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Rheumatology Advance Access published online on June 24, 2008
Rheumatology, doi:10.1093/rheumatology/ken231
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large patient population

Y. Takizawa1, S. Inokuma1,2, Y. Tanaka1, K. Saito3, T. Atsumi4, M. Hirakata5, H. Kameda6, S. Hirohata7,8, H. Kondo8, S. Kumagai9 and Y. Tanaka3

1Department of Allergy and Immunological Diseases, Tokyo Metropolitan Komagome Hospital, 2Rheumatology Center, Japanese Red Cross Medical Center, Tokyo, 3First Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, 4Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, 5Department of Internal Medicine, School of Medicine, Keio University, Tokyo, 6Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical School, Saitama, 7Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, 8Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa and 9Department of Clinical Pathology and Immunology, Kobe University School of Medicine, Kobe, Japan.

Correspondence to: Y. Takizawa, Department of Allergy and Immunological Diseases, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, 3-18-22 Honkomagome, Tokyo 113-8677, Japan. E-mail: ytaki-tky{at}umin.ac.jp


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To survey and elucidate the clinical characteristics of CMV infection in rheumatic disease patients.

Methods. A detailed questionnaire survey on CMV infection was carried out against rheumatic disease patients hospitalized in member hospitals, and the obtained clinical and/or laboratory data were analysed.

Results. Out of 7377 patients, 151 were diagnosed as having CMV infection. The underlying diseases ranged broadly, but SLE, microscopic polyangiitis, and dermatomyositis were the most common. Four were diagnosed histopathologically, and the others via positive CMV antigenaemia. In addition to oral corticosteroid for all but one patient, 81 were treated with pulsed methylprednisolone (MPSL), 64 with cyclophosphamide (CYC) and 36 with other immunosuppressants. Forty-four had a fatal outcome, for which presence of clinical symptoms, other infectious complications, lymphopenia, an older age (>59.3 yrs) and the use of pulsed MPSL were significant risk factors (P < 0.05) by univariate analysis. Multivariate analysis retained the first three (P < 0.05). The CMV antigenaemia count was significantly higher for the symptomatic than asymptomatic [10.1 (0.0–2998.0) vs 4.0 (1.3–1144.4)/105 PMNs, respectively, P < 0.05; threshold count: 5.6/105 PMNs]. No treatment benefit by anti-viral agent was observed as for survival.

Conclusion. CMV infection was mostly diagnosed by antigenaemia, and occurred among patients under strong immunosuppressive therapy using pulsed MPSL and/or immunosuppressants. Lymphopenia, presence of symptoms and other infections are significant risk factors for a poor outcome and pulsed MPSL and an older age may predict it. Patients were prone to be symptomatic with anti-genaemia count over 5.6/105 PMNs.

KEY WORDS: Cytomegalovirus, Rheumatic diseases, Immunosuppressive therapy, Pulsed methylprednisolone, Cyclophosphamide, Cytomegalovirus antigenaemia count, Old age, Lymphopenia


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Infectious disease is one of the major causes of life-threatening complications in patients with rheumatic diseases [1–3]. Although community-acquired infections are common, patients are also prone to opportunistic infections.

CMV, a β-herpesvirus, is not only the cause of serious congenital infection and non-EBV infectious mononucleosis, but also a major cause of morbidity and mortality in immunocompromised hosts [4–7]. Like other herpesviruses, CMV remains latent in the infected host throughout the life and is rarely reactivated to cause clinical illness. However, when anti-viral immunity is compromised, it may become reactivated with fever, lethargy and may cause damage to organs such as the lung, liver, gastrointestinal (GI) tract, bone marrow and retina.

Until recently, very few reports were available on CMV infection in rheumatic disease patients [8–14]. However, more attention is now being paid to this organism as methods for its detection have become more refined and accessible. The CMV antigenaemia test is one of the well-established assays for CMV infection, which detects the virus-specific lower matrix protein pp65 in the nuclei of PMNs. This has been shown to correlate with the clinical course or severity of CMV disease in organ transplantation or acquired immune deficiency syndrome (AIDS) patients, and is now widely used as a marker of viral reactivation or a threshold to start anti-viral therapy [15–22]. We were greatly intrigued as to whether it is useful in the field of rheumatic disease as well.

Former articles reported that most rheumatic patients with CMV infection had been treated with high-dose corticosteroid including pulsed methylprednisolone (MPSL) and/or immunosuppressants like cyclophosphamide (CYC) [8–14], but whether these drugs are really associated should be determined on a larger scale. In addition, although the presence of CMV disease may increase mortality, those who need such strong immunosuppressive treatments usually have severe underlying disease symptoms, and are also susceptible to other serious infections. The prognosis of CMV-infected rheumatic patients has not yet been clarified.

This is the first large-scale, multi-centre, detailed retrospective survey on CMV infection among hospitalized rheumatic disease patients. First, those infected by this virus were selected, and we carried out a detailed questionnaire survey on matters relating to CMV infection, so that the clinical manifestations, characteristics and prognosis of, and risk factors for, CMV disease could be clarified and the utility of the CMV antigenaemia test could be evaluated.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Study design
This study was conducted as a project by the Research Committee on Surveillance and Estimation of Treatments and Complications in Systemic Autoimmune Diseases, guided and ethically approved by the Ministry of Health, Labor and Welfare. The member institutes include the University of Environmental and Occupational Health, Hokkaido University, Keio University, Saitama Medical Center, Teikyo University, Kitasato University, Kobe University and Tokyo Metropolitan Komagome Hospital.

We carried out a questionnaire survey on matters relating to CMV infection among patients who were hospitalized in the above hospitals between April 2000 and March 2005, and those regarded as having CMV infection were further investigated closely. The questionnaire contents are shown in Table 1. Those without CMV infection were spared further investigation, but all information available was collected on their underlying diseases and it was subjected to analysis.


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  		TABLE 1. The items of the questionnaire conducted among CMV-infected patients

 
The diagnosis of CMV infection
CMV infection was defined in this study either by the detection of CMV pp65 antigenaemia in blood samples or by compatible tissue biopsy findings.

CMV pp65 antigenaemia assay
CMV pp65 antigenaemia was examined by the conventional method using pp65-specific monoclonal antibodies [15]. Briefly, blood samples were drawn into heparinized tubes and PMNs were fractionated by dextran sedimentation, cytocentrifuged, fixed onto slides and stained with enzyme-conjugated anti-pp65 monoclonal antibodies.

This test may have been repeated for each patient, but we only adopted data at the point of diagnosing CMV infection to analyse their utility and significance.

Statistical analysis
All clinical quantitative data were treated as non-parametric in our study. The significance of quantitative, non-parametric data was analysed using the Mann–Whitney U-test. The correlation between antigenaemia and lymphocyte counts or the immunoglobulin G (IgG) level was assessed using the Spearman rank correlation coefficient test. Significance between qualitative data was analysed using the {chi}2-test. To identify risk factors for mortality, both univariate analysis using {chi}2-test or Mann–Whitney U-test and multivariate analysis using logistic regression model were performed. For the latter method the numerical variables, i.e. age, CMV antigenaemia count, serum IgG level and peripheral blood lymphocyte count, were divided into two nominal variables using the cut-off lines for each parameter. The cut-off thresholds for age and lymphocyte count were determined by ROC (receiver operating characteristic) analysis: the details were mentioned afterwards. In the same way, the cut-off threshold for antigenaemia count was determined by the ROC curve, but it was intended to clarify not the risk for mortality but for the presence of clinical symptoms as described afterwards. Serum IgG levels were divided at 8.7 g/l, the lower normal limit. A P-value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Patient profiles
Based on the questionnaire descriptions provided by the member hospitals, the total number of inpatients during the 5-yr surveillance period was 7377, and 151 of these were regarded as having CMV infection throughout all member institutes.

The median (range) age of infected patients was 56.9 (14.3–83.2) yrs, and the male:female ratio was 1 : 4.2, i.e. 29 males : 122 females.

As shown in Table 2, CMV-infected patients exhibited a wide range of underlying diseases, but the dominant ones were SLE (n = 74), dermatomyositis (n = 15) and microscopic polyangiitis (n = 13). Meanwhile, the entire distribution of rheumatic disease patients who required hospitalized care, regardless of whether they were infected by CMV or not, was calculated as follows from the available data: SLE 27.8%, RA 32.0%, pSS 9.8%, dermatomyositis 6.0%, SSc 5.8%, MCTD 4.0%, rheumatoid vasculitis 4.0%, microscopic polyangiitis 2.4%, Behçet's disease 2.0%, adult-onset Still's disease 2.0%, WG 1.1% and PAN 0.8%. When compared with the entire distribution, it was further reconfirmed that the patients with systemic lupus erythematosus, dermatomyositis and microscopic polyangiitis were more prone to CMV infection. The median (range) duration of underlying diseases was 1.6 (0.2–34.0) yrs.


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  		TABLE 2. Profile of rheumatic patients affected by CMV infection

 
Diagnosis of CMV infection
Of the 151 patients, 149 were diagnosed by positive CMV antigenaemia. Two out of the 149 showed CMV infection in the GI tract, and other two were revealed to have had CMV pneumonia on autopsy. Two patients were negative for antigenaemia, but diagnosed by compatible tissue findings from the GI tract.

Treatment for underlying diseases
Maximal treatment for underlying disease within a year before CMV diagnosis was surveyed. All except one patient (n = 150) were taking oral corticosteroid, at a median (range) equivalent dose of 60 mg (5–100 mg) prednisolone (PSL). In addition, 81 were treated with 500 mg or 1000 mg of MPSL per day over three consecutive days (pulsed MPSL), 48 received intravenous CYC (IV-CYC), 16 oral CYC (oral-CYC) and 36 immunosuppressants other than CYC including cyclosporin, MTX or AZA. As shown in Fig. 1, a large number of them were treated with a combination of the above agents. Judging from the available data (n = 56), the duration between the start of maximal treatment and the diagnosis of CMV infection diagnosis was 36 (10–152) days.


Figure 1
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  		FIG. 1. Maximal treatment for underlying rheumatic diseases within 1 yr prior to the diagnosis of CMV infection. Oral corticosteroid was administered to all patients except one with Behçet's disease, who was treated with MTX. Eighty-one patients were treated with pulsed MPSL additionally to oral corticosteroid, while 69 were not. Immunosuppressants other than CYC included cyclosporin, AZA and MTX. CYC was administered orally (oral-CYC) or intravenously (IV-CYC) to 64 patients in total and other immunosuppressants to 36 patients. Eighty-three patients were treated with a combination of these agents.

 
Clinical symptoms at the onset of CMV infection
One hundred and seventeen patients were regarded as symptomatic, and the other 34 patients were asymptomatic. To facilitate investigation with such a wide variety of symptoms presumably caused by CMV infection, we narrowed them down to: (i) fever, (ii) cough or dyspnoea, (iii) abdominal pain or mucous and/or bloody stools and (iv) visual disturbance, considering the frequency of symptoms and susceptibility of organs.

Fever was the most common symptom, being observed in 92 patients. Respiratory symptoms, cough and dyspnoea, were the second most common (n = 16), followed by GI symptoms, e.g. bloody stools and abdominal pain (n = 15). Visual disturbance was only observed in one patient.

Clinical characteristics in patients with and without a fatal outcome
Although the direct causes of deaths were not surveyed, finally 44 patients died, whereas 106 survived. The outcome was unknown for one patient. The median (range) age of those with a fatal outcome was 61.3 (15.9–83.1) yrs, whereas it was 50.5 (6.5–83.2) yrs in surviving patients. Patients with a fatal outcome were significantly older than those surviving (P = 0.003). The age indicating a poorer outcome risk was determined to be 59.3 yrs by ROC analysis, with a sensitivity of 62.4% and specificity of 61.0%. As for sex, 11 out of 29 male and 33 out of 121 female patients died. Overall, males showed a fatal outcome tendency, but with no significance (P = 0.23).

The distribution of the deceased differed from that of the entire patient as shown in Table 2. Although the sample number for each disease was generally quite small, the mortality rate was higher in dermatomyositis, rheumatoid vasculitis, SS, RA and adult-onset Still's disease in comparison with the overall mortality rate (29.1%). On the contrary, it was not as high in SLE, the most commonly observed disease (Table 3).


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  		TABLE 3. Mortality rate in each patient group classified by underlying diseases

 
Focusing on immunosuppressive treatment used before the onset of CMV infection, all but one patient (n = 150) were taking oral corticosteroid as described before. The median corticosteroid doses did not differ between the deceased [60 (10–100) mg] and survivors [60 (5–100) mg] (P = 0.89). The median (range) dose when CMV infection became apparent was 40 (5–100) mg. All patients with a fatal outcome were treated with pulsed MPSL and/or immunosuppressants additionally to oral corticosteroid, as shown in Table 4, except for two patients who were taking only corticosteroid equivalent to 100 mg PSL. The patients treated with pulsed MPSL were compared with those without it, and it turned out that the use of pulsed MPSL significantly raised the mortality rate when additionally administered to other therapeutic agents (P = 0.03, Table 4).


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  		TABLE 4. Maximal treatment for underlying disease given to CMV-infected patients

 
Next, the relationship between the outcome and presence of presumed CMV-associated symptoms at diagnosis was analysed. Symptomatic patients at diagnosis showed a significantly higher mortality rate than the asymptomatic (P = 0.004).

Inquiring into other infectious complications, 24 out of the 44 deceased concurrently showed bacterial infection (n = 11), fungal infection (n = 6) and Pneumocystis jirovecii (n = 7). Among the 106 survivors, 27 were complicated by other infections: bacterial (n = 17), fungal (n = 7) and P. jirovecii (n = 3). Deceased patients were more frequently afflicted by other infections, with significance (P = 0.007).

As for the treatment for CMV infection, ganciclovir was administered to 84 patients, and one was treated with foscarnet. A more frequent use of anti-viral agents was observed among the symptomatic, with significance (P = 0.03). However, no treatment benefit was confirmed as far as the patient outcome was concerned.

CMV antigenaemia count
The CMV antigenaemia count at the point of diagnosis was analysed in terms of whether it was correlated with the presence of clinical symptoms or the patient outcome.

The median (range) value of symptomatic patients (n = 117) was 10.1 (0.0–2998.0)/105 PMNs, whereas that of asymptomatic patients (n = 34) was 4.0 (1.3–1144.4)/105 PMNs. Significance was observed between the two groups (P = 0.001). By ROC analysis, a level of 5.6/105 PMNs was determined to be the optimal threshold value for the prediction of CMV-associated symptoms, with a sensitivity of 66.6% and specificity of 64.7%. To scrutinize the more precise relationship between CMV infection and symptoms that were surveyed, patients with other infections were excluded and the data for the remaining 100 (71 symptomatic, 29 asymptomatic) were further analysed. The median (range) antigenaemia counts were 9.1 (0.0–1582.6) and 4.0 (1.3–221.7) for the symptomatic and the asymptomatic, respectively, and the difference reached the statistical significance (P = 0.005). In addition, the threshold of 5.6/105 PMNs was as well validated with the sensitivity of 63.0% and the specificity of 60.5%. On the other hand, the CMV antigenaemia count did not have a predictive value for patient outcome.

Peripheral blood lymphocyte count, serum IgG level and patient outcome
Lymphocyte counts in peripheral blood and serum IgG levels at CMV infection diagnosis were analysed in terms of whether they were associated with the antigenaemia count or patient outcome.

The lymphocyte count at diagnosis was significantly associated with the patient outcome (P = 0.009). The median (range) count of deceased patients was 492 (0–1778)/mm3, whereas that of surviving patients was 762 (144–3256)/mm3. By ROC analysis, 600/mm3 was determined to be the optimal threshold value to predict a poor outcome. The median (range) serum IgG level of the fatal cases was 10.70 (4.68–28.20) g/l, and that of survivors was 12.45 (3.09–41.84) g/l. No significance was observed between the two. No significant correlation was observed either between the lymphocyte and CMV antigenaemia counts, or between the serum IgG level and antigenaemia count.

Multivariate analysis for the identification of risk factors for mortality
Each clinical factor had been assessed whether it could be a risk for mortality in the above parts by univariate analyses, but to further reconfirm the validity and significance of the risk factors identified in that way, we adopted and performed the logistic regression model. As a result, the presence of clinical symptoms, other infectious complications, peripheral blood lymphopenia were identified as significant risks for mortality [odds ratio (OR) (95% CI): 6.95 (1.62–28.9), 2.43 (1.05–5.52), 0.32 (0.14–0.74), respectively; Table 5]. An age over 59.3 yrs and the use of pulsed MPSL, regarded as risk factors by univariate analyses, retained the high ORs but could not achieve the statistical significance [OR (95% CI): 1.72 (0.74–3.71) and 1.59 (0.69–3.62), respectively].


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  		TABLE 5. Survival outcomes in association with each questionnaire item among CMV-infected patients

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
The risk of severe morbidity or mortality from CMV infection is known to increase once the CMV-associated disease manifests itself pronouncedly. CMV dissemination in blood has now been established as a significant risk factor for such a progression of CMV-associated clinical abnormalities, from mere infection. The CMV antigenaemia test is performed for this purpose, and it is also a preferred method because of its convenient and quantitative character [15–19].

Since the 1990s, the CMV antigenaemia test has been extensively studied regarding its utility as a predictive marker of the development of severe CMV diseases, and also as a cut-off to start pre-emptive or preventive anti-viral therapy before the infection becomes too severe, and many studies have proven its efficacy. This progress in laboratory methods was a huge step forward, but created some new problems for physicians unfamiliar with CMV, as a reliance on such useful and convenient laboratory tools makes it rather difficult to observe the real features of virus-associated diseases.

This important virus was mostly ignored in the rheumatic disease field and is not familiar to many rheumatologists, despite the fact that strong immunosuppression is very common during the treatment of underlying diseases and patients are susceptible to all manner of opportunistic infection [1–3]. Very few reports, mostly case reports, were published before our study [8–14], making our article the first ever large-scale survey on CMV infection among rheumatic patients.

In our study, the diagnosis of CMV infection was dependent mainly on positive antigenaemia for all except four cases, who showed histopathological findings. According to the previous articles published before the antigenaemia test became widely available, antigenaemia levels in patients with manifested infection usually reached several hundred per 105 PMNs in organ transplantation or AIDS. Those reports also surveyed the positive predictive values of developing severe diseases, which were distributed between 5 and 20/105 PMNs [15–22]. Referring to these studies and many clinical trials conducted since then, pre-emptive or preventive therapy for cases with detected viraemia is now adopted as an effective therapeutic strategy [5, 15, 23,24]. It is considered to be more beneficial than to wait for some manifestation to occur. Considering these trends, it seems quite natural that many diagnoses were made mainly based on the antigenaemia test in our study.

However, interestingly, symptomatic patients had significantly higher antigenaemia counts than the asymptomatic. The clinical manifestations observed in our study were also common to infections other than CMV. Also, although most patients were recovering from underlying diseases, some had other infectious complications, and the symptoms could have been caused by non-CMV disorders. Despite this, our data clearly demonstrated that CMV reactivation would be a major cause of symptoms, and a threshold antigenaemia count of 5.6/105 PMNs predicts that patients are at a higher risk of being symptomatic, that is to say, a higher mortality rate. Besides, the efficacy of this threshold was verified among patients without non-CMV infections, too, with good sensitivity and specificity as shown above.

We avoided classifying clinical symptoms or abnormal laboratory data into specific CMV-associated organ damages such as CMV pneumonitis, hepatitis, gastroenteritis, bone marrow damage, due to the following reasons. Most patients were critically ill and afflicted by severe underlying diseases and/or other infectious complications. Moreover, the medications they were taking were often accompanied by adverse effects such as liver and bone marrow damage, which overlapped with the common features of CMV infection. Thus we excluded liver and bone marrow abnormality from questionnaire items. Similarly, it was also difficult to attribute the widely ranged clinical symptoms only to CMV. However, considering the overall clinical characteristics such as clinical symptoms, antigenaemia count, X-ray or endoscopic findings and the responses to anti-viral treatment, we presume that many of the symptomatic cases could be predominantly attributed to the virus. Plus, one patient with eye symptom was diagnosed as having CMV retinitis by an ophthalmologist.

Infectious complications other than CMV also increased the risk of mortality in our study. An explanation may be that the patients were so immunocompromised that any kind of infection could occur coincidentally. CMV reactivation itself has been known to cause immunosuppression and facilitate organ damage by other organisms such as fungi and certain viruses [25], and we assume that this second mechanism partly accounted for our results.

Concerning the relationship between immunosuppressive treatment and susceptibility to CMV infection, all but one patient were taking oral corticosteroid, mostly at high doses, and over 80% of them were additionally treated with pulsed MPSL or immunosuppressants, represented by CYC. This clearly suggests that CMV-infected patients were under strong immunosuppressive therapies. However, a precise statistical comparison between CMV and non-CMV infections was not possible as the control patient group without CMV was not prepared in our study. Remarkably, pulsed MPSL raised the mortality rate significantly when administered additionally to other therapeutic agents, although the precise causes of deaths were not known. It should be emphasized that the use of corticosteroid only, especially when combined with pulsed MPSL, led to a risk not only for CMV infection but also for a fatal outcome. Overall, 67 patients were treated only with steroid. Forty additionally underwent pulsed MPSL, out of whom 14 died finally. The immunosuppressive effect of corticosteroid is mainly achieved by the derangement of primarily T lymphocyte and monocyte/macrophage functions, and blockade of the production of inflammatory cytokines such as TNF-{alpha} and IL-1β. Peripheral blood lymphopenia has been suggested to be induced by the redistribution of circulating lymphocytes from the blood to other lymphoid compartments, resulting in the inability to access target organs. Circulating lymphocytes are mostly T cells and play a major role in the initiation and persistence of immune mechanisms by antigen recognition and memory cell recruitment, direct cytotoxicity and the production and release of various immune mediators. The suppression of IL-2 by corticosteroid also impairs T-cell-dependent immunity [26–28] in association with peripheral blood lymphopenia [29, 30]. In reality, our study verified that it increased the risk of mortality. The risk of CMV reactivation on steroid administration was primarily demonstrated by a large-scale study in bone marrow transplantation patients [31], but our data are no less valuable because corticosteroid is now the most basic and indispensable treatment modality for many clinical aspects of rheumatic diseases. Needless to say, other immunosuppressants, represented by CYC, which suppress lymphocyte proliferation and function, may have increased the risk of CMV reactivation. CMV itself causes lymphopenia once reactivated, and this, too, may have contributed to the poor outcome [5]. Though not significant, patients tended to be frequently treated with CYC, which might have impaired anti-CMV immunity by its lymphocytotoxic nature. Indeed, several articles mentioned CYC as a risk factor for the reactivation of CMV [32].

Anti-viral treatment at an early stage of reactivation has been established as a beneficial option in many clinical entities [15, 23, 24]. It was introduced in 85 patients in our survey, but regrettably no benefit was observed in the outcome. A possible explanation might be that it was preferentially introduced for symptomatic patients, who were in a critical condition. In situations where the post-diagnostic courses, including when the anti-viral treatment was started, were not known, anti-viral treatment might have been introduced only after the patients became critically ill. The longitudinal observation of CMV infection among rheumatic patients would further verify whether these explanations are relevant.

Although we could not show the benefit of anti-viral therapy due to the limitations as described above, our data, including threshold antigenaemia counts, presented us with some clues on when to start anti-viral therapy. Taking the outcome into consideration, a higher age (>59.3 yrs), presence of symptoms and lymphopenia may indicate the time to initiate therapy. Besides, the antigenaemia count has an auxiliary role at the threshold of 5.6/105 PMNs, as it was associated with the presence of symptoms, one of the risk factors for a fatal outcome.

The validity of this therapeutic strategy should be confirmed in the near future by following up CMV-infected patients treated with anti-viral agents, and this has to be our next target.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We would like to thank Dr Hiroshi Hashimoto, Juntendo Koshigaya Hospital, for helping us accomplish this study. We also wish to give a sincere compliment to all those who co-operated with us in collecting the valuable clinical data.

Funding: This study was a project by the Research Committee on Surveillance and Estimation of Treatments and Complications in Systemic Autoimmune Diseases, a study group guided by the Ministry of Health, Labor and Welfare.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Wasko MC. Comorbid conditions in patients with rheumatic diseases: an update. Curr Opin Rheumatol (2004) 16:109–13.[CrossRef][Web of Science][Medline]
  2. Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol (2003) 15:11–6.[CrossRef][Web of Science][Medline]
  3. Kang I, Park SH. Infectious complications in SLE after immunosuppressive therapies. Curr Opin Rheumatol (2003) 15:528–34.[CrossRef][Web of Science][Medline]
  4. Koszinowski UH, DelVal M, Reddehase MJ. Cellular and molecular basis of the protective immune response to cytomegalovirus infection. Curr Top Microbiol Immunol (1990) 154:189–220.[Web of Science][Medline]
  5. Preiksaitis JK, Brennan DC, Fishman J, et al. Canadian Society of Transplantation Consensus Workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant (2005) 5:218–27.[CrossRef][Web of Science][Medline]
  6. Bek B, Boeckh M, Lepenies L, et al. High level sensitivity of quantitative pp65 cytomegalovirus(CMV) antigenemia assay for diagnosis of CMV disease in AIDS patients and follow-up. J Clin Microbiol (1996) 34:457–9.[Abstract]
  7. Boeckh M, Bowden RA, Goodrich JM, et al. Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood (1992) 80:1358–64.[Abstract/Free Full Text]
  8. Mori T, Kameda H, Ogawa H, et al. Incidence of cytomegalovirus reactivation in patients with inflammatory connective tissue diseases who are under immunosuppressive therapy. J Rheumatol (2004) 31:1349–51.[Abstract/Free Full Text]
  9. Ward MM, Pyun E, Studenski S. Causes of death in systemic lupus erythematosus. Arthritis Rheum (1995) 38:1492–9.[Web of Science][Medline]
  10. Ikura Y, Matsuo T, Ogami M, et al. Cytomegalovirus-associated pancreatitis in a patient with systemic lupus erythematosus. J Rheumatol (2000) 27:2715–7.[Web of Science][Medline]
  11. Bulpitt KJ, Brahn E. Systemic lupus erythematosus and concurrent cytomegalovirus vasculitis: diagnosis by antemortem skin biopsy. J Rheumatol (1989) 16:677–80.[Web of Science][Medline]
  12. Garcia-Porrua C, Gonzalez-Gay MA, Perez de Llano LA, et al. Fatal interstitial pneumonia due to cytomegalovirus following cyclophosphamide treatment in a patient with systemic lupus erythematosus. Scand J Rheumatol (1998) 27:465–6.[CrossRef][Web of Science][Medline]
  13. Aglas F, Riner F, Hermann J, et al. Interstitial pneumonia due to cytomegalovirus following low-dose methotrexate treatment for rheumatoid arthritis. Arthritis Rheum (1995) 38:291–2.[CrossRef][Web of Science][Medline]
  14. Fraenkel G, Ross B, Wong HC. Cytomegalovirus retinitis in a patient with rheumatoid arthritis being treated with combination immunosuppressive therapy. Retina (1995) 15:169–70.[CrossRef][Web of Science][Medline]
  15. Boeckh M, Boivin G. Quantification of cytomegalovirus: methodologic aspects and clinical applications. Clin Microbiol Rev. (1998) 11:533–4.[Abstract/Free Full Text]
  16. Dodt KK, Jacobsen PH, Hofmann B, et al. Development of cytomegalovirus(CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS (1997) 11:F21–8.[CrossRef][Web of Science][Medline]
  17. Gerna G, Zipeto D, Parea M, et al. Monitoring of human cytomegalovirus infections and ganciclovir treatment in heart transplant recipients by determination of viremia, antigenemia, and DNAemia. J Infect Dis (1991) 164:488–98.[Web of Science][Medline]
  18. Grefte JM, van der Gun BT, Schmolke S, et al. The lower matrix protein pp65 is the principal viral antigen present in peripheral blood leukocytes during an active cytomegalovirus infection. J Gen Virol (1992) 73:2923–32.[Abstract/Free Full Text]
  19. Grossi P, Minoli L, Percivalle E, et al. Clinical and virological monitoring of human cytomegalovirus infection in 294 heart transplant recipients. Transplantation (1995) 59:847–51.[Web of Science][Medline]
  20. Revello MG, Percivalle E, DiMatteo A, et al. Nuclear expression of the lower matrix protein of human cytomegalovirus in peripheral blood leukocytes of immunocompromised viraemic patients. J Gen Virol (1992) 73:437–42.[Abstract/Free Full Text]
  21. van den Berg AP, Klompmaker FI, Hangoma EB, et al. Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation. J Infect Dis (1991) 164:265–70.[Web of Science][Medline]
  22. van den Berg AP, van der Rij W, van Son WJ, et al. Monitoring antigenemia is useful in guiding treatment of severe cytomegalovirus disease after organ transplanton. Transplant Int (1992) 5:101–6.[CrossRef][Web of Science][Medline]
  23. Schmidt GM, Horak DA, Niland JC, et al. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. The City of Hope Stanford Syntex Cytomegalovirus Study Group. N Engl J Med (1991) 324:1005–111.[Abstract]
  24. Small LN, Lau J, Snydman DR. Preventing post-organ transplantation cytomegalovirus disease with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies. Clin Infect Dis (2006) 43:869–80.[CrossRef][Web of Science][Medline]
  25. Boeckh M, Nichols WG. Immunosuppressive effects of beta-herpesviruses. Herpes (2003) 10:12–6.[Medline]
  26. Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid therapy for immune-mediated diseases. Basic and clinical correlates. Ann Intern Med (1993) 119:1198–208.[Abstract/Free Full Text]
  27. Auphan N, DiDonato JA, Rosette C, et al. Immunosuppression by glucocorticoids. Inhibition of NF-kappa B activity through induction of IkB synthesis. Science (1995) 270:286–90.[Abstract/Free Full Text]
  28. Neumann M, Naumann M. Beyond IkappaBs: alternative regulation of NF-kappaB activity. FASEB J (2007) 21:2642–54.[Abstract/Free Full Text]
  29. Connors M, Kovacs JS, Krevat S, et al. HIV infection induces changes in CD4+ T cell phenotypes and depletions within the CD4+ T cell repertoire that are not immediately restored by antiretroviral or immune-base therapy. Nat Med (1997) 3:533–40.[CrossRef][Web of Science][Medline]
  30. Weekes MP, Wills MR, Sissons JG, et al. Long-term stable expanded human CD4+ T cell clones specific for human cytomegalovirus are distributed in both CD45RAhigh and CD45ROhigh populations. J Immunol (2004) 173:5843–51.[Abstract/Free Full Text]
  31. Nichols WG, Corey L, Gooley T, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood (2001) 97:867–74.[Abstract/Free Full Text]
  32. Ho AAM. Observations from transplantation contributing to the understanding of pathogenesis of CMV infection. Transplant Proc (1991) 23:104–9.[Web of Science][Medline]
Submitted 22 December 2007; revised version accepted 23 May 2008.
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