Nosocomial fungal infections are significant concern globally which leads to increase hospitalization costs and takes longer time durations in the treatment and higher mortality rate. Fungal infections pose a economic burden on healthcare system which exceed USD 7.2 billion in USA alone. There is lack of knowledge and recognition of common fungal infections among healthcare professionals. Therefore to educate and raise awareness many initiatives like CDC “Think Fungus” are taken.

Epidemiology & Risk Factors

Among the Candida species the one that mostly causes nosocomial infections is the Candida albicans. The patients prone to Candida infections are immunocompromised patients with neutropenia and the patients who are critically ill coming from central nervous catheters (CVCs) and GIT. Hospital environments and patients’ acquisitions are sources for isolates of these species.

Invasive Aspergillosis is included in some other nosocomial fungal infections and the incidence of this disease has been increasing as there were 32.8 per million persons in 2000 to 46.0 per million in 2013 especially shown in the recipients of solid organ transplant. Out of all invasive fungal infections 59% is accounted for Aspergillosis and 6-week mortality rate of 22% in severely immunocompromised patients is also associated with it.

Laboratory Diagnosis 

There are several laboratory methods by which we can accurately diagnose the invasive candidiasis. Blood cultures are used which have the sensitivity of about 70% but they take longer incubation time and often have negative results when fluconazole prophylaxis is used. Serological tests in which fungal cell wall components are used which include galactomannan and 1, 3-B-D-glucan or Antibodies against galactomannan antigen are specific but they lack in sensitivity. Real time PCR although it has 60% sensitivity but it is invaluable in deep-sited Candidiasis diagnosis with a negative blood culture. Now, a lot of new diagnostic tool are discovered by which detection of fungus in blood is easy and various types of assays are used for fungal diagnosis but specifically for invasive candidiasis, antigen and antibody assays against mannan are used and recommended by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines. Currently, MALDI-TOF is the most promising method used for the rapid diagnosis and identification once a fungal specie is isolated. 

It is really difficult to recommend anti-fungal therapy to all the patients because of increased caused toxicity and ecological pressure for anti-fungal resistance. Although anti-fungal prophylaxis maybe useful but the risk factors and local incidence rates may be increased. Patients that get benefit from fungal prophylactic treatment with fluconazole against invasive candidiasis are those who had gone through recent abdominal and gastrointestinal surgeries. The patient with refractory fever receives broad spectrum anti-bacterial and anti-fungal therapy and a thorough search should be performed to identify alternate causes. Antifungal drugs which are used in the treatment of invasive candidiasis include polyenes (amphotericin B deoxycholate), triazoles (flucanazole), echinocandins (cspofungin) and flucytosin.

Table 1: Risk Factors Associated With Candida Spp Infections In Icu.

Table 2

Aspergillosis

Aspergillus is a fungal genus comprising of hundreds of molds, the most clinically important of which are A. fumigatus, A. flavus, A. terreus, A. niger, and A. nidulans. Recently, Neosartorya udagawae has also emerged with increased clinical impact. This fungal specie usually found to cause infections in immuno-comprimised patients.

Epidemiology and Incidence

In the context of critical care, Aspergillus can grow in poorly maintained ICU water and ventilation systems as well as in other pieces of equipment. But there is challenging to distinguish between infection and colonization when they are separated from the patient. Aspergillus species can infect almost every organ, with invasive pulmonary aspergillosis affecting the sinuses being the most prevalent site of involvement. Patients with HIV and those with hematologic malignancy have the lowest incidence of invasive aspergillosis (IA), which is 0.4%. Patients who have solid organ transplants have an incidence ranging from 0.4% to 2.4%, but those who receive stem cell transplants have an incidence ranging from 0.5 to 3.8%. The incidence rates of autologous and allogeneic stem cell transplantation in patients undergoing hematopoietic stem cell therapy are approximately 5% and 10%, respectively.

The diagnosis is predicated on a triplet that includes clinical and radiological signs and symptoms, (ii) risk and host factors (the latter of which differs from risk factors), and characteristics are suggestive of the illness and (iii) laboratory analysis that establishes Aspergillus's presence either directly or indirectly. Radiological examinations such as CT scans and chest x-rays may be employed. The most typical indicators that could be observed are infiltrates, consolidations, and lumps. Nonetheless, the "halo sign," which appears as a nodule with a dense centre encircled by ground glass opacity in CT images, is the pathognomonic sign. It should be highlighted that the latter is primarily observed in individuals who are neutropenic, whereas pertinent findings in patients who are not neutropenic are vague. PCR, biopsies, cultures, β-D-glucan and galactomannan detection, and other laboratory tests are used to detect Aspergillus. As already stated, the seclusion of the presence of Aspergillus from cultures depends on whether the isolation location is otherwise sterile because a positive culture from respiratory tract secretions could indicate colonization rather than infection regardless of the isolation technique. Body fluids are found to contain galactomannan, which is then measured and used to produce the galactomannan index. Invasive aspergillosis is most likely to be diagnosed when a specific threshold is exceeded. Despite the method's poor sensitivity in the serum, it appears that galactomannan detection in bronchoscopic material, like bronchoalveolar lavage, has greater accuracy and is unaffected by the patient's immunological status. Like galactomannan, β-D-glucan is a component of the cell wall that is present in bodily fluids and signifies the likelihood of infection. PCR, despite having a high sensitivity and specificity, this approach is laborious and cannot distinguish between colonization and infection. For the diagnosis of invasive aspergillosis, quantitative real-time PCR could be a helpful substitute.

Treatment

There are three categories for treating aspergillosis: empirical, preventive, and definitive. The treatment given to patients with neutropenia who are at risk using an empirical method is longer period of fever, in those who have already been treated with a wide range of antibiotics. When there is proof of fungal presence without an infection having occurred, preventive medication is used. When compared to empirical treatment, its efficacy has been questioned. The course of action that is considered definitive is determined by antibiogram results and is initiated once infection has manifested. Combination therapy may be utilized in the salvage context if definitive treatment with a single drug proves ineffective. While provided to individuals with neuropathy, prophylactic therapy has not been adopted for use in critical care environments.

Additional treatments, such as Granulocyte-Colony both interferon-gamma and stimulating factor are possible. In some circumstances, surgical treatment for the removal of the Aspergillus lesion may be a viable alternative Voriconazole is recommended as the first line treatment for Aspergillosis, particularly for the invasive pulmonary form, even though amphotericin B, azoles, and echinocandins can also be utilized.6 mg/kg twice day is the loading dose, which is thereafter decreased to four milligrams per kilogram twice day. Intravenous administration of amphotericin B is carried out as liposomal amphotericin, whose dosage ranges from 3 to 5 mg/kg/day, or as its lipid complex, which has lost its pre-superiority as a result of the potential nephrotoxicity it may cause and the discovery of more recent therapeutic options. It's important to take note of a paradox involving its decreased toxicity when given in high dosages without resulting in better outcomes.

The sole member of the echinocandin class with approval for the treatment Aspergillosis is capsofungin; nonetheless, it is only utilized in cases where other treatments are either not effective or cannot be used because of side effects. When combined with amphotericin, it is mostly utilized in cases where other antifungals have not worked. t is given intravenously at a loading dose of 70 mg/day and a maintenance dose of 50 mg/day. When used in conjunction with the calcineurin pathway inhibitors, it was discovered to have higher in vitro action. Posaconazole and itraconazole are regarded as second-line therapy options. In the European Union alone, posaconazole is authorized as a salvage therapy for invasive aspergillosis. It is given intravenously at a loading dose of 70 mg/day and a maintenance dose of 50 mg/day. When used in conjunction with the calcineurin pathway the patient's immunological condition determines how long the treatment will take. For patients who are not immunosuppressed, it should endure for a minimum of six to twelve weeks. Within patients who are immunosuppressed should have treatment for as long as they are immunosuppressed, and it shouldn't end until the patient's symptoms and signs have resolved clinically and radiologically. It is not advised to use laboratory tests to confirm that the fungus has been eradicated. Relapses may happen as a result of insufficient eradication and inadequate sterilization of underlying foci.

In the critical care context, fungal infections are difficult to diagnose and cure, despite their significance. To reduce the number of people who die from these diseases, more clinical vigilance is required, as is a multimodal diagnostic strategy. With low rates of resistance to the more recent antifungal drugs, the treatment arsenal is successful despite its limited scope. To optimize positive results, however, prompt and careful use are required.

1. CDC - Fungal Diseases.
2. Mc Carty Tp, Pappas PG. Invasive Candidiasis. Infect Dis Clin North Am. 2006; 20: 485-506.
3. Lamoth F, Calandra T. Early diagnosis of invasive mould infections and disease. J Antimicrob Chemother. 2017; 72: 19-28.
4. Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC. Hidden killers: Human fungal infections. Sci Transl Med. 2012; 4: 165rv13.
5. Kontoyiannis DP, Lewis RE. How I treat mucormycosis. Blood. 2011; 118: 1216-1224.
6. Marr KA. Aspergillosis: spectrum of disease, diagnosis, and treatment. Infectious Disease Clinics of North America. 2014; 30: 165-192.
7. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clinical Microbiology Reviews. 2007; 20: 133-163.
8. Patel M. Multidrug-resistant Candida: epidemiology, molecular mechanisms, and treatment. Journal of Antimicrobial Chemotherapy. 2012; 67: 107-118.
9. CDC - Think Fungus.
10. Denning DW, Bromley MJ. Infectious Disease. How to bolster the antifungal pipeline. Science. 2015; 347: 1414-1416.
11. Ruhnke M, Rickerts V, A. Cornely O, Buchheidt D, Glockner A, Heinz W, et al. Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy. Mycoses. 2012; 55: 273-304.
12. Perlroth J, Choi B, Spellberg B. Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Medical Mycology. 2007; 45: 321-346.
13. Slavin MA. Central venous catheter use and outcome from Candidaemia in critically ill patients in Australia and New Zealand: a prospective cohort study. Critical Care. 2015; 19: 435.
14. Bitar D. Increasing incidence of invasive mold infections in France: the SAIF network (2001-2010)". Medical Mycology. 2014; 52: 519-526.
15. Koehler P. The spectrum of fungal infections in hematology patients: from the anticipated to the unknown. Haematologica. 2017; 102: 298-308.
16. Guinea J. Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect. 2014; 20: 5-10.
17. Arendrup MC. Epidemiology of invasive candidiasis. Current Opinion in Critical Care. 2010; 16: 445-452.
18. Hope WW. Invasive fungal infections in immunocompromised patients: strategic and economic challenges to 2020". Lancet Infectious Diseases. 2005; 5: 695-704.
19. Bassetti M. Invasive mold infections in hematologic patients: An epidemiological study. Clinical Microbiology and Infection. 2016; 22: 808-808.
20. Lionakis MS, Lewis RE. Invasive aspergillosis and rhizopus infections: emerging importance and new treatments. Current Opinion in Infectious Diseases. 2011; 24: 519-524.
21. Miceli MH, Kauffman CA. Aspergillus galactomannan and polymerase chain reaction for invasive aspergillosis diagnosis. Clinics in Laboratory Medicine. 2011; 31: 1-27.
22. Ascioglu S, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002; 34: 7-14.
23. Centers for Disease Control and Prevention (CDC). Antifungal Resistance. 2020.
24. Ruhnke M, Maschmeyer G. Management of mycoses in patients with hematologic disease and cancer-review of the literature. European Journal of Medical Research. 2002; 7: 227-235.
25. Richardson M, Lass-Florl C. Aspergillus and aspergillosis: from morphology to genomics and back. Microbiology Spectrum. 2008; 3.
26. Hoenigl M, Gray AJ. The role of β-D-glucan as a diagnostic tool in invasive fungal diseases: current status and future perspectives. Clinical Infectious Diseases. 2018; 66: 1639-1645.
27. Taccone FS, Van den Abeele AM, Bulpa P, Misset B, Meersseman W, Cardoso T, et al. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Critical Care. 2015; 19: 7.
28. Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999; 12: 310-350.
29. Ullmann AJ. ECIL guidelines for antifungal treatment in leukemia and hematopoietic stem cell transplant patients. Hematologica. 2018; 103: 72-76.
30. Chamilos G. Antifungal activity and interactions between echinocandins and amphotericin B against Aspergillus and Fusarium species. Antimicrobial Agents and Chemotherapy. 2008; 52: 2195-2202.