Integrated Pathology: Infectious Disease PDF

Integrated Pathology: Infectious Disease Dr. Katherine Hargreaves 6H6Z1002 Learning Outcomes Pathology and infectious diseases Definition: Infectious disease can be detected when causing pathological effects to tissues and cells. The cause being infectious meaning it is caused by an agent that is...

Integrated Pathology: Infectious Disease Dr. Katherine Hargreaves 6H6Z1002 Learning Outcomes Pathology and infectious diseases Definition: Infectious disease can be detected when causing pathological effects to tissues and cells. The cause being infectious meaning it is caused by an agent that is contagious, or can transmit and cause an infection. To determine the cause of the pathology to be infective has implications for 1) Diagnosis 2) Treatment 3) Prognosis 4) Prevention (control of disease) An infectious disease can be passed easily from one person to another, especially through air or water. (Oxford Dictionary) An infectious disease has a causative agent. (aetiological agent) This causative agent typically is microscopic, termed a microorganism or microbes. Etiological agent, substances that contain the infectious microorganism. An infection is when there is damage to tissues or cells leading to symptomatic disease Causes of infectious disease Includes: Bacteria (Prokaryotes) Each has distinctive Viruses (Non-cellular) characteristics, Fungi (Eukaryotes) e.g. organism type, replicative Protozoa (Eukaryotes) processes, structural and molecular composition, Prions (Proteins, non-cellular) genetics, Helminths (non-microbial, Eukaryotes) which determines how they Arthopods (non-microbial, Eukaryotes) interact with the host and causes disease. *Archaea, have no infectious agent identified to date however possible role in periodontal disease * When infectious diseases occur Commensal: Obligate Pathogen: Opportunistic Pathogen: Recap: what causes infectious diseases Koch’s postulates, 1890 : 1. The agent is present in all cases of disease, not in healthy 2. The agent is obtained in pure culture 3. This pure culture can be used as inoculum and causes disease in model 4. The agent can be re-isolated from disease model and confirmed as the same. Cause and Effect- not simply enough to be “by association” Routes of transmission. Aerosol: by inhalation of air droplets containing microorganism Oral: by ingestion of contaminated food or water Direct contact: contact with infected individual tissues or bodily fluids, via entry sites, e.g. eyes/mouth/nose or wound (e.g. bite/scratch) Fomite transmission: contaminated surfaces of inanimate objects e.g cages/door handles/medical equipment Vector-borne: (by other living organisms e.g. mosquitoes, ticks) Zoonotic: (originating from other animal species through routes above) Transmission of disease causing agents. Infectious agents must be transmitted between hosts Transmission of infectious agents in multiple different routes; Routes are related to the specific type of microorganism and the type of tissue or cell it can infect. For example: Rhinoviruses causing the common cold infect the respiratory tract and are dispersed through coughing and sneezing. Transmitted in air borne droplets of sputum and mucus. Droplets are inhaled by another person and can then infect the respiratory tract of this individual. Bourouba, 2016, N Engl J Med Case study: Bacillus anthracis Gram positive bacilli, endospore forming, Present in the environment, in soils and water and contaminated animal products e.g. wool, hides, or hair Occurs globally Capsule, two toxins – Lethal factor and Edema factor Depending on transmission route may cause; Cutaneous anthrax Gastrointestinal anthrax Inhalation anthrax Injection anthrax: resulting from needle administered drug use Welder’s anthrax Case study: Bacillus anthracis Gram positive bacilli, endospore forming, Present in the environment, in soils and water and contaminated animal products e.g. wool, hides, or hair Occurs globally Capsule(poly-D-glutamic acid (γDPGA) capsule) Two toxins – lethal factor and edema factor Depending on transmission route may cause; Cutaneous anthrax Gastrointestinal anthrax Inhalation anthrax Injection anthrax: resulting from needle administered drug use Welder’s anthrax Case study: pathologies and transmission: Bacillus anthracis Cutaneous anthrax (~95% cases) Contamination of wound with spores from environment or contaminated animal products or injury e.g., biting insect Disease onset 1-6 days from exposure, Source, CDC, Symptoms: typical black eschar https://www.cdc.gov/anth swelling, skin ulcer with black centre, rax/treatment/index.html systemic disease 20% fatality rate if untreated 100% survival with treatment Case study: pathologies and transmission: Bacillus anthracis Gastrointestinal anthrax Ingestion of spores from meat from an animal infected with anthrax Symptoms: diarrhoea or bloody diarrhoea, Stomach pain, Swelling of abdomen (stomach) Headache, Fainting Flushing (red face) and red eyes >50% fatality rate if untreated, 60% survive if treated  Case study: pathologies and transmission: Bacillus anthracis Inhalation anthrax Breathing in of spores from contaminated animal products Onset to disease 1 week-2 months Symptoms: Fever and chills, sweating, Headache, Body aches Cough, Chest Discomfort, Shortness of breath Nausea, vomiting, or stomach pains, extreme tiredness Source, CDC, https://www.cdc.gov/anth rax/treatment/index.html 100% fatality rate if untreated 55% survive with treatment Case study: pathologies and transmission: Bacillus anthracis Injection contracted anthrax from needles contaminated with soil or material, swelling at the injection site, nausea and vomiting, and sweats. Welders anthrax (B. cereus group that produces anthrax toxin) – pneumonia diagnosis with symptoms that included fever or chills, cough, shortness of breath (dyspnea), and coughing up blood (hemoptysis). Source, CDC,  Case study: pathologies and transmission: Gastrointestinal mucosa Bacillus anthracis subcutaneous layer alveolar spaces Spores germinate at sites – low level Phagocytosed by macrophages  Case study: pathologies and transmission: Gastrointestinal mucosa Bacillus anthracis subcutaneous layer alveolar spaces Spores germinate at sites – low level Spores phagocytosed by macrophages Bacilli containing macrophages -> lymph Capsule prevents vegetative cell phagocytosis Case study: pathologies and transmission: Bacillus anthracis Toxins: Edema toxin – Lethal factors (adenylate cyclase increases intracellular levels of cyclic AMP (cAMP)) and protective antigen (binds to cell) Lethal toxin - Zinc metalloprotease results in hyperinflammation-via MAPKK (mitogen- activated protein kinase kinase) ROS and proinflammatory cytokines like TNF-α and IL-1ß Case study: pathologies and transmission: Bacillus anthracis Hemorrhagic lymphadenitis Bacilli in blood -> septicaemia (107 to 108 organisms per milliliter of blood) Spread to the brain and meninges Pulmonary blockage Routes of transmission: RTI agents Diversity of microorganisms via inhalation of air droplets containing microorganism Source: Brock Biology of Microorganisms How can ID be characterised? Infectious diseases were discovered due to medical practitioners trying to work out why certain diseases spread, how to treat them and how to prevent them. Infectious diseases are defined by their; Signs (objective, can be detected/measured) e.g. fever, coughing, vomiting Syndrome Symptoms (subjective, can be described) e.g. pain, nausea Pathology of an infectious disease determines the signs and symptoms resulting in the syndrome Case study: Influenza Syndrome Infectious disease Causative agent - Influenza virus Influenza: Italian form of Latin influentia, “epidemic”, as epidemics believed to originate from Segmented –ve sense ssRNA genome astrological or other “influences”. ICTV, 2021 Pleomorphic nucleocapsid Signs and symptoms Fever Cough Sore throat Congestion Muscle/body aches Fatigue Vomiting and diarrhoea Categorize the signs and the symptoms Source: PHIL CDC, 2021 Clinical signs and symptoms Characteristics of infectious diseases Phases of an infectious disease Duration of infectious disease Location of infectious disease Timing of infectious disease Stages in infection Phases of infectious disease Incubation period – time between infection and the appearance of signs and symptoms Prodromal phase – mild, non-specific symptoms that signal onset of some diseases Clinical phase – a person experiences typical signs and symptoms of disease Decline phase – subsidence of symptoms Recovery phase – symptoms have disappeared, tissues heal, and the body regains strength When is someone the most contagious? Characteristics of infectious diseases By duration: Acute – develops and Chronic – develops slowly Latent – characterised by progresses quickly and less severe but long no symptoms between lasting outbreak and illness  Characteristics of infectious diseases By duration: Acute – develops and Chronic – develops slowly Latent – characterised by progresses quickly and less severe but long no symptoms between lasting outbreak and illness Human Papilloma virus (HPV), Source UCL Ebola- Ebola haemorrhagic fever Herpes Simplex Virus HSV1, HSV2 Genital warts, oropharyngeal cancers HSV1 oral-oral, HSV2 Sexually Transmitted Infection Symptoms onset ~5-9 days Asymptomatic, transformation of cells to maglignant carcinoma ~10 years Blisters/ulcers at site of infection, Early – fever, fatigue reoccur sporadically Later – vomiting, diarrhoea, rash Modelling to suggest by 2120 > 60 million deaths averted in low-,low- Spread to central nervous system, state hemorrhaging, bleeding or bruising middle income countries of quiescence in neuron nucleus Canfell et al., 2020, The Lancet Classification of infectious diseases By location Local – confined to a specific area of the body Systemic – infects across multiple body sites and across tissues Characteristics of infectious diseases By Location Local – confined to a specific area of the Systemic – infects across multiple body body sites and across tissues Characteristics of infectious diseases By Location Local – confined to a specific area of the Systemic – infects across multiple body body sites and across tissues Ringworm (tinea): Trichophyton, Microsporum, and Epidermophyton fungal species Caused by a dermatophyte (temp 27-33°C) 25% population 4-14 days onset Source CDC  Characteristics of infectious diseases By Location Local – confined to a specific area of the Systemic – infects across multiple body body sites and across tissues S. aureus site of infection Bacteraemia on skin Fever, shock, organ failure cutaneous abscess: 20,000 MRSA bloodstream infections 20,000 associated deaths USA in 2017 Red, swollen, painful, heat, pus, fever Source: CDC Classification of infectious diseases By timing Primary – initial infection in a previously healthy person Secondary –infection that occurs in a person weakened by a primary infection Primary infection Example: Human Immunodeficiency virus (HIV), +vs ssRNA genome, enveloped capsid Transmission via bodily fluids Flu like illness 2-6 weeks (80%) Fever, sore throat, body rash T cell infection and decrease in CD4+ cells Deeks (2015) Nature 500 cells and 1,200 cells per μl Development of Acquired Immunodeficiency Syndrome (AIDS) Primary infection HIV infects CD4+ T cells in gut mucosa Primary infection HIV also infects thymus contributes to failure to regenerate more T cells Primary infection HIV infects cells in the secondary lymph nodes resulting in T cell depletion  Primary infection Chronic inflammatory response reduces T cell function impaired haematopoiesis Secondary infection Bowen et al. (2016) Nat Rev Neurobiol Opportunistic infections: Mycobacterium tuberculosis Toxoplasma gondii – protist Deeks (2015) Nature PML JC virus (JCV) polyomavirus (50-90% T cell infection and decrease in CD4+ cells Cytomegalovirus 500 cells and 1,200 cells per μl Cryptococcus neoformans or, C. gattii Pathogenesis of infectious diseases How infectious agents cause disease Mechanisms of pathogenicity depend on infecting pathogen For example: Production of poisons such as toxins and enzymes that destroy cells and tissues (e.g. often produced by bacteria) Direct invasion and destruction of host cells (e.g. viruses, some bacteria). Triggering responses from the host’s immune system leading to disease signs and symptoms (e.g. fever/sneezing/vomiting triggered by the immune system to rid the body of the pathogen). Steps in infection Adapted from 2019 MIMS 6th Ed Entry and Attachment to body. Overcome innate immune response Colonisation, local or/and general spread Invasion into tissues and cells through the body. Access and obtain necessary Replication nutrients/cellular machinery for required for multiplication. replication and evade immune response Leave site or sites for onward Exit (shedding from body) transmission The pathology and damage to the host may result of the above processes. Immune response may contribute to the disease pathology resulting from the blocking, deactivating and clearing of infecting microorganism. Pathogenesis of infectious diseases Some pathological effects of diseases may be caused by more than one causative agent; Some shared pathology by site of infection: Respiratory infections Bloodstream infections Encephalitis (inflammation of the brain) Meningitis (inflammation of the lining around brain and spinal cord) Endocarditis (infection of the heart) Gastrointestinal disease Skin and soft tissue infections Pathogenesis of infectious diseases Example: skin and soft tissue Mucocutaneous lesions Abscess formation – infection and inflammation of hair follicle Spreading infections Necrotizing infections Skin manifestations by systemic infections Pasparakis et al (2014) Nat Rev Micro  Insight to site specific pathogenesis Skin infections from direct contact Adapted from: MIMs 6th Ed Figure Skin structure/site Infection Agent Superficial to A Epidermis Impetigo Streptococcus pyogenes invasive and/or Staphylococcus aureus A Source: Brocks Book of Microbiology  Insight to site specific pathogenesis Skin infections from direct contact Adapted from: MIMs 6th Ed Figure Skin structure/site Infection Agent Superficial to A Epidermis Impetigo Streptococcus pyogenes invasive and/or Staphylococcus aureus B B Dermis Erysipelas S. pyogenes Source: Brocks Book of Microbiology  Insight to site specific pathogenesis Skin infections from direct contact Adapted from: MIMs 6th Ed Figure Skin structure/site Infection Agent Superficial to A Epidermis Impetigo Streptococcus pyogenes invasive and/or Staphylococcus aureus B Dermis Erysipelas S. pyogenes C C Hair follicles Folliculitis, Boils, S. aureus Carbuncles Krishna & Miller, 2012, Semin Immunopathol Insight to site specific pathogenesis Skin infections from direct contact Adapted from: MIMs 6th Ed Figure Skin structure/site Infection Agent Superficial to A Epidermis Impetigo Streptococcus pyogenes invasive and/or Staphylococcus aureus D B Dermis Erysipelas S. pyogenes C Hair follicles Folliculitis, Boils, S. aureus Carbuncles D Subcutaneous fat Cellulitis S. pyogenes Raff & Kroshinsky, 2016 JAMA  Insight to site specific pathogenesis Skin infections from direct contact Adapted from: MIMs 6th Ed Figure Skin structure/site Infection Agent Superficial to A Epidermis Impetigo Streptococcus pyogenes invasive and/or Staphylococcus aureus E B Dermis Erysipelas S. pyogenes C Hair follicles Folliculitis, Boils, S. aureus Carbuncles D Subcutaneous fat Cellulitis S. pyogenes E Fascia Necrotizing fasciitis Anaerobes/polymicrobial/S. pyogenes Hasham, 2005, BMJ  Insight to site specific pathogenesis Skin infections from direct contact Adapted from: MIMs 6th Ed Figure Skin structure/site Infection Agent Superficial to A Epidermis Impetigo Streptococcus pyogenes invasive and/or Staphylococcus aureus F B Dermis Erysipelas S. pyogenes C Hair follicles Folliculitis, Boils, S. aureus Carbuncles D Subcutaneous fat Cellulitis S. pyogenes E Fascia Necrotizing fasciitis Anaerobes/polymicrobial/S. pyogenes F Muscle Gangrene Clostridium perfringens Aggelidakis, 2011, World J Emerg Surg Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Spreading infections Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Skin manifestations by systemic infections An exit and shedding resulting in disease pathology Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Skin manifestations by systemic infections An exit and shedding resulting in disease pathology Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Skin manifestations by systemic infections An exit and shedding resulting in disease pathology Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Skin manifestations by systemic infections An exit and shedding resulting in disease pathology Source: Goering et al., 2019 MIMS 6th Ed Pathogenesis of infectious diseases Example: skin and soft tissue Skin manifestations by systemic infections An exit and shedding resulting in disease pathology Source: Goering et al., 2019 MIMS 6th Ed  Insight to site specific pathogenesis Skin diseases from systemic infections, may shed bacteria Adapted from: MIMs 6th Ed Skin manifestation Disease/Infection Agent A ‘Rose spots’ containing bacteria Enteric fever Salmonella typhi B Petechial/maculopapular lesions Septicaemia, meningitis Neisseria meningitidis containing bacteria C Ecthyma gangrenosum, skin lesion Septicaemia Pseudomonas aeruginosa D Dissemination rash Syphilis/Yaws Treponema pallidum, T. pertenue E Macular or haemorrhagic rash Rocky Mountain Spotted Fever Rickettsia prowazekii, Rickettsia typhi, Rickettsia rickettsii F Rash caused by erythrogenic toxin Scarlet fever S. pyogenes C F A B D E Basnyat et al., 2021., BMJ Baughn,& Musher., 2005 Source: CDC, Abbas, et al., 2017, Clin Microbiol Rev https://www.cdc.gov/mmwr/volumes/65/rr/rr6502a Theulin, et al., 2010 J Med Micro 1.htm#F21_down Source: Brocks Book of Microbiology  Case Study: Enteric Fever: S. Typhi Gram negative bacteria Human specific - high fever, fatigue, headache, nausea, abdominal pain, and constipation or diarrhoea - Host tropism: Vi Capsule – attachment to human cells – (antigen) N-acetylneuraminic acid (Neu5Ac) sialoglycans Primary infection, secondary infection and carrier state Low initial immunological response – regulation of Vi Capsule fimbrae Acute typhoid fever cellular response Elevated anti-Vi antibody Decreased zinc concentration Decreased platelets and lymphocytes (anemia) Markers of liver damage- α1-antitrypsin Dougan & Baker (2014) Case Study: Enteric Fever: S. Typhi Intracellular – Enterocytes/dendritic cells Macrophages Salmonella containing vacuole (SCV) De Jong, 2012 Reducing the spread of infectious diseases Diagnosis Clinical presentation of symptoms Laboratory detection Treatment Antimicrobial drugs Antibiotics- antivirals - antifungals Prevention Vaccines Good hygiene and sanitation Protection against vectors (e.g. mosquitoes/ticks) Isolation or quarantine of patients Treatment of infectious diseases Antibiotics Only work against some bacteria, and do not work against viruses or other agents Target bacteria-specific structures/functions in the prokaryote cell: Resistance of bacteria increasing globally (AMR); CDC identified 18 infectious agents that are of concern.- $4.6 billion annually. Antiviral drugs Work against some viruses Block parts of viral replication; e.g. nucleotide incorporation Antifungal drugs Challenging to develop due to eukaryotic nature of cells targeting/parasitic life cycles Prevention of infectious diseases Vaccines Vaccines consist of either attenuated (weakened), inactivated or dead (killed) or components of the microorganism Work by stimulating the body’s immune system to fight off future infection Vaccination programmes successfully eradicated smallpox Global led campaigns to tackle polio Case study: Influenza Caused by Influenza virus Acute Contagious via airborne transmission/indirect contact Respiratory tract infection, symptoms felt throughout body Epidemics occur seasonally, typically low fatality; pandemics more deadly less frequent Genome structure means it is highly changeable; infect multiple species (humans, pigs, birds). Glycoproteins HA- hemagglutinin M2- ion channel Concerns for avian flu lead to new pandemic H1N1 & H5N1. M1- matrix protein NA– neuraminidase NP- nucleoprotein Source: Nature Scitable, https://www.nature.com/scitable/content/an-influenza-a-v Epidemiology of infectious diseases Is a science that examines patterns causes and effects of disease (not just infectious disease) on the health of a given population. The focus is to control and reduce incidence of disease via identification of factors that : Cause disease Transmission of disease Help prevent/reduce future disease Use of infectious disease epidemiology To identify those factors epidemiologists can breakdown into four branches Disease aetiology (causing agent) Outbreak investigation Disease screening and surveillance Comparisons of treatment or effects (– clinical trials) Reducing the spread of infectious diseases Removal of infectious agent Good personal hygiene and sanitation Basic measures for frequent and thorough handwashing to limit spread of disease Protection against vectors (physical barriers/chemical treatments) E.g. mosquitoes against Malaria and West Nile virus E.g. ticks to prevent Lyme disease Quarantine (physical separation to prevent transmission) Covid-19 and Ebola as recent examples to physically stop transmission occurring Diagnosis of infectious diseases Signs and symptoms Detection of microorganism Pathology - diagnostic histopathology Molecular pathology immunohistochemistry in situ hybridization probes (genome and the transcriptome on formalin fixed paraffin embedded (FFPE) tissues) assess the tissue reaction induced by an infectious organism and lesion characteristics associate morphologically recognized lesions with the presence of an infectious agent --> determine the type of inflammatory reaction (i.e., fibrinous, purulent, lymphocytic, and granulomatous) associated with a specific microbe. Diagnosis using Microscopy Stain for microorganisms A- Leprosy - M. leprae, Ziehl-Neelson B, Histoplasma*, Histoplasmosis, Gomori Grocott C Cryptococcus*, Acian blue, D Syphillis - Treponema pallidum, Warthin Starry Hofman et al., 2017, Virchows Arch  Diagnosis using Microscopy Immunohistochemistry for microorganism Tissue stain such as Hematoxylin and Eosin with antibodies for microorganism A: Cutaneous Leishmaniasis (anti-Leishmania antibody) protozoa B: Lymph node histoplasmosis (anti- Histoplasmosis antibody) C: Cutaneous Cryptococcus (anti-Cryptococcus antibody) D: Gastric syphillis - (anti-Treponema antibody) E: Simian Vacuolating virus 40 (anti-SV40) in brain tissue F Lymph node infection HIV (anti-p24 antibody) – capsule protein) Hofman et al., 2017, Virchows Arch  Diagnosis using Microscopy Other methods for microorganism Tissue samples with in situ hybridization (ISH), electron miscroscopy (EM) A: Head and neck carcinoma (human papillomavirus, ISH, original magnification ×500). B simian vacuolating virus 40 (SV40) infection in cerebral tissue (SV40, ISH, original magnification ×360). C Interaction between Bacillus anthracis (arrows) and an endothelial cell (asterisks) from a pulmonary capillary (arrowheads: capsule remnants of the bacteria) (EM, original magnification ×5400). Hofman et al., 2017, Virchows Arch  Diagnosis using Microscopy Other methods for microorganism Tissue samples with molecular biology (PCR) D (1–3) Infection of the lung due to tularemia. Histology revealed extensive inflammation with granulomatous ( D3 PCR assay for tularemia DNA (arrow)s) and an endothelial cell (asterisks) Hofman et al., 2017, Virchows Arch Diagnosis of infectious diseases Diagnostic histopathology laboratory involvement Uses in emerging infectious diseases such as Zika, initial investigation of HIV and AIDS Observations of associated pathologies contribute to understanding in pathogenic effects/mechanisms of disease by aetiological agents Limitations are availability of specific antibodies, possibility to be replaced by genomics  Emerging infectious diseases Emerging diseases are those that have recently appeared within a population, or incidence in increasing rapidly Can re-emerge Acquisition of resistance of antimicrobial drugs, e.g. MDR Neisseria gonorrhoeae—ceftriaxone last resort Vaccine or preventative measures ineffectual (e.g. measles) Appearance of a previously unknown agent Spread of an infectious agent to a new host Spread of an infectious agent to new locations Zika virus incidence Gonorrhoea — Rates of Reported Cases by Year, United States, 1941–2019, increased 5.7% from 2018 and increased 53.2% since 2015. Source: CDC, https://www.cdc.gov/std/statistics/2019/figures.html Source: CDC, https://www.cdc.gov/measles/cases-outbreaks.html Source: Saiz, et al., 2017 Front. Microbiol. Emerging infectious diseases Bacteria Virus Parasite worm Covid-19, 2021 $11 trillion Other outbreaks $60 billion in 2018 Source: Wellcome Trust, https://wellcome.org/news/cost-of-not-preparing-for-infectious-diseases In Summary Infectious diseases can result in pathological disease Varied and diverse causes of infectious diseases Determining the causative agent permits treatment and helps aid prevention Considerations around detection and causation of infection versus asymptomatic carriage Also insights from microbiota studies examining health and disease states Diagnosis may need combination of signs, symptoms, clinical diagnosis (detection of microorganism/toxin/antibody), and epidemiological insight Infectious disease management Further reading Brock Biology of Microbiology, Harlow, United Kingdom : Pearson Education Limited,. III Immunological and Molecular Tools for Disease Diagnosis References Evans AS. Causation and disease: the Henle-Koch postulates revisited. 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