Clinical significance of respiratory virus detection in patients with acute exacerbation of interstitial lung diseases.

BACKGROUND: The impact of viral infections on acute exacerbations in idiopathic pulmonary fibrosis (IPF) and/or non-IPF interstitial lung disease (ILDs) has been scarcely described. OBJECTIVES: To elucidate the frequency of virus infections in patients with IPF or non-IPF ILDs including idiopathic interstitial pneumonia (IIP) or connective tissue disease (CTD)-associated pneumonia, and its influence on their short-term mortality. METHODS: We prospectively enrolled adult patients with acute exacerbation of IPF and non-IPF ILDs who were admitted to the hospital during the last 3 years, and examined the respiratory samples obtained from nasopharyngeal, sputum, and bronchoalveolar lavage fluid. RESULTS: A total of 78 patients were identified, consisting of 27 patients with acute exacerbation of IPF and 51 patients with non-IPF ILDs (IIP: n = 27, CTD-associated IP: n = 24). Of all patients, 15 (19.2%) had viruses detected in their respiratory samples including the human herpesvirus 7 (HHV7; n = 4) and cytomegalovirus (CMV) plus HHV7 (n = 3). The proportion of virus infections in the IPF and non-IPF ILDs groups was comparable. The Kaplan-Meier survival curves over 60 days revealed a lower survival probability in the virus positive group (n = 15, 60%) than in the virus negative group (n = 60, 83.3%, p < 0.05). However, the virus infection itself could not predict the 60-day survival probability using simple logistic regression analysis. CONCLUSIONS: Viral infections, mostly CMV or HHV7, were identified in both patients with acute exacerbation of IPF and non-IPF ILDs, but the clinical significance on short-term mortality or isolation itself from respiratory samples remains to be determined.

Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases.

BACKGROUND: Little is known about the involvement of human herpesviruses 6 and 7 (HHV-6 and HHV-7) in autoimmune connective tissue diseases (ACTD). OBJECTIVE: To determine the prevalence of active infection with HHV-6 and HHV-7 in patients with ACTD. STUDY DESIGN: The presence and quantity of HHV-6 DNA was determined by quantitative real-time PCR in a cross-sectional study of serum, peripheral blood mononuclear cells, and tissues obtained from 58 ACTD patients and 38 healthy subjects (HS). Specific anti-HHV-6 antibody titer was also measured. RESULTS: HHV-6 serum viremia occurred in a significantly higher proportion of ACTD patients compared to HS [26/58 (44.8%) vs. 1/38 (2.6%), p=0.001] with the highest reactivation frequency [7/10 (70%)] observed in patients with scleroderma. Moreover, HHV-6 in serum was associated with ACTD activity (22/38 vs. 4/20, p<0.05). Higher titers of HHV-6 antibodies were found in ACTD patients than in HS, although HHV-6 seroprevalence among patients with ACTD and HS was similar. HHV-7 viremia was not detected in any patients or HS controls. CONCLUSION: The frequent reactivation of HHV-6 in scleroderma and other ACTD, especially when active, suggests that HHV-6 may play a role in the pathogenesis of these diseases.

Anetoderma: a case report and review of the literature.

Anetoderma is a rare benign dermatosis caused by a loss of mid-dermal elastic tissue resulting in well-circumscribed areas of pouchlike herniations of flaccid skin. Anetoderma is classically categorized as either primary (idiopathic) or secondary (following an inflammatory dermatosis in the same location). We report a case of primary anetoderma (PA) occurring in a human immunodeficiency virus 1 (HIV-1)-infected man. We review the clinical presentation, possible etiologies, associated conditions, and limited treatment options of this disease.

Infections, connective tissue diseases and vasculitis.

In genetically predisposed individuals, viruses, bacteria, or parasitic infectious agents are suspected of inducing autoimmunity and/or exacerbating autoimmune rheumatic diseases (ARD) once self-tolerance is broken. Although direct evidence for this association is still lacking, numerous data from animal models as well as from humans support the hypothesis of a direct contribution of pathogens to the induction of several ARD. This review focuses on the possible role of infectious agents as triggers of autoimmunity in systemic lupus erythematosus, polymyositis-dermatomyositis, antiphospholipid antibody syndrome, and primary vasculitis. Indeed, vasculitis may be a clinical manifestation of an infectious disease (secondary vasculitis). In addition, immune response abnormalities and immunosuppressive medications may be responsible for the high percentage of infectious complications in ARD patients. Recent therapeutic approaches aimed at lowering doses of cytotoxic agents and shortening duration of treatment with the most toxic drugs, have proved to be as effective as conventional regimens. New drugs and strategies aimed at preventing infections could further improve the outcome of ARD patients.

Occult hepatitis C virus infection revisited with ultrasensitive real-time PCR assay.

Occult hepatitis C infection is regarded as a new entity that should be considered when diagnosing patients with a liver disease of unknown origin. Using an ultrasensitive real-time PCR assay, we demonstrated that occult hepatitis C virus (HCV) infection cannot be found in peripheral blood mononuclear cells of patients with cryptogenic liver diseases, HCV--associated systemic vasculitis, or connective tissue diseases. The significance of such occult infection must be elucidated.

Clinical evaluation of patients with inflammatory connective tissue diseases complicated by cytomegalovirus antigenemia.

We evaluated the occurrence of cytomegalovirus (CMV) infection and the background characteristics in twenty-three hospitalized patients with inflammatory connective tissue diseases including systemic lupus erythematosus, polymyositis/dermatomyositis, rheumatoid vasculitis, microscopic polyangitis, and Takayasu's arteritis. Cytomegalovirus antigenemia was demonstrated in 10 of 23 evaluable patients. Five of ten patients with CMV antigenemia developed symptomatic CMV disease (all cases of fever, two cases of liver involvement, two cases of interstitial pneumonia, and one case of unknown organ involvement), whereas the remaining five patients were asymptomatic. Most of CMV antigenemia-positive patients had been administered intravenous steroid pulse, or in combination with immunosuppressive agents intravenously or orally because of refractory disease activity. Particularly, in patients who received intravenous methylprednisolone pulse in combination with additional intravenous cyclophosphamide pulse, the incidence of CMV antigenemia was markedly higher (four out of four). Four of ten CMV antigenemia-positive patients simultaneously showed detection of Pneumocystis jiroveci in induced sputum by PCR, increase in level of serum beta-D-glucan and the finding of geographical ground-glass opacities on chest computed tomography. These findings suggested that patients with connective tissue diseases under intensive immunosuppressive therapies (intravenous steroid pulse in combination with additional intravenous cyclophosphamide pulse in particular) are highly susceptible to CMV infection and disease, and that patients complicated by CMV antigenemia are susceptible to combined opportunistic infection such as Pneumocystis pneumonia.

Analysis of shedding of 3 beta-herpesviruses in saliva from patients with connective tissue diseases.

BACKGROUND: Whether an association exists between infection with beta -herpesviruses and connective tissue diseases remains unclear, as are the mechanisms for the regulation of these infections in the salivary glands. METHODS: Human herpesvirus (HHV)-7 was isolated and viral DNA was quantified by real-time polymerase chain reaction (PCR) in serially collected saliva samples, to determine whether viral load correlated with infectivity. Then, to examine the role played by beta -herpesviruses in connective tissue diseases, cytomegalovirus, HHV-6, and HHV-7 DNA loads were examined by real-time PCR in serially collected saliva samples from 21 patients with connective tissue diseases. RESULTS: Although subjects with frequent HHV-7 shedding were more likely to have a high viral load than were other subjects, high viral loads were detected in saliva samples from a portion of the subjects with low viral shedding rates. No significant difference between the quantity of HHV-7 DNA in saliva samples from which active virus was isolated and that amplified from samples without detectable virus was observed. Patients with adult-onset Still disease consistently had high HHV-7 DNA loads, in contrast to patients with other connective tissue diseases (P=.0003) and healthy adults (P=.0224). The mean HHV-6 (P=.012) and HHV-7 (P<.0001) DNA loads in patients with connective tissue diseases were lower than those in healthy adults. CONCLUSION: These data suggest that a number of host factors in patients with adult-onset Still disease may function to accelerate HHV-7 replication in the salivary glands.

Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. RESULTS: HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. CONCLUSIONS: These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load.

Elevated immunoglobulin G antibodies to the proline-rich amino-terminal region of Epstein-Barr virus nuclear antigen-2 in sera from patients with systemic connective tissue diseases and from a subgroup of Sjögren's syndrome patients with pulmonary involvements.

Associations of Epstein-Barr virus (EBV) and autoimmune diseases have been hypothesized. We have analysed IgG antibodies to EBV nuclear antigen (EBNA)-2 in sera from Japanese patients with autoimmune systemic connective tissue diseases (CTD), exemplified by systemic lupus erythematosus (SLE), primary Sjogren's syndrome (SS), rheumatoid arthritis (RA), systemic sclerosis (SSc) and secondary SS (classical CTDs complicated with SS). An enzyme-linked immunosorbent assay (ELISA) which uses glutathione-S-transferase polypeptides fused to EBV nuclear antigen (EBNA)-2 and EBNA-1 was developed. Ratios of IgG antibody reactivity to whole IgG concentrations of sera were calculated to normalize EBNA-2 and EBNA-1 antibody levels to the hypergammaglobulinaemia that occurs in CTD. The ELISA optical density OD(450) readings of IgG antibodies to both the amino-terminal aa 1-116 of EBNA-2 and carboxyl-terminal aa 451-641 of EBNA-1 were elevated significantly in patients with SLE, primary SS, RA, SSc and secondary SS when compared to EBNA-1. The OD readings were divided by serum IgG concentrations to normalize for the hypergammaglobulinaemia. The specific levels of IgG antibodies to the amino-terminal region of EBNA-2 were elevated in patients with SLE, primary SS or RA, as well as those with secondary SS complicated with SLE or RA. The EBNA-2 amino-terminal region contains a polyproline tract and a proline-rich sequence and has considerable amino acid sequence homology with many cellular proline-rich proteins. High ratios of EBNA-2 aa 1-116 to EBNA-1 aa 451-641 IgG antibody levels which probably suggest reactivation of EBV latent infection were associated significantly with pulmonary involvement in SS patients. These results are consistent with the hypothesis that the sequence similarity between the amino-terminal region of EBNA-2 and proline-rich cellular proteins is associated with pathogenesis in a subpopulation of CTD patients, possibly by the molecular mimicry-epitope shift mechanism.

HIV-associated musculoskeletal involvement.

Various rheumatic manifestations associated with HIV infection have been recognized, ranging from infectious conditions, such as septic arthritis, to seronegative spondyloarthropathy. Other musculoskeletal manifestations include lupus-like and Sjögren-like diseases and HIV-related malignancy. The introduction of HAART has changed the spectrum of the clinical manifestations of rheumatic disease seen today, with infections and articular involvement being the most frequently observed.

Rheumatic manifestations of HIV-AIDS.

Infection by human immunodeficiency virus is characterized by a myriad of clinical manifestations affecting almost every organ system in the body. If untreated, it follows an inexorable course, leading to a profound state of immunosuppression and eventually death from opportunistic infection and/or development of lymphoproliferative malignancy and Kaposi's sarcoma. Rheumatic manifestations may develop at any time of the clinical spectrum, but usually are more often seen in late stages. A variety of disorders may be seen, particularly Reiter's syndrome and undifferentiated spondyloarthropathy. Most patients do well with conventional anti-inflammatory therapy, but some will require the use of immunosuppressive-cytotoxic therapy.

Parvovirus-associated arthritis.

Human parvovirus B19 is the cause of several distinct clinical syndromes. The most common is erythema infectiosum (fifth disease), a febrile exanthem occurring primarily in children. Recent studies have shown that parvovirus B19 can cause acute arthritis and occasionally a chronic arthropathy, both in children and adults. Parvovirus B19 DNA has been detected in studies in the synovial tissue of patients with rheumatoid arthritis, but other studies have varied in their findings. Recent studies also indicate a possible connective tissue disease-like syndrome with parvoviral infections. The common features of this syndrome are malar eruption, arthralgias, arthritis, and laboratory abnormalities including antinuclear antibody and rheumatoid factor positivity. However, the data indicate it is unlikely that B19 infection causes rheumatoid arthritis or systemic lupus erythematosus. Continued studies of the pathogenesis of acute and chronic parvoviral B19 infections and arthropathy may provide insights into virus-host interactions and mechanisms of joint disease and connective tissue disease.

[Rheumatological manifestations in HIV infections]. / Revmatiske manifestasjoner ved HIV-infeksjon.

BACKGROUND: The recognised clinical spectrum of disease associated with HIV infection is rapidly expanding and now includes a variety of rheumatological manifestations. MATERIAL AND METHODS: In this review of the literature of the last 15 years, we present the most common rheumatic manifestations described in association with HIV infection. RESULTS: Manifestations include a wide array of articular syndromes and autoimmune manifestations such as Reiter's syndrome, psoriatic arthritis, HIV associated arthritis and septic arthritis. Autoimmune diseases associated with HIV infection include a Sjögren-like syndrome, myopathies and systemic vasculitis. INTERPRETATION: Rheumatological manifestations of HIV infection may present earlier than clinical signs of the infection itself. Steroid and cytostatic treatment of rheumatic diseases may worsen the HIV disease.

The significance of chronic hepatitis B and C virus infections in some connective tissue diseases: the association with chronic liver disease.

BACKGROUND/AIM: We investigated the pathogenic role of chronic hepatitis B virus (HBV) and C virus (HCV) in some connective tissue diseases including systemic lupus erythematosus (SLE), overlap syndrome, rheumatoid arthritis (RA), seronegative spondylarthritis (SS) and the association with chronic liver disease. METHODOLOGY: There were studied 155 patients, aged among 18 to 64 years old: 57 with SLE, 22 with overlap, 26 with RA, 30 with SS. The diagnoses were established using modified ARA criteria. There were performed complex immunology tests, percutaneous liver biopsy, HLA, Elisa tests with Riba confirmation for detecting HCV and HBV. RESULTS: 17% of SLE patients were infected with hepatitis viruses, predominantly B (70%). Half of them had a hepatic involvement due to the hepatitis viruses. 23% of RA patients were equally B\C infected with only one case of hepatic involvement secondary to hepatitis viruses. All the HCV infected patients had rheumatoid factor (RF) IgG-IgM type, with low serum levels of haemolytic complement (CH50), increases serum levels of circulating immune complexes (CIC) and evidence of HLA DR4 In the group of SS 40% of patients were infected mostly with HBV. In HLA B27 (+) anchylosing spondylitis (AS) the incidence of HBV was 100%. CONCLUSIONS: There is no high prevalence of HCV infection in SLE, overlap syndrome or RA, compared to the control group. In SS the prevalence is increased (40%), especially HLA B27 (+) AS group (33%), in which HBV is noticed at a rate of 100%. The association SLE-HCV favours the visceral involvement especially renal ones, while the presence of HBV is associated with decrease of lupus activity. In RA, HCV induces IgG-IgM RF with complement activation, being considered as a trigger of the disease in HLA DR4 patients. In HLA B27 (+) AS. HBV may trigger the development of disease in genetically susceptible individuals.

Autoimmune phenomena and hepatitis C virus in lymphoproliferative and connective tissue disorders.

Since hepatitis C virus (HCV) infection is frequently detected in patients with lymphoproliferative or autoimmune disorders and since the virus may infect lymphocytes, the question is raised whether malignant transformation and autoimmune manifestations in the presence of HCV are HCV-related or merely fortuitous. A close association has been firmly established between HCV infection and essential type II mixed cryoglobulinemia (ECM), an indolent lymphoproliferative disorder characterized by cryoprecipitable immune-complexes (IC) that may evolve into classical non Hodgkin's lymphomas (NHL) retaining the ability to produce cryoprecipitable rheumatoid factor (RF). It is reasonable to consider HCV as one cofactor in lymphomagenesis, even if the precise pathogenetic relationship between HCV infection, the chronic presence of cryoprecipitable IC and the development of NHL have not been established yet. Several epidemiological studies have documented the ability of chronic HCV infection to favour the production of autoAb. It is not clear why only some patients with HCV infection develop autoAb, nor why the most frequent autoAb detected in HCV-infected subjects are cryoglobulins. Though a high prevalence of anti-HCV has been found in a variety of systemic and organ-specific autoimmune diseases, it is likely that several of these associations are fortuitous with the notable exception of membranoproliferative glomerulonephritis. As HCV can provoke or exacerbate inflammatory signs and cause the production of RF, it is reasonable to suspect that HCV infection may be able to trigger the development of some connective tissue diseases or to exacerbate their clinical course. Nonetheless, it is clinically prudent to conclude that the pathogenetic relationships of Sjögren syndrome, rheumatoid arthritis and polyarthritis with HCV infection are more likely to be regarded as mediated via the intermediate development of ECM.

A novel hypothesis to explain the hemorrhagic and connective tissue manifestations of Ebola virus infection.

The hemorrhagic and connective tissue complications of infection with Ebola virus are poorly understood. While searching for homologies and motifs of the aortic aneurysm-associated autoantigenic protein 40 kDa (AAAP-40), we have noted some short sequences (possibly shared epitopes) that occur in the envelope glycoprotein (40 kDa) of the Ebola virus. As a first step toward determining whether molecular mimicry of human matrix proteins by the Ebola virus protein might explain some of the severe connective tissue manifestations of infection, we have tested whether immunoglobulin (IgG) purified from the sera of patients with abdominal aortic aneurysm (AAA) are immunoreactive with the 40-kDa protein of the Ebola virus. Immunoblots of soluble Ebola proteins (strain Mayinga/Zaire) were probed with IgG's purified from the sera of eight patients with AAA and two healthy young control volunteers. The proteins were also probed with IgG extracted from the walls of two surgical aneurysm specimens. Serum IgG from eight consecutively studied AAA patients was immunoreactive with an Ebola virus protein of 40 kDa, consistent with the envelope glycoprotein. IgG's extracted from the walls of two AAAs were also reactive. The control sera were not reactive. In addition to the Ebola sequences in AAAP-40, an Ebola sequence also occurs in the microfibril-associated glycoprotein-4 (MAGP-4), which is distributed ubiquitously throughout connective tissue with elastin. We hypothesize that the catastrophic hemorrhagic and connective tissue complications of Ebola virus infection may be the result of these shared epitopes.

The expression of human endogenous retrovirus-3 in fetal cardiac tissue and antibodies in congenital heart block.

Endogenous retrovirus-3 (ERV-3) is an endogenous retrovirus encoding an open reading frame for an envelope protein expressed in placenta. In this study we also found high levels of expression in fetal heart, with peak expression occurring between 11 and 17 weeks of gestation. Antibodies to a peptide corresponding to a predicted epitope of ERV-3 were studied by ELISA in sera from 32 healthy women, 47 women during pregnancy, 19 post-partum, 34 with Sjogren's syndrome (SS), 28 with systemic lupus erythematosus (SLE) and 48 mothers of babies with congenital heart block (CHB). Elevated levels of antibodies to ERV-3 were found in normal pregnancy and in patients with SS or SLE. Compared with normal sera the highest levels occurred in mothers of CHB babies (P < 0.001). Antibodies from sera from three CHB mothers bound to recombinant transmembrane protein of ERV-3 on immunoblots, and to sections of fetal cardiac tissue and placenta. This study has shown evidence of autoimmunization to ERV-3 during pregnancy, with particularly high levels of antibodies in mothers of CHB babies. The expression of ERV-3 in fetal heart and the presence of antibodies in maternal sera suggest a possible role in the pathogenesis of CHB.

Polymerase chain reaction fails to incriminate exogenous retroviruses HTLV-I and HIV-1 in rheumatological diseases although a minority of sera cross react with retroviral antigens.

OBJECTIVES: To investigate the presence of antibodies to HTLV and HIV retroviral antigens in the rheumatological diseases rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM), primary Sjögren's syndrome (pSS), and systemic lupus erythematosus (SLE), and to use polymerase chain reaction (PCR) to seek these exogenous retroviruses in proviral form in cellular DNA from these patients. METHODS: Thirty patients with active RA, 13 with PM, 14 with pSS and five with SLE were recruited and their sera tested for antibodies to HTLV-I in enzyme linked immunosorbent assay (ELISA) and Western blot analysis. Seropositivity to HIV-1 was also sought. DNA was extracted from peripheral blood lymphocytes, synovial tissue and muscle biopsies and tested by polymerase chain reaction using consensus primers for HTLV-I and HIV-1. RESULTS: In HTLV-I ELISA, nine rheumatological sera (4/30 RA, 3/13 PM/DM and 2/5 SLE patients) were considered positive; 14 from pSS patients and 30 from normal subjects were negative. In a control group which included osteoarthritis, Crohn's disease and bacterial endocarditis patients, only two of 80 proved positive in this system. Validation of these sera by Western blotting generally revealed weak reactivity against a variety of HTLV-I antigens. PCR of genomic DNA derived from patients' peripheral blood mononuclear cells did not reveal the presence of HTLV-I and HIV-1 target sequences. CONCLUSIONS: This study shows that PCR precludes HTLV-I and HIV-1 infection as causative agents in these rheumatological diseases although a minority of patients possess antibodies that are weakly cross-reactive with retroviral antigens.

Retroviruses and autoimmune rheumatic diseases.

In autoimmune rheumatic diseases, retroviruses have been repeatedly discussed as important etiologic factors. However, despite a considerable amount of indirect evidence that retroviruses might indeed be involved in triggering or perpetuating autoimmune rheumatic diseases, clear cut direct evidence is still missing. Studies on arthropathies associated with HIV-1 or HTLV-1 infection as well as new experimental animal models like the Tax transgene mice and new data from the MLR/lpr mouse model might help to answer the questions how and by what mechanisms retroviral infection may lead to autoimmune rheumatic diseases. From data obtained in the MLR/lpr mouse it seems obvious that a potential link of retroviruses, apoptosis and autogenes to autoimmune diseases opens exciting new approaches to the study of rheumatic disease pathogenesis.