Fever, Headache, and Abdominal Pain in an African Male

Size: px

Start display at page:

Download "Fever, Headache, and Abdominal Pain in an African Male"

Kerry Brown
5 years ago
Views:

1 Fever, Headache, and Abdominal Pain in an African Male Michael L. Cimo, MD, Rita Gander, PhD, Paul M. Southern, MD (Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX) DOI: /K9VGYGA4RC0D6RBX Patient 44-year-old African male. Chief Complaint The patient came to the emergency room complaining of fever, headache, and abdominal pain. History of Present Illness The patient began having steadily worsening fevers 5 days prior to admission. He also experienced global headaches that increased in intensity 2 days prior to admission. On the night before coming to the emergency department, his headaches went away, but he experienced nausea, night sweats, and cramping abdominal pain with non-bloody diarrhea. Questions 1. What is (are) this patient s most striking laboratory result(s)? 2. How do you explain this patient s most striking laboratory result(s)? 3. Which additional laboratory test(s) is (are) paramount to the accurate diagnosis of this patient s condition? 4. What is this patient s most likely diagnosis? 5. What is the etiology of this patient s disease? 6. What is the pathogenesis of this patient s disease? 7. What are the principal complications found in this patient s condition? Possible Answers 1. Slightly decreased hemoglobin and hematocrit; decreased platelet count; increased serum glucose; increased total and indirect bilirubin; increased lactate dehydrogenase (LD); increased ferritin (Table 1 and Table 2). 2. The slightly decreased hemoglobin and hematocrit, decreased platelet count, coupled with the values for our patient s other hematologic indices (Table 1) are consistent with a mild normocytic-hypochromic anemia and thrombocytopenia. The increased serum glucose concentration turned out to be a transient elevation, as the rest of the patient s serum glucose Past Medical History The patient suffered from malarial infections on 5 separate occasions during his childhood. Since then he has experienced no other medical problems. Family/Social History The patient is a native of the Congo and recently traveled there with use of chloroquine as prophylaxis against malaria. Medications Acetominophen for headaches. Physical Examination The patient appeared tired and weak, but in no acute distress. His vital signs were within Received Revision Received Accepted normal limits. No scleral icterus or jaundice was observed. The cardiovascular system was normal and the lungs were clear. The abdomen was slightly tender, but no organomegaly was noted. The extremities were without abnormality, and the neurological exam was normal except for slight weakness in the flexor muscles. Results of Additional Diagnostic Procedures Chest x-ray and 12-lead EKG revealed no abnormalities. Principal Laboratory Findings Table 1 and Table 2 measurements were normal. Increased LD concentration can be seen in a variety of malignancies (eg, leukemias, lymphomas, and most carcinomas) due to a high rate of cell turnover, and in certain infectious disease processes, hypoxia, liver disease, and megaloblastic or hemolytic anemia. However, the combination of hypochromic anemia, unconjugated hyperbilirubinemia (indirect bilirubin concentration was 1.7 mg/dl), and increased LD are highly suggestive of intravascular hemolysis. Moreover, the presence of thrombocytopenia suggests that the spleen (though not palpable) may be clearing platelets as well as red blood cells from the circulation. The increased ferritin concentration is likely part of an acute phase response. Thus, this patient is most likely suffering from a combined extra- and intra-vascular hemolytic process. The medical history strongly suggests that this process may be due to a recurrence of malarial infection. 3. Preparation and examination of a thin and thick peripheral blood smear to identify the presence of malarial organisms followed by speciation to rule in or out infection with the most pathogenetic malarial species, Plasmodium falciparum. A variety of techniques are used to produce thin and thick smears. A thin smear is basically a normal peripheral blood smear, while a thick smear is prepared mechanically via cytocentrifugation. A simpler and faster method for preparing thick smear, recommended by the Centers for Disease Control and Prevention (CDC) involves placing a drop of finger-stick blood on a glass slide such that the drop is thick enough to obscure newsprint. 90 LABMEDICINE Volume 36 Number 2 February 2005 labmedicine.com

A B C D E F Image 1_Patient s peripheral blood smear illustrating (A) the presence of a crescent-shaped gametocyte; (B) a non-enlarged singly-infected red blood cell; (C) a red blood cell singly

schizont of P. falciparum; (F) a ring trophozoite of P. ovale in a tear drop-shaped, fimbriated red blood cell.

Because the blood smear from finger-stick blood is prepared immediately, there is less time for malarial parasites to transform into less easily distinguishable forms.

Sometimes, both thin and thick preparations can be made on the same glass slide. Buffering the Wright-Giemsa stain to a ph of 7.2 to 7.

The thin smear allows visualization of parasites within red blood cells and thus provides an estimation of the degree of parasitemia.

Thus, the thick smear has the advantage of screening a larger amount of blood for the presence of parasites.

2 A B C D E F Image 1_Patient s peripheral blood smear illustrating (A) the presence of a crescent-shaped gametocyte; (B) a non-enlarged singly-infected red blood cell; (C) a red blood cell singly infected with a trophozoite that is pressed against the inner surface of the cell membrane (accole or appliqué form); (D) a non-enlarged multiply infected red blood cell with trophozoites; (E) a schizont of P. falciparum; (F) a ring trophozoite of P. ovale in a tear drop-shaped, fimbriated red blood cell. Finger-stick blood is more ideal than blood collected in a purple-top tube for the preparation of thin and thick smears. Because the blood smear from finger-stick blood is prepared immediately, there is less time for malarial parasites to transform into less easily distinguishable forms. When preparing both thin and thick smears, the blood smear is treated with an agent such as methanol to lyse the red blood cells prior to staining with Wright-Giemsa stain. Sometimes, both thin and thick preparations can be made on the same glass slide. Buffering the Wright-Giemsa stain to a ph of 7.2 to 7.4 results in the most useful and characteristic parasite morphology. The thin smear allows visualization of parasites within red blood cells and thus provides an estimation of the degree of parasitemia. The thick smear concentrates the blood by a factor of 20 to 30 and renders the red blood cells invisible, leaving behind only leukocytes and parasites. Thus, the thick smear has the advantage of screening a larger amount of blood for the presence of parasites. Both types of blood smears are indispensable in diagnosing and speciating malarial infection. The microscopic examination of the peripheral blood remains the gold standard for the diagnosis of malaria because it is relatively inexpensive, easy to perform, highly specific, and quantitative. Other diagnostic methods for malarial infection include fluorescence microscopy and serological and molecular methods, but so far none of these methods has equaled or exceeded the diagnostic efficacy of microscopy in identifying malarial organisms. 1-3 Examination of Table 1_Principal Laboratory Findings Test Patient s Normal Reference Result Range Hematology WBC count x 10 3 /µl RBC count x 10 6 /µl Hemoglobin g/dl Hematocrit % MCV fl MCHC g/dl RDW % Platelet count x 10 3 /µl Differential: neutrophils % bands % lymphocytes % monocytes % eosinophils 1 1-7% basophils 1 0-1% metamyelocytes 1 myelocytes 2 Coagulation PT sec aptt sec WBC, white blood cell; RBC, red blood cell; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration; RDW, red blood cell distribution width; PT, prothrombin time; aptt, activated partial thromboplastin time labmedicine.com February 2005 Volume 36 Number 2 LABMEDICINE 91

3 Table 2_Principal Laboratory Findings Test Patient s Result Normal Reference Range Chemistry Glucose mg/dl Sodium mmol/l Potassium mmol/l Bicarbonate mmol/l Chloride mmol/l Calcium mg/dl Magnesium meq/l Phosphorus mg/dl BUN mg/dl Creatinine mg/dl Total protein g/dl Albumin g/dl Bilirubin, total mg/dl Bilirubin, direct mg/dl LD U/L AST U/L ALT U/L ALP U/L GGT U/L Uric acid mg/dl Iron µg/dl Ferritin ng/ml TIBC µg/dl %Transferrin % G6PD Not deficient Not deficient Urinalysis Specific gravity ph Macroscopic findings All dipstick tests All dipstick tests negative negative Microscopic findings No RBCs; no WBCs; moderate bacteria; occasional calcium oxalate crystal BUN, blood urea nitrogen; LD, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, gammaglutamyl transferase; TIBC, total iron binding capacity; G6PD, glucose-6-phosphate dehydrogenase our patient s thin smear revealed the presence of several crescent-shaped gametocytes (Image 1A), many non-enlarged red cells that were singly (Images 1B and 1C) or multiply (Image 1D) infected with trophozoites, a schizont of P. falciparum (Image 1E), and tear drop-shaped, fimbriated red blood cells containing trophozoites of P. ovale (Image 1F). The trophozoites were characterized by incomplete rings that terminate onto 2 dense chromatin dots, while some red cells were singly infected with a trophozoite that appeared to be pressed against the inner surface of the cell membrane (Image 1C). These are termed accole or appliqué forms because of their resemblance to a large ornamental ring. Moreover, such forms are characteristic of P. falciparum infection. However, no Maurer rods were seen, and this is most likely because of the improper ph of the stain. The presence of a P. falciparum schizont is rare because P. falciparum schizonts normally express cytoadherence factors that cause most of these forms to be sequestered in small capillaries, thus preventing their appearance in peripheral blood. This finding usually correlates with very high parasitemia levels; however, our patient s parasitemia was only modestly elevated. The degree of parasitemia can be important in terms of treatment decisions. Red blood cells infected with trophozoites of P. ovale can be slightly enlarged, mis-shapened, or round or oval with fimbriated membranes (Image 1F). The schizonts of P. ovale, unlike those of P. falciparum, have no more than 10 to 12 merozoites. The patient s thick smear demonstrated many small, round gametocytes (not pictured in Image 1) consistent with those of P. ovale. 4. Most likely diagnosis: co-infection with P. falciparum and P. ovale. 5. The vector for malarial parasites is the female Anopheles mosquito. During a blood meal, sporozoites leave the mosquito s salivary glands, gain entrance into the human host s bloodstream, and are taken up by hepatocytes in the liver. During this extra-erythrocytic phase, most sporozoites undergo schizogony, whereby repeated divisions produce many merozoites (thousands) within each hepatocyte. Eventually the cells lyse, and merozoites are released into the hepatic sinusoids. Some species (ie, P. vivax and P. ovale) are also capable of delayed schizogony after a period of dormancy as hypnozoites within hepatocytes. After release from hepatocytes, most malarial organisms are taken up and destroyed within Kupffer cells, but eventually, merozoites invade erythrocytes percolating through the sinusoids. Thus a second intra-erythrocytic phase is initiated, and again, schizogony leads to a build up of merozoites (5 to 20, depending on species) within the red blood cell with eventual rupture of the cell and release of the merozoites into the circulation. 4 Each merozoite has the potential of infecting a new red blood cell, and the organisms are sustained by metabolizing the host cell hemoglobin. However, after several generations in the intra-erythrocytic phase, some merozoites undergo sexual differentiation and develop into male and female gametocytes. These forms can circulate in the peripheral blood, and are thus, transmissible to mosquitoes during a blood meal. The cycle then perpetuates itself in a sexual manner within the mosquito, culminating in the appearance of sporozoites within the insect s salivary glands. These different stages of the life cycle (among other criteria) aid the physician in determining the species of malarial parasite infecting their patient. When studying malarial parasites microscopically, one should evaluate several parameters, including the size and shape of infected red blood cells, the number of parasites within infected cells, the size, shape, and unique characteristics of each stage of parasite present, and the presence of non-parasitic red cell inclusions (ie, Schüffner granules and Maurer rods). As the malarial organisms metabolize hemoglobin, a dark, golden-brown malarial pigment, termed hemozoin, accumulates within the red blood cell, but this occurs with all malarial species and is therefore a non-specific finding. The microscopic characteristics that are useful in determining the species of malarial organism(s) present are listed in Table The asexual intra-erythrocytic stage is the only part of the malarial life cycle that is pathogenic in humans. Consequently, all pathophysiological processes are the result of red cell lysis, release of parasite or red cell material into the circulation, or the host s reaction to these events. 5 In general, clinical disease begins to manifest approximately 1 week after inoculation, and is usually in the form of a classic febrile paroxysm. The typical paroxysm begins with chills and rigors lasting 1 to 2 hours. The patient then spikes a high fever and the skin is warm and dry for a few hours. Subsequently, over the next few hours, the patient develops severe diaphoresis and body temperature rapidly falls. For many years, physicians determined malarial species based on the periodicity of these paroxysms. Specifically, P. malariae tends to cause paroxysms that last 72 hours, whereas those of P. vivax and P. ovale usually last 48 hours, and those of 92 LABMEDICINE Volume 36 Number 2 February 2005 labmedicine.com

4 P. falciparum can be as frequent as every 36 hours. The modern diagnosis of malaria, however, is more dependent on laboratory data. Anemia in malaria develops rapidly and is the result of both red blood cell lysis (intravascular hemolysis) and splenic sequestration (extravascular hemolysis). Non-infected red blood cells coated with immune complexes are also removed by the spleen. In addition, other pathophysiologic processes occur which further worsen the anemia, including bone marrow suppression, decreased incorporation of iron into heme, increased red blood cell fragility, and autoimmune lysis of red blood cells. 5 Anemia tends to be less severe in P. vivax and P. ovale infection, because these organisms tend to infect only reticulocytes. In addition to anemia, the common symptomatology of malaria is also defined by nausea, vomiting, anorexia, lethargy, diarrhea, and headache. Falciparum malaria has the propensity to cause sequestration of infected red blood cells within the microvasculature of vital organs, and it is this unique characteristic which makes falciparum malaria so much more deadly than other species. Accordingly, the most severe complications seen in falciparum malaria include petechial hemorrhages within the white matter of the brain (cerebral malaria), hepatic dysfunction, acute renal failure, disseminated intravascular coagulopathy, shock ( algid malaria ), and pulmonary edema. Hypoglycemia is also common and due to increased glycolytic demand (of both the host and the parasite) as well as depressed hepatic gluconeogenesis. Marked hemoglobinuria ( blackwater fever ) occurs with massive intravascular hemolysis. In contrast to these life-threatening complications, it should also be noted that malarial organisms are perhaps also responsible for benign red cell abnormalities, but in a much more indirect fashion. That is, malaria has been such a widespread disease entity that it has probably served as a significant selection pressure for many hemoglobinopathies, red blood cell cytoskeletal disorders, and red blood cell membrane diseases that are commonly seen in populations where malaria is endemic. 6 These red blood cell disorders include sickle cell trait, the thalassemias, Hemoglobin C disease, and Hemoglobin E disease, all of which result in abnormal hemoglobins that fail to sustain the intra-erythrocytic stage of malarial organisms. In addition, negativity for the Duffy blood group antigen and ovalocytosis, which results in red blood cells with enhanced ability to retard the entry of parasites, can also occur. Glucose-6-phosphate dehydrogenase deficiency (G6PD), the most common enzyme deficiency in humans, is yet another disease thought to be selected for by malaria because of the similarity of its geographical distribution with the historical endemicity of malaria. However, like homozygous sickle cell disease, the intrinsic morbidity of G6PD is a more powerful disadvantage than the malarial resistance is an advantage Appropriate selection of antimalarial chemotherapy depends on not just the species of malaria present, but also the degree of parasitemia and the geographic/travel history of the patient. These ancillary data aid the clinician in determining the likelihood of resistance to various antimalarial drugs. Antimalarial drugs can be categorized based on their selective action within the parasite s life cycle sporonticidal, blood schizonticidal, tissue schizonticidal, or gametocidal. Some drugs are also effective against dormant hypnozoites within hepatocytes. Most antimalarials are quinoline-based, but other types include antifolates, tetracyclines, derivatives of artemisinine, and naphthoquinolones. The most widely used treatment for the past several decades has been chloroquine due to its effectiveness against all 4 pathogenic malarial species in addition to its relative cheapness. However, Table 3_Characteristic Features of Malarial Species 1-3 Feature P. vivax P. malariae P. ovale P. falciparum Infected RBC characteristics Enlarged + ± Oval, fimbriated edges + Multiple organisms a + Decolorized + + Schüffner granules b + + Maurer rods + Parasite characteristics Degree of parasitemia Low Very low Low High All stages present + ± c + Very rare Trophozoite form Double chromatin dots a + Heavy chromatin dot + + Large, coarse rings ± + + Band forms + Ameoboid forms + ± Appliqué forms a + Schizont form Number of merozoites Daisy head configuration + ± Gametocyte form Banana/crescent shape + Oval, large + + Round, compact + ± a More commonly seen with P. falciparum, but can actually occur in any Plasmodium infection. b Termed James dots in P. ovale. c Ring form trophozoites are observed less commonly than other stages. chloroquine-resistance (largely due to P. falciparum) has become a serious problem in almost all parts of the world, most notably, Africa. To a lesser degree, P. vivax has also mounted resistance to chloroquine in parts of Southeast Asia. Consequently, other medications such as mefloquine and Fansidar (sulfidoxine + pyrimethamine) have been used against chloroquine-resistant malaria, but P. falciparum has quickly developed resistance against these drugs as well. A particularly alarming fact is that certain strains of P. falciparum in Thailand and Cambodia have demonstrated resistance to all known antimalarials. 8 However, in cases of non-resistant falciparum malaria, chloroquine or primaquine are usually adequate treatments. Primaquine is usually effective against P. ovale and P. vivax because it is hypnozoiticidal, but it can induce severe oxidant stress in patients with G6PD. The occurrence of this problem, however, is somewhat rare because individuals with G6PD are basically protected against infection by P. falciparum and P. vivax. 6 Treatment of severe falciparum malaria consists of an appropriate drug regimen based on the known local pattern of drug resistance. It is administered parenterally along with a loading dose of slowly-infused quinine or quinidine. Ancillary treatment includes antipyretics, adequate hydration, blood products, dialysis, and red blood cell exchange transfusion. It also should be noted that in patients failing to respond to chemotherapy and who have high levels of P. falciparum parasitemia with circulating schizonts, red blood cell exchange can be particularly useful. Its effectiveness has been attributed to (1) direct removal of parasites; (2) decreased risk of severe intravascular hemolysis; (3) improved blood flow due to decreased microcirculatory sludging; and (4) improved oxygenation. 9 However, despite many case reports praising these life-saving qualities, there has yet to be a randomized, controlled study demonstrating unequivocal benefit. The reason for this is probably due to the lack of comparability of control groups. 10 For travelers labmedicine.com February 2005 Volume 36 Number 2 LABMEDICINE 93

5 to endemic malarial areas, current CDC guidelines recommend prophylaxis with chloroquine, except in areas with reported chloroquine-resistance, where mefloquine, doxycycline, or Malarone (atovaquone + proguanil) are preferred. A recent study suggests that delayed-onset malaria in travelers occurs more frequently than was once thought. Accordingly, some have proposed a more complete prophylactic regimen for travelers, including hypnozoiticidal medications (primaquine). 11 Most antimalarials are well tolerated except for mefloquine whose potential side effects include neurotoxicity and cardiotoxicity. Non-chemotherapeutic prophylaxis includes wearing protective clothing, limiting nocturnal mosquito exposure, and using N,N-diethyl-m-toluamide (DEET)-containing insect repellant. LM Keywords Plasmodium, malaria, parasitemia, trophozoite, gametocyte, schizont, hypnozoite, merozoite 1. Antunano FJL, Schmunis G. Diagnosis of Malaria. Pan American Health Organization, Washington, Garcia LS. Diagnostic Medical Parasitology, Fourth Edition. Washington, DC: ASM Press, Warrell DA, Gilles HM. Essential Malariology, Fourth Edition. New York: Arnold, White NJ. Malaria pathophysiology. In Sherman IW. Malaria: Parasite Biology, Pathogenesis, and Protection. Washington, DC: ASM Press, 1998, Sherman IW. Malaria: Parasite Biology, Pathogenesis, and Protection. Washington, DC: ASM Press, Carter R, Mendis KN. Evolutionary and historical aspects of the burden of malaria. Clin Microbiol Rev. 2002;15: Ruwende C. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to malaria. Nature. 1995;376: Longworth DL. Drug-resistant malaria in children and in travelers. Pediatr Clin North Am. 1995;42: Phillips P, Nantel S, Benny WB. Exchange transfusion as an adjunct to the treatment of severe falciparum maliaria: case report and review. Rev Infect Dis. 1990;12: Riddle MS, Jackson JL, Sanders JW, et al. Echange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis. 2002;34: Schwartz E, Parise M, Kozarsky P, et al.. Delayed onset malaria implications for chemoprophylaxis in travelers. New Engl J Med. 2003;349: LABMEDICINE Volume 36 Number 2 February 2005 labmedicine.com

PARASITOLOGY CASE HISTORY #14 (BLOOD PARASITES) (Lynne S. Garcia)

PARASITOLOGY CASE HISTORY #14 (BLOOD PARASITES) (Lynne S. Garcia) A 37-year-old woman, who had traveled to New Guinea for several weeks, presented to the medical clinic with fever, chills, and rigors within