- Email: [email protected]
Venous thrombosis in immunocompetent patients with acute cytomegalovirus infection: a complication that may be underestimated
Research Notes
CMI
to consider patient treatment history when interpreting currently used genotypic antiretroviral resistance tests.
Acknowledgements The pNL4-3 plasmid was obtained through the NIH AIDS Reagent Program.
Transparency Declaration This work was supported in part by VI Programma Nazionale di Ricerca AIDS, Italian Ministry of Health (grant 30G.58). The authors do not have an association that might pose a conflict of interest.
851
patients with multiple therapy failures. J Clin Virol 2005; 34: 288– 294. 12. Loubser S, Balfe P, Sherman G, Hammer S, Kuhn L, Morris L. Decay of K103N mutants in cellular DNA and plasma RNA after single-dose nevirapine to reduce mother-to-child HIV transmission. AIDS 2006; 20: 995–1002. 13. Joly V, Descamps D, Peytavin G et al. Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs. Antimicrob Agents Chemother 2004; 48: 172–175.
Venous thrombosis in immunocompetent patients with acute cytomegalovirus infection: a complication that may be underestimated P. Abgueguen1, V. Delbos2, A. Ducancelle3, S. Jomaa1, S. Fanello4 and E. Pichard1 1) Service des Maladies Infectieuses et tropicales, 2) Unite´ de pre´vention
References
et de lutte contre les infections nosocomiales, 3) Laboratoire de Bacte´riologie-Virologie and 4) De´partement de Sante´ Publique, 1. Hirsch MS, Gu¨nthard HF, Schapiro JM et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis 2008; 47: 266– 285. 2. Schuurman R, Demeter L, Reichelderfer P, Tijnagel J, de Groot T, Boucher C. Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase. J Clin Microbiol 1999; 37: 2291–2296. 3. Quin˜ones-Mateu ME, Arts EJ. Virus fitness: concept, quantification, and application to HIV population dynamics. Curr Top Microbiol Immunol 2006; 299: 83–140. 4. Venturi G, Romano L, Carli T et al. Divergent distribution of HIV-1 drug-resistant variants on and off antiretroviral therapy. Antivir Ther 2002; 7: 245–250. 5. Johnson JA, Li JF, Wei X et al. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naı¨ve populations and associate with reduced treatment efficacy. PLoS Med 2008; 5: 1112–1122. 6. Louvel S, Battegay M, Vernazza P et al. Detection of drug-resistant HIV minorities in clinical specimens and therapy failure. HIV Med 2008; 9: 133–141. 7. Paredes R, Marconi VC, Campbell TB, Kuritzkes DR. Systematic evaluation of allele-specific real-time PCR for the detection of minor HIV-1 variants with pol and env resistance mutations. J Virol Methods 2007; 146: 136–146. 8. Svarovskaia ES, Moser MJ, Bae AS, Prudent JR, Miller MD, BorrotoEsoda K. MultiCode-RTx real-time PCR system for detection of subpopulations of K65R human immunodeficiency virus type 1 reverse transcriptase mutant viruses in clinical samples. J Clin Microbiol 2006; 44: 4237–4241. 9. Viard JP, Burgard M, Hubert JB et al. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 2004; 18: 45–49. 10. Martinson NA, Morris L, Gray G et al. Selection and persistence of viral resistance in HIV-infected children after exposure to single-dose nevirapine. J Acquir Immune Defic Syndr 2007; 44: 148–153. 11. Boucher S, Recordon-Pinson P, Neau D et al. Clonal analysis of HIV-1 variants in proviral DNA during treatment interruption in
Centre Hospitalier Universitaire, Angers, France
Abstract In the present study, we retrospectively studied clinical and laboratory findings associated with cytomegalovirus (CMV) infection in immunocompetent patients. We focused on severe CMV infection. Among 38 patients, five had a severe form of infection: one had meningitis, one had symptomatic thrombocytopenia and three had venous thromboses with pulmonary embolism, a rarely described complication. CMV-induced thrombosis has been reported in immunocompromised patients such as transplant recipients and patients with AIDS. Recent case reports have also described thrombotic phenomena in immunocompetent patients with CMV infection. Our study suggests that venous thrombosis during acute CMV infection is an underestimated complication.
Keywords: Complications, cytomegalovirus infection, immunocompetent patient, venous thrombosis Original Submission: 23 June 2009; Revised Submission: 23 July 2009; Accepted: 23 July 2009 Editor: E. Gould Article published online: 28 October 2009 Clin Microbiol Infect 2010; 16: 851–854 10.1111/j.1469-0691.2009.03022.x
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
852
Clinical Microbiology and Infection, Volume 16 Number 7, July 2010
Corresponding author and reprint requests: P. Abgueguen, Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire, 4 rue Larrey, 49933 Angers Cedex 9, France E-mail: [email protected]
Acute cytomegalovirus (CMV) infection in immunocompetent patients is common worldwide, with seroprevalence rates ranging from 40% to 100%, depending on country, socio-economic conditions and age [1,2]. In immunocompetent adults, CMV infection is most often asymptomatic. In about 10%, a subclinical, mononucleosis-like syndrome occurs, characterized by malaise, fever, mild liver function abnormalities and lymphocytosis with atypical lymphocytes. Illness in these cases is usually mild and self-limiting [3]. More rarely, acute CMV infection is revealed by prolonged fever, cervical lymphadenitis and arthralgia. Multiple organ involvement can also occur. The gastrointestinal tract (colitis) and the central nervous system (meningitis, encephalitis and transverse myelitis) are the most frequent sites of severe CMV infection, but other manifestations can be observed, such as haematological disorders (haemolytic anaemia and thrombocytopenia), thrombosis of the venous or arterial vascular system, ocular involvement and lung disease [4]. We decided to conduct a retrospective study in immunocompetent patients with evidence of CMV infection, with the objective of describing the symptoms and abnormal laboratory findings, and to assess the proportion of severe cases of CMV infection. In this study, we selected and reviewed all
CMI
records of outpatients or hospitalized patients in the infectious and tropical diseases department at Angers Hospital, from 1 January 1995 to 31 December 2006, who were coded in the PMSI system (hospital medical informatic systems, used throughout France) with ‘cytomegalovirus’ as the principal or an associated diagnosis. Our exclusion criteria were age under 16 years, pregnancy and immunocompromised status. Confirmed acute CMV infection was defined as infection with CMV IgM and/or IgG seroconversion (by ELISA) and/or a four-fold increase in CMV IgG titre between two samples collected at least 2 weeks apart and/or PP65-positive antigenaemia (by immunofluorescence) and/or CMV-positive viraemia. Probable acute CMV infection was defined as infection in the presence of CMV IgM with epidemiological features strongly suggestive of a flu-like syndrome and/or a mononucleosis syndrome and/or altered liver function. A mononucleosis syndrome was defined as more than 50% of lymphocytes with a large, hyperbasophilic form. We defined as severe any CMV infection for which the patient was hospitalized with organ involvement, i.e. of the gastrointestinal tract, central nervous system, lungs, eyes or skin, and with haematological disorders. In addition, any CMV infection causing vascular thrombosis was included. We retrieved information from the records demographic (age and sex), clinical (cause of hospitalization, medical history and initial general and organ-specific symptoms), laboratory and other work-up (chest radiography and biopsies) findings. Finally, we recorded the treatment and the disease course for each patient. TABLE 1. Clinical and laboratory
Horwitz [8], n = 82, 1986
Clinical symptoms (%) Fever Duration of fever (days) Asthenia Headache Sweats Chills Myalgia Arthralgia Cough Diarrhoea Abdominal pain Weight loss Nausea, vomiting Maculopapular rash Hepatomegaly Splenomegaly Lymphadenopathy Pharyngeal pain Abnormal laboratory findings (%) Anaemia Thrombocytopenia Lymphocytosis with atypical lymphocytes Hepatitic cytolysis
93.5 – – 8.5 – – 15.8 – – 2.4 9.7 – – 7.3 – 26.8 17.1 30.9
67.4 12.5 100 94.8
Ragnaud [9], n = 34, 1994
Faucher [10], n = 116, 1998
Bonnet [11], n = 115, 2001
Wreghitt [3], n = 124, 2003
100 25 – 53 50 21 53 15 15 21 21 21 – 21 9 24 15 –
99 21.5 72.4 54 35.4 38.8 45.6 12 26.3 6.3 17.4 4.9 – 6.1 11.4 35.7 21.2 13.1
94.8 25 73 51.3 42 32.2 31.3 23.5 20 10.4 26 35.6 10.4 20 25 23.5 19.1 9.6
46
8.8 2.9 91
21.4 1.8 94.6
97
87.8
Present study, n = 38
– 14 46 – 36 17 – 5 4 2 – 2 – 3 24 –
92.1 18 68.4 50 23.7 39.5 42.1 15.8 23.7 15.8 10.5 7.9 10.5 10.5 10.5 15.8 18.4 7.9
20 25 64
– 3 –
15.8 28.9 39.5
90
–
91.9
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
findings associated with cytomegalovirus infection
Research Notes
CMI
During the study period, 70 patients were reviewed and 38 fulfilled the inclusion criteria. The mean patient age was 45 ± 16 years (range, 23–80 years). The ratio of male to female patients was 1 : 2.2. Patients were seen mainly because they sought medical advice or were hospitalized for fever of unknown origin, hepatitis, weight loss, haematological disorders. The most typical symptoms associated with CMV infection in these immunocompetent patients are shown in Table 1 and are compared with those reported in other studies. Fever was noted in 92% of patients, with a mean duration of 18 days. In these cases, asthenia, headache and chills were the main clinical symptoms. Abnormal laboratory findings were mainly hepatic cytolysis (in 92%) and thrombocytopenia (in 29%). A mononucleosis syndrome was found in only 40% of patients. The average length of hospitalization was 7 ± 7 days (range, 2–35 days). All patients recovered completely, but we identified five patients (13.2%) with severe CMV infection. The first one had a central nervous system disorder with meningitis. He did not receive any specific antiviral therapy and remained well after a hospitalization period of 7 days. The second patient had severe symptomatic thrombocytopenia requiring treatment with corticosteroids; he recovered completely. The three remaining patients (7.9%) had vascular thrombosis with pulmonary embolism. A 38-year-old white woman had CMV-associated acute ulcerative colitis. CMV inclusion antibodies were found in rectal and colic biopsy samples, and CMV inclusions were confirmed by immunofluorescence. A few days after hospitalization, the patient had a thrombosis of the right iliac vein with bilateral pulmonary embolism of moderate severity, confirmed by ventilation–perfusion scintigraphy. A coagulation screen revealed no pathological values. In addition to intravenous heparin treatment, anti-CMV therapy with intravenous ganciclovir was started. The patient recovered in 1 week. The second case was that of a 32-year-old white woman with a typical CMV infection with prolonged fever who became asymptomatic 20 days after the first symptoms. Subsequently, 4 days after hospitalization, she had fever again. Doppler ultrasound revealed a left internal jugular vein thrombosis associated with a pulmonary embolism of moderate severity in the left chest. After initial treatment with low molecular weight heparin, and then with oral anticoagulants, the patient recovered. A factor V Leiden heterozygous mutation was found. These two cases have previously been reported in detail [5]. The third case was that of an 82-year-old white woman, also with evidence of recent CMV infection, who quickly recovered after several days of hospitalization. Two weeks later, she was hospitalized again for persistent fever (38C) and dyspnoea that worsened gradually over several days. A bilat-
853
eral pulmonary embolism of moderate severity was confirmed. A coagulation screen revealed no pathological values. She recovered completely after anticoagulant treatment for 6 months. In these three cases, the diagnosis of acute CMV infection, as defined above, was confirmed. CMV can cause severe disease in immunocompromised patients. Clinical symptoms are well described and can be observed especially in patients with AIDS or after transplantation following high-dose immunosuppressive therapy [6,7]. On the other hand, there are only several reports describing symptoms of CMV infection in immunocompetent patients, because in this case infection is considered to have a benign, self-limiting course. However, a considerable number of case reports describing severe clinical manifestations can be found. A recent review retrieved articles reporting such cases [4]. The authors found 290 immunocompetent patients with severe CMV infection. Colitis (91 patients) and central nervous system problems (56 patients) were the most frequent manifestations of severe CMV infection. Haematological disorders (35 patients) with haemolytic anaemia and thrombocytopenia, ocular involment (16 patients) and lung involment (nine patients) were also described. They also found 19 cases, from all over the world, of venous thrombosis with various types of blood vessel thrombosis and pulmonary embolism, which is described as a very rare manifestation of severe CMV infection. Concerning the frequency of symptoms and abnormal laboratory findings in cases of severe CMV infection, our results do not differ from those of other studies, except for mononucleosis syndrome, which was found more rarely [4,8–11]. More surprising were the frequencies and types of severe CMV infection associated with venous thrombosis, which was seen in three cases (7.9%). These cases were diagnosed not during initial hospitalization but long after the onset of symptoms and after patient discharge. No comprehensive interpretation of this association is yet available. Venous thrombosis could be explained by hospitalization itself in patients who are bedridden and suffer from severe infection, but, in the literature, data strongly support a causal relationship, owing to the intrinsic procoagulant properties of CMV. Several mechanisms have been proposed for the role of CMV-induced vascular thrombosis. The virus can directly invade endothelial cells, causing vascular endothelium damage that activates coagulation factors. Another explanation is that CMV can enhance coagulant properties by increasing thrombin production and decreasing the production of prostaglandin and interleukin-2, both of which support platelet adhesion [12]. It has also been suggested that one of the immediate-early gene products of CMV, namely IE84, binds to P53 and
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
854
Clinical Microbiology and Infection, Volume 16 Number 7, July 2010
inhibits the transcriptional activity of its gene, thus inhibiting P53-mediated apoptosis and enhancing smooth muscle cell proliferation, which is a crucial event in the development of atherosclerosis and restenosis [13]. Finally, CMV may also induce the production of antiphospholipid antibodies [14,15]. In conclusion, our study suggests that thrombosis in immunocompetent patients with CMV infection may not be as rare as previously thought. This complication is sometimes discovered only several weeks after the initial diagnosis of CMV infection. This is, to our knowledge, the first study to show a large percentage of venous thromboses among a population of immunocompetent patients with acute CMV infection. As it has been performed in a single centre, it must be confirmed by larger studies.
Transparency Declaration The undersigned authors affirm the absence of conflicting or dual interests.
References 1. Carlstro¨m G. Virologic studies on cytomegalovirus inclusion disease. Acta Paediatr Scand 1965; 54: 17–23. 2. Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis 2006; 43: 1143–1151. 3. Wreghitt TG, Teare EL, Sule O, Devi R, Rice P. Cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 2003; 37: 1603–1606.
CMI
4. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Matthew E. Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review. Virol J 2008; 5: 47. 5. Abgueguen P, Delbos V, Chennebault JM, Payan C, Pichard E. Vascular thrombosis and acute cytomegalovirus infection in immunocompetent patients: report of 2 cases and literature review. Clin Infect Dis 2003; 36: E134–E139. 6. Bowen EF, Griffiths PD, Davey CC, Emery VC, Johnson MA. Lessons from the natural history of cytomegalovirus. AIDS 1996; 10 (suppl 1): S37–S41. 7. Busca A. Cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation: significant progress, but many unresolved problems. Expert Opin Biol Ther 2009; 9: 383–385. 8. Horwitz CA, Henle W, Henle G et al. Clinical and laboratory evaluation of cytomegalovirus-induced mononucleosis in previously healthy individuals. Report of 82 cases.. Medicine (Baltimore) 1986; 65: 124–134. 9. Ragnaud JM, Morlat P, Gin H et al. Clinical, biological and developmental aspects of cytomegalovirus infection in immunocompetent patients: apropos of 34 hospitalized patients. Rev Med Interne 1994; 15: 13–18. 10. Faucher JF, Abraham B, Segondy M, Jonquet O, Reynes J, Janbon F. Acquired cytomegalovirus infections in immunocompetent adults: 116 cases. Presse Med 1998; 27: 1774–1779. 11. Bonnet F, Neau D, Viallard JF et al. Clinical and laboratory findings of cytomegalovirus infection in 115 hospitalized non-immunocompromised adults. Ann Med Int 2001; 152: 227–235. 12. Squizzato A, Gerdes VE, Buller HR. Effects of human cytomegalovirus infection on the coagulation system. Thromb Haemost 2005; 93: 403– 410. 13. Speir E, Modali R, Huang ES et al. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 1994; 265: 391–394. 14. Avcin T, Toplak N. Antiphospholipid antibodies in response to infection. Curr Rheumatol Rep 2007; 9: 212–218. 15. Delbos V, Abgueguen P, Chennebault JM, Fanello S, Pichard E. Acute cytomegalovirus infection and venous thrombosis: role of antiphospholipid antibodies. J Infect 2007; 54: 47–50.
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
CMI
to consider patient treatment history when interpreting currently used genotypic antiretroviral resistance tests.
Acknowledgements The pNL4-3 plasmid was obtained through the NIH AIDS Reagent Program.
Transparency Declaration This work was supported in part by VI Programma Nazionale di Ricerca AIDS, Italian Ministry of Health (grant 30G.58). The authors do not have an association that might pose a conflict of interest.
851
patients with multiple therapy failures. J Clin Virol 2005; 34: 288– 294. 12. Loubser S, Balfe P, Sherman G, Hammer S, Kuhn L, Morris L. Decay of K103N mutants in cellular DNA and plasma RNA after single-dose nevirapine to reduce mother-to-child HIV transmission. AIDS 2006; 20: 995–1002. 13. Joly V, Descamps D, Peytavin G et al. Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs. Antimicrob Agents Chemother 2004; 48: 172–175.
Venous thrombosis in immunocompetent patients with acute cytomegalovirus infection: a complication that may be underestimated P. Abgueguen1, V. Delbos2, A. Ducancelle3, S. Jomaa1, S. Fanello4 and E. Pichard1 1) Service des Maladies Infectieuses et tropicales, 2) Unite´ de pre´vention
References
et de lutte contre les infections nosocomiales, 3) Laboratoire de Bacte´riologie-Virologie and 4) De´partement de Sante´ Publique, 1. Hirsch MS, Gu¨nthard HF, Schapiro JM et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis 2008; 47: 266– 285. 2. Schuurman R, Demeter L, Reichelderfer P, Tijnagel J, de Groot T, Boucher C. Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase. J Clin Microbiol 1999; 37: 2291–2296. 3. Quin˜ones-Mateu ME, Arts EJ. Virus fitness: concept, quantification, and application to HIV population dynamics. Curr Top Microbiol Immunol 2006; 299: 83–140. 4. Venturi G, Romano L, Carli T et al. Divergent distribution of HIV-1 drug-resistant variants on and off antiretroviral therapy. Antivir Ther 2002; 7: 245–250. 5. Johnson JA, Li JF, Wei X et al. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naı¨ve populations and associate with reduced treatment efficacy. PLoS Med 2008; 5: 1112–1122. 6. Louvel S, Battegay M, Vernazza P et al. Detection of drug-resistant HIV minorities in clinical specimens and therapy failure. HIV Med 2008; 9: 133–141. 7. Paredes R, Marconi VC, Campbell TB, Kuritzkes DR. Systematic evaluation of allele-specific real-time PCR for the detection of minor HIV-1 variants with pol and env resistance mutations. J Virol Methods 2007; 146: 136–146. 8. Svarovskaia ES, Moser MJ, Bae AS, Prudent JR, Miller MD, BorrotoEsoda K. MultiCode-RTx real-time PCR system for detection of subpopulations of K65R human immunodeficiency virus type 1 reverse transcriptase mutant viruses in clinical samples. J Clin Microbiol 2006; 44: 4237–4241. 9. Viard JP, Burgard M, Hubert JB et al. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 2004; 18: 45–49. 10. Martinson NA, Morris L, Gray G et al. Selection and persistence of viral resistance in HIV-infected children after exposure to single-dose nevirapine. J Acquir Immune Defic Syndr 2007; 44: 148–153. 11. Boucher S, Recordon-Pinson P, Neau D et al. Clonal analysis of HIV-1 variants in proviral DNA during treatment interruption in
Centre Hospitalier Universitaire, Angers, France
Abstract In the present study, we retrospectively studied clinical and laboratory findings associated with cytomegalovirus (CMV) infection in immunocompetent patients. We focused on severe CMV infection. Among 38 patients, five had a severe form of infection: one had meningitis, one had symptomatic thrombocytopenia and three had venous thromboses with pulmonary embolism, a rarely described complication. CMV-induced thrombosis has been reported in immunocompromised patients such as transplant recipients and patients with AIDS. Recent case reports have also described thrombotic phenomena in immunocompetent patients with CMV infection. Our study suggests that venous thrombosis during acute CMV infection is an underestimated complication.
Keywords: Complications, cytomegalovirus infection, immunocompetent patient, venous thrombosis Original Submission: 23 June 2009; Revised Submission: 23 July 2009; Accepted: 23 July 2009 Editor: E. Gould Article published online: 28 October 2009 Clin Microbiol Infect 2010; 16: 851–854 10.1111/j.1469-0691.2009.03022.x
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
852
Clinical Microbiology and Infection, Volume 16 Number 7, July 2010
Corresponding author and reprint requests: P. Abgueguen, Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire, 4 rue Larrey, 49933 Angers Cedex 9, France E-mail: [email protected]
Acute cytomegalovirus (CMV) infection in immunocompetent patients is common worldwide, with seroprevalence rates ranging from 40% to 100%, depending on country, socio-economic conditions and age [1,2]. In immunocompetent adults, CMV infection is most often asymptomatic. In about 10%, a subclinical, mononucleosis-like syndrome occurs, characterized by malaise, fever, mild liver function abnormalities and lymphocytosis with atypical lymphocytes. Illness in these cases is usually mild and self-limiting [3]. More rarely, acute CMV infection is revealed by prolonged fever, cervical lymphadenitis and arthralgia. Multiple organ involvement can also occur. The gastrointestinal tract (colitis) and the central nervous system (meningitis, encephalitis and transverse myelitis) are the most frequent sites of severe CMV infection, but other manifestations can be observed, such as haematological disorders (haemolytic anaemia and thrombocytopenia), thrombosis of the venous or arterial vascular system, ocular involvement and lung disease [4]. We decided to conduct a retrospective study in immunocompetent patients with evidence of CMV infection, with the objective of describing the symptoms and abnormal laboratory findings, and to assess the proportion of severe cases of CMV infection. In this study, we selected and reviewed all
CMI
records of outpatients or hospitalized patients in the infectious and tropical diseases department at Angers Hospital, from 1 January 1995 to 31 December 2006, who were coded in the PMSI system (hospital medical informatic systems, used throughout France) with ‘cytomegalovirus’ as the principal or an associated diagnosis. Our exclusion criteria were age under 16 years, pregnancy and immunocompromised status. Confirmed acute CMV infection was defined as infection with CMV IgM and/or IgG seroconversion (by ELISA) and/or a four-fold increase in CMV IgG titre between two samples collected at least 2 weeks apart and/or PP65-positive antigenaemia (by immunofluorescence) and/or CMV-positive viraemia. Probable acute CMV infection was defined as infection in the presence of CMV IgM with epidemiological features strongly suggestive of a flu-like syndrome and/or a mononucleosis syndrome and/or altered liver function. A mononucleosis syndrome was defined as more than 50% of lymphocytes with a large, hyperbasophilic form. We defined as severe any CMV infection for which the patient was hospitalized with organ involvement, i.e. of the gastrointestinal tract, central nervous system, lungs, eyes or skin, and with haematological disorders. In addition, any CMV infection causing vascular thrombosis was included. We retrieved information from the records demographic (age and sex), clinical (cause of hospitalization, medical history and initial general and organ-specific symptoms), laboratory and other work-up (chest radiography and biopsies) findings. Finally, we recorded the treatment and the disease course for each patient. TABLE 1. Clinical and laboratory
Horwitz [8], n = 82, 1986
Clinical symptoms (%) Fever Duration of fever (days) Asthenia Headache Sweats Chills Myalgia Arthralgia Cough Diarrhoea Abdominal pain Weight loss Nausea, vomiting Maculopapular rash Hepatomegaly Splenomegaly Lymphadenopathy Pharyngeal pain Abnormal laboratory findings (%) Anaemia Thrombocytopenia Lymphocytosis with atypical lymphocytes Hepatitic cytolysis
93.5 – – 8.5 – – 15.8 – – 2.4 9.7 – – 7.3 – 26.8 17.1 30.9
67.4 12.5 100 94.8
Ragnaud [9], n = 34, 1994
Faucher [10], n = 116, 1998
Bonnet [11], n = 115, 2001
Wreghitt [3], n = 124, 2003
100 25 – 53 50 21 53 15 15 21 21 21 – 21 9 24 15 –
99 21.5 72.4 54 35.4 38.8 45.6 12 26.3 6.3 17.4 4.9 – 6.1 11.4 35.7 21.2 13.1
94.8 25 73 51.3 42 32.2 31.3 23.5 20 10.4 26 35.6 10.4 20 25 23.5 19.1 9.6
46
8.8 2.9 91
21.4 1.8 94.6
97
87.8
Present study, n = 38
– 14 46 – 36 17 – 5 4 2 – 2 – 3 24 –
92.1 18 68.4 50 23.7 39.5 42.1 15.8 23.7 15.8 10.5 7.9 10.5 10.5 10.5 15.8 18.4 7.9
20 25 64
– 3 –
15.8 28.9 39.5
90
–
91.9
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
findings associated with cytomegalovirus infection
Research Notes
CMI
During the study period, 70 patients were reviewed and 38 fulfilled the inclusion criteria. The mean patient age was 45 ± 16 years (range, 23–80 years). The ratio of male to female patients was 1 : 2.2. Patients were seen mainly because they sought medical advice or were hospitalized for fever of unknown origin, hepatitis, weight loss, haematological disorders. The most typical symptoms associated with CMV infection in these immunocompetent patients are shown in Table 1 and are compared with those reported in other studies. Fever was noted in 92% of patients, with a mean duration of 18 days. In these cases, asthenia, headache and chills were the main clinical symptoms. Abnormal laboratory findings were mainly hepatic cytolysis (in 92%) and thrombocytopenia (in 29%). A mononucleosis syndrome was found in only 40% of patients. The average length of hospitalization was 7 ± 7 days (range, 2–35 days). All patients recovered completely, but we identified five patients (13.2%) with severe CMV infection. The first one had a central nervous system disorder with meningitis. He did not receive any specific antiviral therapy and remained well after a hospitalization period of 7 days. The second patient had severe symptomatic thrombocytopenia requiring treatment with corticosteroids; he recovered completely. The three remaining patients (7.9%) had vascular thrombosis with pulmonary embolism. A 38-year-old white woman had CMV-associated acute ulcerative colitis. CMV inclusion antibodies were found in rectal and colic biopsy samples, and CMV inclusions were confirmed by immunofluorescence. A few days after hospitalization, the patient had a thrombosis of the right iliac vein with bilateral pulmonary embolism of moderate severity, confirmed by ventilation–perfusion scintigraphy. A coagulation screen revealed no pathological values. In addition to intravenous heparin treatment, anti-CMV therapy with intravenous ganciclovir was started. The patient recovered in 1 week. The second case was that of a 32-year-old white woman with a typical CMV infection with prolonged fever who became asymptomatic 20 days after the first symptoms. Subsequently, 4 days after hospitalization, she had fever again. Doppler ultrasound revealed a left internal jugular vein thrombosis associated with a pulmonary embolism of moderate severity in the left chest. After initial treatment with low molecular weight heparin, and then with oral anticoagulants, the patient recovered. A factor V Leiden heterozygous mutation was found. These two cases have previously been reported in detail [5]. The third case was that of an 82-year-old white woman, also with evidence of recent CMV infection, who quickly recovered after several days of hospitalization. Two weeks later, she was hospitalized again for persistent fever (38C) and dyspnoea that worsened gradually over several days. A bilat-
853
eral pulmonary embolism of moderate severity was confirmed. A coagulation screen revealed no pathological values. She recovered completely after anticoagulant treatment for 6 months. In these three cases, the diagnosis of acute CMV infection, as defined above, was confirmed. CMV can cause severe disease in immunocompromised patients. Clinical symptoms are well described and can be observed especially in patients with AIDS or after transplantation following high-dose immunosuppressive therapy [6,7]. On the other hand, there are only several reports describing symptoms of CMV infection in immunocompetent patients, because in this case infection is considered to have a benign, self-limiting course. However, a considerable number of case reports describing severe clinical manifestations can be found. A recent review retrieved articles reporting such cases [4]. The authors found 290 immunocompetent patients with severe CMV infection. Colitis (91 patients) and central nervous system problems (56 patients) were the most frequent manifestations of severe CMV infection. Haematological disorders (35 patients) with haemolytic anaemia and thrombocytopenia, ocular involment (16 patients) and lung involment (nine patients) were also described. They also found 19 cases, from all over the world, of venous thrombosis with various types of blood vessel thrombosis and pulmonary embolism, which is described as a very rare manifestation of severe CMV infection. Concerning the frequency of symptoms and abnormal laboratory findings in cases of severe CMV infection, our results do not differ from those of other studies, except for mononucleosis syndrome, which was found more rarely [4,8–11]. More surprising were the frequencies and types of severe CMV infection associated with venous thrombosis, which was seen in three cases (7.9%). These cases were diagnosed not during initial hospitalization but long after the onset of symptoms and after patient discharge. No comprehensive interpretation of this association is yet available. Venous thrombosis could be explained by hospitalization itself in patients who are bedridden and suffer from severe infection, but, in the literature, data strongly support a causal relationship, owing to the intrinsic procoagulant properties of CMV. Several mechanisms have been proposed for the role of CMV-induced vascular thrombosis. The virus can directly invade endothelial cells, causing vascular endothelium damage that activates coagulation factors. Another explanation is that CMV can enhance coagulant properties by increasing thrombin production and decreasing the production of prostaglandin and interleukin-2, both of which support platelet adhesion [12]. It has also been suggested that one of the immediate-early gene products of CMV, namely IE84, binds to P53 and
ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854
854
Clinical Microbiology and Infection, Volume 16 Number 7, July 2010
inhibits the transcriptional activity of its gene, thus inhibiting P53-mediated apoptosis and enhancing smooth muscle cell proliferation, which is a crucial event in the development of atherosclerosis and restenosis [13]. Finally, CMV may also induce the production of antiphospholipid antibodies [14,15]. In conclusion, our study suggests that thrombosis in immunocompetent patients with CMV infection may not be as rare as previously thought. This complication is sometimes discovered only several weeks after the initial diagnosis of CMV infection. This is, to our knowledge, the first study to show a large percentage of venous thromboses among a population of immunocompetent patients with acute CMV infection. As it has been performed in a single centre, it must be confirmed by larger studies.
Transparency Declaration The undersigned authors affirm the absence of conflicting or dual interests.
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ª2009 The Authors Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 848–854