Index of Suspicion

Abstract

A 16-month-old boy had been diagnosed with B-cell acute lymphoblastic leukemia (ALL). Past medical and birth histories were unremarkable. Over the past 48 hours, he received and tolerated a slow transfusion of packed red blood cells for an Hgb concentration of 4.9 g/dL (49 g/L). Currently, he is receiving maintenance intravenous hydration. Physical examination shows no evidence of distress. His temperature is 97.5°F (36.4°C), respirations are 24 breaths/min, heart rate is 126 beats/min, blood pressure is 95/64 mm Hg, and oxygen saturation is 98% on room air. His chest is clear to auscultation, with normal heart sounds. Abdominal examination shows mild hepatosplenomegaly. He has scattered petechiae. Current laboratory results are: WBC count of 14.8×103/mcL (14.8×109/L), Hgb of 10.4 g/dL (104 g/L), Hct of 28.9% (0.29), and platelet count of 48×103/mcL (48×109/L). The values for serum electrolytes, BUN, creatinine, liver enzymes, and uric acid as well as results of coagulation studies are within normal limits. Chest radiography reveals normal findings. Prior to surgery for central line placement, he receives 1 unit of irradiated, leukocyte-reduced platelets.A central line is placed without difficulty. Within 2 hours of the platelet transfusion, he experiences acute cardiorespiratory deterioration (heart rate 165 beats/min, blood pressure 65/42 mm Hg, respiratory rate 48 breaths/min, oxygen saturation 78% on room air, and temperature 99°F [37.2°C]). Examination reveals symmetrically decreased breath sounds and diffuse crackles bilaterally, with normal heart sounds and capillary refill. Repeat radiography shows extensive “diffuse bilateral infiltrates consistent with pulmonary edema.” He is intubated and transferred to the intensive care unit. Additional evaluations reveal the diagnosis.A 13-month-old boy presents with a history of fever for 2 days and nonbloody diarrhea for 2 weeks. Other family members also report diarrhea over the past 2 weeks. He has been healthy, except for a 4-month history of easy bruising and a recent history of oral thrush. He is not taking any medications.On physical examination, his temperature is 102.9°F (39.4°C) and other vital signs are normal. He appears ill but not toxic. He has multiple petechiae and ecchymoses all over his body, white plaques on the oral mucosa, and bilateral anterior cervical lymphadenopathy. The remaining findings of his physical examination are normal. Initial laboratory tests show a WBC count of 2.3×103/mcL (2.3×109/L), with 62% bands, 22% neutrophils, 18% lymphocytes, and 5% monocytes; Hgb of 8.8 g/dL (88 g/L); and platelet count of 11×103/mcL (11×109/L). Stool studies yield negative results.He is started on empiric cefepime and fluconazole but soon becomes more irritable and develops nuchal rigidity as well as bilateral sixth cranial nerve palsy. A CT scan of his head shows mild ventriculomegaly. A lumbar puncture is performed, and analysis of the CSF shows glucose of 37 mg/dL, protein of 300 mg/dL, 420 red blood cells/mm3 and 1,319 WBCs/mm3. Blood and CSF cultures subsequently grow Listeria monocytogenes. Antibiotics are changed to ampicillin and gentamicin. An intraventricular catheter (IVC) is placed to relieve the increased intracranial pressure. Additional studies reveal why this patient contracted this unusual infection.A 17-year-old Hispanic boy presents to the ED with a 5-day history of fever and severe abdominal pain. The pain is intermittent and localized to the epigastrium and right flank. He denies vomiting, diarrhea, and bloody stools but complains of loss of appetite, weight loss, constipation, mild headache, and a dry cough over the past 2 weeks. The past medical history is unremarkable. There is no history of recent international travel or exposure to animals.Physical examination reveals an obese, alert adolescent whose temperature is 101.2°F (38.5°C), heart rate is 114 beats/min, respiratory rate is 24 breaths/min, blood pressure is 118/68 mm Hg, and oxygen saturation is 97% on room air. He has right upper quadrant abdominal tenderness, but his liver and spleen are not enlarged. Results of the rest of the examination are unremarkable.Laboratory studies show a WBC count of 24.1×103/mcL (24.1× 109/L) with 68% neutrophils, 13% bands, 13% monocytes, and 6% lymphocytes; Hgb of 14.3 g/dL (143 g/L); and platelet count of 334×103/mcL (334×109/L). The ESR is 62 mm/hr and C-reactive protein is 390.1 mg/L (39.0 mg/dL). Measurements of electrolytes, amylase, and lipase as well as renal function tests, liver function tests, and urinalysis are normal. ALT is mildly elevated at 44 U/L (normal, 10 to 40 U/L). Serologic tests for HIV and hepatitis A, B, and C are negative. Blood and stool cultures are negative for bacteria. Fecal ova and parasite examinations are negative. A purified protein derivative skin test is positive. Chest radiography shows increased interstitial markings with patchy opacities in the right middle lobe and both lower lobes.Imaging of the abdomen leads to an additional test that reveals the diagnosis.Immediately after the onset of respiratory symptoms, the serum electrolytes, BUN, and creatinine values were normal. His intake and output over the previous 24 hours were matched, and he had appropriately colored urine output. ECG was read as normal, and echocardiography showed normal anatomy with normal cardiac function and no evidence of left atrial hypertension. There was no obvious evidence of circulatory overload, underlying infection, bacterial contamination of the donor unit, or acute hemolytic or anaphylactic transfusion reactions. Transfusion-related acute lung injury (TRALI) was diagnosed.The patient was placed on mechanical ventilation for 2 days and started on prednisone for his induction chemotherapy protocol for ALL. He subsequently was extubated, received supportive management, and was discharged from the hospital on day 7.TRALI is a diagnosis of exclusion in a patient who presents with symptoms of acute respiratory distress, such as hypoxemia, tachycardia, or tachypnea, with bilateral diffuse infiltrates on frontal chest radiograph and no evidence of left atrial hypertension, noncardiogenic pulmonary edema, or pre-existing acute lung injury (ALI). The presentation occurs classically within 6 hours of receiving any blood product. In TRALI, a temporal relationship to an alternate risk factor for ALI, such as transfusion-associated circulatory overload (TACO), does not exist. TRALI is the leading cause of death in transfusion medicine, having an estimated mortality rate of 10%.TRALI and acute respiratory distress syndrome (ARDS) have many common clinical features, but there are notable clinical differences. In TRALI, most patients show clinical, physiologic, and radiographic resolution of symptoms within 2 to 3 days of the onset of the condition. Moreover, their underlying pulmonary injury is reversible, and there are no long-term residual pulmonary function deficits.All blood components have been implicated in TRALI, including red blood cells, platelets, plasma, cryoprecipitate, granulocytes, stem cells, immune globulin concentrates, and autologous red cells. The estimated incidence is 1 in 5,000 to 1 in 25,000 transfusions. There is consensus that many cases are not reported and mild cases may be unrecognized. Because there is no specific diagnostic test, the 2004 consensus panel on TRALI developed clinical guidelines (TableT1) to enhance awareness and improve reporting to local transfusion services. (1)The pathogenesis of TRALI is understood incompletely, but there are two major schools of thought. The first hypothesis involves the infusion of a blood product that contains an antibody against the human leukocyte antigen (HLA) or human neutrophil antigen (HNA) for which the recipient has the cognate antigen. This situation leads to leukoagglutination, congestion of the pulmonary vasculature, neutrophil degranulation, and subsequently, endothelial injury and capillary leak. The second hypothesized mechanism is a “two-hit” model in which the first hit is the underlying clinical condition that leads to the elaboration of cytokines, which causes pulmonary endothelial activation resulting in pulmonary sequestration of neutrophils. The second hit is the infusion of the blood product that contains a biologically active lipid (lysophosphatidylcholine) that causes neutrophils to degranulate, resulting in endothelial damage and subsequent capillary leak.The laboratory evaluation of TRALI and donor management is expensive and involves donor testing for antibodies against classes I and II HLA and HNA from a residual volume of the transfused blood component or a fresh blood specimen obtained from the blood donor. HLA typing on the recipient also is performed. A donor is regarded as “implicated” in TRALI if he or she is found to have HLA class I or II antibodies or HNA antibodies that have specificity for the recipient's WBCs. Once a donor has been implicated, the consensus panel recommends that the he or she be deferred permanently from donation, which is not applied universally because of a smaller donor pool. This recommendation is based on instances in which donors who had specific antibodies have been implicated in TRALI reactions involving multiple recipients.For patients experiencing acute pulmonary insufficiency following blood product transfusion, the differential diagnosis includes TACO, which may present as respiratory distress, hypertension, and tachycardia when there is a mismatch of intake and output. Patients who have TACO show rapid resolution and improvement with aggressive diuresis. Anaphylactic transfusion reactions develop very rapidly and commonly present with erythema, urticaria, bronchospasm, and laryngeal edema rather than the noncardiogenic pulmonary edema seen in TRALI. Bacterial contamination of the blood product, leading to sepsis, presents as a sudden high fever, with or without rigors or chills, and cardiovascular collapse. Among these patients, respiratory symptoms usually are not prominent. Acute hemolytic transfusion reactions may present with signs of intravascular hemolysis that typically would not be confused with TRALI. ARDS, due to causes such as toxins or infections, also may present as respiratory distress and needs to be considered in the appropriate clinical setting.Early recognition and prompt respiratory and hemodynamic supportive measures are the hallmarks of management. Almost all patients require supplemental oxygen. In severe hypoxemia, intubation and mechanical ventilation with relatively high positive end-expiratory pressure are necessary. Inotopes may be needed to support the hemodynamic status. Although patients may not experience volume overload, diuresis commonly is undertaken. The role of steroids is somewhat controversial, but many clinicians choose to administer a short course. Intravenous immunoglobulin administration does not alter the clinical course or outcome and is not indicated routinely. With appropriate timely management, most patients who have TRALI recover completely within 96 hours. Delay in management may lead to unnecessarily prolonged hospitalization as well as additional morbidity and mortality. Because anti-HLA antibodies may be implicated in TRALI and because multiparous women often have multiple HLA antibodies, some have recommended that such individuals be screened for HLA antibodies or excluded as donors of fresh frozen plasma and other blood products containing plasma.TRALI is a diagnosis of exclusion and should be considered in all patients who develop acute cardiorespiratory symptoms within 6 hours of blood product transfusion. Clinical criteria, developed by a TRALI consensus panel, serve as a useful diagnostic tool. Timely recognition and prompt supportive management are critical to decreasing mortality. Appropriate reporting and donor management also are critical and may serve to enhance understanding of the pathogenesis of TRALI. (Amir Mian, MD, David Becton, MD, Douglas P. Blackall, MD, University of Arkansas for Medical Sciences, Little Rock, Ark.)The occurrence of listeriosis at an atypical age in the setting of pancytopenia warranted additional investigation. T- and B-lymphocyte enumeration showed CD4 lymphopenia with 4% CD4 cells (normal, 31% to 54%) and an absolute CD4 count of 0.18×109/L (normal, 1 to 4.6×109/L). Results of human immunodeficiency virus (HIV) enzyme immunoassay and HIV DNA polymerase chain reaction (PCR) were negative. Immunoglobulin values and specific antibody titers were within normal limits. A bone marrow aspiration and biopsy revealed hypocellularity with an increased number of histiocytes demonstrating hemophagocytosis, but there were no blast cells, dysplasia, or fibrosis.Hemophagocytic lymphohistiocytosis was considered, but several key diagnostic features such as splenomegaly, hypofibrinogenemia, and hypertriglyceridemia were absent. Investigation into possible viral causes detected Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) by PCR. The patient was treated supportively with packed red blood cell and platelet transfusions, as well as with granulocyte-colony stimulating factor injections. The IVC was removed after 3 days. He completed a 21-day course of ampicillin and gentamicin. Although he improved clinically, his cell counts failed to improve. Therefore, a repeat bone marrow aspiration and biopsy were performed, which showed aplastic anemia. The patient did not have an HLA-matched bone marrow donor, so he underwent immunosuppressive therapy with cyclosporine and antithymocyte globulin (ATG). He responded well, and a follow-up bone marrow aspiration 1 year later yielded normal results.Listeria monocytogenes is a facultatively anaerobic gram-positive bacillus that most commonly causes illnesses in infants younger than 2 months of age, pregnant women, the elderly, and persons who have impaired cell-mediated immunity. Bacteremia and meningitis are the two most common invasive infections caused by Listeria. In contrast to other forms of bacterial meningitis, Listeria infection may involve the brain parenchyma and has been associated with encephalitis and brain abscesses. Listeria also causes a self-limited febrile gastroenteritis. Foods such as soft cheeses, deli meats, raw vegetables, unpasteurized milk, and poultry are common sources of Listeria.Gastrointestinal Listeria infections do not require treatment, but ampicillin is the antibiotic of choice for invasive listeriosis. Gentamicin may be added for synergistic effect. Trimethoprim-sulfamethoxazole is an alternative for penicillin-allergic patients. CNS infections should be treated for at least 21 days; bacteremia without meningitis may be treated with a shorter course.Aplastic anemia (AA) is defined as pancytopenia that has an underlying hypocellular bone marrow. Its annual incidence is estimated to be 2 to 4 cases per 1 million, with a peak in adolescents, young adults, and the elderly. AA has inherited, acquired, and idiopathic forms. Examples of inherited AA forms are Fanconi anemia and Shwachman-Diamond syndrome. Acquired AA may be due to irradiation, drugs (nonsteroidal anti-inflammatory drugs, cancer chemotherapeutic agents, chloramphenicol, psychotropic agents), chemical toxins (benzene), viruses (EBV, HHV-6, cytomegalovirus, herpes simplex virus, parvovirus, HIV, hepatitis virus), immune dysfunction (hypogammaglobulinemia, graft versus host disease, defects in cell-mediated immunity), and pregnancy. Myelodysplastic syndromes, malignancy, and other infections (babesiosis, ehrlichiosis, and tuberculosis) must be differentiated from AA as causes of pancytopenia and hypocellular bone marrow.The most common presentations of AA are symptoms related to low peripheral blood cell counts. Thrombocytopenia may present with easy bruising, petechiae, gingival bleeding, and epistaxis. Anemia may cause fatigue, lightheadedness, and dyspnea on exertion. Neutropenia presents with several bacterial or fungal infections.AA occasionally may be associated with a hemophagocytic syndrome, usually of viral origin, which was the case in this patient. Hemophagocytosis results when erythrocytes, leukocytes, platelets, and their precursors undergo phagocytosis by macrophages in the bone marrow, a process that is believed to be mediated by overproduction of cytokines. (1) Hemophagocytic syndromes cause pancytopenia, which develops during the convalescent phase of many viral infections, most commonly with the herpesviruses, but also with parvovirus and HIV. Hemophagocytosis also can be caused by bacterial, parasitic, and fungal infections.Clues in the history, physical examination, and laboratory data may point toward AA, but the diagnosis cannot be made without examination of the bone marrow and the finding of hypocellularity. After being diagnosed, AA should be considered a medical emergency, due to the potential complications of pancytopenia. Definitive treatment is with allogeneic hematopoietic stem cell transplantation, ideally from an HLA-matched sibling donor. Immunosuppressive therapy with cyclosporine or ATG is the treatment of choice if transplantation is not an option. Management also consists of correcting any significant cytopenias. Opportunistic infections should be treated aggressively, and prophylaxis should be provided until leukopenia resolves.The prognosis of AA is correlated directly with the severity of blood cell count depression at presentation, especially the degree of neutropenia. Untreated severe AA almost invariably is fatal, whereas more moderate AA has a very good long-term survival if treated. Some mild forms of AA are self-limited and do not require treatment.In the pediatric population, listeriosis after 2 months of age is unusual and should raise suspicion for an underlying deficiency in cell-mediated immunity. AA occasionally can be a cause of such an immunodeficiency due to profound leukopenia. In the setting of pancytopenia, bone marrow aspiration is necessary to distinguish among AA, hemophagocytic syndrome, malignancy, myelodysplastic syndromes, and viral suppression. If AA of any cause is found, definitive treatment with allogeneic stem cell transplantation should be undertaken as soon as possible. Immunosuppressive therapy is needed if a matching family or unrelated donor is not available. (Scott H. James, MD, University of Alabama at Birmingham, Birmingham, Ala; David M. Berman, DO, All Children's Hospital, St. Petersburg, Fla.)Contrast-enhanced CT scan of the abdomen (FigureF1) revealed a 5.7×7.2-cm peripherally enhancing, low-density lesion in the posterior right hepatic lobe, which was most suggestive of hepatic abscess. The differential diagnosis includes pyogenic and amebic liver abscesses (ALA). Distinguishing between them is critical because the treatment and prognosis differ. The microbiology of pyogenic abscesses is highly variable because infection can occur by hematogenous seeding or by contiguous spread from an intra-abdominal source. Leading causative organisms include Staphylococcus aureus, Salmonella, Klebsiella pneumoniae, Escherichia coli, and anaerobes. Among the other unusual pathogens are Bartonella henselae, Nocardia asteroides, Yersinia pseudotuberculosis, and Y enterocolitica. Nonpyogenic liver abscesses are rare in developed countries. Organisms causing nonpyogenic liver abscesses include amoeba, mycobacteria, Echinococcus, and fungi.The patient was admitted to the pediatric infectious disease service and was started on intravenous metronidazole, clindamycin, and ceftriaxone to treat both amebic and pyogenic infection. Percutaneous drainage of the abscess under fluoroscopy and ultrasonographic guidance was carried out for diagnostic purposes. Culture of abscess fluid was negative for bacteria and fungi. Serologic testing for Entamoeba histolytica antibodies was strongly positive (immunoglobulin G, 7.32; normal, <0.9). On the third day of hospitalization, the boy became afebrile and improved clinically. A repeat abdominal CT scan on day 6 of hospitalization showed significant decrease in the size of the abscess cavity. He received a 7-day course of intravenous metronidazole and was discharged to complete a 20-day course of iodoquinol at home. Although this patient had not traveled, he may have acquired this amebic infection from a family member who visited him from Mexico several months prior to presentation.Amebiasis, caused by the intestinal protozoal parasite Entamoeba histolytica, remains a global health problem, infecting about 50 million people and resulting in 40,000 to 100,000 deaths per year. The prevalence may be as high as 50% in tropical and subtropical countries where overcrowding and poor sanitation are common. In the United States, E histolytica infection is seen most commonly in immigrants from developing countries, long-term travelers to endemic areas (most frequently Mexico or Southeast Asia), institutionalized individuals, and men who have sex with men. In 1993, the previously known species E histolytica was reclassified into two genetically and biochemically distinct but morphologically identical species: the pathogenic E histolytica and the nonpathogenic commensal E dispar.E histolytica is transmitted via the fecal-oral route. The ingested amebic cysts are resistant to gastric acid and undergo excystation in the small intestine, releasing mobile trophozoites that infect the colon. The trophozoites adhere to the colonic epithelium, where pathogenic strains produce ulcerative lesions, resulting in colitis. Asymptomatic cyst excreters can transmit infection for years if left untreated. Extraintestinal disease results when trophozoites breach the colonic mucosal barrier and enter the portal circulation. The organ affected most commonly is the liver, although cases of lung, brain, and skin involvement have been reported. The abscess usually is solitary, and the right lobe of the liver is affected most commonly (80%), a finding attributed to the right lobe receiving most of the blood draining from the cecum and ascending colon.Most patients who have ALA present acutely (<10 days in duration) with fever, right upper quadrant abdominal pain, and weight loss. In general, amebic colitis precedes the development of ALA, but only 30% of patients report concurrent active dysentery. Hepatomegaly and weight loss often are encountered in patients who have a chronic illness (2 to 12 weeks in duration). Jaundice is unusual but may occur in patients who have severe disease and multiple abscesses. Cough may be present, and pulmonary examination may reveal dullness and rales in the right lung base. Approximately 4% to 9% of patients who have ALA may present with referred shoulder pain, which is related to involvement of the diaphragmatic surface of the liver. In neonates, ALA has a rapidly progressing course, mimicking neonatal sepsis.Laboratory abnormalities noted in patients afflicted with ALA include leukocytosis without eosinophilia, anemia, an elevated alkaline phosphatase, and minimal elevations in serum bilirubin and transaminase. Currently, serum antibody detection using indirect hemagglutination assay is the most useful diagnostic test for ALA and is positive in 95% to 99% of cases. It is unusual to find trophozoites in liver abscess aspirate. Stool microscopy usually is negative for E histolytica trophozoites or cysts. Molecular methods (using PCR) are the most sensitive for identifying and differentiating Entamoeba sp in stool. Chest radiography may reveal an elevated right hemidiaphragm and right-sided pleural effusion. Both ultrasonography and CT scan are sensitive in the detection of ALA, but ultrasonography is the preferred method due to its low cost, availability, and lack of adverse effects.Medical therapy with a 7- to 10-day course of intravenous or oral metronidazole alone can cure invasive disease in more than 95% of cases. Metronidazole is effective for elimination of both intestinal and extraintestinal infection. Percutaneous drainage is considered for large abscesses (>5 cm) to prevent spontaneous rupture, left-lobe abscesses that may rupture into the pericardial space, and failure to respond to medical therapy within 5 to 7 days. The need for open surgical drainage is rare. Following a course of metronidazole, patients should receive treatment with iodoquinol, paromomycin, or diloxanide furoate to treat the luminal carrier state. Serial radiographic studies indicate that ALA usually resolves within 6 months of treatment. Antimotility agents and corticosteroids can worsen symptoms of amebiasis and, therefore, are not recommended.Control measures for amebiasis include maintaining hand hygiene and good sanitation. Research is ongoing toward development of a vaccine against amebae. Oral and DNA-based vaccines have been tested successfully in animal models for immunogenicity and efficacy. Additional research is needed to determine the efficacy of the vaccine in humans.In developed nations where amebiasis is rare, failure to consider the infection may delay diagnosis. Hepatic amebiasis may be encountered in immigrants from resource-limited countries even if they have no history of recent travel. ALA may be the first manifestation of amebiasis without any preceding diarrheal illness. The diagnosis should be considered if aspirated material does not show bacteria and serologic testing for E histolytica is positive. Treatment with metronidazole alone may be curative in 95% of those who have ALA. (James A. Owusu, Charles Turner, MD, Laurence B. Givner, MD, Avinash K. Shetty, MD, Wake Forest University Health Sciences and Brenner Children's Hospital, Winston-Salem, NC)