What changes should I consider in my diagnostic approach to hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA)?

Compared to 2007,1 the 2019 ATS/IDSA guidelines2 have 2 major “Do’s” and 2 major “Dont’s” in the diagnostic approach to CAP in hospitalized patients:

  • DO order sputum and blood cultures in patients empirically treated for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa—in addition to those with severe CAP as in 2007.  
  • DO order rapid influenza molecular assay—in preference to antigen test— when influenza viruses are circulating in community, irrespective of pneumonia severity
  • DON’T routinely order urine antigens for pneumococcal or Legionella antigens, except in severe CAP or in the presence of suggestive epidemiological factors (eg. Legionella outbreak, recent travel)
  • DON’t routinely order serum procalcitonin to determine need for initial antibacterial therapy

Patients at risk of MRSA or P. aeruginosa include those with prior infection with the same pathogens as well as those with hospitalization and treated with parenteral antibiotics—in or out of the hospital— in the last 90 days; HCAP is no longer recognized as an entity.

The definition of severe CAP is unchanged: 1 of 2 major criteria (septic shock or respiratory failure requiring mechanical ventilation) or 3 or more of the following minor criteria or findings listed below:

  • Clinical
    • Respiratory rate ≥30 breath/min
    • Hypotension requiring aggressive fluid resuscitation
    • Hypothermia (core temperature <36 ᵒC, 96.8 ᵒF)
    • Confusion/disorientation
  • Radiographic 
    • Multilobar infiltrates
  • Laboratory 
    • Leukopenia (WBC <4,000/ul)
    • Thrombocytopenia (platelets <100,000/ul)
    • BUN ≥20 mg/dl
    • Pa02/FI02 ratio ≤250

Keep in mind that these guidelines focus on adults who are not immunocompromised or had recent foreign travel and are often based on expert opinion but low or very low quality evidence due to the dearth of properly designed studies.

Bonus Pearl: Did you know that the urine Legionella antigen only tests for L. pneumophila type I, with an overall sensitivity ranging from 45% to 100%!3,4

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References

  1. Mandell LA, Wunderink RG, Anzueto A. Infectious Disease Society of America/American Thoracic Society Consensus Guidelines on the Management guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72. https://www.ncbi.nlm.nih.gov/pubmed/17278083
  2. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2019;200:e45-e67. https://www.ncbi.nlm.nih.gov/pubmed/31573350
  3. Blazquez RM, Espinosa FJ, Martinez-Toldos CM, et al. Sensitivity of urinary antigen test in relation to clinical severity in a large outbreak of Legionella pneumonia in Spain. Eur J Clin Microbiol Infect Dis 2005;24:488-91. https://www.ncbi.nlm.nih.gov/pubmed/15997369
  4. Marlow E, Whelan C. Legionella pneumonia and use of the Legionella urinary antigen test. J Hosp Med 2009;4:E1-E2. https://www.ncbi.nlm.nih.gov/pubmed/19301376

 

 

What changes should I consider in my diagnostic approach to hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA)?

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

 Absolutely! Although trauma, toxins, exertion, and medications are often listed as common causes of rhabdomyolysis, infectious etiologies should not be overlooked as they may account for 5% to 30% or more of rhabdomyolysis cases (1,2).

Rhabdomyolysis tends to be associated with a variety of infections, often severe, involving the respiratory tract, as well as urinary tract, heart and meninges, and may be caused by a long list of pathogens (1).  Among bacterial causes, Legionella sp. (“classic” pathogen associated with rhabdomyolysis), Streptococcus sp. (including S. pneumoniae), Salmonella sp, Staphylococcus aureus, Francisella tularensis have been cited frequently (3).  Some series have reported a preponderance of aerobic gram-negatives such as Klebsiella sp., Pseudomonas sp. and E. coli  (1,2).   Among viral etiologies, influenza virus, human immunodeficiency virus, and coxsackievirus are commonly cited (2,3).  Fungal and protozoal infections (eg, malaria) may also be associated with rhabdomyolysis (5).

So how might sepsis cause rhabdomyolysis? Several potential mechanisms have been implicated, including tissue hypoxemia due to sepsis, direct muscle invasion by pathogens (eg, S. aureus, streptococci, Salmonella sp.), toxin generation (eg, Legionella), cytokine-mediated muscle cell toxicity (eg, aerobic gram-negatives) as well as muscle ischemia due to shock (1,5).

Bonus Pearl: Did you know that among patients with HIV infection, infections are the most common cause (39%) of rhabdomyolysis (6)? 

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References

1. Kumar AA, Bhaskar E, Shantha GPS, et al. Rhabdomyolysis in community acquired bacterial sepsis—A retrospective cohort study. PLoS ONE 2009;e7182. Doi:10.1371/journa.pone.0007182. https://www.ncbi.nlm.nih.gov/pubmed/19787056.

2. Blanco JR, Zabaza M, Sacedo J, et al. Rhabdomyolysis of infectious and noninfectious causes. South Med J 2002;95:542-44. https://www.ncbi.nlm.nih.gov/pubmed/12005014

3. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis:three case reports and review. Clin Infect Dis 1996;22:642-9. https://www.ncbi.nlm.nih.gov/pubmed/8729203

4. Shih CC, Hii HP, Tsao CM, et al. Therapeutic effects of procainamide on endotoxin-induced rhabdomyolysis in rats. PLOS ONE 2016. Doi:10.1371/journal.pone.0150319. https://www.ncbi.nlm.nih.gov/pubmed/26918767

5. Khan FY. Rhabdomyolysis: a review of the literature. NJM 2009;67:272-83. http://www.njmonline.nl/getpdf.php?id=842

6. Koubar SH, Estrella MM, Warrier R, et al. Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes. BMC Nephrology 2017;18:242. DOI 10.1186/s12882-017-0656-9. https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-017-0656-9

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

My hospitalized patient with pneumonia has now suffered an acute myocardial infarction (MI). Can acute infection and MI be related?

Yes! Ample epidemiological studies implicate infection as an important risk factor for MI.1 The increased risk of MI has been observed during the days, weeks, months or even years following an infection.

A 2018 paper reported a several-fold risk of MI during the week after laboratory-confirmed infection caused by a variety of respiratory pathogens such as influenza virus (6-fold), respiratory syncytial virus (4-fold), and other respiratory viruses (3-fold). 2 Among patients hospitalized for pneumococcal pneumonia, 7-8% may suffer an MI.3,4 One study found a 48-fold increase in the risk of MI during the first 15 days after hospitalization for acute bacterial pneumonia.5 Similarly, an increase in the short-term risk of MI has been observed in patients with urinary tract infection and bacteremia.6

The risk of MI appears to be the highest at the onset of infection and correlates with the severity of illness, with the risk being the highest in patients with pneumonia complicated by sepsis, followed by pneumonia and upper respiratory tract infection. Among patients with pneumonia, the risk exceeds the baseline risk for up to 10 years after the event, particularly with more severe infections.1

Potential mechanisms of MI following infections include release of inflammatory cytokines (eg, interleukins 1, 6, tumor necrosis factor alpha) causing activation of inflammatory cells in atherosclerotic plaques, in turn resulting in destabilization of the plaques. In addition, the thrombogenic state of acute infections, platelet and endothelial dysfunction may increase the risk of coronary thrombosis at sites of plaque disruption beyond clinical resolution of the acute infection. 1

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References

  1. Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med 2019;380:171-6. https://www.ncbi.nlm.nih.gov/pubmed/30625066
  2. Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018;378:345-53. https://www.nejm.org/doi/full/10.1056/NEJMoa1702090
  3. Musher DM, Alexandraki I, Graviss EA, et al. Bacteremic and nonbacteremic pneumococcal pneumonia: a prospective study. Medicine (Baltimore) 2000;79:210-21. https://www.ncbi.nlm.nih.gov/pubmed/10941350
  4. Musher DM, Rueda Am, Kaka As, Mapara SM. The association between pneumococcal pneumonia and acute cardiac events. Clin Infect Dis 2007;45:158-65. https://www.ncbi.nlm.nih.gov/pubmed/17578773
  5. Corrales-Medina VF, Serpa J, Rueda AM, et al. Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes. Medicine (Baltimore) 2009;88:154-9. https://www.ncbi.nlm.nih.gov/pubmed/19440118
  6. Dalager-Pedersen M, Sogaard M, Schonheyder HC, et al. Risk for myocardial infarction and stroke after community-acquired bacteremia: a 20-year population-based cohort study. Circulation 2014;129:1387-96. https://www.ncbi.nlm.nih.gov/pubmed/24523433

 

My hospitalized patient with pneumonia has now suffered an acute myocardial infarction (MI). Can acute infection and MI be related?

Can my patient contract influenza more than once in a season?

It’s not common but reinfection with influenza can definitely occur, either due to the same viral strain, or due to a different one altogether.

One study reported influenza reinfection due to H1N1 in otherwise healthy patients within 12-20 days of the original infection after an apparent period of full recovery. 1 There was no evidence of resistance to oseltamivir among isolates and all patients recovered after the second infection.

Reinfection with the same viral strain within 2-3 weeks of the initial bout of influenza shouldn’t be too surprising since it takes 4-7 weeks for antibody response to the infection to peak. 2 Reexposure to the same circulating strain of influenza virus (the season can last 6 weeks or longer) can then result in reinfection when the body hasn’t had enough time to make significant amount of protective antibodies following the first infection.

Another explanation is that more than 1 strains of influenza virus often circulate during any given season.   This places patients at risk of infection due to strains of influenza virus that do not confer significant cross-immunity between each other,  resulting in getting “the flu twice in 1 season.” 3

References

  1. Perz CM, Ferres M, Labarca JA. Pandemic (H1N1) 2009 reinfection, Chile. Emerg Infect Dis 2010;16:156-57. https://wwwnc.cdc.gov/eid/article/16/1/pdfs/09-1420.pdf
  2. Treanor JJ. Influenza viruses, including avian influenza and swine influenza. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed. New York: Elsevier; 2010. p 2265-2293.
  3. Rettner R. Can you get the flu twice in 1 season? Scientific American, LiveScience, February 4, 2018. https://www.scientificamerican.com/article/can-you-get-the-flu-twice-in-1-season/ . Accessed February 5, 2018.

 

Can my patient contract influenza more than once in a season?

Are neuraminidase inhibitors (NAIs) such as oseltamivir (Tamiflu) still effective for treatment of influenza in my hospitalized patient with greater than 48 hours of symptoms?

Although there are no randomized controlled studies, several observational studies support  the benefit of NAIs even when initiated after 48 h of onset of symptoms. 

Although the sooner NAIs are initiated the more likely the odds of a favorable impact on the course of influenza, the FDA approval of these drugs was based on analysis of data in relatively healthy ambulatory patients not those who are often sicker and require hospitalization. 

A retrospective study reported improvement in survival even when treatment was delayed for 4-5 days after symptom onset (1). Other studies have reported more rapid viral clearance and clinical benefit in severe infections even when antivirals were initiated after 48 h (2).  

Collectively , these data suggest that in the presence of ongoing symptoms and likely active viral replication, NAI treatment should be seriously considered in hospitalized patients who are likely to have more severe disease.

In fact, CDC recommends  “initiation of antiviral treatment as early as possible” in hospitalized patients with influenza, and asserts that “antiviral treatment might be effective in reducing morbidity and mortality in hospitalized patients even if treatment is not started until >48 hours after onset of illness” (3).  

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References

  1. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1) pdm09. Clin Infect Dis 2012;44:1198-1204. https://www.ncbi.nlm.nih.gov/pubmed/22843781
  2. Lee N, Ison MG. “Late” treatment with neuraminidase inhibitors for severely ill patients with influenza: better late than never? Clin Infect Dis 2012;55:1205-8. https://www.ncbi.nlm.nih.gov/pubmed/22843780
  3. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR 2011;60 (RR01):1-24.
Are neuraminidase inhibitors (NAIs) such as oseltamivir (Tamiflu) still effective for treatment of influenza in my hospitalized patient with greater than 48 hours of symptoms?

Is there a seasonal variation in the incidence of cardiovascular (CV) events or venous thromboembolism (VTE)?

Seasonal variation, primarily characterized by a winter peak, has been reported for acute CV events, such as acute myocardial infarction (AMI) and sudden death, aortic rupture or dissection, and ischemic or hemorrhagic stroke, and VTE (1). A meta-analysis involving patients with VTE, primarily with a diagnosis of pulmonary embolism, revealed a 20% absolute increase in the incidence of VTE during January (1).  

Potential physiological mechanisms for these observations include increased sympathetic activity, decreased loss of fluids and sodium, increase in LDL cholesterol, increase in serum fibrinogen levels and other coagulation markers and C-reactive protein, and lower vitamin D levels due to shorter daylight hours during winter months (1,2).  At least in the case of AMI in the U.S., the higher incidence in winter is not affected by climate (2).  

Respiratory virus infections as a cause of acute inflammation leading to  CV or VTE events is another intriguing explanation (3). Indeed, influenza vaccination has been associated with reduction in hospitalization for cardiac disease and stroke among the elderly (4) and, in patients with cardiovascular disease, a reduction in death due to combined cardiovascular disease events such as heart attacks and strokes (5).

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References

  1. Dentali F, Ageno W, Rancan E, et al. Seasonal and monthly variability in the incidence of venous thromboembolism. A systematic review and a meta-analysis of the literature. Thromb Haemost 2011;106:439-447. https://www.ncbi.nlm.nih.gov/pubmed/21725580
  2. Spencer FA, Goldberg RJ, Becker RC, et al. Seasonal distribution of acute myocardial infarction in the Second National Registry of Myocardial Infarction. J Am Coll Cardiol 1998;31:1226-33.h ttps://www.ncbi.nlm.nih.gov/pubmed/9581712
  3. Woodhouse PR, Khaw KT, Plummer M, et al. Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet 1994;343:435-39.  https://www.ncbi.nlm.nih.gov/pubmed/7508540
  4. Nichol KL, Nordin J, Mulloly J, et al. Influenza vaccination and reduction in hospitalization for cardiac disease and stroke among the elderly. N Engl J Med 2003; 348:1322-1332. http://www.nejm.org/doi/full/10.1056/NEJMoa025028
  5. Clar C, Oseni Z, Flowers N, et al. Cochrane Database of Systematic Reviews 2015. DOI: 10.1002/14651858.CD005050.pub3h ttp://www.cochrane.org/CD005050/VASC_flu-vaccines-for-preventing-cardiovascular-disease  

 

 

 

 

Is there a seasonal variation in the incidence of cardiovascular (CV) events or venous thromboembolism (VTE)?

Are GI symptoms such as nausea, vomiting, and diarrhea common in patients with influenza?

Typically, GI symptoms are more prominent in children with influenza than adults but during the H1N1 epidemic in 2009 (which has subsequently become endemic), up to 26% of hospitalized adults with H1N1 infection had abdominal pain or vomiting and up to 25% had diarrhea (1). 

In fact, H1N1 virus has been isolated from stool of adult hospitalized patients (2,3) and receptors of influenza virus have been identified in human GI epithelial cells, the correlation between GI symptoms and isolation of virus from stool is poorly defined (4).

Interestingly, the mechanism involved in influenza-mediated intestinal injury may have less to do with direct invasion of the intestinal mucosa by the virus and more to do with immune mediated changes  related to alterations in the intestinal microbiota induced by influenza virus infection itself (4,5)! 

Aside from direct or indirect effects of influenza virus on the GI tract, oseltamivir and non-steroidal anti-inflammatory use may also contribute to GI symptoms (4).

 

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References

  1. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 2010;362:1708-19. https://www.ncbi.nlm.nih.gov/pubmed/20445182
  2. Yoo SJ, Moon SJ, Kuak E-Y, et al. Frequent detection of pandemic (H1N1) 2009 virus in stools of hospitalized patients. J Clin Microbiol 2010; 48:2314-2315. https://www.ncbi.nlm.nih.gov/pubmed/20375236
  3. Minodier L, Charrel RN, Ceccaldi PE, et al. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Virol J 2015;12:215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676820/
  4. Shu Y, Li CK, Gao R, et al. Avian influenza A(H5N1) viruses can directly infect and replicate in human gut tissues. J Infect Dis 2010;201:1173-7. https://www.ncbi.nlm.nih.gov/pubmed/20210629
  5. Wang J, Li F, Wei H, et al. Respiratory influenza virus infection induces intestinal immune injury via microbiota mediated Th17 cell-dependent inflammation. J Exp Med 2014;211:2397-2410. http://europepmc.org/article/PMC/4235643
Are GI symptoms such as nausea, vomiting, and diarrhea common in patients with influenza?