Infectious Diseases Pathophysiology PDF

Mandana Naderi, PharmD, MPH, BCIDP November 21, 2023 1 Objectives Describe Understand Identify Describe the relationship among the host-agentenvironment interaction model Understand the process of host defense against infection Identify the pathophysiologic characteristics for various infectious...

Mandana Naderi, PharmD, MPH, BCIDP November 21, 2023 1 Objectives Describe Understand Identify Describe the relationship among the host-agentenvironment interaction model Understand the process of host defense against infection Identify the pathophysiologic characteristics for various infectious diseases 2 Infectious Diseases Background 3 Age-adjusted death rates for the 10 leading causes of death in 2017: United States, 2016 and 2017 WHO Global Health Estimates. Dec 2020 Epidemiologic Triad Host Virulence, Infectious infectivity, Agent adaptability to survive outside body Genetic susceptibility, resiliency, nutritional status, behavior Environment Sanitary conditions, season, availability of health care 4 Essentials of Epidemiology in Public Health. 2014 Agent Attributes  Bacteria  Staphylococcus, Mycobacterium  Viruses  Influenza, hepatitis  Fungi  Candida, Aspergillus  Protozoan  Variety of factors will influence whether exposure to the organism will cause disease:  Virulence factor  Microbial inoculum  Giardia, Toxoplasmosis  Worms  Trichinella, Strongyloides 5 Common Etiologic Bacteria Pulmonary CAP: S. pneumo, H. flu, M. catarrhalis, Legionella HAP: S. aureus, Pseudomonas, Enteric GNR Gastrointestinal Enteric GNR, Pseudomonas, Enterococcus, Anaerobes, C. diff. Skin Staph and Strep species Diabetic Foot Infection Superficial: S. aureus, betahemolytic Strep, S. epidermidis Deep: Usually polymicrobial Meningitis S. pneumo, N. meningitidis, Listeria, GNR ENT Otitis media: S. pneumo, H. influenzae, Moraxella catarrhalis Sinusitis: S. pneumo, H. influenzae Cardiovascular Endocarditis: S. aureus, Enterococcus, Viridans group Strep Genitourinary UTI/Pyelonephritis: E. coli, Proteus, Klebsiella, Enterococcus spp. 6 Environment Attributes  Vectors  Insects and other carriers that transmit infectious agents  Zoonotic hosts  Animals that harbor infectious agent and often act to amplify the infectious agent  Climate  Living conditions/population density  Access to health care services  Availability of nutrients 7 Host Attributes  Immune status  Sex  Age  History/personal choices/hygiene  Nutritional status  Microbiome  Presence of disease or medications 8 Finding Balance 9 https://cursos.campusvirtualsp.org/mod/tab/view.php?id=23154 Obtaining a History for Diagnosis Feature Site of Acquisition (i.e. home, skilled nursing facility, hospital) Season Outdoor Activities Travel Comorbid diseases Examples of Infection Multi-drug resistant bacteria more commonly cultured from patient in a nursing home or hospital Influenza epidemics limited to fall and early spring Arthropod-borne infections (ex: Rocky Mountain spotted fever) Internationally acquired infections (ex: malaria) Soft tissue infections in diabetic patients 10 Obtaining a History for Diagnosis Feature Immunocompromised (ex. HIV, organ transplant, corticosteroid use, chemotherapy) Substance Abuse (route of illicit drug use) Sexual Contacts Examples of Infection Pneumocystis jirovecii pneumonia (PCP) in patients with AIDS Endocarditis associated with injection drug use due to seeding of bloodstream with bacteria Risk for STI such as syphilis 11 Human Microbial Flora  Skin  Staphylococci, streptococci  Oropharynx  Viridans group streptococci  Peptostreptococcus  Gastrointestinal  Enterococcus  Bacteroides  Gram-negative enteric bacilli (GNRs) 12 Human Microbial Flora Pattern recognition receptors (PRR) include toll-like receptors Toll-like receptors = (TLR) 13 Human Microbial Flora  Microbes exist in complex communities and habitats  Habitat imbalance is associated with infection and disease  Normal flora OR invasive pathogen  Colonization vs. infection  Colonization: presence of bacteria on a body surface without causing disease  Infection: invasion of the tissues by a microorganism that causes disease  Microorganisms in sterile sites is diagnostic of infection 14 Host Defense Mechanisms to Prevent Colonization  Establishment of normal flora  Selective advantage over colonizers since they’re established in an anatomic area  Deprivation of necessary nutrients  Mechanical clearance  Phagocytic killing Successful colonizers adapt an ability to evade or overcome these defenses 15 Host Defenses Against Infections Innate Immune System  Non-specific immune response  Rapid response; multiple mechanisms to protect host from infection  Present at birth  Consists of:  Barriers  Physical and chemical  Activation of inflammatory cells and proteins  Neutralize organisms, recruit phagocytic cells  Activation of adaptive immune system  Induce response through humoral and cell-mediated immunity 16 Innate Immune System Physical and Chemical Barriers  Skin  Squamous epithelial cells  Sebaceous and sweat glands  Mucous membranes  Mouth, pharynx, esophagus, and lower urinary tract  Protective layer of mucus  Not all pathogens entering the human body will cause disease since humans are protected by normal flora and their immune systems 17 Innate Immune System Inflammatory Response  Pattern recognition receptors (PRRs)  Activated through sensing of pathogen-associated molecular patterns (PAMPs)  Stimulates activation of a pro-inflammatory cascade  Do not require prior contact with organism to be activated  Signs of inflammation  Increased blood supply  Decreased pH  Pro-inflammatory cytokines  Histamine, bradykinin  Interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor, interferon-γ 18 Innate Immune System Complement System  Two pathways:  Classic  Alternative  Both form C3 convertase  Cleaves C3 component  Membrane attack complex  C5-C9 19 Host Defenses Against Infections Adaptive Immune System  Acquired immunity or antigen-specific immunity  Antigen must first be recognized and processed  Rapid increase of T and B lymphocyte clones  Each clone has the same antigen receptor as the original and fights the same pathogen Protective Immunity  Occurs after initial exposure to a pathogen (via infection or vaccination)  Memory lymphocytes and pathogen-specific antibodies are generated and allows 20 a rapid response to infection Infections Due to Common Host Defects in Immune Response 21 Development of Infectious Diseases Pathogen Encounters Host Gains Entry into Host Multiplies and Spreads from Site of Entry Causes Host Tissue Injury 22 Characteristics of Infections  Location  Localized: pathogen only present at original infection site  Systemic: pathogen is carried to other parts of the body by blood, lymph, etc  Severity of infection  Asymptomatic to life-threatening  Clinical Course  Acute, subacute, or chronic  Outcomes  Resolution  Chronic infection  Prolonged asymptomatic excretion of the agent  Latency of agents within host tissue  Death 23 Signs vs. Symptoms of a Disease Signs • Evidence of a disease found or seen by the doctor • Abnormal heart or breath sounds, microbiology results, radiographic imaging Symptoms • Evidence of a disease felt and explained by the patient • Headache, pain, nausea, fatigue 24 Pathophysiology of Various Infectious Diseases 25 Infective Endocarditis (IE) 26 Normal Heart Left-sided Endocarditis Right-sided Endocarditis 27 Etiology of IE  Most common bacterial pathogens are gram-positive bacteria  Viridans group streptococci  Staphylococcus aureus  Coagulase-negative Staph (S. epidermidis, etc)  Enterococci (E. faecalis, E. faecium)  Most common risk factors  Presence of a prosthetic valve (highest risk)  Previous endocarditis (highest risk)  Congenital heart disease  IV drug use (IVDU) 28 Pathogenesis of IE Endothelial surface of heart is injured Adherence of platelets and fibrin on abnormal epithelial surface Platelet-fibrin clot becomes infected with bacteria circulating in the blood Vegetation forms Vegetation/bacteria continue to grow Bacteria are protected by platelet-fibrin “scaffold” 29 Pathogenesis of IE  Tissue Factor Activity = TFA 30 Clinical Manifestations of IE  Local perivalvular damage  Can lead to acute heart failure  Embolization of septic fragments (septic emboli)  Right-sided endocarditis – lungs  Left-sided endocarditis – brain, spleen, kidney, extremities  Formation of antibody complexes  Humoral and cellular immune systems stimulated  Immune complex deposition along renal membrane  Persistent bacteremia with metastatic seeding of infection  Abscesses or septic joints 31 Cutaneous Manifestations of IE A. Splinter hemorrhages B. Conjunctival petechiae C. Osler nodes D. Janeway lesions  Roth spots  Clubbing of the fingers  Septic emboli Mylonakis E, et al. N Engl J Med. 2001;345:1318-1330 32 Meningitis 33 Meningitis  Meninges – 3 separate membranes that surround the brain and cerebrospinal fluid (CSF)  Dura mater, arachnoid, and pia mater  Meningitis – inflammation of subarachnoid space or CSF due to viral, bacterial, or fungal infection 34 Etiology of Bacterial Meningitis  Varies according to age  Neonates – translocation of vaginal flora during birth  Group B streptococci (Streptococcus agalactiae), E. coli  Adults  Streptococcus pneumoniae  Neisseria meningitidis  Haemophilus influenzae  Elderly, immunocompromised, or pregnant patients  Food-borne pathogen– Listeria monocytogenes 35 Pathogenesis of Bacterial Meningitis 36 CSF Inflammatory Cascade Manifestations  Abnormalities in cerebral blood flow  Cerebral edema  Increased permeability of blood-brain barrier  Cytotoxic edema from substances released by bacteria/neutrophils  Interstitial cerebral edema results in obstructed flow of CSF  Neuronal cell death (apoptosis)  Cerebral hypoperfusion  Due to local vascular inflammation  Brain herniation  Increased intracranial pressure 37 Pathophysiological Alterations Resulting in Neuronal Injury  CBV= cerebral blood volume  BBB= blood-brain barrier 38 Clinical Manifestations of Bacterial Meningitis  Rapid onset fever, headache, neck stiffness or pain  Nausea/vomiting  Photophobia  Confusion/lethargy  Signs of herniation: coma, papilledema, bradycardia, respiratory depression, hypertension 39 Pneumonia 40 Pneumonia  Acute infection of the lung tissue  Inflammation of lung parenchyma  Accumulation of inflammatory exudate in airways  Infection usually starts in the alveoli, and may spread to other areas of the lung 41 Etiology of Pneumonia  Types of Pneumonia  Common Bacteria  Community-acquired pneumonia (CAP)  Streptococcus pneumoniae (most  Hospital-acquired pneumonia (HAP)  Mycoplasma pneumoniae  Outpatient or ≤ 48 hours of hospital admission  > 48 hours after hospital admission  Staphylococcus aureus  Pseudomonas aeruginosa  Ventilator-associated pneumonia (VAP)  > 48 hours after endotracheal intubation common)  Haemophilus influenzae  Chlamydia pneumoniae  Legionella species  Respiratory viruses*  No causative agent identified ~50% of CAP cases *Influenza, adenovirus, respiratory syncytial virus (RSV), parainfluenza 42 Pathogenesis of Pneumonia  Acute pneumonia occurs when:  Defect in host defenses  Ex: Impaired cough reflex or cell-mediated immune dysfunction  Infection with virulent microorganism  Exposure to large inoculum  Pathogens reach lungs by:  Direct inhalation of infectious respiratory droplets  Aspiration of oropharyngeal contents  Hematogenous spread 43 Pathogenesis of Pneumonia  Pulmonary defenses  Changes in airflow  Epiglottis and cough reflex  Cilia and mucus  Alveoli  Impairment in host defenses increases risk of pneumonia 44 Clinical Manifestations of Pneumonia  Fever, cough (usually productive), tachypnea, tachycardia, x-ray infiltrates 45 Normal chest x-ray Pneumonia Sepsis and Septic Shock 46 Sepsis  Clinical syndrome characterized by a dysregulated inflammatory response to infection  Leading cause of morbidity and mortality in the U.S.  Septic shock = sepsis + hypotension requiring vasopressor support to maintain MAP >65 mmHg AND lactate >2 mmol/L  Predicted mortality of 40% 47 Pathogenesis of Sepsis Localized infection Bacteria directly invade the bloodstream OR proliferate locally and release toxins into the bloodstream Overstimulation of the host inflammatory response & uncontrolled release of inflammatory mediators 48 Pathophysiology of Sepsis  Hemodynamic alterations  Vasodilation  hypotension and hypoperfusion due to nitric oxide released from endothelial cells in response to bacterial endotoxin  Distributive shock produces imbalances in blood flow and hypoperfusion of some organs  Vascular and multiorgan dysfunction  Organ failure from microvascular injury by local and systemic inflammatory responses to infection  Decreases in the number of functional capillaries, resulting in an inability to extract oxygen maximally  Aggregation of neutrophils and platelets may also reduce blood flow  Complement system components are activated, attracting neutrophils and releasing 49 locally active substances (prostaglandins and leukotrienes) Pathogenesis of Sepsis  Toxins may arise from a lipopolysaccharide outer membrane component of gramnegative bacteria (endotoxins) or from proteins synthesized and released by bacteria (exotoxins)  CD4 cells get stimulated to secrete cytokines with either inflammatory (type 1 helper T cell) or anti-inflammatory (type 2 helper T-cell) properties  Stimuli include organism, microbial inoculum, and site of infection 50 Pathogenesis of Sepsis 51 Clinical Manifestations of Sepsis  Systemic response to infections: tachycardia, tachypnea, alterations in body temperature and leukocyte count  Specific organ system dysfunction  Cardiovascular  Respiratory  Renal  Hepatic  Hematologic 52 Infectious Diarrhea 54 Infectious Diarrhea  More than 5 million people die of acute infectious diarrhea worldwide annually  In the U.S., 200 million episodes per year, 1.8 million hospitalizations, costs $6 billion per year  “Gastroenteritis” refers to bacterial or viral infections that affect both the stomach and small/large intestines 55 Etiology of Infectious Diarrhea  Most cases are due to viral pathogens  Rotavirus, norovirus, astrovirus  Environmental factors:  Person-to-person transmission  Fecal-oral spread of Shigella or Rotavirus  Water-borne transmission  Cryptosporidium, Vibrio cholerae  Food-borne transmission  Salmonella or S. aureus food poisoning 56 Pathogenesis of Infectious Diarrhea  Host factors that influence GI tract infections:  Highest risk populations are very young or elderly, comorbid conditions (i.e. HIV)  Use of medications that alter normal GI flora (antacids or antibiotics)  Infectious agent (bacterial, viral, protozoal) factors:  Propensity to attach to different sites of GI tract (stomach, small bowel, colon)  Pathogenesis (enterotoxigenic, cytotoxigenic, enteroinvasive)  E. coli typically colonizes the human GI tract, however there are 5 major classes of E. coli that can cause diarrhea  All can evade host defenses, colonize intestinal mucosa, and multiply with host cell injury 57 Types of E. coli in Diarrheal Disease Enterotoxigenic E. coli Enteroinvasive E. coli Enterohemorrhagic E. coli Enteropathogenic E. coli Enteroaggregative E. coli 58 Infectious Diarrhea of Small and Large Bowel  Secretory diarrhea: superficially attach to enterocytes in the small bowel lumen  Symptoms: combination of diarrhea, vomiting, and abdominal pain  Pathogens include: Vibrio cholerae, ETEC, EAEC, rotavirus, norovirus, protozoa (Giardia, Cryptosporidium)  Some of these pathogens release enterotoxins, which are proteins that increase cyclic adenosine monophosphate (cAMP) production, causing dramatic efflux of water and secretion of electrolytes by intestinal villi, leading to profuse watery diarrhea  May progress to dehydration and vascular collapse unless vigorous volume and electrolyte resuscitation is given 59 Pathogenesis of Infectious Diarrhea Vibrio cholerae and Enterotoxigenic E. coli (ETEC) 60 Infectious Diarrhea of Small and Large Bowel  Inflammatory diarrhea: bacterial invasion of the mucosal lumen resulting in cell death  Symptoms: fever, crampy, lower abdominal pain, & diarrhea which may contain visible mucus  Pathogens include: EIEC, Shigella, Salmonella, Campylobacter, Entamoeba histolytica  Hemorrhagic diarrhea: EHEC produces 2 Shiga-like toxins; A subunit of Shiga toxin catalyzes the destructive cleavage of ribosomal RNA and halts protein synthesis, leading to cell death  Shiga toxin can enter systemic circulation and is phagocytosed by neutrophils, and in turn endocytosed by target epithelial cells  vascular damage and possible pro-thrombotic state preceding hemolytic-uremic syndrome  Broad spectrum of clinical disease: asymptomatic infection; watery (non-bloody diarrhea); hemorrhagic colitis (blood, inflammatory diarrhea); hemolytic-uremic syndrome (characterized by anemia and renal failure) 61 Questions? 62