Today, Michael presented the case of a young woman with history of Sickle Cell Disease who presented with acute onset of CP, SOB, and pain, found to have new opacities on chest imaging and fevers concerning for Acute Chest Syndrome (ACS) with worsening symptoms requiring transfer for exchange transfusion.
- Leading cause of death in patients with SCD is acute chest syndrome (ACS)
- ACS is defined as new radio density on chest imaging with fevers and/or respiratory symptoms.
- Most common causes of ACS are bone marrow/fat embolism and CAP
- There is no clinical/laboratory standard for diagnosing acute sickle cell crisis.
- Hydroxyurea can decrease crisis frequency, ACS events, need for transfusions, hospitalizations, and death.
DDx of liver injury in the setting of SCD
- Hepatic sequestration
- Viral hepatitis
- Iron overload from transfusions
- Sickle cell intrahepatic cholestasis
Acute SCD complications
- Severe anemia (due to splenic sequestration, aplastic crisis, or hyperhemolysis)
- Vaso-occlusive phenomena
- Renal infarction or med toxicity
- Dactylitis/bone infarction
Acute chest syndrome
- Defined as a new radio density on chest imaging with fever (38.5) and/or respiratory symptoms
- >2% decrease in SpO2 from a documented steady-state value on room air
- PaO2<60 mmHg
- Use of accessory muscles of respiration
- Chest pain
- Leading cause of death for patients with SC disease
- Etiology of ACS in adults is commonly due to bone marrow or fat emboli followed by PNA
- 50% of patients with SCD will have an episode of ACS
- 80% of ACS episodes are associated with a vaso-occlusive pain episode
- Morality rate is 4.3%
- Clinical approach
- Determine severity (affects treatment)
- SpO2 >90% on RA
- 1 lobe affected by infiltrates
- SpO2 >85%
- 2 lobes affected
- Respiratory failure à mechanical ventilation
- 3 lobes affected
- Acute episode
- Pain control
- IVF (prevent hypovolemia but also avoid volume overload because it can worsen ACS)
- Blood transfusion:
- Mild ⇒ no transfusion
- Moderate ⇒ simple transfusion
- Severe ⇒ exchange transfusion (Goal Hg =10, HgS <30%)
- For CAP and atypicals x 7 days
- Supplementary O2
- Incentive spirometry
- DVT ppx
- Hydroxyurea (decreased incidence of ACS by 50%)
- Not good for acute episode
- Chronic transfusion therapy
- For those with > 2 episodes of moderate to severe ACS in 24 months despite hydroxyurea therapy
Today, we talked about a middle aged man presenting with acute onset of abdominal pain and weight loss, found to have a consolidation on chest imaging, low SAAG ascites, and a nodular omentum, work up revealing disseminated cocci! For more cases like this, check out http://www.humandx.org. If you’d like to hear some expert diagnosticians take a crack at this case and learn from their reasoning, check out thecurbsiders.com.
- Patients with immunosuppression, pregnancy, and DM2 are at risk of developing disseminated cocci.
- The most common manifestation of cocci is pneumonia which can be consolidative, nodular, or cavitary. Other manifestations include the skin (erythema nodosum and erythema multiforme), joints (arthralgias, vertebra, osteo), meningitis, SSTI, and visceral organs (rare).
- Cocci should be on your differential of infections that can cause eosinophilia and a low SAAG ascites.
Approach to eosinophilia
- Neoplasm ⇒ hypereosinophilic syndrome, T cell lymphoma, hodgkins lymphoma, solid organs (cervical, ovarian, gastric, colon, and urothelial cell carcinoma)
- Allergies ⇒ atopy, medication induced
- Adrenal insufficiency ⇒ rare cause
- Connective tissue disease ⇒ EGPA (formerly known as Churg Strauss), RA
- Parasites: strogyloides, toxocara, lymphatic filariasis, isospora, dientamaeoba, sarcocystis (note Giardia does NOT cause eosinophilia)
- Viruses: HTLV, HIV
- Fungi: aspergillus (ABPA), cocci, paracocci, histo, crypto
- Primary eosinophilic syndromes (typically single organ involvement of eos, may not have blood eosinophilia) ⇒ eosinophilic fasciitis, eosinophilic cellulitis
Differential for ascites based on SAAG
- Peritoneal carcinomatosis
- Infections (tuberculosis, bacteria, fungi including cocci, schistosomiasis)
- Biliary ascites
- Portal HTN
- Liver (cirrhosis, acute failure, alcoholic hepatitis, budd chiari, mets)
Coccidioidomycosis: Refer to this prior post on our blog for more details.
- Airborne fungal infection transmitted by cocci immitis and cocci posadasii
- Geographic distribution is southwest US and central valley
- Most common time for transmission is summer and fall seasons
- Risk factors for developing severe disease
- Immunosuppression (HIV with CD4 <250, steroids, chemo)
- DM2 (more likely to develop cavitary disease)
- Clinical manifestations
- Incubation period is 7-21 days
- Primary manifestation is CAP
- Other manifestations
- Skin: erythema nodosum and erythema multiforme
- Joints: arthralgias (desert rheumatism), osteo of joints and vertebrae
- Visceral organs and omentum (rare)
- Imaging (CXR can be normal in 50% of patients)
- Cocci EIA to screen
- Cocci immunodiffusion and complement fixation to confirm
- Immunocompetent and minimal symptoms? No treatment, most resolve spontaneously
- Severe disease/disseminated
- First line is fluconazole or itraconazole
- If no response, can try posaconazole
- Last resort is amphotericin B
- Duration of treatment can be up to a year
- Repeat anti-coccidioidal Abs in 2-4 weeks after starting treatment to ensure treatment response
Tim presented a young man with no medical history presenting with a chronic cough with intermittent trace hemoptsis. Other than this cough and mild shortness of breath when he exerted himself, this pt had no other symptoms. A CXR revealed bilateral pleural effusion, and upon thoracentesis, milky fluid drained out with an elevated triglyceride content consistent with a chylothorax. Subsequent biopsy of a lymph node revealed a diagnosis of follicular lymphoma!
Since we are talking about pleural effusion, Light’s Criteria will inevitably come up. For both real life (and boards!) purposes, know this criteria really well!
- SENSITIVE but NOT SPECIFIC for exudative effusions.
Any one of these criteria = exudative
- Fluid protein/Serum protein > 0.5
- Fluid LDH/Serum LDH > 0.6
- Fluid LDH > 2/3 upper limit of normal of serum LDH
False positive is possible in certain settings:
- Chronic diuretic use can falsely elevate fluid LDH (KNOW THIS)
- Transudative effusion that’s been sitting there chronically can appear exudative like
The following tests can help us distinguish between a falsely positive exudative effusion from a true exudative effusion:
- Pleural cholesterol > 45 mg/dL has high sensitivity and specificity for exudative effusions.
- Can also use serum albumin – fluid albumin < 1.2g/dL to confirm exudative effusion
Pleural Fluid Analysis: Clues
Upon performing a thoracentesis, certain characteristics can potentially give us some clues to the etiology of the effusion…
Fluid WBC Count
Fluid Predominant Myelocyte Type
Lastly, how do you diagnose a chylothorax and what are some potential causes?
- Definition: Triglyceride > 110 mg/dL = slam dunk
- 50 – 110: Less clear, cannot rule out, obtain liproprotein analysis. If presence of chylomicron is detected, likely chylothorax
- < 50: Less likely
- Malignant: Lymphomatous is most common, can also be other cancers i.e. lung, mediastinal mets, sarcoma, leukemia
- Non-malignant: Idiopathic, benign tumors, protein losing enteropathy, thoracic aortic aneurysm, TB, Sarcoid, amyloidosis, thyroid goiter, tuberous sclerosis, congestive heart failure, mitral stenosis
- Surgical is most common
- External trauma
- Trivial “trauma:” Stretching while yawning, coughing, hiccupping, sneezing (I’m not kidding)
Management of a malignant pleural effusion, as seen in this case, can be potentially challenging. After the patient was discharged, his pleural effusion on the right recurred within 3 days and completely filled up his right lung!
Several options are available for management of malignant pleural effusions. The decision is complicated and will goals of care discussion
- Indwelling pleural catheter
- Advantage: Pt managed, can drain at home
- Disadvantage: Catheter related complications
- Talc, slurry or poudrage, is the preferred agent. 60-90% success rate in reducing recurrence at 30 days.
- Doxycycline can also be used but not as popular any more
- Advantage: Eliminates the potential space for fluid reaccumulation
- Disadvantage: Pain, potential for surgical failure, invasive
- Combination: Talc + IPC
Katie presented a case of an elderly man with history of non-anuric ESRD on HD three times a week, NIDDM2, CMML, Klinefelter Syndrome, HTN, chronic anemia, and prior GIB secondary to gastric AVM who presented with shortness of breath. Earlier during the day he was at the transfusion center where he received a unit of PRBC. He was restless after the transfusion but he refused to stay for post-transfusion monitoring. He has been compliant with dietary restrictions and his HD sessions, but that evening after he went home, he started having difficulty breathing and hence he came to the ED. He was significantly hypertensive on presentation, and he went into respiratory failure requiring NIPPV. CXR revealed significant bibasilar pulmonary infiltrates c/w pulmonary edema. After diuresis and dialysis, his symptoms resolved. This presentation is consistent with transfusion associated circulatory overload, or TACO!
Let’s use this case to go over different types of transfusion reaction since you:
- Will encounter this during your career
- Will definitely get paged about this on nights
- Might encounter the more rare but potentially life-threatening reactions
- Common presentation
- Fever (defined as > 1 degree Celsius from baseline)
- Stable: Likely febrile non-hemolytic transfusion reaction
- Tylenol, slow rate of infusion, observe
- ABO incompatibility
- Bacterial contamination
- Hemolytic transfusion reaction
- TA Graft vs Host Disease (4-30 days after, delayed rxn, attack by immunocompetent donor lymphocytes on an immunocompromised recipient’s antigen presenting tissues. In immunocompetent recipients, reaction can occur if recipient is heterozygous for an HLA for which the donor is homozygous)
- Mild allergic reaction to plasma protein, common, resume transfusion at slower rate, anti-histamine PRN.
- Dyspnea or hypoxia
- Assess for anaphylaxis
- Yes: Treat for anaphylactic allergic reaction
- No: Consider circulatory overload
- E/O vol overload, diuretic responsive: TACO (transfusion related circulatory overload)
- Signs of instability, diuretic non-responsive: Suspect TRALI
- Hemolysis 1-4 weeks after transfusion: Delayed hemolytic transfusion reaction, usually very mild
Epidemiology: 1% of transfusions in general, higher in the ICU.
Pathophysiology: Circulatory overload leading to pulmonary edema
- Preexisting renal or cardiac dysfunction
- Higher transfusion volume
- Small stature
- Low body weight
- Extremes of age
- Development of respiratory distress or hypertension during or within 6 hours of completing a transfusion.
- May see concurrent headache
- Hypoxia, HTN, tachycardia, wide-pulse pressure, JVD, S3, crackles/wheezing
- Nt-proBNP elevated but non-specific
- Stop transfusion
- Report to transfusion service or blood bank. Get consultation for future transfusions i.e. smaller units, lower volume, or only during dialysis
- Rare, estimated 1 in 12000, leading cause of transfusion related mortality in the US
- Seen in all age groups and both sexes
- Not completely understood, but thought to be a neutrophil mediated reaction in setting pre-existing endothelial injury in the lungs, or antibodies to HLA
- ICU patients
- Multiparous female donors (OR 4.5)
- Heme malignancies
- Chronic EtOH
- Liver dysfunction
- Tobacco use
- Positive fluid balance
- Mechanical ventilation
- Note: Transfusion of older blood products was once thought to be a risk factor, but disproved by multiple RCTs around 2010-2012.
- During or within 6 hours after blood product transfusion
- Hypoxia, pulmonary infiltrates on exam, fever, hypotension
- May see elevated peak/plateau airway pressures in vented patients
- Non-responsive to diuretics
- ARDS like picture, sometimes diagnosis can be unclear, recent nomenclature of transfused ARDS.
- May have coexisting TACO
- Stop transfusion
- Notify blood bank/transfusion service
- Oxygen/ventilatory support, ARDS protocol (lower tidal volume) has generally been used
- Hemodynamic support, pts often hypovolemic, give fluids, pressors if needed.
- Corticosteroid historically has been used with inconsistent results
- Mortality as high as 41-67% in ICU population. Non-ICU patients have much lower morality, 5-17%. Almost all will recover their resp function, and they can still safely receive blood transfusions in the future.
- Identify implicated donor
- Irradiate blood products for immunocompromised recipients
- Avoid transfusion of blood product from a relative
- Blood donated by men has lower incidence for unclear reasons
Bri presented a case of a gentleman with multiple medical comorbidities with a recent lap chole presenting with confusion. His labs were significant for anemia, thrombocytopenia, elevated indirect bilirubin, elevated LDH, and undetectable haptoglobin. A smear revealed numerous schistocytes concerning for MAHA. ADAMTS13 levels were found to be very low, and the presence of an ADAMTS13 inhibitor was detected as well. This presentation is consistent with thrombotic thrombocytopenic purpura (TTP)!
Common differential for microangiopathic hemolytic anemia (MAHA):
- TTP/HUS, atypical HUS
- Mechanical heart valves
- Severe B12 deficiency
- Rare, most often > 40 in adults, congenital ADAMTS13 deficiencies can be seen in kids (Upshaw-Schulman Syndrome, autosomal recessive)
- 2:1 female to male predominance
- Non-immune mediated platelet and RBC destruction due to mechanical shearing of platelets and RBC when they pass through platelet/fibrin deposits on small vessel walls in absence of ADAMTS13 activity.
- Further consumption of plts via formation of microthrombi in small arterioles/capillaries, brain/heart/kidneys are especially affected.
- ADAMTS13 cleaves VWF, preventing large multimer formation on vessel walls
J Evan Saldler. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008 112:11-18; doi: https://doi.org/10.1182/blood-2008-02-078170
- Drug-induced (Immunosuppressants, chemo)
- Pregnancy (preeclampsia/eclampsia)
- Hemorrhagic colitis
- HUS: more likely in kids, more commonly presents with AKI and in higher severity. Associated with E.coli O157:H7 infection and some strains of Shigella
- Atypical HUS: very similar to TTP but differnet pathophys (congenital complementary activation defect)
- Pentad of FATRN: < 1/3, can be indolent (days to weeks of malaise)
- Fever( 10%)
- Anemia (100%)
- Thrombocytopenia (100%)
- Renal dysfunction, more common in HUS
- Neuro (encephalopathy): More common in TTP (53%), less in HUS
- Triad that’s almost always present:
- LDH elevation
- Sx: Non-specific, encephalopathy, abd pain, N/V, diarrhea, arrhythmia.
- Exam: SICK compared to pts with ITP.
- E/O hemolysis: Anemia, polychromasia, elevated retic, reduced hepato, elevated LDH, elevated indirect bilirubin
- Fibrinogen is normal (although early DIC can also be relatively normal)
- PT/PTT are normal (vs elevated in DIC!)
- Low ADAMTS13 level (<10%) is highly specific for TTP
- ADAMTS13 inhibitor usually seen in adults, suggestive of autoimmune related deficiency of ADAMTS13. Generally responsive to immune suppression.
- Emergent consultation with specialists, coordinate with MICU, Heme/Onc, and Renal!
- FFP can be given to temporize things, fastest treatment option
- DO NOT TRANSFUSE PLATELETS
- 90% mortality without tx
- Emergent PLEX: reduces mortality to 20-30%, but those who survive the initial episode can have relapses 20-50% of the time.
- Low ADAMTS13 activity and higher titers of ADAMTS13 inhibitor are associated with worse prognosis.
- Plasma exchange usually continued until e/o dz activity has decreased (nrl plt, nrl LDH)
- Immune suppression with corticosteroids, rituximab can be considered in refractory cases.
- For HUS, tx is mainly supportive +/- dialysis but Eculizumab can be used.
Yonglu presented a middle age man with no medical history presenting with syncope. In the preceding months, he has been having non-specific fatigue, decreased exercise tolerance, dizziness, and diaphoresis. He was found to be hypoglycemic after this syncopal episode, and in the hospital his labs were consistent with hyperinsulinism when he was in a hypoglycemic state. CT revealed diffuse liver masses concerning for HCC, as well as a lesion on his left iliac crest appearing to be an osteosarcoma. He was also found to have a pancreatic mass as well…
Three malignant processes? Octreotide scan revealed increased uptake at these regions, and biopsy of the liver revealed a diagnosis of a neuroendocrine tumor!
When we think about hypoglycemia, its pattern can actually give us a clue.
- Fasting: Most common
- Post-prandial: non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), post-bariatric surgery hyperinsulinemic hypoglycemia
- Both: Insulin autoantibody, insulinoma
- Rare, not enough data
- Small cohort: median age 48 years, 77% men
- MEN Type 1: Younger presentation, 20s
- Pancreatic islet cell origin
- Generally benign, single vs multiple
- Rare to be malignant (10%)
- Pattern: fasting hypoglycemia mainly but can be both
- May have some sympathoadrenal sx i.e. palpitations, diaphoresis (seen in this patient), tremulousness
- Likes to spread to liver, rarely can have bony mets (~13%)
Whipple’s Triad: Presence of all three demonstrates “true” hypoglycemia
- Symptoms of hypoglycemia
- Low plasma glucose at time of symptoms
- Relief of symptoms when glucose is back to normal
- Evidence of inappropriately high serum insulin during episode of hypoglycemia
- 72 hour fasting plasma glucose test: Supervised fast in order to bring on hypoglycemia in order to evaluate etiology. If pt has underlying hyperinsulinism, 95-99% of the time they will be hypoglycemia within 48 hours of fasting.
- Blood test is drawn when pt has sx of hypoglycemia
- Test: Glucose, insulin, proinsulin, and c-peptide level.
- Normal: suppression of endogenous insulin
- Abnormal: Inappropriately elevated insulin, pro-insulin, and c-peptide in setting of hypoglycemia.
- Octreotide scan: Increased uptake seen in tumors of neuroendocrine etiology, more sensitive than US, CT, or MRI for detection of somatostatin receptor positive tumors
- Evidence of hyperinsulinism
- Low BHB
- High insulin level
- High C-peptide
- High pro-insulin
- Chromogranin A: used to help diagnose carcinoid tumors (NET of the digestive tract and lungs). Nowadays carcinoid is generally used to refer to well differentiated NETs originating in the lungs. GI tract tumors are now termed NET.
- Localized lesion: Surgical resection is curative
- Somatostatin analogy
- Octreotide: Inhibits growth hormone secretion, can switch to Q-monthly formulation
- Diazoxide: Diminishes insulin secretion, side effects include hirsutism and edema
- Radiation therapy: Data also limited in utility but can be consider if evidence of bony mets (which is also rare for NET)
- Minority of NET, namely high-grade, well differentiated with Ki67 index > 20%, are rare and there is no consensus on how to treat these patients. These patients generally respond poorly to platinum/etoposide based regimens used to treat most NETs.
- Other options: Temozolomide, Sunitinib (RTK inhibitor), Everolimus (mTOR inhibitor)
Helpful table for hypoglycemia work up.
Beta-hydroxybutyrate (BHB) is by product of alternate metabolism (more specifically ketone bodies) in a fasting state, so it can be elevated in setting of prolonged fasting (not just DKA).
Also thanks to Arathi for pointing out that insulin has a negative feedback on this process, hence in a hyperinsulinemic state (despite concurrent hypoglycemia), beta hydroxybutyrate would be very low!
Insulinomas can appear like hypoglycemia secondary to oral glycemic agents, but the key is the oral glycemic agent screen would be positive in the latter case!
IGF-omas can cause s/sx hypoglycemia due to similarity with insulin. Expect IGF2 levels to be elevated in such cases and elevated BHB.
Please refer to this helpful review article if you want to know more about NETs!
Also please refer to this paper for a case report on AFP-producing pancreatic NET (AFP elevated in this patient!)
Thanks to Barnie for presenting the case of a middle-aged woman who was admitted with acute onset of SOB, found to have submassive PE.
- Risk stratification tools are helpful in estimating the pre-test probability of PE. The best and most validated is Wells criteria.
- YEARS items is a newer tool that was studied in an RCT in the Netherlands and found to lower the number of CTPA scans ordered by 14% without a significant impact on rates of missed PE diagnoses.
- For patients at low risk of PE according to Wells, PERC is useful in ED or outpatient setting to rule out PE without ordering a d-dimer (see graphic below).
- Age-adjusted d-dimer is age x 10 for patients older than 50 years. This accounts for the increase in d-dimer baseline related to aging. ADJUST-PE trial showed that age-adjusted d-dimer leads to higher specificity without subsequent VTE.
- Studies have shown an 11.6% reduction in CTPA scans with the use of this correction factor without an appreciable increase in missed diagnoses of PE.
- Think of PE in three broad categories:
- Massive PE = hemodynamically unstable ⇒ anticoagulation + thrombolysis
- Submassive PE = hemodynamically stable + RV strain ⇒ anticoagulation + thrombolysis
- Low risk PE = hemodynamically stable, no RV strain ⇒ anticoagulation. Use the PESI score to determine if your patient can be treated outpatient.
- Remember that the most common EKG finding in PE is normal sinus rhythm! The most common abnormal EKG finding is sinus tachycardia. S1Q3T3 pattern is only seen in 10% of patients with PE.
Suggested algorithm for diagnostic work up of suspected PE:
Remember that the scoring tools above are only there to add to your clinical judgment, not replace it!
Recent study in the Lancet looked at the utility of a different diagnostic algorithm, using the three most predictive items on Wells together with d-dimer. Compared to Wells, this diagnostic tool led to a 14% reduction in unnecessary CTPA!
- Remember that clot burden does not factor into the treatment categories of PE. Low clot burden in a patient with baseline cardiopulmonary disease can still lead to hemodynamic compromise and would be considered massive PE.
- Submassive PE treatment is an area of much debate. A famous trial (PEITHO trial) in 2014 randomized 1006 patients to receive heparin + placebo vs heparin + tenecteplase (European version), and found a >50% reduction in combined death and cardiovascular collapse at 7 days but a > four-fold increase in risk of major bleed including intracranial hemorrhage. Subsequent meta-analyses (and this one) found that the risk of major bleeding was highest in people >65 years of age. So treatment decisions here are tricky and require consulting multiple services!
Signs of RV strain:
- EKG findings:
- S1Q3T3: this is a sign of cor pulmonale and can be seen in a number of conditions in addition to PE
- Bronchospasm (really bad asthma)
- Echo findings:
- Elevated RVSP
- Septal bowing
- McConnell’s sign (regional wall motion abnormality sparing the RV apex)
- Not sensitive but helpful in distinguishing RV strain due to chronic pulmonary HTN from RV strain due to acute PE
- Increased RV size
- Decreased RV function
- Tricuspid regurgitation
- Elevated troponin
- Elevated BNP