A 73-year old Italian man with a history of diabetes, hypertension, hyperthyroidism,
atrial fibrillation and obesity was transferred to our hospital on March, 1, 2020
due to pneumonia associated with confirmed diagnosis of SARS-CoV-2 infection. On February
29, he was initially admitted, to the Emergency Department of another city hospital
complaining of a 3 days high fever (38,5 °C) and non-productive cough. A chest X-ray
showed a picture of interstitial pneumonia with enlarged heart.An arterial blood gas
demonstrated a pH of 7.45, PaO2 61 mm Hg, PCO2 44 mm Hg, HCO3 29 mmol/L; he was put
on oxygen supplementation and the following day transferred to our hospital. On admission
he was alert, with a BMI 32,72, blood pressure 135/80 mm Hg, respiratory rate 24/min,
heart rate 72/bpm with an oxygen saturation of 95% with 2 L O2/m administered by nasal
cannula. A chest X-ray showed interstitial opacities with focal consolidation in the
upper right lobe (Fig. 1
A). His medical treatment comprised bisoprolol 2.5 mg/day, methimazole 5 mg/day, rosuvastatin
10 mg/day, dabigatran 150 mg BID, insulin lispro 20 + 25+20 U/day and insulin glargine
40 U/day at bedtime. The patient was given antibacterial treatment (levofloxacin 750
mg/day plus ceftriaxone 2 g/d) for 3 days plus lopinavir/ritonavir 400/100 mg twice
daily and hydroxychloroquine 200 mg twice daily; dabigatran was substituted by low
molecular weight heparin (8000 UI). On hospital day (HD) 5, he was transferred to
the ICU requiring endotracheal intubation and mechanical ventilation for progressive
worsening of the radiological picture (Fig. 1B) with refractory hypoxia despite non-invasive
positive pressure ventilation; at this time laboratory exams were as follow: white
blood cells (WBC) 8,300/μL, total bilirubin 1,46 mg/dL, aspartate aminotransferase
(AST) 194 U/L, alanine aminotransferase (ALT) 81 U/L, serum creatinine 2,26 mg/dL,
C-reactive protein 109,7 mg/dL, procalcitonin (PCT) 8,9 μg/L. On HD 8 of hospitalization
an increase of WBC (13,620/μL) and PCT (15,8 μg/L) was observed together with altered
liver enzymes (AST 323 U/L, ALT 238 U/L), total bilirubin (3,1 mg/dL) and renal failure
requiring continuous renal replacement therapy (CRRT); a picture of septic shock was
evident from HD 9 and antibiotic therapy was changed from piperacillin-tazobactam
to meropenem (2 g every 8 hour) and ceftaroline (600 mg every 8 hour). Blood cultures
were repeatedly negative. A bronchoalveolar aspirate done on HD 9, grew Aspergillus
fumigatus 104 CFU/mL prompting the request for serum galattomannan antigen. On HD
11, on the basis of a positive (8.6 OD index) serum galactomannan (GM) antigen the
patient was started with antifungal therapy with liposomal amphotericin B because
of severe liver dysfunction (ALT 323 U/L, ALT 238 U/L, total bilirubin 4,36 mg/dL)
and concomitant therapy with amiodarone (1200 mg/24 h) due to the onset of high frequency
atrial fibrillation. WBC count increased from 28,980/μL (81% neutrophils) on HD10
to 45,250/μL (83% neutrophils) on HD 13 with very high CRP (323 mg/dL); A chest X-ray
on HD 13 showed an improvement of the bilateral interstitial picture (Fig. 1C). The
patient deceased on the morning of HD 14 due to respiratory and hemodynamic instability
(after having received an initial dose of isavuconazole initially unavailable in our
pharmacy). Post-mortem lung examination confirmed invasive pulmonary aspergillosis,
that was characterised by bronchial wall ulceration associated with multiple spots
of necrotizing pneumonia. Septate, dichotomously and progressively branching hyphae
(stained with haematoxylin and eosin) consistent with Aspergillus spp (Fig. 1D) were
more easily recognizable on Grocott-Gomori stain (Fig. 1E). The residual lung parenchyma
displayed an acute lung injury pattern with diffuse alveolar damage, both in the exudative
and in the proliferative phases; reactive atypical enlarged type II pneumocytes with
large nuclei, prominent nucleoli and finely granular cytoplasm were present. Furthermore
Aspergillus spp DNA was confirmed by PCR-amplification on paraffin block tissue.
Fig. 1
(A,B,C) Sequential chest X-ray findings in a COVID-19 pneumonia complicated by invasive
pulmonary aspergillosis. Interstitial opacities with focal consolidation in the right
upper lobe (1A); worsening of the radiologic picture with involvement of the medium
and upper right lobe and interstitial opacities in the left medium basal lobe (1B);
partial regression of bilateral interstitial infiltrates (1C). 1D Autopsy lung section
stained with haematoxylin and eosin showing spot of necrotizing pneumonia with several
dichotomously branching septate hyphae consistent with Aspergillus spp (arrow and
inset) surrounded by interstitial pneumonia with reactive atypical enlarged type II
pneumocytes (arrow-heads) (H&E, 10x).1E Lung section stained with Grocott methenamine
silver shows a branching septate hyphae (white arrow) 100x
Fig. 1
Our case report illustrates the importance of considering invasive pulmonary aspergillosis
as a possible complication of critically ill patients hospitalized in ICU for ARDS
due to SARS-CoV-2 infection. Several laboratory findings observed in this case of
IPA complicating COVID-19 pneumonia need to be emphasized; first our patient presented
with leucocytosis (up to 45,250/μL with neutrophilia), high value of PCT and C-reactive
protein all of these findings generally associated with bacterial sepsis. Nevertheless,
blood cultures were negative and despite aggressive empirical antibiotic therapy the
patient rapidly worsened and eventually died. It should also be highlighted that high
leucocytes and PCT values are more frequently detected among non-survivor patients
with COVID-19 pneumonia and could be considered as a marker of disease severity thus
making even more difficult to discriminate between a severe viral infection and a
possible bacterial of fungal coinfection. If we consider the EORTC/MSG criteria our
patient might have been classified as a possible case of IPA (only mycological criteria)
whereas according to the clinical algorithm for ICU patients it would be classified
as a colonized patient.
We treated our patient with liposomal amphotericin B, a drug that is considered a
second-line option for IPA because of high liver enzymes value and renal failure.
However, we started antifungal therapy with a delay of two days only when we received
the result of GM antigen and it is unknown if an earlier treatment could have affected
the outcome of our patient. We advise that even a positive sample for Aspergillus
spp. from upper respiratory tract in a COVID-19 positive patient should prompt antifungal
therapy.
Declaration of competing interest
All the Authors: no conflict of interests to disclose.