Infections that occur mainly in patients with local or general impaired immunity or immunodeficiency are called opportunistic. The deep mycoses and fungal infections occurring in the Netherlands belong exclusively to this category, although they are sometimes observed in patients who have no apparent immune disorders. In other parts of the world, endemic fungi are found that often cause deep infections in people with normal immunity, the so-called primarily pathogenic fungi, such as Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum in the USA and Penicillium marneffei in Southeast Asia, mainly in Thailand . In rare cases, as an imported disease, these infections are observed in the Netherlands, and in immunocompromised patients the risk is much higher than in healthy ones.
Table 1. The relationship between host immunity and mycoses

Immunity ImpairedSuperficial infection
 deepAsper-cryptogillus coccus
Nonspecific immunity
Reduction of the skin and mucous barrier+
Intravascular catheter+
Decreased resistance and colonization+±
Phagocyte deficiency+++
Specific immunity
Decrease in humoral immunity
Decrease in cellular immunity+±++
Note. + obvious connection, -no connection, ± doubtful connection

The main causative agents of opportunistic mycoses in Holland are some species of Candida, Aspergillus and Cryptococcus neoformans. Less common are Mucorales (pathogens of mucosal mycosis), Pseudoallescheria boydii, Fusarium and Trichosporon beigelii. An increase in the intensity of treatment of hematological malignant neoplasms and an increase in the number of organ transplants, apparently, led to an increase in the number of opportunistic mycoses.
Possible relationships between fungus, host and treatment are shown in Fig. 1. The occurrence of generalized fungal infections is determined by the balance between the virulence of the fungus and the patient’s immunity. We will not consider virulence factors. Almost all parts of the immune system are involved in defense against fungal infections, but the role of specific host mechanisms in different fungal infections is different. We will consider this in more detail later when discussing the most important opportunistic mycoses.

Diagnosis of generalized mycoses is difficult, since it is often impossible to distinguish between colonization and infection (mainly with Candida infection), crops become positive only in the late stages of the disease, and currently there are no reliable serological techniques for routine diagnosis of most infections. The treatment of generalized mycoses is also complicated. Available drugs are ineffective (compared with the effectiveness of antibiotics against bacteria), and the use of older drugs, amphotericin B (arnfotericine B) and flucytosine (flucytosine), is limited by their toxicity. Impaired host immunity, insufficiently sensitive diagnostic methods and treatment imperfections are the reasons why mortality from generalized mycoses is still unacceptably high.

Predisposition and epidemiology. Most Candida infections are caused by C. albicans, but infections can also occur with species such as C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata. Immunity is multifactorial precisely against Candida infections . Violation of the integrity of the skin and mucous membranes when using cytostatic drugs or burns, impaired colonization resistance due to the use of antibiotics, and hormonal imbalance (for example, in diabetes mellitus) play an important role in the pathogenesis of superficial Candida infections. Granulocytopenia and the presence of intravascular catheters are important risk factors for candidaemia. Factors causing the occurrence of superficial infections can also indirectly predispose to the development of candidaemia and deep infections. A recent epidemiological study has shown that this is mainly true for antibiotic use. Our own research has shown that in patients with granulocytopenia who are colonized by Candida and are receiving treatment for proven bacteremia, the incidence of candidaemia can reach up to 50%. The best prevention of deep Candida infections, in our opinion, is strict monitoring of the use of antibiotics in the hospital.

Violations of T-cell immunity that occur with the use of glucocorticosteroids and with AIDS lead exclusively to superficial infections of Candida. Deep infections in AIDS patients are observed only in the presence of granulocytopenia caused by HIV infection itself or taking myelosuppressive medications, or when a deep intravenous catheter for parenteral nutrition is administered to the patient.
For Candida infections, it is important to distinguish between superficial and deep infections. Oropharyngeal candidiasis is the most common superficial Candida infection. Vaginal candidiasis and a rare hereditary syndrome of chronic mucocutaneous candidiasis, which may be accompanied by endocrinopathies, are not considered in this article.
Oropharyngeal and esophageal candidiasis. The clinical manifestation of oropharyngeal candidiasis is most often pseudomembranous mucositis (“thrush of the mouth”), but other manifestations, such as acute erythematic mucositis, chronic atrophic candidiasis (such as angular cheilitis) and chronic hyperplastic candidiasis, are possible and are more difficult to diagnose based on clinical data. Oropharyngeal candidiasis in AIDS patients must be distinguished from “oral hairy leukoplakia”, which is most often limited to the edge of the tongue, and from sores caused by herpes simplex virus. Oropharyngeal candidiasis without a clear reason (poorly fitting denture, the use of antibiotics or glucocorticosteroids) is an indication for an HIV test. Ultimately, more than 70% of AIDS patients experience oropharyngeal candidiasis.
The most important symptoms of esophageal candidiasis are pain and impaired food passage. In many patients, symptoms are absent and the disease is detected by chance during an endoscopic examination. In patients with esophageal candidiasis, oropharyngeal candidiasis is not always present. If an AIDS patient with oropharyngeal candidiasis complains of esophagitis, it is reasonable to assume that the cause is Candida. Only in case of doubt in the diagnosis or treatment failure is endoscopy indicated. In other immunocompromised patients, such as those undergoing bone marrow transplantation, an invasive examination should be performed earlier, as they are more likely to have other diseases, such as esophagitis caused by herpes simplex virus or cytomegalovirus.

Candidemia in patients without granulocytopenia. This complication is observed mainly in patients in intensive care units after abdominal surgery, in those receiving parenteral nutrition and after treatment with broad-spectrum antibiotics. Fever is often the only symptom, and a positive blood culture on Candida is often a surprise. Given the risk of focal scattering, treatment is shown, in our opinion, even if there is only one positive sowing of shelter and . The situation is much more complicated if the patient in the intensive care unit with constant fever has a colonization of Candida respiratory, digestive and genitourinary tracts. Due to the fact that blood cultures often become positive only in the late stage, it is difficult to distinguish between colonization and invasive infection. Modern molecular biological studies may show that an isolated strain is identical to the strain by which the patient has previously been colonized. Empirical antifungal treatment is sometimes indicated to begin, even if it is not possible to clearly determine when exactly this treatment should have been started. However, the threshold for initiating antifungal therapy under these circumstances decreased, since less toxic fungostatic agents became available.
Disseminated candidiasis in patients with granulocytopenia. This is the most severe form of Candida infection. Fever, general malaise, and worsening general condition are the most important symptoms. Specific symptoms such as skin lesions or fungal lesions are absent in most cases. Sometimes disseminated candidiasis can manifest with sepsis or septic shock. Blood cultures often become positive only in the late stage of the disease or remain negative. There are no reliable serological tests for an early diagnosis. If there is no recovery from granulocytopenia, then mortality is very high, despite antifungal treatment. An autopsy often reveals common lesions of the heart (endocarditis, myocarditis), brain, liver, spleen and kidneys.
Deep localized candidiasis. Deep localized Candida infections, such as osteomyelitis, spondylodiscitis, arthritis, endophthalmitis, and liver abscess, are sporadically occurring. In most cases, candidaemia, which led to the appearance of a scattered lesion, goes unnoticed. In addition, deep localized infections can occur as ascending urinary tract infections, which happens in patients with diabetes mellitus or after a kidney transplant. In some cases, this can lead to the formation of the so-called fungus ball in the pelvis. Very rarely, Candida infection leads to isolated pneumonia. In the vast majority of immunocompromised patients with pulmonary infiltrate, in which Candida is sown from sputum, colonization occurs.
Chronic disseminated candidiasis. Initially, this disease was called hepatosplenal candidiasis. The new name is more accurate, since in addition to the liver and spleen, other organs, such as the kidneys, can be affected [4]. The classical clinical picture consists of a period of prolonged incomprehensible fever in a patient with leukemia, and the fever persists after recovery from granulocytopenia. The presence of abdominal pain of an indeterminate nature and increased activity of alkaline phosphatase in the blood should suggest a chronic disseminated candidiasis. The disease is diagnosed by ultrasound or computed tomography of the liver and spleen.
Punctures sometimes show the presence of characteristic content, but the results of sowing in most cases are negative. Failing antifungal treatment often interferes with further antileukemic treatment.

Aspergillus Infections

Aspergillus species can cause disease in humans in various ways. Allergic aspergillosis is a disease in which, due to the presence of Aspergillus spores, type 1 allergic reactions or external alveolitis occur in the bronchial tree. In principle, these diseases are treated with glucocorticosteroids. In the case of aspergilloma, saprophytic growth of Aspergillus in the previously existing cavity in the lung is noted. Next, we consider the clinical manifestations.
Aspergillus infections most often occur aerogenically due to spore inhalation. The most important predisposing factors for invasive infections of A. fumigatus and other Aspergillus species are neutropenia and prolonged use of high doses of glucocorticosteroids, mainly after bone marrow transplantation, as well as after kidney transplantation. Aspergillus infections often occur immediately in a group of individuals during construction work. Initially, these infections rarely occurred in HIV-seropositive patients, but have been reported more frequently in recent years. These infections occur mainly during the final stage of AIDS [5]. The most important invasive infections of Aspergillus are given in table. 3.

Rhinocerebral aspergillosis. Chronic sinusitis due to Aspergillus can occur in immunocompromised patients, mainly in tropical areas where there is intense contact with fungal spores. Acute sinusitis due to Aspergillus occurs only in immunocompromised patients, in most cases against the background of severe granulocytopenia. The most important symptoms are pain, swelling around the eye, retroorbital pain, then proptosis, chemosis and ophthalmoplegia of the eye develop. Due to blockage of the vessel, the formation of a blood clot and local necrosis, the infection can spread to the brain, resulting in a decrease in consciousness and epileptic seizures. The clinical picture cannot be distinguished from that of rhinocerebral mucosal mycosis, and this disease is often fatal. With severe sinusitis in a patient with graulocytopenia, therefore, the possibility of a fungal infection should always be considered. Diagnosis can be made by computed tomography, paranasal sinuses and biopsy. Intensive surgical treatment and high doses of amphotericin B are the means of choice, if the patient’s condition permits.
Pulmonary aspergillosis. The most important clinical manifestations are cough, fever and hemoptosis due to necrotizing pneumonia. However, these are already late symptoms of the disease. More often only fever is noted, and in the first instance there are slight deviations in the chest radiograph, which may not be. With the help of computed tomography, sometimes with a still normal chest x-ray, it is already possible to identify multinodular pulmonary foci with a halo or cavity characteristic of Aspergillus. Pneumonia caused by Aspergillus infection can give a picture of a lung infarction or even diffuse interstitial pneumonia on a chest x-ray. Inoculation of Aspergillus from sputum or bronchoalveolar fluid in an immunosuppressed patient is highly indicative of invasive aspergillosis and is an absolute indication for treatment. The final diagnosis (based on tissue biopsy results) often cannot be made due to coagulation problems. For serological diagnosis, there are the same limitations as in disseminated candidiasis. In the future, it may be possible to use molecular biological techniques to detect Aspergillus DNA.
Disseminated aspergillosis. In patients with persistent granulocytopenia, dissemination of infection to other organs may occur, most often from the focus of pulmonary aspergillosis. Foci of scattering can occur in the skin, which makes it possible to diagnose, in the bones or internal organs (liver, spleen, kidneys, thyroid gland). Localization in the brain (hematogenous abscess of the brain) is the most dangerous, it is characterized by very high mortality. Despite a common disseminated infection, Aspergillus is almost never able to be sown from blood or cerebrospinal fluid.
Chronic necrotizing Aspergillus pneumonia. Several years ago, it was not possible to recognize that patients with chronic pulmonary diseases receiving glucocorticosteroids may develop invasive aspergillosis. This disease was called chronic necrotizing Aspergillus pneumonia. The most important differences from the already considered Aspergillus pneumonia in patients with granulocytopenia are that the disease progresses slowly, dissemination to other organs occurs very rarely. The diagnosis is made on the basis of the clinical picture, Aspergillus culture from sputum or bronchoalveolar fluid and in the absence of other pathogens of chronic pneumonia, such as anaerobes and mycobacteria.

Cryptococcal meningitis

Cryptococcus neoformans is a ubiquitous yeast that can be isolated mainly from bird excrement. Meningitis due to C. neoformans is observed exclusively in patients with reduced T-cell immunity (see Table 1). In the past, this infection was observed in patients after transplants who received treatment with glucocorticosteroids or thymocytic immunoglobulin; in some patients it was not possible to indicate predisposing factors. Currently, we observe cryptococcal meningitis, mainly with HIV infection [6].
Cryptococcal meningitis occurs in the Netherlands in 4-10% of AIDS patients and is an indicator disease for the diagnosis of AIDS. The infection occurs aerogenically, but the primary pulmonary infection is often asymptomatic. The pia mater and the brain are the site of primary localization, as well as the prostate gland, where relapses can often occur.
Symptoms can range from mild headaches to severe clinical meningitis and coma.
Sometimes patients are treated with extra-neural manifestations, such as lung or skin lesions. A persistent headache in an HIV-seropositive patient is always an indication for lumbar puncture if CT scan of the brain does not find sufficient explanation for the complaints. Regardless of the cell number, the concentration of protein and glucose in the cerebrospinal fluid (these three indicators in a patient with cryptococcal meningitis may be normal), a patient with AIDS should always quantify cryptococcal antigens in the cerebrospinal fluid, since this test has high sensitivity and specificity. In approximately 75% of cases, cryptococci can become visible when stained with an East Indian ink preparation.
Ultimately, the diagnosis must be confirmed by a positive culture result.

Other systemic opportunistic mycoses

Other opportunistic mycoses are also increasingly recorded in the United States, but in the Netherlands they are still rare.

The most important infections are Mucoraceae, Pseudoallesheria boydii, Fusarium and Trichosporon beigelii.
Mucoric mycosis is an invasive fungal infection, the causative agents of which are most often the species Rhizopus, Rhizomucor, Mucor and Absidia, belonging to the genus Mucoraceae. In many ways, mucous mycosis is similar to invasive aspergillosis. In addition to patients with granulocytopenia, mucosal mycosis occurs in patients with ketoacidotically deregulated diabetes mellitus and in patients with iron accumulation disease, regardless of whether they received treatment with desferoxamine or not. As with aspergillosis, there are rinocerebral, pulmonary and disseminated forms. For treatment, it is important to distinguish between aspergillosis and mucosal mycosis, because Mucoraceae are always resistant to azole derivatives.
With Pseudoallesheria boydii infection, the clinical picture may be similar to that of aspergillosis. Differential diagnosis is extremely important because this fungus is resistant to amphotericin B.
Disseminated infections caused by Fusarium or Trichosporon beigelii are rare. Clinical characteristics are not very specific, the diagnosis is made mainly on the basis of positive blood culture results.

Exotic mycoses

The so-called primarily pathogenic fungi in the Netherlands are not endemic, but can be observed as imported diseases. Therefore, a thorough history of recent and past travels is crucial.
Histoplasmosis is caused by the dimorphic yeast fungus Histoplasma capsulatum and is sometimes observed in the Netherlands from natives of Suriname and Indonesia. Histoplasmosis can also occur in patients who have traveled throughout the United States, mainly in the states of Mississippi and Ohio. Primary infection may be asymptomatic or manifest as pneumonia. As with tuberculosis, an infection acquired at a young age can become manifest at an older age due to a decrease in immunity. Histoplasmosis in AIDS patients is most often manifested by disseminated infection with fever, general malaise, hepatosplenomegaly, damage to the skin and mucous membranes, and nodular pulmonary infiltrates. Diagnosis is by blood culture or biopsy of affected organs. Sometimes a diagnosis can be quickly made by directly examining a bone marrow aspirate, if the laboratory is specifically asked about it.
Penicillium marneffei infections are endemic in Southeast Asia, mainly in Thailand [7]. In HIV seropositive patients with fever, general malaise, papulopustular skin lesions, hepatosplenomegaly, anemia, and lung lesions who have traveled to Southeast Asia, a diagnosis of P. marneffei infection should be taken into account. In most cases, patients have advanced AIDS and the number of CD4 + lymphocytes does not exceed 100 • 1 O6 / L. Differential diagnosis of disseminated histoplasmosis, cryptococcosis and mycobacterial infections based on only clinical data is difficult, so the anamnesis of travel is extremely important here. The diagnosis is based on blood culture, bone marrow examination, or biopsy of affected organs.
Coccidioidomycosis, endemic in the southwestern United States (Arizona, New Mexico and Texas), and blastomycosis, endemic in the northern states of the United States, are very rarely seen as imported diseases.

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