key: cord-0891262-subnmxzk authors: Menon, Aravind A.; Berg, David D.; Gay, Elizabeth B. title: Reply to Blaize et al.: COVID-19–related Respiratory Failure and Lymphopenia Do Not Seem Associated with Pneumocystosis date: 2020-12-15 journal: Am J Respir Crit Care Med DOI: 10.1164/rccm.202008-3174le sha: 3f51122750c91ea098d4e7b7891fa275a4654940 doc_id: 891262 cord_uid: subnmxzk nan Reply to Blaize et al. 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)-b-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)-b-Dglucan is not a reliable biomarker of response to P. jirovecii treatment (3); however, in some patients, such as ours, decreasing (1,3)-b-D-glucan levels have been shown to correlate with improved clinical outcomes in Pneumocystis pneumonia (4). In our patient, the serum (1,3)-b-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)-b-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)-b-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 3 10 3 DNA copies/ml) and a (1,3)-b-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) (10) (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 1 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) -b-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. n To the Editor: Early prediction of failure of noninvasive ventilation (NIV) in patients with de novo acute hypoxemic respiratory failure is crucial to prevent patient self-inflicted lung injury and avoid delayed intubation. NIV should cope with the elevated respiratory drive to deliver effective yet still protective ventilation. However, drive increases for many different reasons: lung collapse and shunt lead to hypoxia, high dead space and elevated metabolic demand raise the concentrations of CO 2 , lung inflammation and altered mechanics activate chemoreceptors and mechanoreceptors, and anxiety and subjective discomfort act on the neural respiratory drive, amplifying the response to chemical and mechanical stimuli (1). The clinical study by Tonelli and colleagues (2) testing the hypothesis that inspiratory effort estimated by esophageal balloon manometry might be an early predictor of NIV failure and worsening lung injury is a valuable addition to the field. Tonelli and colleagues report that lack of reduction in the swing of esophageal pressure (DPes) after 2 hours from start of NIV is an accurate predictor of NIV failure. According to the study protocol, pressure support (PS) was initially set at 10 cm H 2 O and then modified to maintain the expired VT (VTe) of ,9.5 ml/kg predicted body weight (PBW) and the respiratory rate of ,30 breaths/min. Of note, as a consequence of these per-protocol adjustments, PS level at 2 hours was significantly lower in the NIV failure group, whereas VTe did not differ (3) . 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COVID-19 in patients with HIV: clinical case series Concurrent COVID-19 and Pneumocystis jirovecii pneumonia in a severely immunocompromised 25-year-old patient Author disclosures are available with the text of this letter at www.atsjournals.org.