Journal of Hospital MedicineVolume 14, Issue 4 p. 257-258 Editorial Transthyretin (Prealbumin) and the Ambiguous Nature of Malnutrition Jessica L Lee MD, MS, Corresponding Author Jessica L Lee MD, MS Jessica.lee@uth.tmc.edu Assistant Professor, The University of Texas Health Science Center at Houston, Houston, TexasCorresponding Author: Jessica L Lee; E-mail: Jessica.lee@uth.tmc.edu; Telephone: 713-500-5457Search for more papers by this authorThomas E Finucane MD, MACP, Thomas E Finucane MD, MACP Emeritus Professor of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MarylandSearch for more papers by this author Jessica L Lee MD, MS, Corresponding Author Jessica L Lee MD, MS Jessica.lee@uth.tmc.edu Assistant Professor, The University of Texas Health Science Center at Houston, Houston, TexasCorresponding Author: Jessica L Lee; E-mail: Jessica.lee@uth.tmc.edu; Telephone: 713-500-5457Search for more papers by this authorThomas E Finucane MD, MACP, Thomas E Finucane MD, MACP Emeritus Professor of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MarylandSearch for more papers by this author First published: 01 April 2019 https://doi.org/10.12788/jhm.3144Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume14, Issue4April 2019Pages 257-258 RelatedInformation

This letter responds to the letter by Thomas E. Finucane

This is a response to the article by Teng et al.

See the response from Teng et al .

This letter comments on the letter by Irving H. Gomolin

Urinary tract infection (UTI) is an ambiguous, expansive, overused diagnosis that can lead to marked, harmful antibiotic overtreatment. Significant bacteriuria, central to most definitions of UTI, has little significance in identifying individuals who will benefit from treatment. Urinary symptoms are similarly uninformative. Neither criterion is well defined. Bacteriuria and symptoms remit and recur spontaneously. Treatment is standard for acute uncomplicated cystitis and common for asymptomatic bacteriuria, but definite benefits are few. Treatment for UTI in older adults with delirium and bacteriuria is widespread but no evidence supports the practice, and expert opinion opposes it. Sensitive diagnostic tests now demonstrate that healthy urinary tracts host a ubiquitous, complex microbial community. Recognition of this microbiome, largely undetectable using standard agar-based cultures, offers a new perspective on UTI. Everyone is bacteriuric. From this perspective, most people who are treated for a UTI would probably be better off without treatment. Elderly adults, little studied in this regard, face particular risk. Invasive bacterial diseases such as pyelonephritis and bacteremic bacteriuria are also UTIs. Mindful decisions about antibiotic use will require a far better understanding of how pathogenicity arises within microbial communities. It is likely that public education and meaningful informed-consent discussions about antibiotic treatment of bacteriuria, emphasizing potential harms and uncertain benefits, would reduce overtreatment. Emphasizing the microbiome's significance and using the term urinary tract dysbiosis instead of UTI might also help and might encourage mindful study of the relationships among host, aging, microbiome, disease, and antibiotic treatment.

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INTRODUCTION: Among survivors of intensive care, many remain dependent on mechanical ventilation and are discharged to long-term chronic ventilator units or to skilled nursing facilities. Few long-term outcome data are available on patients transferred from long-term chronic ventilator units. METHODS: We retrospectively followed subjects discharged from a long-term chronic ventilator unit from 2010-2012. We determined where these subjects went, evaluating whether location of discharge had an effect on mortality. RESULTS: We followed 79 subjects who were 64.9 +/- 15.9 y old. Average stay in the long-term chronic ventilator unit was 38.5 +/- 20.1 d. Within the first year after discharge, 24 (30.3%) subjects died: 17 in a skilled nursing facility, 7 at home. Of those who survived the first year, 28 had been discharged to a skilled nursing facility and 27 to home. Survivors were younger (62.6 +/- 12.4 vs 70.4 +/- 13.1 y, P = .03), had shorter intensive care unit lengths of stay (10.4 +/- 5.0 vs 16.4 +/- 11.5 d, P = .03), and were more likely discharged home from long-term chronic ventilator unit (49.0% vs 29.1%, P =.040). CONCLUSIONS: Subjects discharged from an long-term chronic ventilator unit and were alive at 1 y had shorter stays in the ICU and were more likely to be discharged home. Further attention is warranted to assure the survival of critical care patients once they are discharged from intensive care units.

Background: Agonistic angiotensin II type 1 receptor autoantibodies (AT1RaAbs) have not been associated with functional measures or risk for adverse health outcomes. AT1RaAbs could be used to stratify patient risk and to identify patients who can benefit from angiotensin receptor blocker treatment. Methods: Demographic and physiological covariates were measured in a discovery set of community-dwelling adults from Baltimore (N=255) and AT1RaAb associations with physical function tests and outcomes assessed. A group from Chicago (N=60) was used for validation of associations and to explore the impact of angiotensin receptor blocker treatment. Results: The Baltimore group had 28 subjects with falls, 32 frail subjects, and 5 deaths. Higher AT1RaAbs correlated significantly with interleukin-6 (Spearman r=0.33, P<0.0001), systolic blood pressure (Spearman r=0.28, P<0.0001), body mass index (Spearman r=0.28, P<0.0001), weaker grip strength (Spearman r=–0.34, P<0.01), and slower walking speed (Spearman r=–0.30, P<0.05). Individuals with high AT1RaAbs were 3.9 (95% confidence interval, 1.38–11.0) times more likely to be at high risk after adjusting for age (P<0.05). Every 1 µg/mL increase in AT1RaAbs increased the odds of falling 30% after adjusting for age, sex, body mass index, and blood pressure. The Chicago group had 46 subjects with falls and 60 deaths. Serum AT1RaAb levels were significantly correlated with grip strength (Spearman r=–0.57, P<0.005), walking speed (Spearman r=–0.47, P<0.005), and falls (Spearman r=0.30, P<0.05). Every 1 µg/mL increase in AT1RaAbs, decreased time to death by 9% after adjusting for age, sex, body mass index, and blood pressure. Chronic treatment with angiotensin receptor blockers was associated with better control of systolic blood pressure and attenuation of decline in both grip strength and time to death. Conclusions: In older individuals, higher AT1RaAb levels were associated with inflammation, hypertension, and adverse outcomes. Angiotensin receptor blocker treatment may blunt the harm associated with high levels of AT1RaAb.

IN RESPONSE: We share Dr. Finucane's concern about the overuse of pharmacologic therapy, and this concern applies to many diseases beyond insomnia. Therefore, comparing the benefits of pharmacologic therapy for insomnia with the harms and costs before initiating it is incredibly important. We recommended cognitive behavioral therapy for insomnia as first-line treatment rather than pharmacologic therapy. We also advocated for a shared approach to decision making with the patient and caution when considering pharmacologic options. In addition, our guideline contains a high-value care section promoting cognitive behavioral therapy for insomnia over medications. We agree that focusing on patient-centered outcomes is important. We did not consider evidence on laboratory-measured sleep outcomes; instead, the evidence review collected data on global outcomes when available, which included questionnaires that addressed problems and worry about sleep and accompanying distress or dysfunction. We also acknowledged the limitations of these studies and the evidence. However, the sleep outcomes reported in the evidence review and guideline were collected from patient diaries. Although patients may incorrectly estimate numbers, such as total sleep time or wake after sleep onset, they are still patient-centered.

The current paradigm for managing uncomplicated “urinary tract infection” (“UTI”) is deeply flawed. “UTI” is ambiguously defined, and coupled with a belief that “bacteria are not normal inhabitants of the urinary tract,”1Hooton T.M. Bradley S.F. Cardenas D.D. Colgan R. Geerlings S.E. Rice J.C. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.Clin Infect Dis. 2010; 50: 625-663Crossref PubMed Scopus (1323) Google Scholar the diagnosis often leads to unnecessary, harmful antibiotic treatment. Although bacteriuria identified by standard clinical cultures (which we will call standard bacteriuria) is central to most definitions, more sensitive diagnostic tests now demonstrate that “urine is not sterile”2Hilt E.E. McKinley K. Pearce M.M. et al.Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.J Clin Microbiol. 2014; 52: 871-876Crossref PubMed Scopus (427) Google Scholar and that standard bacteriuria represents a fraction of the diverse microbiota hosted by the urinary tract. Knowledge of this complex, generally beneficial microbiome deeply undermines the current paradigm, which relies on the findings of standard culture. By acknowledging this microbiome, a successor paradigm will generate new questions about relationships among host, microbiome, and antibiotic use, and will almost surely show additional serious harms from antibiotic overtreatment. Shifting the paradigm for managing the urinary microbiome will be slow and difficult. Emphasizing the current paradigm's shortcomings may reduce antibiotic overuse in the short run, and in the long run help in development of a successor. This discussion concerns medically stable, nonpregnant adults with normal urinary tract structure and function. The role of antibiotics in patients with abnormalities of anatomy or physiology, such as spinal cord injury, urinary obstruction, or catheters, will require careful investigation. New insight into pyelonephritis and bacteremic bacteriuria is likely to develop. The ambiguous definition of “UTI” seems to promote antibiotic overuse. In one common usage, “urinary tract infection is defined as microbial infiltration of the normally sterile urinary tract.”3Barber A.E. Norton J.P. Spivak A.M. et al.Urinary tract infections: current and emerging management strategies.Clin Infect Dis. 2013; 57: 719-724Crossref PubMed Scopus (159) Google Scholar With this definition, asymptomatic bacteriuria is a “UTI” and is often treated, even in patient groups where strong evidence shows lack of benefit.4Nicolle L.E. Bradley S. Colgan R. et al.Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.Clin Infect Dis. 2005; 40: 643-654Crossref PubMed Scopus (1196) Google Scholar A second common definition, “significant bacteriuria in a patient with symptoms or signs attributable to the urinary tract and no alternate source”1Hooton T.M. Bradley S.F. Cardenas D.D. Colgan R. Geerlings S.E. Rice J.C. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America.Clin Infect Dis. 2010; 50: 625-663Crossref PubMed Scopus (1323) Google Scholar seems more restrictive but does not define what symptoms or signs may be attributed to the urinary tract. This ambiguity creates opportunities for overtreatment. “UTI” may be suspected in patients without urinary tract symptoms who develop any of a wide variety of nonspecific findings, such as change in cognitive or physical function, or change in the appearance or odor of urine. The diagnosis is confirmed (using the first definition) if bacteriuria is present. To satisfy the second definition a clinician need only attribute the nonspecific findings to the urinary tract. Antibiotic treatment of “UTI” often follows, even though no data have shown that these changes respond to treatment. Canonically, “all symptomatic UTI should be treated,”5Sobel J.D. Urinary tract infections.in: Mandell G.L. Douglas Jr., R.G. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Elsevier Churchill Livingstone, Philadelphia, PA2009: 957-985Google Scholar but actual benefit is limited. Hooton6Hooton T.M. Uncomplicated urinary tract infection.N Engl J Med. 2012; 366: 1028-1037Crossref PubMed Scopus (473) Google Scholar emphasizes that in acute uncomplicated cystitis, “the primary goal of treatment is to ameliorate symptoms.” Foxman7Foxman B. The epidemiology of urinary tract infection.Nat Rev Urol. 2010; 7: 653-660Crossref PubMed Scopus (885) Google Scholar summarizes that symptoms are usually self-limited, of brief duration, and only slightly shortened by antibiotic treatment; that cystitis rarely progresses to pyelonephritis; and that randomized trials show no reduction in the risk of progression to pyelonephritis with antibiotic treatment. The generally benign (other than symptoms) nature of “symptomatic UTI” is suggested by the billions of persons around the world and over the eons who have suffered “UTI” without access to antibiotics and have recovered fully. With its various meanings, convenient diagnosis, long tradition, suggestive link to treatment, and uncritical acceptance by clinicians, patients, families, and insurers, “UTI” remains heavily embedded in practice; “one of the most common bacterial infections worldwide.”3Barber A.E. Norton J.P. Spivak A.M. et al.Urinary tract infections: current and emerging management strategies.Clin Infect Dis. 2013; 57: 719-724Crossref PubMed Scopus (159) Google Scholar The paradigm provides tidy management for a patient with “UTI” who expects antibiotics. Further, the current paradigm does account for several findings. Standard bacteriuria is associated with pyuria, fever, and dysuria, for example; and these often improve with treatment, as do a wide variety of findings seemingly unconnected with the urinary tract. Antibiotic treatment improves outcomes for asymptomatic pregnant women who have standard bacteriuria. Pyelonephritis and bacteremic bacteriuria probably arise in the urinary tract and do require antibiotic treatment. To diagnose “UTI” and determine antibiotic sensitivity based on results of standard cultures, however, is to rely on familiar, accessible data and to ignore the dozens of bacterial species,2Hilt E.E. McKinley K. Pearce M.M. et al.Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.J Clin Microbiol. 2014; 52: 871-876Crossref PubMed Scopus (427) Google Scholar as well as intracellular bacterial colonies and urinary virome5Sobel J.D. Urinary tract infections.in: Mandell G.L. Douglas Jr., R.G. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Elsevier Churchill Livingstone, Philadelphia, PA2009: 957-985Google Scholar known to reside in the urinary tract. Current discussions of symptomatic or asymptomatic bacteriuria or sterile urine are similarly problematic. To attribute delirium to standard bacteriuria seems unjustifiable, knowing that most or all people with or without delirium have bacteriuria. The current paradigm is defensible only if all pathogenic organisms are identified with standard cultures and all organisms more difficult to identify can be safely ignored. We propose instead that urinary symptoms, bacteremia, pyelonephritis, and other recognizable disturbances of the urinary tract are the dysbiotic tip of a much larger iceberg of complex host–microbe interactions that are occurring out of sight of standard cultures. As expected in the era of the microbiome, stable bacterial communities are generally beneficial. For example, compared with the instillation of sterile saline, “bladder colonization with (the nonpathogenic) E. coli HU2117 safely reduces the risk of symptomatic urinary tract infection in patients with spinal cord injury.”8Darouiche O. Green B.G. Donovan W.H. et al.Multicenter randomized controlled trial of bacterial interference for prevention of urinary tract infection in patients with neurogenic bladder.Urology. 2011; 78: 341-346Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Of 699 young women with asymptomatic bacteriuria, half of whom were randomized to receive no antibiotic treatment, “treatment was associated with a higher rate of symptomatic UTI … (thus) asymptomatic bacteriuria … may play a protective role in preventing symptomatic recurrence” during 12-month follow-up.9Cai T. Mazzoli S. Mondaini N. et al.The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat?.Clin Infect Dis. 2012; 55: 771-777Crossref PubMed Scopus (179) Google Scholar The normal urinary tract is an open system bearing urine from renal tubules to urethra without discrete anatomic interruption. Sensitive diagnostic techniques, for example, gene-sequencing and expanded quantitative urine cultures, confirm that the tract hosts diverse bacterial communities.2Hilt E.E. McKinley K. Pearce M.M. et al.Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.J Clin Microbiol. 2014; 52: 871-876Crossref PubMed Scopus (427) Google Scholar The respiratory tract–open from alveolus to mouth, traditionally considered sterile, now known to host complex microbial communities–may provide useful analogies for investigation. Could viruses, common respiratory pathogens, be pathogenic in the urinary tract? Might cystitis be analogous to pharyngitis? Might uropathogenic E. coli be analogous to pneumococcus, prevalent and sporadically pathogenic? Do fever, pyuria, duration of symptoms or other clinical features help distinguish between patients who would do well with urinary tract analgesia and those who would be safer with antibiotic treatment? Costello et al10Costello E.K. Stagaman K. Dethlefsen L. Bohannan B.J. Relman D.A. The application of ecological theory toward an understanding of the human microbiome.Science. 2012; 336: 1255-1262Crossref PubMed Scopus (925) Google Scholar outline a broader paradigm shift in the general approach to infection; “transitioning clinical practice from the Body-as-Battleground to the Human-as-Habitat perspective will require rethinking how one manages the human body.” To help in this transition, mindful language will be important. We suggest that authors use “UTI” only within quotation marks and that clinicians use the bimanual “air quotes” gesture in discussions. This small, repetitive annotation is intended to disrupt the term's complacent usage and encourage rethinking of how one manages bacteriuria. The term “urinary tract dysbiosis” may be useful for otherwise well patients with urinary tract symptoms. When improved technology provides laboratory results that display the full array of microbes resident in a patient's urinary tract, antibiotic overuse may be reduced. Current within-paradigm efforts aiming to reduce overuse should continue, and more are needed. “UTI” is an ill-defined, glibly over-diagnosed and over-treated “infection.” Current management ignores modern science. The associated antibiotic overuse causes serious harm to patient safety and to public health. Instead of the current-paradigm question, “Does this patient have a UTI?,” the successor-paradigm question will be, “Does evidence show that antibiotic treatment is likely to benefit this patient?” Shifting the paradigm is an urgent matter.

more-severe dementia because Parkinson’s disease may cause psychosis as well, but psychosis in Parkinson’s disease was not sufficient to account for the difference because it could occur regardless of the severity of dementia, and its incidence rate has been reported to be low (79.7 per 1,000 person-years). Moreover, Parkinson’s disease and Lewy body disease were adjusted for in regression models. As to their final comment, we appreciate that Iraqi and Hughes highlighted the availability of once-daily galantamine since 2004 in the United States. The proportion of users of twice-daily galantamine was 86%, versus 14% for once daily in the study, which indicates that the majority of physicians considered twice-daily formula of galantamine.

This study was supported by the Department of Veterans Affairs Quality Enhancement Research Initiative Rapid Response Project (RRP 10–105) (VSF). The views expressed in this article are solely those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. Conflict of Interest: All authors report no conflicts of interest. Author Contributions: Drafting and final approval of the manuscript: Cooper, Trivedi, Nelson, Reiber, Eugenio, Beaver, and Fan. Sponsor’s Role: The Department of Veterans Affairs Quality Enhancement Research Initiative Rapid Response Project funded this study but had no role in the design, methods, analysis, or preparation of the paper.

Purpose Undernutrition is often suspected in patients when serum albumin or prealbumin levels are low. We asked whether these measures are indeed low in undernourished people if no inflammatory illness is present. Methods We did a systematic review to identify otherwise healthy subjects who were severely nutrient-deprived due to poor access to food or unwillingness to eat. We excluded children and pregnant women. We tabulated available measures of nutrient intake, anthropometry, serum albumin and prealbumin, and, when available, changes in these measures during nutritional intervention. Results In otherwise healthy subjects, serum albumin and prealbumin levels remained normal despite marked nutrient deprivation until the extremes of starvation, that is, body mass index <12 or more than 6 weeks of starvation. Conclusions In these otherwise healthy subjects, serum albumin and prealbumin levels are not "markers of nutritional status." The "markers" failed to identify subjects with severe protein-calorie malnutrition until extreme starvation. That is, they failed to identify healthy individuals who would benefit from nutrition support, becoming abnormal only when starvation was already obvious. In contrast, serum albumin and prealbumin levels are known to fall promptly with injury or illness regardless of nutrient intake. They are negative acute-phase reactants. When these measures are low in sick patients, this cannot be assumed to reflect nutritional deprivation. Decisions about nutrition support should be based on evidence of meaningful benefit from this treatment rather than on assessment of "nutritional markers."