Meylan, Pascal R. A.

Zanetti, Giorgio

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CORRESPONDENCE • JID 2005:191 (15 June) • 21531 5 J U N ECorrespondenceCytomegalovirus Loadin Bronchoalveolar LavageFluid: A Clue to the Diagnosisof CytomegalovirusPneumonia?To the Editor—We read with interest thearticle by Westall et al. [1], recently pub-lished in the Journal of Infectious Diseases,addressing the issue of human cytomeg-alovirus (HCMV) load in lung transplantrecipients (LTRs) with or without HCMVpneumonia. Although these authors adda substantial amount of data to the fewpublished studies that include histopath-ological documentation of HCMV pneu-monia [2, 3], we feel that some clarifica-tions are necessary.As shown by Westall et al., the contri-bution of qualitative polymerase chain re-action, be it on bronchoalveolar lavage(BAL) or plasma samples, to the diagnosisof HCMV pneumonia is limited by theless-than-perfect specificity of positive re-sults for the presence of pneumonia in thispatient population. In addition, the re-ported series included 2 patients withplasma samples that were negative at thetime of pneumonia, suggesting that a neg-ative plasma sample cannot be used toexclude HCMV pneumonia. This is con-sistent with our own unpublished obser-vations. We are interested to know whetherthe quantitation of HCMV load in respi-ratory samples can provide more infor-mation as to the presence of HCMV pneu-monia. However, the way Westall et al.arrived at their HCMV load threshold of46,000 copies/mL is unclear. We concurthat “intuitively, higher virus loads are morelikely to be associated with more-severeHCMV disease in LTRs” (p. 1081) and thata threshold above which the likelihood ofHCMV pneumonia is high might possiblybe defined. This threshold should be setsomewhere between the HCMV loads foundin patients with and without HCMVpneumonia—for example, “a virus load2 SD above the mean virus load of allthose LTRs without histological evidenceof HCMV infection” (p. 1081). However,as stated by the authors in the subsectionentitled “HCMV DNAemia in BAL andplasma samples: histologically provenHCMV infection,” the mean HCMV loadin the BAL samples from those LTRs inwhom HCMV pneumonia was not de-tected histologically (and not, as writtenby the authors, “from those LTRs inwhom HCMV DNA was not detected”[p. 1079], an apparent typographical er-ror) was copies/mL, which5873 1543should point to a threshold of ∼9000copies/mL. This is substantially differentfrom the 46,000 copies/mL computed bythe authors. Setting a threshold of 46,000copies/mL appears, therefore, to be bothinconsistent with the proposed method (i.e.,different from the choice of an HCMV load2 SD above the mean) and illogical (i.e.,higher than the HCMV load of 19,4604917 copies/mL observed in patientswith proven HCMV pneumonia). Per-haps a convenient way to clarify thispoint would be to explicitly demonstrate,in Westall et al.’s figure 3, which thresh-olds correspond to the different points ofthe receiver operating characteristic curve,since the best threshold appears obviouson the basis of the curve shape.Clarifying these points is important,since other authors have presented evi-dence similar to that of Westall et al.—namely, evidence that a substantial overlapdoes exist in the BAL HCMV loads in pa-tients with and without HCMV pneumo-nia [2–4]. Whether this diagnostic prob-lem could be resolved by expressing therelationship between HCMV load andthe probability of HCMV pneumonia asa sigmoid curve for HCMV load varyingfrom 10,000 to 30,000 copies/mL ratherthan as a dichotomous relationship, asshown by Riise et al. [3], or by estimatingHCMV load in the epithelial lining fluid(as computed using urea dilution) witha cutoff of ∼10,000 copies/mL, similarlyto Zedtwitz-Liebenstein et al. [4], is yetunclear to us. We hope this letter willprovide Westall et al. with an opportunityto clarify these points in their interestingarticle.Pascal R. A. Meylan and Giorgio ZanettiInstitute of Microbiology and Service of InfectiousDiseases, Centre Hospitalier Universitaire Vaudois,Lausanne, SwitzerlandReferences1. Westall GP, Michaelides A, Williams TJ, SnellGI, Kotsimbos TC. Human cytomegalovirusload in plasma and bronchoalveolar lavagefluid: a longitudinal study of lung transplantrecipients. J Infect Dis 2004; 190:1076–83.2. Chemaly RF, Yen-Lieberman B, Castilla EA, etal. Correlation between viral loads of cytomeg-alovirus in blood and bronchoalveolar lavagespecimens from lung transplant recipients de-termined by histology and immunohistochem-istry. J Clin Microbiol 2004; 42:2168–72.3. Riise GC, Andersson R, Bergstrom T, Lund-mark A, Nilsson FN, Olofsson S. Quantificationof cytomegalovirus DNA in BAL fluid: a lon-gitudinal study in lung transplant recipients.Chest 2000; 118:1653–60.4. Zedtwitz-Liebenstein K, Jaksch P, Bauer C, et al.Association of cytomegalovirus DNA concentra-tion in epithelial lining fluid and symptomaticcytomegalovirus infection in lung transplant re-cipients. Transplantation 2004; 77:1897–9.Reprints or correspondence: Dr. Pascal Meylan, Institut de Mi-crobiologie, Centre Hospitalier Universitaire Vaudois, LausanneCH-1011 Switzerland (pascal.meylan@hospvd.ch).The Journal of Infectious Diseases 2005;191:2153 2005 by the Infectious Diseases Society of America. Allrights reserved. 0022-1899/2005/19112-0021$15.00Reply to Meylan and ZanettiTo the Editor—We thank Meylan and Za-netti [1] for their positive review of ourarticle [2] and are encouraged to see that

Cytomegalovirus Load in Bronchoalveolar Lavage Fluid: A Clue to the Diagnosis of Cytomegalovirus Pneumonia?

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