TO THE EDITOR

We read with interest a case report by Wu

[1], who described a case of a 29-year-old male, immunocompetent host with cryptococcal pneumonia accompanied by pleural effusion. In that case, chest imaging showed scattered numerous cavities in the superior segment of the left lower lobe with a rough cavity wall and a cavity and pleural effusion in the anterior segment of the left lower lobe[1].

is an invasive fungus that causes cryptococcosis, a disease that is common in immunocompromised people and rare in healthy individuals.

and

are the two

species most frequently associated with human cryptococcal infections. The organism is found globally. The most common kind of exposure involves a history of contact with soil contaminated with bird droppings. The fungus capsule contains the polysaccharides glucuronoxylomannan and glucuronoxylomannogalactan, which are the major components that contribute to the fungus's virulence[2]. Immune suppression is the most important underlying mechanism in the development of cryptococcal infection. Disorders like acquired immune deficiency syndrome (AIDS), diabetes mellitus, and chronic liver and renal disease, prolonged administration of steroids, use of immunosuppressive agents, such as monoclonal antibodies, and solid organ transplantation are commonly associated with the development of cryptococcal disease[3].

species spread by inhalation, and despite the fact that the virus most commonly enters the body through the lungs, meningoencephalitis is the most prevalent clinical manifestation of the infection[4]. According to several studies, in pulmonary cryptococcosis, pulmonary nodules are the most prevalent computed tomography findings of pulmonary cryptococcosis in immunocompetent hosts, with multiple nodules being more common than solitary lesions. The majority of them are poorly defined and inhomogeneous, with air-bubble signs seen. Consolidation, ground glass opacities, and masses are also described. The halo, air bronchogram, and cavity signs can also be seen. In these individuals, the pulmonary lesions are mostly seen in the lower lung lobes and the lung periphery[5,6]. In immunocompromised patients, the most common imaging findings are multiple nodules, which are usually larger than those in normal hosts, pulmonary cavitations, and single or multiple consolidations. Adenopathy and pleural effusions, which are sometimes small and unilateral, are usually observed in cases of extensive lung infection[7].

Pleural involvement of cryptococcal infection is rarely observed and is more commonly seen in immunocompromised hosts than in immunocompetent ones[8]. Pleural effusion associated with cryptococcal infection in an immunocompetent host was described for the first time in 1941[9]. Since then, approximately 50 cases of pleural effusion related to cryptococcal infection due to

in the context of both lung and disseminated disease, have been described[10]. A total of 32 cases out of 50 had only pulmonary cryptococcosis, and 18 out of 50 patients were related to disseminated disease. Eight patients experienced severe pulmonary cryptococcosis, requiring, in some cases, surgical management with decortication and lobectomy. The immunosuppressive risk factors identified in these 50 cases were solid organ transplantation, AIDS, hematological malignancies, administration of corticosteroids, diabetes mellitus, chronic obstructive pulmonary disease, bronchial asthma, liver cirrhosis, and end-stage renal disease. Interestingly, 14 patients were immunocompetent. The majority of pulmonary nodules were observed in the lower lobes and in a subpleural distribution. Of note, 26 patients had only pleural effusion on computed tomography imaging[11,12].

The diagnosis of cryptococcal pleural infection requires proof of the presence of

in the effusion or pleura and is typically established by examination of pleural biopsy, fluid culture, and/or detection of cryptococcal antigen (CrAg) in the pleura or pleural fluid[13]. Detecting

by histopathological examination is the gold standard for confirming the diagnosis. The detection rates of

with Gomori-methenamine silver stain and periodic acid-Schiff stain are 100%. The morphology present in tissue with

infection using Gomori-methenamine silver and periodic acid-Schiff (PAS) staining reveals arrow-based budding yeasts (4-10 μm) with a thick capsule, while the morphology present in tissue with histoplasmosis reveals small yeasts (2-4 μm) with narrow-based budding grouped in clusters inside macrophages[14].

Cryptococcal pleural effusions are usually located in the right hemithorax. They vary in size from minimal to massive and are almost always related to parenchymal lesions ranging from subpleural nodules to interstitial infiltrates or pulmonary lesions. The character of the fluid is usually bloody or serosanguinous[11]. Pleural fluid total cell counts range from 169/mm

to 12000/mm

, with lymphocytes predominating in most cases, but neutrophils and eosinophils have also been reported[16]. The fluid is traditionally exudative; however, cases of transudative fluid have also been described, bringing awareness of this diagnosis in immunocompromised patients regardless of the transudative pleural effusion[24].

Pleural fluid cultures for

are frequently negative, most likely due to the small number of fungi present[11]. CrAg test is considered an effective non-invasive diagnostic tool, with its role in serum and cerebrospinal fluid being well accepted with high sensitivity and specificity[12]. Additionally, this test has a low incidence of false-positive reactions, making it valuable in diagnosing cryptococcosis when cultures of pleural fluid are negative[11]. Moreover, it has been reported that pleural effusion CrAg has higher sensitivity than serum CrAg test in patients with pleural effusion as the only clinical presentation of cryptococcal infection[17]. However, the diagnosis of cryptococcal pleural effusion in the case by Wu

[1] was made by positive serum CrAg, positive India ink staining of bronchoalveolar lavage fluid, and positive PAS staining for

of lung tissue obtained by percutaneous lung biopsy, while neither pleural aspiration nor pleural biopsy was reported[1].

The classic approach for diagnosing

is Indian ink staining, in which the refractile mucinous capsule around the pathogen is delineated, resulting in a distinctive "starry night" appearance. The sensitivity and specificity of India ink stains, on the other hand, are very heterogeneous and usually operator-dependent[15]. Polymerase chain reaction (PCR) analysis of pleura tissue has also been used for the identification of

in cryptococcocal pleuritis[16].

The patient in case by Wo

[1] was initially treated with a daily dose of 400 mg of fluconazole, but he had not a satisfactory clinical outcome a week later and the therapy was modified to voriconazole 200 mg twice daily. Complete resolution of the lesions was observed after 8 wk of therapy. In nonimmunocompromised patients with pulmonary cryptococcal infection, it is recommended the administration of fluconazole 400 mg daily and switching to itraconazole (200 mg twice per day orally), voriconazole (200 mg twice per day orally), or posaconazole (400 mg twice per day orally) in cases with no clinical improvement, no fluconazole availability, or contraindication[23].

In recent years, molecular identification and strain typing methods have been used to analyze

. The identification methods include DNA-DNA hybridization and nested, multiplex and realtime PCR. Regarding

typing, the following techniques have demonstrated the best ability to differentiate between fungal serotypes and molecular types: Serotyping, random amplified polymorphic DNA, multilocus enzyme electrophoresis, restriction fragment length polymorphism, electrophoretic karyotyping, PCR-fingerprinting, amplified fragment length polymorphism, multilocus microsatellite typing, single locus and multilocus sequence typing, matrix-assisted laser desorption/ionization time of flight mass spectrometry, and whole genome sequencing. These typing methods have contributed in revealing the phylogenetic pattern, the origin of numerous lineages and their scattering patterns, the distribution of genetic variation among geographic regions and ecosystems, and precise mutations during infections[18,19]. In addition, the cloning of

gene,

gene, and recombinant DNA is helpful to study the taxonomic status, phylogenetic origin, and epidemiological investigation of

[20-22].

4.Large apple tree:According to Frazer, in Germany and other parts of Europe there was a tradition of planting a tree at the birth of a child, the growth of the tree representing the growth of the child (682). The tree was tended with special care (682). In the story, the father does not show this special care for he is willing to trade the tree so quickly. In Switzerland, a pear tree was planted for a girl, an apple tree for a boy (Frazer 682) and the people think that the child is then believed to grow with the tree (Frazer 682).

There lives, he said, in a neighbouring country, a mighty emperor who has a beautiful golden bird in a cage, and this is the creature who steals the golden apples, but it flies so fast that it is impossible to catch it at its theft

It is worth-mentioning that cryptococcal pleural effusion may have high levels of adenosine deaminase (ADA), making the discrimination between this fungal infection and tuberculosis difficult. Yoshino

[25] described a case of cryptococcal pleuritis, diagnosed by the isolation of

in the culture of the pleural effusion, containing a high level of ADA in a patient with AIDS. Wee

[10] also reported a case of a patient with acute myeloid leukemia and a cryptococcal pleural effusion with increased pleural fluid ADA level[4]. Previous research has shown that ADA levels in the pleural fluid > 40 IU/L demonstrate a high sensitivity (81%-100%) and a high specificity (83%-100%) for diagnosing tuberculosis pleuritis[26]. ADA is an enzyme present in most cells, notably lymphocytes, that catalyzes the conversion of adenosine to inosine. As a result, it is hypothesized that ADA levels would be higher in lymphocyte-rich pleural effusions, such as those seen in cryptococcal infections[25]. Some studies found that an increased level of ADA was rarely observed in nontuberculous lymphocytic pleural effusions and that a level of ADA greater than 40 IU/L ruled out tuberculosis; however, cases of cryptococcosis were not included in these studies[27]. ADA test has high negative predictive value and is an excellent test to rule out tuberculosis[28]. Some studies demonstrate that an ADA level > 45 to 60 units/L has a sensitivity of 100% and a specificity up to 97% for tuberculous pleural effusion[29,30].

15. Lose them again: That the scenario81 is repeated could be read as the child s need to master not only the internal world, but also the external-as much scarier place sometimes, with circumstances and events beyond one s control. Return to place in story.

The authors have no conflict of interest to declare.

Damaskos C and Sklapani P designed research; Trakas N performed research; Georgakopoulou VE wrote the letter; Gkoufa A revised the letter.

” Very soon it was said that the prince must marry, and that the beautiful daughter of a neighboring king would be his wife, for a fine ship was being fitted out

FOOTNOTES

Pleural involvement in cryptococcal infections is under-appreciated. When biopsy results are inconclusive, further testing for invasive granulomatous infections, such as pulmonary cryptococcosis, should be conducted. Where needed, pleural effusion should be evaluated using a sensitive CrAg assay as well as fungal culture. Furthermore, clinicians should consider pleural cryptococcosis in cases of pleural nodules without pleural effusion, especially in the context of immunosuppression, even if the CrAg test is negative.

In addition, pleural involvement in cryptococcal infections includes pleural infection without pleural effusion. Of interest, pleural cryptococcosis without pleural effusion has been described only in one case in the literature. The authors described this extremely uncommon entity in a patient suffering from rectal carcinoma under chemotherapy and mentioned as a possible explanation for this finding that lung cryptococcosis, developed in the peripheral lung parenchyma during chemotherapy, had a rupture into the pleural cavity space[31].

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Greece

When he looked about he found that he was in the very same place he had jumped from; there was the palace, there the garden and the deer! Eight times he leaped over the wall and eight times found himself where he had started from; but after the ninth leap there was a change, there was a palace and there was a garden, but the deer were gone

Vasiliki E Georgakopoulou 0000-0003-0772-811X; Christos Damaskos 0000-0002-5454-2564; Pagona Sklapani 0000-0001-7347-8433; Nikolaos Trakas 0000-0001-8157-1304; Aikaterini Gkoufa 0000-0001-5644-8208.

Liu JH

Filipodia

I remember some ten years ago when he was made a King s Counsel, Amos and I, seeing him get off the London train, went to congratulate him. We grinned with pleasure; he merely looked as miserable as though he d received a penal6 sentence. It was the same when he was knighted; he never smiled a bit, he didn t even bother to celebrate with a round of drinks at the Blue Fox . He took his success as a child does his medicine. And not one of his achievements brought even a ghost of a smile to his tired eyes.

Liu JH

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