Neutralizing Antibody Response against Human Cytomegalovirus in ...

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2Universitätsklinikum Rudolf Virchow, Abteilung Innere Medizin und. Poliklinik, Berlin, and 3Medizinische Klinik und Poliklinik Universität. Tübingen, Abteilung II ...


CORRESPONDENCE Neutralizing Antibody Response against Human Cytomegalovirus in Allogeneic Bone Marrow–Transplant Recipients

Table 1. Outcome of bone marrow–transplant recipients with cytomegalovirus (CMV) active infection, according to serologic response and neutralizing antibody (NA). With CMV disease (n = 18)

To the Editor—We read with great interest the paper by Schoppel et al. [1] in which they reported that high titers of antibodies to individual cytomegalovirus (CMV) glycoproteins (including those inducing neutralizing antibodies [NA]) in response to viral replication are associated with the survival of allogeneic bone marrow–transplant (BMT) recipients with CMV disease [1]. We have analyzed the NA to the AD169 strain of CMV in 193 serum samples from 58 CMV-seropositive patients undergoing allogeneic BMT. In this retrospective study, we included all allogeneic BMT patients with CMV biopsy-proven gastrointestinal (GI) disease (n = 7 ) and CMV interstitial pneumonia (n = 11) diagnosed between January 1991 and June 1996. An additional 22 and 18 asymptomatic BMT recipients with and without CMV active infection (positive antigenemia or viremia), respectively, were randomly chosen from the remaining persons undergoing BMT during the same period. None of the patients received prophylactic intravenous immunoglobulins. Both viremia and antigenemia were determined, as reported elsewhere [2], weekly from day 27 to posttransplant day 100 and thereafter on suspicion of CMV infection. Patients with 2 consecutive positive antigenemia and/or viremia results or with CMV GI disease were treated with ganciclovir or foscarnet. Nine of the 11 patients with interstitial pneumonia received ganciclovir and immunoglobulins [3]. NA activity against CMV was measured in sera collected weekly and stored at 2207C until tested. We used a modified version of a previously described microneutralization assay, using the laboratory strain of CMV AD169 [4]. Patients were classified as serologic responders when at least a 4-fold increase in titer was detected in 2 serum samples collected before and after a positive antigenemia or viremia result, respectively. NA titers at or above the 90th percentile of those found after transplant in asymptomatic patients without CMV active infection (>1 : 640) were considered high. Posttransplant evidence of active infection was detected in 40 of 58 patients; 18 developed CMV disease. Table 1 shows the percentages of responders and those with high NA titer by infection outcome. Serologic response was detected in 26 of the 40 patients: 14 (64%) among the 22 asymptomatic patients with active infection and 12 (66%) among the 18 recipients who developed CMV disease. Seventeen (77%) of the 22 asymptomatic patients had high NA titers during active infection, compared with 14 (78%) of the 18 BMT recipients who had CMV disease (P = .7; unless stated otherwise, all P values shown are by Fisher’s exact test). Finally, among the 18 patients with CMV disease, survival was associated neither with NA response nor with presence of high titers of NA. Seven of 10 patients who died and 5 of 8 patients who survived mounted a 4-fold

Patients (n = 40) a

Serologic responders (n = 26) With high NA titers during a active infection (n = 31)

Asymptomatic (n = 22)


Died (n = 19)

Survived (n = 8)

14 (64)

12 (66)

7 (70)

5 (63)

17 (77)

14 (78)

7 (70)

7 (87)

NOTE. Data are no. (%). a See text for definitions.

increase in NA titers before the onset of the disease (P = .8). Seven of the 10 who died and 7 of 8 who survived had high NA titers at the time of the disease (P = .7); geometric mean titers of NA were slightly higher among survivors (1 : 3620 vs. 1 : 2560), but the difference was not statistically significant (P = .65, Mann Whitney U test). It is of interest that all 4 patients who died of CMV GI disease had low NA titers before clinical manifestation, compared with 1 of 6 who died of interstitial pneumonia (P = .024). There are several methodologic differences between our study and that of Schoppel et al. [1]. We detected NA activity by using a biologic assay and active infection by means of viremia and/or antigenemia tests rather than by antibody response to CMV-specific proteins and by polymerase chain reaction, respectively. However, even when taking into account these differences, we were unable to confirm that high NA titers are correlated with absence of detectable active infection and survival in persons with CMV disease. It is possible that differences in CMV strains are important regarding the outcome [5, 6] and that NA response to the AD169 laboratory strain of CMV does not reflect the neutralizing activity against autologous strains, as conflicting results have been reported elsewhere [7, 8]. Other factors, such as pretransplant serostatus of donor and recipient, conditioning regimen, posttransplant immunosuppression, antiviral treatment, use of immunoglobulins, patient age, and time of primary infection could account for the different results between the two studies. Finally, it should be mentioned that we observed wide variations in NA response according to the clinical manifestations of CMV infection. In conclusion, we believe that several factors may contribute to the outcome of CMV infection in BMT patients, and the role of NA deserves further research. Antonio Volpi,1 Francesca Pica, 1 Giuseppe Gentile, 2 Angela Capobianchi, 2 Marzia Fraschetti, 1 and Pietro Martino 2 Departments of 1Public Health and Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,” and 2Cellular Biotechnology and Hematology, University of Rome “La Sapienza,” Rome, Italy



References 1. Schoppel K, Schmidt C, Einsele H, Hebart H, Mach M. Kinetics of antibody response against human cytomegalovirus-specific proteins in allogeneic bone marrow transplant recipients. J Infect Dis 1998; 178:1233–43. 2. Mastroianni CM, Sebastiani G, Folgori F, Ajassa C, Vullo V, Volpi A. Detection of cytomegalovirus-matrix protein (pp65) in leukocytes of HIVinfected patients with painful peripheral neuropathy. J Med Virol 1994; 44: 172–5. 3. Gentile G, Donati PP, Capobianchi A, Rolli M, Iori AP, Martino P. Evaluation of a score system for the severity and outcome of cytomegalovirus interstitial pneumonia in allogeneic bone marrow recipients. J Infect 1997; 35: 117–23. 4. Andreoni M, Faircloth M, Vugler L, Britt WJ. A rapid microneutralization assay for the measurement of neutralizing antibody reactive with human cytomegalovirus. J Virol Methods 1989; 23:157–67. 5. Rasmussen L, Hong C, Zipeto D, et al. Cytomegalovirus gB genotype distribution differs in human immunodeficiency virus–infected patients and immunocompromised allograft recipients. J Infect Dis 1997; 175:179–84. 6. Torok-Storb B, Boeckh M, Hoy C, Leisenring W, Mayerson D, Gooley T. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood 1997; 90:2097–102. 7. Chou S. Neutralizing antibody responses to reinfecting strains of cytomegalovirus in transplant recipients. J Infect Dis 1989; 160:16–21. 8. Klein M, Schoppel K, Amvrossiadis N, Mach M. Strain-specific neutralization of human cytomegalovirus isolates by human sera. J Virol 1999; 73:878–86. Reprints or correspondence: Dr. Antonio Volpi, Dept. of Public Health, University of Rome “Tor Vergata,” Via di Tor Vergata 135, 00133 Rome, Italy (volpi The Journal of Infectious Diseases 1999; 180:1747–8 q 1999 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/1999/18005-0050$02.00

Reply To the Editor—We appreciate the comments of Volpi et al. [1] about our study [2]. Our results clearly showed an enormous variation in antibody levels against human cytomegalovirus (HCMV) in individual patients after bone marrow transplantation. Eight- to 10-fold changes in titer within a 2-week period were not uncommon, regardless of whether viral replication or HCMV disease was detected. Thus, we feel it is essential to evaluate the kinetics of antibody response in the individual patient. Statistical analyses of a few time points after transplantation or grouping of patients, especially when there are few samples or patients, are not meaningful, since the antibody response after transplantation is so different between patients. Volpi et al. consider a neutralizing antibody response greater than the 90th percentile of asymptomatic patients to be high and postulate a lack of correlation between high neutralizing antibody titers and clinical outcome of the infection. It would be important to know (1) what posttransplantation time point(s) was used to calculate those titers, (2) the range of neutralizing antibody titers in these patients, and (3) the variation of the assay. Volpi et al. [1] also considered patients showing a 4-fold increase in neutralizing antibody titer to be serologic responders and concluded that serologic response is

JID 1999;180 (November)

not important for the clinical outcome of the infection. As mentioned above, we have seen much higher titer fluctuations in individual asymptomatic patients in the absence of any sign of viral replication (determined by polymerase chain reaction and/or antigenemia). Again, it would be important to see the changes in neutralizing titers over time in the individual person. We agree with our colleagues that HCMV strain variations might have a significant effect on the evaluation of neutralizing antibody titers in human sera [3] and that more studies are needed to establish the role of anti-HCMV antibodies for the clinical course of the disease in transplant recipients. Konrad Schoppel,1 Christian Schmidt, 2 Hermann Einsele, 3 Holger Hebart, 3 and Michael Mach 1 1

Institut fu¨r Klinische und Molekulare Virologie, FriedrichAlexander–Universita¨t Erlangen-Nu¨rnberg, Erlangen, 2 Universita¨tsklinikum Rudolf Virchow, Abteilung Innere Medizin und Poliklinik, Berlin, and 3Medizinische Klinik und Poliklinik Universita¨t Tu¨bingen, Abteilung II, Tu¨bingen, Germany

References 1. Volpi A, Pica F, Gentile G, Capobianchi A, Fraschetti M, Matimo P. Neutralizing antibody response against human cytomegalovirus in allogeneic bone marrow transplant recipients [letter]. J Infect Dis 1999; 180:1747–8. 2. Schoppel K, Schmidt C, Einsele H, Hebart H, Mach M. Kinetics of the antibody response against human cytomegalovirus-specific proteins in allogeneic bone marrow transplant recipients. J Infect Dis 1998; 178:1233–43. 3. Klein M, Schoppel K, Amvrossiadis N, Mach M. Strain-specific neutralization of human cytomegalovirus isolates by human sera. J Virol 1999; 73:878–86. Reprints or correspondence: Dr. Michael Mach, Institut fu¨r Klinische und Molekulare Virologie, Schloßgarten 4, 91054 Erlangen, Germany ([email protected] The Journal of Infectious Diseases 1999; 180:1748 q 1999 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/1999/18005-0051$02.00

TT Virus—Part of the Normal Human Flora? To the Editor—Since the original description of TT virus (TTV) [1], intensive efforts have been made to determine the clinical significance of TTV infection, such as a possible etiologic role in posttransfusion, fulminant, and idiopathic chronic hepatitis. These studies have been hampered by difficulties in diagnosing current or past infection with TTV; for example, titers of viremia are low, and it is unclear whether currently used polymerase chain reaction (PCR)–based methods for screening are adequate to detect all genetic variants of TTV. Problems with current PCR-based methods for TTV detection were illustrated in the recent publication by Desai et al. [2], who reported a high frequency of discrepant results between different sets of N22-specific primers. The authors suggested that multiple primer pairs must be used to maximize the sensitivity of the PCR. Takahashi et al. [3] developed a PCR for TTV using

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