Virus-specific IgG and IgM antibodies in normal and immunocompromised subjects infected with cytomegalovirus

Levels of IgG and IgM antibodies t human cytomegalovirus (CMV) were measured using a solid-phase radioimmunoassay. Individuals positive by complement-fixation test consistently had detectable IgG titers by radioimmunoassay, but no quantitative relationship was apparent. An elevated IgM titer was considered specific for CMV infection because sera from individuals with other herpesvirus infections did not cross-react. In patients with mononucleosis, elevated titers of IgM antibody to CMV correlated (P less than 0.001) with active infection and were highest during viremia. Titers of IgG antibody to CMV during and after symptomatic infection were similar to those of asymptomatic positive individuals. Increases in CMV-specific IGM were observed in both primary and reactivated infections in cardiac transplant recipients. In a small group of cardiac transplant recipients with recurrent symptomatic disease, IgM titers were low at the time of viruria and did not increase with CMV tissue involvement, a result which suggests that quantitative deficiencies in IgM may be related to the severity of CMV infections.     

Studies of cytomegalovirus infection in renal allograft recipients. II. Serological response to various viral antigens

In a prospective study the antibody response to various cytomegalovirus (CMV) antigens was examined in 28 renal allograft recipients. Both primary and secondary infections were investigated. Antibodies against immediate early (IEA) and early antigens (EA) were studied by anti-complement immunofluorescence; IgM and IgG antibodies to nuclear late antigens were differentiated by enzyme-linked immunosorbent assay (ELISA). The results of the tests were compared with each other and with those of the complement fixation (CF) test. 5/7 susceptible patients (71%) contracted primary infections. Both IgM and IgG antibodies developed and antibodies to IEA and EA appeared somewhat later. The antibodies to IEA and EA remained detectable throughout the observation period. Secondary infections developed in 20/21 (95%) patients. All initially had CMV antibody levels in ELISA and CF. Rising CMV titers of IgG antibodies were taken as a measure of secondary infection. IgM antibodies developed in only 10/20 (50%) patients. The highest titers of CMV IgM antibody levels were lower in secondary than in primary infections. Antibodies to IEA and EA were present prior to transplantation in some patients, but did not develop in all with secondary infections. The antibody titers were lower just after than before the transplantation in some patients. but subsequently increased again. It thus seems as if the humoral immune response to these CMV antigens differs in primary and secondary infections.     

Relation of titers of antibodies to CMV in blood donors to the transmission of cytomegalovirus infection

Titers of antibody to cytomegalovirus (CMV) of 529 persons whose blood had been supplied to 51 selected patients who underwent open-heart surgery were determined by indirect hemagglutination (IHA) and IgM-specific indirect immunofluorescence (IFA). Twenty-eight patients showed evidence of active CMV infection after transfusion (seroconversion or a fourfold rise in titer by IHA), whereas 23 showed no serological change. Patients with active CMV infections had received, on average, a greater number of blood units (12.9 vs. 7.9), of which more were seropositive (6.9 vs. 3.5), than did patients who showed no serological change. Those seropositive units of blood that had been transfused into the group that showed evidence of active infection, however, had a lower geometric mean titer than did those transfused into the group that showed no serological change (1:654 vs. 1:1,360). Seven (1.3%) of the 529 blood donors had CMV-specific IgM titers (by IFA) of greater than or equal to 1:16; each of the seven recipients of their blood subsequently showed evidence of active CMV infection. This study suggests that donor blood with high IHA titers may prevent transmission of CMV infection, whereas blood from donors with IgM antibody to CMV may transmit CMV.     

Infection with cytomegalovirus during pregnancy: specific IgM antibodies as a marker of recent primary infection

Specific IgM antibodies that persisted for up to four months were detected by radioimmunoassay (RIA) in the sera of 16 (55%) of 29 women with primary infections due to cytomegalovirus (CMV). The RIA for IgM detected primary infections in six (86%) of seven sera obtained within four months of seroconversion. In contrast, IgM antibodies were never detected by RIA in 104 serum samples from 18 women with recurrent infections due to CMV, irrespective of whether intrauterine transmission of virus had occurred. Specific IgM antibodies were also detected in the earliest samples during pregnancy of serum from three (14%) of 21 women whose type of infection with CMV was unknown but who had been delivered of congenitally infected infants. All of these results show that primary infection with CMV in the first trimester of pregnancy can be diagnosed by testing a single serum sample by RIA for IgM antibodies. Attempts to measure IgM antibodies by immunofluorescence gave a high frequency (19 [18%] of 104) of false-positive reactions.     

Virus-specific antibodies to Epstein-Barr virus, varicellazoster virus and rubella virus in renal transplant patients with cytomegalovirus infections

Renal transplant patients with primary and recurrent cytomegalovirus (CMV) infection had higher antibody titres to Epstein-Barr virus viral capsid antigen (EBV-VCA-IgG) before and after transplantation than healthy blood donors. The geometric mean titres (GMT) of EBV-VCA-IgG were higher in renal transplant patients without CMV infection than in renal transplant patients with CMV infection. Four-fold or greater rises in EBV-VCA-IgG antibody were detected in six patients and a similar rise in antibody to EBV early antigen (EBV-EA-IgG) was detected in one other patient. IgM antibody to EBV-VCA (EBV-VCA-IgM) was detected in only three of these patients. EBV-EA-IgG was present in 39% patients and in 30% control subjects. IgG titres to varicella zoster virus (VZV-IgG) and rubella virus (rubella HI) were higher in patients without CMV infection compared to the patients with CMV infection. Raised titres were detected to VZV in five patients and to rubella virus in three patients. Reductions in antibody titre of four-fold or more were also detected in EBV-EA-IgG (one patient) and to rubella virus (one patient). Raised antibody titres to EBV, VZV, and rubella virus in renal transplant patients may indicate reactivation of these viruses without any symptoms.     

Immunoglobulins A, G, and M to cytomegalovirus during recurrent infection in recipients of allogeneic bone marrow transplantation.

Occurrence and significance of specific IgA and IgM to cytomegalovirus (CMV) in recurrent CMV infection was evaluated in 21 allogeneic T lymphocyte-depleted bone marrow transplantation (BMT) recipients who had been previously CMV seropositive. Of 17 patients with CMV infection, viruria was detected in 94%, CMV-specific IgA in 88% and IgM in 76%, and a fourfold rise in IgG in 65%. The median time between BMT and detection of viruria was 69 days, of IgA 70, of IgM 62, and of IgG 88 days. The IgM and IgA responses lasted for 14 and 30 days (median time), whereas high IgG titers persisted. Twelve patients developed CMV disease; in these the appearance of viruria, IgA, and IgM preceded the rise of IgG (P less than .02). CMV-specific IgA and IgM are valuable diagnostic tools in BMT recipients with recurrent CMV infection.     

Enhanced antibody responses to Epstein-Barr virus in HIV-infected homosexual men

We investigated the association between human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) infections in 593 homosexual men. The status of EBV infection in this group was evaluated based on serological evidence of EBV-specific antibody responses. The geometric mean titers (GMT) of antibody to EBV capsid antigen (EBV-VCA) (1:154) and EBV early antigen (EA) (1:16) in 141 HIV-seropositive men were significantly higher than respective titers in 452 HIV seronegative men (1:95 and 1:12). Antibody titers to EBV were higher in HIV-infected men with lymphadenopathy than in asymptomatic HIV-seropositive men. However, these correlation were less evident in patients with AIDS-related complex. Elevated antibody titers to EBV were found to be independent of levels of total serum IgG. Cytomegalovirus (CMV) antibody titers were also found to be significantly increased among HIV-seropositive men, independent of total IgG. Antibody titers to EBV were not correlated with those to CMV in either HIV-seronegative or HIV-seropositive men. Subjects without evidence of HIV infection, but who had high antibody titers to EBV-VCA and EBV-EA, had elevated mean numbers of CD3+, CD4+, and CD8+ cells, and lower levels of CD4+/CD8+ cell ratios compared to subjects with low EBV-antibody titers. This study suggests that the elevated levels of circulating antibodies against EBV in homosexual men are associated with loss of control of latent EBV due to HIV infection.     

Dual antibody rises to cytomegalovirus and human herpesvirus type 6: frequency of occurrence in CMV infections and evidence for genuine reactivity to both viruses

The frequency of high (greater than 256) IgG anti-human herpesvirus type 6 (HHV-6) titers in sera known to be positive for IgM anti-cytomegalovirus (CMV) or IgM anti-Epstein Barr virus (EBV) was significantly greater than in sera from healthy controls or from a group of ill patients who were CMV and EBV IgM-negative (15/25 and 17/25 vs. 1/25 and 2/25, respectively, P less than .001). There was serologic evidence of simultaneous HHV-6 infection or reactivation (a rise in IgG anti-HHV-6 titer or the presence of IgM anti-HHV-6) in sera from 14 of 17 primary CMV infections. In 5 of the 10 patients with concurrent rises in IgG titers to both viruses, the rise in IgG anti-HHV-6 preceded that of IgG anti-CMV. Complete removal of IgG anti-CMV reactivity from 5 sera from patients who had a primary CMV infection with a rise in IgG anti-HHV-6 titer had no effect on the IgG anti-HHV-6 titer of those sera, demonstrating that the rise in HHV-6 IgG titer was not a consequence of anti-CMV antibodies cross-reacting in the HHV-6 IgG assay.     

Primary Cytomegalovirus Infection in an Outpatient Setting—Laboratory Markers and Clinical Aspects

Abstract. Background: Occasionally, primary cytomegalovirus (CMV) infection may give rise to more or less severe clinical illness in immunocompetent adults. We retrospectively analyzed cases of acute CMV infection in medical outpatients. Patients and Methods: Over a 6-year period, we identified 22 patients with a febrile illness and hepatitis suffering from primary CMV infection. This was diagnosed on the basis of a strongly positive CMV IgM antibody test result and/or CMV IgG seroconversion. Clinical features as well as relevant laboratory results were analyzed. We also tested available samples for CMV glycoprotein B-specific antibodies and CMV IgG avidity and analyzed results of Epstein-Barr virus (EBV)-specific antibody assays. In addition, current age-specific CMV IgG seroprevalence rates were determined using 9,870 routine patient samples. Results: At presentation, all patients complained of malaise and fever higher than 38 °C, and many also complained of cephalgia. Most patients who underwent abdominal ultrasonography had an enlargement of the spleen. Most patients had a relative lymphocytosis but only three had a mild leukocytosis. C-reactive protein was only slightly elevated in 13 patients; all 22 patients had elevated levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH). Half the patients reported travel to areas outside western Europe, mostly to tropical and subtropical areas, within 3 weeks before onset of illness. Primary CMV infection was confirmed by negative anti-gB antibody test results and the absence of high-avidity CMV antibodies. In contrast, despite past EBV infection demonstrated by positive anti-EBNA-1 results, 15 out of 21 patients tested for EBV markers had positive or nonspecific IgM test results. The overall CMV IgG seroprevalence rate in the routine samples was 64.4%, with marked age-dependent increases. Conclusion: CMV is a relevant differential diagnosis in feverish illnesses accompanied by hepatitis in otherwise healthy adults, about 40% of whom are CMV-naïve. Half our patients seem to have acquired their CMV infection abroad, so that a diagnosis of CMV infection needs to be taken into account in travelers, in addition to infectious illnesses more commonly considered in this context, such as dengue or hepatitis A. For diagnosis, both CMV and EBV antibody studies should be performed and the inclusion of assays able to demonstrate past infection is helpful for achieving a definite diagnosis.     

Late onset of fatal cytomegalovirus infection after renal transplantation. Primary or reactivation infection?

Cytomegaloviurs (CMV) infections are a recognized problem in the first six months after renal transplantation. Studies have suggested that primary infections produce symptomatic disease, whereas reactivation infections are usually asymptomatic. Two patients are described who developed fatal CMV infections in the second year after transplantation. Both patients had typical CMV disease with fever, pneumonitis, and hepatitis. Results of serologic studies in one patient were characteristic of primary infection, with seroconversion at the time of disease and appearance of specific IgM antibodies. The other patient had a similar antibody response at the time of his illness, but serial antibody tests showed that he had had a transient seroconversion earlier, in the second month after transplanation, that was not associated with clinical symptoms. These patients indicate that CMV infection must be considered in the differential diagnosis of serious febrile illnesses even in the late posttransplantation period and may occur either as the result of primary or reactivation infection. Serologic studies at the time of illness may not allow distinction between the types of infection.     

Persistence of serum antibodies to Borrelia burgdorferi in patients treated for Lyme disease.

To determine if antibodies to Borrelia burgdorferi persist after antibiotic treatment, we recalled 32 patients with Lyme disease from a primary care practice a mean of 16 months after treatment and analyzed initial and follow-up serum samples by ELISA and immunoblot assays. Of the eight patients whose initial serum specimens were positive for IgM antibody by ELISA, three had positive titers of IgM antibody at follow-up; of the 23 patients whose initial serum specimens were positive for IgG antibody by ELISA, 19 had positive titers of IgG at follow-up. Of the five patients whose initial serum specimens were positive for IgM antibody by immunoblot, two had positive titers of IgM antibody at follow-up; of the 30 patients whose initial serum specimens were positive for IgG antibody by immunoblot, 29 had positive titers of IgG antibody at follow-up. The bands on the IgG immunoblot remained remarkably constant during the period from analysis of the initial specimen to that of the follow-up specimen. Nine of the 32 patients had persistent or recurrent symptoms, and ELISA and immunoblot were not helpful for identifying these nine patients.     

Subclass distribution of the serum and intrathecal IgG antibody response in varicella-zoster virus infections

The subclass distribution of the varicella-zoster virus (VZV)-specific IgG antibody response was studied in serum samples from 22 patients with primary varicella and 34 with recurrent VZV infections and in cerebrospinal fluid (CSF) samples from 22 patients with recurrent infection who presented with symptoms of aseptic meningitis. IgG1 and 3 were the dominant subclasses among patients with primary and recurrent infections; IgG1 was also prevalent in the CSF samples. The VZV IgG subclass distribution patterns did not allow differentiation between primary and recurrent infections. However, seroconversions for IgG2, 3, or 4 were observed among patients with recurrences who were negative for specific IgM, suggesting that qualitative tests for serum IgG subclass antibody could be helpful for diagnosis in such cases. Herpes simplex virus-specific IgG was found in CSF samples from several patients with meningitis. The results suggest that calculation of the antibody to albumin index is better than IgG subclass antibody assays for discriminating the causative agent in these cases.     

Heterophil-negative infectious mononucleosis and mononucleosis-like illnesses. Laboratory confirmation of 43 cases.

During a 50-month period the diagnosis of heterophil antibody negative infectious mononucleosis or of a mononucleosis-like illness was made in 43 patients with a variable clinical picture and significant numbers of atypical lymphocytes. Epstein-Barr virus (EBV)-related serologic tests revealed that seven patients had primary EBV infections based on the detection of immunoglobulin M (IgM) antibodies to EB-viral capsid antigens (IgM-VCA) and the absence of anti-Epstein-Barr virus associated nuclear antigen (EBNA) on most initial specimens (six of seven cases). Thirty cases were due to active cytomegalovirus (CMV) infections and both detectable CMV-macroglobulins (≧1:32) and significant anti-CMV titers were present by a complement fixation technic. Abnormalities in liver function were less marked in CMV than in EBV infections in age-matched subjects. Of the remaining six cases, one was due to rubella and one to toxoplasmosis. Four cases were of undetermined etiology. Serums from 38.1 per cent of the patients with heterophil-antibody positive infectious mononucleosis were found to “cross react” in the IgM-CMV test, but serums from patients with acute CMV infection did not cross react in the VCA-specific IgM test. In nine of 36 cases without heterophil antibody (six due to CMV, one due to toxoplasmosis and one apparent infectious hepatitis), anti-D or -R of the early-antigen (EA) complex was detected (1:10 to 1:40), raising the question of reactivation of the EBV-carrier state by intervening infections mainly of viral origin.     

Cytomegalovirus colitis mimics amebic colitis in a man with AIDS

Opportunistic gastrointestinal infections are common in patients with HIV infection; both amebic colitis and cytomegalovirus (CMV) colitis are common causes of chronic diarrhea. It is difficult to distinguish these 2 diseases by nonspecific clinical symptoms such as diarrhea, abdominal pain, and weight loss. Here we report a case of CMV colitis mimicking amebic colitis with elevated indirect hemagglutination assay antibody titer against Entamoeba histolytica and negative IgM antibody titer against CMV. The diagnosis of CMV colitis was confirmed by eosinophilic nucleoli and inclusion bodies in colon biopsies. The patient recovered after ganciclovir and highly active antiretroviral therapy. Exact diagnoses are important for treating opportunistic infections. Other pathogens should be considered in patients with chronic diarrhea who are refractory to initial treatments. Our case highlights the importance of histopathological diagnosis for chronic diarrhea in patients with HIV infection and the possibility of false-positive results for indirect hemagglutination assay antibody against Entamoeba histolytica despite high titers.     

Complications of infections attributed to cytomegalovirus in a group of 52 kidney transplant patients

Cytomegalovirus (CMV) infection after renal transplantation was studied over a one year period in 52 patients receiving immunosuppressive drugs. During the infectious episodes, viral shedding was systematically detected in the blood and urines by culture on MRC5 cells and CMV antibodies were titrated in the serum by ELISA (IgG: M. A. Bioproducts, IgM: immunocapture Wellcome) and compared to the initial antibody titer determined the day of transplantation. Primary CMV infection was observed in 6 of 22 seronegative patients, attested by CMV shedding from urine and/or blood and by the emergence of CMV IgM antibodies. This primary infection was severe, including at least 4 of the following features: fever greater than 38 degrees C, neutropenia, thrombocytopenia, cytolytic hepatitis, pneumonia, impaired renal function, neurological syndrome, usually occurring about 6 weeks after transplantation. Reactivation was found in 12 of 30 seropositive patients, as shown by excretion of CMV in the urine and significant rise of specific antibodies. This reactivation occurring about 9 weeks after surgery was symptomatic in 5 patients with severe illness and associated with the presence of IgM antibodies in 2 cases. Rise of CMV antibodies was observed in 10 seropositive patients without excretion of virus. It coincided with symptomatic infection in only three patients who displayed severe symptoms, with presence of CMV IgM antibodies in one case. As previously reported, we confirm that CMV infection is a frequent complication of organ transplantation. It may be clinically silent in renal transplant patients or cause problems ranging from fever to pneumonia or retinitis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Specific impairment of cell-mediated immunity in mothers of infants with congenital infection due to cytomegalovirus.

Specific lymphocyte-mediated cytotoxicity to cytomegalovirus (CMV) in eight infants (six to 27 months old) with congenital CMV infection and in the mothers of six of these infants was evaluated with use of a 51chromium (51Cr)-release microassay. The control population consisted of 25 normal newborns, children, and adults. The titers of indirect hemagglutinating (IHA) antibody to CMV in the infected infants ranged from 1:16 to 1:1,024. All of these infants had detectable specific immune release of 51Cr that ranged from 3.3% to 48.9% (mean +/-SE, 21.0%+/-5.6%). The mothers of these infants demonstrated significantly elevated titers of IHA antibody to CMV (geometric mean titer, 1:410) as compared with a mean titer of 1:22 in controls (t = 5.71; P less than 0.001) but showed significantly depressed specific immune release (9.2% +/- 3.2%) compared with that of normal seropositive controls (24.8% +/- 2.8%; t = 3.31; P less than 0.001). In addition, two adult nulliparous women with persistent CMV viruria were also found to have depressed specific immune release to CMV (10.8% and 16.2%). These data suggest that a specific impairment in cell-mediated immunity to CMV occurs in mothers of infants with congenital CMV infection and in some persons who persistently excrete CMV.     

Selective immunoglobulin M deficiency in an adult with Streptococcus pneumoniae sepsis and invasive aspergillosis.

Primary selective immunoglobulin (Ig) M deficiency usually presents early in life with recurrent or severe infections caused by encapsulated and gram-negative organisms. Primary selective IgM deficiency in adults is rare and is usually associated with autoimmune diseases or malignant neoplasm. We performed an extensive immunological analysis of innate and adaptive immunity in an adult patient with possible primary selective IgM deficiency who presented with life-threatening Streptococcus pneumoniae septic shock and invasive Aspergillus fumigatus infection. The patient had no evidence of autoimmune disease or malignant neoplasm. Serum IgG, IgA, and IgE were normal; however, serum IgM levels and specific antibody titers against all 14 pneumococcal polysaccharide serotypes were consistently low. Complement CH50, C3, C4, and neutrophil phagocytosis and oxidative burst were normal. Toll-like receptor expression on monocytes was also normal. Therefore, adult patients with serious life-threatening and unusual infections should be investigated for possible selective primary IgM deficiency.     

BK virus infection in patients with AIDS

Antibodies to the human papovavirus BK (BKV) were determined in a group of 25 homo- and bisexual males with AIDS, 24 men with AIDS-related complex (ARC) and 18 healthy male homosexual controls from Copenhagen. The AIDS patients had a significantly lower prevalence and level of anti-BKV antibodies tested by IgG-ELISA, hemagglutination inhibition and neutralization tests than the ARC patients. About half of the anti-BKV antibody positive AIDS patients demonstrated primary infections or reactivations but without specific IgM production. The titers were low compared to primary infections in children. At least 2 of the patients lost their serological markers in the late phase of the disease. It is therefore possible that the low prevalence of BKV infection in AIDS patients is caused by loss of serological markers even if the level of total IgG is normal or increased.     

Longitudinal study of serological response to Bartonella henselae by indirect fluorescence assay in cat scratch disease

Sequential serologic testing for IgG and IgM titers to Bartonella henselae were evaluated by an indirect fluorescence assay (IFA) in patients with CSD. The IFA test for the detection of IgG and IgM antibodies to B. henselae in 52 CSD patients showed that 40 (76.9%) were positive for IgG antibody and 9 (17.3%) were positive for IgM antibody. Two or more consecutive serum samples from 30 patients with CSD were assessed. In regard to the detection of IgG antibody, 5 patients had rapidly elevated titers in the acute phase, 12 patients had high titers from the acute phase, and 5 patients had a positive titer 24 weeks after the onset. B. henselae IgM antibody kinetics varied widely between patients with CSD. The seropositive rate for the antibody to B. henselae was analyzed at overtime after the onset and we found that the IgG-seropositive rate was high from 2 weeks after the onset and low after 25 weeks. The sensitivity of the IgM IFA was low, and IgM antibody to B. henslelae was not detected from 9 weeks. The detection from consecutive serum samples of antibodies to B. henselae by IFA is very useful for diagnosis in the case of clinically suspected CSD.     

High levels of complement fixing antibodies against cytomegalovirus in patients with primary Sj?gren's syndrome

Antibodies to cytomegalovirus (CMV) were examined in sera from 21 consecutive patients with primary Sj?gren's syndrome (SS) and 19 consecutive patients with secondary SS, using a complement fixation (CF) test and an antibody capture enzyme-linked immunosorbent assay (ELISA). Sera from 15 CMV-negative subjects, 15 CMV-positive subjects, 3 patients with primary CMV infection and 3 patients with recurrent CMV infection served as controls. The prevalence of CMV antibodies in the patients with primary and secondary SS was found similar to the prevalence known to occur in the normal adult population. Unrelated to clinical parameters, 5 patients with primary SS (24%) had high levels of CF antibodies against CMV. Ig class antibodies to CMV were not elevated in these 5 patients. Preferential production of CF antibodies to CMV may be a pathogenetic factor in some patients with primary SS.