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Infectious Diseases Infection and Immunity Definition of infection ① Complex process of interaction between pathogen and human body Infection is composed of three factors: pathogen, host and environment There are commensalisms and opportunistic infection ② ③ • Infectious disease kill more people each year than do all cancers and cardiovascular diseases. • The impact of infectious diseases is greatest in lessdeveloped countries, where millions of people, mostly children younger than 5 years of age, die of treatable or preventable infectious diseases. Classification of infections 1. Primary infection: Initial infection with organism in host. 2. Reinfection: Subsequent infection by same organism in a host (after recovery). 3. Superinfection: Infection by same organism in a host before recovery. 4. Secondary infection: When in a host whose resistance is lowered by preexisting infectious disease, a new organism may set up in infection. Classification of infections 5. Focal infection: It is a condition where due to infection at localized sites like appendix and tonsil, general effects are produced. 6. Cross infection: When a patient suffering from a disease and new infection it set up from another host or external source. 7. Nosocomial infection: Cross infection occurring in hospital. 8. Subclinical infection: It is one where clinical affects are not apparent. Infectivity and Virulence • Infectious organisms cause diseases in which tissue dysfunction results from an invading transmissible agent. • Virulence refers to the complex of properties that allows that agent to achieve infection and cause diseases of different degrees of severity. • The organism must (1) gain access to the body, (2) avoid multiple host defenses, (3) accommodate to growth in the human, and (4) parasitize human resources. • Virulence reflects both the structures inherent to the offending microbe and the interplay of those factors with host defense mechanisms. Sources of infection in Man Man: Man is himself a common source of infection from a patient or carrier. Healthy carrier is a person harboring pathogenic organism without causing any disease to him. A convalescent carrier is one who has recovered from disease but continues to harbor the pathogen in his body. Sources of infection in Man Animals: Infectious diseases transmitted from animals to man are called zoonosis. Zoonosis may be bacterial, (e.g. Plague from rat), rickettsial, (e.g. Murine typhus from rodent), viral, (e.g. Rabies from dog), protozoal, (e.g. Leishmaniasis from dogs), helminthic, (e.g. Hydatid cyst from dogs) and fungal (zoophilic dermatophytes from cats and dogs). Sources of infection in Man Insects: The diseases caused by insects are called arthropod borne disease. Insects like mosquitoes, fleas, lice that transmit infection are called vector. Transmission may be mechanical (transmission of Dysentery or typhoid bacilli by housefly) and these are called mechanical vector. They are called biological vector if pathogen multiplies in the body of vector, e.g. Anopheles mosquito in Malaria. Sources of infection in Man Some vectors may acts as reservoir host, (e.g. ticks in Relapsing fever and Spotted fever). Soil: Spores of tetanus bacilli, Gasgangrene infection remain viable in soil for a long time. Clostridium tetani Sources of infection in Man Water: Vibrio cholerae, infective hepatitis virus (Hepatitis A and Hepatitis E) may be found water. Food: Contaminated food may be source of infection. Presence of pathogens in food may be due to external contamination, (e.g. food poisoning by Staphylococcus). Methods of transmission of infection • Contact contact): gonorrhea. (sexual syphilis, • Inhalation: influenza, tuberculosis, smallpox, measles, mumps, etc. Methods of transmission of infection • Ingestion: cholera (water), food poisoning (food) and dysentery (hand borne). • Inoculation: tetanus (infection), rabies (dog), arbovirus (insect) and serum hepatitis, i.e. Hepatitis B (infection). Human hand contaminated with colonies of bacteria (blue/pink patches) Methods of transmission of infection • Congenital: syphilis, rubella, toxoplasmosis, cytomegaloviruses Eight week old fetus attached to its placenta by the umbilical cord Methods of transmission of infection • Insects: they act as mechanical vector (dysentery and typhoid by housefly) or biological vector (malaria) of infectious disease • Jatrogenic and laboratory infections: infection may be transmitted during procedures Infecting dose • The minimum infection dose (MID) or minimum lethal dose (MLD) is the minimum number of organism required to produce clinical evidence of infection or dearth of susceptible animal. • Route of infection • Vibrio cholerae is effective orally. No effect when it is introduced subcutaneously. • Streptococci can initiate infection whatever be the mode of entry. Types of infectious diseases • Infectious diseases may be localized or generalized. Localized infections may be superficial or deep-seated. • Circulation of bacteria in the blood is known as bacteremia (viruses – virusemia). Types of infectious diseases • Septicemia is the condition where bacteria circulate and multiply in the blood, form toxic products and cause swinging type of fever. • Pyemia is a condition where pyogenic bacteria produce septicemia with multiple abscesses in the internal organs such as the spleen, liver and kidney. Stages of infectious disease • Incubation period – no symptoms. • Prodromal period – mild and generalized symptoms (fever, weakness, headache). • Invasive stage – symptoms specific to the disease. • Decline stage – symptoms subside. • Convalescence – no symptoms, health returns to normal. Host Defense Mechanisms • The means by which the body prevents or contains infections. • There are major anatomical barriers to infection mainly the skin and the aerodynamic filtration system of the upper airway that prevent most organisms from ever penetrating the body. • The mucociliary blanket of the airways is also an essential defense, providing a means of expelling organisms that gain access to the respiratory system. • The microbial flora normally resident in the gastrointestinal tract and in various body orifices compete with outside organisms, preventing them from gaining sufficient nutrients or binding sites in the host. Age Influences the Outcome of Infection • The effect of age on the outcome of exposure to many infectious agents is illustrated by fetal infections. • Some organisms produce more severe disease in utero than in children or adults. • Infections of the fetus with cytomegalovirus (CMV), rubellavirus, parvovirus B19, and Toxoplasma gondii interfere with fetal development. • Fetal protection is dependent on the presence of maternal IgG antibodies, which cross the placenta. An acute infection in a nonimmune pregnant woman may allow the organism to infect the fetus. • These infections are usually subclinical or produce minimal disease in the mother but may lead to major congenital abnormalities or death in the fetus • Age also affects the course of common illnesses, such as the diverse viral and bacterial diarrheas. • Age also affects the course of common illnesses, such as the diverse viral and bacterial diarrheas. In older children and adults, these infections cause discomfort and inconvenience, but rarely severe disease. • The elderly fare more poorly with almost all infections than younger persons. • Common respiratory illnesses such as influenza and pneumococcal pneumonia are more often fatal in those older than 65 years of age. People with Compromised Defenses are More Likely to Contract Infections and to Have More Severe Infections • Disruption or absence of any host defense mechanism results in increased numbers and severity of infections. • Disruption of epithelial surfaces by trauma or burns frequently leads to invasive bacterial or fungal infections. • Injury to the mucociliary apparatus of the airways, as in smoking or influenza, impairs clearance of inhaled microorganisms and leads to an increased incidence of bacterial pneumonia. • Congenital absence of complement components C5, C6, C7, and C8 prevents formation of a fully functional membrane attack complex and permits disseminated, and often recurrent, Neisseria infections. • Diseases such as diabetes mellitus and chemotherapeutic drugs that interfere with the production or function of neutrophils increase the likelihood of bacterial infections or invasive fungal infections. • Organisms that cause disease mainly in hosts with impaired immunity are termed opportunistic pathogens. These organisms, many of which are part of the normal endogenous human or environmental microbial flora, take advantage of a host's inadequate defenses to stage a more violent and sustained attack. Categories of infectious agents 1. Viral Infections • Viruses range from 20 to 300 nm and consist of RNA or DNA contained in a protein shell. Some are also enveloped in lipid membranes. • Viruses do not engage in metabolism or reproduction independently, and thus are obligate intracellular parasites that require living cells in order to replicate. • After invading cells, they divert the cells' biosynthetic and metabolic capacities toward the synthesis of virus-encoded nucleic acids and proteins. • Viruses often cause disease by killing infected cells, but many do not. • Viruses may also promote the release of chemical mediators that elicit inflammatory or immunologic responses. • The symptoms of the common cold are due to the release of bradykinin from infected cells. • viruses cause cells to proliferate and form tumors. Human papillomaviruses (HPVs), for instance, cause squamous cell proliferative lesions. • Viruses can cause acute illness (common cold, influenza) or chronic disease (HBV, HIV) and long term reactivation (herpes virus). • Some viruses infect and persist in cells without interfering with cellular functions, a process known as latency. • Latent viruses can emerge to produce disease years after the primary infection. • Opportunistic infections are frequently caused by viruses that have established latent infections. • CMV and herpes simplex viruses are among the most frequent opportunistic pathogens because they are commonly present as latent agents and emerge in persons with impaired cell-mediated immunity • Finally, some viruses may reside within cells, either by integrating into their genomes or by remaining episomal, and cause those cells to generate tumors. Examples of this are Epstein-Barr virus (EBV), which causes endemic Burkitt lymphoma in Africa, and other tumors in different settings, and human T-cell leukemia virus-1 which causes a form of Tcell lymphoma. Classification of viruses 1. 2. DNA RNA Further classification: Single or double strand Envelope on no envelope RNA Viruses • A number of important pathogenic RNA viruses (e.g., human immunodeficiency virus [HIV]-1, hepatitis C virus) differ from many DNA viruses in that the RNA viral polymerases do not proofread the RNA strand being synthesized. • This has two important consequences. First, the mutation rate and therefore the plasticity of these viruses in circumventing therapies is very high. Second, a greater percentage of daughter virions are inactive. • The common cold is an acute, self-limited upper respiratory tract disorder caused by infection with a variety of RNA viruses, including more than 100 distinct rhinoviruses and several coronaviruses. • Infection is more likely during the winter months in temperate areas and during the rainy seasons in the tropics, when spread is facilitated by indoor crowding. • The viruses infect the nasal respiratory epithelial cells, causing increased mucus production and edema, viruse have a tropism for respiratory epithelium and optimally reproduce at temperatures well below 37° C. • The resulting stasis of secretions may predispose to secondary bacterial infection and lead to bacterial sinusitis and otitis media. DNA Viruses • The virus family Herpesviridae includes a large number of enveloped, DNA viruses, many of which infect humans. Almost all herpes viruses express some common antigenic determinants, and many produce type A nuclear inclusions (acidophilic bodies surrounded by a halo). • The most important human pathogens among the herpes viruses are varicella-zoster, herpes simplex, EBV, human herpesvirus 6 (HHV6, the cause of roseola), and CMV. Recently, HHV8 was implicated in the pathogenesis of KS in HIV-infected patients. These viruses are also distinguished by their capacity to remain latent for long periods of time This is cytomegalovirus (CMV) infection in the lung. Note the very large cells that have large violet intranuclear inclusions with a small clear halo. Basophilic stippling can be seen in the cytoplasm. This is a microscopic section from the edge of one of a group of small round clear vesicles on the skin, just above the lip. Notice the mauve to pink homogenous intranuclear inclusions in the epithelial cells of the epidermis. This is typical for Herpes simplex virus (HSV) infection. The most common sites for Herpes simplex virus infections (either primary or reactivation) are skin and mucus membranes. HSV type I is seen most often in oral cavity, while HSV type II is more commonly a sexually transmitted disease. Herpes simplex By electron microscopy, viral particles of any herpesvirus appear as arrays and scattered single particles as shown here in a nucleus of a neuron from the cerebrum from a patient with herpes simplex encephalitis. Herpesviruses are large encapsulated viruses that contain double-stranded DNA in the nucleocapsid surrounded by the viral envelope. 2. Bacteria • Lack nuclei but have rigid cell wall containing two phospholipid bilayer (gram negative species) or single bilayer( gram positive species). • Are major cause of sever infectious disease. • Grow extracellularly (e.g.: pneumococcus) or intracellularly (mycobacterium tuberculosis). 14 12 • Normal person carry 10 bacteria on the skin and 10 bacteria in GIT, 99.9 of them are anaerobic Exotoxins • proteins • usually enzymes • destroy cellular structures • destroy extracellular matrix •Can be produced by either Gram (+) or Gram (-) organisms Endotoxin • Lipopolysaccharide - endotoxin • peptidoglycan -endotoxin-like action • cell envelope components • not proteins/enzymes • Gram negative LPS cell wall components (Lipid A and Core Sugars) 3. chlamydiae, Rickettsia and mycoplasma. • Similar to bacteria but lack certain structures ( a cell wall in mycoplasma)or metabolic capabilities (ATP synthesis in chlamydia). • Chlamydia cause genitourinary infection, conjunctivitis and RT infection in newborn. • Rickettsia transmitted by insect vectors and cause hemorrhagic vasculitis, Q-fever, or encephalitis. • Mycoplasma bind to surface epithelial cells and cause atypical pneumonia or nongonococcal urethritis. 4. Fungi • Have thick, chitin containing cell wall and grow in humans as budding yeast cell and slender tube (hyphae). • In healthy person fungi produce; superficial infection (athletes foot caused by tinea), abscess (sporotrichosis) and granuloma (Histoplasma). • In immunocompromised hosts, opportunistic fungi (candidia and aspergillus) cause systemic infection characterized by tissue necrosis, hemorrhage and vascular occlusion. With a PAS stain, the budding cells and pseudohyphae (short filaments that are not true hyphae) of Candida stain bright red. 2nd Year Pathology 2010 5. protozoa. • Single cell with nucleus, a pliable plasma membrane and complex cytoplasmic organelles. • Trichomonas vaginalis is transmitted sexually. • Intestinal protozoa (Entameba histolytica and giardia) are infective when swallowed. • Blood born protozoa (leishmanial species) are transmitted by blood-sucking insects. Protozoal Infections • Protozoa cause human disease by diverse mechanisms. Some, such as Entamoeba histolytica, are extracellular parasites capable of digesting and invading human tissues. • Others, such as plasmodia, are obligate intracellular parasites that replicate in, and kill, human cells. Still others, such as trypanosomes, damage human tissue largely by eliciting inflammatory and immunologic responses. Some protozoa (e.g., Toxoplasma gondii) can establish latent infections and cause reactivation disease in immunocompromised hosts. 6. Prions • Composed of modified host protein. • They are not virus because they lack RNA or DNA. • Cause spongiform encephalopathies. • Associated with neurodegenerative disease, including fatal familial insomnia. How microorganism cause disease ? • Infectious agents damage tissue by entering cells, releasing toxins or damaging blood vessels. • Microbes induce host cellular responses that cause additional tissue damage including suppuration, scarring, hypersensitivity reaction. Viruses injury to host tissue A. Viruses enter host cell by. 1. Binding to host cell surface protein (e.g. HIV to CD4 cells). 2. Translocation into cytosol from plasma membrane or endosomal membrane. 3. Replication via virus specific enzyme. B. Viral infection can be abortive, latent ( e.g-varicella zoster virus) and or persistent (HBV). C. Virus kill host cells by 1. Inhibiting host cell DNA, RNA or protein synthesis(polio virus). 2. Damaging the plasma membrane. 3. Lysing cells ( influenza virus). Inducing a host immune response to virus infected cells (HBV). Bacterial injury to host cells A. Bacterial injury depend on ability to deliver toxins ( vibrio cholera )or to adhere to host cells and enter them (listeria monocytogens). B. Bacterial adhesins include filamentous pilli (Escherichia coli and Neisseria gonorrhea) that determine to which host cells the microbe will attaches (bacterial tropism). C. Bacterial endotoxins is a lipopolysaccharide that induce fever via host lymphokines, including TNF and IL-1. D. Bacterial exotoxins are composed of binding part and a catalytic part, and inactivate host protein or degrades it (botulim toxins). E. Bacteria may reproduce within the phagolysosome (Mycobacterrium) or cytosol (Shigella) Immune evasion (avoid)by Microbes 1. Remaining inaccessible within the lumen of small intestine (toxin –producing Clostridium difficile) or rapidly entering host cells(malaria in to liver). 2. Producing a capsule that cover the antigens and preventing phagocytosis (streptococcus pneumoniae). 3. Changing their surface antigens(rhino virus). 4. Infecting lymphocytes(HIV and EBV) and damaging host immune system. Spectrum of inflammatory response to infection. 1. Suppurative inflammation-mostly extracellular gram positive cocci and gram negative rods-haemophilus influenza. 2. Mononuclear inflammation. 3. Cytopathic-Cytoproliferative inflammation: virus mediated damage to individual host cells in the absence of host inflammatory response-it may show inclusion bodies (CMV), polykaryones (measles), Blisters (herpes), warty changes (HPV). 4. Necrotizing inflammation-caused by uncontrolled viral infection-sever tissue necrosis in absence of inflammatory infiltrate as in bacterial toxins (Clostridium difficile) Actinomycosis • Actinomycosis is a slowly progressive, suppurative, fibrosing infection involving the jaw, thorax, or abdomen. • The disease is caused by a number of anaerobic and microaerophilic bacteria termed Actinomyces, and the most common is Actinomyces israelii. • These organisms are branching, filamentous, gram-positive rods that normally reside in the oropharynx, gastrointestinal tract, and vagina without producing disease. • Pathogenesis and Pathology: Actino-myces can cause disease only if inoculated into anaerobic deep tissues. Trauma can produce tissue necrosis, providing an excellent anaerobic medium for growth of Actinomyces and can inoculate the organism into normally sterile tissue. • Actinomycosis occurs at four distinct sites: 1. Cervicofacial actinomycosis results from jaw injury, dental extraction, or dental manipulation. 2. Thoracic actinomycosis: aspiration of organisms contaminating dental debris. 3. Abdominal actinomycosis traumatic or surgical disruption of the bowel, especially the appendix. 4. Pelvic actinomycosis is associated with the prolonged use of intrauterine devices • Actinomycosis begins as a nidus of proliferating organisms that attract an acute inflammatory infiltrate. • The small abscess grows slowly, becoming a series of abscesses connected by sinus tracts that burrow across normal tissue boundaries and into adjacent organs. • Eventually, a tract may penetrate onto an external surface or mucosal membrane, producing a draining sinus. • Within the abscesses and sinuses are pus and colonies of organisms that appear as hard, yellow grains, known as sulfur granules, because of their resemblance to elemental sulfur. • Histologically, the colonies appear as rounded, basophilic grains with scalloped eosinophilic borders. Syphilis • Syphilis is a chronic systemic infection that is transmitted almost exclusively by sexual contact or from an infected mother to her fetus (congenital syphilis). • Infection is caused by Treponema pallidum, a thin, long spirochete. • Pathogenesis and Pathology: Person-to-person transmission requires direct contact between a rich source of spirochetes (e.g., an open lesion) and mucous membranes or abraded skin of the genital organs, rectum, mouth, fingers, or nipples. • The organisms reproduce at the site of inoculation, pass to regional lymph nodes, gain access to systemic circulation, and disseminate throughout the body. • Although T. pallidum induces an inflammatory response and is taken up by phagocytic cells, it persists and proliferates. • Chronic infection and inflammation cause tissue destruction, sometimes for decades. • The course of syphilis is classically divided into three stages. 1. Primary Syphilis is Characterized by the Chancre: ulcer at the site of T. pallidum entry. It appears 1 week to 3 months after exposure and tends to be solitary. • Spirochetes tend to concentrate in vessel walls and in the epidermis around the ulcer. The vessels display a characteristic vasculitis, in which endothelial cells proliferate and swell, and vessel walls become thickened by lymphocytes and fibrous tissue. • Chancres are painless and heal without scarring. 2. Secondary Syphilis Features the Systemic Spread of the Organism • In secondary syphilis, T. pallidum spreads systemically and proliferates to cause lesions in the skin, mucous membranes, lymph nodes, meninges, stomach, and liver. • Lesions show perivascular lymphocytic infiltration and endarteritis obliterans. The most common presentation of secondary syphilis is an erythematous and maculopapular rash, involving the trunk and extremities and often includes the palms and soles. • The rash appears 2 weeks to 3 months after the chancre heals. Lesions on mucosal surfaces of the mouth and genital organs, called mucous patches, teem with organisms and are highly infectious. 3. The Gumma is the Hallmark Lesion of Tertiary Syphilis • Following secondary syphilis, an asymptomatic period lasts for years. However, spirochetes continue to multiply, and the deep-seated lesions of tertiary syphilis gradually develop in one third of untreated patients. • The appearance of a gumma in any organ or tissue is the hallmark of tertiary syphilis. • Gummas are most commonly found in the skin, bone, and joints, although they can occur anywhere. • These granulomatous lesions are composed of a central area of coagulative necrosis, epithelioid macrophages, occasional giant cells, and peripheral fibrous tissue. • Gummas are usually localized lesions and generally do not contribute to the disease process. • Rather, the underlying mechanism for much of the damage associated with tertiary syphilis is focal ischemic necrosis secondary to obliterative endarteritis. • T. pallidum induces a mononuclear inflammatory infiltrate composed predominantly of lymphocytes and plasma cells. These cells infiltrate small arteries and arterioles, producing a characteristic obstructive vascular lesion (endarteritis obliterans). Tuberculosis • Tuberculosis is a chronic, communicable disease in which the lungs are the prime target, although any organ may be infected. • The disease is mainly caused by M. tuberculosis hominis (Koch bacillus) but also occasionally by M. tuberculosis bovis. • The characteristic lesion is a spherical granuloma with central caseous necrosis. M. tuberculosis is an obligate aerobe, a slender, beaded, nonmotile, acid-fast bacillus. • Tuberculosis is one of the most important human bacterial diseases. • M. tuberculosis is transmitted from person to person by aerosolized droplets. • Coughing, sneezing, and talking all create aerosolized respiratory droplets; usually, droplets evaporate, leaving an organism (droplet nucleus) that is readily carried in the air. • Pathogenesis: • The course of tuberculosis depends on age and immune competence, as well as the total burden of organisms. Some patients have only an indolent, asymptomatic infection, whereas in others, tuberculosis is a destructive, disseminated disease. • Many more persons are infected with M. tuberculosis than develop clinical symptoms. Thus, one must distinguish between infection and active tuberculosis. • Tuberculous infection refers to growth of the organism in a person, whether there is symptomatic disease or not. • Active tuberculosis denotes the subset of tuberculous infections manifested by destructive and symptomatic disease. • Primary tuberculosis occurs on first exposure to the organism and can pursue either an indolent or aggressive course . • Secondary tuberculosis develops long after a primary infection, mostly as a result of reactivation of a primary infection. Secondary tuberculosis can also be produced by exposure to exogenous organisms and is always an active disease. This is an acid fast stain of Mycobacterium tuberculosis (MTB). Note the red rods--hence the terminology for MTB in histologic sections or smears: acid fast bacilli. Giardia lamblia Most prevalent pathogenic intestinal protozoan worldwide. Infection may be subclinical or may cause acute or chronic diarrhoea. Not killed by chlorine. Reside in duodenum. Adhere to but do not invade intestinal epithelial cells. Diagnosis of infectious diseases Epidemiological dates Clinical features Symptoms and signs Laboratory findings Routine examination of blood, urine, feces Bio-chemical examinations Etiological examinations Direct exam Isolation of pathogen Molecular biological examinations Immunological examinations Endoscope examinations Image examinations Treatment of infectious disease General and supporting therapy Isolation of patients, rest, diet, nursing Pathogen or specific therapy Symptomatic therapy Rehabilitation Physiotherapy acupuncture Chinese herbs or tradition medicine Prevention of infectious disease Management of source of infection Cut off of route Personal hygiene, public hygiene, insecticide, disinfection Protect susceptible population Active immunization Passive immunization