Keywords
COVID-19 - diabetes - renal mucormycosis
Introduction
The coronavirus disease 2019 (COVID-19) pandemic continues despite affecting more
than 196 million cases and claiming more than 4.2 million lives globally.[1] Adding to the disease burden, we also have incidences of opportunistic fungal infections
including aspergillosis, candidiasis, and mucormycosis in patients either after recovery
or during the resolving phase of COVID-19 pneumonia.[2] There has been a surge of the COVID-19-associated mucormycosis (CAM) especially
in India.[3] The various presentations of mucormycosis in decreasing order of frequency include
oculo-rhino-cerebral, pulmonary, gastrointestinal, cutaneous, and disseminated mucormycosis.[4] There has been a case report of fatal primary renal mucormycosis in a post-COVID
young male with no prior risk factors, with the imaging finding of renal infarct;
the prior history of COVID pneumonia could have been coincidental rather than contributory
in that case.[5] There has been another case report of renal mucormycosis with a nonfunctioning kidney
and main renal artery thrombosis in a post-COVID patient; much similar to our case.[6] Till date there have been no reports of emphysematous pyelonephritis with main renal
artery and vein thrombosis; an aggressive presentation of renal mucormycosis in a
post-COVID individual. Here, we report one such rare case.
Case Report
A 64-year-old male patient presented to the emergency department with complaints of
abdominal pain, dysuria, hematuria, and decreased urine output for 1 week. He was
a known diabetic and hypertensive on oral hypoglycemic agents and antihypertensives
for the past 10 years. There were no presenting complaints of fever, breathing difficulty,
or loss of consciousness. There was history of fever 1 month back with a positive
reverse transcription polymerase chain reaction test for COVID-19; he was treated
at an outside hospital and discharged following which he was apparently asymptomatic
till a week back, when he developed the abovementioned symptoms and was referred to
our hospital for further management. On examination, the patient was tachypneic and
afebrile; blood pressure and oxygen saturation were within normal limits. Diffuse
abdominal tenderness more over bilateral loin region was noted.
Laboratory examination revealed normal serum creatinine (0.9 mg/dL) initially and
an increased total leukocyte count (23,000 cells/mm3) with neutrophilia (94%) and severe lymphopenia (2%). There was elevated erythrocyte
sedimentation rate (118 mm/h), C-reactive protein (26.6 mg/dL), D-dimer (1,670 ng/mL),
and procalcitonin (6.2 ng/mL) levels pointing toward sepsis. The patient also had
poor glycemic control with increased random blood sugar (253 mg/dL), serum ketones
(28.0 mg/dL), and glycated hemoglobin levels (11.7%). Urine analysis showed few pus
cells and red blood cells on microscopy; no fungal elements were seen. Urine dipstick
reflectance photometry detected protein, blood, and glucose but was negative for ketones
in urine. There was no growth in aerobic bacterial culture from urine sample.
An unenhanced computed tomography (CT) of the patient's abdomen and pelvis was performed
using 128 slice Multidetector CT-Optima 660 (GE Healthcare, Milwaukee, Wisconsin,
United States); following which 100 mL of iodinated contrast Omnipaque (GE Healthcare,
Shanghai, China) was administered at a flow rate of 4 mL/s using a pressure injector.
Images with a slice thickness of 5 mm and 0.625 mm reconstruction in the nephrogenic,
excretory, and delayed phase were obtained at a time-delay of 55 seconds, 90 seconds,
and 5 minutes, respectively. The study revealed an enlarged left kidney with perinephric
fat stranding, thickening of Gerota's fascia, and multiple air pockets in the left
kidney, left upper ureter, urinary bladder, and surrounding soft tissues ([Figs. 1] and [2]). There was complete absence of contrast enhancement in the left renal parenchyma
([Fig. 3]) with thrombosis of the left main renal artery ([Fig. 4]) and thrombosis with air foci within the left main renal vein ([Fig. 5]). No evidence of extension of thrombus into the great vessels noted. There were
no renal or perinephric abscess/collections. There was no excretion of contrast into
the left pelvicalyceal system ([Fig. 6]). Visualized lung bases showed an area of consolidation with central ground-glass
opacity (atoll sign) and cavitation in left lower lobe and bilateral minimal pleural
effusion ([Fig. 7A and B]). A possibility of renal mucormycosis with superadded anaerobic infection was considered.
Fig. 1 Axial noncontrast-enhanced computed tomography image showing the bulky left kidney
with air pockets and extensive surrounding perinephric fat stranding (arrow).
Fig. 2 Axial contrast-enhanced computed tomography image showing the partially filled urinary
bladder with Foley's bulb in situ and extensive air pockets in the bladder wall mainly
the left lateral wall (arrow) extending into the surrounding soft tissues.
Fig. 3 Coronal reformatted contrast-enhanced computed tomography image showing complete
absence of contrast enhancement of left kidney with air pockets in renal parenchyma
(arrow).
Fig. 4 Coronal reformatted contrast-enhanced computed tomography image showing complete
thrombosis of left main renal artery (arrow).
Fig. 5 Axial contrast-enhanced computed tomography image showing thrombosis of left main
renal vein with air foci within the thrombus (arrow), inferior vena cava appears normal.
Fig. 6 Coronal reformatted contrast-enhanced computed tomography delayed phase image showing
normal excretion of contrast into the right pelvicalyceal system (long thin arrow)
and no excretion of contrast in the left pelvicalyceal system (short broad arrow).
Fig. 7 Axial contrast-enhanced computed tomography images of the lung bases in lung window
(A) and mediastinal window (B) showing bilateral minimal pleural effusion and areas of consolidation with atoll
sign and cavity (arrow) in left lower lobe.
Cystoscopy was done under general anesthesia which revealed a pus-filled bladder and
multiple bladder washes were given. The right ureteric orifice was identified and
a double-J stent was placed in the right-side collecting system. The left ureteric
orifice could not be identified. The patient was then explored through a left flank
cutting incision; left nephrectomy along with removal of left upper ureter and adrenal
gland was performed with multiple washes and closed. Gross examination revealed the
entirely necrosed left kidney with surrounding fat saponification ([Fig. 8]). The histopathological examination ([Figs. 9], [10], [11]) showed the necrotic renal parenchyma with neutrophilic infiltration and fungal
hyphae with evidence of angioinvasion. The hyphae were aseptate, ribbon-like with
a large diameter, irregular width, and were branching at right angles. The left ureter
and adrenal gland were not involved.
Fig. 8 Cut surface of the enlarged left kidney showing extensive areas of blackish discoloration
(white arrow) and surrounding fat saponification (black arrow).
Fig. 9 Renal parenchyma showing extensive coagulative necrosis with neutrophilic infiltration
and fungal hyphae (thin long arrow). Hematoxylin and eosin stain, ×400.
Fig. 10 Pleomorphic, ribbon-like, broad and aseptate fungal hyphae (arrows) seen along the
vessel wall (periodic acid–Schiff stain, ×100) (A) and in the necrotic renal parenchyma (periodic acid–Schiff stain, ×400) (B).
Fig. 11 Fungal hyphae seen in the renal parenchyma (arrows in A) and seen invading the blood vessel (arrows in B) (Gomori methenamine silver stain, ×100).
Despite treatment, the sepsis worsened and the patient continued to deteriorate. The
attenders wished to continue his treatment elsewhere and got discharged against medical
advice and had succumbed to the disease in a week.
Discussion
Mucormycosis is caused by a group of angioinvasive fungi under the order Mucorales;
the most common species involved are the Rhizopus and Mucor.[7] Various risk factors are known to be associated, the most common being uncontrolled
diabetes mellitus; others include hematological malignancy, stem cell or organ transplant
recipients, neutropenia, desferrioxamine therapy, and corticosteroid use.[8]
[9] An increase in the incidence of CAM is attributed to the widespread use of steroids,
hypoxemia, prolonged hospitalization needing intensive care, and previously immunocompromised
individuals; but cases have also been reported in immunocompetent individuals with
no prior risk factors.[10] The COVID upregulates the glucose receptor protein GRP-78 which helps in the penetration
and damage of endothelial cells by Mucor fungi leading to angioinvasion.[11] Glucose, iron, and β-hydroxybutyrate enhance the fungal growth.[12] The COVID-associated inflammation or its treatment modalities might contribute to
the increase in these metabolites predisposing the individual to fungal infections.[3] There might exist a deeper pathophysiological link between the two pathogens that
waits to be unraveled yet.
Phagocytes (neutrophils) are the first line of body's defense against fungal pathogens.
These white blood cells engulf them in a process called phagocytosis. Sometimes a
reverse process occurs, called the “vomocytosis,” in which the pathogen is ejected
back out of the cell without the lysis of either the host cell or the pathogen. There
has been no study regarding the demonstration of vomocytosis with Mucor fungi yet.
There has been a study which showed viral coinfection can enhance the rate of vomocytosis
of fungus by macrophages.[13] We hypothesize that COVID coinfection could enhance the vomocytosis of Mucor by
macrophages and when at the wrong time and wrong place be catastrophic for the patient.
COVID has altered the immune system of our patient predisposing him to fungal infection;
the lungs were already affected by the COVID, hence the primary site of inoculation
could have been the lung and being an uncontrolled diabetic with ketoacidosis provided
a favorable environment for the growth of fungi; the Mucor could have then reached
the kidney with the help of phagocytosis and vomocytosis by the neutrophils.
Ultrasonography remains the first line of investigation and can show the enlarged
echogenic kidneys with hypoechoic areas of abscesses, perinephric fluid collections,
hydronephrosis, and cystitis.[14] CT features include diffuse patchy nephrogram, inhomogeneous enhancement with areas
of low attenuation, perinephric fluid collections, and no contrast excretion.[15] There can be multiple hypodense nonenhancing areas (intrarenal segmental infarcts)
or even complete absence of contrast enhancement of the kidney. There can be thrombosis
of the main renal artery and vein, but are usually spared with thrombosis of intrarenal
segmental branches leading to infarction, which can be demonstrated on Doppler sonography.
Magnetic resonance imaging study will show hypointense signal on T1-weighted imaging
(WI) and hypointense signal on T2WI with diffusion restriction; in contrast to other
infections which will be hypertintense on T2WI with diffusion restriction owing to
the edema and inflammation.[16] This typical T2 hypointensity with diffusion restriction seen in mucormycosis might
be attributed to the completely infarcted tissue with necrotic debris and fungal filled
abscesses with high iron (paramagnetic element) content in these tissues and fungi.[17] Other renal fungal infections like candidiasis present as multiple microabscesses,
papillary necrosis, and fungal balls within the collecting system whereas renal aspergilloma
present as focal mass lesions.[18]
Though the suspicion of mucormycosis can be made with supportive clinical and imaging
findings, a definitive diagnosis can be made only with histopathological findings.
The treatment of renal mucormycosis is intravenous liposomal amphotericin B and emergency
nephrectomy with debridement of nearby involved tissues. Despite treatment, the mortality
rate associated with mucormycosis in general are very high averaging around 54% with
the highest mortality rate of 96% for disseminated mucormycosis.[7]
