Patients admitted with AECOPD are commonly on maintenance tiotropium and are frequently treated with additional inhaled anticholinergic agents (eg, ipratropium) during hospitalization. However, the scientific evidence justifying IDAT in patients with AECOPD is lacking, and is quite limited even in patients with stable COPD1-3. Two small, randomized double-blind studies compared the impact of tiotropium combined with either ipratropium or placebo in outpatients with stable COPD. Both studies selected FEV1 alone as their primary end-point and found only a marginal benefit with IDAT2,3.
A population-based study of acute urinary retention in persons with COPD aged ≥66 years found a significantly higher odds of acute urinary retention among those on IDAT vs monotherapy or no anticholinergics (odds ratios 1.4 and 2.7, respectively)4.
In short, routine use of IDAT in patients with AECOPD lacks firm evidence in its clinical efficacy and may be associated with acute urinary retention.
- Cole JM, Sheehan AH, Jordan JK. Concomitant use of ipratropium and tiotropium in chronic obstructive pulmonary disease. Ann Pharmacother 2012;46:1717-21.
- Kerstjens HA, Bantje TA, Luursema PB, Sinninghe Damste HE, de Jong JW. Effects of short-acting bronchodilators added to maintenance tiotropium therapy. Chest 2007;132:1493-9.
- Cazzola M, Santus P, D’Adda A, et al. Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD. Pulm Pharmacol Ther 2009; 22:177-82.
- Singh S, Furbergt CD. Inhaled anticholinergic drug therapy and the risk of acute urinary retention in chronic obstructive pulmonary disease. Arch Intern Med 2011;171:920-2.
Contributed by Josh Ziperstein, MD, Massachusetts General Hospital, Boston.
Hyponatremia, defined as a serum sodium <135 meq/L, is observed in ~20% of patients hospitalized with ADCHF, and is often dilutional, not “depletional” (ie, not associated with hypovolemia) in this condition1.
In ADCHF, hyponatremia is primarily caused by the production of arginine vasopressin (AVP) (also known as anti-diuretic hormone, or ADH) as a result of decreased perfusion pressures in the aortic arch and renal afferent arterioles, and increased thirst due to the activation of the renin-angiotensin system. Hyponatremia correlates with the severity of ADCHF and adverse clinical outcomes2.
A common approach to dilutional hyponatremia in ADCHF is fluid restriction. Other potential therapies include angiotension converting enzyme inhibitors (by increasing cardiac output and decreasing thirst), loop diuretics (by reducing water reabsorption in the renal distal tubule), and AVP antagonists (eg, tolvapatan, satavaptan)1,3. Otherwise, in the absence of symptoms, no specific therapy is generally indicated for serum sodium levels ≥ 120mEq/L.
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- Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WHW, Mullens W. Hyponatremia in acute decompensated heart failure: Depletion versus dilution. J Am Coll Cardiol 2015;65:480-92. https://www.sciencedirect.com/science/article/pii/S073510971407394X?via%3Dihub
- Leier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J. 1994;128:564. https://www.sciencedirect.com/science/article/pii/0002870394906335
- Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C, SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099. https://www.ncbi.nlm.nih.gov/pubmed/17105757
Contributed by Ricardo Ortiz, Medical Student, Harvard Medical School
Up to 20% of cases of jaundice in community hospitals may be due to sepsis and bacterial infections, often occurring within a few days of onset of bacteremia or even before other clinical features of infection become apparent. 1
Although biliary obstruction as the cause of jaundice is usually suspected, many patients lack extrahepatic cause for their jaundice. Gram-negative bacteria (eg, E. coli) are often the culprit with intraabdominal or urinary tract infection, pneumonia, endocarditis, and meningitis sources also often cited. Hyperbilirubinemia (often 2-10 mg/dl) is commonly associated with elevated alkaline phosphatase and mild aminotransferases elevations, and usually resolves with treatment of infection.1
Although factors such as increased bilirubin load from hemolysis, hepatocellular injury, and drugs (eg, penicillins and cephalosporins) may play a role, cholestasis—likely due to cytokines such as tumor necrosis factor (TNF)α— is the predominant cause. 1
Interestingly, anti-TNF-α antibodies block reduction in bile flow and bile salt excretion in laboratory animals2.
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- Chand N, Sanyal AJ. Sepsis-induced cholestasis. HEPATOLOGY 2007;45: 230-240. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.21480
- Whiting J, Green R, Rosenbluth A, Gollan J. Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. HEPATOLOGY 1995;22:1273-1278. https://www.deepdyve.com/lp/wiley/tumor-necrosis-factor-alpha-decreases-hepatocyte-bile-salt-uptake-and-J9rdeMQBpF
Yes! As early as 1979, case series of patients on methadone developing peripheral edema within 3-6 months of therapy appeared in the literature1.
Subsequent studies revealed that edema may develop from 1 week to 6 months or longer following initiation of methadone, its severity is dose-dependent, and that it improves with reduction of methadone dose or discontinuation of therapy. Distal extremities or the face are often involved and pulmonary edema may also occur1-3. It is often resistant to diuretics.
The mechanism by which methadone causes peripheral edema is unclear but several hypotheses have been forwarded. The high volume of distribution and accumulation of methadone in tissues results in higher oncotic pressures in the extravascular space which in combination with reduced oncotic pressures in blood vessels due to venodilatation may lead to edema. Other potential mechanisms include opioid-induced histamine release directly from mast cells causing venous permeability, and opioid-induced secretion of antidiuretic hormone 1-3.
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- Dawson C, Paterson F, McFatter F, Buchanan D. Methadone and oedema in the palliative care setting: a case report and review of the literature. Scottish Med J 2014;59: e-11-e14. https://www.ncbi.nlm.nih.gov/pubmed/24676025.
- Mahè I, Chassany O, Grenard A-S, Caulin C, Bergmann J-F. Methadone and edema: a case-report and literature review. Eur J Clin Pharmacol 2004;59:923-924. \https://www.deepdyve.com/lp/springer-journals/methadone-and-edema-a-case-report-and-literature-review-PfvnmhB1ia
- Kharlamb V, Kourlas H. Edema in a patient receiving methadone for chronic low back pain. Am J Health-Syst Pharm 2007;64:2557-60.https://www.ncbi.nlm.nih.gov/pubmed/18056943
Absolutely! As early as 1959, Guyton and Lindsey demonstrated the importance of serum colloid osmotic pressure in the pathogenesis of pulmonary edema1.
Specifically, they found that in dogs with normal plasma protein concentrations fluid began to transudate into the lungs when the left atrial pressure rose above an average of 24 mm Hg vs only 11 mm Hg when plasma protein concentration was reduced by about 50%.
Fast forward to 2003, Arques et al studied serum albumin and pulmonary artery wedge pressures in 4 groups of patients: acute HFpEF, heart failure with reduced ejection fraction (HFrEF), acute dyspnea from pulmonary origin and normal controls2. Patients with HFpEF were significantly more likely to have hypoalbuminemia , compared to those with HFrEF, pulmonary disease or normal controls. The main cause of hypoalbuminemia in the HFpEF was malnutrition in 77% and/or sepsis in 41% of patients. Hypoalbuminemia was inversely related to age and plasma C-reactive protein.
Perhaps, we should pay more attention the nutritional status of our patients with HFpEF!
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- Guyton AC, Lindsey AW. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 1959;7: 649-657.
- Arquès S, Ambrosi P, Gélisse R et al. Hypoalbuminemia in elderly patients with acute diastolic heart failure. J Am Coll Card 2003;42:712-16. http://www.onlinejacc.org/content/42/4/71
Great question! “Carotenoderma” refers to the yellow discoloration of the skin caused by increased serum carotenoids1. Carotenoids are absorbed by passive diffusion from the gastrointestinal tract which are partially metabolized in the intestinal mucosa and liver to vitamin A, and then transported in the plasma into the intercellular lipids of stratum corneum of the skin which has a high affinity for carotene1,2.
The maximal accumulation of carotenoids occurs in areas with an abundance of sweat glands (eg, the palms, soles, nasolabial folds). In the absence of strateum corneum, the sclera is spared.
Of note, there are many causes of carotenoderma besides excessive ingestion of carrots. Among foods, increased ingestion of tomatoes, tangerines, red palm oil, and squash may also be responsible1,2. Systemic diseases associated with increase in serum carotenoids (possibly related to decreased conversion to vitamin A, hyperlipidemia, or other factors) include hypothyroidism, diabetes mellitus, anorexia nervosa, nephrotic syndrome, and liver disease.
- Horev L, Ramot Y, Klapholz L. Yellow feet in a patient with breast and thyroid carcinoma, due to oral intake of turmeric. Drug Saf-Case Rep 2015;2:4.https://link.springer.com/article/10.1007/s40800-015-0006-4
- Maharshak N, Shapiro J, Trau H. Carotenoderma-a review of the literature. Int J Dermatol 2003;42:178-181. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-4362.2003.01657.x/epdf
Contributed by Clara Yang, Medical Student, Harvard Medical School
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Patients with newly-diagnosed TB are ~20 times more likely to be coinfected with HIV than those without TB. Unfortunately, the diagnosis of TB in HIV-infected patients is often delayed in part related to its atypical presentation1.
In HIV-infected patients with high CD4 counts, clinical manifestations of TB are usually similar to those without HIV infection (eg, subacute fever, weight loss, cough) with CXR often showing upper lobe infiltrates and/or cavitations typically seen in reactivation TB.
Lower CD4 counts, however, are associated with atypical CXR findings, including pleural effusions, lower or middle lobe infiltrates, mediastinal adenopathy, and lack of cavitary lesions1,2. A normal CXR has been reported in 21% of patients with CD4 <200 cells/μl (vs 5% in those with higher counts)2.
Advanced immune suppression in HIV infection is also associated with negative sputum smears for acid-fast bacilli, concurrent extra-pulmonary disease, and immune reconstitution symptoms after initiation of anti-TB therapy1.
- Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev 2011;24:351-376.
- Greenberg, SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994;193:115-9.
Worldwide prevalence of SI may be as high as 100 million people, with an increasing number seen in developed countries among immigrants (including those from Latin America), refugees, and travelers. “Autoinfection” by Strongyloides allows it to complete its life cycle between the GI tract and the lung without leaving the host, and is often associated with chronic asymptomatic infection in the immunocompetent persons1.
Immunocompromised patients, however, particularly those treated with corticosteroids (including systemic courses as short as 6 days, or local injection) are at increased risk of developing an accelerated form of autoinfection due to SI, also known as hyperinfection syndrome (HIS)1,2. HIS has been reported as late as 64 years after leaving an endemic area!1. When Strongyloides larvae disseminate away from the lung or GI tract into other organs (e.g. brain) the mortality rate may approach 100%, if untreated.
Due to the potential complications associated with untreated SI, particularly in the immunocompromised , routine screening of anyone with a potential Strongyloides-exposure history (irrespective of symptoms or years since exposure) has been advocated1,3. In our patient with COPD, screening for asymptomatic SI by a highly sensitive test (eg serology) should be considered (as early as possible if corticosteroids are being considered for treatment of his COPD). Some have also advocated empiric treatment with ivermectin in “at risk patients” in whom testing is not feasible or practical1,4.
- Mejia R, Nutman TB. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis 2012;25:458-463.
- Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208-217.
- CDC. Strongyloides. http://www.cdc.gov/parsites/strongyloides/helath_professionals/ , accessed September 20, 2016.
- Santiago M, Leitão B. Prevention of strongyloides hyperinfection syndrome: a rheumatologic point of view. Eur J Intern Med 2009;20:744-748.
Simultaneous presence of PE in patients with AE-COPD is not rare, particularly in those with unexplained AE-COPD. A recent systematic review and meta-analysis reported a pooled PE prevalence of 16.1% (95% C.I. 8.3%-25.8%) in unexplained AE-COPD, with 68% of emboli found in the main pulmonary arteries, lobar arteries or inter-lobar arteries (i.e. not subsegmental); the pooled prevalence of deep venous thrombosis (DVT) was 10.5% (95% C.I. 4.3%-19.0%) 1. Pleuritic chest pain and signs of cardiac failure were associated with AE-COPD, while symptoms suggestive of a respiratory tract infection argued against PE.
It remains unclear, however, if the threshold for evaluation of venous thromboembolism (VTE) should necessarily differ between patients with explained vs unexplained AE-COPD. In one small study, the prevalence of VTE in “unexplained” AE-COPD was significantly higher (25%) than “explained” AE-COPD (including cases with tracheobronchitis, pneumonia, cardiac disorders, exposure to irritant inhalants, and lack of compliance with treatment), but the VTE prevalence for the latter group was still 8.4%2. Serum D-dimer level and Wells criteria may help exclude VTE in this patient population.
- Aleva FE, Voets LWLM, Simons SO, et al. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: A systematic review and meta-analysis. CHEST (2016), doi: 10.1016/j.chest.2016.07.034.
- Gunen H, Gulbas G, In E, Yetkin O, Hacievliyagil SS. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;35:1243-1248.
Contributed by Jeff Greenwald, MD, Core Educator Faculty, Department of Medicine, Massachusetts General Hospital
Active TB should be suspected based on a combination of epidemiological (eg, exposure, travel to, or residence in a high prevalence area, history of prior TB), clinical (eg, cough lasting 2-3 weeks or longer, fever, night sweats, weight loss, fatigue, less commonly, chest pain, dyspnea, and hemoptysis), chest radiograph abnormalities (eg, infiltrates, fibrosis, cavitation), and histopathologic (eg, caseating granuloma)1.
Among HIV-negative patients, the highest prevalence of TB is found those who have been incarcerated, use intravenous drugs, have alcohol use disorder, or are immunocompromised (including diabetes mellitus)2,3. Patients suspected of TB based on clinical criteria should undergo chest radiography. Reactivation pulmonary TB (~90% of TB in adults) classically presents with upper lobe and/or the superior segment of the lower lobe disease. Up to 5% of patients with active pulmonary TB have normal chest radiograph, however4. All hospitalized patients suspected of having active TB should be placed on appropriate isolation precautions.
- Sia IG, Wieland ML. Current concepts in the management of tuberculosis. Mayo Clin Proc. 2011;86:348-361.
- Center for Disease Control. Tuberculosis: Data and Statistics. https://www.cdc.gov/tb/statistics/default.htm. Accessed October 3, 2016.
- World Health Organization. Tuberculosis. http://www.who.int/mediacentre/ factsheets/fs104/en/. Accessed October 3, 2016.
- Marciniuk, D, McNab, BD, Martin WT, Hoeppner, VH. Detection of pulmonary tuberculosis in patients with a normal chest radiograph. Chest 1999;115:445-452.
Contributed by Charles C. Jain MD, Medical Resident, Massachusetts General Hospital