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What is cryptococcosis. Cryptococcosis: A Comprehensive Overview

by alexxlab

What is cryptococcosis? How does it affect the human body? What are the common symptoms and physical exam findings? How is cryptococcosis evaluated and managed?

Understanding Cryptococcosis

Cryptococcosis is an invasive fungal infection caused by the encapsulated yeast-like fungi Cryptococcus neoformans and Cryptococcus gattii. This infection is primarily associated with individuals who are immunosuppressed, such as those living with HIV/AIDS, undergoing organ transplantation, or receiving long-term steroid treatment. The infection is acquired through the inhalation of fungal spores, which can then disseminate hematogenously to cause a wide range of clinical manifestations, with the most common being cryptococcal meningitis.

Epidemiology and Risk Factors

Globally, it is estimated that approximately 1 million cases of cryptococcosis occur each year, resulting in approximately 625,000 deaths. In the United States, the incidence of cryptococcosis is around 0.4-1.3 cases per 100,000 population, with a higher incidence of 2-7 cases per 100,000 in individuals living with HIV/AIDS. The incidence of cryptococcal infections has declined significantly over the last two decades due to advancements in antiretroviral therapy.

Cryptococcus neoformans is typically associated with infections in immunocompromised individuals, while Cryptococcus gattii is more commonly found in immunocompetent patients. Underlying conditions that increase the risk of cryptococcosis include HIV/AIDS, diabetes, chronic liver or kidney disease, and organ transplantation.

Pathogenesis and Pathophysiology

Cryptococcus fungi are commonly found in soil contaminated by bird droppings, as well as in decaying wood and tree hollows. The capsule of the fungus, composed of polysaccharides such as glucuronoxylomannan and glucuronoxylomannogalactan, is a major contributor to the pathogen’s virulence. Infection typically occurs through the inhalation of fungal spores from the environment.

In healthy individuals, the initial infection is often asymptomatic and contained. However, in immunocompromised patients, the infection can spread hematogenously from the initial site of infection, leading to disseminated disease. Reactivation of the organism at the initial site of infection can also occur in individuals who become immunocompromised later in life.

Clinical Presentation and Physical Examination

The most common clinical manifestation of cryptococcosis is cryptococcal meningitis, which typically develops within 1-2 weeks of infection. Patients may present with fever, malaise, headache, neck stiffness, photophobia, nausea, and vomiting. In rare cases, the disease may progress to coma and death.

Other less common symptoms, such as cough, dyspnea, and skin rash, have been reported in the literature. Physical examination findings may include focal neurological deficits and elevated diastolic blood pressure, indicative of increased intracranial pressure.

Diagnostic Evaluation

Patients presenting with symptoms of central nervous system involvement, such as meningitis, are evaluated with radiographic imaging of the brain, typically using computed tomography (CT) or magnetic resonance imaging (MRI). Lumbar puncture is performed to obtain cerebrospinal fluid (CSF) for analysis, which may reveal an elevated opening pressure, elevated protein levels, and low glucose levels.

The diagnosis of cryptococcosis is confirmed by the detection of cryptococcal antigen in the CSF or blood, or by the visualization of the characteristic encapsulated yeast cells on microscopic examination of the CSF or other clinical samples.

Treatment and Management

The mainstay of treatment for cryptococcosis is antifungal therapy, typically with amphotericin B and flucytosine, followed by a prolonged course of fluconazole. The treatment regimen and duration may vary depending on the severity of the infection and the patient’s underlying condition.

In addition to antifungal therapy, the management of cryptococcosis often requires a multidisciplinary approach involving healthcare professionals from various specialties, such as infectious disease specialists, neurologists, and pharmacists. This collaboration is essential for providing prophylactic treatment, monitoring the patient’s response to therapy, and ensuring optimal outcomes.

Prognosis and Prevention

The prognosis for cryptococcosis can vary depending on the patient’s underlying condition and the severity of the infection. In general, the case fatality ratio for cryptococcosis is around 12% in the United States. Advances in antiretroviral therapy have significantly improved the prognosis for individuals living with HIV/AIDS who develop cryptococcosis.

Preventive measures, such as the use of prophylactic antifungal therapy in high-risk populations, can help reduce the incidence of cryptococcosis and improve patient outcomes. Healthcare professionals play a crucial role in implementing these preventive strategies and providing prompt and effective treatment for individuals diagnosed with cryptococcosis.

Cryptococcus – StatPearls – NCBI Bookshelf

Continuing Education Activity

Cryptococcus is an invasive fungus, transmitted through the inhalation of spores and causes cryptococcosis, an infection commonly associated with immunosuppressive individuals. Patients present with fever, headache, malaise, photophobia and neck stiffness as cryptococcal meningitis sets in. This activity describes the evaluation and management of cryptococcosis and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

  • Identify the cryptococcal species in the etiology of cryptococcosis.

  • Describe the typical patient history and physical exam findings in cryptococcosis.

  • Outline the use of cerebrospinal fluid analysis in the evaluation of cryptococcosis.

  • Review the importance of collaboration and communication among the interprofessional team to provide prophylactic treatment for cryptococcal infection to improve outcomes in immunocompromised patients by preventing cryptococcosis.

Access free multiple choice questions on this topic.

Introduction

Cryptococcus is an invasive fungus that causes cryptococcosis an infection commonly associated with immunosuppressive individuals while being rare in healthy individuals.  The two species of Cryptococcus that are commonly associated with infections in humans are Cryptococcus neoformans and Cryptococcus gatti. The organism is widely prevalent in certain regions of the world. However, the most common forms of exposure include a history of exposure to soil, bird droppings. 

Etiology

Cryptococcal species are fungal pathogens which are encapsulated yeasts morphologically. Immune suppression is the major underlying mechanism that is involved in the causation of cryptococcal disease. Diseases like AIDS, diabetes, chronic liver disease, chronic renal disease, prolonged use of steroids and patients who undergo organ transplantation are commonly associated with the development of cryptococcal disease. [1]

Epidemiology

Globally approximately 1 million cases of cryptococcosis are reported each year resulting in 625,000 deaths approximately.[2] In the United States incidence of cryptococcosis is estimated to be about 0.4-1.3 cases per 100,000 population and 2-7 cases per 100,000 in people affected with AIDS with a case fatality ratio of about 12%. [3]The incidence of cryptococcal infections has declined drastically over the last two decades owing to advances in the anti-retroviral therapy. Cryptococcus neoformans is usually associated with infections in immunocompromised patients while Cryptococcus gatti is associated with infections in immunocompetent patients.

Pathophysiology

Cryptococcus fungi are commonly found in soil contaminated by bird droppings and in decaying wood and in tree hollows. The capsule of the fungus comprises polysaccharides glucuronoxylomannan and glucuronoxylomannogalactan which are the major factors contributing to the virulence of pathogen. [4] Infection usually occurs through inhalation of spores from the environment. The initial infection is mostly asymptomatic and is contained in healthy individuals. Spread of the disease from initial site of infection occurs through hematogenous dissemination in patients who are immune suppressed. Another mechanism through which the infection can develop is reactivation of the organism at the initial site of infection after several years when the patient becomes immunocompromised. [5]

Histopathology

They are facultative intracellular organisms. Cryptococcal fungi exist in asexual forms (yeast) and sexual forms (telomorphs). They produce white mucoid colonies when grown on a wide variety of agars. The two-predominant species of Cryptococcus are differentiated by growth features on canavanine-glycine-bromo methyl blue agar. Histological identification can be performed by methenamine silver stain for yeast forms, mucicarmine stain for yeast and capsule forms and Fontana-Masson stain for the melanin in the yeast.

History and Physical

Cryptococcus neoformans and Cryptococcus gatti both spread through inhalation and cause a similar spectrum of illness. Despite lung being the common site where the pathogen enters the body meningoencephalitis is the most common clinical manifestation of the infection. Clinical features of cryptococcal meningitis typically manifest with in 1-2 weeks and include fever, malaise, headache, neck stiffness, photophobia, nausea, and vomiting. The disease may rarely progress to coma and death. Symptoms such as a cough, dyspnea, skin rash have been reported to occur rarely in the literature.[6] Physical examination findings may sometimes reveal focal neurological deficits, and elevated diastolic pressure indicative of raised intracranial pressure.

Evaluation

Patients presenting with symptoms of central nervous system are evaluated with radiographic imaging of the brain to rule out the presence of elevated cerebrospinal fluid pressure. Cerebrospinal fluid analysis, culture, staining and immunodiagnostic tests of cerebrospinal fluid are the primary diagnostic tests that are performed to diagnose meningitis caused by Cryptococcus. Analysis of the fluid usually shows low white blood cell count, low glucose, and elevated protein but could also be normal in approximately 25-30% of the cases.[7] The culture of the infected fluid reveals cream colored colonies in about 3-7 days while staining with Indian ink helps in identifying the organism rapidly. Detection of cryptococcal antigen through immunodiagnostic tests of the serum and the cerebrospinal fluid provide a definitive diagnosis of the infection. Different techniques such as latex agglutination, enzyme-linked immunosorbent assay (ELISA) and lateral flow assay can be used to confirm the diagnosis of cryptococcal antigen.[8]

Disseminated Cryptococcus infection is defined by a positive blood culture or a positive culture from at least two different sites. Disseminated infection is commonly associated with HIV infection or several other immunocompromised states. 

Treatment / Management

Pharmacological treatment for cryptococcal infections depends on the site of infection and the severity of symptoms.  Per the 2010 IDSA Guidelines, non-immunosuppressive patients suspected of having a pulmonary cryptococcal infection with mild-to-moderate symptoms can be treated with fluconazole at a dose of 400mg daily for 6-12 months. This is also the treatment recommendation for non-meningeal, non-pulmonary cryptococcosis in patients where CNS disease was ruled out. In non-immunocompromised patients, a lumbar puncture should be considered ruling out asymptomatic CNS involvement, but the guidelines state that an LP can be avoided in asymptomatic, immunocompetent patients with no CNS symptoms.

Management of CNS cryptococcosis and in immune-compromised hosts involves treatment targeting the fungal pathogen, reducing the intracranial pressure, and improvising the immune status of the patient. Antifungal therapy that targets Cryptococcus comprises induction, consolidation, and maintenance phase. Amphotericin B and flucytosine, for a minimum duration of 2 weeks are recommended antifungal therapies that are used for induction phase and fluconazole for a duration of eight weeks is the recommended drug for consolidation phase of the therapy. [9]The medication choices are usually similar in HIV-positive patients, patients with organ transplantation and patients suffering from other conditions that cause immune suppression. After 2 weeks of induction therapy a repeat examination of cerebrospinal fluid is recommended and the duration of induction therapy can further be extended if the cultures remain positive.[10] Maintenance therapy is recommended with fluconazole after eight weeks of induction and consolidation phases and the duration of maintenance phase is generally for a period of 1 year. Maintenance therapy can be discontinued if the patient achieves a healthy immune status clinically correlated as CD4 cell count of more than 100 cells/microL.[11]

Monitoring intracranial pressure and keeping it under check plays an important role in reducing the mortality associated with cryptococcal meningitis.[12] Lumbar puncture is the recommended option for management of intracranial pressure and either a ventricular drain or ventriculo peritoneal shunt is used in patients who require frequent lumbar punctures. [13] Use of medications such as acetazolamide, mannitol and dexamethasone which normally used in bacterial meningitis for lowering intracranial pressure is not recommended in cryptococcal meningitis.[14][15] Another crucial aspect of the management of cryptococcosis includes improving the immune status of the patient. For HIV-positive patients, anti-retroviral therapy is recommended after a duration of 2-10 weeks after initiation of the anti-fungal therapy. Delayed initiation of the anti-retroviral therapy has been associated with better survival rates when compared to early initiation.[16] For patients who have organ transplantations, a reduction in the immunosuppressive therapy in a phased manner while maintaining the balance with a risk of organ rejection would be a recommended approach to enhance the immune status.[17]

There has been a steep decline in the mortality rates associated with cryptococcal infections because of advancements in the anti-retroviral therapy. The prognostic predictors of the disease associated with poor outcomes include altered mental status, cerebrospinal fluid antigen titer greater than 1:1024 and cerebrospinal fluid white blood cell count less than 20/microL. [18]

Differential Diagnosis

  • Histoplasmosis

  • Lipomas

  • Syphilis

  • Toxoplasmosis

  • Tuberculosis

Enhancing Healthcare Team Outcomes

Prevention:

Prophylactic treatment for cryptococcal infection is recommended in HIV-positive patients with a CD4 count of fewer than 100 cells/microL. Fluconazole and Itraconazole are the recommended drugs for prophylaxis against cryptococcosis.

Current research:

Efficacy of sertraline an antidepressant as an adjunct therapy with fluconazole is being studied in preventing cryptococcal infections in asymptomatic patients who test positive for cryptococcal antigen. A long-term prospective study is being performed to have a better understanding of the immunogenetic defects that might play a role in the pathogenesis of cryptococcal infections.

Review Questions

  • Access free multiple choice questions on this topic.

  • Comment on this article.

Figure

Cryptococcus showed in different fungal stains. Contributed by Pradeep Kumar Mada

References

1.

Lin YY, Shiau S, Fang CT. Risk factors for invasive Cryptococcus neoformans diseases: a case-control study. PLoS One. 2015;10(3):e0119090. [PMC free article: PMC4352003] [PubMed: 25747471]

2.

Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009 Feb 20;23(4):525-30. [PubMed: 19182676]

3.

Mirza SA, Phelan M, Rimland D, Graviss E, Hamill R, Brandt ME, Gardner T, Sattah M, de Leon GP, Baughman W, Hajjeh RA. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis. 2003 Mar 15;36(6):789-94. [PubMed: 12627365]

4.

Srikanta D, Santiago-Tirado FH, Doering TL. Cryptococcus neoformans: historical curiosity to modern pathogen. Yeast. 2014 Feb;31(2):47-60. [PMC free article: PMC3938112] [PubMed: 24375706]

5.

Eisenman HC, Casadevall A, McClelland EE. New insights on the pathogenesis of invasive Cryptococcus neoformans infection. Curr Infect Dis Rep. 2007 Nov;9(6):457-64. [PubMed: 17999881]

6.

Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol. 1996 May;132(5):545-8. [PubMed: 8624151]

7.

Garlipp CR, Rossi CL, Bottini PV. Cerebrospinal fluid profiles in acquired immunodeficiency syndrome with and without neurocryptococcosis. Rev Inst Med Trop Sao Paulo. 1997 Nov-Dec;39(6):323-5. [PubMed: 9674282]

8.

Boulware DR, Rolfes MA, Rajasingham R, von Hohenberg M, Qin Z, Taseera K, Schutz C, Kwizera R, Butler EK, Meintjes G, Muzoora C, Bischof JC, Meya DB. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis. 2014 Jan;20(1):45-53. [PMC free article: PMC3884728] [PubMed: 24378231]

9.

Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 01;50(3):291-322. [PMC free article: PMC5826644] [PubMed: 20047480]

10.

Sloan DJ, Parris V. Cryptococcal meningitis: epidemiology and therapeutic options. Clin Epidemiol. 2014;6:169-82. [PMC free article: PMC4026566] [PubMed: 24872723]

11.

Mussini C, Pezzotti P, Miró JM, Martinez E, de Quiros JC, Cinque P, Borghi V, Bedini A, Domingo P, Cahn P, Bossi P, de Luca A, d’Arminio Monforte A, Nelson M, Nwokolo N, Helou S, Negroni R, Jacchetti G, Antinori S, Lazzarin A, Cossarizza A, Esposito R, Antinori A, Aberg JA. , International Working Group on Cryptococcosis. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis. 2004 Feb 15;38(4):565-71. [PubMed: 14765351]

12.

Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, Musubire A, Rajasingham R, Williams DA, Thienemann F, Muzoora C, Meintjes G, Meya DB, Boulware DR. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014 Dec 01;59(11):1607-14. [PMC free article: PMC4441057] [PubMed: 25057102]

13.

Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, Riser L, Hamill R, Dismukes W. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000 Jan;30(1):47-54. [PubMed: 10619732]

14.

Newton PN, Thai le H, Tip NQ, Short JM, Chierakul W, Rajanuwong A, Pitisuttithum P, Chasombat S, Phonrat B, Maek-A-Nantawat W, Teaunadi R, Lalloo DG, White NJ. A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis. Clin Infect Dis. 2002 Sep 15;35(6):769-72. [PubMed: 12203177]

15.

Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN., CryptoDex Investigators. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med. 2016 Feb 11;374(6):542-54. [PMC free article: PMC4778268] [PubMed: 26863355]

16.

Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G., COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487-98. [PMC free article: PMC4127879] [PubMed: 24963568]

17.

Singh N, Lortholary O, Alexander BD, Gupta KL, John GT, Pursell K, Munoz P, Klintmalm GB, Stosor V, del Busto R, Limaye AP, Somani J, Lyon M, Houston S, House AA, Pruett TL, Orloff S, Humar A, Dowdy L, Garcia-Diaz J, Kalil AC, Fisher RA, Husain S., Cryptococcal Collaborative Transplant Study Group. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis. 2005 Jun 15;40(12):1756-61. [PubMed: 15909263]

18.

Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar AM, Tuazon CU, Fisher JF. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. 1992 Jan 09;326(2):83-9. [PubMed: 1727236]

Disclosure: Pradeep Kumar Mada declares no relevant financial relationships with ineligible companies.

Disclosure: Radia Jamil declares no relevant financial relationships with ineligible companies.

Disclosure: Mohammed Alam declares no relevant financial relationships with ineligible companies.

Cryptococcus – StatPearls – NCBI Bookshelf

Continuing Education Activity

Cryptococcus is an invasive fungus, transmitted through the inhalation of spores and causes cryptococcosis, an infection commonly associated with immunosuppressive individuals. Patients present with fever, headache, malaise, photophobia and neck stiffness as cryptococcal meningitis sets in. This activity describes the evaluation and management of cryptococcosis and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

  • Identify the cryptococcal species in the etiology of cryptococcosis.

  • Describe the typical patient history and physical exam findings in cryptococcosis.

  • Outline the use of cerebrospinal fluid analysis in the evaluation of cryptococcosis.

  • Review the importance of collaboration and communication among the interprofessional team to provide prophylactic treatment for cryptococcal infection to improve outcomes in immunocompromised patients by preventing cryptococcosis.

Access free multiple choice questions on this topic.

Introduction

Cryptococcus is an invasive fungus that causes cryptococcosis an infection commonly associated with immunosuppressive individuals while being rare in healthy individuals.  The two species of Cryptococcus that are commonly associated with infections in humans are Cryptococcus neoformans and Cryptococcus gatti.  The organism is widely prevalent in certain regions of the world. However, the most common forms of exposure include a history of exposure to soil, bird droppings. 

Etiology

Cryptococcal species are fungal pathogens which are encapsulated yeasts morphologically. Immune suppression is the major underlying mechanism that is involved in the causation of cryptococcal disease. Diseases like AIDS, diabetes, chronic liver disease, chronic renal disease, prolonged use of steroids and patients who undergo organ transplantation are commonly associated with the development of cryptococcal disease.[1]

Epidemiology

Globally approximately 1 million cases of cryptococcosis are reported each year resulting in 625,000 deaths approximately.[2] In the United States incidence of cryptococcosis is estimated to be about 0.4-1.3 cases per 100,000 population and 2-7 cases per 100,000 in people affected with AIDS with a case fatality ratio of about 12%. [3]The incidence of cryptococcal infections has declined drastically over the last two decades owing to advances in the anti-retroviral therapy.  Cryptococcus neoformans is usually associated with infections in immunocompromised patients while Cryptococcus gatti is associated with infections in immunocompetent patients.

Pathophysiology

Cryptococcus fungi are commonly found in soil contaminated by bird droppings and in decaying wood and in tree hollows. The capsule of the fungus comprises polysaccharides glucuronoxylomannan and glucuronoxylomannogalactan which are the major factors contributing to the virulence of pathogen.[4] Infection usually occurs through inhalation of spores from the environment. The initial infection is mostly asymptomatic and is contained in healthy individuals. Spread of the disease from initial site of infection occurs through hematogenous dissemination in patients who are immune suppressed. Another mechanism through which the infection can develop is reactivation of the organism at the initial site of infection after several years when the patient becomes immunocompromised. [5]

Histopathology

They are facultative intracellular organisms. Cryptococcal fungi exist in asexual forms (yeast) and sexual forms (telomorphs). They produce white mucoid colonies when grown on a wide variety of agars. The two-predominant species of Cryptococcus are differentiated by growth features on canavanine-glycine-bromo methyl blue agar. Histological identification can be performed by methenamine silver stain for yeast forms, mucicarmine stain for yeast and capsule forms and Fontana-Masson stain for the melanin in the yeast.

History and Physical

Cryptococcus neoformans and Cryptococcus gatti both spread through inhalation and cause a similar spectrum of illness. Despite lung being the common site where the pathogen enters the body meningoencephalitis is the most common clinical manifestation of the infection. Clinical features of cryptococcal meningitis typically manifest with in 1-2 weeks and include fever, malaise, headache, neck stiffness, photophobia, nausea, and vomiting. The disease may rarely progress to coma and death. Symptoms such as a cough, dyspnea, skin rash have been reported to occur rarely in the literature. [6] Physical examination findings may sometimes reveal focal neurological deficits, and elevated diastolic pressure indicative of raised intracranial pressure.

Evaluation

Patients presenting with symptoms of central nervous system are evaluated with radiographic imaging of the brain to rule out the presence of elevated cerebrospinal fluid pressure. Cerebrospinal fluid analysis, culture, staining and immunodiagnostic tests of cerebrospinal fluid are the primary diagnostic tests that are performed to diagnose meningitis caused by Cryptococcus. Analysis of the fluid usually shows low white blood cell count, low glucose, and elevated protein but could also be normal in approximately 25-30% of the cases.[7] The culture of the infected fluid reveals cream colored colonies in about 3-7 days while staining with Indian ink helps in identifying the organism rapidly. Detection of cryptococcal antigen through immunodiagnostic tests of the serum and the cerebrospinal fluid provide a definitive diagnosis of the infection. Different techniques such as latex agglutination, enzyme-linked immunosorbent assay (ELISA) and lateral flow assay can be used to confirm the diagnosis of cryptococcal antigen.[8]

Disseminated Cryptococcus infection is defined by a positive blood culture or a positive culture from at least two different sites. Disseminated infection is commonly associated with HIV infection or several other immunocompromised states. 

Treatment / Management

Pharmacological treatment for cryptococcal infections depends on the site of infection and the severity of symptoms.  Per the 2010 IDSA Guidelines, non-immunosuppressive patients suspected of having a pulmonary cryptococcal infection with mild-to-moderate symptoms can be treated with fluconazole at a dose of 400mg daily for 6-12 months. This is also the treatment recommendation for non-meningeal, non-pulmonary cryptococcosis in patients where CNS disease was ruled out. In non-immunocompromised patients, a lumbar puncture should be considered ruling out asymptomatic CNS involvement, but the guidelines state that an LP can be avoided in asymptomatic, immunocompetent patients with no CNS symptoms.

Management of CNS cryptococcosis and in immune-compromised hosts involves treatment targeting the fungal pathogen, reducing the intracranial pressure, and improvising the immune status of the patient. Antifungal therapy that targets Cryptococcus comprises induction, consolidation, and maintenance phase. Amphotericin B and flucytosine, for a minimum duration of 2 weeks are recommended antifungal therapies that are used for induction phase and fluconazole for a duration of eight weeks is the recommended drug for consolidation phase of the therapy. [9]The medication choices are usually similar in HIV-positive patients, patients with organ transplantation and patients suffering from other conditions that cause immune suppression. After 2 weeks of induction therapy a repeat examination of cerebrospinal fluid is recommended and the duration of induction therapy can further be extended if the cultures remain positive.[10] Maintenance therapy is recommended with fluconazole after eight weeks of induction and consolidation phases and the duration of maintenance phase is generally for a period of 1 year. Maintenance therapy can be discontinued if the patient achieves a healthy immune status clinically correlated as CD4 cell count of more than 100 cells/microL.[11]

Monitoring intracranial pressure and keeping it under check plays an important role in reducing the mortality associated with cryptococcal meningitis.[12] Lumbar puncture is the recommended option for management of intracranial pressure and either a ventricular drain or ventriculo peritoneal shunt is used in patients who require frequent lumbar punctures.[13] Use of medications such as acetazolamide, mannitol and dexamethasone which normally used in bacterial meningitis for lowering intracranial pressure is not recommended in cryptococcal meningitis.[14][15] Another crucial aspect of the management of cryptococcosis includes improving the immune status of the patient. For HIV-positive patients, anti-retroviral therapy is recommended after a duration of 2-10 weeks after initiation of the anti-fungal therapy. Delayed initiation of the anti-retroviral therapy has been associated with better survival rates when compared to early initiation. [16] For patients who have organ transplantations, a reduction in the immunosuppressive therapy in a phased manner while maintaining the balance with a risk of organ rejection would be a recommended approach to enhance the immune status.[17]

There has been a steep decline in the mortality rates associated with cryptococcal infections because of advancements in the anti-retroviral therapy. The prognostic predictors of the disease associated with poor outcomes include altered mental status, cerebrospinal fluid antigen titer greater than 1:1024 and cerebrospinal fluid white blood cell count less than 20/microL.[18]

Differential Diagnosis

  • Histoplasmosis

  • Lipomas

  • Syphilis

  • Toxoplasmosis

  • Tuberculosis

Enhancing Healthcare Team Outcomes

Prevention:

Prophylactic treatment for cryptococcal infection is recommended in HIV-positive patients with a CD4 count of fewer than 100 cells/microL. Fluconazole and Itraconazole are the recommended drugs for prophylaxis against cryptococcosis.

Current research:

Efficacy of sertraline an antidepressant as an adjunct therapy with fluconazole is being studied in preventing cryptococcal infections in asymptomatic patients who test positive for cryptococcal antigen. A long-term prospective study is being performed to have a better understanding of the immunogenetic defects that might play a role in the pathogenesis of cryptococcal infections.

Review Questions

  • Access free multiple choice questions on this topic.

  • Comment on this article.

Figure

Cryptococcus showed in different fungal stains. Contributed by Pradeep Kumar Mada

References

1.

Lin YY, Shiau S, Fang CT. Risk factors for invasive Cryptococcus neoformans diseases: a case-control study. PLoS One. 2015;10(3):e0119090. [PMC free article: PMC4352003] [PubMed: 25747471]

2.

Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009 Feb 20;23(4):525-30. [PubMed: 19182676]

3.

Mirza SA, Phelan M, Rimland D, Graviss E, Hamill R, Brandt ME, Gardner T, Sattah M, de Leon GP, Baughman W, Hajjeh RA. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis. 2003 Mar 15;36(6):789-94. [PubMed: 12627365]

4.

Srikanta D, Santiago-Tirado FH, Doering TL. Cryptococcus neoformans: historical curiosity to modern pathogen. Yeast. 2014 Feb;31(2):47-60. [PMC free article: PMC3938112] [PubMed: 24375706]

5.

Eisenman HC, Casadevall A, McClelland EE. New insights on the pathogenesis of invasive Cryptococcus neoformans infection. Curr Infect Dis Rep. 2007 Nov;9(6):457-64. [PubMed: 17999881]

6.

Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol. 1996 May;132(5):545-8. [PubMed: 8624151]

7.

Garlipp CR, Rossi CL, Bottini PV. Cerebrospinal fluid profiles in acquired immunodeficiency syndrome with and without neurocryptococcosis. Rev Inst Med Trop Sao Paulo. 1997 Nov-Dec;39(6):323-5. [PubMed: 9674282]

8.

Boulware DR, Rolfes MA, Rajasingham R, von Hohenberg M, Qin Z, Taseera K, Schutz C, Kwizera R, Butler EK, Meintjes G, Muzoora C, Bischof JC, Meya DB. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis. 2014 Jan;20(1):45-53. [PMC free article: PMC3884728] [PubMed: 24378231]

9.

Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 01;50(3):291-322. [PMC free article: PMC5826644] [PubMed: 20047480]

10.

Sloan DJ, Parris V. Cryptococcal meningitis: epidemiology and therapeutic options. Clin Epidemiol. 2014;6:169-82. [PMC free article: PMC4026566] [PubMed: 24872723]

11.

Mussini C, Pezzotti P, Miró JM, Martinez E, de Quiros JC, Cinque P, Borghi V, Bedini A, Domingo P, Cahn P, Bossi P, de Luca A, d’Arminio Monforte A, Nelson M, Nwokolo N, Helou S, Negroni R, Jacchetti G, Antinori S, Lazzarin A, Cossarizza A, Esposito R, Antinori A, Aberg JA., International Working Group on Cryptococcosis. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis. 2004 Feb 15;38(4):565-71. [PubMed: 14765351]

12.

Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, Musubire A, Rajasingham R, Williams DA, Thienemann F, Muzoora C, Meintjes G, Meya DB, Boulware DR. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014 Dec 01;59(11):1607-14. [PMC free article: PMC4441057] [PubMed: 25057102]

13.

Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, Riser L, Hamill R, Dismukes W. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000 Jan;30(1):47-54. [PubMed: 10619732]

14.

Newton PN, Thai le H, Tip NQ, Short JM, Chierakul W, Rajanuwong A, Pitisuttithum P, Chasombat S, Phonrat B, Maek-A-Nantawat W, Teaunadi R, Lalloo DG, White NJ. A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis. Clin Infect Dis. 2002 Sep 15;35(6):769-72. [PubMed: 12203177]

15.

Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN., CryptoDex Investigators. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med. 2016 Feb 11;374(6):542-54. [PMC free article: PMC4778268] [PubMed: 26863355]

16.

Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G., COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487-98. [PMC free article: PMC4127879] [PubMed: 24963568]

17.

Singh N, Lortholary O, Alexander BD, Gupta KL, John GT, Pursell K, Munoz P, Klintmalm GB, Stosor V, del Busto R, Limaye AP, Somani J, Lyon M, Houston S, House AA, Pruett TL, Orloff S, Humar A, Dowdy L, Garcia-Diaz J, Kalil AC, Fisher RA, Husain S., Cryptococcal Collaborative Transplant Study Group. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis. 2005 Jun 15;40(12):1756-61. [PubMed: 15909263]

18.

Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK, Thompson SE, Sugar AM, Tuazon CU, Fisher JF. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. 1992 Jan 09;326(2):83-9. [PubMed: 1727236]

Disclosure: Pradeep Kumar Mada declares no relevant financial relationships with ineligible companies.

Disclosure: Radia Jamil declares no relevant financial relationships with ineligible companies.

Disclosure: Mohammed Alam declares no relevant financial relationships with ineligible companies.

Cryptococcosis in hematological practice

CT scan

PCT – polychemotherapy

CSF – cerebrospinal fluid

CNS – central nervous system

Cryptococcosis is an invasive mycosis caused by the yeast fungi Cryptococcus spp. The infection occurs predominantly in patients with T-cell immunodeficiency and is characterized by frequent involvement of the central nervous system (CNS). The main causative agent of cryptococcosis is Cryptococcus neoformans , rarely cause the disease C. laurentii and C. albidus . Risk factors that induce the development of infection include the use of glucocorticoid and immunosuppressive drugs, such as alemtuzumab, fludarabine, cyclosporine A, tacralimus, etc. [1–3]. Cryptococcosis predominates in HIV-infected patients and the highest frequency of this infection was before the introduction of highly active antiretroviral therapy for AIDS. Thus, according to a multicenter study conducted in the United States since 1992 to 1994, the incidence of cryptococcosis in HIV infection was 1700-6600 cases per 100 thousand of the population, while in HIV-uninfected patients this figure was 0.2-0.9 cases per 100 thousand of the population [1 ]. According to another multicenter study (USA, 1990-1996), in the structure of HIV-negative patients with cryptococcosis, the main proportion were patients taking glucocorticoid drugs for a long time (28%), recipients of organs and tissues (18%), patients with rheumatological diseases ( 13%), hemoblastoses (9%) and solid tumors (9%) [4].

Infection with cryptococci usually occurs by inhalation. Spores of the fungus, getting into the lungs, cause the development of bronchopneumonia. Against the background of T-cell immunity deficiency, hematogenous dissemination of cryptococci occurs with damage to the central nervous system. In 25-50% of patients with a disseminated process, damage to other organs, such as the prostate, skin, liver, kidneys, spleen, and bones, is possible. Infection of the prostate may further be a source of reactivation of cryptococcosis after discontinuation of treatment. Infection with cryptococci is possible by contact in case of injury to the skin [4–6].

Clinical manifestations of cryptococcosis are nonspecific and depend on the localization of the process. The most common are febrile body temperature, headache, dizziness, impaired consciousness, less often symptoms such as cough, shortness of breath, skin rashes.

In HIV-infected patients with cryptococcal meningitis or meningoencephalitis, about 75% of cases have high intracranial pressure caused by the rapid growth of fungi in the cerebrospinal fluid (CSF) [3].

Until recently, the main method of diagnosing cryptococcal infection was the detection of cryptococci under microscopy using India ink smear and/or in culture in the study of CSF, blood and other substrates. This method is most informative in HIV-infected patients due to the rapid growth of cryptococcus, especially in the CSF [7]. Currently, rapid diagnostics of cryptococcal infection is available, which is based on the determination of the cryptococcal antigen (glucuronoxylomannan) in blood, CSF, bronchoalveolar lavage fluid (BAL) and urine. It should be noted the high sensitivity (92%) and specificity (>93%) of this test, even with a latex test. False-positive results in determining the antigen of cryptococcus are rare, they are possible with a malignant neoplasm, a high titer of rheumatoid factor in the blood serum, as well as with infections caused by Trichosporon spp ., Capnocytophaga canimorsus and Stomatococcus mucilaginosis [8, 9].

Our study presents the clinical manifestations, diagnostic features and treatment results of cryptococcosis in patients with hematological malignancies.

Materials and methods

A retrospective analysis of clinical manifestations, features of diagnosis and results of therapy of cryptococcosis in patients with tumors of the hematologic system treated at the State Scientific Center of the Ministry of Health of the Russian Federation from 2005 to 2011 was carried out.

The diagnosis of cryptococcosis was established according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria based on obtaining a culture of fungi from blood, CSF and other sterile samples and (or) determining a positive antigen of cryptococcus in the blood and (or) cerebrospinal fluid in patients with symptoms of infection [10].

Cryptococcus antigen (glucuronoxylomannan) was determined using the Pastorex Crypto Plus latex test (BIO-RAD, France).

When body temperature rose above 38°C, blood for microbiological examination was taken from a peripheral vein and/or from a central venous catheter into commercial bottles designed for a Becton-Dickinson automatic blood culture analyzer (USA). Fungi were identified using API 20AUX test systems (bioMerieux, France).

Results

Within 7 years (2005-2011) cryptococcosis was diagnosed in 19 patients with diseases of the blood system (12 men, 7 women) aged 19 to 68 years (median 47 years). The structure of cryptococcosis was dominated by patients with lymphoma (31%) and acute lymphoblastic leukemia (26%) at the stages of induction (32%) and consolidation (26%) of remission of hemoblastosis (see table). In 13 (68%) of 19 patients, cryptococcosis was diagnosed after a course of polychemotherapy (PCT), in 4 (21%) patients with relapse or resistant course of hemoblastosis (the duration of administration of cytostatic drugs was more than 3 months), in 1 patient after allogeneic stem transplantation. hematopoietic cells in the treatment of chronic graft-versus-host disease with prednisolone, in one case – when using cyclosporine A for more than 3 months in the treatment of aplastic anemia. The median from the end of the course of chemotherapy and the development of cryptococcosis was 9days (from 0 to 49 days), while in 5 (38%) patients the infection occurred after courses of high-dose PCT, and in 8 (62%) after standard courses of PCT. Glucocorticoid preparations were used in 12 (63%) patients. At the time of infection diagnosis, 8 (42%) patients had granulocytopenia (granulocytes 9/l), the median duration of which was 9 days (range 1 to 44 days).

As already noted, cryptococcosis was diagnosed in all patients in accordance with the EORTC/MSG criteria [10]. In 17 (89%) patients with symptoms of CNS lesions, a positive antigen of cryptococcus in the CSF was detected, in one patient with sepsis, a blood culture was obtained Cr. neoformans , in one patient with pneumonia and fever, a positive antigen was detected in 2 repeated blood tests (considered as possible cryptococcal pneumonia). Repeated determination of the antigen in the CSF was carried out in 13 patients, of which 8 (61%) positive antigen of cryptococcus was repeatedly detected.

Thus, taking into account the clinical manifestations of the infection and the results of studies, 17 (78%) patients were diagnosed with cryptococcal meningitis or meningoencephalitis, one with cryptococcal sepsis (lymphogranulomatosis, 6th course of chemotherapy with prednisolone), one with possible cryptococcal pneumonia with treatment of graft-versus-host disease following transplantation of allogeneic hematopoietic cells with prednisolone.

The main manifestation (78%) was CNS involvement in the form of meningitis or meningoencephalitis. The leading symptoms in this localization of the infection were headache (69%) and impaired consciousness to stupor (56%), less often – dizziness (25%) and nausea (19%), coma developed in 1 patient. At the same time, 5 patients had stiff neck muscles, and 4 had focal neurological disorders. It should be noted that 9 (47%) patients with cryptococcal lesions of the central nervous system were diagnosed in the intensive care unit, to which they were transferred due to the development of severe neurological disorders.

In 2 patients, cryptococcosis proceeded without CNS damage. In a patient with cryptococcal sepsis, the main symptom was prolonged febrile fever against the background of the use of broad-spectrum antibiotics. In a patient with suspected cryptococcal lung disease, the main clinical symptoms were body temperature over 38.5 °C and pneumonia with respiratory failure.

At the time of diagnosis of cryptococcosis, 17 patients underwent computed tomography (CT) of the chest, and 57% had nonspecific changes in the lung tissue. In all cases of meningitis/meningoencephalitis, CT or magnetic resonance imaging of the brain was performed. Changes were found in 12 (71%) patients, including hydrocephalus in 47%, foci in 32%, thickening of the meninges in 8% (see picture). Figure 1. Cryptococcal meningoencephalitis in patients with aplastic anemia (a; CT scan of the brain: a low-density, irregularly shaped focus with clear contours, 42.4 × 27.8 × 20 mm in size), lymphosarcoma (b; magnetic resonance imaging — MRI brain: foci of irregular rounded shape ranging in size from 5 to 9 mm in the occipital regions of both hemispheres of the brain) and acute lymphoblastic leukemia (c; MRI of the brain: uniform thickening of the dura mater up to 2-3 mm with intensive accumulation of a contrast agent).

All patients were prescribed antifungal drugs. At the induction stage, with symptoms of meningitis/meningoencephalitis, 15 patients were treated with one drug (one patient with fluconazole at a dose of 800 mg/day intravenously, the rest with amphotericin B at a dose of 0.7–1.0 mg/kg/day intravenously) and 2 patients with a combination amphotericin B with flucytosine (100 mg/kg/day) or fluconazole (800 mg/day). The median duration of induction therapy was 17 days (7–42 days). Consolidation therapy was performed in 8 patients, 50% of them with voriconazole tablets (400 mg/day) and 50% with fluconazole (400 mg/day). The median duration of the consolidation phase was 38 days (8-60 days). In cryptococcal sepsis, at the first stage, amphotericin B was prescribed for 21 days, and then fluconazole (400 mg/day) for 30 days. A patient with cryptococcal pneumonia was treated with amphotericin B for 2 weeks, then with fluconazole for 55 days.

Curing was achieved in 12 (64%) patients. Within 30 days from the moment of diagnosis of cryptococcosis, 5 (26%) patients died. The cause of death in 1 (5%) case was cryptococcal meningoencephalitis, in 2 (10.5%) — mixed infection (cryptococcosis and other infection), in 2 (10.5%) — progression of the underlying disease in combination with infectious complications.

Talk

Currently, in HIV-infected patients, cryptococcosis ranks 4th among infections caused by opportunistic pathogens, and is one of the main causes of meningitis [1, 8]. Much less often, this complication occurs in other diseases, including those that occur with T-cell immunodeficiency. Thus, within 10 years, cryptococcosis was diagnosed in 20 oncohematological patients at the M. Anderson Center (USA) and in 17 patients at 21 centers in Italy (data from the GIMEMA study) [11, 12]. Due to the low prevalence of cryptococcosis in patients with tumors of the blood system, partly due to shortcomings in diagnosis, there are few publications on the epidemiology, clinical course and results of therapy.

Cryptococcosis in oncohematology occurs primarily in patients with lymphatic tumors [11-13]. So, in the study by D. Kontoyiannis et al. [11], 17 (85%) of 20 patients with cryptococcosis had lymphoma and chronic lymphocytic leukemia. At the same time, according to a multicenter study in Italy, the group of 17 patients with cryptococcosis included 47% of patients with acute myeloid leukemia and 41% with lymphatic tumors. The authors explain this by the predominance of patients with acute leukemia among those hospitalized in hematological hospitals in Italy [12]. In our study, cryptococcal infection was observed mainly in patients with lymphatic tumors (74%), however, in addition to the prevalence in lymphomas (31%), a significant percentage was also detected in acute lymphoblastic leukemia (26).

The main risk factors for the development of cryptococcosis in patients with tumors of the blood system were previous cytostatic exposure, the use of glucocorticoid and immunosuppressive drugs. It should be noted that in invasive mycosis, in contrast to invasive aspergillosis, granulocytopenia is less common (16–35%) and its median duration is about 5 days [11–14]. In our study, the number of patients with granulocytopenia was slightly higher (42%) and, probably, this indicator is determined by the intensity of the cytostatic effect in the hospital for various hemoblastoses.

Both in HIV-infected patients and in patients with tumors of the blood system, involvement in the infectious process of the central nervous system in cryptococcosis predominates, but the clinical manifestations are not identical. So, in patients with hemoblastoses, the symptoms of cryptococcal meningitis and meningoencephalitis are not so pronounced, most often they are concerned about fever, headache, impaired consciousness, and with delayed treatment, stupor develops. In terms of diagnostics, it is also necessary to note the low percentage of obtaining a culture of cryptococcus from the CSF in patients with hematological malignancies compared with HIV-infected patients [4, 6, 13], therefore, the diagnosis of cryptococcosis in most cases is established on the basis of determining a positive antigen of cryptococcus in the CSF or isolating a culture of fungi from blood [11-14]. In a multicenter study by L. Pagano et al. [12], the diagnosis of cryptococcosis was established in 8 (47%) of 17 patients when determining the positive antigen of cryptococcus, and in 9(53%) – when isolating culture C. neoformans mainly from blood.

There are some peculiarities in the treatment of patients with cryptococcosis: firstly, it is long-term and includes such stages as induction, consolidation and maintenance therapy; secondly, the choice of an antifungal drug at the first stage of treatment (induction) is determined by the localization of the infection [15]. In the cerebral form, treatment is started with amphotericin B (0.7-1 mg/kg/day) as monotherapy or in combination with flucytosine (100 mg/kg/day, this dose is divided into 4 doses). The duration of this stage (induction) is from 2 to 6 weeks. Amphotericin B lipid formulation (liposomal amphotericin B 3–4 mg/kg or amphotericin B lipid complex 5 mg/kg) should be given for intolerance or toxicity seen with conventional amphotericin B. forms of amphotericin B as the initial regimen for the treatment of infection. When using flucytosine, suppression of bone marrow hematopoiesis is possible [16]. Subsequently, with improvement, consolidating (8 weeks) and maintenance (6-12 months) therapy with fluconazole is carried out.

In isolated non-severe pulmonary cryptococcosis, treatment is with fluconazole (400 mg/day) for 6–12 months [15]. In the case of severe cryptococcal pneumonia or with dissemination to the central nervous system, an approach similar to that for the cerebral form is used.

An alternative drug for the treatment of cryptococcosis is voriconazole, which has a high in vitro activity , penetrates the blood-brain barrier, has two forms of administration and is less toxic than amphotericin B or flucytosine [17-19]. So, in a global multicenter study, including the study of the activity of in vitro 1800 strains of Cryptococcus spp. , growth inhibition was noted in 99% of fungi at low concentrations of voriconazole equal to 0. 5 µg/ml or less [17]. For the treatment of patients with cryptococcosis, voriconazole can be prescribed both at the first stage of the disease and in resistant course. The effectiveness of the combined use of voriconazole and amphotericin B as second-line drugs for cryptococcal meningitis in HIV-infected patients was noted [19].

According to the literature, with adequate antifungal therapy, mortality from cryptococcosis in patients with tumors of the blood system does not exceed 40%. Most often, patients with uncontrolled tumor process and CNS lesions die with cryptococcosis [11–14]. In our study, mortality in cryptococcosis within 30 days was 26%, and in 40% of cases, deaths were observed with an uncontrolled tumor process.

Conclusion

Thus, in the era of modern therapy for tumors of the blood system, when, on the one hand, there is an intensification of chemotherapy programs, and, on the other hand, the use of drugs that suppress predominantly the T-cell link of immunity, there is an expansion of potential pathogens of invasive mycoses. In this case, the infectious process can be caused not only by fungi Candida spp. or Aspergillus, but also other pathogens such as Cryptoccocus spp . With cryptococcosis, the involvement of the CNS in the infectious process predominates, therefore, the determination of the cryptococcus antigen in the CSF with symptoms of meningitis or meningoencephalitis in patients with tumors of the blood system, especially lymphatic, should be carried out in all cases. In the case of timely diagnosis and adequate therapy, mortality from cryptococcosis in a controlled tumor situation is much lower than in other invasive mycoses.

Cryptococcosis treatment consultation St. Petersburg clinic ID-CLINIC

Cryptococcosis treatment consultation St. Petersburg clinic ID-CLINIC

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Cryptococcosis is a fungal infection that affects the lungs, nervous system, skin and mucous membranes. The disease is quite rare, at risk are people with a reduced immune status: primary and secondary immunodeficiencies, malignant neoplasms, sarcoidosis, as well as patients who take corticosteroids for a long time. Men get sick 2 times more often than women, the peak of diagnosis falls on the age after 40 years. Diagnosis and treatment of cryptococcosis involved infectious disease specialists ID-clinic.

Causal agent and routes of infection

Cryptococcosis is considered an opportunistic infection caused by the fungus Cryptococcus neoformans. The infection is carried by birds that excrete the pathogen with droppings. In the conditions of the city, the main carrier is pigeons. Infection of a person occurs by inhalation of dust particles with a fungus fixed on them, after which the infection affects the lung tissue, and with the blood flow can enter other organs.

Manifestations of cryptococcosis

In pulmonary cryptococcosis in people who do not have aggravating factors, the clinical picture resembles pneumonia: prolonged dry cough, fever, moderate chest pain. A distinctive feature is the absence of signs of general intoxication. Cryptococcosis of the central nervous system and skin occurs more often in immunocompromised patients. In this case, a rapid deterioration in the condition, the development of multiple organ damage, and cardiopulmonary insufficiency are possible.

Cryptococcosis and HIV

Cryptococcosis is one of the most dangerous AIDS-associated infections for HIV-positive patients who are not receiving antiretroviral therapy. The main form of cryptococcosis in this case is the CNS lesion by the type of meningitis, which in some patients can occur with minimal clinical symptoms: headaches, blurred vision, depression. The disease has a severe course, in 20-30% of cases there is a fatal outcome.

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Patients with suspected cryptococcosis are examined by infectiologists at ID-Clinic. A medical appointment is held in person at the clinic, online via video link or at the patient’s home by appointment. It should be borne in mind that during an online consultation, the doctor gives general recommendations, but he does not have the right to make a final diagnosis and prescribe drugs without a personal examination of the patient.

Diagnosis of cryptococcosis

● X-ray and CT of the lungs to identify foci of fungal infection
● bronchoscopy and sampling of bronchial swabs for microbiological diagnosis
● CT or MRI of the brain to assess the degree of damage in cerebral cryptococcosis
● lumbar puncture with CSF analysis
● laboratory methods – agglutination test, ELISA, PCR diagnostics
● determination of the level of CD4 cells in patients with HIV-positive status

Treatment of cryptococcosis

Treatment of immunocompetent patients is done only when symptoms are present and usually includes an oral antifungal drug given for 6-12 months. Treatment of immunocompromised patients requires an initial course of intensive antifungal therapy for 2-8 weeks. Then they switch to a maintenance course of medications lasting up to 1 year. Therapeutic schemes are selected individually for each patient.

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  • SavchenkoMikhail Andreevich

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