Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

The answer is “NO”! With an estimated 20% to 50% of acute chronic obstructive pulmonary disease (COPD) exacerbations attributed to noninfectious factors (1,2), routine inclusion of antibiotics in the treatment of this condition is not only unnecessary but potentially harmful.

Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommends the use of antibiotics in patients who have dyspnea, increased sputum volume, and increased sputum purulence—or at least 2 of these 3 criteria when sputum purulence is one of them (3)—, these recommendations are not based on robust evidence and have not been widely corroborated (2,4-6).

That’s why the findings of a 2019 New England Journal of Medicine study (PACE) supporting the use of serum C-reactive protein (CRP) as an adjunctive test in COPD exacerbation is particularly welcome (1). In this multicenter randomized controlled trial performed in the U.K., the following CRP guidelines (arrived from prior studies) were provided to primary care clinicians to be used as part of their decision making in determining which patients with COPD exacerbation may not need antibiotic therapy:

• CRP less than 20 mg/L: Antibiotics unlikely to be beneficial
• CRP 20-40 mg/L: Antibiotics may be beneficial, mainly if purulent sputum is present
• CRP greater than 40 mg/L: Antibiotics likely to be beneficial

Adoption of these guidelines resulted in significantlly fewer patients being placed on antibiotics without evidence of harm over a 4-week follow-up period (1).  Despite its inherent limitations (eg, single country, outpatient setting), CRP testing may be a step in the right direction in curbing unnecessary use of antibiotics in COPD exacerbation.  


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1. Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med 2019;381:111-20.
2. Llor C, Moragas A, Hernandez S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:716-23.
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2019 (
4. Brett AS, Al-Hasan MN. COPD exacerbations—A target for antibiotic stewardship. N Engl J Med 2018;381:174-75.
5. Miravitlles M, Moragas A, Hernandez S, et al. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest 2013;144:1571-7.
6. Van Vezen P, Ter Riet G, Bresser P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomized double-blind placebo-controlled trial. Lancet Respir Med 2017;5:492-9.

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

My postop patient now has fever with atelectasis on her chest X-ray one day after surgery. Does atelectasis cause fever?

Although fever and atelectasis often coexist during the early postop period, there is no evidence that atelectasis causes fever.

A 2011 systematic analysis of 8 published studies found that all but 1 study failed to find a significant association between postop fever and atelectasis.A 1988 study reported a significant association between postop fever during the first 48 h and atelectasis on day 4 postop, but not each postop day.2  Even in this study, however, fever as a predictor of atelectasis performed poorly with a sensitivity of 26%, specificity of 75% and accuracy of 43%.

In another study involving postop cardiac surgery patients, despite a fall in the incidence of fever from day 0 to day 2, the incidence of atelectasis based on serial chest X-rays actually  increased. 3

Experimental studies in dogs and cats in the 1960s also support the lack of a causative relationship between atelectasis and fever. 4,5 Although fever was observed within 12 hrs of placement of cotton plugs in the left main bronchus of these animals, almost all animals also developed pneumonia distal to the plug.  Antibiotic treatment was associated with resolution of fever but not atelectasis.

So if it’s not atelectasis, what’s the explanation for early postop fever? The great majority of postop fevers during the first 4 days postop are unlikely to be related to infections. Instead, a more plausible explanation is the inflammatory response to the tissue injury as a result of the surgery itself causing release of cytokines (eg, interleukin-1 and -6 and tumor necrosis factor) associated with fever. 6


  1. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever. Where is the clinical evidence? CHEST 2011;140:418-24.
  2. Roberts J, Barnes W, Pennock M, et al. Diagnostic accuracy of fever as a measure of postoperative pulmonary complications. Heart Lung 1988;17:166-70.
  3. Engoren M. Lack of association between atelectasis and fever. CHEST 1995;107:81-84.
  4. Lansing AM, Jamieson WG. Mechanisms of fever in pulmonary atelectasis. Arch Surg 1963;87:168-174.
  5. Jamieson WG, Lansing AM. Bacteriological studies in pulmonary atelectasis. Arch Surg 1963;87:1062-66.
  6. Narayan M, Medinilla SP. Fever in the postoperative patient. Emerg Med Clin Nam 2013;31:1045-58. 

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My postop patient now has fever with atelectasis on her chest X-ray one day after surgery. Does atelectasis cause fever?

Should my patient with COPD and recurrent exacerbations undergo evaluation for antibody deficiency?

Although there are no consensus guidelines on when to evaluate patients with COPD for antibody deficiency, we should at least consider this possibility in patients with recurrent exacerbations despite maximal inhaled therapy (long-acting beta-2 agonist-LABA, long-acting muscarinic antagonist-LAMA and inhaled corticosteroids).1

Couple of retrospective studies of common variable immunodeficiency (CVID) in patients with COPD have reported a prevalence ranging from 2.4% to 4.5%. 1 In another study involving 42 patients thought to have had 2 or more moderate to severe COPD exacerbations per year—often despite maximal inhaled therapy— 29 were diagnosed  with antibody deficiency syndrome, including 20 with specific antibody deficiency (SAD), 8 with CVID and 1 with selective IgA deficiency.2  Although systemic corticosteroids may lower IgG and IgA levels, the majority of the patients in this study were not taking any corticosteroids at the time of their evaluation.

In another study involving patients undergoing lung transplantation, pre-transplant mild hypogammaglobulinemia was more prevalent among those with COPD (15%) compared to other lung conditions (eg, cystic fibrosis), independent of corticosteroid use.3  A favorable impact of immunoglobulin therapy or chronic suppressive antibiotics on reducing recurrent episodes of COPD exacerbation in patients with antibody deficiency has also been reported, supporting the clinical relevance of hypogammaglobulinemia in these patients. 2,4 

Remember that even normal quantitative serum immunoglobulin levels (IgG, IgA, and IgM) do not necessarily rule out antibody deficiency. Measurement of IgG subclasses, as well as more specific antibodies, such as those against pneumococcal polysaccharides may be required for further evaluation.

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Contributed in part by Sydney Montesi, MD, Mass General Hospital, Boston, MA.


  1. Berger M, Geng B, Cameron DW, et al. Primary immune deficiency diseases as unrecognized causes of chronic respiratory disease. Resp Med 2017;132:181-188.
  2. McCullagh BN, Comelias AP, Ballas ZK, et al. Antibody deficiency in patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD). PLoS ONE 2017; 12: e0172437.
  3. Yip NH, Lederer DJ, Kawut SM, et al. Immunoglobulin G levels before and after lung transplantation 2006;173:917-21.
  4. Cowan J, Gaudet L, Mulpuru S, et al. A retrospective longitudinal within-subject risk interval analysis of immunoglobulin treatment for recurrent acute exacerbation of chronic obstructive pulmonary disease. PLoS ONE 2015;10:e0142205.

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Should my patient with COPD and recurrent exacerbations undergo evaluation for antibody deficiency?

How can I distinguish cardiac asthma from typical bronchial asthma?

Certain clinical features of cardiac asthma, defined as congestive heart failure (CHF) associated with wheezing, may be useful in distinguishing it from bronchial asthma, particularly in older patients with COPD (1-3).

• Paroxysmal nocturnal dyspnea associated with wheezing
• Presence of rales or crackles, ascites or other signs of CHF
• Poor response to bronchodilators and corticosteroids
• Formal pulmonary function test with bronchoprovocation demonstrating minimal methacholine response.

Cardiac asthma is not uncommon. In a prospective study of patients 65 yrs of age or older (mean age 82 yrs) presenting with dyspnea due to CHF, cardiac asthma was diagnosed in 35% of subjects. Even in non-elderly patients, cardiac asthma has been reported in 10-15% of patients with CHF (2).

The mechanism(s) underlying cardiac asthma is likely multifactorial. Pulmonary edema and pulmonary vascular congestion have traditionally been considered as key factors either through edema in the interstitial fluid of bronchi squeezing the bronchiolar lumen or by externally compressing the entire airway structure and the bronchiole wall. Reflex bronchoconstriction involving the vagus nerve, bronchial hyperreactivity, systemic inflammation, and airway remodeling may also play a role (1,3). 

Treatment of choice for cardiac asthma typically includes diuretics, nitrates and morphine, not bronchodilators or corticosteroids (1,3). 

Bonus Pearl: Did you know that the term “cardiac asthma” was first coined by the Scottish physician, James Hope, way back in 1832 to distinguish it from bronchial asthma!


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1. Litzinger MHJ, Aluen JKN, Cereceres R, et al. Cardiac asthma: not your typical asthma. US Pharm. 2013;38:HS-12-HS-18.
2. Jorge S, Becquemin MH, Delerme S, et al. Cardiac asthma in elderly patients: incidence, clinical presentation and outcome. BMC Cardiovascular Disorders 2007;7:16.
3. Tanabe T, Rozycki HJ, Kanoh S, et al. Cardiac asthma: new insights into an old disease. Expert Rev Respir Med 2012;6(6), 00-00.


How can I distinguish cardiac asthma from typical bronchial asthma?

Why are patients with acute exacerbation of COPD at higher risk of venous thromboembolism (VTE)?

Patients admitted to the hospital for acute exacerbation of COPD are generally regarded as being at high risk of venous thromboembolism (VTE) (prevalence 5%-29%), possibly due to the frequent coexistence of other risk factors, such as immobility, history of smoking, and venous stasis.1 The exact mechanism(s) behind this association remains poorly understood, however.

Among patients with moderate-very severe COPD (GOLD criteria stage II-IV),  high BMI, low exercise tolerance, history of pneumothorax, congestive heart failure, and peripheral vascular disease have also been associated with VTE.1

Systemic inflammation has also been implicated in increasing the risk of VTE in patients with COPD. Although the pathophysiology of COPD is largely defined by the local inflammatory response to airway injury, evidence suggests that there is also a systemic inflammatory response in COPD.2,3 This systemic inflammation could in turn contribute to the increased risk of vascular disease, including VTE, coronary artery disease, and cerebrovascular disease.4

Bonus pearl: Did you know that VTE may be 3x more prevalent among patients with COPD exacerbation without known cause (vs those with identifiable cause) and is associated with a 1-year mortality of 61.9%! 5


  1. Kim V, Goel N, Gangar J, et al. Risk factors for venous thromboembolism in chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis 2014;1: 239-249.
  2. Lankeit M, Held M. Incidence of venous thromboembolism in COPD: linking inflammation and thrombosis? Eur Respir J 2016;47(2):369-73.
  3. Sinden NJ1, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010;65:930-6.
  4. King PT. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clinical and Translational Medicine 2015;4:26.
  5. Gunen H, Gulbas G, In E, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;36:1243-8. 

Contributed by Camilo Campo, Medical Student, Harvard Medical School, Boston, MA.

Why are patients with acute exacerbation of COPD at higher risk of venous thromboembolism (VTE)?

My patient with COPD has new clubbing of his finger tips. What is the mechanism of clubbing?

The mechanism behind digital clubbing has yet to be fully elucidated, with hypotheses ranging from a circulating vasodilator, tissue hypoxia, a neurocirculatory reflex, and genetic factors. 1 Although hypoxemia is often cited as a cause of clubbing, it is often absent in the presence of clubbing and many patients with hypoxemia do not have clubbing.

A potentially unifying pathophysiologic mechanism of clubbing revolves around platelet clustering and associated growth factor release. 2.3 Platelet clumps/megakaryocytes—either because of circumvention of the lung capillary network (eg, in intracardiac shunts or lung cancer) or increased production (eg, in left-sided endocarditis or chronic inflammatory conditions)—may wedge in the fine vasculature of distal fingertips or toes and cause release of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).

Together, PDGF and VEGF promote neovascularization, increase vessel dilation and permeability, and modify connective tissue to create the distinct club-like appearance. Local hypoxic condition from reduced capillary perfusion is thought to further stimulate the release of these growth factors.

Potential causes of clubbing in our patient include lung cancer, interstitial lung disease, bronchiectasis, core pulmonale and secondary polycythemia, among many others. 1

Fun Fact: Did you know that clubbing, also known as “Hippocratic finger”, was first described by Hippocrates in a patient with chronic empyema (don’t ask how chronic empyema was diagnosed in 400 BC!)?1



  1. McPhee SJ. Clubbing. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths;1990. Chapter 44. Available from
  2. Dickinson CJ, Martin JF. Megakaryocytes and platelet clumps as the cause of finger clubbing. Lancet 1987;2:1434-4. 
  3. Atkinson S, Fox SB. Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol 2004;203:721-8.


Contributed by George Bugarinovic, Medical Student, Harvard Medical School

My patient with COPD has new clubbing of his finger tips. What is the mechanism of clubbing?

My previously healthy 55 year old patient is admitted with a respiratory tract infection and a respiratory rate of 22 breaths/min. Should I be concerned?

Any respiratory rate (RR) greater than 20/min in an adult patient may be cause for concern, particularly in the setting of potentially serious disease and absence of an obvious cause such as pain or fever.

Our patient’s RR is outside the commonly cited normal range of 12-20/min. It indicates increased alveolar ventilation which may in turn be caused by hypoxia, hypercapnea, or metabolic acidosis, all portending possibly poor outcome, if left untreated.It’s no surprise that an abnormal RR is often the first sign of clinical deterioration.2 RR is also the least likely of the vital signs to be affected by polypharmacy (eg, NSAIDs affecting temperature, beta-blockers affecting heart rate and blood pressure). 

Another reason for not dismissing an RR of 22 in our patient is the common practice of guessing rather than measuring the RR by healthcare providers in part likely due to the  more “labor-intensive” nature of measuring RRs compared to other vital signs and lack of appreciation for its importance in assessing severity of disease. 1 Of note, in an experimental study of doctors viewing videos of mock patients, over 50% failed to detect abnormal RR when using the “spot” technique of estimating without a timer.3 Even when presented with a RR of 30/min, over 20% of doctors reported it as normal (12-20/min)!

Final tidbit: Do you want to know what a RR of 20/min really feels like? Take a breath every 3 seconds.  If you are like most, it doesn’t feel “normal”!

1. Cretikos MA, Bellomo R, Hillman K. Respiratory rate: the neglected vital sign. MJA 2008;188:657-59.
2. Flenady T, Dwer T, Applegarth J. Accurate respiratory rates count: So should you! Australas Emerg Nurs J 2017; 20:45-47.
3. Philip KEJ, Pack E, Cambiano V et al. The accuracy of respiratory rate assessment by doctors in a London teaching hospital: a cross-sectional study. J Clin Monit Comput2015;29:455-60.

My previously healthy 55 year old patient is admitted with a respiratory tract infection and a respiratory rate of 22 breaths/min. Should I be concerned?

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

Evidence supporting the efficacy of direct oral anticoagulants (DOACs) in obesity is limited. A major concern is the possibility of subtherapeutic anticoagulation in obese patients when standard doses of DOACs are used.

The International Society on Thrombosis and Haemostasis recommends1:

  • Standard fixed dosing of DOACs for patients with BMI ≤ 40 kg/m2 or weight ≤ 120 kg.
  • Avoiding DOACs in patients with BMI > 40 kg/m2 or weight > 120 kg. However, if a DOAC is needed, laboratory confirmation of therapeutic drug concentrations (eg, by checking anti-factor Xa depending on the agent) should be performed, and if subtherapeutic, a vitamin K antagonist (eg, warfarin) is recommended instead.

Based on the individual comparison of DOACs with warfarin in patients with “high” body weight (cut-off of 90 kg or 100 kg, depending on the study) and limited data, apixaban may be more effective in preventing recurrent venous thromboembolism or its related deaths. However, other DOACs, such as rivaroxaban, dabigatran, and edoxaban have also been used in patients with high body weight2.  

To add to the controversy, the efficacy of fixed dose dabigatran in obese patients has been questioned3 and some have recommended avoiding DOACs altogether in patients with BMI ≥ 35 kg/m2 or weight > 120 kg, until more data become available4.

As in many situations in medicine, a case-by-case decision based on clinical judgment and patient preferences may be the best way to go!


  1. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 1308–13.
  2. Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med 2015; 47: 61-8.
  3. Breuer L, Ringwald J, Schwab S, et al. Ischemic Stroke in an Obese Patient Receiving Dabigatran. N Engl J Med 2013; 368: 2440–2.
  4. Burnett AE, Mahan CE, Vasquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE Treatment. J Thromb Thrombolysis 2016; 41: 206-32.


Contributed by Mahesh Vidula, MD, Mass General Hospital, Boston, MA.

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

What could be causing low serum haptoglobin in my patient with no evidence of hemolysis?


There are many causes of low serum haptoglobin besides hemolysis, including1-4:

  • Cirrhosis of the liver
  • Disseminated ovarian carcinomatosis
  • Pulmonary sarcoidosis
  • Elevated estrogen states
  • Repetitive physical exercise
  • Hemodilution
  • Blood transfusions
  • Drugs (eg, oral contraceptives, chlorpromazine, indomethacin, isoniazid, nitrofurantoin, quinidine, and streptomycin)
  • Iron deficiency anemia
  • Megaloblastic anemia (by destruction of megaloblastic RBC precursors in the bone marrow)
  • Congenital causes

Less well-known is that congenital haptoglobin deficiency (“anhaptoglobinemia”) may not be so rare in the general population at a prevalence of 1% among whites and 4% among African-Americans (>30% in blacks of West African origin)3. Measurement of serum hemopexin, another plasma protein that binds heme, may help distinguish between this condition and acquired hypohaptoglobinemia— in the absence of hemolysis, hemopexin levels should remain unchanged3,5.

Final Fun Fact: Did you know that serum haptoglobin is often low during the first 6 months of life?


  1. Shih AWY, McFarane A, Verhovsek M. Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol 2014;89: 443-47.
  2. Sritharan V, Bharadwaj VP, Venkatesan K, et al. Dapsone induced hypohaptoglobinemia in lepromatous leprosy patients. Internat J Leprosy 1981;307-310.
  3. Delanghe J, Langlois M, De Buyzere M, et al. Congenital anhaptoglobinemia versus acquired hypohaptoglobinemia. Blood 1998;9: 3524.
  4. Haptoglobin blood test. Accessed August 6, 2017.
  5. Smith A, McCulloh RJ. Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders. Front. Physiol 2015;6:187.


In collaboration with Kris Olson, MD, MPH, Mass General Hospital, Boston, MA

What could be causing low serum haptoglobin in my patient with no evidence of hemolysis?

My patient with a thrombosed hemodialysis access is found to have an asymptomatic segmental pulmonary embolism following a vascular access declotting procedure. Does he need systemic anticoagulation?

There is no firm evidence either for or against the use of systemic anticoagulants (ACs) in patients with asymptomatic pulmonary embolism (PE) following hemodialysis vascular access declotting (HVAD).  

However, despite the common occurrence of asymptomatic PE following HVAD procedures (~40%), symptomatic PE—at times fatal—has also been reported in these patients1,2.

In the absence of hard data and any contraindications, anticoagulation can be justified in our patient for the following reasons:

  • Asymptomatic segmental PE is commonly treated as symptomatic PE irrespective of setting2,3
  • Hemodialysis patients are often considered hypercoagulable due to a variety of factors eg, platelet activation due to extracorporeal circulation, anti-cardiolipin antibody, lupus anticoagulant, decreased protein C or S activity, and/or reduced anti-thrombin III activity4-7
  • Overall, chronic dialysis patients have higher incidence of PE compared to the general population8
  • There is no evidence that asymptomatic PE following HVAD has a more benign course compared to that in other settings
  • Untreated PE may be associated with repeated latent thrombosis or progression of thrombosis in the pulmonary artery5



  1. Calderon K, Jhaveri KD, Mossey R. Pulmonary embolism following thrombolysis of dialysis access: Is anticoagulation really necessary? Semin Dial 2010:23:522-25.
  2. Sadjadi SA, Sharif-Hassanabadi M. Fatal pulmonary embolism after hemodialysis vascular access declotting. Am J Case Rep 2014;15:172-75.
  3. Chiu V, O’Connell C. Management of the incidental pulmonary embolism. AJR 2017;208:485-88.
  4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. CHEST 2016;149:315-52.
  5. Yamasaki K, Haruyama N, Taniguchi M, et al. Subacute pulmonary embolism in a hemodialysis patient, successfully treated with surgical thrombectomy. CEN Case Rep 2016;5:74-77
  6. Nampoory MR, Das KC, Johny KV, et al. Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 2003;42:797-805.
  7. O’Shea SI, Lawson JH, Reddan D, et al. Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg 2003;38: 541-48.
  8. Tveit DP, Hypolite IO, Hshieh P, et al. Chronic dialysis patients have high risk for pulmonary embolism. Am J Kidney Dis 2002;39:1011-17.
My patient with a thrombosed hemodialysis access is found to have an asymptomatic segmental pulmonary embolism following a vascular access declotting procedure. Does he need systemic anticoagulation?