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Pathology of Chronic Infectious DiseasesA.Gh.MD,AP&CPMycobacteriaMycobacteria are aerobic rods that grow in straight or branching chains. They are called "Acid-Fast :Because of the presence of mycolic acid in their cell wall, they will retain stains even on treatment with a mixture of acid and alcohol. Mycobacteria stain weakly positive with Gram stain.Epidemiology:Tuberculosis affects 1.7 billion individualsworldwide, After HIV, tuberculosis is the leadinginfectious cause of death in the world. Infectionwith HIV makes people susceptible to rapidlyprogressive tuberculosis.Certain diseases increase the risk :Diabetes mellitus, Hodgkin's lymphoma, chroniclung disease (particularly silicosis), chronic renalfailure, malnutrition, alcoholism, andimmunosuppression.

Tuberculosis flourishes wherever there ispoverty, crowding, and chronic debilitatingillness. Infection with M. tuberculosis is different fromdisease. Infection is the presence of organisms, which may or may not cause clinically significant disease.

PathogenesisMost infections are acquired by person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host. M. tuberculosis enters macrophages by endocytosis .M. tuberculosis replicates within the phagosome by blocking fusion of the phagosome and lysosomeThere is proliferation of bacteria in the pulmonary alveolar macrophages and airspaces, with resulting bacteremia and seeding of multiple sites. Despite the bacteremia, most patients at this stage are asymptomatic or have a mild flulike illness. About 3 weeks after infection, a TH 1 response against M.tuberculosis is mounted .Immunity to M. tuberculosis is primarily mediated by TH 1 cells, which stimulate macrophages to kill the bacteriaThis immune response, while largely effective, comes at the cost of hypersensitivity and the accompanying tissue destruction. Reactivation of the infection or re-exposure to the bacilli in a previously sensitized host results in rapid defensive reaction but also increase tissue necrosis. The loss of hypersensitivity (indicated by tuberculinnegativity in a previously tuberculin-positive individual)may show that resistance to the organism is weakened.

Clinical Features of Tuberculosis Primary tuberculosis:The form of disease that develops in apreviously unexposed, unsensitized, person.About 5% of newly infected people developclinically significant disease. In primarytuberculosis, the source of the organism isexogenous.Most patients with primary tuberculosis areasymptomatic, although it may cause fever andpleural effusion ,most have latent disease,butprogressive infection occurs in someThe diagnosis of progressive primary tuberculosis inadults is difficult. Contrary to the usual picture of"adult type" (or reactivation) tuberculosis (apicaldisease with cavitation) progressive primarytuberculosis more often resembles an acute bacterialpneumonia: lower and middle lobe consolidation hilar adenopathypleural effusionCavitation is rare, especially in patients with severe immunosuppression.Lymphohematogenous dissemination is acomplication and may result in the development oftuberculous meningitis and miliary tuberculosis. Morphology: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. 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 .

Ghon complexHistologically, sites of active involvementare marked by a characteristic granulomatousinflammatory reaction that forms bothCaseating and non-caseating tubercles usually enclosed within a fibroblastic rimpunctuated by lymphocytes. MultinucleatedGiant cells are present in the granulomas.Immunocompromised people do not form thecharacteristic granulomas

Tuberculosis of lungSecondary tuberculosis :Disease that arises in a previously sensitized host. Itmay follow shortly after primary tuberculosis, but more commonly, it arises from reactivation of primary lesions many decades after initial infection, particularly when host resistance is weakened. The source of the organis is usually endogenous but it may also result from exogenous reinfection because of waning of the protection afforded by the primary disease or because of a large inoculum of virulent bacilli. Secondary pulmonary tuberculosis is localized tothe apex of the upper lobes of one or both lungs.Because of the preexistence of hypersensitivity, theBacilli evoke a prompt tissue response that walls offthe focus of infection. As a result of this localization,the regional lymph nodes are less involved early inthe secondary disease than they are in primarytuberculosis.Cavitation occurs readily in the secondary form,resulting in dissemination of mycobacteria along theairways. Erosion into an airway becomes an important sourceof infection because the patient coughs sputumthat contains bacilli.Morphology:The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1 to 2 cm of the apical pleura. They are sharply circumscribed, firm, gray-white to yellow areas that have central caseation and peripheral fibrosis In favorable cases, the initial parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars.

Secondary pulmonary tuberculosis Histologically, the active lesions showcharacteristic coalescent tubercles with centralcaseation. Bacilli can be demonstrated in early exudative and caseous phases of granuloma formation, it is usually impossible to find them in the late, fibrocalcific stages.Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either spontaneously or after therapy, or the disease may progress

Systemic miliary tuberculosis:when infective foci in the lungs seed the pulmonary venous return to the heart; the organisms disseminate through the systemic arterial system. Almost every organ in the body can be seeded. Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis

Miliary tuberculosis of the spleenDiagnosisTubrcle bacilli must be identified.Acid-fast smears: more than 10,000 organisms required for smear-positivity.Sputum culture:Conventional cultures required up to 10weeks, but now liquid media-based culture can provide ananswer within 2 weeks.PCR amplification of M. tuberculosis DNA allows for rapid diagnosis. PCR assays can detect as few as 10 organisms in clinical specimensStill, culture remains the gold standard because it alsoallows testing of drug susceptibility. Multidrug resistanceis now more commonly seen.Tuberculin testInfection with M. tuberculosis leads to the development of delayed hypersensitivity to M. tuberculosis antigens, which can be detected by the tuberculin (Mantoux) test.About 2 to 4 weeks after infection, intracutaneousinjection of purified protein derivative of M.tuberculosis (PPD) induces a visible and palpableinduration that peaks in 48 to 72 hours. A positive tuberculin test result signifies cellmediated hypersensitivity to tubercularantigens. It does not differentiate betweeninfection and disease. False-negative reactions may be produced by certain viral infections, sarcoidosis,malnutrition, Hodgkin disease,immunosuppression, and (notably)overwhelming active tuberculous disease.False-positive reactions may also result from infection by atypical mycobacteria.

Tuberculosis in HIV patientsHIV infection is associated with an increased risk of tuberculosis.Patients with CD4+ T-cell counts greater than 300 cells/ml present with usual secondary tuberculosis (apical disease with cavitation).Patients with more advanced immunosuppression (CD4+ T-cell counts less than 200 cells/ml ) present with a clinical picture that resembles progressive primary tuberculosis (lower and middle lobe consolidation, hilar lymphadenopathy, and noncavitary disease). There is also :increased frequency of sputum-smear negativity for acid-fast bacilli false-negative PPD because of tuberculin anergy,lack of characteristic granulomas in tissues, particularly in the late stages of HIV.Numerous acid fast organisms within macrophages (Mycobacterium Avium Intracellular)

26ProtozoaMalariaCaused by the intracellular parasite Plasmodium, is a worldwide infection that affects 300 million and kills 1 million people each year. 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. 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

Life cycleThe infectious stage of malaria, the sporozoite, is found in the salivary glands of female mosquitoe When the mosquito takes a blood meal, sporozoites are released into the human's blood within minutes attach to and invade liver cellsWithin liver cells, malaria parasites multiply rapidly, merozoites are released when infected hepatocyte ruptures. P. vivax and P. ovale form latent hypnozoites in hepatocytes, which cause relapses of malaria long after initial infection.After release from the liver, Plasmodiummerozoites bind to sialic residues onglycophorin molecules on the surface of redblood cells.Within the red blood cells, the parasitesgrow in a membrane-bound digestivevacuole, hydrolyzing hemoglobin throughsecreted enzymes.

Malaria life cycle

Plasmodium In The RBCSThe trophozoite is the first stage of the parasite in the red blood 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 blood cell, the new merozoites infect additional red blood cells.Although most malaria parasites within the red blood cells develop into merozoites, some parasites develop into sexual forms called gametocytes that infect the mosquito when it takes its blood meal.

Plasmodium vivax in RBCPlasmodium vivax Trophozoite

Plasmodium vivax schizont

Plasmodium falciparum,ring (with double chromatin ) and gametocyte

A Few Notes On Plasmodium falciparum P. falciparum infects RBCs of any age, leading to high parasite burdens and severe anemia. The other species infect only new(p.vivax and ovale) or old(P.malariae) red blood cells, which are a smaller fraction of the red blood cell pool. P. falciparum causes infected red blood cells to clump together (rosetting) and to stick to endothelial cells lining small blood vessels (sequestration), which blocks blood flow.Ischemia due to poor perfusion causes the manifestations of cerebral malaria, which is the main cause of death due to malaria in children.

P. falciparum stimulates production of high levels of cytokines, including TNF, IFN-, and IL-1.Merozoite surface antigens, are released from infected red blood cells and induce cytokine production by host cells. These cytokines:suppress production of red blood cells, increase fever induce nitric oxide production leading to tissue damageinduce expression of endothelial receptors for PfEMP1, increasing sequestration.P. falciparum uses antigenic variation to escape from antibody responses to PfEMP1. Each P. falciparum genome has about 50 var genes, each encoding a different form of PfEMP1. at least 2% of the parasites switch PfEMP1 genes each generation. MorphologySpleen:P. falciparum infection initially causes splenomegaly, which may eventually exceed 1000 gm in weight. Parasites are present within red blood cells. There is increased phagocytic activity of the macrophages in the spleen. In chronic malaria infection, the spleen becomes fibrotic, with a thick capsule and fibrous trabeculae. The parenchyma is gray or black because of phagocytic cells containing granular, brown-black, hemozoin pigment. Liver:With progression of malaria, the liver becomes progressively enlarged and pigmented. Kupffer cells are heavily laden with malarial pigment, parasites, and cellular debris, while some pigment is also present in the hepatocytes. Pigmented phagocytic cells may be present throughout the bone marrow lymph nodes, subcutaneous tissues, lungs and kidneys.

Malignant cerebral malaria :Caused by P. falciparum, brain vessels are occluded with parasitized red cells, each cell containing dots of hemozoin pigment With more severe hypoxia, there is degeneration of neurons with focal ischemic softening of brain . P. vivax, P. ovale, and P. malariae cause:low parasitemia, mild anemia, and, in rare instances, splenic rupture and nephrotic syndrome. P. falciparum causes high levels of parasitemia, severe anemia, cerebral symptoms, renal failure, pulmonary edema, and death. LeishmaniasisLeishmaniasis is a chronic inflammatory disease of the skin, mucous membranes, or viscera caused by obligate intracellular, kinetoplastid protozoan parasites transmitted through the bite of infected sandflies. Leishmaniasis is endemic throughout the Middle East, South Asia, Africa, and Latin America. Leishmaniasis may also be epidemic, as is tragically the case in Sudan, India, Bangladesh, and Brazil, where tens of thousands of people have died of visceral leishmaniasis. Finally, leishmanial infection, like other intracellular organisms (mycobacteria, Histoplasma, Toxoplasma, and trypanosomes), is exacerbated by AIDS.

Pathogenesis:The life cycle of Leishmania involves two forms: the promastigote, which develops and lives extracellularly in the sandfly vector,the amastigote, which multiplies intracellularly in host macrophages. Mammals, including rodents, dogs, andfoxes, are reservoirs of Leishmania. When sandflies bite infected humans or animals, macrophages harboring amastigotes are ingested. The amastigotes differentiate into promastigotes and multiply within the digestive tract of the sandfly and migrate to the pharynx, When the infected sandfly bites a person, the infectious flagellated promastigotes are released into the host dermis along with the sandfly saliva.

The promastigotes are phagocytosed by macrophages, and the acidity within the phagolysosome induces them to transform into round amastigotes that lack flagella but contain a single DNA-containing specialized mitochondrion called the kinetoplast.Amastigotes proliferate within macrophages, and dying macrophages release amastigotes which can infect additional macrophages

Leishmania amastigote

Leishmania amastigote

Leishmania ,Bone marrow aspiration

Leishmania donovani parasites within the macrophages of a lymph node

Leishmania Promastigote(in sand fly)

Morphology:In visceral leishmaniasis, L. donovani or L. chagasi parasites invade macrophages throughout the mononuclear phagocyte system and cause severe systemic disease marked by hepatosplenomegaly, lymphadenopathy, pancytopenia, fever, and weight loss. Spleen:The spleen may weigh as much as 3 kg, and the. Phagocytic cells are enlarged and filled with Leishmania, many plasma cells are present, and the normal architecture of the spleen is obscured .

Liver: In the late stages, the liver becomes increasingly fibrotic. Phagocytic cells crowd the bone marrow and also may be found in the lungs, gastrointestinal tract, kidneys, pancreas, and testes.

Kidneys: 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 bacterial infections, the usual cause of death. Hemorrhages related to thrombocytopenia may also be fatal.

Cutaneous leishmaniasis, caused by L. major, L. mexicana, and L. braziliensis, is a relatively mild, localized disease consisting of a single ulcer on exposed skin. The lesion (often called tropical sore) begins as an itching papule surrounded by induration, changes into a shallow ulcer with irregular borders, and usually heals by involution within 6 months without treatment. On microscopic examination, the lesion is granulomatous, usually with many giant cells and few parasites.Other forms of Leishmaniasis:Mucocutaneous leishmaniasisDiffuse cutaneous leishmaniasisHydatid CystHydatid disease is caused by ingestion of eggs ofechinoccal species.For Echinococcus granulosus(causing Unilocular cysts) the definitive hosts are dogs, and sheep are the usual intermediate hosts. For Echinoccus multilocularis(causing multilocular cysts )foxes are the most important definitive host, and rodents are 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. MorphologyAbout 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. In the various organs, the larvae remain within the capillaries and evoke an inflammatory reaction composed of mononuclear leukocytes and eosinophils. Many larvae are destroyed, but others encyst. The cysts enlarge gradually. The cyst wall is composed of 3 layers:An inner, nucleated germinative layer An outer, nonnucleated layer. The outer nonnucleated layer has innumerable delicate laminations. Outside this 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. Hydatid cyst

Hydatid cyst

When these cysts have been present for about 6 months, daughter cysts develop within them. These appear first as minute projections of the germinative layer that develop central vesicles and form tiny brood capsules. Scolices of the worm develop on the inner aspects of these brood capsules and separate from the germinative layer to produce a fine, sand like sediment within the hydatid cyst.Echinococcus granulosus,protoscolex

Echinococcus granulosus,protoscolex

Echinococcus granulosus scolex

SchistosomiasisSchistosomiasis is transmitted by freshwater snails that live in tropical rivers.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, traverse to the lung, and settle in the portal or pelvic venous system, where they develop into adult male and female schistosomes Morphology:In mild S. mansoni or S. japonicum infections, 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. In severe S. mansoni or S. japonicum infections, pseudopolyps may form in the colon. There is granulomatous inflammation of liver and fibrous portal enlargement ( named pipe-stem fibrosis ) There is portal hypertension and severe congestive splenomegaly, esophageal varices, and ascites. Patients with hepatosplenic schistosomiasis also have an increased frequency of mesangioproliferative or membranous glomerulopathy , in which glomeruli contain deposits of immunoglobulin and complement but rarely schistosome antigen.In S. haematobium infection, There is granulomatous inflammation of bladder, when they erode mucosa, they cause hematuria. Later, the granulomas calcify forming calcified bladder view on radiographic films. 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 Pipe-stem fibrosis of the liver due to chronic Schistosoma japonicum infection

Schistosoma hematobium

Schistosoma Mansoni