CHAPTER 16 INFECTIOUS DISEASES

Some Characteristics of Human Infectious Agents

My = mycobacteria S=Sporothrix H=HistopIasma sp = species T = Trypanosoma L= Leishania E = Enterobius W = Wuchererla Tr = Trichinella

Transmission of Infectious Agents.

1. Direct spread.This occurs through contact or airborne particles from sick individuais.Direct spread is characteristic of contagious diseases such as measles or chickenpox,and may result in epidemics.Asymptomatic carriers in some diseases act as human reservoirs of infection.

2. Spread through contaminated food, water or soll. Sick individuais and asymptomatic carriers serve as Sources of contamination.Sometimes the sources are environmental,such as Legionella.a small coccobacillus present in water tanks,cooling devices.Naegleria fowleri is a free-Iiving ameba in ponds that can produce lethal meningoencephalitis in swimmers by penetratlng the cribriform plate of the nasaI roof.

3. Vertical spread.This refers to infections acquired prenatally (transpl- acentaI), or perinataIIy,transmitted shortly after delivery.

4.Zoonotic spread.These are infections spread from an animal host or reservo in.This spread can occur with aII types of infectious agents, from viruses to helminths.Zoonotic infections can be more pathogenic or less pathogenic for humans than for their norma I anima I hosts.

Host Tissue Responses to Infection

The range of tissue responses is limited, and at the microscopic level many pathogens evoke the same reaction patterns.In general,there are five microscopic patterns of reaction:

1. Exudative inflammation.This familiar pattern has been described in the chapter on inflammation.There is increased blood flow and vascular permeabiIlty that result in leukotaxis,neutrophilic infiltration, with or without the formation of pus.

2. Necrotizing inflammation,in the case of highly virulent or toxic agents, cell death can be the dominant feature, with relatively slight exudation.

3. Granulomatous inflammation.This pattern is characterized by a mononuc- lear phagocytic infiltrate.It is evoked by relatively slow-dividing agents,those too large to be handled by neutrophiis alone,and infections by facultative intracellular organisms.Granulomas therefore suggest certain specific agents such as mycobacteria, fungi or parasites.

4. Interstitial inflammation. In acute disease a mononuclear interstitlal infiItrate usually indicates viral infection.All chronic inflammatory processes are marked by a predominantly mononuclear infiltrate, Some infections such as earIy TreponemaI and typhoid infections may aiso stimulate a mononuclear infiItrate.Therefore this histologic pattern may be quite difficult to interpret in terms of its possible cause.

5.Cytopathic-cytoproliferative inflammation.When cell damage of a certain type precedes cell destruction,it may initiate cell repIication and the formation of inclusion bodles and perikaryons.Such a reaction suggests an obligate intracellu]ar agent,usually a virus.

These five patterns serve as guides in the analysis of infectious proceeses, but they rarely appear in pure form.They are aiso not restricted to infectious agents, being seen as well in tissue responses to physicochemicaI agents and diseases of unknown cause.Therefore,histopathologic features must be reviewed and interpreted together with other patient data such as clinical and microbiologic findings.

BAOTERIAL INFECTIONS

Tuberculosis

Epidemloiogy.Despite great advances made in the general knowledge of the disease and its treatment,tuberculosis still ranks as the single most Important bacterial infection,affecting millions in communities around the world.According to WHO statistics,tuberculosis causes 3 miIIion deaths per year worldwide, ranking fifth behind cardiovascular disease,diarrhea,cancer and pneumonia.The disease ilIustrates well some basic features of bacterial Infections, especially the influence of host factors such as immunity and hypersensitivity on disease expression and spread witin the body.

In Western Europe and North America,the incidence of tuberculosis has declined as a resuIt of better nutrition and housing.Undemourishment Iowers an inividuaI's resistance,and predisposes to tubercuIosis. Overcrowding,poor personaI hygiene and sanitation contaminate the environment and facilitate the spread of tuberculosis within families.In such communities,infants,children and young adults are affected,and mortaIity is reIatively high.In more affIuent commun ities new cases appear In middIe-aged and oIder aduIts, and represent reinfection from earIy dormant lesions acquired when the disease was more prevalent.

Incidence and Prevaience.The true incidence and prevalence of tuberculosis are difficuIt to determine precisely.This is because of the Iarge number of asymptomatlc infections and the dormant nature of the disease,which means that infected persons remain permanently at risk of developing active disease.Another problem is the administration of routine neonatal BCG vaccination,which is carried out in many countries.Although this practice provides a measure of immunity to the disease, it invalidates skin testing as an index of infection.

In the United States,where BCG vaccination is not routinely administered, 15 million tubercul in reactors (positive skin test) and 30,000 active cases of tuberculosis were reported in 1980.In 1986 the number of active cases dropped to 22,800 (9.4/100;000 population).

Causatlve organism.Tuberculosis is caused by the tubercle bacillus,or Mcobacterlum tuberculosis, which belongs to a famiIy of Gram positire, aerobic bacilli with thick waxy cell walis. Mycobacteria are difficult to stain,but once stained they resist decolorization by strong acids and alkalis, and hence are aiso referred to as acid-fast bacilli(AFB).The common stain,employed for tubercle baciIIi is the ZiehI -NieIsen stain.

M.tuberculosis is a sIender, deIicateIy beaded rod 4 microns in Iength.Its growth in culture is slow,therefore,direct microscopic diagnosis by examination of sputum,exudates,sediments and biopsies, is employed as a time-saving measure.Culture,however,is necessary to verify the species. other diagnostic toois used in some areas include gas chromatography for tuberculostearic acids, and mycobacterial DNA hybridization.

Pathogenesis. Three factors are important in its pathogenesis: (1) viruIence of the organism,(2) induced hypersensitivity and (3) immunity or resistance.

1. Virulence. Mycobacterium tuberuiosis has no known exotoxins,endotoxins, or histolytic enzymes,It has approximately 30 different antigens, but these seem to play no role in its virulence. Of importance to its virulence are the mycosides (complex liDids and carbohydates) in its cell wall.

One derivative known as"cord factor"is essential for the virulence of M. tubercuIos is in ani maIs. Strains that possess cord factor aiso possess a sul fat ide that prevents fusion of phagosomes and lysosomes, and thus favors the survival of mycobacteria within macrophages. A cell wall glycollpid wax D, when injected with proteins of the organism (tuberculoproteins) induces strong hypersensitivity to the protein.This property of wax D forms.the basis of its use as an adjuvant (Freund's adjuvant). Thus the lipid and carbohydrate fract ions of the organ ism contribute both to virulence and to the hypersensitivity state associated with tuberculosis.

2. Induced hypersensitivity. The degree of hypersensitivity correlates with the amount of tissue destruction seen in Individual cases,of tuberculosis. Sensitization appears 2-4 weeks after infection, and is indicated by a positive tuberculln.test (Mantoux or Tine). In tubercul in testing an intradermat injection of purified protein derivatlve (PPD) is given. PPD is derived from the culture medium In which tubercle bacilli have grown. In a sensi tized individual an area of lnduration (not simply erythema) at least 5 mm in diameter, will appear in 48 hours, In very sensitive individuais the lesion may become necrotic. A posit ive tubercul in test is thus an indicat ion of Infection, but not necessarily of disease. It is due to the development of cell-mediated immunity, or tyloe IV (delayed) hypersensitivity in which sensitized T Celis react directly with bacterial antigens expressed on the surface of infected macrophages. Once an indivldual becomes tuberculin positive, he usually remains so for the rest of his life. This is thought to be due to the persistence of bacilli in the body, in either latent or active form. Faise-negative reactions may De caused by viral infections, drugs, neoplasms, malnutrition, immunosuppressive therapy, or Hodgkin's disease. Faise-positive reactions may occur following infection with other mycobacteria. In over- whe Iming disseminated tuberculosis. tudercul in testing can be. negative or revert from positive to negative (tuberculin artery).

With the deyelopment of induced nypersensitivity the inflammatory reaction changes from a neutrophillc to a granulomatous one. The centers of the granulomas often undergo caseation necrosis to form tubercles. Hypersansit- tivity thus forms the basis of the caseation and tissue destruction in tuberculosis. However, with the appearance of hypersensitivity there is a concomitant increase in resistance to the organism, i.e. an increased caoacity to phagocytize and inhibit its intracellular redlication.

3. Immunity, Efforts have been made to determine whether hypersensitivity and resistance (immtnity) are separate phenomena or two expressions of a single process. BCG vaccination, which uses attenuated bovine strains of the organism, confers tuberculin positivity, but there is no agreement whether It aiso confers resistance to virulent infection. Estimates of the protective efficacy of 803 range from 0-80%. At present no firm conclusions have been drawn about the relationship of hypersensitivity to increased res i stance.

Basic. Histologlc Responses in Tuberculosis

1. Exudation, In the early stage of infection the tubercle bacilli evoke a nonspecific inflammatory reaction with exudation of fluid and ceiis from the blood into the extracellular compartment. The fluid is either serous or fibrinous. The cellular response is initially neutroohilic but neutrophiis are later replaced by hisiocytes and lympnocytes.

2. Prolifeeation. The onset of proliferative changes corresponds to the development of sensitization to the bacilli. The distinctive histologic proliferative lesion is the tuberculous granuloma, or tubercle. A tubercle consists of a microscopic aggregate of rounded histiocytes that resemble epithelioid cells, and are called epithelioid histiocytes, surrounded by plump fibroblasts and lymphocytes, There may aiso be multinucleate giant cells called Langhans' cells, which are formed by fusion of macrophages or by nuclear division without cytoplasmic division.

3. Necrosis. Often the central portion of the tubercle undergoes a distinct- ive type of granular necrosis known as caseous necrosis, This "soft tubercie" is the hall mark of tuberculosis. The degree of necrosis reflects the degree of hyersensitivity possessed by the host to the tubercle bacilli,

Sequela of Changes in Tuberculosis

1. Resorption. This occurs with early exudative lesions.

2. Flbrosis, encapsulation and calclflcatlon. Proliferative lesions heal by fibrosis, leaving scars. These flbrotic lesions frequently encapsulate and may even calcify and ossify. It has been shown that tubercle bacilli can survive in a dormant state for many years in these healed lesions, and become active as a result of malnutrition or ln the presence of debilitating diseases such as diabetes mellitus, cancer or immunosuopression.

3. Cavltatlon. Large foci of necrosis that cannot be totally Pesorbed either undergo organization and fibrosis, or cavitation. This occurs commonly in the lungs. Necrotic foci can erode into bronchi, drain, and leave abscess cavities. Such cavities can cause serious, and even fatal hemoptysis.

PULMONARY TUBERCULOSIS

This is the most common form of tuberculosis, and is still the major cause of tuberculous morbidity and mortality.

A. Primary Pulmonary Tuberculosis Priamary. tuberculosis is defined as infection in an indlvidual lacking previous contact with tubercle bacilli. In the Iung the focus of primary tubercuIosis is Known as the Ghon complex, and consists of: (1) a subpleural lung lesion (Ghon focus), and (2) enlarged caseous lymph nodes draining the parenchymal focus.

Morphology. The Ghon focus is usually single, 1.0 -1.5 cm in diameter. It is a circumscribed gray-white area of consolidation beneath the pleura, it is found either in the lower part of the upper lobe or in the upper part of the lower lobe, where the lung receiyes the greatest volume of inspired air.

Histologic sections in the first week show exudation and a neutrophilic response. By the second week the focus develops a soft, caseous necrotic center, and typical caseating granulomas are seen on microscopic examination. Tubercle bacilli, either free or within macrophages, drain along the peri- bronchial lymphatics to the tracheobronchial lymph nodes, which enlarge and develop a caseatirg granulomatous infiammation.

Progressive Primary Tuberculosis. MOSt cases of primary tuberculosis do not progress but undergo fibrosis and cad calcification. Progression of primary tuberculosis is more likely to affect children, except in areas where the infection is less common and occurs later in life.

1. Bronchial spread. The primary lung lesion enlarges rapidly and erodes into the bronchial tree, giving rise to satellite lesiors in the lungs. This ts accompanied by enlargement of hilap nodes, which may become huge.

2. Hematogenous spread. Primary lung lesions may aiso invade the bloodstream and undergo widespread miliary dissemination. The term miliary describes the small yellow lesions the size of millet seeds. Entry of organisms into veins leads to systemic dissemination, commonly to the lungs, brain, liver and kidney. Invasion of arteries, or entry from hilar nodes into inominate vein, internaI carotid vein or superior vena cava, then right heart, leads to miliary dissemination within the lungs.

In adults the course of progressive primary tuberculosis is less fulminant. The usual picture is that of bilateral lung lnvolvement and enlargement of mediastinal nodes. The apices are spared. This combination of mediastinal lesions without apical lesions is rare in secondary tuberculosis.

Secondary Pulmonary Tuberculosis

Secondary tuberculosis is infection that arises in a previously sensitized individual, whether the organism is derived from endogenous or exogenous sources. Most cases are due to reactivation of asymDtomatic primary disease, and may manifest years following the primary infection, at a time of lowered host resistance.

In most cases of secondary tuberculosis the apices of the lungs are involved, close to the clavicle on chest X-rays. These focl are referred to as Simon's focl. The lesions are located in the apices probably because of the high oxygen partial pressure. Reactivation is uncommon in other parts of the lung. The pulmonary lesions of secondary tuberculosis tend to remain localized or progress slowly; at the same time caseation occurs more rapidly because of the sensitized state of the host. The caseous lesions undergo fibrosis and encapsulation. Regional nodal involvement is rare. Morphology. The apical lesions are 0.5 -1.0 cm . in diameter and are usually located 1 -2 cm from the pleural surface. Histologically there are prolifet- ative changes with or without caseation.

Sequela of Focal Secondary Tuberculosis

1.Heallng. This leads to scarring, fibrosis and calcification. Healed apical infection is Known as fibrocalcific tuberculosis.

2.Infiltration. This is an intermediate stage between fibrocalclfic and cavitary tuberculosis. In the presence of lowered resistance In the host, apical tuberculosis infiltrates and extends downwards below the clavicle.

Exudative changes predominate and may or may not become granulomatous and caseous. In immunosuppressed patients an lnflammatory reaction may be virtually absent, the lesiors showing only caseation and organisins.

3.Cavitation. Cavitary tuberculosis is the outcome of progression and caseation. When pulmonary lesions erode into bronchi caseous material is coughed up, and the foci become transformed into cavitles.

Cavitary tuberculosis can be acute or chronic. Acute tuberculous cavities are lined by necrotic material. The walis of chronic tuberculous cavities have three Iayers: an inner necrotic layer surrounded by granulationt issue and walled off by a layer of fibrous tissue. Not uncommonly thrombosed arteries traverse these cavitles. Cavitation is clinically important because erosion and destruction of blood vesseis within the cavities leads to hem optysis which can be massive and ratal.

Cavities heal by granulation tissue, or, in the case of large cavities, by re-epithelialization. However, usually cavitation sets the stage for further dissemination through bronchi, lymphatics or bloodstream.

4. Miliary spread. This occurs in both primary and secondary tuberculosis. The pattern is similar: invasion of arteries, or lymphatic drainage into major lymphatics and thence Into the right heart, results in miliary lesions restricted to the lungs, invasion of pulmonary veins leads to systemic lesions-in virtually any organ of the body. Individual lesions vary from one to several millimeters in diameter. They are distinct yellow-white, flrm and do not have central caseation necrosis.

5. Tuberculous bronchopneumonla. In highly sensitized individuais and those with very low resistance the infection soreads rapidly throughout large areas of lung to produce a diffuse bronchopneumonla. There is extensive consolld- ation involving a single lobe or several lobes (galloping consumption). Well- formed tubercles may not be present, but acid-fast stain usually reveais numerous bacilli.

6. Tuberculous pleurltis. In progresslve tuberculosis, both primary and secondary, the pleura Is inevitably involved.

Pleural disease can be exudative or proliferatlve. Exudative disease occurs in children and young adults, and are characterizeal by serous or serofibr in- ous Dleural effusions that is often bloody, Proliferative disease Is characterized by prol iferative ieslons. There is no pleural effusion, but fibrosis and adhesions are common. TUberculous empyema (pus in the pleural space) is a compli cation of very chronic disease.

7. Tuberculoma. These are circumscribed tuberculous lesions that occur in the lungs, brain or other organs. They are 2 -5 cm in diameter, circumscribed and usually solitary. They can be misdiagnosed as neoplasms.

C. Extrapukmonar Tuberculosis

Extrapulmonary tuberculosis occurs in both primary and secondary tuberculosis and is usually the outcome of miliary spread, It may be associated with lesions in the lungs or other organs, or it may occur as an isolated-organ Infections. Any organ or tissue may be affected, but the most common sites of isoiated-organ tubercuIosis are the cervical lymph nodes, meninges, kidneys, adrenais, bones, fallopian tubes and epidldymis.

1. Gastrolntestinal Tract, The intestine can involved in both primary and secondary tuberculosis. Primary disease results from ingestion of milk contaminated with bovine tuberculosis.Secondary tuberculosis occurs when bacilli are coughed up from pulmonary Iesions and then swallowed, Swallowed bacilli infect lymphoid tissue in the small bowel causing intestinal disease.

Morphology. Two types of lesions are seen in the gut. In ulceratlve lesions lymphoid tissue in the wall of the small Intestine undergoes caseation and uiceration. The ulcers are oval and are arranged in a circular or transverse manner, l.e. with their long axes perpendicular to that of the intestine. The ulcer margins are irregular and the bases are composed of necrotic tissue and granulation tissue. Flealing and healing can lead to stricture.

Lymphoid hyperplasia without caseation is seen in prollferatiVe lesions. The hypepplastic tissue projects into the lumen as polyps. Granulation tissue and fibrosis lead to thickening of the wall and narrowing of the lumen.

2. Peritoneum. Some cases are due to hematogenous spread, but the majority follow gastrointestinal tuberculosis of the ulcerative type. There are two varieties of tubercuious peritenitis, wet and dry. In the wet form the peritoneal tubercles produce a serous exudate and ascites. In dry peritonitis peritoneal tubercles are associated with a predominantly fibrinous exudate. This form of tuberculous peritonitis predisposes to fibrosis and formation of intestinal adhesions.

3. Meninges. This is described in CNS infections (chapter 15).

4. genitourinary System. Infection is usually unilateral (90%) The lesions are located at the cortico-medullary junction. Caseation necrosis may lead to destruction of renal Papillae and the formation of cavitles. From the renal pelvis infective material drains through the urine and causes seeding of the bladder and the develooment of tuberculpus cystitis. in males, further dissemination through the urinary tract can lead to infection of the prostate, vas deferens and epidydmis, Tuberculous salpingitis in females is due to hematogenous dissemination. and can spread by direct extension to the endometrium (endometritis) and pelvic peritoneum.

5. Bone. Tuberculous osteomyelitis is usually the result of seeding of the bone marrow in hematogenous dissemination, although it may aiso arise from direct extension, for example, from the lung into a rib, or from tracheo- bronchial nodes into adjacent vertebrae. It is a chronic infection with an insidious onset. The long bones of the extremities and the spine are preferential sites. Infection spreads through the medullary cavity, causing extensive necrosis of cortical bone and production of multiple sinuses through soft tissue and skin. Extension through epiphyseal cartilages into the joint spaces may aiso occur.

Tuberculosis of the spine is Known as Port's disease. Spinal infection can destroy intervertebral discs and cause compression fractures and serious defcrmities (kyphosis and scoliosis). Spinal infection can extend from the vertebral bodies into the paravertebral soft tissues. in one characteristic pattern infective material tracks along the sheath of the psoas muscle to produce a psoas abscess. Such lnfections can present as cold abscesses in the inguinal regiors and nodes.

6. Joints. Tuberculous arthritis is an insidious chronic disease that is more common in children. It arises either as a comolicatlon of tuberculous osteomyelitis or following hematogenous spread. Usually only one joint is invol ved. The most common site is the soine (tuberculous spondyl it is), followed by the hip, Knee, elbow, wrist, ankle and sacroiliac joints. There is seeding of the synovium with formation of caseating granulomas, Because the infection is chronic, there is formation of a thick layer of inflammatory tissue over the articular surface (pannus). The underlying articular surface and bone unaergo ulceration, destruction and erosion.

The seauela of tuberculous arthritis inciude: extensive fibrosis, achesions and obliteration of the joint space: calcification of the pannus and arkylosis of the joint; erosion through the joint capsule and formation of draining sinuses through the skin.

7. Lymph nodes. lnvolvement of lymph nodes may be primary or secondary. The most commonly involved nodes are those in the neck, mediastinum and mesentery. Primary tuberculosis with oropnaryngeal, gastrointestinal or pulmonary portais of entry spreads directly to draining lymph nodes of the neck, mesentery or mediastinum. Secondary tuberculous lymphadenltis results from miliary and/or lymphatic spread from primary foci, usuallyin the lungs. Discharging tuberculous cervical nodes is known as scrofula.

LEPROSY

Leprosy is a disease of tropical regions. It is an infection of skin and peripheral nerves caused by Mycobacterium leprae, an acid-fast obligate intracellular organism with optimal growth at 36 degrees C. The only naturally susceptible hosts are humans and armadillos. The agent has never been gown in cell-free media. A bacterial extract of glycoliDids and glycoproteins (lepromin) elicits hypersensitivity in the form of a skin reaction ( lepromin test ).

As in the case of tuberculosis, host resistance correlates with degree of cellular immunity rather than antibody formation. The strength of the cell- mediated immunity influences the presentation and course of the disease.

In tuberculold leprosy (TT form) T-cell mediated Immunity is strong. This causes aggregation and actlvation of macrophages, and the formation of tuberculoid granulomas. Thses granulomas contain few bacilli. The lepromin skin test is strongly positive.

At the other end of the clinical spectrum is lepromatous leprosy (LL form), where T-cell immunity is weak and resistance is, therefore, poor. Lepromin test is'negative. Large rulers of bacilli areseen in the lesions, within macrophages, Typical LL lesiors consist of ill-defined nodules of foamy macrophages rather than epithelioid cell granulomas. The infection is more extensive and more difficult to treat. Between LL and TT is a spectrum of intermediate forms with variable bacillary load and leoromin test results.

Transmission of the disease is direct, from active LL cases. The TT form is not contagious. Mode of entry is unknown, probably by, droplet tnhalatlon or skin contact. Prolonged close contact is reauired. The disease pursues an extremely slow course.

Morphlogy. In LL leprosy, nodules of lipid-laden macroohages (lepra eelis) filled with acid-fast bacilli (globi) are seen in the subcutaneous tissues of the face, ears, elbows, knees, wrists and buttocks. Most of these skin lesions are hypoeSthetic or anesthetic. Perioheral nerves are symmetrically affected. The peroneal and ulnar nerves are commonly involved where they run close to the skin surface. Loss of sensation leads to tropic changes in the hands and feet. Coll ections of foamy macrophages are seen in the paracortex of lymph nodes, in splenic red oulp and in liver. The testes are usually extensively involved, resulting in sterility. TT leprosy manifests as indurated, macular skin lesions with irregular elevated margins and depressed pale centers. Nerve involvement is prominent, especially involvement of the ulnar and peroneal nerves. This leads to skin and muscle atrophy, trophic ulcers, joint contractures, paralyses, and autoamputation of fingers and toes. HistologicaIIy the nerves are encircIed by a granulomatous inglammatory reaction resembling hard tubercles. Bacilli are almost never found in these lesions.

TYPHOID FEVER

Typhoid fever is caused by Salmonella typhi, a gram negative coliform organism. Salmonella typhi is shed in the feces, urine, vomitus and oral secretions of infected individuais and chronic carriers. Infection occurs through oral-fecal contamination.

Clinical features. The incubation period lasts one to two weeks. During this period S. typhi proliferate in the gut, penetrate the mucosa, and are carried within macrophages to the lymphatic tissues of the gut wall and the mesenteric lymph nodes. This is followed by a phase of baCteremia asting about one week, during which classic typhold fever symptoms of malaise, headache and aftenoon fever are seen.

In the second week the fever staDilizes, then gradually declines in the third and fourth weeks. Abdominal symptoms such as distention, pain, constipation alternating with diarrhea, are present. Duning the second week a character- istic skin rash may appear. The rash is described as "rose spots" and consists of 1 -5 mm diameter macules that blanch on pressure. They appear. briefly on the lower anterior chest and upper abdomen and fade. There are aiso splenohepatomegaly. bradycardia and leukopenla.

Dlagnosis is confirmed by isolation of the organism from the blood during the first week, and from the urine and stoois In thethlrd to fifthweeks, Antibodies are detected by the Widal reaction during the second week and show progressively rising titers. Mirphology. There is en largement of lymphoid and mononucl ear-phagocytic tissues throughout the body. Lymphoid tissue in the wall of the gut become swollen,forming plaque—like elevations, which, In untreated cases, may undergo ulceration to form oval ulcers patallel to the long axis of the gut This is in contrast to the ulcers of intestinal tuberculosis, which are circular. Sequela of typhoid ulcers are hemorrhage, which can be profuse, and perforation. Spleen. livet and mesenteric nodes are aiso enlarged.

Histologically there is proliferation of macrophages, lympnocytes and plasma cells in the spleen. liver, bone marrow and lymph nodes. They form small aggregates and contain red eelis and nuclear debris within the cytplasm. Neutrophiis are not prominent. There is leukopenia in the peripheral blood The enlarged spleen shows sinus histiocytosis. The liver contains necrosis. Dead hepatocytes are replaced by aggregates of mononuclear cells (typhoid nodules). Typhoid nodules are aiso found in the bore marrow, lymph nodes, and rare sites such as the brain and meninges, kidneys, conjunctivae, joints and gallbladder. Gallbladder infections are are associated with the chronic carrier state.

BACILLARY DYSENTERY

Bacillary dysentery is infection by the Shtgella species: S. dysenteriae, S. flexneri, S. boydli and S. sonnei. S. dysenteriae cause severe epidemics, while S. flexneri and boydii cause comparatively milcier infections. The Shigellae are gram negative coliform bacilli. They are facultative anaerobes and are infectious only for man, Transmission is oral-fecal, and animal reservoirs and human carriers play no significant roles,

Shigella orgaisms invade colonic mucosa and multiply in the lamina prooria. From here they are carried to the regional lymph nodes, but, unlike Salmonella typhi, do not cause bacteremia or localize in distant organs. The organism releases an exotoxin at the infection site which causes tissue necrosis.

Clinical course. The incubation period is less than 48 hours. Onset is acute, with diarnhea, nausea, vomiting and cramoy abdominal pain. Stoois are scanty, mucold and contain blood and pus. Numerous white cells are seen in the stoois. Systemic symptoms include fever and headache. Mild cases resemble food posoning, whereas severe cases may result in dehydration, prostration, neck stiffness, coma and death. Morpholgy, In severe cases the colonic mucosa is congested and edematous. There is enlargement of the lymphoid tissue of the wall, which projects as small nodules. Within 24 hours a fibrlnopurulent exudate covers the mucosa as a dirty yellowish-sray pseudomembrane. The underlying mucosa becomes soft friable and focally ulcerated. These ulcers are shallow and rarely extend below the mucosa. Perforation is an uncommon complication.

Histologically, there is a predominantly mononuclear Infiltrate within the I amina propria. On the surface of the ulcers, however, the infiltrate is neutrophilic. The ulcers bases contain necrotic debris and fibrtn. The ulcers heal by granulation tissue and surface re-epithelialization.

LEPTOSPIROSIS

Leptosoirosis is an acute, self-limited, febrile illness that may or may not be associated with jaundice, bleeding and renal failure. The presence of the latter symptoms produces severe leptospirosis, or WelI's disease. The causal agents are Leptospira (L. icterohemorrhagica, L. cantcoia), which are spirochetes measuring up to) 13 microns. The disease tands to occur in warm, moist environments, and is usual ly transmitted from infected dogs or rodents. Clinical features. Leptospira inhabit warm, alkaline soil or water. Human infection occurs through contact or aerosol inhalation, Farmers and abattoir workers have a higher risk of Infection.

The incubation period is from 5-14 days. Mild (anicteric) leptospirosis is a biphasic febrile illness that lasts 1-3 weeks. Relapses are common. At the onset there is fever with chilis, headache, and severe muscle pain or with nausea and vomiting (septicemic phase). Fever subsides after 3-7 days, then recurs, accompanied by signs of meningeal imitation (immune phase).

In Weil's disease there jaundice, Penal failure, puroura or hypotension, appearing within 2-3 days of onset and peaking in the second week. ConJunct- ival irritation and hyperemia appear early in both forms of the disease. Morphoiogy. In mild antcteric leptosplrosis, during the septicemic phase, organisms are seen in the liver, spleen, kidney, CNS, muscles and other sites. There is no cellular reaction. Later, during the immune phase, there is a prominent mononuclear reaction, especially associated with focl of cell necrosis, such as in striated muscle or kidney. The picture strongly resembles viral meningitis.

In Well's disease there is mild hepatocellular degeneration, cholestasis, Interstitial nephritis, tubular necrosis, focal neocosis of striated muscles and general ized proliferatlon of mononuclear phagocytes, Diagnsis is suggested by severe jaundice, hemorrhage, conjunctivitis and fever combined with mild abnormalitles of liver functlon,

FUNGAL INFECTIONS

Fungal infections are very commonly encountered in clinical medicine. Fungi exist in tissues as yeastlike forms and as thin tubular hyphae. The walis of fungal cells contain ergosterol and polysaccharldes. Some species have slimy antiDhagocytic capsules, others have wall components resistant to attack by phagolysosomes. Therefore, fungi can incite the whole range of inflammatory responses from acute pyogenic to chronic granulomatous.

Because of their thick cell walis, fungi are detectable microscopically, and can be tentatively Identified in tissue sections, Growth In labopatory media is slow, hence culture and tissue stantng form the usual method of diagnosis. iathogenic fungi prodiJce mycotoxins and enzymes, but their function in human disease is still unclear. Phagocytlc competence plays a larvae role in amti- fungal defense, and leUkopenic patients are as vulnerable to fungi as to bacteria. Cortlcosterolds and immunosuppressive drugs favor fungal infectlos of all types and spec ies. In pat ients with depressed immune systems fungal Infection is widespread and severe. Extension into vesseis with hemorrhage, thrombosis and Infarction is seen. The combination of necrosis, hemorrhage and infarcts should arouse suspicion of a fungal cause.

CANDIDIASIS

Candida infections are the most frequent fungal Infections. Most cases of candidiasis are caused by Candida albicans. It is Dresent in tissues as chains of nonbranching rectangular cells called pseudohyphae, from whict small 2-4 micron yeast forms called blastospores bud off. Both forms May be seen in infected tissue. Candida stains with Gram, PAS and silver stains.

Candida albicans is found in the normal flora of the oral cavity, gastroint- estinal tract and vagina of many individuais. Three disease patterns are seen: (1)superficial proliferation at sites normally colonized by the fungus, (2) deep invasion from surface lesions in immunocompromised hosts, and (3) severe, disseminated disease from direct Inoculation of the bloodstream in immunocompromised hosts.

Superficial candidlasis, This affects the mucosae of the oral cavity, vagina esophagus and skin. Candldiasis of the oral cavity is known as thrush. The mucosal lesions are white, circumscribed, slightly elevated plaques with a curdy consistency. When removed, the undertying mucosa is red though not usually ulcerated. Thrush is most commonly seen in newborns, whereas in adults it may follow administration of wldespectrum antibiotics or immunosupressive drugs. Candlda lnfections are common in diabetes mellitus. Vaginal candldiasis may arise in any of the above situations are well as in healthy young women taking contraceptives or during pregnancy.

Histologically the lesions show nonspeciftc acute and chronic inflammation. Acute infect ions may contain abscesses and chronic infections granulomas.

lnvasive candldlasis, This condition usually indicates severe immunodepress- ion or phagocyte depletion. lnvasion of deep soft tissues from superficial lesions and/or Invasion of the bloodstream may be present. Direct inoculation of the blood may occur with intravenous needles, catheters or other forms of instrumentation. Candidal sepsis may result in shock and DIC. The most common targets are the kldneys, cardiac valves, lungs and liver.

The kidney are involved in over 90% of invasive infections, Grossly there are innumerable microabscesses in both cortex and medulla. Sections yeast and hyphal elements surrounded by necrotic tissue and neutrophilic infiltrates. Candida endocarditis gives rise to large friable vegetations that can break off and occlude arteries, in the lungs the lesions may be spherical or Irregular in shape, and consists of abscesses, infarcts (due to Invasion of vesseis) and hemorrhages. Other manifestations of invasive candidlasis Include meningitis, osteomyelitis, intracerebral abscesses, arthritis, subcutaneous abscesses. In olden lesions a granulomatous response is semeti rues seen.

CRYPTOCOCCOSIS

This commonly occurs as an opportunistic infection, Particularly in Patients with leukemia, lymphoma or AIDS. It is caused by Cryptococcus neoformams. a round-to-oval yeast 4-10 microns in diameter. The yeast form divides in tissues by budding, hence no hyphae are seen. Virulent strains have thick slimy capsules that appear as clear haloes on routine histologic sections. The capsules stains bright red with the mucicarmine stain. India ink is used to visual ize the capsules by negative staining. Birds, especially pigeons, excrete the agent without suffering from disease. Inhalation of the fungi from bird droppings is the normal route of entry, and hence the lungs is the primary site of infection. However the lung infection may be mild and asymptomatic,

The most frequent manifestation of cyrptococcosis is meningitis, The onset is insidious and is characterized by headache, dizziness, or cranial nerve impairments. Usually the Datient has little fever, Capsular antigens present in body fluids are detected by the latex cryptococcat agglutinin test (LCAT). This test is positive in over 90% of cases of crytococcal meningitis. Morphology, The CSF contains crytococci with or wlthout accompanying white cells. In the immunosuppressed there is little cellular reaction, whereas in normal patients the response may be neutrophilic and suppurative, or chronic granulomatous, with macroohages. Iymphocytes and foreign body-type giant cells. In about 50% of cases there is extension into the underlying brain around the perivascular spaces, Someti rues there are small cysts in the gray matter filled with cryptococci (" soap-bubble lesions" ).

The lung infection may consist of focal nodules or diffuse infiltration. Localized collections of organisms with or without a granulomatous reaction is seen. These may be mistaken for tumors (crytococcoma). From the lung cryptococcl can disseminate widely in the bloodstream to the skin, liver, spleen, adrenaIs or other tissues, usually in debilitated or severely i mmuno- compromised patients.

ASPERGILLOSIS

The Aspergillus species (A. fumigatus, A. niger) rank behind the Candida species-as the commonest cause of funsal infections in hospitais. Three types of aspergillosis are seen in humns: allergic. colonizing and invasive. In addition the toxin of A. flavus is important as a liver carcinogen when ingested with food.

Allergic aspergillosis is a cause of bronchial asthma, and is clue to inhalat- ion of aspergillus spores.

Colonizing aspergillosis is growth of the fungus in pulmonary cavities, such as those resulting from tuberculosis, bronchiectasis or old Infarcts. Masses of fungal hyphae called "fungal bal is" are seen within the cavities, The fungus is ldentifled in tissues by septate hyphae 5-10 microns wlde, that show acute-angle brandying (40 degrees), and frulting bodles;

Invaslve aspergillosis is an opportunistic infection. Primary lesions are usually in the lungs, but rare cases occur in the eyes and paranasal sinuses. Widespreaddissemination to the cardiac valves, brain and kldneys are common. The lung lesions("target lesions") consist of gray focl of necrotizing pneumonia sharply outl ined by hemorrhagic rims. Septate hyphae and fruitlng bodles are seen. There is a tendency to invade blood vesseis, causing infarction and hemorrhage in addition to necrosis.

MUCORMYOOSIS (ZYOOMYCOSIS, PHYCOMYCOSIS)

Mucormycosis is an opportunistlc infection. The fungi that comprise the Phycomycetes include Mucor, Absidla, Rhizoous "ana Cunninghamella. These fungi are widely distributed in nature and are not harmful to normal individuais. Infections occur in patients with diabetic ketoaciaosis, advanced malignancy, lymphoma, leukemia, immunodeficiency and in Datients receiving wide-spectrum antibiotics, corticosteroids and cytotoxic orugs. Many infect ions are hospital acauired (nosocomial).

Morphology. The pcimary sites of invasion are the nasal sinuses, lungs, and gastrointestinal tract, depending on whether the spores are ingested or inhaled. Spread from the natal sinues to the brain is not uncommon. The fungi at first cause tissue necrosis, but later invade arterial walis and lead to meningoencephalitis or cerebral infarction. Direct invasion of the cerebral hemispheres may aiso occur. The fungi are identified in tissue by their nonseptate, lrregularly wide (6-50 mlcrons) hyphae with right-angle branching. The thick cell walis are readily stained with H&E. The hyphae have an "empty" took. Lung lesions consist of hemorrlqa&ic necrotizing pneumonia with areas of infarction, vascular thrombosis and hemorrhage.

Mucormycosis is a ser ious cordition sirice it arises in already severely debilitated patients. Some cases of nasal mucormycosis have recovered with antifungal therapy, but the put monary and dissemi rated forms carry a very poor prognosis.

ACTINOMYCOSIS

This is a chronic supurative infection caused by the Actinomycetales. Although the disease is traditionally described with fungal infections, the actinomycetes are organisms closeIy related to mycobacteria. They show some similarities with fungi, such as branching and the formation of a mycelial network, but the presence of muramic acid in their cell walis and the absence of a membrane-bound nucleus clearly allgns them with bacteria.

Actinomycosis is usually localized to the neck, lung or abdomen. Most human infections are caused by Actinomyces israelii. Lesions consist of indurated masses and abscesses that drain to the surface by sinuses. The discharge from the sinuses contains grossly visible yellow colonies (sulfur granules). The organism is a gram-positive, non acid-fast, sirict anaerobe. They are commensais within the oral cavity, alimentary tract and vatira, and invade only when tissue is devitaiized.

Three classic forms of actinomycosis are recognized, cervicofacial, abdominal and thoraClc. Clinically there are few symptoms even in the presence of fistulae or discharging siruses.

Cervicofaclal actinomycosis is the most frequent pattenn. There is swellin g and induration of the ginglva and adjacent soft tissue followed by a large woody swelling over the angle of the jaw ("lumpy jaw"). Extension to the skin with formation of muitlple sinuses is common. Histologically there is suppurative necrosis surrounded by granulation tissue and fibrosis. At the center of,each abscess is a bacterial colony consisting of radiating fi laments capped by hyallre material (clubs), creating a sunburst pattern.

Abdmominal actinomycosis follows invasion of intestinal mucosa, most commonly that of the appendix, leading to the formation of a peritoneal abscess.The abscess may extend posteriorly to the retroperitoneum space, superiorly to the liver and subdiaphragmatic recess, and anteriorly. Sinuses may form through the anterior abdominal wall. Increasing use of intrauter lne contrac- eptive devices has led to a pelvic form of actinomycosis affecting the uterine cervix, fal Iopian tubes and ovaries.

PSRASITIC DISEASES

AMEBIASIS

Amebiasis is caused by the protozoa Entameba histolytica. It is primarlly an infection of the colon whlch can spread to the liver, lungs and brain. The disease is transmitted by fecal contamination of food and water by patients and asymptomatic carriers, which constitute the reservoir of infection. Amebiasis is endemic in many deveioping countries, such as Mexico, Colombia and India. In the United States 3600 cases were reported in 1988. Intestinal Ameblasis (Ameblc Dysentery)

Causative Organism. The trophozoite of E. histotytica maascres 15-40 microns in diameter. ItS-distinctive nucleus contains a central Karyosome and finely clumped, perlpheral.ly-aligned chromatin. The cytoplasm is bubbly, and contains glycogen rosettes and Ingested red blood cells and debris. when conditions are unfavorabte E. histolytica forms quadrinucleate cysts which are excreted in the stoois. FolIowing insestion by a second host the cyst wall is digested in the stomach and motile trophozoites are released.

Pathogenesis. Entamebae can colonize the gut without causing disease, or cause only a diarrheal illness, depending on the balance between virulence of the strain and defense capacity of the host. Virulence of E. histolytica is due partly to Its motillty and partly to the generation of an "amebopore protein" that induces the formatlon of pores in host cell membranes. These pores cause sudden influxes of solutes into cells that are lethal.

Clinical features. The intestinal manifestations may be acute or chronic, and range from mild discomfort to classic dysentery with blood and mucus in the stoois. lnvaslve amebiasis is usually accompanied by abdominal cramps.

Morpholosgy. The cecum and ascending colon are most often affected, followed by the sigmoid, rectum and appendix. In severe cases the entire colon may be Involved. The trophozoites invade the mucosa of the colonic crypts and enter the lamina propria. In the lamina propria they spread laterally, creating shallow flask-shaped ulcers with narrow necks and wide bases. The bases of the ulcers rest on the muscular is mucosae, Sometirues adjacent ulcers coalesce an the overlying mucosa sloughs off leaving large irregular ulcers. These ulcers typically have clean bases and undermined margins.

In the early stages the response is neutrophiilc. Later the cellular response subsides, and typically there is little cellular infiltrate around the lesions. This Is because the tissue destruction is largely due to liquefaction necrosis. The mucosa between ulcers is normal or only mi Idly inflammed.

Complications. Gut perforation occurs rarely, and mostly in Children, immunosuppressed individuais and those inadvertently given corticosteroids. Gut perforation leads to amebic peritonitis. Another rare complication is colonic narrowing or constriction, This is due to overgrowth of granulation tissue, which forms a napkin ring-like constriction (ameboma). This lesion clinical ly and radiosraDhically resembles carcinoma.

Extrainfestlnal Ameblas Is

The commonest sites are the liver. lung and brain. Abscesses in these sites may present as solitary lesions in the absence of intestinal symptoms.

Amebic liver abscess. In about 40% of cases trophozoites penetrate branches of the mesenteric vein and are carrled to liver, where they form abscesses. Abscesses are usually solltary and more frequent in the right lobe. Patients present with abdominal enlargement and exquisite tenderness over the liver.

The abscess may be huge, measuring 10 cm in diameter. The contents consist of a pinkish-brown, relatively odorless, pasty material (anchovy paste), The abscess is surrounded by partially digested liver and fibrin, which form a shaggy layer. The surrounding liver contains little inflammatory reaction, Amebae can be identified in the wall of the abscess and not ln its contents ("sterile abscess").

Amebic lung abscess. Amebic lung abscess develops as a cemplication of livet abscess. Amebae reach the lung vla the bloodstream or by direct extension through the liver capsule, diaphragm and pieura. Left-sided abscesses can extend directly into the pericardial sac. As with amobic abscesses eisewhere histology Shows tissue lysis without a prominent inflammatory reaction.

Ameblc braln, abscess. This is the consequence of embolic dissemination. There may be one, or more than one abscess. "The lesions resemble those eisewhere, showing lysis without many inflamatory cells.

SCHISTOSOMIASIS

Schistosomes are trematodes, or flukes, that reoroduce in the venous system. The ova of schistosomes induce hypersensitlvity reactiors in many organs that may leads to fibrosis (livet) and obstruction (bladder). The three main schistosomes that cause disease in humans are Schistosoma mansoni (Africa, Latin America, the Caribbean), S. japonicum (China, the Philipioines, other parts of the Far East), S. hematobium (Africa, parts of the Near East).

Epidemiology. Schistosomiasis is one of the most important chronic endemic parasitic infections in the world. It is a tropical infection, occurring wherever the specific snail intermediate hosts are found. Worldwide there are an estimated 250 million sufferers. The number of people infected in China is estimated at 10 million. The disease is endemic in 13 provinces and cities in the middle and lower reaches of the Yangzi River.

Route of Infection. Endemic schistosomiasis is transmitted by contact with water containing fork-tailed cercariae. Cercariae develop from mature eggs in urine or stoois that are deposlted in water. Schistosome eggs measure to 150 microns in length and have terminal (S. hematoblum) or lateral (S. mansoni) spines. They contain miracidial larvae which hatch in water and enter specific snail intermediate hoots. In the Intermediate host the miracldia complete the asexual part of their life cycle and develop into free-swimming cercariae.

Cercariae burrow through unprotected skin and develop into young worms or schistosomuta. These enter the bloodstream and reach the lungs where they ann sequestered for 4-14 days before continuing their circulation In the blood. When they reach the portal vein radicles they mature into 1.5 cm long males and females. The adult flukes migrate into tributaries of the pelvic or mesenteric veins, where they mate and lay large numbers of eggs. Each fertilized female can lay up to 500 eggs a day. The eggs pass through the walis of the venules and organs and enter the lumen where they ape excreted. Some eggs may be trapped in the organ wall, while others may be carried in a retrograde direction into the liver or lung.

Pathosenesis. After the cencariae penetrate the skin some individuais develop hypersensitivity reactions, such as a rash at the site of penetration ("swimmer's itch"), or cough, fever and asthma-like symptoms during the brief sequestration of cercariae in the lungs.

After the schistosomes mature and begin egg-laying, individuais, especially those from outside the endemic areas, may develop fever, eosinophilia, hepatosplenemesaly, diarrhea and allergic symptoms. This symptom complex is called acute schistosomlasis, toxemic schistosomiasis or Katayama fever. These symptoms subside spontaneously and are followed by a period of clinical latency. When Infection is light this latent state can persist indefinitely, but in severe infections it is succeeded years later by chronic disease.

Clinical features. In areas of endemic schistosomiasis mansoni or Japonlcum, affected chlldren with albuminuria and hepatomesaly may otherwise appear well. Hematurla Is the first indication of S. hematobium infections. After a variable latent ioerlocl chronic disease supervenes. The peak incidence of chronic schistosomiasis in endemic areas is in thethird decade, when egg production may already have declined. Liver involvement resembles cirrhosis. and patients may present with hemetemesis, anemia and symptoms of portal hypertension. The disease can aiso cause stunted growth, renal failure, or protein-losing enteropathy due to colonic polyposis.

Lesions of Schistooomiasis. The "swimmer's itch", or cercarial dermatitis, is a hypersensitivity - dermatitis dominated histologicallY by the presence of large numbers of eosinopiis.

Adult flukes do not incite much tissue response, until they die, when they give rise to large necrotizing granulomas.

Schistosome ova release soluble antigens which stimulate cell-mediated immunity and the formation of granulomas. Ova trapped in tissues or vesseis form acute granulomas containing macrophages, lymphocytes and eosinophiis. When the ovadie and no longer release antigens the granulomas heal although new granulomas continue to form until the adults die, These healed or chronic granulomas are marked by fibrosis with little cellular reaction.

Morphology

S. japonlctml and S, mansoni. In light infections scattered eggs and granulomas are found in the gut, liver and lung. These granulomas are tiny, white andmeasure 1 -2 mm in diameter, In the liver they are best seen beneath the liver capsule. The liver and spleen often appear darker than normal due to accumulation of heine-tierived pigment in Kupffer oelis and splenic macrophages. The pigment is Prussian-blue negative."

In severe Infections pseudopolyps are present in the colon. The liver is dark and has. a lobulated surface. Its cut surface shows granulomas and wldepread fibrosis of the portal tracts, The cut surface of the fibrosed portal tracts resemble the cross-section of a clay pire, hence the name "plpe-stem fibrosis," There are no regenerative nodules as seen In cirrhosis, However, distortion of the portal vasculature leads to portal hypertension, congestive splenomegaly, vari ces and ascites.

Schistosome ova can be carried in the bloodstream to the lungs, where they produce a granulomatous arterltis of the pulmonary vesseis at the site of impactien. Histologically the arteries show Intiaal hyperplasia, disruption of the elastic lamira and organizing thrombi. With large numbers of ova the arteries may become obetructed and lead to cot pulmonale.

Apart from the lungs, ova may be deposited in many organs, Most cases of ectopic ova deposition are of little clinical significance, but S, japonlcum infection of the brain or meninges, and S. mansoni infection of the spinal cord can cause a variety of neurologic symptoms.

S. haematobium. The morDhologic changes are due to the presence of trapped ova in the bladder wall. The ova cause granulomatous inflammation in the submucosa. These are visible grossly as areas of fibrosis, Dead ova become calcified; in longstanding cases the entire bladder may be outlined by a layer of calcification.

Similar involvement of the ureters leads to inflammation, fibrosis and form- ation of multiple stenoses along the ureters. Fibrosis and distortion of the vesico-ureteric junction predisposes to reflux, pelvic and interstitial Inflammation. cortical atrophy and pylonephrltis. There is aiso an associat- ion between urinary schistosomiasis and sqluamous cell cancer of the bladder. Liver and lung lesions In S. haematoblum infections are rarely seen.

FILARIASIS

Epidemiology. Filariae are nematodes, or roundworms that cause filariasis. Lymphatic filariasis is caused by Wuchereria bancrofti and Brugia malayi, It is estimated that 240 million peopie are infected by lymphatic fllariae. The disease in endemic in the lowlands and coastal plains of tropics. In China it is endemic in 15 provinces, cities and autonomous regions, Including Shandons, Henan, Jiangsu, Shanghai, Zhejiang, Anhul, Hubei, Hunan, Jiangxi, Fujiian, Taiwan, Guangcdng, Guangxi. Sichuan and Guizhou.

W. bancrofti has a worldwide distribution; B. malayi is found chiefly in Asia (Southeast Asia, central China, lndia, Sri Lanka). W. bancrofti has no Known animal reservoir, while B. malayi has strains that infect cats and monkeys (potential reservoirs). The vector for urban bancroftion fitariasis is the mosquito Culex fatigans. ln rural areas a large number of mosquito species can transmit the disease.

Route of infection. Adult W. banorofti is 100 mm long, B. malayi 25 mm long, Fetilized females release tiny microfilariae into the lymph, blood or skin, These microfilariae are taken in by biting insects and metamorphose into infective third-stage larvae which are transmitted into a new host through insect bites. Once in the human body the larvae itligpa~ to their definitive habitat and mature into adult worms.

Clinlcal features. Residents in endemic areas are usually asymptomatic. Acute disease is seen in newcomers, and manlfests as episodic fever, urticarial rash, scrotal pain and swelling and swelling and tenderness of lymph nodes. The peripheral blood shows eosinophilia, but microfilariae may or may not be detected. Acute symptoms subside spontaneously, but may recur or be succeeded gradually by chronic disease.

Morphology. Larvae that are injected into the body with the bite of an infected mosquito usually cause no reaction except when they die. Dead larvae stimulate a foreign-bedy reaction. Later these lesions become fibrotic and may calcify.

Adult filariae live in lympatic channeis. They can obstruct the lymphatics and produce lymphedema, Chronic filarlasis is characterized by persistent lymphedema, especially in dependent parts such as the scrotum, penis, vulva and leg. In severe and tong-standing. Infections the scrotum or leg may become hugely distended. The tissues show epithelial hyperkEatosis and subcutaneous fibrosis. This is known as elephantiasis.

Histologically adult worms can be found in lymphatics and lymph nodes in all infectlons, either allve or dead and calcified. They may or may not cause a lymphangitis. The most severe reactions are seen around disintegrating worms, which induce first an acute and later a granulematous inflammation. Microfilariae are difficult to find in histologIc sections.

OLONORCHIASIS

Epidemiology. Clonorchiasis is caused by Clonorchis sinensis, a live fluke found in the Far East, including Japan, Korea, Southeast Asia and Hong Kong. in China clonorchlasis is endemic in 19 provinces, including Guandong. Taiwan, Guan8xi, Fujian, jiangxi Hunan, Hubel, Jianssu, Anhui, Sichuan, Guizhou, Henan, Hebei, Shandon8, Liaoning, Heilongjiang, Yunnan, Zhejiang and Jilin. The incidence is especially high in Guan8clong and Taiwan.

Clinical features. Infection is acquired by the eating of raw or semi-cooked fish and shrimp. These intermediate hosts harbor metacercariae. Adult flukes live in the small and large intrahepatic bite ducts where they cause a cholansitis with extensive liver damage and intrahepatic galistones. The disease begins insidiously with anorexia, diarrhea, slight jaundice, and right upper quadrant discomfort. Hepatomegaly is often present. Cholangiog- raphy shows irregularities of the intrahepatic bile ducts with multiple narrowinss and dilatattons. Distinctive eperculated ova can be found in the stopis,

Morphology. The liver is often enlapged. Cut section, shows irregularly dilated bile ducts with thick fibrotic walis. Parasites can be seen in the ducts. Some cases are complicated by stone formation or bacterial infection which may take the form of multiple abscesses centered around bile ducts.

Histoiogically, in the early stases, the bile ducts show nonspecific acute inflammation. In chronic cases there is proliferation and metaplasia of the bile duct epithelium, and periductal fibrosis. Bile duct epithelial prolif- eration and metaplasia are belleved to be precusors of Cholansiocarcinoma, a form of liver cancer which is common in areas where ctonorchiasis is endemic. The extrahepatic bile ducts are normal.

PARAGONIMIASIS

Epidemiology. This disease is caused by six lung flukes of the species Paragonimus, of which the most important is P. westermani. Paragonimiasis is seen the Far East, the Philippines and in tropical countries of Central and South America and West Africa. There are 11 orovinces in China where the disease is endemic: Liaoning, Jilin. Heilongjians, Zhejiang, Taiwan, Sichuan, Yunnan, Jiangxi, Hunan, Henan and Guizhou.

Route of infection. Paragonimus ova are coughed up, swallowed, and excreted in the feces. In water they hatch and release miracidia, which enter snaiis. Snaiis constitute the first intermediate host. In the snaiis miracidia develop into cercariae. These are liberated and attack crustacea which constitute the second intermediate host. In the second intermediate host the parasite encysts and is eaten by man.or other definitive hosts.

Pathogenesis. After excystation the young fluKes penetrate the gut wall, peritoneum and diaphragm, and reach the lungs. At this stage the parasites do not cause sisnificant lesions or symptoms. In heavily infected persons parasites migrate to ectopic locations, such as the gut wall, pancreas and brain where they die and give rise to focal abscesses.

In the lung the parasites cause an eosinophilic encapsulating reaction in the host. The parasites then form multiole cysts. Within the cysts they lay large numbers of thtck-shelled operculated ova.

Sooner or later the cysts ruoture into bronchi and the ova are either expectorated or swallowed. Adult flukes cause a chronic bronchial irritation with pneumonitis and bronchiectasis. Bacterial infection may supervene.

Clinical features. Clinical manifestations include cough with blood-streaked sputum. The disease resembles tuberculosis, with which it may coexist. Paragonimiasis due to ectopic migration is common In highly endemic areas such as Korea, Japan and parts of China. Cerebral paragonimiasis simulates brain tumor, epilepsy or meningitis. Focal brain calcifications are frequent X-ray findirgs.

Morphology. The lung cysts measure several centimeters in diameter, and contain brownish material, Histologically the cysts contain eosinoohiis and Charrot-Leyden crystais. The walis of the cysts contain granulomas. Granulomas are aiso seen in cerebral and ectopic paragonimiasis.

ECHINOCOCCOSIS (HYDATID DlSEASE)

Epidemlology. The two common species that cause disease in man are Echinococcus granulosis and Echinococcus multi tocularis, E. granularis is common in sheep-rearing regions such as Australia, New Zealand, Argentina and the western part of the United States. In China it is seen in Xizang, Xinjiang, Qinghai, Gansu, Ningxia, Inner Mongolia, Shaanxi and Sichuan. E. multilocularis shares the same distribution but is aiso found in central and eastern Europe.

Route of infection. The genus Echinococcus are small tapeworms whose definitive hosts include dog and sheep. Man is an intermed late host, but sometimes becomes an accidental host by ingesting the ova. The ova hatch in the duodenum and release Invasive embryos that penetrate the mucosa, enter the portal circulatlon and are cart led to the liver as well as other organs. After a period of silent growth, large parasitic cysts known as thydatids are formed in the liver and eisewhere. These cause disease by compressing vital structures, releasing allergenic cyst fluid and forming "daughter cysts."

Morphology. E. granulosus causes uni Iocular cysts. About two-thirds are found in liver, 5-15% in lung and the remainder in bones, brain and other organs. The larvae lodge within capillaries and incite an inflammatory response with eosinophi is and lymphocytes. Larvae that are not destroyed encyst, The cysts slowly enlarge, and may reach diameters of 10 cm or more.

The cysts contain thin milky fluid. The cyst lining consists of an inner nucleated germinatire layer and an outer non-nucleated layer with numerous I aminations. Surrounding this is an inflammatory reaction with fibroblasts, lymphocytes, giant cells and eosinophiis. Older cysts contain "daushter cysts". At first these are minute projections of the germinative layer, which later develop central vesicles, They are aiso known as "brood capsules." Scolices develop on the inner aspects of these brood capsules, and separate from the germlnative layer to form a fine sediment withinthe hydatld fluid ("hydatid sand").

Pulmonary cysts eventually erode into bronchi and are coughed up. This may result in spontaneous cure. Liver and other abdominal cysts somet imes leak and become shrunken, fibrosed and calcified. Rupture of a liver.cyst into a large bile duct can result in acute cholangltis or cholecystitis. E. multiiocularis causes multlIocular (alveolar) hydatid cysts, with unrestricted budding and without scolices. The cysts invade the liveF like malignant tumors, and can even invade portal and cavat veins and metastasize to" the lungs.

Clinicel Features. The clinical symptoms of tydatid disease are due mainly to cyst complications. Leakage of cyst fluid caused by trauma or. during surgical excision can cause acute anaphylaxis, In unllocular.hydatid disease spillage of fluid during surgery, can result in multiple cysts in the abdomen.

Multi locular hydatid disease resembles liver cell tumor. Treatment is generally unsatisfactory. Untreated cases have a 100% mortality rate.