Hydrops Fetalis

• Parvovirus infection: B19 virus
• secondary to severe anemia
• may result in heart failure and hydrops
• excessive accumulation of fluid in the tissues of the fetus
• mother transfers to fetus (vertical transmission) 30% of time 

Requirements for an Antiviral Drug

• inhibit an essential viral enzyme or protein (Viral encoded DNA polymerase)
• inhibit pathway important to the virus but not the cell (interferon effect on protein synthesis)
• target is unique to virus
• minimal effect on host cells
• minimal toxic side effects

Treatable Viruses

• Herpes Simplex Virus
• Varicella zoster virus
• cytomegalovirus
• HIV
• Influenza viruses
• Respiratory Syncytial virus
• Hep B and C
• Poxviruses
• Lassa Fever

Mechanisms of Resistance

• high mutation rate in viruses
• mutation in active site of target: polymerase, thymidine kinase and protease
• mutation affecting binding site of drug (if different from active site)

Nucleotide Analogues

(Examples)

• Acyclovir: penciclovir, valacyclovir, famciclovir (HSV, VZV)
• Ganciclovir )CMV)
• Cidofovir
• Azidothymidine
• DDI, DDC, 3TC, d4t (HIV)
• Ribavirin (RSV, Hep C)

Acyclovir, Peniclovir

• activated by viral thymidine kinase (TK)
• inhibits viral DNA polymerase
• REsistance due to mutation of either DNA polymerase or Thymidine Kinase
• given for HSV??
• guanosine analogue

Ganciclovir

• activated by kinase for CMV (Thymidine kinase (TK) for HSV)
• inhibits viral DNA polymerase
• risistance due to mutation of DNA polymerase or Kinase
• Toxic (much more toxic than acyclovir or penciclovir)
• guanosine analogue

Ribavirin

• guanosine analogue
• promotes hypermutation of rNA viruses and 
•  inhibits G related activities (mRNA? capping)
• resistance: havent seen resistance yet
• Targets: RSV and HCV (w/ INF alpha)
• used to treat Lassa Fever
• has broad spectrum of action
• nasty toxic drug

Pyrimidine Nucleotide Analogues

• Anti-HIV: Azidothymidine (AZT), stavudine(d4t) and Lamivudine (3TC)
• AZT is thymidine and lamivudine is cytidine
• Anti-CMV, Anti Pox, Anti-BK/JC: cidofovir (cytidine)
• Anti-HCV (hep C): sofusbuvir (weird strange sugars/less toxic): NEW

Protease Inhibitors

• HCV (Hep C): Boceprevir, simprevir, and they used to use telaprevir
• HIV: saquinavir, ritonavir, indinavir, nelfinavir
• all HIV ones end in navir which means no virus

Amantadine and Rimantadine

• target virus: Influenza A not influenza B
• Target protein: M2 Channel
• prevents uncoating of virus
• prevents proper assembly (effect on HA structure)
• effective early treatment or prophylactic
• side effect is a mind altering substance (Blocks NMDA channel): makes depressed and high?
• has mostly been replaced with neuraminidase inhibitors

Oseltamivir (TAMIFLU)

and

Zanamivir (RELENZA)

• inhibitors of influenza neuraminidase
• works on both Influenza A and B
• must be given w/i 48 h of symptoms
• better than amantadine which only works on A

Pleconoril

• picornavirus inhibitor
• binds to cleft in capsid to prevent uncoating
• effective for rhinovirus, echovirus etc: echovirus 11 meningitis
• on the shelf but not used very often****

Immunomodulators

• Interferon and interferon induces
• Imiquimod (Aldara) and Resiquimod
• binds to toll like receptor (TLR) and activates dendritic and other cells (directly or indirectly)
• HPV
• HSV??
• side effect is flu like symptoms

Herpes Virus Groups 

• Alpha Herpesvirinae: Neurotropic site of latency, Lytic, Latent, recurrent, and Thymidine Kinase
• Gamma Herpesvirinae: Lymphotropic limited tropism, immortalizing
• Betaherpesvirinae: lympho/fibro/neurotropic; transcriptionally regulated, persistent infections

Triggers of HSV Recurrences 

• UV-b radiation (Skiing, tanning)
• Fever (hence the name fever blister)
• emotional stress (tests, big date)
• physical stress: irritation, menstruation
• foods: acidic, spicy, allergies
• immunesuppression: transient (stress-related), chemo-, radiotherapy and HIV

HSV-1 Diseases

• alpha herpes (simplex) virus)
• Primary Oral Herpes: Benign, but painful
• Reccurrence Herpes: same location, shorter duration
• Encephalitis: Usually HSV-1

HSV-2 Diseases

• alpha herpes (simplex) virus
• Genital Herpes
• Neonatal: Usually HSV-2 but 1 is worse if contracted
• can cause menigitis

Varicella Zoster Vrius (alpha Herpes)

Comparison

• VZV
• Properties like HSV: encodes thymidine kinase(TK), neurotropic, sensitive to same drugs as HSV
• Properties different from HSV: AEROSOL TRANSMISSION, viremia from lungs to skin (on T cells)   (etc), antibody more important for protection against it and LIVE VACCINE and VZIG
• harder to treat than HSV

VZV Primary Disease

• Varicella Zoster Virus (alpha herpes)
• Varicella/Chicken Pox
• benign in children
• severe in adults (Pneumonia)
• life threatening in immunocompromised

Reccurent VZV Disease

• Varicella Zoster Virus (alpha herpes)
• causes Zoster/Shingles
• usually an adult disease
• due to decreased specific immunity
• single dermatome spread
• post herpetic neuralgia (ouch)

Other Mononucleosis Syndromes 

• mono: excessive T cell numbers due to response to infection of white blood cells
• Heterophile antibody Negative mono: CMV, HIV and toxoplasmosis
• consequence: swollen nodes, spleen and liver
• fever, malaise

Enteroviruses

• type of picornavirus
• poliovruses
• coxsackievirus group A and B
• echoviruses
• enteroviruses
• all fecal oral route (polio could be oral oral)
• no animal reservoir**** (allows possible erradication)

Picornavirus Vaccine 

• Salk Vaccine (inactivated three polio virus serotypes)
• Sabin vaccine (attenuated live poliovirus)
• Hepatitis A vaccine available and in use
• pleconaril and other anti-viral drugs

Clinical manifestations

Type 1 Hypersensitivity

• Allergic Rhinitis, Sinusitis (Hay fever): increased mucus secretion; inflammation of upper airways, sinuses
• Food Allergies: increased peristalsis due to contraction of intestinal muscles
• Bronchial asthma: Bronchial hyper-responsiveness caused by smooth muscle contraction; inflammation and tissue injury caused by late phase reaction
• Anaphylaxis (drugs, food, bee sting): fall in blood pressue (shock) caused by vascular dilation; airway obstruction due to laryngeal edema

Diagnosis of Allergic Response

• Establish it is an allergic reaction: demonstracte elavation of serum tryptase and eosinophils in inflammatory exudate
• Define the cause of the allergic reaction: in vivo-skin testing or bronchial challange; in vitro - demonstrate specific IgE in serum
• ELISA can be used to detect IgE in serum (immobilized antigen and labled ligand)

Frustrated Phagocytes (tissue deposition of antibodies/complement activation)

Type II Hypersensitivity

• Pemphigus vulgaris: epidermal cadherin; antibody mediated activation of proteases and adhesion disruption; skin vesicles (bullae)
• Goodpasture's Syndrome: noncollagenous protein in BM of glomeruli and lung alveoli; complement and Fc receptor mediated inflammation; nephritis and lung hemorrhage
• Acute Rheumatic Fever: GAP cell wall antigen, antibody cross reacts w/ myocardial antigen; inflammation and macrophage activation; myocarditis and arthritis

Immune Cytopenias - AHA, ITP

• Type II hypersensitivity
• Autoimmune Hemolytic anemia: RBC membrane proteins (Rh blood group and I antigen); hemolysis, anemia
• Autoimmune (idiopathic) thrombocytopenic purpura: Platelet membrane proteins (gpIIb:IIIa integrin); bleeding
• both involve opsinization and phagocytosis in the spleen

Type II Hypersensitivity

(antibodies inc or block receptors)

• myasthenia gravis: ACh rec; inhibits binding; muscle weakness, paralysis
• Graves' disease (hyperthyroidism): thyroid stimulating hormone (TSH) receptor; antibody mediated stimulation of TSH rec; hyperthyroidism
• Pernicious anemia: intrinsic factor of gastric parietal cells; neutralizing of intrinsic factor, dec absorption of VB12; abnormal erythropoiesis, anemia

Systemic Autoimmune Diseases

• often Type III hypersensitivity Mechanism
• Systemic Lupus erythematosus: DNA, nucleoproteins: complement and Fc rec mediated inflammation: nephritis, arthitis and vasculitis
• Polyarteritis nodosa: Hep B virus surface antigen: vasculitis
• Post-strep glomerulonephritis: strep cell wall antigens: nephritis
• all the mechanisms are complenet and Fc mediated inflammation

Absence or loss of the spleen

• major impairment of the immune system
• red pulp of the spleen serves as a general filter for pathogens in the blood
• white pulp of the spleen contains approx. 25% of the mature lymphocytes and in its marginal zone, circulation antigens interact w/ APC, T and B cells to cause an immune reaction

Congenital Immune Deficiences

Frequency and screening evaluation

• Frequency of congenital immune deficiences
• Antibody deficiences - 50%
• T cell or combined B and T cell - 30%
• Innate Immune System defects - 20% (phagocytes > pattern recognition > complement)
• Cost effective preliminary evaluation
• CBC (number adn morphology of cells)
• serum immunoglobulin levels
• flow cytometry for T cells (CD3, 4 & 8), B cells (CD19) and N-K cells (CD16)

Management of Immune Deficiencies

• treat the cause of acquired immune deficiencts (eg HEART)
• no good management for innate immune system disorders, can manage acutely with transfusion
• most T cell deficiency states requires bone marrow transplant w/ its risk of graft vs host disease
• B cell deficency is often managed by administration of immunoglobulin: immune serum globulin (ISG) is given IM and used for specific infections, it has few side effects but has unreliable blood levels and is painful to recieve
• also for B cell def: IV Ig is given and is the usual management tool but it requires a prolonged administration and is expensive

Small Pox Differential Diagnosis

• Varicella (chickenpox): dense rash on the trunk and appearance in different stages
• Monkeypox: more lymphadenopathy
• Cowpox: lesion are localized and pustular 

Orf Virus Differential Diagnosis

• Tularemia and erysipeloid (associated w/ exposure to rabbits or sylvan rodents and swine respectively)
• Anthrax (associated w/ sheep and goats): anthrax usually has lots of edema, unlike the poxviruses

 Paramyxoviruses

• Morbillivirus: measles virus
• Rubulavirus: Mumps and parainfluenza virus (Types 2 and 4)
• Respirovirus: Parainfluenza viruses (types 1 and 3)
• Pneumovirus: respiratory syncytial virus and human metapneumoviruses

Immunity Thresholds for the Community

(measles and mumps)

• Measles: greater than 94%: 5% of population remains susceptible even after bing vaccinated; 10% if they do not recieve booster
• Mumps: greater than 86% 

Parainfluenza Virus Respiratory

Diseases

• paramyxovirus
• Bronchitis: inflammation of bronchial tubes
• bronchiolitis: inflammation of bronchioles (however, CSV is number 1 cause of this)
• Croup: laryngotracheitis; most common significant illness caused by PIV, accounts for 20-40% of all cases

Orthomyxovirus Envelope 

• Lipid bilayer derived from cell membrane
• viral envelope proteins:
• Hemagglutinin (HA) major virion glycoprotein; attachment to cell surface (essential for entry)
• Neuraminidase (NA) hydrolyzes sialicacid from glycoproteins and glycolipids (essential for exit)
• M2 protein: mediates release of viral RNA from tight forming protein complexes so that free RNA can migrate to the nucleus

Influenza Complications

(orthomyxoviruses)

• primary viral pneumonia occuring in the elderly or patients w/ cardiovascular or pulmonary disease; high mortality rate
• secondary bacterial pneumonia; especially S. pneumoniae, H. influenzae and staphylococcus speces
• Reye's syndrome (complication of given aspirin to a child with flu)

Antigenic Variation

(viruses)

• seen in influenza viruses (orthomyxovirus)
• Antigenic Drift: mutations w/i viral genome that alter antigenic determinants that allow virus to escape neutralization
• Antigenic Shift: appearance of new HA and NA subtypes; results from the co-infection of a cell w/ two HA subtypes and genetic reassortment

Flu Mist

• cold adapted live virus vaccine
• live mutant influenza viruses A and B that have several mutations in viral genes (polymerase components) such that they can only grow well at 25 F
• the genes for hemagglutinin and meuraminidase from the projected wild type viruses for the new year are reassorted into the mutant viruses
• results in a live attenuated vaccine that is given by nasal spray
• for ages 2 to 50

Random Autoimmune Mechanisms  

• incomplete clonal deletion of anti-self
• decreased immunosuppression
• polyclonal activation (EBV)
• cytokine storm after viral infection or superantigen (inappropriate activation of APCs and T cells)
• sex (more common in females than males)
• genetic predisposition: HLA and non HLA

MHC association w/ Autoimmunity

• Ankylosing spondylitis: HLA-B27: risk 90 fold 
• Rheumatoid Arthritis: HLA-DRB1*10/*04/*01: risk 4-12 fold
• Type 1 Diabetes mellitus: HLA-DRB1*0301/0401: risk 35 fold
• Pemphigus vulgaris: HLA-DR4: risk 14 fold

Antibodies and Disease

• systemic lupus Erythematosus: anti nuclear and anti DNA antibodies (same as most connective tissue diseases) 
• Vasculitis: anti-neutrophil cytoplasmic antibody (ANCA)
• CREST variant of scleroderma: anti centromere antibody

Autoimmune Hepatitis 

• 75% female, usually adolescent
• symptoms of other autoimmune diseases: hashimotos, PSS, diarrhea
• Type 1 - anti-smooth muscle Ab, ANA
• Type 2 - Anti liver kidney microsomes (Cyt P450D2)
• 10-15% have low titer AMA

Anti-Giladin Ab

• celiac diseas autoantibody
• gliadin is protein derived from gluten
• both IgG and IgA antibodies to gliadin are found in celieac disease
• convential wisdom: IgG assay more sensitive and IgA assay are more specific
• IgA deficiency occurs more frequently in celiac disease than in general population (4% in celiac disese)
• ELISA and Luminex Assays
• Deamidated Gliadin has been shown to be a more sensitive and specific antigenic target than unmodified gliadin

Tissue Transglutaminase (TTG)

• enzyme that can deamidate gliadin 
• the antigenic target of the anti-endomysial antibody
• ELISA and multiplex tests for anit TTG antibodies provide objectivity and both increased sensitivity and specificity when compared ot the anti-endomysial IFA test
• some evidence points to IgA anti TTG is the best single test for Celiac Disease 

Teratogen

• environmental agent which causes developmental defects directly on the fetus
• two well characterized viral teratogens are rubella virus (togavirus) and Cytomegalovirus (CMV) (Beta Herpes)

Toga and Flavivirus 

Vaccines

• Rubella virus vaccine;MMR;   live attenuated
• yellow fever virus vaccine; live attenuated
• Japanese B encephalitis virus vaccine; inactivated
• Easter and Western encephalitis virus vaccine: inactivated; available for horses and lab workes

Bunyaviridae Classifications

• Orthobunyaviruses: LaCrosse Virus
• Hantaviruses: Hantaan virus and Sin Nombre virus

Clinical Features to differentiate Hantavirus pulmonary infection from other acute resp illnesses

• Three clinical characteristics at admission: dizziness, nausea or vommiting and absence of cough
• Three initial laboratory abnormalities: low platelet count, low serum bicarbonate level, and elvated hematocrit level

Arenaviruses in the USA

Public Health 

• wash hands w/ soap and water after handling pet rodents
• never allow pet rodents to come into contact w/ wild rodents
• while pregant avoid contact w/ all rodents: Lymphocytic choriomeningitis virus (LCMV) may cause developmental defects in the fetus