Infectious diseases20

Pathology of Infectious Diseases V. Žampachová

Categories of infectious agents Subcellular infectious entities : prions; viruses (20–200 nm) Prokaryota : Chlamydiae (0.3–1 µ m); Rickettsiae (0.3–1 µ m); Mycoplasmas; classic bacteria (1-5 µ m) Eukaryotic microorganisms : Fungi (yeasts 5–10 µ m, size of mold fungi indeterminable); Protozoa (1–150 µ m) Helminths, Arthropods

Categories Saprophytes: nonpathogenic; in dead organic matter Parasites: living in or on an host on his the expense – Commensals: normal inhabitants of skin and mucosa; – Opportunists or facultatively pathogenic microorganisms: in an “opportune” situation; frequently from the normal flora, may be from the surrounding environment or other germ carriers – Pathogenic microorganisms: Classic disease-causing pathogens

RESIDENT FLORA NO disease under normal conditions Includes bacteria, fungi, protozoa, viruses and arthropods (mites) Most areas of the body in contact with the outside environment harbor resident microbes; large intestine has the highest numbers of bacteria Internal organs , tissues , fluids microbe-free Bacterial flora benefit host by preventing overgrowth of harmful microbes

OPPORTUNISTIC FLORA P otentially pathogenic organisms that do not cause disease in their normal habitat in a healthy person Organisms that gain access into the tissue through b ro ken skin or mucous membranes H ost already weakened or compromised by infection.

TRUE PATHOGENS capable of causing disease in healthy persons with normal immune defenses (i.e. i nfluenza virus, plague bacillus, malarial protozoan , …) Pathogenicity: capacity of a pathogen species to cause disease Virulence: sum of the disease-causing properties of a strain of a pathogenic species

Extent of h ost i nvolvement Local infection : Pathogens are limited to a small area of the body Systemic infection : An infection throughout the body Focal infection : Systemic infection that began as a local infection

Extent of Host Involvement Sepsis : Toxic inflammatory condition arising from the spread of microbes, especially bacteria or their toxins, from a focus of infection Bacteremia : Bacteria in the blood Septicemia : Growth of bacteria in the blood

Extent of Host Involvement Toxemia : Toxins in the blood Viremia : Viruses in the blood Primary infection : Acute infection that causes the initial illness Secondary infection : Opportunistic infection after a primary (predisposing) infection Subclinical disease : No noticeable signs or symptoms (inapparent infection)

Host i nvolvement Endogenous infection from the colonizing flora Exogenous infection from invasion of host by microorganisms from external sources Nosocomial infection acquired during hospitalization (urinary tract infections, infections of the respiratory organs, wound infection, sepsis)

Host i nvolvement Superinfection: occurrence of a second infection in the course of a first infection Relapses: series of infections by the same pathogen Reinfection: series of infections by different pathogens Subclinical disease : No noticeable signs or symptoms (inapparent infection)

Host i nvolvement Local infection restricted to the portal of entry and surrounding area Generalized (systemic) infection Lymphogenous and/or haematogenous spread of pathogen from the portal of entry; organotropism; three stages: incubation, generalization, organ manifestation

Host i nvolvement Sepsis Systemic disease by microorganisms and/or their toxic products; often a localized focus of infection from which pathogens or toxic products enter the bloodstream continuously or in intermittent phases, -> shock Septicemia Growth of (pathogenic) bacteria in the blood Pyemia Bacteria in blood in aggregates (microemboli) + toxemia, -> pyemic abscess, septic infarction Transitory bacteremia/viremia/parasitemia Brief presence of microorganisms in the bloodstream

Epidemic process and epidemic factors of infectious disease Source of infection (basic conditions) Patients (acute, chronic), c overt infection, c arrier, i nfected animal Route of transmission Contact transmission (direct and indirect), blood-borne, soil- borne, f ood + water - borne, a ir-borne , i nsects, … Susceptibility of population Factors of influencing epidemic process nature factors, social factors

Reservoirs of i nfection Continual sources of infection Human: AIDS, gonorrhea Carriers may have inapparent (subclinical) infections or latent diseases Animal: Rabies, Lyme disease Some zoonoses may be transmitted to humans Nonliving: Botulism, tetanus Soil

TRANSMISSION OF DISEASE The causative agents of disease can be transmitted from the reservoir to a susceptible host by 4 routes. Contact — d irect A common vehicle — i ndirect Airborne route Vectors

CONTACT TRANSMISSION DIRECT CONTACT - reservoir to host INDIRECT CONTACT - reservoir to vehicle to host. Vehicle – inanimate material, food, water, drugs, biological products, … DROPLET - reservoir to air (short distance) to host Airborne transmission - spread of agents by droplet nuclei or dust at a distance of more than 1 meter from the reservoir to host

VECTORS V ector s: animal s that carry pathogens from one host to another. Biological: Bite or feces Mechanical: Transported on feet

Pathogen c haracteristics f avoring e nvironmental t ransmission Multiple sources and high endemicity in humans, animals and environment High concentrations released into or present in environmental media (water, food, air) Proliferate in water and other media High carriage rate in human and animal hosts Asymptomatic carriage in non-human hosts Adapt to and persist in different media or hosts mutation and gene expression Seasonality and climatic effects Natural and anthropogenic sources

Pathogen c haracteristics f avoring e nvironmental t ransmission Ability to p ersist or p roliferate in e nvironment and s urvive or p enetrate t reatment p rocesses Stable environmental forms ; mechanisms to survive/multiply spores, cysts, oocysts, stable outer viral layer (protein coat), capsule, etc. Colonization, biofilm formation, resting stages, protective stages, parasitism Spatial distribution Aggregation, particle association, etc. Resistance to environmental stressors and antagonists: Biodegradation, heat, cold (freezing), drying, dessication, UV light, ionizing radiation, pH extremes, etc. Resist proteases, amylases, lipases and nucleases Posses DNA repair mechanisms and other injury repair processes

Pathogen c haracteristics f avoring e nvironmental t ransmission Ability to cause colonization, infection and illness Low infectious dose Infects by multiple routes ingestion (GI) inhalation (respiratory) cutaneous (skin) eye etc. Does not kill off its hosts “ agreeable” host-parasite relationship

Virulence p roperties of p athogenic b acteria f avoring e nvironmental t ransmission S tructures or chemical constituents that contribute to pathophysiology: Outer cell membrane of Gram negative bacteria: endotoxin (fever producer) Exotoxins Pili , etc. Spores : High resistance to physical and chemical agents very persistent in the environment Others : plasmids, lysogenic bacteriophages, etc .

Bacterial pathogenicity and virulence Adhesion to host cells (adhesins). Breaching of host anatomical barriers (invasins) and colonization of tissues (aggressins). Strategies to overcome nonspecific defenses , i.e. antiphagocytic mechanisms (impedins). Strategies to overcome specific immunity , production of IgA proteases (impedins), molecular mimicry, and immunogen variability. Damage to host tissues due to direct bacterial cytotoxicity, exotoxins and exoenzymes (aggressins). Damage due to inflammatory reactions in the macroorganism: activation of complement and phagocytosis; induction of excess cytokine production (modulins)

1. Adhesins. They facilitate adhesion to specific target cells. 2. Invasins. They are responsible for active invasion of the cells of the macroorganism. 3. Impedins. These components disable host immune defenses in some cases. 4. Aggressins. These substances include toxins and tissue-damaging enzymes. 5. Modulins. Substances that induce excess cytokine production (i.e., lipopolysaccharides of Gram-negative bacteria, superantigens, murein fragments).

Host f actors in p athogen t ransmission Age (old age, extreme youth – prematurity, infancy) Immune status (inborn and/or acquired defects, incl. immunosuppressive therapy, stress, etc.) Concurrent illness or infirmity Genetic background Pregnancy Nutritional status Demographics of the exposed population (density, etc.) Social and behavioral traits

Sensitive p opulations – i ncreased i nfectious d isease r isks Infants and young children Elderly Immunocompromized Persons with AID S Cancer patients Transplant patients Pregnant Malnourished

Infection and i llness f actors in p athogen o ccurrence and t ransmission Duration of illness Severity of illness Infectivity Morbidity, mortality, sequelae of illness Extent or amount of secondary spread Quality of life Chronicity or recurrence

Characteristics of p athogen i nteractions with h osts Persistence in hosts: Chronicity Persistence Recrudescence Sequelae and other post-infection health effects cancer, heart disease, arthritis, neurological effects Secondary spread

Outcomes of i nfection p rocess Hospitalization Infection Asymptomatic i nfection Mortality Disease Advanced i llness, c hronic i nfections and s equelae Acute s ymptomatic i llness: s everity and d ebilitation Exposure Sensitive p opulations

INFECTIOUS DISEASES SYMPTOMS - subjective evidence of disease as sensed by the patient. SIGNS - objective evidence of disease as noted by an observer. SYNDROMES - a specific group of symptoms or signs which accompany a particular disease.

Common signs and symptoms Signs Symptoms Fever Chills Septicemia Fatigue, soreness Skin eruptions Itching Chest sounds Dyspnoea

Health o utcomes of m icrobial i nfection Acute o utcomes Diarrhea, vomiting, rash, fever, etc. Chronic o utcomes Paralysis, hemorrhagic uremia, reactive arthritis, encephalitis, heart disease, etc. Hospitalizations Deaths

Acute and c hronic o utcomes a ssociated with m icrobial i nfections

Portals of e ntry Skin Gastrointestinal t ract Respiratory Urogenital Via p lacenta Parenteral (injection, bite)

Attachment Fimbriae Glycocalyx Hooks Suction discs Viral spike

Cellular mechanisms of clinical disease Cytopathic effect (i.e. obligate intracellular parasites) Exotoxins (AB toxins, membrane toxins, superantigenes) Hydrolytic exoenzymes (proteases, …) Secretion of virulence proteins. Cell wall (lipopolysaccharides etc.) Inflammation

EXOTOXINS Both Gram + and Gram – bacteria produce exotoxins. Exotoxins have very specific damaging effects which are disease and/or organ specific . Exotoxins are secreted by bacterium or leak into surrounding fluids following cell lysis.

EXOTOXINS In most cases, the pathogen must colonize a body surface or tissue to produce enough toxin to cause damage. Exotoxins can act locally, or they may be carried in the bloodstream throughout the body, causing systemic effects. Exotoxins are proteins, therefore, the immune system can generally produce protective antibodies.

The A-B toxins can be grouped into functional categories as well: Neurotoxins Cause damage to nervous system Major symptom is paralysis Enterotoxins Damage to intestines and tissues of digestive tract Major symptom is vomiting and diarrhea Cytotoxins Damage to variety of cells Damage caused by interference with cell function or cell lysis EXOTOXINS

Disrupt plasma membrane Cause cell lysis, therefore they are cytotoxins. Lysis of RBC is an example. Can be termed hemolysins or cytolysins. Some membrane-damaging toxins produce pores that allow fluids to enter causing cell destruction. Streptococcus pyogenes on blood agar plates. MEMBRANE DAMAGING TOXINS

Phospholipases are group of potent membrane-damaging toxins Remove polar heads of phospholipid Destabilizes membrane Clostridium perfringens which causes gas gangrene is a phospholipase. MEMBRANE DAMAGING TOXINS

SUPERANTIGENS Override specificity of T cell response Causes toxic effects due to massive release of cytokines by large number of helper T cells

SUPERANTIGENS Superantigens short-circuit normal control mechanisms of antigen process and presentation Superantigens also suspected in contributing to autoimmune disease

ENDOTOXINS Endotoxins are lipopolysaccharides, part of the outer leaflet of the outer membrane of Gram- bacteria. Thus it is a fundamental part of Gram- bacteria. The lipid A component is responsible for the toxic properties of LPS.

ENDOTOXINS All endotoxins produce the same signs and symptoms, regardless of the species of microorganism, although not to the same degree. Responses by the host include fever, weakness, and generalized.

ENDOTOXINS The symptoms associated with endotoxins are due to a vigorous innate immune response. Endotoxins exert their effects when Gram- bacteria die and their cell walls undergo lysis liberating the endotoxin. This is why antibiotics used to treat diseases may lead to an immediate worsening of the symptoms, but the condition improves as the antibiotics begin to exert its effect.

ENDOTOXINS If the lipid A is in a localized region the magnitude of the reaction is small. If the lipid A is systemic, such as a septicemia, the reactions can result in septic shock or endotoxic shock.

COMPARISON OF EXOTOXINS AND ENDOTOXINS

Additional Virulence Factors

Virus and host cell reactions Cytocidal infection (necrosis): viral replication results directly in cell destruction Apoptosis : in most cases interrupting the viral replication cycle. Noncytocidal infection : the host cell survives, possible destruction by secondary immunological reactions. Latent infection : the viral genome inside the cell, no viral replication or cell destruction. Tumor transformation : the host cell into a cancer cell, viral replication +/-, depending on the virus and/or cell type involved.

TRANSMISSION Common vehicle transmission refers to the transmission of disease agents by a common inanimate reservoir (food, drugs, blood) to an individual. Airborne transmission refers to the spread of agents by droplet nuclei or dust at a distance of more than 1 meter from the reservoir to host.

Host defense mechanisms Nonspecific defenses including mechanical, humoral, and cellular systems. Phagocytosis the most important process Specific immune responses based on antibodies and specific reactions of T lymphocytes (see immunology).

Nonspecific host defenses Mechanical factors Anatomical structure of skin and mucosa Mucus secretion and mucus flow from mucosa Mucociliary movement of the ciliated epithelium in the lower respiratory tract Digestive tract peristalsis Urine flow in the urogenital tract

Nonspecific host defenses Humoral factors Microbicidal effect of the dermal acidic mantle, lactic acid from sweat glands, hydrochloric acid in the stomach, unsaturated fatty acids secreted by the sebaceous glands Lysozyme in saliva and tear fluid: splitting of bacterial murein Complement (alternative activation pathway) Acute phase reactants : serum proteins, i.e. C-reactive protein, haptoglobin, serum amyloid A, fibrinogen, transferrin Fibronectin (a nonspecific opsonin); antiviral interferon Mannose-binding protein : to the outer bacterial surface, alternative activation of complement

Nonspecific host defenses Cellular factors Normal flora of skin and mucosa Natural killer cells (large, granulated lymphocytes; null cells) Professional phagocytes: microphages (neutrophilic and eosinophilic granulocytes); mononuclear phagocytes (macrophages, monocytes, etc.)

EXTENT OF HOST INVOLVEMENT LOCALIZED INFECTION– microbes enters body & remains confined to a specific tissue. SYSTEMIC INFECTION– infection spreads to several sites and tissue fluids usually in the bloodstream. FOCAL INFECTION– when infectious agent breaks loose from a local infection and is carried to other tissues.

EXTENT OF HOST INVOLVEMENT A PRIMARY INFECTION—is an acute infection that causes the initial illness. A SECONDARY INFECTION—is one caused by an opportunist microbe or is the result of the primary infection. A SUBCLINICAL INFECTION—is one that does not cause any noticeable illness.

DAMAGE TO THE HOST Damage due to infection can be result of direct effects of the pathogen. Or indirect effects, such as the immune response.

Nosocomial i nfections Figure 14.9

Common Causes of Nosocomial Infections Percentage of Total Infections Percentage Resistant to Antibiotics Coagulase-negative staphylococci 25% 89% S. a ureus ( MRSA) 16% 80% Enterococcus (vancomycin-res.) 10% 29% Gram-negative rods 23% 5-32% C. difficile 13% None

Nosocomial i nfections Source : hands of healthcare workers contaminated surfaces other patients (incl. contaminated biological material)

Most important risk p rocedure s MRSA

Staphylococcus aureus the most virulent pathogenic species in the group implicated in a variety of infections including skin, respiratory tract, post-op infections and other systemic infections such as TSS. S. aureus also causes food poisoning. All Staph group species, including S. aureus, can lead a commensal existence (as an opportunistic pathogen) in the skin and mucous membranes of humans and many other animals, including domestic pets and farm animals.

General c linical s ignificance Staphylococcal infections are generally acute, often involve inflammation and suppuration A small percentage of staphylococcal infections spread hematogenously to all regions of the body = systemic = bacteremia, and likely toxemia.

P redisposing factors Immune system suppressed or otherwise compromised. Skin injuries (e.g. burns, surgical incisions, cuts, etc) Presence of foreign bodies (e.g intravenous lines, prosthetic devices, sutures, tampons-TSS) Pre-existing infections Chronic underlying conditions (e.g. auto-immune conditions, malignancies, alcoholism, heart disease, etc.) Compromised microbiota via antimicrobial therapy Infants susceptible: oral, skin: impetigo, “scalded skin”, respiratory, other

S. aureus is a problem S. aureus has been generally considered the #1 human pathogen since the 1980s. Why: It is everywhere Nosocomial: big problem in hospitals Antibiotic resistance: 25% increase in MRSA isolates Lots of toxins Good at immune evasion, rapid growth + spread = bacteremia Numerous types of infections

S. aureus pneumonia S. aureus - uncommon cause of community acquired pneumonia (both primary and secondary) , nosocomial cases more common. H igh mortality rate due to the immune compromised status of the patient, and high degree of antibiotic resistance of strains in the hospital.

Skin + mucous membranes infections / wounds S. aureus - common resident of the skin and exposed mucus membranes: respiratory, genitourinary , gastrointestinal. S aureus - most common cause of pathogenic integument infection in humans. S. aureus – leading cause of post-operative infection, later often systemic , with high mortality rates

Skin + mucous membranes infections / wounds Folliculitis (infected hair follicles) -> more deep seated furuncle. Multiple furuncles coalesce into a carbuncle. Source of hematogenous spread S tfl . aureus , S tr . pyogenes - impetigo, the most common skin infection in children – highly contagious S calded-skin syndrome (Ritters syndrome) in infants via production of an exfoliating toxin , rare

Food poisoning S. aureus - most common cause of food poisoning , mostly mild Symptoms : nausea, vomiting, diarrhea, abdominal cramping and mild fever. Symptom onset can be within minutes or hours of ingestion, with similar duration Source : handled foods: wet, sugary or salty, handled after some preparation – cooked, mixed, then served cold, at least initially

S. aureus – other pathology *S. aureus - classic cause of “toxic shock syndrome,” a highly acute and highly toxigenic condition – “super-infection” + “super-antigens” result in organ destruction, shock, hypotension and death Acute or chronic osteomylitis, mainly in children Endocarditis Septic arthritis Mastitis Meningitis Phlebitis / thrombophlebitis (clotting)

Emerging i nfectious d iseases Diseases that are new, increasing in incidence, or showing a potential to increase in the near future Newly recognised infectious causes of known diseases (Borrelia; hepatitis viruses – HCV, HEV, HGV; H. pylori, etc.) Opportunistic infections in immunocompromised patients (MAC, Pneumocystis, HHV-8)

Emerging i nfectious d iseases Geographic spread of known infections (West Nile virus, Plasmodium falciparum) Crossing of interspecies barrier (SARS coronavirus, Ebola) Re-emerging infections, new strains (TBC, Vibrio cholerae)

Emerging i nfectious d iseases Mutation of organism to new serovar iant (antigenic type) Migration of humans and animals into new environments Travel War and natural disasters Decline in vaccination rates Climatic changes

Emerging i nfectious d iseases Contributing factors Genetic recombination E. coli O157, avian influenza (H5N1) , pandemic influenza (H1N1) Evolution of new strains V. cholerae O139 Inappropriate use of antibiotics and pesticides Antibiotic-resistant strains Changes in weather patterns Hantavirus

Emerging i nfectious d iseases Modern transportation West Nile virus Ecological disaster, war, and expanding human settlement Coccidioidomycosis Animal control measures Lyme disease Public health failure Diphtheria

Crossing the Species Barrier Clinical Focus, p. 371

Lower respiratory tract It is sometimes difficult to establish the cause of an LRT without the use of an invasive procedure because so many species of bacteria are picked up from the URT. Non-bacterial LRTs: viruses are not an infrequent cause of LRTs fungal pathogens, especially Aspergillus sp,, and Pneumocystis carinii are found in immuno-compromised patients

FLORA of the RESPIRATORY SYSTEM

FLORA of the UPPER RESPIRATORY SYSTEM Oral Streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Neisseria sp., and Haemophilus. Most microbes are inhaled, the filtered out, destroyed, or expelled.

FLORA of the LOWER RESPIRATORY SYSTEM Usually no permanent residents are present.

Respiratory tract infections ↓ local host defences – mucociliary clearance (smoking, cystic fibrosis, preexisting inflammation), phagocytosis immunodeficiency – mycotic infections evasion by microorganisms – influenza virus binding to mucus; cilia paralyzing toxin (Bordetella pertussis, H. influenzae); TB intracellular parasite;

Respiratory tract infections Viral Rhinoviruses, Influenza, Bacterial Str. pneumoniae, Haemophilus infl., Chlamydia, TB, Fungal Histoplasmosis, Coccidioimycosis,

Upper respiratory tract Rhinitis + Sinusitis serous – viral (rhinoviruses, RSV, etc.); purulent – bacterial (Haemophilus, etc.); granulomatous – fungal (Aspergillus, …) Laryngitis – pseudomembranous (Diphteria); acute epiglottitis in children (H. influenzae); papillomatosis - HPV

Upper respiratory tract Many bacterial species and viruses alike cause some manner of upper respiratory tract infection. S. aureus common with strep throat-like symptoms. Can co-reside with S. pyogenes or respiratory viruses such as influenza or RSV. Often as secondary infections following respiratory viral infection. Uncommon cause of accute sinusitis and otitis media

Lower respiratory tract Bronchitis – nonpurulent viral - RSV; purulent H. influenzae, Str. pneumoniae, etc.; fungal (mycetoma in bronchiectasis – Aspergillus)

Lower respiratory tract Pneumonia – lobar (pneumococcus, Klebsiella); bronchopneumonia (Staph., H. infl., Str.) atypical: viral – Infl., RSV, adenovirus, CMV, HSV, Mycoplasma, Legionella, Chlamydia, fungal – Aspergillus, Pneumocystis, Cryptococcus, Candida, granulomatous: TB, MAC, Histoplasma

Influenza Acute respiratory illness caused by influenza viruses. Typical symptoms-fever, chills, myalgia, headache, sore throat, cough. Serious cases in young children and elderly.

Influenza e pidemiology Transmission : primarily via respiratory droplets. person to person (hand-to-hand, hand-to-mouth) direct contact aerosols—sneezing, coughing. S usceptible : the immunity in the population at risk is the major determinant of the extent and severity of an outbreak. Pandemic H1N1 : antibodies in persons born ≤ 1930, less in ≤ 1960, after 1960 – susceptible. At risk – children, young adults, pregnant, obese, immunocompromised patients

Influenza p athogenesis Histopatholog y : degenerative cell changes, incl . granulation, vacuolization, swelling, pyknotic nuclei. The severity of illness correlate s with the quantity of virus shed in secretions; R arely detected in extra pulmonary sites. Primary influenza viral pneumonia ( risk patients) interstitial lymphoplasmocytic infiltration , ARDS posible .

Influenza m anifestations Incubation period: 1-3 days Typical influenza abrupt onset of systemic symptoms. Headache, fever, chills, myalgia, or malaise , respiratory tract signs, particularly cough and sore throat. Ocular signs and symptoms include pain on motion of the eyes, photophobia, and burning of the eye.

Influenza m anifestations Physical findings: examination of the pharynx: severe sore throat. injection of the mucous membranes and postnasal discharge. mild cervical lymphadenopathy. Chest examination: largely negative. rhonchi, wheezes, and scattered rales. last s for 4-7days.

Influenza m anifestations Primary influenza virus pneumonia: presents as acute influenza , not resolv ing, progress ion with persistent fever, dyspnea, eventual cyanosis. S putum production generally scanty. ARDS + respiratory failure. Possible cardiac failure, liver failure and renal failure. Physical findings: no consolidation signs.

Perez-Padilla R et al. N Engl J Med 2009;10.1056/NEJMoa0904252 Initial Radiograph of the Lung and Lung-Tissue Sample from Patient 3

Influenza m anifestations Mild form influenza Other forms: stomach flu encephalitis, transverse myelitis, myocarditis and pericarditis, myositis

Influenza c omplications Secondary bacterial infection: pneumonia: cough, purulent sputum, physical and x-ray signs of consolidation. Most common bacterial pathogens are S treptococcus pneumoniae, S taphylococcus aureus, H aemophilus influenzae.

Influenza c omplications Reye's syndrome : fatty liver with minimal inflammation, severe encephalopathy (with swelling of the brain). L iver slightly enlarged , firm, jaundice not usual. Early diagnosis vital, otherwise death or severe brain damage may follow. Mitochondrial hepatopathy children ≤ 4 yrs; 3-5 days after viral illness

Differential diagnosis On clinical grounds alone, an individual case of influenza may be difficult to differentiate from an acute respiratory illness caused by any of a variety of respiratory viruses or by M ycoplasma pneumoniae. V irus isolation and serum test or antigens detect are very important. Epidemiologic situation

Avian influenza A/H5N1 outbreak, an influenza-like illness typically appeared early in the course of the disease, and conjunctivitis was seen in some patients. Pneumonia. Some patients had prominent GI symptoms with abdominal pain, diarrhea, and vomiting. Severe cases progressed to respiratory distress in a week, physical examination would find the consolidation signs.

Laboratory findings The 1st day after the admission The 2nd day after the admission

The 4th day after the admission

GIT infections mostly by contaminated food or water ↓ local host defences (↓ gastric acidity, ↓ enzymatic secretion, loss of normal flora, obstruction) general immunodeficiency (-> fungal, CMV, MAC infection) resistant microorganisms (hepatitis A virus, rotavirus, H. pylori, protozoan cysts,…)

FLORA of the ORAL CAVITY Streptococcus, Neisseria, Staphyloccoccus, Lactobaccillus, Actinomyces, Bacteroides. Colonize in the epidermal layer of the cheeks, gingiva, and on the surface of teeth. Found in saliva in large numbers

Oral cavity and oesophagus infections Viral – herpetic stomatitis (HSV-1, less common HSV-2), vesicles -> ulcers; herpes zoster; EBV, CMV, measles Fungal – superficial pseudomembranous oral candidiasis Sialoadenitis – non-purulent viral (mumps); purulent bacterial (Stph. aureus, Str. viridans)

Infectious Mononucleosis Caused by B-lymphocytic Epstein-Barr Virus (EBV) Acute self limiting disease of adolescents & young adults (cytomegalovirus has a similar picture  serological separation) Infection characterised by Fever, sore throat & generalised lymphadenopathy Reactive leukocytosis (atypical morphology) Humoral antibody response URT-I manifestations Epidemiology Low socio-econ o mic Asymptomatic infection in early life 50% become virus shedders Developed regions Infection delayed  adolescent/adulthood More effective immune response to virus  prolongs infection 20% become virus shedders

Viral transmitted via direct oral contact (kissing disease)  Virus initially penetrates nasopharynx, orophanynx & salivary gland epitheliod cells  Subclinical infection  Spreads to underlying lymphoid tissue  B-Lymphocytes infected  Majority of cases the virus becomes associated with a genome (latent effect)  Minority release virons via lysis of B-cells (spreads)

Clinical Course Classical presentation Fever sore throat lymphadentitis Aberrent behaviour Little or no fever with malaise, fatigue & lymphadenopathy Fever with unknown origin without lymphadenopathy Hepatitis difficult to differentiate Hepatic dysfunction Jaundice Increased liver enzymes Diagnosis Lymphocytosis  enlarged atypical lymphocytes Specific EBV antigens Usually self-limiting  4-6 weeks  fatigue may be longer

Complications Predisposed patients E.g. HIV/AIDS; immunosuppressive therapy Can easily die from the infection EBV is a potent transforming oncogenic virus Malignant lymphomas (Hodgkin, non-Hodgkin) Squamous cell carcinomas (nasopharynx, oral cavity) X-linked lymphoproliferative syndromes Immunodeficieny Inherited Inability to maintain immune response against EBV Fatal infection

Stomach infections H. pylori – acute infection mostly asymptomatic; chronic infection may lead to chronic gastritis Viral gastroenteritis – acute; rotavirus, adenovirus, calicivirus (Norwalk-like) eosinophilic gastritis – may be due to parasites

FLORA of the LARGE INTESTINES Bacteroides, Fusobacterium, Eubacterium, Clostridium, Lactobacillus, coliforms. Candida fungus may be present. Flora consists predominantly of strict anaerobes. Feed on wastes materials in the large intestines.

Intestinal infections Enterocolitis – usual manifestation as diarrhea, may be pseudomembranous, ulcerative, non-purulent worldwide more than 3 millions deaths annually, mainly children ≤ 5 yrs chronic or recurrent enterocolitis – parasites, protozoa

Infectious diarrhea Viral : rotavirus, enteric adenovirus, echovirus Bacterial : Salmonella sp., Shigella, E. coli (enterotoxigenic, enteropatgogenic), Campylobacter jejuni, Vibrio cholerae, Yersinia enterocolica, Clostridium difficile Parasitic : Giardia lamblia, Entamoeba histolytica

Types of diarrhea Secretory – isotonic, persist during fasting, etiology: viral; bacterial enterotoxin (cholera, E. coli, Clostridium perfringens, etc.) Exudative – purulent + bloody stools, persist during fasting etiology: Shigella spp., Salmonella spp., Campylobacter spp., Entamoeba histolytica Malabsorption – Giardia lamblia

Entamoeba histolytica pathology 1. COLONIZATION OF THE LARGE INTESTINE primary ulcer: Mucosa submucosa

Entamoeba histolytica trophozoites

Entamoeba histolytica mature cysts quadrinucleate or mature cysts – diagnostic in feces

Entamoeba histolytica pathology 3. EXTRA-INTESTINAL LESIONS occur in 3 ECTOPIC SITES A. HEPATIC AMEBIASIS Trophozoites in submucosa are carried by hepatic portal vein to the liver -> abscess B. PULMONARY AMEBIASIS following l iver abscess rupture C. CEREBRAL AMEBIASIS Trophozoites in bloodstream

2 Groups of Parasitic Amebae ____________________parasites – can only exist as parasites - amebae in the family Entamoebidae - occur in the digestive tracts of vertebrates ____________________parasites – free-living soil and water amebae that can become parasitic if they enter vertebrate tissues

Entamoeba histolytica pathology 1. COLONIZATION OF THE LARGE INTESTINE flask-shaped lesions: proteolytic enzymes : Symptoms: Ulcers may form sinuses and extend into the submucosa

Liver abscess Diagram of pathology from text on page 112 Shows movement of trophozoites from large intestine to lungs via hepatic portal vein

Pathology of Ascaris lumbricoides Roundworm, 1 billion patients infected worldwide, larval migration into systemic circulation -> hepatic abscess, eosinophilic pneumonitis. Adults in large numbers -> intestinal obstruction

Pathology of Ascaris lumbricoides Larvae cause problems in the lungs when they break through the lung capillaries to enter the respiratory tree. S mall hemorrhages , inflammatory response -> pneumonia-like symptoms The more eggs ingested, the more migrating larvae, the greater the pathology. larva Inflammatory cells

Pathology of Visceral Larva Migrans PATHOLOGY - dependent upon which organs are invaded by the Toxocara canis ______________________ is commonly invaded - hepatomegaly & cirrhosis may occur __________________________ invasion results in a severe tissue reaction that can result in death 3. _____________________________may be invaded - scar tissue deposition in the retina can result in blindness Scar tissue in retina L 3 in retina

Pathology of Enterobius vermicularis Pinworms do not invade any tissue , live intraluminally. Nightly egg deposition on the perirectal mucosa -> irritation of the anal region , itching, possible s econdary bacterial infection in scratched .

Pathology of Enterobius vermicularis DIAGNOSIS - Eggs are distinct. football-shaped with one side flattened eggshell is smooth

Trematodes of medical importance Schistosoma, blood flukes Clonorchis & Opistorchis, liver flukes with metacercaria in fish Paragonimus, lung flukes with metacercaria in crabs Fasciolopsis, Fasciola, Dicrocoelium, intestinal and liver flukes with metacercaria on plants

Schistosomiasis granulomatous reaction to eggs bleeding, obstruction, stenosis intestinal, hepatic + biliary, (urogenital system)

Human liver fluke disease Caused by Clonorchis sinensis and Opistorchis felinus and viverini All locally common in East Asia and Eurasia ~20 million people infected

Human liver fluke disease Pathology depends on worm burden, generally infections are light and free of major symptoms Heavy infections Flukes residing in the bilary ducts can chronically iritate the epithelium resulting in hyperplasia of the epithelium and fibrosis around the ducts (pipe stem fibrosis) Blockage of bile ducts and impairment of liver function, liver swelling

Human lung fluke disease Adults are encapsulated in a granuloma (often two at a time) Cyst rupture can result in cough and increase sputum, and chest pain Chronic high worm burden can result in chronic bronchitis and dyspnea and increasing fibrosis -- symptoms can be very similar to pulmonary tuberculosis Cerebral paragonimiasis produces headaches, fever, nausea, visual disturbances and convulsive seizures

Infectious hepatitis Viral hepatitis – part of systemic disease (EBV, CMV, yellow fever, rarely rubella, herpesvirus, etc. Viral hepatitis – liver specific (HAV, HBV, HCV, HDV, HEV, HGV…) Bacterial – Stph. aureus, Salmonella typhi, Treponema pallidum Parasitic – abscesses - Entamoeba, Echinococcus; malaria, schistosomiasis, cryptosporidiosis, etc.

Viral hepatitis Acute asymptomatic infection with recovery Acute symptomatic infection with recovery Fulminant hepatitis – acute hepatic failure (mostly HAV, HBV), noninfectious causes (toxic); high mortality ( ~ 80%) Chronic hepatitis „ Carrier state“ – no manifest symptoms, usually very mild chronic hepatitis, non-progressive, reservoir for infection

FLORA of the URINARY SYSTEM Staphylococcus, Streptococcus, and coliforms. In females, flora exists only in the first portion of urethra, the remainder of the tract is sterile. In males, the entire reproductive and urinary tract is sterile except for a short portion of the anterior urethra.

FLORA of the REPRODUCTIVE SYSTEM Lactobacillus, Strptococcus, Corynebacterium, Mycobacterium. Candida albicans In females and males , flora occupies the external genitalia. Internal reproductive structures normally remain sterile.

Urogenital tract infections Ascending infection via urethra most usual (G- fecal bacteria – E. coli, Proteus,…) Anatomy – 5 cm lenght in women, 20 cm in men Predisposing factors – obstruction, reflux, loss of protective vaginal flora, mucosal microtraumata

Urogenital tract infections Hematogenous spread (septicemia – Stph., bacteremia, viremia, rare fungal inf. - Candida) Immunocompromised – CMV, polyomavirus, etc. Acute pyelonephritis – purulent Chronic pyelonephritis – chronic tubulointerstitial inflammation + renal scarring

Sexually Transmitted Infections Sexually Transmitted Disease - STD I nfection transmitted through vaginal, anal or oral sex Every sexually active individual is at risk Women acquire infections from men more than men from women 2/3 of STD occur in people under 25 yrs of age Infection by multiple agents common (↑ risk) Fetus or i nfants – vertical transplacental or perinatal transmission of STD -> abortus, inborn defects, neonatal infection. Diagnosis + treatment!!

STD Viruses : HSV, HPV, HIV, hepatitis B,C Chlamydiae : Ch. trachomatis Mycoplasmas : M. urealyticum (urethritis) Bacteria : Neisseria gonorrhoeae, Treponema pallidum, Haemophilus ducreyi (chancroid), Klebsiella granulomatis (granuloma inguinale) Protozoa : Trichomonas vaginalis (urethritis, balanitis, vaginitis)

Chlamydia: Manifestations In women often asymptomatic until uterus and tubes infected; may present with dysuria, urinary frequency , vaginal discharge 1/3 of men may be asymptomatic; dysuria, urethral discharge , testicular pain Patient infectious even if asymptomatic

Chlamydia: Complications May result in PID (pelvic inflammatory disease) Major cause of infertility , ectopic pregnancy in women; may cause stillbirth or spontaneous abortion (miscarriage) In men, may result in epididymitis, prostatitis, sterility , Reiter’s syndrome In neonates, may cause blindness , pneumonia

Genital Herpes: Pathophysiology About a week after exposure, painful red, fluid-filled blisters in the genital area (vagina, labia, cervix, penis, anus) Blisters filled w ith clear fluid containing the virus , highly contagious Rupture -> ulcers may last up to 6 weeks The first outbreak - the first episode infection Subsequent episodes ( recurrent infections ) usually less severe

Genital Herpes: Pathophysiology L atency period , no symptoms , the virus may be shed , p atient infectious The virus dormant in nerve fibers in the spinal cord in between outbreaks

Genital Herpes: Pathophysiology Prodromal symptoms: burning itching, tingling or throbbing Pain may radiate to the legs, thighs, groin or buttocks; pat ient may be more infectious during the prodromal period Recurrent infections- herpetic lesions reappear, general malaise, headache, fever, dysuria, urinary retention, vaginal/urethral discharge may occur

Genital Warts C ondyloma acuminatum - HPV Most HPV infections asymptomatic or unrecognized Mostly found in young, sexually active; associated w ith early onset of sexual activity , multiple sexual partners Transmitted b y all types of sexual contact

Genital Warts May be asymptomatic; single or multiple painless cauliflower-like growths on the vulva, vagina, perineum, penis, urethra, cervix, or anus Productive infection Other subtypes of HPV (i.e. 16, 18) strongly associated w ith cervical dysplasia and/or ca rcinoma HPV - higher risk of vaginal, vulvar, penile , anal dysplasia/ ca rcinoma Some types in oral/laryngeal carcinoma

Genital Warts: Complications Possible urethral obstruction or destruction of normal tissue Can be transferred to fetus during pregnancy or delivery Large warts may obstruct the birth canal; c esarean section may be necessary Infants infected may develop a chronic respiratory condition – laryngeal papillomatosis

Gonorrhea ‘ clap’; one of the most common STDs ( second only to Chlamydia ) Caused by Neisseria gonorrhoeae ; incubation period is 2-8 days Transmitted by sexual contact , during passage through the birth canal Usually targets the cervix , male urethra

Gonorrhea Female : most ly asymptomatic until advanced disease; dysuria, urinary frequency or abnormal vaginal discharge M ale : dysuria, serous, milky or purulent urethral discharge; regional lymphadenopathy Complications: prostatitis, epididymitis, sterility; PID, endometritis, salpingitis, peritonitis; in neonates gonorrhea can infect the eyes, nose or anorectal region

Syphilis S pirochete Treponema pallidum Transmitted from open lesions during sexual contact Organism can survive days in fluids May also be transmitted by infected blood, body fluids, including saliva Average incubation is 20-30 days Spreads through blood , lymphatic system Congenital syphilis - trans placental

Syphilis: P rimary s tage Chancre: painless ulcer in the site of innoculation; regional lymph adenopathy chancre appears 3-4 weeks after infectious contact , disappears within 4-6 weeks Chancre may go unnoticed in women Highly infectious during primary stage even if no symptoms are present

Syphilis: Secondary s tage Symptoms of secondary syphilis appear any time from 2 weeks to 6 months after initial chancre disappears , in 75% of untreated people Primary generalisation , flu-like symptoms , sore throat; generalized lymphadenopathy S kin rash (especially on palms of hands and soles of feet) maculopapular, pustular ; condylomata lata - mucus patches + erosions in oral cavity ; flat, broad-based wart-like papules on labia, anus or corner of mouth , highly infectious ; secondary alopecia D isappear within 2-6 weeks

Syphilis: Latency p eriod Usually NOT counted as a “stage” During this period no symptoms; 5- 50 years N ot transmissible by sexual contact; it CAN be spread by blood during this time M uch shorter in HIV infected

Syphilis: Tertiary s tage in 1/3 of untreated patients cardiovascular syphilis (mesaortitis), neurosyphilis (progressive paresis, dementia), benign tertiary syphilis: gummas in skin, mucous membranes, bones , liver; specific granulomas – delayed hypersensitivity reaction

FLORA of the SKIN Staphylococcus, Micrococcus, Corynebacterium, Mycobacterium. Yeast Most live in the upper dead layers of the epidermis, glands, and follicles. Present in sebaceous glands and hair follicles. Dependent on skin lipids for growth.

FLORA of the SKIN Staphylococcus, Micrococcus, Coryne-bacterium, Mycobacterium. Yeast Most live in the upper dead layers of the epidermis, glands, and follicles. Present in sebaceous glands and hair follicles. Dependent on skin lipids for growth.

Skin infections Viral exanthematic inflammations – HSV, varicella-zoster, etc. Viral pseudotumorous lesions – warts (HPV), molluscum contagiosum (poxvirus) Bacterial infections – superficial (impetigo – Stph. aureus, blisters + neutrophils), deep (panniculitis, phlegmona, ulcers) Fungal inf. – superficial (Tinea – dermatophytes) Parasitic inf. – scabies etc.

Human Anthrax Infections Cutaneous Respiratory Gastrointestinal

Common c hildhood v iral i nfections Measles (rubeola, red measles) Rubella (German measles) Erythema infectiosum (Fifth disease) Mumps Varicella-Zoster (Chickenpox) Coxsackievirus and Echovirus associated infections (hand-foot-and-mouth disease)

Measles Transmission: direct droplet contact; incidence greater in winter months Incubation: 2 weeks Rash evolves from face to trunk to extremities (including palms and soles) Fever and the three Cs: cough, coryza and conjunctivitis Koplik spots (little sugary spots on the mucosa next to the molar teeth) Diagnosis: antibody detection (IgM)

Measles Complications are common in the very young and older kids and young adults: Malnutrition esp . vitamin A deficiency is a major cause of mortality Complications include: Otitis media Pneumonia Encephalitis Death

Rubella Also known as German measles Transmission: respiratory droplets Incubation period is 2-3 weeks Infections may be sub-clinical esp . in young kids Mild to no prodromal phase; Rash (face to body notoriously difficult to make a clinical diagnosis) Adenopathy (swollen lymph nodes) Adults may also get mild arthritis

Rubella Congenital rubella is the most severe complication Most infections and complications occur in the first 16 weeks of pregnancy (90% transmission rate to fetus) Infants are born with numerous defects Cardiac abnormalities Cataracts Deafness Brain, liver and organ damage

Erythema infectiosum Also known as Fifth disease Caused by Parvovirus B19 infection Small single-stranded icosahedral DNA virus Worldwide infection Seroprevalence increases with age (15-60% by age 5-9) Transmission: Respiratory droplets Vertical

Erythema infectiosum Distinct facial rash: “slapped cheek” sparing the area around the mouth Lacy pink rash of the extremities Resolves within one week but can return with exposure to heat May cause fetal abnormalities if pregnant women are infected Diagnosis: Antibody detection (IgM )

Mumps Occurs worldwide Uncommon because of vaccine use and esp . after the introduction of a second dose of MMR Transmission: Droplet spread Incubation: 2-3 weeks

Mumps No rash; parotid gland swelling associated with ear ache is seen in 95% Other salivary glands and lymph nodes in head and neck: 10% Menningitis in 15%, encephalitis is rare Occasionally orchitis (common in young men but rarely leads to sterility), ooph o ritis Diagnosis: Antibody testing or finding the virus in saliva or urine (culture or PCR).

Chickenpox Varicella-zoster virus Infection is primarily by the airborne route Very infectious (90% of non-immune household contacts will become infected). Almost all children will be infected by the age of 15 Unlike other human herpes viruses almost all infections are symptomatic. Infections in immune compromised and neonates can produce encephalitis, pneumonia or disseminated infection.

Chickenpox (varicella) Chicken pox is usually characterized by fever and a generalized vesicular eruption. The virus replicates in the throat and subsequently spreads during secondary viremia to the skin, reticuloendothelial tissue and rarely to lungs and brain. The incubation time is usually 11-13 days. Typical progression is: Macule>papule>vesicle>pustule>ulcer>crust “ Dew drop on a rose petal”

Complications of chickenpox Pneumonia ( Approximately 15% of adults with chickenpox) Varicella in the immuno-compromised host: Varicella causes severe infections in newborns whose mothers are non-immune Patients with ↓ cell mediated immunity Central nervous system involvement (rare , 1 : 200) Bacterial super-infection (usually due to S. aureus and to S. pyogenes).

Shingles (varicella zoster) The incidence increases with age, 10-20% of adults will eventually get shingles The virus becomes latent in dorsal root and cranial nerve ganglia, reactivating later in life Shingles are characterized by inflammation of sensory nerve and their ganglia and a localized vesicular rash along the distribution of that nerve. Intense post-herpetic neuralgia is the principal complication

Coxsackieviruses and Echoviruses Enteroviruses, members of the Picornavirus family Transmission: fecal-oral 50-80% of infections are asymptomatic skin rash , mimic of other virus infections Common cause of meningitis, myocarditis Hand-foot-and-month disease (vesicular type) Usually secondary to Coxsackie A16 Children <10 Sore throat, vesicles, fever, cutaneous lesions including hand and feet

Coxsackieviruses and Echoviruses Diagnosis: virus isolation Antibody detection not useful (too many serotypes )

CNS infections bacteria viruses protozoa metazoa fungi prions

CNS infections Meningitis acute pyogenic (bacterial) aseptic (acute viral) chronic (+ encephalitis; tbc, borrelia, T. pallidum, cryptococcus) Brain abscess (bacterial, Naegleria) Viral encephalitis (+ meningitis) acute (arboviruses, herpetic, CMV, poliomyelitis, rabies, HIV), persistent (progressive multifocal leukoencephalopathy – JC virus, subacute sclerosing panencephalitis – measles) Fungal (cryptococcus etc.), parasitic (Toxoplasma)

Transmission of infection to C NS blood borne septicaemia, viraemia, infected blood cells, septic embolism (e.g. endocarditis, bronchiectasis, IV drug use) direct spread adjacent infection, head injury etc trauma (including iatrogenic - LP, ventriculo-peritoneal shunts) vertical transmission in pregnancy important role of immunosuppression

Bacterial infections problems arise because of inflammatory reaction or tissue destruction result in meningitis or abscess

Meningitis inflammation in subarachnoid space (arachnoid and pia mater) strictly speaking = leptomeningitis pachymeningitis = predominantly dural disease usually direct spread of infection from skull (otitis media, mastoiditis or fracture) Gram- bacilli from middle ear, haemolytic S tr . from sinuses or mixed organisms, often with Staph . aureus, from skull fractures. can cause dural abscess

Pachymeningitis epidural infection suppuration between dura and skull or vertebral column - abscess subdural infection abscess unusual pus spreads in subdural space over hemispheres causing subdural empyema. involvement of subdural vessels may cause thrombophlebitis and venous infarction of brain

Meningitis (i.e. leptomeningitis) usually blood-borne infection, but can be direct spread from the skull bones most common bacteria – neonates: coliforms, streptococci 2-5 years: haemophilus older children - adults: meningoccus, pneumococcus old age: pneumococcus in immunocompromised pneumococcus, meningococcus, listeria TB and syphilis also important causes

Meningitis incubation period ~ 4 days once in SA space, bacteria multiply fever and acute inflammation (hyperaemia, exudation , etc . ) inflammatory exudate can raise ICP and can reduce cerebral blood flow

Pathology of bacterial meningitis meningeal and superficial cortical vessels congested, often haemorrhagic neutrophil ic infiltrate -> suppuration – basal cisterns and sulci CSF often turbid - reduced glucose, increased cells (neutrophils) and increased protein complications (~ 25% die) include – cerebral abscess, subdural empyema, cerebral infarction, obstructive hydrocephalus, epilepsy, cranial nerve palsies (VI & VIII) and DIC if meningococcal

Meningococcal meningitis commonest variety worldwide, sporadic or epidemics in small communities (droplet spread from asymptomatic nasal carriers) petechial rash can herald DIC accompanied by potentially lethal adrenal haemorrhage (Waterhouse-Friederichsen syndrome) vaccinat ion only partially possible

Cerebral abscess usually from direct spread – sinuses (frontal) or middle ear septic sinus thrombosis - spread of infection from mastoid or middle ear via sigmoid sinus blood spread, e.g. infective endocarditis, bronchiectasis etc - often multiple abscesses in parietal lobes adjacent brain markedly oedematous abscesses frequently enlarge and become multiloculate

Cerebral abscess presentation can be similar to meningitis, but often with focal signs, epilepsy and fever but also as space-occupying lesions complications – meningitis focal neurological deficit epilepsy herniation of the brain

C NS tuberculosis secondary to infection (75% in primary) elsewhere meningitis (espec. in young) and/or abscesses (tuberculomas) meningitis from rupture of subependymal tubercles (rarely from direct spread from vertebral body) thick gelatinous exudate in basal cisterns and sulci causes subacute meningitis with occasional isolated cranial nerve palsies but can be non-specific and diagnosed only after LP tuberculomas present like other cerebral abscesses

C NS syphilis hematogenous spread effects include – silent meningitis during prim. and sec . stages meningeal thickening in tertiary stage -> cranial nerve palsies gummas -> cerebral or spinal compression tabes dorsalis due to degeneration of dorsal columns “ general progressive paralysis” due to cerebral atrophy in chronic infection

Viral infections of C NS usually haematogenous spread during viraemia neural spread along peripheral sensory nerves by retrograde axonal transport, e.g. rabies some viruses are neurotropic - tend to spread specifically to CNS from initial site of infection, e.g. polio virus from the gut pathogenetic effects because of multiplication inside NS cells or immune response (with lymphoid infiltration) to virus

Effects of viral infections usual ly acute meningitis less commonly acute encephalitis others reactivation of latent viral infection (e.g. zoster) acute disseminated encephalomyelitis, demyelinating disorder, resulting from virus-induced immune reaction

Viral meningitis common acute onset, but usually less severe than bacterial meningitis usually haematogenous spread common organisms – arboviruses mumps echovirus coxsackie HSV

Viral meningitis meninges infiltrated by mononuclear cells (lymphocytes, plasma cells and macrophages) with typical perivascular lymphocytic cuffing in meninges and superficial brain characteristic CSF – normal glucose, increased cells (lymphocytes) and slight protein increase

Viral encephalitis most commonly HSV, EBV, zoster and arboviruses mode of spread varies with virus viral type may also determine part of brain affected pathology mononuclear infiltration - as perivascular cuffing +/- cell lysis and phagocytosis of cell debris by macrophages - when neurones involved -> neuronophagia reactive astrocytes and microglia, often in cell clusters vasogenic oedema viral inclusions may be diagnostic, e.g. 'owl-eyes‘ CMV and Negri bodies in rabies

Viral encephalitis most cases mild, self-limiting conditions, but may result in death or severe most common effects – fever, personality change and seizures focal neurological signs very unusual (some viruses can also damage brain not by invasion, but secondary to an immune mediated demyelination)

Perivascular cuffing in viral encephalitis

West Nile Encephalitis Virus - Epidemiology First isolated in West Nile district, Uganda in 1937 Historically, in Eastern Europe, Middle East, Africa, and West Asia Western Hemisphere: 1999-2001

West Nile Virus Transmission Normally between birds and mosquitoes Can incidentally be transferred to many types of mammals, including humans Transmission occurs to humans from mosquitoes by direct inoculation

Clinical Features of WNV Infection 5-15 day incubation period post mosquito bite Typical case is mild: fever, HA, myalgia/arthralgia, anorexia (symptoms last 3-6 days) Sore throat and GI complaints (N/V/D) may occur Occasional maculopapular rash (trunk>extremities) (rare in US cases) In elderly or patients with co-morbidities, may progress to aseptic meningitis or encephalitis Rare complications include myocarditis and pancreatitis

Neurologic involvement in severe cases encephalitis meningitis meningoencephalitis anterior myelitis, encephalopolyradiculitis Clinical Features of WNV Infection West Nile virus found in brain and spinal cord on autopsy

West Nile Virus - Differential Diagnosis Meningitis/Encephalitis - bacterial, viral, fungal, rickettsial CNS tumor/bleed/CVA/pyogenic abscess Sepsis - bacterial Shock syndrome - DIC Endocrine - adrenal insufficiency, thyroid storm Drug reaction Vascular - Bechet’s, vasculitis, SLE Post-infectious encephalomyelitis (children post-immunization)

Fetal C NS infections rubella (deafness, blindness, microcephaly) necrotising encephalomyelitis -> developmental malformations and microcephaly, particularly if infected during first trimester CMV (microcephaly) toxoplasma (microcephaly) syphilis (tertiary forms include GPI, tabes dorsalis and meningovascular syphilis) (HIV)

Congenital and childhood viral disease CMV and rubella commonest C NS viruses necrotising encephalomyelitis -> developmental malformations and microcephaly, particularly if infected during first trimester persistent viral infections - rare diseases in which infection occurs in early life, with NS disease occurring years later e.g. subacute sclerosing panencephalitis caused measles virus

Parasitic inf. - Naegleria fowleri After entering the nose and nasal cavities, the trophozoites actively migrate to the brain and cause purulent meningoencephalitis - abscess. Symptoms : headache, fever, neck rigidity, and mental confusion followed by coma and death

Facultative Amebae Facultative amebae are normal inhabitants of soil and water where they feed on bacteria. A few members have the ability to become parasitic when an opportunity to enter a vertebrate exists. Three are able to infect humans: Naegleria fowleri This ameba is responsible for over 200 cases of _____________________________________________________ During 1989-2000, CDC documented 24 fatal cases of PAM in the United States. Only 7 cases were successfully treated; all others were fatal!

Naegleria fowleri DIAGNOSIS – most cases have been diagnosed at _____________________by identification of large numbers of amebae in the brain tissues Look for trophozoites each with a nucleus with _____________________________ - Disease is so rare and the brain tissue destruction is so rapid that diagnosis is seldom made in time

Parasitic infections - toxoplasmosis most frequent cause of focal NS disease in AIDS ~ 50% patients in Africa and Europe often constitutional symptoms/signs at first, but then more obviously neurological ones, sometimes with localising signs ICP may be raised with coma/death if untreated

Parasitic infections - neurocystocercosis (all parasitic infections uncommon unless human parasites endemic) most important here is taenia solium, causing neurocystocercosis predeliction for NS, causing cysts in brain parenchyma and/or subarachnoid space either SOLs in brain (typically seizures) or cord - or meningitis, often more important in chronic repair phase (obstr. hydrocephalus, cranial nerve palsies)

Cerebral malaria usually only seen in children under 10 or newcomers to falciparum malarial areas acute diffuse parenchymal disease accompanied by fever +/- meningitis rapidly fatal in ~ 25-50% histological hallmark is sequestration of microcirculation by parasitised/non-parasitised red cells causes ring-like lesions in brain

Cerebral malaria – parasites in vessels

Other parasitic infections trypanosomaiasis chronic meningoencephalitis entamoeba histolytica amoebic abscess echinococcus granulosus hydatid cyst toxocara canis eosinophilic meningitis with granulomas

Fungal infections of NS more common in immunosuppression usually blood spread from lungs, but also direct cryptococcus usually causes meningitis candida and aspergillus usually cause abscesses mucormycosis usually uncontrolled diabetics – granulomatous nasal infection spreading to brain

Prion disease CJD (Creuzfeldt-Jakob disease ) variant CJD

CJD (Creuzfeldt-Jakob disease) presents in adults as rapidly progressive dementia often with focal signs – always fatal sporadic disorder in 1:1 000 000 per year worldwide transmissible to primates by modified host protein, prion protein human-human transmission recorded from electrode implantation, grafts and human growth hormone cortical atrophy, neuron loss and reactive proliferation of astrocytes, but no inflammation numerous small vacuoles present in neuron and glial processes, so known as spongiform encephalopathy akin to kuru in New Guinea

Variant CJD new variant form of CJD , first identified in young patients in UK probably from transmission of BSE (bovine spongiform encephalopathy - 'mad cow' disease) to humans by contaminated beef several hundred cases of variant CJD so far

BACTERIA of the EYE Staphylococcus aureus and Staphylococcus epidermidis. The conjunctiva, a continuation of the skin and a mucous membrane, contains basically the flora of the skin. Lacrimal fluid contains mucus, antibodies, and lysozyme, an enzyme that destroys bacteria.

Complications ARDS Lung hemorrhage pleural effusions Renal failure Shock sepsis Reye syndrome

Differential diagnosis Influenza Cold Bacterial pneumonia SARS Infectious mononucleosis chlamydia pneumonia mycoplasma pneumonia

Malaria Malaria has long been recognized as an important parasitic disease of humans, having been described by the early Egyptians in the third millennium B.C., Despite the introduction of control programs in many parts of the world over the past few decades, the impact of malaria on human populations continues to increase. Recent estimates suggest, (1) that 1.5 billion persons live in areas of the world where malaria is an endemic disease, (2) that the number of infected humans exceeds 500,000,000, and, (3) that 1-3 million persons die each year, including about 1 million children under 5 years old (3,000 per day).

Malaria’s Range (cross hatching) Science : Volume 289, Number 5485 (2000), p. 1763

General Malaria Pathology …more later. Host (human) inflammatory response resulting in severe chills and fever, paroxysms , Anemia due to loss of red blood cells, Recurrence of paroxysms at periodic intervals.

Tertian Malaria The paroxysms commence with the patient having a feeling of intense cold (15 min - 1 hour), this is due to a rapid rise in body temperature to 104-106 o F, accompanied with violent shivering, often with nausea and vomiting. Followed by the hot phase, which includes headache and often delirium (2 - 6 hours). The fever breaks with the copious production of perspiration. The body temperature drops back to normal after 2 - 4 hours. The patient may sleep for 8-12 hours and feel well until the next paroxysm.

Malaria decreased flexibility and increased sticking/rosetting of red cells occlude microcirculation probably cause hypoxia, often with petechial haemorrhages and tiny granulomas curiously, raised ICP not due to oedema, but ?increased blood volume mechanism of coma is not clear ? increased cerebral glycolysis producing lactate and/or interference with neurotransmission

P. falciparum - malignant tertian malaria The time between the onset of paroxysms is 48 hours, but the period of fever is prolonged, lasting from 24-36 hours, The course of this disease is very rapid and it is not uncommon to see more than 60% of a patient's red blood cells infected. When the number of infected cells rises above 25% the disease is usually fatal, in spite of treatment. “ knobs” Knobs promote cell clumping… clogging veins and arteries.

Ascarid Nematodes – Chapter 26 Ascaris lumbricoides Common parasite of humans. Disease is called ______________________________ Cosmopolitan in distribution. - flourishes in warm, moist climates where the eggs may remain viable in warm soil for many years. - use of ___________________________ to fertilize vegetables is common source of infection. - Children are most likely to become infected by ingesting eggs by eating dirt or placing soiled fingers or toys into the mouth.

FUNGI EUCARIOTIC ORGANISMS TWO BASIC FORMS: - YEASTS - MOLDS

MYCOSES 1. SUPERFICIAL 2. CUTANEOUS 3. SUBCUTANEOUS

MYCOSES 4. ENDEMIC (PRIMARY, SYSTEMIC): Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Paracoccidioides brasiliensis

MYCOSES 5. OPPORTUNISTIC endogenous - Candida (different species) - Pneumocystis carinii

MYCOSES 5. OPPORTUNISTIC exogenous - Cryptococcus neoformans - Aspergillus (different species) - Zygomycetes - MANY OTHER FUNGI

Candida albicans and other Candida species Harmless inhabitants of the skin and mucous membranes of all humans Normal immune system keeps candida on body surfaces

MAIN DEFENSE MECHANISMS AGAINST CANDIDA I. skin and mucous membranes integrity presence of normal bacterial flora

MAIN DEFENSE MECHANISMS AGAINST CANDIDA II. phagocytosis killing, mostly in polymorphonuclear cells, less in macrophages T-cells (CD4)

THE MOST IMPORTANT RISK FACTORS 1. Neutropenia 2. Diabetes mellitus 3. AIDS 4. SCID 5. Myeloperoxidase defects 6. Broad-spectrum antibiotics

THE MOST IMPORTANT RISK FACTORS 7. Indwelling catethers 8. Major surgery 9. Organ transplantation 10. Neonates 11. Severity of any illness 12. Intravenous drug addicts

CLINICAL FORMS OF CANDIDIASIS 1. Cutaneous and mucosal candidiasis

INVASIVE CANDIDIASIS Usually begins with candidemia (but in only about 50% of cases candidemia can be proven) If phagocytic system is normal, invasive infection stops here

INVASIVE CANDIDIASIS If phagocytic system is compromised, infection spreads to many organs and causes focal infection in these organs mortality of candidemia is 30-40%

Pneumocystis carinii Present in lungs of many mammals, including humans, in persistent but harmless infection

Pneumocystis carinii Main defense mechanism is T-cell mediated causes interstitial pneumonitis in compromised patients treatment and prevention: cotrimoxasole or pentamidine

Cryptococcus neoformans Occurs worldwide in soil and in bird droppings Prominent feature: thick polysaccharide capsule , which causes evasion from phagocytosis

Aspergillus species Aspergilli are worldwide occurring saprophytes, living in soil and on plants; they have small conidia that form aerosols

The most frequent syndromes are: - aspergilloma - invasive aspergillosis (high mortality rate) Treatment : amphotericin B, itraconazole, flucytosine and surgery Prevention : avoid exposure to conidia (new buildings in the hospital!)

ZYGOMYCETES Zygomycetes are ubiquitous saprophytes main host defense is phagocytosis main risk factors are diabetes, hematological malignancies, corticosteroid therapy

Major clinical syndrome is: Rhinocerebral mucormycosis (infection of nasal passages, sinuses, eyes, cranial bones and brain) Treatment : surgery and amphotericin B Prognosis : very poor

OPPORTUNISTIC FUNGAL INFECTIONS ARE: difficult to diagnose difficult to treat difficult to prevent more and more frequent a great challenge for a future work in all fields

Upper respiratory tract Many bacterial species and viruses alike cause some manner of upper respiratory tract (URT) infection. S. aureus URT infection is fairly common with strep throat-like symptoms. Can co-reside with S. pyogenes or respiratory viruses such as influenza or RSV. Often causes secondary infections following respiratory viral infection. Uncommon cause of accute sinusitis and otitis media

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