How is Cryptococcus neoformans transmitted. What are the key statistics on C. neoformans infections. How does C. neoformans affect people with HIV/AIDS. What is the global impact of cryptococcal meningitis.

Understanding Cryptococcus Neoformans: A Threat to Immunocompromised Individuals

Cryptococcus neoformans is an invasive fungus that poses a significant risk to individuals with weakened immune systems. This opportunistic pathogen is primarily transmitted through the inhalation of spores, leading to a condition known as cryptococcosis. While rare in healthy individuals, C. neoformans infections can be life-threatening for those with compromised immunity, particularly people living with HIV/AIDS.

Key Characteristics of Cryptococcus Neoformans

• Invasive fungal pathogen
• Transmitted through inhalation of spores
• Causes cryptococcosis
• Major threat to immunocompromised individuals
• Rare in healthy individuals

Is Cryptococcus neoformans the only species causing cryptococcosis in humans? No, while C. neoformans is the most common cause, Cryptococcus gattii is another species that can lead to cryptococcal infections in humans. However, C. gattii infections are less frequent and have different epidemiological patterns.

Epidemiology of Cryptococcus Neoformans Infections: Global and US Perspectives

The prevalence and impact of C. neoformans infections vary significantly between developed countries and resource-limited regions. Understanding these differences is crucial for healthcare professionals to effectively manage and prevent cryptococcal infections.

Global Burden of Cryptococcal Meningitis

Cryptococcal meningitis, a severe manifestation of C. neoformans infection, remains a major health concern worldwide, particularly in regions with high HIV prevalence and limited healthcare access.

• Estimated 152,000 cases of cryptococcal meningitis occur globally each year
• Results in nearly 112,000 deaths annually
• Sub-Saharan Africa bears the highest burden
• Leading cause of meningitis in adults in many African countries
• May cause more deaths than tuberculosis in some regions of sub-Saharan Africa

Why is sub-Saharan Africa disproportionately affected by cryptococcal meningitis? The high prevalence of HIV/AIDS, limited access to antiretroviral therapy, and inadequate healthcare infrastructure contribute to the substantial burden of cryptococcal infections in this region.

Cryptococcus Neoformans Infections in the United States

The landscape of C. neoformans infections in the United States has changed significantly since the introduction of antiretroviral therapy (ART) for HIV/AIDS patients.

• Incidence of cryptococcosis in AIDS patients decreased by approximately 90% in the 1990s
• Annual incidence among persons with AIDS: 2 to 7 cases per 1,000
• Overall incidence in the general population: 0.4 to 1.3 cases per 100,000
• Case-fatality ratio: approximately 12%
• Prevalence of cryptococcal antigenemia in HIV patients with low CD4 counts: 2.9%

How has antiretroviral therapy impacted C. neoformans infections in the US? The widespread availability of ART has significantly reduced the incidence of opportunistic infections, including cryptococcosis, by helping maintain stronger immune systems in people living with HIV/AIDS.

Clinical Presentation and Diagnosis of Cryptococcal Infections

Recognizing the symptoms and effectively diagnosing cryptococcal infections are critical steps in managing this potentially life-threatening condition.

Common Symptoms of Cryptococcal Meningitis

• Fever
• Headache
• Malaise
• Photophobia
• Neck stiffness

What is the primary diagnostic tool for cryptococcal meningitis? Cerebrospinal fluid (CSF) analysis is crucial in evaluating suspected cases of cryptococcal meningitis. This procedure involves examining the CSF for the presence of Cryptococcus, as well as assessing other parameters such as white blood cell count, protein levels, and glucose concentration.

Diagnostic Approaches for Cryptococcosis

1. CSF analysis
2. Cryptococcal antigen testing (blood and CSF)
3. Culture of CSF, blood, or tissue samples
4. Histopathological examination
5. Neuroimaging studies (CT or MRI of the brain)

Why is early diagnosis of cryptococcal infections important? Early detection and treatment of cryptococcosis can significantly improve patient outcomes, particularly in immunocompromised individuals where the infection can rapidly progress to life-threatening conditions.

Treatment Strategies for Cryptococcus Neoformans Infections

Effective management of C. neoformans infections requires a multifaceted approach, tailored to the patient’s immune status and the severity of the infection.

Antifungal Therapy for Cryptococcosis

• Induction therapy: Amphotericin B and flucytosine
• Consolidation therapy: Fluconazole
• Maintenance therapy: Long-term fluconazole

How long should antifungal treatment be continued in cryptococcal meningitis? The duration of treatment depends on various factors, including the patient’s immune status and response to therapy. Typically, induction therapy lasts for at least two weeks, followed by 8 weeks of consolidation therapy. Maintenance therapy may be required for several months to years in immunocompromised patients.

Management of Increased Intracranial Pressure

In cases of cryptococcal meningitis, managing increased intracranial pressure is crucial for improving outcomes. This may involve:

• Serial lumbar punctures
• Temporary CSF shunting
• Use of medications to reduce intracranial pressure

Why is managing intracranial pressure important in cryptococcal meningitis? Elevated intracranial pressure can lead to neurological complications and poor outcomes. Prompt recognition and management of this complication can significantly improve patient prognosis.

Prevention Strategies for Cryptococcus Neoformans Infections

Preventing C. neoformans infections is particularly important for individuals at high risk, such as those with advanced HIV/AIDS or other immunocompromising conditions.

Key Prevention Approaches

• Early initiation of antiretroviral therapy in HIV patients
• Targeted screening for cryptococcal antigen in high-risk populations
• Prophylactic antifungal therapy for those with positive cryptococcal antigen
• Improving access to healthcare in resource-limited settings
• Education and awareness programs for healthcare providers and at-risk populations

Can cryptococcal infections be completely prevented in immunocompromised individuals? While complete prevention may not be possible, implementing comprehensive prevention strategies can significantly reduce the incidence and severity of cryptococcal infections in high-risk populations.

The Role of Healthcare Professionals in Managing Cryptococcus Neoformans Infections

Healthcare professionals play a crucial role in the prevention, diagnosis, and management of C. neoformans infections. A collaborative, interprofessional approach is essential for optimal patient outcomes.

Key Responsibilities of Healthcare Professionals

1. Early identification of at-risk patients
2. Prompt diagnosis and initiation of appropriate treatment
3. Monitoring treatment response and managing complications
4. Providing patient education on prevention and management
5. Collaborating with other healthcare team members for comprehensive care

How can interprofessional collaboration improve outcomes in cryptococcal infections? A team-based approach involving infectious disease specialists, neurologists, pharmacists, and other healthcare professionals ensures comprehensive patient care, optimizes treatment strategies, and improves overall outcomes.

Future Directions in Cryptococcus Neoformans Research and Management

As our understanding of C. neoformans and cryptococcal infections continues to evolve, several areas of research and development hold promise for improving prevention, diagnosis, and treatment.

Emerging Research Areas

• Development of more effective and less toxic antifungal agents
• Exploration of immunomodulatory therapies
• Improvement of rapid diagnostic techniques
• Investigation of host-pathogen interactions
• Development of potential vaccines for high-risk populations

What potential impact could a Cryptococcus vaccine have on global health? A successful vaccine against C. neoformans could dramatically reduce the incidence of cryptococcal infections, particularly in regions with high HIV prevalence, potentially saving thousands of lives annually.

Challenges in Cryptococcus Management

Despite advancements in our understanding and management of cryptococcal infections, several challenges remain:

• Limited access to diagnostics and treatment in resource-poor settings
• Emergence of antifungal resistance
• Complexity of managing cryptococcal immune reconstitution inflammatory syndrome (IRIS)
• Need for more effective strategies to manage increased intracranial pressure
• Improving outcomes in non-HIV immunocompromised patients

How can healthcare systems address the challenges in managing cryptococcal infections in resource-limited settings? Implementing point-of-care diagnostics, improving access to essential antifungal medications, and strengthening healthcare infrastructure are crucial steps in addressing these challenges.

Importance of Continued Education and Awareness

Ongoing education and awareness about C. neoformans infections are essential for healthcare professionals, patients, and the general public. This knowledge is crucial for early detection, effective management, and prevention of cryptococcal infections.

Key Areas for Education and Awareness

• Risk factors for cryptococcal infections
• Importance of early HIV diagnosis and treatment
• Recognition of symptoms and when to seek medical care
• Adherence to antifungal prophylaxis and treatment regimens
• Importance of follow-up care and monitoring

How can healthcare professionals stay updated on the latest developments in cryptococcal management? Attending continuing medical education programs, participating in professional conferences, and regularly reviewing current literature and guidelines are effective ways for healthcare professionals to stay informed about advancements in cryptococcal infection management.

In conclusion, Cryptococcus neoformans remains a significant threat to immunocompromised individuals worldwide. While progress has been made in understanding and managing this pathogen, continued research, improved access to care, and ongoing education are essential to reduce the global burden of cryptococcal infections. Healthcare professionals play a pivotal role in this effort, and their continued vigilance and expertise are crucial in combating this challenging fungal infection.

C. neoformans Infection Statistics | Fungal Diseases

How common are

C. neoformans infections?

C. neoformans infections are rare among people who have healthy immune systems; however, C. neoformans is a major cause of illness in people living with HIV/AIDS, with an estimated 152,000 cases of cryptococcal meningitis occurring worldwide each year.¹

C. neoformans infections in the United States

Before antiretroviral therapy was discovered, fungal and other opportunistic infections were a major problem for people with advanced HIV/AIDS. Since then, the numbers of fungal infections and deaths due to fungal infections in people with advanced HIV/AIDS have decreased substantially in the US and other developed countries.^2,3 For example, one study showed that the incidence of cryptococcosis in AIDS patients in the US decreased by approximately 90% in the 1990s.² The decrease in opportunistic infections is primarily because earlier diagnosis of HIV and initiation of antiretroviral therapy (ART) helps keep people with HIV from reaching the stage where their immune systems leave them most vulnerable to fungal infections and other infections. ⁴ However, fungal diseases, particularly cryptococcosis, are still a concern for people living with HIV/AIDS in the US.

Nationally representative estimates for the incidence of cryptococcosis are difficult to establish because cryptococcosis is only reportable in a few states. Results from active, population-based surveillance in two US locations in the year 2000 indicated that the annual incidence of cryptococcosis among persons with AIDS was between 2 and 7 cases per 1,000, and the overall incidence was 0.4 to 1.3 cases per 100,000 population; the case-fatality ratio was approximately 12%.² More recently, an analysis of stored serum samples from HIV-infected persons with low CD4 counts enrolled in studies in the US during 1986–2012 found the prevalence of cryptococcal antigenemia to be 2.9%, indicating that the prevalence of cryptococcal infection among HIV patients in the US may be high enough to consider targeted screening.⁵

C. neoformans infections worldwide

Although the widespread availability of antiretroviral therapy (ART) in developed countries has helped improve the immune systems of many HIV patients so that they don’t become vulnerable to infection with Cryptococcus, cryptococcal meningitis is still a major problem in resource-limited countries where HIV prevalence is high and access to healthcare is limited. An estimated 152,000 cases of cryptococcal meningitis occur among people with HIV/AIDS worldwide each year, resulting in nearly 112,000 deaths.¹ Most cryptococcal meningitis cases occur in sub-Saharan Africa (Figure 1). Throughout much of sub-Saharan Africa, Cryptococcus is now the most common cause of meningitis in adults. Cryptococcal meningitis is therefore one of the leading causes of death in HIV/AIDS patients in sub-Saharan Africa, where it may kill more people each year than tuberculosis.

Figure 1: global burden of HIV-related cryptococcal meningitis

Adapted from R Rajasingham et al., Lancet Infectious Diseases 2017.

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]

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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]

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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]

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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]

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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]

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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]

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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]

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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]

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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.

Cryptococcal meningitis: symptoms, treatment, clinical guidelines

This disease is treated by Neurologist

The information provided on this page should not be used for self-treatment or self-diagnosis. If you suspect a disease, you should seek help from a qualified specialist. Only your doctor can diagnose and prescribe treatment.

Article content:

• Causes and risk factors
• Pathogenesis
• Clinical picture
• Complications and consequences
• Diagnostics
• Methods of treatment
• Prognosis and prevention

What is cryptococcal meningitis?

Cryptococcal meningitis is a clinical form of cryptococcosis, an infectious disease caused by the fungus Cryptococcus
neoformans. Yeast fungi enter the body by airborne droplets, spread to all organs, in
including penetrate into the brain Source:
Cryptococcosis in hematological practice. Khodunova E.E., Frolova I.N.,
Parovichnikova E.N., Kravchenko S.K., Galstyan G.M., Kostina I.E., Mikhailova E.A., Gracheva A.N., Klyasova
G.A. Therapeutic archive. 2013. No. 11. pp.41-46. Inflammation of the membranes of the brain develops –
meningitis. The disease proceeds severely, often leads to death, in recovered patients remain
lifelong neurological disorders.

Causes and risk factors

The main cause of cryptococcal meningitis is infection of the meninges by the yeast Cryptococcus neoformans. The reservoir of fungi in nature is soil contaminated with pigeon droppings, humus from vegetables and fruits. A person becomes infected mainly by airborne droplets, less often through damaged skin or mucous membranes. Infection from birds, animals or other people has not been established.

Cryptococcosis is an opportunistic infection. In healthy people with normal immunity, the ingress of fungi into the body does not lead to the development of the disease. But in people with various immunodeficiencies, the immune system is not able to destroy the pathogen, so clinical forms of cryptococcosis develop.

Risk factors contributing to the development of cryptococcal meningitis:

• HIV infection without ongoing antiretroviral therapy, with a decrease in the level of CD4 cells less than 500 per 1 ml of blood Source:
  Infectious lesion of the central nervous system as a secondary manifestation of HIV infection. Yesareva D.O. Bulletin of SMUS74. 2016. No. 4. pp.30-33;
• oncological diseases;
• rheumatological diseases in which a person takes immunosuppressants;
• long-term use of corticosteroids;
• absence of spleen;
• decompensated diabetes mellitus;
• renal and hepatic insufficiency;
• congenital immunodeficiency.

Pathogenesis

The portal of entry for Cryptococcus neoformans is the respiratory tract. The fungi that have entered the body are fixed in the lungs, and then they are carried through the bloodstream to all organs. Infection of the meninges with the development of meningitis is the most common clinical form of cryptococcosis, it is observed in 90% of patients. Cryptococcal meningitis is rarely isolated, it is often combined with pneumonia, damage to the liver, kidneys and heart.

Fungi that have penetrated the internal organs cause an inflammatory-allergic reaction. Tissue edema develops due to the active release of inflammatory exudate. The action of the fungi themselves, compression of tissues by edema leads to cell death. Source:
HIV-associated lesions of the nervous system in the pathogenesis of neuroAIDS. Shchigoleva E.V. Bulletin of SMUS74. 2017. No. 4. pp. 80-83.

Clinical presentation

Symptoms of cryptococcal meningitis are similar to those of any meningitis, regardless of the cause. The main signs of damage to the meninges:

• unbearable headache;
• hypersensitivity to light and sound;
• body temperature 37.5-38 degrees, fever over 38 degrees is less common;
• drowsiness, lethargy, impaired attention;
• convulsions;
• vomiting;
• during examination, the rigidity of the occipital muscles is determined.

Cryptococcal meningitis almost always leads to the spread of infection to the substance of the brain with the development of meningoencephalitis. In this case, neurological symptoms appear:

• paresis and paralysis;
• violation of temperature and tactile sensitivity;
• visual and auditory hallucinations;
• violation of coordination of movements.

Complications of cryptococcal meningitis occur in about half of patients. Increasing swelling of the meninges, the substance of the brain causes compression of the auditory and optic nerves. Patients develop progressive visual and hearing loss, leading to blindness and deafness. Compression of the cerebral cortex by edema leads to impaired cognitive function. A decrease in concentration of attention, a weakening of the intellect remain even after recovery.

Diagnosis

All HIV-infected patients in the AIDS stage, with a level of CD4 cells less than 200 per 1 ml of blood, all patients with immunodeficiencies with signs of pneumonia and meningitis are subject to examination for cryptococcosis Source:
Determination of cryptococcal antigen in the complex noah diagnosis of cryptococcal meningitis in immunocompromised patients in St. Petersburg. Ignatieva S.M. et al. Advances in medical mycology. 2014. p.13.. The following tests are used to diagnose cryptococcal meningitis:

• blood test for antibodies to Cryptococcus neoformans;
• examination of cerebrospinal fluid to determine the inflammatory process;
• CSF culture and visual detection of Cryptococcus neoformans under a microscope.

To determine the degree of brain damage, computed or magnetic resonance imaging is performed. General diagnostics includes:

• general clinical blood and urine tests;
• study of the function of the immune system;
• HIV test, viral hepatitis;
• analysis for tumor markers;
• ultrasound examination of the abdominal organs, heart, kidneys;
• chest x-ray.

Patients with HIV infection are prescribed to study the immune status – the level of CD4 cells, viral load. Based on the results of the tests, patients are shown a consultation with an infectious disease specialist, an immunologist.

Treatment of cryptococcal meningitis is carried out only in stationary conditions – in the infectious or neurological department, and in severe cases in intensive care. As an etiotropic treatment of cryptococcal meningitis, according to clinical recommendations, antifungal drugs are used – amphotericin B and flucytosine.

Amphotericin B damages the fungal cell membrane, causing the microorganism to lose viability. Also, the drug contributes to the production of active oxygen, which has an antifungal effect. The course of treatment is long, on average 10 weeks. Amphotericin B is more effective in cryptococcal meningitis without HIV infection, leading to recovery in more than 50% of cases.

Flucytosine destroys the nucleic acids of fungi, which also leads to their death. The drug dissolves well in water and penetrates into all tissues of the body, which allows them to treat all clinical forms of the disease. However, many strains of fungi have developed resistance to flucytosine, so it is recommended to use it in combination with amphotericin B.

Antiretroviral therapy is indicated in patients with HIV infection. All patients with cryptococcal meningitis are treated symptomatically:

• detoxification;
• antipyretics;
• preparations for improving microcirculation;
• diuretics.

To reduce cerebral edema, lumbar punctures are indicated to remove excess CSF. With severe edema, a temporary catheter is installed in the ventricles of the brain, or an operation is performed to install a ventriculo-peritoneal shunt. In this case, the catheter is passed from the ventricles of the brain to the abdominal cavity, where the outflow of CSF will go.

Those who have recovered from cryptococcal meningitis are registered with a neurologist and immunologist. Patients with HIV infection should be regularly monitored at an AIDS center and receive antiretroviral therapy. Source:
A case of successful treatment of cryptococcal meningoencephalitis in a patient with chronic lymphocytic leukemia. Hostelidi S.N. etc. Problems of medical mycology. 2013. p.15.

Prognosis and prevention

Prognosis for cryptococcal meningitis depends on the initial state of the human immune system, the possibilities of medicine. In underdeveloped countries with a high incidence of HIV infection, mortality from cryptococcal meningitis reaches 40%. In highly developed countries, where the majority of HIV-infected people are under medical supervision and receive therapy, the mortality rate is 10-15%.

Everyone who has been ill with cryptococcal meningitis has certain consequences – impaired hearing, vision, and cognitive function. The severity of residual phenomena depends on the severity of the transferred meningitis, the degree of brain damage.

Prevention of all forms of cryptococcosis – timely correction of immunodeficiency states. Patients with established immunodeficiencies should be seen by an immunologist. Patients with HIV infection are shown on a permanent basis of antiretroviral therapy. Its goal is to achieve a level of CD4 cells above 500, suppressing the viral load. HIV-infected people with low CD4 counts should take antifungal drugs as a preventive measure.

All immunocompromised patients should avoid contact with wild birds, soil contaminated with pigeon or chicken droppings.

• Cryptococcosis in hematological practice. Khodunova E.E., Frolova I.N., Parovichnikova E.N., Kravchenko S.K., Galstyan G.M., Kostina I.E., Mikhailova E.A., Gracheva A.N., Klyasova G. .A. Therapeutic archive. 2013. No. 11. p.41-46
• Infectious lesion of the central nervous system as a secondary manifestation of HIV infection. Yesareva D.O. Bulletin of SMUS74. 2016. No. 4. p.30-33
• HIV-associated lesions of the nervous system in the pathogenesis of neuroAIDS. Shchigoleva E.V. Bulletin of SMUS74. 2017. No. 4. p.80-83
• Determination of cryptococcal antigen in the complex diagnosis of cryptococcal meningitis in immunocompromised patients in St. Petersburg. Ignatieva S.M. et al. Advances in medical mycology. 2014. p.13.
• A case of successful treatment of cryptococcal meningoencephalitis in a patient with chronic lymphocytic leukemia. Hostelidi S.N. etc. Problems of medical mycology. 2013. p.15

Article published : 02/01/2023
Last updated : 02/18/2023

See also

Cerebellar stroke

Purulent meningitis

Serous meningitis

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