Pulmonary cryptococcosis is a common but underdiagnosed opportunistic fungal infection in both immunocompromised and immunocompetent patients. The causal agents include at least eight evolutionary distinct haploid lineages as well as their hybrids of the human pathogenic Cryptococcus complex. In this update, we review recent advances in epidemiology, mode of transmission, risk factors, diagnostic methods, and therapy of pulmonary cryptococcosis. Our review suggests significant challenges and opportunities for research, from bedside to benchside and back to bedside.

Update on Pulmonary Cryptococcosis.

Introduction Cryptococcus spp. infection of the central nervous system (CINS) is a devastating opportunistic infection that was historically described in patients with acquired immunodeficiency syndrome (AIDS). Cryptococcus spp. infections are also associated with sarcoidosis; the impairment of cell-mediated immunity and long-term corticosteroid therapy being evoked to explain this association. Nevertheless, this assertion is debated and the underlying pathophysiological mechanisms are still unknown. The aims of this study were (i) to describe the clinical and biological presentation, treatments, and outcomes of CINS patients with and without sarcoidosis and (ii) to review the pathophysiological evidence underlying this clinical association. Patients and Methods Every patient with positive cerebrospinal fluid (CSF) cryptococcal antigen testing, India ink preparation, and/or culture from January 2015 to December 2020 at a tertiary university hospital were included, and patients with sarcoidosis were compared with non-sarcoidosis patients. Quantitative variables are presented as mean ± SD and are compared using the Mann-Whitney Wilcoxon rank-sum test. Categorical variables are expressed as the number of patients (percentage) and compared using the χ2 or Fisher's tests. Results During the study period, 16 patients experienced CINS, of whom 5 (31%) were associated with sarcoidosis. CINS symptoms, biological, and CSF features were similar between CINS patients with and without sarcoidosis except regarding CD4 cells percentages and CD4/CD8 ratio that was higher in those with sarcoidosis (47 ± 12 vs. 22 ± 18, p = 0.02 and 2.24 ± 1.42 vs. 0.83 ± 1.10, p = 0.03, respectively). CINS patients with sarcoidosis had less often positive blood antigen testing than those without sarcoidosis (2/5 vs. 11/11, p = 0.02). CINS patients with and without sarcoidosis were treated with similar drugs, but patients with sarcoidosis had a shorter length of treatment. CD4 cell levels do not seem to explain the association between sarcoidosis and cryptococcosis. Conclusion Sarcoidosis was the most frequently associated condition with CINS in this study. CINS patients associated with sarcoidosis had overall similar clinical and biological presentation than CINS patients associated with other conditions but exhibited a lower rate of positive blood cryptococcal antigen testing and higher CD4/CD8 T cells ratio. Pathophysiological mechanisms underlying this association remain poorly understood but B-1 cell deficiency or lack of IgM could be a part of the explanation. Another plausible mechanism is the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in a subset of patients with sarcoidosis, which could impair macrophage phagocytic function. Further studies are strongly needed to better understand those mechanisms and to identify at-risk patients.

Central Nervous System Cryptococcosis in Patients With Sarcoidosis: Comparison With Non-sarcoidosis Patients and Review of Potential Pathophysiological Mechanisms

Abstract Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and prevention of transplant rejection, which may affect human defence mechanisms against cryptococcosis. In this review, we comprehensively investigated the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affects the Th1/macrophage activation pathways, such as tumour necrosis factor-α (TNF- α) antagonists, Bruton tyrosine kinase (BTK) inhibitors, fingolimod, JAK/STAT inhibitors, and monoclonal antibody against CD52. Other risk factors, such as age, underlying condition, and concurrent immunosuppressants especially corticosteroids, should also be taken into account during risk stratification. 

Cryptococcosis associated with biologic therapy – a narrative review

Recent advances in the treatment of hematologic malignancies have improved the overall survival rate, but the number of patients at risk of developing an invasive fungal infection (IFI) has increased. Invasive infections caused by non-Candida albicans species, non-Aspergillus molds, and azole-resistant Aspergillus fumigatus have been increasingly reported in recent years. We developed a cross-sectional multicenter survey which involved a total of 55 hematologists and infectious disease specialists from a total of 31 Spanish hospitals, to determine the most frequent strategies used for the management of IFIs. Data collection was undertaken through an online survey which took place in 2022. Regarding key strategies, experts usually prefer early treatment for persistent febrile neutropenia, switching to another broad-spectrum antifungal family if azole-resistant Aspergillus is suspected, broad-spectrum azoles and echinocandins as prophylactic treatment in patients receiving midostaurin or venetoclax, and liposomal amphotericin B for breakthrough IFIs after prophylaxis with echinocandins in patients receiving new targeted therapies. For antifungals failing to reach adequate levels during the first days and suspected invasive aspergillosis, the most appropriate strategy would be to associate an antifungal from another family.

IFISTRATEGY: Spanish National Survey of Invasive Fungal Infection in Hemato-Oncologic Patients

The use of Bruton tyrosine kinase (BTK) inhibitors for the treatment of a number of hematological conditions is rapidly increasing. Ibrutinib is the most clinically advanced and common BTK inhibitor currently utilized. Its use, however, comes with increasing reports of immunosuppression and increased risk of opportunistic infections.1 We present the case of a widespread papulonodular eruption secondary to disseminated cryptococcal disease after ibrutinib therapy, which the authors believe is the first reported case with widespread cutaneous involvement.

A case of disseminated cryptococcal disease after Bruton tyrosine kinase inhibitor therapy: A brief review in the Australian context.

Purpose Invasive fungal diseases and especially Cryptococcus neoformans infections are increasingly reported in patients with hematological malignancies receiving ibrutinib, a Bruton's tyrosine kinase inhibitor. Patients and method We reported three additional cases and reviewed 16 previous published cases together with cases from the international pharmacovigilance database. Results Patients were mainly treated for chronic lymphocytic leukemia. Cryptococcosis mostly occurred during the first six months (66%) and especially the first two months (44%) of treatment. Clinical presentation is often pulmonary (68%) and the outcome is usually favorable despite ibrutinib continuation. Conclusion Clinicians must be aware of this infection in patients with hematological malignancies on ibrutinib.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, a new risk factor for cryptococcosis

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Ibrutinib, a Bruton’s tyrosine kinase inhibitor, a new risk factor for cryptococcosis