Leukemoid Reaction

Brief HPI:

An approximately 80-year-old male with unknown medical history is brought to the emergency department from a skilled nursing facility after unwitnessed arrest – EMS providers established return of spontaneous circulation after chest compressions and epinephrine. On arrival, the patient was hypotensive (MAP 40mmHg) and hypoxic (SpO2 85%) with mask ventilation. The patient was intubated, resuscitated with intravenous fluids and started on vasopressors. Imaging demonstrated lung consolidation consistent with multifocal pneumonia versus aspiration. Laboratory studies were obtained:

CBC: WBC: 49.2 (N: 64%, Bands: 20%)
ABG: pH: 7.07, pCO2: 73mmHg
Lactate: 9.1mmol/L

CT Pulmonary Angiography

Peribronchial opacities and patchy consolidation in the lungs which may represent multifocal pneumonia and/or aspiration in the appropriate clinical setting.
Mildly dilated main pulmonary artery suggestive of pulmonary arterial hypertension.

ED Course:

The patient was admitted to the medical intensive care unit for cardiopulmonary arrest presumed secondary to hypoxia and septic shock from healthcare-associated pneumonia or aspiration. The markedly elevated white blood cell count was attributed to a combination of infection and tissue ischemia from transient global hypoperfusion.

Definition: ¹

Markedly elevated leukocyte (particularly neutrophil) count without hematologic malignancy
Cutoff is variable, 25-50k

Review of Available Literature

Retrospective review of 135 patients with WBC >25k ²: 48% infection; 15% malignancy; 9% hemorrhage; 12% glucocorticoid or granulocyte colony stimulating therapy
Retrospective review of 173 patients with WBC >30k ³: 48% infection (7% C. difficile); 28% tissue ischemia; 7% obstetric process (vaginal or cesarean delivery); 5% malignancy
Observational study of 54 patients with WBC >25k ⁴: Consecutive patients presenting to the emergency department; Compared to age-matched controls with moderate leukocytosis (12-24k); Patients with leukemoid reaction were more likely to have an infection, be hospitalized and die.

Differential Diagnosis of Leukemoid Reaction ^1,5-8

References

Sakka V, Tsiodras S, Giamarellos-Bourboulis EJ, Giamarellou H. An update on the etiology and diagnostic evaluation of a leukemoid reaction. Eur J Intern Med. 2006;17(6):394-398. doi:10.1016/j.ejim.2006.04.004.
Reding MT, Hibbs JR, Morrison VA, Swaim WR, Filice GA. Diagnosis and outcome of 100 consecutive patients with extreme granulocytic leukocytosis. Am J Med. 1998;104(1):12-16.
Potasman I, Grupper M. Leukemoid reaction: spectrum and prognosis of 173 adult patients. Clin Infect Dis. 2013;57(11):e177-e181. doi:10.1093/cid/cit562.
Lawrence YR, Raveh D, Rudensky B, Munter G. Extreme leukocytosis in the emergency department. QJM. 2007;100(4):217-223. doi:10.1093/qjmed/hcm006.
Marinella MA, Burdette SD, Bedimo R, Markert RJ. Leukemoid reactions complicating colitis due to Clostridium difficile. South Med J. 2004;97(10):959-963. doi:10.1097/01.SMJ.0000054537.20978.D4.
Okun DB, Tanaka KR. Profound leukemoid reaction in cytomegalovirus mononucleosis. JAMA. 1978;240(17):1888-1889.
Halkes CJM, Dijstelbloem HM, Eelkman Rooda SJ, Kramer MHH. Extreme leucocytosis: not always leukaemia. Neth J Med. 2007;65(7):248-251.
Granger JM, Kontoyiannis DP. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study. Cancer. 2009;115(17):3919-3923. doi:10.1002/cncr.24480.

Bleeding Disorders

Overview

Disorders of primary hemostasis
- General: present with mucocutaneous, post-operative bleeding
- vWD
- Platelet disorders
  - Medication-induced: NSAID, valproate, B-lactam, SSRI
  - Systemic disease: hepatic, renal failure
- ITP: antibody-mediated platelet destruction
Disorders of secondary hemostasis
- General: present with bleeding into soft-tissue, joints
- Hemophilia A (VIII)
- Hemophilia B (IX)
Disorders of both primary and secondary hemostasis
- DIC
- Liver disease
- Severe vWD
Evaluation
- PT: VII, vitamin K
- PTT: VIII, IX, XI, XIII, vWD, heparin
- Increased PT/PTT: XI, V, vitamin K, heparin, DIC
- CBC: degree of anemia, platelet count, differential (hematopoetic disorders)
Management
- Thrombocytopenia
  - Prophylactic transfusion for avoidance of spontaneous hemorrhage for platelet count <10,000
  - Transfusion for active bleeding at platelet count <50,000
  - Dosing
    - Adults: one RDP increases platelet count by 7-10,000
    - Pediatrics: 5-10ml/kg
  - ITP
    - Transfuse platelets for active bleeding
    - High-dose steroids (prednisone 1mg/kg)
    - IVIG (1g/kg/d)
  - Uremia
    - Hemodialysis
    - DDAVP (0.3ug/kg IV)
  - vWD
    - DDAVP (0.3ug/kg IV)
    - Severe: VWF (Humate-P) 40-80IU/kg
    - Tranexamic acid
  - Hemophilia A
    - Minor: 20IU/kg
    - Major: 50IU/kg
  - Hemophilia B
    - Minor: 40IU/kg
    - Major: 100IU/kg

DIC/TTP/HUS

Disseminated Intravascular Coagulation
- Etiology: severe systemic illness/injury
  - Trauma, burn, crush
  - Sepsis
  - Malignancy
  - Obstetric complication: abruption, amniotic fluid embolism
  - Hemolytic anemia
- Exam: petechiae/purpura, hemorrhage (puncture site, GI, GU, pulmonary)
- Labs:
  - PT/PTT
  - Fibrinogen
  - CBC: schistocytes, thrombocytopenia
  - FDP/D-Dimer
- Management
  - Treat underlying illness
  - Transfuse (PRBC, FFP for INR > 2, cryoprecipitate for fibrinogen < 100)
  - Heparin if apparent embolic events
  - Consult hematology
TTP/HUS
- Presentation
  - Thrombocytopenia
  - Altered mental status
  - Renal dysfunction
  - Fever
  - MAHA
- TTP: more commonly associated with altered mental status
  - Etiology: drugs, pregnancy, infection (HIV)
  - Mechanism: ULvWF uncleaved by dysfunctional ADAMTS-13
- HUS: more commonly associated with renal dysfunction
  - Mechanism: toxin from E. coli, Shigella
  - Timing: 1-2wks after diarrheal illness
- Evaluation
  - CBC: anemia, schistocytes, thrombocytopenia
  - PT/PTT (normal)
  - BUN/Creatinine
  - LDH
- Management
  - Platelets contraindicated except as stopgap measure in ICH (can worsen process)
  - Plasma exchange with FFP (replaces functional ADAMTS-13)
  - Steroids (prednisone 1mg/kg daily)
  - Hematology consultation

Complications of anti-thrombotic therapy

Agents
- Anti-platelet
  - TXA: Aspirin
  - ADP: clopidogrel, ticagrelor, prasugrel
  - GPIIb/IIIa: abciximab, eptifibatide, tirofiban
- Anti-coagulants
  - Anti-thrombin: heparin, LMWH (enoxaparin, dalteparin)
  - Vitamin K antagonist: warfarn (anti-II, VII, IX, X)
  - Direct thrombin inhibitor: bivalirudin, argatroban, dabigatran
  - Xa inhibitor: rivaroxaban, apixaban
- Fibrinolytics
  - Alteplase, tenectaplase
Complications
- HIT: platelet count decrease >50% at 5 days

Summary of Management

Agent	Reversal
Aspirin, clopidogrel	5-10U platelets DDAVP 0.3ug/kg
GPIIb/IIIa	Abciximab: 5-10U platelets Eptifibatide/tirofiban: none
Heparin	Protamine 1mg/100mg heparin in last 2-3 hours
LMWH	Enoxaparin: 1mg/1mg Dalteparin: 1mg/100U
Warfarin	See supratherapeutic INR algorithm
DTI	Dabigatran: Praxbind, hemodialysis, consider Factor VIIa
Xa	PCC
Fibrinolytics	10U cryoprecipitate, 2U FFP, consider platelets and aminocaproic acid (4-5g IV)

Anemia

HPI

70M with a history of dementia presenting with 3 days of fatigue. The patient was unable to provide detailed history, however family members reported worsening fatigue with the patient requiring assistance with ambulation for several days. The patient was referred from an outside clinic after point-of-care hemoglobin of 6.7. No reported history of anemia, and no history suggestive of obvious external bleeding.

Vital signs stable, tachycardia and tachypnea noted with minimal exertion but saturating well on ambient air and in no acute distress. Examination notable for conjunctival pallor without scleral icterus, systolic flow murmur, brown stool guaiac negative.

CBC with hemoglobin of 7.5 , MCV 80.3 , RDW 22.4 , no leukocytosis and normal platelets. Also noted was an alkaline phosphatase of 828 , normal total and direct bilirubin, and undetectable serum troponin. Chest x-ray showed a possible pleural-based mass.

The patient was transfused two units of PRBC’s and admitted for further evaluation. CT chest/abdomen/pelvis revealed sternal and rib-based pleural soft-tissue mass, prostate mass, pelvic and retroperitoneal lymphadenopathy as well as extensive bony metastatic disease consistent with primary prostate cancer with diffused metastasis. Serum PSA was 2,087 . Iron studies suggested anemia of chronic disease. Reticulocytes were not obtained but may have suggested inadequate production index given extensive bony metastases and possible associated myelosuppression. The patient was symptomatically improved after transfusion and discharged with outpatient follow-up for discussions regarding possible biopsy and treatment.

Images

Areas of pleural thickening. Possible pleural based mass in left mid lung.

CT Chest: Lung Window

Rib-based pleural soft tissue masses.
Large 5.6 x 4.4cm anterior sternal soft-tissue mass.

CT Body: Bone Window

Extensive bony metastatic disease.
Prostate mass, large pelvic and retroperitoneal lymphadenopathy.
Consistent with primary prostate cancer with diffuse metastasis.

Algorithm for the Evaluation of Anemia ^1,2

References:

Zaiden R, Rana F. Evaluation of Anemia. BMJ Best Practice. Oct 2014. http://us.bestpractice.bmj.com/best-practice/monograph/93/overview.html. Last accessed 15 May 2015.
Janz, T. G., Johnson, R. L., & Rubenstein, S. D. (2013). Anemia in the emergency department: evaluation and treatment. Emergency medicine practice, 15(11), 1–15– quiz 15–6.
WiKEM: Anemia

Pulmonary Embolism in Hospitalized Patients

Brief Progress Note

Notified by nursing of abnormal vital signs, SpO2 91%. Briefly, this patient is a 52 year-old G1P1 with no prior medical history who is post-operative day three status post total abdominal hysterectomy, bilateral salpingoophorectomy as well as tumor debulking and staging for suspected primary ovarian adenocarcinoma based on peritoneal fluid cyctology.

On evaluation, the patient denied shortness of breath, chest pain, pleuritic chest pain, cough/hemoptysis, or calf/thigh pain. She states that she had been ambulating around the ward prior to having her vital signs assessed.

Physical Exam:

VS:	T	98.9	HR	94	RR	18	BP	117/72	O2	91% RA
Gen:	No acute distress, speaking in full sentences.
HEENT:	No jugular venous distension.
CV:	RRR, normal S1/S2, no prominent P2, no additional heart sounds.
Lungs:	Decreased breath sounds at inferior 1/3 posterior lung fields bilaterally, faint crackles above, no wheezing. Dullness to percussion in inferior lung fields.
Ext:	Warm, well-perfused. Sequential compression devices on bilateral lower extremities, removed revealing trace pitting edema symmetric bilaterally, no tenderness to palpation of posterior leg, no pain with passive dorsiflexion.

Medications:

Lovenox 40mg s.q. daily
Norco 5-325mg p.o. q.4.h. p.r.n. pain
Morphine 2mg i.v. q.3.h. p.r.n. breakthrough pain
Colace 100mg p.o. b.i.d. p.r.n. constipation
Zofran 4mg i.v. q.6.h. p.r.n. nausea/vomiting

Imaging:

CXR

Bilateral pleural effusions with pleural fluid tracking along the minor fissure.

CT Chest

No evidence of pulmonary embolism, study performed 5 days prior to onset of symptoms.

CT Abdomen/Pelvis

Significant peritoneal carcinomatosis, ascites delineates peritoneal from retroperitoneal spaces.

Assessment and Plan:

52yo G1P1 with likely primary ovarian adenocarcinoma with extensive peritoneal involvement, complicated by malignant ascites and pleural effusions with hypoxemia. The primary concern in this post-operative patient with a history of malignancy is venous thromboembolism, particularly pulmonary embolism. Aside from hypoxemia, this patient had no symptoms suggestive of pulmonary embolism (denied dyspnea, chest pain, cough, or lower extremity pain). Her examination had some signs infrequently associated with pulmonary embolism which were otherwise adequately explained by known bilateral pleural effusions (including decreased breath sounds, rales, and tachypnea), she was not tachycardic, had no evidence of jugular venous distension, nor a prominent P2. In addition, she was receiving appropriate VTE prophylaxis (both pharmacological and mechanical). The application of the Modified Wells clinical decision rule suggests low likelihood of pulmonary embolism (with 2.5 points assigned for recent surgery and history of malignancy). The patient had a recent CT chest without evidence of pulmonary embolism, and given that an elevated D-dimer was virtually assured which would have necessitated repeat imaging (and the associated risks of radiation exposure and contrast injury), the episode was ascribed to ventilation/perfusion mismatch secondary to large pleural effusions. Hypoxemia resolved after several minutes at rest and no further testing was performed.

Signs and Symptoms of Pulmonary Embolism¹

Signs	Symptoms
Tachypnea	Dyspnea (rest/exertion)
Tachycardia	Pleurtic chest pain
Rales	Cough
Decreased breath sounds	Orthopnea
Prominent P2	Calf/thigh pain or swelling
JVD	Wheezing

Modified Wells Criteria^1,2

Feature	Points
Clinical symptoms of DVT (leg swelling, tenderness to palpation)	3.0
Pulmonary embolism most likely diagnosis	3.0
Tachycardia (HR >100)	1.5
Immobilization >3d, surgery in prior 4 weeks	1.5
Prior DVT/PE	1.5
Hemoptysis	1.0
Malignancy	1.0

>4.0 Likely
≤4.0 Unlikely

Algorithm for Evaluation of Suspected Pulmonary Embolism²

Utility of D-Dimer:²: Of limited utility in patients with high suspicion for pulmonary embolism; Decreased specificity: malignancy, hospitalized patients, pregnancy, elderly
Efficacy of DVT prophylaxis:³: LMWH prevents approximately ½ of VTE events (including PE, symptomatic and asymptomatic DVT)

References:

Kruip, M. J. H. A., Söhne, M., Nijkeuter, M., Kwakkel-Van Erp, H. M., Tick, L. W., Halkes, S. J. M., Prins, M. H., et al. (2006). A simple diagnostic strategy in hospitalized patients with clinically suspected pulmonary embolism. Journal of internal medicine, 260(5), 459–466. doi:10.1111/j.1365-2796.2006.01709.x
Tapson, V. F. (2008). Acute pulmonary embolism. The New England journal of medicine, 358(10), 1037–1052. doi:10.1056/NEJMra072753
Själander, A., Jansson, J.-H., Bergqvist, D., Eriksson, H., Carlberg, B., & Svensson, P. (2008). Efficacy and safety of anticoagulant prophylaxis to prevent venous thromboembolism in acutely ill medical inpatients: a meta-analysis. Journal of internal medicine, 263(1), 52–60. doi:10.1111/j.1365-2796.2007.01878.x

Lymphadenopathy Applied: Lymphoma

HPI:

27 year-old female with no medical history presenting with neck swelling. She describes one month of progressive enlargement of a left-sided neck mass, and in the past two weeks has noted a new right-sided neck mass. This has been associated with worsening dysphagia to solids, describing a sensation of food lodging in the mid-chest and requiring liquids for passage – she attributes her recent 10lb weight loss to this. She also reports a non-productive cough for the past two weeks and generalized fatigue. She otherwise denies fevers, night sweats, chest pain, shortness of breath, nausea/vomiting, or changes in bowel/urinary habits. She has no known sick contacts or TB exposure risk factors. She has no medical history, no prior surgeries, does not take any medications and denies tobacco, alcohol or drug use.

Physical Exam:

VS:	T	38.4	HR	98	RR	14	BP	108/68	O2	99% RA
Gen:	Well-appearing young female, in no acute distress.
HEENT:	PERRL, EOMI, MMM without lesions. There is a 2x3cm firm, non-tender, mobile left supraclavicular lymph node, as well as two 1x1cm firm, non-tender lymph nodes in the left and right anterior cervical chains.
CV:	RRR, normal S1/S2, no murmurs. No JVD.
Lungs:	Clear to auscultation bilaterally. There is a transition to bronchial breath sounds along the trachea inferior to the sternal angle with normal tracheal sounds superiorly.
Abd:	Soft, non-tender without organomegaly.
Ext:	Warm and well-perfused with normal peripheral pulses. No axillary or inguinal lymphadenopathy.
Neuro:	Alert and oriented, responding appropriately to questions. PERRL, EOMI, facial sensation symmetric, facial muscles symmetric, hearing grossly normal, palate rises symmetrically, tongue movements normal without fasciculation, SCM/trapezius normal. Normal FTN, RAM. Gait intact. Peripheral sensation and motor grossly normal.

Imaging:

CT Chest - Axial

Anterior mediastinal mass with a wide differential - likely represents lymphoma or germ cell tumor. Less likely thymic or thyroid origin.

CT Chest - Sagittal

Anterior mediastinal mass with a wide differential - likely represents lymphoma or germ cell tumor. Less likely thymic or thyroid origin.

Assessment/Plan:

27F with no PMH presenting with progressive localized lymphadenopathy. Resultant dysphagia, cervical and supraclavicular distribution as well as abnormal tracheal sounds concerning for mediastinal involvement. The patient is currently stable without evidence of airway compromise. A CT of the chest was obtained to evaluate for thoracic malignancy, which showed a large anterior mediastinal mass concerning lymphoma or germ cell tumor. The location of the mass likely explains the patient’s dysphagia due to compression of the esophagus, as well as the abnormal pulmonary exam with compression potentially irritating the trachea and triggering her non-productive cough. The patient was admitted for further workup.

Lymphadenopathy Applied – Lymphoma

This case applies the differential diagnosis of lymphadenopathy. The most abnormal finding on examination was non-tender, left supraclavicular lymphadenopathy. The duration of symptoms and lack of tenderness is concerning for malignancy, and the left supraclavicular location suggests a thoracic or intra-abdominal source.

Cervical Lymphadenopathy

32 year-old male, previously healthy, with slowly-progressive right and left cervical lymphadenopathy over the past three years. He first noted the development of a mass on the lateral neck below the ear three years ago. This mass was non-tender and remained stable at approximately the size of a marble for nearly one year. He later developed more and larger masses, but never experienced any constitutional symptoms like fevers, night sweats, fatigue or weight loss. Examination reveals a healthy, well-nourished male with multiple, hard, mobile, non-tender right posterior cervical and submandibular lymph nodes and a large left supraclavicular lymph node, protruding above the clavicle and measuring ~4x3cm.

Imaging:

Cervical Lymphadenopathy - Axial

- Left supra-clavicular lymph node, 4.5 x 2.9 cm
- Right posterior submandibular lymph node, 3.5 x 2.7 cm
- Multiple other small cervical lymph nodes, more on the right

Cervical Lymphadenopathy - Coronal

- Left supra-clavicular lymph node, 4.5 x 2.9 cm
- Right posterior submandibular lymph node, 3.5 x 2.7 cm
- Multiple other small cervical lymph nodes, more on the right

He has undergone several diagnostic procedures during this time including aspirations and core biopsies with inconclusive pathology and he is currently admitted for an excisional biopsy of the supraclavicular lymph node. Infectious and rheumatologic workup has remained negative including: HIV, bartonella, Quantiferon TB Gold, cocci, histo, toxo, CMV, EBV, ANA, RF, ACE.

The patient tolerated the excisional biopsy without complication and was discharged. Preliminary pathology suggests Castleman’s disease.

Lymph nodes and their drainage: ^1,2

Evaluation of Lymphadenopathy: ^2,3,4

References:

Ferrer R. Lymphadenopathy: differential diagnosis and evaluation. Am Fam Physician. 1998;58(6):1313–1320.
Henry PH, Longo DL. Chapter 59. Enlargement of Lymph Nodes and Spleen. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 18e. New York: McGraw-Hill; 2012.
Armitage JO. Chapter 171. Approach to the Patient With Lymphadenopathy and Splenomegaly In: Cecil, Russell L., Lee Goldman, and Andrew I. Schafer. Goldman’s Cecil medicine. Philadelphia: Elsevier/Saunders, 2011.
Motyckova G, Steensma DP. Why does my patient have lymphadenopathy or splenomegaly? Hematol. Oncol. Clin. North Am. 2012;26(2):395–408– ix. doi:10.1016/j.hoc.2012.02.005.

Brief HPI:

CT Pulmonary Angiography

ED Course:

Definition: 1

Review of Available Literature

Differential Diagnosis of Leukemoid Reaction 1,5-8

References

Overview

DIC/TTP/HUS

Complications of anti-thrombotic therapy

Summary of Management

HPI

Images

CT Chest: Lung Window

CT Body: Bone Window

Algorithm for the Evaluation of Anemia 1,2

References:

Brief Progress Note

Physical Exam:

Medications:

Imaging:

CXR

CT Chest

CT Abdomen/Pelvis

Assessment and Plan:

Signs and Symptoms of Pulmonary Embolism1

Modified Wells Criteria1,2

Algorithm for Evaluation of Suspected Pulmonary Embolism2

References:

HPI:

Physical Exam:

Imaging:

CT Chest - Axial

CT Chest - Sagittal

Assessment/Plan:

Lymphadenopathy Applied – Lymphoma

Imaging:

Cervical Lymphadenopathy - Axial

Cervical Lymphadenopathy - Coronal

Lymph nodes and their drainage: 1,2

Evaluation of Lymphadenopathy: 2,3,4

References:

Definition: ¹

Differential Diagnosis of Leukemoid Reaction ^1,5-8

Algorithm for the Evaluation of Anemia ^1,2

Signs and Symptoms of Pulmonary Embolism¹

Modified Wells Criteria^1,2

Algorithm for Evaluation of Suspected Pulmonary Embolism²

Lymph nodes and their drainage: ^1,2

Evaluation of Lymphadenopathy: ^2,3,4