Fever, Night Sweats, Headache, Cough, and Myalgias in a 60-Year-Old Man

Transcription

1 Fever, Night Sweats, Headache, Cough, and Myalgias in a 60-Year-Old Man Matthew P. Thompson, MS III, Franklin Fuda, DO, Rita M. Gander, PhD (Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX) DOI: /22AA5T4PUHEUM0GK Received Revisions Received Accepted Clinical History Patient 60-year-old man. Chief Complaint Three-week history of fever, chills, nonproductive cough, night sweats, and headache. History of Present Illness The patient originally presented to the Emergency Department (ED) complaining of fever, chills, myalgias, headache, and nonproductive cough. At that time, he was prescribed Valcyte (900 mg per day) for a viral illness and discharged. Three weeks later, he returned to the ED with unresolved fever (greater than 101 F), chills, nonproductive cough, night sweats, nausea, and headache. Of note, he claimed that he had undergone a removal of a painless, 0.6 cm erythematous papule with a 1 mm to 2 mm central crust on his upper left back 3 days prior to this current visit. Questions 1. What are the patient s most striking clinical findings and laboratory results? 2. How do you explain this patient s most striking clinical findings and laboratory results? 3. What is this patient s most likely diagnosis? 4. What are the clinical manifestations of this patient s disease? 5. What are the pulmonary manifestations of this patient s disease? 6. What factors influence the severity and clinical manifestations of this patient s disease? 7. What are the key laboratory tests to confirm this patient s diagnosis? 8. What is the most appropriate treatment of this patient s disease? Possible Answers 1. History of recent renal transplant, current immunosuppression therapy, fever, night sweats, headache, and a focal back lesion. Pancytopenia; bone marrow biopsies showing the presence of yeast; decreased serum albumin and total protein with increased AST, ALT, alkaline phosphatase, GGT, and lactate Past Medical History His past medical history included hyperlipidemia, bilateral generalized osteoarthritis, type II diabetes mellitus, and long-standing hypertension with associated secondary retinopathy and end-stage renal disease requiring dialysis. His hypertension and diabetes were currently well controlled with medication. Past Surgical History The patient s past surgical history included arteriovenous fistula construction, left eye cataract removal, and kidney transplantation. Drug History The patient was currently taking Tacrolimus, Prednisolone, Valcyte, Bactrim, Nystatin swish and swallow, Calcitriol, Senna, Colace, calcium citrate, Pravastatin, Nisoldipine, Reglan, aspirin, and insulin. Family and Social History The patient denied a family history of heart disease, diabetes, hypertension, and cancer, and claimed that he had never abused drugs, tobacco, or alcohol. Physical Examination Findings The patient was an ill-appearing, shivering Hispanic male with a temperature of 38.3 C, a pulse rate of 91 beats per minute, a respiratory rate of 20 per minute, and a blood pressure of 142/66 mm Hg. He had right, tender, submandibular lymphadenopathy. There was a midline abdominal scar, and his abdomen was tender upon palpation. The remainder of his physical exam was unremarkable. Principal Laboratory Findings Table 1 Results of Additional Diagnostic Procedures and Laboratory Tests Due to the prolonged signs and symptoms along with a history complicated by immunosuppression and a failed course of antiviral therapy, additional microbiology tests were ordered (Table 2). Chest radiographs and abdominal ultrasound (US) were unremarkable, and computed tomography (CT) and magnetic resonance imaging (MRI) of the head revealed no evidence of an acute cranial process, masses, or lesions. Microscopic examination of a biopsy specimen from the ulcerative skin lesion on the patient s back demonstrated the presence of intracellular fungal elements (Image 1), while a bone marrow biopsy demonstrated the presence of granulomas with scattered histiocytes containing yeast (Image 2). dehydrogenase; increased D-dimer with normal fibrinogen; normal serum creatinine and blood urea nitrogen; positive cerebrospinal fluid (CSF) and urine Histoplasma antigen tests and recovery of Histoplasma capsulatum from blood and tissue from his back lesion. (Table 1 and Table 2). 2. The patient had a history of end-stage renal disease secondary to diabetes mellitus and hypertension, for which he had undergone a zero-mismatch renal transplant 5 years previously and had been receiving immunosuppressive medications (Tacrolimus and Prednisolone) to prevent graft rejection. Health risks related to the transplant and immunosuppression include graft rejection, graft-verses-host disease, bone marrow failure, post-transplant lymphoproliferative disorder, neoplasm, and infection. In this case, the immunosuppressive therapy most likely resulted in bone marrow suppression and pancytopenia. 1 The low leukocyte counts created an opportunity for infection. Although the patient s symptoms (ie, fever, night sweats, and headache) could be manifestations of multiple potential disease states, and difficulty is created in elucidating an etiology by the patient s complex history, it seems reasonable that his symptoms were most likely related to infection. Cultures, PCR assays, antigen and serological tests for bacterial, fungal, and viral organisms 352 LABMEDICINE Volume 38 Number 6 June 2007 labmedicine.com

2 Table 1_Principal Laboratory Findings Test Patient s Result Reference Interval 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 Coagulation PT sec INR 1.1 PTT sec D-dimer mg/dl Thrombin time sec Fibrinogen mg/dl Chemistry Total protein g/dl Albumin g/dl BUN mg/dl Creatinine mg/dl Total bilirubin mg/dl Direct bilirubin mg/dl AST U/L ALT U/L ALP U/L GGT U/L LD U/L CSF protein mg/dl CSF glucose mg/dl Immunology HCV Ab Negative Negative HBsAb Negative Negative HAV Ab Reactive Negative Anti-blastomyces Ab <1:2 <1:2 Anti-coccidiodes Ab <1:2 <1:2 Anti-histoplasma mycelial Ab <1:2 <1:2 Anti-histoplasma yeast Ab <1:2 <1:2 Urinalysis Qualitative screen (dipstick) All negative except Negative Glu (>1,000 mg/dl) and trace Bld WBC, white blood cell; RBC, red blood cell; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration; RDW, red cell distribution width; PT, prothrombin time; INR, International Normalized Ratio; PTT, partial thromboplastin time; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glytamyltransferase; LD, lactate dehydrogenase; HCV, hepatitis C virus; Ab, antibody; HBsAb, hepatitis B surface antibody; HAV, hepatitis A virus; Glu, glucose; Bld, blood. are useful in elucidating the etiology. The results of these studies highlight important issues regarding infectious disease testing in immunosuppressed patients and demonstrate the necessity for appropriate test ordering. For instance, indirect serologic analysis of infection based upon circulating antibody levels, while potentially very beneficial, could have proven misleading. For obvious reasons, immunosuppressed patients often have decreased levels of circulating antibodies leading to negative serologic testing for these antibodies, which necessitates direct testing for antigen specific to a suspected organism. 2 The patient s CSF Histoplasma antibody titer was negative; however, the CSF and urine Histoplasma antigen tests were able to identify the cause of the patient s infection, as the presence of Histoplasma antigen in CSF Table 2_Microbiology Findings Test Patient s Result Reference Range CSF Bacterial culture Negative Negative Fungal culture Negative Negative Histoplasma EIA antigen Units VDRL Negative Negative Cryptococcal antigen Negative Negative EBV PCR Negative Negative CMV PCR Negative Negative HSV PCT Negative Negative Blood Bacterial culture Negative Negative Fungal culture H. capsulatum Negative BKV PCR Negative Negative Parvovirus B19 PCR Negative Negative CMV PP65 antigen Negative Negative Urine Histoplasma EIA antigen Units Back lesion Bacterial culture, aerobic Negative Negative Fungal culture H. capsulatum Negative NP secretion Influenza A antigen Negative Negative Influenza B antigen Negative Negative CSF, cerebrospinal fluid; EIA, enzymeimmunoassay; VDRL, Venereal Disease Research Laboratory; EBV, Epstein-Barr virus; PCR, polymerase chain reaction; CMV, cytomegalovirus; HSV, human syncytial virus; BKV, BK virus; NP, nasopharyngeal. and urine (Table 2) provides nearly irrefutable evidence of the presence of this organism. 3 In addition to direct antigen testing, cultures can be very helpful. For instance, isolating an organism from culture often indicates a heavy organism load. 4 As with serologic testing, however, negative culture results must be interpreted with caution. Although blood cultures are positive in 85% of cases of disseminated histoplasmosis, H. capsulatum recovery in CSF cultures is seen in only 50% of patients with H. capsulatum infection and documented CNS involvement. 4 In this case, CSF cultures failed to recover the organism, while blood cultures revealed positive growth. Many of the other laboratory findings in this case are nonspecific. Elevation of lactate dehydrogenase is a broad indicator of tissue damage and can be seen in conditions such as diabetes mellitus, cholestasis, myocardial infarction, liver disease, hepatitis, malignancy, pancreatitis, inflammation, and systemic infection. 5 Elevation of alkaline phosphatase and gamma glutamyl transferase are commonly seen together in disease states involving intrahepatic and extrahepatic bile ducts. 5 Decreased serum albumin and total protein with increased ALT and AST is indicative of liver disease secondary to conditions such as alcoholism, hepatic steatosis, hepatic congestion, cholestasis, cirrhosis, viral hepatitis, neoplasm, and sepsis. 6 D-dimer elevation indicates coagulation activity and is seen in thrombotic states, disseminated intravascular coagulation, pulmonary embolism, neoplasm, liver disease, or septic infection. 5 An elevated D-dimer with normal fibrinogen, prothrombin time, and partial thromboplastin time is sometimes seen in systemic septic infections. 7 Hence, while nonspecific, the patient s results for these tests were consistent with systemic infection and liver failure. Moreover, chest radiographs and CT and MRI scans performed on our patient helped in ruling out pneumonia, tuberculoid lesions, pulmonary infiltrate, acute intracranial bleed, infarction, and mass lesions as the cause of his signs and symptoms. In addition, abdominal US and blood labmedicine.com June 2007 Volume 38 Number 6 LABMEDICINE 353

3 A B C Image 1_Patient s skin biopsy showing A) necrosis (hematoxylin-eosin [H&E] stain; 100x magnification); B) an area of necrosis containing yeast cells with basophilic cytoplasm retracted from thin cell walls creating a false impression of unstained yeast capsule (H&E stain; 1,000x magnification); and C) aggregates of budding and single yeast cells of H. capsulatum (Gomori s methenamine silver [GMS] stain; 500x magnification). chemistry tests helped in evaluating the integrity of his transplanted kidney, which, based on the results of these tests, appeared to be functioning well. 3. Most likely diagnosis: disseminated histoplasmosis. Negative radiographic imaging results and normal kidney function tests decreased the likelihood of a neoplasm or transplant rejection as the cause of the patient s signs and symptoms. Negative bacterial cultures and no clinical response to vancomycin therapy decreased the likelihood of a bacterial etiology for his signs and symptoms. The patient s history of immunosuppression therapy, positive morphologic identification of yeast in the back lesion and bone marrow, positive CSF and urine Histoplasma antigen tests, and positive blood and tissue fungal cultures were consistent with a diagnosis of disseminated histoplasmosis. 4. Although most Histoplasma infections are asymptomatic, histoplasmosis can be a severe, or even fatal, disease in patients who have experienced heavy exposure to H. capsulatum or have underlying immune defects. 3 The diagnosis of histoplasmosis depends on recognizing the different clinical manifestations of the infection caused by this organism and awareness of the limitations of diagnostic tests used to evaluate a presumptive diagnosis of this condition. 3 In immunocompetent individuals, Histoplasma infection occurs after inhalation of the microcondia of the mold phase of the organism, resulting in a localized or patchy pneumonitis. Hematogenous dissemination occurs during the first 2 weeks of infection before specific immunity has developed. 8,9 Exposure in an immunocompromised individual follows the same sequence but without formation of specific immunity. Prior belief that progressive disseminated histoplasmosis (PDH) in immunosuppressed and immunocompromised hosts occurs as a result of reactivation of quiescent infection has recently been challenged. 10,11 Recent investigations suggest that reactivation is rare and that PDH more likely results from exacerbation of low-grade infection or newly-acquired disease The majority of cases of disseminated histoplasmosis begin as pulmonary histoplasmosis; however, there are some reports of documented transmission of H. capsulatum by renal allograph transplantation. 16,17 5. The pulmonary manifestations of histoplasmosis are a subacute flu-like illness with a dry cough, low-grade fever, and fatigue. Chest radiographs usually show evidence of enlarged hilar or mediastinal lymph nodes and patchy infiltrates. However, not all patients with pulmonary histoplasmosis demonstrate evidence of these findings on chest radiograph. 18 Disseminated histoplasmosis occurs mainly in immunocompromised patients and those at extremes of age. 19,20 6. Severity of the disease varies with the degree of immunodeficiency present in the patient. Patients often present with signs and symptoms ranging from fever, night sweats, dry cough, fatigue, and myalgias to shock, respiratory distress, hepatic and renal failure, obtundation, and coagulopathy Occasionally, skin lesions and CNS infection are also present in the patient; CNS involvement may manifest as meningitis, stroke, hydrocephalus, or encephalitis. 3,23 7. General laboratory evidence for disseminated disease includes anemia, leukopenia, thrombocytopenia, elevated hepatic enzymes, elevated bilirubin, and elevated lactate dehydrogenase. 3,24 Diagnosis of disseminated histoplasmosis requires a variety of laboratory tests. 4 In this patient, fungal cultures were performed on blood, skin lesions, and CSF. The limitation of cultures is that they require several weeks to grow in vitro, and, therefore, treatment initiation cannot be deferred for the results of the cultures. Serologic tests for antibodies to H. capsulatum are positive in 80% of patients with disseminated disease. 25 However, limitations of serologic testing include a 2 to 6 week lag in antibody production after exposure, low to absent titers of antibody in immunocompromised patients, and positive titers resulting from prior inconsequential or asymptomatic infection. 3,22,26 Antigen detection testing for H. capsulatum offers a method for rapid diagnosis of disseminated disease and H. capsulatum antigen can be detected in the urine of 95% of patients with acquired immunodeficiency syndrome (AIDS) and disseminated Histoplasma infection, 3,27,28 and 82% to 85% of non-aids patients with disseminated disease. 3,4,27,28 Histoplasma antigen can also be detected in the CSF of patients with CNS involvement; 75% of AIDS patients, and 25% of non-aids patients demonstrate positive CSF antigen results. 29 Interestingly, false-positive serum Histoplasma antigen tests have been reported in renal transplant patients who had received antithymocyte globulin. 30 Peripheral blood smears, bone marrow biopsies, CSF preparations, and scrapings of skin lesions (if present) also allow for rapid identification of yeast or fungi. However, it is impossible to identify Histoplasma based solely on morphology from a pathological examination; further tests such as cultures or immunohistochemistry need to be performed before a definitive diagnosis can be made. As occurred in this patient, it is often the pathologist who first recognizes the presence of the fungus and brings it to the attention of the clinician. In this patient, the identification of intracellular fungal elements 354 LABMEDICINE Volume 38 Number 6 June 2007 labmedicine.com

4 A B Image 2_Bone marrow biopsy demonstrating A) interstitial, noncaseating granulomas consisting of epithelioid histiocytes (H&E stain; 100x magnification) and B) budding yeast cells (GMS stain; 500x magnification). from the skin lesion on his back was the first indication that the pathogen responsible for the patient s disease was a fungus, and this finding prompted the workup that led to the diagnosis (Image 1). Part of this workup included a bone marrow biopsy to assess the spread of the organism, which revealed intracellular yeast (Image 2). 8. The mortality rate for disseminated histoplasmosis without treatment is approximately 80%, underscoring the need for early, accurate diagnosis and treatment. 31 Treatment trials with amphotericin B have shown a reduction in the mortality of disseminated histoplasmosis to less than 25%. 20,32-34 Treatment of patients with PDH with liposomal amphotericin B has shown a decrease in time to resolution and increased overall survival compared with standard amphotericin B and may be preferred in patients with severe disease or underlying immunodeficiency. 35 Following an initial response to treatment with amphotericin B, consolidation therapy with itraconozole is initiated and continued for up to 18 months in an immunocompetent patient or lifelong in an immunodeficient patient. 3,36 Regardless of treatment, relapse occurs in 10% to 80% of patients with disseminated histoplasmosis depending on immune status. 3 Acknowledgements: We thank Dominick Cavuoti, DO, for assistance in photographing the slides and Bobbie Wortham for administrative assistance in manuscript preparation. Keywords: disseminated histoplasmosis, Histoplasma capsulatum, renal transplant, immunosuppression 1. Lake DF, Akporiaye ET, Hersh EM. Immunopharmacology. In: Katzung BG, ed. Basic and Clinical Pharmacology, 8th ed. New York: Lange; 2001: Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Terapy, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999: Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am. 2003;17: Williams B, Fojtasek M, Connolly-Stringfield P, et al. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind. Arch Pathol Lab Med. 1994;118: Sacher RA, McPherson RA. Widmann's Clinical Interpretation of Laboratory Tests, 10th ed. Philadelphia, PA: FA Davis Co; 1991: Friedman LS. Liver, biliary tract, and pancreas. In: Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. New York: Lange; Linker CA. Blood. In: Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. New York: Lange; Newman SL. Cell-mediated immunity to Histoplasma capsulatum. Semin Respir Infect. 2001;16: Woods JP, Heinecke EL, Luecke JW, et al. Pathogenesis of Histoplasma capsulatum. Semin Respir Infect. 2001;16: Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area. Am J Med. 1978;64: Keath EJ, Kobayashi GS, Medoff G. Typing of Histoplasma capsulatum by restriction fragment length polymorphisms in a nuclear gene. J Clin Microbiol. 1992;30: Vail GM, Young RS, Wheat LJ, et al. Incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area. Transpl Infect Dis. 2002;4: Wallis, RS, Broder M, Wong J, et al. Reactivation of latent granulomatous infections by infliximab. Clin Infect Dis. 2005;41:S194 S Wheat J. Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol. 1996;7: Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with Anti-TNF-{alpha} Therapy. Am J Respir Crit Care Med. 2003;167: Limaye AP, Connolly PA, Sagar M, et al. Transmission of Histoplasma capsulatum by organ transplantation. N Engl J Med. 2000;343: Wong SY, Allen DM. Transmission of disseminated histoplasmosis via cadaveric renal transplantation: Case report. Clin Infect Dis. 1992;14: Wheat LJ, Slama TG, Eitzen HE, et al. A large urban outbreak of histoplasmosis: Clinical features. Ann Intern Med. 1981;94: Goodwin RA Jr, Shapiro JL, Thurman GH, et al. Disseminated histoplasmosis: Clinical and pathologic correlations. Medicine (Baltimore). 1980;59: Sathapatayavongs B, Batteiger BE, Wheat J, et al. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine (Baltimore). 1983;62: Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: Clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore). 1990;69: Wheat L. Histoplasmosis in the acquired immunodeficiency syndrome. Curr Top Med Mycol. 1996;7: Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system. A clinical review. Medicine (Baltimore). 1990;69: labmedicine.com June 2007 Volume 38 Number 6 LABMEDICINE 355

5 24. Corcoran GR, Al-Abdely H, Flanders CD, et al. Markedly elevated serum lactate dehydrogenase levels are a clue to the diagnosis of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis. 1997;24: Wheat LJ. Laboratory diagnosis of histoplasmosis: Update Semin Respir Infect. 2001;16: Specht CS, Mitchell KT, Bauman AE, et al. Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Ophthalmology. 1991;98: Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med. 1986;314: Durkin MM, Connolly PA, Wheat LJ. Comparison of radioimmunoassay and enzyme-linked immunoassay methods for detection of Histoplasma capsulatum var. capsulatum antigen. J Clin Microbiol. 1997;35: Wheat LJ, Garringer T, Brizendine E, et al. Diagnosis of histoplasmosis by antigen detection based upon experience at the histoplasmosis reference laboratory. Diag Micro Inf Dis. 2002;43: Wheat LJ, Connolly P, Durkin M, et al. False-positive Histoplasma antigenemia caused by antithymocyte globulin antibodies. Transplant Infec Dis. 2004;6: Rubin H, Furcolow ML, Yates JL, et al. The course and prognosis of histoplasmosis. Am J Med. 1959;27: Furcolow ML. Comparison of treated and untreated severe histoplasmosis. JAMA. 1963;183: Sarosi GA, Voth DW, Dahl BA, et al. Disseminated histoplasmosis: Results of long-term follow-up. A Center for Disease Control cooperative mycoses study. Ann Intern Med. 1971;75: Wilson DA, Muchmore HG, Tisdal RG, et al. Histoplasmosis of the adrenal glands studied by CT. Radiology. 1984;150: Johnson PC, Wheat LJ, Cloud GA, et al. U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137: Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America. Clin Infect Dis. 2000;30: LABMEDICINE Volume 38 Number 6 June 2007 labmedicine.com