Skip to main content

Emerging complications of COVID-19 in a subset of Indian population: a pathological review with clinico-radiological case scenarios

Abstract

Background

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was declared a pandemic by the World Health Organization on 11 March 2020 has been reported in most countries around the world since its origins in Wuhan, China. As of September 2021, there have been over 229 million cases of COVID-19 reported worldwide, with over 4.7 million COVID-19–associated deaths.

Body

The devastating second wave of the COVID-19 pandemic in India has seen a rise in various extrapulmonary manifestations. One of key components in the pathogenesis of COVID-19 is downregulation of ACE-2, which is expressed on many organs and counterbalances the pro-inflammatory effects of ACE/angiotensin-II axis. This leads to influx of inflammatory cells into alveoli, increased vascular permeability and activation of prothrombotic mediators. Imaging findings such as ground glass opacities, interlobular septal thickening, vascular dilatation and pulmonary thrombosis correlate well with the pathogenesis.

Conclusion

We hypothesize that the systemic complications of COVID-19 are caused by either direct viral invasion or effect of cytokine storm leading to inflammation and thrombosis or a combination of both. Gaining insights into pathobiology of SARS-CoV-2 will help understanding the various multisystemic manifestations of COVID-19. To date, only a few articles have been published that comprehensively describe the pathophysiology of COVID-19 along with its various multisystemic imaging manifestations.

Background

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is an enveloped beta coronavirus [1]. COVID-19 had its origins in Wuhan, China in December 2019 which spread worldwide resulting in lockdowns and restrictions. World Health Organization (WHO) had officially declared COVID-19 as a pandemic on 11 March 2020.

The binding and entry into the host cell is mediated by its surface protein S (the spike protein) that recognizes the angiotensin converting enzyme 2 (ACE-2) receptors present on epithelial surfaces of the lungs, heart, kidney, and intestines, followed by biosynthesis, maturation and release of new virus particles. COVID-19 follows a biphasic pattern of illness which constitutes an early viral response and a late inflammatory phase [2].

Most patients experience a mild flu-like illness and have favourable prognosis, however the elderly and immunocompromised are more predisposed to severe and critical illness [3]. In patients with severe illness, SARS-CoV-2 elicits an aberrant response which may quickly progress to severe pneumonia and acute respiratory distress syndrome (ARDS) with or without other end organ failures [4].

Main text

In this article, we provide an insight into the pathophysiology and radiological appearances of few multisystemic manifestations of COVID-19, which are becoming more commonly recognized with increasing case load and use of imaging.

We conducted a literature search in Pubmed, Scopus and Google Scholar for articles relevant to pathogenesis of SARS-Cov-2 and searched for terms coronavirus, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, cytokine storm, clinical complications related to different organ systems from January 2020 to March 2021. The articles closely related to our study were included in this review and have been mentioned in references as they appear in the discussion.

Virology

SARS-CoV-2 is an enveloped single stranded ribonucleic acid (RNA) beta coronavirus. Its genome shows 80% similarity to SARS-CoV-1 and 96% similarity to bat coronavirus RaTG13 [1]. Out of six types of coronaviruses that have been identified to cause human disease, SARS-CoV-1 and Middle East respiratory syndrome (MERS) have already resulted in pandemics. SARS-CoV-2 is more infectious than SARS-CoV-1 because of structural differences in its surface proteins that enables stronger binding to ACE-2 receptors and greater affinity for upper respiratory tract and conjunctiva making it more efficient at invading the host cell [5,6,7].

Epidemiology

Since the first reports of cases from Wuhan, a city in the Hubei Province of China, at the end of 2019, the disease has spread like a wildfire in more than 200 countries globally involving all continents barring Antarctica. More than 229 million cases have been reported worldwide as of 21 September 2021 with more than 4.7 million deaths. India accounts for more than 33 million reported cases and 445,000 deaths [8].

It has been reported that the official counts represent only the tip of the iceberg underestimating the overall burden of COVID-19, as only a fraction of acute infections are diagnosed and reported. Seroprevalence surveys in the United States and Europe have revealed that the rate of prior exposure to SARS-CoV-2, as reflected by seropositivity, exceeds the incidence of reported cases by approximately tenfold or more [9, 10].

The primary mode of transmission is via respiratory droplets with infection occurring when these particles are inhaled or deposited on nasal, conjunctival or oral mucous membranes [7].

Most transmission occurs through close range and more duration of contact especially 15 min face to face and within 2 m [11]. Transmission via aerosol in poorly ventilated settings is also known to play an important role, while extent of fomite transmission and role of fecal shedding are not fully understood [2, 12].

Diagnosis

Real-time reverse transcriptase polymerase chain reaction (RTPCR) test from nasopharyngeal and oropharyngeal swabs is considered the gold standard for diagnosis, however recent variants like the delta variant are capable of evading the test rendering it false negative. False negative results may occur with any molecular test for the detection of SARS-CoV-2 if a mutation occurs in the part of the virus’ genome assessed by that test [13].

Other causes of false negative RTPCR test are mutations in the primer and probe target regions in SARS-CoV-2 genome, viral load kinetics and faulty sampling procedures. Thus, a negative RTPCR should not be used as the sole criterion for treatment and management decisions in suspected cases of COVID-19, in presence of strong clinical suspicion and prevailing epidemiology of COVID-19 [14]. The WHO recommends the use of chest imaging in cases where RTPCR is not available or has delayed results or when there is high clinical suspicion despite negative RTPCR [15].

Pathophysiology

The Renin-angiotensin-system along with the mechanism of SARS-CoV-2 invasion into host cells and the ensuing effects has been briefed in Figs. 1, 2 and 3.

Fig. 1
figure 1

The renin angiotensin system. ACE: Angiotensin converting enzyme; ACE-2: Angiotensin converting enzyme-2; AT1R/AT2R: Angiotensin I receptor/Angiotensin II receptor; Angiotensin 1–7 and 1–9: shorter peptides of angiotensin

Fig. 2
figure 2

Distribution of ACE-2 receptors and underlying co-morbid conditions

Fig. 3
figure 3

Pathogenesis of COVID-19. T: TMPRSS2 (transmembrane serine protease 2)

The spike protein, present on cell surface of SARS-CoV-2 contains receptor binding domain that attaches to ACE-2 receptor present on nasal epithelium, eyes, lungs, gastrointestinal tract, liver, pancreas, heart and blood vessels. TMPRSS2 (transmembrane serine protease 2) or furin (enzyme) primes the S protein and also cleaves the ACE-2 receptor causing downregulation of ACE-2. This mediates invasion of the virus into the host cell which is then followed by biosynthesis, maturation and release of new particles [16] (Fig. 3).

One of key components to understanding the pathogenesis of COVID-19 is ACE-2, which is a negative regulator of renin angiotensinogen aldosterone system (RAAS) and counterbalances the pro-inflammatory effects of angiotensin-II/AT1R receptor axis by breaking down angiotensin-II to shorter peptides namely angiotensin 1–9 and angiotensin 1–7 (Fig. 1). As the viral replication occurs, ACE-II downregulates, thus inhibiting breakdown of angiotensin-II thereby causing hypokalemia, vasoconstriction and ARDS like features [17,18,19,20,21,22].

In parallel to viremia which occurs with capillary damage, there is surge in inflammatory mediators leading to cytokine storm which leads to overexpression of ACE-2 response so as to counterbalance the ACE/angiotensin-II axis mediated inflammatory effects. Given the fact that ACE-2 receptors are expressed on most human organs, which is now exaggerated because of the cytokine storm, the circulating viruses use this window to attack these organs (Fig. 3). This vicious cycle then continues leading to systemic failure [23].

The cytokine release syndrome (CRS) or cytokine storm is the uncontrolled systemic inflammatory response that occurs due to immunological misfiring that causes release of high amounts of proinflammatory cytokines along with complement components and coagulation dysfunction [23, 24].

We hypothesize that various multisystemic complications caused by SARS-CoV-2 can be explained by direct viral attack (by means of ACE-2 receptors), or immune cell mediated cytokine storm related pro-inflammatory signals along with upregulation of ACE/angiotensin-II axis (due to downregulation of ACE-2) or a combination of both. This may cause myriad of systemic complications.

Pancreatic islet cells and exocrine cells of pancreas express ACE-2 receptors. Acute pancreatitis may be idiopathic or caused by several etiological factors such as gall stones, alcohol abuse, metabolic disorders, autoimmune diseases, drugs, toxins and viruses such as mumps, Coxsackie B, measles, Epstein–Barr and hepatitis A, B and E. Association between H1N1 influenza and acute pancreatitis has also been reported [25, 26]. One study has also suggested a direct impact of COVID-19 infection on the pancreas [27]. There were  no reasons for clinical suspicion or direct evidence of above-mentioned etiological factors in our case presented later (Case 1, Fig. 4). The best possible diagnosis was COVID-19 induced pancreatitis.

Evidence of raised serum amylase and lipase should not be directly attributed to acute pancreatitis as many patients with COVID-19 who present with gastrointestinal symptoms may show elevated pancreatic enzymes [28]. Hence, imaging is necessary to rule out acute pancreatitis. Ultrasound is the initial imaging modality of choice. In our case, ultrasound (done outside) did not reveal any abnormality. Therefore, non-contrast CT scan of abdomen was done in view of raised serum creatinine. Contrast enhanced computed tomography provides over 90% sensitivity and specificity for the diagnosis of acute pancreatitis [29].

The current second wave of the COVID-19 pandemic in India has seen a rise in the rhino-orbital mucormycosis co-infections in COVID-19 patients.

Fungal sinusitis is broadly classified as invasive and non-invasive. Invasive fungal sinusitis consists of fungal hyphae within the mucosa, submucosa, bone, or blood vessels of the paranasal sinuses [30].

Mucormycosis is an angioinvasive disease caused by fungi of the order Mucorales such as Rhizopus, Mucor, Rhizomucor, Cunninghamella and Absidia. The prevalence of mucormycosis in India is approximately 0.14 cases per 1000 population, about 80 times the prevalence in developed countries [31]. Underlying immunosuppressive states such as diabetes, hematological malignancies, organ transplantations, treatment with immunosuppressants are common predisposing factors. COVID-19 has been associated with increasing trend in fungal infections. Complications of orbital and cerebral involvement are more frequent in diabetic ketoacidosis and with concomitant use of steroids [32]. Prolonged use of corticosteroids at a therapeutic dose of ≥ 0.3 mg/kg for at least three weeks in the past 60 days is considered a risk factor for invasive fungal diseases [33]. Further, IL-6-inhibiting drugs such as tocilizumab, used for mitigation of cytokine storm, may cause immune dysregulation thereby increasing the risk of secondary infections, without much clinical benefit in patients with COVID-19 [34, 35]. COVID-19 with acute respiratory distress syndrome may also predispose patients to secondary infections as a result of immune dysregulation [36]. SARS-CoV-2 directly impairs cell-mediated immune response, by virtue of reduced levels of circulating lymphocytes and T cell subsets [37].

Rhino-orbito-cerebral mucormycosis is considered as the most common manifestation of mucormycosis that is thought to be acquired via the inhalation of fungal spores into the paranasal sinuses. The spores invade the nasal mucosa and form angio-invasive hyphae that cause infarction of involved tissue which manifests as black palatal or gingival eschars. It may lead to maxillary and subsequent orbital spread via ethmoidal sinus. Perforation of the nasal septum may also be seen. It usually presents with an acute onset of fever, facial pain, nasal congestion, headache, perinasal swelling, facial numbness, and visual changes such as diplopia and proptosis [38].

The multiplanar capabilities of MRI with its superior soft tissue depiction make it a valuable modality that is used not merely in the diagnosis of mucormycosis, but also in delineating the anatomical extent of disease as well as its complications [32, 39]. Bony changes are better assessed by CT.

Both MRI and non-contrast CT demonstrate mucosal thickening and/or soft-tissue within the lumen of the involved paranasal sinus and nasal cavity. The soft tissue contents show variable signal intensity on T1- and T2-weighted images. Hypertrophy of nasal turbinates is seen with nasal involvement. Post-contrast enhancement can be seen in the thickened mucosa and involved tissues. However, contiguous areas of non-enhancing soft tissue may be seen within the necrosed turbinates and/or paranasal sinuses, known as the “black turbinate sign”. The infarcted mucosa may show restriction of diffusion [40]. In general, sinusitis demonstrates enhancement of the peripheral mucosa on T1 weighted post contrast sequence. Lack of enhancement of the mucosa is typical of rhinocerebral mucormycosis because the hyphae invade smaller vessels supplying the mucosa [40].

Severe unilateral nasal cavity soft-tissue thickening is the most consistent, though nonspecific, feature [40]. Mild fat stranding in pterygopalatine fossa, peri-antral, malar, masticator spaces with even subtle findings in sinuses is suggestive of invasive fungal sinusitis in appropriate clinical setting. More extensive changes such as retroantral fat pad inflammation, bone erosion, and orbital or intracranial invasion are more specific but late features [41].

In contrast, allergic fungal sinusitis shows bilateral asymmetrical involvement, usually pansinusitis causing expansion of sinuses, with hyperdense fungal contents on CT due to allergic mucin. There is typical low signal intensity or signal void on T2W images due to high concentration of metals like iron, magnesium, manganese concentrated by the fungal organisms along with high protein and low free water content of the allergic mucin [41].

Aggressive bone destruction of the sinus walls occurs rapidly with intracranial and intraorbital extension [41]. Sometimes, bone erosion and mucosal thickening may be subtle. Extension beyond the sinuses may occur with intact bony walls as they tend to spread along vessel walls. Facial numbness, caused by fifth cranial nerve involvement, indicates that the infection has spread beyond the sinuses. Orbital involvement occurs in the form of inflammatory changes in the orbital fat and extraocular muscles and resultant proptosis. Obliteration of the peri-antral fat is a subtle sign of such extension [41]. Intracranial invasion occurs in the form of leptomeningeal enhancement in early infection and cerebritis, granulomas, and cerebral abscess formation may be encountered in advanced stages. Intracranial granulomas appear hypointense on T1- and T2-weighted images with minimal enhancement on post contrast images [41]. Spread to the brain may occur via the orbital apex, orbital vessels or via the cribriform plate causing fungal abscess, cranial nerve palsy, cavernous sinus thrombosis, carotid artery involvement and stroke [42].

Rhino-orbital mucormycosis may occur even in patients who have been recently discharged after recovering from COVID-19 as seen in case number 2 illustrated below in Figs. 5 and 6.

A common fungal infection that can cause secondary pulmonary infection in severely immunocompromised patients is aspergillosis, which is caused by Aspergillus fumigatus, an opportunistic fungal pathogen. Recent studies reveal occurrence of aspergillosis in 20–30% of the severely ill or ventilated COVID-19 patients, hence establishing an association between COVID-19 and pulmonary fungal infections, which is referred to as COVID-19 Associated Pulmonary aspergillosis (CAPA) [43]. CAPA's risk factors are similar to those of severe COVID-19 [44]. It has been shown that hospitalized COVID-19 patients who develop ARDS become more susceptible to acquire superimposed infections caused by bacteria and Aspergillus species, which is associated with high mortality rates and may prolong the acute phase of COVID-19 [45].

In view of the high morbidity and mortality, early diagnosis and treatment are imperative. A combination of HRCT chest and Aspergillus antigen tests on bronchoalveolar lavage (BAL) and serum, including galactomannan enzyme-linked immunosorbent assay or lateral flow tests, or Aspergillus PCR are required for diagnosis of CAPA. As BAL is an aerosol generating procedure, an alternative is the beta-D-glucan [46].

The reverse halo sign refers to the peripheral consolidation surrounding a central area of ground-glass opacity. Associated irregular and intersecting areas of stranding or irregular lines may be present within the area of ground-glass opacity or a cavity which along with surrounding consolidation is referred to as the bird’s nest sign (Fig. 7). These signs are suggestive of invasive fungal infection (e.g., angioinvasive Aspergillus infection or mucormycosis) in susceptible patient populations [47].

COVID-19, being a pro-inflammatory and pro-thrombotic condition as detailed above (Fig. 1 and 3), produces a state of hypercoagulability thereby leading to clot formation in vessels. Predisposing vascular risk factors such as diabetes, hyperlipidemia, smoking may further exacerbate the risk. In milder cases of COVID-19, direct viral invasion leading to endothelitis is thought to be the causative factor, whereas in individuals with severe COVID-19, the pro-inflammatory cytokine storm increases the chances of pre-existing plaque rupture and subsequent thrombus formation [48].

The article has been enriched with few interesting multisystemic post COVID complications.

Case 1 A 52-year-old female, recently recovered from RTPCR proven COVID-19, presented with nausea, vomiting and acute upper abdominal pain radiating to back for the last 2 days. There was history of mild diarrhea during initial phase of COVID-19 along with mild upper respiratory tract symptoms. Vaccination status was negative. Laboratory investigations revealed raised serum amylase and lipase (910 U/L and 652 U/L respectively); normal liver profile; raised total leukocyte count (19,300/mm3); raised CRP (30 mg/L) and raised serum creatinine (1.7 mg/dL). The lipid profile was normal.

The physical examination revealed nondistended, soft abdomen with epigastric tenderness. No mass was palpable. Rest of the general physical examination was unremarkable with no signs of dehydration or jaundice. There was past history of cholecystectomy 14 years back due to gall stones, however, without any history of biliary calculi or pancreatitis. The patient did not undergo any invasive procedure, namely endoscopic retrograde cholangiopancreatography or recent surgery. No history of trauma, or recent hospitalization was present. The patient was non-alcoholic.

Ultrasound was unremarkable. Non-contrast CT abdomen revealed enlarged pancreas with peripancreatic fat stranding with no evidence of peripancreatic fluid collection or ascites (Fig. 4a–c).

Fig. 4
figure 4

Non contrast CT images (AC) reveal bulky pancreas with peripancreatic fat stranding. No free fluid is seen. Evidence of post cholecystectomy clips is noted in image A. D Lung window of the same patient shows COVID-19 changes in both lung fields

Limited sections of thorax revealed multifocal patchy subpleural ground glass opacities in both lower lobes (Fig. 4d). The patient was treated conservatively and recovered well.

Case 2 A 54-year-old non-hypertensive male with uncontrolled diabetes, recently recovered from RTPCR positive moderate COVID-19, who was discharged 10 days back after being admitted in hospital for 7 days, presented with headache, swelling around left eye with painful restriction of eye movements and blurring of vision for the last 3 days. The right eye was unaffected. On general physical examination, the patient was febrile with normal vitals and oxygen saturation of 96%. During hospital stay, he had received intravenous methylprednisolone 40 mg BD which was tapered gradually.

On ophthalmological examination, mild periocular edema and proptosis were seen. Best corrected visual acuity was 6/6 in right eye and 6/12 in left eye. Left eye abduction was severely limited.

Intraocular pressure 16 mm Hg in right eye, 20 mm Hg in left eye.

Ocular motility of left eye abduction: − 2, elevation: − 2.

Pupils round, regular, reacting to light, no relative afferent pupillary defect. Confrontation of visual field was full.

Lid edema.

Slit lamp examination Conjunctival chemosis was present in left eye. Cornea, anterior chamber, iris and lens were normal.

Fundoscopy was unremarkable.

Laboratory parameters CRP: 55 mg/L; D-dimer: 913 ng/ml; serum ferritin: 703 ng/ml. TLC was elevated (14,500/mm3). Rest of the parameters (LFT, KFT, thyroid profile) were within normal limits.

CEMRI of paranasal sinuses and orbits revealed evidence of rhino-orbital mucormycosis as shown in Figs. 5 and 6.

Fig. 5
figure 5

T1W coronal images (A, B) show bulky superior rectus, lateral rectus and superior oblique muscles and intraconal fat stranding along with bulky middle and inferior turbinates. Polypoidal mucosal thickening is also seen in both maxillary sinuses. C T2W axial image shows proptosis of left orbit with preseptal swelling along with mucosal hypertrophy and T2 hyperintense contents in ethmoid sinus predominantly on left side (white arrow). D T1 post contrast axial image shows contiguous non-enhancing areas involving the walls of ethmoid sinus and middle turbinate on left side- black turbinate sign (blue arrow). Walls of right ethmoid sinus show lack of enhancement (red arrow)

Fig. 6
figure 6

(same patient as in Fig. 5: A, B: T2W axial images showing T2 hyperintense contents in ethmoid and sphenoid sinuses on left side with areas of signal void  (red arrows) suggestive of fungal contents within. T1 post contrast coronal (C) and axial (D) images show patchy non-enhancing walls of sphenoid sinus on left side (white arrows) with normal enhancement of adjacent walls. E Microphotograph from debrided material showing magenta coloured aseptate fungal hyphae seen in the necrotic material likely to be mucormycosis (PAS stain X400)

Case 3 A 71-year-old female patient with uncontrolled diabetes mellitus and hypertension, was admitted with severe COVID-19 one month back. The patient recovered well and was discharged from hospital after a stay of 10 days. She received methylprednisolone 80 mg IV BD for 10 days. She was prescribed dexamethasone 6 mg BD for 3 days followed by 6 mg OD × 3 days on discharge among other medicines. Now the patient complaints of fever and cough of 3 days duration, 20 days after dis- charge from hospital. Repeat RTPCR was negative.

HRCT was done for further evaluation which revealed bird nest sign suggestive of mucormycosis, on the background of COVID-19 as shown in Fig. 7.

Fig. 7
figure 7

HRCT chest lung window. (AD) Two large thick walled cavities are seen in left lower lobe with internal soft tissue density contents giving bird’s nest appearance on the background of changes of COVID-19 pneumonia. E, F Mediastinal window images showing soft tissue density contents within cavity and left pleural effusion along with an enlarged aorto-pulmonary node (F). G Microphotograph from lung biopsy specimen showing magenta coloured septate fungal hyphae in the necrotic material likely to be mucormycosis (H&E stain X400)

Case 4 An 80-year-old non-hypertensive non-diabetic male admitted with severe COVID-19 complained of sudden onset of severe headache, loss of vision in left eye, periorbital swelling with painful restriction of eye movement, nasal stuffiness and discharge with mild epistaxis, facial pain and swelling. The patient has history of chronic kidney disease for 3 years.

Patient was on intravenous methylprednisolone 40 mg BD for last 12 days.

On examination, the patient was febrile (102.4 degrees Fahrenheit) with swelling in orbit and alveolar region of the face on left side.

Ophthalmological examination Right Left
General condition of eye Normal Swelling, DOV, drooping
Vision with pin hole 6/36 PL negative
Vision unaided 6/36 PL negative
Non-contact tonometry 12 mm Hg 13 mm Hg
Ocular motility Normal Severely limited
Pupil Poorly reacting Mid-dilated/fixed
Slit-lamp Unremarkable Conjunctival chemosis
Fundoscopy Unremarkable Unremarkable

Laboratory parameters CRP: 28 mg/L; D-dimer: 855 ng/ml; serum ferritin: 470 ng/ml. CBC showed TLC of 13,000/mm3. Rest of the parameters (LFT, KFT, thyroid profile) were within normal limits.

CEMRI of paranasal sinuses and orbits revealed evidence of rhino-orbital mucormycosis as shown in Fig. 8.

Fig. 8
figure 8

T2 fat suppressed coronal (A) and T1W coronal (B) images show evidence of extensive hypertrophy of turbinates on left side with opacification of bilateral maxillary and left ethmoidal sinuses with heterogeneous T2 hyperintense contents showing foci of signal void consistent with fungal elements. There is involvement of left orbit in contiguity with left ethmoid sinus in the form of bulky superior oblique, medial and inferior recti muscles with orbital fat stranding. Preseptal swelling and proptosis of left orbit were also present (not shown here). C, D T2W fat suppressed axial images showing complete opacification of sphenoid sinus in addition to above-mentioned findings along with hyperintensity in peri-alveolar (white arrow), pterygoid muscle (yellow arrow), pterygopalatine fossa (black arrow) and infratemporal fossa (red arrow) with corresponding enhancement on post contrast images (EG T1 post contrast images). Post contrast images also show black turbinate sign. H: Microphotograph from debrided material showing black coloured aseptate fungal hyphae seen in the necrotic slough likely to be mucormycosis (GMS stain X400).

Case 5 A 59-year-old female patient with uncontrolled diabetes mellitus and hypertension, was admitted with severe COVID-19. The patient was recovering well and was about to be discharged from hospital after a stay of 12 days. She received methylprednisolone 80 mg IV BD for 12 days which was to be tapered gradually. Now the patient complaints of fever, headache, altered consciousness and 2 episodes of seizures for the last 2 days.

CEMRI of paranasal sinuses with orbits and brain revealed evidence of rhino-orbito-cerebral mucormycosis as shown in Fig. 9.

Fig. 9
figure 9

A (T2 axial) and B (T1 post contrast axial) images show mucosal thickening and opacification in bilateral maxillary sinuses with hypertrophy of turbinates on right side along with involvement of anterior and posterior periantral fat (yellow arrows) on right side with contiguous involvement of infratemporal fossa. C (T2 coronal), D (T1 post contrast coronal) images show involvement of inferior rectus muscle and fat stranding in right orbit. E (T2 axial), F (T1 post contrast axial) images of brain showing an abscess in right temporal lobe with hypointense wall on T2W image showing post contrast enhancement (white arrows). The wall of the abscess shows restriction of diffusion on DWI (G) with loss of signal intensity on ADC image (H). The internal contents do not show restriction of diffusion, suggesting fungal abscess. I Microphotograph from debrided material showing aseptate fungal hyphae seen in the necrotic material likely to be mucormycosis (H&E stain X400)

Case 6 A 46-year-old male, known diabetic and hypertensive, with moderate COVID-19 pneumonia presented with sudden onset of left hemiparesis. MRI brain (Fig. 10) revealed acute infarct with non-visualization of right internal carotid artery. Carotid doppler (not shown) revealed thrombus in proximal internal carotid artery.

Fig. 10
figure 10

A (DWI) and B (ADC) images show acute infarct in right internal artery territory. C (MR angiography thick slab image): There is non-visualization of right internal carotid artery. Carotid Doppler (not shown) revealed a thrombus in proximal right internal carotid artery. Right middle cerebral artery is seen to be partly reformed by collaterals

Conclusion

COVID-19 predominantly presents with respiratory symptoms and may cause a multitude of systemic complications involving various organs systems. One of the key components to understanding the pathogenesis of COVID-19 is downregulation of ACE-2, which is expressed on multiple organs and also counterbalances the pro-inflammatory ACE/angiotensin-II axis. This leads to influx of inflammatory cells into alveoli, increased vascular permeability and activation of prothrombotic mediators. We hypothesize the complications to be caused by either direct viral invasion or effect of cytokine storm leading to inflammation and thrombosis or a combination of both.

Imaging plays a key role in the early identification of COVID-19 related complications. Imaging findings such as ground glass opacities, interlobular septal thickening, vascular dilatation and pulmonary thrombosis correlate well with the pathogenesis described above. Rhino-orbital mucormycosis, a rare angio-invasive fungal infection has shown a rising trend in the setting of COVID-19, and requires prompt diagnosis and treatment to reduce the associated mortality and morbidity.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

COVID-19:

Coronavirus disease 2019

SARS-CoV-2:

Severe acute respiratory syndrome corona virus 2

WHO:

World Health Organization

ACE-2:

Angiotensin converting enzyme

CEMRI:

Contrast enhanced magnetic resonance imaging

CT:

Computed tomography

T1W:

T1 weighted

T2W:

T2 weighted

ARDS:

Acute respiratory distress syndrome

RTPCR:

Reverse transcriptase polymerase chain reaction

CRP:

C reactive protein

TLC:

Total leukocyte count

CBC:

Complete blood count

LFT:

Liver function test

KFT:

Kidney function test

OD:

Once a day

BD:

Twice a day

BAL:

Broncho-alveolar lavage

References

  1. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q (2020) Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367:1444–1448. https://doi.org/10.1126/science.abb2762

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cevik M, Kuppalli K, Kindrachuk J, Peiris M (2020) Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ 371:m3862. https://doi.org/10.1136/bmj.m3862

    Article  PubMed  Google Scholar 

  3. Huang C, Wang Y, Li X, Ren L, Zhao J, Yi Hu et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506

    CAS  Article  Google Scholar 

  4. Mangalmurti N, Hunter CA (2020) Cytokine storms: understanding COVID-19. Immunity 53:19–25. https://doi.org/10.1016/j.immuni.2020.06.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Wrapp D, Wang N, Corbett KS et al (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367:1260–1263. https://doi.org/10.1126/science.abb2507

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Wölfel R, Corman VM, Guggemos W et al (2020) Virological assessment of hospitalized patients with COVID-2019. Nature 581:465–469. https://doi.org/10.1038/s41586-020-2196-x

    CAS  Article  PubMed  Google Scholar 

  7. Hui KPY, Cheung MC, Perera RAPM et al (2020) Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med 8:687–695. https://doi.org/10.1016/S2213-2600(20)30193-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. COVID-19 Coronavirus Pandemic. https://www.worldometers.info/coronavirus/. Accessed 21 Sep 2021.

  9. Stringhini S, Wisniak A, Piumatti G, Azman AS, Lauer SA, Baysson H et al (2020) Seropravelence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study. Lancet 396(10247):313–319

    CAS  Article  Google Scholar 

  10. Havers FP, Reed C, Lim T, Montgomery JM, Klena JD, Hall AJ et al (2020) Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23-May 3. JAMA Intern Med 180(12):1576–1586. https://doi.org/10.1001/jamainternmed.2020.4130

    CAS  Article  Google Scholar 

  11. European Centre for Disease Prevention and Control (2020) Surveillance definitions for COVID-19. https://www.ecdc.europa.eu/en/covid-19/surveillance/surveillance-definitions

  12. Cevik M, Marcus JL, Buckee C, Smith TC (2021) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission dynamics should inform policy. Clin Infect Dis Off Publ Infect Dis Soc Am 73(Suppl 2):S170–S176. https://doi.org/10.1093/cid/ciaa1442

    CAS  Article  Google Scholar 

  13. https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-viral-mutations-impact-covid-19-tests

  14. Agarwal A, Kumar N (2021) CT chest with pulmonary angiography as a diagnostic tool in clinically suspected RT-PCR-negative COVID-19 pneumonia with pulmonary artery aneurysm. Indian J Case Rep 7(3):79–82. https://doi.org/10.32677/IJCR.2021.v07.i03.002

  15. World Health Organization (2021) Use of Chest Imaging in COVID-19: A Rapid Advice Guide, WHO Reference Number. Geneva: World Health Organization. Available from: WHO/2019-nCoV/Clinical/Radiology_imaging/2020.1. Accessed 21 Jul 2021

  16. Hoffmann M, Kleine-Weber H, Schroeder S et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(2):271–280. https://doi.org/10.1016/j.cell.2020.02.052

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Kuba K, Imai Y, Penninger JM (2006) Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol 6:271–276

    CAS  Article  Google Scholar 

  18. Bindom SM, Lazartigues E (2009) The sweeter side of ACE2: physiological evidence for a role in diabetes. Mol Cell Endocrinol 302:193–202

    CAS  Article  Google Scholar 

  19. Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM (2010) Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circ J 74:405–410

    CAS  Article  Google Scholar 

  20. Donoghue M, Hsieh F, Baronas E et al (2000) A novel angiotensin converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 87(5):E1-9

    CAS  Article  Google Scholar 

  21. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275(43):33238–33243

    CAS  Article  Google Scholar 

  22. Li XC, Zhang J, Zhuo JL (2017) The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 125:21–38

    CAS  Article  Google Scholar 

  23. Trougakos IP, Stamatelopoulos K, Terpos E et al (2021) Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications. J Biomed Sci. https://doi.org/10.1186/s12929-020-00703-5

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lucas C, Wong P, Klein J et al (2020) Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 584:463–469. https://doi.org/10.1038/s41586-020-2588-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Agzarian AE, Agzarian AY (2016) Influenza A as a cause of acute pancreatitis: a case report. Proc UCLA Healthc 20:1–2

  26. Habib A, Jain A, Singh B, Jamshed N (2016) H1N1 influenza presenting as severe acute pancreatitis and multiorgan dysfunction. Am J Emerg Med 34(9):1911. https://doi.org/10.1016/j.ajem.2016.01.019

    Article  PubMed  Google Scholar 

  27. Wang F, Wang H, Fan J, Zhang Y, Wang H, Zhao Q (2020) Pancreatic injury patterns in patients with COVID-19 pneumonia. Gastroenterology 5:434–435

    Google Scholar 

  28. Kumaran NK, Karmakar BK, Taylor OM (2020) Coronavirus disease-19 (COVID-19) associated with acute necrotising pancreatitis (ANP). BMJ Case Rep CP 13:e237903

    Article  Google Scholar 

  29. Banks PA, Freeman ML (2006) Practice guidelines in acute pancreatitis. Am J Gastroenterol 101(10):2379–2400

    Article  Google Scholar 

  30. DeShazo RD, Chapin K, Swain RE (1997) Fungal sinusitis. N Engl J Med 337(4):254–259

    CAS  Article  Google Scholar 

  31. Skiada A, Pavleas I, Drogari-Apiranthitou M (2020) Epidemiology and diagnosis of mucormycosis: an update. J Fungi 6:265. https://doi.org/10.3390/jof6040265

    CAS  Article  Google Scholar 

  32. Prakash H, Chakrabarti A (2019) Global epidemiology of mucormycosis. J Fungi 5:26. https://doi.org/10.3390/jof5010026

    CAS  Article  Google Scholar 

  33. Donnelly JP, Chen SC, Kauffman CA et al (2020) Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin Infect Dis Off Publ Infect Dis Soc Am 71(6):1367–1376

    Article  Google Scholar 

  34. Kimmig LM, Wu D, Gold M et al (2020) IL-6 inhibition in critically Ill COVID-19 patients is associated with increased secondary infections. Front Med (Lausanne) 7:583897. https://doi.org/10.3389/fmed.2020.583897

    Article  Google Scholar 

  35. Furlow B (2020) COVACTA trial raises questions about tocilizumab’s benefit in COVID-19. Lancet Rheumatol 2(10):592

    Article  Google Scholar 

  36. Clancy CJ, Nguyen MH (2020) Coronavirus disease 2019, superinfections, and antimicrobial development: what can we expect? Clin Infect Dis 71(10):2736–2743

    CAS  Article  Google Scholar 

  37. Chen G, Wu D, Guo W et al (2020) Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Investig 130(5):2620–2629

    CAS  Article  Google Scholar 

  38. Afroze SN, Korlepara R, Rao GV, Madala J (2017) Mucormycosis in a diabetic patient: a case report with an insight into its pathophysiology. Contemp Clin Dent 8(4):662–666

    Article  Google Scholar 

  39. Herrera DA, Dublin AB, Ormsby EL, Aminpour S, Howell LP (2009) Imaging findings of rhinocerebral mucormycosis. Skull Base 19(2):117–125. https://doi.org/10.1055/s-0028-1096209

    Article  PubMed  PubMed Central  Google Scholar 

  40. Safder S, Carpenter JS, Roberts TD, Bailey N (2010) The “Black Turbinate” sign: an early MR imaging finding of nasal mucormycosis. AJNR Am J Neuroradiol 31(4):771–774. https://doi.org/10.3174/ajnr.A1808

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Aribandi M, McCoy VA, Bazan C 3rd (2007) Imaging features of invasive and noninvasive fungal sinusitis: a review. Radiographics 27(5):1283–1296. https://doi.org/10.1148/rg.275065189

    Article  PubMed  Google Scholar 

  42. Sheman DD (1992) Orbital anatomy and its clinical applications. Lippincott-Raven, Philadelphia, pp 1–26

    Google Scholar 

  43. Fekkar A, Lampros A, Mayaux J, Poignon C, Demeret S, Constantin JM et al (2020) Occurrence of invasive pulmonary fungal infections in severe COVID-19 patients admitted to the ICU. Am J Respir Crit Care Med 203(3):307–317. https://doi.org/10.1164/rccm.202009-3400OC

    Article  Google Scholar 

  44. Bartoletti M, Pascale R, Cricca M, Rinaldi M, Maccaro A, Bussini L et al (2020) Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study. Clin Infect Dis 1(1):e3606–e3614

    Google Scholar 

  45. Zhu X, Ge Y, Wu T, Zhao K, Chen Y, Wu B, Zhu F, Zhu B, Cui L (2020) Co-infection with respiratory pathogens among COVID-2019 cases. Virus Res 11:198005. https://doi.org/10.1016/j.virusres.2020.198005

    CAS  Article  Google Scholar 

  46. Armstrong-James D, Youngs J, Bicanic T, Abdolrasouli A, Denning DW, Johnson E et al (2020) Confronting and mitigating the risk of COVID-19 associated pulmonary aspergillosis. Eur Respir J 56:2002554

    CAS  Article  Google Scholar 

  47. Walker CM, Abbott GF, Greene RE, Shepard JA, Vummidi D, Digumarthy SR (2014) Imaging pulmonary infection: classic signs and patterns. AJR Am J Roentgenol 202(3):479–492. https://doi.org/10.2214/AJR.13.11463

    Article  PubMed  Google Scholar 

  48. Mohamud AY, Griffith B, Rehman M, Miller D, Chebl A, Patel SC et al (2020) Intraluminal carotid artery thrombus in COVID-19: another danger of cytokine storm? AJNR Am J Neuroradiol 41:1677–1682. https://doi.org/10.3174/ajnr.A6674

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

None.

Author information

Affiliations

Authors

Contributions

AA: Conception, design, analysis, interpretation of data, drafted the work. P: Drafted and supervised the work. AH: Conception, design, analysis. EL: Supervised the work. AA: Helped with interpretation, Supervised the work. SA: Helped with interpretation, Supervised the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Aniket Agarwal.

Ethics declarations

Ethics approval and consent to participate

Not applicable. Patients were screened for any contraindications for MRI. This was not a clinical trial. Written and informed consent was obtained from patients undergoing hospital admissions and investigations as per the protocols. No personal information has been used in the dataset. Only radiological images have been used and all details of the patients have been cropped from the images.

Consent for publication

Not applicable.

Competing interests

The authors have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Agarwal, A., Prachi, Haider, A. et al. Emerging complications of COVID-19 in a subset of Indian population: a pathological review with clinico-radiological case scenarios. Egypt J Radiol Nucl Med 53, 42 (2022). https://doi.org/10.1186/s43055-021-00680-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43055-021-00680-1

Keywords

  • COVID-19
  • Pathogenesis of COVID-19
  • Cytokine storm
  • Systemic complications of COVID-19