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1

Infectious Disease

Signs and symptoms resulting from destruction or damage which is directly attributed to a pathogenic organism; damage to other sources in the host that lead to an inflammatory pathway.
Pathogen: capacity to cause disease
-Principal, can cause infections in normally healthy hosts: E coli, Strep., Enterobacteriaceae (anything in gut), S. aureus.
-Opportunistic: Pneumocystis jirovecii (AIDS related HIV), TB,
Infectivity: ability to cause infection in susceptible host (s. aureus vs epidermitis)
Pathogenicity: ability to induce disease.
Virulence: a measure of severity of disease.

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Timeline

1. No infection or taking prophylaxis for an infection; at the time not actively infected.
2. Infection; pre-emptive stages of infection (early signs and symptoms of infection); assess for symptoms related to what type of infection.
3. Symptoms; Empiric therapy-evidence that this is the likely pathogen based on the presentation, symptoms, covering every pathogen you suspect being causative of infection rather than causing something very narrow, broad spectrum type of agents, where is it coming from, where does it reside and cause infection.
4, Pathogen Isolation; Definitive therapy; empiric therapy would be fine, would lead to collateral damage of treating other organisms that don't need to be treated, not pathogen of interest, limit damage important to public health and patient; narrow to most narrow spectrum active agent.
5. Resolution; suppressive therapy; can be lifelong or shorter period of time depending on infection.

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Non-specific indicators in infection

Fever: "Hallmark" of Infectious Disease; robust immune response, trying to kill the organism through temperature control; good that the patient is mounting an immune response.
Temperature control: Hypothalamus, temperature cycle; daily variations in temperature occur.
Increased temperature T greater than or equal to 100.4 F (38 C); caused by pyrogen such as Interleukins (IL-1, TNF-alpha-predominant acute cytokines related to bacterial pathogens, acute inflammatory response); cytokines and chemokine; other causes: autoimmune disease, drug induced (antibiotics, etc, fever around the dose of medication and does not resolve over the course of therapy).
Biomarkers for disease diagnosis and treatment response; understanding what inflammatory markers are, related to viral, bacterial or fungal pathogens; help decide what to treat with or if at all.

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Non-specific Indicators of Infection: Signs and Symptoms

Leukocytosis (leukocyte elevation); differential WBC: 5-10,500 cells/mm cubed-normal range.
Elevated immunoglobulins (non-specific antibodies related to your pathogen).
Physical Evidence: pain, swelling, inflammation, erythema (superficial reddening of the skin), tenderness, purulent drainage; interview with patient to assess non measurable symptoms.
Radiological evidence pneumonia or bone and joint infections; help predict what the response to therapy might be.

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Leukocytes

WBC
Do they have granules in the cytoplasm that can combat certain types of pathogens?
Agranular:
-Lymphocytes (20-25%): T cell, B cell, NK cell.
-Monocytes (3-8%)
Granular:
-Basophils (.5-1%)
-Neutrophils (60-70%)
-Eosinophils (2-4%)

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Macrophage/monocyte

Antigen presenting cell Surveillance of antigens that are presented to it.

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Neutrophils

Defense against bacteria and fungus; first responders.

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Eosinophils

Defense against parasites
Response agains allergic reactions

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Basophil

Allergic response

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B lymphocyte

Antibody production
Antigen presenting cell

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T lymphocyte

Cellular immunity against viruses and tumors
Regulation of the immune system

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Neutrophil response at presentation

Neutrophils are the most common type of WBC, ~70% of total.
Low neutrophil counts (<500 cells/mm cubed) increase risk of bacterial and fungal infection.
Response to bacterial/function infection.
First things see is fever, and increased immature neutrophils if bacterial and fungal infection; increased number of neutrophils that are responding to infection; immature=body is producing them to fight off the infection.
Segmented mature neutrophils; circulating normally in the body at 70% rate.
Banded immature neutrophils; shift over to these (nofsegmented neutrophil); left shift of neutrophils;percent goes up of these during infection process (5-20% increase).

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Host Defenses-Mechanical and Non-specific factors

-Skin and mucous membranes; primary means of prevention of infection; physical protection; provide effective barriers against microbes. Very few organisms can penetrate the skin; secrete lysozyme, IgA, prostatic spermine and mucociliary system-upper respiratory etc.
Prevent attachment and reproduction of bacteria and other organisms.
-Desquamation: epithelial cell turnover at body surfaces remove large numbers of adhering microbes. Skin conditions not ideal; dry, acidic, salt, temperature <37 C; prevents organism from establishing itself within host.
-Elimination; secretion of fluid, urine, sputum production; tearing, peristalsis, defecation, urination, etc.
-Acidity; skin and urine, the saliva, prevents pathogen attachment and infection; GI tract pH, urine etc., decreases pathogen ability to invade, e.g., TB, aspiration pneumonia; bacteria and fungal infections don't like this, prevent replication.
-Cytokines; hormone like polypeptides produced in response to invading microorganisms; trigger immune system; composition is independent of stimulating antigen; Inflammatory: IL-1, IL-6, IL-8, TNFalpha, etc.
Anti-inflammatory: IL-10 -Inflammatory biomarkers
Fever
-Innate immunity: provides immediate defense against infection; mediated by cells, proteins, and cytokines.
-Adaptive (cellular) immunity: combats pathogens that proliferate intracellularly; T lymphocytes, macrophages, and NK cells.
-Fever: temperature > or equal to 100.4 F (38 C): hypothalamus reaction to IL-1, TNF alpha interferon.

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Granulocytic cells

Granulocytic-phagocytes-leukocytes: consists of neutrophils, basophils, and eosinophils; characterized by granules in their cytoplasm.
Eosinophils (parasites)/basophils (allergic response): tissued based with limited phagocytic activity.
Neutrophils: most numerous WBC, travel by ameboid action and engulf bacteria at sites of infection; first at the site of infection followed by monocytes and macrophages.

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Cell-mediated immunity

-Macrophage: large bone marrow derived phagocytic cell; process and present antigens to lymphocytes.
-T lymphocytes: thymus derived lymphocytes involved in cell mediated immunity include:
Type 1 and 2 helper (Th) cells: initiate effector function.
Mediated by CD4 (T4) surface antigen; deficiency in CD4 associated with HIV/AIDS.
-Suppressor cells: suppress effector function; mediated by CD8 (T8) surface antigen.
-Cytotoxic lymphocytes: lyse cells.
-Chemotherapy, malignancy (Hodgkin's disease) reduce effectiveness of T8 cells...increasing risk of infection.

16

Innate Immunity: The Acute Inflammatory Response

Bacteria reproducing, releasing substances.
Damages tissue
Roll neutrophil, starts to adhere to blood vessels and get into tissue to engulf bacteria, binding event, LPS of GN bacteria, IL 1 and TNF alpha lead to this attachment, other attracting molecules like complement molecules, chemokine, histamine, prostaglandins, leukotrienes that lead to aggregation and activation of the neutrophil to the site of the pathogen.
Leads to engulfment of bacteria at specifics site and initial response, which leads initial activation of inflammatory and phagocytic process.
Inflammation; Pain, swilling , fever if systemic infection; leads to symptoms.

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Excessive Inflammatory Responses in Sepsis

Downside of infection effect or if you have a very virulent pathogen; can lead to over exaggeration of immune response.
Factors that bind and respond to bacteria; TLR responsible for initial recognition
TLR4; GN bacteria
TLR2: GP bacteria
Genetic mutations in patients; think about whether patients are more at risk because they have a genetic snip in these TLRs.
Dysregulation can lead to significant vasodilation and NO release, which can lead to detrimental effects, difficult to control.
Imbalance between pro and anti inflammatory cytokines that allow the pathogen to persist and prevents from host form responding appropriately in that fashion.

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Inflammatory mediators of infections and response

How do we differentiate between infection and other things going on?
Inflammation markers; typically non specific, so could be due to other inflammatory symptoms and not infection, but you combine with other symptoms to determine if it is an infection.
-C-reactive protein (CRP): NON-SPECIFIC, acute phase reactant, normal 0-1.0 mg/dl.
Binds to pathogen polysaccharides, activating the classical complement pathway.
Rapid half-life (14h)= rapid antibiotic response; good with long term infections so you can track it over time and see how effective your drug is.
-Erythrocyte Sedimentation Rate (ESR): NON-SPECIFIC measure of inflammation, normal 0-29 mm/hr.
Rate at which RBC settle in one hour.
Crude assay; not a lot of value, but ordered with CRP as a combined lab.
More non-specific than CRP; don't see a rapid recovery back to normalization that you would see with CRP; but some use in studies to track AB efficacy.
Slow response to infection convalescence.
-Procalcitonin
How we would effectively use AB; development in these biomarkers.
Precursor of the hormone calcitonin, normal 0-0.5 ng/ml.
Rapid response to bacterial infection; have a viral infection these marker should not be elevated; differentiating between bacterial and viral infection, respiratory disease; many are viral and not bacterial.
Now use this in CAP in the hospital setting; treat with AB or hold and wait and not treat with anything; rapid response when bacteria is cleared; nice way to rapidly track when you can discontinue or de escalate AB, more narrow or less potent.
Currently used to guide need for antibiotics in septic patients.
Also applied in outpatient setting; differentiate between bacterial and viral disease.
Also used to track bone and joint infections over a prolonged time; but when do we stop therapy in those patients; bacterial clearance or a non infected patients after prolonged weeks of AB.
A lot of potential uses.

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Specific Immune system Defense

Immunoglobulins
B-lymphocytes: derived from bone marrow produce the circulating antibodies termed immunoglobulins:
-IgG-circulatory, 75% of immunoglobulins
-IgA-bound to mucosal membranes, prevent bacterial adherence, account for 15%
-IgM-circulatory accounts for 10%
-IgD-0.2%; surface receptor on lymphocytes.
-IgE-0.004%-initiates allergic reaction.
Serology directed typically to IgG and IgM antibodies-most circulating immunoglobulins are IgG derived; IgA and IgM make up the majority of the rest.
FUNCTIONS:
Bind and fix complement: activates host defense.
Opsonization: C4a initiation; lead to rapid response in patient and neutralizing any effects of bacteria/virus.
Neutrophil activation
Call-free lysis
Develop specific antibodies
Neutralize toxins
Virus neutralization

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Making the Diagnosis

Clinical signs and symptoms
-General; fever, WBC, HR, BP; non specific.
-Site specific: localized inflammatory response (sputum production (resp disease), puss, redness (SSTI), pain-dysuria (UTI), coughing); imaging (X-rays-chest (pneumonia), sinuses, bone/joint for infection), CT scans (abscesses); track infections over long period of time, used in diagnosis and progression of pathogen clearance.
A normal functioning patient will have a robust immune response.
-Fever (vs normal of 37 C or 98.6 F)
Oral; 38 C (100.4 F) over at least 1 hour
Rectal temp; subtract 0.4C (0.8F)
Axillary temp; add 1 C (1.8 F)
Pattern not diagnostic, may be suggestive.
-Hypothermia is BAD; risk or mortality in CAP is as much with Tmax<35C (<95F) as >40C (>104F); keeping patients in normal range is an important thing.
Not normal immune function, AB augment robust response and help the patient, functioning immune system the patient is likely to have a positive outcome.
-WBCs: normal 5-10.5 x 10^3 cells/mcl
Lower in elderly and malnourished
Includes phagocytes and lymphocytes
Elevated WBC is a normal immune response to infection, may exceed 40.
WBC <3 is poor prognostic finding: pt already immunocompromised (from the drug), deranged immune response to overwhelming infection.
C diff colitis leads to excessive elevation in WBC.
Differential
-Phagocytes: Granulocytes
Neutrophils
PMN (45-73%) elevated in bacterial infection
Bands (3-5%) immature PMNs, >8-10% bands called a "left shift: and is suggestive of acute infection!
Neutropenia: severely immunocompromised; ANC < 500 at profound risk (<1,500 at increased risk); Absolute Neutrophil count= WBC x (% PMN + %Bands).
Eosinophils (0-4%) and Basophils (0-1%); elevated in allergic reactions, Eosinophils with parasitic infection.
-Phagocytes: Non-granulocytes; monocytes (2-8%) not sure what they do.
-Lymphocytes (20-40%)
T lymphocytes (T cells); CD4 (2/3) and CD8 (1/3)
B lymphocytes (B cells)
-Dramatically increased WBC, Lymphocytes seen in myeloproliferative states-may be functionally immunocompromised.
Organism Identification
-Serology (IgM, IgG) to specific organisms; correspond to a particualr infection can use as a diagnostic means in these patients.
-Sample of usually sterile site:
Blood, urine, tissue, CSF...
Gram or other stain for direct visualization
Culture for fastidious organisms
Specific identification methods; latex agglutination (for example, meningitis); Western Blot !!! ID if there is pathogen there and not stain it.

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Specimen and Culture collection

Proper collection and handling of specimen; junk-pathogen or culture?
Rapid test like MALDI-TOFF; Id thousands of organisms in one culture-contaminants, pathogen or something we need to disregard-things we never heard of; information only as good as user.
Specimen is collected into an appropriate holding or growth media.
Antibiotic removal or inactivation to allow organism to grow uninhibited.
Can lead to negative culture if AB treatment; ideally we want culture before treatment.

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Blood Culture

Severe infection or sepsis you would get a blood culture.
Systemic disease.
Don't exist in high quantities in the blood; don't have a lot of reserve for high pathogen in the bloodstream.
Takes time, delays in therapy and complications in patients.
Blood- two sets, 4 bottles total.
Each set: 1 aerobic and 1 aerobic bottle.
Aseptically prepare site; increase specificity by reducing contamination.
Collect adequate volume (increase sensitivity)
-75% sensitivity with 5 mL per bottle (20mL total)
-90-95% sensitivity with 8-10mL per bottle.
-97% sensitivity with 3 sets.
Draw from 2 sites (distinguish contaminates); 2 peripheral or 1 central and 1 peripheral.
Growth in 24-48 hours
-ID and sensitivity in another 24 h
24-48 to ID and categorize as S or R.
-Significant results:
-Potentially any organism esp GN, rapid sepsis.
-about 3% contamination rate, usually with skin flora especially CoNS (S. epidermidis), diphtheroids, etc., coryeniforms bacteria.
-May be true pathogen if in multiple bottles, patient is symptomatic, and foreign device in place.

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Urine Culture -Clean-Catch

Bacteriauria: 1bug/oil field=1-^5 bug/mL
100,000 cfu/mL is significant for Enterobacteriaceae in asymptomatic women
Lower threshold with other bugs, in men, with symptoms.
Pyuria: >5-10 WBC/HPF= 50-100 cells/mm cubed; lower threshold; WBC in urine
Leukocyte Esterase (released by WBC in the event of inflammatory process): Neg or TRace; S=+, M= ++, L= +++
Not specific for infection in urine, can be inflammation.
Dipstick 75-96% sensitive for pyuria.
Nitrite: bacterial metabolism byproduct; + in the present of Enterbacteriaceae (UTI due to GN organism)
Inflamamtion in the urine and what pathogens; consistent with the amount of organism with infection?
Can be contaminated, but an infection?
Ecoli=UTI

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Cerebrospinal Fluid (CSF)

-Bacterial Meningitis; acute infection processes.
-increased WBC to 1000-5000/ mm cubed (normally NONE!!!) with greater than or equal to 80% neutrophils
-Increase protein to 100-500 mg/dL; protein leaks into CSF bc of inflammation
-Decrease glucose to <40 mg/dL; bacteria take glucose and metabolize and leaky tissues can lead to changes in CSF glucose over time.
-Gram Stain positive in 60-90% as long as no AB before culture.
-Culture positive in 70-85%; can grow organism form CSF as far as trying to treat.
-Bacterial Antigen Detected 50-100%
-Latex Agglutination

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Respiratory Cultures

Sputum-hihgly controversial; cough up something as deep as they can; junk in sample.
Good sample if:
- >25 PMN cells and immature neutrophils in sample and <10 squamous epithelial cell
>10 WBC/ squamous epithelial cell.
Yield 29-90% for hospitalized patients; 50-60% sensitivity and >80% specificity for pneumococcal pneumonia.
Very low yield because of condition; low sensitivity but can have good specificity especially for patients for community into hospital.
Trachea aspirate slightly better but invasive; would give higher sensitivity and specificity, but can present risks.
-Bronchial-Alveolar Lavage (BAL); fluid culture from alveoli.
Invasive; 13-18% ventialted patients get hypoxic
Lavage-wash 100 million alveoli; >10^4 (10,000) CFU/mL significant, some use 10^5.
Brush-protected, samples 10-20 million alveoli; >10^3 (1000) CFU/mL significant.
Sensitivity 91%, Sepcificty 78-100%
Positive predictive value 83%, NPV 87%.

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Outcomes in pneumonia with Invasive vs non-invasive Culture Methods

Mixed data
Some good, some not a lot of value
Overall: numebrs trend positive
Noninvasive (sputum culture) and more invasive managemtn.
Can reduce AB adminsitration
AB treatment days; easier ID and tailor down effectively.
Overall outcomes not that different, small markers change but not large differences.
Non invasive can have impact, but not overall change in overall outcome.
Studies need to be done to determine most useful technique in patients.

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Point of care testing for infectious disease: opportunities, barriers, and considerations in community pharmacy.

Lessen inappropriate AB use; segregate patients that don't need to be treated.
Reduce transmission
Monitor population exposure to infectious agent (Hepatits or influenza).
Challenges:
Lack specific training
Regulatory variability and vagueness; what happens here is not the same everywhere as far as what pharmacists can do.
You may want to do it; CVS not; limited implementation of services.