Cerebrospinal fluid fistula as a complication of reverse transcriptase–polymerase chain reaction collection for the detection of coronavirus disease 2019: illustrative cases

Abstract

BACKGROUND

The most used method to detect coronavirus disease 2019 during the pandemic is reverse transcriptase–polymerase chain reaction with nasal swab. Despite being highly effective, the test does not leave the patient risk-free and can lead to serious complications. These can be traumatic nasal cerebrospinal fluid (CSF) fistula and its consequences, such as meningitis.

OBSERVATIONS

In this article, the authors present 4 case reports and a literature review. The following MeSH terms in the research were used: “CSF leak case report and covid 19.” Six results were found and after searching the references and keywords 16 articles were identified. By using them, the authors tried to clarify the etiology of the fistula, its influences, and complications.

LESSONS

The authors conclude that professionals must receive training, since CSF fistula originates from technical failure and lack of anatomical knowledge. The diagnosis cannot be neglected because it can bring complications to the patient’s health.

The coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented impacts on health, economy, and education. According to the World Health Organization, the total number of cases of COVID-19 worldwide exceeds 591 million so far, having a daily average of approximately 1 million new cases.¹ One of the main tests used to detect this disease is the reverse transcriptase–polymerase chain reaction (RT-PCR),² which is acquired through nasal swab, requiring the introduction of a swab to the roof of the nasal cavity to obtain secretion.³ Despite being quick to perform and apparently not very invasive, this procedure is not risk-free and can lead to serious complications.²

The upper border of the nasal cavity and the floor of the anterior fossa of the skull comprise the nasal mucosa, a thin bony layer, and the dura mater. If the shaft used to collect the nasal swab is introduced with excessive force, it can breach these structures and cause a fistula, i.e., an abnormal connection between the anterior fossa of the brain and the nasal cavity. This abnormal connection allows the cerebrospinal fluid (CSF) to leak, which generates symptoms such as a decrease in intracranial pressure accompanied by headaches.⁴ In addition, it can also develop into more serious and potentially fatal consequences, such as meningitis.⁵ The diagnosis of CSF fistula is made when the clinical history shows mainly continuous or intermittent nasal flow of clear liquid associated with headache and/or dizziness, as well as imaging examinations, which can detect structures of the upper nasal cavity and skull base in detail. In addition to thin-slice computed tomography (CT) and magnetic resonance imaging (MRI), concentration of beta-2 transferrin (substance found almost exclusively in the CSF) used as an endogenous marker of CSF leakage is also performed to confirm the diagnosis.⁶

The CSF fistula post-examination to detect COVID-19 is a rare complication and rarely described in the scientific literature. Its diagnosis became more frequent after the beginning of the pandemic. Given the exceptionality of the condition and its increase during pandemic, this article proposes to review cases of CSF fistula related to nasal swab in the literature and presents 4 cases described at hospitals in Sorocaba, São Paulo State, Brazil.

In this study we performed a qualitative description and systematic literature review. We retrospectively evaluated 4 cases of nasal CSF fistula after PCR examination for COVID-19 detection in hospitals in Sorocaba. The literature revision was conducted on the PubMed platform. Inclusion criteria were studies described as “Case Report”; presenting case of CSF fistula after RT-PCR nasal test; being related to suspicion of COVID-19. No specific time frame was adopted for the present study. The following MeSH terms were used: “CSF leak case report and COVID-19,” yielding 6 results. After reading the abstracts, we excluded 2 articles, and the final number was 4. By reading the documents, we investigated the references, making it through this and the manual descriptors: “CSF leak and COVID-19,” “CSF after COVID-19,” “Cerebrospinal fluid leak and COVID-19,” “nasal CSF fistula after COVID-19,” “CSF after COVID-19 test.” The search resulted in 16 articles (Fig. 1) that fit into our inclusion criteria.

FIG. 1.

Identification of studies via databases and registers.

The analysis of the 16 articles allowed us to divide the reported cases taking previous existence of a lesion that could be associated with CSF fistula into consideration. Because some articles participated in more than one division, we considered 19 cases. They were divided as follows: 3 of the articles reporting CSF post-COVID test had a previous skull injury (Table 1); 6 had another significant pathology related to the injury (Table 2); 8 had no relevant medical history associated with or that could influence in CSF post-COVID test (Table 3); 3 had meningitis as a serious complication after CSF. A detailed overview of the criteria used for divisions can be seen in Tables 1–3.^7–21

TABLE 1.

Patients with previous skull injury

Authors & Year	Identification	Previous Skull Injury	Medical Examination	Conclusion
Yılmaz et al., 20217	M, 47-yr-old, rt rhinorrhea & headache	Patient had medical history of minor TBI that occurred 4 yrs earlier	Physical examination; CT; MRI	Report aims to encourage medical community to question patients’ preexisting conditions & medical history to assess risk of adverse effects of nasal swab sampling
Sullivan et al., 20208	F, 40-yr-old, unilateral rhinorrhea, metallic taste, headache, neck stiffness, & photophobia	Patient had an undiagnosed skull base defect at the ethmoid fovea that was present on images dating back 5 yrs	CT; MRI; beta-2 transferrin; Nasopharyngoscopy	Alternative methods to nasal screening should be considered in patients w/ known prior skull base defects, history of sinus or skull base surgery, or conditions predisposing to skull base erosion
Knížek et al., 20219	M, 40-yr-old, presented clear water rhinorrhea on the rt side in December 2020	Prior CT scan (11 yrs prior) showed a defect at the base of the skull	CT; Nasal endoscopy; beta trace protein	Because of increase in PCR testing for COVID-19 & its complications, every case of unilateral rhinorrhea after transnasal testing should be considered a possible CSF leak because even healthy individuals w/out preexisting diseases are susceptible to this condition

TBI = traumatic brain injury.

TABLE 2.

Patients with a medical history influential in the appearance of the fistula

Authors & Year	Identification	Significant Medical History	Medical Examination	Conclusion
Samadian et al. 202110	F, 47-yr-old, Unilateral rhinorrhea on rt, headache, progressive & photophobia for 1 wk	Patient presented w/ a deviated nasal septum & nasal spur	Physical examination; Cisternography; beta-2 transferrin; CT; MRI	Hypothesized that the anatomical abnormalities caused the swab to deflect to meet the base of the skull & erode the cribriform lamina
Holmes A, Allen B. 20215	F, 54-yr-old, acute onset symptoms of severe headache & neck & back pain	This case demonstrates the presence of an unusual congenital anomaly (meningocele) that was injured during testing for COVID-19	MRI; beta-2 transferrin; Nasal endoscopy; Lumbar puncture	Although such abnormalities are rare, the dramatic increase in nasopharyngeal swabs performed during the COVID-19 pandemic created an increased risk of injury
Mistry SG, et al. 202111	F, 67-yr-old, Patient presented w/ unilateral rhinorrhea, headache, nausea, & photophobia	Patient was recently treated for a bacterial meningitis	CT; intraop evaluation	Recommended that a safe & effective approach for deep nasal & nasopharyngeal sampling should not rely on any head extension
Abohimed, et al. 202212	1) F, 45-yr-old, rhinorrhea, mild cough & intense headache; 2) F, 36-year-old, Patient presents w/ symptoms of headache & clear nasal discharge for 10 days	1) IIH; 2) Medical past marked by chronic headache, & according to MRI done a few years earlier, showed signs of IIH	CT; MRI; beta-2 transferrin	Alternative methods, including oropharyngeal swabbing, should be considered in patients w/ signs & symptoms of ICH & known preexisting skull base defects
Asiri et al. 202113	F, 36-yr-old, presented to the emergency service w/ fever, headache, altered level of consciousness & agitation, headache & rt-sided watery rhinorrhea	Patient w/ IIH	CT; MRI; beta-2 transferrin; Lumbar puncture	Decision made to start patient on intravenous antibiotics; Patient progressed adequately after treatment & was discharged after 13 days of hospitalization
Sullivan et al., 20208	F, 40-year-old, unilateral rhinorrhea, metallic taste, headache, neck stiffness & photophobia	The patient w/ a history of IIH & removal of nasal polyps	CT; MRI; beta-2 transferrin; Nasopharyngoscopy	Alternative methods to nasal screening should be considered in patients w/ known prior skull base defects, history of sinus or skull base surgery, or conditions predisposing to skull base erosion

ICH = intracerebral hemorrhage; IIH = idiopathic intracranial hypertension.

TABLE 3.

Patients without injury

Authors & Year	Identification	Medical Examination	Conclusion
Rajah & Lee, 202114	M, 59-year-old, presented w/ 2 mos persistent rhinorrhea in the lt nostril	CT; beta- 2 transferrin; MRI; Visual examination; fundoscopy; Lumbar puncture	Education about safe angles & insertion depth, as well as an understanding of possible complications, will reduce the overall risk profile when performing PCR for COVID-19
Dündar et al. 202215	F, 61-yr-old, came to hospital complaining of unilateral transparent nasal discharge increasing on stooping	CT; MRI; Clinical examination; Anterior rhinoscopy; Fiberoptic Nasopharyngoscopy	It is very important that, to avoid complications during nasopharyngeal swab collection for COVID-19 diagnosis, physicians are trained in details & samples are collected w/ the correct application of the method
Paquin et al. 202116	F, 38-yr-old, presented to the hospital after experiencing severe pain during examination w/ a swab for COVID-19 followed by clear rhinorrhea for 2 days, which worsened when bending forward	CT; MRI; Nasal endoscopy;	This case highlights need for education of proper swab technique for healthcare professionals & education on the signs & symptoms of CSF rhinorrhea for patients
Agamawi et al. 202117	M, 40-yr-old, presented to clinic for evaluation of CSF leak following COVID-19 testing by nasopharyngeal swab	CT; beta-2 transferrin	W/ the scale-up of COVID-19 testing, it is crucial that the team administering the COVID-19 test swabs not only appreciate the flat, nonsloping direction from the nasal cavity to the nasopharynx, but be extremely cautious when inserting the swab
Sadashiva et al. 202118	M, 48-year-old, presented w/ a complaint of watery nasal discharge from rt side of nostril	CT; MRI	CSF rhinorrhea is serious complication of nasopharyngeal swab testing
Ovenden et al. 202119	F, 34-yr-old, experienced significant amount of pain during epistaxis swab immediately after the procedure, she developed intermittent clear rhinorrhea from rt nostril that was precipitated by forward bending or straining	CT; MRI; MR venography	Currently, a large number of nasopharyngeal swabs are being performed in an attempt to manage & control the spread of COVID-19
Amores et al. 202120	F, 41-yr-old, holocranial headache aggravated by position changes & fever, 1 wk later developed metallic taste & rhinorrhea	MRI; beta-2 transferrin	Reported iatrogenic CSF leaks from intranasal procedures or surgical trauma to the cribriform plate account for up to 16% of secondary causes of CSF fistula, & contrast-enhanced MRI cistern is the gold standard
Ku J, Chen et al.21	M, 41-year-old, pain after collection for COVID-19 by nasal swab & referred to continued rhinorrhea after 5 days	CT; MRI; beta-2 transferrin	CSF fistula is a medical complication that can be mistaken for allergic rhinitis, & if lt untreated, can cause serious CNS damage

CNS = central nervous system.

Illustrative Cases

Treatments for the 4 cases were similar, being surgical correction by endoscopic endonasal approach of the CSF fistula. We located and delimitated the bone flaw caused by the swab, debridement, and occlusion of the fistula with nasal mucosa flap and synthetic dura mater substitute, besides dural sealant (Table 4).

TABLE 4.

Report of the four cases

Gender & Age (yr)	Identification	Medical Examination	Fistula Location
Female, 39	Reported worsening nasal discharge after testing for COVID-19 w/ a nasal swab. The patient sought an otorhinolaryngologist’s office, where fibroscopy was used to verify the exit of CSF through the nostril. The fistula was corrected w/ surgery, which resulted in a good recovery for the patient	Cerebral sinus CT, cisternography	Failure in middle fossa & pterygopalatine fossa
Female, 44	Hours after the examination for COVID-19 w/ nasal swab, where she felt pain, the patient evolved w/ clear liquid coming out of her rt nostril. The next day she had headache w/ vertigo, which worsened when she stood up. After the 1st surgical correction, the patient reported the same symptoms after physical effort, & was diagnosed w/ a 2nd CSF fistula, which was corrected w/ a 2nd surgical procedure	Nasal fibroscopy & sinus CT w/ bone window, thin sections; After the 1st correction, the patient was diagnosed w/ a 2nd fistula through clinical & radiological exams	Ethmoid sinus on the lt
Female, 67	She reported extreme discomfort during the test for COVID-19, & afterwards persisted w/ nasal pain & irritation. The next day she noticed clear liquid coming out of her rt nostril, which was constant, w/ an increase in flow when she was standing up, & a reduction in the amount when she was lying down. At times of more intense outflow of liquid through the nostril, she felt dizzy & had headaches, w/ episodes of dimming of the vision. She was diagnosed w/ CSF fistula, & was corrected w/ surgical treatment, which promoted good recovery & repair of the fistula	Physical examination, nasofibroscopy, & CT of sinuses	Bone dehiscence of the rt ethmoid fovea, causing a perforation that communicates w/ the anterior-basal cranial fossa
Male, 34	Already operated previously for pansinusectomy, w/ success. After doing nasal swab, lt started w/ rhinoliquorrhea & did an ethmoidal meningocele	CT	Expansive lesion in the lt ethmoid sinus

Case 1

A 39-year-old female performed a COVID-19 test with nasal swab and began to present nasal secretion of clear liquid on the following day, which persisted for a week. She sought an otorhinolaryngologist’s office where, by nasofibroscopy, a colorless liquid was seen coming from the pterygopalatine fossa. A CT scan of the facial sinuses showed bone defects in the middle and pterygopalatine fossa. Cranial cisternography confirmed the CSF fistula. Surgical correction of the fistula was performed by endoscopic transnasal access with localization of the fistulous point and plugging of the orifice with nasal cavity mucosa and biological glue.

The patient had no signs of the fistula postoperatively, and she resumed all daily activities after a resting period. The patient had no previous injuries or conditions that could be related to the injury (Supplemental Fig. 1).

Case 2

A 44-year-old female underwent a nasal swab for COVID-19 by PCR. She reported feeling strong pain in the nasal cavity during the test, which persisted after the examination. A clear liquid came out of the right nostril in the subsequent hours. The next day a headache with dizziness appeared, which worsened when the patient stood up. This condition persisted for the following days. The patient sought an otorhinolaryngologist and neurosurgeon and the diagnosis of traumatic nasal CSF fistula was established after evaluation with nasal fibroscopy and CT scan of the facial sinuses with thin slices in a bone window.

The patient had mild systemic hypertension controlled with hydrochlorothiazide. A month after presentation, she underwent endonasal endoscopic surgical correction of the CSF fistula. The bone flaw was located and delimited by swabbing with a cotton swab. The fistula hole was debrided and occluded with nasal mucosa flap and synthetic dura mater substitute. Dural sealant was also applied. The patient was hospitalized during a 5 days’ rest to heal the fistula repair. The symptoms of nasal CSF flow and headache improved. She returned to the office a week after discharge showing no signs of fistula.

Almost a year after initial presentation, after physical effort in her work environment where she works as a nurse, the patient showed signs and symptoms of a CSF fistula again. Clinical and radiological exams confirmed displacement of the graft from the fistula site. She then underwent surgical treatment of the fistula by endoscopic endonasal approach again. She showed no signs of CSF leakage through the nasal cavity in the first postoperative period. She was discharged after 5 days and returned to the office, showing no signs of nasal fistula. The patient did not present permanent anosmia; this symptom appears only during the patient’s recovery phase (Supplemental Fig. 2).

Case 3

A 67-year-old female underwent a COVID-19 test by PCR performed by a nasal swab sample. She reported extreme discomfort during the test, as well as persistent nasal pain and irritation afterwards. She noticed a clear liquid constantly coming out of her right nostril the next day. The liquid flow increased when she stood up and decreased when she lay down. She felt dizzy and had headaches when the liquid flowed more intensely, and she also experienced episodes of blurred vision. She sought an otorhinolaryngologist, who verified through physical examination and nasofibroscopy that it was a traumatic nasal liquor fistula with a solution of continuity of the right ethmoid fovea. A CT scan of facial sinuses was requested, which revealed bone dehiscence of the right ethmoid fovea, leading to a perforation that communicates with the antero-basal cranial fossa. The patient was evaluated by a neurosurgeon and underwent endoscopic transnasal access for correction of the cerebrospinal fluid fistula 3 months after her initial presentation. The lesion was localized and plugged with a nasal septal flap, an artificial dura mater substitute, and dural sealant glue. The patient had excellent postoperative results and complete resolution of the fistulous condition. She was discharged from the office a month after the correction, showing no signs of the fistula. The patient had no preexisting lesions or conditions related to CSF (Supplemental Fig. 3).

Case 4

A 43-year-old male patient presented with a history of pansinusectomy for nasosinusal polyps from 4 years earlier. Postoperative evolution of the nasosinusal polyposis was good. After suspecting COVID-19, he underwent RT-PCR collection. He was presenting hyaline rhinoliquorrea in the left nasal fossa associated with intermittent headache. MRI of the skull and paranasal sinuses showed a meningocele in the region of the left ethmoid fiber, where the swab of PCR collection had injured it.

The surgery performed for correction consisted of reducing the meningocele and closing the peritoneum with dura substitute and glue. The case was closed after this surgery (Supplemental Fig. 4).

Discussion

Observations

Based on the 15 articles found in the literature, 8 of them^14–20 respectively shown in Table 3 do not present cases with influential medical history and/or previous complications. Likewise, in the description of the 4 cases presented in this article, 3 of them had no history of injuries or malformations that could be correlated to the onset of CSF postnasal swab. It is evident that the major and main cause of this complication is the failure of health professionals’ technique, increasing the rate of patients with nasal CSF fistula by swab.

According to Rajah and Lee,¹⁴ the correct technique is based on the inclination of the head, with 70 degrees recommended to facilitate the insertion of the swab, parallel to the palate from 2 to 3 cm (Supplemental Fig. 5). However, flaws in technique such as incorrect inclination, no parallel insertion to the palate, and greater depth can damage the mucosa and skull base, causing the appearance of CSF nasal fistula (Supplemental Fig. 6).

Furthermore, it is notable that patients with significant medical history found in Table 2, such as septal deviation, idiopathic intracranial hypertension, intranasal meningocele, and meningitis may influence the appearance of fistulas after nasal swab. Therefore, it is important that screening of individuals who are suitable for testing with nasal swab insertion is expanded. Healthcare professionals involved should be educated about the possibility of such preexisting lesions.^14–16

In our third case, the patient had a history of polyp removal surgery. We did not find any other citation in the literature in which the removal of nasal polyp influenced the appearance of CSF fistula after nasal swab. Therefore, we think this relationship is unlikely, but it is worth having more studies about possible influence of this association. Three cases reviewed in the literature and none of the case studies presented evolved to meningitis.^5,13,20 The authors^5,13 emphasize the importance of rapid intervention to avoid such developments.

The majority of CSF fistula have surgical treatment. However, there is 1 report of drug intervention.¹³ Studies that report surgical intervention are endonasal endoscopic with placement of flaps, which may be muscle fascia, nasal septum in addition to the use of synthetic dura mater substitute and dural sealant.

No other article reports recurrence after surgical intervention. To our knowledge, this is the first article reporting this situation, being described an atypical situation related to work effort in the case of patient 2. It is worth mentioning that doctors who treat patients in this situation should advise them to not exert maximum effort for at least 7 days. Keep in mind that this was an isolated case.

Lessons

Considering the literature review and our description, we may clarify that the main causes of CSF fistula as a complication of the nasal swab for COVID-19 19 are technical failure and lack of knowledge of possible complications that poor swab insertion can cause.

The literature review and the current study reveal the existence of this complication in this procedure, leading to occurrence of cases of CSF fistula, and it is complications. This explains it is severity and why it must be treated urgently. Such complications can be intracranial hypotension, bacterial meningitis, and anosmia, which negatively impact the biopsychosocial sphere of these patients, who need highly complex surgical treatments as well as being away from their personal activities for a prolonged time.

Health professionals who perform this examination must be properly trained to do this procedure and know about the risks that patients are subject to when the swab is introduced.

Based on the literature, the importance of anatomical knowledge is evident to avoid major complications such as cerebrospinal fluid fistula and its possible consequences.

Therefore, the neurosurgeon must be aware while evaluating a patient with signs of spontaneous CSF leak about the possibility of PCR nasal swab for COVID-19 test performed incorrectly being the etiological agent. This information can help the neurosurgeon plan the diagnosis and treatment.

Disclosures

Dr. Palavani reported grants from NEPI during the conduct of the study. Dr. C. Andrade reported grants from NEPI during the conduct of the study. Dr. Barbieri reported grants from NEPI during the conduct of the study. No other disclosures were reported.

Author Contributions

Conception and design: all authors. Acquisition of data: Palavani, CVF Andrade, RA Andrade, Barros. Analysis and interpretation of data: Palavani, CVF Andrade, Barros, Barbieri. Drafting the article: Palavani, CVF Andrade, RA Andrade, Barbier.i Critically revising the article: Palavani, CVF Andrade, RA Andrade, Barbieri. Reviewed submitted version of manuscript: Palavani, CVF Andrade. Approved the final version of the manuscript on behalf of all authors: Palavani. Statistical analysis: Palavani, CVF Andrade, Barbieri. Administrative/technical/material support: Palavani, CVF Andrade, Barros. Study supervision: Barbieri.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

Supplemental Figs. 1–6. https://thejns.org/doi/suppl/10.3171/CASE22478.