W2P2 Flashcards
Define Systemic Autoimmune Rheumatic Diseases
A disease resulting form a disordered* immune reaction in which there is an antibody or cell mediated attack against one’s own tissues.
What clues about SLE are revealed by determining WHICH organs are affected?
- Confirmation: the potential presence of an autoimmune disease
- Diagnosis: Which auto-immune disease it is
- Prognosis: The severity of the problem
What are some systemic symptoms that signal a potential autoimmunity
Weight loss
Poor appetite
Fever
… these are quite vague and could be associated with anything.
What are some non-specific signs and symptoms of Autoimmunity?
Raynaud’s: hyper-reactivity of blood vessels. They turn white, then blue, then red as they get re-vascularized
Sicca: dry eyes and dry mouth
Diffuse lymphadenopathy
Certain manifestations that are highly associated with Autoimmunity
- Arthritis
- Certain types of skin rashes
- Mucosal ulcers
- Ocular symptoms
- Lung involvement
- Renal dysfunction
- Peripheral nerve defect
What are examples of general laboratory tests when you suspect AID
- CBC
- Renal Function Test (Creatinine)
- Liver function tests
- Urine Analysis
- Urine protein measurement
What are some examples of laboratory tests for “inflammation”
these are very non-specific
They would be elevated in
- inflammation of any cause
- infection
- cancer
some examples?
- Erythrocyte Sedimentation Rate (ESR)
- C-reactive protein (CRP)
What is an Auto-Antibody Test
- limitations
An antibody that an organism produces against any of its own tissues, cells, or cell components
found in association with many autoimmune disease
LIMITATIONS:
- their presence does NOT guarantee that there is an autoimmune disease (false positive, false negative)
- does not correlate to disease severity
Best way to diagnose and give prognosis for AID
Through tissue biopsy
- the presence of immune cells or immune complex deposits can confirm that the process is auto-immune
What are the four types of autoimmune rheumatic diseases
- Connective Tissue Diseases
- Inflammatory Arthropathies
- Inflammatory Myositis
- Systemic Vasculitis
What are some examples of Connective Tissue Diseases
Systemic Lupus Erythematosus (SLE)
Scleroderma (limited or diffuse)
Sjogren’s Syndrome
Mixed Connective Tissue Disease (MCTD)
Define Scleroderma
- types
- common signs
- which organs are most affected
Autoimmune disease (CT type) characterized by uncontrolled severe fibrosis of the skin, blood vessels and other affected organs
Types:
diffuse or limited (CREST syndrome)
Most patients have Raynaud’s and a positive ANA
organs most affected: Skin, lungs, blood vessels, GI tract, kidneys
the fibrosis makes their skin thick i.e. they aren’y able to flex their fingers or lips
Sjogren’s Syndrome
- common manifestations
- associated markers
- common body parts it affects
Autoimmune disease which mainly affects the exocrine glands
Manifests as dry mouth (Xerostomia) and dry eyes (Xerophthalmia) also called Sicca symptoms
Associated with the anti-Ro (SSa) and anti-La (SSb) autoantibodies
Can also affect the joints, lung, kidneys, CNS..
Mixed CT Disease
Autoimmune disease with manifestations normally seen in 3 other autoimmune diseases:
- SLE
- Scleroderma
- Inflammatory myositis
Raynaud’s and lung involvement are common
Associated with the anti-RNP antibody
SLE
Systemic
Lupus
Erythematosus
A systemic autoimmune disease affecting primarily young women of child-bearing age, and characterized by immune complex deposition in the affected organs
F:M = 9:1
incidence is greater in ages below 50
What is the gold standard for SLE (and other autoimmune diseases) for making a clinical diagnosis?
It is the “expert opinion” of the clinician based on the presence of clinical signs and symptoms and supported by the presence of appropriate diagnostic tests.
SLE clinical manifestations
- Cutaneous Manifestations
- Mucosal Ulcers
- Arthritis
- Lupus Nephritis
- Serositis
- Hematological problems
- Autoantibodies
Lupus: Cutaneous Involvement
Acute LE
Subacute LE
Chronic LE
Acute LE cutaneous examples
Generalized and Localized (Malar)
Malar Rash
- Butterfly distribution
- Spares nasolabial folds
- Photosensitive (caused by UV light exposure)
- Induration and edema
- Non-scaring
Subacute Cutaneous Lupus Erythematosus (SCLE)
There are two forms:
- Annular
- Papulosquamous
Characteristics:
- Photosensitive
- Scaly
- Non-scaring
Discoid Lupus Erthematosus (DLE) = chronic form
- Involvement of the deeper layer of the skin (dermis)
- Alopecia
- Depigmentation
- Scarring
Muscosal Ulcers
Oral, Nasal, genital
Painful or painless
Difficult to differentiate from aphthous ulcers
May come in clusters, be larger or last longer
Arthritis in SLE
Most SLE patients have musculoskeletal involvement
Inflammatory Arthritis
- Jacoud’s arthropathy
- Erosive polyarthritis
Arthralgias, osteonecrosis, osteoporosis, fibromyalgia…
Jacoud’s Arthropathy
Tendons are more affected
you’d see deformities
They are fixed if you pull on the finger, the deformity will not change. Vs in lupus you can put it back because it is the TENDONS and NOT the joints that are affected.
Lupus Nephritis
Up to 60% of SLE patients will develop
nephritis over their disease course
Major cause of long-term morbidity and mortality
All lupus patients should be monitored on a regular basis with:
Renal functions
Urine analysis
Urine protein quantification
Renal biopsy is essential for accurate diagnosis and prognosis
Lupus Serositis
It is inflammation of the serous tissues of the body, the tissues lining the lungs (pleura), heart (pericardium), and the inner lining of the abdomen (peritoneum) and organs within.
more common: Pleuritis and Pericarditis
- Pleuritic chest pain
- Shortness of breath
very rare: Peritonitis
- Diffuse abdominal pain
Hematological Involvement in Lupus
Anemia - Hemolytic - Chronic disease Thrombocytopenia - ITP - Rarely TTP Leuko- and lymphopenia - Rarely see infections
Auto-Antibodies in SLE
ANA: Antinuclear Antibodies
used for screening
all of lupus pts have ANA
using the conjugated anti-human immunoglobulin fluorescence
must use when you have reason to be suspicious of it because people without lupus also have ANA, so you can get a false positive
you can have different patterns (peripheral, diffuse, speckled, nuclear) and they indicate specific diseases
Notable Extractable Nuclear Antigens
Anti Sm: common in lupus but NOT in any other of the types of AID so it is diagnostic for lupus
Antiphospholipids Antibodies
- what are the three types
Increased the risk of thrombosis
Arterial or venous thrombosis
Obstetrical events
Commonly found in SLE patients (25%)
Can be found in non-SLE patients
Primary anti-phospholipid syndrome
Three types:
- Anticardioipins
- Lupus Anticoagulant
- Anti Beta-2 Glycoprotein-1
What are Autocoids?
- What are some examples of Autocoids?
Autacoidsare biological factors which act like localhormones, have a brief duration, and act near the site of synthesis.
histamine serotonin endogenous peptides prostaglandins leukotrienes
Histamine Release process:
- Describe the TWO types
Immunologic Release:
The most important mechanism for histamine release is in response to an immunological stimulus.
In mast cells, if sensitized by surface IgE, degranulate when exposed specific antigen.
Degranulation means liberation of the contents of the mast cell granules, including histamine.
Degranulation is involved in the immediate (type I) allergic reaction.
Mechanical/Chemical Release:
- released following injury to mast cells, the injury itself causes degranulation
What are the Types of Histamine Receptors?
H1 – Gq-coupled to phospholipase C (PLC)
H2 – Gs-coupled to adenylyl cyclase (AC)
H3
H4
Distribution and function of H1 Receptor?
H1 – Smooth muscle, endothelium, CNS.
Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness.
DIstribution and Function of H2 receptors
H2 – gastric parietal cells, vascular smooth muscle cells, basophils.
Regulate gastric acid secretion, vasodilation, inhibition of IgE-dependent degranulation
What are the physiological actions of Histamine
Primary stimulant for gastric acid and pepsin secretion (H2, acid secretion is enhanced by gastrin and vagal stimulation)
Has a role as a neurotransmitter (H3) (both in the CNS and peripheral sites)
Pathophysiological Actions of Histamine
Cellular mediator of immediate hypersensitivity reaction and acute inflammatory response
Anaphylaxis
Seasonal allergies (asthma?)
Duodenal ulcers
Systemic mastocytosis (mast cell disease, a myeloproliferative neoplasm)
Gastrinoma (Zollinger-Ellison Syndrome)
What are some clinical symptoms associated with Histamine Release for
mild
moderate
severe/anaphylactic
MILD: erythema, urticaria (hives), and/or itching
MODERATE: skin reactions, tachycardia, dysrhythmias, moderate hypotension, mild respiratory distress
ANAPHYLACTIC: severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest
Three therapeutic uses of anti-histamines
- Allergic Reactions
- Motion Sickness: Vestibular disturbances
- Sedation and hypnotics
What are some first generation antihistamine examples
These are H1r blockers, but not fully specific
Ethanolamines: DIPHENHYDRAMINE (Benadryl)
CLEMASTINE
Ethylenediamine: TRIPELENNAMINE
Alkylamine: CHLORPHENIRAMINE
Phenothiazine: PROMETHAZINE Piperazines: HYDROXYZINE, MECLIZINE, CYCLIZINE
First Generation Agents
What are they used to treat
Adjunctive in anaphylaxis and other cases where histamine release can occur (H2-antagonist, and epinephrine must also be used in anaphylaxis)
Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis)
Sedative/sleep aid
To prevent motion sickness (meclizine, cyclizine)
First generation antihistamines, what are the side effects/effects
Sedation (paradoxical excitation in children) Dizziness Fatigue Tachydysrhythmias in overdose - rare Allergic reactions with topical use Peripheral anti-muscarinic effects Dry mouth Blurred vision Constipation Urinary Retention
Benadryl
This is a type of first generation antihistamine- blocks H1
it is a POTENT ANTICHOLINERGIC
Ethanolamines*
also used for motion sickness?
First gen anti H1 potentiate what?
CNS depressants opioids sedatives general and narcotic analgesics alcohol
Absorption of First Gen H1 blockers
Well-absorbed from the GI-tract
Widely distributed
Cross BBB
Placental transfer
Hepatic transformation, renal elimination of the metabolites (induce hepatic microsomal enzymes)
Uses of Second gen anti Histamines
- what is the key difference between second vs first gen?
antiallergy only lol
second gen does NOT cross BBB
In general, much lower incidence of adverse effects than the first generation agents.
Which second gen anti-Hist. were removed from the market?
Terfenadine (Seldane) and Astemizole (Hismanal) were removed from the market due to effects on cardiac K+ channels - prolong QT interval (potentially fatal arrhythmia “torsades de pointes”)
Examples of second gen anti-hist
Allegra, Claritin, intranasal spray
P450 drug interactions
3 considerations
- Substrate: Is the drug metabolized via a specific hepatic isoenzyme?
- Inhibitor: does a specific drug inhibit a specific hepatic isoenzyme?
- Would expect this to interfere with drug inactivation - Inducer: does a specific drug enhance a specific hepatic isoenzyme?
Would expect this to speed up drug inactivation
Whats an examples of a P450 inhibitor?
grapefruit*
erythromycin
What is an example P450 inducer?
Ethanol, smoking
Cetirizine
Second Generation antiHIST
Cetirizine appears to have more CNS actions (sedative) than fexofenadine or loratadine- it is recommended that cetirizine not be used by pilots.
What receptor do second gen anti-histamines inhibit?
H1
both first gen and second gen are H1 inhibitors
Examples of H2 receptor blockers
H2 Receptor Antagonists (Ranitidine, Cimetidine)
Secondary or Associated Immunodeficiencies
Focus is on hereditary disorders in which immunological abnormalities occur within a group of associated features - part of a syndrome.
DiGeorge Syndrome
- What chromosomal abnormality?
- What features?
Deletion 22q11
Dysmorphic features
- Telecanthus (lateral displacement of eye)
- Puffy eyelids
- Wide and prominent nasal bridge and root
- Small mouth
What are some presentations of DiGeorge syndrome
*****Thymus hypoplasia: immune deficiency
Parathyroid hypoplasia: hypocalcemia
Malformations: Cleft palate, kidney
Heart malformations (75%): tetralogy of Fallot, most frequent; ventricular septal defect and interrupted aortic arch
Developmental delay
Psychiatric disorders in adulthood: schizophrenia, anxiety, depression
Thymic Hypoplasia
Failure in development of 3rd and 4th pharyngeal pouches
Variable loss of T cell mediated Immunity
Recurrent infection sin DiGeorge syndrome
- Overall incidence 77%
- CHD, hypocalcemia manifest in neonatal period
- Recurrent infections later but a major problem, impt. cause of later mortality
- Increased susceptibility to infections caused by organisms typically assoc. with T-cell dysfunction: systemic fungal infections, pneumocystis (carinii), disseminated viral infections
Autoimmune disease such as autoimmune cytopenia, thrombocytopenia, and juvenile rheumatoid arthritis
Autoimmune thyroid disease, autoimmune uveitis, and selective IgA deficiency may occur
Severe eczemaand asthma
What test would you order to diagnose DiGeorge Syndrome
FISH analysis of a deletion
Fluorescence In Situ Hybridization
- pts DNA competes with control DNA
equal light = normal
high control = pt loss dna
high pt = pt gain dna
What type of deletion syndrome is DiGeorge
It is a Contiguous Gene Deletion Syndrome
What’s another well known microdeletion syndrome
Williams: deletion of chromosome 7
Diagnosis and management for DiGeorge Syndrome
Follow up with investigations of affected persons:
- Work up for cardiac malformations, calcium and parathyroid status, immune function, renal anomalies
- Early intervention programs for devel delay, ADHD etc
- Monitor for psychiatric disease (schizophrenia-like episodes in adult life)
Which is the most frequent hereditary systemic autoinflammatory Syndrome?
Familial Mediterranean Fever
Familial Mediterranean Fever
- Most frequent hereditary systemic autoinflammatory syndrome
- Recurrent attacks of fever, peritonitis, pleurisy, painful, swollen joints (arthralgia and occasionally arthritis), and a characteristic ankle rash, 24 – 72 hrs
- Symptoms and severity vary among affected individuals, sometimes even among members of the same family
- Amyloidosis, which can lead to renal failure, is the most severe complication
What is the most severe complication of Familial Mediterranean Fever
Amyloidosis, (is a rare disease that occurs when an abnormal protein, called amyloid, builds up in your organs and interferes with their normal function)
which can lead to renal failure, is the most severe complication
What is the most characteristic presentation of Familial Mediterranean Fever?
Ankle Rash, 24-72 hours
What is the clinical course of Familial Mediterranean Fever
80 - 90% patients experience 1st episode by age 20
The type of attack - whether abdominal, pleural or arthritic - may also vary over time.
Between attacks, symptom-free
Symptoms mimic many common acquired disorders such as infections, acute appendicitis, cholecystitis, and arthritis
Diagnosis can be delayed many years, subject patients to extensive evaluations, unnecessary surgery
What causes Familial MEditerranean FeVer
MEFV gene mutations
locus is at 16p13.3
What do you know about Pyrin
The MEFV gene codes for pyrin
- Normal function is to assist in controlling inflammation by inhibiting the inflammasome
- Mutated pyrin inappropriate or prolonged inflammatory response
- Dysregulation of inflammasome involved in several autoinflammatory and autoimmune diseases
- Cryopyrin‐associated periodic fever syndrome
- Familial Mediterranean fever***
- Rheumatoid arthritis
- Systemic lupus erythematosus
Inheritance pattern of FMF
Familial Mediterranean Fever
Most cases autosomal recessive (AR)
Why is the mutated MEFV gene frequency higher amoung certain groups?
if an affected individual happens to be a part of a small group of people who migrate, they now realtively make up a sig proportion of that population in the new area
in bredding = increased risk of that gene mutation being passed on
Why would mutated gene prevalence persist in large populations?
High frequency of deleterious alleles may be explained by heterozygote advantage – increased resistance to disease. Some examples:
anemias (sickle cells, thalassemia) = malaria resistance
Diagnosis of FMF
DIFFICULT
Yes, there is genetic testing, but
Still based on symptoms and physical exam
Suspected in children with episodic fever with an ethnic origin typical for FMF
Takes careful observation, diary keeping
Exam during episode can detect signs of inflammation
Treatment of FMF
Acute episodes: mainly supportive, including IV saline for hydration and use of NSAIDs, paracetamol, or dipyrone for pain relief
Routine treatment of end-stage renal disease, including live related-donor renal transplantation
Preventative treatment option for FMF?
COLCHICINE
- Lifelong treatment with colchicine (1-2 mg/day orally in adults and 0.5-1 mg/day in children) prevents inflammatory attacks and the deposition of amyloid
- Works by reducing the number of white blood cells which travel into the inflamed areas.
- Vast majority of patients have normal quality of life including childbearing.
- No increased risk in pregnancy or breastfeeding.
- 5-10% do not respond to colchicine, however.
Proposed mechanism of Colchicine
Interferes with tubulin, destabilizes microtubules
Used as the cell cycle inhibitor in cytogenetic karyotyping, arresting cells at metaphase.
leads to anti-inflammatory
Diagnosis and Management Considerations for FMF
Elicit and document history carefully Take into account ethnicity Send for genetic testing to confirm dx Can still be FMF even if genetic testing finds only 1 or no mutation Try colchicine Monitor for amyloidosis
Difference between cells involved in Autoinflammatory vs Autoimmune
Autoinflammatory: DOES NOT involve T cells, abs,
it involves defects in innate immunity
Autoimmunity: defects in adaptive immune response
Loss of Tolerance
Ag specific T cells, auto-abs
Which TLR recognize Lipoproteins?
TLR 1, 2, 6
Which TLR recognize lipopolysacharide?
TLR 4
Which TLR on are CELL SURFACE
1,2, 6 (the lipoproteins ones). and 4 (the lipopolysacharide one)
Activation of Inflammasomes
I think these are referring to NOD like receptors (NLR) , RIG like receptors (RLR), NALP3?
which are activated through TLR bindings?
What are the activities of IL-1B
- 3 different targets
a. endothelial cells to release IL-6 -> Liver -> Acute phase proteins (CRP) +TPO, platelets
b. brain: hypothalamus -> fever
c. Bone marrow: cartilage breakdown, bone resorption, marrow release of : lymphocytes, neutrophils and platelets
How is CVD plaque activation and rupture linked to TH1 effects?
IFN-γ induces CD 40 ligand
boosts production of proteases that degrade collagen, weakening the fibrous cap
- making it prone to destablization
CD 40 – CD 40L
elicit tissue factor triggering the coagulation cascade and thrombus formation
Causes displacmeent of SM cells in the plaque and decreased collagen production = destabalizing the plaque
Role of Netrin-1 in atherosclerosis
Macrophages in plaques promote inflammatory processes
Why does the macrophage stay there?
Chemoattractants bring them there. There is a push and a pull that keeps these cells in the plaque: NETRIN-1 keeps macrophage here
If you block NETRIN1 that macrophage can leave the subintimal space
Another potential target to treat atherosclerosis
Statins role as Immunomodulating agents
DON’T memorize the details, just know there are many immune mechanisms that statins modulate
Interfere with antigen presentation inhibiting MHC Class II, CD40, CD80/CD86 upregulation
Bind to adhesion molecule (LFA-1) impairing leucocyte activation and migration by interfering with lipid raft formation
Inhibit T cell proliferation
Impair TH1 differentiation
Inhibit expression of adhesion molecules on endothelial cells
Affect leucocyte motility
Induce Fox P3 expression on naïve CD4+ T cells → functional CD4+ Fox P3+ regulatory T cells
How do statins promote regression of athersclerosis
They remove macrophages from the plaque
and increase the stability of the plaque
Treg cells role in atherosclerosis
T regs help decrease atherosclerotic risks
mutations in them can promote atherosclerosis
Inflamm-aging
Chronic disease causes time dependent tissue remodelling
- your tissue age increases faster than your actual age when you have a chronic disease
What are the age related changes of CD28 expression on lymphocytes?
Essentially leads to accumulation of CD4+CD28NULL T cells and they become more like NK cells (no clonal expansion)
Over time, with recurrent events,
Lymphocytes are triggered and activated, leads to loss of CD28 on their surface.
Changes appearance and function, become more like NK T cells
these cells are found in patients with chronic inflammation and accelerated atherosclerosis (because of iflamm-aging)
What is the role of CD28 Tcells in atherosclerosis?
Stable Angina and Unstable Angina patients differ in their repertoire of cytokine-producing T lymphocytes
high CD28null is associated with increase mortality and increased CVD events
______ is the hallmark of atherosclerosis, leading to MI and other CV events
- Which is a key agent?
- What is a key therapy?
INFLAMMATION*
IL-1B is instrumental in driving atherosclerosis
Canakinumab: monoclonal ab against IL1B to block inflammatory pathway
(demonstrated the anti-inflammatory mechanism to help treat CVD that was INDEPENDENT of lipids)
CANTOS study findings
demonstrated that canakinumab is the first antiinflammatory therapy to demonstrate reduced risk of major CVD events particularly in subgroup of CRP repsonders.
HOWEVER;
not clinically significant/ no diff in stroke an dCVD death and it is VERY expensive**
The importance of CANTOS was a proof of concept study on the importance of chronic inflammation in cardiovascular disease
Colchicine
given too patients who recently had and MI: lead to sig lower percentage of patients with MI
Clonal Hematopoiesis of Indeterminate Potential (CHIP).
Somatic mutations in hematopoietic stem cells generate clonal progeny of mutant leukocytes in blood.
They double the risk of coronary heart disease and ischemic stroke, and worsened heart failure outcomes independent of traditional cardiovascular risk factors.
Relavence of CMV in CVD and immunity?
study found; CMV positivity in adults associated with accelerated epigenetic age and immune dysregulation
The CD8 T-cell phenotype is altered in cytomegalovirus (CMV)-infected participants.
Immune Senescence
Immune senescence, or the aging of the immune system, particularly its effect on changes in lymphocyte development and function, predisposes older adults to a higher risk of latent virus reactivation.
chronic inflammation can lead to this.
What are senolytics?
alleviate age-related diseases
What contributes to destabilization of plaques?
Pattern Recognition Receptors Scavenger Receptors (SR-A, CD 36 ):
Damage is in the intimal layer of the artery
Monocytes become macrophages which become foaming macrophages: through receptors (CD36) take in LDL and oxidize. Inside cell triggers things that general IL1/18
Destabilizaiton of the plaque and myocardial infarction or stoke. People don’t realize heart attack is an immune event.
What activates the NLRP3 inflammasome in CVD?
Cholesterol
Increased cholesterol= Increased IL1B
Neutropenia
Absolute neutrophil count (ANC) <0.5 x 10^9/L following cytotoxic chemotherapy or HSCT (hematopoietic stem cell transplant)
What temperature signals fever?
Oral
Greater than or equal to 38.3 degrees on one occasion
Greater than or equal to 38.0 sustained for 1 hour or more
Rectal temperature should never be done on patients being treated for _______
Cancer!
What is the good role of Neutrophils
These are innate responders: phagocytes!
They eliminate:
Bacteria
Fungi
Mycobacteria
What type of patients are prone to Febrile Neutropenia
Fever occurs in 1/3 of neutropenia episodes in Oncology/SCT patients
What are the origins of gram negative vs gram positive bacteria?
positive: URT, mouth and skin
negative: GI, urogenital
What are some causes of Fever?
Infectious causes:
Bacteria, Fungi, Viruses
Non-Infectious causes of Fever: Drug-related, Malignancy related Thrombosis Transfusion reactions
When seeing patients that are FEBRILE, what are IMPORTANT practical points for Initial Assessment
- What should you watch out for when taking vitals
- What specific medications should you flag??**
- Assessing patients: Airways, Breathing, Circulation
- Take Vital signs
- Watch out for: WIDENED pulse pressure and BOUNDING PULSES - Act QUICKLY, and assume the WORST
- i.e. Bacteremia, impending sepsis*
Be aware of patients on STEROIDS: steroids blunt fever, severity of symptoms*
What is Sepsis
Sepsis is the body’s extreme response to an infection. It is a life-threatening medical emergency. Sepsis happens when an infection you already have triggers a chain reaction throughout your body. Infections that lead to sepsis most often start in the lung, urinary tract, skin, or gastrointestinal tract.
On exam, what are you looking for in a patient with Febrile Neutropenia
Whether they are
Stable vs Not stable
Whether they look well or not well looking
- all to determine/prevent septic shock or organ failures
do a very thorough exam
Investigations for Febrile Neutropenia
Serum:
- Blood culture
Ideally peripheral and central but don’t delay trying to get peripheral is difficult
CBC, electrolytes and renal function
Liver enzymes, bilirubin
Coags with dimers if sepsis suspected
CRP: Not important. Does not guide therapy in this scenario**
Urine
- culture
- start antibiotics even if you don’t have culture results yet
Which blood element quantity is NOT important when investigating for Febrile Neutropenia
CRP: Not important. Does not guide therapy in this scenario
What qualifies as HIGH/SEVERE Neutropenia?
<0.1 x10^9/L
What is a significant co-morbid condition for Neutropenia?
Trisomy 21
- ANY significant co-morbid condition puts them at a higher risk (i.e. hypotension, GI symptoms*, chronic lung disease, mental status changes, reduced creatinine clearance)
- AML
- Aplastic Anemia
- Burkitt’s L
- ALL
- post allogeneic HSCT, or with chronic GVHD
What characteristics of suspected Febrile Neutropenia put them in LOW risk?
Must meet all criteria:
Anticipated duration of neutropenia <7 days
No active medical co-morbidity (as per previous list)
Adequate hepatic and renal function
Stable clinical condition
Can consider outpatient therapy (ceftriaxone + tobra and then switch to oral antibiotics until start of count recovery)
What are the commonly used antibiotics for stable Febrile Neutropenia?
Ceftriaxone and aminoglycoside give complementary broad coverage and can be given as outpatient
Levofloxacin, broad coverage and can be given orally
What are the commonly used antibiotics for UNstable Febrile Neutropenia?
TOBRAMYCIN +/- VANCOMYCIN.
When to initiate anti-fungal therapy
Risk factors for invasive fungal disease are increased in
AML
Relapsed or high-risk ALL
Prolonged neutropenia (>10 days)
Highly myelosuppressive chemotherapy, or high dose glucocorticoid therapy (>0.5 mg/kg/day prednisone equivalent)
SCT recipient
GVHD
evaluations include:
CT
biopsy of suspicious lesions
What are some antifungal therapies for febrile neutropenia
Regimens may take into account previous prophylaxis, concurrent therapies
Amphotericin B (liposomal)
Echinocandins (caspofungin)
Triazole derivatives (voriconazole, posaconazole)
Duration
Continue until resolution of neutropenia and no fungal infection identified
What are the MAIN takeaways for managing someone you suspect of Febrile Neutropenia
Though infrequent, patients with fever and neutropenia can deteriorate rapidly. Goal is to avoid sepsis and organ dysfunction
Act quickly and deliberately: Assess PATIENT and VITALS (ABC’s)
Blood Cultures then start broad spectrum antibiotics
Resuscitate as necessary: Fluid, blood transfusion, pressors, resp support. Call ICU early if any cardio-resp support required
Think and tweak later (management after initial treatment)
What are the classifications of food allergies?
a. Immune Mediated
i. IgE mediated
ii. Non-IgE mediated
b. Non Immune Mediated
i. Enzymatic
ii. Pharmacologic
iii. TOXIC
iv. Undefined
Diagnosis of Food allergies
SPT: skin test
Why would doing an IgE count NOT be helpful in diagnosing a food allergy?
More than 90% of the those who have high Levels of IgE in the general population tolerate milk, egg or peanut
high IgE finding can be a false positive because a lot of people have them
Oral Food Challenge
- which are the high risk infants
I think this is just seeing what kids are reactive too after they’ve been exposed to different foods (for IgE mediated?)
high risk infants were efined as those with either EGG allergy or early onset MOD/SEVERE ECZEMA (less than 6 months of age)
What product is responsible for 50-60% of food-induced allergic fatalities
- what age does it manifest
PEANUT ALLERGY
Usually manifested prior to age 2 yrs
Generally lifelong, but 20% may resolve
Studies suggest increased prevalence.
Oral Allergy Syndrome
(pollen-food allergy syndrome*)
Reactions confined to the oral mucosa* in patients with IgE cross- reacting with pollen heat labile allergens, which can progress to severe reactions in 1-2%
so someone with a pollen allergy can get a flare up while eating something during pollen system because of this cross reactivity*
i.e. can have apple but can’t eat apple pie*
infantile colic
episodes of crying or fussing most frequently after a feeding
signs of a cow’s milk allergy
Cows milk hydrolysates
given for babies with cow’s milk allergies/intolerances*
Milk allergy
When IgE mediated is the systemic type where it will present anywhere on skin
(pollen-food allergy is limited to the mucosal area)
What is the major allergen in milk?
Caseins
pasteurization increases the allergenicity of b lactglobulin
- CMA associated with other types of milk allergies and beef allergies
Cows milk allergy is an early indicator of ??
ATOPY: asthma, hay fever (allergic rhinitis) or dermatitis to inhalant allergens later in life
Shellfish allergies
- what is the major allergen shrimps
Shellfish is a major cause of food allergy in the adults .
Crustaceans include- shrimp, lobster, crab.
Mollusks contain clams, squids.
Those allergic to some type of crustacea present a 75 % risk of cross reactivity.
Tropomyosin is the major allergen in shrimps (part of crustacea) There is cross reactivity with homologous tropomyosin in dust mite and cockroach but not vertebras’ tropomyosin.
No association with contrast material that doesn’t contain tropomyosin.
Exercise induced anaphylaxis
or Food Dependant Exercise-induced Anaphylaxis
Onset of anaphylaxis during ( or soon after ) exercise which was preceded by the ingestion of the causal food allergen (usually within 2 h). Both the food and the exercise are independently tolerated…
All phases of exercise: warm-up, initiation phase . . . .can occur if the food is ingested soon after the completion of exercise.
It is suggested that exercise enhances allergen absorption from the GIT
What is anaphylaxis
An allergic reaction involving at least 2 systems
treatment of anaphylaxis
In any case of anaphylaxis ( allergic reaction involving at least 2 systems ) the recommended treatment will be epinephrine IM.
Elimination of the food and carriage of EAI (epinephrine auto-injector).
Oral desensitization more recently gains acceptance in routine clinical practice
What is the treatment for FDEIA
FOOD DEPENDENT EXERCISE INDUCED ANAPHYLAXIS
Avoide exercise for 4 h- 6h after eating
(… but some patients experience anaphylaxis even after mild exercise as walking …)
Return to exercise should always be supervised
Avoid simultaneous intake of salicylates, alcohol other known triggers
Refrain exercise aroud menses
Cease exercise at first sx
Epinephrine auto-injector
Medicalert bracelet
How can you prevent episodes of anaphylaxis for unknown allergies
Randomly assigned infants with severe eczema/ eggallergy to consume
or avoid peanuts until 60 months of age.
Early introduction of peanuts significantly decreased the frequency of the development ofpeanut allergy
so for prevention: ADD foods to diet, DON’T avoid
Kids with EITHER egg allergy OR eczema are at risk for….
IgE food allergies?
if baby has mild to moderate eczema, should you give them Peanuts?
YES, around 6 months
(mod to severe eczema is when you should get them TESTED first)
if they have an egg allergy is automatically puts them at HIGH risk regardless of eczema status
Oral Immunotherapy (OIT) - goal
In most OIT protocols, small amounts of allergen are administered orally to patients in gradually increasing amounts, with the immediate goal to induce desensitization.
With desensitization, the treated patient manifests a decreased response to the ingested food allergens but must continue to take daily food doses.
goal: building tolerance
A patient is considered tolerant when they can safely consume the food without following a daily oral food regimen to maintain clinical non reactivity.
What is Sustained Unresponsiveness
in terms of oral immunotherapy
lack of dose limiting symptoms during DBPCFC and also 4-6 weeks after stopping OIT.
