Month: October 2020

How long should I expect Legionella urine antigen test to remain positive after diagnosis of legionnaire’s disease in my patient with pneumonia?

FA Manian MD, MPH, , , , Leave a comment

The urine antigen test for detection of Legionnaire’s disease (LD) can remain positive for weeks or months after initial infection. So a positive test in a patient with pneumonia may not just be suggestive of an acute infection but also the diagnosis of LD during recent weeks or months (1,2).

In a study of Legionella urine antigen detection as a function of days after onset of symptoms, 11 of 11 (100%) patients tested remained positive after day 14 (1). In the same study, 10 of 23 (43%) patients excreted antigen for 42 days or longer following initiation of therapy, with some patients remaining positive for more than 200 days!

In another study involving 61 patients with Legionella pneumophila pneumonia, 25% excreted Legionella antigen for 60 or more days (2). Longer duration of antigen excretion was significantly associated with immunosuppressed patients in whom the time to resolution of fever was > 72 h.

The long duration of excretion of Legionella antigen in urine following LD is not surprising. Pneumococcal pneumonia has also been associated with prolonged antigen excretion, some for as long as 6 months after diagnosis of pneumonia (3). It is thought that some microbial polysaccharides may be degraded very slowly or not at all by mammalian tissues which could explain their prolonged appearance in the urine long after active infection has resolved (1).

Bonus pearl: Did you know that the sensitivity of Legionella urinary antigen for LD varies from 94% for travel-associated infections to 76%-87% for community-acquired infection, and to as low as ~45% for nosocomially-acquired infections (4)?

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References

  1. Kohler RB, Winn WC, Wheat J. Onset and duration of urinary antigen excretion in Legionnaires disease. J Clin Microbiol 1984;20:605-7. https://pubmed.ncbi.nlm.nih.gov/6490846/
  2. Sopena N, Sabria M, Pedro-Bolet ML, et al. Factors related to persistence of Legionella urinary antigen excretion in patients with legionnaire’s disease. Eur J Clin Microbiol Infect Dis 2002;21:845-48. https://europepmc.org/article/med/12525918
  3. Andreo F, Prat C, Ruiz-Manzano J, et al. Persistence of Streptococcus pneumoniae urinary antigen excretion after pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 2009;28:197-201. https://pubmed.ncbi.nlm.nih.gov/18830727/
  4. Helbig JH, Uldum SA, Bernander S, et al. Clinical utility of urinary antigen detection for diagnosis of community-acquired, travel-associated, and nosocomial Legionnaire’s disease. Clin Microbiol 2003;41:838-40. https://pubmed.ncbi.nlm.nih.gov/12574296/

 

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 long should I expect Legionella urine antigen test to remain positive after diagnosis of legionnaire’s disease in my patient with pneumonia?

How might measuring viral load in respiratory specimens be helpful clinically in patients with Covid-19?

FA Manian MD, MPH, , , , , , Leave a comment

Although far from being perfect, there are emerging scientific data that suggest measuring viral load in respiratory specimens of patients with Covid-19 could be helpful in at least 2 ways: 1. Help determine who may be infectious (therefore isolated or undergo contact tracing); and 2. Identify patients at high risk for severe disease and death (1-4).

In a study involving 3,790 nasopharyngeal samples testing positive for SARS-CoV-2 by PCR, a significant correlation was found between isolation of the virus by culture—therefore potential contagiousness—and viral load determined by cycle threshold (CT) (ie, the number of cycles needed to detect the virus with higher numbers thought to be associated with lower risk of contagion) (2). Some have suggested that patients with CT above 33-34 are no longer contagious (3).

In another study involving 978 patients with Covid-19, high viral load in nasopharyngeal specimens was associated with higher risk of intubation (O.R. 2.7, 1.7-4.4), and mortality (6.1, 2.9-12.5) (4).

In addition, simultaneous presence of high viral loads in the respiratory specimens in the population suggests an expanding outbreak, while low viral loads may imply that the outbreak is waning (1).

Some have cautioned against over-reliance on viral loads in Covid-19 due to factors such as variation in the technique of obtaining specimens and testing instruments (5).

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References
1. Service RF. Covid-19. A call for diagnostic tests to report viral load. Science 2020, October 2;370:22. https://www.sciencemag.org/news/2020/09/one-number-could-help-reveal-how-infectious-covid-19-patient-should-test-results
2. Jaafar R, Aherfi S, Wurtz N, et al. Correlation between 3790 qPCR positives samples and positive cell cultures including 1941 SARS-CoV-2 isolates. Clin Infect Dis 2020, September. https://pubmed.ncbi.nlm.nih.gov/32986798/
3. La Scola B, Le Bideau M, Andreani J, et al. Viral RNA as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards. Eur J Clin Microbiol Infect Dis 2020;39:1059-1061. https://pubmed.ncbi.nlm.nih.gov/32342252/
4. Magleby R, Westblade LF, Trzebucki A, et al. Impact of severe acute respiratory syndrome coronavirus 2 viral load on risk of intubation and mortality among hospitalized patients with coronavirus disease 2019. Clin Infect Dis 2020. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa851/5865363
5. Rhoads D, Peaper DR, She RC, et al. College of American Pathologists (CAP) Microbiology Committee perspective: caution must be used in interpreting the cycle threshold (Ct) value. Clin Infect Dis 12 August, 2020. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1199/5891762

 

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 might measuring viral load in respiratory specimens be helpful clinically in patients with Covid-19?

Why would my patient with Covid-19 infection test negative by PCR?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

There are several potential reasons why someone who is infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of Covid-19, may test negative by PCR. These including the threshold for detection of virus (which can vary among different manufacturers from as low as 100 viral copies/ml to >6,000 copies/ml),1 timing of the sample collection with respect to infection stage (lowest false-negative rate [~20%] on day 3 of symptoms or 8 days post-infection),2  specimen storage and transport and, particularly in the case of nasopharyngeal specimens, the adequacy of the sample obtained. 3

Suboptimal specimen collection from nasopharynx has long been suspected as an explanation for false-negative PCR tests in patients who subsequently have a positive test or are highly suspected of having Covid-19, but without any good support data. Until now…

A clever study looked at the presence of human DNA recovered from nasopharyngeal swabs as a marker for adequate specimen collection quality and found that human DNA levels were significantly lower in samples from patients with confirmed or suspected Covid-19 that yielded negative results compared to those of representative pool of samples submitted for Covid-19 testing.3

Interestingly, major commercial assays do not include any internal controls that ensure adequate sampling before testing for SARS-CoV2.

A typical microbiology lab can reject a sputum culture if gram-stain suggests poor quality specimen (eg, saliva only) but it looks like no similar rule exists for nasopharyngeal PCR tests for SARS-CoV-2 through commercial labs. Apparently, the US-CDC diagnostic panel does include a human RNAseP RNA-specific primer/probe set but the interpretation criteria for this control may also be too liberal.3

For these reasons, in patients highly suspected of having Covid-19 but with a negative initial PCR test, a repeat test on the same day or next 2 days is recommended.4

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References

  1. Prinzi A. False negatives and refinfections: the challenges of SARS-CoV-2 RT-PCR testing. Available at https://asm.org/Articles/2020/April/False-Negatives-and-Reinfections-the-Challenges-of     Accessed October 5, 2020.
  2. Kucirka LM, Lauer SA, Laeyendecker O, et al. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med 2020 May 13:M20-1495. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240870/
  3. Kinloch NN, Ritchie G, Brumme CJ, et al. Suboptimal biological sampling as a probable cause of false-negative COVID-19 diagnostic test results. J Infect Dis 2020;222:899-902. https://academic.oup.com/jid/article/222/6/899/5864227
  4. Green DA, Zucker J, Westbade LF, et al. Clinical performance of SARS-CoV-2 molecular testing. J Clin Microbiol 2020. DOI:10.1128/JCM.00995-20. https://jcm.asm.org/content/58/8/e00995-20

 

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!

Why would my patient with Covid-19 infection test negative by PCR?