Cryptococcosis: causes, symptoms, diagnosis, treatment

Cryptococcosis is a disease caused by a representative of yeast-like fungi of the genus Cryptoccocus, which refers to opportunistic infections. In immunocompetent persons, the pathogen is localized in the lungs, with immunodeficiency states, the process is generalized with the involvement of the meninges, kidneys, skin, bone apparatus. Cryptococcosis refers to AIDS-marker diseases.

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Epidemiology of cryptococcosis

Fungi of the genus Cryptoccocus are ubiquitous, they are constantly found in the external environment. The neoformans variant is found mainly in North America, Europe and Japan. The gatti variant is common in Australia, Vietnam, Thailand, Cambodia, Nepal, Central America. Mushrooms were isolated from milk, butter, various vegetables and fruits, from the air of the premises. It is believed that the main source of infection of people is the pigeon droppings and abundantly contaminated soil. Infection occurs aerogenously by inhaling small yeast cells with dust particles, but under certain conditions it is possible to infect and through damaged skin, mucous membranes, alimentary tract. Intrauterine transmission, as well as transmission from a person to a person are not described. Given the widespread distribution of cryptococcus, it is commonly believed that virtually all people are infected, but the risk of developing manifest clinical forms is very small. Groups of risk of developing clinically expressed forms of the disease are people with different immunodeficiency conditions.

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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 to be pathogenic to humans. It grows well on most nutrient media, in a wide temperature range from -20 ° C to + 37 ° C. The causative agent has considerable resistance to environmental factors, it persists in the soil for a long time.

There are two varieties of C. Neoformans. In Europe and North America, C. Neoformans var. Neoformans, and in the tropical and subtropical zones - C. Neoformans var. Gatti. Both variants are pathogenic for humans. In patients with AIDS, C. Neoformans var. Neoformans (even in tropical regions where only C. Neoformans var. Gatti was previously spread, now C. Neoformans var. Neoformans is found in HIV-infected people). The yeast phase of C. Neoformans has a spherical, round or oval shape, an average cell size of 8 μm to 40 μm, with both small and large varieties in the same patient. The causative agent multiplies by budding. The thick wall of the fungus is surrounded by a light-refracting mucopolysaccharide capsule, the dimensions of which vary from practically undetectable to a thickness equal to two diameters of the fungal cell itself. The phenomenon of filamentation of S. Neoformans in sections of brain and lung tissue is described. In culture, the formation of mycelia and pseudomycelia is possible. Perfect forms have hyphae, on which a large number of lateral and terminal basidia form, from which haploid basidiospores are formed.

The most common form in the 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 that explain the neurotropism of this parasite. It is believed that the serum of a person contains an anti-cryptococcal (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 in a high concentration of thiamine, glutamic acid, carbohydrates, in excess of those present in the cerebrospinal fluid. In the central nervous system there are no cellular immunity factors that play a leading role in limiting the growth of fungal flora. However, the main factor of pathogenicity in cryptococcus is a polysaccharide capsule, which contributes to its introduction, reproduction and generalization in the infected organism. In addition to capsular antigens, the pathogen has somatic antigens possessing the properties of endotoxin of gram-negative bacteria. It should be noted that all the antigens of cryptococci, despite the pronounced pathogenic effect, have low immunogenicity.

Pathogenesis of cryptococcosis

The entrance gate of the infection is the respiratory tract. The aerosol containing the pathogen (dust separated from the mucous patient or carrier) entering the respiratory tract leads to the formation of a primary focus in the lungs, which in immunosuppressive individuals can be a source of further hematogenous dissemination into organs and tissues. It is believed that infectious are small, noncapsular, yeast-like cells with a diameter of less than 2 microns, capable of reaching the alveoli with air current. It is assumed that basidiospores, because of their small size, can also be considered pathogenic. In the human body, cryptococci can also get through damaged skin, mucous membranes, gastrointestinal tract. In immunocompetent individuals, the disease is erased, locally and spontaneously ends with the sanation of the body. The factor contributing to the development of cryptococcal infection is congenital or acquired immunodeficiency, mainly of its cellular link. In individuals with preserved immune status, the causative agent of cryptococcus, after hitting the lungs, persists there for months or years and only if the conditions change (immunosuppression) begins to multiply and disseminate in the body, affecting the difference in tissue and organs. Indirect evidence of this situation 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. Among the manifest forms distinguish the chronic course of infection in practically healthy persons (chronic recurrent meningoencephalitis) and acute, often lightning, in persons with various immune system defects.

The course of infection in immunocompetent persons is usually erased, the symptoms of cryptococcosis are nonspecific - headaches, at first periodic, and then persistent, dizziness, nausea, vomiting, irritability, fatigue, memory loss, mental disorders. As a result of increased intracranial pressure, a stagnant disc of the optic nerve, symptoms of meningism are revealed. Due to damage to the cranial nerves, visual acuity may decrease, diplopia, neuroretinitis, nystagmus, anisocaria, ptosis, optic nerve atrophy, facial paralysis appear. The temperature can be slightly increased, but sometimes there is a persistent subfebrile condition; there are night sweats, pains in the chest. In healthy individuals, manifestations of the respiratory tract are sometimes possible - a small cough, occasionally with phlegm. In many cases, the disease is self-eliminated, being detected mainly in the preventive X-ray study in the form of residual phenomena in the lungs. In persons without immunodeficiency, skin lesions can be affected if they are damaged. In general, cryptococcal infection in persons with normal immune status proceeds benignly, ends with recovery and leaves after itself residual changes, especially after meningoencephalitis.

The course of cryptococcosis in immunosuppressed individuals is acute. Most often, the disease of cryptococcosis begins with the phenomena of acute meningoencephalitis with fever and fast growing signs of brain dysfunction: apathy, ataxia, impaired consciousness, somnolentia, coma. The process quickly assumes a generalized character. The patient quickly develops the phenomenon of hypotension, acidosis with a rapidly increasing imbalance of perfusion-ventilation indicators, which is associated with the secondary involvement of lung interstitium in the process. Sometimes the primary lesion is localized in the lungs, in this case the process begins with the appearance of dull, aching pains in the chest, cough with sputum and blood streaks. Given that the process covers the interstitium of the lung tissue, the rapidly developing respiratory failure (tachypnea, choking, rapidly accruing acrocyanosis) comes to the fore. On the X-rays with pulmonary cryptococcosis, isolated parenchymal infiltrates are revealed, isolated insuffiltts appear in the form of "coins", well-defined in the middle or lower lobes of the lung (2-7 cm in diameter). But there may be large, fuzzy infiltrates, often reminiscent of malignant lung damage. Caseous cavities are extremely rare and not typical, but sometimes small focal lung lesions resemble miliary tuberculosis. At the same time, cryptococcosis is not characterized by calcification, and there is also no fibrosis. In patients with generalized form, skin on the face, neck, trunk, extremities in the form of small papules, pustules, ulcerative vegetative foci or ulcerative defects similar to basal skin can be affected. Lymph nodes are not enlarged. With disseminated lesions, it is possible to introduce cryptococci into the skull bones, ribs, large tubular bones. In the place of lesion, swelling and tenderness are revealed, so-called cold abscesses may appear, as in tuberculosis of bones. When X-ray examination, as a rule, destructive focal changes are visualized. With disseminated cryptococcosis, adrenal, myocardium, liver, kidney, and prostate can be affected.

The course of infection in HIV patients is unique. The share of cryptococcosis of the CNS accounts for 60 to 90% of all cases of cryptococcosis in HIV. CNS lesion unfolds in HIV patients at the AIDS stage against the background of a generalized form of cryptococcosis. The temperature response rarely exceeds 39 ° C, the main symptom is a pronounced, exhausting headache. Fast signs of cryptococcosis join in: nausea, vomiting, convulsions, hyperesthesia (light, auditory, tactile). Symptoms of meningitis may or may not be present. The clinic of meningitis is similar to the clinic of bacterial meningitis. In the case of cryptococcosis of the central nervous system, the process encompasses the meningeal envelope, subarachnoid space, perivascular sites, which is characteristic of meningoencephalitis. A distinctive feature of cryptococcal meningoencephalitis is a characteristic picture of cerebrospinal fluid: it is slightly turbid or cream colored and does not have a purulent character, in the presence of a large number of cryptococci 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 to the subarachnoid space is disrupted with the development of occlusive hydrocephalus and ependymatitis. Localized lesions of the central nervous system may take the form of a well-defined granuloma that resembles gummy.

Cryptococcosis of the lungs in patients with HIV occurs with a decrease in body weight, fever, cough, sometimes with the separation of scant sputum, dyspnoea, the appearance of pain in the chest, due to the involvement of the pleura. X-ray revealed both single and diffuse interstitial infiltrates with lesions of the roots of the lung and sometimes the presence of pleural effusion. In the case of disseminated cryptococcosis of the lungs, acute interstitial pneumonia develops with the accumulation of cryptococci in the alveolar interstitium.

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

In patients with HIV, the kidneys are often affected, and the process proceeds asymptomatically, but can proceed according to the type of pyelonephritis with medullary necrosis of the kidneys. And after the primary treatment, the focus of a persistent infection can be the prostate gland.

Diagnosis of Cryptococcosis

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

Diagnosis of cryptococcosis is based on a complex of clinical and laboratory data. In patients with HIV infection, with development of meningoencephalitis and meningitis, a test for cryptococcosis is always shown, it is this pathogen that is one of the leading causes of CNS damage in these patients. Laboratory diagnostic methods include a microscopic examination of mascot-dosed preparations of spinal fluid, sputum, pus, other biological detachable and body tissues. It is possible to detect the C. Neoformans antigen by the latex agglutination reaction in the same biological media.

The diagnosis is made when detecting budding yeast cells surrounded by a transparent capsule when staining with ink. The diagnosis can be confirmed by obtaining a pure culture and identifying the causative agent, since C. Neoformans is easily isolated from the blood of AIDS patients.

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Treatment of cryptococcosis

With the development of cryptococcal meningitis in persons without HIV infection, amphotericin B is recommended in the intravenous infusion of 0.7-1.0 mg / kg once daily in combination with flucytosine iv 25 mg / kg 4 times a day for 2 weeks, then fluconazole inside 0.4 g once a day - 10 weeks, then maintenance therapy with fluconazole is given inside 6-12 months by 0.2-0.4 g once a day or by intraconazole inside 0.2 g 2 times a day or Amphotericin B in IV 1 mg / kg 1-3 times a week. Against the background of HIV infection, amphotericin B is prescribed in the intravenous infusion of 0.7-1.0 mg / kg once a day in combination with flucytosine iv in 25 mg / kg 4 times a day for 3 weeks, then fluconazole is administered internally 0.4 g once a day - 10 weeks, then the maintenance treatment of cryptococcosis with fluconazole inside is used 0.2 g once a day for life. Pulmonary cryptococcosis without HIV infection is treated with fluconazole inside 0.2-0.4 g once a day for 3-6 months. In the case of pulmonary cryptococcosis against the background of HIV infection, fluconazole is shown inside by 0.2-0.4 g once a day or itraconazole inside 0.2 g 2 times a day for life.