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ORIGINAL ARTICLE
Year : 2022  |  Volume : 38  |  Issue : 2  |  Page : 115-120
 

Renal mucormycosis presenting during the COVID-19 pandemic: A series of 11 cases from a tertiary care center in India


Department of Urology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Date of Submission20-Nov-2021
Date of Decision27-Feb-2022
Date of Acceptance15-Mar-2022
Date of Web Publication1-Apr-2022

Correspondence Address:
Rahul Jena
Department of Urology, All India Institute of Medical Sciences, Jodhpur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/iju.iju_437_21

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   Abstract 

Introduction: Renal mucormycosis has been documented to occur even in apparently immunocompetent individuals. Owing to the rarity of this disease, literature on its management is small. We present our experience of diagnosing and managing 11 cases of primary renal mucormycosis who presented during the second wave of the COVID-19 pandemic in India.
Methods: We reviewed the records of all patients presenting to our institute with a diagnosis of acute pyelonephritis from March 2021 to September 2021. All patients with a radiological, microbiological, or histopathological diagnosis of renal mucormycosis were included in the analysis and all demographic and clinical details, including a history of COVID-19 disease and its treatment, were noted. All patients were treated by a combination of intravenous antifungal therapy and aggressive surgical debridement including nephrectomy and multivisceral resection as required. Predictors of mortality were evaluated by statistical analysis.
Results: A total of 93 patients presented to our hospital with features of acute pyelonephritis of which 11 patients were suspected to have primary renal mucormycosis based on characteristic imaging features and confirmed on microbiological and histopathological examination. Of these, four patients had a history of COVID-19 infection. Only one patient had diabetes mellitus. Ten patients underwent nephrectomy and seven needed resections of surrounding organs. The colon was the most commonly involved organ. Five patients (45.5%) died of progressive sepsis. None of the predictors of mortality that were analyzed showed statistical significance.
Conclusion: A high index of suspicion, early cross-sectional imaging, prompt institution of antifungal therapy, and aggressive surgical extirpation are very important for achieving good outcomes in patients of primary renal mucormycosis.



How to cite this article:
Madduri VK, Jena R, Baid G, Choudhary GR, Sandhu AS. Renal mucormycosis presenting during the COVID-19 pandemic: A series of 11 cases from a tertiary care center in India. Indian J Urol 2022;38:115-20

How to cite this URL:
Madduri VK, Jena R, Baid G, Choudhary GR, Sandhu AS. Renal mucormycosis presenting during the COVID-19 pandemic: A series of 11 cases from a tertiary care center in India. Indian J Urol [serial online] 2022 [cited 2022 Aug 9];38:115-20. Available from: https://www.indianjurol.com/text.asp?2022/38/2/115/342461



   Introduction Top


The causative agent in mucormycosis is a fungus of the order Mucorales and these fungi are ubiquitous in our surroundings and are of low virulence.[1] Isolated or primary renal mucormycosis is a rare entity and renal involvement by systemic mucor infection is usually a part of disseminated mucormycosis in immunocompromised states.[2] Although there are many case reports and series on primary renal mucormycosis in immunocompetent individuals, in most cases, predisposing factors are apparent.[3],[4] There are multiple reports of craniofacial, rhinocerebral, and pulmonary mucormycosis in patients after Sars-CoV2 (COVID-19) infection.[5] The first two cases of primary renal mucormycosis in post-COVID patients have also been from India.[6],[7] The most common predisposing factor associated with renal mucormycosis is poorly controlled diabetes.[8] Other predisposing conditions are immunosuppression, history of renal transplantation, and intravenous (IV) drug abuse. It has been postulated that the immune dysregulation caused by COVID-19 infection acts as a facilitator for invasive mucormycosis.[9] By itself, renal mucormycosis is an aggressive disease and any delay in the diagnosis and treatment leads to high morbidity and mortality. Due to the limited amount of published data on this disease in apparently immunocompetent individuals, it is imperative that more reports on the experience of dealing with such cases be available to clinicians worldwide. We reviewed data patients of primary renal mucormycosis who presented to our institute during the second wave of the COVID-19 pandemic for possible predisposing factors and outcomes and present our algorithm for the diagnosis and management of these cases.


   Materials and Methods Top


We retrospectively reviewed the records of all patients presenting with history and clinical features suggestive of acute pyelonephritis to our institute from March 2021 to September 2021. All patients with radiological diagnosis of mucormycosis later confirmed by either microbiological or histopathological examination were included in this study. This study was approved by the Institutional Ethics Committee. We maintained a prospective database of all patients, including demographic data (age, sex, comorbidities, history of COVID-19 disease, treatment details during COVID-19 disease if any, status of COVID-19 vaccination, etc.), laboratory parameters (hemoglobin, total leukocyte count [TLC], platelet counts, renal function tests, glycosylated hemoglobin levels, etc.), and radiological investigations (contrast-enhanced computed tomography (CECT) of the abdomen and pelvis). All patients were managed as per the algorithm outlined in [Figure 1]. At presentation, all patients were assessed by the Quick Sequential Organ Failure Assessment Criteria and total score was calculated. Resuscitation was carried on as indicated and after drawing blood for laboratory parameters and cultures, empirical IV antibiotic therapy with cefoperazone sulbactam was instituted and radiological imaging (CECT abdomen) was carried out. The clinical diagnosis of renal mucormycosis was established based on characteristic imaging findings of renal infarction and vessel thrombosis on CT scan. The extent of renal involvement along with the involvement of the surrounding bowel, solid organs, great vessels, and the abdominal wall was also noted. Urine KOH mounts were then examined for the presence of mucor and a positive finding confirmed the diagnosis. However, the absence of characteristic findings on KOH mount did not rule out the diagnosis. Irrespective of the absence or presence of microbiological findings, IV liposomal amphotericin was instituted in all patients in the dose of 5–10 mg/kg/day.
Figure 1: Algorithm showing diagnosis and management of renal mucormycosis cases presenting to us during the study

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Exploration of the abdomen through midline incision was done for all patients along with nephrectomy. This was done preferably 24 h after initiation of antifungal therapy, but emergency laparotomy was done if there were signs of peritonitis, hemodynamic instability or radiological features suggestive of bowel involvement with perforation or ischemia. Nephrectomy of the affected kidney was done with cross clamping and mass ligation of the renal hilum because the tissues and vascular structures were friable and most of the cases had thrombus in the renal vein which could potentially migrate during dissection. Postsurgery, patients were managed in the intensive care unit. Repeat exploration of the abdomen and auxiliary procedures such as debridement of necrotic soft tissue was done as per requirement after multidisciplinary consultation. After stabilization, patients were shifted to the ward as per the protocol. Liposomal amphotericin B was continued up to a maximum cumulative dose of 5 g in each patient. Oral antibiotics were started only when the patient was afebrile with normal TLC, vitals were accepting oral diet, ambulatory and did not have any evidence of surgical site infections (SSIs) for at least 72 h. After the completion of the course of liposomal amphotericin B, all patients were started on oral Posaconazole, which was continued for 3 months. Length of hospital stay was noted for each patient. All the data about the patients collected from the hospital records are presented in [Supplementary Table 1][Additional file 1]. Statistical analysis was done using Wizard for Mac version 2 ©Evan Miller (available at https://www.wizardmac.com/). Chi-squared and Mann–Whitney U test were used to assess the difference of various variables between the mortality and survival groups and P values were calculated. Multivariate analysis would then be done if any predictor showed a significant P value.


   Results Top


A total of 93 patients presented to the outpatient and emergency department of our institute with a clinical diagnosis of acute pyelonephritis. Of these, 63 patients had infected hydronephrosis/pyonephrosis secondary to obstructing calculi, 11 had emphysematous pyelonephritis and 8 had acute pyelonephritis in a setting of uncontrolled diabetic mellitus with or without papillary necrosis. The remaining 11 patients had mucormycosis, and their details are mentioned in [Supplementary Table 1]. Nine (81.8%) out of 11 patients were <50 years of age, with the remaining 2 being in the age group of 50–70 years. Eight patients were male and 3 were female. Only one patient had uncontrolled diabetes mellitus. Another patient had a history of ulcerative colitis for the last 20 years and was on long-term oral steroid therapy. Fever was the most common presenting complaint, occurring in 10 out of the 11 patients and flank pain was the next most common (9 out of 11 patients). Two of the patients had discoloration and edema of the skin of the flank on the affected side a presentation and 2 developed it subsequently [Figure 2]. Two patients had symptoms suggestive of peritonitis.
Figure 2: Discolouration of the skin of the flank in a patient with renal mucormycosis

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A total of 4 patients had a history of COVID-19 disease during the preceding 6 months, of which 2 patients had required treatment in the hospital setting and had been administered injectable and oral steroids along with inhalational oxygen therapy. The other two patients had received only oral steroids for a period of 4 weeks and 6 weeks, respectively. Two of the patients had received their first dose of the COVID vaccine within the last 6 weeks of their presentation, of which one patient had developed post-vaccination fever requiring oral paracetamol for 2 days. The findings on CECT seen in the patients are enumerated in [Supplementary Table 1] and [Table 1]. A typical CECT image is shown in [Figure 3]. One patient had KOH mount examination of the urine sample, positive for mucor. Only 3 of the 11 patients underwent nephrectomy alone. Seven patients needed resection of surrounding organs, most common of which was the colon, and debridement of necrotic material from the anterior and posterior abdominal wall. A total of two patients required re-operative surgery, of which one patient underwent peritoneal lavage and feeding jejunostomy and secondary suturing for burst abdomen. The other patient underwent debridement of necrotic tissue from the flank and split skin grafting at a later stage to cover the defect. The intraoperative findings are described in [Supplementary Table 1]. A total of five (45.5%) of the patients died, of which 4 died on postoperative days ranging from 2 to 37. One patient died before he could undergo surgery. The cause of death was systemic sepsis with multiorgan dysfunction syndrome in all five patients. Predictors of mortality on univariate analysis are shown in [Table 2]. None of these factors showed a significant P value.
Table 1: Diagnostic signs of mucormycosis present in the patients as seen on cross sectional imaging

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Figure 3: Contrast enhanced computed tomography section of the abdomen showing non enhancing kidney on the right side, typical of infarcted kidney seen in renal mucormycosis

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Table 2: Predictors of mortality on univariate analysis

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   Discussion Top


To our knowledge, this is the largest series of primary renal mucormycosis recorded during the COVID-19 pandemic. The two largest series of primary renal mucormycosis from India documented details of 17 and 10 patients, over 6 and 13 years, respectively.[3],[4] In our series, there were 11 patients over a period of 7 months. Most human infections occur due to inhalation of fungal sporangiospores borne in the air.[10] Renal seeding can then occur during fungemia from a pulmonary or rhinocerebral focus. Many risk factors for rhinocerebral mucormycosis have been postulated. During the second wave of the COVID-19 pandemic, many patients were treated with industrial-grade oxygen inhalation therapy in hospitals and homes facing medical oxygen shortages. Contamination of this industrial grade oxygen by fungal spores and the attendant immune dysregulation caused by COVID-19 and its treatment can be postulated to be contributory factors toward the increased incidence of systemic mucormycosis.[11],[12] The use of steroids and anti-interleukin 6 directed therapies and other invasive procedures such as mechanical ventilation, extracorporeal membrane oxygenation, prolonged hospital stays along with poor nursing ratios and breaches in asepsis are the perfect setting for secondary fungal infections.[13] Worldwide, the majority of systemic mycoses in the COVID setting comprises COVID-19-associated pulmonary aspergilloses. However, in India, the epidemiology reveals a significant burden of invasive mucormycosis.[13] Invasive mucormycosis has been seen to occur even in patients with mild to moderate SARS-CoV-2 infections. Hyperglycemia further amplified by corticosteroid use and the attendant immunosuppression appears to be the strongest predisposing factor.[8] This makes the diabetic COVID-19 patient receiving corticosteroids or other immunosuppressants exceptionally vulnerable to the development of mucormycosis and this association has been definitely shown in rhinocerebral mucormycosis.[14],[15],[16] In our series, there was no association between COVID-19 disease, use of industrial-grade oxygen therapy, steroid use, and the occurrence of primary renal mucormycosis.

Fever and flank pain usually for several days before a presentation is the most common presenting complaints. Local findings may include flank tenderness, pitting edema of the skin, and sometimes blackish discoloration or necrosis of the soft tissue of the flank.[3] This is due to the extensive perinephric inflammation of the surrounding perinephric tissue and the nearby parietal wall. Many of these cases will be initially treated as bacterial pyelonephritis with IV antibiotics. Unrelenting fever not responding to treatment is an important pointer toward the diagnosis of renal mucormycosis. The algorithm we followed to diagnose and manage our patients ensured prompt initiation of antibiotic therapy and immediate cross-sectional imaging via CECT abdomen. Raised serum creatinine should not be a deterrent in getting a contrast-enhanced CT scan urgently for diagnostic purposes. A cautious approach to contrast-enhanced cross-sectional imaging in the face of renal failure may be a contributor to an adverse clinical outcome and we have published our experience on this in one of our patients.[6] The findings on CT scan as enumerated in [Table 1] are the strong pointers toward mucormycosis and combined with the clinical picture described, they make the need for preoperative tissue diagnosis redundant. A CT scan is also useful in estimating the extent of surrounding organ involvement and helps in preoperative planning. Certain findings on CT scan may also denote severity and be predictors of the clinical course and may help in management decisions. However, no such predictors were seen in our study and they need to be evaluated in larger studies. KOH mount examination of urine has low yield and only one out of the 11 patients in our series had a positive result.

The European Confederation of Medical Mycology and European Conference on Infections in Leukemia recommends amphotericin B lipid in combination with surgery as the treatment of choice for mucormycosis.[17] There are the reports of renal mucormycosis being treated entirely with IV amphotericin B without the need for surgery.[18] However, theoretically, we are dealing with an infected kidney with a compromised blood supply due to the angioinvasive mucor. Adequate delivery of the blood-borne antifungal agent to such a kidney is questionable and therefore an aggressive surgical extirpation of the affected kidney and wide excision of the affected surrounding organs whenever necessary should be carried out as soon as possible after the institution of antifungal therapy. Therefore, we do not recommend conservative management and monitoring the patient for improvement after starting amphotericin B. We recommended early and aggressive surgical debridement. In our series, 7 out of the 10 patients who went on to have surgery had resection of surrounding organs also. A total of 5 out of the 11 patients (45.4%) died in our series. Of these one patient died before surgery and 4 died of progressive sepsis after surgery. Our mortality rate is similar to that published by Devana et al. and is significantly lower than the rates in older literature.[3] We believe that early institution of IV liposomal amphotericin B at least 24 h before emergency nephrectomy and continuing the same during the perioperative period could be one of the reasons for the improved outcomes. This protocol ensures high serum levels of antifungal medication during surgery and it counteracts the possible fungemia occurring during intraoperative handling of the involved kidney. It is worthwhile to mention that in all our cases, the hilum was cross clamped as a whole and individual hilar structures were not dissected out. After dividing the hilum, it was oversewn using proline 2–0 sutures. There were two main reasons for the above step. First, the intense inflammation and ischemia in the area of the hilum had rendered all tissues friable and there was a risk of injuring the aorta or the inferior vena cava during dissection of the hilum. Second, most of these cases had thrombus in the renal vein which could have potentially migrated into the systemic circulation during the hilar dissection.

Our study has several limitations. First is the small sample size, which prevents us from identifying factors predictive of mortality and morbidity with statistical significance. Although we did see 4 out of 11 patients with a history of previous COVID-19 disease and steroid use, the small sample size failed to show a statistically significant association. Second, the diagnosis of mucormycosis postoperatively was confirmed only on histopathology. The microbiological culture was not done and we have not identified the individual species of the offending fungi which would have better helped us to understand the aetiological agent and maybe tailor antifungal therapy accordingly.


   Conclusion Top


We have presented our experience in the management of 11 cases of primary renal mucormycosis in apparently immunocompetent individuals who presented to us in a short time of 6 months. A high index of suspicion along with early cross-sectional imaging, prompt institution of antifungal therapy and abdominal exploration, and aggressive resection helped us to achieve good outcomes in most patients. The significant association of history of COVID-19 infection and steroid use observed with rhinocerebral and pulmonary mucormycosis was not seen in our series.

Acknowledgments

The authors wish to acknowledge the contributions of Dr Amit Aggarwal, Dr Raghav Nayar, Dr Kumar Madhavan, Dr Vaibhav Varshney, Dr Vidhi Jain, Dr Ponam Elhence and Dr Mahendra Singh for their valuable contributions toward the writing of this paper.

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

 
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