All posts by cauriemma

Moffittt Pearls 6.23.17 – Medicine Report

Thank you to Daniel Kwon for presenting a case of a older gentleman with ESRD, NAFL cirrhosis with HCC presenting with sepsis and RUQ pain 1 week after receiving nivolumab. On imaging he was found to have gas within the liver parenchyma in addition to gram positive rod bacteremia, inspiring HH to take to the board for an approach to GPR (more details below)!

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KEY PEARLS

  • Nivolumab is an example of immune checkpoint blockade that acts by blocking a negative regulator (PD-1) of T-cell activation and response, thus allowing the immune system to attack the tumor.
  • As the PD-1 inhibitors become more broadly used, we are seeing new immune-mediated complications of therapy.
  • The differential for GPR bacteremia can be guided by the appearance of the rods – with a clear distinction between filamentous (long & sleek) and non-filamentous rods (short & stout). Call the lab to get a head-start on your diagnosis based on the appearance of the rods!

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PD-1 Inhibitors

pd1.png

PD-1 (programmed cell death 1) and its association with the ligand (PD-L1) is a necessary step in stimulating apoptosis of T-cells, serving as an immune checkpoint. PD-L1 is generally expressed by native cells, signaling to the T-cell “I’m one of you! Don’t hurt me”.  Some tumors have been found to also express PD-L1, enabling them to evade destruction by T-cells.  In order to treat these malignancies, PD-1 inhibitors (pembrolizumab, nivolumab) serve to block the interaction between PD-1 and PD-L1, enabling T-cells to stay “programmed on”, and thus enable immune-mediated destruction of tumor.

Because of this mechanism of action, a common consequence is the upregulation of cell-mediated immunity and, unfortunately, inhibition of native tissues to turn off T-cells. As a result, we commonly see autoimmune-mediated inflammation manifested as new rash, diabetes, thyroid disease, pneumonitis, hepatitis, colitis, etc.

Nivolumab – Drug Information

According to the FDA, Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody. It is first line treatment for inoperable or metastatic melanoma, as a second-line treatment for squamous non-small cell lung cancer, and as a second-line treatment for renal cell carcinoma.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s012lbl.pdf

Common Immune-Mediated Toxicities Seen with Check-point Inhibition:

Organ System Manifestation Management
Skin & Mucosa Pruritic rash (most common!)

Alopecia

Vitiligo

Mucositis

Topical corticosteroids

Oral antipruritics

Consider oral steroids

GI Tract Diarrhea/colitis – presents ~6wks into treatment R/O infxn

Anti-motility agents

Steroids if severe

Liver Hepatitis (rate <5%, severe toxicity very rare) Stop therapy if moderate-severe.

Steroids + mycophenolate given rarely.

Lung Pneumonitis – (rate <5%, but occasionally fatal) Steroids common. Infliximab, cyclophosphamide also used, though patients requiring therapy beyond steroids have nearly 100% mortality.
Endocrine Hypophysitis

Autoimmune thyroid disease

Adrenal Insufficiency T1 DM

Hormonal replacement

Steroids

Less commonly reported immune-mediated adverse events include the following: acute renal injury, pancreatitis, neurotoxicity (GBS, myasthenia gravis, PRES, aseptic meningitis, autoimmune encephalitis), cardiotoxicity (myocarditis), hematologic (cytopenias), and ocular inflammation.

Many of the adverse events described above can be managed with continued use of PD-1 inhibitors if mild. However, for severe adverse reactions, PD-1 inhibitors are withheld and potential discontinued permanently.

 A Simple Approach to Gram Positive Rods (courtesy of HH!)

  Aerobic Anaerobic
Filamentous

(long & sleek)

Nocardia*

Streptomyces

Actinomyces
Non-Filamentous

(short & stout)

Listeria

Corynebacterium

Lactobacillus

“professional” AFBs*

Clostridium perfringens

Bacillus

Gardnerella

Propionibacterium

* Also stains Acid-Fast

Evernote: https://www.evernote.com/shard/s462/sh/c1863bdf-8d2a-41e6-a42f-645f6c35d432/b20b319afdd90b1051ce1020a198ada1

 

Moffitt Pearls 6.19.2017 – Rheumatology Report

Thank you to Vincent (our pulmonary fellow) for presenting a fascinating case of a young man with who was otherwise healthy presenting with muscle pain and hemoptysis found to have diffusive GGOs and cavitary nodular opacities. We discussed evaluation of hemoptysis in addition to pulmonary-renal syndromes. Final diagnosis was GPA!!

KEY PEARLS

  1. Massive hemoptysis is defined as either ≥500 mL of expectorated blood over a 24 hour period or bleeding at a rate ≥100 mL/hour.
  2. CT Approach to Hemoptysis
    1. Diffuse – corresponds with DAH
      1. Inflammatory – capillaritis
      2. Non-inflammatory or bland – cardio-pulmonary
    2. Focal
      1. Vascular: PE, AVM
      2. Nodular/Cavity lesions: Infection, Neoplasm, Rheum
      3. Mass – malignancy
      4. Septic emboli
  3. For evaluation of DAH consider CTPE as first line imaging study – You’ll get the information from the non-contrast series PLUS the addition of contrast will help r/o PE, possibly identify AVMs and provide a potential target for future interventions if needed.

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Evaluation of Hemoptysis

  • Approach to hemoptysis: airways disease (most common), pulmonary parenchymal disease, or pulmonary vascular disease, or may be idiopathic
  • CT Approach to Hemoptysis
    • Diffuse – DAH (capillaritis, vasculitis), cardio-pulmonary edema
    • Focal – Cavity, AVM, bronchiectasis,
  • Massive hemoptysis as either ≥500 mL of expectorated blood over a 24 hour period or bleeding at a rate ≥100 mL/hour.
  • History: include age, smoking history, duration and quantity of hemoptysis, and association with symptoms of acute bronchitis or an acute exacerbation of chronic bronchitis or bronchiectasis (change in sputum, blood streaking superimposed upon purulent sputum)
  • Laboratory studies to consider: Hgb, platelet count, a coagulation profile, urinalysis w/ micro, blood urea nitrogen, plasma creatinine concentration, ESR/CRP and collection of sputum for microbiologic studies.
    • ANCA, ANA, anti-GBM, complement levels
  • Imaging: Can start with CXR, but would quickly move towards CTPE – r/o PE, assess for AVMs and provides a potential target for future interventions if needed
  • DAH diagnosis: gold standard diagnosis is via BAL

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Approach to VasculitisBold face indicates can present with a pulmonary-renal syndrome

Small vessel

  • ANCA- associated or “pauci immune”
  1. GPA: c-ANCA
  2. Microscopic polyangitis: p-ANCA
  3. Eosinophilia granulomatosis with polyangitis: p-ANCA
  • Anti-GBM
  • Lupus – low C3/C4
  • Cryoglobulinemic – low C4

 

 

 

Medium vessel

  • PAN –often spares the lung
  • Kawasaki disease

Large vessel

  • Giant cell arteritis
  • Takayasu arteritis

Check out the algorithm below for an approach glomerulonephritis that highlights pulmonary-renal syndromes from Orlando Regional Medical Center:

https://www.slideshare.net/zunaira8/pulm-renal-syndromes

Picture1

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ANCA Testing

  • Immune-fluorescence testing is ideal, though in some institutions (including our own), results are reported as positivity with a secondary test for the associated antigens (as opposed to describing the location of the immune-fluorescence).
  • At Moffitt, the antigen testing comes back as a quantitative assessment of the circulating antibody to the following antigens:
    • MPO – which generally corresponds to p-ANCA antibodies
    • PR3 – which generally corresponds to c-ANCA antibodies
    • See the associated image from the Cleveland Clinic below
  • c-ANCA is associated with GPA, p-ANCA is associated with MPA and GPA, though is negative in up to 50% of cases!!
  • We don’t usually follow ANCA levels in the setting of flares as this does not correlate well with disease activity

rheumatic-fig2_large

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatology/laboratory-evaluation-rheumatic-diseases/

Moffitt Pearls 6.14.17 – GI Report

Pearls 6.14.17 – GI – Morning Report

Thank you to Salman for presenting an amazing case of a young woman with history of EtoH hepatitis p/w with fatigue, lightheadedness found to be severely anemic with evidence of active hemolysis and new cirrhosis. Work-up is ongoing.

**KEY PEARLS**

  1. Acute alcoholic hepatitis is a chronic disease (despite the name!). Presentation is based on predominantly cumulative burden – a single binge in a patient with otherwise minimal alcohol intake is unlikely to cause severe alcoholic hepatitis.
  2. In a young patient (< 35 yo) with new diagnosis of liver injury consider genetic causes including Wilson’s, hemochromatosis and alpha-1 antitrypsin disease in addition to autoimmune, vascular and infectious hepatitis.
  3. The smear and reticulocyte count are the key initial lab studies to frame your differential for hemolytic anemia.

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For those who want more information:

Alcoholic Hepatitis

The clinical syndrome of acute alcoholic hepatitis includes the following compilation of laboratory and clinical features:

  • Moderately elevated transaminases in a 2:1 ratio of AST/ALT
    • Typically less than 300, rarely greater than 500
  • Elevated bilirubin and Jaundice
    • Jaundice generally develops within 3 months prior to presentation
  • Fever & Neutrophilic Leukocytosis
    • Both should only be ascribed to alcoholic hepatitis after ruling out infection!
  • Right upper quadrant pain – can often palpate tender hepatomegaly
  • Clinical history of chronic drinking with or without recent bing
    • It’s not uncommon that patients have actually decreased their drinking in the weeks-months preceding acute alc hep due to the onset of symptoms with alcohol intake.

See this RCT from NEJM regarding pentoxifylline vs. prednisolone for the treatment of alcoholic hepatitis. Bottom line:  Acute alcoholic hepatitis is a profoundly morbid disease with very high mortality (30-40% in 6 months).  Prednisolone was associated with a reduction in 28-day mortality, but did not reach significance and there were no improvements in 90-day or 1 year mortality.

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Approach to abnormal liver function tests (table from UptoDate.com):

table

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Approach to Hemolytic Anemia:

Picture2.png

 

Moffitt Pearls 6.12.17 – Pulm Report

Today in Pulmonary report Saate presented an amazing case of a middle age man w/ no past medical history found down with initial broad w/u notable for elevated Alk-Phos and recurring fevers of unknown origin!! In this case we discussed refractory acidosis, granulomatous hepatitis and finally the definition, evaluation and workup for fever of unknown origin. After broad w/u this patient was found to have miliary TB and infiltrative granulomatous hepatitis!! WOW and big thank you Saate for a truly amazing case!

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KEY PEARLS:

  1. Remember, whenever a patient is not getting better as expected, to come back to the problem representation and consider reframing à it can be difficult to separate out noise from signal, but that’s also what’s fun about clinical problem solving!
  2. An isolated elevated alkaline phosphatase is highly suggestive of infiltrative disease.
  3. The differential for an FUO can be guided by sub-classifying the FUO into 1 of 4 different subtypes: Check out this review for more details.
    1. Classic FUO
    2. Nosocomial FUO
    3. Immune-deficient FUO
    4. HIV-related FUO

Differential for Lactic Acidosis:

lactic acidosis.png

Granulomatous Hepatitis Ddx

Infectious:

  • TB
  • Fungal
  • Syphillis

Non-infectious:

  • Sarcoid
  • Drugs
  • Malignancy
  • Idiopathic

Great review:  https://www.ncbi.nlm.nih.gov/pubmed/?term=22541705

Fever of Unknown Origin

Definition

  • Fever > 38.3ºC on several occasions
  • Duration of fever for at least three weeks
  • Uncertain diagnosis after one week of study in the hospital (exact duration of inpatient work-up varies by source from 3-7days of inpatient work-up)FUO can be subclassified into 4 different subtypes:

 

  1. Classic FUO
  2. Nosocomial FUO
  3. Immune-deficient FUO
  4. HIV-related FUO

Etiologies for FUO often Three Broad Categories:

  • Infectious – endocarditis, fungal infections
  • Inflammatory including connective tissue disease
  • Malignancy

Initial Work-Up:

  • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
  • Serum lactate dehydrogenase
  • TB skin test or Quanta gold
  • HIV antibody assay and HIV viral load for patients at high risk
  • Three routine blood cultures drawn from different sites over a period of at least several hours without administering antibiotics, if not already performed
  • Rheumatoid factor
  • Creatine phosphokinase
  • Heterophile antibody test in children and young adults
  • Antinuclear antibodies
  • Serum protein electrophoresis
  • Computed tomography (CT) scan of abdomen
  • CT scan of chest

Great review on FUOs: http://www.clinmed.rcpjournal.org/content/8/5/526.long

Moffitt HemOnc Report 6/9/17

Thanks to Megan for presenting today at Hem-Onc report! We discussed a young woman with NICM s/p LVAD c/b drive line infxns on Coumadin transferred to UCSF for recurrent, nontraumatic intracranial hemorrhage. Hematology was consulted for two issues:  (1) how do we manage the bleeding, and (2) what was causing the bleeding?

Key Pearls:

  1. For an approach to non-traumatic bleeding, think about congenital and acquired issues with vessels, platelets, and the coagulation cascade.
  2. Patients with LVADS often have an acquired von Willebrand Disorder thought due to the high shear forces (see paper below).
  3. If you suspect an acquired form of vWD it’s appropriate to send the multimer studies concurrent with vWD screening tests.

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BLEEDING AND CLOTTING WITH LVADS:

  • Thrombosis: varies by the particular model, but in general patients are treated with therapeutic anticoagulation. Even with anticoagulation, patients have risk for pump thrombosis, stroke and other thromboembolic events.
    • Risk factors: inadequate anticoagulation, atrial fibrillation, hypercoagulable states, coexistent infection
  • Bleeding: greatest risk is perioperatively, often related to the coagulopathic effect of extracorporeal circulation. As time goes on, usually at least a week in to LVAD therapy, a significant proportion of patients can develop an acquired vWD (thought due to the high intravascular shear forces) – similar to what we see in Heyde’s Syndrome with aortic stenosis.

General Approach to Bleeding

  • Vessel
    • Acquired:
      • infection, amyloid, vitamin C deficiency, vasculitis (and others!)
    • Inherited:
      • aneurysmal
  • Platelets
    • quantitative – low platelets
    • qualitative – malfunctioning platelets
  • Coagulation cascade
    • intrinsic – PTT (F VIII, IX, X, XIII)
    • extrinsic – PT (F VII)

Evaluation for vWD (Thank you, Pat, for this approach!)

  1. Initial screening tests:
    1. Plasma vWF antigen
    2. Plasma vWF activity (ristocetin cofactor activity)
    3. Factor VIII activity

NB: If the above tests are negative, but you still have a high index of suspicion, the tests should be repeated. If negative x2, start looking for another explanation of bleeding!  If you’re suspicion is for ACQUIRED DISEASE, as in this patient, you would skip the first step and go right to sending the multimers.

  1. Specialized assays (performed if one of the above tests is abnormal)
    1. vWF multimer distribution using gel electrophoresis
    2. Restocetin-induced platelet aggregation (RIPA)

Bleeding Rescue Products:

  • Kcentra AKA Prothrombin Complex Concentrate (PCC) – combination of vitamin K-dependent coagulation factors (II, VII, IX, and X).
    • has small risk of clotting
  • Novo7 – recombinant factor 7A.
    • has small risk of clotting
  • Humate – Human-plasma derived von Willebrand factor – (contains factor VIII)
    • has small risk of clotting
  • Cryoprecipitate – VIII, fibrinogen, and vWF
  • DDAVP

Resources:

Acquired von Willebrand syndrome associated with left ventricular assist device.https://www.ncbi.nlm.nih.gov/pubmed/27143258

Moffitt Intern Report Pearls 6.8.17

CONGRATS INTERNS ON YOUR LAST INTERN REPORT!!! And HUGE thank you to Lev for presenting a fascination case of middle aged man s/p prolonged treatment with steroids for EtoH hepatitis who presented with fevers and abdominal pain found to be in decompensated cirrhosis and later found to have semi-invasive pulmonary aspergillosis – wow!

Key Pearls

  1. If the direct bilirubin makes up greater than 20% of total bilirubin this is defined as direct predominance.
  2. Patients likely have impaired cellular immunity when steroid dosing reaches 20 mg for at least 14 days. At this dosing level you should consider starting PCP prophylaxis. More details below…
  3. Classical risk factors for semi-invasive Aspergilosis pulmonary infection:
    • severe or prolonged neutropenia
    • receipt of high dose corticosteroids per above
    • Other drugs or conditions that lead to chronically impaired cellular immune responses (e.g. AIDs, immunosuppressive regimen)

Thank you, Brad Monash, for sharing some more info on PCP prophylaxis in the setting of steroid use:

  1. The evidence for when to start PCP prophylaxis is weak. Some say that PCP ppx should be considered for patients on > 20 mg prednisone for > 2-3 weeks.
  2. Most evidence pertains to patients on steroids + underlying immunosuppressed state. Many experts will not use PCP ppx for steroids alone in the absence of other immunodeficiency.
  3. Here’s a fantastic review of PCP ppx from 2004, and one of the most cited papers on the topic (https://www.ncbi.nlm.nih.gov/pubmed/8274607)
  4. The article below cites the lowest dose of steroids on which patients developed PCP as 16 mg daily. (https://www.ncbi.nlm.nih.gov/pubmed/?term=8538233)
  5. Interestingly, PCP has been described in Cushing syndrome!
  6. Check out this outstanding review of glucocorticoids and infection from 2008. (https://www.ncbi.nlm.nih.gov/pubmed/18703175)

Evernote: https://www.evernote.com/shard/s462/sh/99f2ebe3-feca-4157-9b2b-cdb1eaf7299a/f8290e4be68e855deb8518055c4693e8

 

 

Moffitt Pearls 6.6.17 – Chest Pain s/p CABG

Thank you to Satvik for sharing a great case of an elderly man w/ multiple co-morbities s/p CABG (several years prior) presenting with chest pain and hypertensive emergency. We discussed the management of HTN emergency and how to approach chest pain in a patient s/p CABG. We loved the lively discussion so thank you everyone for your participation!

Key Learning Points

Causes of chest pain in pt w/ hx of CABG vary by time

  • Recurrent angina during the early postoperative period is usually due to a technical problem with a graft or with early graft closure. This is indication for prompt coronary angiography with percutaneous coronary intervention (PCI), if feasible.
  • Recurrent angina after the first few months and beyond, called late recurrent angina, can occur with the development of stenosis in a bypass graft (either saphenous vein or arterial) or with progression of atherosclerosis in non-bypassed vessels.

Ashman’s Phenomenon

  • Functional right bundle branch block (RBBB) in atrial fibrillation occurring in the short cycle following a preceding long cycle that lengthened the refractory period in the right bundle branch (the Ashman phenomenon).

 

ffoashman