Cryptococcosis – Infections – Merck Manuals Consumer Version

By

Sanjay G. Revankar

, MD, Wayne State University School of Medicine

Reviewed/Revised Apr 2021 | Modified Sep 2022

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Topic Resources

Cryptococcosis is an infection caused by the fungus Cryptococcus neoformans or Cryptococcus gattii.

• People may have no symptoms or may have headache and confusion, a cough and an achy chest, or a rash, depending on where the infection is.

• The diagnosis is based on culture and examination of tissue and fluid samples.

• Antifungal drugs are given by mouth or, if the infection is severe, intravenously.

(See also Overview of Fungal Infections Overview of Fungal Infections Fungi are neither plants nor animals. They were once thought to be plants but are now classified as their own kingdom. Some fungi cause infections in people. Because fungal spores are often… read more .)

Cryptococcus neoformans occurs primarily in soil that is contaminated with bird droppings, particularly those of pigeons. It is found all over the world. Cryptococcus gattii usually is present in the soil around trees. Outbreaks have occurred in the Pacific Northwest, Papua New Guinea, northern Australia, and in the Mediterranean region of Europe. Unlike Cryptococcus neoformans, Cryptococcus gattii is not associated with birds.

Cryptococcus infection was relatively rare until the AIDS epidemic began. Cryptococcosis is the most common potentially fatal fungal infection in people with AIDS.

The fungus tends to infect people who have a weakened immune system, including those with the following:

• AIDS Acquired immunodeficiency syndrome (AIDS) Human immunodeficiency virus (HIV) infection is a viral infection that progressively destroys certain white blood cells and is treated with antiretroviral medications. If untreated, it can cause… read more

• Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a cancer of a type of white blood cell called lymphocytes and is distinguished from other lymphomas by the presence of a particular kind of cancer cell called a Reed-Sternberg… read more or another lymphoma

• Sarcoidosis Sarcoidosis Sarcoidosis is a disease in which abnormal collections of inflammatory cells (granulomas) form in many organs of the body. Sarcoidosis usually develops in people aged 20 to 40 years, most often… read more

• Use of drugs that suppress the immune system Some Drugs That Can Cause Immunodeficiency , such as those used to prevent rejection of an organ transplant and, when taken for a long time, corticosteroids

However, cryptococcosis caused by Cryptococcus gattii can also develop in people with a normal immune system. It is also more likely to occur in people who have other lung disorders, are 50 years old or older, or smoke tobacco.

Infection usually occurs when people inhale the spores of the fungus. Thus, cryptococcosis typically affects the lungs. It most commonly spreads to the brain and tissues covering the brain and spinal cord (meninges), resulting in meningitis Subacute and Chronic Meningitis Subacute meningitis is inflammation of the layers of tissue that cover the brain and spinal cord (meninges) and of the fluid-filled space between the meninges (subarachnoid space) when it develops… read more .

Cryptococcosis may also spread to the skin and other tissues, such as the bones, joints, liver, spleen, kidneys, and prostate. Except for skin infections, these infections usually cause few or no symptoms.

Cryptococcosis usually causes mild and vague symptoms. Other symptoms vary depending on where the infection is:

• Lung infection: No symptoms in some people, a cough or an aching chest in others, and, if the infection is severe, difficulty breathing

• Meningitis: Headache, blurred vision, depression, agitation, and confusion

• Skin infection: A rash, consisting of bumps (sometimes filled with pus) or open sores

Lung infection is rarely dangerous. Meningitis is life threatening.

To diagnose cryptococcosis, a doctor takes samples of tissue and body fluids to be cultured and examined. A spinal tap Spinal Tap Diagnostic procedures may be needed to confirm a diagnosis suggested by the medical history and neurologic examination. Electroencephalography (EEG) is a simple, painless procedure in which… read more (lumbar puncture) is done to obtain cerebrospinal fluid (the fluid that surrounds the brain and spinal cord).

Blood and cerebrospinal fluid may be tested for certain substances released by Cryptococcus.

Doctors also take a chest x-ray to check for signs of infection in the lungs.

• Antifungal drugs

Antifungal drugs are usually used to treat cryptococcosis.

If the infection affects only a small part of lung and does not cause any symptoms, usually no treatment is needed. However, some doctors prefer to always treat cryptococcosis. Fluconazole is given by mouth to shorten the duration of the illness and reduce the risk of the infection spreading.

If a lung infection causes symptoms, fluconazole is given by mouth for 6 to 12 months.

For meningitis, treatment is amphotericin B, given intravenously, plus flucytosine, given by mouth, followed by fluconazole, given by mouth, for many months.

For an infection in the skin, bone, or other sites, people are usually given fluconazole by mouth. If the infection is severe, people are given amphotericin B intravenously, plus flucytosine, given by mouth for several weeks.

People with a weakened immune system always require treatment.

Mild to moderate lung infection may be treated with fluconazole given by mouth for 6 to 12 months.

Severe lung infection or meningitis may be treated with amphotericin B, given intravenously, plus flucytosine, followed by fluconazole, both given by mouth.

After cryptococcosis is treated, people with AIDS usually need to continue taking an antifungal drug (such as fluconazole) until their CD4 count CD4 count Human immunodeficiency virus (HIV) infection is a viral infection that progressively destroys certain white blood cells and is treated with antiretroviral medications. If untreated, it can cause… read more (the number of one type of white blood cell that decrease when AIDS is uncontrolled) is more than 150 cells per microliter of blood and they have taken antifungal drugs for at least a year.

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Continuing Education Activity

Cryptococcosis is an opportunistic infection that causes more than 100,000 HIV-related deaths each year. Although the infection is usually HIV-related, it is also seen in other conditions, such as in patients under immunosuppressive treatments or patients with organ failure syndromes, organ transplants, innate immunologic problems, common variable immunodeficiency syndrome, and hematological disorders. This activity outlines the pathophysiology, evaluation, and management of cryptococcal meningitis and highlights the role of the interprofessional team in the management of these patients.

Objectives:

• Identify the etiology of cryptococcal meningitis.

• Outline the presentation of a patient with cryptococcal meningitis.

• Describe the treatment and management options available for cryptococcal meningitis.

• Explain interprofessional team strategies for improving care coordination and communication to advance the treatment of cryptococcal meningitis and improve outcomes.

Access free multiple choice questions on this topic.

Introduction

Cryptococcosis is an important opportunistic infection that causes more than 100,000 HIV-related deaths each year. It was named the Busse-Buschke disease because of its first description by Otto Busse and Abraham Buschke in 1894.[1]

Even though the infection is usually HIV-related, in many centers (especially in developed countries), most of the non-HIV-related cases include patients under immunosuppressive treatments or with organic failure syndromes, transplants, innate immunological problems, common variable immunodeficiency syndrome, and hematological disorders.[2]

Etiology

There are more than 50 species of Cryptococcus;  C. neoformans and C. gattii cause the majority of infections, and some consider them the only pathogens in humans.

C. neoformans is an encapsulated yeast that can be found in aged pigeon droppings which causes mild infections, from airway colonization or asymptomatic ones in laboratory workers to severe infections like meningitis or disseminated disease. It is the most common species from the Cryptococcus genre in our region (Brazil) and other temperate weathers around the world. [3]

The major predisposing factor to cryptococcal infection is HIV; however, the predisposing factors in non-HIV patients are as follows[4]:

Syndromes and Autoantibodies

• Idiopathic CD4 lymphopenia

• Pulmonary alveolar proteinosis with autoantibodies to granulocyte-macrophage colony stimulating factor

• Autoantibodies to interferon-gamma

Monogenic Disorders

• Primary immunodeficiency owing to GATA2 mutations.

• Chronic granulomatous disease

• Hyperimmunoglobulin E recurrent infection syndrome (Job syndrome)

• X-linked CD40L deficiency (hyper-IgM syndrome)

Polygenetic modifiers

Comorbidities

• Sarcoidosis, autoimmune disease, steroid treatment

• Hepatic disease

• Solid organ transplant conditioning

Epidemiology

Approximately 1 million cases of cryptococcal meningitis are reported annually. The incidence have markedly increased since 1950s because of corticosteroid use and improvement of survival in cancer patients. However, most of the cryptococcal reports come from the 1980s and are predominantly AIDS-related cases. Approximately 6% of patients with AIDS develop cryptococcal infections, and patients with AIDS-associated cryptococcosis account for 85% of all patients diagnosed with cryptococcosis. [2][1]

Pathophysiology

The organism is acquired by inhalation. After being deposited into the pulmonary alveoli, the yeast spores must survive the normal to high pH and the physiological concentrations of carbon dioxide before they are phagocytized by alveolar macrophages, a more acidic environment, and disseminated after a latent period of containment in the lung lymph nodes. The essential factor in the survival of C. neoformans in this extracellular environment is glucosylceramide synthase. [5]

The host response includes both cellular and humoral components. Possibly, the eradication of Cryptococci relies on natural killer cells and antibody-dependent cell-mediated killing. [6]

While all organs can be involved, Cryptococcus spp. have a strong affinity for the central nervous system. This neurotropism is linked to several cryptococcal-specific factors which facilitate the permeability of the blood-brain barrier; between them, metalloproteinases and ureases enzymes cause neuromodulation and mechanisms facilitate survival in the nutrient-deprived environment of the brain (autophagy and high-affinity sugar transporters).  [7][8]

There can be little or no necrosis or organ damage until later disease. In patients with heavy infections, organ dysfunction may be accelerated, primarily due to tissue distortion caused by the growing fungal burden. [9]

Histopathology

C. neoformans reproduces by budding and forms round yeast-like cells that are 3 to 6 micrometers in diameter. In the host and culture media, each cell is surrounded by a large polysaccharide capsule that has antiphagocytic properties and may be immunosuppressive. It can form smooth, convex, yellow, or tan colonies on solid media at 20 to 37 degrees C. The non-pathogenic strains do not grow at this temperature. [10]

History and Physical

Cryptococcal meningitis usually presents as a subacute meningoencephalitis. The patient commonly presents with neurological symptoms such as a headache, altered mental status, and other signs and symptoms include lethargy along with fever, stiff neck (both associated with an aggressive inflammatory response), nausea and vomiting. Some patients who are HIV positive may have minimal or nonspecific symptoms at presentation.

The duration of symptoms from onset to a presentation is usually 1 to 2 weeks in HIV cases and 6 to 12 weeks in non-HIV cases.

Visual symptoms include diplopia and photophobia at the onset, and reduced acuity later in the disease (due to high cerebrospinal fluid (CSF) pressure or compression of the optic nerve and tracts). Other findings include hearing defects, ataxia, aphasia, seizures, and chorea.

Although C. neoformans enters the body through the lungs, the central nervous system (CNS) is the main site of evident clinical infection. [4]

Evaluation

The workup at initial evaluation should depend on CSF lab tests. However, to prevent a post-dural puncture cerebral herniation, a CT scan or MRI of the brain or a fundus examination should be considered before performing a lumbar puncture. [4]

Blood and CSF should be cultured for fungi and tested for cryptococcal antigen. Routine lab tests may be normal even with widespread disease. Opening pressure has to be measured at the first spinal tap, a pressure over 25 cm of water is a predictor of a poor prognosis. [4]

CSF usually presents low glucose and high protein levels. White cell count can be normal or higher than 20 microL and have a lymphocyte predominance. Nevertheless, CSF can be normal and have positive results on India ink stain and antigen testing (especially in HIV-positive patients who do not have an adequate inflammatory response). [11]

Treatment / Management

Treatment has not varied for a decade, according to recommendations from the 2010 IDSA (Infectious Diseases Society of America) update. The first-line antifungal treatment is based on the induction, consolidation, and maintenance of the following three types of patients[12][9]:

HIV-Related Disease

• Induction therapy

  • Amphotericin B deoxycholate (0.7 to 1.0 mg/kg/day) + flucytosine (100 mg/kg/day orally) for 2 weeks (A1 Evidence)

  • Liposomal amphotericin B (3 to 4 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day; kidney function surveillance) + flucytosine (100 mg/kg/day) for 2 weeks (B2 Evidence)

  • Amphotericin B deoxycholate (0. 7 to 1.0 mg/kg/day) or liposomal amphotericin B (3 to 4 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day, for patients who do not tolerate flucytosine) for 4 to 6 weeks (B2 Evidence)

• Induction therapy alternatives

  • Amphotericin B deoxycholate + fluconazole (B1 Evidence)

  • Fluconazole + flucytosine (B2 Evidence)

  • Fluconazole (B2 Evidence)

  • Itraconazole (C2 Evidence)

• Consolidation therapy

• Maintenance therapy

• Maintenance therapy alternatives

  • Itraconazole (400 mg/day) for 1 or more years (C1 Evidence)

  • Amphotericin B deoxycholate (1 mg/kg/week) for 1 or more years (C1 Evidence)

Transplant Related Disease

• Induction therapy

  • Liposomal amphotericin B (3 to 4 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day) + flucytosine (100 mg/kg/day) for 2 weeks (B3 Evidence)

• Induction therapy alternatives

  • Liposomal amphotericin B (6 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day) for 4 to 6 weeks (B3 Evidence)

  • Amphotericin B deoxycholate (0. 7 mg/kg/day) for 4 to 6 weeks (B3 Evidence)

• Consolidation therapy 

• Maintenance therapy

Not HIV/Transplant Related Disease

• Induction therapy

  • Amphotericin B deoxycholate (0.7 to 1.0 mg/kg/day) + flucytosine (100 mg/kg/day) for 4 or more weeks (B2 Evidence)

  • Amphotericin B deoxycholate (0.7 to 1.0 mg/kg/day) for 6 weeks (B2 Evidence)

  • Liposomal amphotericin B (3 to 4 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day) combined with flucytosine, 4 weeks (B3 Evidence)

  • Amphotericin B deoxycholate (0.7 mg/kg/day) + flucytosine (100 mg/kg/day) for 2 weeks (B2 Evidence)

• Consolidation therapy

• Maintenance therapy

The combination of amphotericin B and flucytosine has proved the most effective measure to clear the infection, and it showed a greater survival benefit over amphotericin alone. However, due to its cost, flucytosine is often unavailable in poor-resource settings where the disease burden is significant. Combinations of amphotericin B and fluconazole have been studied, and greater results have been found over amphotericin B alone. [13],[14],[15]

Without treatment, the clinical course progresses to confusion, seizures, reduced level of consciousness, and coma.

Headache refractory to pain-killers can be treated with spinal decompression after an adequate neuroimaging evaluation with a CT scan or MRI. The safe maximum volume of CSF that can be drained at one lumbar puncture is unclear, but up to 30 mL are frequently removed with the pressure checked after each 10 mL removed. [4],[16]

Differential Diagnosis

The differential diagnosis is based upon the following causes of intracranial mass lesions and infections[4]:

• Pyogenic, Nocardial or Aspergillus abscess

• Mycobacterium tuberculosis infection

• Histoplasma capsulatum infection

• Acanthamoeba infection

• Neurosyphilis

• Lymphomas, lymphocytic meningitis, meningeal metastases

• Hemorrhages

Prognosis

The initial prognosis depends on mortality predictors such as the following[2],[4],[17],[18]:

• CSF opening pressure of more than 25 cm of water

• Low CSF white cells count

• Sensory impairment

• Delayed diagnosis

• Elevated CSF antigen titers

• Rate of infection clearance

• CSF yeast count more than 10 mm^3 (a common practice in Brazil)[19]

• Non-HIV-related patients and the prognostic factors in these patients, in addition to the already mentioned:

  • Markers of a poor inflammatory response

  • Absence of headache

  • Underlying hematological malignancy

  • Chronic renal or liver disease

Mortality varies from country to country depending on the resource settings. It remains high in the United States and France, with a 10-week mortality of 15% to 26%, and it is even higher in non-HIV patients because of the delayed diagnosis and dysfunctional immune responses. On the other hand, in poor-resource countries, mortality increase from 30% to 70% in 10 weeks because of the late presentation and lack of access to drugs, manometers, and optimal monitoring.[12]

Complications

Complications include the following[4]:

• Persistent Infection – Persistently positive results of cultures of CSF after 4 weeks of proven antifungal therapy at an established effective dose is a reasonable starting point.

• Relapsed Infection (based upon two main characteristics)

  1. The recovery of viable Cryptococci from a previously checked sterile body site is essential.

  2. Recrudescence of signs and symptoms at the previous site of disease supports the presence of disease.

• Elevated CSF Pressure – Acute elevated symptomatic CSF pressure (sometimes due to initial antifungal therapy) should be managed rapidly by decompression via repeated lumbar taps, transitory lumbar drainage catheter, or ventriculostomy in some patients.

• Immune Reconstitution Inflammatory Syndrome (IRIS):

  • Unmasking IRIS, in which cryptococcal symptoms appear after the initiation of antiretroviral therapy.

  • Paradoxical IRIS during the treatment of cryptococcosis and administration of antiretroviral therapy.

Cerebral cryptococcomas can cause significant short- and long-term neurological complications. They are hard to treat and normally require a long-term antifungal therapy.

Hydrocephalus is a later complication and can present as dementia or chronic headache.

Pearls and Other Issues

HIV-Infected Patients

• The incidence of cryptococcal meningitis has diminished in patients with antiretroviral therapy (ART).

• Symptoms typically begin insidiously during a 2-week period. The most common symptoms are fever, malaise, and headache. Cranial neuropathies may also be present. Symptoms like cough, dyspnea, and skin rash suggest a disseminated disease.

• The antifungal prophylaxis is not recommended as a routine for cryptococcal disease (II-B Evidence).

Non-HIV-Infected Patients

• C. neoformans disseminates hematogenously from the respiratory tract and has a propensity for the central nervous system. The inflammatory response in the brain is usually milder than the one in bacterial meningitis. The inflammatory infiltrate is comprised of mononuclear cells predominantly with occasional polymorphonuclear leukocytes. Generally, brain involvement is diffuse but localized infection can occur (cryptococcoma).

• Most individuals with cryptococcal meningitis are immunocompromised. The most common cases include glucocorticoid therapy, organ transplantation, cancer, and other conditions such as sarcoidosis and hepatic failure.

• Symptom presentation is variable. Some patients have symptoms for up to 2 to 8 months before diagnosis while others can present an acute illness in a few days. Approximately 50% of cases have fever. Generally, headache, lethargy, personality changes, and memory loss can appear over 2 to 4 weeks. Some patients can also present as a disseminated disease.

The definitive diagnosis of cryptococcal meningitis is made by culture from the CSF. The opening pressure should be measured along with India ink evaluation, cryptococcal antigen testing, fungal culture, and routine spinal fluid studies. A positive cryptococcal antigen in the CSF or serum can strongly suggest the infection before the cultures become positive in high-risk patients.

Neuroimaging must be performed prior to lumbar puncture if there is a concern for a high intracranial pressure.

The principal antifungal agents for the treatment of cryptococcal meningitis are intravenous amphotericin B deoxycholate and its lipid formulations, oral flucytosine, and oral fluconazole. While amphotericin B and flucytosine are fungicidal, fluconazole is only fungistatic. Lipid formulations of amphotericin B are preferred on patients with renal dysfunction or at risk for renal failure.

Cryptococcal meningitis is fatal if untreated. The therapeutic regime includes three phases: Induction followed by consolidation for a total of 10 weeks (to rapidly sterilize the CSF and to decrease early mortality) and maintenance therapy to prevent relapses.

Enhancing Healthcare Team Outcomes

Cryptococcal meningitis is a serious disorder with high mortality and thus best managed by an interprofessional team that includes a radiologist, emergency department physician, internist, infectious disease specialist, infectious disease nurse, neurologist and a pharmacist. Patients are usually treated with two antifungal agents and the treatment duration can be as long as 6-24 months.

Patients who are immunocompromised as well as those with neurological symptoms tend to have poor outcomes despite optimal treatment.

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

Figure

Expected CSF Findings in Bacterial versus Viral versus Fungal Meningitis 2. Contributed by Kenadeed Hersi

Figure

Figure 3 has a reference of PMID 22844374, A case of carcinomatous meningitis despite prophylactic cranial irradiation in small cell lung cancer during treatment with amrubicin. Contributed by Ayesha Anwar, MBBS

Figure

Meningitis, Carcinomatous Flow Chart. Contributed by Ayesha Anwar, MBBS

References

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May RC, Stone NR, Wiesner DL, Bicanic T, Nielsen K. Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol. 2016 Feb;14(2):106-17. [PMC free article: PMC5019959] [PubMed: 26685750]

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Pappas PG. Cryptococcal infections in non-HIV-infected patients. Trans Am Clin Climatol Assoc. 2013;124:61-79. [PMC free article: PMC3715903] [PubMed: 23874010]

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Takahara DT, Lazéra Mdos S, Wanke B, Trilles L, Dutra V, Paula DA, Nakazato L, Anzai MC, Leite Júnior DP, Paula CR, Hahn RC. First report on Cryptococcus neoformans in pigeon excreta from public and residential locations in the metropolitan area of Cuiabá, State of Mato Grosso, Brazil. Rev Inst Med Trop Sao Paulo. 2013 Nov-Dec;55(6):371-6. [PMC free article: PMC4105083] [PubMed: 24213188]

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Williamson PR, Jarvis JN, Panackal AA, Fisher MC, Molloy SF, Loyse A, Harrison TS. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol. 2017 Jan;13(1):13-24. [PubMed: 27886201]

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Rittershaus PC, Kechichian TB, Allegood JC, Merrill AH, Hennig M, Luberto C, Del Poeta M. Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans. J Clin Invest. 2006 Jun;116(6):1651-9. [PMC free article: PMC1466548] [PubMed: 16741577]

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Schmidt S, Zimmermann SY, Tramsen L, Koehl U, Lehrnbecher T. Natural killer cells and antifungal host response. Clin Vaccine Immunol. 2013 Apr;20(4):452-8. [PMC free article: PMC3623417] [PubMed: 23365210]

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Vu K, Tham R, Uhrig JP, Thompson GR, Na Pombejra S, Jamklang M, Bautos JM, Gelli A. Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease. mBio. 2014 Jun 03;5(3):e01101-14. [PMC free article: PMC4049100] [PubMed: 24895304]

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Stie J, Fox D. Blood-brain barrier invasion by Cryptococcus neoformans is enhanced by functional interactions with plasmin. Microbiology (Reading). 2012 Jan;158(Pt 1):240-258. [PMC free article: PMC3352358] [PubMed: 21998162]

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Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: What do we know now. Fungal Genet Biol. 2015 May;78:49-54. [PMC free article: PMC4395512] [PubMed: 25312862]

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Nyazika TK, Hagen F, Meis JF, Robertson VJ. Cryptococcus tetragattii as a major cause of cryptococcal meningitis among HIV-infected individuals in Harare, Zimbabwe. J Infect. 2016 Jun;72(6):745-752. [PubMed: 27038502]

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Abassi M, Boulware DR, Rhein J. Cryptococcal Meningitis: Diagnosis and Management Update. Curr Trop Med Rep. 2015 Jun 01;2(2):90-99. [PMC free article: PMC4535722] [PubMed: 26279970]

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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]

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Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, Phu NH, Nghia HD, Phong ND, Thai CQ, Thai LH, Chuong LV, Sinh DX, Duong VA, Hoang TN, Diep PT, Campbell JI, Sieu TPM, Baker SG, Chau NVV, Hien TT, Lalloo DG, Farrar JJ. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013 Apr 04;368(14):1291-1302. [PMC free article: PMC3978204] [PubMed: 23550668]

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Campitelli M, Zeineddine N, Samaha G, Maslak S. Combination Antifungal Therapy: A Review of Current Data. J Clin Med Res. 2017 Jun;9(6):451-456. [PMC free article: PMC5412516] [PubMed: 28496543]

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Merry M, Boulware DR. Cryptococcal Meningitis Treatment Strategies Affected by the Explosive Cost of Flucytosine in the United States: A Cost-effectiveness Analysis. Clin Infect Dis. 2016 Jun 15;62(12):1564-8. [PMC free article: PMC4885648] [PubMed: 27009249]

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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]

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Panackal AA, Wuest SC, Lin YC, Wu T, Zhang N, Kosa P, Komori M, Blake A, Browne SK, Rosen LB, Hagen F, Meis J, Levitz SM, Quezado M, Hammoud D, Bennett JE, Bielekova B, Williamson PR. Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. PLoS Pathog. 2015 May;11(5):e1004884. [PMC free article: PMC4447450] [PubMed: 26020932]

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Disclosure: Marco Pescador Ruschel declares no relevant financial relationships with ineligible companies.

Disclosure: Bicky Thapa declares no relevant financial relationships with ineligible companies.

Cryptococcosis of the central nervous system | #10/13

Over the past decades, fungal diseases have not lost their relevance. Among all invasive mycoses, cryptococcal infection occupies one of the most significant places, as it is a life-threatening disease. Even with timely treatment, mortality is from 10% to 25%, and in developing countries it reaches 90%. About 1 million cases of cryptococcosis are registered annually in the world. In Russia, at this stage, there is no mandatory registration of deep mycoses. The true incidence is not known, but according to the North-Western State Medical University. II Mechnikov in St. Petersburg, there is a significant increase in cryptococcosis with a fatal outcome in the period from 2002 to 2010 [1–5].

The genus Cryptococcus includes more than 70 species of encapsulated basidiomycete yeasts, of which Cryptococcus neoformans and Cryptococcus Gatti are of medical importance. Cryptococcus Gatti is most common in countries with a tropical climate; Cryptococcus neoformans dominates in Europe and Russia. The pathogenicity factors of Cryptococcus include its ability to grow at a temperature of 37 °C (i.e., at the body temperature of warm-blooded animals), as well as the ability to form a polysaccharide capsule, which is a protection against phagocytosis and humoral immunity factors. Cryptococci synthesize a number of enzymes, including urease and phospholipase. Urease promotes yeast adhesion to endothelial cells and forms mucosal “cysts” without initiating an inflammatory response. Phospholipase destroys human cell membranes, facilitates attachment to the lung epithelium. The ability of fungi to form melanin serves as protection against antibody-mediated phagocytosis [6–10].

People with impaired immune systems are susceptible to the disease with clinically pronounced forms of cryptococcosis. Most often these are patients with acquired immunodeficiency syndrome (AIDS), leukemia, sarcoidosis, lymphoma, as well as patients after organ transplantation and patients receiving high doses of cytostatics or corticosteroids. Infection occurs by inhalation, the lungs are the organ of the primary localization of the pathogen, where it can be in a latent state for a long time. When the functioning of the immune system is impaired, the infection is activated [11, 12].

The clinic of cryptococcosis depends on the localization and prevalence of the process. According to ICD-10, pulmonary cryptococcosis, cerebral cryptococcosis, skin cryptococcosis, bone cryptococcosis are distinguished. Cryptococcosis of the lungs may be asymptomatic or accompanied by a cough with mucous sputum, mild fever, malaise, and rarely shortness of breath. Radiologically visualized nodular infiltrates and confluent foci located subpleurally. In AIDS patients, cryptococcal pneumonia is detected in 1/3. The disease is characterized by rapid progression with the development of respiratory distress syndrome and acute respiratory failure. Cryptococcosis of the skin occurs in 10–15% of cases. It is characterized by the appearance of papules, which transform into a plaque with compaction and subsequent ulceration in the center of the element. They are localized more often on the scalp and face. Cryptococcosis of bones is characterized by osteolysis, the frequency of occurrence is 5%. The bones of the pelvis, spine, skull, and ribs are affected [13].

The most common clinical form is cerebral cryptococcosis, which in 80-90% occurs in the form of meningoencephalitis. In the central nervous system (CNS), the pathogen disseminates hematogenously. The target for the pathogenic effects of cryptococci is the endothelium of the vessels of the microvasculature. The main method of penetration of the pathogen into the substance of the brain is the destruction of the vessel wall. As a result, there is a violation of microcirculation, which entails degeneration of neurons and the development of foci of necrosis. Due to the sharply increased vascular permeability, fluid accumulates in the substance of the brain. Histologically, there is proliferation of yeast-like fungi with infiltration, represented mainly by lymphocytes, histiocytes, a small number of plasmocytes, and single neutrophils. At autopsy, the lesion of the meninges is characterized as serous-productive meningitis with petechial hemorrhages in the pia and dura mater. The shells are thickened, cloudy, on the surface there are numerous small tubercles (accumulation of fungi). The pathological process can also cover the basal surface of the brain. The cause of death is cerebral edema with dislocation of stem structures [13, 14].

The dominant complaint is a persistent headache of a diffuse nature, the intensity of which gradually increases. Nausea and vomiting occur in 40% of patients. The febrile reaction is not constant, body temperature varies widely from 37.2 to 39.5 °C. Meningeal symptoms (stiff neck, Kernig’s sign, Brudzinsky’s sign) are often absent or ambiguous. Convulsions, impaired consciousness occur in isolated cases and, as a rule, in the later stages of the disease. In some patients, congestive optic discs, visual impairment, and focal neurological symptoms may be detected. In the study of cerebrospinal fluid (CSF), inflammatory changes are mild. Usually there is an increased content of protein and lymphocytic two-three-digit pleocytosis. Characterized by a progressive decrease in glucose levels [7, 12, 13, 15, 16].

For the diagnosis of cryptococcal lesions of the central nervous system, the main method is the microbiological examination of the CSF. For microscopy, smears are filled with 1-2 drops of ink. Capsule Cryptococcus neoformans is not completely stained and forms specific rims. Cryptococcus cells are spherical or elliptical in shape. The diameter varies from 5 to 7 microns, rarely from 2 to 15 microns. The capsule stains well, according to the Mowry method with alcian blue in a blue-green color. This staining method allows visualization of phagocytosed cryptococci. The efficiency of this method reaches 97% [5, 17].

Culture is critical to confirm the diagnosis. Grows Cryptococcus neoformans from 48 to 72 hours on wort agar or Sabouraud’s medium at 37°C. Outwardly, these are white, smooth, shiny, mucus-viscous colonies. Obtaining a culture of cryptococcus allows you to determine the sensitivity of the isolated strain to antimycotic drugs. Microbiological diagnostics is also used in other forms of cryptococcal infection. Substrates for research are blood, sputum, separated skin elements. Of the additional methods, latex agglutination is used. Specificity and sensitivity of standard tests exceed 90%. In recent years, polymerase chain reaction (PCR) has been increasingly used for diagnostic purposes; the value of this method lies in the fact that it allows the diagnosis to be established in the shortest possible time [14, 16, 17].

Neuroimaging methods (computed tomography and magnetic resonance imaging) in some cases provide additional data on the nature of the process. In 34%, atrophy of the cerebral cortex is noted, in 11%, damage to the substance of the brain, both diffuse and focal in nature (cryptococcus). Hydrocephalus is detected in 9%, in 50% pathological changes are not detected [13, 17].

For the treatment of meningoencephalitis of cryptococcal etiology, it is necessary to use antimycotic drugs that penetrate the blood-brain barrier (BBB) ​​in therapeutic concentrations. These include flucytosine, amphotericin B, fluconazole. Flucytosine has both fungistatic and fungicidal effects. By integrating into the ribonucleic acid (RNA) of the pathogen, it disrupts the formation of proteins, and also by inhibiting the activity of thymidylate synthetase, it prevents the synthesis of fungal deoxyribonucleic acid (DNA). Its concentration in the CSF is 75% of the concentration in plasma. Amphotericin B has a more fungistatic effect. The mechanism of action is the ability to bind to the ergosterol of the cell membrane of the pathogen. Pores are formed in the membrane, the barrier function is disturbed, which leads to the loss of cellular structures and the death of the fungus. Its concentration in the CSF when administered intravenously is 5%, so endolumbar administration is preferred. The combination of these two drugs gives the best therapeutic effect, in contrast to monotherapy. In addition, this allows you to reduce the dose of amphotericin B and, thereby, reduce its toxic effect and shorten the duration of treatment. The use of combination therapy can prevent or delay the development of pathogen resistance. Sensitivity Cryptococcus neoformas to amphotericin B is 68%, flucytosine 54%. Fluconazole penetrates equally well into the biological environment of the body, its concentration in the CSF is about 85%. The fungistatic effect of this drug lies in the ability to inhibit the synthesis of ergosterol in the fungal membrane. Sensitivity to it is 74% [16, 22, 23].

Currently the following regimen is used: amphotericin B 0.7-1.0 mg/kg/day in combination with flucytosine 100 mg/kg/day for two weeks, followed by fluconazole 800-400 mg/day for at least 10 weeks . If the patient’s condition does not improve in the first two weeks of treatment, then treatment with amphotericin B is extended. For individuals with a persistent risk factor for re-infection (AIDS patients), maintenance therapy with fluconazole 200-400 mg / day is recommended from 6 months to a year. The main side effect of this treatment is kidney toxicity, which can occur in up to 80% of patients. Therefore, it is advisable to use the liposomal drug amphotericin B (Ambizom), which has less toxicity. It is also possible endolumbar administration of amphotericin B at a dose of 0.25-1.0 mg 2-4 times a day. If a relapse of the disease occurs, it is recommended to use amphotericin B or liposomal amphotericin B at a dose of 1 mg / kg / day for 4-10 weeks. As maintenance therapy, fluconazole 800–1200 mg/day for at least 10–12 weeks. During treatment, regular monitoring of the sensitivity of cryptococcus strains to antimycotic drugs is necessary to adjust therapy in case of resistance of the pathogen [5, 16, 24].

In addition to etiotropic therapy, correction of intracranial pressure is necessary, since its persistent increase indicates the possibility of developing cerebral edema and swelling (ONGM) with dislocation, which is the main cause of mortality. This complication is also possible against the background of specific therapy, since the lysis of cryptococcus leads to the release of toxic components of the cell, which contribute to an increase in vascular permeability. Therefore, it is necessary to systematically conduct dehydration therapy using loop and osmotic diuretics. When CSF pressure is above 250 mm. Art. daily punctures are recommended until the indicators decrease. A persistent increase in CSF pressure requires permanent drainage (ventriculoperitoneal shunt) [5].

The effectiveness of treatment is judged by the clinical condition of the patient and the improvement in the composition of the CSF. First of all, the normalization of glucose levels, a negative result of microscopic and bacteriological examination of the cerebrospinal fluid, as well as the results of PCR. A decrease in the microbial load by 2–3 orders of magnitude within two weeks is a good prognostic sign and a criterion for the adequacy of therapy [2, 16].

Mortality in cryptococcosis without the use of antimycotic therapy reaches 100%. It is due to: late diagnosis, resistance of the pathogen, the possibility of developing ONHM against the background of antimycotic therapy, low adherence of patients to treatment or refusal to treat it (primarily HIV-infected) [16, 25].

Thus, the problem of cryptococcal lesions of the central nervous system is becoming increasingly important. Low information content of the clinical picture of the disease requires physicians when neurological symptoms appear, especially prolonged headache in patients at risk of early CSF examination, even in the absence of meningeal symptoms. In the process of treatment, it is necessary to pay increased attention to the patient’s condition (possibility of sudden development of ONGM), microbiological control of CSF with determination of the sensitivity of the pathogen (possibility of formation of resistance) and determination of the microbial load by PCR as the most reliable method for assessing the effectiveness of treatment.

Literature

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O. E. Volkova ¹
Yu. Ya. Vengerov, doctor of medical sciences, professor

GBOU VPO MGMSU im. A. I. Evdokimova Ministry of Health of the Russian Federation, Moscow

¹ Contact information: [email protected]

Cryptococcal meningitis – causes, symptoms, diagnosis and treatment Clinically manifested by symptoms of meningitis, hydrocephalus.

When the process spreads to the cerebral tissue, focal disorders are added. Diagnosis is based on the results of lumbar puncture, cerebral CT, MRI, microbiological and serological tests, immunograms. Therapy is carried out with antimycotic pharmaceuticals, symptomatic agents. It is necessary to treat the underlying disease and detoxification therapy, in case of hydrocephalus – to ensure an adequate outflow of cerebrospinal fluid.

General information

Cryptococcal meningitis is one of the etiological variants of inflammation of the membranes of the CNS organs. Common among individuals with significantly reduced cell-mediated immunity. 80-95% of the sick are patients suffering from AIDS. Cryptococcal meningitis is the main cause of death in this group. In African countries, the number of deaths reaches 500-600 thousand per year. The last 30 years have been characterized by a trend towards a significant increase in the incidence, which is explained by the global increase in the prevalence of HIV.

Cryptococcal meningitis

Causes

Cryptococcus neoformans and Cryptococcus gattii are considered to be the main pathogens causing cryptococcal meningitis. In encapsulated form, they are transmitted by airborne droplets with dust particles. The ecological reservoir of both subtypes is bird droppings, decaying organic matter, and soil.

Cryptococci are saprophytic fungi and do not cause disease if the immune system functions normally. Opportunistic infection develops with immunodeficiency, accompanied by a decrease in the number of T-helpers (CD4) less than 100 per 1 ml (normal 600-1200). Risk factors for meningitis are immunodeficiency states with impaired T-cell immunity:

• AIDS. The human immunodeficiency virus has a cytolytic effect on T-helpers, significantly reducing their number.
• Immunodeficiencies. Primary immunodeficiency states with damage to the cellular link manifest in early childhood. Includes DiGeorge syndrome, combined immune deficiency.
• Iatrogenic decrease in immunocompetence. Artificial immunosuppression is required for organ transplantation. Therapy with cytostatic drugs, carried out in oncopathology, autoimmune diseases, leads to a decrease in immunity.

Pathogenesis

In immunocompetent individuals, the penetration of cryptococcal infection does not cause pathological changes, since the spread of fungi throughout the body is suppressed by a normally functioning immune system. In immunosuppression with damage to the cellular component, T-lymphocytes do not recognize the pathogen and do not prevent its penetration into the blood.

Cryptococci enter the CNS through the bloodstream, cross the blood-brain barrier and enter the meninges. By persisting and multiplying in the cerebral membranes, cryptococci cause damage to them with the development of an inflammatory reaction, impaired circulation of the cerebrospinal fluid.

Morphologically, inflammation leads to thickening of the membranes. Their turbidity, petechial hemorrhages are macroscopically noted. The surface becomes bumpy. With the spread of inflammatory changes to the cerebral substance, concomitant encephalitis develops.

Cryptococcal meningitis

Symptoms of cryptococcal meningitis

Manifestation of the disease is nonspecific. Patients report persistent intense headaches, nausea, loss of appetite. Repeated vomiting is possible, which does not bring relief. Subfebrile condition is typical, in some patients the body temperature reaches 38-39degrees. There is weakness, fatigue, drowsiness, some inhibition of reactions. Patients do not tolerate bright lighting. In some cases, there is a disorder of consciousness, convulsive syndrome, anxiety.

With the development of meningoencephalitis, focal symptoms in the form of paresis, paralysis, sensory disturbances are added to the clinical picture of meningitis. Increasing hydrocephalus is characterized by increased cephalgia, increased vomiting, signs of visual and auditory dysfunction. Possible discoordination when walking.

Complications

Impaired outflow and accumulation of cerebrospinal fluid in the cerebrospinal fluid spaces of the brain leads to compression of the optic nerve. A progressive decrease in vision develops, which, if not adequately treated, quickly leads to a complete loss of visual function. Similar complications are possible from the organ of hearing. Thickening of the cerebral membranes and overflow of the arachnoid spaces in them with cerebrospinal fluid cause compression of the underlying cerebral cortex, which leads to cognitive disorders. Complications are observed in 48-50% of cases of cryptococcal meningitis.

Diagnosis

The neurological status shows signs of increased intracranial pressure. Stiff neck and other meningeal symptoms are determined only in 20% of patients. A neurologist can suspect a cryptococcal etiology of the disease if the patient has an immunodeficiency pathology in the anamnesis. Confirmation of the clinical diagnosis is possible after the following studies:

• Cerebrospinal puncture. CSF leakage under high pressure indicates hydrocephalus. Microscopic examination of the CSF reveals lymphocytic pleocytosis and signs of inflammation. In 10-15% of patients, no changes are found.
• Microbiological examination of cerebrospinal fluid. Pathogen identification is traditionally done by light microscopy after ink staining, but this method is not always sensitive. CSF inoculation on Sabouraud’s medium makes it possible to isolate creptococci and determine their sensitivity to pharmaceuticals.
• Serological tests. Detection of cryptococcal antigen is performed using a latex agglutination test or immunoassay. Research sensitivity 85-90%.
• Immunogram. The drop in the number of T-helper cells to 100 cells per ml (normal 600-1200) testifies in favor of the cryptococcal etiology of meningitis.
• Neuroimaging. Performed to exclude other intracranial pathology. It is typical of fungal meningitis. CT of the brain reveals an increase in the cerebral membranes, aggregates of cryptococci, hydrocephalus. Cerebral MRI is more informative in terms of detecting cryptococcus, localized in the membranes, medulla, basal ganglia. AIDS patients are characterized by atrophic signs of the cerebral cortex.

Differential diagnosis

Cryptococcal meningitis has no specific clinical manifestations. It should be differentiated from meningitis of another origin: bacterial, viral, oncogenic. Bacterial meningitis is characterized by febrile temperature, intoxication, pronounced meningeal signs. Neoplasms of the membranes and the underlying medulla are well visualized on tomograms. The differential diagnosis should include chronic or subacute meningoencephalitis.

Tests for cryptococcus

Treatment of cryptococcal meningitis

Drug therapy

Basic therapy is carried out with antifungal drugs. Recent clinical studies in the field of neurology have shown an increase in the effectiveness of treatment when using a combination of two drugs. An indicator of the success of the therapy is the rate of elimination of fungi from the cerebrospinal fluid. In parallel, symptomatic therapy, antiretroviral treatment, and detoxification measures are being carried out. In the complex pharmacotherapy of cryptococcal meningitis, the following are used:

• Antifungals. Treatment is carried out in 3 phases. Induction is carried out by intravenous administration of a combination of two antimycotics for 2 weeks. Oral use of the second drug is possible. The consolidation phase lasts 8 weeks and is administered orally. Then supportive therapy is applied. Doses of drugs in all phases are calculated by the doctor individually, according to the severity of the process. In order to reduce the nephrotoxic effect, liposomal forms of antifungal agents are recommended.
• Detoxification. Aimed at leveling the toxic side effects of antimycotics. It is carried out by intravenous drip infusions of electrolyte solutions.
• Antiretroviral therapy. Essential for AIDS patients. It is carried out by modern inhibitors of protease, reverse transcriptase, integrase.

Medical treatment of hydrocephalus in patients with cryptococcal meningitis is ineffective. Reduction of intracranial pressure is carried out by regular therapeutic spinal punctures. A temporary catheter for drainage or a ventriculo-peritoneal shunt may be performed.

Experimental treatment

Immunotherapy options for cryptococcal infection are currently being studied. The most promising therapy is considered to be monoclonal antibodies to cryptococcal capsule polysaccharides. These drugs have shown efficacy in animal models. The first stage of clinical studies of the effect of anti-cryptococcal antibodies in patients recovering from HIV-associated meningitis was carried out.