A man with culture sterile cavitating lung lesions: molecular techniques can provide the key to diagnosis
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A 20-year-old male presented to the Emergency Department with pyrexia, dyspnoea, chest pain and haemoptysis. Cavitating lung lesions were noted on chest X-ray and the patient was admitted to the intensive care unit where he was intubated and ventilated. Routine investigations including serial cultures did not provide an aetiological diagnosis. As such, a CT-guided lung biopsy was carried out and 16S rDNA PCR was undertaken on the sample. This identified Fusobacterium necrophorum as the causative organism. The patient was treated for Lemierre’s syndrome and successfully discharged from hospital. This case highlights how DNA tissue typing on a lung biopsy sample can be the key to successful diagnosis in an atypical pneumonia and raises the question as to whether this infrequently used approach should be added to forthcoming community acquired pneumonia guidelines.
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Thank you for so thoroughly revising your case report in line with the reviewers' comments. The clarity and quality of the report have improved during peer review, and I'm delighted to accept your report. This case report will be a useful addition to the literature.
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The work presented is clear and the arguments well formed. This study would be a valuable contribution to the existing literature. The reviewers have highlighted minor concerns with the work presented. Please ensure that you address their comments.
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Comments to Author
1. Description of the case(s) The authors described an interesting case of infection with Fusobacterium necrophorus but serial culture remained negative with multiple tissue samples (blood, bronchoalveolar lavage, lung biopsy) for at least 18 days after admission in a urband hospital in the UK. The final diagnosis of Lemierre's syndrome was made after the bacterium was identified by 16S rRNA gene sequencing before the patient was treated with appropriate antibiotics successfully and was discharged home after a 27-day hospital stay. 2. Presentation of results The detail and clear description of the case was presented by the corresponding physicians and the microbiologist. The X-ray and CT scan slides in Fig 1 demonstrated cavitary lesions in the lungs. The result of 16S-rRNA gene sequencing …
Comments to Author
1. Description of the case(s) The authors described an interesting case of infection with Fusobacterium necrophorus but serial culture remained negative with multiple tissue samples (blood, bronchoalveolar lavage, lung biopsy) for at least 18 days after admission in a urband hospital in the UK. The final diagnosis of Lemierre's syndrome was made after the bacterium was identified by 16S rRNA gene sequencing before the patient was treated with appropriate antibiotics successfully and was discharged home after a 27-day hospital stay. 2. Presentation of results The detail and clear description of the case was presented by the corresponding physicians and the microbiologist. The X-ray and CT scan slides in Fig 1 demonstrated cavitary lesions in the lungs. The result of 16S-rRNA gene sequencing was presented. 3. How the style and organization of the paper communicates and represents key findings The manuscript was descriptive in discussion style, and is easy to be conprehensive to clinical community. 4. Literature analysis or discussion Literature analysis and discussion were complete and appropriate. 5. Any other relevant comments It might be more meaningful to include the discussion of how to make timely diagnosis in the future for such rare infections.
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
Dear author, after reviewing your manuscript, I found some notes that needed revision. First, you must write the complete term for the first time mentioned (lines 21, 125). Second, the scientific name should be italicized (line 51). You didn't indicate figure 1 in the manuscript text; it should display in the correct position.
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves …
Comments to Author
Dear author, after reviewing your manuscript, I found some notes that needed revision. First, you must write the complete term for the first time mentioned (lines 21, 125). Second, the scientific name should be italicized (line 51). You didn't indicate figure 1 in the manuscript text; it should display in the correct position.
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
-
Comments to Author
Broad Summary This case describes a gentleman requiring invasive ventilation for community acquired pneumonia with cavitation, in which 16S rDNA sequencing assisted in identification of Fusobacaterium necrophorum and subsequent diagnosis of Lemierre's syndrome. It is a short article that reads well as an evolving clinical case with discussion as it happens. It raises the important and interesting consideration of molecular testing in critical care respiratory infection, where there has been much progress but little practical bedside utility. History I was interested to read of the gentleman's Iranian origin (particularly that he was Kurdish), and his recent infection with COVID-19. However, there is no description of the time since COVID-19 infection or of its confirmation (e.g. PCR positivity) or …
Comments to Author
Broad Summary This case describes a gentleman requiring invasive ventilation for community acquired pneumonia with cavitation, in which 16S rDNA sequencing assisted in identification of Fusobacaterium necrophorum and subsequent diagnosis of Lemierre's syndrome. It is a short article that reads well as an evolving clinical case with discussion as it happens. It raises the important and interesting consideration of molecular testing in critical care respiratory infection, where there has been much progress but little practical bedside utility. History I was interested to read of the gentleman's Iranian origin (particularly that he was Kurdish), and his recent infection with COVID-19. However, there is no description of the time since COVID-19 infection or of its confirmation (e.g. PCR positivity) or clinical course (assuming he was not admitted) or overlap with symptoms. Please also ensure including whether any sore throat or neck swelling were present at onset. The nature of his chest pain (type, location, severity) and haemoptysis (description, frequency, volume) would be important to describe. I was surprised that there was no brief or speculation over the possibility that COVID-19 infection may have predisposed this gentleman to his infection. Some may even have included the post-COVID-19 status with prominence, even in the title - I do not recommend necessarily doing this but recommend at least describing the time lapse between infections and the absence of any PCR positivity for SARS-CoV-2. Examination The clinical assessment is concise. as well as (i) the oxygen delivery method and flow rate at each point (line 37 and line 42) (ii) presence of sinus rhythm (iii) presence of any confusion (iv) abdominal examination (v) presence of any rash, particularly since the possibility of vasculitis is raised (53) (vi) leg swelling, if known. The gentleman's sore finger is mentioned, but not elaborated on later (was this thought to represent a septic embolus? Did this resolve?). Please state the PaO2 and PaCO2 and pH at which this gentleman was diagnosed as being in respiratory failure (line 40). Investigations The differential diagnosis is listed similarly around line 50 and 59. Please consider concatenation. The notion of "ruling out" vegetations by TTE is technically incorrect (line 66), please consider rephrasing to say only that no vegetations were seen, since TOE would be required to effectively rule out from a clinical perspective. The methodology of the 16S rDNA PCR would be useful to know to ensure this paper's findings can be replicated and acted on. A "broad range" 16S rDNA was requested (line 81), but with what kit etc? How broad was the testing used (how many species)? Were any other organisms identified? Where there any other notable negatives or false positives? Management I would be interested to know why was the left-sided effusion drained (line 73), given that the CT scan in particular only seems to show the right-sided element? Was the right-sided effusion larger? Was the left-sided effusion easier to drain? How much fluid was drained? How many days did the chest drain remain in for? What was the reason for escalation of antibiotics on day eleven? (line 85). The article states that a minimum of 4 weeks antibiotics are essential (line 126), but that this patient only received a total of 25 days (149). Additionally, why were antibiotics IV for so long? Diagnosis The statement "enabling us to clinch the diagnosis of" sounds a little triumphant. Perhaps more appropriate to say "pointing towards the diagnosis of". The authors raise the possibility of F. necrophorum being part of normal flora in humans and animals (cockatoos? There is no literature, apparently). There is no comment on the possibility that this is a false positive or potentially a representation of normal flora. There is no statement on the percentage of individuals that have identifiable 16S rDNA PCR in healthy/unwell patients, or those with cavitatory pneumonia. Please consider stating a specificity and sensitivity for the test, or whether these data are available, particularly in lining up the syndrome with the molecular identification. Metagenomic testing would be the next question. Would the authors see an advantage to having performed the test earlier, or to having a broader or more accurate set of tests? The argument made by the authors is that use of molecular testing "can prevent delayed diagnosis"; at what point would you recommend testing, then? Many advocate for PCR panels in diagnosis of respiratory infection (and commercial companies produce such tests). What would your recommendation to NICE be? In this case, there was no delayed management. You recommend consideration of the 16S rRNA approach in "forthcoming BTS community acquired pneumonia guidelines" (line 20). However, my understanding is that BTS are not due to be improved (https://www.brit-thoracic.org.uk/quality-improvement/guidelines/) since NICE are in the process of development of guideline GID-NG10357 on Pneumonia in adults (https://www.nice.org.uk/guidance/indevelopment/gid-ng10357) and is due in 2024. You could mention that 16S rRNA is not mentioned in the guideline from 2014 (CG191), though this guideline is only 22 pages, and does not mention PCR or any other molecular techniques. However, the UK Standards for Microbiology Investigations (SMI) guideline B 57 does mention the use of PCR, especially for time sensitive investigations (https://www.gov.uk/government/publications/smi-b-57-investigation-of-bronchoalveolar-lavage-sputum-and-associated-specimens). I recommend that the authors consider emailing the NICE guideline development team (pneumoniaupdate@nice.org.uk) to open discussion. Perhaps the identification of F. necrophorum led to the return to the bedside and repeat assessment and identification of the IJV thrombus, and this was the key step in improving management. It is notable that the original therapy included pip-taz. and metronidazole. This case demonstrates the power of anaerobic cover in treating an anaerobic organism at the outset; I wonder if this point should be emphasised, as this is the ultimate treatment decision that covered the infection. The presence of an IJV thrombus is arguably what "clinches" the diagnosis of the syndrome in question. So, why was an IJV thrombus not identified earlier? One would presume this gentleman had received more than one central venous catheter during his stay, for which the most likely site would have been the right IJV, where the thrombus was eventually identified (line 91). Perhaps the vascular ultrasound operator did not identify this, perhaps it was not present, perhaps there is a need for further training in venous thrombosis assessment? Please consider noting whether or this was detected earlier or not, with any additional opinions if necessary. Furthermore, I could not see a discussion or mention of anticoagulation for this patient. Did the authors anticoagulate? Was prophylactic low molecular weight heparin (as I assume he was on) enough in their opinion? Is there a lack of consensus on this point? Finally, please consider whether the patient might be willing to give an opinion on their case and management, as per CARE case report guidelines (https://www.care-statement.org/checklist). Other suggestions from the CARE checklist are (i) fewer key words (I suggest abandoning Lemierre's syndrome, it gives the game away under the title) (ii) inclusion of "case report" in the key words (iii) removal of "BTS pneumonia guidelines" (iv) include dose and strength of antimicrobials (v) any long term post-ICU follow-up. Please would you additionally address stylistic comments relating to the following lines: 1: "Dilemma" - Cambridge online dictionary defines a dilemma as a "a situation in which a difficult choice has to be made between two different things you could do." What dilemma are you referring to? I recommend considering the use of another title that indicates the case's main story: the major challenge of diagnosis without use of a molecular technique. 16: Please consider use of "CT-guided lung biopsy" for clarity in the abstract to specify the methodology. 28, 41, 45, 67, 72, 83, 87, 105, 135: Please consider standardising the term "ICU" or "ITU." I recommend using the term "ICU" exclusively and abandoning "ITU."I would also be interested to know whether the ICU SHO and registrar are core trainees in e.g. Internal Medicine, Anaesthesia, or whether they are a Specialty doctor or fellow, et cetera. Or perhaps a single CCT trainee in Intensive Care Medicine, et cetera. 32: "pack year history": over what time period? 33: "but denied any recent": please consider rephrasing e.g. "and denied any other recent." 38, 47 "54mmHg": please have a space between numbers and units. 50 "multiple, bilateral": please remove comma. 51 "Staphylococcus aureus": please italicise. 71 "Panton Valentine Leucocidin Staphylococcus aureus": please phrase as in other literature as "Panton-Valentine Leucocidin-producing Staphylococcus aureus".
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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