Fever, Skin Rash Causes and Mechanisms PDF

Thermoregulation and pathogenesis of fever **Mechanisms of Heat Production and Heat Loss:11** - Heat production: - Basal metabolic rate (BMR): Energy required for essential bodily functions at rest. - Muscle activity: Generates heat through muscle contraction. - Ther...

Thermoregulation and pathogenesis of fever **Mechanisms of Heat Production and Heat Loss:11** - Heat production: - Basal metabolic rate (BMR): Energy required for essential bodily functions at rest. - Muscle activity: Generates heat through muscle contraction. - Thermogenesis: Heat production by brown adipose tissue. - Heat loss: - Radiation: Transfer of heat as infrared waves from the body\'s surface. - Conduction: Transfer of heat through direct contact with a cooler surface. - Convection: Transfer of heat through air or water currents. - Evaporation: Cooling effect when sweat evaporates from the skin. - Respiration: Heat loss through warm air exhaled during breathing. **Mechanism of Thermoregulation and the Role of Hypothalamic Set Point:** - Hypothalamic Set Point: - Hypothalamus maintains a set point for core body temperature. - Monitors core temperature through temperature receptors. - Involvement of Autonomic Nervous System (ANS): - Hypothalamus communicates with ANS to initiate responses. - Heat conservation: - Vasoconstriction: Reduces blood flow to the skin, conserving heat. - Shivering: Involuntary muscle contractions generate heat. - Heat dissipation: - Vasodilation: Increases blood flow to the skin, promoting heat loss. - Sweating: Facilitates evaporative cooling. **Application of Thermoregulation Principles to Fever:** - Fever: - Elevated hypothalamic set point due to infection or other factors. - Vasoconstriction, shivering, and behavioral changes increase body temperature. - Sweating may occur as body approaches new set point. - Medical intervention may be necessary to manage fever and prevent complications. ### Bacterial and viral causes of fever/skin rash **Bacterial Causes of Fever and Skin Rash:** - Streptococcus pyogenes (Group A Streptococcus) - Staphylococcus aureus - Neisseria meningitidis - Borrelia burgdorferi (causes Lyme disease) - Rickettsia rickettsii (causes Rocky Mountain spotted fever) **Signs and Symptoms of Fever and Skin Rash due to Bacterial Infections:** - Fever (elevated body temperature) - Skin rash (can vary in appearance, such as maculopapular, petechial, vesicular, etc.) - Localized redness, swelling, and tenderness in affected areas. - Systemic symptoms like headache, body aches, fatigue, and malaise - In severe cases, symptoms may progress to include septicaemia or meningitis **Diagnosis of Fever and Skin Rash due to Bacterial Infections:** - Clinical evaluation by a healthcare professional - Physical examination and medical history review - Laboratory tests, including blood cultures, skin swabs, or biopsies. - Serological tests to detect specific bacterial antigens or antibodies. - Polymerase chain reaction (PCR) testing to identify bacterial DNA. **Pathophysiology of Fever and Skin Rash due to Bacterial Infections:** - Bacterial infections can trigger an immune response, leading to the release of inflammatory mediators such as cytokines and chemokines. - These mediators cause dilation of blood vessels, increased vascular permeability, and recruitment of immune cells to the site of infection, resulting in the characteristic rash. - Fever occurs as a response to pyrogens (substances that induce fever) released by the immune system, which act on the hypothalamus to raise body temperature. **Medically Important Viruses that Cause Fever and Skin Rash:** - Measles virus (causes measles) - Rubella virus (causes rubella, also known as German measles) - Varicella-zoster virus (causes chickenpox and shingles) - Dengue virus (causes dengue fever) - Zika virus (can cause rash along with other symptoms) **Risk Factors, Pathophysiology, Signs and Symptoms, Diagnosis, Management, Prevention, and Control of Fever and Skin Rash due to Viral Infections:** - Risk Factors: Lack of vaccination, close contact with infected individuals, travel to endemic regions, certain age groups (e.g., children, pregnant women) - Pathophysiology: Viral replication and invasion of host cells, immune response triggering inflammation, and systemic effects - Signs and Symptoms: Fever, skin rash, malaise, headache, joint pain, respiratory symptoms (vary depending on the specific virus) - Diagnosis: Clinical evaluation, physical examination, laboratory tests (serology, PCR), viral culture, and antigen detection tests - Management: Supportive care, antipyretics for fever, symptomatic relief, hydration, rest, antiviral medications (where available and appropriate) - Prevention and Control: Vaccination programs, public health measures (e.g., hygiene practices, mosquito control), outbreak surveillance, isolation and quarantine measures ### Drug treatment of malaria **Mechanism of action and pharmacological effects:** - Quinolines and related compounds (chloroquine, quinine/quinidine): - Mechanism of action: Inhibits the heme polymerase enzyme, leading to the accumulation of toxic heme metabolites in the parasite. - Pharmacological effects: Blood schizonticide (kills the asexual erythrocytic stages of the parasite). - Important pharmacokinetic features: Chloroquine has a large volume of distribution and extensive tissue binding and storage. - Therapeutic uses: Treatment of uncomplicated malaria caused by susceptible Plasmodium species. - Common adverse effects: Gastrointestinal symptoms, visual disturbances, retinopathy, and, in individuals with G6PD deficiency, hemolytic anemia. - Artemisinin compounds: - Mechanism of action: Generate highly reactive free radicals in the parasite. - Pharmacological effects: Rapidly acting blood schizonticide, particularly effective against multidrug-resistant strains. - Therapeutic uses: First-line treatment of uncomplicated falciparum malaria in combination with other antimalarials (artemisinin-based combination therapy). - Common adverse effects: Generally well-tolerated, but safety is not well-established in young children and pregnant women. - Fansidar (sulfadoxin + pyrimethamine): - Mechanism of action: Sulfadoxine inhibits dihydropteroate synthase, and pyrimethamine inhibits dihydrofolate reductase, both enzymes involved in folate synthesis in the parasite. - Pharmacological effects: Slow-acting blood schizonticide. - Therapeutic uses: Treatment of chloroquine-resistant P. falciparum malaria in combination with other antimalarials. - Common adverse effects: Adverse effects are mainly associated with the sulfonamide component and can include severe cutaneous reactions. - Tetracyclines/clindamycin: - Mechanism of action: Inhibition of protein synthesis in the parasite. - Pharmacological effects: Slow-acting blood schizonticide. - Therapeutic uses: Tetracycline is used in combination with quinine in cases of drug-resistant malaria. Clindamycin is used in children. - Common adverse effects: GI symptoms, photosensitivity. - Proguanil: - Mechanism of action: Unclear, but it is metabolized to cycloguanil, which inhibits dihydrofolate reductase. - Pharmacological effects: Slow-acting blood schizonticide, effective against primary liver forms. - Therapeutic uses: Used in combination with other drugs for multidrug-resistant falciparum malaria. - Common adverse effects: Generally well-tolerated. - Atovaquone: - Mechanism of action: Interferes with mitochondrial functions of the parasite. - Pharmacological effects: Antiparasitic activity similar to proguanil. - Therapeutic uses: Used in fixed-dose combination with proguanil for drug-resistant malaria. - Common adverse effects: Gastrointestinal symptoms, not recommended for children and pregnant women. - Primaquine: - Mechanism of action: Inhibits the respiratory processes in the parasite. - Pharmacological effects: Effective against primary and latent hepatic stages. - Therapeutic uses: Radical cure and prevention of relapse in P. vivax and P. ovale infections. - Common adverse effects: Gastrointestinal symptoms, contraindicated in individuals with G6PD deficiency. **Preferred drugs for the treatment and prophylaxis of malaria:** - Treatment of uncomplicated malaria caused by susceptible Plasmodium species: Artemisinin-based combination therapy (e.g., artemether-lumefantrine, artesunate-mefloquine). - Prophylaxis of malaria: Mefloquine, atovaquone-proguanil, doxycycline, or chloroquine (in areas with chloroquine-sensitive malaria). **Preferred drugs for the treatment of chloroquine-resistant and multidrug-resistant falciparum malaria:** - Artemisinin-based combination therapy (e.g., artemether-lumefantrine, artesunate-mefloquine). - Other options: Quinine + doxycycline/tetracycline, quinine + clindamycin, or atovaquone-proguanil. ### Innate immunity  **Components of Innate Immunity:** 1. Physical Barriers: Physical barriers, such as the skin and mucous membranes, serve as the first line of defense by preventing the entry of pathogens into the body. 2. Cellular Components: - Phagocytes: Phagocytes, including neutrophils and macrophages, engulf and destroy pathogens. - Natural Killer (NK) Cells: NK cells are responsible for recognizing and eliminating infected or abnormal cells, such as tumor cells. - Dendritic Cells: Dendritic cells capture antigens and present them to immune cells to initiate an adaptive immune response. 3. Chemical Barriers: - Antimicrobial Peptides: These small proteins have antimicrobial properties and can directly kill pathogens. - Complement System: The complement system consists of a group of proteins that work together to enhance the immune response, including opsonization (marking pathogens for phagocytosis), inflammation, and direct pathogen killing. 4. Pattern Recognition Receptors (PRRs): - PRRs are proteins expressed by cells of the innate immune system that recognize specific patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs). - PRRs include Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs). **Leukocyte Circulation:** - Leukocytes, also known as white blood cells, circulate throughout the body in the bloodstream and lymphatic system. - They are produced in the bone marrow and released into the bloodstream, where they can migrate to various tissues and organs to perform their functions. - Leukocytes can be categorized into granulocytes (neutrophils, eosinophils, basophils), monocytes (which differentiate into macrophages), and lymphocytes (including T cells, B cells, and NK cells). - Leukocyte circulation allows them to survey the body for pathogens and respond to infections or other immune challenges. **Types of Antigens:** - Antigens are substances that can induce an immune response. They are recognized by the immune system as foreign or non-self. - There are different types of antigens, including: - Pathogen-Derived Antigens: Antigens derived from microorganisms such as bacteria, viruses, fungi, and parasites. - Self-Antigens: Antigens derived from the body\'s own cells, which are typically tolerated by the immune system. - Allergens: Antigens that trigger an allergic response in susceptible individuals. - Autoantigens: Antigens derived from self-components that are mistakenly recognized as foreign, leading to autoimmune reactions. **Pattern Recognition Receptors (PRRs):** - PRRs are receptors expressed by cells of the innate immune system and are involved in recognizing specific patterns associated with pathogens (PAMPs). - Toll-like receptors (TLRs) are a prominent group of PRRs that recognize various PAMPs, such as bacterial lipopolysaccharides, viral nucleic acids, and fungal cell wall components. - NOD-like receptors (NLRs) recognize bacterial components and play a role in activating inflammatory responses and initiating antimicrobial defense. - RIG-I-like receptors (RLRs) are involved in detecting viral RNA and triggering antiviral immune responses. - PRRs play a crucial role in initiating innate immune responses by activating signaling pathways that lead to the production of inflammatory cytokines, antimicrobial molecules, and the recruitment of other immune cells to the site of infection. ### Adaptive immunity: Specificity- Immunology **Epitopes:** - Epitopes are specific regions or sites on antigens that are recognized by the immune system. - They can be linear, consisting of a continuous sequence of amino acids, or conformational, involving a specific three-dimensional structure. - Epitopes are crucial for the specific recognition of antigens by immune cells and the generation of an immune response. **Structure of MHC I and MHC II:** - Major Histocompatibility Complex (MHC) molecules are cell surface proteins involved in antigen presentation. - MHC I molecules are found on the surface of all nucleated cells. They present antigens derived from intracellular pathogens to CD8+ cytotoxic T cells. - MHC I molecules consist of a heavy chain and a small peptide called a peptide antigen. The peptide antigen is derived from proteins degraded within the cell. - MHC II molecules are mainly expressed on antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B cells. They present antigens derived from extracellular pathogens to CD4+ helper T cells. - MHC II molecules consist of two chains (alpha and beta) and bind to peptide antigens derived from exogenous antigens that have been engulfed, processed, and presented on the cell surface. **Antigen-Presenting Cells (APCs):** - APCs are specialized cells that capture, process, and present antigens to T cells. - Dendritic cells (DCs) are the most potent APCs and play a crucial role in initiating adaptive immune responses. - Macrophages and B cells also act as APCs. - APCs internalize antigens through phagocytosis or receptor-mediated endocytosis. The antigens are then processed into peptide fragments that are presented on MHC molecules for recognition by T cells. **Antigen Presentation and Recognition:** - Antigen presentation is the process by which antigenic peptides are displayed on the cell surface in association with MHC molecules. - MHC I presents antigens to CD8+ cytotoxic T cells, which recognize the antigen-MHC I complex through their T cell receptor (TCR). - MHC II presents antigens to CD4+ helper T cells, which recognize the antigen-MHC II complex through their TCR. - TCRs and B cell receptors (BCRs) are membrane-bound molecules on T cells and B cells, respectively, that specifically recognize antigens. - TCRs and BCRs are composed of variable regions that confer antigen specificity and constant regions that provide structural stability. **Co-stimulators and Co-inhibitors:** - Co-stimulatory and co-inhibitory molecules play a critical role in regulating immune responses and maintaining immune tolerance. - Co-stimulatory molecules, such as CD28 on T cells and CD80/CD86 on APCs, provide additional signals to promote T cell activation. - Co-inhibitory molecules, such as CTLA-4 and PD-1 on T cells, help regulate immune responses and prevent excessive activation. **Clonal Selection Theory:** - The clonal selection theory is a fundamental concept in immunology proposed by Frank Macfarlane Burnet. - According to this theory, the immune system contains a diverse population of lymphocytes (B cells and T cells) with different specificities for antigens. - When an antigen encounters a lymphocyte with a matching receptor (BCR or TCR), that lymphocyte is activated and undergoes clonal expansion, producing a large number of identical cells (clones) with the same antigen specificity. - The selected clones differentiate into effector cells that directly combat the antigen or into memory cells that provide long-term immunity. - The clonal selection theory explains how the immune system generates a specific and tailored response to diverse antigens. **Primary and Secondary Immune Response:** - The primary immune response is the initial immune response when the immune system encounters an antigen for the first time. - It takes time for the immune system to mount an effective response, and the production of specific antibodies or activated T cells gradually increases. - B cells undergo clonal selection, leading to the production of plasma cells that secrete antibodies. - T cells are activated, and cytotoxic T cells eliminate infected or abnormal cells. - The secondary immune response occurs upon re-exposure to the same antigen at a later time. - Memory B cells and memory T cells, generated during the primary response, rapidly recognize the antigen and initiate a faster and more robust immune response. - The secondary response leads to a higher antibody titer and a more rapid clearance of the antigen, providing long-term protection against the specific pathogen. ### Adaptive immunity- Diversity and Immunological tolerance **Importance of Immune Tolerance:** - Immune tolerance refers to the ability of the immune system to distinguish between self and non-self-antigens, thereby preventing unnecessary immune responses against the body\'s own tissues. - Immune tolerance is crucial for maintaining normal physiological functions and preventing autoimmune diseases, where the immune system mistakenly attacks self-antigens. - Without immune tolerance, the immune system would indiscriminately attack both foreign pathogens and healthy cells, leading to chronic inflammation, tissue damage, and autoimmune disorders. **Central Tolerance:** - Central tolerance refers to the mechanisms that occur during the development of immune cells in the central lymphoid organs (thymus for T cells and bone marrow for B cells) to eliminate or control self-reactive lymphocytes. - Positive Selection: In the thymus, developing T cells that can recognize self-MHC molecules are positively selected to ensure their ability to interact with MHC molecules and undergo further maturation. - Negative Selection: Self-reactive T cells that strongly recognize self-antigens presented by self-MHC molecules undergo negative selection, leading to their elimination or functional inactivation to prevent autoimmune responses. **Peripheral Tolerance:** - Peripheral tolerance mechanisms operate outside the central lymphoid organs and are responsible for maintaining self-tolerance in mature immune cells. - Anergy: Functional inactivation of self-reactive T cells or B cells upon encountering self-antigens in the absence of co-stimulatory signals. - Regulatory T cells (Tregs): Tregs are a specialized subset of T cells that suppress the activation of other immune cells, including self-reactive T cells, to maintain immune tolerance. - Peripheral deletion: Self-reactive lymphocytes that escape central tolerance mechanisms can be eliminated in the peripheral tissues by induction of apoptosis. **VDJ Recombination:** - VDJ recombination is a process that occurs during the development of B cells and T cells, allowing them to generate a diverse repertoire of antigen receptors. - VDJ recombination involves the rearrangement and recombination of gene segments encoding the variable regions of B cell receptors (BCRs) and T cell receptors (TCRs). - This process results in the generation of unique antigen receptor specificities in each individual lymphocyte, enhancing the ability of the immune system to recognize a wide range of potential antigens. **Consequences of Loss of Tolerance:** - Loss of immune tolerance can lead to the development of autoimmune diseases, where the immune system attacks and damages the body\'s own tissues. - Autoimmune diseases can affect various organs and systems, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes. - In autoimmune diseases, self-reactive immune cells escape tolerance mechanisms and mount inappropriate immune responses, leading to chronic inflammation, tissue destruction, and organ dysfunction. - Loss of tolerance can also result in allergies, where the immune system overreacts to harmless substances, such as pollen or certain foods, causing allergic reactions.