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\begin{document}

\title{Unusual manifestation of COVID-19-associated pulmonary aspergillosis, A
case report}



\author[1]{Maryam Albaji}%
\author[1]{Mohammad Reza Fattahi}%
\author[1]{Arad Iranmehr}%
\affil[1]{TUMS}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
A young man, a recent coronavirus patient, was readmitted with
hypoesthesia and dysarthria following a rapid deterioration of
respiratory symptoms. The brain and lung CT scans revealed ischemia and
cavitary lung lesions. Clinical suspicion for aspergillus leads to
prompt treatment, confirmed by biopsy. Neurologic and pulmonary symptoms
resolved ultimately.%
\end{abstract}%



\sloppy


\textbf{Title} : Unusual manifestation of COVID-19-associated pulmonary
aspergillosis, A case report

\textbf{Abstract}

A young man, a recent coronavirus patient, was readmitted with
hypoesthesia and dysarthria following a rapid deterioration of
respiratory symptoms. The brain and lung CT scans revealed ischemia and
cavitary lung lesions. Clinical suspicion for aspergillus leads to
prompt treatment, confirmed by biopsy. Neurologic and pulmonary symptoms
resolved ultimately.

\textbf{Key Summary Point}

This case report highlights the potentially effective and on-time
diagnosis and treatment of the Aspergillus involvement in a
non-immunocompromised patient with covid-19 admitted with a neurological
ischemic symptom.

\textbf{Introduction}

Since December 2019, an outbreak of coronavirus pneumonia caused by
SARS-COV-2 started in Wuhan, China (1) and later spread worldwide.
Severe viral pneumonia-causing hospitalization and respiratory failure
is an essential feature of this disease (2). Invasive Aspergillosis
infections have been reported in severe respiratory syndrome-coronavirus
(SARS-CoV) in 2003 and Middle East Respiratory Syndrome-coronavirus (3,
4). In critically ill patients of influenza, the Influenza-associated
pulmonary Aspergillosis (IAPA) is a risk factor for morbidity (5, 6).
Several studies from Wuhan (7, 8), Belgium (9), France (10), Netherland
(11), and Germany (12) have reported COVID-19 associated pulmonary
Aspergillosis (CAPA) in critically ill patients and mainly on mechanical
ventilation. Corticosteroid use in the treatment of Covid-19 patients
may contribute to CAPA risk. This report presents a young man with
neurologic presentation and cavitary lung lesions with a history of
recent hospitalization for moderate Covid-19 pneumonia.

\textbf{Clinical} \textbf{case}

A thirty years old male was admitted to the emergency room with a chief
complaint of hypoesthesia in both lower limbs, right hand, and
dysarthria since the day before. He had no history of loss of
consciousness or head trauma, diplopia, dysphagia, facial weakness,
fecal or urinary incontinence, dysarthria, nausea or vomiting, articular
pain or swelling, oral ulcer, photosensitivity nasal discharge. However,
he was complaining of headaches, fever, and vertigo. The patient also
mentioned exertional dyspnea since getting infected with Covid-19, which
led to hospitalization 20 days ago. The patient's past medical history
had no significant reporting except for the recent admission for
Covid-19 infection, which was treated with Remdesivir and Dexamethasone
for five days in another healthcare center. His habitual history was
positive for hookah, but no further history of smoking or alcohol use
was mentioned. There were construction works in the patient's
neighborhood recently. He noted that his mother has a history of
hypertension. The patient's signs improved since their onset but did not
resolve completely. In the physical examination, the patient was
slightly ill but had no respiratory distress; blood pressure was 110/80
mmHg, the pulse rate: was 80 b/min, respiratory rate of 18/min, the
temperature of 36.8 \^{}c, and O2 saturation: was 96\%.

Moreover, muscle forces and the other neurologic examinations were
normal. Lung and brain CT scans were done and had no obvious
abnormality. Brain MRI was performed, and there was an abnormal signal
intensity in the left frontal region in T2/FLAIR, which indicates a
restriction in Diffusion-Weighted Imaging (DWI) in favor of acute
infarction in the left middle cerebral artery (MCA) territory (figure
1). The bilateral carotid Doppler ultrasound revealed low resistance
arterial flow without evidence of significant narrowing or dissection.
Initial lab data is shown in Table 1.

Neurologic consult recommended treatment with Aspirin (80 mg oral intake
daily), Clopidogrel (75 mg oral intake daily), and Atorvastatin (20 mg
oral intake daily). On the day after admission, the patient had dyspnea,
and the level of O2 saturation dropped to 77\% with rose to 95\% with
oxygen therapy, and he developed tachycardia (PR=120b/min). Lung CT
angiography to rule out pulmonary thromboembolism (PTE) was performed.
There was no evidence of thrombosis in the main and segmental branches
of the pulmonary artery. There was evidence of previous Covid-19
infection in lung parenchyma and nodular opacities with some cavitation
suggesting superimposed infections or possibly due to septic emboli
(figure 2). Broad-spectrum antibiotics were initiated, and blood
cultures were sampled. Transthoracic echocardiography (TTE) was done,
which had a poor view due to the patient's obesity and tachypnea; then,
Transesophageal echocardiography (TEE) was performed, which reported
normal RA size with a moderate, fluffy, network-shaped mobile mass in
the Right Atrial (RA); however, the operator could not determine the
lesion was a pathologic or not. The other findings were normal and had
no evidence of RV strain, vegetation, or significant valve abnormality,
and cardiac MRI was suggested for better evaluation. The patient's
exertional dyspnea was aggravated, resulting in immobility; therefore,
the patient needed urinary catheterization. For reevaluation, we
repeated pulmonary CT angiography. The cavitary lesions progressed in
size and distribution with a dominant cavity sized 107, 70, and 50 mm in
the superior segment of the left lower lobe with internal fluid level
septation, suggesting fungal infections. An infectious disease
specialist consults recommended antifungal therapy with intravenous
Voriconazole (200mg every 12 hours) was started. Sputum exam for fungal
and bacterial infections was negative. Bronchoscopy and Bronchoalveolar
lavage were performed, and the smear and culture for alveolar lavage
were negative for bacterial and fungal infection. The patient had an
episode of hematuria; urine analysis revealed microscopic hematuria
without dysmorphic RBC and pyuria.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Lab test & Result & Reference\tabularnewline
\midrule
\endhead
WBC count & 13,200/HPF & 4000-11000/HPF\tabularnewline
CRP & 8.2 mg/L & 0-10\tabularnewline
ESR & 36 mm/hr. & up to 18\tabularnewline
LDH & 509 U/L & Up to 480 U/L\tabularnewline
D-Dimer & 292 ng/ml & Up to 500 ng/ml\tabularnewline
Troponin I. Quantitative & 139.2 ng/ml & Up to 26 ng/ml\tabularnewline
Covid-19/PCR Qualitative & Not detected & Negative\tabularnewline
\bottomrule
\end{longtable}

Table 1: Laboratory findings of the patient

Evaluation for vasculitis because of hematuria, cavitary lung lesions,
and neurologic presentation of the disease by testing for ANA, Anti ds
DNA, RF, Anti CCP Ab, P-ANCA, and C-ANCA was performed. All the tests
were negative, and the level of serum complements was normal. Thoracic
surgery consults for the dominant cavity in left lung management
recommended radiologic intervention by inserting a pneumothorax
catheter. Unfortunately, this intervention failed due to technical
difficulties. The patient's general condition improved gradually.
Cardiac MRI was carried out in another center, and there was no evidence
of RA mass or any other significant cardiac abnormalities. Hematuria
resolved independently, and we assumed that it was due to trauma during
urinary catheterization. As the antifungal treatment continued, the
patient's condition improved. We referred the patient for cavity
sampling under the CT guide. The sample's PCR test result was positive
for aspergillosis. Treatment with intravenous Voriconazole continued for
three weeks in the hospital, and a follow-up chest CT scan revealed
significant improvement (figure 3). A neurologic consult recommended
extending the antiplatelet therapy for three months after discharge and
performing cardiac Holter monitoring and checking coagulation profile,
including fibrinogen level, protein C, protein S, and Antithrombin III
level. All of these tests were normal. The Holter monitor device did not
reveal any abnormality. The patient was followed for three months in the
clinic while continuing oral Voriconazole. After three months, lung
cavitary lung lesions disappeared completely, and the patient got
symptoms free. The patient's neurologic symptoms also improved, and
antiplatelet therapy was terminated after consultation with a
neurologist.

\textbf{Discussion}

The COVID-19 disease caused by the coronavirus has a broad spectrum of
features, in the severe form causing acute respiratory distress syndrome
(ARDS) (1). The previous influenza pandemic described co-infections and
superinfections of viral, bacterial, and fungal infections (13). In the
current pandemic of COVID-19, in the studies from China (7, 8),
aspergillosis was isolated from the patient's respiratory tract. Also,
in case series from other regions in the world, there were reports of
CAPA in about 20-35\% of mechanically ventilated patients (9-12). Since
there are similarities between Influenza and COVID-19 clinical features,
we expect a similar rate of aspergillus infection in COVID-19 patients.

Nevertheless, aspergillus infection in COVID-19 patients is uncommon
(14). In these patients, aspergillosis infection was mainly associated
with tracheobronchitis, prior lung disease, prolonged mechanical
ventilation, and high immunosuppressor doses or diabetes (14). The
corticosteroid uses in treating COVID-19 disease may increase the risk
of aspergillus infection. The diagnosis of invasive pulmonary
aspergillosis (IPA), according to the European Organization for Research
and Treatment of Cancer/Mycosis Study Group (EORTC/MSG), is categorized
into proven, probable, and possible. When a combination of host
characteristics, clinical manifestations, and positive mycology leads to
proven invasive aspergillosis.

Moreover, possible IPA is considered when there are clinical features
and host factors but negative mycology results (15). The modified
definition of invasive pulmonary aspergillosis (AspICU criteria)
developed lately and is based on positive results of BAL culture,
positive BAL, or serum galactomannan in the absence of histopathology.
The radiologic criteria include any pulmonary infiltration rather than
EORT radiologic criteria (e.g., halo sign or air-crescent sign) because
this criterion is applied more for neutropenic patients (16). Chen L et
al. indicated that the immunocompetent patients with IPA who were
hospitalized with influenza showed a significant correlation between
using corticosteroids before diagnosis and acquiring IPA (17). In the
study evaluating reported cases of CAPA in the ICU, steroid exposure,
diabetes, and chronic lung disease were the more frequent risk factors.

Moreover, pulmonary nodules and cavitary/halo-sign were the dominant
radiologic findings of the IPA patient (18). CNS aspergillosis occurs
mainly in immunocompromised patients with advanced conditions. CNS
aspergillosis may occur in immunocompetent patients and have a different
clinical course and prognosis than immunocompromised patients (19).
Hematogenous spread of aspergillus can involve all parts of the CNS,
including the anterior and middle branches of the cerebral artery, which
can be infiltrated by the hyphae leading to direct and indirect damage,
especially in frontal, temporal, and parietal lobes (20). In a study
evaluating CNS aspergillosis in immunocompetent patients, the frequent
etiologies of CNS involvement were nasosinusitis, diabetes, and
craniotomy. Cerebral infarction occurred in 26.1\% of the patients, with
meningeal participation (21). In this report, we present a patient
admitted to our hospital for a neurologic complaint of hemiparesis,
without any known underlying disease, including immunodeficiency, except
for recent glucocorticoid consumption for COVID-19 disease treatment for
five days. We assumed that the neurologic involvement was due to the
patient's pulmonary aspergillosis infection. Furthermore, the early
starting of the treatment in response to our suspicion of IPA may
improve this patient's outcome compared to similar case studies
discussed in this paper (17, 21).

\textbf{Conclusion}

The reported cases of CAPA were more in the critically ill patients
admitted to the ICU. It is an interesting feature of aspergillosis
infection in a relatively immunocompetent patient with moderate COVID
-19 pneumonia, and this may warrant more precaution in prescribing
glucocorticoids and other immunosuppressive drugs in order to prevent
patients from getting superinfections with these opportunistic organisms
and their debilitating complications. Finally, it is essential to
consider the possibility of superinfection by these organisms and the
other opportunistic infections resulting in starting the appropriate
diagnostic evaluations and treatments as soon as possible.

\textbf{Disclosures}

Authors declare that they have no conflict of interest.

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