UMMSM

Hematology and Oncology

“Christina is tired”

STUDENT

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Case Authors: Julie Belkowitz, M.D.

Daniel Lichtstein, M.D.

Case Editors: Gauri Agarwal, M.D.

Mark A. Gelbard, M.D.
Morton Levitt, M.D., M.H.A., F.C.A.P.
Willis K. Paull, Ph.D.
Rainald Schmidt-Kastner, M.D.
Julie C. Servoss, M.D., M.P.H.
Stephanie Wragg, Ph.D.

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Case title: Christina is tired

Session 1
Part 1

Christina Adams, a three-year old Jamaican girl, wakes up late one morning. Christina
complains to her mother about how tired she has been feeling the past couple of days.
She has not been able to ride on her tricycle with her friends on the playground as she
usually does, and has had trouble catching her breath.

Christina’s mother is very concerned as this seems so out of character for her daughter.
She is also concerned because she has had quite a few illnesses in recent months.
She just had a diarrheal illness last week and missed school last month because of
“walking pneumonia.” The pediatrician said it was probably because she has just
entered school for the first time. Mrs. Adams is very worried about her daughter.

Questions:

1. What should be considered as possible causes of Christina’s fatigue?

2. How should Christina’s parents proceed?

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Case title: Christina is tired

Session 1
Part 2

Christina has not yet seen a pediatrician since the family moved here from Jamaica.
Her mother completed school forms at a clinic earlier this year and has gone to different
clinics when her daughter was ill, but she has not obtained a primary care provider as
she is uninsured. However, Christina’s younger sister was born in the U.S. and has
Florida KidCare. The baby sees a pediatrician, Dr. Lichtenberg. Mrs. Adams calls her
right away to schedule an appointment.

Dr. Lichtenberg asks Mrs. Adams about her daughter’s symptoms. They both agree that
the symptoms are of concern. Mrs. Adams has never seen her daughter as tired and
weak as she seems now, and she thinks that she looks pale. She currently does not
have any coryza symptoms, fever or diarrheal symptoms. She is eating a typical amount
of food for her, but her activity level is markedly decreased.

Previous medical and surgical histories are unremarkable

Medications: Pediatric multivitamin once daily. She takes acetaminophen as needed for
“growing pains” about two times per year.

Allergies: No known drug, seasonal or contact allergies

Immunizations: She is up to date with all of her vaccinations, including influenza.

Social history: One of two children. She is currently in preschool and is doing very well.
She loves music and art. The family moved here from Jamaica about two years ago.
Both parents work in sales for a small company.

Family history: Christina has a healthy, 9 month-old sister. No family history of blood
diseases or cancer.

Review of systems

General                   no weight loss

HEENT                    no headaches, no recent sore throat
Chest                       no cough or chest pain
Cardiac, GI, GU       no current symptoms
Extremities               no pain

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Case title: Christina is tired

Session 1 (Wednesday)
Part 3

Physical examination:

Young black girl who appears mildly ill, with no respiratory distress.

Anthropometrics Weight, height and BMI 10th percentile for age

Blood pressure 90/50 mm Hg, sitting
Pulse 145 beats/minute, regular
Respiratory rate 24 breaths/minute
Temperature 98.8oF

HEENT Conjunctivae are pale; sclerae are slightly icteric.

Neck A few < 1 cm tender lymph nodes are felt in the anterior
cervical region bilaterally
Chest Clear to percussion and auscultation bilaterally
Cardiac PMI is laterally displaced. Regular rhythm. III/VI systolic
murmur heard maximally at the upper, left sternal border
Abdomen Bowel sounds are normal; non-distended; no masses,
tenderness or organomegaly
Rectal Guaiac negative brown, formed stool
Extremities No edema; dorsalis pedis pulses are 2+ bilaterally
Skin no rash is seen
Neurologic Muscle strength 5/5 throughout and reflexes 2+
throughout

Questions:

1. What are the important findings so far and what is the potential
significance of each?

2. What laboratory tests would be indicated?

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Case title: Christina is tired

Session 1
Part 3 (Cont’d)

Dr. Lichtenberg is able to do the CBC in her office which reveals the following:

White blood cells 12,000 cells/mm3 (56 neutrophils, 30 lymphocytes, 4

eosinophils, 5 monocytes, 3 basophils, 2 unidentified large
mononuclear cells)
Hemoglobin 4.5 grams/dL
Hematocrit 13%
Platelet count 350,000/mm3

Dr. Lichtenberg advises the family that it would be best for Christina to be admitted to
the hospital without delay for further evaluation.

Questions:
1. How should Dr. Lichtenberg proceed?

(Covers objectives 3, 4)

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Case title: Christina is tired

Session 2

Christina and her mother go to the hospital admitting office, and are promptly taken up
to a private room on the pediatric floor. Dr. Lichtenberg orders some laboratory studies
to be sent immediately as well as oxygen (via nasal cannula) and intravenous fluid
administration. Mrs. Adams’s concern has multiplied by now, and she is eager to hear
the laboratory results. She worries the family does not have health insurance, but right
now her main concern is her child’s health.

The next morning, Rachel, a third year medical student assigned to the case, arrives to
meet the family. She introduces herself and indicates that she works with Dr.
Lichtenberg and will be taking Christina’s history and performing a physical
examination.

Rachel takes Christina’s history. Midway through the history, Rachel asks Mrs. Adams
a specific question, and when the question is answered, Rachel smiles to herself and
believes she may have “hit gold,” though she still needs some more information.
Rachel performs a careful physical examination.

Once completed, Rachel heads straight to the computer to see if Christina’s laboratory
studies have returned.

MCV 75 fL
MCHC 36 g/% RBC (normal range 32-36)
RDW 16 % (normal range 11.5- 15)
Coombs’ test Negative
Reticulocyte count 0%
Total bilirubin 4.2 mg/dL
Direct bilirubin 0.2 mg/dL
Indirect bilirubin 4.0 mg/dL
LDH 800 U/L
Haptoglobin 15 mg/dL (normal for age 25-185)
Folate 10 ng/mL (normal for age 5 -21)
Iron 75 micrograms/dL (normal for age 50 – 120)
TIBC 375 micrograms/dL (normal for age 250 -500)
Ferritin 100 ng/mL (normal for age 7-140)

Hemoglobina electrophoresis: Hemoglobin A 0%

Hemoglobin A2 2%
Hemoglobin S 90%
Hemoglobin F 8%

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Rachel presents her findings, including the additional history, to Dr. Lichtenberg on
rounds. Dr. Lichtenberg is impressed with Rachel’s approach to the patient and orders
an additional laboratory test to be run on the specimen already drawn.

Questions:

1. What is remarkable about the lab tests here?

2. What are the possible causes of the low reticulocyte count in this patient
with sickle cell disease?

3. What would one expect to see on the peripheral blood smear?

4. What might Rachel’s key question have been?

5. What is the potential impact of Cristina’s lack of health insurance on her

medical care? What about her chronic disease?

(Covers objectives 1- 5)

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Session 3 : Presentations
Case objectives:

1. Review the histology of blood components.

2. Discuss the clinical utility of the red blood cell indices and reticulocyte count in
the evaluation of anemia.
3. Discuss the differential diagnosis of anemia in patients with normally functioning
bone marrow.
4. Discuss the differential diagnosis of anemia in patients with hypofunctioning bone
marrow. Include nutritional deficiencies, parvovirus infection and drug-induced
marrow failure.
5. Recognize the utility of specific laboratory studies in the evaluation of hemolytic
anemia, i.e. reticulocyte count, LDH, haptoglobin, indirect and direct bilirubin.
6. Recognize normal and abnormal cells that can be seen in a peripheral blood
smear.
7. Understand the impact of sickle cell disease as a chronic illness on the patient
and family.
8. Recognize the importance of culturally competent care in the approach to
patients with chronic disease.
9. Recognize the impact of socioeconomic status, race, ethnicity and culture (as it
relates to ethnicity as well as occupation and social context) on patients’ health
and medical decision-making.
10. Review any pharmacologic agents presented in this case.
11. Review the interpretation of laboratory findings presented in this case.

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Vocabulary
Coombs’ test
reticulocyte count
haptoglobin
hemoglobin electrophoresis
Howell-Jolly bodies
target cells
Parvovirus B19

References:

The following references are listed to provide assistance with this case.

Because problem-based learning is a student-driven and student-centered process, it is

the responsibility of each student to participate in order to promote individual learning
and for the benefit of other members of the small group.

Kumar, Abbas, Fausto and Aster. Robbins & Cotran, Pathologic Basis of Disease,
Saunders, 9th edition, 2014.

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Case title: Christina is tired

Session 2 (Friday)
Part 1
Rachel’s question, which prompted the additional laboratory test, was about any recent
illnesses or sick contacts. Dr. Lichtenberg recalls a phone call received from
Christina’s mother a few weeks ago. The baby had a fever and rash. Since the fever
and rash already seemed to be resolving, Dr. Lichtenberg did not feel an office visit was
necessary at the time. She realizes now that Christina likely contracted the infection
from her baby sister.

Questions:

1. What viral illness likely contributed to Christina’s presentation today? Most

likely, it was a viral illness caused by Parvovirus B19, which can attack the
erythroblasts in bone marrow causing a red blood cell aplasia and severe anemia
in children with sickle cell disease.

2. How should further evaluation and management proceed?

Tutor guide only: Review of the peripheral smear. A blood transfusion should be
considered. Consideration should also be given to obtaining blood for serology
for Parvovirus B19 before any transfusion.

(Covers objectives 1)

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Case title: Christina is short of breath

Session 2 (Friday)
Part 2

Dr. Lichtenberg and Rachel then walk over to the hospital laboratory to review the
results and the peripheral smear with the pathologist.

The smear is shown here:

One high-power field: Another high-power field:

The pathologist, with whom they review the smear, shows them the abnormal cells as
well as the Howell-Jolly bodies.

Dr. Lichtenberg returns to the bedside to discuss the results with the Adams family.
Christina is still very fatigued, and the recent lab data shows that her symptoms are not
likely to improve on their own for at least a few days. Dr. Lichtenberg also considers
that the parvovirus infection could have also exacerbated the anemia from her
underlying sickle cell disease, so she orders a transfusion of packed red blood cells.

Questions:
1. What is remarkable about the blood smear?
Notable sickled cells, target cells, nucleated RBC’s.

(Covers objective 6)

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Case Title: Christina is short of breath

Session 2 (Friday)
Conclusion

Christina tolerates the transfusions very well and feels much stronger. She is able to
walk the hallways of the hospital without any difficulty breathing. Christina’s parents are
struggling to believe that their little girl has a serious chronic disease that will affect her
throughout her lifetime. Fortunately, a representative from the local sickle cell support
group visits the family during the admission and provides the family with resources for
follow-up.

During the admission, Dr. Lichtenberg requests a consultation from the social worker to
assist the family in obtaining health insurance. Christina has now been diagnosed with
a chronic disease and will require close outpatient follow-up and consultation with a
hematologist specializing in sickle cell disease.

By the third hospital day, her reticulocyte count is reported as 1.5%. Two days later, it is
7%. At that time, her hemoglobin and hematocrit are 7 g/dL and 21%, respectively, and
Dr. Lichtenberg feels she may be safely discharged from the hospital and even return to
school the following day. Prior to discharge, Christina receives the pneumococcal
conjugate vaccine (PCV13). The 23 valent pneumococcal polysaccharide vaccine is
planned for later. She is also placed on daily folic acid and penicillin prophylaxis and
her family is educated about the risks and warning signs of serious bacterial infection in
children with sickle cell disease. They are also scheduled to see a hematologist, who
specializes in sickle cell disease, to discuss the need for transcranial Doppler
examination to evaluate for stroke risk.

Dr. Lichtenberg recommends that she return to her office in two weeks for a follow-up
check-up and blood test.

Questions

1. What follow-up blood test(s) was Dr. Lichtenberg likely referring to?
Tutor guide only: Repeat CBC, reticulocyte count, and convalescent serology
for Parvovirus B19 (to be done about 4 weeks later).

2. Why was Christina placed on daily penicillin prophylaxis and given the
pneumococcal vaccine? Tutors guide only: Children with sickle cell
disease are especially prone to infection with encapsulated bacteria
(including pneumococcus, H. influenza, meningococcus, Salmonella) and

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 are placed on daily penicillin prophylaxis until at least age 5 years. The
vaccination also helps to give protection.

(Covers objectives 7-9)

Epilogue

At her follow-up visit, Christina’s CBC results include: hemoglobin and hematocrit
values of 8.1 g/dL and 25%, respectively, and reticulocyte count 8%.

Serology results confirm that Christina had indeed been recently exposed to Parvovirus
B19.

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Facilitator guide

Objective 1.Review histology of blood components.

Facilitators are encouraged to refer students to their FBS notes from the year 1 courses.

Objective 2. Discuss the clinical utility of the reticulocyte count in the evaluation
of anemia.

The reticulocyte count is most useful in helping to determine if the bone marrow is
hypoproliferative or normal. When the cause of anemia is deficiency of a necessary
ingredient for RBC production (as in iron, folic acid, B12 deficiency) the reticulocyte
count will be low. In aplastic anemia, the reticulocyte count should be very low. In
conditions where abnormal cells (leukemic cells, metastatic cells from a distant tumor)
or fibrosis of the marrow is present, the reticulocyte count is generally low.

On the other hand, when all ingredients for normal RBC production are present, and
there are no other primary bone marrow abnormalities, the reticulocyte count should be
appropriately increased when the need for additional RBCs is present (bleeding or
hemolysis), including a typical patient with sickle cell disease.

In anemic patients with an elevated reticulocyte count, examination of the bone marrow
would not be expected to be diagnostic. On the contrary, in anemic patients with a low
reticulocyte count, bone marrow examination may be diagnostic.

Objective 3. Discuss the differential diagnosis of anemia in patients with normally

functioning bone marrow.

Anemia is not a specific entity but, rather, the result of many underlying pathologic
processes. In patients with normally functioning bone marrow (ability to generate a
reticulocytosis when appropriate), the differential revolves around blood loss (usually
acute) and hemolysis. The causes of hemolysis are many: extravascular (including
immune related, hereditary spherocytosis, hemoglobinopathies), and intravascular
(microangiopathic hemolysis: DIC, TTP, prosthetic valves; transfusion reaction; malaria;
G6PD deficiency).

The first step in evaluation is to look at important red blood cell indices, especially the
mean corpuscular volume (MCV) and the appearance of RBCs on a peripheral blood
smear to help differentiate the many possible underlying diagnoses.

The table below lists a differential using this approach.

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From: Nelson Textbook of Pediatrics 18th Edition.

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Objective 4. Discuss the differential diagnosis of anemia in patients with
hypofunctioning bone marrow. Include nutritional deficiencies, parvovirus
infection and drug-induced marrow failure.

In the presence of anemia, erythropoietin production and the absolute number of

reticulocytes should rise. A normal or low absolute number or percentage of
reticulocytes in response to anemia indicates relative bone marrow failure or ineffective
erythropoiesis. These include conditions of iron deficiency, folic acid deficiency, Vitamin
B12 deficiency. Also, aplastic anemia, pure RBC aplasia (may be secondary to
parvoviral infection in patients with underlying hemolytic anemia, such as sickle cell
anemia) and drugs (chloramphenicol, carbamazepine, ticlopidine).

Facilitator: please note that other items on the differential, i.e., PNH, infiltrative diseases
and myelodysplastic syndromes, will be covered elsewhere.

Again, RBC indices and evaluation of the peripheral smear are important to differentiate
the various types of anemia listed in the table under Objective 3.

Objective 5. Recognize the utility of specific laboratory studies in the evaluation

of hemolytic anemia, i.e. reticulocyte count, LDH, haptoglobin, indirect and direct
bilirubin.

Whatever the mechanism, intravascular hemolysis is manifested by (1) anemia, (2)

hemoglobinemia, (3) hemoglobinuria, (4) hemosiderinuria, and (5) jaundice. The large
amounts of free hemoglobin released from lysed red cells are promptly bound by
haptoglobin, producing a complex that is rapidly cleared by mononuclear phagocytes.
As serum haptoglobin is depleted, free hemoglobin oxidizes to methemoglobin, which is
brown in color. The renal proximal tubular cells reabsorb and catabolize much of the
filtered hemoglobin and methemoglobin, but some passes out in the urine, imparting a
red-brown color.

Heme groups derived from hemoglobin/haptoglobin complexes are catabolized to

bilirubin within mononuclear phagocytes, leading to jaundice.

In all types of uncomplicated hemolytic anemias, the excess serum bilirubin is

unconjugated. The level of hyperbilirubinemia depends on the functional capacity of the
liver and the rate of hemolysis. When the liver is normal, jaundice is rarely severe.

(Adapted from Robbins and Cotran Pathologic Basis of Disease, Professional Edition ,
9th ed.)

As described above, in the presence of a hemolytic anemia, there should be increased

reticulocyte count, and an increased LDH from release of intracellular enzymes .

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Objective 6. Recognize normal and abnormal cells that can be seen in a
peripheral blood smear.

Objective 7. Understand the impact of sickle cell disease as a chronic illness on

the patient and family.

Sickle cell anemia is a chronic disease. It manifests itself at a young age, and typically
leads to multiple hospitalizations (painful crises, hemolysis, infections), often includes
chronic pain, transfusions (with associated potential complications), risk for stroke and
frequently psychosocial issues, including depression, disability.
Often, more than one family member is affected, compounding the effect on the family.
In addition, issues of genetics are involved, at times including guilt, and questions of
marriage and child-bearing.

Objective 8. Recognize the importance of culturally competent care in the

approach to patients with chronic disease.

Objective 9. Recognize the impact of socioeconomic status, race, ethnicity and

culture (as it relates to ethnicity as well as occupation and social context) on
patients’ health and medical decision-making.

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