamna bodies).Chronically, there is progressive loss of pigment, and parasites become scanty.

25. Liver changes in Malaria Macro; The liver is slightly enlarged and has a slate- gray appearance ( hemozoin staining). with progression of malaria, it becomes progressively enlarged, oedematous with tense glisson’s capsule. There’s a slaty grey hue or pale yellow colour if anaemia is severe Micro; Kupffer cells are heavily laden with malarial pigment, parasites and parasitized RBC. The sinusoids and other vessels are usually congested. Focal areas of fatty change may be seen while some pigment is also present in the parenchymal cells more in zone 3. striking paracentral hemorrhagic necrosis in acute severe malaria in the non immune. Hepatic sinusoidal lymphocytosis (dilated sinusois filled with lymphocytes and monocytes) seen in TSS but not pathognomonic.

26. Black water fever Characterized by fever, hyperbilirubinemia , hemoglobinuria , vomiting, shock, and acute renal failure. It derives its name from the brown red colour of the urine produced. It occurs in the non-immune. Pathogenesis: underlying disorder is acute massive intravascular hemolysis usually associated with quinine therapy but has been described in P. falciparum malaria in the absence of quinine use. Acute renal failure is a prominent feature produced by shock due to the toxic action of free hemoglobin in circulation Morphology: Enlarged edematous kidneys with pale cortices (showing petechiae ) and congested medulla. Microscopy: bloodless glomeruli, amorphous hyaline material in bowmans capsule, patchy necrosis of distal tubules sparing proximal tubule which may be dilated and contain casts. Prognosis: the sole danger to life is ureamia and metabolic acidosis due to acute renal failure. Sound management is essential for good outcome

27. Renal Changes in Malaria Renal changes depend on the plasmodium specie involved, as well as level of parasitaemia and host immunity. The changes associated with black water fever have been outlined and though may be fatal, ultimately the most life threatening renal pathology is associated with P. malariae infection….. P malariae nephropathy several features of chilhood nephrotic syndrome in the tropics point to P malariae as a cause. It peaks about 5 years as against chilhood nephrotic syndrome in europe and north africa that is due to minimal change disease, and peaks between 6months and 2 years of age. The proteinuria is nonselective and the overall long term prognosis is bad. The classical minimal change disease is uncommon and has an excelent outcome. Pathogenesis: in this disease glomerular damage is due to in situ immune complex deposition within the GBM and mesangium . Complement activation causes acute inflammatory damage. Microscopy: absent hemozoin . Thickened GBM with Glomerular Hypercellularity . Immunoflourescence shows deposits of IgG , IgM , and C3. Electron microscopy: deposits within GBM and sub-endothelial space, but in a pattern different from that of acute post streptococcal glomerulonephritis.

28. Acute diffuse Glomerulonephritis : in cerebral malaria, severe glomerular congestion, with hemozoin pigment and parasitized red cells are seen in the glomeruli. About 2% of patients may develop proteinuria up to nephrotic range. Long term sequelae is unknown but likely completely resolve with the acquisition of immunity. Morphology: Macro ; kidneys are often enlarged and congested, ± cortical petechial hemorrhages. Micro; hypercellularity , hemozoin pigment in the glomeruli and mesangium , and hemoglobin casts in the tubules. The cortico -medullary capillaries show parasitized RBCs and haemoglobin in tubules Immunnoflorescence shows granular deposits of IgG , IgM but not IgA in the mesangium . Electron microscopy: deposits in expanded mesangial matrix.   Renal Changes in Malaria

29. The Heart and Malaria Nonspecific focal hypoxic lesions in may be induced by the progressive anemia and circulatory stasis in chronically infected people. Heart muscle shows features of hyperdynamic circulation and volume overload. Macro: The heart may be dilated, flabby with dilated chambers and valve rings at autopsy. Micro: pericardial/ endocardial petechiae and congested capillaries which may contain parasitized RBC. In some, the myocardium shows focal interstitial infiltrates and focal myocytolysis . Increased lipofusin deposition but no hemozoin in the myocytes .

30. The Lungs and Malaria In endemic areas post mortem findings in the lungs are difficult to attribute to malaria alone because co-morbidities are not uncommon especially in children. In non- immune adults features like adult respiratory distress syndrome have been described. Fibrin may be deposited in alveoli resulting in shock lung or ARDS. In the nonimmune , pulmonary edema or shock with DIC may cause death The lungs are heavier than normal, congested and oedematous with occassional parasitized erythrocytes in pulmonary capillaries. The alveoli are filled with fluid ± hyaline membrane formation, thickened alveolar septae and areas of intra alveolar hemorrhage. Sometimes in the absence of other characteristic lesions. pigmented phagocytic cells may be found in the lungs.

31. GIT and Malaria The GIT is oedematous , congested and contain focal/diffuse haemorrhage . Small vessels of the intestinal mucosa contain parasitized RBC; sometimes in massive numbers. Massive sequestration and parasitisation of the GIT is sometime associated with vasomotor collapse resulting in the clinical syndrome of Algid malaria.   Malaria and the Placenta The placenta bed is markedly parasitized in malarial infestation. This may be a source for maternal anaemia , recrudescence of disease when inadequately cleared, pregnancy wastage and intrauterine growth retardation. In active disease massive parasitization of the intervillous space occurs, while old infection appears as peri-villous fibrosis and hemozoin deposition. Hemozoin takes some weeks to clear.

32. LEISHMANIASIS (9) Leishmaniasis Leishmaniasis is a chronic inflammatory disease of the skin, mucous membranes, or viscera caused by obligate intracellular, kinetoplast -containing ( kinetoplastid ) protozoan parasites transmitted through the bite of infected sandflies ( phlebotomus spp ). Leishmaniasis is endemic in the Middle East, South Asia, Africa, and Latin America. It is epidemic, in Sudan, India, Bangladesh, and Brazil, where tens of thousands of people have died of visceral leishmaniasis . Leishmanial infection, like other intracellular organisms (mycobacteria, Histoplasma , Toxoplasma , and trypanosomes), is exacerbated by conditions that interfere with T-cell function, such as AIDS. Culture or histologic examination is used to diagnose the infection

33. Pathogenesis. The life cycle of Leishmania involves two forms: the promastigote, in the sandfly, and the amastigote, in host macrophages. Mammals (rodents, dogs, and foxes) are reservoirs. When sandflies bite infected humans or animals, macrophages harboring amastigotes are ingested. The amastigotes differentiate into promastigotes, multiply within the digestive tract of the sandfly and migrate to the salivary gland. When the infected fly bites a person, the slender, flagellated infectious promastigotes are released into the host dermis along with the sandfly saliva. The promastigotes are phagocytosed, the acidity of the phagolysosome induces them to transform into round amastigotes that lack flagella but contain a single mitochondrion with its DNA massed into a kinetoplast. Amastigotes proliferate within macrophages, and dying macrophages release progeny amastigotes that can infect additional macrophages.

34. The spread of amastigotes in the body depends on the Leishmania species and host. Cutaneous disease is caused primarily by Leishmania tropica and Leishmania major in the middle east, africa , and the mediteranian . Leishmania mexicana and Leishmania braziliensis in mucocutaneous disease (also called espundia ) in central and south america ; and visceral disease involving the liver, spleen, lymph nodes and bone marrow is caused by Leishmania donovani and Leishmania infantum in africa and the middle east; and Leishmania chagasi in the americas . Tropism of Leishmania species seems to be linked in part to the optimal temperature for their growth. Parasites that cause visceral disease grow better at 37°C in vitro, whereas parasites that cause mucocutaneous disease grow better at lower temperatures. However, “cutaneous” Leishmania species often are viscerotropic in HIV patients .

35. Morphology. Leishmania species produce four different types of lesions in humans: visceral, cutaneous, mucocutaneous , and diffuse cutaneous. In visceral leishmaniasis ; parasites invade macrophages throughout the mononuclear phagocyte system, and cause severe systemic disease marked by hepatosplenomegaly , lymphadenopathy, pancytopenia, fever, and weight loss. The spleen may weigh as much as 3 kg, with congestion and meaty red appearance, caapsule is thickened and fibrotic. Lymph nodes may measure 5 cm in diameter. They are initially enlarged and rubbery, later they become matted. The liver is enlarged and rubberry cut surface shows accentuated lobulated pattern. Bone marrow is hyperplastic in the acute phase and fibroblastic in the chronic phase.

36. LEISHMANIASIS Microscopy LNs show Histiocytes filled with Leishmania , which can be demonstrated using geimsa stain chronic lymphadenitis is marked by severe fibrosis with compact collections of Histiocytes containing LD bodies and giant cells in the sinuses. Spleen shows areas of infarction and necroses and many plasma cells are present, and the normal spleen architecture is obscured.there may be foci of extramedullary hemopoiesis . Liver kuffer cells are packed with parasites, the portal tracts with histiocytes as wellas lymphocytes and plasma cells. In the late stages the liver, spleen and LNs becomes increasingly fibrotic.

37. LEISHMANIASIS Phagocytic cells crowd the bone marrow and may also be found in the lungs, gastrointestinal tract, kidneys, pancreas, and testes. Myeloid and megakaryotic lineage depression may occur. Skin hyperpigmentation may occur ( kala-azar or “black fever” in Urdu, the language spoken in India and Pakistan). In the kidneys there may be an immune complex–mediated mesangioproliferative glomerulonephritis, and in advanced cases there may be amyloid deposition. The overloading of phagocytic cells with parasites predisposes the patients to secondary bacterial infections, the usual cause of death. Hemorrhages related to thrombocytopenia may also be fatal.

38. LEISHMANIASIS Cutaneous leishmaniasis , caused by L. major, L. mexicana , and L. braziliensis , is a relatively mild, localized disease consisting of ulcer(s) on exposed skin. The lesion begins as a papule surrounded by induration, changes into a shallow and slowly expanding ulcer, often with heaped-up borders, and usually heals by involution within 6 to 18 months without treatment. Histologic findings depend on the stage of the disease. Early stages show massive infiltration of the dermis byhistiocytes containig LD bodies. The epidermis is proliferatived but the basal layer shows degenerative changes. In later stages tuberculoid granulomas, may be seen usually with many giant cells and few parasites.

39. LEISHMANIASIS Mucocutaneous leishmaniasis , found only in the New World. Moist, ulcerating or nonulcerating lesions, which may be disfiguring, develop in the nasopharyngeal areas. Lesions may be progressive and highly destructive. Microscopic examination reveals a mixed inflammatory infiltrate composed of parasite-containing macrophages with lymphocytes and plasma cells. Later the tissue inflammatory response becomes granulomatous, and the number of parasites declines. Eventually, the lesions remit and scar, although reactivation may occur after long intervals by mechanisms that are not currently understood.

40. LEISHMANIASIS Diffuse cutaneous leishmaniasis is a rare form of dermal infection, thus far found in Ethiopia and adjacent East Africa and in Central and South America. Diffuse cutaneous leishmaniasis begins as a single skin nodule, which continues spreading until the entire body is covered by generations of satelite nodular lesions. Microscopically, they contain aggregates of foamy macrophages stuffed with leishmania .

41. TRYPANOSOMIASIS (10): African Trypanosomiasis African trypanosomes are kinetoplastid parasites that proliferate as extracellular forms in the blood and cause sustained or intermittent fevers, lymphadenopathy, splenomegaly, progressive brain dysfunction (sleeping sickness), cachexia, and death. Trypanosoma brucei rhodesiense infections, which occur in East Africa, are often acute and virulent. Trypanosoma brucei gambiense infection tends to be chronic and occurs most frequently in the West African bush. Tsetse flies (genus Glossina ) transmit African Trypanosoma to humans either from the reservoir of parasites found in wild and domestic animals (T. brucei rhodesiense ) or from other humans (T. brucei gambiense ) . Within the fly, the parasites multiply in the stomach and then in the salivary glands before developing into nondividing trypomastigotes , which are transmitted to humans and animals.

42. TRYPANOSOMIASIS: African Trypanosomiasis PATHOGENESIS. African trypanosomes are covered by a single, abundant, glycolipid-anchored protein called the variant surface glycoprotein (VSG) . As parasites proliferate in the bloodstream, the host produces antibodies to the VSG, which, in association with phagocytes, kill most of the organisms, causing a spike of fever. A small number of parasites, however, undergo a genetic rearrangement and produce a different VSG on their surface and so escape the host immune response. These successor trypanosomes multiply until the host mounts an antibody response against their VSG and kills most of them, and another clone with a new VSG takes over. In this way, African trypanosomes escape the immune response to cause waves of fever before they finally invade the CNS.

43. TRYPANOSOMIASIS: African Trypanosomiasis Trypanosomes have many VSG genes, which are expressed one at a time, and are turned on and off by an elegant mechanism. Although VSG genes are scattered throughout the trypanosome genome, only VSG genes found within chromosomal regions called bloodstream expression sites , are expressed these regions are located in telomeres (the ends of chromosomes). New VSG genes are moved into the bloodstream expression sites mainly by homologous recombination. A poorly understood transcription apparatus, which includes the RNA polymerase that transcribes VSG genes, associates with a single bloodstream expression site to limit expression to one VSG gene at a time.

44. TRYPANOSOMIASIS: African Trypanosomiasis MORPHOLOGY. A large, red, rubbery chancre forms at the site of the insect bite, where large numbers of parasites are surrounded by a dense, predominantly mononuclear, inflammatory infiltrate. With chronicity, the lymph nodes and spleen enlarge due to infiltration by lymphocytes, plasma cells, and macrophages, which are filled with dead parasites. Trypanosomes, concentrate in capillary loops, such as the choroid plexus and renal glomeruli. When parasites breach the blood-brain barrier and invade the CNS, a leptomeningitis develops that extends into the perivascular Virchow-Robin spaces, and eventually a demyelinating panencephalitis occurs. Plasma cells containing cytoplasmic globules filled with immunoglobulins are frequent and are referred to as Mott cells. Chronic disease leads to progressive cachexia, and patients, devoid of energy and normal mentation, waste away.

45. TRYPANOSOMIASIS: American Trypanosomiasis CHAGAS DISEASE Trypanosoma cruzi is a kinetoplastid , intracellular protozoan parasite that causes American trypanosomiasis , or Chagas disease. Chagas disease occurs rarely in the United States and Mexico but is more common in South America, particularly Brazil. T. cruzi parasites infect many animals, including cats, dogs, and rodents. The parasites are transmitted between animals and to humans by “kissing bugs” ( triatomids ), which hide in the cracks of loosely constructed houses, feed on the sleeping inhabitants, and pass the parasites in the feces; the infectious parasites enter the host through damaged skin or through mucous membranes. At the site of skin entry there may be a transient, erythematous nodule called a chagoma .

46. TRYPANOSOMIASIS: American Trypanosomiasis PATHOGENESIS. While most intracellular pathogens avoid the toxic contents of lysosomes, T. cruzi actually requires brief exposure to the acidic phagolysosome to stimulate development of amastigotes , the intracellular stage of the parasite. To gain exposure to lysosomes, T. cruzi trypomastigotes stimulate an increase in the concentration of cytoplasmic calcium in host cells, which promotes fusion of the phagosome and lysosome. The low pH stimulates amastigote development, it also activates pore-forming proteins that disrupt the lysosomal membrane, releasing the parasite into the cell cytoplasm.

47. TRYPANOSOMIASIS: American Trypanosomiasis Parasites reproduce as rounded amastigotes in the cytoplasm of host cells and then develop flagella, lyse host cells, enter the bloodstream, and penetrate smooth, skeletal, and heart muscles. In acute Chagas disease , which is mild in most individuals, cardiac damage results from direct invasion of myocardial cells by the organisms and the subsequent inflammation. Rarely, acute Chagas disease presents with high parasitemia , fever, or progressive cardiac dilation and failure, often with generalized lymphadenopathy or splenomegaly.

48. TRYPANOSOMIASIS: American Trypanosomiasis In chronic Chagas disease , which occurs in 20% of people 5 to 15 years after initial infection, the mechanism of cardiac and digestive tract damage is controversial; it probably results from an immune response induced by T. cruzi parasites, which are still present in small numbers. A striking inflammatory infiltration of the myocardium may be induced by the scant organisms. Alternatively, parasites may induce an autoimmune response, such that antibodies and T cells that recognize parasite proteins cross-react with host myocardial cells, nerve cells, and extracellular proteins such as laminin . Damage to myocardial cells and to conductance pathways causes a dilated cardiomyopathy and cardiac arrhythmias, whereas damage to the myenteric plexus causes dilation of the colon ( megacolon ) and esophagus.

49. TRYPANOSOMIASIS: American Trypanosomiasis MORPHOLOGY. In lethal acute myocarditis, the changes are diffusely distributed throughout the heart. Clusters of amastigotes cause swelling of individual myocardial fibers and create intracellular pseudocysts . There is focal myocardial cell necrosis accompanied by extensive, dense, acute interstitial inflammatory infiltration throughout the myocardium, often associated with four-chamber cardiac dilation. In chronic Chagas disease the heart is typically dilated, rounded, and increased in size and weight. Often, there are mural thrombi that, in about half of autopsy cases, have given rise to pulmonary or systemic emboli or infarctions.

50. TRYPANOSOMIASIS: American Trypanosomiasis On histologic examination, there are interstitial and perivascular inflammatory infiltrates composed of lymphocytes, plasma cells, and monocytes. There are scattered foci of myocardial cell necrosis and interstitial fibrosis, especially toward the apex of the left ventricle, which may undergo aneurysmal dilation and thinning. In the Brazilian endemic foci, as many as half of the patients with lethal carditis also have dilation of the esophagus or colon, related to damage to the intrinsic innervation of these organs. At the late stages, however, when such changes appear, parasites cannot be found within these ganglia. Chronic Chagas cardiomyopathy is often treated by cardiac transplantation.

51. Schistosomiasis (METAZOA) (6) Schistosomiasis infects approximately 200 million persons and kills over 100,000 individuals annually. Most of the mortality comes from hepatic cirrhosis, caused by Schistosoma mansoni in Latin America, Africa, and the Middle East and Schistosoma japonicum and Schistosoma mekongi in East Asia. In addition, Schistosoma haematobium , found in Africa, causes hematuria and granulomatous disease of the bladder, resulting in chronic obstructive uropathy .

52. Schistosomiasis Pathogenesis. Schistosomiasis is transmitted by freshwater snails that live in the slow-moving water of tropical rivers, lakes, and irrigation ditches, ironically linking agricultural development with spread of the disease. Infectious schistosome larvae ( cercariae ) swim through fresh water and penetrate human skin with the aid of powerful proteolytic enzymes that degrade the keratinized layer. Schistosomes migrate into the peripheral vasculature, travel to the lung, and mature and mate in hepatic vessels, then migrate out as male-female worm pairs and settle in the portal or pelvic venous system. Females produce hundreds of eggs per day, around which granulomas and fibrosis form. Schistosome eggs produce proteases and elicit prominent inflammatory reactions. This inflammatory response is necessary for passive transfer of eggs across the intestine and bladder walls, allowing the eggs to be shed in stool or urine, respectively. Infection of freshwater snails completes the life cycle.

53. Schistosomiasis Eggs that are carried by the portal circulation into the hepatic parenchyma cause prominent inflammatory reactions. This immune response to S. mansoni and S. japonicum eggs in the liver causes the severe pathology of schistosomiasis . While the immune response does provide some protection in animal models, the price of this response is granuloma formation and hepatic fibrosis. Acute schistosomiasis in humans can be a severe febrile illness that peaks about 2 months after infection. The helper T-cell response in this early stage is dominated by T H 1 cells that produce IFN-γ, which stimulates macrophages to secrete high levels of the cytokines TNF, IL-1, and IL-6 that cause fever. Chronic schistosomiasis is associated with a dominant T H 2 response, although T H 1 cells persist. Stimulation of T H 2 cells may be due to proteins in the parasite egg that cause mast cells to produce IL-4, which induces further T H 2 differentiation and amplifies the response. Both types of helper T cells contribute to the formation of granulomas surrounding eggs in the liver. Severe hepatic fibrosis is a serious manifestation of chronic schistosomiasis . In animal models, IL-13, produced by T H 2 cells, increases fibrosis by stimulating the synthesis of collagen.

54. Schistosomiasis Morphology . In mild S. mansoni or S. japonicum infections, white, pinhead-sized granulomas are scattered throughout the gut and liver. At the center of the granuloma is the schistosome egg, which contains a miracidium ; this degenerates over time and calcifies. The granulomas are composed of macrophages, lymphocytes, neutrophils, and eosinophils ; eosinophils are distinctive for helminth infections. The liver is darkened by regurgitated heme -derived pigments from the schistosome gut, which, like malaria pigments, are iron-free and accumulate in Kupffer cells and splenic macrophages. In severe S. mansoni or S. japonicum infections, inflammatory patches or pseudopolyps may form in the colon. The surface of the liver is bumpy, and cut surfaces reveal granulomas and widespread fibrosis and portal enlargement without intervening regenerative nodules. Because these fibrous triads resemble the stem of a clay pipe, the lesion is named pipe-stem fibrosis .

55. Schistosomiasis The fibrosis often obliterates the portal veins, leading to portal hypertension, severe congestive splenomegaly, esophageal varices , and ascites. Schistosome eggs, diverted to the lung through portal collaterals, may produce granulomatous pulmonary arteritis with intimal hyperplasia, progressive arterial obstruction, and ultimately heart failure ( cor pulmonale ). The most frequent complication of S. haematobium infection is inflammation and fibrosis of the ureteral walls, leading to obstruction, hydronephrosis , and chronic pyelonephritis. There is also an association between urinary schistosomiasis and squamous cell carcinoma of the bladder .

56. Schistosomiasis On histologic examination, arteries in the lungs show disruption of the elastic layer by granulomas and scars, luminal organizing thrombi, and angiomatoid lesions similar to those of idiopathic pulmonary hypertension. Patients with hepatosplenic schistosomiasis also have an increased frequency of mesangioproliferative or membranous glomerulopathy . In S. haematobium infection, inflammatory cystitis due to massive egg deposition and granulomas appear early, leading to mucosal erosions and hematuria. Later, the granulomas calcify, develop a “sandy” appearance, and, if severe, cause a dense concentric rim (calcified bladder) on radiographic films

57. Onchocerciasis (4) Onchocerca volvulus , a filarial nematode transmitted by black flies, affects millions of people in Africa, South America, and Yemen. Its endemic in equitorial West and East Africa; Central America and tropical South America It is characterised by changes in the skin and subcutaneous tissue, and changes in the eye leading to blindness. It is transmitted from man to man by the simulium ‘black’ fly. These flies inhabit banks of large rivers and breeds during the wet season, the period of peak transmission of the infection. Ivermectin treatment has dramatically reduced the incidence of Onchocerca infection in West Africa; however, it remains the second most common preventable cause of blindness in sub-Saharan Africa. It is estimated that there are half a million people who are blind due to onchocerciasis .

58. Onchocerciasis (river blindness) The adult worms are found in subcutaneous tissue. Male and female worms coil up together in skin nodules. The females produce microfilariae which are picked up when the simulium flies bite. The microfilariae develop for aprox . 15 days within the flies thoracic muscles, then migrate to its mouth parts to be injected into the next victim as infective larvae which develop and attain sexual maturity in about a year. Adult O. volvulus parasites mate in the dermis, where they are surrounded by a mixed infiltrate of host cells that produces a characteristic subcutaneous nodule ( onchocercoma ) .

59. Onchocerciasis (river blindness) The major pathologic process is caused by large numbers of microfilariae, released by females, that accumulate in the skin and in the eye chambers. Punctate keratitis is caused by inflammation around a degenerating microfilaria. Unfortunately, it is sometimes accentuated by treatment with antifilarial drugs ( Mazzotti reaction). Ivermectin kills only immature worms, not adult worms, so parasites repopulate the host a few months after treatment. Doxycycline treatment blocks reproduction of O. volvulus for up to 24 months. Doxycycline kills Wolbachia , symbiotic bacteria that live inside adult O. volvulus and are required for the fertility of the worm.

60. Onchocerciasis (river blindness) Onchocerca volvulus causes chronic, itchy dermatitis with focal darkening or loss of pigment and scaling, referred to as leopard, lizard, or elephant skin . Foci of epidermal atrophy and elastic fiber breakdown may alternate with areas of hyperkeratosis, hyperpigmentation with pigment incontinence, dermal atrophy, and fibrosis. The subcutaneous onchocercoma is composed of a fibrous capsule surrounding adult worms and a mixed chronic inflammatory infiltrate that includes fibrin, neutrophils , eosinophils , lymphocytes, and giant cells. The progressive eye lesions begin with punctate keratitis along with small, fluffy opacities of the cornea caused by degenerating microfilariae , which evoke an eosinophilic infiltrate. This is followed by a sclerosing keratitis that opacifies the cornea, beginning at the scleral limbus . Microfilariae in the anterior chamber cause iridocyclitis and glaucoma, whereas involvement of the choroid and retina results in atrophy and loss of vision.

61. Tuberculosis (18). Mycobacterium tuberculosis is responsible for most cases of tuberculosis; the reservoir of infection is humans with active tuberculosis. Oropharyngeal and intestinal tuberculosis contracted by drinking milk contaminated with M. bovis is rare ,but is still seen in countries that have tuberculous dairy cows and unpasteurized milk.

62. Epidemiology. Tuberculosis is estimated to affect 1.7 billion individuals worldwide, with 8 to 10 million new cases and 1.6 million deaths each year, a toll second only to HIV disease. Infection with HIV makes people susceptible to rapidly progressive tuberculosis; over 10 million people are infected with both HIV and M. tuberculosis . Tuberculosis flourishes wherever there is poverty, crowding, and chronic debilitating illness. Certain disease states also increase the risk : diabetes mellitus, Hodgkin lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression.

63. It is important that infection with M. tuberculosis be differentiated from disease . Infection is the presence of organisms, which may or may not cause clinically significant disease. In most people primary tuberculosis is asymptomatic, although it may cause fever and pleural effusion. If immune defenses are lowered, the infection may reactivate to produce disease. Infection leads to the development of delayed hypersensitivity to M. tuberculosis antigens, detectable by the tuberculin ( Mantoux ) skin test, 2 to 4 weeks after infection. A positive tuberculin test result signifies T cell–mediated immunity to mycobacterial antigens, but does not differentiate between infection and disease. False-negative reactions may occur in the setting of certain viral infections, sarcoidosis , malnutrition, Hodgkin lymphoma, immunosuppression, and (notably) overwhelming active tuberculous disease. False-positive reactions may result from infection by atypical mycobacteria or prior vaccination with BCG ( Bacillus Calmette -Guerin ).

64. Pathogenesis . The pathogenesis of tuberculosis in a previously unexposed, immunocompetent person depends on the development of anti-mycobacterial cell-mediated immunity, which confers resistance to the bacteria and also results in development of hypersensitivity to mycobacterial antigens. The pathologic manifestations of tuberculosis, such as caseating granulomas and cavitation, are the result of the hypersensitivity that develops in concert with the protective host immune response. Because the effector cells that mediate immune protection also mediate hypersensitivity and tissue destruction, the appearance of hypersensitivity also signals the acquisition of immunity to the organism

65.    Macrophages are the primary cells infected by M. tuberculosis . Early in infection, tuberculosis bacilli replicate essentially unchecked, while later in infection, T-cell response stimulates macrophages to contain the proliferation of the bacteria.    M. tuberculosis enters macrophages by endocytosis mediated by several macrophage receptors: mannose receptors bind lipoarabinomannan , a glycolipid in the bacterial cell wall, and complement receptors bind opsonized mycobacteria.  Inside the macrophage, M. tuberculosis organisms replicate within the phagosome . It blocks phagolysosome formation by inhbiting Ca 2+ signals and the recruitment and assembly of the proteins that mediate phagosome -lysosome fusion.

66. Thus, during the earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual, bacteria proliferate in the pulmonary alveolar macrophages and airspaces, resulting in bacteremia and seeding of multiple sites. D espite the bacteremia, most people at this stage are asymptomatic or have a mild flulike illness .   The genetic makeup of the host may influence the course of the disease. In some people with polymorphisms in the NRAMP1 gene, the disease may progress due to the absence of an effective immune response   About 3 weeks after infection, a T-helper 1 (T H 1) response is mounted that activates macrophages to become bactericidal. Differentiation of T H 1 cells depends on IL-12, which is produced by antigen-presenting cells that have encountered mycobacterial antigens in the lymph nodes.

67. Mature T H 1 cells, both in lymph nodes and in the lung, produce IFN-γ. INF- γ is the critical mediator that enables macrophages to contain the M. tuberculosis infection . IFN-γ stimulates formation of the phagolysosome in infected macrophages, IFN-γ also stimulates expression of inducible nitric oxide synthase, which produces nitric oxide, capable of destroying several mycobacterial constituents, from cell wall to DNA. the T H 1 response orchestrates the formation of granulomas and caseous necrosis. Macrophages activated by IFN-γ differentiate into the “ epithelioid histiocytes ” that characterize the granulomatous response, and may fuse to form giant cells. In many people this response halts the infection before significant tissue destruction or illness. In other people the infection progresses due to advanced age or immunosuppression, and the ongoing immune response results in tissue destruction or caseation leading to cavitation.

68. Activated macrophages also secrete TNF, which promotes recruitment of more monocytes.   defects in any of the steps in generating a T H 1 response result in absence of resistance and disease progression. In summary, immunity to M. tuberculosis is primarily mediated by T H 1 cells, which stimulate macrophages to kill the bacteria. This immune response, while largely effective, comes at the cost of hypersensitivity and accompanying tissue destruction. Reactivation of the infection or re-exposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as hypersensitivity and resistance are related, so, too, the loss of hypersensitivity (indicated by tuberculin negativity in a previously tuberculin-positive individual) may be an ominous sign that resistance to the organism has faded.

69. Clinical Features of Tuberculosis . Primary tuberculosis is the form of disease that develops in a previously unexposed, and therefore unsensitized , person . About 5% of newly infected people develop clinically significant disease. The elderly and profoundly immunosuppressed persons may lose their immunity to M. tuberculosis and so may develop primary tuberculosis more than once. With primary tuberculosis the source of the organism is exogenous.

70. Localized secondary tuberculosis may be asymptomatic. manifestations, they are usually insidious in onset. Systemic symptoms, often appear early in the course and include malaise, anorexia, weight loss, and fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then subsiding), and night sweats occur. With progressive pulmonary involvement, increasing amounts of sputum, at first mucoid and later purulent, appear. Some degree of hemoptysis is present in about half of all cases of pulmonary tuberculosis. Pleuritic pain may result from extension of the infection to the pleural surfaces. Extrapulmonary manifestations of tuberculosis are legion and depend on the organ system involved. The diagnosis of pulmonary disease is based in part on the history and on physical and radiographic findings of consolidation or cavitation in the apices of the lungs . Ultimately, however, tubercle bacilli must be identified . Acid-fast smears and cultures of the sputum of patients suspected of having tuberculosis should be performed. PCR amplification of M. tuberculosis DNA allows for even more rapid diagnosis. However, culture remains the gold standard because it also allows testing of drug susceptibility. Multidrug resistance is now seen more commonly than it was in past years All stages of HIV infection are associated with an increased risk of tuberculosis.

71. Morphology. Primary Tuberculosis . In countries where infected milk has been eliminated, primary tuberculosis almost always begins in the lungs. Typically, the inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization develops, a 1- to 1.5-cm area of gray-white inflammation with consolidation emerges, known as the Ghon focus. In most cases, the center of this focus undergoes caseous necrosis. Tubercle bacilli, either free or within phagocytes, drain to the regional nodes, which also often caseate. This combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex. During the first few weeks there is also lymphatic and hematogenous dissemination to other parts of the body. In approximately 95% of cases, development of cell-mediated immunity controls the infection. Hence, the Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex), and despite seeding of other organs, no lesions develop.

72. Histologically, sites of active involvement are marked by a characteristic granulomatous inflammatory reaction that forms both caseating and noncaseating tubercles. Individual tubercles are microscopic; it is only when multiple granulomas coalesce that they become macroscopically visible. The granulomas are usually enclosed within a fibroblastic rim punctuated by lymphocytes. Multinucleate giant cells are present in the granulomas. Immunocompromised people do not form the characteristic granulomas . Secondary Tuberculosis. T he initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1 to 2 cm of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a variable amount of central caseation and peripheral fibrosis. In immunocomptetent individuals, the initial parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars. Histologically, the active lesions show characteristic coalescent tubercles with central caseation. Tubercle bacilli can often be identified with acid-fast stains in early exudative and caseous phases of granuloma formation but are usually too few to be found in the late, fibrocalcific stages. Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways.

73. Progressive pulmonary tuberculosis may ensue in the elderly and immunosuppressed. The apical lesion expands into adjacent lung and erodes into bronchi and vessels. This evacuates the caseous center, creating a ragged, irregular cavity walled off by fibrous tissue. Erosion of blood vessels results in hemoptysis . With treatment the process may be arrested, although healing by fibrosis often distorts the pulmonary architecture . The cavities may persist or become fibrotic. Infection may spread via airways, lymphatic channels, or the vascular system. Miliary pulmonary disease occurs when organisms draining through lymphatics enter the venous blood and circulate back to the lung. Individual lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered through the lung parenchyma (the adjective “miliary” is derived from the resemblance of these foci to millet seeds). Miliary lesions may expand and coalesce, resulting in consolidation of large regions or even whole lobes of the lung. With progressive pulmonary tuberculosis, the pleural cavity is invariably involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop.

74. Endobronchial, endotracheal, and laryngeal tuberculosis may develop by spread through lymphatic channels or from expectorated infectious material. The mucosal lining may be studded with minute granulomatous lesions that may only be apparent microscopically. Systemic miliary tuberculosis occurs when bacteria disseminate through the systemic arterial system. Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis, but could involve any organ. Isolated tuberculosis may appear in any of the organs or tissues seeded hematogenously and may be the presenting manifestation. Organs that are commonly involved include the meninges ( tuberculous meningitis ), kidneys ( renal tuberculosis ), adrenals (formerly an important cause of Addison disease), bones ( osteomyelitis ), and fallopian tubes ( salpingitis ). When the vertebrae are affected, the disease is referred to as Pott disease . Paraspinal “cold” abscesses in these patients may track along tissue planes and present as an abdominal or pelvic mass.

75. Lymphadenitis is the most frequent presentation of extrapulmonary tuberculosis, usually occurring in the cervical region (“scrofula”). It tends to be unifocal and localized. In HIV, it is almost always multifocal, with systemic symptoms, and either pulmonary or other organ involvement by active tuberculosis. Intestinal tuberculosis contracted by the drinking of contaminated milk was a fairly common primary focus of disease, In years past. Where milk is pasteurized, it is more commonly caused by the swallowing of coughed-up infective material. Typically the organisms seed to mucosal lymphoid aggregates of the small and large bowel, which undergo granulomatous inflammation leading to ulceration of the overlying mucosa, particularly in the ileum.

76. Primary pulmonary tuberculosis, Ghon complex. The gray-white parenchymal focus under the pleura in the lower part of the upper lobe, and Hilar lymph nodes with caseation . Characteristic tubercle at low magnification and in detail. Non caseating granuloma . Sheets of foamy macrophages packed with mycobacteriaI in immunosuppressed individuals .

77. Mycobacterium avium-intracellulare Complex Mycobacterium avium and M. intracellulare are separate species, but the infections they cause are so similar that they are simply referred to as M. avium-intracellulare complex, or MAC. MAC is common in soil, water, dust, and domestic animals. Clinically significant infection with MAC is uncommon except among people with AIDS and low numbers of CD4+ lymphocytes (<60 cells/mm 3 ). In AIDS patients MAC causes widely disseminated infections, and organisms proliferate abundantly in many organs, including the lungs and gastrointestinal system. Unchecked by the immune response, the organisms reach very high levels: up to 10 4 organisms/mL of blood and 10 6 organisms/gm in tissue. Patients are feverish, with drenching night sweats and weight loss. In the rare case of MAC in a person without HIV, the organisms primarily infect the lung, causing a productive cough and sometimes fever and weight loss.

78. There may be a yellowish pigmentation to these organs secondary to the large number of organisms present in swollen macrophages. Granulomas, lymphocytes, and tissue destruction are rare. Morphology. The hallmark of MAC infections in patients with HIV is abundant acid-fast bacilli within macrophages. Depending on the severity of immune deficiency, MAC infections can be widely disseminated throughout the mononuclear phagocyte system, causing enlargement of involved lymph nodes, liver, and spleen, or localized to the lungs.

79. Leprosy (6) Leprosy, or Hansen's disease, is a slowly progressive infection caused by Mycobacterium leprae that mainly affects the skin and peripheral nerves and results in disabling deformities. M. leprae is likely to be transmitted from person to person through aerosols from asymptomatic lesions in the upper respiratory tract. Inhaled M. leprae , like M. tuberculosis , is taken up by alveolar macrophages and disseminates through the blood, but replicates only in relatively cool tissues of the skin and extremities. Despite its low communicability, leprosy remains endemic among an estimated 10 to 15 million people living in poor tropical countries.

80. Pathogenesis . M. leprae is an acid-fast obligate intracellular organism that grows very poorly in culture but can be propagated in the armadillo. It proliferates best at 32° to 34°C, the temperature of the human skin and the core temperature of armadillos. Like M. tuberculosis , M. leprae secretes no toxins, and its virulence is based on properties of its cell wall. The cell wall is similar enough to that of M. tuberculosis that immunization with BCG confers some protection against M. leprae infection. Cell-mediated immunity is reflected by delayed-type hypersensitivity reactions to dermal injections of a bacterial extract called lepromin . M. leprae causes two strikingly different patterns of disease . People with the less severe form, tuberculoid leprosy , have dry, scaly skin lesions that lack sensation. They often have asymmetric involvement of large peripheral nerves. The more severe form, lepromatous leprosy , includes symmetric skin thickening and nodules. This is also called anergic leprosy , because of the unresponsiveness (anergy) of the host immune system. Cooler areas of skin, including the earlobes and feet, are more severely affected than warmer areas, such as the axilla and groin.

81. In lepromatous leprosy, widespread invasion of the mycobacteria into Schwann cells and into endoneural and perineural macrophages damages the peripheral nervous system. In advanced cases of lepromatous leprosy, M. leprae is present in sputum and blood. People can also have intermediate forms of disease, called borderline leprosy The T-helper lymphocyte response to M. leprae determines whether an individual has tuberculoid or lepromatous leprosy. People with tuberculoid leprosy have a T H 1 response associated with production of IL-2 and IFN-γ. As with M. tuberculosis , IFN-γ is critical to mobilizing an effective host macrophage response. Lepromatous leprosy is associated with a weak T H 1 response and, in some cases, a relative increase in the T H 2 response. The net result is weak cell-mediated immunity and an inability to control the bacteria. Occasionally, most often in the lepromatous form, antibodies are produced against M. leprae antigens. Paradoxically, these antibodies are usually not protective, but they may form immune complexes with free antigens that can lead to erythema nodosum, vasculitis, and glomerulonephritis.

82. Morphology Tuberculoid leprosy begins with localized flat, red skin lesions that enlarge and develop irregular shapes with indurated, elevated, hyperpigmented margins and depressed pale centers (central healing). Neuronal involvement dominates tuberculoid leprosy. Nerves become enclosed within granulomatous inflammatory reactions and, if small (e.g., the peripheral twigs), are destroyed. Nerve degeneration causes skin anesthesias and skin and muscle atrophy that render the person liable to trauma of the affected parts, leading to the development of chronic skin ulcers. Contractures, paralyses, and autoamputation of fingers or toes may ensue. Facial nerve involvement can lead to paralysis of the eyelids, with keratitis and corneal ulcerations. On microscopic examination, all sites of involvement have granulomatous lesions closely resembling those found in tuberculosis, and bacilli are almost never found, hence the name “paucibacillary” leprosy. The presence of granulomas and absence of bacteria reflect strong T-cell immunity. Because leprosy pursues an extremely slow course, spanning decades, most patients die with leprosy rather than of it.

83. Lepromatous leprosy involves the skin, peripheral nerves, anterior chamber of the eye, upper airways (down to the larynx), testes, hands, and feet. The vital organs and CNS are rarely affected, presumably because the core temperature is too high for growth of M. leprae . Lepromatous lesions contain large aggregates of lipid-laden macrophages (lepra cells), often filled with masses (“globi”) of acid-fast bacilli. Because of the abundant bacteria, lepromatous leprosy is referred to as “multibacillary”. Macular, papular, or nodular lesions form on the face, ears, wrists, elbows, and knees. With progression, the nodular lesions coalesce to yield a distinctive leonine facies. Most skin lesions are hypoesthetic or anesthetic. Lesions in the nose may cause persistent inflammation and bacilli-laden discharge. The peripheral nerves, particularly the ulnar and peroneal nerves where they approach the skin surface, are symmetrically invaded with mycobacteria, with minimal inflammation. Loss of sensation and trophic changes in the hands and feet follow the nerve lesions. Lymph nodes contain aggregates of bacteria-filled foamy macrophages in the paracortical (T-cell) areas and reactive germinal centers. In advanced disease, aggregates of macrophages are also present in the splenic red pulp and the liver. The testes are usually extensively involved, leading to destruction of the seminiferous tubules and consequent sterility.

84. Syphilis(15) Syphilis is a chronic venereal disease with multiple presentations. The causative spirochete, Treponema pallidum subsp. pallidum , referred to simply as T. pallidum , is too slender to be seen in Gram stain, but it can be visualized by silver stains, dark-field examination, and immunofluorescence techniques. Sexual contact is the usual mode of spread. Transplacental transmission of T. pallidum occurs readily, and active disease during pregnancy results in congenital syphilis. T. pallidum cannot be grown in culture.

85. Primary Syphilis. This stage, occurring approximately 3 weeks after contact with an infected individual, features a single firm, nontender, raised, red lesion (chancre) located at the site of treponemal invasion on the penis, cervix, vaginal wall, or anus. The chancre heals in 3 to 6 weeks with or without therapy. Spirochetes are plentiful within the chancre and can be seen by immunofluorescent stains of serous exudate . Treponemes spread throughout the body by hematologic and lymphatic dissemination even before the appearance of the chancre.

86. Secondary Syphilis. This stage occurs 2 to 10 weeks after the primary chancre, due to proliferation of spirochetes within the skin and mucocutaneous tissues. Occurs in approximately 75% of untreated people. The skin lesions, which frequently occur on the palms or soles of the feet, may be maculopapular, scaly, or pustular . Moist areas of the skin, such as the anogenital region, inner thighs, and axillae, may have condylomata lata , which are broad-based, elevated plaques. Silvery-gray superficial erosions may form on any of the mucous membranes but are particularly common in the mouth, pharynx, and external genitalia. All these painless superficial lesions contain spirochetes and so are infectious. Lymphadenopathy, mild fever, malaise, and weight loss are also common in secondary syphilis. The symptoms of secondary syphilis last several weeks, after which the person enters the latent phase of the disease. Superficial lesions may recur during the early latent phase, although they are milder.

87. Tertiary syphilis. This stage is rare where adequate medical care is available, but it occurs in approximately one third of untreated patients, usually after a latent period of 5 years or more. Tertiary syphilis has three main manifestations, which may occur alone or in combination. Cardiovascular syphilis , in the form of syphilitic aortitis , accounts for more than 80% of cases of tertiary disease. The aortitis leads to slowly progressive dilation of the aortic root and arch, which causes aortic valve insufficiency and aneurysms of the proximal aorta. Neurosyphilis may be symptomatic or asymptomatic. Symptomatic disease manifests in several ways, including chronic meningovascular disease, tabes dorsalis , and a generalized brain parenchymal disease called general paresis . Asymptomatic neurosyphilis , which accounts for about one third of neurosyphilis cases, is detected when patient's CSF shows pleocytosis (increased numbers of inflammatory cells), elevated protein levels, or decreased glucose.

88. Antibodies stimulated by the spirochetes, discussed below, can also be detected in the CSF, and this is the most specific test for neurosyphilis . Antibiotics are given for a longer time if the spirochetes have spread to the CNS, and so patients with tertiary syphilis should be tested for neurosyphilis even if they do not have neurologic symptoms Benign tertiary syphilis is characterized by gummata in various sites. Gummata are nodular lesions probably related to the development of delayed hypersensitivity to the bacteria, occuring any organ but most commonly in bone, skin, and the mucous membranes of the upper airway and mouth. Skeletal involvement characteristically causes local pain, tenderness, swelling, and sometimes pathologic fractures. Involvement of skin and mucous membranes may produce nodular lesions or, rarely, destructive, ulcerative lesions that mimic malignant neoplasms. Gummata are now very rare because of antibiotics and are seen mainly in AIDS.

89. Congenital Syphilis . T. pallidum crosses the placenta from an infected mother to the fetus most frequently during primary or secondary syphilis, when the spirochetes are most numerous. Because the manifestations of maternal syphilis may be subtle, routine serologic testing for syphilis is mandatory in all pregnancies. Intrauterine death and perinatal death each occurs in approximately 25% of cases of untreated congenital syphilis. Manifestations of congenital disease are divided into early (infantile), occuring before 2 years of age; and late (tardive) syphilis. Early congenital syphilis is often manifested by nasal discharge and congestion (snuffles) in the first few months of life. A desquamating or bullous rash can lead to sloughing of the skin, particularly of the hands and feet and around the mouth and anus. Hepatomegaly and skeletal abnormalities are also common. Nearly half of untreated children with neonatal syphilis will develop late manifestations.

90. Serologic Tests for Syphilis. Serology is the mainstay of diagnosis. Microscopy and PCR are also useful. Serologic tests include Nontreponemal tests measuring antibodies to cardiolipin , a phospholipid present in both host tissues and T. pallidum . These antibodies are detected in the Rapid plasma reagin and Venereal Disease Research Laboratory (VDRL) tests . They become positive 4 to 6 weeks after infection,. The nontreponemal tests are nearly always positive in secondary syphilis, but they usually become negative in tertiary syphilis. They are used as screening tests for syphilis and to monitor response to therapy, since these tests become negative after successful treatment of infection. Treponemal antibody tests measure antibodies that specifically react with T. pallidum . These include the fluorescent treponemal antibody absorption test and the microhemagglutination assay for T. pallidum antibodies . These tests also become positive 4 to 6 weeks after infection, but unlike nontreponemal antibody tests, they remain positive indefinitely, even after successful treatment. They are not recommended as primary screening tests. Serologic response may be delayed, absent, or exaggerated (false-positive results) in some persons co-infected with syphilis and HIV, but in most cases, these tests remain useful. Immunofluorescence of exudate from the chancre is important for diagnosis in early infection.

91. Morphology In primary syphilis a chancre occurs on the penis or scrotum of 70% of men and on the vulva or cervix of 50% of women. The chancre is a slightly elevated, firm, reddened papule, up to several centimeters in diameter, that erodes to create a clean-based shallow ulcer. The contiguous induration creates a button-like mass directly adjacent to the eroded skin, providing the basis for the designation hard chancre . Histology; Treponemes are visible at the surface of the ulcer with silver stains (e.g., Warthin -Starry stain) or immunofluorescence techniques. The chancre contains an intense infiltrate of plasma cells, with scattered macrophages and lymphocytes and a proliferative endarteritis. The endarteritis, which is seen in all stages of syphilis, starts with endothelial cell activation and proliferation and progresses to intimal fibrosis. The regional nodes are usually enlarged due to nonspecific acute or chronic lymphadenitis, plasma cell–rich infiltrates, or granulomas.

92. In secondary syphilis widespread mucocutaneous lesions involve the oral cavity, palms of the hands, and soles of the feet. The rash frequently consists of discrete red-brown macules less than 5 mm in diameter, but it may be follicular, pustular , annular, or scaling. Red lesions in the mouth or vagina contain the most organisms and are the most infectious. Histology; the mucocutaneous lesions of secondary syphilis show the same plasma cell infiltrate and obliterative endarteritis as the primary chancre, although the inflammation is often less intense.

93. Tertiary syphilis; most frequently involves the aorta; the CNS; and the liver, bones, and testes. Aortitis is caused by endarteritis of the vasa vasorum of the proximal aorta. Occlusion of the vasa vasorum results in scarring of the media of the proximal aortic wall, causing a loss of elasticity. There may be narrowing of the coronary artery ostia caused by subintimal scarring with resulting myocardial ischemia. Neurosyphilis takes one of several forms, designated meningovascular syphilis (), tabes dorsalis , and general paresis .

94. Syphilitic gummas are white-gray and rubbery, occur singly or multiply, and vary in size from microscopic lesions resembling tubercles to large tumor-like masses. They occur in most organs but particularly in skin, subcutaneous tissue, bone, and joints. In the liver, scarring as a result of gummas may cause a distinctive hepatic lesion known as hepar lobatum . Histology; the gummas have centers of coagulated, necrotic material and margins composed of plump, palisading macrophages and fibroblasts surrounded by large numbers of mononuclear leukocytes, chiefly plasma cells. Treponemes are scant in gummas and are difficult to demonstrate.

95. Congenital syphilis; The rash of is more severe than that of adult secondary syphilis. It is a bullous eruption of the palms and soles of the feet associated with epidermal sloughing. Syphilitic osteochondritis and periostitis affect all bones, but lesions of the nose and lower legs are most distinctive. Destruction of the vomer causes collapse of the bridge of the nose and, later on, the characteristic saddle nose deformity. Periostitis of the tibia leads to excessive new bone growth on the anterior surfaces and anterior bowing, or saber shin. There is also widespread disturbance in endochondral bone formation. The epiphyses become widened as the cartilage overgrows, and cartilage is found in displaced islands within the metaphysis. The liver is often severely affected in congenital syphilis. Diffuse fibrosis permeates lobules to isolate hepatic cells into small nests, accompanied by the characteristic lymphoplasmacytic infiltrate and vascular changes.

96. Gummas are occasionally found in the liver, even in early cases. The lungs may be affected by a diffuse interstitial fibrosis. In the syphilitic stillborn, the lungs appear pale and airless (pneumonia alba). The generalized spirochetemia may lead to diffuse interstitial inflammatory reactions in virtually any other organ (e.g., the pancreas, kidneys, heart, spleen, thymus, endocrine organs, and CNS). The late manifestations of congenital syphilis include a distinctive triad of interstitial keratitis, Hutchinson teeth, and eighth-nerve deafness. In addition to interstitial keratitis, the ocular changes include choroiditis and abnormal retinal pigmentation. Hutchinson teeth are small incisors shaped like a screwdriver or a peg, often with notches in the enamel. Eighth-nerve deafness and optic nerve atrophy develop secondary to meningovascular syphilis.

97. Pathogenesis Our scant knowledge of the pathogenesis comes from observations of the disease in humans. T. pallidum has never been cultured (it lacks genes for making nucleotides, fatty acids, and most amino acids), and there are no good animal models of syphilis. Much of the pathology of the disease, like aortitis , can be ascribed to the vascular abnormalities. Proliferative endarteritis occurs in all stages of syphilis. The pathophysiology of this is not known, although the scarcity of treponemes and the intense inflammatory infiltrate suggest that the immune response plays a role in the development of these lesions. The T cells that infiltrate the chancre are T H 1 cells, suggesting that activation of macrophages to kill bacteria may cause resolution of the local infection.

98. Although there are treponeme -specific antibodies, the antibody response does not eliminate the infection. The outer membrane of T. pallidum seems to protect the bacteria from antibody binding by some poorly understood mechanism. The immune response is ultimately inadequate, since the spirochetes disseminate, persist, and cause secondary and tertiary syphilis. A ntibiotic treatment of syphilis, in patients with a high bacterial load, can cause a massive release of endotoxins, resulting in a cytokine storm that manifests with high fever, rigors, hypotension, and leukopenia. This syndrome, the Jarisch-Herxheimer reaction , is also seen in other spirochetal diseases, like Lyme disease, and can be mistaken for drug allergy.

99. TAPEWORMS Cysticercosis Taenia solium is a cestode with a complex life cycle requiring two mammalian hosts: a definitive host, in which the worm reaches sexual maturity, and an intermediate host, in which the worm does not reach sexual maturity. Taenia solium tapeworms consist of a head ( scolex ) that has suckers and hooklets that attach to the intestinal wall, a neck, and many flat segments called proglottids that contain both male and female reproductive organs. they can detach and be shed in the feces. T. solium can be transmitted to humans in two ways, with distinct outcomes. (1) Ingestion of undercooked pork containing larval cysts, called cysticerci , leads to development of adult tapeworms in the intestine. Ingested cysticerci attach to the intestinal wall and develop into mature adult tapeworms.

100. ( 2) When pigs or humans ingest eggs in food or water contaminated with human feces, the larvae hatch, penetrate the gut wall, disseminate hematogenously, and encyst in many organs. Convulsions, increased intracranial pressure, and neurologic disturbances are caused by T. solium cysts in brain tissue. Taenia saginata , the beef tapeworm, and Diphyllobothrium latum , the fish tapeworm, are acquired by eating undercooked meat or fish. In humans these parasites live only in the gut, and they do not form cysticerci. Hydatid disease is caused by ingestion of eggs of echinococcal species. For Echinococcus granulosus the definitive hosts are dogs, sheep are intermediate hosts. For Echinoccus multilocularis foxes are definitive host, and rodents, intermediate hosts. Humans are accidental intermediate hosts, infected by ingestion of food contaminated with eggs shed by dogs or foxes. Eggs hatch in the duodenum and invade the liver, lungs, or bones.

101. Morphology. Cysticerci may be found in any organ, but the more common locations include the brain, muscles, skin, and heart. Cerebral symptoms depend on the precise location of the cysts, which may be intraparenchymal, attached to the arachnoid, or freely floating in the ventricular system. The cysts are ovoid and white to opalescent, often grape-sized, and contain an invaginated scolex with hooklets that are bathed in clear cyst fluid The cyst wall is more than 100 μm thick, is rich in glycoproteins, and evokes little host reaction when it is intact. When cysts degenerate, however, there is inflammation, followed by focal scarring, and calcifications, which may be visible by radiography. About two thirds of human E. granulosus cysts are found in the liver, 5% to 15% in the lung, and the rest in bones and brain or other organs

102. The cysts begin at microscopic levels and progressively increase in size, so that in 5 years or more they may have achieved dimensions of more than 10 cm in diameter. Enclosing an opalescent fluid is an inner, nucleated, germinative layer and an outer, opaque, non-nucleated layer. The outer non-nucleated layer is distinctive and has innumerable delicate laminations. Outside this opaque layer, there is a host inflammatory reaction that produces a zone of fibroblasts, giant cells, and mononuclear and eosinophilic cells. In time a dense fibrous capsule forms. Daughter cysts often develop within the large mother cyst. These appear first as minute projections of the germinative layer that develop central vesicles and thus form tiny brood capsules. Degenerating scolices of the worm produce a fine, sandlike sediment within the hydatid fluid (“hydatid sand”) .