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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 337-341

Diagnostic errors of coronavirus infection: Role of fluorodeoxyglucose positron emission tomography/computed tomography scan


1 Department of Nuclear Medicine, Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran-, Iran
2 Department of Radiology, Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran-, Iran

Date of Submission24-Aug-2020
Date of Acceptance26-Sep-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. Abtin Doroudinia
Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_161_20

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  Abstract 


Background: In the era of coronavirus disease 2019 (COVID-19) pandemic, many cases may be misdiagnosed based on their semiology, laboratory tests or chest computed tomography (CT) images and further evaluation might be helpful in appropriately selected cases. Methods:We are discussing usefulness of fluorodeoxyglucose (FDG) positron emission tomography PET/CT scan in appropriately selected suspicious cases of COVID-19 infection. We are discussing two interesting cases on how18F-FDG PET/CT scan might be helpful to avoid COVID-19 infection diagnostic error. Both cases had clinical symptoms suggestive for COVID-19 infection with nonspecific chest CT scan findings including lung nodules, ground glass opacities (GGOs), consolidations, and mosaic perfusion patterns. This case series was approved by our institutional review board and informed consent obtained from both patients. Results: In one case,18F-FDG PET/CT images demonstrated hypermetabolic mostly peripheral GGOs and nodules in both lungs with subsequent evaluation confirming COVID-19 infection. The second case demonstrated right perihilar consolidation, not well appreciated on noncontrast chest CT images in addition to GGOs and further evaluation confirmed diagnosis of poorly differentiated squamous cell carcinoma of the lung. Conclusion: During COVID-19 pandemic, many cases might be misdiagnosed by either clinicians or radiologists. In appropriately selected cases, FDG PET/CT scan may be helpful during COVID-19 outbreak to avoid diagnostic errors.

Keywords: COVID-19, fluorodeoxyglucose positron emission tomography/computed tomography, misdiagnosis


How to cite this article:
Doroudinia A, Hosseinzadeh E, Asli IN, Karam MB, Mehrian P. Diagnostic errors of coronavirus infection: Role of fluorodeoxyglucose positron emission tomography/computed tomography scan. Biomed Biotechnol Res J 2020;4:337-41

How to cite this URL:
Doroudinia A, Hosseinzadeh E, Asli IN, Karam MB, Mehrian P. Diagnostic errors of coronavirus infection: Role of fluorodeoxyglucose positron emission tomography/computed tomography scan. Biomed Biotechnol Res J [serial online] 2020 [cited 2021 May 17];4:337-41. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/337/305636




  Introduction Top


Coronavirus disease 2019 (COVID-19) is a potentially severe acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clinical presentation includes a respiratory infection with symptom severity ranging from mild common cold like illness to severe viral pneumonia, leading to acute respiratory distress syndrome that is potentially fatal.[1]

The World Health Organization first declared a public health emergency of international concern on January 30, 2020 and then formally declared it a pandemic on March 11, 2020.[2] The situation is evolving rapidly with global case counts and deaths increasing each day. Clinical trials and investigations to learn more about the virus, its origin, and how it affects humans are ongoing.[3]

Early recognition and rapid diagnosis are essential to prevent transmission and provide supportive care in a timely manner. It is essential to have a high index of clinical suspicion for COVID-19 in all patients who present with fever and/or acute respiratory illness and who report a travel history to an affected area or close contact with a suspected or confirmed case in the 14 days prior to symptom onset.[4]

The most common laboratory abnormalities in patients hospitalized with COVID-19 pneumonia include leukopenia, lymphopenia, leukocytosis, elevated liver transaminases, elevated lactate dehydrogenase, and elevated C-reactive protein (CRP). Other abnormalities include neutrophilia, thrombocytopenia, decreased hemoglobin, decreased albumin, and renal function impairment.[5],[6],[7],[8],[9]

Clinical diagnosis is generally based on exposure history, clinical symptoms, results of blood and biochemical tests, and findings on chest computed tomography (CT) scan which typically consists of ground-glass opacities (GGOs) or bilateral pulmonary consolidations/nodules in multiple lobular and sub-segmental areas. Mediastinal and hilar enlarged lymph nodes and pleural effusions are very uncommon.[10]

Detection of viral RNA is gold standard for diagnosis of COVID-19 infection. The American College of Radiology recommends reserving chest CT scan for hospitalized, symptomatic patients with specific clinical indications for CT scan, and emphasizes that a normal chest CT does not mean that a patient does not have COVID-19 and that an abnormal chest CT is not specific for COVID-19 diagnosis.[11] Abnormal chest CT findings have been reported in up to 97% of COVID-19 patients in one meta-analysis of 50,466 hospitalized patients.[12] Evidence of pneumonia on chest CT may precede a positive real-time reverse transcription polymerase chain reaction (RT-PCR) result for SARS-CoV-2 in some patients.[13] CT imaging abnormalities may be present in minimally symptomatic or asymptomatic patients.[14],[15] Some patients may present with a normal chest finding despite a positive RT-PCR.[16] Furthermore, results of RT-PCR testing may be false-negative, so patients with typical CT findings should have repeat RT-PCR testing to confirm the diagnosis.[17] Sensitivity and specificity of RT-PCR for diagnostic testing are unknown.[18] There are little data available on the rates of false-positive and false-negative results for the various RT-PCR tests available; however, both have been reported.[19]

Considering the above stated facts, in this era of COVID-19 pandemic, there is significant chance for diagnostic errors with possible tendency to over diagnose the suspicious cases. However; performing complementary investigations including fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan in the appropriately selected cases may be helpful to avoid diagnostic errors as we are discussing in our cases.


  Case Presentation Top


This case series was approved by our institutional review board and informed consent obtained from both patients.

This scientific work was approved by our institutional review board (IRB) and informed consent obtained from the two participating patients

Case 1

The patient is a 56-year-old woman with unremarkable past medical history. She had recent intermittent fever and dry cough. Her primary care physician requested a plain chest X-ray which revealed a nodule in the left upper lung zone and she preceded with standard whole body FDG PET/CT scan for further evaluation.

The FDG PET/CT scan was performed on February 25, 2020; when the COVID-19 outbreak was still unrecognized in the country and the virus infectivity was still unknown. A retrospective review of the patients' medical history, clinical data, as well as imaging findings strongly suggested diagnosis of COVID-19.

FDG PET/CT images demonstrated diffuse inflammatory pattern in both lungs. There was diffuse GGOs with associated metabolic activity in both lungs, most prominent in the lungs periphery. There were also few hypermetabolic nodules, more prominent in the left lung. There was no evidence of prominent and hypermetabolic mediastinal or hilar lymph nodes. There was also no evidence of pleural effusion [Figure 1].
Figure 1: Fluorodeoxyglucose positron emission tomography/computed tomography scan in Case-1 demonstrating hypermetabolic bilateral ground glass opacities and nodules, more prominent on the left side and lungs periphery, strongly suggestive for coronavirus disease 2019 infection

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Subsequent laboratory test revealed mild leukopenia with WBC count of 1500. She had also increased CRP and erythrocyte sedimentation rate levels and search for known respiratory pathogens was negative. Unfortunately, SARS-CoV-2 nucleic acid testing (RT-PCR) was not available at the time.

We referred the patient to infection diseases service and according to her general condition with no prominent feature of shortness of breath or oxygen desaturation, she was discharged with isolation precautions and outpatient medical treatment protocol including oseltamivir (Tamiflu) and hydroxychloroquine in addition to rest, hydration, and also medication for fever and pain control.

Case 2

The patient is a 55-year-old man with unremarkable past medical history. He had recent productive cough and fever. The symptoms started on March 15, 2010 when the COVID-19 epidemic was well recognized in the country. Fortunately, by that time; SARS-CoV-2 nucleic acid testing (RT-PCR) became available.

He was referred for RT-PCR and chest CT scan. RT-PCR was performed two times with 1 week interval. Both RT-PCR tests were reported as negative. His chest CT scan on March 22, 2020 demonstrated air space consolidation with surrounding nodular infiltration in right mid lung zone, and mild bilateral GGOs mostly consistent with COVID-19 pneumonia according to the radiologist report.

Subsequently he underwent bronchoscopy/bronchoalveolar lavage with  Escherichia More Details coli isolation, sensitive to levofloxacin. Medical instructions based on chest CT scan and bronchoscopy findings were given to the patient.

Within next 2 weeks, his clinical symptoms demonstrated no significant improvement, with new onset of mild hemoptysis. Subsequently, his pulmonologist referred the patient for FDG-PET/CT scan.

FDG PET/CT scan on April 14, 2020 demonstrated hypermetabolic right central parahilar consolidation which was not appreciated on previous noncontrast chest CT scan. Interestingly, there was no other evidence of hypermetabolic lesion or contralateral lung nodule, consolidation or GGO [Figure 2].
Figure 2: Fluorodeoxyglucose positron emission tomography/computed tomography scan in Case-2 demonstrating hypermetabolic right perihilar consolidation consistent with biopsy proven poorly differentiated squamous cell carcinoma of lung

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Subsequent repeat bronchoscopy and biopsy demonstrated poorly differentiated squamous cell carcinoma and patient was referred to oncology service for further management.


  Discussion Top


In the era of COVID-19 pandemic, clinicians must be very cautious about potential diagnostic errors as we demonstrated in our two cases.

As stated earlier clinical symptoms, laboratory tests, RT-PCR and chest CT scan have pivotal role in establishing diagnosis of COVID-19 infection.

One or more RT-PCR result for SARS-CoV-2 do not rule out the possibility of COVID-19 infection. If a negative result is obtained from a patient with a high index of suspicion for COVID-19, additional specimens should be collected and tested, especially if only upper respiratory tract specimens were collected initially.[19] Guidelines recommend that two consecutive negative tests (at least 1 day apart) are required to exclude COVID-19; however, there is a case report of a patient who returned two consecutive negative results and did not test positive until 11 days after symptom onset and confirmation of typical chest CT findings.[20] It is also important to note that co-infections can occur, and a positive test for a non-COVID-19 pathogen does not rule out COVID-19.[21]

In a cohort of over 1000 patients in a hyperendemic area in China, chest CT had a higher sensitivity for diagnosis of COVID-19 compared with initial RT-PCR from swab samples (88% versus 59%). Improvement of abnormal CT findings also preceded change from RT-PCR positivity to negativity in this cohort during recovery. The sensitivity of chest CT was 97% in patients who ultimately had positive RT-PCR results. However, in this setting, 75% of patients with negative RT-PCR results also had positive chest CT findings. Of these patients, 48% were considered highly likely cases, while 33% were considered probable cases.[22]

Chest CT abnormalities can rapidly evolve from focal unilateral to diffuse bilateral GGOs that progress to or coexist with, consolidations within 1–3 weeks.[14] The greatest severity of CT findings is usually visible around day 10 after symptom onset, and imaging signs associated with clinical improvement (e.g., resolution of consolidative opacities, reduction in number of lesions and involved lobes) usually occur after week 2 of the disease.[23] Older people are more likely to have extensive lung lobe involvement, interstitial changes, and pleural thickening compared with younger patients.[24] Small nodular GGOs and consolidation with surrounding halo signs are typical in children.[25] Atypical CT features appear to be more common in the later stages of disease, or on disease progression.[5],[24]

Our first case was diagnosed to have COVID-19 infection based of FDG PET/CT images while RT-PCR test still was not widely available. She presented early during the pandemic in February 2020, with FDG PET/CT scan demonstrating diffuse GGOs with associated metabolic activity in both lungs, most prominent in the lungs periphery. There were also few hypermetabolic nodules, more prominent in the left lung and no evidence of prominent and hypermetabolic mediastinal or hilar lymph nodes nor evidence of pleural effusion. Her final diagnosis of COVID-19 infection was based on imaging findings and clinical symptoms and she responded well to subsequent treatment instructions.

Our second case can be considered an over diagnosis of COVID-19 infection, as he presented while the pandemic was well recognized. Many articles were already published regarding the role of chest CT scan in diagnosis of COVID-19 infection, even in the absence of RT-PCT confirmation.[12] The diagnosis of COVID-19 infection in this case was suggested by chest radiologist, despite of two consecutive negative RT-PCRs. He did not show any improvement after medical treatment and subsequent evaluation by FDG PET/CT scan demonstrated hypermetabolic right parahilar consolidation, which was not appreciated on his prior chest CT scan. Unfortunately, there was significant delay for his final diagnosis of poorly differentiated squamous cell carcinoma of the lung.

Recently, FDG PET/CT scan findings in COVID-19 has been discussed in a case series including four patients by Qin et al.[12],[26] In accordance with recently published cases,[10] our first case demonstrated peripheral GGOs and consolidative/nodular opacities in both lungs with high FDG uptake. Although bilateral involvement of the lung parenchyma may be present in several benign and malignant lung diseases, usually tumors presenting as GGOs are less likely to be FDG-avid.[13],[27] The high FDG uptake that characterized COVID-19 pulmonary infection reflects a significant inflammatory process.[26] COVID-19 infections usually do not seem to be accompanied by lymphadenopathy, and no obvious nodal enlargement was evident in our first case. However, lymphadenopathy was reported in 3 of 4 cases in Qin et al. case series.[26]

It must be noted that there are high-false negative rates with SARS-CoV-2 nucleic acid testing, possibly related to differences in sample handling, storage, and processing; in addition to differences in disease stages and different viral loads according to anatomical site (e.g., alveoli versus upper respiratory tract). There is also possibility of lack of independent validation of current testing and also potential high mutation rates of COVID-19.[13],[14],[23],[26] This may justify ignoring two consecutive negative RT-PCR tests in our second case and suggesting COVID-19 infection based on chest CT images.

Although FDG PET/CT cannot be routinely used in an emergency situation and is not usually recommended for infectious diseases, our current findings demonstrate that FDG PET/CT scan might be helpful in equivocal cases of COVID-19 infection and interpreters must be aware of imaging manifestations of COVID-19 to avoid diagnostic errors during disease pandemic as we demonstrated in our cases.


  Conclusion Top


Imaging findings in addition to clinical and laboratory data are the cornerstone for COVID-19 infection diagnosis and treatment initiation. FDG PET/CT scan might be helpful in equivocal and appropriately selected cases and interpreters must be aware of imaging manifestations of COVID-19 to avoid diagnostic errors during disease pandemic as we demonstrated in our cases.

Acknowledgment

We would like to thank our hospital dedicated and brave authorities, physician, and nurses for providing excellent help and treatment for the COVID-19 patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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