Objective: To discuss a comprehensive diagnostic approach to an active duty patient presenting with dyspnea on exertion, fatigue, and pallor. A 50-year-old active duty E-6 white male in Al Udeid, Qatar, presented with progressive dyspnea on exertion, fatigue, and new pallor. This case illustrates the course of events from Al Udeid to the Walter Reed Army Medical Center, where the final diagnosis was made. Along the way, questions with discussions explore the various diagnostic and management aspects of his case and highlight military relevant issues that include efficient diagnostic algorithms in the field and transfusion of scarce blood products.
Introduction
A 50-year-old active duty E-6 white male was deployed in February 2002 to Al Udeid, Qatar. A week into his deployment, he presented to the infirmary with a fever of 104.0[degrees]F, rigors, dyspnea on exertion, and a cough productive of green sputum for 2 days. He denied any other symptoms and a chest X-ray showed a left lower lobe infiltrate. The patient was treated with a 10-day course of levofloxacin, but noted residual dyspnea on exertion and fatigue. In April, he again presented to the infirmary with continuing dyspnea on exertion, fatigue, and newly observed pallor. He was afebrile and denied cough, orthopnea, paroxysmal nocturnal dyspnea, swelling, wheezing, or bleeding. A review of systems was otherwise negative.
1. In addition to a complete history and physical, which of the following should be pursued NEXT to expeditiously determine his diagnosis?
a. Complete blood count
b. Chest X-ray
c. Transthoracic echocardiogram
d. Serum measurement of thyroid-stimulating hormone
e. Urinalysis
Formulating an efficient diagnostic approach to common medical complaints is essential to the military physician, particularly when operating in deployments where resources are limited. A complete blood count to evaluate for anemia would be the best initial test because anemia would explain each of the patient's symptoms- dyspnea, fatigue, and pallor. Although a chest X-ray can show causes for dyspnea and fatigue, such as pneumonic processes, pleural and pericardial effusions, malignant lesions or adenopathy, and pulmonary vascular congestion, it would be less efficient than the complete blood count in explaining the patient's pallor. Of note, the presence of a radiographic infiltrate in this patient may not be helpful, since an infiltrate from a previous pneumonia can take 4 to 12 weeks to resolve depending on the patient's age and cardiopulmonary status.
The absence of orthopnea, paroxysmal nocturnal dyspnea, or lower extremity swelling argues against a diagnosis of a cardiomyopathy; thus, a transthoracic echocardiogram would likely not be helpful. Similarly, although hypothyroidism can cause pulmonary symptoms, fatigue, and pallor, his age, onset of symptoms, and lack of other manifestations make a serum thyroid-stimulating hormone a low yield test. Finally, a urinalysis may indicate proteinuria and thus potentially lead to a diagnosis of nephrotic syndrome, which can also present with pulmonary symptoms and fatigue. However, the absence of generalized swelling makes this diagnosis unlikely.
A complete blood count was ordered which showed a white blood cell count of 1.2/mm^sup 3^ (4.8-10.8/mm^sup 3^), with no manual differential available, hemoglobin of 3.0 g/dL (14.0-18.0 g/dL), and platelets of 16/mm^sup 3^ (130-400/mm^sup 3^).
2. The patient's complete blood count can be explained by all of the following EXCEPT
a. Parvovirus B19 infection
b. Paroxysmal nocturnal hemoglobinuria
c. Hypothyroidism
d. B12 deficiency
e. Lymphoma
Simultaneously reduced values for the white blood cell, red blood cell, and platelet indices indicate that the patient has pancytopenia. The differential for pancytopenia is quite extensive and includes infection by parvovirus B19. This virus is more commonly associated with a pure red blood cell aplasia, but can also damage the pluripotent stem cells of the bone marrow, resulting in pancytopenia. Other viruses that can cause pancytopenia include the non-A,B,C hepatitis viruses, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV).1 Paroxysmal nocturnal hemoglobinuria is a syndrome in which acquired genetic defects in stem cell membrane proteins lead to bone marrow failure and a resultant pancytopenia. Also, patients with paroxysmal nocturnal hemoglobinuria are commonly hypercoaguable, have a hemolytic anemia, and often develop myelodysplastic disorders or acute leukemia.2 Hypothyroidism is not associated with pancytopenia. The hematological effects of hypothyroidism are limited to a decrease in red blood cell mass with a resultant normocytic anemia. Vitamin B12 deficiency, more commonly known for causing a macrocytic anemia, also causes pancytopenia. This occurs via concomitant methionine deficiency and deficient conversion of deoxyuridate to thymidylate-hindering DNA synthesis, thus leading to slowed nuclear maturation.3 Finally, lymphoma can cause pancytopenia through direct infiltration of the bone marrow and subsequent replacement of stem cells.
3. Regarding this patient's management, which of the following options should be pursued next?
a. Transfuse to a hemoglobin of 10 g/dL and platelets of 20/mm^sup 3^
b. Transfuse only to a hemoglobin of 7 g/dL
c. Transfuse to a hemoglobin of 12 g/dL and platelets of 50/mm^sup 3^
d. Start subcutaneous injections of granulocyte colony-stimulating factor
e. Administer broad-spectrum intravenous antibiotics
During the Persian Gulf conflict in 1994, 73,180 units of packed red blood cell units were deployed to the theater of operation.4 Although it may appear that blood banks, usually available in the field at Echelon Levels II, III, IV, are sufficiently stocked, their supplies can be quickly exhausted during intense combat. In fact, this reality has driven the military to explore the feasibility of depositing autologous blood products before military action. Judicious use of blood products will not only lessen the strain placed on the military blood bank system, but also minimize the multiple dangers of transfusing blood products.
When considering transfusing packed red blood cells, it is important to determine whether the patient has any symptoms from anemia, such as fatigue, shortness of breath, chest pain, etc. One must consider the target hemoglobin to which the patient should be transfused. For symptomatic patients, transfusions should generally be undertaken in a stepwise manner until the anemia-related symptoms resolve. Concerning the level of hemoglobin, one prospective, randomized trial revealed that mortality rates were lower in critically ill patients (age
The patient was transfused 2 units of packed red blood cells and subsequently air evacuated to Walter Reed Army Medical Center for further evaluation. On arrival, he was asymptomatic. He denied any significant past medical/surgical history or drug allergies. He was taking no medications, herbs, dietary supplements, or over-the-counter products. The patient denied any alcohol, cigarette, illicit drug use, or high-risk sexual behaviors. He was working on the security detail in Al Udeid, but denied any chemical or unusual environmental exposures. His family history was noncontributory. The patient was afebrile with normal vital signs upon presentation. Physical examination was pertinent for generalized pallor, but without any findings of petechiae, lymphadenopathy, or splenomegaly. The rest of the examination was within normal limits. Laboratory values included a white blood cell count of 1.2/mm^sup 3^ (4.8-10.8/mm^sup 3^), hemoglobin of 6.3g/dL (14.0-18.0g/dL), hematocrit of 18.6% (42.0%-52.0%), and platelets of 29/mm^sup 3^ (130-400/ mm^sup 3^). The manual differential of the white blood cell count was 34% polymorphonuclear neutrophils (35%-66%), 8% bands (0%-11%), 54% lymphocytes (24%-44%), and 4% monocytes (0%-10%). The peripheral smear revealed slight anisocytosis and poikilocytosis, with no evidence of shistocytes. Prothrombin time/activated partial thromboplastin time, electrolytes, liver function tests, urinalysis, and chest X-ray were normal.
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.
The patient was then discharged with a stable hemoglobin, platelet count, and frequent follow-up. Cytogenetics were normal, bone marrow cultures negative, CD55 normal, and the CD59 abnormal. The Ham test was negative. With the equivocal CD55/CD59 and negative Ham test, the patient was thought not to have paroxysmal nocturnal hemoglobinuria, but aplastic anemia with an idiopathic etiology. A therapeutic trial of immunomodulation with cyclosporine, antithymocyte globulin, and FK-506 was instituted.
Discussion
Aplastic anemia is an important cause of pancytopenia, involving 2 to 4 million patients worldwide per year. By definition, the pancytopenia of aplastic anemia must have stem cell aplasia as the common final pathway. Stem cell aplasia refers to either a primary congenital or, more commonly, an acquired quantitative deficiency, not a qualitative one. For example, entities such as neoplastic marrow infiltration and myelodysplasia cause qualitative stem cell failure, not stem cell aplasia.9
A major cause of acquired aplastic anemia is medications, which include nifedipine, sulfonamides, gold, nonsteroidal anti-inflammatory drugs (particularly phenylbutazone), chloramphenicol, and felbamate. The aplasia is theorized to be attributable to genetic defects that predispose to toxic levels of medication.10 Furthermore, cytotoxic chemotherapy agents, chemicals such as benzene and lindane, glue sniffing, and external radiation cause aplastic anemia through direct stem cell injury. Also, viruses such as parvovirus B19, EBV, CMV, the non-A,B,C hepatitis viruses (2%-5% of aplastic anemia cases in the west), and HIV have been identified as agents that cause aplastic anemia.1 However, most commonly, the etiology is never found. The common final pathway in aplastic anemia is thought to involve activation of [gamma]-interferon or its cascade, which then triggers cellular apoptosis and T-cell mediated killing of stem cells.11
Aplastic anemia most commonly presents with recurrent infection or bleeding complications, although fatigue can be the presenting complaint. The physical examination may demonstrate petechiae and pallor. The gold standard for diagnosis is the bone marrow examination which demonstrates a hypoplastic marrow consisting mostly of fat/stroma, normal residual stem cells, absence of infiltration by tumor/fibrosis, and absence of megaloblastic hematopoiesis.9 Five-year survival rates range between 21% and 86%, depending on the degree of aplasia and patient's age. Healthy individuals under 45 years of age respond best to allogenic bone marrow transplantation (if matched sibling donor available), with prevention of fatal graft-versus-host disease through immunomodulation. Because of this severe complication, this treatment is not recommended for patients older than 45 years and those without a favorable functional status or suitable donor. For these patients, immunomodulation is recommended, which usually includes combinations of antithymocyte globulin, steroids, cyclophosphamide, or cyclosporine.12 In conclusion, this case should guide the military physician through key aspects of pancytopenia to include efficient diagnosis in a limited care setting, transfusion criterion for blood products, interpretation of pancytopenia-related laboratory values, and the entity of aplastic anemia.
Answers
1. a; 2. c; 3. b; 4. b; 5.d.
References
1. Kurtzman G, Young N: Viruses and bone marrow failure. Baillieres Clin Haematol 1989; 2: 51-67.
2. Rosse WF: PNH as a molecular disease. Medicine (Baltimore) 1997; 76: 63-93.
3. Allen RH, Stabler SP, Savage DG, Lindenbaum J: Metabolic abnormalities in cobalamin and folate deficiency. FASEB J 1993; 9: 1334.
4. Webster NR: Battlefield transfusions. JAMA 1994; 271: 319.
5. Hebert PC, Wells G, Blajchman MA: A multicenter, randomized, controlled, clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340: 409-17.
6. Wandt H, Frank M, Ehninger G: Safety and cost effectiveness of a 10 x 10^sup 9^/L trigger for prophylactic platelet transfusions compared with the 20 x 10^sup 9^/L trigger. Blood 1998; 91: 3601-6.
7. Erdman DD, Usher J, Tsou C: Human parvovirus B19 specific antibodies in serum specimens from persons with erythema infectiosum. J Med Virol 1991; 35: 110-15.
8. Marchand A, Galen RS. Van Lente F: The predictive value of serum haptoglobin. JAMA 1980; 243: 1909-11.
9. Young NS: Aplastic anaemia. Lancet 1995; 346: 228-32.
10. Calado RT, Garcia AB, Falcao RP: Decreased activity of the multidrug resistance P-glycoprotein in acquired aplastic anaemia. Br J Haematol 1998; 102: 1157-61.
11. Luther-Wyrsch A, Nissen C, Wodnar A: Intracellular Fas ligand is elevated in T lymphocytes in severe aplastic anaemia. Br J Haematol 2001; 114: 884-90.
12. Passweg JR, Socie G, Hinterberger W: Bone marrow transplantation for severe aplastic anemia: has outcome improved? Blood 1997; 90: 858-64.
Guarantor: CPT Pramvir S. Verma, MC
Contributors: CPT Pramvir S. Verma, MC; MAJ Christopher M. Gallagher, MC
Department of Internal Medicine, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307-5001.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.
This manuscript was received for review in January 2003 and accepted for publication in March 2003.
Copyright Association of Military Surgeons of the United States Jul 2003
Provided by ProQuest Information and Learning Company. All rights Reserved
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