1. 09/10/2013
Nader Tashtoush
Grand round Case

2. History 75 Years old female Pt.
HTN, DM, breast cancer had mastectomy in 2010.
She had a follow up visit to her Plastic Surgeon's office for cellulites of left breast for which she had an implant after her mastectomy .
Clindamycin 10 days.
She didn't improve and return to the clinic , her WBCs were only 0.5, and referred her to her PCP.
her PCP redrew my labs and found my WBCs to be 0.4 and low platelets at 69. bone marrow aspiration w/ bx 08/29/13 in which the preliminary report suggested APL.
Admitted in 8/30 referred from Crittenton Hospital for induction chemotherapy.

3. ID was consulted for her cellulites despite cefepime and vancomycin Rx for the last 4 days in 09/03/2013.
Pt is afebrile, her cellulites is slightly better according to the PT.
She denies any fever, nausea, vomiting, Cough, SOB, wheezing, Diarrhea.
ROS: Insignificant.
Family Hx.: Hx. of breast Ca in mother
Social Hx: Non smoker, non alcoholic, no drug abuse.

4. Hospital medications:
Home medications
Alendronate
AmLODIPine-valsartan
Atenolol
Calcium-vitamin D
Pravastatin.
Hospital medications:
Cefepime.
Vancomycin
ARTA.
Arsenic Trisenox.

5. Physical examination General: Alert and oriented, No distress.
HENT: Normocephalic, Atraumatic, No sinus tenderness.
Respiratory: GBAE, No wheeze, No crepitation.
Cardiovascular: Regular rate, Regular rhythm, S1 auscultated, S2 auscultated, No murmur, No gallop.
Breast: left breast erythema improving without marked tenderness..
Gastrointestinal: Soft, Non-tender, Non-distended, Normal bowel sounds, No organomegaly.
Integumentary: Warm, Dry, Intact.
Neurologic: Alert, Oriented, No focal defects.
Psychiatric: Cooperative, Appropriate mood & affect.

6. Investigation WBC Neut HG PLT BUN Creat. 0.8 0.1 7.2 88 17 0.7 PT INR
PTT
D -Dimer
FDP
Fibrinogen
13.7 1 23
6.89
Positive
248
US Breast: No obvious mass or abscess identified by ultrasound. No ultrasound evidence of cellulites.
TTE: EF 55-60%

7. 09/05/2013
She developed sudden SOB overnight with wheezing and dry cough.
Chest: Bilateral wheezing and bilateral crepitations.
Bilateral lower limb edema
WBC: 7.1

8. 09/07/2013 Worsening SOB and Labored breathing .
She was transferred to MICU for close monitoring.
Exam: Temp: 37.2 RR: 32
Chest: Bilateral wheezing and crepitations.
Bilateral lower limb edema.
WBC
PLT
INR
PTT
Fibrinogen
14000
85000 1 24
271

9. DDx and questions

10. Differentiation (retinoic acid) syndrome
Fatal complication of induction chemotherapy in patients with acute promyelocytic leukemia (APL).
Cytokine release syndrome.
25 % of patients . ( ATRA, and arsenic trioxide).
Time to occurrence of moderate and severe differentiation syndrome.
Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood January 22, 2009vol. 113 no. 4 

11. Pathogenesis
ATRA and ATO may induce release of cytokines from differentiating myeloid cells that cause a capillary leak syndrome.
ATRA and ATO may enhance the migration of maturing leukocytes, with subsequent organ infiltration resulting in respiratory and renal dysfunction.
ATRA and ATO may induce upregulation of the expression of integrins (cellular adhesion molecules) in leukocytes, resulting in their increased adherence to capillary endothelium and consequent capillaries .

12. Clinical features
46% of patients developing clinical manifestations within one week and 38% developing symptoms between the third and fourth weeks.
Dyspnea (59 to 95 percent)
Edema (53 to 81 percent)
Unexplained fever (53 to 74 percent)
Hypotension (12 to 39 percent)

13. Chest X-ray findings
A chest radiograph is typically obtained to evaluate dyspnea, cough, or fever. The main findings on chest radiography are:
An increased cardiothoracic ratio 87 %
Septal lines and peribronchial cuffing (87%).
Ground glass opacity 60 %.
Parenchymal consolidation 47%
Nodular opacities 47 %.
Air bronchogram 33 %.
Pleural effusion 73%

14. Diagnosis
Fever
Weight gain (from capillary leak and soft tissue edema).
Respiratory distress.
Radiographic opacities.
Pleural or pericardial effusion.
Hypotension.
Renal failure

15. Treatment
Main line of treatment is glucocorticoid. Dexamethasone 10 mg q12h.
Without glucocorticoid treatment, patients treated with all-trans retinoic acid (ATRA) or Arsenic trioxide (ATO) who develop the differentiation syndrome have a mortality rate as high as 30 %.
With treatment, most patients demonstrate improvement within 12 hours and complete resolution of symptoms within 24 hours, although approximately 5 % will not survive.

16. Thank You