Cryptococcosis: causes, symptoms, diagnosis, treatment

Cryptococcosis- a disease caused by a representative of the yeast-like fungi of the genus Cryptoccocus, related to opportunistic infections. In immunocompetent individuals, the pathogen is localized in the lungs; in immunodeficient states, the process generalizes with the involvement of the meninges, kidneys, skin, and bone apparatus. Cryptococcosis is related to AIDS marker diseases.

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Epidemiology of cryptococcosis

Fungi of the genus Cryptoccocus are ubiquitous and are constantly found in the environment. The neoformans variant is found mainly in North America, Europe, and Japan. The gatti variant is common in Australia, Vietnam, Thailand, Cambodia, Nepal, and Central America. Fungi have been isolated from milk, butter, various vegetables and fruits, and from indoor air. It is believed that the main source of human infection is pigeon droppings and soil heavily contaminated with their droppings. Infection occurs airborne by inhaling small yeast cells with dust particles, but under certain conditions infection is also possible through damaged skin, mucous membranes, and by the alimentary route. Intrauterine transmission, as well as human-to-human transmission, have not been described. Given the widespread distribution of cryptococcus, it is generally accepted that almost all people are susceptible to infection, but the risk of developing manifest clinical forms is very small. Risk groups for developing clinically expressed forms of the disease include individuals with various immunodeficiency states.

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What causes cryptococcosis?

Cryptococcosis is caused by yeast-like fungi of the genus Cryptoccocus, which includes a large number of species, of which only C. neoformans is considered pathogenic for humans. It grows well on most nutrient media, in a wide temperature range from -20 °C to +37 °C. The pathogen has significant resistance to environmental factors and persists in the soil for a long time.

There are two varieties of C. neoformans. In Europe and North America, C. neoformans var. neoformans is common, while in tropical and subtropical zones, C. neoformans var. gatti is common. Both varieties are pathogenic for humans. In AIDS patients, C. neoformans var. neoformans predominates (even in tropical regions, where previously only C. neoformans var. gatti was common, now C. neoformans var. neoformans is predominantly found in HIV-infected patients). The yeast phase of C. neoformans is spherical, round, or oval, with an average cell size of 8 µm to 40 µm, and both small and large varieties can be isolated from the same patient. The pathogen reproduces by budding. The thick wall of the fungus is surrounded by a light-refracting mucopolysaccharide capsule, the size of which varies from virtually undetectable to a thickness equal to two diameters of the fungal cell itself. The phenomenon of filamentation of C. neoformans in brain and lung tissue sections is described. Mycelium and pseudomycelium may form in culture. Perfect forms have hyphae on which a large number of lateral and terminal basidia are formed, from which haploid basidiospores are formed.

The most common form in tissues are round, encapsulated cells. Although the causative agent of cryptococcosis has the ability to affect all tissues of the body, but mainly reproduction occurs in the central nervous system. There are several assumptions explaining the neurotropism of this parasite. It is believed that human blood serum contains an anticryptococcal (according to other sources, a more universal - fungistatic) factor, which is absent in the cerebrospinal fluid. The growth of the pathogen is also facilitated by the presence of a high concentration of thiamine, glutamic acid, carbohydrates, which are present in excess in the cerebrospinal fluid. The central nervous system does not have cellular immunity factors that play a leading role in limiting the growth of fungal flora. However, the main pathogenicity factor in cryptococcus is the polysaccharide capsule, which promotes its introduction, reproduction and generalization in the infected organism. In addition to capsular antigens, the pathogen has somatic antigens that have the properties of endotoxin of gram-negative bacteria. It should be noted that all cryptococcal antigens, despite their pronounced pathogenic effect, have low immunogenicity.

Pathogenesis of cryptococcosis

The entry point for infection is the respiratory tract. Aerosol containing the pathogen (dust, mucous membrane secretions of the patient or carrier), entering the respiratory tract, leads to the formation of a primary lesion in the lungs, which in immunosuppressed individuals can be a source of further hematogenous dissemination to organs and tissues. It is believed that the infecting cells are small, non-capsular, yeast-like cells with a diameter of less than 2 μm, capable of reaching the alveoli with the air flow. It is assumed that basidiospores, due to their small size, can also be considered pathogenic. Cryptococci can also enter the human body through damaged skin, mucous membranes, and the gastrointestinal tract. In immunocompetent individuals, the disease is latent, local, and spontaneously ends with the sanitation of the body. A factor contributing to the development of cryptococcal infection is congenital or acquired immunodeficiency, mainly of its cellular link. In people with preserved immune status, the cryptococcus pathogen, having entered the lungs, persists there for months or years and only under changed conditions (immunosuppression) begins to multiply and disseminate in the body, affecting various tissues and organs. Indirect evidence of this position is the high incidence of cryptococcosis in AIDS patients.

Symptoms of cryptococcosis

Symptoms of cryptococcosis are determined by the state of the immune system of the infected person. Among the manifest forms, a chronic course of infection in practically healthy individuals (chronic recurrent meningoencephalitis) and an acute, often fulminant course in individuals with various defects of the immune system are distinguished.

The course of infection in immunocompetent individuals is usually latent, the symptoms of cryptococcosis are nonspecific - headaches, initially periodic and then constant, dizziness, nausea, vomiting, irritability, fatigue, memory loss, mental disorders. As a result of increased intracranial pressure, congestion of the optic disc and symptoms of meningism are revealed. Due to damage to the cranial nerves, visual acuity may decrease, diplopia, neuroretinitis, nystagmus, anisocaria, ptosis, optic nerve atrophy, and facial nerve paralysis may appear. The temperature may be slightly elevated, but sometimes persistent subfebrile condition is observed; there are night sweats, chest pain. In healthy individuals, manifestations from the respiratory tract are sometimes possible - a slight cough, occasionally with sputum. In many cases, the disease is self-eliminated, detected mainly during preventive X-ray examination as residual effects in the lungs. In people without immunodeficiency, skin lesions may occur if they are damaged. In general, cryptococcal infection in people with normal immune status is benign, ends in recovery and leaves residual changes, especially after meningoencephalitis.

The course of cryptococcosis in immunosuppressed individuals is acute. Most often, cryptococcosis begins with acute meningoencephalitis with fever and rapidly increasing signs of brain dysfunction: apathy, ataxia, impaired consciousness, somnolence, coma. The process quickly becomes generalized. The patient quickly develops hypotension, acidosis with a rapidly increasing imbalance of perfusion-ventilation parameters, which is associated with secondary involvement of the pulmonary interstitium in the process. Sometimes the primary lesion is localized in the lungs, in which case the process begins with the appearance of dull, aching pain in the chest, cough with sputum and streaks of blood. Given that the process involves the interstitium of the lung tissue, rapidly increasing respiratory failure (tachypnea, suffocation, rapidly increasing acrocyanosis) comes to the fore. Radiographs of pulmonary cryptococcosis reveal isolated parenchymatous infiltrates, the appearance of isolated infiltrates in the form of "coins" well outlined in the middle or lower lobes of the lung (2-7 cm in diameter) is very characteristic. But large, unclear infiltrates can also be found, often resembling a malignant lesion of the lungs. Caseous cavities are extremely rare and uncharacteristic, but sometimes small focal widespread lung lesions resembling miliary tuberculosis are found. At the same time, calcification is not characteristic of cryptococcosis, and fibrosis is absent. In patients with the generalized form, the skin on the face, neck, trunk, limbs can be affected in the form of small papules, pustules, ulcerative-vegetative foci or ulcerative defects similar to basalioma of the skin. The lymph nodes are not enlarged. With disseminated lesions, cryptococci can be introduced into the bones of the skull, ribs, large tubular bones. Swelling and soreness are detected at the site of the lesion, so-called cold abscesses may appear, as in tuberculosis of the bones. X-ray examination, as a rule, visualizes destructive focal changes. In disseminated cryptococcosis, damage to the adrenal glands, myocardium, liver, kidneys, and prostate is possible.

The course of infection in HIV patients is unique. CNS cryptococcosis accounts for 60 to 90% of all cases of cryptococcosis in HIV. CNS damage develops in HIV patients at the AIDS stage against the background of a generalized form of cryptococcosis. The temperature reaction rarely exceeds 39 °C, the main symptom is a severe, debilitating headache. Symptoms of cryptococcosis quickly join: nausea, vomiting, convulsions, hyperesthesia (light, auditory, tactile). Signs of meningitis may or may not be detected. The clinical picture of meningitis is similar to the clinical picture of bacterial meningitis. In CNS cryptococcosis, the process covers the meningeal membrane, subarachnoid space, perivascular areas, which is typical for meningoencephalitis. A distinctive feature of cryptococcal meningoencephalitis is the characteristic picture of the cerebrospinal fluid: it is slightly turbid or cream-colored and is not purulent in nature; if there are a large number of cryptococci in it, it can acquire a jelly-like character. As a result of all these changes in the cerebrospinal fluid, the outflow of cerebrospinal fluid from the ventricles into the subarachnoid space is disrupted with the development of occlusive hydrocephalus and ependymatitis. Localized CNS damage can have the appearance of a well-defined granuloma resembling a gumma.

Cryptococcosis of the lungs in patients with HIV occurs with weight loss, fever, cough, sometimes with the separation of scanty sputum, dyspnea, the appearance of chest pain caused by the involvement of the pleura. Radiologically, both single and diffuse interstitial infiltrates with damage to the roots of the lung and sometimes the presence of pleural effusion are detected. In the case of disseminated cryptococcosis of the lungs, acute interstitial pneumonia develops with the accumulation of cryptococci in the alveolar interstitium.

Skin lesions by cryptococcus in patients with HIV are represented by pigmented papules, pustules, ulcerative-necrotic foci. Skin lesions are both local and diffuse.

Patients with HIV often have kidney damage, and the process is asymptomatic, but can proceed as pyelonephritis with medullary necrosis of the kidneys. Moreover, after primary treatment, the prostate gland can become the source of persistent infection.

Diagnosis of cryptococcosis

Symptoms of cryptococcosis are so polymorphic that differential diagnosis has to be made depending on the localization of the lesion, and it is necessary to remember that this disease may simply reflect an immunosuppressive state caused by the underlying disease or unfavorable factors leading to immunosuppression, or it may act as a marker for HIV infection. Cryptococcal meningitis is differentiated from tuberculous meningitis, viral meningoencephalitis, metastatic process, meningitis of various mycotic origin, bacterial meningitis. Pulmonary lesions force us to exclude lung tumor, metastases of malignant neoplasms, tuberculosis, sarcoma. Skin lesions in cryptococcosis, due to their non-pathognomonic nature, require exclusion of syphilis, tuberculosis of the skin, basal cell skin cancer. Bone lesions should be distinguished from osteomyelitis, periostitis of bacterial or tuberculous origin.

Cryptococcosis diagnostics is based on a set of clinical and laboratory data. In patients with HIV infection, if meningoencephalitis and meningitis develop, examination for cryptococcosis is always indicated, since this pathogen is one of the leading causes of CNS damage in these patients. Laboratory diagnostic methods include microscopic examination of ink-stained preparations of cerebrospinal fluid, sputum, pus, other biological secretions and body tissues. It is possible to detect the C. neoformans antigen using the latex agglutination reaction in the same biological media.

The diagnosis is made by finding budding yeast cells surrounded by a clear capsule when stained with India ink. The diagnosis can be confirmed by obtaining a pure culture and identifying the pathogen, since C. neoformans is easily isolated from the blood of AIDS patients.

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Treatment of cryptococcosis

In the development of cryptococcal meningitis in individuals without HIV infection, amphotericin B is recommended intravenously 0.7-1.0 mg/kg once a day in combination with flucytosine intravenously 25 mg/kg 4 times a day for 2 weeks, then fluconazole orally 0.4 g once a day for 10 weeks, then maintenance therapy is prescribed with fluconazole orally for 6-12 months at 0.2-0.4 g once a day or intraconazole orally 0.2 g 2 times a day or amphotericin B intravenously 1 mg/kg 1-3 times a week. Against the background of HIV infection prescribe: amphotericin B intravenously 0.7-1.0 mg/kg once a day in combination with flucytosine intravenously 25 mg/kg 4 times a day - 3 weeks, then fluconazole is prescribed orally 0.4 g once a day - 10 weeks, then maintenance treatment of cryptococcosis is used with fluconazole orally 0.2 g once a day for life. Pulmonary cryptococcosis without HIV infection is treated with fluconazole orally 0.2-0.4 g once a day for 3-6 months. In case of pulmonary cryptococcosis against the background of HIV infection, fluconazole orally 0.2-0.4 g once a day or itraconazole orally 0.2 g 2 times a day for life is indicated.