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Incidence of Cytomegalovirus Antigenemia in patients with autoimmune rheumatic diseases: a 3-year retrospective study

Advances in Rheumatology201959:18

https://doi.org/10.1186/s42358-019-0061-0

  • Received: 31 July 2018
  • Accepted: 16 April 2019
  • Published:

Abstract

Objective

To determine the incidence of positive CMV antigenemia (CMV-Ag) in patients with autoimmune rheumatic diseases (AIRD) and to describe the outcomes of these patients.

Methods

From January 2011 to December 2014, a total of 443 patients with AIRD were enrolled in this retrospective analysis. Demographic, clinical and laboratory data, current clinical manifestations, organs affected by CMV infection, therapeutic management and outcomes were evaluated. The CMV-Ag was considered positive when one cell was detected at least.

Results

CMV-Ag was requested in 70 (15.8%) patients with suspicious CMV infection and was positive in 24 (34.3%). The incidence rate of positive CMV-Ag was 4.97% (95% CI 3.1–7.4%). Systemic lupus erythematosus (SLE) (59%), followed by ANCA-related vasculitis (18.2%) and rheumatoid arthritis (9%) were the diseases more associated with positive CMV-Ag. At the time of CMV infection, SLE patients had moderate to severe disease activity, with high frequency of positive anti-dsDNA antibody (69.2%) and complement consumption (61.5%), as well as high doses of corticosteroids and use of immunosuppressants. The main CMV sites involved were lung (45.5%), bone marrow (40.9%) and gut (27.3%). Mortality rate was 45.5%, especially in those with higher doses of daily oral corticosteroids (107 ± 55.4 mg vs. 71.7 ± 46.3 mg; p = 0.07) and lower number of lymphocytes (309 ± 368.2/mm3 vs. 821 ± 692.9/mm3; p = 0.06).

Conclusions

Our data showed high incidence of CMV-Ag in AIRD patients, particularly those with SLE and greater disease severity. In addition, it was observed high mortality in these patients, highlighting the CMV infection should be included in differential diagnosis.

Keywords

  • Cytomegalovirus
  • Infection
  • Antigenemia
  • Autoimmunity
  • Incidence

Introduction

Cytomegalovirus (CMV) is related to opportunistic infections in immunocompromised patients with autoimmune rheumatic diseases (AIRD) [1, 2]. Several studies have highlighted its pathogenic role in triggering or hampering some AIRD [3]. In immunocompromised individuals, the reactivation of latent CMV infection may cause fever, chills, weight loss, asthenia, hematological disorders (anemia, leukopenia, and thrombocytopenia) or severe symptomatic organ involvement, including hepatitis, chorioretinitis, encephalitis, pneumonitis and digestive hemorrhage [4].

The CMV antigenemia (CMV-Ag) is the main method for the diagnosis of infection due its high sensitivity (91%) and specificity (95%), as well as early and fast detection and therapeutic monitoring by number of affected cells [3]. On the other hand, it has some limitations, such as neutropenia below 1000/mm3 (false-negative) and other tests should be necessary for a better diagnosis [5, 6].

There are some epidemiological data and management guidance addressed to immunosuppressed patients, including AIDS and after solid organ and bone marrow transplantation [711]. However, there is a lack of evidence in patients with AIRD and the recommendations for managing these patients are extrapolated from transplantation data [12].

Thus, the aim of this study was to evaluate the incidence of CMV-Ag and describe the main outcomes over time in AIRD patients.

Patients and methods

Patients

Patients admitted to the rheumatology service at a tertiary university hospital in São Paulo/ SP, Brazil, from 01/JAN/2011 to 31/DEC/2014, were analyzed and those with clinical CMV suspicion infection and positive CMV-Ag for one cell, at least, were included. A total of 443 patients with AIRD were enrolled in this retrospective analysis. Patients with other viral infections, including hepatitis B and C, HIV, and Epstein-Barr were excluded. The positive CMV-Ag was defined when one cell was detected at least.

Clinical evaluation

Demographic, clinical and laboratory data were recorded for all patients. Specific details of each AIRD and current clinical manifestations, including disease activity, organs affected by CMV infection, therapeutic management (initial and secondary prophylaxis) and outcomes were also explored. For assessment of disease activity were used the Systemic Lupus Erythematosus Disease Activiy Index (SLEDAI) for SLE [13] and Birmingham Vasculitis Activity Score (BVAS) for ANCA associated vasculitis [14].

Laboratory evaluation of the CMV viremia

CMV-pp65 antigen detection was undertaken by the monoclonal antibody indirect immunofluorescence (IF) method (CMV Brite Turbo Kit, IQ Products, Gronigen, The Netherlands). The number of leukocytes stained positive every 200,000 neutrophils in peripheral blood was then documented.

Quantitation of CMV-DNA was undertaken by real-time fluorescence quantitative polymerase chain reaction (RT- PCR-fluorecence) technology (CMV nuclei acid quantitative assay kit, TaqMan® Roche – FAM, Branchburg, USA) when available. The criteria for positive result was CMV-DNA ≥ 500copies/ml. Viral inclusion bodies found in the tissue biopsy, stained with hematoxylin-eosin, were also considered positive for CMV infection.

Definition of CMV disease and follow-up protocol

Patients with laboratory abnormalities (anemia, leukopenia, thrombocytopenia or liver enzymes) or clinical manifestations, such as fever, gut or eye symptoms or lung injury, excluding other infection causes, were considered as suspicious symptomatic for CMV infection. CMV disease was defined when the confirmation had been performed by biopsy and identification of positive viral inclusion corpuscles or immunohistochemistry of affected organ.

After treatment with antivirals, patients had CMV-Ag repeated weekly until becoming negative. This outcome was defined as improvement of CMV infection.

Statistical analysis

All analyses were proceeded using SPSS 20.0 (IBM, New York, USA). Shapiro-Wilk or Kolmogorov-Smirnov tests were applied to assess the normality of the variables. To compare continuous variables, Student-t test or Mann-Whitney test were used. Pearson and Spearman correlation tests were used to analyse the correlation between variables. Categorical data were analyzed by chi-square test or Fisher’s exact test. Significant variables in the univariate analysis or correlation tests were used for tailoring the multivariate regression models in which the positive CMV-Ag was considered as dependent variable and all other as independent, in order to explore main prognostic factors. Besides, ROC analysis was performed to determine the absolute cut-off value of the positive CMV-Ag related to death. P value below 0.05 was set as significant.

This study was approved by the Ethics and Research Committee of Hospital São Paulo / Unifesp (506.406).

Results

From 443 patients with AIRD hospitalized in a tertiary university center, the CMV-Ag was requested to 70 (15.8%) patients with suspicious CMV infection and it was positive in 24 (34.3%).

Two positive CMV-Ag were excluded because one patient had cutaneous lupus (not systemic) and the other had Behcet’s disease whose clinical manifestation of possible viral infection (acute diarrhea) was attributed later to adverse event by using of colchicine. Thus, 22 patients with AIRD and positive CMV-Ag were evaluated (Fig. 1). The incidence global rate of the positive CMV-Ag was 4.97% (95% CI 3.1 to 7.4%). Considering only lupus hospitalized patients, the CMV-Ag rate was 16.5% (95% CI 9.7 to 51.9%).
Fig. 1
Fig. 1

Recruitment of positive CMV antigenemia for the study

The main sites involved by CMV infection were lung, bone marrow and gut. Tables 1 and 2 show the main characteristics of AIRD patients with positive CMV-Ag. Lupus patients were younger than those with other AIRD (29.1 ± 13.4 years vs. 54.2 ± 21.1 years; p = 0.03). In addition, the majority of patients had high disease activity associated with severe infection, such as lupus patients (SLEDAI = 15.3 ± 9) and patients with ANCA-associated vasculitis (BVAS = 5.2 ± 3.8).
Table 1

Clinical and laboratory data of 22 patients with autoimmune rheumatic disease (AIRD) and positive cytomegalovirus antigenemia

Patient

Age (years)/ Sex

AIRD

Immunosuppressive therapy in hospital

Lymphocyte Count (/μl)

Positive CMV antigenemia nuclei (/200.000PMN)

Sites involved by CMV infection

Symptoms

Outcome

1

67/F

SLE

CFA, PDN 130 mg/day

1311

32

Gut

Esophageal ulcers

Death

2

34/F

SLE

AZA, CFA, PDN 80 mg/day

1356

1

Lung

Cough, dyspnea, fever

Improvement

3

17/F

SLE

PDN 200 mg/day

444

2

Cytopenia

Neutropenia, Thrombocytopenia

Improvement

4

22/F

SLE

PDN 60 mg/day

695

5

Gut

Mouth ulcers

Improvement

5

21/F

SLE

PDN 60 mg/day

135

500

Cytopenia / Lung

Trombocyotpenia, Cough, dyspnea, fever

Death

6

25/F

SLE

PDN 180 mg/day

525

1

Lung

Cough, dyspnea, fever

Death

7

16/F

SLE

MP + CFA, PDN 50 mg/day

850

108

Cytopenia

Febrile neutropenia

Improvement

8

20/F

SLE

MP + CFA, PDN 60 mg/day

792

1

Gut

Esophageal ulcers

Improvement

9

38/F

SLE

PDN 60 mg/day

2751

2

Lung

Cough, dyspnea, fever

Improvement

10

30/F

SLE

CFA, PDN 60 mg/day

659

2

Cytopenia

Pancytopenia, fever

Death

11

25/F

SLE

MMF, MP, PDN 50 mg/day

853

164

Cytopenia

Anemia, Thrombocytopenia

Improvement

12

37/F

SLE

PDN 60 mg/day

80

46

Cytopenia /Gut

Anemia, diarrhea

Improvement

13

26/F

SLE

MP + CFA, PDN 90 mg/day

714

2

Lung

Cough, dyspnea

Improvement

14

77/F

SE

125

1

Cytopenia

Pancytopenia, fever

Death

15

29/M

Overlap Sd.

PDN160mg/day

246

16

Lung

Cough, dyspnea

Death

16

70/M

RA

MP, PDN 20 mg/day

77

1

Cytopenia

Pancytopenia, fever

Improvement

17

17/M

RA

PDN 160 mg/day

689

1

Lung

Cough, dyspnea

Death

18

42/F

MPA

PDN 100 mg/day

197

4

Lung

Cough, dyspnea, Fever

Death

19

77/F

MPA

PDN 100 mg/day

372

500

Cytopenia / Lung

Anemia, Leukopenia, Cough, Fever

Death

20

63/F

GPA

CFA, PDN 30 mg/day

857

9

Gut

Gastric ulcer

Improvement

21

58/M

GPA

AZA, MP, PDN 120 mg/day

213

73

Gut

Gastric ulcer

Death

22

55/F

Anti-sintetase Sd.

CFA, PDN 100 mg/day

975

7

Lung

Cough, dyspnea

Improvement

CMV cytomegalovirus, SLE Systemic Lupus Erythematosus, SE Systemic sclerosis, Overlap syndrome Systemic Lupus Erythematosus + Systemic sclerosis + polymyositis, RA rheumatoid arthritis, MPA microscopic polyangiitis, GPA granulomatosis with polyangiitis, F Female, M, Male, AIRD autoimmune rheumatic disease, PDN Prednisone, AZA Azathioprine, MMF mycophenolate mofetil, CFA Cyclophosphamide (pulse), MP Methylprednisolone (pulse), MP + CFA combined pulse: methylprednisolone and cyclophosphamide. a: Maximum dose during hospitalization. b: methylprednisolone pulse 1 g / day for 3 consecutive days

Table 2

Demographic and clinical data of 22 patients with autoimmune rheumatic disease (AIRD) and positive cytomegalovirus antigenemia

Female sex

19 (90%)

Age (years)a

39.4 ± 20.8

AIRD

 SLE

13 (59%)

 ANCA-associated Vasculitis

4 (18.2%)

 RA

2 (9%)

 Systemic sclerosis

1 (4.5%)

 Overlap syndrome

1 (4.5%)

 Anti-sintetase syndrome

1 (4.5%)

Diagnosis AIRDb Time (months)

10.5 (0–276)

Hospitalization causea

 Activity + Infection

11 (50%)

 Infection only

8 (36.5%)

 Activity only

3 (13.6%)

AIRD treatment

Maximum dose of corticosteroids in hospital (mg/ day)a

87.7 ± 52.5

 Corticosteroids dose above 1 mg /kg/ daya

19 (86.4%)

 Methylprednisolone Pulse Therapya

11 (50%)

Immunosuppressant medicationsa

11 (50%)

Site of CMV infectiona

 Lung

10 (45.4%)

 Cytopenia

9 (40.9%)

 Gastrointestinal tract

6 (27.3%)

Hospitalization timea(days)

41.9 ± 34.1

Hospitalization time until CMV-Ag be requesteda(days)

11.5 ± 12

Time of symptoms until CMV-Ag be requesteda(days)

7.8 ± 7.1

Time from the first positive CMV-Ag to specific treatment be starteda(days)

3.3 ± 3.1

Number of positive CMV-Ag nuclei after specific treatment

 With Ganciclovirb

15 (1–500)

 No ganciclovirb

7 (1–4)

Co-Infectionsa

16 (72.7%)

Polymicrobial Infections

5 (22.7%)

CMV reactivation during hospitalization

0

Prophylaxis after standard Ganciclovir treatment

0

aMean ± standard deviation; bMedian (minimum and maximum); AIRD Autoimmune Rheumatic Diseases, CMV-Ag cytomegalovirus antigenemia, SLE Systemic Lupus Erythematosus, RA Rheumatoid Arthritis

The length of hospital stay (11.5 ± 12 days) was long and there was a delay time between the beginning of symptoms and the CMV-Ag has been requested (7.8 ± 7.1 days). Besides, 16 (72.7%) patients had co-infections with other antimicrobial agents, such as Candida albicans and Acinetobacter baumannii, and there were five cases of polymicrobial infections.

Regarding the treatment for AIRD, 19 (86.4%) patients used corticosteroid (up to 1 mg/ kg/ day of prednisone or equivalent) and 11 (50%) patients used other immunosuppressants drugs during hospitalization, including cyclophosphamide.

Concerning the treatment for CMV, 15 (68.2%) of them received ganciclovir. In general, these patients tended to have more positive cells than those untreated [16 (1–500) vs. 1 (1–4); p = 0.05]. Only three patients reported adverse events related to ganciclovir, including cutaneous and cytopenia reaction.

Lupus patients had greater number of positive CMV-Ag than other AIRD. These patients were using high doses of corticosteroids and had received methylprednisolone pulse therapy in the last 6 months prior to infection. Moreover, the median time of disease was only 12 months (0–276), suggesting higher likely of viremia and CMV involvement in early disease. They had higher predominance of joint, kidney and hematological involvement, as well as higher positivity for anti-dsDNA antibody (69.2%) and complement consumption (61.5%). Few lupus patients had cutaneous or neurological involvement.

The mortality rate was 45.4% (10 deaths in total: 4 in SLE patients; 3 in patients with ANCA-associated vasculitis, 1 patient had systemic sclerosis, 1 with RA and other with overlap syndrome). Three deaths were observed between the seven patients who did not receive specific treatment for CMV, although not significant.

After assessing the risk factors for death, there was no difference among patients who survived or died regarding to age, average number of positive cells on antigenemia, site of virus involvement, hospitalization, symptoms until the first CMV-Ag be requested and pulse therapy in the last 6 months. However, there was a tendency to higher doses of oral corticosteroids (107 ± 55.4 mg/day vs. 71.7 ± 46.3 mg/ day; p = 0.07) and lower number of lymphocytes when patients who died were compared to those who survived (309 ± 368.2/ mm3 vs. 821 ± 692.9/ mm3; p = 0.06). Moreover, the surviving patients remained hospitalized for longer time than those who died (24.3 ± 23.9 days vs. 56.6 ± 35.1 days; p = 0.017) (Table 3).
Table 3

Comparison of clinical and demographic characteristics of patients with positive cytomegalovirus antigenemia according to the outcome: survivor or death

 

Death

n = 10

Survivor

n = 11

p

Ageb (years)

44.3 ± 23.4

35.5 ± 18.3

0.32

Lymphocyte Count (/μL)b

447.2 ± 368.2

870.3 ± 692.9

0.06

CMV-Agb,c

113 ± 205,2

29 ± 52.9

0.67

Oral glucocorticosteroids (mg/ day)a,b

107 ± 55.4

71.7 ± 46.3

0.07

Methylprednisolone Pulse Therapy, n

 Yes

3 (30%)

8 (72.2%)

0.19

 No

7 (70%)

4 (36.6%)

Hospitalization timeb

24.3 ± 23.9

56.6 ± 35.1

0.017

Hospitalization time until CMV-Ag be requested (days)b

9.9 ± 14

12.9 ± 10.5

0.42

Time of symptoms until CMV-Ag be requested (days)b

7.9 ± 8.2

7.8 ± 6.4

0.77

Time from the first positive CMV-Ag to specific treatment be started (days) b

3.4 ± 2.6

3.3 ± 3.7

0.54

CMV suspicious cause, n

 Cytopenia

2 (20%)

4 (36.4%)

 

 Cytopenia e GIT

0 (0)

1 (9.1%)

 

 GIT

2 (20%)

3 (27.3%)

0.59

 Pneumonia

4 (40%)

4 (36.3%)

 

 Cytopenia e Pneumonia

2 (20%)

0 (0)

 

CMV-Ag: cytomegalovirus antigenemia, b mean ± standard deviation, c cels / 200.000polimorphonuclear. aMaximum corticosteroid dose during hospitalization. GIT gastrointestinal tract. Cutoff value of 10 positive cores for CMV antigenemia

Regarding absolute CMV-Ag, three (13.6%) patients had values above five cells and eight patients (36.4%) had values above 10 cells. However, none of these two cutoffs CMV-Ag had significant association with death or poor outcome.

Discussion

Our data showed high incidence of positive CMV-Ag in hospitalized patients with AIRD, as well as severe disease severity and poor prognosis, including death.

To our the best knowledge, this is the first study to highlight the incidence of positive CMV-Ag in hospitalized patients with severe AIRD, especially SLE and ANCA-associated vasculitis. Thus, it could not be compared with another retrospective studies no incidence data and heterogeneous prevalence (from 2 to 50%) [4, 8, 15, 16].

In addition to severity and high disease activity, it is worthy emphasizing that high doses of corticosteroids may have impaired the immune response in our patients [4, 17, 28]. Considering that over 95% of general population have immunological memory for CMV, likely these three aspects together could be involved for reactivation of latent viral infection [4, 12, 17, 18]. On the other hand, other authors found no association between CMV infection and immunosuppressive medications, especially corticosteroids [3, 8, 16].

The lung (45.5%) was the organ with the highest suspect involvement by CMV infection in our patients, confirming that the viral reactivation data in tracheal aspirates from immunosuppressed patients must be the main pathophysiologic mechanism, as well as pneumonitis reports and respiratory failure [21, 22]. However, it is important to state the possibility of pneumonia caused by multiple microbial agents. Cytopenia had the second place in frequency (40.9%), unlike recent retrospective report of 105 patients with SLE and active CMV infection related 81% of patients with some cytopenia [23]. The simultaneous involvement of various organs can also occur in immunosuppressed patients and was observed in 3 (13.6%) of our patients. Although the presence of cytopenia may constitute a simple and early warning for CMV infection in immunocompromised patients with AIRD, this finding was not specific, since it can also mean disease activity and toxicity to immunosuppressants.

Several mechanisms may explain the role of CMV and the onset of rheumatic disease or as a possible trigger, as well as its association with increased mortality in lupus patients [23]. Due to their broad cell tropism, CMV has great variety of clinical manifestations in immunocompromised patients and can even be confused with the disease activity [3, 12, 19, 23, 25]. At diagnosis of CMV infection, SLE patients had higher incidence of hematologic, joint and kidney activity. Unlike cytopenias, articular and kidney involvement did not usually occur in reactivation of CMV infection and may be useful for the differential diagnosis between both clinical scenarios (infection vs. disease activity) [23].

Tasai et al. (2012) showed SLE patients infected by CMV had higher scores of SLEDAI, poor prognosis and increased mortality [12]. Our data confirm these interesting epidemiological features, since more than half of patients with positive CMV-Ag had SLE, particularly with early-onset disease and were youth. Thus, these findings address the role of CMV as trigger, as well as by collaborating on innate immunity and dysfunction of humoral and cellular immune response [4, 15, 24, 26, 27].

The diagnosis of CMV infection is not performed routinely by rheumatologists and there is no active search or specific treatment for patients with AIRD. Our study provides a new information about modern strategies headed for these patients. First of all, it is an alert to the presence of infection or co-infection with CMV, according to our high incidence of CMV-Ag in the first 10 days of hospitalization. Secondly, the red flag is the fast and sensible methodology for detecting suspicious cases of CMV infection in AIRD patients. Thirdly, the delay for requesting CMV-Ag and the risk of severe disease severity and higher mortality rate.

There are well-established recommendations for screening, treatment and prevention of CMV infection in immunocompromised patients with other conditions, such as cancer, AIDS and transplants [5, 711, 20]. However, there are a lack of information about management of AIRD patients, highlighting the relevance of current study and supporting the necessity for the development of specific protocols in this scenario.

In 2008, Takizawa et al. suggested the cut-off of 11.2 cells/ 200,000/ neutrophils as a significant value for distinguishing symptomatic and asymptomatic infections as well as higher positive predictive value for CMV infection and mortality in patients with AIRD [16]. As there is no consensus about the significant number of cells for AIRD patients, we considered at least one cell for the first investigation associated to clinical findings (fever plus cytopenias and/ or pulmonary infiltrates and/ or gut lesions and/ or hepatitis). However, in further re-analyses with several cut-off points, including 5 and 10 cells, we did not also find a significant CMV-Ag cut-off. Thus, our data confirm that, regardless age, duration of symptoms, number of positive cells, viral involvement site, the simple presence of CMV-Ag was associated with severe illness and higher risk of death, especially in those with shorter hospital stay and higher dose of corticosteroids.

Considering that AIRD hospitalized patients have multiple and complicated medical conditions, such as systemic inflammation, co-infections and renal failure, it is very difficult to assure the real direct cause of death and the multifactorial aspects altogether may occur among themselves.

Nonetheless, our study has some limitations. Firstly, it is related to CMV-Ag definition itself, because we cannot be sure that the presence of only one positive cell could be indicative of CMV infection. Secondly, is related to sample size, lack of control group and the heterogeneity of autoimmune diseases. Thirdly, we should not generalize our findings for outpatient patients or systematically request CMV-Ag for all hospitalized patients without a clinical suspicion. In addition, it is important to state that in any suspected case is need to confirm the CMV disease by histopathological analysis, for instance.

Although the survival patients with DRAI have kept imunossupression, none of them reactivated CMV over time (mean follow-up time 2 years), even without receiving prophylactic treatment with ganciclovir as suggested by protocols for transplanted patients. These new data emphasize that specific protocols are necessary for establishing appropriate diagnosis, treatment and monitoring CMV status in patients with AIRD, including prospective randomized controlled trials.

Conclusions

Our data showed high incidence of CMV-Ag in AIRD hospitalized patients, particularly early-onset lupus, severe disease activity, and higher mortality. Thus, the possibility of CMV infection should be included in differential diagnosis in AIRD patients.

Declarations

Acknowledgements

None.

Funding

There was no financial support for this study.

Availability of data and materials

The data of this article can be found at Rheumatology Division of Universidade Federal de São Paulo / Unifesp.

Author’s contributions

All authors made substantial contributions to the acquisition of data, have been involved in drafting the manuscript revising it critically and approved the final manuscript.

Ethics approval and consent to participate

The study was approved by the Ethics and Research Committee of Hospital São Paulo / Unifesp (number 506.406).

Consent for publication

All the patients signed the informed consent form.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Division of Rheumatology, Universidade Federal de São Paulo, São Paulo, SP, Brazil
(2)
Disciplina de Reumatologia, Escola Paulista de Medicina – Universidade Federal de São Paulo, Rua Leandro, Dupré, 204, conjunto 74, Vila Clementino, São Paulo, SP, 04025-010, Brazil

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