Case management study Walter Reed Army Medical Center: Dyspnea on exertion, fatigue, and pallor in a 50-year-old active duty soldier

Military Medicine,  Jul 2003  by Verma, Pramvir S,  Gallagher, Christopher M

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4. Which of the following would be the LEAST helpful in further elucidating the diagnosis?

a. Bone marrow biopsy

b. Serum parvovirus B19 IgG titers

c. Serum haptoglobin levels

d. Serum folate levels

e. HIV enzyme-linked immunosorbent assay

The bone marrow biopsy is the test of choice in the evaluation of pancytopenia, since it can differentiate whether the bone marrow is aplastic, infiltrated by a neoplastic process, or even infected. Parvovirus B19 is an established agent that causes pancytopenia; however, without comparison to previous titers, serum IgG titers would not be helpful, since they merely indicate a previous history of parvovirus B19 infection. In comparison, serum IgM titers could verify the presence of an acute infection that clinically presents as fevers, rash, malaise, myalgias, and symmetric arthralgias/arthritis.1,7

Disease processes such as disseminated intravascular coagulation, systemic lupus erythematosus, and paroxysmal nocturnal hemoglobinuria can cause both pancytopenia and a hemolytic anemia. Haptoglobin is a hepatic protein that binds to free hemoglobin released during red blood cell hemolysis and is quite useful in evaluating a hemolytic anemia. One study indicated a sensitivity of 83% and specificity of 96% for haptoglobin levels

Further laboratory evaluations were then obtained: 786 units/L serum lactate dehydrogenase (313-618 units/L), lt]10.0 mg/dL serum haptoglobin [ (30-200 mg/dL), 1.4% reticulocyte (0.5%-1.5%), 163 [mu]g/dL serum iron (49-181 [mu]g/dL), 5.8 ng/ml serum folate (4.2-19.9 ng/ml), 264 pg/ml serum B12 (243-894 pg/ml), HIV enzyme-linked immunosorbent assay negative, 0.00 serum CMV IgM titers (0.00-1.10), serum EBV capsid IgM titers negative, 0.1 serum parvovirus B19 IgM titers (

5. With the additional laboratory information presented above, the most LIKELY diagnosis is?

a. Parvovirus B19 infection

b. B cell lumphoma

c. Acute myelogenous leukemia

d. Paroxysmal nocturnal hemoglobinuria

e. Idiopathic thrombocytopenic purpura

Parvovirus B19 infection is unlikely with negative serum IgM titers. The IgM antibody should persist for at least 2 months and possibly up to 6 or more months with a sensitivity and specificity ranging between 70% and 100% and 76% to 100%, respectively.7 Furthermore, the patient never complained of any rash, arthralgias/arthritis that would suggest parvovirus B19 infection. Similarly, pancytopenia via infiltration from B cell lymphoma and acute myelogenous leukemia would be evident on the bone marrow examination.

However, some of the additional data presented above is consistent with a diagnosis of paroxysmal nocturnal hemoglobinuria. The low serum haptoglobin and high lactate dehydrogenase levels are consistent with a hemolytic anemia, a component of paroxysmal nocturnal hemoglobinuria. Furthermore, the biopsy results indicate a hypoplastic bone marrow, which is compatible with paroxysmal nocturnal hemoglobinuria, as there is an acquired genetic defect in the stem cell membranes. Also supporting the diagnosis of paroxysmal nocturnal hemoglobinuria is the positive sucrose lysis test. In this screening test, red blood cell membranes are made more susceptible to complement binding by the low ionic strength of a sucrose solution. In paroxysmal nocturnal hemoglobinuria, the now weakened red blood cell membranes absorb more sucrose molecules than normal red blood cells, resulting in hemolysis. The test is considered positive when >5% of the cells hemolyze, but is not sufficient for diagnosis. Even more sensitive and specific than the sucrose lysis test, but more complicated and expensive, is the Ham test, which is an acid-based lysis test. In addition, CD55/CD59 testing is another highly specific ancillary test, which directly evaluates the cell membrane proteins that are abnormal in paroxysmal nocturnal hemoglobinuria.2 In idiopathic thrombocytopenic purpura, there is an immune-mediated thrombocytopenia, with a preservation of red and white blood cell numbers. Given the patient's findings on bone marrow examination and laboratory results consistent with hemolysis, a preliminary diagnosis of paroxysmal nocturnal hemoglobinuria seems reasonable.