Severe Ehrlichia chaffeensis infection in a lung transplant recipient: a review of ehrlichiosis in the immunocompromised patient. (Dispatches).We describe a case of human ehrlichiosis in a lung transplant recipient and review published reports on ehrlichiosis in immunocompromised immunocompromised /im·mu·no·com·pro·mised/ (-kom´pro-mizd) having the immune response attenuated by administration of immunosuppressive drugs, by irradiation, by malnutrition, or by certain disease processes (e.g., cancer). patients. Despite early therapy with doxycycline, our patient had unusually severe illness with features of thrombotic thrombocytopenic purpura thrombotic thrombocytopenic purpura
A disease of unknown origin, characterized by abnormally low levels of platelets in the blood, the formation of blood clots in the arterioles and capillaries of many organs, and neurological damage. . Of 23 reported cases of ehrlichiosis in immunocompromised patients, organ failure occurred in all patients and 6 (25%) died.
Since the discovery in 1987 of Ehrlichia as a cause of tick-borne disease in humans (1), ehrlichiosis has been recognized as an increasingly important cause of acute febrile illness acute febrile illness A nonspecific term for an illness of sudden onset accompanied by fever (2,3). The two main pathogenic species are Ehrlichia chaffeensis, which causes human monocytic ehrlichiosis human monocytic ehrlichiosis Infectious disease An infection by Ehrlichia chaffeensis Vector Lone Star tick–Amblyomma americanum, possibly also Dermacentor variabilis (HME), and the as-yet-unnamed agent of human granulocytic ehrlichiosis human granulocytic ehrlichiosis: see ehrlichiosis. (HGE HGE
hemorrhagic gastroenteritis. ) (4). A third species, E. ewingii, which has been recently described, causes clinical disease indistinguishable from infection caused by E. chaffeensis or the agent of human granulocytic ehrlichiosis (5).
Delineation of the epidemiology of human ehrlichiosis has greatly enhanced our understanding of this emerging infection. However, information on the manifestations of ehrlichiosis in immunocompromised patients is limited. We report a case of severe monocytic ehrlichiosis in a lung transplant recipient who had pancytopenia pancytopenia /pan·cy·to·pe·nia/ (-sit-ah-pe´ne-ah) abnormal depression of all the cellular elements of the blood.
n. , acute renal failure acute renal failure Acute kidney failure Nephrology An abrupt decline in renal function, triggered by various processes–eg, sepsis, shock, trauma, kidney stones, drug toxicity-aspirin, lithium, substances of abuse, toxins, iodinated radiocontrast. , and encephalopathy. Despite early diagnosis and treatment with doxycycline, his illness progressed and took on features of thrombotic thrombocytopenic purpura (TTP TTP (thymidine triphosphate): see thymine. ). A review of reported cases of Ehrlichia infection in immunocompromised patients shows that the infection is far more severe in this population and is often fatal.
A 38-year-old man with cystic fibrosis had undergone bilateral lung transplantation in 1998 and had been well. In September 2000, he visited a physician with a 3-day history of fever as high as 38.3 [degrees] C, myalgias, and headache. A resident of Columbia, Missouri, the patient had spent much time outdoors but did not recall tick infestation infestation /in·fes·ta·tion/ (-fes-ta´shun) parasitic attack or subsistence on the skin and/or its appendages, as by insects, mites, or ticks; sometimes used to denote parasitic invasion of the organs and tissues, as by helminths. or recent tick bite. His medications included cyclosporine, mycophenolate, prednisone prednisone (prĕd`nĭsōn): see corticosteroid drug. , diltiazem, trimethoprim-sulfamethoxazole, and valacyclovir.
On physical examination, the patient appeared acutely ill with temperature 38.3 [degrees] C, blood pressure 140/64, heart rate 110 per minute, and respiratory rate 20 per minute. He was lethargic but could follow commands, and his neurologic exam was unremarkable. Fine bibasilar crackles were present bilaterally, but heart sounds were normal. Examination of the abdomen was negative. Synovitis synovitis /syno·vi·tis/ (sin?o-vi´tis) inflammation of a synovial membrane, usually painful, particularly on motion, and characterized by fluctuating swelling, due to effusion in a synovial sac. was not evident, and no cutaneous lesions were found.
The leukoctye count was 3.7x[10.sup.9] per L with 68% neutrophils, hemoglobin was 64 g/L, and platelet count was 23,000/ L. Serum creatinine was 4.6 mg/dL, aspartate aminotransferase 420 U/L, alanine aminotransferase 96 U/L, and bilirubin Bilirubin
The predominant orange pigment of bile. It is the major metabolic breakdown product of heme, the prosthetic group of hemoglobin in red blood cells, and other chromoproteins such as myoglobin, cytochrome, and catalase. 3.2 mg/dL. International normalized prothrombin time ratio (INR INR
In currencies, this is the abbreviation for the Indian Rupee.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. ) was 1.4. Examination of a peripheral blood smear showed schistocytes and other microangiopathic changes.
Multiple blood cultures were negative. Cytomegalovirus DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. was not detected in peripheral blood. Noncontrast computed tomography of the brain was normal. Chest radiograph radiograph /ra·dio·graph/ (-graf?) the film produced by radiography.
n. showed bilateral infiltrates.
The patient was treated initially with intravenous piperacillin-tazobactam and vancomycin. Cyclosporine and trimethoprim-sulfamethoxazole were discontinued. The next day, his mental status continued to deteriorate. Lumbar puncture was deferred because of thrombocytopenia Thrombocytopenia Definition
Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets. . Antibiotic therapy was changed to intravenous meropenem. Four days after admission, the bone marrow was examined because of worsening pancytopenia; intracytoplasmic intracytoplasmic /in·tra·cy·to·plas·mic/ (-si?to-plaz´mik) within the cytoplasm of a cell. morulae were seen in monocytoid monocytoid /mono·cy·toid/ (mon?o-si´toid) resembling a monocyte. cells, characteristic of monocytic ehrlichiosis (Figure). Leukocytes in a peripheral blood smear also contained morulae. Intravenous doxycycline was begun for treatment of presumed Ehrlichia infection. Whole-blood polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) ) (Viromed, Minneapolis, MN) in the first week of illness was subsequently reported positive for E. chaffeensis DNA. Serology Serology
The division of biological science concerned with antigen-antibody reactions in serum. It properly encompasses any of these reactions, but is often used in a limited sense to denote laboratory diagnostic tests, especially for syphilis. by immunofluorescence antibody testing for both E. equi and E. chaffeensis performed 2 weeks after onset of illness was negative, with titers < 1:40.
Despite treatment with doxycycline, the patient's confusion, thrombocytopenia, and microangiopathic anemia did not improve, and on the fifth hospital day he was transferred to the University of Wisconsin Hospital and Clinics The University of Wisconsin Hospital and Clinics (UWHC) constitute the academic health care system for the University of Wisconsin System, with more than 60 locations throughout the state, including the UW Hospital and American Family Children’s Hospital in Madison, Wisconsin. . Physical examination showed blood pressure 144/94 mmHg, heart rate 77/ minute, temperature 36.5 [degrees] C, and respiratory rate 24/minute. Multiple ecchymoses Ecchymosis (plural, ecchymoses)
The medical term for a bruise. Ecchymoses may develop around the eyes following a nasal fracture.
Mentioned in: Nasal Trauma were present on the torso and extremities. Neurologic examination was nonfocal. There were coarse bibasilar crackles in the lungs bilaterally. Examination of the heart and abdomen was unremarkable.
Leukocytes were 2.9 x [10.sup.9]/L, hemoglobin 86 g/L, and platelets 30,000/L. Serum creatinine was 6.2 mg/dL (548 mol/ L), total bilirubin 2.0 mg/dL, aspartate aminotransferase 105 U/L, and alanine aminotransferase 55 U/L. INR was 1.1, and the activated partial thromboplastin time Activated partial thromboplastin time
Partial thromboplastin time test that uses activators to shorten the clotting time, making it more useful for heparin monitoring. was 26 seconds. A peripheral blood smear showed numerous fragmented red blood cells Red blood cells
Cells that carry hemoglobin (the molecule that transports oxygen) and help remove wastes from tissues throughout the body.
Mentioned in: Bone Marrow Transplantation
red blood cells . Chest radiograph showed persistence of bilateral infiltrates.
The patient's fever resolved 2 days after doxcycline was started; however, oliguric renal failure necessitated hemodialysis. Hematologic hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. studies showed progressive microangiopathic anemia and thrombocytopenia with a normal INR, suggestive of TTP, presumably pre·sum·a·ble
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster. secondary to Ehrlichia infection. Daily plasmaphereses were begun and continued for 8 weeks. Gradually the hematologic abnormalities and renal function improved, and the patient's mental status returned to normal. Doxycycline was given for 2 weeks.
The patient ultimately made a full recovery with no apparent sequelae sequelae Clinical medicine The consequences of a particular condition or therapeutic intervention . Cyclosporine was not resumed, and he was maintained on sirolimus and prednisone to prevent transplant rejection. No rejection occurred, despite a reduction in immunosuppressive therapy during the treatment of Ehrlichia infection.
Review of Published Reports
Ehrlichiosis is a zoonotic Zoonotic
A disease which can be spread from animals to humans.
Mentioned in: Zoonosis illness caused by Ehrlichia species, which are pleomorphic pleomorphic adjective Referring to a variable appearance or morphology , intracellular, rickettsia-like organisms (2-4). The clinical spectrum of ehrlichisis varies from a mild, influenzalike illness to a fulminant ful·mi·nant
Occurring suddenly, rapidly, and with great severity or intensity, usually of pain.
ful sepsis syndrome, but in most patients is self-limiting and not fatal. Death rates of documented ehrlichial infection in large, unselected series have been 1% to 8% (3,6-8). This low rate contrasts sharply with the high death rate of ehrliochiosis in immunocompromised patients (Table).
Cellular immunity represents the most important host defense against rickettsial infection (23). Acute-phase sera of patients with HGE contain elevated levels of interferon gamma, which is associated with the clearance of Ehrlichia from peripheral blood (24). In a mouse model of ehrlichiosis, immunocompromised mice have persistent infection, and most eventually die (25). Impairment of cellular immunity, whether from immunosuppresssive therapies or underlying disease, retards recovery, leading to more severe disease and higher death rates.
The population of immunocompromised patients is large and growing; many have asplenia or solid organ or bone marrow transplants (26). An analysis of the published reports of ehrlichial infection shows that the disease in immunocompromised patients is far more severe and prolonged and more likely to be fatal (Table) (5,7-22). Virtually all these patients had signs of organ dysfunction, including pancytopenia (40%), renal failure (24%), respiratory distress (14%), shock (28%), and neurologic dysfunction (18%). Six (25%) of 23 patients died; 4 of the 6 deaths were in HIV-infected patients. Two patients died within 24 hours after coming to medical attention, despite initiation of appropriate antimicrobial therapy; in the third, the diagnosis was not considered until late in the hospital course; and in the fourth, the diagnosis was made postmortem. Two deaths occurred in asplenic patients; in both, Ehrlichia infection was not suspected until I week after onset of illness.
In a recent series of ehrlichial infection in 21 HIV-infected patients, 6 of which are included in our review, Paddock et al. reported a high frequency (71%) of moderate to severe disease in HIV-infected patients, particularly with E. chaffeensis (27). Low CD4 counts were associated with a poor outcome.
To our knowledge, this is the first reported case of acute ehrlichiosis in a lung transplant recipient. Our patient had laboratory features typical of Ehrlichia infection (thrombocytopenia, leukopenia leukopenia /leu·ko·pe·nia/ (-pe´ne-ah) reduction of the number of leukocytes in the blood below about 5000 per cubic mm.leukope´nic
basophilic leukopenia basophilopenia. , and transaminase transaminase /trans·am·i·nase/ (-am´i-nas) aminotransferase.
See aminotransferase. elevation). However, he also had microangiopathic anemia, renal failure, and neurologic dysfunction characteristic of TTP. Ehrlichiosis with features of TTP has been described in two reports (28,29), one case each of HME and HGE. Both cases were in immunocompetent im·mu·no·com·pe·tent
Having the normal bodily capacity to develop an immune response following exposure to an antigen.
im persons: one was treated with doxycycline and plasmapheresis plasmapheresis, see apheresis. ; in the other, the diagnosis was made postmortem.
Our patient's multiorgan failure and hematologic aberrations persisted, despite doxycycline therapy, until he underwent plasmapheresis. He was receiving cyclosporine, which is a well-known cause of a rare hemolytic he·mo·lyt·ic
Destructive to red blood cells; hematolytic.
Referring to the destruction of the cell membranes of red blood cells, resulting in the release of hemoglobin from the damaged cell. uremic uremic
pertaining to or emanating from uremia.
see uremia, visceral gout.
uremic toxins syndrome-TTP-like condition that does not respond to plasmapheresis and nearly always proves fatal (30). That our patient's TTP-like illness coincided with Ehrlichia infection and responded to doxycycline and plasmapheresis makes it most likely that it was a consequence of acute ehrlichiosis, not cyclosporine.
Neurologic manifestations, ranging from confusion to frank meningitis, have been reported in up to 20% of patients with erhlichiosis (31). Our patient had obtundation and delirium that persisted after doxycycline therapy was initiated and his fever had resolved. The presence of headache and confusion in conjunction with pancytopenia and transaminase elevation should raise suspicion of Ehrlichia infection, especially if the patient has had potential tick exposures.
The diagnosis of ehrlichiosis is often delayed because of its nonspecific clinical and laboratory manifestations. In the immunocompromised person, the search for opportunistic infections may further preclude consideration of Ehrlichia infection. The empiric antimicrobial regimens used in immunocompromised patients for suspected cryptogenic cryptogenic /cryp·to·gen·ic/ (krip?to-jen´ik) of obscure or doubtful origin.
Of obscure or unknown origin. Used of diseases. bacterial and fungal sepsis rarely include a drug or drugs effective against Ehrlichia. PCR to detect Ehrlichia DNA is invaluable for the diagnosis and has >90% sensitivity and even better specificity (32). This technique is particularly useful in the immunocompromised host in whom rapid diagnosis is of utmost importance. Peripheral blood and bone marrow examinations show intracellular morulae in HME in only 1% to 5% of cases and cannot be relied on diagnostically, unless positive. Serologic testing does not allow rapid diagnosis and may be negative in the immunocompromised patient (21), as was the case with our patient.
The diagnosis of ehrlichiosis should be considered in any patient with fever, transaminase elevations, and new-onset thrombocytopenia or leukopenia who has had potential tick exposures in an endemic area. In the immunocompromised host, clinical manifestations are more severe and can include neurologic deterioration, multiorgan failure, and even a TTP-like illness. Response to appropriate therapy with doxycycline may be delayed. A high index of suspicion index of suspicion Medtalk A phrase broadly used to indicate how seriously a particular disease is being entertained as a diagnosis; as an example, there is a high IOS that rapid and unexplained weight loss in an elderly Pt is due to pancreas CA, and a low IOS that , the use of PCR for confirmatory diagnosis and early empiric therapy can be life-saving.
Table. Reports of immunocompromised patients with Ehrlichia infection Immunocompromised state Age Form of ehrlichiosis Rheumatoid arthritis, on methotrexate 49 Ehrlichia ewingii Emphysema, on prednisone 65 E. ewingii Renal transplant 11 E. ewingii Liver transplant 47 HME (a) Leukemia 6 HME Asplenia 71 HGE Asplenia 30 HGE HIV infection (CD4 45/[mm.sup.3]) 33 HME Renal transplant 35 HME HIV infection (CD4 NS) 38 HME Sickle beta-thalassemia NS HME Renal transplant NS HME HIV infection (CD4 164/[mm.sup.3]) 52 HME Renal transplant 67 HGE HIV infection CD4 (18/[mm.sub.3]) 36 HME Liver transplant 51 HME Asplenia, chronic lymphocytic 80 HGE leukemia, on steroids HIV infection (CD4 199/[mm.sub.3]) 37 HME Splenectomy 46 HME HIV infection (CD4 64/[mm.sub.3]) 41 HME Asplenia 67 E. canis Crohn disease requiring prednisone 57 E. canis Bilateral lung transplant 38 HME Immunocompromised state Clinical features Rheumatoid arthritis, on methotrexate Fever, headache Emphysema, on prednisone Fever, headache Renal transplant Lyphadenopathy, fever Liver transplant Multiorgan failure Leukemia Hepatitis, pancytopenia, rash, renal failure Asplenia Fever, neurologic dysfunction Asplenia Rash, fever HIV infection (CD4 45/[mm.sup.3]) Cardiomyopathy, heart failure Renal transplant Rash, pancytopenia, renal failure HIV infection (CD4 NS) Multiorgan failure Sickle beta-thalassemia Respiratory failure Renal transplant NS HIV infection (CD4 164/[mm.sup.3]) Hepatitis, thrombocytopenia Renal transplant Pancytopenia, renal failure, hepatitis HIV infection CD4 (18/[mm.sub.3]) Hepatitis, renal failure Liver transplant Pancytopenia, shock Asplenia, chronic lymphocytic Multiorgan failure leukemia, on steroids HIV infection (CD4 199/[mm.sub.3]) Fever, pancytopenia, toxic-shock-like illness Splenectomy Pancreatitis, shock, encephalitis HIV infection (CD4 64/[mm.sub.3]) Pancytopenia, pulmonary hemorrhage Asplenia Renal failure respiratory failure, encephalitis Crohn disease requiring prednisone Pancytopenia, hepatitis Bilateral lung transplant Pancytopenia, renal failure, TTP-like illness Immunocompromised state Outcome Reference Rheumatoid arthritis, on methotrexate Survived 5 Emphysema, on prednisone Survived 5 Renal transplant Survived 5 Liver transplant Survived 9 Leukemia Survived 10 Asplenia Survived 11 Asplenia Survived 11 HIV infection (CD4 45/[mm.sup.3]) Survived 12 Renal transplant Survived 13 HIV infection (CD4 NS) Died 14 Sickle beta-thalassemia Survived 15 Renal transplant Survived 15 HIV infection (CD4 164/[mm.sup.3]) Died 16 Renal transplant Survived 17 HIV infection CD4 (18/[mm.sub.3]) Died 18 Liver transplant Survived 19 Asplenia, chronic lymphocytic Died 7 leukemia, on steroids HIV infection (CD4 199/[mm.sub.3]) Survived 20 Splenectomy Survived 20 HIV infection (CD4 64/[mm.sub.3]) Died 21 Asplenia Died 8 Crohn disease requiring prednisone Survived 22 Bilateral lung transplant Survived Current case (a) HME = human monocytic ehrlichiosis; HGE = human granulocytic ehrlichiosis; NS = not specified
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Cardiomyopathy is a chronic disease of the heart muscle (myocardium), in which the muscle is abnormally enlarged, thickened, and/or stiffened. in patients with AIDS. Clin Infect Dis 1999:28:140.
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adj. ehrlichiosis in a patient with HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. infection. N Engl J Med 1993;329:1164-7.
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(26.) UNOS UNOS United Network for Organ Sharing Transplant surgery A database dedicated to optimizing the use of transplantable organs; according to UNOS statistics–1995, ± 20,000 major organs and tissues are transplanted/yr; since successful survival of transplant patient data base. Available at URL URL
in full Uniform Resource Locator
Address of a resource on the Internet. The resource can be any type of file stored on a server, such as a Web page, a text file, a graphics file, or an application program. : http:// www.patients.unos.org
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Nasia Safdar, * Robert B. Love, * and Dennis G. Maki *
* University of Wisconsin Medical School, Madison, Wisconsin, USA
Dr. Safdar is a clinical and research fellow in infectious diseases at the University of Wisconsin, Madison.
Address for correspondence: Dennis G. Maki, Section of Infectious Diseases, University of Wisconsin, Madison, H4/574 CSC, 600 Highland Avenue, Madison, WI 53792, USA; fax: 608-263-4464; e-mail: email@example.com