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 Table of Contents  
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 278-282

Dual Invasive fungal infection by aspergillus and mucor in COVID-19 patient: A rare case report with literature review

1 Department of Pulmonary Medicine, AIIMS, Patna, Bihar, India
2 Department of Radio-diagnosis, AIIMS, Patna, Bihar, India

Date of Submission27-Sep-2021
Date of Decision19-Oct-2021
Date of Acceptance02-Nov-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Dr. Deependra Kumar Rai
Department of Pulmonary Medicine, AIIMS, Patna, Bihar
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_218_21

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Patients with COVID-19, especially those with severe disease, in intensive care units, are particularly vulnerable to bacterial and fungal infections. The most common fungal infections reported include aspergillosis, candidiasis, and mucormycois. Mucormycosis, a potentially life-threatening fungal infection, has contributed to India's COVID-19-related deaths, especially during the second wave of pandemic. Several cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been reported from many countries in Europe, Asia, Australia, and South America. Recently, several cases of rhino-orbito-cerebral mucormycosis in patients with COVID-19 (ROCM) have been reported from India. However, case of COVID-19-associated pulmonary mucormycosis (CAPM) is rarely described in the literature. It has been hypothesized to affect patients recovering from COVID-19 who are immunocompromised due to COVID-19 disease or due to the usage of steroids and/or concomitant diabetes. The authors hereby report a combination of CAPM and CAPA in the same patient and perform a systemic review of the published cases highlighting the differences between these two-life-threatening pulmonary fungal infections.

Keywords: COVID-19, invasive pulmonary aspergillosis, pulmonary mucormycosis, reverse halo sign

How to cite this article:
Rai DK, Kumar S. Dual Invasive fungal infection by aspergillus and mucor in COVID-19 patient: A rare case report with literature review. Arch Med Health Sci 2021;9:278-82

How to cite this URL:
Rai DK, Kumar S. Dual Invasive fungal infection by aspergillus and mucor in COVID-19 patient: A rare case report with literature review. Arch Med Health Sci [serial online] 2021 [cited 2023 Feb 2];9:278-82. Available from: https://www.amhsjournal.org/text.asp?2021/9/2/278/334010

  Introduction Top

The novel coronavirus disease 2019 pandemic (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing. A high proportion of the infected individuals require respiratory support and intensive care unit (ICU) treatment.[1] Secondary infections were rarely reported in the early part of the pandemic; however, recently, there have been several reports of secondary fungal infections. One of them, the COVID-19-associated invasive pulmonary aspergillosis (CAPA) affects the COVID-19 patients with acute respiratory distress syndrome who require ICU care. More than 100 cases of CAPA have been reported till date from almost all the regions of the world.[2],[3] India had its second COVID-19 wave in early 2021, and several cases of mucormycosis, especially the rhino-orbito-cerebral mucormycosis (ROCM) were reported during and immediately after this wave. However, COVID-19-associated pulmonary mucormycosis (CAPM) is rarely described in the literature. The authors came across an unique case wherein dual pathology of CAPA and CAPM was seen.

  Case Report Top

A 56-year-old male presented with left-sided chest pain, cough, dyspnea on exertion, and generalized body weakness. At admission, he was afebrile, had heart rate of 98 beats/min, respiratory rate of 22 breaths/min, and oxygen saturation of 92% at room air, but desaturated to 88% soon after exertion. Chest auscultation demonstrated fine crepitation in the left infra-axillary area. He had type 2 diabetes mellitus and a history of severe COVID-19 disease which was managed in another hospital. A high-resolution computed tomography (HRCT) scan of the chest performed after 4 days of admission to that hospital had shown patchy peripheral ground-glass opacities in both lungs [Figure 1]a. He had been managed with supplemental oxygen through nasal cannula injection dexamethasone and remdesivir. A follow-up HRCT scan performed 20 days later showed lesions giving the “reverse halo sign” in the left upper and lower lobes, apart from patches of ground-glass opacities and consolidation [Figure 1]b. The patient then self-reported to our otorhinolaryngology outpatient department seeking consultation for possible ROCM, even though there were no attributable symptoms, but probably because there was extensive media coverage for this condition termed the “black fungus”. Anterior rhinoscopy showed deviated nasal septum to the left side with blackish crust on the middle turbinate. The crust was removed and fungal potassium hydroxide (KOH) mount showed septate hyphae. The patient was admitted next day in the pulmonary medicine department with suspicion of invasive fungal infection. Therapy was started with supplemental oxygen, injectable voriconazole, and meropenem. A video bronchoscopy was performed and bronchoalveolar lavage (BAL) sample was tested for bacterial pathogen and fungal KOH stain; however, both yielded negative result. GeneXpert of the BAL fluid detected mycobacterium in traces with rifampicin sensitivity but later on acid-fast bacilli culture was found negative. Serum and BAL GALCTOMANN both were positive (0.93 and 3.21, respectively). Blood investigations revealed hemoglobin 11.7 g/dl, total leukocyte count 15.8/mm3, neutrophil 95.2%, and lymphocyte 3.2%. Liver and kidney function tests were within the normal limit except low total protein (4.32 g%) and albumin (2.33 g%) levels. A provisional diagnosis of CAPA was then made, considering the radiological findings, fungal hyphae demonstration in the nasal crust, and the positive GALCTOMANNAN antigen test in both serum and BAL fluid. A contrast magnetic resonance imaging scan of the head and paranasal sinuses was performed, which showed the nonenhancing left inferior turbinate (“the black turbinate sign”) and nonenhancing fluid/collection in the left ethmoid sinus. Small ring-enhancing lesion was seen in the right parietal region [Figure 2]. The patient deteriorated at day 6 of admission with increase in the oxygen requirement, hence was shifted to the ICU and was given oxygen supplementation at 15 L/min with nonreservoir mask. HRCT scan was again performed and showed increased opacities in the left lung with consolidation and cavitatory lesions [Figure 1]c. A polymerase chain reaction (PCR) test for mucorales species in the BAL fluid came positive and the patient was started on lyophilized amphotericin-B injection considering a possibility of CAPM. However, there was progressive and rapid deterioration clinically, and in spite of mechanical ventilation, he expired 2 days later.
Figure 1: High-resolution computerized tomography scan of the chest performed on June 17, 2021 showing ground-glass opacity predominantly in the lower lobe during the acute phase of severe COVID-19 (a). Follow-up computed tomography performed on July 7 showed the development of patch of consolidation with reverse halo sign (blue arrow) (b). High-resolution computed tomography performed on July 13 as worsening of chest X-ray and clinical failure showed cavitation with increased in extent of consolidation (c)

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Figure 2: Postcontrast magnetic resonance imaging images of head and paranasal sinuses (a) coronal image showing nonenhancing material in the left ethmoid sinus (dashed white arrow), the left inferior turbinate in nonenhancing (black turbinate sign) (b) sagittal image showing small ring-enhancing lesion in the right parietal region

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  Discussion Top

The incidence of invasive pulmonary fungal infection has increased rapidly in recent years and is not limited to immunocompromised patients. Patients suffering from severe COVID-19 disease that requires ICU care are prone for fungal infections.[4] Pulmonary aspergillosis is more common than mucormycosis, and it holds true for COVID-19-associated infections also. Several case reports of CAPA are available in literature, CAPM reports are few. These two entities have different treatment as well as prognosis; hence, differentiation is critical for appropriate patient care. CAPA is defined as invasive pulmonary aspergillosis (IPA) in temporal proximity to a preceding SARS-CoV-2 infection and is categorized as possible, probable, or proven CAPA depending upon the evidence at hand.[5] Demonstration of fungal elements which are morphologically consistent with Aspergillus species by histopathological examination or direct microscopy is essential to classify pulmonary or tracheobronchial CAPA as “proven.” CAPA is considered “probabal” in the presence of pulmonary infiltrates or nodules, preferably documented with chest CT, or cavitating infiltrates (not attributable to another cause), or both, combined with mycological evidence. CAPA is considered “possible” in presence of pulmonary infiltrates or nodules, preferably documented by chest CT, or cavitating infiltrates (not attributable to another cause) in combination with mycological evidence (e.g., microscopy, culture, or galactomannan antigen test, alone or in combination) obtained through nonbronchoscopic lavage. This case suffered with severe COVID-19 disease and required ICU care with noninvasive ventilatory support. Radiological presence of consolidation with lesions showing the “reverse halo” sign and with elevated serum and BAL fluid galactomannan favored a diagnosis of probable CAPA. However, the patient did not respond either clinically or radiologically with injectable voriconazole. Although BAL fluid not grows any bacterial or fungal pathogen, PCR for mucorales infection came out positive. The diagnosis of CAPM was thus made and injectable amphotericin-B was started. The diagnosis of pulmonary mucormycosis is difficult because the clinicoradiological manifestations do not differ significantly from invasive pulmonary aspergillosis (IPA). Isolating mucorales fungi from respiratory cultures in a high-risk patient with a compatible clinical presentation is an indication for starting empirical antifungal therapy. Definitive diagnosis requires the demonstration of the organism in tissue. Because obtaining tissue can be difficult in these cases, we generally depend on radiographic evidence to support the diagnosis. In our patient, pulmonary mucormycosis was considered due to the combination of clinical and radiological (reverse halo sign) features and the positive PCR for mucorales species in the BAL sample. PCR test for mucorales in the BAL sample is frequently performed as cultures is generally negative. In 2014, Lengerova et al. validated a PCR test to detect mucorales in BAL samples from the immunocompromised patients.[6] It showed a high rate of sensitivity (100%) and specificity (93%), suggesting relevance for mucorales DNA detection in BAL samples.

There are a total of nine case reports of CAPM published till June 5, 2021[7],[8],[9],[10],[11],[12],[13],[14],[15] as per the authors' search, out of which only is from India. Pooled data from these studies show mucormycosis to be more prevalent in males and diabetes mellitus to be the most common comorbidity. Our case was a male diabetic suffering with severe COVID-19 disease, which required ICU care, and received parenteral steroids, which could be risk factors for mucormycosis. The comparison of our case with previous case reports of CAPM is summarized in [Table 1].
Table 1: Comparison of various case reports of coronavirus disease-associated pulmonary mucormycosis coronavirus disease associated with pulmonary mucormycosis

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Imaging characteristics of invasive fungal disease depend upon the type or degree of immunodeficiency and the underlying comorbidities. During immune recovery, the lesions may enlarge which does not necessarily indicate treatment failure. Chest radiographs or CT scans may demonstrate focal consolidation, masses, pleural effusions, or multiple nodules.[16] A halo sign is characteristic of angioinvasive fungal infection, but a reversed halo sign, which is a focal area of ground-glass attenuation surrounded by a ring of consolidation, has been also reported. The halo sign reportedly has good specificity (>90%) and positive predictive value (>60%) for the diagnosis of IPA in several studies.[17],[18] The reverse halo sign was originally described in patients with cryptogenic organizing pneumonia. Mucormycosis appears to be the most common condition to produce it in immunocompromised hosts.[19] A recent study suggested it occurs more frequently in patients with mucormycosis (54%) than aspergillosis (6%).[20] The key differences between invasive pulmonary aspergillosis and pulmonary mucormycosis are summarized in [Table 2].
Table 2: Clinical and radiological difference between invasive pulmonary aspergillosis and pulmonary mucormycosis

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  Conclusion Top

This case highlights the possibility of co-presence of both aspergillosis and mucormycosis in the same patient. As mucormycosis treatment requires amphotericin-B rather than voriconazole, diagnosis is of paramount importance. All the severe COVID-19 patients with persistent fever and hypoxemia or deteriorating after recovery should be evaluated for fungal infection. There is a need to have a high index of suspicion and a low threshold to begin treatment for mucormycosis, especially in diabetics and immunosuppressed patients. Although none of the imaging features reliably differentiate invasive pulmonary aspergillosis from pulmonary mucormycosis, the halo sign favors the former and the reverse halo sign favors the latter.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese center for disease control and prevention. JAMA 2020;323:1239-42.  Back to cited text no. 1
van Arkel AL, Rijpstra TA, Belderbos HN, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-associated pulmonary aspergillosis. Am J Respir Crit Care Med 2020;202:132-5.  Back to cited text no. 2
Sharma A, Hofmeyr A, Bansal A, Thakkar D, Lam L, Harrington Z, et al. COVID-19 associated pulmonary aspergillosis (CAPA): An Australian case report. Med Mycol Case Rep 2021;31:6-10.  Back to cited text no. 3
Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128.  Back to cited text no. 4
Koehler P, Bassetti M, Chakrabarti A, Chen SC, Colombo AL, Hoenigl M, et al. Defining and managing COVID-19-associated pulmonary aspergillosis: The 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis 2021;21:e149-62.  Back to cited text no. 5
Lengerova M, Racil Z, Hrncirova K, Kocmanova I, Volfova P, Ricna D, et al. Rapid detection and identification of mucormycetes in bronchoalveolar lavage samples from immune compromised patients with pulmonary infiltrates by use of high-resolution melt analysis. J Clin Microbiol 2014;52:2824-8.  Back to cited text no. 6
Pasero D, Sanna S, Liperi C, Piredda D, Branca GP, Casadio L, et al. A challenging complication following SARS-CoV-2 infection: A case of pulmonary mucormycosis. Infection 2021;49:1055-60.  Back to cited text no. 7
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Kanwar A, Jordan A, Olewiler S, Wehberg K, Cortes M, Jackson BR. A fatal case of Rhizopus azygosporus pneumonia following COVID-19. J Fungi (Basel) 2021;7:174.  Back to cited text no. 10
Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. Coronavirus disease (COVID-19) associated mucormycosis (CAM): Case report and systematic review of literature. Mycopathologia 2021;186:289-98.  Back to cited text no. 11
Hanley B, Naresh KN, Roufosse C, Nicholson AG, Weir J, Cooke GS, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: A post-mortem study. Lancet Microbe 2020;1:e245-53.  Back to cited text no. 12
Placik DA, Taylor WL, Wnuk NM. Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia. Radiol Case Rep 2020;15:2378-81.  Back to cited text no. 13
Bellanger AP, Navellou JC, Lepiller Q, Brion A, Brunel AS, Millon L, et al. Mixed mold infection with Aspergillus fumigatus and Rhizopus microsporus in a severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) patient. Infect Dis Now 2021;51:633-5.  Back to cited text no. 14
Zurl C, Hoenigl M, Schulz E, Hatzl S, Gorkiewicz G, Krause R, et al. Autopsy proven pulmonary mucormycosis due to Rhizopus microsporus in a critically Ill COVID-19 patient with underlying hematological malignancy. J Fungi (Basel) 2021;7:88.  Back to cited text no. 15
Murphy RA, Miller WT Jr. Pulmonary mucormycosis. Semin Roentgenol 1996;31:83-7.  Back to cited text no. 16
Blum U, Windfuhr M, Buitrago-Tellez C, Sigmund G, Herbst EW, Langer M. Invasive pulmonary aspergillosis. MRI, CT, and plain radiographic findings and their contribution for early diagnosis. Chest 1994;106:1156-61.  Back to cited text no. 17
Qin J, Meng X, Fang Y, Xu C, Zhu K, Wu B, et al. Computed tomography and clinical features of invasive pulmonary aspergillosis in liver transplant recipients. J Thorac Imaging 2012;27:107-12.  Back to cited text no. 18
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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