Infectious Diseases I: Bacterial Infections I Lecture Notes PDF

PATHOLOGY | TRANS 4B LE Infectious Diseases I: Bacterial Infections I DR. ARLENE SANTOS, MD| Lecture Date (09/27/20...

PATHOLOGY | TRANS 4B LE Infectious Diseases I: Bacterial Infections I DR. ARLENE SANTOS, MD| Lecture Date (09/27/2024) | Version 1 01 OUTLINE PATHOLOGIC FINDINGS IN STAPHYLOCOCCAL I. Gram Positive Bacterial B. Whooping Cough/Pertussis INFECTIONS Infections C. Pseudomonas A. Staphylococcal Infections D. Chancroid FURUNCLE / BOIL B. Streptococcal & E. Granuloma Inguinale → Focal suppuration, inflammation of the skin and Enterococcal Infections III. Mycobacteria subcutaneous tissue C. Diphtheria A. Tuberculosis → Frequently seen in moist/ hairy areas D. Listeriosis B. Mycobacterium ▪ Face E. Anthrax avium-intracellulare ▪ Axilla F. Nocardia complex II. Gram Negative Bacterial C. Leprosy ▪ Submammary folds Infections IV. Sample Questions ▪ Groin A. Neisseria V. Appendix ▪ Legs → Starts in a single hair follicle Must Lecturer Book Previous Youtube ▪ which develops into a growing and deepening ❗️ Know 💬 📖 📋 Trans 🔺 Video abscess SUMMARY OF ABBREVIATIONS MAC M. avium-intracellulare complex MTb Mycobacterium tuberculosis LEARNING OBJECTIVES ✔ Compare and contrast the different Gram positive and Gram negative bacterial infections, Mycobacterial infections and diseases in terms of their: o Etiologic agent o General morphologic features of the infectious agent o Diseases they cause o Pathogenesis o Clinical findings Figure 2. Furuncle [Lecturer’s PPT] o Laboratory findings o Gross and histopathological findings in the CARBUNCLE organs/tissues most commonly involved → Involves a deeper suppuration, spreading laterally I. GRAM-POSTIVE BACTERIAL INFECTIONS beneath the deep subcutaneous fascia Staphylococcal Infections ▪ burrows superficially to erupt in multiple adjacent skin Streptococcal and Enterococcal Infections sinuses Diphtheria Listeriosis Anthrax Nocardia A. STAPHYLOCOCCAL INFECTIONS Gram-positive cocci in clusters Produce disease by: → Multiplication and spread in the tissue → Production of toxins and enzymes CONSEQUENCES OF STAPHYLOCOCCAL INFECTION Figure 3. Carbuncle [Lecturer’s PPT] HIDRADENITIS SUPPURATIVA → chronic suppurative infection of apocrine gland → Most common location : Axilla → Starts as pea-sized lesion which may disappear or rupture and ooze pus ▪ Sinus tracts may form under the skin that breaks out on the surface → leaking of pus Figure 1. Consequences of Staphylococcal Infection[Lecturer’s PPT] LE 2 TG 2 | Alameda, Alcantara, Alcid, Aldas, Alfelor TE | Alforte AVPAA | Boque PAGE 1 of 21 TRANS 4 VPAA | Arcega, Cambas PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD STAPHYLOCOCCAL SCALDED SKIN SYNDROME → Seen in infants and young children with S. aureus infection of skin or nasopharynx → Exfoliative toxin destroys the protein binding the keratinocyte together ▪ detachment of keratinocytes at the level of the granular layer (superficial epidermis) ▪ Bullae Formation → Starts as a sunburn-like rash which spreads over the entire body → evolves in to fragile bullae → lead to partial or total skin loss → Erythematous bullae rupture easily ▪ after rapture, there is marked epidermal exfoliation at the level of the granulosa layer with skin peeling in sheets Figure 4. Hidradenitis suppurativa [Lecturer’s PPT] → Vesicle-fluid-filled lesion ▪ less than or equal to 5mm PARONYCHIA- NAIL BED INFECTION → Bullae-Fluid-filled lesion → Tender swelling of lateral nail folds with erythema ▪ greater than 5mm → Pustule can evolve into an abscess → Results in: → Follow trauma or embedded splinter ▪ Moist, red, tender areas − Localized: Bullous impetigo − Generalized: Staph scalded skin syndrome Figure 7. Staphylococcal Scalded Skin Syndrome [Lecturer’s PPT] Figure 5. Paronychia: Nail bed infection [Lecturer’s PPT] Histologic Finding → LUNG ABSCESS STAPHYLOCOCCAL BULLOUS IMPETIGO ▪ Extensive neutrophilic infiltrate within the alveoli → Staphylococcus aureus produces exfoliative A and B ▪ Destruction of alveoli toxins → cleave desmoglein 1 ( ɑ desmosomal protein) → keratinocyte detaches from one another and from underlying basement membrane → exfoliation at localized site of infection → Clinical Findings: ▪ Surface honey yellow crusting ▪ Blisters − Lesions tend to be itchy Figure 8. Lung Abscess [Lecturer’s PPT] Figure 6. Staphylococcal Bullous [Lecturer’s PPT] PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 2 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD STREPTOCOCCAL & ENTEROCOCCAL INFECTIONS Table 1. Common and Important Diseases caused by Streptococci Infectious Agent Disease/s Streptococcus pyogenes Pharyngitis, Impetigo, Rheumatic fever, Glomerulonephritis Streptococcus agalactiae Neonatal sepsis, Meningitis Enterococcus faecalis Abdominal abscess, Other enterococci Urinary tract infection (UTI), Endocarditis Viridans streptococci S. mutans (multiple species) - Dental caries - Endocarditis Figure 10. Histological findings of Streptococcal Erysipelas. - Abscesses Acute Lesion, neutrophilic infiltration (red arrow) an Streptococcus Pneumonia, meningitis, subepidermal edema (yellow arrow) [2026 Trans]] pneumoniae Endocarditis STREPTOCOCCAL PHARYNGITIS HISTOPATHOLOGY OF STREPTOCOCCAL → Epiglottic swelling INFECTIONS → Punctuate abscesses of the tonsillar crypts Neutrophilic infiltration of tissues Minimal tissue destruction PATHOLOGIC FINDINGS IN STREPTOCOCCAL ERYSIPELAS ERYSIPELAS → Rapidly spreading erythematous cutaneous swelling with well-demarcated, serpigenous border → Microscopic: ▪ Neutrophilic infiltration of Epidermi, Dermis, Subcutaneous tissue ▪ Minimal tissue necrosis → Affects bilateral cheeks and bridge of the nose (Butterfly Figure 11. Staphylococcal Pharyngitis [Lecturer’s PPT] distribution) → Sharp demarcation between the erythematous area and DIPHTHERIA the normal skin CORYNEBACTERIUM DIPHTHERIAE → Advance border - Strep Sign Gram (+) rod → colonizes the oropharynx Transmission → respiratory droplets or skin shedding Exotoxin (phage encoded A-B) → Blocks protein synthesis of host cells → Mediates formation of pseudomembrane Tough pharyngeal pseudomembrane and toxin-mediated damage in the heart, nerves and other organs Note: Inclusion of diphtheria toxoid in the childhood vaccine (DPT) does not prevent the colonization of C. diphtheria, but protects immunized children from the lethal effects of the toxin PATHOGENESIS OF DIPHTHERIA Corynebacterium diphtheriae Figure 9. Erysipelas[Lecturer’s PPT] ↓ Attaches and proliferates on mucosa of nasopharynx, → Acute lesion of erysipelas oropharynx, larynx, or trachea ▪ Neutrophilic infiltration and minimal tissue destruction ↓ ▪ Marked subepidermal edema Release an exotoxin ↓ Causes necrosis of epithelium ↓ Outpouring of a dense fibrinosuppurative exudate ↓ Coagulation of exudate on ulcerated necrotic surface PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 3 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD ↓ Figure 14. Cardiac myocytes; Mononuclear inflammatory A tough, dirty gray to black superficial membrane cells. Cardiac myocytes (Blue arrow), mononuclear (called a pseudomembrane because it is not composed of inflammatory cells (Green arrow) [Lecturer’s PPT] viable tissue) PATHOLOGIC FINDINGS IN DIPHTHERIA HISTOLOGIC FINDINGS Thick, gray coating at the black of the throat that can block respiration Figure 15. Pseudomembrane (1) is pulled away from the Figure 12. Pseudomembrane in a child with diptheria [Lecturer’s PPT] tracheal lining during histological processing, (2) is the cartilage [Lecturer’s PPT] Membrane of diphtheria lying within a transverse bronchus Figure 16. Pseudomembrane (yellow arrow) HPO view. A part of the pseudomembrane is seen attached to the ulcerated mucosa (blue arrow). The remaining cells are seen Figure 13. (L) Membrane of diphtheria lying within transverse in the glands (Black arrows) [Lecturer’s PPT] bronchus; (R) Diphtheria Pseudomembrane [Lecturer’s PPT] ANTRAX DIPHTHERIC MYOCARDITIS → Interstitial mononuclear inflammation BACILLUS ANTHRACIS → More common finding in the heart : fatty change w/ A gram (+) bacillus isolated myofiber necrosis Potentially fatal → May also cause the following: “Biologic weapon” ▪ Nerves - polyneuritis w/ myelin sheath and axis → Category A Agent degeneration ▪ Highest risk and can be easily disseminated or ▪ Parenchymal cells in liver, kidneys and adrenal transmitted from person to person glands - fatty change and focal necrosis ▪ Can cause high mortality Mode of Spread: → Entry of spored through injured skin or mucous membranes → Inhalation of spores → Eating contaminated or uncooked meat Clinical forms → Cutaneous anthrax → Inhalation anthrax → Gastrointestinal anthrax ▪ Uncommon Histologic findings → Necrosis → Exudative inflammation w/ infiltration by neutrophils and macrophages PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 4 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD CUTANEOUS ANTHRAX Pathologic findings → Initially starts as a pustule that develops into a vesicle w/c ruptures revealing a black eschar at the base & an inflammatory ring around the eschar → Classically found on hands, forearm, or head → Painless Figure 19. Extensive dermal necrosis (Black arrow) with intense neutrophilic infiltration (blue arrow) [Lecturer’s PPT] RESPIRATORY OR INHALATION ANTHRAX Figure 17. Black eschar at the base (Green arrow) [Lecturer’s PPT] Woolsorter’s disease Macroscopic Findings Fever, dyspnea, hypotension and death → Epidermis 90% mortality rate ▪ Necrosis Characteristic x-ray ▪ Hemorrhage → symmetric widening of mediastinum with mediastinitis ▪ Acantholysis Macroscopic Findings: ▪ Ulceration w/ Polymorphonuclear infiltrates → Lungs → Dermis ▪ Pleural effusion ▪ Edema ▪ Pulmonary edema ▪ Coagulation necrosis → Mediastinum ▪ Hemorrhage ▪ Hemorrhagic mediastinitis ▪ Vasculitis w/ marked perivascular inflammatory → Hilar and Mediastinal lymph nodes infiltrate ▪ Hemorrhagic lymphadenitis Histologic Findings: Microscopic Findings → Lungs ▪ Perihilar interstitial pneumonia ▪ infiltrated by macrophages and neutrophils ▪ Pulmonary vasculitis → Mediastinal LN ▪ Lymphocytosis ▪ Macrophages w/ phagocytosed apoptotic lymphocytes ▪ Fibrin-rich edema fluids Figure 18. Massive subepidermal edema (Green arrow) [ Lecturer’s PPT] Figure 20. Bacillus anthracis in the subcapsular sinus of a patient who died of inhalation antrax [Lecturer’s PPT] GRAM-NEGATIVE BACTERIAL INFECTIONS NEISSERIAL INFECTIONS Neisseria species → Gram-negative diplococci, usually occurring in pairs with or inside WBCs → Neisseria meningitidis ▪ attach to epithelial cells of the nasopharynx PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 5 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD → Neisseria gonorrheae ▪ 1-2 mm areas of hemorrhage on the skin or mucous ▪ attach to epithelial cells of mucous membranes of membranes GUT, eye, rectum and throat → Purpura → Antigenic variation ▪ 3 mm or more areas of hemorrhage ▪ mode to escape the immune response → Ecchymoses Infections and Diseases caused by Neisseria species ▪ 1-2 cm areas of subcutaneous hematoma → Neisseria meningitidis → Vasculitic purpura ▪ Bacterial meningitis ▪ initiated by emboli of meningococci ▪ Meningococcemia → Neisseria gonorrhoeae Waterhouse-Friderichsen Syndrome ▪ Male: Urethritis or asymptomatic → Bilateral adrenal hemorrhage ▪ Female: symptomatic ▪ Children: Gonococcal ophthalmia neonatorum ▪ Individuals who lack the complement protein that form the membrane attack complex − Disseminated gonococcal disease (gonococcal arthritis-dermatitis syndrome) ▪ Uncommon: Meningitis and Eye infections in adults NEISSERIA MENINGITIDIS PATHOGENESIS OF MENINGOCOCCAL INFECTION Meningococci (N. meningitidis) → Enter the body via the Upper Respiratory Tract & Conjunctiva → Colonize the mucous membranes of nasopharynx → Disseminate through the bloodstream → Meninges (meningitis); eyes (conjunctivitis); skin; lungs (pneumonia); pericardium (purulent pericarditis); joints (septic arthritis). Figure 22. Bilateral adrenal hemorrhage [Lecturer’s PPT] Less common sites of dissemination: epiglottis, sinuses and ears (otitis) → Hemorrhage in the adrenal gland (Yellow arrows) Persistence of Meningococci in the Blood → leads to → More common in children Meningococcemia → Involves any organ; Adrenal gland → Basis of hemorrhage is uncertain but may be due to: (Waterhouse- Friderichsen syndrome), DIC and Gram ▪ Direct bacterial seeding of small vessels in the negative shock → May lead to Death, Survive with no adrenals detectable sequelae or survive with sequelae (Eight nerve ▪ Development of disseminated intravascular deafness, CNS damage, Necrosis of skin or tissue coagulation secondary to vascular thrombosis. ▪ Endothelial dysfunction caused by microbial products Invasive diseases consists of bacteremia (presence of and inflammatory mediators bacteria in the blood → Characterized by → May or may not lead to shock and meningitis ▪ Rapidly progressive hypotension leading to shock → Has abrupt onset of signs and symptoms ▪ DIC with purpura of skin ▪ fever, weakness, cold and pale extremities, organ ▪ Rapidly developing adrenocortical insufficiency with failure and DIC bilateral adrenal hemorrhage → Complications ▪ Hemorrhage into the adrenal gland with resultant Meningococcal meningitis hypoadrenergic state (Waterhouse- Friderichsen → Polymorphonuclear infiltration of meninges syndrome → Clinical findings: ▪ Myocarditis ▪ Headache ▪ photophobia PATHOLOGIC FINDINGS IN MENINGOCOCCAL ▪ altered mental status INFECTION ▪ irritability Vasculitic purpura ▪ neck stiffness → Hallmark of meningococcal disease → Lab tests: ▪ Gram stain: blood and cerebrospinal fluid (CSF) ▪ Direct PCR - may be useful Figure 21. Vasculitic purpura[Lecturer’s PPT] → Petechiae PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 6 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD WHOOPING COUGH Caused by Bordetella pertussis → Gram-negative coccobacilli Paroxysmal stage → cough develops its explosive character and characteristic whoop upon inhalation PATHOGENESIS OF WHOOPING COUGH Enters through the Respiratory Tract Then adheres and multiplies on the epithelial surface of trachea and bronchi → Filamentous hemagglutinin adhesin ▪ enables bacteria to bind to cilia upon entry into respiratory tract Once attached, it releases of toxins and substances which Figure 23. Polymorphonuclear inflammatory cells (green irritate surface cells and interfere with ciliary action arrow) Meninges of the brain (blue arrow) [Lecturer’s PPT] → Tracheal cytotoxins ▪ inhibit movement of cilia → decreases clearance of NEISSERIA GONORRHOEAE mucus → leads to extreme cough GONORRHEA → Pertussis toxin Caused by Neisseria gonorrhea ▪ inhibits phagocytosis through phagocyte adenylase Adolescent are at high risk cyclase production of cyclic AMP → inhibits Transmitted by oral, anal, or vaginal intercourse neutrophil and macrophage recruitment and Perinatal transmission activation → impairs host defenses → paralyzes cilia Signs and Symptoms Results in Coughing and Lymphocytosis → urethral infection → Lymphocytes fail to migrate to lymph nodes → → vaginal discharge Lymphocytosis → “Morning drop” Leads to focal necrosis of the bronchial epithelium Diagnosis → Polymorphonuclear infiltration → Gram stain → Peribronchial inflammation → Culture → Interstitial pneumonia → DNA screening Causing obstruction of smaller bronchioles by mucus plugs Leading to Atelectasis PATHOLOGIC FINDINGS IN GONOCOCCAL → Decreased oxygenation of blood INFECTION Results in Convulsions in infants with Whooping cough Pathogenesis in males → Acute urethritis with purulent discharge and dysuria PATHOLOGIC FINDINGS IN WHOOPING COUGH (pain on urination) Macroscopic → Infection may extend to the epididymis → Laryngotracheobronchitis Pathogenesis in Females ▪ Inflammation of larynx and trachea → Primary infection is in the endocervix → extends to → Bronchopneumonia or interstitial pneumonia urethra and vagina → resulting in a mucopurulent → Peribronchial lymph node enlargement discharge → may progress to fallopian tubes Microscopic → cause salpingitis (inflammation of fallopian tubes), → Bronchi fibrosis and obliteration of tubes ▪ Respiratory epithelium coated with bacteria → Consequence: Infertility ▪ Mucosal erosion Histologic findings: In untreated cases ▪ Hyperemia → Acute suppuration → progresses to chronic ▪ Mucopurulent exudate inflammation → fibrosis ▪ Neutrophils within walls of trachea and bronchi → Hypercellularity Mucosal lymphoid follicles Figure 24. Symptomatic gonococcal urethritis[Lecturer’s PPT] PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 7 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD Figure 25. Bacilli entangled with cilia of the bronchial Microscopic epithelial cells [Lecturer’s PPT] → Bacilli forming a perivascular blue haze with thrombosis → Hemorrhage is highly suggestive of P. aeruginosa infection Figure 26. Haze of bacilli entangles with cilia of bronchial epithelial cells[Lecturer’s PPT] Inset-highlights haze of bacteria by immunohistochemistry using a monoclonal antibody reactive to the Figure 28. Microscopic Necrotizing Pneumonia. lipooligosaccharide A of Bordetella pertussis Gram-negative vasculitis or Pseudomonas vasculitis. Bacilling forming a perivascular purplish haze (yellow arrow) [Lecturer’s PPT] PSEUDOMONAS INFECTION Caused by Pseudomonas aeruginosa → Gram-negative bacillus CHANCROID → Causes opportunistic infections in the following settings: Caused by Haemophilus ducreyi ▪ Disruption of skin and mucosa → Gram-negative bacillus ▪ Use of intravenous or urinary catheters Acute, sexually transmitted, ulcerative infection ▪ Neutropenia One of the most common causes of genital ulcers in Africa − Example: During cancer chemotherapy and Southeast Asia Infections and Diseases caused by P. aeruginosa Manifests as a painful genital ulcer → Infection of wounds and burns → Chancroid or soft chancre → Meningitis Diagnosis: Culture → Necrotizing pneumonia → Otitis externa PATHOLOGIC FINDINGS IN CHANCROID → Eye infection Males: Primary lesion is on the penis → Ecthyma gangrenosum Females: Primary lesion is on the vagina or periurethral ▪ Skin lesions in sepsis due to Pseudomonas area aeruginosa Initially starts as a tender, red papule with ulcerates to form ▪ Necrotic and hemorrhagic oval skin lesions a painful ulcer Base is covered by a shaggy yellow exudate with a PATHOLOGIC FINDINGS NECROTIZING PNEUMONIA non-indurated border Macroscopic Deep ulcer → Lungs-lesions distributed in the terminal airways → Fleur-de-lis pattern: ▪ Center of lesion: pale ▪ Peripheral areas: red, hemorrhagic Figure 29. Chancroid in a female [Lecturer’s PPT] Figure 27. Macroscopic Necrotizing Pneumonia. Pale area (yellow arrow), Hemorrhagic areas (green arrow) [Lecturer’s PPT] PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 8 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD Figure 33. Chancroid in a Male. Ulcer has undermined edges Figure 30. Chancroid in a female [Lecturer’s PPT] and covered by a gray-yellow exudate [Lecturer’s PPT] Lesions of Chancroid in a female lie on the mons pubis. HISTOLOGIC FINDINGS IN CHANCROID → Accompanied by enlarged and tender lymph nodes (buboes) → Superficial zone Lymph nodes may erode on the overlying skin to produce ▪ Contains Neutrophilic debris and Fibrin draining ulcers → Underlying zone ▪ Contains granulation tissue with areas of Necrosis and Thrombosed vessels → Beneath the Granulation Tissue ▪ Contains lymphoplasmacytic infiltration → Coccobacilli appears on Gram Stain or Silver Stain GRANULOMA INGUINALE Caused by Klebsiella granulomatis (Calymmatobacterium donovani) → Coccobacillus Disease also known as Donovanosis → Old name → A chronic, sexually transmitted ulcerative infection Mode of transmission: Sexual contact Figure 31. Multiple Soft and Painful Ulcerated Nodules PATHOLOGY OF GRANULOMA INGUINALE [Lecturer’s PPT] Gross → Painless ulcers with rolled borders and a friable base → Ulcers can be single or several Soft, sharply demarcated areas of granulation tissue that bleeds easily Begins as a papule on the moist, stratified, squamous epithelium of the external genitalia → Rarely on the Oral Mucosa or Pharynx Ulceration forms a painless ulcer with rolled(raised) borders and a friable base Regional lymph nodes are spared or show only reactive changes Figure 32. Chancroid in a Male. Ulcer is ragged with undermined and non-indurated borders and a rim of erythema [Lecturer’s PPT] PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 9 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD Figure 37. Painless genital ulcer with Beefy red granulation tissue at the base[Lecturer’s PPT] HISTOLOGIC FINDINGS IN GRANULOMA INGUINALE [Lecturer’s PPT] Figure 34. Granuloma Inguinale → Border of the ulcer: Pseudoepitheliomatous hyperplasia → Base of the ulcer and Beneath the surrounding epithelium: Infiltrated with neutrophils and mononuclear inflammatory cells → Giemsa Stain of Exudate: Donovan bodies ▪ Can also use Wright stain and Silver Stain ▪ Donovan bodies − encapsulated coccobacilli within macrophages − Safety-pin shaped organisms Figure 35. Painless genital ulcer with rolled borders and a friable base[Lecturer’s PPT] Figure 38. Wright stain of a smear of the Lesion with Donovan bodies [Lecturer’s PPT] Figure 36. Painless genital ulcer with rolled borders and a friable base with Beefy red granulation tissue at the base[Lecturer’s PPT] Figure 39. Giemsa stain-Smear from Genital Ulcer. Note the presence of Coccobacilli inside the macrophages [Lecturer’s PPT ] PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 10 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD MYCOBACTERIA − Stimulates maturation of phagolysosome in Characteristics infected macrophages → Exposes bacteria to an → Acid-fast bacilli (red rods against a blue background) acidic, oxidizing environment due to the presence of mycolic acid in its cell wall − Stimulates expression of inducible nitric oxide → Aerobic synthase to produce NO → Formation of reactive → Non-encapsulated nitrogen intermediates → Kills mycobacterium → Non-spore forming − Mobilize antimicrobial peptides (defensins) → Slow-growing (doubling time of 15 hours) against the bacteria Infections and Diseases caused by Mycobacteria − Critical mediator that enables macrophages to → Tuberculosis contain M. tuberculosis infection. → Mycobacterium-avium intracellulare Complex (MAC) → Granulomatous inflammation and tissue damage ▪ Widely disseminated infection in AIDS patients ▪ TH1 response orchestrates the formation of ▪ Abundant acid-fast bacilli within macrophages granulomas and caseous necrosis → Leprosy ▪ Macrophages activated by IFN-gamma differentiates Mode of Transmission into “epithelioid histiocytes” that aggregate to form → Mycobacterium tuberculosis : Aerosol spread granulomas; some may fuse to form giant cells → Mycobacterium bovis: ingestion of unpasteurized milk ▪ Immunocompetent: Granuloma formation halts infection TUBERCULOSIS ▪ Immunocompromised: Formation of caseation Caused by Mycobacterium tuberculosis necrosis Mode of transmission: Aerosol spread → Role of other immune cells ▪ NKT cells recognize mycobacterial lipid antigens PATHOGENESIS bound to CD1 on APC or T cells that express T-cell Ability to escape killing by macrophages receptor producing IFN-gamma Type IV hypersensitivity reaction → Host susceptibility to disease increased by ▪ AIDS and other forms of immunosuppression (such 📋 → Cord factor Elicits granuloma formation, attacks mitochondrial membranes and inhibits PMN leukocyte migration as glucocorticoids, TNF inhibitors, transplants) ▪ Genetic deficiencies in IL-12 and IFN-gamma → Lipoarabinomannan (LAM) pathways including STAT-1, a signal transducer for ▪ Inhibits macrophage activation IFN-gamma → Secretion of TNF alpha and IL-1 by macrophages ▪ Polymorphisms in HLA, IFN-gamma, IFN-V ▪ Causing Malaise, Anorexia, Fever and Weight Loss receptor, TLR2 Steps to Infection → Entry into macrophages THE NATURAL HISTORY AND SPECTRUM OF ▪ M. tuberculosis enters macrophages through TUBERCULOSIS phagocytosis, mediated by several receptors Clinical-pathologic patterns of tuberculosis expressed on phagocytes (such as mannose → Primary TB binding lectin and type 3 complement receptor/ ▪ TB in a previously unexposed and therefore CR3) unsensitized person; → Replication in macrophages ▪ May be contained; followed by a latent infection or ▪ Coronin is recruited → Activating phosphatase progresses calcineurin → inhibiting phagosome-lysosome → Secondary TB fusion ▪ TB occurring in a previously sensitized person − Maturation of phagosomes is inhibited and ▪ Occur as a result of reactivation or reinfection form phagolysosome fusion is blocked permitting M. an exogenous source tuberculosis to replicate unchecked within the ▪ Characterized by apical lesion with cavitation vesicle, protected from microbicidal mechanisms of lysosomes → Innate immunity: Multiple pathogen-associated molecular patterns made by M. tuberculosis are recognizable ▪ Mycobacterial lipoarabinomannan binds TLR2 ▪ Unmethylated CpG nucleotides binds TLR9 → T-helper 1 (TH1) response activates bactericidal macrophages through initiation of mycobacterial antigens that enter lymph nodes and are displaced to T-ce;;s ▪ IL-12 is produced by APC that encounter the mycobacteria upon stimulation of TLR2 ▪ Differentiation of TH1 cells depends on IL-12 → TH1-mediated macrophage activation and killing of Figure 40. Natural History & Spectrum of Tuberculosis [Lecturer’s PPT] bacteria ▪ TH1 cells produce IFN-gamma: PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 11 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD CLINICAL FINDINGS IN SECONDARY TUBERCULOSIS parenchymal lung lesion plus a lymph node involved by TB Malaise (Ghon complex) [Lecturer’s PPT] Anorexia Weight loss Fever Sputum (Mucoid → Purulent) Night sweats Hemoptysis in 50% of cases → Hemoptysis: erosion of TB granuloma into a blood vessel Pleuritic pain → Due to extension of the infection in the pleura Four symptoms due to production of IL-1 and TNF: → Low grade and remittent fever → Hemoptysis → Pleuritic pain Figure 42. Tubercle at LPO. The usual response of persons DIAGNOSIS OF PULMONARY TUBERCULOSIS who have developed cell-mediated immunity to the TB bacilli [Lecturer’s PPT] Clinical history PE findings Radiographic findings Acid–fast stain → To visualize the organism (e.g., sputum, CSF in TB meningitis) Culture → Gold standard because it allows testing of drug susceptibility PCR → Detects organism more quicky Tuberculin Skin Testing → Used to detect exposure by reaction to an intradermal 📋 dose of purified protein derivative Interferon release assays (ELISA based assays) → Used to determine release of gamma-interferon in response to multiple, purified MTB products [2026 Trans] Figure 43. Tubercle at HPO. Tubercle/TB Granuloma may be caseating or noncaseating; Central area of caseous necrosis (yellow arrow) surrounded by epithelioid cells. Langhans giant cell (blue arrow), and fibroblasts; Lymphocyte is also seen (green arrow) [Lecturer’s PPT] Figure 41. Primary Pulmonary Tuberculosis. Inhaled TB Figure 44. Histopathology of Tuberculosis. Lymph node bacilli drain into the lower part of the upper lobe or upper part with a caseating granuloma [Lecturer’s PPT] of the lower lobe where a granulomatous reaction develops followed by caseation of granuloma (usually near the pleura) indicated by the yellow arrow (Ghon focus); TB bacilli drains into the regional lymph nodes (blue arrow) wrestling in a caseating granuloma in the lymph node (on the left); PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 12 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD FATE OF PRIMARY TUBERCULOSIS Healed and become calcified: 90% Progression of TB or spread by contiguity or by erosion into bronchi → dissemination Miliary TB: hematogenous spread of TB throughout the body → numerous minute yellow-white foci SECONDARY TUBERCULOSIS Also known as Postprimary tuberculosis Reactivation of primary tuberculosis or reinfection Site: apex Two features: → Caseation necrosis → Cavities Resistant to TB: heart, striated muscle, thyroid gland and pancreas FATE OF SECONDARY TUBERCULOSIS Figure 45. Granuloma without central caseation. Progressive Secondary Pulmonary Tuberculosis Epithelioid cell (yellow arrow); Langhans giant cell (blue → Apical lesion expands to adjacent lung arrow); Lymphocytes (green arrow) [Lecturer’s PPT] → Erodes into the bronchi and blood vessels (hemoptysis) → Apical lesion heals either spontaneously or after treatment to form a fibrocalcific scar Miliary Pulmonary Disease → Occurs when TB bacilli drain through the lymphatics, enter the venous blood and circulate back to the lungs → Lesions: small foci of consolidation throughout the lungs → If treatment is inadequate or host defenses are impaired, the TB bacilli may disseminate through the bloodstream, lymphatics or airways Endobronchial, Endotracheal and Laryngeal TB → Occurs when the TB bacilli disseminate through the lymphatic channels or from expectorated infectious material → Minute granulomas are located on the mucosa; may only be seen on microscopic examination Systemic Miliary TB Figure 46. Acid-Fast Stain of Mycobacterium tuberculosis. → Occurs when TB bacilli disseminate through the Note the red rods in histologic sections or smears in acid-fast systemic arterial system bacilli [Lecturer’s PPT] → Most common organs involved: ▪ Liver ▪ Bone marrow ▪ Spleen ▪ Adrenal gland ▪ Meninges ▪ Kidney ▪ Fallopian tubes ▪ Epididymis Isolated Organ TB → Occurs as a result of hematogenous dissemination → Most common organs involved: ▪ Meninges ▪ Kidneys Figure 47. Macrophages packed with Mycobacteria. In ▪ Adrenal gland immunosuppressed individuals without cellular immunity: NO ▪ Bones granuloma formation; Microscopic finding: macrophages with ▪ Fallopian tubes large numbers of mycobacteria [Lecturer’s PPT] ▪ Vertebrae − When involved, it is known as Pott disease Immunosuppressed individuals without cellular TB Lymphadenitis (Scrofula) immunity DO NOT form granulomas → Most common site: cervical lymph nodes → Instead, foamy macrophages containing → HIV-negative individual: unifocal and localized mycobacterium are found → HIV-positive individual: multifocal + systemic symptoms + pulmonary or extrapulmonary TB → Most frequent presentation of extrapulmonary TB Intestinal TB PATHOLOGY Infectious Diseases I: Bacterial Infections I PAGE 13 of 21 PATHOLOGY | LE 2 Infectious Diseases I: Bacterial Infections I | DR. ARLENE SANTOS, MD → Occurs as a result of drinking contaminated milk or → T-cell immunodeficiency due to AIDS and swallowing expectorated infective material by persons immunosuppression, resulting from treatment for with active TB transplant rejection or autoimmune disease ▪ Granulomas are seen on mucosal lymphoid tissues → Unchecked by the immune system: organisms can of the small and large intestine reach levels up to 104 organisms/ml in blood & 106 organisms/gm in tissue CLINICAL FINDINGS OF MAC INFECTIONS With HIV: → Fever → Drenching night sweats → Weight loss Without HIV: → Productive cough → Fever → Weight loss PATHOLOGIC FINDINGS Organs affected: → Lungs → Lymph nodes Figure 48. Secondary Pulmonary Tuberculosis. Upper areas → Liver with gray-white areas of caseation with softening and → Spleen cavitation [Lecturer’s PPT] Gross findings: → Yellow pigmentation of the organs Figure 49. Miliary Tuberculosis of the Spleen. Minute granulomas are located on the mucosa and may only be Figure 50. Mycobacterium avium infection in a patient seen microscopically [Lecturer’s PPT] with AIDS. Abundant acid-fast bacilli within macrophages Cut surface shows numerous gray-white tubercles (TB (hallmark or MAC infection in HIV patients); Th2 cells granulomas) stimulate macrophages to kill the mycobacteria and → TB granulomas look like bird or millet seeds orchestrate granuloma formation and caseation necrosis [Lecturer’s PPT] KEY CONCEPT: DIAGNOSIS OF TUBERCULOSIS Clinical history PE Radiologic findings Histologic findings PCR-assay (advanced, rapid and sensitive) Culture → Gold standard; for testing of drug susceptibility MYCOBACTERIUM AVIUM-INTRACELLULARE COMPLEX (MAC) Common among people with: → AIDS and low numbers of CD4+ lymphocytes (