How “sensitive” is the PCR in diagnosing coronavirus/Covid-19?

A definite diagnosis of Covid-19 requires viral testing, usually through PCR performed on upper (nasopharyngeal or oropharyngeal) or lower respiratory samples (sputum, bronchoalveolar lavage [BAL] fluid). Rates of positive PCR may be affected by stage of the disease and/or its severity.
Nasopharyngeal sample: This seems to be the most practical and readily available means of confirming Covid-19 diagnosis, with positive rates of ~75% during the first 2 weeks of illness in patients considered to have severe disease. For patients with mild Covid-19, a positive PCR rate of 72% has been reported during the 1st week, dropping to 54% during the 2nd week (1).
Oropharyngeal sample: Lower positive PCR rates have been observed with throat swabs, as low as ~30% in mild Covid-19 during the 2nd week of the illness and ~60% in severe disease during the first week of illness (2).
Sputum: Sputum may have the highest positive rates ranging from ~75% in mild disease during the second week of illness to ~90% during the 1st week of severe disease. The problem with sputum sampling is that less than one-third of patients with Covid-19 can provide a sample given the usually dry nature of their cough (1,4).
BAL fluid: In a limited number of patients with severe disease who had bronchoalveolar lavage sampling during the 2nd week of illness, 3 (25%) of 12 patients with positive PCR on BAL had negative upper respiratory samples (1). So in severe disease, the virus definitely prefers to replicate in the lower respiratory tract.
Potential explanations for a negative PCR include low viral titers and specimen handling. So, in patients suspected of having Covid-19 based on clinical/laboratory/radiograph grounds, a negative upper respiratory sample, particularly oropharyngeal source, should not rule out this disease.

 

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References

1. Yang Y, Yang M, Shen C, et al. Evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding of 2019-nCoV infections. MedRxiv. 2020. DOI: http://doi.org/10.1101/2020.02.11.20021493
2. Ai T, Yang Z, Hou H, et al. Correlation of chest CT and RT-PCR testing in Coronavirus disease 2019 (COVID-19) in China: A report of 1014 cases. Radiology 2020. https://pubs.rsna.org/doi/10.1148/radiol.2020200642
3. Bai HX, Hsieh B, Xiong Z, et al. Performance of radiologists in differentiaging COVID-19 from viral pneumonia on chest CT. Radiology 2020. https://pubs.rsna.org/doi/10.1148/radiol.2020200823 
4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

How “sensitive” is the PCR in diagnosing coronavirus/Covid-19?

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)?

Can the elevation of AST and ALT in my patient with rhabdomyolysis be related to the muscle injury itself?

Yes! Elevated serum AST and ALT in the setting of rhabdomyolysis is not uncommon and, at least in some cases, appears to be related to the skeletal muscle injury itself.1,2

In a study of 16 patients considered to have significant muscle necrosis due to extreme exercise, polymyositis or seizures without evidence of liver disease (eg, viral hepatitis, exposure to hepatotoxic drugs, heart failure, biliary tract disease, recent hypotension) AST and, to lesser degree, ALT was elevated. For extreme exercise, the median AST and ALT concentrations were 2,466 IU/L and 497 U/L, respectively, while for seizures these levels were 1,448 U/L and 383 U/L respectively.1  

Another study reported AST elevation (>40 U/L) in 93.1% of patients with rhabdomyolysis and ALT elevation (>40 U/L) in 75.0% of patients with serum creatine kinase ≥1000 U/L. Further supporting a skeletal muscle origin for AST elevation was the finding that AST concentrations fell in parallel with CK drop during the first 6 days of hospitalization for rhabdomyolysis. It was posited that ALT concentrations dropped slower because of its longer serum half-life (47 hours vs 17 hours for AST).2 Despite these findings, concurrent liver injury as an additional source of AST or ALT elevation cannot be excluded.

Elevation of AST and ALT with muscle injury should not come as a surprise. AST is found in heart and skeletal muscle among many other organs. Even ALT which is considered more specific to liver is found in organs such as skeletal muscle, heart and kidney, though at lower concentrations.3

Bonus Pearl: Did you know that the first description of rhabdomyolysis in the literature involved English victims of crush injuries during World War II?2

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References

  1. Nathwani RA, Pais S, Reynolds TB, et al. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005;41:380-82. https://www.ncbi.nlm.nih.gov/pubmed/15660433
  2. Weibrecht K, Dayno M, Darling C, et al. Liver aminotransferases are elevated with rhabdomyolysis in the absence of significant liver injury. J Med Toxicol 2010;6:294-300. https://link.springer.com/article/10.1007%2Fs13181-010-0075-9
  3. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guidance for clinicians. CMAJ2005;172:367-79. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guidance for clinicians. CMAJ 2005;172:367-79. https://www.ncbi.nlm.nih.gov/pubmed/15684121
Can the elevation of AST and ALT in my patient with rhabdomyolysis be related to the muscle injury itself?

My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

The weight of the evidence to date suggests that immunosuppressive therapy, including steroids, other oral immunosuppressants and anti-tumor-necrosis factor (TNF) agents, may negatively impact IGRA results.1

In some ways the finding of false-negative IGRA in the setting of immunosuppression is intuitive since many immunosuppressive agents are potent inhibitors of T cells and interferon-gamma response. 1,2 Despite this, the initial reports have been somewhat conflicting which makes a 2016 meta-analysis of the effect of immunosuppressive therapy on IGRA results in patient with autoimmune diseases (eg, rheumatoid arthritis, lupus, inflammatory bowel disease) particularly timely. 1

This meta-analysis found a significantly lower positive IGRA results among patients on immunosuppressive therapy ( O.R. 0.66, 95% C.I. 0.53-0.83). Breakdown by IGRA test showed a significant association between QuantiFERON-TB Gold In-Tube and lower positive results and a trend toward the same with T-SPOT though the latter did not reach statistical significance with fewer evaluable studies (O.R. 0.81, 95% C.I 0.6-1.1).   Breakdown by type of immunosuppressant showed significantly negative impact of corticossteroids, other oral immunosuppressants, and anti-TNF agents for all. Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 3,4

So, whenever possible, testing for latent TB should be performed before immunosuppressants are initiated.

Bonus Pearl: Did you know that an estimated one-third of the world’s population may have latent TB?

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References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Sester U, Wilkens H, van Bentum K, et al. Impaired detection of Mycobacterium tuberculosis immunity in patents using high levels of immunosuppressive drugs. Eur Respir J 2009;34:702-10. https://erj.ersjournals.com/content/34/3/702
  3. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  4. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

Although serum gamma-glutamyl transpeptidase or GGT is a very sensitive test for liver disease, especially of biliary origin, it’s by no means a very specific test. Besides the liver, GGT is found in the kidneys, pancreas, prostate, heart, brain, and seminal vesicles but not in bone (1-4).

 
Obesity, alcohol consumption and drugs are common causes of GGT elevation (2). As early as 1960s, elevated GGT was reported in such seemingly disparate conditions as diabetes mellitus, congestive heart failure, myocardial infarction, nephrotic syndrome and renal neoplasm (3). Nonalcoholic steatohepatitis, viral hepatitis, biliary obstruction, COPD, liver metastasis, drug-induced liver injury can all cause GGT elevation (1-4).

 
An isolated GGT does not necessarily indicate serious or progressive liver disease. That’s one reason it’s often not included in routine “liver panel” lab tests (1).

What to do when GGT is high but other liver panel tests such as ALT, AST, albumin, and bilirubin are normal? If your patient is at risk of acquired liver disease, then further workup may be necessary (eg, hepatitis B and C screening tests). Alcohol consumption should be queried. Don’t forget conditions associated with iron overload. If your patient is obese, diabetic or has elevated both lipids, an ultrasound of the liver to look for fatty liver should be considered. In the absence of risk factors, symptoms, or physical exam suggestive of liver disease, isolated GGT elevation should not require further investigation (1).

 
One good thing that may come out of finding an isolated elevated GGT is to encourage your patient to curb alcohol consumption or lose weight when indicated. But don’t rely on a normal GGT to rule out heavy alcohol consumption as it may miss 70% to 80% of cases (6)! 

 
Bonus Pearl: Did you know that GGT activity is thought to increase in alcohol use due to its role in maintaining intracellular glutathione, an anti-oxidant, at adequate levels to protect cells from oxidative stress caused by alcohol?

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References

1. Carey WD. How should a patient with an isolated GGT elevation be evaluated? Clev Clin J Med 2000;67:315-16. https://www.ncbi.nlm.nih.gov/pubmed/10832186
2. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut 2018;67:6-19. https://gut.bmj.com/content/gutjnl/67/1/6.full.pdf
3. Whitfield JB, Pounder RE, Neale G, et al. Serum gamma-glutamyl transpeptidase activity in liver disease. Gut 1972;13:702-8. https://www.ncbi.nlm.nih.gov/pubmed/4404786
4. Tekin O, Uraldi C, Isik B, et al. Clinical importance of gamma glutamyltransferase in the Ankara-Pursaklar region of Turkey. Medscape General Medicine 2004;6(1):e16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140713/
5. Van Beek JHDA, de Moor MHM, Geels LM, et al. The association of alcohol intake with gamma-glutamyl transferase (GGT) levels:evidence for correlated genetic effects. Drug Alcohol Depend 2014;134:99-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909645/

6. Bertholet N, Winter MR, Cheng DM, et al. How accurate are blood (or breath) tests for identifying self-reported heavy drinking among people with alcohol dependence? Alcohol and Alcoholism 2014;49:423-29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060735/pdf/agu016.pdf

What’s causing an isolated GGT elevation in my patient with an abnormal alkaline phosphatase on her routine admission lab?

Could measurement of urinary albumin-protein ratio be useful in my patient with renal insufficiency and proteinuria?

A spot urine test for determination of albumin-protein ratio (uAPR) may be useful in distinguishing glomerular vs tubulointerstitial source of proteinuria. A low (<0.4) uAPR, defined as urinary albumin to creatinine ratio(uACR)/urinary protein to creatinine ratio (uAPR) is more suggestive of a tubulointerstitial renal disease and less suggestive of glomerular pathology.1-3  

A 2012 study involving simultaneous measurements of urinary albumin and total protein in over 1000 proteinuric patients found a relatively high (0.84) area under curve (AUC) in a receiver operating characteristic curve analysis for uAPR (vs 0.74 for uACR and 0.54 for uPCR) in discriminating between tubular and non-tubular proteinuria pattern on urine protein electrophoresis and immunofixation. An uAPR cut-off of <0.4 was found to be 88% sensitive and 99% specific for the diagnosis of primary tubulointerstitial disorders on renal biopsy.1  

Due to the limitations of this study (including a relatively small subset of patient who had renal biopsy), a related editorial concluded that a low uAPR gives a “reasonable prediction of a tubular electrophoretic proteinuria”, but that it warrants further validation. Nevertheless, uAPR could potentially be useful in patients with moderate proteinuria (>300 mg/day to <3 g/day) who have not had renal biopsy and  where assessment of likelihood of tubulointerstitial vs glomerular source of proteinuria is desired.3 Interestingly, the utility of uAPR in predicting non-glomerular source of hematuria has also been reported.4

Bonus pearl: Did you know that the negatively-charged glomerular capillary wall repels negatively charged albumin thus preventing its filtration (charge-barrier) (5)?  

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References

  1. Smith ER, Cai MMX, McMahon LP, et al. The value of simultaneous measurement of urinary albumin and total protein in proteinuric patients. Nephrol Dial Transplant 2012;27:1534-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035283/
  2. Fraser SDS, Roderick PJ, McIntyre NJ, et al. Assessment of proteinuria in patients with chronic kidney disease stage 3: albuminuria and non-albumin proteinuria. PLOS ONE 2014;9:e98261. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035283/pdf/pone.0098261.pdf
  3. Ellam T, Nahas ME. Urinary albumin to protein ratio: more of the same or making a difference. Nephrol Dial Transplant 2012;27:1293-96. https://www.ncbi.nlm.nih.gov/pubmed/22362784
  4. Ohisa N, Yoshida K, Matsuki R, et al. A comparison of urinary albumin-total protein ratio to phase-contrast microscopic examination of urine sediment for differentiating glomerular and nonglomerular bleeding. Am J Kidney Dis 2008;52:235-41. https://www.ajkd.org/article/S0272-6386(08)00828-7/pdf
  5. Venkat KK. Proteinuria and microalbuminuria in adults: significance, evaluation, and treatment. S Med J 2004;97:969-79. https://internal.medicine.ufl.edu/files/2012/07/5.18.05.04.-Proteinuria-review.pdf
Could measurement of urinary albumin-protein ratio be useful in my patient with renal insufficiency and proteinuria?

Should I use aPTT or anti-Xa levels to monitor my patient on IV heparin infusion?

Despite more than half a century of use unfractionated heparin (UFH), the optimal method to monitor its anticoagulation effect remains unclear, with arguments for and against continued use of activated partial thromboplastin time, aPTT) vs switching to antifactor Xa heparin assay (anti-Xa HA). 1-4

The advantage of aPTT include decades of use and familiarity by providers, and its relative accessibility, ease of automation and cost.1 Its disadvantages include variation among the sensitivities of different aPTT reagents as well as susceptibility to factors that do not reflect intrinsic heparin activity (eg, liver dysfunction, hypercoagulable states). 1,2 Thus patients may receive unnecessarily high or low heparin doses because of physiologic and non-physiologic influences on aPTT.

In contrast, since anti-XA HA measures the inhibition of a single enzyme (factor Xa)1, it is a more direct measurement of heparin activity, with less variability and minimal interference by certain biological factors (eg, lupus anticoagulants). Anti-Xa monitoring may also improve the time to therapeutic anticoagulation and lead to fewer dose adjustments compared to aPTT monitoring.2

The disadvantages of anti-Xa HA include inaccuracy in the setting of hypertriglyceridemia (>360 mg/dL), hyperbilirubinemia (total bilirubin >6.6 mg/dL), recent use of low molecular weight heparin, fondaparinux and direct oral factor Xa inhibitors. Its relative expense and generally less laboratory availability among healthcare facilities may also limit its use in monitoring patients on therapeutic UFH. 1-3

Somewhat unsettling is the frequent discordance between aPTT and anti-Xa values having been reported in 46% to 60% of instances that may result in either thromboembolic or bleeding complications. 1,4 One study reported that aPTT may be therapeutic only 35% of the time that anti-Xa is also therapeutic! 2

What’s clearly missing are definitive studies that can shed light on the clinical impact of these intriguing findings on patient outcomes. So stay tuned!

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References

  1. Guervil DJ, Rosenberg AF, Winterstein AG, et al. Activated partial thromboplastin time versus antifactory Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother 2011;45:861-68. https://www.ncbi.nlm.nih.gov/pubmed/21712506
  2. Whitman-Purves E, Coons, JC, Miller T, et al. Performance of Anti-factor Xa versus activated partial thromboplastin time for heparin monitoring using multiple nomograms. Clinical and Applied Thromosis/Hemostasis 2018;24:310-16. https://www.ncbi.nlm.nih.gov/pubmed/29212374
  3. Fruge KS, Lee YR. Comparison of unfractionated heparin protocols using antifactory XA monitoring or activated partial thrombin time monitoring. Am J Health-System Pharmacy. 2015; 72: S90-S97, https://doi.org/10.2146/sp150016
  4. Samuel S, Allison TA, Sharaf S, et al. Antifactor XA levels vs activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study. J Clin Pharm Ther 2016;41:499-502.
  5. doi:10.1111/jcpt.12415. https://www.ncbi.nlm.nih.gov/pubmed/27381025
Should I use aPTT or anti-Xa levels to monitor my patient on IV heparin infusion?

When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

Think of invasive pulmonary aspergillosis (IPA) in your patient when she or he has a COPD exacerbation that appears refractory to broad-spectrum antibiotics and high doses of steroids. Heighten your suspicion even more in patients with severe-steroid dependent COPD, presence of a new pulmonary infiltrate or isolation of Aspergillus spp from respiratory cultures. 1

It’s worth remembering that although dyspnea and bronchospasm are found in most COPD patients with IPA, in contrast to haematological patients, fever, chest pain and hemoptysis are usually absent in this patient population.1

Diagnosis of IPA in this patient population is challenging for several reasons including: 1. A definitive or “proven” diagnosis requires histopathologic evidence of Aspergillus invasion of lung tissue which is not possible without subjecting an already fragile patient to invasive procedures (eg, lung aspiration or biopsy); 2. In contrast to IPA in highly susceptible immunocompromised patients with cancer and recipients of hematopoietic stem cell transplants, standardized definition of IPA in patients with COPD is lacking; 1,3 and 3. Frequent colonization of the respiratory tract of COPD patients with Aspergillus spp (16.3 per 1000 COPD admission in 1 study) 4,5, makes it difficult to diagnose IPA based on cultures alone.

Aside from respiratory cultures, another non-invasive test, serum galactomannan (GM, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp and released into the blood during its growth phase 6) may have some utility in suggesting IPA in COPD patients, albeit with a mediocre sensitivity (~30-60%) but respectable specificity (>80 %). In contrast, bronchoalveolar lavage fluid GM may have better sensitivity  (~75%-90%) with similar specificity as that of serum GM in the diagnosis of IPA in these patients 7-8

Bonus pearl: Did you know that the incidence of IPA appears to be increasing in COPD patients requiring ICU admission, with reported mortality rates of 67% to 100%? 7

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References

  1. Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Res J 2007;30:782-800. https://www.ncbi.nlm.nih.gov/pubmed/17906086
  2. Bulpa P, Bihin B, Dimopoulos G, et al. Which algorithm diagnoses invasive pulmonary aspergillosis best in ICU patietns with COPD? Eur Resir J 2017;50:1700532 https://www.ncbi.nlm.nih.gov/pubmed/28954783
  3. Barberan J, Garcia-Perez FJ, Villena V, et al. Development of aspergillosis in a cohort of non-neutropenic, non-transplant patients colonized by Aspergillus spp. BMC Infect Dis 2017;17:34. https://link.springer.com/article/10.1186/s12879-016-2143-5
  4. Guinea J, Torres-Narbona M, Gijon P, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010; 16:870-77. https://www.sciencedirect.com/science/article/pii/S1198743X14617432
  5. Blot Stijn I, Taccone FS, Van den Abeele A-M, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 202;186:56-64. https://www.atsjournals.org/doi/full/10.1164/rccm.201111-1978OC
  6. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417-27. https://academic.oup.com/cid/article/42/10/1417/278148
  7. He H, Ding L, Sun B, et al. Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. Critical Care 2012;16:R138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066034/
  8. Zhou W, Li H, Zhang Y, et al. Diagnostic value of galactomannan antigen test in serum and bronchoalveolar lavage fluid samples from patients with nonneutropenic invasive pulmonary aspergillosis. J Clin Microbiol 2017;55:2153-61. https://www.ncbi.nlm.nih.gov/pubmed/28446576
When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

How useful is serum 1, 3-β-D-glucan in diagnosing Pneumocystis jiroveci pneumonia and invasive fungal disease?

Serum 1, 3-β-D-glucan (BG) is highly accurate for Pneumocystis jiroveci pneumonia (PJP), but only moderately accurate for diagnosing invasive fungal disease (IFD).

For PJP, a meta-analysis of studies looking at the performance of BG found a pooled sensitivity of 96%, specificity of 84% and area under receiver operating characteristic curve (AUC-ROC) of 0.96. 1 Thus, a negative BG essentially rules out PJP.

For IFD (primarily invasive candidiasis or aspergillosis), data based on 3 separate meta-analyses came to similar conclusions with a pooled sensitivity and specificity of ~80% and AUC-ROC of ~0.89 each.1-3 In some of the studies,2,3 the sensitivity of BG for IFD was between 50% to 60% which makes it difficult to exclude IFD when BG is normal.

Remember that BG may be false-positive in a variety of situations, including patients receiving immunological preparations (eg albumin or globulins), use of membranes and filters made from cellulose in hemodialysis, and use of cotton gauze swabs/packs/pads and sponges during surgery. 1 In addition, although BG is a component of the cell wall of most fungi, there are some exceptions including Zygomycetes and cryptococci.

Bonus pearl: Did you know that BG assay is based on Limulus amoebocyte lysate, extracted from amoebocytes of horseshoe crab species? 3

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References

  1. Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum 1,3-β-D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol 2012;50:7-15. https://www.ncbi.nlm.nih.gov/pubmed/22075593
  2. He S, Hang JP, Zhang L, et al. A systematic review and meta-analysis of diagnostic accuracy of serum 1,3–β-D-glucan for invasive fungal infection: focus on cutoff levels. J Microbiol Immunol Infect 2015;48:351-61. https://www.ncbi.nlm.nih.gov/pubmed/25081986
  3. Karageogopoulos DE, Vouloumanou EK, Ntziora F, et al. β-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 2011;52:750-69. https://academic.oup.com/cid/article/52/6/750/361658/

 

How useful is serum 1, 3-β-D-glucan in diagnosing Pneumocystis jiroveci pneumonia and invasive fungal disease?

My patient with COPD exacerbation has an elevated venous blood PCO2. How accurate is the peripheral venous blood gas PC02 in patients with hypercarbia?

Short answer: Not as accurate as we might like! An elevated venous pC02 is a good indicator of the presence of arterial hypercarbia but beyond that if you really want to know what the arterial pC02 is in your patient with hypercarbia, you should get an arterial blood gas (ABG).

 
A meta-analysis of studies involving patients with COPD presenting to the emergency department (ED) found a good agreement for pH and bicarbonate values between arterial and venous blood gases but not for pC02 or p02 (1). More specifically, the 95% limit of agreement varied widely from -17 to +26 mmHg between venous and arterial pC02 (average difference ~6.0 mm). In the same study, a venous pC02 of ~45 mmHg or less correctly identified patients who were hypercarbic based on ABG. Similar results have been reported by other studies involving patients with COPD exacerbation (2,3).

 
Another meta-analysis involving all comers (COPD and non-COPD patients) concluded that venous pC02 should not be used as a substitute for arterial pC02 when accurate pC02 is required (4). In fact, they emphasized that venous pC02 was not always greater than arterial pC02!

 
Bonus pearl: Did you know that an unexpectedly low bicarbonate level in a patient with COPD and CO2 retention should alert us to the possibility of concurrent metabolic acidosis (eg, due to lactic acidosis, uremia)?

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References
1. Lim BL, Kelly AM. A meta-analysis on the utility of peripheral venous blood gas analyses in exacerbations of chronic obstructive pulmonary disease in the emergency department. Eur J Emerg Med 2010;17:246-48. https://journals.lww.com/euro-emergencymed/Abstract/2010/10000/A_meta_analysis_on_the_utility_of_peripheral.2.aspx
2. McCanny P, Bennett K, Staunton P, et a. Venous vs arterial blood gases in the assessment of patients presenting with an exacerbation of chronic obstructive pulmonary disease. Am J Emerg Med 2012;30:896-900. https://www.sciencedirect.com/science/article/abs/pii/S0735675711002865
3. McKeevere TM, Hearson G, Housely G, et al. Using venous blood gas analysis in the assessment of COPD exacerbations: a prospective cohort study. Thorax 2016;71:210-15. https://www.researchgate.net/publication/285545995_Using_venous_blood_gas_analysis_in_the_assessment_of_COPD_exacerbations_A_prospective_cohort_study
4. Byrne AL, Bennett M, Chatterji R, et al. Peripheral venous and arterial blood gas analysis in adults:are they comparable? A systematic review and meta-analysis. Respirology 2014;19:168-75. https://onlinelibrary.wiley.com/doi/full/10.1111/resp.12225

My patient with COPD exacerbation has an elevated venous blood PCO2. How accurate is the peripheral venous blood gas PC02 in patients with hypercarbia?