Antimicrobial resistance (AMR) is a global public health threat that warrants urgent attention. Countries developed their national action plans (NAPs) following the launch of the Global Action Plan on AMR in 2015. The development and implementation of NAPs are often complicated due to the multifaceted nature of AMR, and studies analyzing these aspects are lacking. We analyzed the development and implementation of the Philippine NAP on AMR with guidance from an AMR governance framework. We conducted in-depth interviews with 37 participants across the One Health spectrum. The interviews were transcribed verbatim and were analyzed thematically, adopting an interpretative approach. The enabling factors for NAP implementation include (1) a high level of governmental support and involvement of relevant stakeholders, (2) the development of policies to support improved responses in infection prevention and control and antimicrobial stewardship, and (3) better engagement and advocacy by professional associations and civil society groups. The challenges include (1) a lack of resources and regulatory capacity, (2) insufficient impetus for AMR research and surveillance, and (3) limited One Health engagement. Although there has been considerable progress for human health, strengthening the involvement and representation of the animal health and environment sectors in the AMR scene must be undertaken. Developing well-defined roles within policies will be paramount to the strong implementation of AMR strategies. In recent years, antimicrobial resistance (AMR) has emerged as one of the major global public health threats. Human activities have been shown to contribute to the evolution and spread of AMR in the environment . The misFurther, it is alarming that AMR is increasing when the development of novel antibiotics is slowing down. This poses a risky situation in which some infections could no longer be treated, leading to loss of life, especially in resource-limited countries . ConsequThe Philippines’ experience in addressing AMR started over three decades ago, as early as 1988, with the establishment of the Antimicrobial Resistance Surveillance Program (ARSP). This is a laboratory-based surveillance program that facilitates the consolidation of data from sentinel sites and prepares the national and sub-national AMR surveillance reports. Through the ARSP, the country provides annual surveillance reports on the existing patterns of AMR in the country to various agencies, particularly to the WHO’s Global Antimicrobial Surveillance System. There have been two NAPs on AMR (2015–2017 and 2019–2023) issued in the past decade.The 2015 NAP to Combat AMR was developed to provide the country strategies and aimed to control the emergence of AMR . It ensuChua et al. previously published an AMR governance framework after an analysis of ten AMR NAPs from the member states of the Association of Southeast Asian Nations (ASEAN) . This frThis is a qualitative study involving in-depth interviews (IDIs). Data collection, including recruitment and interviews, was conducted from October 2020 to May 2021. Potential participants were purposively sampled to capture a wide range of responses across the human health, animal health, and environmental sectors. These stakeholders were from the government sector , medical and veterinary health bodies, regulatory authorities, pharmaceutical industry, animal feed industry, environmental groups, and civil society groups. Participants were approached for an IDI via email and phone calls explaining the purpose of the research. The invitation was deemed as rejected if no response was received after two reminder emails. The research team reached out to 108 potential participants, and a total of 37 individuals agreed to participate . The majThe interviews were conducted by five researchers  who had prior qualitative research training. A total of 33 interviews were completed, with 37 respondents participating in the research. Two of the sessions had multiple respondents because they belonged to the same program or organization and opted to participate together. There was no prior engagement nor established relationship between the researchers and the interviewees. The interviews were conducted virtually over Zoom in view of the COVID-19 pandemic, with only the researcher and interviewee present. Each interview was one-off and lasted an hour on average. These were each audio-recorded and transcribed verbatim. A semi-structured question guide was used to explore our research aim based on participants’ areas of expertise and areas of interest. The question guide  was deveAll audio recordings were transcribed verbatim in English. Interviews that were not in English were translated from Filipino to English before transcription. Identifying data were removed from all research documents to maintain confidentiality. Each transcript was coded with an interview number and the relevant One Health sector so that extracts from the same individual can be linked. QSR NVivo software (Release 1.5.1) was used for data management and sharing among team members. We adopted an interpretative approach that focuses on participants’ perceptions and interpretations of the discussion topic. We used Chua’s AMR governance framework to deductively guide our coding process while allowing codes that did not fit into the framework to develop as emerging themes inductively. Coding was conducted in an iterative manner, where we performed line-by-line analysis, constantly reassessing documents coded initially and comparing emerging codes. The first round of coding was performed by at least two research associates (A.Q.C. and K.A.) independently, followed by a second round completed by M.M.M.L., E.A.R., S.Y.A.M.V., and K.A.V.R. All researchers agreed that we were able to provide a thorough analysis of all the themes identified. Thematic saturation was established when we identified ‘rich information’ in each of the themes and we discussed and agreed that no new themes were emerging from the data. Findings were reported according to the COREQ checklist .Ethical approval was obtained from the University of the Philippines Manila Research Ethics Board (UPMREB Code 2020-485-01) and the National University of Singapore, Saw Swee Hock School of Public Health Department Ethics Review Committee (SSHSPH-038). Our protocol adheres to the Data Privacy Act of 2012  and the National Ethical Guidelines for Health and Health-Related Research 2017  of the Philippines. All respondents were provided an information sheet and were asked to review and sign a consent form, or, if they are unable to provide a signed copy, to indicate their consent through email or before the interview process started. Consent was also obtained for audio-recording the session. Respondents were able to ask questions and express their concerns at any point during the interview. Each respondent kept a copy of both the information sheet and consent form for participation in the study. Identifying information was removed to ensure anonymity and confidentiality. In addition, confidentiality was ensured by giving each respondent the option of not being quoted, even anonymously, in the study and subsequent publications. All research-related files were password-protected and access was restricted to the research team.The findings are presented under five main themes in accordance with the five domains in Chua’s AMR governance framework: policy design, implementation tools, sustainability, monitoring and evaluation, and One Health engagement.The themes under the policy design domain included participation, accountability and coordination, strategic vision, transparency, and equity.The action against AMR was steered by an Inter-agency Committee on AMR (ICAMR) led by the Department of Health (DOH) and the Department of Agriculture (DA), which formulate policies on AMR and ensure and regulate access to quality and affordable antimicrobials . The memThe NAP was developed in consultation with stakeholders from the ICAMR and their attached agencies, as well as professional associations from the animal and human health sectors, representatives from academia, and, to a lesser extent, the pharmaceutical industry. These organizations were consulted regarding the plan and were invited to subsequent meetings. The stakeholders would also hold sectoral or similar meetings to discuss AMR. They would also coordinate with regulatory agencies, such as the Philippine Food and Drug Administration (FDA), regarding the implementation of rules and regulations. However, most respondents felt that more could be done to improve the engagement of the various stakeholders.“What needs to be improved is the active engagement of the other ICAMR agencies, and also to expand more, to engage more sectors to take part in AMR initiatives so that the Action Plan becomes more holistic.”In particular, most respondents from the environment sector said they were aware of some of the plans and programs but were not directly involved. However, the current work priorities of environmental science specialists did not necessarily connect with AMR policymaking. Several respondents perceived this as unintentional since the priorities of the environmental sciences were different, and they proposed solutions to improve their involvement:“What I see in my opinion, there is a little disconnect between the environmental sciences and the policymaking bodies about AMR. So, it is not intentional, but … since the priority of the environmental sciences is different… AMR seems to be masked by other priorities, and so if the policymaking bodies could also tap us in proposing projects that could also deal with the AMR, then I think our involvement will start there.”Given the scale of coordination work and resources required for the NAP, the proponents endeavored to have official government support in the form of an Administrative Order.“Our first target to produce, even before an action plan, was to have a policy, so that the policy signed by the Office of the President will make it easier for us to mobilize funds.”The ICAMR was the primary body for coordination and implementation. The secretariat was with the Pharmaceutical Division of the DOH. Some respondents also associated NAP accountability with the DOH due to its visibility compared to the DA. If certain agencies were unable to meet the targets, their representatives were requested to discuss their plans or proposals for resolving the gaps. In a devolved setting, the local implementation of AMR-related programs was bridged by sub-national offices of the respective government agencies to ensure that these efforts contribute to national targets. For example, the DA formed regional councils and technical working groups on AMR.“Definitely on their role, we meet the TWG , say DA. After that, we present the output to stakeholders through consultation meetings. There are other topics as well wherein even in the initial meetings the stakeholders were already there. We present the idea to them and (listen to) what they can say about their contribution.”From a One Health perspective, one pain point was the regulation of veterinary drugs and products that were mainly used by stakeholders governed by the DA. The regulation of these products, however, was being transferred to the FDA, which is an attached agency of the DOH. Coordinating the lines of regulation over products on the one hand and activities on the other would be a challenge, according to several respondents who were aware of the developments in this area. The Joint Administrative Order was readopted in 2020, which sets a transition period of six months for the transfer of the following functions to the FDA: the regulation of veterinary drugs and products, veterinary biological products, and establishments.“In some parts, from the BAI , they have, I would say, lower-level regulations. Because previously there was an MOU (Memorandum of Understanding)… regarding this regulation, and it expired. When it expired, there was some gap on how to implement.”Although relevant department orders have been issued, most respondents emphasized the need for intersectoral coordination to address inappropriate antibiotic use, along with other control measures.“…there are a lot of very good department orders that they have issued, both DOH and DA, but not sufficient emphasis was put up in terms of the coordination efforts, and addressing the misuse, the overuse, underuse of all these antibiotics plus all the other controls that must be addressed…”The fragmented nature of the Philippine health system, stemming from the devolution of health services to LGUs, presented challenges to both policymakers and implementers . In term“In this country, the main challenge is (that) it is fragmented… Another thing, the standard is rich LGUs, rich provinces, always have better quality than poor ones… now with antibiotic restriction, at the minimum, you need a doctor, so no doctor in an LGU means no antibiotic.”“I also think that greater emphasis should be given in coordination with the LGUs because both DA and DOH were devolved when the Local Government Code of 1991 was passed… I think the next thing that should happen is they should mobilize the LGUs, the civil societies.”A strategic vision through clearly defined goals and objectives is necessary for the development of effective plans. The NAP envisions “a nation protected against the threats of antimicrobial resistance” using “a multifaceted and holistic strategy to consolidate the fragmented efforts and systems in the country by enabling different stakeholders such as health professionals, policymakers, and other government systems to use it as a platform for national campaigns on prudent antibiotic use” ,16.In the latest NAP (2019–2023), the ICAMR aimed to maximize the One Health approach and further clarify and align the mandates, roles, and responsibilities of the member agencies. The body also emphasized the need to harmonize policies, protocols, and guidance, and to “continue capacity building, education, awareness and advocacy” . In part“I would say both sectors, the DOH and the Department of Agriculture. They agreed on how to set up the priorities for the year, (and) on what they will be working (on). And based on those agreed priorities, and based of course on the allocation of resources, I know both of them. They also get a special fund from the government to implement the National Action Plan, apart from the external donor support. They agree on these certain priority activities and agree to implement at the same time.”In animal health, there were four key areas, namely: (1) AMR and antimicrobial use (AMU) awareness, (2) surveillance, (3) governance, and (4) good practices. The Food and Agriculture Organization provides support to the DA in the development of AMR plans. The components of the plan in animal health were AMR surveillance in healthy food animals by the National Meat Inspection Service; pathogens in diseased animals, including livestock and poultry, by the Bureau of Animal Industry; and aquaculture and fisheries by the Bureau of Fisheries and Aquatic Resources.It was reported that the NAP development also planned for monitoring targets, which were mostly centered around the reduction in, or maintenance of, the prevalence of resistant organisms. Other targets included a reduction in the antibiotic use in humans and animals and identification of the baseline AMR and antibiotic use in animals .Among the ICAMR member agencies, there were discussions on the progress and milestones related to the strategies identified in the NAP. The Antimicrobial Resistance Surveillance Program (ARSP) has been consistent in publishing annual reports on AMR surveillance, while the DOH Pharmaceutical Division also provides progress on AMR through the agency’s annual report, all of which are publicly available.“There are published surveillance reports yearly… we come up with the annual report by May of the succeeding year, this is because… data would be in by January of the succeeding year, so we also need time for analysis, verify, and publish.”Some stakeholders expected greater transparency in the AMR policy process, with reports as one of the main outputs they would like to have access to. There were a number of reporting requirements for the national AMR Program, but not all reports are made publicly available. A few respondents, ranging from patient representatives to local implementers, mentioned that there was no feedback on the information requested from them. More importantly, most reported that they would like to have clarity on success indicators and how they, as stakeholders, can contribute. One participant from the environmental sector shared similar sentiments.“…hopefully on the policymakers’ end, we get updates or we get the latest information on what is the status already, and then what do we have to watch out for?…What are the indicators of success? Again, it has not been disclosed to us or shared with us.”Similarly, it was reported that the lack of auditing impacts the management and quality of information.“There is no audit… The reporting side is very poor. In fact, if it were not made into a rule that it could be punishable, the reportable diseases, there would be no one to report. There is also no one to audit. So if there’s no report and there’s no audit, how do you get the information? This is one of the big gaps.”Most stakeholders held the view that one of the AMR interventions should be to help to promote access to healthcare as this means access to services and products, including safe, quality, and effective antimicrobials. In some barangays or rural health units, it was reported that there are efforts to implement the Botika ng Barangay, literally “village drugstore”, which was a strategy that expanded access to essential drugs based on current standards and regulations.“One thing that’s very clear with us is that the public health interventions that we want to put in terms of AMR, we don’t want them ultimately to become anti-access.”In the human health sector, the most mentioned focus was on understanding the perspectives of patients, consumer groups, and civil society because these things affected access and the quality of health services. The Joint Administrative Order issued by the DA and the FDA was among the initiatives helping to improve access to healthcare products and services. The FDA was tasked with issuing marketing authorizations and licenses to operate and sell antimicrobials for human and veterinary use.The themes under the implementation tools domain included surveillance, infection prevention and control (IPC), optimizing AMU, AMR research, education and public awareness, and international collaboration.AMR surveillance was led by the Research Institute for Tropical Medicine (RITM) and was limited to selected tertiary hospitals and laboratories that conduct sentinel surveillance. Based on a respondent from the government, lower-level hospitals could only collect and transport specimens of suspected cases to these sentinel sites.A respondent reported that the surveillance activities for animals were irregular and usually only conducted upon request. A few respondents also noted that there were reporting delays.“You can have more data in humans but there is still a vacuum or limited data for animals. If we see humans, animals and then (the) environment. Because we don’t see that.”The Bureau of Animal Industry has been mobilized to develop their existing surveillance for AMR in animals, led by an AMR team within the bureau. Three components have been identified by the participants for AMR surveillance in animals, which entail collaboration and coordination among multiple agencies. The National Meat Inspection Service, the Bureau of Animal Industry, and the Bureau of Fisheries and Aquatic Resources were involved in the sampling of (1) food animals, (2) diseased animals, and (3) fish and seafood, respectively. The residues in pork and beef were reportedly being monitored in partnership with academic institutions.According to a few respondents, there were no mechanisms in place for the environmental monitoring of AMR. Only a few laboratories had the capacity for these surveillance activities, with the data primarily generated by research groups. Additionally, in the animal and environmental health sectors, several standards and guidelines were still being reviewed or not firmly in place even if surveillance is being conducted. For example, as the next quote illustrates:“Environmental health per se and surveillance, it’s not yet established… there’s still so much to do. There’s still no standards, so how would you say that the water is safe? Let’s say you were able to identify residues, what are the safety levels? We still do not have that.”AMU surveillance has been reported to be lacking as well. A few participants mentioned that, in hospital settings, there was no system in place to support the monitoring, evaluation, and regulation of antibiotics that were subsidized by PhilHealth . The NatIn 2009, the DOH published the National Standards in Infection Control for Healthcare Facilities to strengthen the IPC programs nationwide and prevent healthcare-associated infections. In 2016, priority strategies were defined in the national policy on IPC in healthcare facilities, including the institutionalization of an antimicrobial stewardship (AMS) program . The InfThe Infection Control Committee is composed of “management, physicians, and other healthcare workers from clinical microbiology, pharmacy, sterilizing service, housekeeping, and training services” . IPC traVaccination of patients and healthcare workers has been cited by some respondents as an essential strategy against infections. Vaccines were procured by the National Health Department at the centralized level and distributed to the sub-national offices. As part of the National Immunization Program, it was mentioned that primary vaccines were given to vulnerable populations. In addition, healthcare workers might be provided with free vaccines from their respective institutions. In the following quote, an interviewee from an International Non-governmental Organization highlights the importance of “up-to-date vaccination” in reducing the incidence of infection:“Reducing the incidence of infection is the third key strategic objective of the Global Action Plan, which is also adopted in the National Action Plan. When we talk about reducing the incidence of infection, that’s where vaccination comes in, keeping vaccinations up-to-date, and infection prevention and control measures.”Meanwhile, several participants highlighted that good housing and engineering in farms were promoted to prevent infections among farm animals, such as poultry or pigs. However, a respondent involved in animal production said that vaccination in food animals usually depends on client requirements:“… my concern was the advent of several diseases which we cannot identify, many of them among our farms and the level of mortality was high. So we asked them, the hatchery practitioners, what vaccines do you use? When do you use the vaccines in your hatchery? I will tell you, their answers varied. Like, it depends on what their client wants.”Several respondents held the view that the government should strengthen the monitoring of IPC measures. Although there is a national plan for infection control and education, most respondents believe that hospitals must be made more accountable as there were a scarcity of data on healthcare-associated infections.Optimizing AMU involves the implementation of AMS strategies and regulations to ensure reductions in inappropriate AMU.With the support of the World Health Organization (WHO), the Philippines became one of the pilot sites for the implementation of the AMS program in hospitals. According to the ICAMR, this program has been considered for adoption in other countries .The AMS program was developed to “strengthen the knowledge, attitude and practices of involved stakeholders on rational prescribing, dispensing and use of antimicrobials; and, to improve patient outcomes by decreasing infections caused by resistant organisms” . SpecifiMost respondents had a favorable view of AMS, especially at the primary care level as it helps to ensure access to the appropriate drugs. If AMS was strictly followed, then there should be no problems with misuse, according to several respondents.As a participant emphasized, the success of AMS implementation also relied on the ability to train all health professionals and all stakeholders in both public and government health institutions.“The implementation’s goal really is to be able to train all health professionals and all stakeholders in both public and government health institutions, so that is the main goal, that all of us will be together in fulfilling and achieving AMS.”Although tertiary hospitals had personnel trained regarding AMS, it was mentioned that there was a lack of infectious disease doctors and clinical pharmacists in most hospitals, which raises the question of how these facilities approve restrictions and monitor AMS.On the regulation front, several respondents discussed how the “no prescription, no dispensing” policy (Republic Act 10918) enabled the FDA to issue a notice of violation to pharmacies that sell antimicrobials without a prescription. In the next quote, a participant believes that the DOH “no prescription, no dispensing” policy improved the dispensing of antibiotics:“In terms of preventing the misuse or overuse of antimicrobials, I would say the no prescription, no dispensing policy of the DOH somehow made a dent and improved the dispensing of antibiotics.”However, some also mentioned that patients were still able to buy antibiotics from “sari-sari” stores  or obtain them from LGUs. For over-the-counter medicines, these stores were also required to apply for authorization from the FDA. In addition, it was reported that the “no prescription, no antibiotic” policy was not effectively implemented in the animal and agriculture sectors. The over-the-counter sale of antibiotics remains, according to our interviewees, one of the biggest issues in AMR for the animal health sector.In terms of completing antibiotic therapy, some participants mentioned there were cases in which patients discontinued their antibiotic regimen once they felt better in order to save money. Some respondents added that the Philippine Health Insurance Corporation  should reimburse drugs, including selected and restricted antimicrobials, under the National Formulary, but they were unsure about the stage of implementation.In terms of research focused on AMR, it was reported that the funders are mostly from advanced economies, particularly in environmental health. Programs such as veterinary medicine also collaborate with institutions abroad, but these opportunities have reportedly been infrequent. One participant mentioned that the situation was such that basic data on AMR and relevant indicators were not readily available or monitored, making it difficult to generate complementary research data using techniques such as genomic sequencing.“I would like to have the data to see. You are going to base your data on WASH, but do we have the WASH data? How many wastewater treatment plants can we really survey? Do municipalities actually use wastewater treatment plants? Are wastewater systems integrated? So, even the basic stuff, we still don’t have data for them, that’s why I am thinking that this will take a long time because if we don’t have the data for basic sanitation how can we get a higher-level genomic sequencing for these data sets.”Most stakeholders reported that education and public awareness on AMR still needed substantial improvement in several areas, such as the proper use of antibiotics. However, campaigns such as the annual World Antimicrobial Awareness Week and its national counterpart, the Philippine Antimicrobial Awareness Week, had reportedly been instrumental in disseminating information on AMR, broadening awareness and support for the national and global AMR campaign. An example provided was the campaign on the “no prescription, no dispensing policy”.The respondents cited that other platforms being used for raising awareness and information dissemination include social media, webinars, conferences, and learning modules. Some awareness initiatives were conducted through social media platforms  and student competitions, such as poster-making contests. Social media was viewed favorably, largely because it appealed to the younger generation.“becauseits  reach is wide, it gets a lot of traction also for the younger people”Some participants mentioned that there was growing support for AMS in the form of professional development programs for community and hospital pharmacists. Online training sessions are regularly conducted for physicians, including infectious disease specialists, residents, and general practitioners, on the proper prescription of antimicrobials. It was mentioned that some training opportunities, including those on AMR and AMS, were supported by drug companies.“… drug companies still have quite a lot of influence… There are a lot of so-called interventions in terms of educational activities, but many of them are sponsored by drug companies”Some interviewees mentioned that there were efforts to broaden the geographic scope of training, with some provided by sub-national hospitals in the hope that they would cascade and equip other facilities and stakeholders in the region.Several respondents said that, in general, it was more challenging for the animal sector because of the complexity and scope of issues involved. Professionals in the veterinary sector said they recognized their role as educators. The animal producers supported the AMR advocacy because they understood that the issue affected their bottom line.“You will hear from them, the backyard raisers, that regulation is difficult in the animal health sector. I think in terms of awareness-raising, they are the ones that are still not being reached.”A respondent pointed out the impact of limited information and engagement with related businesses in the animal sector, which was a major source of environmental contamination. The next quote highlights the need for education versus just having a punitive approach:“We really need proper education. Let us make it easier for them [animal producers]. It cannot be all regulation then pay the penalties. You have not even started your business [but] you are already at a loss. And everything is costly.”Some respondents reported that AMR was still not a core subject in environmental science programs. A respondent explained that the closest topics were water quality modeling and hydrology, which also tackle bacteria in water. Overall, as the next quote illustrates, there is a perception that there is still not an in-depth understanding of environmental AMR:“In-depth understanding on environmental AMR is not there yet.”From an AMR governance perspective, the Philippines was described by a respondent as a showcase country at the regional and global levels. The country’s efforts on the ICAMR and on the environmental health agenda were viewed as instrumental in generating funding support. In fact, the ARSP at RITM was one of the earliest programs on surveillance for AMR. To support this area, a respondent said there was a need to:“Understand our current surveillance systems in terms of resistance and antibiotic use, and how we can then build on the current system”Several respondents identified international donors as the biggest funding source of the national AMR program, especially during its formative years. The country situation analysis and AMS training package were among the first initiatives with global partners. As a development partner, a few respondents reported that the WHO provides some funding support for the AMR program, primarily to establish guidelines, such as the AMS guidelines for hospitals and guidelines for primary healthcare.“We have a lot of technical support coming from the tripartite. So it is just a matter of agencies having a serious commitment to implement.”In providing the needed financial resources , it was mentioned that the development partners made it possible for the program to gain momentum despite resource constraints. In addition, the country’s AMR awareness campaign was reportedly based on the annual World Antimicrobial Awareness Week held every second week of November, which carries the WHO theme. While several respondents noted that there was some government funding for this activity through the ICAMR, it was reported that the investment from each sector remains minimal.Monitoring and evaluation involve reviewing the effectiveness of implementation plans, reporting them to relevant stakeholders, and developing feedback mechanisms for future improvements.At the point of writing, surveillance was largely on the monitoring targets defined in the NAP . For hum“So I would say that it’s a continuous engagement to implement by the government. In terms of accountability, if they could not comply or achieve what is in the NAP, what would happen? So it’s being reported, that’s it.”Staphylococcus aureus were on the decline. Multidrug-resistant Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii, and Pseudomonas aeruginosa persisted, while penicillin resistance in Streptococcus pneumoniae was increasing.Based on the RITM 2020 Annual Report, there were fewer isolates reported by bacteriology laboratories compared to 2019. The data showed that vancomycin and linezolid resistance continue to be reported for enterococci, and the rates of methicillin resistance in Prior to the COVID-19 pandemic, the participants mentioned regular monitoring meetings at the ICAMR level involving the government, the industry, the producers, the academia, the research groups, and other stakeholders. This provided a platform for evaluation and feedback, which informed areas for improvement in policy and program implementation. The next quote illustrates how meetings are organized:“Normally what we do is, there’s an agenda. There’s a presentation of where we are in terms of the objectives and mission of the NAP. Where we are, then we try to ask from the sectors the constraints and problems they have been encountering regarding AMR.”Outside of the national government, a few respondents reported that, although data collection is conducted at the hospital level and supervised by the sub-national health office, there was no feedback provided to sub-national offices apart from the publication of the results in an annual report.Sustainability was an issue viewed with both concern and optimism. Some stakeholders argued that sustainability was possible with more awareness, better regulatory oversight, as well as a level of behavior change among the population, but others viewed it as a major setback, with AMR being less prominent in a health system struggling to address the COVID-19 pandemic. It was suggested that a review of the global strategy presents an opportunity to recalibrate and build on the initial successes and momentum of the national plan and program. A respondent cited that good health outcomes of constituents were a major driver for political will.“So, nobody will not follow because all these local officials, you know what’s important for them—they want to win the elections. So if you won’t take good care of the health of your people, then you will not win.”Similar to other program activities, funding for AMR remained a significant challenge. Despite their limited funding streams, ICAMR agencies strived to allocate budgets for their AMR activities. Several respondents observed that the roles and impacts of the animal and environmental health sectors on the issue of AMR were not the main focus of decision-makers, contributing to the continued neglect and underdevelopment of this component of the AMR program.With a few exceptions, the stakeholders were aware of the One Health approach and its importance in addressing AMR. They mentioned that it was fundamentally about collaboration and involvement within and outside the three sectors. Several respondents observed that this concept seems to resonate strongly with practitioners, some of whom belong to the Philippine One Health Network. Others pointed out that the human and animal sectors appear to be doing better at integration, even if One Health was not as prominent in the discourse or practice of healthcare professionals. The environment sector, however, was missing from the equation. This seeming detachment was a common observation from the respondents in other sectors working on AMR.“For the animals and humans, the integration is good. I see some positive signs in terms of integrating humans and animals, but the environment side is detached, it is not yet fully integrated.”This study has detailed the development and implementation of the NAP on AMR in the Philippines following an AMR governance framework. Our respondents highlighted areas that have been executed well, including (1) a high level of governmental support and involvement of relevant stakeholders, (2) the development of policies to support improved responses in infection prevention and control (IPC) and antimicrobial stewardship (AMS), and (3) better engagement and advocacy by professional associations and civil society groups. However, there were some areas that were lacking and could be further improved. These included (1) a lack of resources and regulatory capacity, (2) insufficient impetus for AMR research and surveillance, and (3) limited One Health engagement.A high level of governmental support and the involvement of relevant stakeholders provided an enabling environment for AMR policies. Technical assistance and funding from the tripartite, particularly in the initial phases of research and policy development, strengthened the evidence base and capacity for improved AMR responses at the national level . A countThe study respondents have noted that, over the years, there were improved responses in the areas of IPC and AMS in human health, mainly because of enabling policies that institutionalized these activities in the hospitals. Part of the response to improve IPC involves the establishment of the Infection Control Committee, which was composed of management staff, physicians, and other healthcare workers from clinical microbiology, pharmacy, sterilizing service, housekeeping, and training services. This multidisciplinary committee ensured the implementation of infection control strategies by formulating and updating infection control policies, guidelines, and procedures. The National Standards in Infection Control for Healthcare Facilities were published in 2009 to strengthen the IPC programs nationwide and prevent healthcare-associated infections, highlighting criteria, including IPC training and related indicators, as part of the hospital licensing requirements. In animal health, the harmonization of IPC standards and practices was being pursued at the ASEAN level. The AMS activities started in the Philippines with support from the WHO. This was subsequently expanded to the national level with the launch of the national AMS program in 2015 ,26.Better engagement and advocacy by professional associations and civil society groups have been highlighted as factors that are relevant to increased efforts regarding education and public awareness, as well as the optimization of antimicrobial usage. Our respondents reported that various medical practitioners, academic institutions, and patient groups are doing their part in curbing AMR either by their own initiatives or participating in ICAMR-led awareness efforts. For instance, AMR has been included in continuing professional development programs among professional societies, and pharmacists and drug stores have been ensuring the implementation of the FDA policy of “no prescription, no dispensing” for antimicrobials and the Philippine Pharmacy Act (Republic Act No. 10918). The increased level of engagement was also observed in the animal health sector, as is evident in the “IAMResponsible” campaign for the animal and agricultural sector, specifically targeting veterinarians, farmers, students, and the general public. This finding is similar across other ASEAN countries and could likely be attributed to the increased awareness and advocacy at the global level through international initiations, such as the WHO’s World Antimicrobial Awareness Week in November annually ,27. HoweThe respondents highlighted that there was a lack of resources and capacity, which could have impeded the progress of implementation plans. Although more emphasis has been placed on AMR recently, it was still reported to be low on the hierarchy when benchmarked against other issues at the national level. For example, at the DA, funding was mostly for crops, such as rice and corn, and animals accounted for a small proportion of the funds. In the Inter-agency Committee on Environmental Health, in which the DOH and the Department of Environment and Natural Resources were represented, there is no mention of AMR in the main policy areas. A study suggested that, although external funding support from international organizations helped initiate some of the plans, sustainability was largely dependent on internal government funding and sustained support from policymakers . BesidesThe research and surveillance on AMR could be improved in the Philippines. Our respondents highlighted that, overall, there were very few specialists and researchers focusing on AMR. In addition, although there was research funding available from agencies, such as the Department of Science and Technology, the funding allocation for research was largely based on approved research grants that were subject to competition from other non-AMR topics. Other studies have also reported a lack of adequate capacity to support research and development in similar settings ,30. BesiFinally, although One Health engagement has been mentioned, the respondents felt that it was limited. Apart from the work of the ICAMR, the One Health approach was not fully realized in the agency-led programs and coordination mechanisms. The interventions and resources remain sector-specific rather than integrated or multisectoral in implementation. This could be due to a varied representation and involvement in AMR across sectors. Specifically, the human health sector was relatively more established as compared to the animal health and environmental sectors. The respondents highlighted two possible reasons for this: (1) incomplete and insufficiently well-defined roles of different stakeholders in the NAP, and (2) differences in priorities for AMR among the various sectors. Cross-sectoral coordination has been highlighted to be difficult in other countries due to fragmented and inflexible structures for bridging sectors ,32,33. IBased on our study results, recommendations from our respondents, and findings from international literature, we came up with a package of policy recommendations in To our knowledge, this is one of the first studies to explore the development and implementation of the AMR NAP in the Philippines. We utilized Chua’s AMR governance framework to guide our analysis, which allowed us to review our data in a structured manner. We were able to recruit and gather the perspectives of multiple stakeholders from the human health, animal health, and environmental sectors. There were some limitations. Firstly, the online interviews conducted due to COVID-19 restrictions could have constrained personal interactions, often crucial in maximizing the value of interviews. For sampling, even with due diligence to ensure that the respondent is the best authority to represent a perspective or opinion, the extent of their actual involvement in the policy process of developing and implementing the NAP on AMR is beyond our control. The representation from the animal health and environment sectors was much less compared to that from the human health sector. However, this was expected given that the DOH was much more involved and invested compared to the other agencies.The magnitude of the AMR problem has prompted a high-level response from the national government and led to the creation of the ICAMR. Although there has been considerable progress for human health, strengthening the involvement and representation of the animal health and environment sectors in the AMR scene must be undertaken. The development of well-defined roles within policies will be paramount to the strong implementation of strategies to combat AMR. The enhancement of IPC strategies, surveillance and research capacities, AMS, and education and awareness campaigns across all three sectors will contribute to establishing a robust and comprehensive AMR program in the Philippines.


It has been reported that polysaccharides in wine can interact with tannins and other wine components and modify the sensory properties of the wine. Unfortunately, the contribution of polysaccharides to wine quality is poorly understood, mainly due to their complicated structure and varied composition. In addition, the composition and molecular structure of polysaccharides in different wines can vary greatly. In this study, the polysaccharides were isolated from pinot noir wine, then separated into high-molecular-weight (PNWP-H) and low-molecular-weight (PNWP-L) fractions using membrane-based ultrafiltration. Each polysaccharide fraction was further studied using size exclusion chromatography, UV–Vis, FT-IR, matrix-assisted laser desorption/ionization–high-resolution mass spectrometry, and gas chromatography-mass spectrometry (GC-MS). The results showed that PNWP-L and PNWP-H had different chemical properties and compositions. The FT-IR analysis showed that PNWPs were acidic polysaccharides with α- and β-type glycosidic linkages. PNWP-L and PNWP-H had different α- and β-type glycosidic linkage structures. FT-IR showed stronger antisymmetric and symmetric stretching vibrations of carboxylate anions of uronic acids in PNWP-L, suggesting more uronic acid in PNWP-L. The size exclusion chromatography results showed that over 72% of the PNWP-H fraction had molecular sizes from 25 kDa to 670 kDa. Only a small percentage of smaller molecular polysaccharides was found in the PNWP-H fraction. In comparison, all of the polysaccharides in the PNWP-L fraction were below 25 KDa, with a majority distributed approximately 6 kDa (95.1%). GC-MS sugar composition analysis showed that PNWP-L was mainly composed of galacturonic acid, rhamnose, galactose, and arabinose, while PNWP-H was mainly composed of mannose, arabinose, and galactose. The molecular size distribution and sugar composition analysis suggested that the PNWP-L primarily consisted of rhamnogalacturonans and polysaccharides rich in arabinose and galactose (PRAG). In comparison, PNWP-H were mostly mannoproteins and polysaccharides rich in arabinose and galactose (PRAG). Further research is needed to understand the impacts of these fractions on wine organoleptic properties. Many consumers much appreciate wine due to its organoleptic properties . In addiViticulture and enology practices can affect wine polysaccharide composition and characteristic profiles. It has been reported that grape maturity could influence the contents of PRAG, mannoproteins, and rhamnogalacturonans II in the wine ,14. ApolThe mannoproteins are derived from yeast during fermentation, whereas the arabinogalactan proteins and rhamnogalacturonans-II are derived from grapes. The distribution of the yeast-derived polysaccharides and grape-derived polysaccharides is dynamic during the maceration, fermentation, and aging processes. The grape-derived arabinogalactan proteins are the predominant polysaccharides in young wines, whereas the yeast-derived mannoproteins are the primary type in aged wines. Furthermore, the high molecular weight of mannoproteins and arabinogalactan proteins can precipitate during maturation, further complicating polysaccharide composition . All aspAlthough significant progress has been made in recent years on wine polysaccharides, the chemical structures, composition, and properties of polysaccharides in different wines are largely unexplored. Wine polysaccharide characterization is a challenging field that needs to be explored to better understand the organoleptic functions of the wines. Hence, the scope of this study is to isolate polysaccharides from pinot noir wine and fractionate them based on molecular size using ultrafiltration, analyze their composition by measuring α- and ß-/furanosides and pyranosides derivative of each fractionation, and characterize each fraction using size-exclusion chromatography, UV–Vis, FT-IR, and matrix-assisted laser desorption/ionization–high-resolution mass spectrometry.The polysaccharides (PNWPs) from pinot noir wine were concentrated using a membrane ultrafiltration technique. A 2 kDa membrane was successful in retaining the polysaccharides. A 100 kDa membrane could further fractionate the polysaccharides into low molecular weight (PNWP-L) and high molecular weight (PNWP-H) fractions. Next, ethanol was added to carefully precipitate the polysaccharides while leaving other impurities in the solution. The polysaccharides were first washed with 80% ethanol, followed by 100% ethanol until the supernatant was colorless. The process yielded 0.8 g PNWPs from 500 mL wines.The yields and impurity analysis of PNWPs are shown in The UV-Vis spectra of PNWPs are shown in −1 corresponded to the stretching vibration of the O-H, and the small bands near 2931 cm−1 represented the asymmetric vibration of C-H of polysaccharides [−1 was derived from the C=O stretching vibration of the carbonyl group of the esters [−1 and 1418 cm−1 were associated with the antisymmetric and symmetric stretching vibrations of carboxylate anions (COO-) of uronic acids [−1 to 1200 cm−1 than the PNWP-L. This wavelength region was associated with the stretching vibration of C-O-H (ring vibrations) and C-O-C (glycosidic bond), indicating different types of pyranose/furanose rings [FT-IR is an essential analytical technique for carbohydrate analysis, allowing for the rapid and non-destructive evaluation of structural information of wine polysaccharides . The chacharides . The smae esters . Two intic acids ,26,27, ase rings ,29.−1 could be attributed to the β-type glycosidic linkages [−1 was likely related to α-type glycosidic linkages [Moreover, the absorption at approximately 891 cmlinkages , and thelinkages . The FT-linkages . The abslinkages .Polysaccharide molecular sizes directly affect their physical properties. The molecular size of polysaccharides is typically measured by high-resolution size-exclusion chromatography with a refractive index detector using a standard curve  or multiMultiple molecular weight determination methods were carried out in this study. In addition to the traditional SEC, MALDI-TOF analysis was also investigated. Compared to traditional SEC, MALDI-TOF analysis is a more advanced and accurate technique to determine the molecular weight of biological macromolecules, including low molecular weight polysaccharides. The MALDI-TOF spectrum of the PNWP-L is shown in Monosaccharide profiling is critical to understanding the structure of wine polysaccharides. Typically, the wines are concentrated, and the small molecular weight compounds in the samples are removed by dialysis ,36,37,38O-(trimethylsilyl)-galactofuranoside, α-methyl 2,3,4,6-tetrakis-O-(trimethylsilyl)-galactopyranoside, ß-methyl 2,3,5,6-tetrakis-O-(trimethylsilyl)-galactofuranoside, ß-methyl 2,3,4,6-tetrakis-O-(trimethylsilyl)-galactopyranoside, α-methyl 2,3,4,6-tetrakis-O-(trimethylsilyl)-glucopyranoside, and ß-methyl 2,3,4,6-tetrakis-O-(trimethylsilyl)-glucopyranoside, respectively. The two distinct peaks (peak numbers 7–8) shown at 40–45 min were lactose-TMSs when the methanolysis conditions were carried out at lower temperatures or shorter times.Lactose was selected for the methanolysis optimization study. The effect of temperature  and time  on methanolysis for lactose were studied. Representative chromatograms under different methanolysis conditions are shown in As illustrated in The GC-MS chromatograms of PNWPs clearly illustrated the compositional differences between the PNWP-H and PNWP-L . As showThe Ara/Gal ratio was the feature of PRAG-related structures, and the value was related to the pectin hairy regions, and a higher value indicated a more pectin-related structure. The P-L had a total Ara content of 5.4%, and a total Gal content of approximately 7.0%. In comparison, the PNWP-H had a total Ara content of 30.4% and a total Gal content of approximately 33.0%. The Ara/Gal ratio for the PNWP-H was bigger than that of the PNWP-L, suggesting the PNWP-H had a more pectin-related structure. The Rha/GalA ratio was related to rhamnogalacturonan and homogalacturonans-related structures . This raA higher percentage of galacturonic acid, rhamnose, galactose, and arabinose was found in the PNWP-L, suggesting the fraction mainly consisted of rhamnogalacturonans and PRAG. While the PNWP-H mainly contained mannose, arabinose, and galactose, suggesting it primarily consisted of mannoproteins and PRAG. The results demonstrated the polysaccharide compositions in wine were diverse and were derived from both grapes and wine. More research is needed to understand how the wine polysaccharide composition is related to grape varieties, enology practices, and maturation.The complete elucidation of the wine polysaccharide structure is beyond the scope of this exploratory study. Detailed NMR experiments and branching analysis are underway to obtain more structural information and molecular characteristics.Pinot noir wines produced at Oregon State University Research Winery were used for wine polysaccharide isolation. All chemicals were of analytical grade unless otherwise specified. Ethanol  was purchased from Pharmco . Acetyl chloride (≥99%), D-glucose (99%), D-galacturonic acid monohydrate (97%), L-arabinose (99%), L-fucose (99%), and L-rhamnose (99%) were purchased from Alfa Aesar . Dextran standards, myo-inositol (≥99%), lactose (≥99%), and D-galactose (≥99%) were purchased from Sigma-Aldrich . N-trimethylsilylimidazole (>98%) was bought from TCI Chemicals , ammonium formate (99%) was obtained from BeanTown Chemical , and D-glucuronic acid (≥98%) was purchased from ICN Biomedicals . Methanol , pyridine , D-mannose (≥99%), and D-xylose (≥99%) were obtained from Acros Organics .PNWPs were extracted using a previously reported method with minor modifications  36,43,4,443,44. Protein content was measured by the Bradford method with bovine serum albumin as a reference material . The totPNWPs were dissolved in Milli-Q water to a suitable concentration (0.1 mg/mL) and filled in a quartz cuvette. The ultraviolet spectrum of the PNWPs was scanned from 190 to 600 nm using a UV–visible spectrophotometer . Water was used as blank according to the method described previously with minor modifications .−1 and 16 scans per spectrum in the 4000–600 cm−1 infrared region at room temperature. The background spectrum was collected in the air before each sample was measured. The sampling stage was cleaned with isopropanol after each measurement to avoid cross-contamination. The prominent absorption peaks of obtained results were performed using OMNIC 32 software and plotted as transmittance (%) vs. wave numbers (cm−1).The IR spectra of the PNWPs were obtained using an FT-IR spectrophotometer  coupled with an Attenuated Total Reflectance sampling accessory (Smart iTR with diamond plate) with minor modifications . The FTIMolecular weight distribution was measured by high-performance size-exclusion chromatography with some modifications ,49. A SuA small amount (1 mg) of the PNWP-L was mixed with 10 μL of 2,5-dihydroxybenzoic acid (DHB) matrix (50 mg/mL of DHB in 50% methanol and 0.1% TFA). The spectrum was recorded in an Ultraflex  using negative and positive ion modes. Raw data were processed using DataAnalysis V4.1 .The methanlysis and derivatization optimization and gas chromatography-mass spectrometry (GC-MS) were performed according to previous methods with some modifications ,51,52. LThe monosaccharide composition of the PNWPs was determined by gas chromatography-mass spectrometry (GC-MS) using the optimized methanolysis and derivatization parameters. For the sugar composition analysis, about 0.7 mg of the PNWPs were dissolved in 0.5 mL 0.5 M dry HCl-methanol (acetyl chloride in dried methanol), and the methanolysis was performed at 85 °C for 18 h. After cooling to room temperature, the solution was mixed with 0.2 mL internal standard solution (0.1 mg/mL of myo-inositol in pyridine). The mixed solution was evaporated to dryness under a nitrogen gas flow. Finally, the residue was mixed with 0.1 mL N-trimethylsilylimidazole (TMSI) and incubated at 80 °C for 30 min. The final solution was analyzed by GC-MS on an Agilent 6890N-5973 system  equipped with an HP-5MS column . The GC-MS program conditions were as follows: inlet temperature, 270 °C; hydrogen flow, 1.5 mL/min; split ratio: 10:1; the oven program . MS transfer line and ion source temperatures were 280 and 230 °C, respectively. Electron ionization mass spectrometric data from m/z 50 to 350 were collected with an ionization voltage of 70 eV.The hybrid standard monosaccharides  were derivatized and analyzed under the same conditions described previously. Identification was achieved with the standard compounds and with the NIST library (Rev. D05.01). The calculation was processed using ChemStation software .t-test were performed by SPSS statistics 20 software; p < 0.05 was considered significant.The results were exhibited as mean ± standard deviation (SD) in triplicate (n = 3). Duncan’s test and an independent sample In this study, two fractions of wine polysaccharides were isolated by ultrafiltration technology. FT-IR results showed that the PNWPs were acidic polysaccharides with α- and β-type glycosidic linkages. GC-MS analysis revealed the PNWP-L was mainly composed of α-galactofuranosiduronic acid, α-galactopyranosiduronic acid, α-mannopyranoside, α-rhamnopyranoside, ß-galactofuranosiduronic acid, α-glucopyranoside, and ß-galactopyranosiduronic acid. In comparison, the PNWP-H was mainly composed of α-mannopyranoside, α-galactopyranoside, α-arabinopyranoside, α-arabinofuranoside, ß-galactopyranoside, α-rhamnopyranoside, and ß-arabinopyranoside. Moreover, relatively more glucuronic acid in the PNWP-L was found. The compositional analysis and molecular weight characterization showed that the low molecular weight polysaccharides in pinot noir wine were mainly rhamnogalacturonans and polysaccharides rich in arabinose and galactose (PRAG). In contrast, the high molecular weight polysaccharides in pinot noir wine were mainly mannoproteins and polysaccharides rich in arabinose and galactose (PRAG). This information provided the molecular basis to further study the effect of these polysaccharides on the organoleptic attributes of pinot noir wine.


Antibody‐mediated rejection (AMR) is a major barrier preventing successful discordant organ xenotransplantation, but it also occurs in allotransplantation due to anti‐HLA antibodies. Symptomatic acute AMR is rare after heart allograft but carries a high risk of mortality, especially >1 year after transplant. As complement activation may play a major role in mediating tissue injury in acute AMR, drugs blocking the terminal complement cascade like eculizumab may be useful, particularly since “standards of care” like plasmapheresis are not based on strong evidence. Eculizumab was successfully used to treat early acute kidney AMR, a typical condition of “active AMR,” but showed mitigated results in late AMR, where “chronic active” lesions are more prevalent. Here, we report the case of a heart recipient who presented with acute heart failure due to late acute AMR with eight de novo donor‐specific anti‐HLA antibodies (DSA), and who fully recovered allograft function and completely cleared DSA following plasmapheresis‐free upfront eculizumab administration in addition to thymoglobulin, intravenous immunoglobulins (IVIG), and rituximab. Several clinical , biological (sudden high‐level production of DSA), and pathological features  of this cardiac recipient are shared with early kidney AMR and may indicate a strong role of complement in the pathogenesis of acute graft injury that may respond to drugs like eculizumab. Terminal complement blockade should be further explored to treat acute AMR in recipients of heart allografts and possibly also in recipients of discordant xenografts in the future. We suggest that blocking the terminal complement pathway may become a useful strategy to treat cardiac acute AMR associated with abruptly occurring severe allograft dysfunction, intense DSA production, evident microvascular injury, and C4d deposition on EMB. In the future, similar therapeutic strategies may also apply to treat AMR in discordant xenotransplantation.22 and SvO2 49% on dobutamine 400 μg/min). The EMB revealed a pAMR2 rejection with four de novo circulating anti‐HLA class‐I DSA (anti‐B27/B52/A1/Cw12 at 4041/2234/1685/1298 MFI) and four de novo anti‐HLA class‐II DSA (anti‐DQ6/DQ5/DR15/DR1 at 15011/8637/8477/4866 MFI)  at presentation (9% on cardiac MRI), severe functional mitral regurgitation, and poor response to medical therapy, the patient was rapidly listed for HTx and a left ventricular assist device (LVAD)  was inserted 4 weeks after admission as a bridge to transplantation. Screening for HLA antibodies class I and II (single antigen bead assay by Luminex technology) was negative <1000 MFI) before LVAD and slightly positive 3 weeks after for one epitope later classified as non‐donor‐specific (anti‐Cw15 1500 MFI). HTx occurred 16 weeks after LVAD placement. No detectable anti‐HLA antibodies were present at the time of transplant. Induction immunosuppression included basiliximab 20 mg at days 0 and 4 and five daily doses of intravenous methylprednisolone (500 mg at day 0 to 125 mg at day 4). Maintenance immunosuppression consisted of ciclosporin, mycophenolate, and oral prednisolone as per our standard protocol. At 1 year, the patient was doing well (NYHA2) and underwent per‐protocol investigations showing 61% LVEF on echocardiography, no circulating DSA, no rejection (0R/pAMR0) on EMB, and no cardiac allograft vasculopathy (CAV) on coronary angiography  18 h after infusion, and at 3.2 L/min/m2 respectively 64% on dobutamine 200 μg/min, 36 h after infusion. Inotropic support terminated on day 5 and LVEF increased to 28%, 35%, 39%, and 47% on days 3, 6, 12, and 30, respectively, before normalization on day 85 (58%). DSA progressively decreased over 4 weeks and was undetectable for 6 months after treatment with no CAV at angiography  working formulation, the diagnosis of cardiac AMR is based on morphological and immune‐pathological abnormalities found on EMBs. The main histopathologic feature of cardiac AMR is microvascular injury, with “activated mononuclear cells” accumulating against interstitial capillary walls, whereas the immunophenotypic characteristics of AMR consist of multifocal C4d staining on ≥50% capillary endothelium or occurrence of ≥10% CD68‐positive cells (macrophages) within capillary walls. Depending on the evidence of only morphological (pAMR1 H+), immune‐pathological (pAMR1 I+), or both (pAMR2) features on an EMB, AMR is regarded as “suspicious” or “definite,” with “severe” AMR (pAMR3) being eventually considered when additional extensive tissue injury is also observed.Actually, the clinical presentation of cardiac AMR ranges from asymptomatic detection on routine EMB to severe allograft dysfunction and cardiogenic shock despite a seemingly similar appearance on EMB.As opposed to heart transplantation, early renal AMR is restricted to a very specific phenotype of humoral rejection. Indeed, it occurs within the first 30 postoperative days as an anamnestic response of memory B‐cells in presensitized patients with or without DSA at transplant time. Its clinical course is very aggressive, with an abrupt and intense rise of DSA accompanied by a fast eGFR decline eventually followed by oliguria and graft loss if untreated. By contrast, late AMR usually presents as a more indolent process, with usually no or only mild allograft dysfunction at diagnosis, progressive GFR loss over years, and it is associated with either preexisting or de novo DSA. At the biopsy level, early and late AMR also differ in both morphologic and immune‐pathologic patterns. Whereas early AMR always displays typical features of “active AMR,” late AMR may exhibit both “active” and/or “chronic active” lesions. “Active AMR” is characterized by acute tissue injury  and is interpreted as an initial and reversible process in the evolutive course of humoral rejection, while “chronic active AMR,” depicted by transplant glomerulopathy, peritubular capillary basement membrane multilayering or arterial intimal fibrosis, feature more advanced and definitive lesions.In addition, early and late kidney AMR also differ in their immune‐phenotypic pattern, with almost invariable C4d deposition in early disease but frequent C4d negative specimen in late cases.Notwithstanding post‐transplant timing, our acute AMR case shares many characteristics with early kidney AMR that may hypothetically suggest complement‐dependent tissue injury and sensitivity to therapeutic terminal complement blockade. First, DSA increased extremely abruptly and intensely, with a transition from undetectability to 46,249 MFI in total after 32 days. Although pretransplant screening did not reveal any relevant anti‐HLA antibodies to the implanted organ in our patient, we cannot exclude cryptic pre‐sensitization and late anamnestic response at the time of steroid tapering, especially since pretransplant LVAD use confers a significant risk factor for anti‐HLA antibodies production,To our best knowledge, our case report is the first detailed description of the successful use of eculizumab to treat acute cardiac AMR. It contrasts with the series reported by Law et al, where six of the 11 eculizumab‐treated pediatric heart recipients with AMR expired at a median time of 21 days.Finally, the treatments implemented beyond eculizumab and aimed at DSA suppression also likely contributed to the remarkable long‐term outcome of our patient, with no relapsing AMR and no subsequent CAV. Indeed, DSA strikingly decreased over 4 weeks, enabling eculizumab discontinuation after only two doses, and were undetectable 6 months after treatment initiation. The control of DSA production is usually attempted with agents targeting B‐  and T‐cells  in different combinations despite few supporting data and conflicting results.Prospective multicenter randomized‐controlled studies will be needed in the future to assess the optimal timing of eculizumab administration, to compare its efficacy and safety with more established therapeutic modalities like plasmapheresis, and to precise which clinical profile can best predict treatment benefit. Meanwhile, we believe that our experience added to the recent knowledge on prevention and treatment of AMR with eculizumab may help to reduce the high fatality burden of this syndrome in heart transplantation.1.We also believe that experience with eculizumab in allotransplantation may be relevant in discordant xenotransplantation, particularly in the near upcoming trials of pig‐to‐human kidney transplantation. Although the use of organs from triple KO pigs  is anticipated to lessen the risk of hyper‐acute rejection in humans,


Urinary stones usually start at a young age and tend to recur. Therefore, preventing stone occurrence and recurrence in young people is crucial. We aimed to investigate the association between subcutaneous adipose tissue, visceral adipose tissue, and stone episodes in young people.We retrospectively studied patients aged below 40 years with kidney or ureteral stones. Data on demographic and metabolic characteristics, urolithiasis history, subcutaneous fat area (SFA), and visceral fat area (VFA) were collected. We evaluated the association between SFA or VFA and the occurrence or recurrence of stone episodes using binary logistic regression and Poisson regression analyses.2 had a higher risk of episode occurrence. SFA and VFA accumulation were independently associated with episode recurrence , and SFA had a stronger association than VFA did.In total, 120 patients were included. Abdominal obesity, overweight or obesity, dyslipidemia, metabolic syndrome, SFA, and VFA increased with the number of stone episodes . The increase in SFA was independently associated with episode occurrence (p = 0.015). Patients with an SFA > 97 cmIn young people, SFA accumulation is an independent and early risk factor for the occurrence and recurrence of stone episodes. Subcutaneous fat could be a convenient and effective indicator to assess the risk of stone episodes before the development of metabolic disorders. Urolithiasis is one of the diseases that often affect young people. Among people under 40 years of age, nearly 1 in 10 suffers from urolithiasis . Young pIn this study, we aimed to investigate the association between SAT, VAT, and urinary stone episodes, with the intention of identifying the risk factors of the stone episodes, and then provide effective methods and a theoretical basis for stone prevention among young individuals.This was a retrospective study involving patients from PRE-STONE, a metabolic evaluation database established by Peking Union Medical College Hospital. The inclusion criteria for the patients were as follows: the patients had to be (1) aged 18 years or over but below 40 years; (2) diagnosed with kidney or ureteral stone by either a definite kidney or ureteral stone history or abdominopelvic non-contrast computed tomography (NCCT); and (3) have completed metabolic evaluation in our hospital between May 2016 and January 2019. The exclusion criteria were as follows: (1) patients on lipid-lowering medications; (2) patients taking stone-related medications such as potassium citrate, allopurinol, or thiazides; (3) patients with a known metabolic or anatomic cause of urolithiasis; or (4) patients with a history of bariatric surgery or surgery in the upper urinary tract. A stone episode was defined as the onset of renal colic, hematuria, hydronephrosis, UTI, or flank pain related to urinary stones. The occurrence of stone episodes was defined as the presence of at least one stone episode. Recurrence of stone episodes was defined as the occurrence of at least two episodes. Only stone episodes that occurred in the past 10 years were considered for the purposes of this study.Demographic and clinical data, including age, gender, history of stone episodes, family history of kidney or ureteral stone, past medical history, medications, vital signs, laboratory blood tests, and imaging examinations were recorded. Two urologists, both with three years of experience in the metabolic evaluation of urinary stones, collected the demographic and clinical data, and evaluated the history of SF with regard to stone episodes by face-to-face consultation. The results of blood tests were collected from clinical laboratory, and imaging examinations were collected from Picture Archiving and Communication Systems (PACS).2 or more was considered obesity and a BMI of 24 kg/m2 or more, but less than 28 kg/m2, was considered overweight . The VFA and SFA were measured as pixels within an attenuation range of −250 to −50 Hounsfield units, also using the ImageJ software (2). All NCCT examinations were performed using a third-generation dual-source computed tomographic (CT) system  with a regular dose of 120 kV and a slice thickness of 5 mm. The scan was performed by technicians in the Department of Radiology of our hospital.Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured at the umbilical level on an NCCT axial slice and used as an indicator to estimate the total amount of abdominal VAT and SAT. The adipose tissue area was delineated by two urologists using ImageJ software .Demographic and clinical data were expressed as means ± standard deviation for continuous variables with a normal distribution and as percentage for categorical variables. Between-group comparisons for categorical variables were performed using chi-squared test. One-way analysis of variance (ANOVA) was used for evaluation of continuous variables with a normal distribution, and non-parametric analysis was performed for continuous variables with an abnormal distribution. The association between the occurrence or recurrence of stone episode and SFA or VFA was calculated using the binary logistic regression model . The association between SFA or VFA and the number of stone episodes was assessed using Poisson regression. Covariates in Poisson regression included age, gender, family history of stone, MetS, and renal insufficiency. A receiver-operating characteristic (ROC) curve analysis was used to evaluate the effects of SFA and VFA in estimating the occurrence of stone episode. The area under the curve (AUC) was used to evaluate the performance of variables in identifying stone episodes. All tests were of two-tailed type, and a Based on the inclusion criteria, 131 patients were included in this study. Of these, 11 were excluded, including nine patients who had a known metabolic or anatomic cause of urolithiasis , one patient who was using the lipid-lowering medication atorvastatin, and one who was using stone-related medication potassium citrate. Therefore, a total of 120 patients, including 86 (71.7%) men and 34 (28.3%) women, were enrolled in this study. The patients had an average age of 31.9 ± 5.2 years. We observed that the proportion of abdominal obesity, overweight or obesity, dyslipidemia, and MetS, as well as the values of SFA and VFA, increased significantly with the increase in the number of stone episodes (p < 0.05). However, there were no statistical differences between stone episodes and family history, hypertension, DM, or renal insufficiency  after adjustment. These factors, including MetS , were not related to the occurrence of stone episodes. Even in SFs without MetS, the increase in SFA was still significantly associated to the occurrence of stone episodes after adjustment . No significant association was found between VFA and the occurrence of stone episodes  than VFA  after adjustment. In SFs without MetS, SFA is still associated with the recurrence of stone episode , although the relationship was not statistically significant after the adjustment  after adjustment. The association between SFA and the number of stone episodes was also significant before adjustment  and less statistically significant after adjustment  in SFs without MetS. However, no significant association was observed between VFA and the number of stone episodes (p > 0.05).The Poisson regression in SFA = 0.718; 95% CI, 0.624–0.812) was significantly more than the AUC of VFA , and SFA was adopted as an indicator of the stone episode occurrence. The cutoff point of SFA for predicting the occurrence of stone episode was 97 cm2 in all SFs based on ROC curve analysis, with sensitivity of 72.2%, specificity of 66.7%, and the Youden index of 0.389; while the cutoff point of VFA was 174 cm2, with a sensitivity of 61.1%, specificity of 56.2%, and a Youden index of 0.173.In this study, ROC curves were plotted to compare between VFA and SFA in terms of the predictive power for the occurrence of the stone episode. The ROC curve analysis with the AUC of VFA and SFA are demonstrated in Many studies have shown the association between urolithiasis and MetS or its components –5. VAT sp < 0.05). This is consistent with the current understanding that metabolic disorders are associated with urolithiasis in SFs of all ages  . Some st2 of SFA. This suggested that a slight increment in the SFA might increase the risk of stone episodes, which highlights the significance of controlling the SAT in young SFs. Although the association between SFA and the number of stone episodes was less significant after adjustment, this might due to the small sample size.Both SFA and VFA were independently related to the recurrence of stone episodes, and SFA had a closer relationship with stone recurrence than VFA did in our study. Yamashita and Bos both found that recurrent SFs had a higher %VFA (%VFA=VFA/[VFA + SFA]) than first-time SFs of all ages , 26. SevRace may also be an important factor for the closer relationship of the occurrence and recurrence of stone episodes with SFA. Previous studies have shown that VFA or %VFA were associated with stone formation or recurrence; however, most of these studies were performed in Caucasian populations , 19. SomWe found that SFA was a better independent indicator than VFA in assessing the risk of occurrence and recurrence of stone episodes and the number of stone episodes in young SFs. Based on this finding, young SFs could assess their risk of occurrence and recurrence of stone episodes simply by measuring their abdominal subcutaneous fat in a quick test. This will enable young SFs to take actions to prevent future stone episodes as early as the compensation state of metabolic imbalance, instead of waiting until MetS develops.Our study has a few limitations. First, it was a single-center retrospective study, and all subjects enrolled in this study were SFs. Patients who did not or were unwilling to complete the metabolic evaluation were not included. Second, the number of patients enrolled in this study was relatively small; therefore, a larger sample size is needed to verify the results.The accumulation of SFA is an independent risk factor for the occurrence and recurrence of stone episodes in young people. Self-measurement of subcutaneous fat may be a very simple and effective method to assess the risk of stone episodes and could help prevent their occurrence or recurrence even before the development of metabolic disorders. The association between stone episodes and SFA may also help further explore the mechanism of urolithiasis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was reviewed and approved by the Institutional Review Board of Peking Union Medical College Hospital (Protocol number: S-K1961). All data was collected after obtaining signed informed consent of the patients.Study design: ZY, YQ, and HX; data collection: YZ, HX, GL, YQ, YZ, ZJ, XF, RL, and OW; data analysis: ZY, HX, and GL; statistical analysis and data interpretation: ZY and YZ; literature search: ZY, HX, GL, YQ, YZ, XF, RL, and OW; generation of figures: ZY and HX; writing of the manuscript: ZY and HX. All authors had final approval of the submitted and published versions.This research was supported by The National Key Research and Development Program of China .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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Kaposi’s Sarcoma (KS) is a neoplasm derived from endothelial cells and is associated with human herpesvirus-8 (HHV-8) infection. It is mostly seen in patients suffering from AIDS and/or chronic immunosuppression. Currently, systemic chemotherapy is the primary treatment option for the advanced KS. However, there is no consensus on the treatment of KS. In this case, an 84-year-old man with a history of psoriasis developed multiple painful dark purple nodules on the trunk and extremities during the treatment of drug reaction with eosinophilia and systemic symptoms (DRESS). KS was confirmed by the skin biopsy, and the immunohistochemical staining demonstrated the positivity for HHV-8 while the anti-HIV test was negative. The patient then received anlotinib treatment, a tyrosine kinase inhibitor, for 5 months, and his skin lesions subsided. This case indicates that anlotinib may be a potential treatment option for KS. Kaposi’s Sarcoma (KS) is an HHV-8 associated angiogenic sarcoma that predominantly develops in lower extremities and was first described in 1872 by Kaposi , soft tiAn 84-year-old man presented with multiple dark purple and painful nodules on the trunk and extremities. He had a history of psoriasis for 3 years and was well-controlled by acitretin and topical corticosteroids. Body surface area (BSA) of the initial psoriasis was 13%, and the psoriasis area and severity index (PASI) score was 17.6. About 9 months ago, the patient was admitted to the hospital 3 weeks after taking traditional Chinese medicine. He presented with fever, mild facial edema, widespread erythema (BSA = 75%), and icteric sclera. The patient’s laboratory results were as follows: Eosinophil count of 2,640/μl; alanine aminotransferase, 283 U/L; aspartate aminotransferase, 173 U/L; serum lipase(Rate method) of 163 u/L; and hemoglobin of 89 g/L. The patient was assessed using a diagnostic score according to the RegiSCAR. The final score was six, suggesting probable DRESS syndrome. Methylprednisolone (1 mg/kg/day) and plasmapheresis were immediately administered. After 1 month of admission, the DRESS syndrome improved, but two localized purplish nodules were noticed in his lower limbs. The nodules were painful with a coarse texture and had a diameter of 2–3 cm . Then, tcis-retinoid acid can also be used , and iatrogenic subtypes observed in patients receiving immunosuppression, especially organ transplant recipients . DRESS i be used . PLD and be used . But PLD be used , 14.via targets VEGFR1, VEGFR3, VEGFR2/KDR, PDGFR-α, c-kit, and fibrogenic growth factor receptors(FGFR). It may inhibit more targets than other RTK inhibitors  and its receptor (VEGFR) expression to participate in the activation of angiogenesis, thereby inducing the formation of new blood vessels . An incrhibitors , 18. Thehibitors . This poThe underlying mechanism of action of anlotinib on KS is related to VEGFR and PDGFR pathways. However, its potential in the treatment of KS has not been reported. Therefore, anlotinib may be a new potential treatment for KS. With future studies and increased clinical experience, anlotinib is expected to be used for the treatment of other cancers.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committee of the First Affiliated Hospital of Fujian Medical University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ML, RL, and PZ conceptualized and designed the study and wrote the manuscript. TG and CJ critically revised the manuscript for important intellectual content. PZ and ZX collected clinical pictures and analyzed data. All authors read and approved the final 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Kaposi sarcoma (KS) is a multifocal lympho-angioproliferative, mesenchymal low-grade tumor associated with a γ2-herpesvirus, named Kaposi sarcoma-associated virus or human herpesvirus (KSHV/HHV8). The lung is considered a usual anatomical location of KS, despite being infrequent, often in association with extensive mucocutaneous lesions and very uncommonly as an isolated event. We report a case of a pulmonary KS (pKS) in a human immunodeficiency virus (HIV) naïve patient, which was atypical due to a lack of cutaneous involvement and an absence of respiratory symptoms. The pKS was initially identified as a tumoral suspected nodular lesion and only after immunohistochemical analysis was it characterized as KS. Furthermore, the diagnosis of pKS led to the discovery of the HIV-seropositive status of the patient, previously unknown. Our report underlines the importance of considering pKS even without skin lesions and as a first manifestation of HIV infection. We also reviewed literature on the current knowledge about pKS in people living with HIV (PLWH) to underline how one of the most common HIV/acquired immunodeficiency syndrome (AIDS) associated tumors can have a challenging localization and be difficult to recognize. The achievements of contemporary medicine and the development of new antiretroviral drugs have enabled people to grow old with HIV ,2. ConteOver time, the incidence of AIDS-defining cancers (ADCs), such as non-Hodgkin lymphoma and KS, and Hodgkin lymphoma, breast, prostate, and colorectal cancer, has decreased ,11,12,13Nonetheless, only a low percentage of PLWH undergo any screening test for cancers. PLWH come to the doctor’s attention when they are symptomatic and, unfortunately, often in an advanced stage of cancer ,22,23. Moreover, neoplasia is often concomitant to opportunistic infections that can occur at the same site, not only poorly affecting the prognosis but also delaying the diagnosis due to the overlapping of symptoms and imaging ,25. Despite the availability of vaccines for human papillomavirus (HPV) and hepatitis B virus (HBV), most neoplasia associated with HIV infection is led by oncogenic viruses, such as Epstein–Barr virus (EBV), HPV, HBV, hepatitis C virus (HCV), and KSHV/HHV8 ,27,28,29KS is a multifocal lympho-angioproliferative, mesenchymal low-grade tumor associated with KSHV, a γ2-herpesvirus, belonging to the family of DNA viruses Herpeseviridae. KSHV is the etiological agent of KS, but it is also pathogenically related to others lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), diffuse large B cell lymphoma, and germinotropic lymphoproliferative disorder ,33,34,35KS presents as four clinical variants: classic KS, which mainly affects the extremities of elderly patients and generally follows an indolent chronical course; African KS; immunosuppression-associated KS; and AIDS-associated KS . The main complications of KS in PLWH, which is remarkable for its morbidity and mortality, include KS inflammatory cytokine syndrome (KICS), an emerging entity characterized by acute respiratory distress syndrome (ARDS), eventually requiring a ventilator and vasopressor support ,38.We report a case of pKS in a patient unknown to be seropositive without any cutaneous involvement nor respiratory symptoms. Our literature review identified only 12 other similar cases. Our report underlines the importance of recognizing this localization of KS especially when it presents without skin lesions and as a first manifestation of HIV infection. We performed a literature review on the current knowledge about pKS in PLWH to draw attention to one of the most common HIV/AIDS-associated tumors that can have challenging localization and diagnosis.Despite a decline in incidence since the introduction of antiretroviral therapy (ART), KS remains the most common cancer in PLWH in sub-Saharan Africa, where it is still endemic, and causes significant morbidity and mortality ,39. The The lung is considered a usual anatomical location of KS, despite being infrequent, and is often in association with extensive mucocutaneous disease and very rarely as an isolated event ,42,43,44The clinical, radiological, and endoscopic features of pKS are summarized in The main presenting symptoms of pKS are cough, dyspnea, and weight loss, but pleuritic pain, hemoptysis, and wheezing can also be present ,51,52. MPneumocystis jiroveci pneumoniae (PJP) [The most suggestive radiological findings are dense, nodular, tumor-like opacities and bilateral linear and/or micronodular opacities around the bronchi and vessels . Pleuralae (PJP) . To our ae (PJP) . Bronchoscopy may be useful in the diagnosis of endobronchial lesions, even if KS is often elusive at bronchoscopy. The endobronchial findings are diagnostic in about 50% of cases and although there is a correlation between tracheobronchial and parenchymal disease, the latter can occur without endobronchial lesions ,60. ThisAlthough possible, significant iatrogenic bleeding during flexible bronchoscopy is a rare and usually self-limiting event .The treatment approach to KS is difficult due to its heterogeneity in terms of localization, extension, and rate of growth. Local or systemic therapy is tailored to patient conditions and KS characteristics ,71. Local therapy is reserved for patients with minimal cutaneous disease or for nonresponders to systemic therapy who have rapidly progressive disease, and it is considered as palliative therapy. Topical alitretinoin gel, intralesional vinblastine, laser therapy, oral etoposide, cryotherapy with liquid nitrogen, and excisional surgery are valid options ,71,72. LIn HIV-related KS, ART is the first-line option and often the only available therapy in lower-income countries, such as South Africa, where treatment with ART alone with stavudine, lamivudine, and nevirapine for KS without visceral involvement showed significant improvement in survival ,79.To date, no comparative studies on the efficacy of different ART regimens for KS have been conducted. At the beginning of this century, a retrospective double-center study in France compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and nucleoside reverse transcriptase inhibitor (NRTI)-based to protease inhibitor (PI)-based regimens and showed that the suppression of HIV replication seemed to be the key factor in KS control, independently of the CD4+ cell count . MoreoveNonetheless, for a long time, PI-based regimens have been considered indispensable in the treatment of KS, alone or in combination therapy. In mice models, the systemic administration of the PI indinavir or saquinavir has been shown to induce regression in the development of angioproliferative KS-like lesions, promoted by primary human KS cells. In addition, PIs reduce basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), both of which are involved in angiogenesis, edema, and KS lesion formation ,82. In vTo date, no comparative studies on the efficacy of integrase inhibitors (INIs) plus chemotherapy or alone versus protease inhibitors (PIs) have been conducted. In some cases, starting ART with a dolutegravir (DTG)-based regimen led to regression of KS with or without chemotherapy ,88. AlthDespite the large percentage of patients responding to ART treatment, in some cases, KS recurs or worsens under ART . AccordiSystemic chemotherapy is necessary in cases of no response to ART and/or locally aggressive, symptomatic, rapidly progressive, or disseminated life-threatening KS with visceral involvement. It is the most effective treatment for pKS and is also recommended for the prevention of immune reconstitution inflammatory syndrome (IRIS) ,73,95,96Besides the pulmonary manifestations of pKS, including airway lesions, peribronchovascular opacities, and characteristic hemorrhagic pleural effusions, uncommon complications of pKS include chylothorax, IRIS, and diffuse alveolar hemorrhage (DAH) . Chylothorax is a rare cause of pleural effusion, characterized by the pleural fluid having a milky white appearance due to its high levels of cholesterol and triglyceride ,104. ChyUntreated chylothorax has a high morbidity and mortality . The manIRIS is syndrome of aberrant reconstituted immunity beginning with a rapid normalization of the CD4+ cell count, resulting in a dysregulated immune response . GeneralPredictors of the development of IRIS in KS patients are still not well defined. Lung involvement is one predictor . LikewisTypically, IRIS presents with the unmasking of covert infections or the worsening of overt diseases . DependiMoreover, Dumic et al.  reportedKICS is an emerging and sometimes difficult to recognize cause of morbidity and mortality. KICS is an MCD-like systemic inflammation, characterized by the classical signs and symptoms of MCD in the absence of MCD-related pathologic evidence . A commoFirstly, in general, KICS has no temporal correlation with ART initiation . From a In sub-Saharan Africa and South America, the coadministration of ART and chemotherapy has reduced the incidence not only of early progression of KS but also IRIS associated with KS compared with ART alone ,131. In DAH is a complication of untreated pKS, which is itself an independent risk factor for DAH ,133. It We report the case of a man, Caucasian, 47 years old, with no significant comorbidities. In August 2021, after the second shot with the mRNA vaccine for SARS-CoV-2, the man started to manifest recidivant fever, which was resistant to treatment, and started noticing weight loss. Until the first hospitalization 1 month later, the case had lost 13 kg. During the first hospitalization, a chest CT scan was performed, and a solitary nodular formation was found in the upper lobe of the right lung, with thickening that was represented more in the right lung, suggesting an interstitiopathy of uncertain nature. No respiratory symptoms were reported. After dismissal, he was admitted to the thoracic surgery unit for further investigations. Physical examination of the thorax was normal except for a pulmonary dullness on the right upper area; no superficial lymphadenopathy of latero-cervicals, retronucals, submandibulars, submentals, supraclavicles, or axillary lymph nodes were found. No appreciable skin lesions were observed. The man was cooperative but showed a general slowness and was partially oriented when he was asked questions. A chest abdomen and brain CT scan was performed, with the following results: solid lesion with spiked margins in the upper right lobe (28 × 19 mm), a consolidation thickening in the right lung, and a general thickening in the interstitium in both lungs with ground glass and crazy paving areas that was represented more in the right lung. No abnormalities were reported in the abdomen. In the brain, an abnormal venous course in the fronto-parietal area was visible. With the suspicion of lung cancer, on the 10th day of hospitalization, the man underwent subtotal lobectomy of the right upper lobe. Biopsy of the lung lesions performed by thorax surgeons showed a proliferation of spindle cells with a slit-like vasculature and erythrocyte exudation. Immunohistochemical analysis showed staining of CD31+, CD34+, D2-40, and HHV8, suggesting the presence of KS, with an MIB 1 of 40%. KS was stadiated and oral and pharyngo-tonsillar lesions, histologically and immunohistochemically characterized as KS, were also found. In early October, an HIV test was performed and the result was positive, as confirmed by Western blot. The man was a late presenter (CD4+ count < 350/mmc/AIDS defining illness regardless of the CD4+ cell count at HIV diagnosis) with an HIV RNA viral load in plasma of 650,000 cps/mL, accompanied by CD4+ count of 9/mmc (2.4%), CD8+ count of 347.2/mmc (54.2%), and CD4+/CD8+ ratio of 0.04. Clinically, the patient complained of asthenia and denied any respiratory symptoms. ART was started with DTG and emtricitabine (FTC)/tenofovir alafenamide (TAF) without chemotherapy. After 1 month, we observed a reduction in the HIV RNA viral load in plasma of 170 cps/mL, accompanied by an increase in the CD4+ count of 27.7/mmc (5.5%), CD8+ count of 245.5/mmc (50.5%), and CD4+/CD8+ ratio of 0.10. The ART was sufficient to stop the KS progression in the oral and pharyngo-tonsillar region. The rhino-laryngoscopy at the 1-month follow-up showed no lesions. To date, no further lesions have developed.KS is still one of the most common ADCs . While mIn our case, pKS was found as an incidental report in the first thorax CT scan, when it was not known that the patient was HIV positive, and, before immunohistochemical analysis revealed it was pKS, clinicians thought it could be pulmonary carcinoma. In the literature, we found 12 cases of pKS in PLWH similar to ours, with atypical presentation without muco-cutaneous involvement, the main features of which are shown in In six cases, the patients were already known to be HIV positive, with insufficient adherence to ART or who had experienced a short period of time under treatment ,66,137. Eleven patients presented due to various clinical manifestations of pKS, most of them involving the pulmonary system, such as a nonproductive cough, dyspnea, and pleuritic pain. Furthermore, in three cases, hemoptysis was reported as an initial symptom ,66,137. The case reported by Young et al.  is the mWith the only exception of Young et al. , in all Chemotherapy was not performed in our patient since the lesion was successfully removed. After the beginning of ART, no IRIS onset nor other KS lesions developed. Notably, in five cases, pKS was treated with ART without chemotherapy, due to the refusal of the patient and his compromised status, as was unable to tolerate chemotherapy ,136,137.Despite the differences in treatments, in six cases, lesions improved and pKS stopped its progression ,136,138.The case we observed is peculiar not only because of the lack of typical skin lesions recognizable for KS but also due to the absence of respiratory symptoms. Although the lung is considered one of the common localizations of visceral KS, it is challenging to recognize it when it presents in an atypical manner. Considering the high mortality of pKS, consideration of potential visceral involvement of KS in patients newly diagnosed with HIV infection, even without muco-cutaneous involvement and specific signs and symptoms of organ compromission, is of the utmost importance.