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Introduction

Professor Yehuda Shoenfeld is the founder and head of the Zabludowicz Center for Autoimmune Diseases at the Sheba Medical Center, which is affiliated to the Sackler Faculty of Medicine at Tel-Aviv University, Israel. He is also the Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel-Aviv University. His clinical and scientific works focus on autoimmune and rheumatic diseases, and he has been the recipient of multiple awards, including a Life Contribution Prize in Internal Medicine in Israel, 2012. In recent years, Professor Shoenfeld noted that four conditions: siliconosis, Gulf War syndrome (GWS), macrophagicmyofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant, and that the patients also presented with similar clinical symptoms. In 2011, this led Professor Shoenfeld to suggest these comparable conditions should be grouped under a common syndrome entitled ‘ASIA’, for ‘Autoimmune (Autoinflammatory) Syndrome Induced by Adjuvants’. In this Q&A we talk to Professor Shoenfeld about ASIA, and discuss his recommendations regarding further research in the field.

What is ASIA?
ASIA is a new syndrome, which refers to autoimmune syndromes induced by adjuvants. It includes several conditions that are not fully characterized as autoimmune diseases like systemic lupus, rheumatoid arthritis or scleroderma, but that are induced by chronic stimulation of the immune system by substances which may react as adjuvants. This chronic stimulation leads to the emergence of these new signs and symptoms, which include fatigue, arthritis, myalgia, and neurological manifestations.

Which adjuvants commonly used in medical practice have been implicated in ASIA?
The idea of ASIA as a new syndrome developed after some studies on Gulf War syndrome reported that soldiers who had not been deployed to the Gulf area were suffering from symptoms such as severe fatigue, cognitive impairment, myalgias and arthralgias. This raised the question of whether it was the vaccines administered to the soldiers that induced these syndromes. The most common adjuvants are silicone implants and aluminum in vaccines.

Are any other adjuvants associated with ASIA?
There are some specific adjuvants which have been shown to induce ASIA; for instance, aluminium. Aluminium is the oldest, the cheapest and the most efficient adjuvant so far, which is why it is still commonly used in the development of vaccines. In 2001, Romain Gherardi and colleagues reported that patients diagnosed with macrophagic myofasciitis, or MMF (a rare muscle disease characterized by specific myopathological alterations, first described by the Groupe d’Etudes et Recherche sur les Ma ladies Musculaires Acquises et Dysimmunitaires (GERMMAD)), had previously been vaccinated with hepatitis vaccines containing aluminium hydroxide. These patients went on to develop severe myalgia with neurological manifestations, cognitive impairment, dizziness, inability to concentrate and poor sleep. Following many studies, Romain Gherardi and colleagues were able to demonstrate that the aluminium is deposited in the muscle, and then via macrophages travels from the muscles to different organs and penetrates the blood-brain barrier. On this basis, MMF is part of the ASIA syndrome. Another condition termed the ‘sick building syndrome’ (SBS) leads to similar clinical symptoms as the Gulf War syndrome, and manifests in people living in a specific room or building. However, once they move to another room or to another building, they completely recover. It is believed that, in that room, there is some substance that reacts or behaves like the adjuvant. I have already mentioned that aluminium is used as an adjuvant in vaccines, but as one of the most common materials in the world its uses are even more widespread, as much of the equipment we use in our daily lives is made from aluminium.

As the use of vaccines, silicone implants, etc., is widespread, what does this mean in terms of public health?
First of all, vaccines are very widespread, and I would like to clarify that I am definitely not against vaccines! Vaccines are the best medical development that humankind has had in the last 300 years, and have helped to bring about almost complete eradication of some viral diseases. However, it should be considered that when you give millions of people an active substance, and vaccines are active substances, then some may suffer from adverse events. After all, vaccines contain viral or synthetic particles emulsified in adjuvant, which is supposed to enhance the immune reaction.

luckily enough the syndrome itself is rare. the mechanism involves the chronic stimulation of the immune system.. kidneys. and actually diffused into the brain through the blood-brain barrier leading to aluminium intoxication. because the vaccines are quite often imposed on them either by the state. and therefore penetration of different substances into the brain. it might be a combination of anti-DNA antibody which is more classic for systemic lupus erythematosus (SLE). and so forth. The dialysate fluid contained aluminium. complications of the lungs. For example. the undefined connective tissue diseases (UCTD) over the years may develop to a specific autoimmune disease. in the 1980s a significant increase in lupus cases was observed in an ex-industrial town in the . I can assume that aluminium and other different materials used in daily life may be associated. DRB1). in addition to silicone implants and the adjuvants in the vaccine. and these particles can cross the blood-brain barrier via macrophages and deposit in the brain. maybe in the future with further advances in personalized medicine. but also anti-mitochondrial antibodies which may indicate primary biliary cirrhosis. over the years many of these patients may go on to develop a more well-defined autoimmune disease. autoimmune diseases which are definitely induced by infections are not as common as the infections themselves. However. chronic stimulation also induces different autoantibodies. that it doesn’t induce granulomas. which is a very common cosmetic operation. the patient presented with symptoms consistent with the ASIA syndrome. I would like to emphasize that currently there are novel adjuvants in development which have to be tested for efficacy. and therefore avoid onset of autoimmune diseases by avoiding administration of vaccines containing adjuvants that are known to be associated with the ASIA syndrome. In addition. but even with unruptured implants. So. What are the current criteria used for diagnosis of ASIA? We have published the criteria and classified it as we do usually with different autoimmune diseases. myalgia and arthralgia. interleukin (IL)-1. there have been claims that the silicone is completely inert. As I mentioned earlier. With regard to silicone implants. In some cases. if they develop scleroderma or systemic sclerosis. Is there any evidence to suggest that environmental or genetic factors may lead to higher risk of developing ASIA? The actual prevalence of environmental factors. one of the mechanisms which has been well defined is that aluminium deposits in the body following vaccine injection. tumor necrosis factor (TNF)α and so forth. but this is misleading. as I mentioned before. Similarly. Major criteria include clinical manifestations such as severe fatigue. With regard to the ASIA syndrome.So. This is because a specific interaction between the infective agent and the genetic components is linked to incidence of autoimmune diseases. the minor criteria include the presence of various autoantibodies and specific HLA (e.g. poor sleep. prevalence is higher in subjects that carry the gene HLA-DRB1. to treat them—and some of them should be compensated. we physicians witnessed this aluminium ‘toxicity’ of the brain in cases where th e patient went through dialysis. etc. In the past. which may then lead to the release of inflammatory cytokines including interferon γ. IL-6. that it doesn’t leak and travel through the body. Therefore we also believe that most cases of UCTD are actually part of ASIA syndrome. In test subjects the type of adjuvant can be replaced with one that might not be associated with the ASIA syndrome. This chronic stimulation may also involve the opening of the blood-brain barrier. So in part. Therefore silicone can be found in different parts. But based on my experience and from reading the literature. there are nanoparticles of silicone that can travel through the body. they will suffer from tight skin. Although the autoantibodies do not necessarily indicate a specific autoimmune disease. this syndrome can be induced by this cascade of cytokines released in response to the chronic stimulation. we have to identify the people who are at risk of suffering from side effects due to the chronic stimulation of their immune system. The re have been recent cases of ruptured silicone implants. For instance. First of all we have to diagnose them. It should be noted that this is the same HLA (human leukocyte antigen) which was found to be present in those who had developed an autoimmune disease following vaccine administration. or following exposure to other sources of aluminium. the chest and the groin. but we hope these might have fewer side effects than aluminium and other established adjuvants. is not yet known. such as the hands. For instance. Although silicone implants are quite common. Have the mechanisms via which adjuvants may cause these effects been established? In part. namely into major criteria and minor criteria. the government. we will be able to screen those at risk based on their genetic composition. interferon α.. or by the employer.

and in addition may help to compensate them if appropriate. from all over the world. I would like to emphasize that this disease is recognized in Finland and is strictly associated with the (HLA) DQB1*0602 genotype. When the vaccine was delivered during the H1N1 epidemic. and to avoid it before they do. which made them more susceptible to developing narcolepsy. What is known about the prevalence of ASIA. We know that vitamin D is associated with many autoimmune diseases. We do know that many of the autoimmune diseases are more prevalent in populations that live further away from the equator. polychlorinated biphenyls. After all. This requires further investigation. but these are just small series of cases. I am still concerned about silicone implants. A lot of research is going on all over the world. trichloroethylene and volatile organic compounds). In the future. and therefore the lack of production of vitamin D. It is believed that limited exposure to sun. Where can I find out more? . then the patient is left without the implants and continue to suffer from the ASIA syndrome. We should learn from ASIA to better understand the etiology of other autoimmune diseases that are currently regarded as ‘idiopathic’ (which means that we are idiots as we don’t know the pathology and etiology!). numerous people are vaccinated regularly. I believe that eventually we will find a correlation between the ASIA syndrome and geographical distribution. What is your advice to clinicians for the management and treatment of patients with autoimmune disorders? Should they be routinely screened for ASIA? As there are no markers for ASIA. I will not see the sentence ‘autoimmune diseases have an unknown etiology’. Mexico. They were completely healthy until they were vaccinated and then suddenly developed the disease. and we should minimize any potential side effects. So. rather than continue to use the drugs that have been. and I hope that in the future we’ll be able to better identify those who are at risk of developing this syndrome. If not. Having said that however. I would like for clinicians to be able to diagnose the patient early on. I would like that in the future. My advice to the clinician is to pay more attention to the history of the patient. may be associated with ASIA. looking at this from a wider context I would say that it can be considered that toxic materials which can act like the adjuvants may underlie what we call ‘idiopathic’ autoimmune diseases. we cannot screen for this. but rather to the genotype of the people who live in the area. especially in vaccines. Following investigations it was found that the area was heavily contaminated with toxic materials (including lead. specifically regarding their vaccine history. after all. maybe clinicians should consider switching to other biological drugs that have not been associated with ASIA. there was a 13-fold increase of narcolepsy in this geographical area. However. whether to recommend these should be explanted or not. which is now recognized as an autoimmune condition. Studies have emerged from the Philippines. as there is no guarantee of full recovery from the ASIA syndrome if the silicone implants are explanted. New York. The therapy for ASIA should be the same therapy as for autoimmune diseases—and until we can understand it better. The researchers correlated this increase of narcolepsy incidences with the vaccines which were administered during the H1N1 (swine flu) epidemic in that region. What do you think are the future directions of research into this field? Efforts should be made to understand the mechanisms behind ASIA and to develop better adjuvants. There are no large epidemiological studies so far that have been able to analyze the geographical distribution. there are a few cases where explanting led to a complete recovery of the patient from the ASIA syndrome. and found the patients had significantly lower levels of vitamin D in comparison with the healthy population within the same geographical area. these patients suffer. For instance. Better understanding of the symptoms and development of serological markers may help to identify the risk factors such as HLA and familial autoimmune background at a very early stage. in one study we analyzed more than 40 different autoimmune diseases. because we are coming closer to better understanding this.United States: East Ferry Street in Buffalo. So the geographic distribution in this case was not connected to the substance. One study from Finland reported a large increase in cases of narcolepsy. particularly in terms of geographical distribution? There is no knowledge about geographical distribution.

the IMAI District Clinician Manual (DCM). Resource-limited setting. Regardless of the etiology. resource-limited settings. Severe illness. the WHO approved the publication of the most recent addition to the integrated management series.Several factors contribute to the high mortality attributed to severe infections in resource-limited settings. and optimization of tissue perfusion using fluids. Infectious diseases have a disproportionate impact on populations in low and middle income countries and cause correspondingly high mortality rates [6. Public health crises such as the 2009 H1N1 influenza pandemic have reinforced concerns about the potential for a rapid overwhelming of the global health system’s capacity to manage patients with severe acute illness. the World Health Organization (WHO) has coordinated the development of a set of integrated management tools. Further along the severity spectru m of this syndrome. In resource-limited settings. comprised of guidelines and health worker training modules. The World Health Organization’s recent publication of the Integrated Management of Adolescent and Adult Illness District Clin ician Manual provides details on how to optimize management of severely ill.11]. Protocol-driven strategies are the basis for the best practice guidelines for sepsis care promulgated by the International Surviving Sepsis Campaign [12]. hospitalized patients in such settings. Thus. While it is poorly quantified. These initial actions are accompanied by support of failing organs and appropriate efforts to minimize complications. Given the importance of this condition. attention to reducing the mortality from sepsis by focusing on improved management in these settings is urgently needed. the Integrated Management of Pregnancy and Childbirth. and red blood cell transfusions. In light of the current deficits in care and the limitations associated with these guidelines. In July 2011. defined by the presence of both infection and a systemic inflammatory response. including those who are critically ill. identify the knowledge gaps and highlight key questions that must be answered to further inform and refine best practice for the management of sepsis in these settings. the global burden of sepsis is undoubtedly massive. the authors propose implementing these standardized best practice guidelines while using them as a foundation for sepsis research undertaken in. Several independent. and directly relevant to. describe the approach used to develop the IMAI DCM sepsis guidelines and their inherent limitations. include the Integrated Management of Childhood Illness. and the Integrated Management of Adolescent and Adult Illness (IMAI). These tools. This document. Extrapolating from North American data. management of severely ill patients is particularly challenging due to a difficult balance between a high caseload of patients and the correspondingly low supply of necessary medical equipment and human resources [3. half of which may be fatal [9]. vasopressors and inotropes. The purpose of this article is to delineate the barriers to optimal sepsis management in resource-limited settings. Many of these tools have been widely disseminated globally [1]. additional source control of infection as needed. guidelines necessary for achieving these improvements may lack applicability or have not been tested in resource-limited settings.7]. multi-site studies from middle and high income countries have demonstrated improved survival in parallel with improvements in compliance with aggregate best practice .4]. process and underpinnings of these sepsis guidelines. such as sepsis. is a two-volume publication providing guidance on the care of hospitalized adult patients in district hospitals from resource-limited settings [2]. one of the most common pathways contributing to this mortality is the ‘sepsis syndrome’. some 15 to 20 million cases of severe sepsis among adults occur worldwide each year. the DCM emphasizes a practical and systematic approach to triage and management of all patients presenting to the hospital in resource-limited settings with an acute illness. This manuscript provides the context. Guidelines Background To provide guidance on a comprehensive approach to the management of children and adult patients with common diseases and conditions in resource-limited settings. To address this challenge. Keywords: Sepsis. Available data on sepsis management of adults in resource-limited settings suggest that this high mortality is associated with ineffective management including delayed and improper empiric antimicrobial therapy as well as sub-optimal fluid resuscitation[10. in 2009 the WHO convened an international group of experts to review the current management of sepsis and to identify an evidence-based strategy and approach for sepsis management in resource-limited settings. While improvements in survival and processes of care have been made in high-income settings among patients with severe conditions. These guidelines were subsequently included in the IMAI DCM as a framework for the management of severe acute illness in adults. particularly in settings with limited resources [5]. These interventions include rapid administration of appropriate antimicrobial therapy. just released on-line and in print. Current standard of care of sepsis in high-resource settings Studies conducted in high-income countries have suggested a benefit from early sepsis identification coupled with targeted interventions in the management of patients with severe sepsis. severe sepsis and septic shock can occur with increasing lethality resulting from progression to end-organ damage and refractory hypotension [8]. including specific guidance on the management of patients with septic shock and respiratory failure without shock.

Finally. In addition. the results of studies re-evaluating the efficacy of certain sepsis bundle components (for example. Consequently. of these components in more recent iterations of the guidelines [23]. mortality among all patients enrolled in the FEAST trial was strikingly lower (9. immune suppression from HIV is an important risk factor for adult sepsis in places where HIV prevalence is high [10]. what level of oxygen should be targeted in septic patients? Furthermore. Development of the guidelines occurred by consensus and recommendations were not necessarily restricted by the lack of a high quality evidence base. Identifying which should be the priority interventions for sepsis management in a resource-limited setting is a further challenge. Three face-to-face meetings (one co-incident with the IMAI DCM pulmonary and emergency expert groups meeting). there is little empirically-derived local or regional data to guide hospital procurement and clinician selection of appropriate antimicrobial treatment. and sometimes removal. a lack of effective antimicrobials. While evidence exists for the benefit of prompt and appropriate antimicrobial therapy. Thus. anesthetics. are intravenous fluid boluses safe in the absence of close patient monitoring and respiratory support equipment? Are central venous catheters beneficial for guiding volume resuscitation in a resource-limited setting when weighed against the attendant risks of mechanical complications and infection? Given global efforts to improve oxygen monitoring capacity and supply. Thus. triage capacity is often absent in district hospitals. emergency medicine. evidence review and numerous email consultations were held. leading to further delays in recognizing ill patients and initiating treatment. Nutritional status. This unexpected finding. suggests that validation studies are required to establish the benefit of the IMAI approach which is largely based on lower level evidence.4%) than in severely ill children enrolled in previous studies from similar settings (28. infectious disease and pulmonology. a working group was convened by the WHO to develop sepsis management guidelines in resource-limited settings. may still result in net benefit. thus precluding the labor-intensive iterative approach that characterizes sepsis management in high resource settings. Furthermore. Moreover. Many other organisms including Plasmodium falciparum. which arguably may be more generalizable to adults in the same setting than findings from studies performed in developed countries. the USA and the UK are underway[24-26]. This effect may be attributable to targeted training of all health staff on triage and monitoring prior to commencement of the study and supports the importance of emergency care training of health workers. In addition. These efforts eventually dovetailed with the IMAI DCM development process (in development since 2006) and in November 2009. Thus. oxygen and intravenous fluids may further impair provision of optimal sepsis care. The etiologies of sepsis in many resource-limited environments differ from high resource settings or have not been well described. For example. Once recognized. access to health care. activated protein C. Bacteraemia studies implicate a wide range of pathogens[10.35-39]. dengue virus. An excellent example of the risk of extrapolating principles of sepsis care across settings was demonstrated by the recent FEAST trial [40]. unbundled from the packages of sepsis care that have been adopted in high resource hospitals. critical care. co-morbidities. Cryptococcus neoformans and Rickettsia species may cause severe clinical illness that cannot be easily distinguished from typical bacterial sepsis [10. This issue is further compounded by the dearth of diagnostic capacity to identify the specific etiologies of sepsis and to determine antimicrobial susceptibility in most district hospitals. the sepsis guidelines were adapted for management of severely ill patients during the H1N1 influenza pandemic [42]. management strategies developed in high-resource populations may not be directly applicable in resource-limited populations.2%) [41]. answering questions regarding the utility of other therapies commonly available in high-resource settings is difficult. . in an effort to independently evaluate goal-directed resuscitation in adults with septic shock. The group comprised 18 international experts from five continents trained in internal medicine. human resources are often scarce with respect to both quantity and expertise. prior to its final approval for publication.32-34]. substantial health system and resource challenges impede the translation of current best practice guidelines in these environments[28-31]. three parallel randomized-controlled multicenter trials in Australia. A sepsis management pathway in resource-limited settings Starting in April 2009. clinical trials of sepsis therapies conducted in high-resource settings and targeting mostly bacterial infection may not be generalizable to resource-limited settings. variable access and long distances to hospitals contribute to severely ill patients presenting to the health system. tight glucose control and low-dose steroids) has led to revision. health seeking behaviors.Mycobacterium tuberculosis. it is not known if (or which) isolated interventions in sepsis. This large trial involving more than 3. Importantly.000 African children with severe acute infections showed that children receiving fluid boluses had a higher mortality than children receiving no fluid bolus. In July 2011.guidance (‘sepsis bundles’) [12-22]. populations in resource-limited settings are likely to differ from those in high-resource settings in a variety of ways. For example. Applicability of existing sepsis guidelines to resource-limited settings While there is some evidence to support the feasibility of implementing modified sepsis management guidelines in resource-limited settings [27]. the WHO held a three-day external review of the IMAI DCM which includes the sepsis guidelines for resource-limited settings. influenza. and use of over-the-counter and sub-standard or counterfeit antimicrobials may all influence the mode of presentation that can impact clinical outcome.

Also. treating infection early and broadly while establishing source control and fixing physiologic aberrations by optimizing tissue perfusion with judicious fluids and oxygen. Guidelines for the management of septic shock and severe respiratory distress without shock in resource-limited settings. circulation (weak or fast pulse. Limitations. A similar training program has already been shown to reduce mortality in pediatric patients in a resource-limited setting [44]. the guidelines specify more conservative fluids for such patients (1 ml/kg/hour intravenously or orally) and other appropriate modifications in the resuscitation strategy. 6 to 24 hours (Figure 1c) and post-resuscitation periods (Figure 1d) [2].) Most importantly. 2 to 6 hours (Figure 1b). most of which was developed in high resource settings. we propose that it is ethically acceptable to provide guidelines to health care providers that are based on the application of sound physiological principles and the best available current evidence. (c) Algorithm for hours 6 to 24 after hospitalization. knowledge gaps and future directions The proposed sepsis pathway is based on a sound physiological rationale and is derived from the best evidence currently available pertinent to the care of adults with sepsis. They provide instruction on sepsis management in resource-limited environments throughout a patient’s hospitalization course with emphasis on the first 2 hours (Figure 1a). To avoid inappropriate guideline implementation. simplified data collection instruments that allow bedside clinical and laboratory documentation are introduced to inform therapeutic adjustments when necessary and facilitate long-term quality improvement and clinical research efforts. The sepsis management algorithm is only triggered once underlying infection is suspected and other causes of circulatory impairment have been excluded. the guidelines emphasize regular and frequent monitoring of the patient's response to treatment and a plan for appropriate action based on changes in clinical status. that research be undertaken to evaluate areas of uncertainty in the guidelines (for example. Ethiopia and Rwanda. Ultimately. Figure 1. acknowledging that much of the world does not have access to advanced diagnostics or resuscitative techniques. Accordingly. Malawi. The guidelines call for the early recognition of two of the most important indicators of organ dysfunction in sepsis: hypotension and acute respiratory distress. capillary refill longer than three seconds. post-partum sepsis and septic abortion) and certain viral hemorrhagic fevers (such as Lassa fever). Thus. using algorithms that rapidly differentiate life threatening emergency conditions from those that require less urgent care. using methods and resources available even in resource-limited settings. specific antimicrobial recommendations for malaria. patients are treated for the most likely and urgent disease syndromes without premature exclusion of alternative diagnoses. tuberculosis. severe respiratory distress). A subsequent independent evidence-based review of sepsis management in resource-limited settings arrived at very similar recommendations and confirmed that evidence from resource-limited settings is deplorably scarce [45]. determining the safest and most efficacious volume of fluid resuscitation for improving sepsis survival) and to validate the effectiveness of the guidelines’ performance in approp riate . It is also essential.The guidelines take into consideration potential resource constraints. Despite the lack of empirically derived data in resourcelimited settings. amnionitis. triage and immediate intervention. Key management principles reiterated through the guidelines include early recognition. They are situated within a larger context of expedited assessment. a district hospital training program based on the DCM to improve the capacity for triage and management of severe acute illness focused on septic shock and respiratory distress has been piloted by the WHO in Uganda. the training also emphasizes the importance of achieving clinical management benchmarks using targeted clinical performance measures based on reasonable standards of care in resource-limited settings. altered level of consciousness or convulsions or pain from a life-threatening cause [43]. heavy bleeding or severe trauma). on improving health worker capacity to manage severely ill patients through effective training to use the algorithm as well as constant revision through new research. emphasis is placed on supporting clinical reasoning and use of differential diagnosis tables. (d) Algorithm for the post-resuscitation period. these guidelines do not exist within a vacuum. In addition to the principles of triage and management. however. (Permission granted by the World Health Organization for reproducing the contents of this figure from the IMAI District Clinician Manual [2]. above all. (a) Algorithm for the first 2 hours of hospitalization. maternal sepsisrelated conditions (for example. Successful sepsis algorithm implementation depends. In addition. central cyanosis. all patients are similarly triaged by assessing whether they exhibit emergency signs related to the airway and breathing (obstruction. In light of the risk of volume overloading patients with possible acute lung injury/acute respiratory distress syndrome. ( b) Algorithm for hours 2 to 6 after hospitalization. including a more conservative fluid management strategy for dengue. careful attention to possible development of fluid overload/pulmonary edema in severe malaria. Further guidance on the management of conditions which may deviate from these guidelines is provided in the DCM.

expanded sentinel surveillance microbiologic laboratory sites or the use of novel rapid diagnostic tests comprising assays which can identify sepsis etiology and/or provide prognostic information at the point of care. such as oxygen. the role of early feeding and micronutrient supplementation and the training of patient relatives as clinical care attendants). there remain many barriers to the adoption of such practices. Improving the recognition and defining the natural history of sepsis caused by organisms endemic in developing countries. Tailoring treatment more effectively by enhancing on-site diagnosis. Given the unique challenges of infrastructure and human capacity limitations and the substantial knowledge gaps specific to resource-limited settings. In resource-limited settings where the burden of disease is highest but least well studied. 6. particularly in patient populations and settings where invasive monitoring and extensive laboratory investigations are absent. in resource-limited settings is essential. Conducting relative cost-benefit analyses addressing supply issues and resource utilization for basic treatments. the use of oral fluids. through either improved basic microbiology services. intravenous fluids and antimicrobials can aid health facilities in determining how to prioritize resources required for sepsis management. a subset of the larger severe illness recognition and management algorithms within the IMAI District Clinician Manual.settings with modification of the guidelines based on these findings. Abbreviations . The essential elements of care of critically ill patients in resourcelimited settings are a triage system that identifies critical illness quickly. the availability of requisite interventions. a robust global effort championing training and research in the management of acute severe illnesses. It should be feasible to design and implement a package comprising these elements adapted for any setting but in order to ensure that such guidelines fulfill their potential for saving lives. 5. key issues for further investigation include: 1. Further clinical research is necessary to determine where and how the proposed guidelines can complement existing disease-specific recommendations and whether specific components require further evaluation. the use of ultrasound to guide amount of fluid resuscitation. Conclusion Current evidence suggests that the mortality and morbidity of severe sepsis can be improved by effective clinical interventions applied in a timely and systematic manner. Through the evaluation of severity scoring systems and differing clinical definitions. and a data collection and quality management system to monitor implementation and impact. 2. Evaluating the efficacy and effectiveness of training in the proposed management pathway for improving patient outcomes and health care worker performance. such as sepsis. This process of validating and revising guidelines mirrors the approach used in high resource settings by the Surviving Sepsis Campaign [46]. This sepsis management pathway for resource-limited settings. Determining the potential benefit of adjunctive treatments (such as non-invasive ventilation) and interventions that may augment current care (for example. appropriate protocols for managing common medical emergencies. adheres to these principles and provides an essential first step in improving outcomes. defining groups for which early intervention may be either particularly beneficial or futile. 3. 4. while refining management of those clinical syndromes where a pathogen-specific guideline may be superior. targeted training of providers in critical care principles.