mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Supplement article
Mucormycosis in India: unique features Arunaloke Chakrabarti and Rachna Singh* Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Summary
Mucormycosis remains a devastating invasive fungal infection, with high mortality rates even after active management. The disease is being reported at an alarming frequency over the past decades from India. Indian mucormycosis has certain unique features. Rhino-orbito-cerebral presentation associated with uncontrolled diabetes is the predominant characteristic. Isolated renal mucormycosis has emerged as a new clinical entity. Apophysomyces elegans and Rhizopus homothallicus are emerging species in this region and uncommon agents such as Mucor irregularis and Thamnostylum lucknowense are also being reported. This review focuses on these distinct features of mucormycosis observed in India.
Key words: Mucormycosis, epidemiology, diabetes, Rhizopus oryzae, Apophysomyces elegans, renal infection.
Introduction Fungi belonging to the class Zygomycetes and order Mucorales often cause devastating angioinvasive fungal infections, primarily in patients with underlying risk factors.1 These moulds gain entry into the human body via respiratory tract or skin, and less commonly through the gastrointestinal tract, eliciting an acute inflammatory response.2 Under favourable conditions such as those in immunocompromised hosts, they invade the blood vessels, causing extensive vessel thrombosis and ischaemic tissue necrosis.2,3 Most of these infections are rapidly progressive and exhibit high mortality (~50%) even after active management; the mortality rates approach nearly 100% among patients with disseminated disease.3–6 The principal risk factors implicated in mucormycosis include uncontrolled diabetes and diabetic ketoacidosis, Correspondence: Dr Arunaloke Chakrabarti, Professor and Head, Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India. Tel.: +91-172-2755173/2755155/2747990. Fax: +91-172-2744401. E-mail: [email protected] * Present address: Centre for Microbial Biotechnology Panjab University Chandigarh India
Submitted for publication 28 December 2013 Revised 21 April 2014 Accepted for publication 22 April 2014
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57 (Suppl. 3), 1–6
prolonged steroid therapy, persistent neutropaenia, desferoxamine therapy, haematological malignancies, illicit use of intravenous drugs, autoimmune disorders, prophylaxis with voriconazole or echinocandins, and the breach of cutaneous or mucous membrane barrier due to trauma, burns and surgical wounds.1,2 However, it has also been described in patients with no underlying disease.1,2 The emergence of mucormycosis is being reported globally, with an alarming rise in the number of cases from developing countries including India.1,2,4,7–9 The precise epidemiology of this disease in developing world is not well known due to limited data as a result of sub-optimal awareness, inadequate reporting and diagnostic facilities at many of the healthcare centers.1 However, the available literature suggests a considerable variation between the developing and developed nations, with differences in the prevalence, risk factors and causative agents involved.1,4–7 Certain peculiarities have been observed in cases of mucormycosis in India compared with the western world, including a high incidence of this disease; uncontrolled diabetes and diabetic ketoacidosis as the principal risk factor; rhino-orbito-cerebral (ROC) form as the most common clinical presentation; isolated renal mucormycosis as a new entity; and a wide and varied spectrum of pathogens involved in such infections.1 Seasonal variations in incidence of mucormycosis with respect to temperature, rainfall and humidity have also been noted.10 In
doi:10.1111/myc.12243
A. Chakrabarti and R. Singh
this review, we highlight these distinct features of mucormycosis with reference to India.
High incidence An upsurge of mucormycosis is being reported throughout the world over the past two decades, however, the rise in developing countries including India has been phenomenal.1,2,4,7–9 Three consecutive case series on mucormycosis have been reported from a single tertiary-care centre in India: 129 cases over 10 years (1990–1999), 178 cases during the subsequent 5 years (2000–2004) and then 75 cases in an 18 month period during 2006–2007.4–6 Many other Indian centres have also subsequently published multiple series of this disease in different risk groups.10–13 This increasingly high incidence of mucormycosis in India has been attributed primarily to a continued increase in the patient population with uncontrolled diabetes, which is a one of the major risk factors for this disease in developing countries.1 In fact, India has the second largest diabetic population globally (65.1 million),14 with nearly 70% of these cases being those of uncontrolled diabetes.15 Environmental factors, such as tropical and sub-tropical humid climate and high environmental temperature in most parts of India, further provide an optimum set-up for survival of these fungi, and perhaps contribute to the disease prevalence.1 Better awareness, expertise and diagnostic facilities in many of the healthcare centres have also significantly contributed to an increased recognition of this disease over the past years.3 Majority of the reported cases from India have been those of proven mucormycosis, diagnosed based on culture and histopathology.3 Very few authors have included probable mucormycosis in their series. It should be noted, however, that proven cases would be smaller in number compared with the actual magnitude of mucormycosis, owing to the often nonspecific clinical signs and symptoms associated with this disease and low sensitivity of the presently available diagnostic modalities.3 In the absence of a population-based study, the exact prevalence of mucormycosis in India remains difficult to elucidate.3 However, on the basis of data available from certain groups of patients, the disease prevalence appears to be nearly 0.16% amongst diabetics and 1.2% amongst renal transplant recipients, with most of these cases manifesting as the ROC form.16,17 Also, gastrointestinal mucormycosis reportedly occurs in nearly 20% of all operated cases of neonatal
2
enterocolitis in one center.18 In fact, the frequency of gastrointestinal mucormycosis was found to be so high in that centre that clinicians suspect the disease in any neonate having intestinal perforation. We recently reviewed Indian literature for the past five decades (1960–2012), and developed a computational model to determine the burden of mucormycosis. The results reveal an overall mucormycosis prevalence of 0.14 cases per 1000 population in India, with the prevalence range between 208 177 and 137 807 cases (Mean: 171 504; SD: 12 365.6; 95% CI: 195 777–147 688) and a mean of 65 500 (38.2%) attributable deaths per year.19 Based on the clinical presentations, ROC is the most common form of mucormycosis in India, possibly due to its association with uncontrolled diabetes and diabetic ketoacidosis.1,3,20 According to the multiple case series reported from our tertiary care centre in North India, the prevalence of different clinical types amongst mucormycosis cases is: ROC (48– 55%), cutaneous (13–15%), pulmonary (7–17%), disseminated (5–12%), gastrointestinal (5–13%) and isolated renal (5–14%).4–6 Likewise, in a meta-analysis of all the zygomycosis cases reported from India, Diwakar et al. describe an overall prevalence of ROC (58%), cutaneous (14%), pulmonary (6%), disseminated (7%), gastrointestinal (7%) and isolated renal (7%).21 This is consistent with the global trend, wherein pulmonary and sinus infections (with/without central nervous system involvement), followed by cutaneous type have been found to be the most prevalent.22–25 Cases of necrotising fasciitis due to zygomycetes, occurring via contaminated intramuscular injections, are also a common finding.7,26 This happens due to compromise in healthcare practices and the use of contaminated needles. In addition, majority of the patients (60%) with cutaneous infections due to Apophysomyces elegans are from India.1,7,27 The patients are usually immunocompetent individuals, who acquire the infection following penetrating trauma or burns.1,7,27 However, no correlation between the environmental prevalence of this fungus and clinical cases has been described yet.1 Furthermore, nosocomial mucormycosis is also being reported from this country, though traditionally the disease was considered to be community acquired.1 In a study from our centre, 9% of all mucormycosis cases were found to be nosocomial in origin. These patients acquired infection either at the site of the ECG leads or the adhesive tapes, or from contaminated intramuscular injections, or from air in the hospital environment.4
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Mucormycosis in India
Diabetes as a risk factor The risk factors for mucormycosis differ significantly amongst the developed and developing world.1,7 While haematological malignancies and transplants are designated as the key risk factors for mucormycosis in developed nations, the disease is majorly associated with uncontrolled diabetes with or without ketoacidosis in developing countries including India.1,7 Nearly 24–64% of the mucormycosis cases reported from India are in patients with uncontrolled diabetes, with or without ketoacidosis.4–6,21 Although other risk factors have also been implicated, the overwhelming number of mucormycosis cases with uncontrolled diabetes overshadows their role.1,7 This is possibly linked to a large diabetic population in such countries, as discussed previously.1 Unless complication develops, these patients avoid seeking medical attention.3 In India, a considerable number (16–23%) of diabetics remain undiagnosed of their underlying disease before presentation of mucormycosis; mucormycosis, in fact, acted as diabetes-defining illness in those cases.4,5 The mean informed duration of diabetes was found to be 6.7 4.6 years before acquiring mucormycosis.16 Amongst the diabetic patients, poorly controlled type II diabetes is the most common risk factor for mucormycosis, being involved in nearly 44–88% of the cases mainly from north to south India, with nearly half of them exhibiting ketoacidosis.4–6,10,21 Type I diabetes (10–15%) and secondary diabetes have also been detected in some patients.5,28,29 In contrast, diabetes was the risk factor in only 36% of the global series of 929 cases,24 17% of the Trans-European series,25 16% of France series,30 6% of Belgium series31 and 18% of Italy series.23 It should be noted, however, that as confounding factors, renal failure and alcoholism related chronic liver disease have also been detected in patients along with diabetes in India.4 Several factors relate the unique predisposition of diabetic patients to mucormycosis. Firstly, diabetes and ketoacidosis render the phagocytic cells dysfunctional. Both neutrophils and macrophages exhibit an impaired chemotaxis and defective killing by both oxidative and non-oxidative pathways under such conditions, although the precise mechanisms mediating these remain to be elucidated.32–34 Secondly, patients with diabetic ketoacidosis have an acidic serum pH with elevated levels of free iron, which is a major nutrient element governing susceptibility to Mucorales.32,35,36 Thirdly, elevated levels of glucose and iron, similar to those observed during diabetic
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ketoacidosis, increase the expression of GRP-78. GRP78 is a glucose-regulated protein belonging to the HSP-70 family, which is mainly present in the endoplasmic reticulum where it mediates several cellular processes as a chaperon, including protein folding, degradation of misfolded proteins, regulation of calcium homeostatis and sensing the endoplasmic reticulum stress.32,37–41 Recent studies indicate that a fraction of GRP-78 is also translocated to the cell surface in many cell types,41 wherein it acts as the receptor mediating penetration and damage of endothelial cells by Mucorales, leading to the observed angioinvasion.32 Mice with diabetic ketoacidosis have an increased expression of GRP-78 in sinus, lungs and brain, and anti-GRP-78 serum can protect such mice from mucormycosis, indicating a plausible role of GRP-78 overexpression in susceptibility of diabetics to this disease.32,39 It is generally believed that distinct clinical presentations of mucormycosis are associated with specific underlying risk factors, with ROC, pulmonary, gastrointestinal and cutaneous types occur in patients with diabetes, haematological malignancies or neutropaenia, severe malnutrition, and trauma or burns respectively.1,4–7 However, uncontrolled diabetes has been found as the major factor in all types of mucormycosis in India except the isolated renal form, although ROC manifestation remains the most common clinical type and is significantly associated with uncontrolled diabetes.1,4–7,20,21 As the majority of Indian patients have diabetes and metabolic acidosis as the major risk factors, the principal management modalities in such cases include a control of hyperglycaemia and prompt reversal of ketoacidosis, along with surgical debridement and amphotericin B therapy.3 It is hypothesised that a decrease in diabetes-associated mucormycosis in USA in recent years may be attributed to an increased use of statins in diabetic patients and the inhibitory action of statins against mucoralean agents.42 Although statins are regularly prescribed in Indian patients with diabetes, no fall in the number of diabetes-associated mucormycosis cases has been reported from this country.3 Therefore, a detailed study is required for assessing the role of statins against mucormycosis. Among the different clinical types of mucormycosis, cutaneous and rhino-cerebral types have a better survival rate due to possibility of an early diagnosis. Though majority of the Indian patients have rhino-cerebral presentation, the mortality rate of mucormycosis remains high (nearly 50%) in India.4 This is largely due to a delay in seeking medical attention, diagnosis and therapy.3
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Isolated renal mucormycosis Apart from the common clinical types, isolated renal mucormycosis in apparently healthy hosts is being reported as a new clinical entity in India.4–6,43 Although the kidney is involved in nearly 22% cases of disseminated mucormycosis,44 isolated renal mucormycosis is described rarely in literature. Other than India, case series of isolated renal mucormycosis has also been reported from China.45–47 However, majority of the patients (75%) suffering from isolated renal mucormycosis in India are apparently healthy individuals;4–6 in contrast, in China, majority of the reported cases possess risk factors for developing mucormycosis, except the paediatric population.45–47 These patients with isolated renal mucormycosis had acute presentations. They developed fever, flank pain, haematuria or anuria.4 Although renal tuberculosis, rapidly progressive glomerulonephritis and acute pyelonephritis may present similarly, enlarged unilateral or bilateral infarcted non-functioning kidneys (no contrast excretion) with low attenuation areas on imaging strongly suggest renal mucormycosis.48 With increased awareness and the combination of clinical and radiological findings at our tertiary-care centre in North India, majority of these cases were diagnosed antemortem, as in 32 (76.2%) of 42 patients in a meta-analysis.4–6 In spite of antemortem diagnosis, mortality remained high (~50%) due to difficulty in managing such patients.4–6 It is still not clear how the fungus enters the kidney, without developing lesion in other organs in majority of patients. Lungs may be the portal of entry, as an additional focus in lungs has been observed in a few patients on autopsy.49 Ascending route may also be the portal of entry, as additional lesion in the urinary bladder has been noted in a recent report.50 Once fungi gain entry into the main vessels of kidney, they can cause cortical and medullary infarction leading to renal failure.51 A detailed investigation of such
patients is required to clarify the unexplained pathogenesis of this mucormycosis.
Spectrum of Mucorales fungi There is a wide spectrum of mucoralean fungi causing human infections. Globally, Rhizopus, Mucor and Lichtheimia (formerly Absidia or Myocladus) spp. represent the most frequent causative agents of this disease, accounting for 70–80% of all cases (Fig. 1).1,4,7,52 Apophysomyces, Saksenaea, Rhizomucor, Cunninghamella, Cokeromyces, Actinomucor and Syncephalastrum spp. have also been reported rarely.1,4,7,52 In India, Apophysomyces elegans is the second most common causative agent, after Rhizopus oryzae (Fig. 1).4,5 Although Mucorales are considered opportunistic pathogens, Apophysomyces elegans and Saksenaea vasiformis can initiate disease in apparently normal hosts, following penetrating trauma during accidents in tropical and sub-tropical areas.1,7,27,52 Majority of these patients present with cutaneous mucormycosis only and do not have any underlying disease; only a few patients manifest rhino-cerebral and pulmonary infections, and have risk factors for developing mucormycosis.1,7,52 Intriguingly, Apophysomyces elegans does not produce spores in the environment easily; its sporulation is induced in the laboratory with care.53 It is therefore unclear as to how the patients with pulmonary, renal or disseminated mucormycosis acquire this agent from environment.3 Rarely, Cunninghamella bertholletiae, Rhizomucor pusillus and Rhizopus microsporus can also initiate infections in immunocompetent individuals.52,54,55 Many uncommon species have also been implicated in infections in India. Rhizopus homothallicus has been reported for the first time from patients with cavitary pulmonary mucormycosis.56 Mucor irregularis, that was initially considered to be involved in an emerging endemic cutaneous mucormycosis limited to China, has been reported from a case of rhino-facial
Figure 1 Aetiological agents of zygomy-
cosis. The data shown are from studies by Chakrabarti et al. [4–6] (India), Mohapatra et al. [59] (India), Skiada et al. [25] (Europe), Lanternier et al. [22] (France) and Pagano et al. [23] (Italy).
4
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Mucormycosis in India
mucormycosis in India.57 Recently, a new mucoralean fungus, Thamnostylum lucknowense has been isolated from a patient with rhino-orbital mucormycosis.58
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Conclusions 5
The epidemiology of mucormycosis in India is intriguing, and varies significantly from the developed nations. The estimated number of cases in India seems to be alarmingly high, with uncontrolled diabetes being the most important risk factor. Certain confounding factors like renal failure and hepatic diseases have also been detected along with diabetes in mucormycosis patients; a detailed multicentric study is therefore warranted to precisely determine the association of diabetes with this invasive mycosis in India. ROC form remains the most common clinical presentation, albeit due to its association with diabetes. Isolated renal mucormycosis amongst immunocompetent, young individuals is an emerging entity in India. Although isolated renal infections have been reported from China as well, but the majority of patients in China have pre-disposing risk factors for developing mucormycosis, except the paediatric population. The disease is highly aggressive but the mode of acquisition and spread of the fungus through the body are not yet known, and demand urgent investigation. Cutaneous infections in apparently healthy individuals due to traumatic implantation of Apophysomyces elegans are also a common finding in India, although uncommon in other countries. The precise ecology, epidemiology and taxonomy of this fungus are not well understood, and further studies on these aspects would provide valuable insights into the presence of mucoralean agents in environment, the susceptible hosts and the mode of fungal acquisition and spread.
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Acknowledgment The position of RS is supported by funding from Council of Scientific and Industrial Research (CSIR), Govt. of India in the form of Senior Research Associateship (Scientists’ pool scheme).
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Conflict of interest None.
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Mantadakis E, Samonis G. Clinical presentation of zygomycosis. Clin Microbiol Infect 2009; 15(Suppl. 5): 15–20. Chakrabarti A, M. D. epidemiology of mucormycosis in India. Curr Fungal Infect Rep 2013; 7: 287–92. Chakrabarti A, Chatterjee SS, Das A et al. Invasive zygomycosis in India: experience in a tertiary care hospital. Postgrad Med J 2009; 85: 573–81. Chakrabarti A, Das A, Mandal J et al. The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus. Med Mycol 2006; 44: 335–42. Chakrabarti A, Das A, Sharma A et al. Ten years’ experience in zygomycosis at a tertiary care centre in India. J Infect 2001; 42: 261–6. Meis JF, Chakrabarti A. Changing epidemiology of an emerging infection: zygomycosis. Clin Microbiol Infect 2009; 15(Suppl. 5): 10– 14. Nucci M, Queiroz-Telles F, Tobon AM, Restrepo A, Colombo AL. Epidemiology of opportunistic fungal infections in Latin America. Clin Infect Dis 2010; 51: 561–70. Queiroz-Telles F, Nucci M, Colombo AL, Tobon A, Restrepo A. Mycoses of implantation in Latin America: an overview of epidemiology, clinical manifestations, diagnosis and treatment. Med Mycol 2011; 49: 225–36. Nithyanandam S, Jacob MS, Battu RR, Thomas RK, Correa MA, D’Souza O. Rhino-orbito-cerebral mucormycosis. A retrospective analysis of clinical features and treatment outcomes. Indian J Ophthalmol 2003; 51: 231–6. Chakravarti A, Bhargava R, Bhattacharya S. Cutaneous mucormycosis of nose and facial region in children: a case series. Int J Pediatr Otorhinolaryngol 2013; 77: 869–72. Chander J, Kaur J, Attri A, Mohan H. Primary cutaneous zygomycosis from a tertiary care centre in north-west India. Indian J Med Res 2010; 131: 765–70. Ramesh V, Ramam M, Capoor MR, Sugandhan S, Dhawan J, Khanna G. Subcutaneous zygomycosis: report of 10 cases from two institutions in North India. J Eur Acad Dermatol Venereol 2010; 24: 1220–5. The IDF Diabetes Atlas. The IDF Diabetes Atlas, 6th edn. Brussels: International Diabetes Federation, 2013. Sanofi National study. Screening India’s twin epidemic (SITE). Mumbai, India: Aventis Pharma Limited, 2011. http://www.sanofi.in/l/in/ en/download.jsp?file=6B525C31-A922-49D0-8175-%20B53FCA430 E00.pdf [accessed on March 31, 2014]. Bhansali A, Bhadada S, Sharma A et al. Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes. Postgrad Med J 2004; 80: 670–4. Godara SM, Kute VB, Goplani KR et al. Mucormycosis in renal transplant recipients: predictors and outcome. Saudi J Kidney Dis Transpl 2011; 22: 751–6. Patra S, Vij M, Chirla DK, Kumar N, Samal SC. Unsuspected invasive neonatal gastrointestinal mucormycosis: a clinicopathological study of six cases from a tertiary care hospital. J Indian Assoc Pediatr Surg 2012; 17: 153–6. Chakarbarti A, Sood P, Denning D. Estimating fungal infection burden in India using computational models: Mucormycosis burden as a case study [Poster number 1044]. Presented at the 23rd ECCMID conference: Berlin, Germany, April 27–30, 2013. Sundaram C, Mahadevan A, Laxmi V et al. Cerebral zygomycosis. Mycoses 2005; 48: 396–407. Diwakar A, Dewan RK, Chowdhary A, Randhawa HS, Khanna G, Gaur SN. Zygomycosis–a case report and overview of the disease in India. Mycoses 2007; 50: 247–54. Lanternier F, Dannaoui E, Morizot G et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005–2007). Clin Infect Dis 2012; 54(Suppl. 1): S35–43. Pagano L, Valentini CG, Posteraro B et al. Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology). J Chemother 2009; 21: 322–9.
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Roden MM, Zaoutis TE, Buchanan WL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634–53. Skiada A, Pagano L, Groll A et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect 2011; 17: 1859–67. Garg A, Sujatha S, Garg J, Chandra SS, Basu D, Parija SC. Fulminant necrotizing fasciitis caused by zygomycetes. J Cutan Pathol 2009; 36: 815–6. Kaushik R. Primary cutaneous zygomycosis in India. Indian J Surg 2012; 74: 468–75. Singh V, Singh M, Joshi C, Sangwan J. Rhinocerebral mucormycosis in a patient with type 1 diabetes presenting as toothache: a case report from Himalayan region of India. BMJ Case Rep 2013; 2013: pii: bcr2013200811. Ganesh R, Manikumar S, Vasanthi T. Rhinocerebral mucormycosis in an adolescent with type 1 diabetes mellitus: case report. Ann Trop Paediatr 2008; 28: 297–300. Bitar D, Van Cauteren D, Lanternier F et al. Increasing incidence of zygomycosis (mucormycosis), France, 1997–2006. Emerg Infect Dis 2009; 15: 1395–401. Saegeman V, Maertens J, Meersseman W, Spriet I, Verbeken E, Lagrou K. Increasing incidence of mucormycosis in University Hospital, Belgium. Emerg Infect Dis 2010; 16: 1456–8. Ibrahim AS, Spellberg B, Walsh TJ, Kontoyiannis DP. Pathogenesis of mucormycosis. Clin Infect Dis 2012; 54(Suppl. 1): S16–22. Chinn RY, Diamond RD. Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. Infect Immun 1982; 38: 1123–9. Waldorf AR, Ruderman N, Diamond RD. Specific susceptibility to mucormycosis in murine diabetes and bronchoalveolar macrophage defense against Rhizopus. J Clin Invest 1984; 74: 150–60. 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. Ibrahim AS, Spellberg B, Edwards J Jr. Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis 2008; 21: 620–5. Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 2007; 67: 3496–9. Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 2006; 6: 45–54. Liu M, Spellberg B, Phan QT et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest 2010; 120: 1914–24. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett 2007; 581: 3641–51. Wang M, Wey S, Zhang Y, Ye R, Lee AS. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal 2009; 11: 2307–16.
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Kontoyiannis DP. Decrease in the number of reported cases of zygomycosis among patients with diabetes mellitus: a hypothesis. Clin Infect Dis 2007; 44: 1089–90. Marak RS, Misra R, Ansari MS et al. Successful medical management of renal zygomycosis: a summary of two cases and a review of the Indian literature. Med Mycol 2010; 48: 1088–95. Ingram CW, Sennesh J, Cooper JN, Perfect JR. Disseminated zygomycosis: report of four cases and review. Rev Infect Dis 1989; 11: 741–54. Jianhong L, Xianliang H, Xuewu J. Isolated renal mucormycosis in children. J Urol 2004; 171: 387–8. Lin CY, Lee SC, Lin CC, Chan SC, Lee CT. Isolated fatal renal mucormycosis in a patient with chronic obstructive pulmonary disease and tuberculosis. Int J Clin Pract 2003; 57: 916–8. Yu J, Li RY. Primary renal zygomycosis due to Rhizopus oryzae. Med Mycol 2006; 44: 461–6. Chugh KS, Sakhuja V, Gupta KL et al. Renal mucormycosis: computerized tomographic findings and their diagnostic significance. Am J Kidney Dis 1993; 22: 393–7. Gupta KL, Khullar DK, Behera D, Radotra BD, Sakhuja V. Pulmonary mucormycosis presenting as fatal massive haemoptysis in a renal transplant recipient. Nephrol Dial Transplant 1998; 13: 3258–60. Gupta K, Nada R, Joshi K, Rohilla M, Walia R. Can ascending infection from bladder serve as the portal of entry for primary renal zygomycosis? Mycopathologia 2010; 170: 357–60. Gupta KL, Joshi K, Sud K et al. Renal zygomycosis: an under-diagnosed cause of acute renal failure. Nephrol Dial Transplant 1999; 14: 2720–5. Gomes MZ, Lewis RE, Kontoyiannis DP. Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species. Clin Microbiol Rev 2011; 24: 411–45. Padhye AA, Ajello L. Simple method of inducing sporulation by Apophysomyces elegans and Saksenaea vasiformis. J Clin Microbiol 1988; 26: 1861–3. Kimura M, Udagawa S, Makimura K, Satoh K, Toyazaki N, Ito H. Isolation and identification of Rhizomucor pusillus from pleural zygomycosis in an immunocompetent patient. Med Mycol 2009; 47: 869–73. Verma R, Nair V, Vasudevan B, Vijendran P, Behera V, Neema S. Rare case of primary cutaneous mucormycosis of the hand caused by Rhizopus microsporus in an immunocompetent patient. Int J Dermatol 2014; 53: 66–69. Chakrabarti A, Marak RS, Shivaprakash MR et al. Cavitary pulmonary zygomycosis caused by Rhizopus homothallicus. J Clin Microbiol 2010; 48: 1965–9. Hemashettar BM, Patil RN, O’Donnell K, Chaturvedi V, Ren P, Padhye AA. Chronic rhinofacial mucormycosis caused by Mucor irregularis (Rhizomucor variabilis) in India. J Clin Microbiol 2011; 49: 2372–5. Xess I, Mohapatra S, Shivaprakash MR et al. Evidence implicating Thamnostylum lucknowense as an etiological agent of rhino-orbital mucormycosis. J Clin Microbiol 2012; 50: 1491–4. Mohapatra S, Jain M, Xess I. Spectrum of zygomycoses in north India: an institutional experience. Indian J Med Microbiol 2010; 28: 262.
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Diagnosis,Therapy and Prophylaxis of Fungal Diseases
Supplement article
Mucormycosis in India: unique features Arunaloke Chakrabarti and Rachna Singh* Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Summary
Mucormycosis remains a devastating invasive fungal infection, with high mortality rates even after active management. The disease is being reported at an alarming frequency over the past decades from India. Indian mucormycosis has certain unique features. Rhino-orbito-cerebral presentation associated with uncontrolled diabetes is the predominant characteristic. Isolated renal mucormycosis has emerged as a new clinical entity. Apophysomyces elegans and Rhizopus homothallicus are emerging species in this region and uncommon agents such as Mucor irregularis and Thamnostylum lucknowense are also being reported. This review focuses on these distinct features of mucormycosis observed in India.
Key words: Mucormycosis, epidemiology, diabetes, Rhizopus oryzae, Apophysomyces elegans, renal infection.
Introduction Fungi belonging to the class Zygomycetes and order Mucorales often cause devastating angioinvasive fungal infections, primarily in patients with underlying risk factors.1 These moulds gain entry into the human body via respiratory tract or skin, and less commonly through the gastrointestinal tract, eliciting an acute inflammatory response.2 Under favourable conditions such as those in immunocompromised hosts, they invade the blood vessels, causing extensive vessel thrombosis and ischaemic tissue necrosis.2,3 Most of these infections are rapidly progressive and exhibit high mortality (~50%) even after active management; the mortality rates approach nearly 100% among patients with disseminated disease.3–6 The principal risk factors implicated in mucormycosis include uncontrolled diabetes and diabetic ketoacidosis, Correspondence: Dr Arunaloke Chakrabarti, Professor and Head, Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India. Tel.: +91-172-2755173/2755155/2747990. Fax: +91-172-2744401. E-mail: [email protected] * Present address: Centre for Microbial Biotechnology Panjab University Chandigarh India
Submitted for publication 28 December 2013 Revised 21 April 2014 Accepted for publication 22 April 2014
© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57 (Suppl. 3), 1–6
prolonged steroid therapy, persistent neutropaenia, desferoxamine therapy, haematological malignancies, illicit use of intravenous drugs, autoimmune disorders, prophylaxis with voriconazole or echinocandins, and the breach of cutaneous or mucous membrane barrier due to trauma, burns and surgical wounds.1,2 However, it has also been described in patients with no underlying disease.1,2 The emergence of mucormycosis is being reported globally, with an alarming rise in the number of cases from developing countries including India.1,2,4,7–9 The precise epidemiology of this disease in developing world is not well known due to limited data as a result of sub-optimal awareness, inadequate reporting and diagnostic facilities at many of the healthcare centers.1 However, the available literature suggests a considerable variation between the developing and developed nations, with differences in the prevalence, risk factors and causative agents involved.1,4–7 Certain peculiarities have been observed in cases of mucormycosis in India compared with the western world, including a high incidence of this disease; uncontrolled diabetes and diabetic ketoacidosis as the principal risk factor; rhino-orbito-cerebral (ROC) form as the most common clinical presentation; isolated renal mucormycosis as a new entity; and a wide and varied spectrum of pathogens involved in such infections.1 Seasonal variations in incidence of mucormycosis with respect to temperature, rainfall and humidity have also been noted.10 In
doi:10.1111/myc.12243
A. Chakrabarti and R. Singh
this review, we highlight these distinct features of mucormycosis with reference to India.
High incidence An upsurge of mucormycosis is being reported throughout the world over the past two decades, however, the rise in developing countries including India has been phenomenal.1,2,4,7–9 Three consecutive case series on mucormycosis have been reported from a single tertiary-care centre in India: 129 cases over 10 years (1990–1999), 178 cases during the subsequent 5 years (2000–2004) and then 75 cases in an 18 month period during 2006–2007.4–6 Many other Indian centres have also subsequently published multiple series of this disease in different risk groups.10–13 This increasingly high incidence of mucormycosis in India has been attributed primarily to a continued increase in the patient population with uncontrolled diabetes, which is a one of the major risk factors for this disease in developing countries.1 In fact, India has the second largest diabetic population globally (65.1 million),14 with nearly 70% of these cases being those of uncontrolled diabetes.15 Environmental factors, such as tropical and sub-tropical humid climate and high environmental temperature in most parts of India, further provide an optimum set-up for survival of these fungi, and perhaps contribute to the disease prevalence.1 Better awareness, expertise and diagnostic facilities in many of the healthcare centres have also significantly contributed to an increased recognition of this disease over the past years.3 Majority of the reported cases from India have been those of proven mucormycosis, diagnosed based on culture and histopathology.3 Very few authors have included probable mucormycosis in their series. It should be noted, however, that proven cases would be smaller in number compared with the actual magnitude of mucormycosis, owing to the often nonspecific clinical signs and symptoms associated with this disease and low sensitivity of the presently available diagnostic modalities.3 In the absence of a population-based study, the exact prevalence of mucormycosis in India remains difficult to elucidate.3 However, on the basis of data available from certain groups of patients, the disease prevalence appears to be nearly 0.16% amongst diabetics and 1.2% amongst renal transplant recipients, with most of these cases manifesting as the ROC form.16,17 Also, gastrointestinal mucormycosis reportedly occurs in nearly 20% of all operated cases of neonatal
2
enterocolitis in one center.18 In fact, the frequency of gastrointestinal mucormycosis was found to be so high in that centre that clinicians suspect the disease in any neonate having intestinal perforation. We recently reviewed Indian literature for the past five decades (1960–2012), and developed a computational model to determine the burden of mucormycosis. The results reveal an overall mucormycosis prevalence of 0.14 cases per 1000 population in India, with the prevalence range between 208 177 and 137 807 cases (Mean: 171 504; SD: 12 365.6; 95% CI: 195 777–147 688) and a mean of 65 500 (38.2%) attributable deaths per year.19 Based on the clinical presentations, ROC is the most common form of mucormycosis in India, possibly due to its association with uncontrolled diabetes and diabetic ketoacidosis.1,3,20 According to the multiple case series reported from our tertiary care centre in North India, the prevalence of different clinical types amongst mucormycosis cases is: ROC (48– 55%), cutaneous (13–15%), pulmonary (7–17%), disseminated (5–12%), gastrointestinal (5–13%) and isolated renal (5–14%).4–6 Likewise, in a meta-analysis of all the zygomycosis cases reported from India, Diwakar et al. describe an overall prevalence of ROC (58%), cutaneous (14%), pulmonary (6%), disseminated (7%), gastrointestinal (7%) and isolated renal (7%).21 This is consistent with the global trend, wherein pulmonary and sinus infections (with/without central nervous system involvement), followed by cutaneous type have been found to be the most prevalent.22–25 Cases of necrotising fasciitis due to zygomycetes, occurring via contaminated intramuscular injections, are also a common finding.7,26 This happens due to compromise in healthcare practices and the use of contaminated needles. In addition, majority of the patients (60%) with cutaneous infections due to Apophysomyces elegans are from India.1,7,27 The patients are usually immunocompetent individuals, who acquire the infection following penetrating trauma or burns.1,7,27 However, no correlation between the environmental prevalence of this fungus and clinical cases has been described yet.1 Furthermore, nosocomial mucormycosis is also being reported from this country, though traditionally the disease was considered to be community acquired.1 In a study from our centre, 9% of all mucormycosis cases were found to be nosocomial in origin. These patients acquired infection either at the site of the ECG leads or the adhesive tapes, or from contaminated intramuscular injections, or from air in the hospital environment.4
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Mucormycosis in India
Diabetes as a risk factor The risk factors for mucormycosis differ significantly amongst the developed and developing world.1,7 While haematological malignancies and transplants are designated as the key risk factors for mucormycosis in developed nations, the disease is majorly associated with uncontrolled diabetes with or without ketoacidosis in developing countries including India.1,7 Nearly 24–64% of the mucormycosis cases reported from India are in patients with uncontrolled diabetes, with or without ketoacidosis.4–6,21 Although other risk factors have also been implicated, the overwhelming number of mucormycosis cases with uncontrolled diabetes overshadows their role.1,7 This is possibly linked to a large diabetic population in such countries, as discussed previously.1 Unless complication develops, these patients avoid seeking medical attention.3 In India, a considerable number (16–23%) of diabetics remain undiagnosed of their underlying disease before presentation of mucormycosis; mucormycosis, in fact, acted as diabetes-defining illness in those cases.4,5 The mean informed duration of diabetes was found to be 6.7 4.6 years before acquiring mucormycosis.16 Amongst the diabetic patients, poorly controlled type II diabetes is the most common risk factor for mucormycosis, being involved in nearly 44–88% of the cases mainly from north to south India, with nearly half of them exhibiting ketoacidosis.4–6,10,21 Type I diabetes (10–15%) and secondary diabetes have also been detected in some patients.5,28,29 In contrast, diabetes was the risk factor in only 36% of the global series of 929 cases,24 17% of the Trans-European series,25 16% of France series,30 6% of Belgium series31 and 18% of Italy series.23 It should be noted, however, that as confounding factors, renal failure and alcoholism related chronic liver disease have also been detected in patients along with diabetes in India.4 Several factors relate the unique predisposition of diabetic patients to mucormycosis. Firstly, diabetes and ketoacidosis render the phagocytic cells dysfunctional. Both neutrophils and macrophages exhibit an impaired chemotaxis and defective killing by both oxidative and non-oxidative pathways under such conditions, although the precise mechanisms mediating these remain to be elucidated.32–34 Secondly, patients with diabetic ketoacidosis have an acidic serum pH with elevated levels of free iron, which is a major nutrient element governing susceptibility to Mucorales.32,35,36 Thirdly, elevated levels of glucose and iron, similar to those observed during diabetic
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ketoacidosis, increase the expression of GRP-78. GRP78 is a glucose-regulated protein belonging to the HSP-70 family, which is mainly present in the endoplasmic reticulum where it mediates several cellular processes as a chaperon, including protein folding, degradation of misfolded proteins, regulation of calcium homeostatis and sensing the endoplasmic reticulum stress.32,37–41 Recent studies indicate that a fraction of GRP-78 is also translocated to the cell surface in many cell types,41 wherein it acts as the receptor mediating penetration and damage of endothelial cells by Mucorales, leading to the observed angioinvasion.32 Mice with diabetic ketoacidosis have an increased expression of GRP-78 in sinus, lungs and brain, and anti-GRP-78 serum can protect such mice from mucormycosis, indicating a plausible role of GRP-78 overexpression in susceptibility of diabetics to this disease.32,39 It is generally believed that distinct clinical presentations of mucormycosis are associated with specific underlying risk factors, with ROC, pulmonary, gastrointestinal and cutaneous types occur in patients with diabetes, haematological malignancies or neutropaenia, severe malnutrition, and trauma or burns respectively.1,4–7 However, uncontrolled diabetes has been found as the major factor in all types of mucormycosis in India except the isolated renal form, although ROC manifestation remains the most common clinical type and is significantly associated with uncontrolled diabetes.1,4–7,20,21 As the majority of Indian patients have diabetes and metabolic acidosis as the major risk factors, the principal management modalities in such cases include a control of hyperglycaemia and prompt reversal of ketoacidosis, along with surgical debridement and amphotericin B therapy.3 It is hypothesised that a decrease in diabetes-associated mucormycosis in USA in recent years may be attributed to an increased use of statins in diabetic patients and the inhibitory action of statins against mucoralean agents.42 Although statins are regularly prescribed in Indian patients with diabetes, no fall in the number of diabetes-associated mucormycosis cases has been reported from this country.3 Therefore, a detailed study is required for assessing the role of statins against mucormycosis. Among the different clinical types of mucormycosis, cutaneous and rhino-cerebral types have a better survival rate due to possibility of an early diagnosis. Though majority of the Indian patients have rhino-cerebral presentation, the mortality rate of mucormycosis remains high (nearly 50%) in India.4 This is largely due to a delay in seeking medical attention, diagnosis and therapy.3
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Isolated renal mucormycosis Apart from the common clinical types, isolated renal mucormycosis in apparently healthy hosts is being reported as a new clinical entity in India.4–6,43 Although the kidney is involved in nearly 22% cases of disseminated mucormycosis,44 isolated renal mucormycosis is described rarely in literature. Other than India, case series of isolated renal mucormycosis has also been reported from China.45–47 However, majority of the patients (75%) suffering from isolated renal mucormycosis in India are apparently healthy individuals;4–6 in contrast, in China, majority of the reported cases possess risk factors for developing mucormycosis, except the paediatric population.45–47 These patients with isolated renal mucormycosis had acute presentations. They developed fever, flank pain, haematuria or anuria.4 Although renal tuberculosis, rapidly progressive glomerulonephritis and acute pyelonephritis may present similarly, enlarged unilateral or bilateral infarcted non-functioning kidneys (no contrast excretion) with low attenuation areas on imaging strongly suggest renal mucormycosis.48 With increased awareness and the combination of clinical and radiological findings at our tertiary-care centre in North India, majority of these cases were diagnosed antemortem, as in 32 (76.2%) of 42 patients in a meta-analysis.4–6 In spite of antemortem diagnosis, mortality remained high (~50%) due to difficulty in managing such patients.4–6 It is still not clear how the fungus enters the kidney, without developing lesion in other organs in majority of patients. Lungs may be the portal of entry, as an additional focus in lungs has been observed in a few patients on autopsy.49 Ascending route may also be the portal of entry, as additional lesion in the urinary bladder has been noted in a recent report.50 Once fungi gain entry into the main vessels of kidney, they can cause cortical and medullary infarction leading to renal failure.51 A detailed investigation of such
patients is required to clarify the unexplained pathogenesis of this mucormycosis.
Spectrum of Mucorales fungi There is a wide spectrum of mucoralean fungi causing human infections. Globally, Rhizopus, Mucor and Lichtheimia (formerly Absidia or Myocladus) spp. represent the most frequent causative agents of this disease, accounting for 70–80% of all cases (Fig. 1).1,4,7,52 Apophysomyces, Saksenaea, Rhizomucor, Cunninghamella, Cokeromyces, Actinomucor and Syncephalastrum spp. have also been reported rarely.1,4,7,52 In India, Apophysomyces elegans is the second most common causative agent, after Rhizopus oryzae (Fig. 1).4,5 Although Mucorales are considered opportunistic pathogens, Apophysomyces elegans and Saksenaea vasiformis can initiate disease in apparently normal hosts, following penetrating trauma during accidents in tropical and sub-tropical areas.1,7,27,52 Majority of these patients present with cutaneous mucormycosis only and do not have any underlying disease; only a few patients manifest rhino-cerebral and pulmonary infections, and have risk factors for developing mucormycosis.1,7,52 Intriguingly, Apophysomyces elegans does not produce spores in the environment easily; its sporulation is induced in the laboratory with care.53 It is therefore unclear as to how the patients with pulmonary, renal or disseminated mucormycosis acquire this agent from environment.3 Rarely, Cunninghamella bertholletiae, Rhizomucor pusillus and Rhizopus microsporus can also initiate infections in immunocompetent individuals.52,54,55 Many uncommon species have also been implicated in infections in India. Rhizopus homothallicus has been reported for the first time from patients with cavitary pulmonary mucormycosis.56 Mucor irregularis, that was initially considered to be involved in an emerging endemic cutaneous mucormycosis limited to China, has been reported from a case of rhino-facial
Figure 1 Aetiological agents of zygomy-
cosis. The data shown are from studies by Chakrabarti et al. [4–6] (India), Mohapatra et al. [59] (India), Skiada et al. [25] (Europe), Lanternier et al. [22] (France) and Pagano et al. [23] (Italy).
4
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Mucormycosis in India
mucormycosis in India.57 Recently, a new mucoralean fungus, Thamnostylum lucknowense has been isolated from a patient with rhino-orbital mucormycosis.58
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Conclusions 5
The epidemiology of mucormycosis in India is intriguing, and varies significantly from the developed nations. The estimated number of cases in India seems to be alarmingly high, with uncontrolled diabetes being the most important risk factor. Certain confounding factors like renal failure and hepatic diseases have also been detected along with diabetes in mucormycosis patients; a detailed multicentric study is therefore warranted to precisely determine the association of diabetes with this invasive mycosis in India. ROC form remains the most common clinical presentation, albeit due to its association with diabetes. Isolated renal mucormycosis amongst immunocompetent, young individuals is an emerging entity in India. Although isolated renal infections have been reported from China as well, but the majority of patients in China have pre-disposing risk factors for developing mucormycosis, except the paediatric population. The disease is highly aggressive but the mode of acquisition and spread of the fungus through the body are not yet known, and demand urgent investigation. Cutaneous infections in apparently healthy individuals due to traumatic implantation of Apophysomyces elegans are also a common finding in India, although uncommon in other countries. The precise ecology, epidemiology and taxonomy of this fungus are not well understood, and further studies on these aspects would provide valuable insights into the presence of mucoralean agents in environment, the susceptible hosts and the mode of fungal acquisition and spread.
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Acknowledgment The position of RS is supported by funding from Council of Scientific and Industrial Research (CSIR), Govt. of India in the form of Senior Research Associateship (Scientists’ pool scheme).
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Conflict of interest None.
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