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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 2  |  Issue : 1  |  Page : 30-33

Deadly dual fungal infections in a chronic kidney disease patient


1 Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of ENT, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of General Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
4 Department of Radiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
5 Department of Pathology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission25-May-2020
Date of Decision03-Jun-2020
Date of Acceptance23-Jun-2020
Date of Web Publication25-Apr-2021

Correspondence Address:
Dr. Prasan Kumar Panda
Department of Medicine, 5th Floor, College Block, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JME.JME_33_20

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How to cite this article:
Shankar R, Tyagi AK, Panda PK, Madaan S, Jeladharan R, Kaistha N. Deadly dual fungal infections in a chronic kidney disease patient. J Med Evid 2021;2:30-3

How to cite this URL:
Shankar R, Tyagi AK, Panda PK, Madaan S, Jeladharan R, Kaistha N. Deadly dual fungal infections in a chronic kidney disease patient. J Med Evid [serial online] 2021 [cited 2022 Aug 12];2:30-3. Available from: http://www.journaljme.org/text.asp?2021/2/1/30/314628


  Introduction Top
Fungal infections complicate the course of 4%–7% of chronic kidney disease (CKD) patients in the tropical countries, with a mortality of over 65%.[1] Mucormycosis is an aggressive opportunistic fungal infection that commonly afflicts patients with underlying immunosuppression, uncontrolled hyperglycaemia, haematological malignancies, solid-organ transplantation, CKD, corticosteroid therapy, malaria, malnutrition and occasionally healthy patients who get inoculated with fungal spores.[2] It is noted that decreased cell-mediated immunity and impaired neutrophil function in CKD are the major causes of increased vulnerability to mucormycosis.[3] The accompanying acidosis releases the iron from transferrin required for hyphal growth. Increased iron availability and corticosteroid use also enhance spore germination increasing susceptibility to mucormycosis.[4] CKD is also a major risk factor for bloodstream infections by Candida spp.[1] Imaging, histopathology and isolation from the tissue samples are useful in diagnosis, but a high index of suspicion is crucial in making an early diagnosis. Systemic antifungal therapy, correcting the underlying medical condition and surgical debridement for eradicating Mucor in necrotic tissues remain the cornerstone of the management. The guidelines on diagnosis and management of each fungal infection are set on the criteria given by the Infectious Diseases Society of America, but specifically in CKD, the management is not clear.[5] Since these fungal infections are subtle in presentation and difficult to manage, early diagnosis and prompt management require a high degree of suspicion and vigilance.[6] Thereby, the present case study describes a rare dual infection (Mucor and Candida) in CKD patients and a review of the literature on their duality. This review is important for all clinicians due to rise of CKD, dialysis and kidney transplants.
  Case Report Top
A 65-year-old female presented in July 2019 with a 1-month history of swelling all over the body, which started from the face and gradually progressed to the entire body. She also had gradual onset of difficulty in breathing, leading to impairment of her daily activities. She complained of pain and burning sensation during urination with low urine volume. She underwent five haemodialyses in the 20 days prior to admission, and just before admission, the patient had generalised tonic–clonic seizures followed by several minutes of confusion and inability to open her right eyelid. There was no prior history of diabetes, hypertension or other chronic debilitating conditions. On examination, she was conscious and oriented and had tachycardia and high blood pressure. She had oedema over her face, neck and both lower limbs without visibly dilated veins; ptosis of the right eye; right-sided non-reacting pupil; right fixed eyeball with complete ophthalmoplegia and palsy of 2nd, 3rd and 4th cranial nerves. Other cranial nerves examination were normal. Chest examination demonstrated bilateral fine basal inspiratory crackles. Other systemic examinations were unremarkable. The provisional diagnoses considered were cavernous sinus thrombosis and cardiovascular disease (ischaemic cardiomyopathy/cardiorenal syndrome) with etiological differential diagnoses of cardioembolism, hypercoagulable states, invasive fungal disease (mainly Candidiasis) and rarely paraneoplastic syndrome of unknown primary. The patient was anaemic with raised serum creatinine (6.3 mg/dl) and blood urea (139 mg/dl) suggesting acute kidney injury, possibly with CKD. A renal ultrasound revealed bilateral contracted kidneys suggestive of CKD. Blood culture grew methicillin-sensitive Staphylococcus aureus. A contrast-enhanced magnetic resonance imaging (MRI) brain and orbit revealed right-sided optic neuritis with thrombosis in the right superior ophthalmic vein and sinusitis in the right maxillary sinus along with bilateral ethmoid and sphenoid sinusitis [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. An ENT consultation was sought and nasal swabs revealed many budding yeast cells with pseudohyphae on KOH mount and subsequently grew Candida tropicalis in culture [Figure 2]a This strain was tested for antifungal susceptibility using CLSI M44 guidelines and was found to be susceptible to amphotericin-B, clotrimazole and nystatin; susceptible dose-dependent to itraconazole and voriconazole and resistant to fluconazole. However, due to strong clinical suspicion of mucormycosis, Endoscopic sinonasal debridement was done under general anaesthesia and the biopsy samples from the right sphenoid and right middle meatus were sent, which revealed angioinvasive mucormycosis with marked autolysis and inflammation [Figure 2]b, [Figure 2]c, [Figure 2]d.
Figure 1: Magnetic resonance imaging images of the brain and base of the skull. Contiguous axial T2-weighted magnetic resonance imaging images show extensive mucosal thickening involving bilateral sphenoid (a: arrow) posterior ethmoid (b: arrow) sinuses with air–fluid level in right sphenoid sinus and oedematous right optic nerve (c: arrow) with orbital fat stranding. FLAIR magnetic resonance imaging image (d) shows well-defined focal hyperintense signal in the right temporal lobe (arrow)

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Figure 2: Microbiological diagnosis and functional endoscopic sinus surgery view. Fungal culture (a) of meatal swab sample from left middle meatus shows creamy discrete colonies suggestive of Candida tropicalis. Histo-pathological examination of specimen from right sphenoid sinus mucosa biopsy (b) shows broad aseptate hyphae invading necrosed blood vessel wall suggestive of Mucorale. Endoscopic sinonasal surgery view (c) shows keel of sphenoid bone (arrow) and ischaemic mucosa invaded by mucormycosis (arrowhead) and of right-side sphenoid sinus (d) after removal of infected mucosa

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In view of the clinical picture and MRI findings of thrombosis, unfractionated heparin infusion (1000 U/h) was started. She was empirically started on caspofungin for the invasive candidiasis, but later changed to liposomal amphotericin-B for mucormycosis on confirmation and nasal douching with plain amphotericin-B was done. Due to economic constraints, liposomal amphotericin (after 1 g total dose) was changed to plain amphotericin-B (1 mg/kg). She was discharged after 21 days of hospital stay in haemodynamically stable condition and advised outpatient parenteral antimicrobial therapy (OPAT) of plain amphotericin, heparin infusion and intermittent haemodialysis in local hospital and followed up with brain imaging. On day 23 after first presentation to the hospital, she had developed continuous high-grade fever with chills and rigors, associated with decreased urine output for one day. During her stay at home, the patient had herself discontinued heparin infusion and amphotericin-B injection. On day 28, she developed altered sensorium for which she was re-admitted. The central line was blocked, a unilateral left upper limb swelling was noted and ultrasonographic Doppler revealed left subclavian vein thrombosis. All the relevant investigations were sent and she was started on heparin infusion (after ruling out haemorrhagic stroke on computed tomography head) and plain amphotericin-B in another central line. Injection vancomycin was added empirically for possible central line-associated bloodstream infection (CLABSI). Blood culture done revealed MDR Klebsiella spp and antimicrobial changed as per sensitivity report. On day 31, she developed stress on breathing and sudden cough. Aspiration was suspected, and clindamycin was started along with stringent oral care and elevation of head end. Her responsiveness decreased with time and attendants requested for home therapy and discharge. She was discharged on day 46 of the first presentation and it was found on follow-up telephonically that next day she expired at home.
  Discussion Top
Invasive fungal infections have recently gained significance due to increased incidence in patients with CKD under the effects of immunosuppression. Aspergillus, Mucor, Rhizopus and Candida have been reported to cause fungal sinusitis. Mucormycosis clinically presents as – pulmonary, gastrointestinal, cutaneous, encephalic and rhinocerebral, with rhinocerebral type being the most common presentation. The major risk factors for mucormycosis include haematological malignancies, diabetes mellitus, post-tuberculosis, CKD, neutropenia, solid-organ transplantation, malnutrition, use of desferroxamine (iron-chelating agent) and IV drug abuse.[7] Concomitant invasive candidiasis and mucormycosis in CKD patient is documented only in one case report by Baig et al. who described both fungus in the caecum presenting as a right iliac fossa mass.[8] In a study by Pasqualotto et al., it was found that candidiasis is more common in patients with kidney disease, who are commonly exposed to haemodialysis.[9] Here, we have reviewed cases of combined mucormycosis and candidiasis (PubMed/MEDLINE databases) in patients [Table 1].
Table 1: Published cases of candidiasis and/or mucormycosis in patients with kidney diseases

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Immune defects in CKD are related to metabolic imbalances due to uremic milieu. There is lymphopenia, decreased response to antigenic stimulation and impaired phagocytosis which predisposes to mucormycosis and candidiasis.[7] The diagnosis of mucormycosis and candidiasis as per our review was done mostly by histopathology supported by KOH mount and radiological findings. A high index of suspicion must be maintained for diagnosis. Microscopic demonstration can be done by tests like 20% KOH, Gomori's methenamine silver staining and H and E staining. On microscopy, the typical picture is of broad ribbon-like aseptate hyphae with right-angle branching. Overall accuracy of microscopic morphological techniques may vary from 20 to 80%.[12] In our patient, biopsies from the lesion had evidence of Mucor and culture proved Candida infections. Radiological findings are useful, but no pathognomonic findings allow differentiation from other infections causing intracranial space-occupying lesion. In a case of neurocandidiasis reported by Lin et al., a MRI brain axial T1 with and without contrast, T2-weighted and diffusion-weighted images demonstrated multiple punctate foci of restricted diffusion in the basal ganglia bilaterally with generalised widening of the ventricles and subarachnoid spaces and no definite contrast enhancement.[13] The mainstay of treatment is systemic antifungal therapy, correcting the underlying medical condition and surgery for debridement of necrotic tissue containing Mucorales.[14] Amphotericin-B is recommended in cases of invasive mucormycosis. Surgical debridement remains a key feature of management as it is difficult to eradicate Mucor with amphotericin-B from necrotic tissue areas.[15] Patients can be switched from a lipid formulation of amphotericin-B to delayed-release posaconazole or isavuconazole tablets for oral step-down therapy once a favourable clinical response has been achieved, which usually takes several weeks. However, posaconazole/isavuconazole are not active against all isolates of Mucorales; therefore, prior susceptibility testing is recommended to prevent relapse in case the isolate is resistant to these azoles. Our patient underwent Endoscopic sinonasal debridement followed by amphotericin-B. Amphotericin-B is favoured empirically in critically ill patients with candidaemia. Transition from amphotericin-B to fluconazole is recommended for patients who are clinically stable and if the isolate is susceptible to fluconazole.[16] Therapy should continue until there is clinical resolution of the signs and symptoms of infection, as well as resolution of radiographic signs of active disease; therapy should also continue until reversal of underlying immunosuppression has been achieved, when feasible.[2] Our patient had been managed with Endoscopic sinonasal debridement, amphotericin-B therapy, unfractionated heparin infusion and maintenance haemodialysis. The patient later had discontinued antifungal therapy at home and expired in due course possibly due to septic shock caused by invasive fungaemia and CLABSI bacteraemia with comorbidities. Without treatment, the case fatality rate is 86% and remained high at 72% despite amphotericin-B treatment for mucormycosis.[7] The factors contributing to this dismal outcome include unhygienic conditions, hot and humid climate, late presentation and high cost of life-saving antifungal agents.[1] Our patient had a mix of these factors; however, she responded initially and was on oral antifungal therapy on OPAT. The patient developed CLABSI and central line thrombosis a week later and had stopped antifungal treatment. Then, the patient did not respond despite re-starting of amphotericin-B and died on due course. In conclusion, the possibility of deadly dual fungal infections (Mucor and Candida) in CKD patients may be considered. Importantly, with increase in the prevalence of CKD patients in the society, it is very crucial to remember this possibility. Because these fungal infections are subtle in presentation and difficult to manage, early diagnosis and prompt management requires high degree of suspicion and vigilance otherwise fatal outcome ensues. In future, study of similar patients will answer pathophysiology, diagnosis and treatment approaches. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

 
  References Top

1.
Jha V, Chugh S, Chugh KS. Infections in dialysis and transplant patients in tropical countries. Kidney Int 2000;57:S85-93.  Back to cited text no. 1
    
2.
Lewis RE, Kontoyiannis DP. Epidemiology and treatment of mucormycosis. Future Microbiol 2013;8:1163-75.  Back to cited text no. 2
    
3.
Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3:1526-33.  Back to cited text no. 3
    
4.
Artis WM, Fountain JA, Delcher HK, Jones HE. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: Transferrin and iron availability. Diabetes 1982;31:1109-14.  Back to cited text no. 4
    
5.
Skiada A, Lanternier F, Groll AH, Pagano L, Zimmerli S, Herbrecht R, et al. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: Guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica 2013;98:492-504.  Back to cited text no. 5
    
6.
Gandhi BV, Bahadur MM, Dodeja H, Aggrwal V, Thamba A, Mali M. Systemic fungal infections in renal diseases. J Postgrad Med 2005;51:30-6.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Van Cutsem J, Boelaert JR. Effects of deferoxamine, feroxamine and iron on experimental mucormycosis (zygomycosis). Kidney Int 1989;36:1061-8.  Back to cited text no. 7
    
8.
Baig WW, Ravindra Prabhu A, Natraj KS, Mathew M. Combined mucormycosis and candidiasis of the cecum presenting as a right iliac fossa mass in a patient with chronic kidney disease. Travel Med Infect Dis 2008;6:145-7.  Back to cited text no. 8
    
9.
Pasqualotto AC, Nedel WL, Machado TS, Severo LC. A comparative study of risk factors and outcome among outpatient-acquired and nosocomial candidaemia. J Hosp Infect 2005;60:129-34.  Back to cited text no. 9
    
10.
Obradovic-Tomasev M, Popovic A, Vuckovic N, Jovanovic M. Mixed fungal infection (Aspergillus, mucor, and Candida) of severe hand injury. Case Rep Infect Dis 2014;2014:954186.  Back to cited text no. 10
    
11.
Pandey D, Agarwal M, Chadha S, Aggarwal D. Mixed opportunistic infection with Mucor, Aspergillus and Candida in oculo-rhino-cerebral mycosis: An uncommon case. J Acad Clin Microbiol 2019;21:47-9.  Back to cited text no. 11
  [Full text]  
12.
Kung VL, Chernock RD, Burnham CD. Diagnostic accuracy of fungal identification in histopathology and cytopathology specimens. Eur J Clin Microbiol Infect Dis 2018;37:157-65.  Back to cited text no. 12
    
13.
Lin DJ, Sacks A, Shen J, Lee TC. Neurocandidiasis: A case report and consideration of the causes of restricted diffusion. J Radiol Case Rep 2013;7:1-5.  Back to cited text no. 13
    
14.
Peterson KL, Wang M, Canalis RF, Abemayor E. Rhinocerebral mucormycosis: Evolution of the disease and treatment options. Laryngoscope 1997;107:855-62.  Back to cited text no. 14
    
15.
Kontoyiannis DP, Lewis RE. How I treat mucormycosis. Blood 2011;118:1216-24.  Back to cited text no. 15
    
16.
Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases Society of America. Clin Infect Dis 2016;62:e1-50.  Back to cited text no. 16
    


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