Reply to Blaize et al.: COVID-19–related Respiratory Failure and Lymphopenia Do Not Seem Associated with Pneumocystosis

From the Authors:

We thank Dr. Blaize and colleagues for their interest and letter in response to our recent publication detailing a case of suspected coronavirus disease (COVID-19) and Pneumocystis jirovecii coinfection (1). The authors correctly note that the decline in serum (1,3)-β-d-glucan level observed in our patient was more rapid than is typically expected following initiation of appropriate therapy (2). Several studies have demonstrated that (1,3)-β-d-glucan is not a reliable biomarker of response to P. jirovecii treatment (3); however, in some patients, such as ours, decreasing (1,3)-β-d-glucan levels have been shown to correlate with improved clinical outcomes in Pneumocystis pneumonia (4). In our patient, the serum (1,3)-β-d-glucan level was elevated at 305 pg/ml on admission, remained persistently elevated at 268 pg/ml on hospital Day 3, at which point trimethoprim-sulfamethoxazole treatment was initiated, and then declined to 90 pg/ml 1 week after initiating treatment.

The diagnosis of P. jirovecii infection can be challenging, particularly in patients without HIV, in whom the fungal burden is generally lower (5). Furthermore, owing to the high sensitivity of P. jirovecii PCR (6), it may be difficult to differentiate between Pneumocystis colonization versus infection, particularly in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which may have similar clinical manifestations as Pneumocystis pneumonia. Nevertheless, the constellation of an elevated (1,3)-β-d-glucan level on two occasions, positive tracheal aspirate qualitative PCR assay, presence of typical cystic changes of P. jirovecii on chest computed tomography, and rapid clinical improvement following initiation of trimethoprim-sulfamethoxazole therapy support our conclusion that our patient indeed had a true P. jirovecii infection. It is worth noting that several studies have suggested that quantitative P. jirovecii PCR and (1,3)-β-d-glucan may be used to distinguish between Pneumocystis pneumonia and colonization (7, 8). Specifically, a positive quantitative PCR from a BAL fluid sample (>1.6 × 10³ DNA copies/μl) and a (1,3)-β-d-glucan level cutoff of 100 pg/ml has been suggested to discriminate between P. jirovecii colonization versus infection (8). Gold-standard staining methods to detect P. jirovecii in respiratory specimens are also useful to confirm P. jirovecii infection, although the sensitivity is low compared with PCR, particularly in HIV-negative immunocompromised patients (9–11). Unfortunately, we do not have quantitative PCR or cytologic/immunofluorescent staining data from our patient, which would have further strengthened our argument for true P. jirovecii infection.

Dr. Blaize and colleagues performed quantitative P. jirovecii PCR testing on 423 respiratory samples obtained from 145 patients at their center with confirmed SARS-CoV-2 infection who required either mechanical ventilation or venovenous extracorporeal membrane oxygenation support. Despite the high prevalence of lymphocytopenia in this population of critically ill patients with COVID-19, there were no true cases of P. jirovecii coinfection. In our patient with SARS-CoV-2 and P. jirovecii coinfection, other than COVID-19–associated CD4⁺ lymphocytopenia, she did not have a known underlying immunodeficiency. She was on oral budesonide for treatment of her ulcerative colitis, which was well controlled, and an albuterol inhaler as needed for mild intermittent asthma (1), but not inhaled corticosteroids as suggested by the authors. Oral budesonide formulations provide topical antiinflammatory activity in the colon but have very little systemic bioavailability owing to their high first-pass hepatic metabolism. As such, oral budesonide formulations have not been associated with increased risk of P. jirovecii infection in patients with ulcerative colitis (12). Although our patient did not have any other classical risk factors for P. jirovecii infection, it is certainly possible that her coinfection was a coincidence (a proof of principle of “Hickam’s dictum” [13]) or that an unbeknownst underlying immune defect predisposed the patient independently to SARS-CoV-2 and P. jirovecii infection.

Given the inherent risk of overextending conclusions from a single case, we were conservative in the interpretation of our case and suggested that it may be reasonable to consider additional diagnostic testing for P. jirovecii by assaying serum (1,3)-β-d-glucan in patients with COVID-19 if there are additional clinical findings, such as cystic findings on chest computed tomography or elevated lactate dehydrogenase that may support coinfection (1). This approach should be considered particularly in patients with classical P. jirovecii risk factors such as HIV, as coinfection with SARS-CoV-2 and P. jirovecii has been reported in both well-controlled (14) and severely immunocompromised patients with HIV (15, 16). We commend the authors for their work and for expanding the COVID-19 evidence base by systematically testing the hypothesis generated by our initial clinical observation. At a minimum, their data provide reassurance that the risk of P. jirovecii coinfection in patients with COVID-19–related lymphocytopenia is likely not high. Further understanding of the clinical features of this novel disease requires a continued collaborative and systematic approach.