When to decide between fatigue and CLL

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A 71-year-old male presents to your ED with a temperature of 99.7F and extreme fatigue. The triage nurse makes him an ESI 3 with concern for an infection. Your medical student picks up the case and finds a small rash made of some mildly erythematous plaques on his chest which Mr. Jones states do not hurt or itch. He denies any prior medical history or comorbidities. As you proceed to examine him, you quickly realize the student did not notice mild edema to Mr. Jones’ hands.

Additionally, he flinches when you place your hands on his abdomen over his LUQ. Your student tells you that she has never palpated a spleen before, but is sure she can feel his. Something about his presentation is telling you that this is not typical fatigue, so you decide to order further tests. The CBC comes back with a WBC of 42,000, but with 62% lymphocytes. It is after midnight and there is no hematologist on call. How would you proceed?


Although fatigue in older adults is common and can be associated with occult infection, electrolyte abnormalities, chronic pulmonary disease, acute cardiac pathology and deconditioning, the localized hand edema and splenomegaly are somewhat atypical for a fatigue presentation. Given this concern, in addition to the typical differential of fatigue, Chronic Lymphocytic Leukemia (CLL) should also be considered.

CLL is primarily a disease of the older population, as >70% of patients diagnosed are over the age of 65 (Woyach, 2017). Caused by a systemic accumulation of abnormal CD5+ B-lymphocytes, CLL begins in the bone marrow and eventually spreads to secondary lymphoid organs such as the spleen and lymph nodes (O’Reilly, 2018).

The disease classically presents with few overt symptoms and is diagnosed based on serial blood examinations showing >5,000 B lymphocytes/µL for three months. It is possible for some cases of CLL to present acutely, mimicking other much more common infectious illnesses.


Approximately 20,000 new cases of CLL are diagnosed annually and can present with broad symptoms such as edematous infiltrates in the hands, feet and face, unintentional weight loss of >10% in the previous six months, mild fevers, night sweats, extreme fatigue, lymphadenopathy, organomegaly and variable rashes including plaques, papules and ulcers. In the case of Mr. Jones, his borderline fever, hand edema, splenomegaly and rash are signs that he may be presenting with some of the acute symptoms of CLL (Siegel, 2018 & Rai, 2018).

Transfusion guidelines for active bleeding in a patient with acute leukemia

(abstracted from Rose-Inman et al, Hematology/Oncology Clinics of North America)

Product Transfusion Guidelines
Platelets Transfuse to platelet count >50,000
Cryoprecipitate Transfuse 10 units if fibrinogen is <125 mg/dL
Packed Red Blood Cells Transfuse for hematocrit <30%
Fresh Frozen Plasma Transfuse to keep INR <2.0


Emergency medicine providers must be aware of the specific issues that can arise for patients with CLL.


A potential issue in patients with any hematologic malignancy is coagulopathy due to a poorly understood mechanism of interrupted clotting. Both thrombosis and bleeding are significant causes of morbidity and mortality in leukemias (Rose-Inman, 2017).

Disseminated Intravascular Coagulation, or DIC, while a rare diagnosis in the ED, is a known sequela of leukemia and should never be missed. Pertinent labs to assess for DIC include prothrombin time and D-dimer, both typically elevated in leukemia associated coagulopathies, as well as a CBC to check for thrombocytopenia.

A full physical exam should be performed to check for bleeding along mucous membranes, in the GI tract and intracranially if focal neurologic deficits are present. If acute, concerning bleeding is noted in a patient with an acute hematologic malignancy, the patient may require more than just packed red blood cells or your hospital’s typical massive transfusion protocol (see table). Clinically, older adults like Mr. Jones presenting with non-descript symptoms and a coagulopathy may warrant consideration of a hematologic malignancy such as CLL.

Patients with CLL can also exhibit elevated serum potassium levels, but normal whole blood potassium levels secondary to pseudohyperkalemia. Although RBC lysis is more commonly associated with hyperkalemia, in CLL, the increased white blood cell count coupled with increased mechanical stress on the white cells is felt to be the cause.

Handswelling from lymphoma

Be careful not to empirically treat for hyperkalemia off the basic chemistry panel before confirming the result on a blood gas panel (Rifkin, 2010). Hyperkalemia should also remind you to review the laboratory tests for signs of tumor lysis syndrome, which will result in a true hyperkalemia in addition to hyperphosphatemia, hypocalcemia, hyperuricemia and elevation in blood urea nitrogen (BUN).

On this night, Mr. Jones was assessed for DIC or any bleeding abnormalities. You realized he needed a hematologist and diagnosed him with likely CLL pending referral to the Hematology/Oncology service. His symptom burden was monitored by the oncologist and he has been initiated on immunotherapy. His WBC varies between 20,000 to 40,000 with >5,000 lymphocytes, and his fatigue, splenomegaly and edema are improving. Due to his CLL, he is at higher risk for infections and complications including transformation to an acute form of leukemia and requires careful evaluation with future ED visits.

The average age of diagnosis for CLL has increased from 65 years old in the 1990s to 70 years of age today (O’Reilly, 2018). With the introduction of next generation therapies such as Ibrutinib, the life expectancies of those living with CLL continue to lengthen and the impact of this disease will continue to grow as the population ages.

There is a pressing need for high quality, evidence-based guidelines for the treatment of CLL in patients ≥65 years of age. Unfortunately, the literature on therapeutic strategies for patients with CLL is skewed toward the younger demographic. Only 5% of trials focused exclusively on those ≥65 years, and 69% of recent trials completely excluded this population (Buske et al., 2017).

While there are few evidence-based guidelines for acute CLL therapy, once treatment has begun, CLL will likely pose little overall mortality risk to the elderly patient. Despite the low mortality risk, it can still be overwhelming for an elderly patient to receive a diagnosis that will require an expensive and lifelong therapeutic regimen.

Appropriate steps should be taken to ensure that patients are provided with the resources necessary to thrive with their new diagnosis, such as prompt connection to local cancer survivor support groups, patient advocate services or ADL-assistive services.

Although you may never personally diagnose CLL, as life expectancy increases, you will certainly care for patients in the ED with the diagnosis. Being aware of the typical laboratory abnormalities and physical manifestations seen in CLL will help you provide the best care to these patients.


1.Buske, C., et al. 2017. ESMO Consensus Conference on malignant lymphoma: general perspectives and  recommendations for the clinical management of the elderly patient with malignant lymphoma. Annals of Oncology, 0, 1-19.

2. Rifkin, S. I. 2011. Pseudohyperkalemia in Patients with Chronic Lymphocytic Leukemia. International      Journal of Nephrology. Article ID 759749, 3 pages.

3. Rose-Inman, H., Kuehl, D. 2017. Acute Leukemia. Hematology/Oncology Clinics of North America, 31: 6,1011-1028.

4. Siegel RL, Miller KD, Jemal A. 2018. Cancer Statistics, 2018. CA Cancer J Clin., Jan;68(1):7-30.

5. O’Reilly, A. O., Murphy, J., Rawe, S., Garvey, M. 2018. Chronic Lymphocytic Leukemia: A Review of Front-Line Treatment Options, With a Focus on Elderly CLL Patients. Clinical Lymphoma, Myeloma,  Leukemia, 18:4, 249-256.

6. Rai, K. R., Stilgenbauer, S., Aster, J. C. Clinical features and diagnosis of chronic lymphocytic         leukemia/small cell lymphocytic lymphoma. UpToDate, last updated Jul 19, 2018, Accessed Nov. 2, 2018 at https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma

7. Woyach, J. 2017. What is the optimal management of older CLL patients? Best Practice & Research Clinical Haematology, 31, 83-89.


Zachary J. Smith is a second-year medical student at The Ohio State University College of Medicine.

Dr. Jason Bischof is an Assistant Professor of Emergency Medicine at The Ohio State Wexner Medical Center.

Dr. Southerland is an Assistant Professor and Director of Geriatric Emergency Care in the Department of Emergency Medicine at the Ohio State University. Her research has focused on older adult injury prevention and management.

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