Missed opportunities to identify cryptococcosis in COVID-19 patients: a case report and literature review

SARS-CoV-2 may activate both innate and adaptive immune responses ultimately leading to a dysregulated immune response prompting the use of immunomodulatory therapy. Although viral pneumonia increases the risk of invasive fungal infections, it remains unclear whether SARS-CoV-2 infection, immunomodulatory therapy, or a combination of both are responsible for the increased recognition of opportunistic infections in COVID-19 patients. Cases of cryptococcosis have previously been reported following treatment with corticosteroids, interleukin (IL)-6 inhibitors, and Janus kinase (JAK) inhibitors, for patients with autoimmune diseases, but their effect on the immunologic response in patients with COVID-19 remains unknown. Herein, we present the case of a patient with COVID-19 who received high-dose corticosteroids and was later found to have cryptococcosis despite no traditional risk factors. As our case and previous cases of cryptococcosis in patients with COVID-19 demonstrate, clinicians must be suspicious of cryptococcosis in COVID-19 patients who clinically deteriorate following treatment with immunomodulatory therapies.

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Risk of infection associated with targeted therapies for solid organ and hematological malignancies

Therapeutic Advances in Infectious Disease ◽

10.1177/2049936121989548 ◽

2021 ◽

Vol 8 ◽

pp. 204993612198954

Author(s):

Isabel Ruiz-Camps ◽

Juan Aguilar-Company

Keyword(s):

Hematological Malignancies ◽

Opportunistic Infections ◽

Respiratory Infections ◽

Fungal Infections ◽

Checkpoint Inhibitors ◽

Janus Kinase ◽

Prolonged Treatment ◽

Solid Organ ◽

Risk Of Infection ◽

Increased Risk

Higher risks of infection are associated with some targeted drugs used to treat solid organ and hematological malignancies, and an individual patient’s risk of infection is strongly influenced by underlying diseases and concomitant or prior treatments. This review focuses on risk levels and specific suggestions for management, analyzing groups of agents associated with a significant effect on the risk of infection. Due to limited clinical experience and ongoing advances in these therapies, recommendations may be revised in the near future. Bruton tyrosine kinase (BTK) inhibitors are associated with a higher rate of infections, including invasive fungal infection, especially in the first months of treatment and in patients with advanced, pretreated disease. Phosphatidylinositol 3-kinase (PI3K) inhibitors are associated with an increased risk of Pneumocystis pneumonia and cytomegalovirus (CMV) reactivation. Venetoclax is associated with cytopenias, respiratory infections, and fever and neutropenia. Janus kinase (JAK) inhibitors may predispose patients to opportunistic and fungal infections; need for prophylaxis should be assessed on an individual basis. Mammalian target of rapamycin (mTOR) inhibitors have been linked to a higher risk of general and opportunistic infections. Breakpoint cluster region-Abelson (BCR-ABL) inhibitors are associated with neutropenia, especially over the first months of treatment. Anti-CD20 agents may cause defects in the adaptative immune response, hypogammaglobulinemia, neutropenia, and hepatitis B reactivation. Alemtuzumab is associated with profound and long-lasting immunosuppression; screening is recommended for latent infections and prevention strategies against CMV, herpesvirus, and Pneumocystis infections. Checkpoint inhibitors (CIs) may cause immune-related adverse events for which prolonged treatment with corticosteroids is needed: prophylaxis against Pneumocystis is recommended.

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Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics

Medical Mycology ◽

10.1093/mmy/myy136 ◽

2019 ◽

Vol 57 (Supplement_3) ◽

pp. S307-S317 ◽

Cited By ~ 4

Author(s):

Christopher P Eades ◽

Darius P H Armstrong-James

Keyword(s):

Intracellular Signaling ◽

Fungal Pathogens ◽

Opportunistic Infections ◽

Fungal Infections ◽

Immunocompromised Host ◽

Adaptive Immune ◽

Mechanistic Approach ◽

Molecular Immunology ◽

Nonspecific Cytotoxicity ◽

Small Molecular Inhibitors

AbstractThe use of cytotoxic chemotherapy in the treatment of malignant and inflammatory disorders is beset by considerable adverse effects related to nonspecific cytotoxicity. Accordingly, a mechanistic approach to therapeutics has evolved in recent times with small molecular inhibitors of intracellular signaling pathways involved in disease pathogenesis being developed for clinical use, some with unparalleled efficacy and tolerability. Nevertheless, there are emerging concerns regarding an association with certain small molecular inhibitors and opportunistic infections, including invasive fungal diseases. This is perhaps unsurprising, given that the molecular targets of such agents play fundamental and multifaceted roles in orchestrating innate and adaptive immune responses. Nevertheless, some small molecular inhibitors appear to possess intrinsic antifungal activity and may therefore represent novel therapeutic options in future. This is particularly important given that antifungal resistance is a significant, emerging concern. This paper is a comprehensive review of the state-of-the-art in the molecular immunology to fungal pathogens as applied to existing and emerging small molecular inhibitors.

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Synthesis and Biological Activity of 3-(substitutedphenyl)-6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine: Part II

Anti-Infective Agents ◽

10.2174/2211352518666200617144227 ◽

2020 ◽

Vol 18 ◽

Author(s):

Niranjan Kaushik ◽

Nitin Kumar ◽

Anoop Kumar ◽

Vikas Sharma

Keyword(s):

Antifungal Activity ◽

Opportunistic Infections ◽

Fungal Infections ◽

Mass Spectral Data ◽

Triazole Derivatives ◽

Mass Spectral ◽

Fungal Strains ◽

Antifungal Properties ◽

Antifungal Potential ◽

Spectral Data Analysis

Background: Fungal infections are opportunistic infections that become a serious problem to human health. Objective: Considering the antifungal potential of triazole nucleus, the study was carried out with the objective to synthesize some novel triazole derivatives with antifungal potential. Method: 1,2,4-triazole derivatives were synthesized via a two step reaction (reported earlier). The first step involves reaction of substituted benzoic acid with thiocarbohydrazide to form 4-amino-3-(substituted phenyl)-5-mercapto-1, 2, 4-triazole derivatives (1a-1k) while in second step, synthesized compounds (1a-1k) were then subsequently treated with substituted acetophenone to yield substituted (4-methoxyphenyl-7H-[1, 2, 4] triazolo [3, 4-b][1,3,4] thiadiazine derivatives (2a-2k). All synthesized compounds were characterized by IR, 1H NMR, and Mass spectral data analysis and were screened for their antifungal properties against different fungal strains i.e. Candida tropicalis (ATCC-13803, ATCC-20913), Candida albicans (ATCC-60193), Candida inconspicua (ATCC-16783) and Candida glabrata (ATCC-90030, ATCC-2001). Results: Compound 2d displayed better percentage inhibition (26.29%, 24.81%) than fluconazole (24.44%, 22.96%) against ATCC-16783, ATCC-2001 fungal strains respectively at 100µg/ml. Compound 2f also displayed better percentage inhibition (28.51%) against ATCC-90030 as compared to fluconazone (27.4%) at 200 µg/ml. Similarly, compounds 2e and 2j also exhibited better antifungal properties than fluconazole at 200µg/ml. Compound 2e was found most potent against ATCC13803 (30.37%) and ATCC-90030 (30.37%) fungal strains as compared to fluconazole (28.14%, 27.4%) at 200 µg/ml respectively whereas compound 2j exhibited better antifungal activity (28.51%) against ATCC-60193 than fluconazole (27.7%) at 200 µg/ml. Conclusion: The results were in accordance with our assertions for triazole derivatives, as all compounds displayed moderate to good antifungal activity.

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Effectiveness of Valganciclovir 900mg Versus 450mg for Cytomegalovirus Prophylaxis in Renal Transplantation: A Systematic Review and Meta-Analysis

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3805b ◽

2017 ◽

Vol 20 ◽

pp. 168 ◽

Cited By ~ 3

Author(s):

Wang Xin ◽

Yang Hui ◽

Zhang Xiaodong ◽

Cui Xiangli ◽

Wang Shihui ◽

...

Keyword(s):

Renal Transplantation ◽

Acute Rejection ◽

Low Dose ◽

Opportunistic Infections ◽

Meta Analysis ◽

High Dose ◽

Renal Transplant Recipients ◽

Significant Difference ◽

Allograft Loss ◽

Cmv Disease

Objectives: Valganciclovir 900 mg/day is approved for cytomegalovirus (CMV) prophylaxis, but 450 mg/day is seems also effective. We systematically reviewed the efficacy and safety of low-dose versus high-dose valganciclovir prophylaxis in renal transplantation recipients. Methods: An electronic search was conducted up to November 29, 2016. The primary outcomes were incidences of CMV, CMV disease, mortality and opportunistic infection. The second outcomes were acute rejection, allograft loss, adverse drug reaction (ADR). Results: 7 cohort studies, all with high quality involving (1431 patients) were included. There was no significant difference of the incidence of following CMV disease (1271 patients, odds ratio [OR] 0.74, 95% confidence interval [CI], 0.38-1.43, p=0.36), acute rejection (1343 patients, OR 0.77, 95%CI 0.53-1.14, p=0.19), allograft loss (1271 patients, OR 0.64, 95%CI 0.31-1.35, p=0.24), mortality (1271 patients, OR 0.55, 95%CI 0.20-1.47, p=0.23) and opportunistic infections (OI) (985 patients, OR 0.76, 95%CI 0.52-1.10, p=0.14) between the low-dose and the high-dose valganciclovir prophylaxis. And no significant difference was observed for premature valganciclovir discontinuation (1010 patients, OR 0.81, 95%CI 0.52-1.25, p=0.33) and the incidence of leukopenia (1082 patients, OR 0.65, 95%CI 0.34-1.22, p=0.18) between the two regimens. Conclusion: 450 mg and 900 mg doses of valganciclovir are equipotent for CMV universal prophylaxis. CMV 450 mg prophylaxis should be used for renal transplant recipients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches.

Allergologia et Immunopathologia ◽

10.15586/aei.v49i1.20 ◽

2021 ◽

Vol 49 (1) ◽

pp. 118-127

Author(s):

Natalia Egri ◽

Ana Esteve-Solé ◽

Àngela Deyà-Martínez ◽

Iñaki Ortiz de Landazuri ◽

Alexandru Vlagea ◽

...

Keyword(s):

Kinase Inhibitors ◽

Fungal Infections ◽

Janus Kinase ◽

Gene Gain ◽

Invasive Infection ◽

Chronic Mucocutaneous Candidiasis ◽

Type I ◽

Therapeutic Approaches ◽

Function Type ◽

Mucocutaneous Candidiasis

Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non invasive infection, mainly due to Candida albicans , in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow widening therapeutic options aimed at restoring immunological function. Type I and II Janus Kinase -inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.

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Practical Approach to the Pathologic Diagnosis of Mixed Filamentous Fungal Infections in Burn Wounds: A Case Series

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.283 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S133-S133

Author(s):

A D Pyden ◽

I Solomon ◽

A Laga Canales

Keyword(s):

Opportunistic Infections ◽

Fungal Infections ◽

Case Series ◽

Fungal Species ◽

Molecular Testing ◽

Burn Wounds ◽

Tissue Sections ◽

True Infection ◽

Extensive Burn

Abstract Introduction/Objective Opportunistic infections by fungi are a major source of morbidity and mortality in patients suffering from extensive burn wounds. Here we review a series of cases of infections by multiple fungi in burn wounds as diagnosed by histopathology and outline the key features for the pathologist to include in the report. Methods/Case Report Biopsies from patients with more than one fungal species identified in the laboratory in a concurrent culture or by PCR were included in this study. Three cases are presented with multiple fungi identified. Each case had yeast and at least one different hyaline mold species present on pathology; two cases additionally had mucormycetes present, with angioinvasion in one case. All organisms requiried microbiologic cultures and variably required molecular testing for full identification. Results (if a Case Study enter NA) N/A Conclusion Pathologists should be aware of the possibility of infection by multiple fungal species in burn wounds. Fungal morphology in tissue sections should allow for detection and distinction of mucormyctes and other hyaline molds. Histopathologic correlation with culture and/or PCR results is essential to distinguish potential contaminants from true infection.

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Graft-versus-host disease: a case report of a rare but reversible cause of constrictive pericarditis

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytaa009 ◽

2020 ◽

Vol 4 (2) ◽

pp. 1-5

Author(s):

Christopher A Pieri ◽

Neil Roberts ◽

John Gribben ◽

Charlotte Manisty

Keyword(s):

Constrictive Pericarditis ◽

Hospital Admissions ◽

High Dose Chemotherapy ◽

Immunomodulatory Therapy ◽

High Dose ◽

Pericardial Disease ◽

Host Disease ◽

Graft Vs Host Disease ◽

Pericardial Thickening ◽

Small Pericardial Effusion

Abstract Background Constrictive pericarditis (CP), although an uncommon cause of heart failure, requires specialist multidisciplinary input and multi-modality imaging to identify the underlying aetiology and treat potentially reversible causes. Case summary We report the case of a 74-year-old gentleman referred for assessment of progressive exertional dyspnoea and peripheral oedema, 30 months following treatment of acute myeloid leukaemia with high-dose chemotherapy and allogeneic stem cell transplantation. Clinical examination and cardiac imaging revealed a small pericardial effusion and pericardial thickening with constrictive physiology; however, no aetiology was identified despite diagnostic pericardiocentesis. The patient required recurrent hospital admissions for intravenous diuresis, therefore, following multidisciplinary discussions, surgical partial pericardectomy was performed. Histology suggested graft-vs.-host disease (GvHD) and post-operatively, the patient improved clinically. Following immunomodulatory therapy with ruxolitinib for both pericardial and pulmonary GvHD, his functional status improved further with no subsequent hospital admissions. Discussion Although pericardial disease in cancer patients is common, CP is unusual. Determining the underlying aetiology is important for subsequent management, and here, we describe the use of multi-modality imaging to diagnose a rare cause, GvHD, which responded to surgical treatment and immunomodulatory therapy.

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Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.10.1092 ◽

1984 ◽

Vol 2 (10) ◽

pp. 1092-1097 ◽

Cited By ~ 19

Author(s):

J Ochs ◽

J A Sinkule ◽

M K Danks ◽

A T Look ◽

W P Bowman ◽

...

Keyword(s):

Steady State ◽

Continuous Infusion ◽

Cytosine Arabinoside ◽

Fungal Infections ◽

Dosage Level ◽

High Dose ◽

Loading Dose ◽

Rapid Infusion ◽

Organ Systems ◽

State Plasma

Ten pediatric patients with refractory leukemia received continuous infusion high-dose cytosine arabinoside (ara-C) according to one of two escalating dosage schedules: (1) a 500-mg/m2 rapid infusion loading dose followed by 3.5 g/m2 per day continuous infusion daily for four consecutive days, or (2) a 600-mg/m2 rapid infusion loading dose followed by 5.0 g/m2 per day continuous infusion daily for four consecutive days. Major toxicity at the lower dosage level was grade IV hematopoietic aplasia of three weeks' duration. At the higher dosage level, there was a prohibitive toxicity in multiple organ systems including transient noncardiogenic pulmonary edema, fungal infections, peritonitis, severe diarrhea, transaminase elevations, and one treatment-related death due to acute renal failure. In contrast to other methods of administration of high-dose ara-C, no CNS toxicity occurred. Oncolytic responses were seen in all patients and two achieved brief, partial remissions. Steady-state plasma ara-C concentrations were 13 to 40 mumol/L at the 3.5-g/m2 dosage level and 10 to 225 mumol/L at the 5-g/m2 dosage level; CSF concentrations at both dosages ranged from 2 to 5 mumol/L. Intracellular levels and ratios of 1-beta-D-arabinofuranosylcytidine-5' triphosphate and endogenous deoxycytidine 5' triphosphate in marrow blasts varied widely at steady state during infusion. No positive correlation existed between steady-state plasma ara-C levels, toxicity, oncolytic effect, or intracellular nucleotide concentration.

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Kaposi's sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon.

Journal of Clinical Oncology ◽

10.1200/jco.1986.4.4.544 ◽

1986 ◽

Vol 4 (4) ◽

pp. 544-551 ◽

Cited By ~ 153

Author(s):

F X Real ◽

H F Oettgen ◽

S E Krown

Keyword(s):

Acquired Immunodeficiency Syndrome ◽

Kaposi's Sarcoma ◽

Opportunistic Infections ◽

Kaposi’S Sarcoma ◽

Response Duration ◽

High Dose ◽

Median Response ◽

Major Response ◽

Acquired Immunodeficiency ◽

Immunodeficiency Syndrome

The efficacy of recombinant leukocyte A interferon (rIFN-alpha A [Roferon-A, Hoffman-La Roche, Nutley, NJ]) treatment of Kaposi's sarcoma in patients with acquired immunodeficiency syndrome was evaluated in sequential trials using high doses (36 X 10(6) units) and low doses (3 X 10(6) units) of interferon. A major response was seen in 38% of patients treated at the high dose, with a median response duration of 18 months. At the low dose, the major response rate was 3%; dose escalation to 36 X 10(6) units resulted in an additional major response rate of 17% in low-dose nonresponders, with a median response duration of 10 months. Four of 11 patients who achieved a complete response remain free of disease, whereas all partial responders have shown disease progression. Unacceptable toxicity occurred in 27% of patients initially treated at the high dose and only in 10% of those who had progressive dose escalation up to 36 X 10(6) units. Prior opportunistic infections correlated negatively with therapeutic response, whereas large tumor burden and gastrointestinal involvement did not. Responding patients showed a significantly longer survival and a lower incidence of subsequent opportunistic infections than nonresponders. However, from our study we cannot determine whether rIFN-alpha A has an effect on the natural history of Kaposi's sarcoma in patients with the acquired immunodeficiency syndrome.

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Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

Current Fungal Infection Reports ◽

10.1007/s12281-019-00350-w ◽

2019 ◽

Vol 13 (4) ◽

pp. 229-243 ◽

Cited By ~ 5

Author(s):

Katie Bechman ◽

James B Galloway ◽

Kevin L Winthrop

Keyword(s):

Protein Kinase ◽

Tyrosine Kinase ◽

Small Molecule ◽

Kinase Inhibitors ◽

Fungal Infections ◽

Break Point ◽

Pharmacokinetic Profile ◽

Protein Kinase Inhibitors ◽

Janus Kinase ◽

The Impact

Abstract Purpose of Review This review discusses fungal infections associated with licenced small-molecule protein kinase inhibitors. For each major drug class, the mechanism of action and targeted pathways and the impact on host defence against fungi are described. Recent Findings Protein kinase inhibitors are successfully used in the treatment of malignancies and immune-mediated diseases, targeting signalling pathways for a broad spectrum of cytokines and growth-stimuli. These agents predispose to fungal infections by the suppression of integral components of the adaptive and innate immune response. Summary The greatest risk of fungal infections is seen with bruton tyrosine kinase inhibitors, e.g. ibrutinib. Infections are also reported with agents that target mTOR, Janus kinase and break point cluster (Bcr) gene–Abelson (Abl) tyrosine kinase (BCR-ABL). The type of fungal infection fits mechanistically with the specific pathway targeted. Infections are often disseminated and present soon after the initiation of therapy. The pharmacokinetic profile, possibility of off-target kinase inhibition, and underlying disease pathology contribute to infection risk.

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