Keywords
COVID-19 - mucorales - aspergillosis - immune dysfunction
Case Presentation
Case A
A 45 year old male patient, non-smoker, diabetic on oral medications with uncontrolled
sugars (HbA1c-10.4), presented with intermittent low-grade fever, progressive shortness
of breath and cough with minimal expectoration for 28 days. The patient was previously
hospitalized around 1.5 months back with sever COVID-19 pneumonia and had received
steroids for 7 days. On examination, the heart rate was 80 per minute, blood pressure
was 122/78 mm Hg, respiratory rate of 18 per minute with a saturation of 95% on room
air. Bilateral scattered rales were heard on auscultations, whereas the rest of systemic
examination was normal. On current admission, a chest radiograph showed bilateral
lower zone opacities. Subsequently, high-resolution computed tomography (HRCT) chest
revealed patchy areas of consolidation in the right middle lobe and both lower lobes
along with bilateral subpleural areas of ground glass opacities ([Fig. 1A]). Keeping a strong differential of infectious etiology, broncho-alveolar lavage
(BAL) was done. BAL for bacterial etiology (Gram stain and bacterial culture) and
tubercular etiology (acid fast bacilli and Genexpert) came out to be negative. Interestingly,
BAL for potassium hydroxide (KOH) mount showed septate hyphae with acute angle branching
and the fungal culture subsequently grew Aspergillus fumigatus ([Fig. 1B]). Narrowing down our differential to pulmonary aspergillosis a serum antibody (IgG
Aspergillus ELISA) against Aspergillus was sent, which was positive. Given the clinical scenario of a subacute (1–3 months),
insidious respiratory pathology, which was fulfilling the European Respiratory Society
(ERS) 2014 diagnostic criteria for pulmonary aspergillosis, a diagnosis of subacute
invasive pulmonary aspergillosis (SAIA) was made. With a given back drop of a recent
severe COVID-19 disease, which may have predisposed to this infection, a final diagnosis
of COVID-19-associated SAIA was kept and the patient was started on voriconazole.
The patient showed steady improvement, and the last follow-up 6 months from treatment
initiation showed clinico-radiological improvement.
Fig. 1 (A) Axial CT image showing patchy areas of consolidation in the right middle lobe and
both lower lobes in posterior basal segments (arrow). There are subpleural areas of
ground glass opacities also seen bilaterally (asterisk). Mediastinal emphysema is
noted anteriorly. (B) Lactophenol cotton blue mount showing typical morphology, suggestive of Aspergillus fumigatus (arrow). (C) Axial CT image showing a thick-walled cavity with air-fluid levels (orange arrow)
involving the right upper lobe with surrounding areas of patchy and peribronchial
ground glass opacities (arrow). (D) Gömöri methenamine silver staining of post lung resection sample showing broad aseptate
hyphae with wide-angled branching (arrow).
Case B
A 55-year-old woman, recently diagnosed diabetic on oral anti-diabetic agents, with
past history of severe COVID-19 pneumonia (2 months ago), now presented with complaints
of cough with expectoration and streaky hemoptysis for 25 days. An initial chest radiograph,
showed a cavitary lesion on the right upper zone. On further evaluation, a HRCT chest
revealed a large thick-walled cavity in the right upper lobe with air fluid level
and surrounding ground glass opacities ([Fig. 1C]). The patient underwent BAL to further evaluate the cause for rapidly evolving (<
12 weeks) cavitary lesion. Ziehl–Neelsen (ZN), Genexpert, Gram staining, and bacterial
culture was negative. However, KOH mount showed broad aseptate hyphae with wide-angled
branching suggestive of mucormycosis. Polymerase chain reaction (PCR) for detection
of Mucorales performed on the BAL sample using commercially available MucorGenius kit (Pathonostics,
The Netherlands), was also positive. A diagnosis of COVID-19-associated pulmonary
mucormycosis (CAPM) was made and the patient was started on liposomal amphotericin-B
at the dose of 5 mg/kg. After 2 weeks of amphotericin-B therapy, she underwent a sub-lobar
resection of right upper lobe with wedge resection of the right lower lobe. Mucor
was also confirmed on the post resection sample of the lungs via broad aseptate hyphae
with wide-angled branching on Gömöri methenamine silver staining ([Fig. 1D]). Postoperatively, the patient was continued on amphotericin-B for 2 weeks with
subsequent switch to posaconazole and showed marked clinical improvement. Currently,
the patient is doing well and is under regular follow-up.
Discussion
Invasive fungal infections associated with COVID-19 pneumonia is a well-known entity.
COVID-19-associated pulmonary aspergillosis (CAPA) has been widely reported across
many countries. Although the exact pathophysiology is unclear, immune dysregulation
following ARDS, immunosuppressing effect of commonly used drugs for treating COVID-19
(corticosteroids, tocilizumab), direct mucosal damage to the respiratory epithelium
by virus and early fungal colonization have all been implicated for the same.[1] While CAPA is a well-established phenomenon, which comprise invasive aspergillosis
in COVID-19 patients, COVID-19-associated SAIA is new and an uncommon etiology. Swain
et al in a recent prospective study have described 10 patients with COVID-19-associated
SAIA.[2] SAIA (previously known as chronic necrotizing or semi-invasive pulmonary aspergillosis)
is a slowly progressive form of invasive aspergillosis typically seen in mildly immunocompromised
conditions, which progress over 1 to 3 months. The immunocompromising conditions include
diabetes mellitus, chronic obstructive lung disease (COPD), radiation therapy, HIV
infection, non-tuberculous mycobacterial infection (NTM), connective tissue disorder,
and low-dose corticosteroid therapy (5–20 mg every other day).[3] Radiological features in SAIA are variable, which include cavitation, nodules, or
consolidation.[4] The diagnosis of SAIA is based on the presence of IgG antibody against Aspergillus in blood with subacute progression of the disease with characteristic radiology,
typically in a mildly immunocompromised patient.[5] Biopsy may or may not be done for diagnosis that demonstrates fungal hyphae invading
lung parenchyma. Oral triazole therapy is recommended for SAIA, preferably voriconazole
typically for 9 months or more as in other form of chronic aspergillosis. Patients
are to be clinically and radiologically followed up. Surgery may be indicated in patients
not responding or deteriorating on systemic antifungals.
Mucormycosis relate to the infections caused by the order Mucorales, with most frequently
reported pathogens includes Rhizopus, Mucor, Lichtheimia (formerly of the genera Absidia and Mycocladus), Rhizomucor, Cunninghamella, Apophysomyces, and Saksenaea.[6] COVID-19-associated mucormycosis (CAM) commonly involves paranasal sinus, orbit
and brain with pulmonary involvement being relatively infrequent.[7] Multiple mechanisms has been put forth to explain the recent rise in the incidence
of mucormycosis (predominately rhino-orbital involvement) in COVID-19 patients. Severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to lymphopenia with
impaired cell-mediated immunity (reduction in CD4+ and CD8+ cell population).[8] Pre-existing hyperglycemia (uncontrolled diabetes mellitus) or steroid-induced hyperglycemia
with or without ketoacidosis is considered as a sine qua non.[9] Hyperglycemia-induced acidosis or ketosis lowers the serum pH, which leads to glycosylation
of ferritin leading to the generation of free iron and facilitating the growth of
mucorales.[10] Low serum pH also reduces chemotaxis; the phagocytic effect macrophages and adequate
functioning of neutrophils. Fungal ligand spore coating homologue (CotH) protein present
on the mucorales binds to the glucose receptor protein-78 (GRP-78) present on host
endothelial cells which aid in attachment to the endothelium and angio-invasion.[11] Both hyperglycemia and COVID-19 are known to upregulate GRP-78 and CotH function.
Interplay of multiple above-described factors along with upregulation of GRP-78 in
COVID-19 disease leads to increased susceptibility as well as angioinvasion of mucorales
in these group of patient.[12] Diagnosis of COVID-19-associated pulmonary mucormycosis (CAPM) is based on radiological
imaging, culture, and microscopy, and histopathology. Consolidation and cavity are
predominate lesions, followed by ground glassing are on CT scan in CAPM, which may
mimic CAPA or other cavitary pneumonia.[13] Strict glycemic control is of paramount importance along with anti-fungal drugs.
Treatment includes liposomal amphotericin B (infusion at a dose of 5–10 mg/kg per
day) initially followed by a switch to posaconazole (gastro-resistant tablets preferred
over syrup) after 4 to 6 weeks. Isavuconazole has also been recently recommended with
moderate strength for the first-line treatment of mucormycosis based on results from
the VITAL study.[14] The optimal duration of anti-fungal therapy is not clear and depends on the clinical
and radiological response of the patients. Surgical intervention is frequently needed
for complete cure.[15]
Conclusion
These two cases exemplify the relatively rarer fungal diseases in the background of
COVID-19. Both of these cases had almost similar clinical presentations which started
∼ 1 month after suffering from COVID-19. Diabetes was a common risk factor for both
patients. The radiological features were non-specific and bronchoalveolar lavage sampling
clinched the diagnosis in both the cases. It is thus important to consider the diagnoses
of SAIA and CAM in the background of COVID-19 even in patients who are not overtly
immunosuppressed. Early diagnosis and prompt treatment can help in appropriate management
of such cases.
