key: cord-0927177-xem7b2gl authors: Rubiano, Carlos; Tompkins, Kathleen; Sellers, Subhashini A; Bramson, Brian; Eron, Joseph; Parr, Jonathan B; Schranz, Asher J title: Pneumocystis and SARS-CoV-2 Co-Infection: A Case Report and Review of an Emerging Diagnostic Dilemma date: 2020-12-18 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofaa633 sha: dedca9e7acd14bec67055cd22a32d71cf1059feb doc_id: 927177 cord_uid: xem7b2gl We present a case of a critically ill patient with COVID-19 found to have AIDS and Pneumocystis jirovecii pneumonia (PCP). COVID-19 and PCP co-occurrence is increasingly reported and may complicate diagnostic and therapeutic strategies. Patients with severe COVID-19 should be screened for underlying immunocompromise and coinfections should be considered. With mounting global cases of Coronavirus Disease 2019 (COVID- 19) , there has been increasing recognition of fungal coinfection complicating COVID-19 care. While Aspergillus spp appears to be the predominant fungal pathogen in persons with COVID-19 pneumonia[1], there are emerging reports of Pneumocysits jirovecii pneumonia (PCP) co-occurring with or following COVID-19. Here we present a case of a patient hospitalized with hypoxemic respiratory failure attributed to COVID-19, found to have a new diagnosis of AIDS and PCP. We review all published literature to date of co-occurring COVID-19 and PCP. A 36-year-old man with no known past medical history presented to an emergency room complaining of shortness of breath, fever, nausea and diarrhea for three weeks. Additional review of systems was positive for chills, sinus congestion, sore throat and cough. He denied anosmia and chest pain. He was Hispanic and lived with two relatives who were asymptomatic. He worked in construction and reported close contacts with coworkers with similar symptoms. On admission, his temperature was 38.7 degrees Celsius, heart rate 121 beats per minute, blood pressure 94/59 mmHg, respiratory rate 40 breaths per minute, and oxygen saturation 89% on 15L high flow nasal cannula, improved in prone positioning. He was ill-appearing, in respiratory distress and without abnormal lung sounds. The white blood cell count was 8600 per microliter (reference range 4,800 to 10,800); absolute lymphocyte count was 400 per microliter (reference 1200 to 3400); absolute neutrophil count was 7800 per microliter (reference 1400 to 6500); CRP 197.72 mg/L (reference <10); Ferritin 1276.1 ng/mL (reference 10-300); LDH 789 IU/L (reference 100-220); procalcitonin 1.87 ng/mL (reference<0.50). A swab for influenza A and B viruses was negative. An oropharyngeal swab for SARS-CoV-2 PCR was positive. Chest radiograph showed diffuse hazy pulmonary opacifications. A contrasted computed tomography angiography of the chest showed diffuse upper and lower lobe ground glass alveolar airspace disease without pulmonary embolism. A c c e p t e d M a n u s c r i p t The patient was admitted to intensive care and started on remdesivir, as well as cefepime and vancomycin for possible bacterial pneumonia. Over the next 48 hours he experienced persistent hypoxemia requiring intubation and transfer to our facility. As part of our institutional protocols for patients admitted with COVID-19 at the time of this encounter, r outine screening with a fourth-generation HIV-1/2 antigen/antibody test was performed and reactive. Reflex HIV RNA testing revealed a viral load of 578,876 copies per mL. His absolute CD4 cell count was <10 cells/microliter and 2% of lymphocytes. Due to the patient's critical illness and clinical condition, additional social and medical history was unobtainable, but medical record review did not report a history of HIV and noted no outpatient medications. A new chest radiograph was reported as heterogeneous bilateral lung opacities with scattered air bronchograms ( Figure 1 ), but treating providers felt the opacities were less dense than expected for COVID-19 and for his level of hypoxemia. He continued remdesivir via emergency use authorization, received a transfusion of COVID-19 convalescent plasma, and antibacterials were narrowed to ceftriaxone and azithromycin. Given the patient's prolonged, subacute symptoms, and x-ray findings, an evaluation for PCP was undertaken and he was started on empiric trimethoprim-sulfamethoxazole and prednisone. A c c e p t e d M a n u s c r i p t The patient completed a course of remdesivir. He received a 21 day course of trimethoprimsulfamethoxazole and prednisone for PCP, and started dolutegravir with combination tenofovir alafenamide/emtricitabine for HIV. His course was complicated by ventilator associated pneumonia due to Pseudomonas aeruginosa, labial ulcer due to herpes simplex virus type 1, persistent hypoxemia and ongoing fevers. He was evaluated for extracorporeal membrane oxygenation but deemed not to be a candidate due to his prolonged ventilation and his immunocompromised state. He continued to experience refractory hypoxemia despite maximal ventilator settings, paralytic agents and prone positioning. On hospital day 26, he developed asystolic cardiac arrest and expired. No autopsy was performed. Consent was unable to be obtained from the patient due to patient being intubated and altered throughout his hospitalization. No family or next-of-kin was available, and, if they had been, obtaining consent would have risked potentially unwanted disclosure of the patient's HIV status. All identifying details of the patient have been removed in accordance with our institutional policy and Oxford University Press publishing policy. Ethical board approval was not felt to be indicated as this did not involve human subjects research. Fig 1) . Thirteen articles were case reports, five of which were case reports of patients with both COVID-19 and PCP (Table 1) . Of these, three were also HIV positive. Two cases were in people newly diagnosed with HIV, underscoring the need for HIV testing in individuals hospitalized for COVID-19 who would not be expected to have a severe course of illness. In one case, the patient was diagnosed with COVID-19, treated with tocilizumab and glucocorticoids, and later diagnosed with PCP, raising the possibility that immunomodulatory treatment for COVID-19 contributed to the development of PCP [2] . The other eight case reports described cases of either PCP or COVID-19 and the challenge in distinguishing between them. A c c e p t e d M a n u s c r i p t This case emphasizes that PCP and COVID-19 can present as co-occurring disease processes and a broad differential should be maintained, especially in immunocompromised patients.. . Pneumocystis jirovecii is an opportunistic fungal pathogen that primarily causes disease in immunocompromised individuals. Although historically associated with advanced HIV, PCP now often impacts persons who are immunosuppressed for other reasons as well, including malignancy [3] , organ transplant [4] , and those requiring other immunosuppressive drugs, particularly corticosteroids [5] . All five previously reported cases of COVID-19 and PCP coinfection identified during our literature review had a documented immunocompromising condition. Notably, none of the other cases of COVID-19 and PCP died. This may be attributable to extent of immunosuppression in our patient as well as his late presentation to care. PCP and moderate-to-severe COVID-19 share many clinical characteristics, making them difficult to distinguish. Both often present with fever, cough and hypoxia [6] and can have a wide range of radiographic findings including diffuse ground-glass opacities [7] . The similarities in presentation may be due to similar underlying mechanisms of pathogenicity between the two infections and their interaction with pulmonary surfactant [8] . Given these similar findings, there is a growing recognition of PCP as a COVID-19 mimicker in severely ill patients [9] . In the case of our patient, the three-week symptom duration prior to presentation was atypically long for COVID-19. For comparison, a large series of patients with COVID-19 alone reported a median 7 days of symptoms preceding hospitalization [10] . Co-infection with both SARS-Co V-2 and P. jirovecii can lead to diagnostic dilemmas. While COVID-19 testing is now readily available via nasopharyngeal swabs with fast turn-around time by most hospital laboratories [11, 12] , PCP is less easy to diagnose. Bronchial alveolar lavage fluid remains the gold standard for PCP diagnosis due higher sensitivity [13] , but performing a bronchoscopy to obtain a bronchial alveolar lavage specimen is an invasive procedure that cannot always be readily performed in severely hypoxic patients and requires additional procedural caution due to the risk of aerosolization of SARS-CoV-2. While the serum fungal marker 1,3-beta-D-glucan can be used to aid in the diagnosis of PCP [14] , additional testing and a compatible clinical A c c e p t e d M a n u s c r i p t presentation are required to confirm the diagnosis. Colonization with P. jirovecii is common in patients with COVID-19, a finding that may further impact challenging diagnostic scenarios. A recent study of 108 critically-ill patients with COVID-19 found that 9% had a positive PCR test for P. jirovecii on bronchial alveolar lavage [15] .,The use of corticosteroids for severe COVID-19 may further delay diagnosis of co-occurring PCP, as such patients may theoretically experience transient improvement, given the known beneficial effect of steroids in severe PCP. As targeted immunomodulators are studied in COVID-19, physicians should be mindful of the risk they may pose for PCP. For example, the anti-IL-6 monoclonal antibody tocilizumab, which was pursued as a potentially promising therapy for COVID-19, has been associated with PCP in the treatment of rheumatoid arthritis (0.28 events per 100 patient-years) [16] . Finally, this case of COVID-19 and AIDS in a Latinx male highlights the disparities intertwined with both COVID-19 and HIV in the United States. COVID-19 has disproportionately affected the Latinx and Black communities in the US[17]populations that experience a greater incidence and prevalence of HIV, have a high rate of progression to AIDS and encounter barriers to HIV testing and care [18] [19] [20] [21] . HIV testing efforts and the continuity of care amongst these vulnerable populations may be disrupted as healthcare resources are shifted toward the pandemic and traditional models of healthcare delivery are redesigned [22, 23] . However, the pandemic also presents new opportunities to engage patients in HIV screening and other preventive care as they seek COVID-19 testing or treatment. Incorporating HIV screening of all patients admitted for COVID-19 into institutional protocols is a sensible approach that would benefit individual patients and impact public health disparities. In summary, there is increasing recognition of PCP co-occurring with or succeeding severe COVID-19, primarily in immunocompromised individuals. Diagnostic uncertainty and anchoring biases can potentially delay diagnosis due to substantial overlap in the clinical presentation. Providers caring for patients with severe COVID-19 should retain a broad differential diagnosis if the clinical syndrome is atypical for COVID-19 or in patients with immunocompromising conditions. It is sensible to consider routine testing of HIV in all patients admitted with COVID-19 as a means of mitigating this diagnostic dilemma and benefitting our public health efforts. 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