Pediatric Lemierre’s Syndrome: A Comprehensive Literature Review

Round 1

Reviewer 1 Report

None.

Author Response

Dear reviewer,

it's a great pleasure to receive such appreciation to our efforts.
Best regards

Author Response File: Author Response.pdf

Reviewer 2 Report

There is an interesting systematic review on the diagnostics and treatment for Lemierre's syndrome.

Although the paper is well written, I would recommend to address severel issues.

1. The mechanisc by which Fusobacteria or other microorganism enter the internal jugular vein from the initial oropharyngeal site of infection. This mechanism actually seems quite obvious - lymphatic vessels draining deep structures od the head go alongside this vein; ther are also many lymph nodes associated with these lymphatics that are located in the proximity of the IJV

2. Diagnostics. The Authors discuss recommendations given in the literature and it is recommended to perform either CT or MR imaging, with ultrasonographic assessment in the current literature is regarded to be of a minor diagnostic accuracy.

Still, such opinions are probably associated with a lack of knowledge how to examine these veins properly (ultrasound examination of the IJV is not a typical part of postgraduate radiological curriculum). Actually, scanning of these veins is easy and of very high accuracy, although tricky. In short, in addition to B-mode scanning (which may not reveal fresh thrombus), it should be checked if the vein collapses. It does not collapse if a thrombus is located inside it. Such a check can be performed in a similar way as the check for venous thrombosis in the extremity veins: gently compressing the vein with the ultrasond probe. Yet, in a case of infected thrombus such a compression may result in clot dislocation, with a risk of life-threatening pulmonary embolism. Thus, an alternative way to assess collapsibility of the IJV is to examine it again either in the sitting or lateral decubitus position.

The Authors can study the following paper or articles that are cited by it.

https://doi.org/10.1016/j.mehy.2019.109397

A discussion on the diagnostic methods would be welcome.

3. The Authors claim for RCT in this area. Yet, given the fact that the disease is very rare, it would be extremly difficult to conduct such a trial, even in the multricentre settings. A meta-analysis of open-label report seems a better tool for such a rare pathology.

4. The same applies to the claim for vaccines. Since the pathology is rare, it is quite likely that vaccine-associated complications would be more common that the disease. Consequently, the final effect of the vaccination could be negative.

5. Lines 314-315.

Since the disease affect the IJV, screening of carotid arteries seems unnecessary (although can be done together with the examination of the IJVs)

Clinical terms "chronic venous insufficiency" and "post-thrombotic syndrome" typically is used regarding pathology of the lower extremities. There could be clinical manifestations following occlusion of the IJVs, but such should be called "chronic cerebrospinal venous insufficiency"

see: Nicolaides AN, Morovic S, Menegatti E, Viselner G, Zamboni P. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound: recommendations for a protocol. Funct Neurol. 2011 Oct-Dec;26(4):229-48. PMID: 22364944; PMCID: PMC3814564.

Author Response

Response to reviewer 2

There is an interesting systematic review on the diagnostics and treatment for Lemierre's syndrome.

Although the paper is well written, I would recommend to address severel issues.

Comments:1. The mechanism by which Fusobacteria or other microorganisms enter the internal jugular vein from the initial oropharyngeal site of infection. This mechanism actually seems quite obvious - lymphatic vessels draining deep structures od the head go alongside this vein; ther are also many l ymph nodes associated with these lymphatics that are located in the proximity of the IJV

Response: dear reviewer, thank you for the suggestion. We added the following sentences: The mechanism by which Fusobacteria or other microorganisms gain entry into the internal jugular vein from their initial point of infection in the oropharynx is indeed quite straightforward[24-28]. The lymphatic vessels responsible for draining the deeper structures of the head run parallel to this vein. Furthermore, numerous lymph nodes associated with these lymphatic vessels are situated near the internal jugular vein[25]. These anatomical relationships facilitate the dissemination of pathogens from localized infections to systemic circulation.

Comment: 2. Diagnostics. The Authors discuss recommendations given in the literature, and it is recommended to perform either CT or MR imaging, with ultrasonographic assessment in the current literature regarded to be of a minor diagnostic accuracy.

Response: we agree with the minor accuracy of US for patients diagnostic. Thus we highlighted more the concept and we rewrote the paragraph and added new informations regarding the limitatios: In the US, internal jugular vein (IJV) thrombophlebitis may manifest as either a hyperechoic or hypoechoic mass, which is indicative of a thrombus within the vessel. Color Doppler and spectral Doppler imaging are utilized to assess blood flow and detect abnormalities or obstructions due to the thrombus[6]. They can also demonstrate the absence of normal respiratory phasicity and cardiac pulsatility. However, as cited in the literature, ultrasonography is known to have a lower diagnostic accuracy when compared to computed tomography (CT) and magnetic resonance imaging (MRI)[10-13]. This includes a lower sensitivity and specificity, as well as challenges in detecting thrombi that are located beneath the clavicle, involvement of infectious processes in the mandible, or in visualizing newly formed clots, which often exhibit poor intrinsic echogenicity. Given these limitations, while ultrasonography can provide supplementary information, it is primarily used to confirm the presence of pre-existing clots[14].

Comment: Still, such opinions are probably associated with a lack of knowledge how to examine these veins properly (ultrasound examination of the IJV is not a typical part of postgraduate radiological curriculum). Actually, scanning of these veins is easy and of very high accuracy, although tricky. In short, in addition to B-mode scanning (which may not reveal fresh thrombus), it should be checked if the vein collapses. It does not collapse if a thrombus is located inside it. Such a check can be performed in a similar way as the check for venous thrombosis in the extremity veins: gently compressing the vein with the ultrasond probe. Yet, in a case of infected thrombus such a compression may result in clot dislocation, with a risk of life-threatening pulmonary embolism. Thus, an alternative way to assess collapsibility of the IJV is to examine it again either in the sitting or lateral decubitus position.

The Authors can study the following paper or articles that are cited by it.

https://doi.org/10.1016/j.mehy.2019.109397

Response: we agree and added the following paragraph: It is crucial, however, to acknowledge that the perceived limitations of ultrasound in evaluating the internal jugular vein (IJV) for thrombophlebitis may be attributed to an operator's lack of experience with the proper techniques for examining these vessels. The process, while technically demanding, can yield high accuracy when performed correctly, as the skill involved is operator-dependent. Scanning these veins is not only feasible but can provide precise information. It is essential not to rely solely on the B-mode scan, which might not always reveal a fresh thrombus due to its limitations. A critical aspect of the ultrasound examination is assessing the vein's collapsibility, which is notably reduced in the presence of a thrombus. To mitigate the risk of dislodging a clot during this compression maneuver, alternative patient positions, such as sitting or lateral decubitus, can be employed[15].

Comment: A discussion on the diagnostic methods would be welcome.

Response: we agree with the comment and added a paragraph discussing diagnostic in the discussion: In the Emergency Department, the detection of IJV thrombophlebitis is common, with ultrasound capable of revealing the thrombus as either a hyperechoic or hypoechoic mass [6]. The application of Color Doppler and Spectral Doppler imaging plays a crucial role in evaluating blood flow and identifying any occlusions or irregular flow patterns indicative of a thrombus. However, it is well-recognized that ultrasound has its limitations regarding diagnostic accuracy, sensitivity, specificity, and its capacity to visualize clots in difficult locations or clots that are newly formed and exhibit low echogenicity [10-14]. The proficiency and experience of the operator is a crucial determinant of the success of US in identifying IJV thrombophlebitis. Employing strategies to evaluate vein collapsibility without direct compression, such as repositioning the patient, can improve the safety and effectiveness of thrombus detection [15]. Despite these limitations, the imaging modality of choice for a definitive diagnosis remains a contrast-enhanced CT scan of the neck and chest. CT scans are particularly effective at delineating the primary site of infection and the specific features associated with it, including filling defects in the IJV and surrounding soft tissue swelling [16]. They are especially skilled at pinpointing complications like osteomyelitis, arthritis, abscesses, and septic pulmonary embolisms, while providing details about their size and spread, often revealing a typical lung pattern [17]. Most cases display the "feeding vessel sign," a unique indication of a blood vessel leading to a lesion [17]. CT also proves invaluable in atypical presentations, such as when thrombosis occurs in veins other than the IJV [18], [18,20], and it is crucial in diagnosing this condition, which can have a high mortality rate [221]. In contrast, MRI offers superior soft-tissue contrast and is particularly sensitive to slow-flowing blood, which gives it an advantage in assessing neck abscesses, intracranial complications, and metastases [9]. However, MRI is less adept at identifying lung parenchymal lesions, a critical aspect given the pulmonary involvement in Lemierre syndrome. Consequently, the choice between CT and MRI depends on the specific clinical circumstances, the information needed for accurate diagnosis and treatment planning, and patient factors. Often, a combination of both imaging methods is employed to ensure a comprehensive and precise diagnostic workup, capitalizing on the strengths of each technique.

Comment: 3. The Authors claim for RCT in this area. Yet, given the fact that the disease is very rare, it would be extremly difficult to conduct such a trial, even in the multricentre settings. A meta-analysis of open-label report seems a better tool for such a rare pathology.

Response: we agree with the concept and discussed the limitations: indeed, considering the rarity of Lemierre syndrome, executing a clinical trial to directly compare the diagnostic accuracy of CT and MRI would be exceedingly challenging, even within a multicenter framework. The low incidence of the disease makes the collection of a substantial sample size for a randomized controlled trial highly improbable. Instead, a meta-analysis of open-label reports and observational studies may be a more practical and effective approach to gather and analyze data on this infrequent condition, allowing for the consolidation of evidence from a range of clinical settings and patient scenarios.

Comment 4. The same applies to the claim for vaccines. Since the pathology is rare, it is quite likely that vaccine-associated complications would be more common that the disease. Consequently, the final effect of the vaccination could be negative.

Response: dear reviewer, we agree with the concept and discussed adequately in this sentence: However, it should be considered that the rarity of the disease makes it more likely that vaccine-associated complications will be more common than the disease, resulting in a negative overall balance for potential indication.

Comment: Lines 314-315.Since the disease affect the IJV, screening of carotid arteries seems unnecessary (although can be done together with the examination of the IJVs)

Response: we agree with you comment, we modified accordingly: Despite the routine administration of antibiotics, the intricate anatomy of the deep neck spaces can conceal the full scope of an infection. Therefore, when there is a significant infection involving the internal jugular veins (IJVs), a concurrent evaluation of the carotid arteries is advisable to exclude the possibility of the infection spreading to these vessels[65]. A thorough understanding of neck anatomy enables radiologists to swiftly trace the likely pathways of infection dissemination, thereby providing surgeons with vital information that can inform surgical planning and intervention strategies. This collaborative approach between radiologists and surgeons is essential for the prompt and effective management of deep neck infections.

Comment: Clinical terms "chronic venous insufficiency" and "post-thrombotic syndrome" typically is used regarding pathology of the lower extremities. There could be clinical manifestations following occlusion of the IJVs, but such should be called "chronic cerebrospinal venous insufficiency". see: Nicolaides AN, Morovic S, Menegatti E, Viselner G, Zamboni P. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound: recommendations for a protocol. Funct Neurol. 2011 Oct-Dec;26(4):229-48. PMID: 22364944; PMCID: PMC3814564.

Response: we change accordingly and cite the reference discussing the specific: such as chronic cerebrospinal venous insufficiency (CCSVI) [54,62, 63]. CCSVI may leadd to narrowing or blockage in the internal jugular veins and/or the azygos vein, disrupted blood flow and the development of alternative venous pathways, or collateral circulation.

Author Response File: Author Response.pdf

Reviewer 3 Report

Please check the attachment.

Comments for author File: Comments.pdf

The English is of good qualityi - in my previous Comments section I only have a couple of minor suggestions on word choice (for instance, the word "infrequency"). 

Author Response

The Authors present a review on Lemierre syndrome, a rare but potentially fatal disease for which little evidence from the literature exists. The topic is of interest to both clinicians (as the awareness on the disease is relatively low and may support early diagnosis and better patient outcomes) and researchers in the topic. The review is comprehensive and well-written. Its strengthpoints are the concise but exhaustive description of the physiopathology and microbiological etiology and the overview of the points of interests for the daily practice of clinicians who may be involved in the disease. The comparison between CT and MRI is relatively novel in this respect and particularly onpoint. I have, however, a number of remarks and suggestions for improvement, especially as regards integrating the literature for clinicians and researchers among the readership, as well as some formal but relatively important points.

Comment: Over the whole article, the statement is made that the incidence of Lemierre syndrome may have increased again and thus experienced a resurgence after a decline in the 20th century. While this has been claimed by several case reports and case series, there is no strong epidemiological evidence to support it; it remains an interesting hypothesis until better data are available. Of course this hypothesis can be mentioned and discussed, but every time that the "resurgence" is mentioned in the article it should be clear that it is a proposed hypothesis, not a fact. For instance: 

• Comment: Abstract "The incidence declined after the antibiotic era but has resurged in recent decades": this point is controversial, as the resurgence is still rather a hypothesis that has been raised by small cases series and has not been confirmed by epidemiological studies. Therefore, some hedging and caution would be appropriate and it would be better to state "it may have resurged". "However, over the past two decades there has been a resurgence of interest and reporting of Lemierre’s syndrome": this is correct, because it is a fact that the number of reports and interest has increased; no statement is made in this sentence about the actual incidence of the disease (but please do correct the name into "Lemierre syndrome" as mentioned in another remark).

Response: dear reviewer we agree and change correctly ‘’it may…’’

• Comment: "This re-emergence is multifactorial, " In contrast, this sentence does suggest an increase in incidence. I would start it by "If it reflects a true epidemiological trend, this re-emergence is multifactorial, ".

Response: dear reviewer we agree and change correctly.

• The resurgence should also be presented as a hypothesis/theory in the Discussion.

2. Comment: Throughout the paper, please correct the bacterial names (in particular, of course, "Fusobacterium necrophorum") according to the standard nomenclature in bacterial taxonomy: the genus with uppercase initial, the species in lowercase initial, and both in italic (see for your reference – not to be cited - doi:10.1099/ijsem.0.005585 or doi: 10.1111/j.1574-6976.1999.tb00397.x and the corresponding instructions on https://wwwnc.cdc.gov/eid/page/scientific-nomenclature).

Response: dear reviewer thanks, we changed accordingly.

3. Abstract: "Conclusions: Lemierre’s syndrome should be suspected in patients with prolonged pharyngitis followed by unilateral neck swelling and fevers." Available evidence does not support at all a high sensitivity of either prolonged pharyngitis or unilateral neck swelling. Only a minority of patients (a relative majority, but still a minority) of patients has had pharyngitis (with a considerable proportion having had either another infection of the head-neck region or no discernible infection at all when history is taken), and even those who have had pharyngitis mostly have had a quite normal pharyngitis with a standard duration that may even have subsided by the time of the presentation that leads to the diagnosis of Lemierre syndrome. The association with fever, instead, is stronger (although this sign is, of course, poorly specific). The clinical message that arises from available literature evidence so far is rather that Lemierre syndrome should be suspected in "unclear sepsis following any head-neck infection"; this statement or a variant thereof would therefore be more appropriate.

Response: thank you, we changed accordingly in Lemierre's syndrome should be suspected in previously healthy children or young adults who reported persistent pharyngitis followed by unilateral neck swelling or pain, accompanied by fever, particularly if symptoms evolve into an unclear septic picture following a head and neck infection. Prompt recognition of these signs is crucial for the early diagnosis and treatment of this potentially life-threatening condition.

5. The section "What imaging modalities are recommended for diagnosis?" puts a slightly too strong emphasis on ultrasound. It is true that thrombosis of the jugular vein is traditionally associated with the disease - in fact, its most famous feature. However, it has been long known that the finding of thrombosis of the jugular vein is neither sensitive nor specific, either because the clinical Lemierre syndrome can occur with a septic thrombotic focus in other smaller veins (see the reference, already in the bibliography as number [3], doi: 10.1111/joim.13114) or because, as already recognized by Riordan in his literature review in the early 2000s, the thrombus in the jugular vein may have subsided by the time of the clinical presentation (Riordan 2007, also already in the references in the references). This point should be mentioned and the role of neck US slightly hedged accordingly. Instead, it should be emphasized that the septic pulmonary emboli - correctly described in this section - are particularly sensitive and specific for the disease, as their differential diagnosis is surprisingly small; therefore, if a CT is performed, it may be recommended to always include the lungs in the imaging window.

Response: dear reviewer, we added all the considerations: It is well-established that the detection of jugular vein thrombosis is not particularly sensitive or specific to Lemierre's syndrome. This is due, in part, to the fact that clinical manifestations of Lemierre's syndrome may arise from a septic thrombotic focus located in veins other than the jugular, which are smaller and less conspicuous[3]. Moreover, by the time patients seek medical care, the thrombus in the jugular vein might have already resolved or diminished in size, making it less detectable through clinical examination or even imaging studies[6,7]. Therefore, clinicians must maintain a high index of suspicion and consider the overall clinical context when evaluating patients who may have Lemierre's syndrome.

6. Comment: "intravenous antibiotics play a pivotal role as the cornerstone of the treatment": the two expressions "play a pivotal role" and "are the cornerstone" have the same meaning and using both is pleonastic. Please choose one for simplicity and conciseness (either "play a pivotal role" or "are the cornerstone of treatment").

Response: we cancelled are the corner…

7. "The typical duration of antibiotic therapy ranges from 3 to 6 weeks [23]." A better references for the duration of antibiotics, which should replace ref. 23, is the high-quality Danish epidemiological survey by Hagelskjaer-Kristensen(https://doi.org/10.1007/s10096-008-0496-4), which is also the only study so far to describe the factors associated with duration of antibiotic therapy.

Response: we added as reference 25. Thank you

8. "although the patient did not develop CNS signs": because the sentence is not about a specific patient, better to write "even in the absence of new CNS signs". 10. In section 6 ("What complications and metastatic foci occur in pediatric Lemierre syndrome?), there are some repetitions: the points that

"Central nervous system complications have been reported in 10-16% of cases" and that

"osteomyelitis, renal abscesses, liver abscesses, endocarditis, and percarditis" may also complicate the disease are repeated twice: the first time between lines 224 and 231 and the second time between lines 234 and 237. Please correct (possibly by simply closing the paragraph at "more frequently in paediatric cases").

Response: dear reviewer, we cancelled both repeated sentences. Thanks

9. Comment: Section 7 on morbidity and mortality: please mention the most recent and so far most comprehensive attempt to estimate mortality, including a confidence interval and a number of sensitivity analyses, in the meta-analysis already in the references as number [3] (DOI:

10.1111/joim.13114) with the rate of 4%. This is more appropriate than citing a single case report (reference 9), that could not provide by definition any evidence on morbidity and mortality.

Response: dear reviewer, we added the paragraph to better express the concept: The latest meta-analysis in the medical literature made a concerted effort to ascertain the mortality rate associated with Lemierre's syndrome[3]. This analysis included not only the calculation of a confidence interval but also a series of sensitivity analyses to ensure the robustness of the findings. The reported overall mortality rate was approximately 4%, reflecting the seriousness of the condition despite advances in medical treatment and diagnostic techniques. [3] It is critical for healthcare providers to recognize the potential severity of Lemierre's syndrome and to manage it aggressively to minimize the risk of fatal outcomes.

10. "With prompt diagnosis and the initiation of appropriate antibiotic herapy, the acute threat to life is greatly diminished, but the journey to full recovery can be fraught with complications and requires extensive medical care [4,15,23]". This is an important point that should be supported by accurate references for the reader interested in more information on the subject. The review by Syed et al. (ref. 4) is correctly chosen because it has historical importance, as it was the first review after a long time, and testifies to how the observation of a complex recovery was already first set in the 1990s. Current reference References 15 (a single-center case series of three cases) and 23 should be replaced by the meta-analysis already included as reference 3 (doi: 10.1111/joim.13182), which identified more cases than [23], also included individual patient level data from the largest single-center studies such as Schubert et al. (doi: 10.1002/lary.24995, which therefore does not need to be cited individually), and provided more specific information on in-hospital and long-term sequelae, including a multivariable analysis of risk factors for in-hospital complications.

Response: thank you for the suggestions, we cited 3,4 references and cancelled the other less relevant.

11. In section 8) on risk factors, the statements on the association between risk factors and Lemierre syndrome are by far too strong relative to the level of evidence. Most of these risk factors have been only suggested based on isolated cases and not based on statistical association in either longitudinal or even only cross-sectional series. Therefore, please adapt the language accordingly: for instance, "a recent history of viral infection has been suggested/hypothesized/proposed to compromise (...)"; "children who are immunocopromised (...) MAY be more at risk". It is very important not to draw any conclusions for association from isolated case reports or very small case series with no statistical power. The wording used for genetic factors is more cautious and acceptable, and the conclusion of the section is very well written and requires no amendment.

Response: we added a specific paragraph discussing limitations and used all the terms suggested: Indeed, all the risk factors often cited in relation to Lemierre's syndrome have typically been proposed based on anecdotal evidence from isolated case reports. They have not been substantiated by statistical associations derived from methodical investigations, such as longitudinal or cross-sectional studies. Therefore, while these factors may provide clinical clues, they lack the empirical validation that would come from more rigorous scientific research.

12. "Most pediatric patients who recover from the acute phase of Lemierre’s syndrome may expect to have favorable long-term outcomes\[23,28,41\]." This is true, but there is a considerable minority of approximately 10% that has permanent sequelae, and this minority is all the more important if the age of the patients is considered (they may suffer from lifelong impairment of quality of life). Therefore, please add this information to the sentence concisely and adapt the references to provide a more comprehensive overview of the evidence on this point. The reference 41 by Briggs et al. is wellchosen, but references 23 and 28 can be replaced by the series by Creemers-Schild (doi:

10.1002/nmi2.39), which specifically focused on a paediatric population and included detailed information on the outcome, and by doi 10.1111/joim.13182 (already in the reference list as reference 3), which collected the most patients and most detailed data on long-term outcomes of all other metaanalyses.

Response: dear reviewer, we added the citations and wrote this paragraph ‘’While the majority of individuals with Lemierre's syndrome recover without lasting effects, there is a significant minority—about 10%—who experience permanent sequelae. This is particularly concerning when taking into account the patient population often affected by Lemierre's syndrome, which predominantly includes children and young adults. The long-term impact on this younger demographic underscores the importance of timely diagnosis, effective treatment, and thorough follow-up care to mitigate the risk of chronic complications’’.

13. Comment: "Given the infrequency of Lemierre syndrome": I suggest that the Authors write instead "given the low incidence of Lemierre syndrome" (more common word usage in epidemiology).

Response: thank you for the suggestion, we corrected accordingly

14. The Authors of reference 3 (Valerio, L.; Fowler, S.; Corbishley, C.; Kerr, M.; Koirala, J. Patients with Lemierre syndrome 443 have a high risk of new thromboembolic complications, clinical sequelae and death: An analysis of 712 cases. Intern. Med. 2021, 289, 325–339. doi: 10.1111/joim.13182.) seem to be wrong as they . Please check and correct.

Response: thank you, we corrected Valerio, L.; Zane, F.; Sacco, C.; Granziera, S.; Nicoletti, T.; Russo, M.; Corsi, G.; Holm, K.; Hotz, M.A.; Righini, C.; et al. Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: An analysis of 712 cases. Journal of Internal Medicine 2021, 289, 325–339. https://doi.org/10.1111/joim.13114.

Thank you for the suggestions and efforts done.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Minor
1. Line 362. Delete "azygos vein"

English is fine, except for some typos