COVID‐associated pulmonary aspergillosis and herpes simplex virus pneumonia in a renal transplant recipient

INTRODUCTION

Organ transplant recipients (OTRs) on immunosuppressive therapy are at increased risk for severe and lethal COVID‐19. In one study, 16% of deaths among renal transplant recipients in 2020 were attributed to COVID‐19. ¹ OTRs are also at risk for opportunistic infections (OIs). Coinfection rates as high as 60% have been previously reported among OTRs with COVID‐19. ² Such concurrent or super‐imposed infections are likely the result of added immunosuppression from critical illness, baseline immunosuppressants, anti‐inflammatory treatments for severe COVID‐19, and possibly the immunomodulating properties of SARS‐CoV‐2 itself. ³

Concurrent COVID‐19‐associated pulmonary aspergillosis (CAPA) and herpes simplex virus (HSV) pneumonia have not been previously described. CAPA is one of the most common OIs among patients with COVID‐19 pneumonia. ⁴ Post‐COVID‐19 HSV‐1 reactivation has been associated with increased hospital acquired pneumonia (HAP) and mortality risk. ⁵

A thorough history and examination can narrow the differential diagnosis among patients with suspected post‐COVID‐19 superinfection. Respiratory support and empiric antimicrobial treatment should be prioritized, with ongoing investigation of causative organisms using labs and imaging. The gold standard for diagnosis of pulmonary infectious pathology is bronchoscopy with bronchoalveolar lavage (BAL) and microbiologic and cytologic analyses.

CASE REPORT

A 55‐year‐old male with history of deceased‐donor kidney transplantation 13 years prior to his presentation, on maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone, type 2 diabetes, and marijuana smoking, presented with cough and dyspnea at a community hospital. He was diagnosed with COVID‐19 pneumonia and treated with dexamethasone (prednisone and mycophenolate were held), empiric antibacterials, and supplemental oxygen. His condition improved, and he was discharged off oxygen to a skilled nursing facility.

The patient was readmitted 10 days later with worsening cough, dyspnea, and new painful mouth ulcers (Figure 1A). He developed acute hypoxemic respiratory failure requiring mechanical ventilation. Chest computed tomography (CT) revealed multifocal pneumonia with a 5 × 7 cm cavitary lesion in the right lower lobe (Figure 1B). SARS‐CoV‐2 PCR at this time was negative. He was started on vancomycin, which was later discontinued following negative MRSA swab, and cefepime. He was then transferred to the medical intensive care unit at the tertiary transplant center. The transplant infectious disease team recommended intravenous ganciclovir (broader and less nephrotoxic than acyclovir) for suspected herpesvirus infection and isavuconazole (weaker CYP inhibitor than voriconazole) for empiric coverage of CAPA. Tacrolimus doses were adjusted according to daily trough levels and goal of 5–7 ng/ml to avoid supratherapeutic dosing in the setting of azole‐induced CYP450 inhibition.

FIGURE 1.

Physical examination findings and imaging: (A) HSV‐1 oral ulcer. (B) Computed tomography (CT) of multifocal pneumonia with cavitary lesion

The patient underwent bronchoscopy with BAL, which demonstrated septate fungal elements and viral inclusions consistent with Aspergillus and herpesvirus infections (Figure 2A), respectively. BAL immunostain was positive for HSV (Figure 2B) and negative for Cytomegalovirus (CMV). Mouth ulcer PCR was positive for HSV‐1; serum galactomannan antigen index (5.72) and Fungitell (>500 pg/ml) were strongly positive. Infectious disease workup was negative for other respiratory viruses, Legionella, Chlamydia, Mycoplasma, and Cryptococcus. The patient's hospital course was complicated by bilateral pneumothoraces requiring chest tube decompression, renal failure requiring renal replacement therapy, ST‐elevation myocardial infarction, and refractory shock. He died on day 5 of his second hospitalization.

FIGURE 2.

Bronchoalveolar lavage histology: (A) Papanicolaou stain of Aspergillus with characteristic acute angle branching septate hyphae and viral inclusions. (B) Herpes simplex virus (HSV) Ab stain positive for virus with endonuclear viral inclusions

DISCUSSION

CAPA incidence varies in the literature. Most patients with CAPA were taking glucocorticoids, and early initiation of triazole therapy may improve mortality. ⁶ Current models propose that structural damage of the lungs by SARS‐CoV‐2 infection and impaired immune system predispose to tissue invasion by Aspergillus hyphae. Moreover, glucocorticoids, such as dexamethasone, impair the activity of alveolar macrophages through the TNF‐a pathway, further predisposing to invasive fungal infections. ⁶ Marijuana smoking is a notorious source of Aspergillus spore inhalation ⁷ and potentially an important diagnostic clue from this patient's social history.

Maintenance immunosuppressant therapy and added glucocorticoid therapy for COVID‐19 pneumonia likely contributed to oral HSV reactivation in this patient, followed by virus aspiration and resultant HSV pneumonia. ⁸ HSV pneumonia was the most likely cause of new profound hypoxia and diffuse “ground glass” infiltrates (Figure 1B), neither of which are common in CAPA, especially given the negative repeat SARS‐CoV‐2 PCR. Oral lesions, when present, are the only suggestive sign of HSV pneumonia on physical examination. A prospective study of critically ill patients found that 39% of patients with a positive oral swab for HSV by viral culture also had HSV identified in lower respiratory tract specimens. ⁹ Antivirals are the mainstay of treatment for HSV pneumonia. In a prospective study assessing the benefit from acyclovir in patients with ventilator‐associated pneumonia (VAP) and HSV identified in respiratory secretions, acyclovir use was associated with increased survival in those with VAP, antibiotic treatment failure, and high levels of HSV replication (HSV viral load > 10⁵ HSV copies/mL). ¹⁰

In conclusion, OTRs with COVID‐19 are at risk for co‐infections, including OIs, given their immunocompromised status at baseline and added immunosuppression from glucocorticoids. A high level of clinical suspicion should prompt diagnostic bronchoscopy in presumed pneumonia, as well as empiric antifungal and/or antiviral treatment.

CONFLICT OF INTEREST

Dr. Farmakiotis has received research support from Astellas. All other authors have no conflict of interest.

Stephens ML, Mathew A, Banerjee D, Farmakiotis D. COVID‐associated pulmonary aspergillosis and herpes simplex virus pneumonia in a renal transplant recipient. Transpl Infect Dis. 2022;24:e13978. 10.1111/tid.13978