(searched for: 10.29328/journal.jccm.1001108)
Frontiers in Medicine, Volume 7; https://doi.org/10.3389/fmed.2020.598037
Candida spp. is one of the most important components of human microecology. Among hospitalized patients, the isolation rate of Candida spp. by active screening is about 15%, while in critically ill patients, the rate can be as high as 25% (1). Although microbial colonization plays an important role in secondary infections, Candida pneumonia is seldom documented even in the intensive care unit (ICU). Thus, the common consensus is that anti-Candida therapy is rarely necessary in most cases and it should be considered as colonization in which Candida spp. are isolated from the respiratory tract (RT) (2). The co-existence of bacteria and fungi has raised great concern in the last decade. It has been indicated by some studies that Candida colonization in the RT might be an independent risk factor that could promote ventilator-associated pneumonia (VAP) and even change the antibiotic resistance patterns of pathogenic bacteria by polymicrobial biofilm formation (3, 4). Therefore, the significance of Candida colonization in RT remains controversial, and many clinical problems need to be reinterpreted. The rate of Candida spp. isolation in the RT is relatively high, especially in those with mechanical ventilation (MV) (3). However, whether VAP can be caused by Candida spp. remains controversial and the main reasons for this are listed as follows: (1) No matter what the pathogenic microorganism is, the diagnosis of VAP is still difficult due to the lack of pathological evidence. The clinical diagnostic criteria for suspected VAP are not specific, and it is difficult to distinguish between colonization and infection (5). (2) The understanding of the importance of bacterial and fungal co-existence is not deep enough. Some microbiological laboratories have not conducted further analysis when fast-growing Candida spp. are isolated from RT samples. What's more, only filamentous fungi isolation were reported in some institutions (6). (3) It is widely accepted that the cutoff value for the number of pathogenic bacteria for VAP diagnosis is 103 cfu/mL (protected specimen brush sample) or 104 cfu/mL (bronchoalveolar lavage fluid sample), but such a threshold has not yet been established for Candida (5). Therefore, Candida pneumonia must be diagnosed by histopathology. Hence, it is generally thought that Candida pneumonia is quite rare in the ICU, and the guidelines for the management of Candida spp. of both the IDSA and ESCMID do not recommend antifungal treatment unless there is clear histological evidence of infection (2, 7). Alveolar macrophages act as the first line of defense against Candida in critically ill patients. Toll-like receptor (TLR) induces a Th1 cytokine pattern to increase the levels of IFN-γ and TNF-α to facilitate the clearance of Candida spores from the alveoli. What is more, other researches have also indicated that IFN-γ favors the intracellular killing of the fungus after internalization in professional phagocytes (8). Thus, it can be inferred that Candida pneumonia may not exist in the ICU. An autopsy study with 135 patients who died of pneumonia showed that among them, 77 (57%) severely affected patients had Candida airway colonization during their hospital stay. However, none of these cases was pathologically confirmed as Candida pneumonia (9). Meanwhile, one controlled before-after study in a microbiology laboratory at Illinois University showed that limiting the identification of respiratory secretions (only filamentous fungi were reported) could reduce the prescription of antifungal drug treatment (21 vs. 39%) and shorten the length of hospital stay (10.1 vs. 12.1 days) compared with full identification (all rapidly growing yeasts were reported), p< 0.05 (6). What should ICU physicians do when they receive a microbial culture report which indicates that Candida spp. are growing fast in airway secretions? The practice guidelines recommend that antifungal therapy should not be routinely used in those with Candida airway colonization (2, 7). However, should Candida colonization in the airway of critically ill patients simply be ignored? Some in vitro experiments on the co-existence of bacteria and fungi came to different conclusions. The cell wall of Candida spp. is combined with polysaccharides and proteins. Among them, Beta-glucan (BG) is a proinflammatory factor that can cause dysfunction of macrophages and neutrophils in alveoli as well as reduce the production of reactive oxygen species (10). It is also reported that there is a strong interaction among Candida, Gram-positive and Gram-negative bacteria through quorum sensing (QS) molecules, and the extensive interaction of metabolic processes and intercellular communication among them are the basis of synergistic and antagonistic interactions (11). Through an observational study of rats injected with active Candida albicans, it was found that the increased production of cellular inflammatory factors, including interleukin-6, interferon-γ and tumor necrosis factor-α, inhibited phagocytosis by alveolar macrophages. This phenomenon led to changes in airway microecology, and an increase in the airway colonization rate of Pseudomonas aeruginosa was found (12). Moreover, this effect was not unique to Pseudomonas aeruginosa. Another study showed that Candida colonization was also beneficial for the colonization of Staphylococcus aureus and Enterobacteriaceae, which led to an increase in bacterial pneumonia (13). Candida biofilms show a reticular structure composed of Candida spores and hyphae and are easily found on the surfaces of artificial materials (such as endotracheal tubes). The biofilm matrix contains polysaccharides, proteins and other unknown components, which show strong adhesion and are difficult to remove (14) (Figure 1). Biofilms not only have a protective effect on Candida but also have a strong adsorption effect on co-existing bacteria. Animal experiments and electron microscopic studies show that bacteria and fungi can produce small molecules to interact with each other and change their morphology, function and growth environment, resulting in bacteria that are firmly adsorbed between Candida spores or biofilms. Such structures are difficult to remove. Even though the spore activity of some Candida spp. is decreased, the adsorption phenomenon is still observed (4, 15). Figure 1. Interaction of Candida spp. and bacteria in patients with mechanical ventilation. Candida biofilms are easily found on the respiratory tract or the surfaces of endotracheal tubes. Biofilms not only have a protective effect on Candida but also have a strong adsorption effect on co-existing bacteria. Multidrug-resistant bacteria could be isolated by the transmission of drug-resistant plasmid transmission and polymicrobial biofilm formation (Drawn by Chunhui Xu). Candida colonization can also change the virulence and/or host immune function of colonized bacteria. A series of animal experiments have shown that after the mixed inoculation of Candida and bacteria in the airway of mice, even if the number of inoculated Candida is very small, the bacterial load still occupies a high percentage of the alveoli. It has been suggested that the presence of Candida albicans protects the bacteria from clearance by normal alveolar macrophages (16). Acinetobacter baumannii can affect the morphology of Candida albicans through the QS molecule N-acyl homoserine lactone, whereas farnesol is the main QS molecule of Candida albicans (11). This can affect the movement ability and virulence factor expression of Acinetobacter baumannii. An animal experiment has also found that the degree of alveolar invasiveness of Acinetobacter baumannii in mice with Candida colonization during pneumonia is much higher than that of Acinetobacter baumannii during pulmonary infection (17). The existence of biofilms can also increase the resistance of bacteria to antibiotics. It is showed that Staphylococcus aureus could form a single biofilm (monoculture biofilm) in serum, but its integrity was poor, and it was easy to dissociate. If there is co-growth with Candida albicans, Staphylococcus aureus can form microcolonies on the fungal biofilm, which is closely connected to the bottom hyphae “scaffold,” to form a multi-bacterial biofilm (polymicrobial biofilm) (Supplementary Figure 1). Staphylococcus aureus matrix staining showed different phenotypes of multi-bacterial biofilms and single cell membranes (18), indicating that Staphylococcus aureus may be encapsulated in the matrix secreted by Candida albicans, resulting in an increase in its resistance to vancomycin. Further studies showed that in the environment of multi-bacterial biofilm formation, 27 Staphylococcus aureus-specific proteins were identified by gel electrophoresis, some of which could upregulate the expression of L-lactate dehydrogenase I, confer the ability to resist host-derived oxidative stress to bacteria and enhance resistance to antibiotics, while other proteins could downregulate the expression of the virulence factor CodY (19). These findings suggest that the occurrence of VAP caused by MRSA in patients with Candida albicans airway colonization is not only the result of the expression of QS molecules but can also be attributed to the differential regulation of specific drug resistance genes and virulence factors. Similar results have been obtained in other studies of Gram-negative bacteria (20, 21). In vitro studies suggest that there is mutual induction of the process of the co-existence of bacteria and fungi, so it is necessary to further describe and study the complex interactions between pathogens at the molecular level. The transition from basic research to clinical research may help to design new treatment or prevention and control strategies for bacterial and fungal superinfection. Clinical studies have pointed out that the isolation rate of Candida from the RT of ICU patients with MV could be as high as 50%, which prolonged the median hospital stay (59.9 vs. 38.6 days, p = 0.006) or even increased the hospital mortality (34.2 vs. 21.0%, p = 0.003) (22). Moreover, it might be associated with persistent immunosuppression and inflammation (23). Candida airway colonization and its concomitant secretion of inflammatory factors may affect host cellular immune function, especially in immunosuppressed hosts with severe monocyte and lymphocyte dysfunction, which results in a decrease in the effective clearance of bacteria and fungi and an increase in the incidence of VAP (24). However, the effect of Candida RT colonization on bacterial colonization and antibacterial resistance patterns has always been controversial in clinical research. It is still unclear whether Candida airway colonization could increase the incidence of VAP and whether patients with Candida airway colonization can benefit from antifungal therapy (Supplementary Table 1). One early prospective cohort study reported that Candida RT colonization could increase the incidence of VAP caused by Pseudomonas aeruginosa (9 vs. 4.8%, p = 0.048), and Candida RT colonization was proven to be an independent risk factor (18). Similarly, another single-center retrospective case-control study indicated that antifungal therapy in those with Candida albicans airway colonization could prevent the occurrence of Pseudomonas aeruginosa VAP (25). Some studies have also pointed out that Candida airway colonization is associated with the pathogenesis of Acinetobacter baumannii VAP. In addition, another cohort study showed that aerosol inhalation of amphotericin B in patients with MV significantly reduced the Candida load in the airway but did not change the morbidity due to VAP or mortality during the ICU stay (26, 27). The EMPIRICUS study is a randomized trial to evaluate the efficacy of micafungin for the treatment of patients with Candida colonization in multiple sites and sepsis with organ failure (28). The study noted that the incidence of VAP and the 28-days mortality during the ICU stay did not decrease in the micafungin group compared with those in the placebo group (32 vs. 39.8%, p > 0.05). Therefore, the above studies led to a change in the understanding of the co-existence of bacteria and fungi and their effects on immune function in clinical studies. FUNGIBACT, as a prospective cohort study, included 146 patients with MV for more than 96 h. After adjusting for the immune index mHLA-DR, it was concluded that there was no correlation between airway Candida colonization and the incidence of VAP [HR: 0.98; 95% CI (0.59–1.65), p = 0.95] (29). Another retrospective study reviewed 269 systemic lupus erythematosus patients with hospital-acquired pneumonia. Among them, 186 (69.1%) were found to have airway Candida colonization. Compared with that in the non-colonized group, the detection rate of multidrug-resistant bacteria was higher (58.6 vs. 36.1%, p< 0.001), and the secreted IgA and IL-17 levels returned to normal range faster after anti-fungal treatment, but this had no effect on 28-days mortality (14.5 vs. 10.8, p > 0.05) (30). One meta-analysis about the influence of Candida spp. airway colonization on clinical outcomes in patients with VAP included four prospective studies, three retrospective studies, and one cross-sectional study (31). It revealed that those with airway Candida colonization had longer durations of MV. The most noteworthy feature of the meta-analysis is that patients with Candida colonization had higher 28-days mortality (RR: 1.64; 95% CI: 1.27–2.12) and ICU mortality (RR: 1.57; 95% CI: 1.26–1.94) than those without Candida colonization. Although it has included almost all the clinical research about airway Candida colonization with high quality, limitations still exist. First, attributable mortality rate could hardly find in these studies duo to the effects of confounding factors and the insufficient sample size. Second, a highly heterogeneity could be recognized in the baseline of the enrolled patients. Reasons for MV, severity of VAP, antibiotic exposures before the diagnosis of VAP and the immune state was probably diverse among studies. Although “Candida pneumonia” is rarely confirmed in critically ill patients, Candida airway colonization may affect bacterial colonization and antibacterial resistance patterns, playing an important role in the development of bacterial pneumonia. However, the conclusions of current clinical studies are not consistent. Future clinical studies are needed to re-evaluate the potential benefits of pre-emptive antifungal therapy for preventing VAP. Y-TY and JL: conception and design. D-CC: administrative support. C-HX: provision of study materials or patients. Y-TY and C-HX: data analysis and interpretation. All authors: collection and assembly of data, manuscript writing, and final approval of manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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(2020) 48:695–701. doi: 10.1016/j.ajic.2019.11.002 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: Candida, colonization, ventilator associate pneumonia, critical ill patients, bioflim Citation: Liu J, Yu Y-T, Xu C-H and Chen D-C (2021) Candida Colonization in the Respiratory Tract: What Is the Significance? Front. Med. 7:598037. doi: 10.3389/fmed.2020.598037 Received: 23 August 2020; Accepted: 18 December 2020; Published: 04 February 2021. Edited by: Reviewed by: Copyright © 2021 Liu, Yu, Xu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: De-Chang Chen, [email protected] †These authors have contributed equally to this work
Published: 5 January 2021
Journal of Cardiology and Cardiovascular Medicine, Volume 6, pp 001-006; https://doi.org/10.29328/journal.jccm.1001108
Objective: Plaque morphology plays an important prognostic role in the occurrence of cerebrovascular events. Echolucent and heterogeneous plaques, in particular, carry an increased risk of subsequent stroke. Depending on the quality of the plaque echogenicity based on B-mode ultrasound examination, carotid plaques divide into a soft lipid-rich plaque and a hard plaque with calcification. The aim of this study was to investigate structural changes in the basement membrane of different carotid artery plaque types. Patients and methods: Biopsies were taken from 10 male patients (average age; 75 + 1 years) and 7 females (68 + 3 years). The study population included patients suffering from a filiform stenosis of the carotid artery, 8 patients with acute cerebrovascular events and 9 with asymptomatic stenosis. Scanning electron and polarised light microscopic investigations were carried out on explanted plaques to determine the morphology of calcified areas in vascular lesions. Results: By means of scanning electron microscopy, multiple foci of local calcification were identified. The endothelial layer was partially desquamated from the basement membrane and showed island-like formations. Polarised light microscopy allows us to distinguish between soft plaques with transparent structure and hard plaques with woven bone formation. Conclusion: The major finding of our study is the presence of woven bone tissue in hard plaques of carotid arteries, which may result from pathological strains or mechanical overloading of the collagen fibers. These data suggest a certain parallel with sclerosis of human aortic valves due to their similar morphological characteristics.
eBioMedicine, Volume 57; https://doi.org/10.1016/j.ebiom.2020.102859
Liver cirrhosis consists of an asymptomatic compensated phase and a decompensated phase, which can cause two pulmonary vascular complications: hepatopulmonary syndrome (HPS) characterized by hypoxia, intrapulmonary microvasculature dilatation, angiogenesis and arterio-venous malformations (AVMs) [ 1 Koch D.G. Fallon M.B. Hepatopulmonary syndrome. Clin Liver Dis. 2014; 18 : 407-420 http://dx.doi.org/10.1016/j.cld.2014.01.003 Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar ]; and portopulmonary hypertension (PoPH) characterized by increased pulmonary vascular resistance and pulmonary arterial hypertension (PAH) in the absence of other etiologies of PAH [ 2 Iqbal S. Smith K.A. Khungar V. Hepatopulmonary syndrome and portopulmonary hypertension. Clin Chest Med. 2017; 38 : 785-795 http://dx.doi.org/10.1016/j.ccm.2017.08.002 Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar ]. Previous studies have shown that PoPH and HPS are associated with markedly reduced bone morphogenetic protein (BMP) 9/10 [ 3 Rochon E.R. Krowka M.J. Bartolome S. Heresi G.A. Bull T. Roberts K. et al. . BMP 9/10 in pulmonary vascular complications of liver disease. Am J Respir Crit Care Med. 2020; http://dx.doi.org/10.1164/rccm.201912-2514le Crossref PubMed Scopus (2) Google Scholar , 4 John M. Kim K.J. Bae S.D.W. Qiao L. George J. Role of BMP-9 in human liver disease. Gut. 2019; 68 : 2097-2100 http://dx.doi.org/10.1136/gutjnl-2018-317543 Crossref PubMed Scopus (5) Google Scholar ] and increased soluble endoglin (sEng) levels [ 5 Owen N.E. Alexander G.J. Sen S. Bunclark K. Polwarth G. Pekpe-zaba J. et al. Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis. EBioMedicine. 2020; 56 102794 http://dx.doi.org/10.1016/j.ebiom.2020.102794 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar ]. Approximately 4–40% of cirrhotic patients could develop into HPS [ 6 Soulaidopoulos S. Cholongitas E. Giannakoulas G. Vlachou M. Goulis I. Review article: update on current and emergent data on hepatopulmonary syndrome. World J Gastroenterol. 2018; 24 : 1285-1298 http://dx.doi.org/10.3748/wjg.v24.i12.1285 Crossref PubMed Scopus (14) Google Scholar ] and PoPH can develop in 1–6% of patients with portal vein hypertension [ 7 Savale L. Guimas M. Ebstein N. Fertin M. Jevnikar M. Renard S. et al. . Portopulmonary hypertension in the current era of pulmonary hypertension management. Journal of Hepatology. 2020; http://dx.doi.org/10.1016/j.jhep.2020.02.021 Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar ]. Both of these complications can increase the mortality rate in liver cirrhotic patients and there are few effective precautionary or therapeutic measurements except liver transplantation [ 8 Cosarderelioglu C. Cosar A.M. Gurakar M. Pustavoitau A. Russell S.D. Dagher N.N. et al. Portopulmonary hypertension and liver transplant: recent review of the literature. Exp Clin Transplant. 2016; 14 : 113-120 PubMed Google Scholar , 9 Sendra C. Carballo-Rubio V. Sousa J.M. Hepatopulmonary syndrome and portopulmonary hypertension: management in liver transplantation in the horizon 2020. Transplant. Proc. 2020; http://dx.doi.org/10.1016/j.transproceed.2020.02.057 Crossref PubMed Scopus (1) Google Scholar ]. The study recently published in EBioMedicine by Owen and co-workers contribute to the literature from three aspects.
Frontiers in Pediatrics, Volume 8; https://doi.org/10.3389/fped.2020.00079
Few FDA approved medical devices are specifically designed for children's needs. FDA approval for clinical indications of medical devices specify procedures and not patient ages. Accordingly, the majority of both devices and drugs in pediatric patients are used for off-label indications. Data suggests that 60–75% of medical devices or drugs in pediatric patients are used for off label indications (1). This approach has drawbacks including safety and performance concerns with lack of proper education and instructions for the use of an adult device for a pediatric patient. Barriers to pediatric medical device development arise from the small numbers of pediatric patients, numbered in the thousands vs. hundreds of thousands in the adult market. The number of cancer patients in pediatrics is ~2,000 vs. 600,000 adult patients; the number of defibrillators use in pediatrics is 1,600 vs. 200,000 in adult cardiology (1). Due to the low volume of patients, clinical trials in children have much slower enrollment than adult trials. Parental consent also complicates the enrollment of children in clinical research protocols. Liability concerns, although not discussed openly, may be another detriment for pediatric drug and device innovation. To encourage pediatric device development, Congress and FDA established the Pediatric Medical Device Safety and Improvement Act of 2007 (PL-110-85). This allowed the FDA to designate a Humanitarian Use Device (HUD) designation for disorders with 4,000 patients annually and allowed a Humanitarian Device Exemption (HDE) marketing approval by the FDA for a device. This approval is based upon “safety and probable benefit” rather than the FDA standard Premarket Approval (PMA) process based upon randomized control trials demonstrating statistically significant “safety and effectiveness.” This approach was due to the low number of patients in many pediatric diseases to perform randomized control trials in a reasonable time frame. The elimination of the profit restriction on devices approved under an HDE also promoted financial incentives for pediatric device development (2). On December 2016 the twenty-first Century Cures Act (PL-114-255) changed the population estimate required to qualify for HUD designation from “fewer than 4,000” to “not more than 8,000” to further incentivize pediatric device development. Even prior to these Congressional mandated incentives for pediatric devices, the passage of the Orphan Drug Act in 1983 (PL-97-414) also encouraged the development and approval of drugs for rare diseases. This Act established the Orphan Products Clinical Trials Grant Program in the FDA's Office of Orphan Products Development (OOPD) to support developing drugs and devices to treat orphan diseases. An orphan disease is defined as a disorder affecting fewer than 200,000 patients in the United States. Since developing a new drug or device is costly with inherent risk, large pharmaceutical drug companies have had little interest due to small market size and difficulty in recruiting sufficient number of subjects to study safety and efficacy of a new compound or device. Accordingly, this Act and its subsequent amendments in 1984, 1985, 1988, and 2007, provided a number of incentives for companies to develop compounds to treat rare diseases, including tax credits for the costs of clinical research, 7-year period of exclusive marketing after an orphan drug is approved, and waiver of Prescription Drug User Fee Act (PDUFA) filing fees (over $1 million). With these incentives interest in orphan disease indications have occurred over the last decade (3, 4). This interest is driven also by the facts that there are ~7,000 rare diseases affecting 30 million people in the United States and 400 million worldwide and the recognition that many of these rare diseases have no effective treatments. Accordingly, small biotechnology companies have been formed with funding from private equity to develop new approaches to the unmet medical needs of orphan diseases due to high potential returns on investment. In fact, drugs to treat orphan diseases have commanded high price tags due to the small number of patients and non-competition (5). A recent study has shown that companies with regulatory approved orphan drugs are more profitable and are more attractive investment opportunities than companies without orphan drugs (6). With this background, the development of a potentially transformative device to treat adult and pediatric ICU patients with acute kidney injury requiring continuous renal replacement therapy(CRRT) provides an illustration of how the regulatory environment and the congressional legislation described above resulted in a pivoted focus on pediatric rather than adult indications. This opinion is based upon a singular experience in the bumpy road to commercialization of an immunomodulatory device named the Selective Cytopheretic Device (SCD). Many scientific discoveries have occurred due to chance observations by scientists with detailed background knowledge and an honest curiosity to understand the unexpected results of planned experiments (7). In this regard, an unanticipated result in a clinical trial led to a platform discovery to immunomodulate the detrimental effects of the activated innate immunologic system in both acute and chronic organ failures. This resulted in the development of a Selective Cytopheretic Device. The SCD originated from the clinical evaluation of a tissue engineered Renal Assist Device (RAD) (8) containing adult human renal epithelial cells as a component of a bioartificial kidney to provide more complete renal replacement therapy (RRT). The use of the metabolic activity of renal tubule cells was evaluated to assess whether this addition could improve the poor outcomes of ICU patients with severe acute renal failure requiring RRT. After safety and efficacy signals in Phase I/II and Phase II clinical trials, a change in clinical protocol was made in the RAD Phase IIb clinical study. Subsets of patients were treated with a cell containing RAD or a sham (non-renal cell containing) RAD cartridge (9). The Phase IIb study was a randomized control, blinded multicenter study in ICU patients with Acute Renal Failure secondary to Acute Kidney Injury (AKI) undergoing continuous renal replacement therapy (CRRT). The clinical study was suspended after an interim analysis due to an unanticipated high survival rate of the sham device arm. In retrospective analysis of the sham control groups, the improved survival rate was demonstrated in the presence of regional citrate anticoagulation (RCA) when compared to systemic heparin anticoagulation (10). Subjects were divided into four groups: (1) RAD with citrate anticoagulation, (2) sham device with citrate anticoagulation, (3) RAD with heparin anticoagulation, and (4) sham device with heparin anticoagulation. The 28-day survival rate in the heparin sham patient group was 50 vs. 75% in the citrate sham group (n = 12 for each treatment arm), and the 90-day survival rate was 25% (heparin) vs. 67% (citrate). The baseline demographics for the two subsets were comparable, with similar sequential organ failure assessment (SOFA) scores (13.4 ± 1.1 vs. 12.2 ± 0.9), organ failure number (4.17 ± 0.46 vs. 3.93 ± 0.36) and incidence of sepsis (58 vs. 58%) for the citrate vs. heparin sham groups, respectively (10). This clinical result, although unexpected, was consistent with a potential clinical benefit of the fiber based sham device without cultured renal cells (RAD sham), when used with RCA, which later became known as SCD therapy (Figure 1). Figure 1. Schematic representation of the circuit used for selective cytopheretic device therapy. The therapeutic benefit afforded by this combination of a device and a compound (citrate) on a systemic clinical disorder can be better understood from the following: (1) Microscopy of the sham cartridges (future SCD) after patient treatment demonstrated adherent leukocytes on the outer surface of the membranes of the cartridge along the blood flow path (Figures 2A,B) (9). The attached leukocytes were dominated by neutrophils and monocytes (Figure 2C), which preferentially adhere, compared to other leukocytes such as lymphocytes (11). The ability of leukocytes to adhere to the outer walls of the hollow fiber membranes rather than the inner walls, which is the conventional blood flow path for renal dialysis/hemofiltration applications, was due to the shear forces of blood flow. The shear stress of blood along the outer wall of the membrane was near capillary force of <1 dyne/cm2 compared to the shear stress of 100 dyne/cm2 for blood flowing along the conventional luminal surface of the hollow fiber membranes. (2) RCA lowers the iCa in blood within the circuit to <0.4 mM, a level which inhibits the coagulation system, has an inhibitory effect on leukocyte and platelet activation (11, 12), and also affects the calcium-dependent selectin and integrin mediated interactions between leukocytes and the membrane (13, 14). Extravasation of neutrophils and monocytes from the systemic circulation into tissues is a highly regulated process. In a low shear force environment like that found in capillaries or created within the SCD, neutrophils and monocytes roll along surfaces and are slowed via selectin binding followed by integrin mediated firm adhesion prior to diapedesis (13). Figure 2. Micrographs of cross-sectional area of sham, acellular cartridges (as part of the regional citrate anticoagulation arm of the Renal Assist Device clinical trial now known as the selective cytopheretic device) (A,B). Low-power micrograph showing adherent cells around each fiber (A, 4× objective). Higher-power micrograph showing clustering of bound leukocytes (B, 20× objective). High-power micrograph of a cytospin prepared from adherent cells washed from the outer membrane of the SCD after 24 h of therapy on the first pediatric patient (C, 63× objective). Patient treatment demonstrated adherent leukocytes with a predominance of neutrophils and monocytes on the outer surface of the membranes along the blood flow path which translated into patient benefit. Data from an in vitro blood study utilizing flow chambers to visualize leukocyte interactions with fiber materials suggested that leukocytes roll, then adhere to fibers, are retained for a significant time period (11) (referred to as sequestration) and are then released. Binding selectivity for more activated leukocytes in the SCD is increased in the low iCa environment where calcium dependent selectin rolling, integrin binding, and downstream conformational changes of attached cells are inhibited (15). Neutrophils (16, 17) and monocytes (18, 19) mobilize intracellular stores of CD11b, to the cell surface as they become (primed) activated. Measurement of CD11b, allows for real time measurement of systemic acute neutrophil (priming) and monocyte activation. Additionally, monocyte populations are heterogeneous in their expression of CD11b, with CD14hiCD16− being the highest, and CD14lowCD16+ being the lowest (20). It follows that the preferential sequestration of inflammatory CD14hi monocytes is enhanced in the low iCa environment. The selectivity of binding of the highest activated leukocytes has been repeatedly observed in preclinical animal models where systemic CD11R3: the porcine analog of human CD11b (21), levels decrease through the treatment course (10, 11, 22, 23). This effect was measured directly in a clinical trial by comparing the CD11R3 relative fluorescence of the circulating cells in the peripheral blood to those directly associated with the SCD (24). These results when taken together (10, 11, 22–25), suggest a SCD mechanism of action with a simultaneous, combination effect to transiently sequester activated circulating neutrophils and monocytes, with enhanced selectivity for inflammatory leukocytes, which alters the overall activation of bound and processed leukocytes. Clinical efficacy in AKI with Multi-Organ Dysfunction (MOD) may be due to sequestration and immunomodulation of leukocytes in the SCD. This process appears to block the inflammatory sequence associated with accumulation and aggregation of leukocytes in the peritubular capillaries and reduce infiltration into interstitial spaces, that when unchecked promotes kidney injury following systemic inflammatory response syndrome (SIRS). Preclinical large animal studies confirmed the efficacy of the SCD in a porcine model of septic shock with concomitant acute tubular necrosis (26). Product development continued with successful Phase I/II and Phase II clinical studies which demonstrated safety and strong signals for efficacy in ICU patients with AKI (11, 27). Accordingly, a phase III multi-center, randomized, controlled, pivotal study to assess the safety and efficacy of a SCD in patients with AKI (IDE G090189, Protocol SCD-003) (28)was initiated. The primary objective of this study was to determine whether CRRT+SCD therapy, compared to CRRT alone, results in a clinically relevant and statistically significant improvement in all-cause mortality through day 60. Secondary objectives included assessment of RRT dependency at day 60, mortality at day 28, number of ventilator free days at day 28, and mortality at day 60 of the subset of patients with severe sepsis. This study was a two-arm, randomized, open-label, controlled multi-center pivotal study that enrolled 134 patients at 21 US medical centers. ICU AKI patients of each participating hospital were randomized to treatment undergoing CRRT or CRRT+SCD. Each participating clinical site used their established RCA protocol for the CRRT+SCD circuits (Study Arm) and for the CRRT only (Control Arm). The recommended iCa (riCa) level (measured post SCD) in the CRRT and SCD circuit was specified to be between 0.25 and 0.4 mmol/L. During the second quarter of the enrollment period, a national calcium shortage occurred in the US from FDA related quality manufacturing issues of the major US supplier. This shortage resulted in most centers unable to recruit to the study, since injectable calcium is required for RCA. Due to reliance of the SCD on a narrow intra-circuit iCa range for functional efficacy and the concern that patients randomized to SCD therapy were not getting effective therapy, the interim analysis was performed early-after enrollment of 134 patients. Enrollment was paused on May 24, 2013, to assess the clinical impact of the calcium shortage on study endpoints. The shortage of calcium infusion solutions resulted in a tendency to minimize citrate infusion rates. Accordingly, iCa levels within the blood circuit tended to be above the recommended (r)iCa of 0.25–0.40 mmol/L. Subsequently, the injectable calcium shortage resulted in 9 of the 21 open clinical sites being unable to enroll patients due to low hospital inventories of injectable calcium, contributing to the early termination of the study. Of the 134 patients in the analysis, 69 received CRRT alone and 65 received SCD therapy. No significant differences were noted between the control and treatment groups in baseline characteristics. No statistically significant difference was found between the treated and control patients with a 60-day mortality of 39% (27/69) and 36% (21/59), respectively, with six patients lost to follow up. The amount of time the patients in both the control and treatment group were maintained in the riCa range (0.25–0.40 mmol/L), as specified in the study protocol, was substantially lower than expected due to the injectable calcium shortage. Of the 134 patients enrolled at the time of the interim analysis, 19 SCD patients and 31 control patients were maintained at riCa for ≥90% of the therapy time. Furthermore, none of the significant adverse events (SAE) were considered device related per the principal investigator and the Data Safety Monitoring Board. Comparison of these subgroups of patients revealed 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the control group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD vs. control patients maintained for >90% of the treatment in the protocol's riCa target range with values of 0% (0/16) and 25% (4/16), respectively (p = 0.10). When the riCa SCD and control subgroups were compared for a composite index of 60-day mortality and dialysis dependency, the percentage in SCD subjects was 16 vs. 58% in the control subjects (p< 0.01). When the riCa subpopulation was considered, a statistically significant difference was detected in several parameters: log urine output substantially increased, and absolute leukocyte and neutrophil counts diminished in the SCD vs. control groups over time (28). The observation that, in those patients who had the riCa level >90% of the time of SCD treatment, mortality improved from 41 to 16%, is clinically compelling. In addition, the observation both that in SCD clinical trials no patient receiving appropriate SCD therapy was dialysis dependent at day 60 is also compelling. Previous large prospective clinical studies in AKI with MOD had >20% incidence of dialysis dependency of patients followed for 60 or more days (29, 30). The effect of SCD therapy to modulate excessive leukocyte activation most likely plays a critical role in the recovery of renal function after a substantive AKI event. The relationship of ongoing inflammation in the kidney after AKI and chronic progressive kidney disease and dialysis dependency has been demonstrated (31, 32). In this patient population, immunomodulation by SCD therapy appears to positively promote kidney healing as evidenced by the lack of dialysis dependency at day 60. Additionally, improvement in overall mortality may suggest improved immune balance that persists through the late SIRS process to ameliorate the compensatory anti-inflammatory response which follows the excessive systemic pro-inflammatory state in AKI and MOD (33). Furthermore, the significant decrease in absolute leukocyte and neutrophil counts, as well as the improvement in urine output over time corroborates the mechanistic and pilot studies previously published (11, 27, 34). With this compelling post-hoc analysis, the company, Cytopherx, which licensed this technology from the University of Michigan to commercialize this therapy, underwent a diligent attempt to obtain private equity to undertake a final Premarket Approval (PMA) clinical trial to use the composite index of 60-day mortality and dialysis dependency for FDA approval and rights to market this device in the United States. This effort proved to be difficult with venture capital and private equity firms hesitant to commit tens of millions of dollars to undertake a final multicenter randomized, control study which failed in the initial attempt. Despite the compelling post-hoc analysis, and the lessons learned regarding careful control of the circuit iCa in the recommended range of 0.25–0.4 mM, the perception of a previously failed trial (minimizing the post-hoc analysis) and the risk of capital was too high of a hurdle to obtain commitment to fund the clinical program to achieve FDA approval. With the failure to obtain funding commitments but being convinced from the compelling preclinical and the safety and efficacy clinical data from adult trials, our group considered testing SCD therapy in the pediatric population for a number of reasons. Since the pediatric patient with AKI and MOD usually is not saddled with various chronic diseases which may cause mortality within 60 days of recovery from AKI and dialysis, this patient population would have less obfuscating co-morbidities. An efficacy signal would be apparent in lesser number of patients, thereby confirming the post-hoc analysis of the Phase III adult trial. In addition, the route to FDA approval would not require a large number of patients due to a Humanitarian Use Designation (HUD) since there are <8,000 pediatric patients with AKI and MOD requiring CRRT annually in the United States. Upon demonstrating safety and probable benefit in this HUD pediatric trial, a Humanitarian Device Exemption (HDE) approval by the FDA will allow marketing and commercial sale of the SCD in the United States. Upon HDE approval, funds derived from private equity or public markets to carry out the PMA adult clinical trial would be more readily obtained. With this strategy, our group contacted the prospective pediatric (pp) CRRT consortium (35, 36) directed by Dr. Stuart Goldstein, who agreed that this direction was feasible. Accordingly, our group with the collaboration of Dr. Goldstein, submitted an FDA Office of Orphan Products Development (OOPD) grant to carry out this clinical study. Funding was received in 2014 and the trial was initiated in 2015. Accordingly, similar to the adult AKI clinical trial, a multicenter US study of the SCD in critically ill children (>15 kg, age up to 22 years) with AKI and MOD receiving CRRT as part of standard of care was initiated and is on-going under the FDA approved IDE#G150179 (clinicaltrials.gov NCT02820350). Mortality rates in pediatric patients with AKI and MOD requiring CRRT has historically approached 50% (35–37). In this clinical trial, pediatric patients have received SCD therapy for up to 7 days or when CRRT is discontinued, whichever comes first. Interim analysis of the 14 patients treated with the SCD revealed compelling safety and efficacy data similar to the post-hoc analysis of the Phase III adult SCD study of patients treated per protocol with the recommended iCa levels below 0.4 mM ninety percent of treatment time. The 14 treated patients had an age range between 5 and 20 years, had multiorgan failure between 2 and 5 organs, averaging 2.92 organ failures as a group. Eight of fourteen treated patients also presented with severe sepsis or septic shock. All patients received RCA per protocol with the recommended iCa levels below 0.4 mM for 90% of measured values during treatment. When compared to the historical control standard of care CRRT treatment of pediatric patients with AKI/MOD, SCD therapy reduced both 60-day mortality and ICU length of stay. No patient was dialysis dependent at 60 days. These results, therefore, support a plan to submit an HUD/HDE application to the FDA. These data also strongly support the post-hoc analysis of the adult study. A final IDE adult study using a composite outcome measure of 60-day mortality or 60-day dialysis independence has been approved by the FDA and successful fundraising is anticipated to move this therapy back to the large adult market which comprises of 160,000 patients in the U.S. on an annual basis. This case study demonstrates that creative strategic planning, recognition of FDA pathways and support for pediatric devices can coalesce to promote the development of a life saving device reaching the bedside to save lives and save hospital costs with decreasing length of stays. The product development of pediatric therapies may provide a unique opportunity to more clearly demonstrate the potential effectiveness of a therapy with a smaller population due to the lack of complications and comorbidities as is often seen in adult disease. The development of a pediatric therapy not only is ethically sound, but can also lead to easier and faster transition into the adult market negating the initial hesitancy from a perceived limited market. This case study provides a perspective of the clinical development of a pediatric device as an important step in the commercialization of an innovative therapy. HH developed the main conceptual ideas of this manuscript. 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Pediatr. 8:79. doi: 10.3389/fped.2020.00079 Received: 13 December 2019; Accepted: 18 February 2020; Published: 07 April 2020. Edited by: Reviewed by: Copyright © 2020 Humes and Westover. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: H. David Humes, [email protected]
Frontiers in Oncology, Volume 9; https://doi.org/10.3389/fonc.2019.00365
Editorial on the Research TopicManagement of Immune-Related Adverse Events for Patients Undergoing Treatment With Checkpoint Inhibitors Immunotherapy with immune checkpoint inhibitors has emerged as the most significant advance in the treatment of cancer in recent years and has revolutionized cancer management (1). Until recently, it had been assumed that the immune system was not effective in protecting humans against the development of neoplastic diseases. Checkpoints inhibitors are co-receptors expressed by T cells. These co-receptors regulate T cell activation negatively and play a central role in the maintenance of peripheral self-tolerance. Co-inhibitory receptor ligands are significantly expressed in a variety of malignancies resulting in evasion of anti-cancer immunity. These molecules include programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and were discovered by Tasuku Honjo and James P. Allison in 1992 and 1996, respectively (2, 3). These scientists were jointly awarded the 2018 Nobel Prize for Physiology or Medicine in recognition of this ground-breaking research. Monoclonal antibodies targeting the CTLA-4 and PD-1 and their ligands have produced significant clinical responses against a variety of malignancies (4). FDA registered checkpoint inhibitors include pembrolizumab (5), nivolumab (6), cemiplimab (7), atezolizumab (8), darvolumab (9) and avelumab (10) for numerous indications including melanoma, lung cancer (small and non-small cell types), bladder cancer, Hodgkin's disease and others (5–10). Other co-inhibitory molecules under research include T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) (11), Lymphocyte activation gene-3 (LAG-3) (12), V-domain Ig-containing Suppressor of T cell Activation (VISTA) (13), and B- and T-lymphocyte attenuator (BTLA) (14). Treatment with antibodies inhi biting immune checkpoints are well-tolerated by the vast majority of patients and are less toxic compared to standard anticancer chemotherapy agents. These immune side-effects are referred to as immune-related adverse events (IrAE) (15). These toxicities include fatigue, dermatological, gastrointestinal, hepatic, pulmonary, endocrine, ocular, neurological, and rare toxicities such as diabetes, cardiac and hematological. Dermatological toxicities can appear following the first dose of an immune checkpoint inhibitor and can be ongoing. These rashes are frequently maculopapular and mild in nature (16). Rash, and generalized pruritus occur more commonly with CTLA-4 inhibitors compared to anti-PD-1 inhibitors (17). Rare cases of serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported (18). The development of vitiligo occurs in a small percentage of patients receiving immunotherapy with checkpoint inhibitors and is associated with long term survival and clinical benefit (19). Gastrointestinal side effects can occur in the form of mucositis, aphthous ulcers, gastritis, colitis, and abdominal pain. Diarrhea, with blood or mucus in the stool, can be observed. In severe cases, these complications can evolve to toxic megacolon and perforation and must be ruled out in patients with peritonitis symptoms (20). Other infectious causes of diarrhea such as Clostridium difficile infection can be associated in severe cases (20). Immune-related pneumonitis is a serious IrAE reported in patients undergoing immune checkpoint inhibition. Pneumonitis is more common with PD-1 and PDL-1 blockers, however the incidence is < 1% and presents later during the treatment phase (21). Patients undergoing immunotherapy, experiencing new symptoms of dyspnea or cough, should alert the clinician. This complication could be fatal (21). Endocrine IrAE symptoms are generally non-specific and include fatigue, mental state changes, headaches and dizziness related to hypotension (22). Hypophysitis and hypothyroidism are the most common abnormalities documented (22). Clinicians should screen for thyroid abnormalities and baseline thyroid function tests. Other hormone assays may be indicated in some patients. Ophthalmological IrAE in the form of mild, moderate or severe episcleritis, uveitis or conjunctivitis has been described (23). Neurological IrAE includes posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis, and Guillain-Barre syndrome (24). Less frequent IrAE's include red cell aplasia (25), neutropenia (25), acquired hemophilia A (25), thrombocytopenia (25), hemolytic-uremic syndrome (25), pancreatitis (26), asymptomatic raise in amylase and lipase (26), renal insufficiency with nephritis (27), arthritis (28), and myocarditis (Tajiri and Ieda). Contributors to this research topic in Frontiers in Pharmacology and Frontiers in Oncology describe the importance of understanding this new class of drugs and their unique toxicities. Other areas covered include a description the current understanding of the basic mechanism of immune dysregulation in cancer patients undergoing immune checkpoint inhibitor treatment as well as potential predictive strategies for future clinical practice (Anderson and Rapoport). A second manuscript describes an unusual patient with persistent pruritus and lichenoid reaction secondary to anti-PD1 checkpoint inhibitor managed with narrowband ultraviolet B phototherapy (Donaldson et al.). A third manuscript explains the management of gastrointestinal toxicity with special reference to the immune homeostasis in the gastrointestinal tract (Dougan) and lastly a meta-analysis describing the relative risk and incidence of immune checkpoint inhibitor related pneumonitis in patients with advanced cancer (Ma et al.). It must be emphasized that IrAEs are usually low-grade and controllable; however, the reporting of these irAEs is generally suboptimal (29). Oncologists should be aware that there is a wide range of additional distinctive toxicities and side effects that can be unpredictable and severe in nature. As these agents will, in the future, be administered with targeted therapies, vaccines, chemotherapy or radiation therapy it is possible that the incidence and severity of these toxocities may change. The different mechanisms of action of anti-CTLA-4 and anti-PD-1/anti-PD-L1 antibodies resulted in the development of clinical studies investigating combination therapies in a variety of malignancies including metastatic renal cell cancer and metastatic malignant melanoma. The incidence of serious grade 3 and grade 4 adverse events due to the combination of ipilimumab and nivolumab were present in approximately half of patients. The incidence of these toxicities was significantly higher than either antibody administered separately resulting in treatment interruption in one-third of patients (30). Clinical recommendations for managing irAEs arise from general clinical consensus and experience, as there are no prospective trials to assess whether one treatment strategy is superior to another. Although controversial; there are reports suggesting that the development of irAEs is associated with improvement in survival in patients with advanced or recurrent malignancy treated with immune checkpoint inhibitors (31). Finally, early detection of IrAEs and proactive and adressive management by clinicians is critical to lower morbidity and mortality. The author confirms being the sole contributor of this work and has approved it for publication. MDS: Advisory Board and Speaker Engagements; BMS: Advisory Board and Speaker Engagements; AstraZeneca: Advisory Board and Speaker Engagements. 1. D'Arrigo P, Tufano M, Rea A, Vigorito V, Novizio N, Russo S, et al. Manipulation of the immune system for cancer defeat: a focus on the T cell inhibitory checkpoint molecules. Curr Med Chem. (2018). doi: 10.2174/0929867325666181106114421. [Epub ahead of print]. PubMed Abstract | CrossRef Full Text | Google Scholar 2. Ishida Y, Agata Y, Shibahara K, Honjo T. 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(2019) 2:479–85. doi: 10.1007/s00432-018-2805-3 CrossRef Full Text | Google Scholar Keywords: immune related adverse effects, colitis, pneumonitis, anti CTLA 4, anti-PD 1 Citation: Rapoport BL (2019) Editorial: Management of Immune-Related Adverse Events for Patients Undergoing Treatment With Checkpoint Inhibitors. Front. Oncol. 9:365. doi: 10.3389/fonc.2019.00365 Received: 28 February 2019; Accepted: 18 April 2019; Published: 08 May 2019. Edited and reviewed by: Copyright © 2019 Rapoport. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Bernardo Leon Rapoport, [email protected]
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