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Personalizing the Management of Pneumonia Personalizing the Management of Pneumonia Samir Gautam, MD, PhD, Lokesh Sharma, PhD, Charles S. Dela Cruz, MD, PhD* KEYWORDS Pneumonia Personalized Precision Individualized Immunomodulation Antibiotic resistance KEY POINTS The current approaches to diagnosing pneumonia and identifying pathogens rely on antiquated methods that have poor test characteristics. Treatment strategies are similarly crude because they rely on broad-spectrum empiric antibiotics, which promotes antimicrobial resistance, and in some cases steroids, which have numerous un- wanted side effects. Emerging genomic methods have the capability to improve microbiologic diagnosis and assess- ment of host immune responses. This information may enable the formulation of personalized treatment of patients, featuring highly selective antimicrobials and targeted immunomodulation. INTRODUCTION similarly faulty, as it reveals a pathogen in less than half of cases.6,7 Lower respiratory tract infections (LRTIs) are the In the absence of dependable diagnostic guide- leading cause of death in developing countries posts, clinicians faced with any suspicion of and account for more than 4 million deaths per 1 pneumonia have traditionally resorted to treating year worldwide. They result in the loss of with empiric broad-spectrum antibiotics ‘just to 103,000 disability-adjusted life years annually, be safe’. However, this time-worn adage is finally making pneumonia the single greatest contributor 2,3 being questioned, as data have accumulated to to human disease burden. It is astonishing, show the danger of indiscriminate antimicrobial therefore, that diagnosis of pneumonia in most use both to society and to individual patients. cases (even at academic centers) still relies on On a population level, antibiotic administration decades-old and highly unreliable clinical criteria 4 for suspected respiratory infection is now appre- such as the chest radiograph, which has a sensi- ciated as a major driver of antibiotic resis- tivity less than 50% and positive predictive value 2,8,9 5 tance, which in turn has been identified by less than 30%. The difficulty only increases in pa- the World Health Organization (WHO) as one of tients with underlying cardiopulmonary disease or the biggest global threats to human health.10 immunosuppression; two of the populations at Meanwhile, the harm of inappropriate antibiotics highest risk of death from LRTI. Microbiological to patients is also becoming recognized.11 In culture, another pillar of pneumonia diagnosis, is addition to the risk of allergy and drug toxicity, Disclosure: This work was supported by grants from the NHLBI (HL126094 and HL103770 to CSD and T32- HL007778 to SG). Pulmonary Critical Care and Sleep Medicine, Center for Pulmonary Infection Research and Treatment, Yale Uni- versity, 300 Cedar Street, TACS441, New Haven, CT 06520-8057, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 39 (2018) 871–900 https://doi.org/10.1016/j.ccm.2018.08.008 0272-5231/18/Published by Elsevier Inc. chestmed.theclinics.com 872 Gautam et al antibiotics produce profound and lasting alter- However, the full realization of personalized ations in the microbiome of the gut and lung medicine requires a complete delineation of dis- (dysbiosis),12 which manifest overtly through sec- ease mechanisms, advanced diagnostics for ondary infections such as Clostridium difficile interrogating these mechanisms in patients, and infection (CDI) but also more subtly through targeted therapies for modulating them. The alterations in host response to infection and con- closest approximation to this vision is in tributions to diabetes mellitus, atherosclerosis, in- oncology, where tumors are sequenced to iden- flammatory bowel disease, and asthma.13,14 It is tify driver mutations for selective targeting (eg, likely that these direct hazards to the patient with tyrosine kinase inhibitors), and the host im- will serve as a greater deterrent to antibiotic over- mune response is assessed to determine candi- use than less tangible risks such as breeding dacy for checkpoint inhibitors. Thus, the field is resistance. beginning to adopt a “tissue-agnostic” approach, If the current methods for diagnosing and man- wherein therapy is guided not by histologically aging pneumonia are inadequate, what are the al- defined tissue of origin but by the molecular ternatives? In general, there are 2 strategies. The biology and immunology of the tumor and host; first relies on guidelines, such as those put forth a dramatic departure from traditional oncologic by the Infectious Diseases Society of America management. (IDSA) and American Thoracic Society (ATS) Respiratory infection has much to learn from for community-acquired pneumonia (CAP) and this paradigm. For pneumonia, personalization for hospital-acquired pneumonia (HAP) and would require a comprehensive molecular ventilator-acquired pneumonia (VAP).15,16 These description of the pathogen, the host, and the guidelines synthesize the best available data into immunologic phenomena that stem from their an evidence-based approach for the management interaction. This description will allow manage- of pneumonia, with goals of simplicity and the abil- ment decisions to be determined by not only ity to generalize. These goals are in part born of ne- data from empiric trials but also basic microbio- cessity, because guidelines must be accessible to logical and immunologic principles. Examples nonspecialists, but it is also an inescapable conse- include delivery of highly selective antimicrobials quence of the large, unstratified patient popula- based on pathogen taxonomy and susceptibility, tions in studies that inform the guidelines. and rational manipulation of dysregulated host Recommendations are similarly monolithic and responses to promote pathogen clearance and therefore have limited relevance for uncommon in- limit immunopathology. fections and unique hosts, such as those with A useful framework for understanding the com- compromised immune or cardiopulmonary func- plex interplay of host and pathogen, based on the tion. Diagnosis and management become signifi- concepts of resistance and tolerance, has been cant challenges in these patients, especially defined by Ayres and Schneider19,20 (graphically during critical illness. In such cases especially, represented in Fig. 1). Resistance refers to the an alternative strategy is needed, one that host’s ability to clear microbes, whereas toler- combines greater diagnostic granularity with indi- ance is a term borrowed from ecological immu- vidually tailored therapy: so-called personalized nology that describes the host’s ability to medicine. endure a microbial insult. Resistance comprises The first step toward personalized medicine is the host’s defenses against an invading path- refinement of diagnostic categories. For pneu- ogen, including intrinsic epithelial mechanisms, monia, this requires subclassification of the syn- innate immunity, adaptive responses, and others drome, which is currently defined broadly by (1) as described later. Tolerance is influenced by a evidence of systemic infection (leukocytosis, fe- more varied set of factors, including the patho- vers, or chills), (2) respiratory symptoms (dys- logic consequences of immune effectors (eg, pnea, cough, sputum), and (3) new radiographic reactive oxygen species [ROS] released from infiltrates.17 This highly inclusive entity could, infiltrating neutrophils) as well as mechanisms for instance, be divided into viral pneumonia, unrelated to resistance (eg, myocardial infarction bacterial pneumonia, and noninfectious respira- in patients with influenza infection).21 To eliminate tory disease using additional diagnostic tech- confusion with the traditional concept of immu- niques (eg, biomarkers)- a preliminary degree of nologic tolerance, this article refers instead to endotyping referred to as stratified medicine.18 resilience, following the example of Mizgerd and Such subgroups remain large enough to enable colleagues.22 Using this this framework, 4 phases well-powered clinical trials and, thus, endotyping in the personalized diagnosis and management at this level may leverage conventional evidence- of pneumonia can be described (summarized in based medicine to guide management. Fig. 1). Personalizing the Management of Pneumonia 873 A B C D Fig. 1. The 4 clinical phases in the management of acute pneumonia. (A) Initial clinical assessment. In this phase, the patient’s baseline level of health and immunologic competency are assessed. Simultaneously, rapid identifi- cation of pathogen is pursued. Health (dependent variable) is a conceptual term that reflects the clinical status of the patient: a composite of criteria including hemodynamic stability and organ function. With increasing path- ogen burden (independent variable), health declines. (B) Host response to pathogen. The slope of the curve is determined by tissue resilience, which depends on characteristics of the host, the pathogen, and their interaction. For instance, host resilience to Pneumocystis jiroveci pneumonia (PJP) is substantially increased in AIDS, permit- ting a high pathogen burden with little disorder but dramatically decreases in the setting of immune reconstitu- tion. Pathogen virulence also affects resilience and therefore the slope of the curve. The rapidity of decline along the curve (over time) is determined by the adequacy of host resistance. (C) Personalized therapy. Based on a comprehensive characterization
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