© Borgis - New Medicine 1/2001, s. 12-15
Fungal infections in diabetes
The Second Department of Paediatrics - Department of Paediatric Diabetology and Birth Defects The Medical University of Warsaw
Head: Lech Korniszewski MD, PhD Warsaw University Medical School
Patients with diabetes mellitus have increased susceptibility to certain mycotic infections. In this article the author describes predisposing factors and presents a clinical picture of fungal infections frequently reported in diabetics.
It is generally known that patients with diabetes mellitus are more prone to fungal infections and that the course of the disease may be more severe. This occurs in some mycoses e.g. mucocutaneous candidiasis or mucormycosis, which are more frequent in diabetes. Most patients, especially those with good metabolic control, show no increased risk. Apart from diabetes, many factors predispose to fungal infections: long-term antibiotic therapy, immunosuppresion, AIDS, neutropaenia, burns, cardiosurgical operations, organ transplantation, renal dialysis, prematurity, pregnancy and others.
One of the causes of increased susceptibility to infections in diabetic patients is an impaired immune function. Impaired leukocyte function is associated with inadequate glucose metabolism. Normal phagocytosis requires energy which is a product of glycolysis. Energy supplies used by phagocytes are small, and therefore the substrate must be obtained from external sources. Glucose is transported via the leukocyte cell membrane without the participation of insulin. However, insulin is required to activate enzymes of the glycolytic cycle i.e., glucokinase and pyruvate kinase. Insulin deficiency leads to impaired glycolysis and this impairs the process of phagocytosis (12).
The disturbed glucose metabolism inside the leukocytes results in a decreased ability of phagocytes to destroy microorganisms. In the aerobic processes which play a significant role in fungal infections, phagocytosis of micoorganisms stimulates respiratory processes within a few minutes, which produces toxic oxidants (14). The action of the NADPH oxidase and displacement of an electron with NADPH onto the molecular oxygen leads to the formation of a superoxide anion, which gives rise to hydrogen peroxide. With the participation of ferrous ions, hydroxyl radicals are formed from hydrogen peroxide and in the myoloperoxidase-catalyse reaction hypochlorous acid is formed. This in reaction with amines, produces cholaramins (4). Reactive oxygen compounds are toxic for bacteria, parasitic fungi and tumour cells. A high level of glycaemia in patients with diabetes means that most glucose is metabolised by aldose reductase, by means of NADPH. These transformations lead to the consumption of NADPH which is indispensible in the oxygen processes involved in destroying microorganisms by phagocytes (14). The significance of these disturbances may be evidenced by the fact that among individuals with myeloperoxidase deficiency who develop severe fungal infections, a large number is represented by patients with diabetes (3).
Patients with diabetes mellitus also have impaired chemotaxis. This seems to have no association with poor metabolic control, but with an independent congenital defect. Impaired chemotaxis has been found in the offspring of patients with diabetes (9).
Factors contributing to the development of mycoses also include vascular alterations and neuropathy which are chronic complications of diabetes.
There are over 150 fungi from the Candida species which are present in our environment as saprophites. Merely a few of those are pathogenic for man, and those most frequenly isolated are: C. albicans, C. tropicalis, C krusei, C. parapsilosis, C. stellatoidea, C. glabrata and the primarily amphotericin B-resistant C. lusitanie (21). The Candida species are commensals on the mucous membranes and the skin. The most frequently isolated are C. albicans (80% jointly with C. tropicalis), whereas C. glabrata and C. parapsilosis are found in 10%-15% of cases (2). In intensive care units in the USA infections due to the Candida species are the fourth most frequent, following Pseudomonas aeruginosa, Staphylococcus aureus and coagulase-negative staphylococci (5). High mortality rates are also noted among patients with systemic candidiasis (10, 11).
Table 1. Types of fungal infections in patients with diabetes.
|Significantly increased incidence
d. ascending pyelonephritis
a. external otitis
Slightly increased incidence
b. prostatic abscess
c. peritonitis in patients undergoing peritoneal dialysis
Possible increased incidence(?)
a. biliary tract infection
b. postoperative peritonitis
Incidence similar to that in general population
a. systemic candidiasis
c. Candida sinusitis
according to J.A. Vazquez, J.D. Sobel
Colonisation and infection of the skin with the Candida species occurs most frequently in patients with diabetes mellitus as compared with the remaining population (2). The most frequently isolated pathogen is C. albicans. Lesions are localised mainly in the skin folds. The most frequent sites are under the breasts, between the toes, in the groin, in the gluteal folds, and around the anus, where increased moisture is a predisposing factor. The lesions are intertriginous, primarily with a white surface which desquamates leaving a moist bright red area and festoon-like rims. A painful and deep fissure develops in the folds. Typical of the condition is the presence of distant, red, erythematous eruptions known as satellites (6).
Infection of the nail and the wall around the nail begins as a painful red swelling which develops scanty mucopurulent pus on pressure. The nail becomes grey, obliquely furrowed and may be separated from the nail bed (10).
Vascular lesions, diabetic neuropathy, impaired collagen synthesis and genetic predisposition contribute to the development of diseases of the oral cavity. Patients with diabetes are more susceptible to gingivitis, paradontitis and caries than a healthy population (20). A high sugar concentration contributtes to oral fungal infections. In their epidemiological study of 439 patients with diabetes, Aly et al. confirmed the presence of fungi in the oral cavity in 54% of the subjects. The most frequent pathogen was C. albicans (67%). Other fungi included C. glabrata, C. parapsilosis, Sacharomyces cervisiae, C. tropicalis, C. pseudotropicalis and C. guilliermondi (1).
Patients with a poor control of diabetes develop persistent perleche at the corners of the mouth. A creamy white coating may appear on the buccal, lingual and palatal mucosa. The patients often experience, a burning sensationin in the oral mucosa, especially of the tongue. The gums and palate reveal redness, particularly at the sites in contact with a prosthetic plate (2).
A high glucose level in the discharge from the reproductive tract in women with diabetes predisposes to the development of fungal infections. The course of infection in patients with poor metabolic control may be persistent - chronic with frequent relapses. The presence of fungi without symptoms of infection may often be noted. It is considered that infections of the reproductive tract may be the initial manifestation of hyperglycaemia in women with undiagnosed diabetes (21). The most frequently - recognised pathogen is C. albicans which infrequently accompanies C. glabrata (18). Poor metabolic control is generally considered to be a predisposing factor in fungal infections. However, not all researchers confirm that view. Liotta et al. conducted a study of a group of children and adults with insulin-dependent diabetes. They did not find any statistically significant correlation between the duration and the degree of metabolic control and existing infection of the reproductive tract. However, they confirmed an increased incidence of infections in patients at puberty (7).
The predominant clinical manifestations of an acute infection in women include persistent pruritus, vulvovaginal burning and increased discharge. Physical examination reveals a red vagina and a thick, white, caseous secretion adherent to the wall. In some cases erosions with a white coating can be present. The risk of transmitting the disease by sexual contact with a Candida-infected partner is 30%.
Men develop lesions of the glans penis and prepuce. Persistent pruritus and burning are present and physical examination reveals a swollen and red glans penis. On its surface, an erosion covered with a white coating can be found. The lesions are accompanied by an abundant, thick, white secretion (8).
It should be remembered that complications may include an infection ascending from the urethra to the urinary bladder. In men the ascending infection may also involve the prostate.
Experimental studies have shown that the growth of the Candida species has particularly favourable conditions in the urinary tract. Due to a high urine glucose concentration, patients with diabetes show increased susceptibility to fungal infections in the urinary tract (2).
Szainert-Milart et al. carried out a mycological study of the urine among 242 children hospitalised for various diseases. The highest percentage of positive results was obtained in children with diabetes (31.6%). Also, in that same group in over 50% of samples, the number of isolated fungi exceeded 200/1 µl. The study showed a total of 48 isolated yeast-like fungal species and C. albicans proved to be the most frequent (66.6%) pathogen (19).
In their study Rivett et al. assessed 29 hospitalised patients with a diagnosis of candiduria. Most patients had diabetes and the Folley catheter had been in place. Urine samples showed the presence of C. albicans; a substantial number of patients also had other fungal species than C. albicans (39%). No symptoms of infection nor generalised fungal infection were observed (17).
Due to the fact that C. albicans is a frequent saprophyte in the urinary tract, it seems controversial to administer treatment in patients with asymptomatic candiduria. However, it should be remembered that those patients are at increased risk of developing an ascending urinary infection (21). Urinary bladder infection has frequently an asymptomatic course: only some patients develop dysuria, pain and haematuria. Most frequently, the infection may develop in patients with an inserted Folley catheter, but candiduria may only result from a saprophytic colonisation of the catheter and the lower urinary tract. It is generally considered that Candida infection confirms the presence of fungal colonies in the urine of patients without the Folley catheter in a proportion of 10, but more than 10 in those catheterised (2).
In organ candidiasis the kidney is most frequently affected. This particular affinity may be related to the fact that intravenous administration of live cells of C. albicans to animals led to their proliferation mainly in the kidneys.
In patients with diabetes a fungal infection of the kidneys is infrequent. Renal papillae become damaged, fungal bezoars form, and impair the urine outflow. The first symptoms are oliguria or anuria and a fever, followed by pyelonephritis. The most frequent fungus found in the urinary tract is C. albicans, which may be associated with its highest degree of adhesion to human cells. It has been confirmed that the administration of nystatin to patients prevents the colonisation of yeasts in the urinary tract (9).
Fluconazole efficacy has been emphasised in the treatment of urinary infections; however, it should be borne in mind that some species, eg. C. glabrata, C. krusei, are fluconazole-resistant.
In spite of the fact that diabetes mellitus is considered to be a factor predisposing to a systemic Candida infection, morbidity and mortality rates in diabetes due to systemic candidiasis does not differ significantly from those in the general population (21).
Mucormycosis is a rare disease caused by various fungal species of the Zygomycetes class belonging to Mucor, Rhizopus and Absidia. The fungi have a wide distribution in nature; they can be found on decaying plant and animal products and their spores are present in the air. There are five clinical forms of mucormycosis including rhinocerebral, pulmonary, abdominal, cutaneous and systemic (16).
A factor predisposing to rhinocerebral mucormycosis is diabetes complicated by ketone acidosis. The fungi inhabit the nasal cavities or hard palate where they rapidly produce hyphae which enter the blood vessels. This leads to the spread of the infection to the paranasal sinuses, to the orbits through the ethmoid cells, and via the internal carotid artery and ophthalmic artery to the central nervous system. Rapidly developing hyphae give rise to thrombi and eventually to the development of ischaemic and necrotic foci. Cranial nerves II, III, IV, and VI are paralysed. Patients complain of headache, impaired nasal patency and nosebleeds. They develop impaired vision, lacrimation, impaired movement of the eyeballs, orbital swelling and proptosis. The nasal cavities reveal the presence of bloody secretion; a dark necrotic focus (a characteristic black crust) appears on the nasal mucosa or hard palate. Radiological examination shows opacity of the sinuses with occasional destruction of the bones forming their walls. The disease is characterised by a fulminant course and, in spite of treatment, the outcome may be fatal within a few days. A frequent complication in rhinocerebral mucormycosis is a thrombus in the cavernous sinus with paralysis of the cranial nerves II, III, IV, VI, and an abscess in the frontal lobes of the brain. The diagnosis can be established only from the presence of hyphae in the biopsy material. It is vital to initiate urgent treatment with amphotericin B, since the mortality rate in rhinocerebral mucormycosis amounts to 50% (14).
Pulmonary mucormycosis occurs most frequently in immuno-compromised patients, and less frequently in patients with diabetes. The infection is mostly due to the inhalation of spores. Having entered the lower respiratory tract, the fungi quickly invade the blood vessels, form thrombi and produce secondary pulmonary infarction. Typically, the disease has an acute onset with a chest pain and haemoptysis. The disease requires an immediate diagnosis (possible only from a biopsy specimen) and an intensive course of treatment with amphotericin B (21).
Patients with diabetes may occasionally have cutaneous mucormycosis. The fungal invasion occurs through the skin and characteristic ulceration appears with a black necrotic focus. In case of superficial lesions, treatment may be confined to surgical cleansing of the wound and a topical application of amphotericin.
Fungi of the Aspergillus species are isolated worldwide from air, soil, water and decaying plant debris. In spite of frequent exposure to spores of the fungi, the infection is rare. Aspergillosis is most frequently due to A. fumigatus and next to A. niger and A. flavus. The infection usually develops in patients with immunodeficiency, neutropaenia secondary to chemotherapy, and those after long-term steroid therapy (15). Despite the fact that diabetes is a predisposing factor in fungal infections, aspergillosis is rarely noted in that group of patients. Most frequently the spores invade the body with the inspired air. They enter the paranasal sinuses and lower respiratory tract, giving rise to infection.
Malignant external otitis is a condition occuring almost exclusively in patients with diabetes. The most frequent aetiological factor is Pseudomonas aeruginosa, but cases have been reported of a similar clinical course resulting from infection by Aspergillus. The presence of the fungus is confirmed on histopathological examination (13).
1. Aly FZ, Blackwell CC, MacKenzie DA, et al.: Identification of oral yeast species isolated from individuals with diabetes mellitus, Mycoses 1995, 38:107-110. 2. Bodey GP, Fainstein V.: Candidiasis, New York Raven Press 1985. 3. Ceh P, Stalder H, Wiudman J, et al.: Leucocyte myeloperoxydase deficiency and diabetes mellitus associated with Candida albicans liver abscess, Am J Med 1979, 66:149-153. 4. Jakóbisiak M.: Immunologia, Warszawa, PWN, 1995. 5. Jarvis WR, Martone WJ: Predominant pathogens in hospital infections, J Antimicrob Chemother 1992, 29:19. 6. Kowszyk-Gindifer Z, Sobiszewski W: Grzybice i ich zwalczanie, Warszawa, PZWL, 1986. 7. Liotta A, Cardella F, Ferara D, et al.: Vaginal infections in a population of diabetic children and adolescents, Pediatr Med Chir 1987, May-June, 9(3):305-8. 8. Michael S Gelfand: Candidiasis: Implications for Intensivists and Pulmonologists, Semin Respir Crit Care Med 1997, May, 18:3. 9. Molenyaar DM, Palumbo PJ, Wilson WR, Rims RE: Leucocyte chemotaxis in diabetic patients and their non-diabetic first degree relatives, Diabetes 1975, 25 (Suppl 2):880-3. 10. Nolla-Salas J, Sitges-Serra A, Leon-Gil C: Candidiemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy, Intensiv Care Med 1997, 23(1):23-30. 11. Pacheco Rios A, Arita Figveroa C, Nobigrot Kleinman D: Mortality associated with systemic candidiasis in children, Arch Med-Res 1997, Summer, 28(2):229-32. 12. Pawlicka-Domanska Z, Prochow M, Sliwinska-Przyjemska H: Aktywno sc kandydobójcza leukocytów wielojadrzastych u dzieci chorych na cukrzyce, Ped Pol. 1978, Aug, 53(8):963-6. 13. Philips P, Bryce G, Shepherd J, et al.: Invasive external otitis caused by Aspergillus, Rev Infect Dis 1990, 12:227-281. 14. Pickup J, Wiliams G: Textbook of Diabetes, Oxford Blackwell Scientific Publication 1991. 15. Rinaldi MG: Invasive aspergillosis, Rev Infect Dis 1983, 5:1061-1077. 16. Rinaldi MG: Zygomycosis, Infect Dis Clin North Am 1989, 3:19-41. 17. Rivett AG, Perry JA, Cohen J: Urinary candidiasis: a prospective study in hospital patients, Urol Res 1986, 14(4):183-6. 18. Sobel JD: Pathogenesis and epidemiology of vulvovaginal candidiasis, Ann NY Acad Sci 1988, 544:547-57. 19. Szajner-Milart I, Wawrzykiewicz K, Zajaczkowska M: Badania mikologiczne moczu u dzieci w przebiegu róznych chorób, Pediatr Pol 1987 Aug, 62(8):567-74. 20. Smielak B, Ruxer J, Romanowicz W: Wplyw cukrzycy typu I na stan uzebienia, przyzebia i blony sluzowej jamy ustnej, Diabet Pol 1998, 5:76-9. 21. Vazquez JA, Sobel JD: Fungal infection in diabetes, Infect Dis Clin North Am 1995 Mar, 9)1):97-116.