December 2020 Flashcards
What antibiotic has been used to treat GPA?
TMP-SMX!
Only for upper respiratory disease
INTERESTING!
Does ALL GPA require treatment?
No! In non-major organs, the benefit of treatment must be weighed against that of treatment
What are the 2 assays used to test for ANCA?
Indirect immunofluorescence assay and ELISA
Framework Question:
What is the difference between the Indirect immunofluorescence assay and ELISA in regards to ANCA testing? Their relationship with one another?
Of these two techniques, the immunofluorescence assay is more sensitive, and the ELISA is more specific.
IFA looks at the presence of a pattern of immunofluorescence while the ELISA is looking for Ab to specific antigens, specifically Proteinase 3 (PR3) and Myeloperoxisdase (MPO)
The optimal approach to clinical testing for ANCA is therefore to perform both immunofluorescence, if available, and ELISA to detect antibodies against the vasculitis-specific target antigens
What is an “immunofluorescence assay”? What is an “ELISA”?
Visual technique: tests are based upon visual interpretation of the immunofluorescence pattern. Immunoflourescent antibody binds to antigen of interest and under microscopy is visualized (can be direct or indirect)
ELISA: Instead of immnunofluorescent antibodies binding to antigens of interest, enzyme-linked antibodies bind to antigens of interest. Then a substrate specific to the enzyme is introduced, causing the enzyme to change color (can be direct or indirect)
What is the difference between “direct” and “indirect” immunofluorescence?
“Direct” and “Indirect” refer to the fluorescent antibody, that is, the antibody that is attached to the fluorochrome, the part the lights up under the microscope
Hence:
Direct immunofluorescence is when the flurorescent antibody binds directly to the antigen of interest
Indirect immunofluorescence is when the an monoclonal Ab (WITHOUT the fluorochrome), binds directly to the antigen of interest. Then, the fluorescent antibody binds to that antibody. Hence, the fluorescent antibody is indirectly binding to the antigen of interest
What is the difference between how the fluorescence is produced in immunofluorescence assay vs ELISA?
In immunofluorescence assays, there are monoclonal antibodies that are attached to fluorochromes, together called fluorescent antibodies. The purpose is to attach to antigens of interest. Now, when light at a certain wavelength is directed over the sample, these fluorochromes will fluoresce.
In ELISA, enzymes that are linked to antibodies are the ones that fluouresce. These enzymes are exposed to substrates, that once bound to the enzymes, will cause conformational change and fluorescence.
TLDR: IFA has Ab + Fluorochromes; ELISA has Ab + enzymes. Light causes fluorescence in the former. Substrate causes fluorescence in the latter
What is the difference between “direct” and “indirect” ELISA?
What is the expected findings of C ANCA vs P ANCA in IFA?
C ANCA shows cytoplasmic staining, hence C
P ANCA shows perinuclear staining, hence staining in the nucleus
What is C ANCA and P ANCA usually associated with in regards to specific Antigens?
C ANCA is usually associated with antibodies against PR3
P ANCA is usually associated with antibodies against MPO
Need a mnemonic: CPR3 (sounds like robot), PMPO (Pimpo!)
What is the #1 part of the body affected in GPA?
95% upper respiratory tract (which includes nasal, sinues, ears, throat)
Clinical tip: if not present, questionable that disease is GPA
What are the 3 characteristic parts of the body affected in GPA?
Upper tract 95%
Lower tract 90%
Kidneys 75%
TIP: G picmonic affecting the upper resp tract, lower tract and kidneys
What is the natural history of renal disease in GPA if left untreated?
Once clinically apparent renal impairment is present, RAPIDLY PROGRESSIVE RENAL FAILURE ensues without treatment
Clinical tip: reason why diagnosis of GPA is urgent if the clinical picture is suggestive, since time without treatment is time for the development of RPGN
Main cause of mortality from GPA?
Renal disease!
Does all GPA require treatment?
No
What type of vessels are affected in ANCA-associated vasculitis?
ALL of them are small vessel vasculitis
GPA – small vessels only
MPA – small and medium size
EGPA – small and medium size
What is the #1 organ involved in MPA?
AKA what is the #1 organ involved in MPA, that if not affected, is questionable if MPA is present?
Kidneys
Clinical tip: the lack of renal involvement suggests another diagnosis other than MPA
What are the most common organs involved in MPA?
renal (80%-100%)
musculoskeletal (56%-76%) - myalgia
neurologic (37%-72%) - mononeuritis multiplex
cutaneous (30%-60%) - palpable púrpura
pulmonary (25%-55%) - pulmonary hemorrhage
gastrointestinal (21%-58%)
What is the #1 organ involved in EGPA?
AKA what is the #1 organ involved in EGPA, that if not affected, is questionable if EGPA is present?
Lungs (lower tract) – as presented as asthma
What are the most commons organs involved in EGPA? (>50%)
Lungs (100%) – Asthma
Peripheral neuropathy: Mononeuritis multiplex (78%)
Sinus (70%): Allergic rhinitis or sinus polyposis
Skin (50%): palpable purpura, subcutaneous nodule
Clinical tip: if patient doesn’t have a history of asthma and allergic rhinitis, they don’t have EGPA
Dynamed
What lab finding is present in almost all patients with EGPA?
Eosinophilia
TIP: “GEM” mnemonic demonstrates the ONE main organ that is most commonly involved in ANCA associated vasculitis
G (GPA): Upper airway tract
E (EGPA): Lungs
M (MPA): Kidneys
Clinical tip: if these are NOT present, the disease is likely not present
What is the cause of the combination of pharyngitis and elevated liver enzymes?
CMV
Diagnosis of acute CMV infection?
IgM elevated and IgG elevated fourfold increase
What is the most common presentation of symptomatic CMV infection?
Heterophile-negative infectious mononucleosis
How does the infectious mononucleosis of CMV differ from that of EBV?
Prolonged fever, mild pharyngitis, hepatitis
Differential diagnosis of diffuse alveolar hemorrhage
List of pulmonary renal syndromes (top causes) and most devastating and treatable ones
What is considered “pulmonary renal” syndrome?
Concurrent alveolar hemorrhage and glomerulonephritis
Dyna med has one section under diffuse alveolar hemorrhage
Framework Question:
What is the layman definition of vasculitis?
Group of diseases characterized clinicopathologically by inflammation of AND damage to blood vessels. Inflammation leads to compromise which causes ischemia to the organs/tissues supplied by the involved vessels
Framework Question:
What are the 3 main players in the pathogenesis of vasculitis?
- Immune complex formation
- ANCA Antibodies
- Pathogenic T lymphocyte response
How may immune complexes play a role in the pathogenesis of vasculitis?
Excess antigen leads to an excess of antigen-antibody complexes
Vasoactive amines such as histamine causes permeability of vessels
Immune complexes then are able to deposit in the vessel walls
Activate the complement system, especially C5a, which is chemotactic
Neutrophils invade the cell walls, phagocytose the immune complexes, release intracytoplasmic enzymes that damage the vessel walls
Compromise vessel
How may ANCA play a role in the pathogenesis of vasculitis?
Tip: there is evidence for and against the idea that they play a role in the pathophysiology
Evidence for: ANCA primed neutrophils will adhere to and kill endothelial cells in vitro
Evidence against:
- GPA does exist even in the absence of PR3 Ab
- GPA activity does NOT correlate with PR3 levels
PR3 levels can remain high for YEARS even in remission
How may pathogenic T cell response play a role in the pathogenesis of vasculitis?
Review: Helper T Cells (CD4) interact with antigen presenting cells via HLA 2 (2x4 = 8)
Vascular endothelial cells can present HLA II molecules when activated by cytokines. They, like antigen presenting macrophages, can interact with CD4 T cells and cause an immune response at the level of the vessels
What diseases are associated with ANCA?
TIP: the diseases with acronyms, mostly SMALL vessel vasculitis
GPA
EGPA
MPA
Tip: though ANCA stands for anti neutrophilic cytoplasmic ANTIBODIES, the renal disease associated with ANCA vasculitides are “pauci” immune, that is, there are NO antibody depositions
What antibodies are C-ANCAs most commonly associated with? P-ANCA?
C- ANCA -> PR3
-TIP: CPR3
P-ANCA -> MPO
-TIP: PMPO
First line treatment for pericarditis?
NSAID and Colchicine if no contraindications
800mg TID and Colchicin 0.5 to 0.6 mg BID
The presence of what clinical features should prompt consideration of an underlying vasculitis?
Glomerulonephritis Palpable purpura Pulmonary infiltrates – so common! Chronic inflammatory sinusitis Unexplained ischemic events Microscopic hematuria Mononeuritis multiplex
IgA presentation
1: persistent microscopic hematuria
Other presentation:
Progressive kidney disease
Glomerulonephritis
Rapidly progressive glomerulonephritis
Nephrotic syndrome
What is it so crucial to distinguish between vasculitis and infection?
There is a lot of overlap
The treatment for vasculitis is immunosuppression which could be devastating in the setting of infection or life-saving in a patient rapidly deteriorating
What size vessels are generally involved in ANCA associated vasculitis?
Small vessels!
What are the 3 main parts of the body classically involved in GPA?
Upper tract 95%
Lower tract 90%
Kidneys 75%
TIP: G picmonic affecting the upper resp tract, lower tract and kidneys
What are the characteristic histopathologic findings consistent with GPA? Vs. EGPA vs MPA?
GPA: Necrotizing vasculitis with granuloma formation
EGPA: Necrotizing vasculitis with granuloma formation with infiltrating eosinophils
- TIP: It’s in the name! Granuloma
MPA: Necrotizing vasculitis W/O granulomas.
- TIP: absence of granulomas is what distinguishes MPA from the other 2
TIP: grandmas are almost dead, hence granulomas are also necrotizing
What is the spectrum of lung findings of GPA?
Multiple, bilateral, nodular cavitary infiltrates
What pattern of immune complexes are expected in a renal biopsy of a patient suspected of having GPA?
Pauci immune!
Don’t get confused. Though ANCA is an antibody we use to diagnoses ANCA vasculitis, there are actually NO immune complexes deposited in the kidneys
What are the types of renal involvement for GPA?
FSGS, but can progress to RPGN
What are the organ systems affected at least >50% of the time in GPA (including the top 3 organs)?
Upper respiratory tract (95%)
Lower respiratory tract (90%)
Renal ( 75%)
Joints (70%)
Eyes (50%)
Fever (50%)
Skin (46%)
What is the #1 part of the body affected in GPA? And its manifestations?
Upper airway tract (95%)
Sinusitis Sinus drainage/purulence Hearing loss Subglottic stenosis Ear pain Oral lesions Otitis media
Strange presentations
Proptosis
Think GPA due to retroorbital mass
What ANCA Ab is associated with GPA?
90% of patients with GPA have PR3-ANCA
Very high specificity
What is the relationship between GPA and VTE?
Higher risk of VTE
What is the definitive diagnosis of GPA? Highest yield biopsy?
Biopsy
Pulmonary tissue offers the highest diagnostic yield
Tip: Definitive diagnosis of all vasculitides is biopsies
Diagnostic Feedback:
Normal UA in the setting of acutely declining renal function does NOT rule out glomerulonephritis as RPGN may not yield hematuria/proteinuria, etc.
Biopsy!
What are the 2 treatments available for Hypertriglyceridemia induced pancreatitis?
Insulin drip or apheresis
What is the goal TG level prior to discontinuing insulin drip for patient with TG induced pancreatitis?
500
How does insulin treat hypertriglycidemia in TG induced pancreatitis?
Insulin lowers triglyceride levels, but the goal of insulin therapy in severe acute pancreatitis associated with severe hypertriglyceridemia is to reverse the stress-associated release of fatty acids from adipocytes, to promote intracellular triglyceride generation within adipocytes, and to promote fatty acid metabolism in insulin sensitive cells, often in the setting of diabetes and peripheral insulin resistance
TIP: insulin promotes TG formation IN tissue and OUT of the blood
What is the role of ANCA in monitoring disease activity in GPA?
No role
What are the 2 phases of treatment for GPA?
Induction of remission
Maintenance of remissioin
What are the 2 main treatments for induction of remission in GPA?
Induction of remission
Maintenance of remissioin
What are the 2 main treatments for induction of remission in GPA?
Cyclophosphamide + steroids
OR
Rituximab + steroids
Both are just as good
What are the 2 main treatments for induction of remission in GPA?
Cyclophosphamide + steroids
OR
Rituximab + steroids
Both are just as good
Dosing of Cyclophosphamide in induction of remission in GPA?
2 mg/kg/day – need to adjust for renal insufficiency
Of the 2 regimens for induction of remission of GPA, which is preferred in cases of imminent life-threatening disease such as RPGN, or pulmonary hemorrhage requiring mechanical ventilation?
Cyclophosphamide/Steroids
What are the options of medications for maintenance of remission for GPA?
Steroids + either the following:
Methotrexate
Azathioprine
Rituximab
MMF
Is treatment for GPA lifelong?
No
Therapy is usually given 2 years after remission, then consideration of tapering is considered
Does ALL GPA require treatment?
No! In non-major organs, the benefit of treatment must be weighed against that of treatment
What is the most common presentation of Microscopic polyangiitis?
dyspnea
cough
hemoptysis
In the pediatric population, what is more effective for fever control and pain management – acetaminophen vs Ibuprofen?
Systematic Review and Meta-analysis
Oct 2020
Jama Open Network Pediatrics
Conclusion: Ibuprofen
-19 studies, 11 randomized/8 non-randomized
-240,000 participants
-
Conclusion: In this study, use of ibuprofen vs acetaminophen for the treatment of fever or pain in children younger than 2 years was associated with reduced temperature and less pain within the first 24 hours of treatment, with equivalent safety.
Tan E, Braithwaite I, McKinlay CJD, et al.Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis.JAMA Netw Open. 2020 Oct 1;3(10):e2022398. doi: 10.1001/jamanetworkopen.2020.22398.
Does early coronary angiography vs none at all following cardiac arrest without STEMI lead to survival benefit?
Circulation Nov 2020
RCT: The PEARL study
- Primary endpoint: composite of efficacy and safety measures, including efficacy measures of survival to discharge, favorable neurologic status at discharge (Cerebral Performance Category score =2), echocardiographic measures of left ventricular ejection fraction >50%, and a normal regional wall motion score of 16 within 24 hours of admission
- 2nd endpoint: presence of culprit lesion
- Patient: >18, out of hospital arrest, no STEMI
- Results:
- premature termination of trial. 49/99 patients with early angiography.
- No difference in composite or simply survival
- 47% of patients with culprit lesion
- Conclusion: Understudied study showed no difference in outcomes for early coronary angiography
Kern KB, Radsel P, Jentzer JC, et al.Randomized Pilot Clinical Trial of Early Coronary Angiography Versus No Early Coronary Angiography After Cardiac Arrest Without ST-Segment Elevation: The PEARL Study.Circulation. 2020 Nov 24;142(21):2002-2012. doi: 10.1161/CIRCULATIONAHA.120.049569. Epub 2020 Sep 28.
Where is alcohol predominantly absorbed?
Proximal small intestine
But small amounts can also be absorbed in the mouth, esophagus, stomach, and large intestines as well
What factors can increase the rate of alcohol absorption?
- rapid gastric emptying, which can be induced by concurrent consumption of carbonated beverages
- the ingestion ofalcoholin the absence of other calorie sources such as proteins, fat, or carbohydrates.
- A final factor that can increase absorption is to drinkalcoholthat is diluted to a modest concentration (~20% or less). AKA lower concentration has higher absorption rate compared to higher
What are atypical presentations of angina that women have when presenting with coronary heart disease?
Nausea, indigestion and upper back pain
What is the difference between the characteristics in men and women with coronary heart disease?
Women present 10-15 years later
Women have more co-morbidities than men
Women present with atypical features
What is the difference in the treatment of men vs women for CAD?
Women are still referred less often by physicians for diagnostic and therapeutic cardiovascular procedures, and there are more false-positive and false-negative diagnostic tests in women. Women are also less likely than men to receive angioplasty, thrombolysis, coronary artery bypass grafting, aspirin, and β-blockers. Despite this, the 5- and 10-year survival rates following coronary artery bypass grafting are the same between the sexes.
What category of bacteria are often implicated in all lung abscesses?
Anaerobic bacteria
It is widely thought that colonization of the gingival crevices by anaerobic bacteria or microaerophilic streptococci (especially in patients with gingivitis and periodontal disease), combined with a risk of aspiration, is important in the development of lung abscesses.
Preceding event for most causes of primary lung abscesses?
Aspiration
Aspiration pneumonia (and abscesses) usually affects what part of the lungs?
Because most cases of lung abscess occur in the context of RECLINING aspiration, the dependent lobes of the lung are most vulnerable. The dependent lobes include the superior segment of the lower lobes and the posterior segment of the upper lobes, with the right lung more commonly involved than the left lung. The middle lobe and the lingula are the most ventral lobes and are therefore nondependent in the supine position.
What is the relationship between aspiration pneumonia and primary lung abscess?
The most common cause of primary lung abscess is aspiration
2nd most common cancer in women worldwide?
Cervical cancer
What are the 2 HPV types that cause most cervical cancers?
HPV-16 and -18 are the types most frequently associated with high-grade dysplasia and targeted by both U.S. FDA–approved vaccines
Interesting: More than 60 types of HPV are known, with approximately 20 types having the ability to generate high-grade dysplasia and malignancy
What is a cofactor as opposed to a risk factor?
Cofactor(epidemiology) is a condition that exacerbates the effects of another condition;
What are risk factors for not only HPV, but also high grade dysplasia?
Risk factors for HPV infection and, in particular, dysplasia include a high number of sexual partners, early age of first intercourse, and history of venereal disease
TIP: all about sexual exposure, hence more partners, earlier age and STD’s because STD’s imply sexual encounters
