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168 Cards in this Set
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Ways to confer immunity:
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Exposure to disease
Mother to fetus antibodies IG administration Vaccination |
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Live attenuated vaccines
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undergo some minimal replication in the body and may confer immunity with one dose (similar to a natural infection).
confers best immune response but not safe in all patients (immunocompromised) |
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Bacterial vaccines are generally.....
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killed whole bacteria or specific bacterial antigens or conjugates
Multiple doses of killed vaccines are required to induce long-lasting effective immunity. Additional doses (boosters) are usually required to maintain immunity for killed vaccines. Composition of killed vaccines can make a difference |
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vaccines are 1 of 2 different formulations
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Live attenuated or killed pathogens
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toxoids
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are inactivated bacterial toxins. They are usually combined with aluminum salts to enhance their antigenicity by prolonging antigen absorption and exposure. Toxoids stimulate the production of antibodies against the bacterial toxins rather than the infecting bacterial pathogens.
creating Igs to the toxin not the bacteria |
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Various factors affect response to vaccines
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Viability of the antigen (live vs. killed), interval between immunization doses, number of doses given, immunocompromised patients, site of injection.
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Active Immunity
(know) |
7-10 days to detect antibodies
Mostly permanent immunity Can be inhibited by passive immunity May not be as effective in immunocompromised Immunity generated by a natural immunologic response to an antigen. Vaccines can be live or killed. Simultaneous administration of inactivated vaccines along with immunoglobulins is not contraindicated; however, different sites of administration are recommended. (giving live vaccine + Igs can blunt the immune response of the vaccine) |
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Passive Immunity
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Acts immediately
Temporary immunity (days-weeks) Specific immune globulins target a specific pathogen Antibodies come from other human or animal sera Igs eventaully go away, they do not stimulate the body to produce its own exogenous Igs |
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Animal Antibodies
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Made by immunizing animals with an antigen and then harvesting the antibodies made against the antigens
Horses, cow, or rabbit taking the animal serum and pooling the Igs |
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Human Immunoglobulins
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Immune Sera
Sterile solution containing antibody derived from human (immunoglobulin) Human sera is preferred Lower incidence of serum sickness (Type III hypersensitivity reaction) and other allergic reactions lower incidence of delayed sensitivity reations |
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Serum Sickness
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Caused by foreign protein or serum
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Manufacturing of Igs
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Derived from donor pools of blood plasma and processed using cold ethanol fractionation to inactivate known potential pathogens
3,000-20,000 patients utilized to make one lot of Immune globulin Components > 90% IgG Trace amount of IgM, IgA, and other plasma proteins |
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Infectious Diseases Indications of Igs
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Induction of passive immunity
Temporary immunity to infection via the administration of antibodies not produced by the host |
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IgG Preparations for Infectious Diseases
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Concentrated immune globulin G (IgG) for human pathogens
High titers of pathogen-specific IgG from pools of plasma obtained from immunized donors Have high affinity for pathogenic antigens |
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Mechanism of Action for Prevention and Treatment of Infectious Diseases
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Use antibodies as drugs to neutralize and Eliminate Pathogenic or Toxic Molecules
Bind to the antigen and form antigen-antibody complexes Eliminated via reticuloendothelial system Antibodies as Drugs to Eliminate Target Cells Complement mediated cytotoxicity Antibody- Dependent Cell-mediated cytotoxicity |
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Complement mediated toxicity
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Antibody binds and lyses cell
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Antibody-dependent cell-mediated toxicity
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Target cell is affected by effector cell. Puts cytotoxic material into target cell. Kills pathogen.
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what part of the Ig is important for exogenouse Igs
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fab fargment (that is the top part/the v shaped part)
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Pharmacokinetics of Igs
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Vd
~ 5% of body weight Does not penetrate into all tissues (No cns) Half-life 18-32 days Varies due to half-life of IgG subclasses elimination: no adjustment of hepatic or renal function |
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IMIG
specific examples |
Hepatitis B
Varicella-Zoster Vaccinia Rabies Tetanus Rho(D) |
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IMIG
non-specific examples |
Non-Specific
Gamastan Gammar |
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IVIG
non-specific examples |
Polygam
Gammagard Gamimune Carimune Octagam Gamunex most hospitals carry these all Igs gathered from all patients |
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IVIG
specific examples |
RSV- IG
CMV – IG |
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Virus Antibody Activity: all have activity against
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Herpes types 1, 2, 6, and 7
Varicella zoster Epstein-Barr Measles, Mumps, Rubella Parvovirus B19 |
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Virus Antibody Activity:: some have activity against
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Adenovirus, Hepatitis, Saint Louis encephalitis, etc.
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Bacterial and Fungal Antibody Activity
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Bacteria (only common ones seen in the community)
Mycoplasma pneumonia Chlamydia pneumonia Helicobacter pylori Tetanus No real fungal or parasitic activity |
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Non-Specific IVIG Indications approved
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Primary immunodeficiency
Immune thrombocytopenic purpura (ITP) Chronic lymphocytic leukemia (CLL) Kawasaki disease Bone Marrow transplant NO ID |
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Non-Specific IVIG Indications off-label use
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Neonatal sepsis
Guillian-Barré Autoimmune diseases Intractable epilepsy Chronic inflammatory demyelinating polyneuropathy SLE |
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Igs Adjunctive to Antibiotics?
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IVIG in Streptococcal Toxic Shock Syndrome associated with Necrotizing Fasciitis
Strep releases exotoxins Release of cytokines, TNF IVIG Theory: Contains high titers of antibodies against strep exotoxins neutralize residual toxicogenic strep and mediators released by infection |
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do AB get rid of toxins already released in the body
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generally no, they only prevent the formation of new toxins released
so give IVIG to bind the toxins |
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SE of IMIG
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Injection site pain, tenderness, muscle stiffness
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SE of IVIG
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infusion reactions
Chills, fever, N/V, hypotension |
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management of the infusion related reactions associated with IVIG
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Slow infusion rate
Tylenol and Benadryl Give more fluid/co-infuse normal saline |
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17 yo male admitted with fever, SOB, N/V, Diarrhea x 3 days.
Temp 101.4, BP 63/40, HR 130, RR 20 Neck mass: 12.5 x 12.5 x 2.5 cm deep Biopsy showed Group A streptococci Developed hypotension, renal and hepatic failure, DIC, and rhabdomyolysis Pt underwent immediate surgical debridement how should this patient be treated |
Antibiotics
Clindamycin 900 mg q8h Ceftriaxone 1g q12h Ampicillin/Sulbactam 3g q6h Adjunctive IVIG therapy 0.5 g/kg/day x 2 days Patient’s wounds finally healed and he was eventually discharged |
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Se in general for IGs
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Arthralgias, myalgia, fever, pruritus, N/V, chest tightness, palpitations, diaphoresis, dizziness, pallor, respiratory distress
Anaphylaxis |
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Consequences of too much IgG
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Acute renal failure
Cryoglobulinemia Keep patient adequately hydrated Give less concentrated IVIG (e.g. 5% vs. 10%) Hematologic Cerebral and coronary thrombosis Acute hemolysis Neutropenia Neurologic Aseptic meningitis Dermatologic Eczema, urticaria, erythema multiforme, cutaneous vasculitis |
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what is the major SE of too much Ig (know)
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Acute renal failure
Cryoglobulinemia Keep patient adequately hydrated Give less concentrated IVIG (e.g. 5% vs. 10%) (less concentrated= more fluid) due to increase in protein and sugars in the product |
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Transmission of Infective Agents with Ig admin
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Immune globulin preparations are obtained from blood, so risk of infectious disease transmission is rare, but possible
A large outbreak of Hepatitis C infection occurred prior to 1994 and was associated with IVIG ? Prions, etc. |
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Vaccine and IG storage
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Generally kept refrigerated to prevent loss of potency
Some are stored frozen, but freezing can result in loss of potency product specific |
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IVIG Administration Stepwise Process
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Start at 0.6 ml/kg/hr x 30 min
If patient tolerates infusion, may increase to 1.2 ml/kg/hr x 30 min If patient tolerates, may increase to 2.4 ml/kg/hr x 30 min If patient tolerates, can increase to maximum rate of 4 ml/kg/hr until entire volume infused remember infusion related reactions are a problem so start slow and work your way up looking for fever, chills , hypotension |
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what has happened to the use of IVIG over the past 10 years
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greatly increased there are national shortages now so the patient may receive different products
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RC is a 24 year old male who works at Jack in the Box. His coworker and cook has just been diagnosed with Measles. RC is likely exposed to measles since he has been working closely with this coworker.
PMH: Has never received any vaccines All: None He presents to the ED asking if there is anything he should do to help prevent getting Measles. The pharmacy does not have any IG specific for measles, so the resident asked if what else he could give to help prevent disease. What would you recommend for RC? Measles Vaccine Measles immune globulin Non-specific immune globulin Non-Specific immune globulin + measles vaccine after passive immunity subsides Measles is generally self limiting, so no therapy is indicated |
Non-Specific immune globulin + measles vaccine after passive immunity subsides
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summary of Immunomodulators
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Immunomodulators play an important role in the prevention and treatment of some infectious diseases
Ig therapy is indicated for only a few disease states, but is commonly given for many off-label uses Efficacy and safety for treatment of infectious diseases has only been established in a few pathogens Ig therapy is not benign Ig therapy is very costly to the health care system and judicious use is necessary |
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Rabies Virology
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Class: Rhabdoviridae
Rod-shaped, single-stranded RNA virus Genus: Lyssavirus Species: Rabies |
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rabies epidemiology
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Animals affected
Dogs – 54% Wildlife – 42% Bats – 4% United States animals Disease has been mostly eliminated from domestic animals Mostly wild animals |
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rabies human infection refelcts.....
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Human rabies reflects local animal rabies infections
In developing countries rabies typically develops from dog bites In countries where dogs are immunized, most human cases result from exposure to rabid wild animals United States Over 20,000 raccoon rabies cases reported Bats |
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is rabies spread human to human
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nope
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mortality of rabies
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Uniformly fatal encephalitis in humans
Remains one of the most common viral causes of mortality in the developing world Almost 4 million people annually receive post-exposure treatment 55,000-100,000 persons die from rabies annually once get disease you die so post-exposure prophylaxis is huge |
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Pathogenesis of rabies
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Virus enters into the body
Usually from the saliva of an infected animal Typically through a break in the skin from a bite Mucosal surface or inhalation also possible mechanism of entry Virus replicates in muscle cells It then infects the nerves that innervate the muscle spindles and moves into the peripheral neurons Virus spreads via peripheral nerves to the spinal cord After reaching the spinal cord the virus spreads throughout the CNS replicates throughout the CNS that is why you go crazy |
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Clinical Manifestations of rabies
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Incubation period
Under 30 days (25%) 30-90 days (50%) 90 days-1 year (20%) > 1 year (5%) Prodrome and early symptoms (duration 2-10 days) Fever, headache, malaise, N/V, paresthesias or pain at the wound site minimun incubation of 10 days it dependson the severity of the bite and the concentration in the saliva |
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acute neurological disease (rabies)
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Acute neurological disease (Encephalitis)
(Duration 2-7 days) Furious rabies (80% of cases) Hallucinations, bizarre behavior, anxiety, agitation, biting, hydrophobia, autonomic dysfunction, SIADH Paralytic rabies (20% of cases) Ascending flaccid paralysis Coma and Death Death occurs an average of 18 days after onset of symptoms |
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what is one of the distinct clinical manifestations of rabies (know)
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hydrophobia
big fear of water, increase of ADH because they are dehydrated |
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diagnosis of rabies
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Signs and symptoms
Hydrophobia Post bite from rabid animal Cerebrospinal fluid Only abnormal in a minority, so usually not able to distinguish rabies virus CT or MRI of the brain Direct fluorescent antibody (DFA) Post-test of brain tissue only absolute way to determine if rabies or not is from the brain tissue |
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FK is a 25 year old male who presents to the UCH emergency department after being bitten by a raccoon.
PMH: non-contributory All: none Meds: none The medical resident is concerned about a possible rabies exposure and consults you for treatment recommendations How would you treat this patient? You can’t, it is too late Rabies Vaccine Rabies Immune Globulin Rabies Immune Globulin + Vaccine I don’t know |
Rabies Immune Globulin + Vaccine
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Prevention Pre-Exposure Prophylaxis of rabies
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Control of animal rabies
Dogs and cats are required (1 or 3 year vaccine) Livestock in areas of increasing rabies prevalence Select humans at high risk of exposure (get a prophylactic vaccine) Veterinarians Lab workers using rabies virus Spelunkers Travelers to areas of high dog rabies |
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Rabies Vaccine (Imovax, Rabavert, etc.)
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Intramuscular injection (1mL) on days 0, 7, and 21 or 28 (Total of 3 doses)
Booster doses every 2-3 years |
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Imovax ® ID rabies vaccine
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(3 doses)
Intradermal injection (0.1mL) on days 0, 7, and 21 or 28 Booster doses every 2 years |
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Post-Exposure Prophylaxis rabies
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Indicated
Persons exposed to a rabid animal either through a bite or contact with saliva Observation of the animal (typically domestic) If possible watch the animal for a minimum of 10 days If abnormal behavior observed, pathologic work-up is necessary |
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what is the 1st step in post-exposre rabies prophylaxis
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Treatment
Wound care - May reduce the risk of rabies by 90% Wash with soap Irrigate with iodine |
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treatment for post-exposre prophylaxis of rabies
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Rabies Immune Globulin (1 dose) (~$500/course)
Purified antirabies immunoglobulins from serum of hyperimmunized donors Dose = 20 IU/kg IM x 1 dose on day 0 Give entire dose into the wound area if anatomically possible, otherwise inject into gluteal region + Rabies Virus Vaccine (5 doses) 1 mL administered IM on days 0, 3, 7, 14, and 28 Administer in the deltoid muscle |
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Persons who have been previously vaccinated and have adequate antibody titers
of rabies how are they treated post exposre |
No immune globulin
Give two booster doses of vaccine Vaccine on days 0 and 3 |
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No established treatment for person with disease
because.... |
All patients infected with rabies will succumb to the disease or its complications despite excellent intensive care unit care, etc.
once the disease is in the brain it is 100% fatal |
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tetnus pathogen
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Clostridium tetani
Gram (+) anaerobic bacillus Spore forming Spores are stable in the environment Resistant to ethanol, etc. Found in soil, feces, IV drugs, etc. Not passed person to person |
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tetnus exotoxins
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Tetanospasmin (tetanus toxin)
The main toxin that causes disease. Potent and fatal at 2.5 ng/kg Tetanolysin only small amount of toxin is required to produce large effects |
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is tetnus spread human to human
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nope
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epidemiology of tetnus
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Global incidence
About 1 million cases per year Mortality (not as bad as rabies) 28 per 100,000 Neonatal deaths account for about 50% US incidence About 35-70 cases per year Mostly in persons > 40 or in persons not vaccinated or who have not gotten their booster vaccine within last 10 years Heroin injectors are an increasing population Mortality < 0.1 per 100,000 Acute injuries account for ~ 70% of cases Punctures or lacerations not a big problem in th eUS because of the vaccine |
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Pathogenesis of tetnus
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Person is infected with clostridium tetani
Typical entry is via wound Clostridium replicates and produces toxins (enters the NS) The tetanus toxin enters the nervous system and is carried to the brain stem and spinal cord Prevents neurotransmitter release from the presynaptic membrane (so cannot stop contracting muscle) Produces muscular rigidity and generates spasms Suppresses autonomic nervous system Hypersympathetic state, release of catecholamines Increased Temp, sweating, increased HR and BP |
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timeline of tetnus
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Incubation period
7-10 days (range 3 days-3 weeks) Onset of symptoms Last for about 2 weeks Recovery period About 1 month progressive |
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four clinical manifestations of tetanus
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Generalized (most common)
Localized Cephalic Neonatal |
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Generalized tetanus
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Most common form (80%)
Trismus (lockjaw) Masseter rigidity Risus sardonicus Increased tone in orbicularis oris (upper lip) Abdominal rigidity Generalized spasm (descending pattern) Posturing – flexion of the arms and extension of the legs Spinal and long bone fractures possible (because such intense contrations) Severe pain with each spasm Laryngospasm (vocal cords) – difficulty breathing Aspiration pneumonia |
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localized tetanus
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Rigidity of muscles at site of spore inoculation
Weakness and decreased muscle tone in most involved muscle near site of inoculation localized to the site of infection |
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Cephalic Tetanus
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Usually occurs following a head wound or otitis media via middle ear exposure to C.tetani
Affects the cranial nerve musculature Facial nerve weakness Extraocular muscle involvement |
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Neonatal Tetanus
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Post infection of the umbilical stump
Due to failure of aseptic technique Generalized weakness and failure to nurse Rigidity and spasms Mortality ~90% Apnea or sepsis are the leading causes of death Developmental delays occur in survivors Only 2 cases in US since 1989 highest mortality rate of tetanus |
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diagnosis of tetanus
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Clinical observation: most patients come in when at the stage of with the facial features being affected
Cannot culture C. tetani from wounds (only found in less than 30% of cases) A positive culture doesn’t mean the patient is infected with a toxin producing strain Positive culture may be present without causing disease in patient who are immunized c. tentani is very hard to culture adn if you do it may not be the strain that is toxic (so not really helpful to culture) |
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DJ is a 8 year old boy who fell off the swing set and cut his leg on a rusty bolt. The wound is fairly deep and may require stitches.
PMH: non-contributory All: None The mother comes into your pharmacy to buy some Band-Aids and asks you if you think she should take the boy to the doctor or if any additional treatment is necessary. What is your recommendation to the Mother? Wash out the wound and put Neosporin on it Depends on the child's vaccination history The boy needs an oral antibiotic No additional treatment is necessary |
Depends on the child's vaccination history
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Treatment (Patients who are actually Infected with tetanus)
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Clean the wound
Remove necrotic tissue Supportive care Airway and Ventilation Benzodiazepines (diazepam, lorazepam, etc) GABA agonists and indirectly antagonize the effects of the toxin Neuromuscular blockers (paralyze patient) Only if patients cannot be managed with benzodiazepines Magnesium infusions α- and β-Blockade Labetalol assists with autonomic dysfunction and excessive catecholamine release |
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can rabies be treated once the patient gets the disease
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nope
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AB and GTIG for tetanus
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Human tetanus immune globulin (HTIG)
500 units IM x 1 Effectively shortens the course of tetanus and lessens its severity Removes unbound toxin, prevents toxin from binding to nerve endings Antibiotics Metronidazole Improved survival, shorter hospitalization, less progression of disease Others: Penicillin, imipenem, doxycycline, etc. |
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tetanus prophylaxis
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Tetanus toxoid vaccine
Diphtheria-Tetanus toxoid vaccine (Td) Primary vaccination (3 doses) 0.5 ml IM at 0, 4-8 weeks, and then 6-12 months Patients younger than 7 (4 doses) Diphtheria-tetanus-pertussis vaccine (DTaP) 4 shots – 2, 4, 6, and 15-18 months of age All Patients - Booster vaccination Every 10 years (exposed or not) |
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Tetanus Vaccine Adverse Effects
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Local reactions
Erythema Pain at injection site Arthritis Systemic reactions High Fever N/V, stomach pain, headache ADRs more severe if high antibody titers already presents e.g. patients getting boosters earlier than 10 years from last vaccination |
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Post-Exposure Prophylaxis
things to consider |
Things to consider:
Clean minor wound vs. contaminated or major wounds Immunization history |
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vaccination history of tetanus and the actions to take
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Vaccination History
Unknown or < 3 dosesClean minor wounds: Td= yes HTIG= no All other wounds: Td= yes HTIG= yes 3+ doses Clean minor wounds Td= no (yes if >10 years) HTIG= no all other wounds Td= no (yes if > 5years) HTIG= no |
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guide to tetanus prophylaxis in wound managment
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Post-Exposure Prophylaxis Example for tetanus
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Patients with wounds that are:
Contaminated with dirt, saliva, or feces Puncture wounds Missile injuries, burns, frostbite, crush injuries PLUS No active immunization or none within the last 5 years if immunocompromised Must receive HTIG 500 IU + vaccination |
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You asked about the boys vaccination history
Mother states that he received all of his tetanus vaccine doses, with the last dose of the DTaP vaccination at 15 months of age What is your recommendation to Mom now? Wash out the wound and use Neosporin Give tetanus vaccine Give tetanus vaccine + immune globulin Give pre-emptive metronidazole therapy |
Give tetanus vaccine
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summary of tetanus and rabies
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Rabies is caused by a virus and causes a fatal encephalopathy
Pre-exposure prophylaxis for patients with high exposure risk Post-exposure prophylaxis is key for preventing disease Tetanus is caused by the bacteria C. tetani Manifestations are a result of the tetanus toxin All patients should received vaccination for tetanus Treatment involves symptom management and antibiotics active against C. tetani |
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what makes up a virus
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Nucleic acid (RNA versus DNA, etc)
Protein coat around the nucleic acid (capsid) (protects genetic material) a lipid envelope. (if don't have = naked) |
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Viral nucleic acid can be....
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SS + sense RNA (mRNA)
SS- sense RNA (complement mRNA) SS of DS DNA (double stranded DNA) Circular, linear, or segments encodes 3-300 proteins |
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1 viral kilobas encodes for ___ protein
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1
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viral capsid=
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protein coat
1 or 2 proteins that are repeated to conserve genetic material |
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examples of capsid shapes
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Helical
Icosahedral |
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viruses without an envelope is considered
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naked
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enveloped viruses
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Viruses acquire envelope from host (cytoplasmic, endoplasmic reticulum, or nuclear envelopes).
Into this envelope, the virus inserts viral proteins (e.g. hemagglutinin, neuraminidase for influenza), which are exposed on the surface of the virus. the virus inserts it's protiens in the envelope and they have a certain affinity to certain receptors in the body (tropism) |
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what does a viral envelope come from
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it is aquired from the host
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picture of viral envelope
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pic of viral envelope
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picture of viral envelope
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viral family orthomyxo
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example: influenza virus
ss-rna segemtns ~ 13 kb evvelope: yes capsid: helical |
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viral family
herper-viridae |
example: herpes simplex
ds dna linear ~200 Kb eveloped: yes capsid: icosahedral |
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Viral particles
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The delivery system protects the virus from the environment and attaches the virus to the target host cells (tropism).
(gives affinity for certain tissues) The payload contains the virus’ genetic information and a few enzymes necessary to initiate the first steps in replication. (contains genetic material and enzymes fro replication) |
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Viral Delivery System
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The delivery system is important for tropism and the mode of transmission.
Viruses with a lipid envelop are often destroyed when dried and are transmitted in secretions (respiratory, parenteral, sexual routes). (desrtoyed in air, so transmitted in secretions) Non-enveloped viruses (naked) can be designed to withstand harsher conditions and are often transmitted via the oral-fecal route. (GI, fecal/oral transmission0 Tells us how the virus is spread |
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Steps in Viral Infection of cell
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Attachment, Penetration, Disassembly, Transcription, Translation (makes viral proteins), Replication, Assembly, Release
Basic knowledge of these steps leads to development of antiviral drugs. |
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Receptor-mediated Attachment of viruses
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Helps determine which tissues will be infected (tropism)
Multiple interactions involved. Area of potential drug development. example: HIV glycoprotein binds to CD4 on T cells CCRS receptor is the secondary binding that allows for the delivery of the payload |
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what is the 1st step in a viral infection
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attachemtn
determines the cells that it is going to infect it may use multiple receptors |
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Penetration and disassembly of viruses
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Envelope fusion (HIV, measles virus)
Receptor-mediated endocytosis (influenza) (binds to the receptor which triggers the cell to endoytose the entire comlpex) delivery of the payload |
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3 life-cycle (survival) problems viruses must solve
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Reproduction in the host cell.
Copying its genetic material. Transcription (viral mRNA). Translation ( viral protein). - stopping the cell from making its own protiens to make viral proteins Spread to new hosts. Evasion of host defenses (at least long enough to replicate and spread). |
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Genetic material replication of viruses
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Many viruses use a viral enzyme to replicate genetic material.
Herpes brings its own kinase (TK) to generate nucleotides needed for viral genetic material synthesis. (when viruses deliver the payload they also deliver its own polymerase to synthasize its own DNA Major target for drugs… HIV Herpes virus Hepatitis B |
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Viruses encode proteins that cause cells ......
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cells to favor viral protein synthesis.
HIV tat programs CD4 cells to “turn on” and churn out viral genetic material and viral protein… |
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do viruses tend to infect large or small organs
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Tend to infect large organs with capacity for cell death
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Host-to-host spread
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critical for the life cycle
Large numbers of viruses can be spread via: Respiratory droplets, aerosols. Fecally contaminated food or water. Body fluids or tissue Blood Saliva Urine Semen, genital fluids Transplanted organ Mother’s milk Birth canal |
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viral spread via respiratory cells
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Inhaled viruses…infect the respiratory epithelial cells.
Common cold (multiple). Influenza. Measles. Small pox. Varicella. RSV Coronavirus (eg SARS). Etc, etc |
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what is the most common spread of viral infections
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respiratory epithilial cells
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viral spread through ingestion
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Ingested viruses [fecal-oral]…infect the epithelial cells in the small intestine.
Tend to have protein coat(s) that withstand acidic environment. Adenovirus Rotavirus Norovirus (Norwalk virus) ("cruise ship") Polio virus |
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viral spread through blood
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Blood borne viruses.
During birth Sex Sharing IV drug parephenalia Mosquitos and ticks Transfusions (rare nowadays) Hepatitis B. Hepatitis C. West Nile HIV |
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viral spread through sex
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Viruses we get from intimate contact...
Can be blood-borne or adherent to foreskin or vaginal epithelium. HIV (blood-borne). Herpes 1 and 2. Human Papilloma virus. aadhering to the epithlium can also be blood borne as well |
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Zoonoses
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Infection with a virus that has an animal as its natural host.
Ebola Hanta Virus Some Encephalitis’ Nipah, Hendra, and Menangle Typically not spread from person-to-person (“dead-end” infections). Can be fatal, as the virus’ natural reservoir is the animal. |
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Zoonoses can establish...
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establish humans as a new host.
The virus learns to spread from person-to-person. HIV Influenza |
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general host defenses against viruses: physical barriers
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Skin (dead cells).
Cilia (respiratory tract). Mucus. Antiviral compounds (e.g. natural proteases in saliva). Acid (stomach). decrease the innoculium |
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general host defenses against viruses: the innate immune system
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The innate immune system (common to all animals).
for cell-free virus: Professional phagocytes (e.g. macrophages). Complement (proteins that puncture viral membranes and “tag” viruses for ingestion). for intracellular virus Interferon (antiviral properties). Natural Killer Cells (kill viral-infected cells that display non-self protein on surface). |
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general host defenses against viruses:the adaptive immune system
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The adaptive immune system (specific and memory (long-acting)).
for cell-free virus B-cells and antibodies (“tagging for destruction” and “neutralization”) For intracellular virus Killer T-cells (kill virally infected cells that display specific viral protein fragments). activated when the innate is overwhelmed |
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Host defenses work in concert
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The “barrier” greatly reduces viral inoculums.
The innate system is the first immune response (rapid). It can “clean up” small inoculums, but will release “battle-cry” cytokines (eg TNF) if the infection looks more serious. These cytokine signals get the adaptive system involved. |
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how do vaccines work
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The “adaptive” immune system is the final blow for most viruses, and it protects the host from future infections with the same virus.
Vaccines attempt to take advantage of “adaptive” immunity to generate specific, long-acting protection against certain viruses. Long acting protection |
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Vaccines against viral disease
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Measles
Mumps Rubella Herpes (in trials) Varicella zoster (chicken pox) Small pox (vaccinia) – ended in 1970s Human papilloma virus (cervical cancer strains) Hepatitis A and B Rotavirus Yellow fever Rabies Influenza Polio virus Japanese encephalitis Tick-borne encephalitis |
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Viral Evasion strategies: hit and run
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“Hit and run” strategy… quickly infect, replicate, spread to other humans (and leave) before the adaptive immune system can kick in.
Rotavirus (enteric virus). Norovirus (“cruise-ship” enteric virus). Rhinovirus (common cold) Immunity to subsequent viral attacks may be weak because there is little adaptive immune response. quickly infects befor the adaptive immune system is able to kick in so do not get long term protections can get thi sinfection more than once |
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Viral Evasion strategies:: antigenic drift
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“Antigenic drift” or “bait and switch”… The virus continuously mutates its protein coat and evades the immune response (mainly RNA viruses).
HIV HCV typically RNA viruses because accumulate more mutations more quickly |
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Viral Evasion strategies trojan horse
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trojan horse” or “undercover”… virus hides in cells that do not alert the immune system…
Herpes HIV |
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Common cold (rhinovirus) problem 1 reproduction
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reproduction.
Brings a RNA polymerase (in payload) Viral RNA has special initiation sequence Reproduction within 8 hrs of infection |
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Common cold (rhinovirus) problem 2 spread
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Favors lower temp of nares (so gets trapped there and can be passed to next host)
Triggers sneeze/cough reflex |
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Common cold (rhinovirus) problem 3 evasion
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Spreads quickly, then surrenders.
hit and run |
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Common cold (rhinovirus)
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Problem 1 – reproduction.
Brings a RNA polymerase Viral RNA has special initiation sequence Reproduction within 8 hrs of infection Problem 2 – Spread. Favors lower temp of nares Triggers sneeze/cough reflex Problem 3 – evasion. Spreads quickly, then surrenders. |
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summary points about viruses
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Viruses are parasites that cannot replicate on their own: RNA or DNA a capsid an envelope.
They bind specific receptors, penetrate, replicate, assemble, release, and spread to other hosts. They must evade the host defenses (barrier, innate, and adaptive systems) long enough to do so. |
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Viral Disease and Pathogenesis in humans
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Entry in the host
Primary replication (where entered) Spread (fromprimary site to other sites depending on tropism) Cell and tissue affinity (tropism) Secondary replication Cell injury (cytolysis)…symptoms… (causes disease) Host immune response…symptoms… (causes disease) Persistence |
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Primary viral replication
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The virus may only replicate locally (primary).
Local examples: influenza, respiratory synsitial virus, rhinovirus, some enteric viruses, dermatological viruses. some viruses don't spread from primary site of infection |
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Secondary viral replication
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Secondary replication- spread to distant organs and sites to replicate.
Spread examples: measles and small pox enter in respiratory droplets (primary replication there) – then spreads to skin and other organs via blood. |
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Routes of viral Spread
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Viremia (throught the blood)
Lymphocytes/macrophages (catching a ride with the immune cells) cytomegalovirus, HIV, measles Nerves herpes simplex, rabies, encephalitis-causing viruses Blood and nerves Varicella-zoster virus |
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Tropism
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The affinity of a virus to infect a distinct group of cells in the host.
The availability of viral receptors Viral Enhancers (such as proteins that facilitate replication) active only in certain tissues Host factors: Age Nutrition Immune status Genetic predisposition |
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host factors that influence tropism
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Age
Nutrition Immune status Genetic predisposition |
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Varicella Zoster / Shingles route of spread
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primary infection (repiratory)-->blood-->endothelin (spleen, lymph)--> secondary site (skin)--> sensory nerves (where it hides)--> shingles
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Chronic viral infection:
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: Persistent shedding of virus for long periods of time.
Hepatitis B/C, HIV Can cause progressive and severe cell destruction (immune or viral-mediated) Evade immune system through “bait and switch” keeps shedding its coat and invading the immune system |
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Latent viral infection:
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Maintenance of the viral genome in the host cell ± viral replication.
Nerve, liver, lymphocytes/monocytes are preferred tissues. Evade immune system through “undercover” |
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Viruses and cancer
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Epstein Barr virus (EBV)
Burkitt’s lymphoma Hodgkin’s lymphoma Leiomyosarcoma Nasopharyngeal cancer HBV and HCV (liver) Human papilloma virus (cervix, anal, penile) Human herpes virus 8 (sarcoma) Human T-cell lymphotrophic virus I and II (leukemia) HIV (lymphoma’s) etc. |
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most viral infections are _____and ______ exccetp in _______
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asymptomatic
self-limiting immunocompromised |
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Human Herpes 8:
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Kaposi Sarcoma in immuno-suppressed
benign virus unless immunocompromised |
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Viral disease characteristics
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Most viral infections are asymptomatic and self-limiting in immune-competent hosts.
Immune-deficiency (HIV, transplant, old age) exaggerates viral illness. Severe re-activation of latent infections (CMV, VZV, herpes) Disease associated with usually innocuous virus (adenovirus, JC, BK) |
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Adenoviridae
(DNA) |
Adenovirus: 50 different strains causing colds, conjuctivitis GI....
Upper respiratory (50% subclinical) Organ transplantees: Hepatitis and hemorrhagic cystitis (fairly common) Cidofovir? |
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Herpesviridae (DNA)
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Herpes simplex I and II (HSV)
Varicella zoster virus (VZV) Cytomegalovirus (CMV) Epstein Barr virus (EBV) 9dont' treat) Herpes 6 and 7 (roseola infantum – 6th disease) (rash of infancy, high fever then gone, no treatment) ~100% seroprevalence at 5 years Herpes 8 – Kaposi’s Sarcoma opportunistic cancer 5% seroprevalence in USA (50% in subsaharan Africa) |
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Papoviridae (DNA)
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Warts (papilloma virus) – common, genital, plantar…
Strain 6, 11, 16 and 18 associated with genital and cancer (cervical – anal) Vaccine (2006) (targeting both boys and girls because protects against colon cancer too) Local therapy with tissue destruction (acids, cryotherapy), indirect action (imiquimod) |
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Parvovirus (DNA)
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Strain B19
In children causes 5th disease (slapped cheek disease) – >50% seroprevalence Immunosuppressed patients or those with high red cell turn over may experience severe RBC aplasia. Congenital exposure may cause fetal anemia IVIG affects RBCs so become very anemic |
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Polyomavirus (DNA)
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JC and BK virus
Widespread (~70%) and asymptomatic (latent infection established) Immunodeficiency: Severe progressive multifocal leukoencephalopathy (PML-JC in brain-fatal) (JC) and/or viruria w/ hemorrhagic cystitis (BK- in bladder in transplant patients). develops latent infections very common |
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many RNA viruses are arboviruses meaning?
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transmitted by arthropods, or by mouse vectors
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Bunyaviridae (RNA)
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Hantavirus – cardiopulmonary syndrome
4 corners region of USA (CO) Rodent vector (zoonoses) High mortality rate (~25%) from pulmonary edema several strains mice are the resivoirs |
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Calciviridae (RNA)
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Norwalk virus
Highly contagious gastroenteritis “Cruise ship” epidemics “Hit and run” virus…so multiple infections possible… (12 hours incubation--> sick--> over in 24-48 hours very hard to get rid of |
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Coronavirus (RNA)
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Common colds (~15% of all colds)
SARS (2002-2003) Probable zoonoses (cat?, dog?, bat?) New drug development |
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Filoviridae (RNA)
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Marburg virus and Ebola virus
Zoonoses (bats?, monkey?) Hemorrhagic fever 25% mortality (up to 75% depending on the strain) |
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Flaviviridae (RNA) – mosquito or tick vector
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Yellow fever
Vaccine (Nobel Prize 1930) Dengue Encephalitis Japanese (vaccine) St Louis Tick-borne (vaccine) West Nile virus (<1% CNS involvement) 90% of the time asymptomatic 1/50 fever and symptoms 1/100 encephlatitis |
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Paramyxoviridae (RNA)
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Measles virus (vaccine)
Mumps virus (vaccine) Respiratory Syncytial Virus (RSV) (in children constrictionof airways) bronchiolitis (aerosalized treatment) Parainfluenza virus Croup |
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Picornaviridae (RNA)
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Enteroviruses
Poliovirus (vaccine) Echoviruses (hemorrhagic conjunctivitis) naked virus most common and wide spread in the world all cause gastrointestinitis Coxsachieviruses 90% asymptomatic Rhinovirus – 50% of all common colds (World’s most popular virus) Plecanoril (rejected by FDA) – binds to capsid |
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Reovirus (RNA)
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Rotavirus
~100% exposure by 2-3 years of age Most important cause of gastroenteritis in kids Vaccine |
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incubation times
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ALMOST IMMEDIATE
Norovirus 1-2 days Coronovirus Rhinovirus Rotavirus infuenza Metapneumovirus parainfluenzaF a little less than a week Adenovirus SARS RSV Colorado tick fever Mosquito encephalitis West Nile Dengue 1 week Parvovirus B19 Marburg/Ebola Lassa Fever 2 weeks Smallpox Mumps Measles Hantavirus 2.5 weeks Rubella months Mononucleosis (EBV) Rabies Molluscum contagiosum papillomavirus |
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General viral treatment considerations
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Most viral infections are self-limiting and asymptomatic.
Immunocompromised patients at most risk for serious disease. |
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CIDOFOVIR (Cytosine nucleotide analog)
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Must be phosphorylated to triphosphate for activity
Blocks viral DNA synthesis (by blocking polymerases) “Broad spectrum” against DNA viruses?? Parenteral only Nephrotoxicity – dose limiting side effect Probenicid and hydration (decreases nephrotoxicity) |
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Interferon
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Approved for HCV
Depression and flu-like SE “Broad-spectrum” activity vs RNA viruses? has a lot of MOA |
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RIBAVIRIN (Guanosine RNA analogue)
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Inhibits synthesis of natural purine nucleotides (antiviral and immunomodulator)
Approved for Respiratory Syncytial Virus in children as inhaled drug and Hepatitis C with interferon- (PO) “broad spectrum for RNA viruses??” sometimes given intravenously for life-threatening RNA viral illness (Lassa fever, Hantavirus, measles hepatitis) Anemia is dose-limiting SE. |
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RIBAVIRIN (Guanosine RNA analogue) pregnancy category
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X
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Immunomodulators
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Passive immunization (usually prophylaxis)
Pooled immune globulin; hepatitis A, measles, parvovirus, enterovirus, etc? Pathogen-specific-immune globulins; (RSV, CMV, HBV, rabies, varicella) Palivizumab: humanized monoclonal antibody for RSV “Therapeutic” vaccines (for viruses with long latency)…eg rabies. Imiquimod (topical immune – cytokine – stimulator for warts) giving passive immunity |
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Antivirals
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Agents inhibit virus-specific steps.
Blockade of viral nucleic acid synthesis Of about 50 antivirals available, ½ are for HIV. “A compound is not an antiviral if it cannot cause viral resistance” In a pinch…DNA viruses might respond to cidofovir and RNA viruses might respond to interferon or ribavirin… gold standard for viral treatment blocking particular steps in viral replication |
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Drug Resistance and viruses
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High viral load
Infections with high/rapid turn-over Viruses with high genetic mutation rate (RNA versus DNA viruses) RNA is more common Immunosuppressed patient The degree/duration of selective pressure – increases with prolonged and repeated use. |
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Combination Antiviral Drug Therapy
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Increases overall antiviral activity
May allow decreased doses (lower toxicity) Multiple selective pressures on different parts of the replication cycle Standard of care for HIV and HCV May become more common for other viruses. |
