Trichosporon asahii opportunistic pneumonia after a severe COVID-19 infection

This is the first reported case of fatal opportunistic Trichosporon asahii pneumonia in the setting of severe COVID-19 pneumonia. The patient had ventilator-requiring respiratory failure secondary to COVID-19 infection. The patient received intravenous broad-spectrum antibiotics, tocilizumab, and corticosteroids with subsequent development of cavitary infiltrates. Bronchoalveolar lavage grew T. asahii. We describe a rare complication of COVID-19 infection and describe the microbial diagnosis, possible mechanism of infection, and optimal treatment.


Introduction
Since 2019, COVID-19 has affected a total of 96 million people with > 1 million deaths in the USA [1]. COVID-19 patients are often placed on high dose corticosteroids and other immunosuppressants increasing the risk of opportunistic infections. Multiple fungal infections have been reported including pulmonary aspergillosis, mucormycosis, and invasive candidiasis [2]. We report the case of a 36-year-old patient with severe pneumonia complicated by fatal T. asahii pneumonia.

Case
A 36-year-old COVID-19 unvaccinated woman presented in April 2021, to a Southern California hospital for a five-day history of shortness of breath, cough, fever, and chills. She was diagnosed with COVID-19 infection and was admitted for acute hypoxic respiratory failure requiring supplemental oxygen. Her past medical history was significant for a BMI of 28 and diet-controlled diabetes (hemoglobin A1c 6.3 %). She lived with her husband and two children and had no recent travel history. She reported vaping tobacco for 2 years and denied alcohol or recreational drug use. On admission, a chest CT angiogram showed bibasilar consolidations ( Fig. 1-a). Laboratory results are shown in the Table 1.
On hospital day 3, her oxygen requirement escalated to 60 liters by high-flow nasal cannula. She received a 5-day course of intravenous (IV) remdesivir, a 10-day course of dexamethasone and one dose of tocilizumab 400 mg. The patient's condition deteriorated and on hospital day eight she was transferred to the intensive care unit (ICU) and required intubation and mechanical ventilation. She developed multi-organ dysfunction syndrome with severe acute respiratory distress syndrome, septic shock, ischemic hepatitis, acute renal failure requiring hemodialysis, and left upper lobe pulmonary embolism. The patient received an empiric course of IV cefepime, metronidazole, vancomycin, and micafungin. Multiple blood cultures, bacterial and fungal sputum cultures, and urine cultures were negative. Serum aspergillus antigen and an interferon gamma assay were negative; beta-D-glucan was not available to order in the institution. Despite broad antimicrobial therapy, the patient had a persistent leukemoid reaction (Table 1) and high oxygenation requirements. Repeat CT scan of the chest without contrast demonstrated bilateral upper lobe cavities which were not present on her prior CT scan ( Fig. 1b). Bacterial culture of endotracheal aspirate on day 20 was negative. Fungal culture grew yeast with hyphae and arthroconidia identified by On day 22, bronchoalveolar lavage (BAL) was performed yielding negative bacterial and mycobacterial cultures. BAL pneumocystis stain was negative. BAL fungal culture grew T. asahii. The patient was initially treated with IV liposomal amphotericin followed by voriconazole based ☆ #COVID19 #trichosporonasahii #opportunisticinfection #fungal #cavitarypneumonia post COVID-19 Trichosporon pneumonia. ☆☆ This is a case report of a fatal Trichosporon asahii opportunistic pneumonia in the setting of severe COVID-19. The discussion reviews reported cases and the pathology and treatment of Trichosporon asahii.

Discussion
Trichosporon is a urease-positive, non-encapsulated basidiomycetous environmental yeast characterized by the development of hyaline, septate hyphae that fragment into oval or rectangular arthroconidia. It is easily mistaken for candida but can be distinguished by the presence of arthroconidia (Fig. 4). Trichosporon is found in soil, water, and plants [3]. It could be part of the normal skin and gut flora. Human pathology ranges from benign superficial infection like white piedra to severe infections. Invasive Trichosporon infection is associated with immune deficiency (myeloproliferative neoplasms, organ transplants, AIDS, burn victims, catheter-acquired fungemia, and peritoneal dialysis catheter infections). It can disseminate into multiple organs and is associated with high mortality [4]. Since the 2019 novel coronavirus outbreak, there have been several reports of T. asahii infection in severe COVID-19 cases. A study in Brazil described invasive Trichosporon opportunistic infections in the setting of COVID-19. The study conducted between July and September 2020 in a single hospital described five T. asahii fungemia cases. Risk factors were older age, morbid obesity, prolonged corticosteroid use, previous broad-spectrum antibiotics and echinocandin exposure [5]. Another study describes nine cases of Trichosporon and COVID-19 coinfection in the world: 6 in Brazil, one in the United States, one in Qatar, and one in Spain. All nine patients had severe COVID-19, received broad-spectrum antibiotics and systemic corticosteroids [6].
Severe alveolar damage caused by ARDS could be a predisposing risk factor for invasive pulmonary disease. An autopsy performed on a triple pulmonary coinfection with T. asahii, Pseudomonas aeruginosa, and Stenotrophomonas maltophila showed diffuse alveolar damage with severe inflammatory exudates [7]. A Hong Kong study intranasally challenged 8 golden hamsters (Mesocricetus auratus) with the COVID-19 virus following them for 14 days and obtaining serial viral loads and histopathologic studies postmortem. Most hamsters had a large number of COVID-19 nucleocapsid proteins in enteric epithelial cells and developed severe epithelial cell necrosis, damaged intestinal villi, and mucosal inflammation [8]. We hypothesize that the pathogenesis of invasive fungal infections in the setting of severe COVID-19 could be the result of mucosal injury and immune barrier disruption combined with the dysbiosis caused by broad-spectrum antibiotics. Furthermore, COVID-19 patients are typically immunosuppressed secondary to corticosteroid and immunomodulator use causing susceptibility to opportunistic infections [5,6].
The 2014 guidelines from European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) recommend treatment with voriconazole based on in vitro studies as T. asahii is often resistant to amphotericin B (MIC > 2 mg/L) and caspofungin (MIC > 16 mg/L) [9]. The MIC breakpoints for T. asahii species are not yet established. Therefore, the breakpoints were extrapolated from Candida albicans as per the CLSI guidelines. A multicenter retrospective Taiwanese study aggregated MIC Fig. 1. a. CT Chest with contrast on admission. b. CT chest without contrast on hospital day 20.  [10].

Conclusion
To our knowledge, this is the first report of fatal pneumonia due to T. asahii as the sole microbial pathogen in the setting of severe COVID-19 infection. T. asahii has been linked to fungemia in critically ill COVID-19 patients, but pneumonia is rare. The delayed identification of T. asahii and the common use of echinocandins may contribute to increased morbidity and mortality. More clinical data are needed to optimize the diagnosis and treatment of severe Trichosporon infections.

Ethical approval
No intervention was done to the patient and no ethical dilemma identified.