Dataset Viewer
pmcid
string | content
string | risk
int64 | event
sequence | timestamp
sequence | __index_level_0__
int64 |
|---|---|---|---|---|---|
PMC10469423 | 2023
Severe pigeon paramyxovirus 1 infection in a human case with probable post-COVID-19 condition
ABSTRACT
Pigeon paramyxovirus 1 (PPMV-1) is an antigenic host variant of avian paramyxovirus 1. Sporadic outbreaks of PPMV-1 infection have occurred in pigeons in China; however, few cases of human PPMV-1 infection have been reported. The purpose of this article is to report a case of severe human PPMV-1 infection in an individual with probable post-COVID-19 syndrome (long COVID) who presented with rapidly progressing pulmonary infection. The patient was a 66-year-old man who was admitted to the intensive care unit 11 days after onset of pneumonia and recovered 64 days after onset. PPMV-1 was isolated from the patient’s sputum and in cloacal smear samples from domesticated pigeons belonging to the patient’s neighbour. Residual severe acute respiratory syndrome coronavirus 2 was detected in respiratory and anal swab samples from the patient. Sequencing analyses revealed that the PPMV-1 genome belonged to genotype VI.2.1.1.2.2 and had the 112RRQKRF117 motif in the cleavage site of the fusion protein, which is indicative of high virulence. This case of cross-species transmission of PPMV-1 from a pigeon to a human highlights the risk of severe PPMV-1 infection in immunocompromised patients, especially those with long COVID. Enhanced surveillance for increased risk of severe viral infection is warranted in this population.
KEYWORDS:
Pigeon paramyxovirus 1, severe acute respiratory syndrome coronavirus 2, human PPMV-1 infection, cross-species, surveillance
Introduction
Newcastle disease (ND) is a common infectious condition found in a wide range of avian species and has caused significant economic losses in the poultry industry [
1–3
]. The causative agent of ND is virulent Newcastle disease virus (NDV), also known as avian paramyxovirus 1 (APMV-1) [
4
]. It belongs to the genus
Avulavirus
, subfamily
Paramyxovirinae
within the family
Paramyxoviridae
[
5
]. NDV is an enveloped virus with a negative-sense, single-stranded, non-segmented RNA genome of 15.2 kb that encodes six structural proteins, including nucleocapsid protein, phosphoprotein, matrix protein, fusion protein, haemagglutinin-neuraminidase, and RNA-dependent RNA polymerase protein [
5–7
]. Based on phylogenetic analysis of the F gene sequence, NDV is divided into class I and class II [
8–10
].
Pigeon paramyxovirus type 1 (PPMV-1) is an antigenic host variant of NDV that causes infection in pigeons [
11
]. Pigeons are the natural hosts of PPMV-1 [
12
]. PPMV-1 was first identified in the Middle East, specifically in Iraq, in the late 1970s. It then spread rapidly across Europe, causing the third epizootic of the 1980s [
13
,
14
]. The first PPMV-1 outbreak in pigeons in China was confirmed in 1985, and since then PPMV-1 has been reported in pigeons in many provinces in China, with genotype VI being dominant [
15–17
]. PPMV-1 infection in humans is usually mild and self-limiting. Therefore, it is rarely reported. However, several immunocompromised cases with pneumonia have died as a result of respiratory failure [
18–20
].
In February 2023, a 66-year-old man was identified to have PPMV-1 infection by metagenomics next-generation sequencing (mNGS). Epidemiological investigation showed that he had been exposed to domesticated pigeons before he became ill. The patient had previously had coronavirus disease 2019 (COVID-19) and had since experienced symptoms of post-COVID-19 syndrome (commonly known as long COVID). PPMV-1 was identified and isolated in a sputum sample from the patient and from cloacal smear samples taken from the pigeons. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was also detected in samples from the patient. In this report, we present the epidemiological features and viral characteristics of human PPMV-1 infection and offer insights into the significance of surveillance for increased risk of severe viral infection in the population with long COVID.
Methods
Collection of clinical and epidemiological data
Our patient was confirmed to have APMV-1 infection based on mNGS sequencing on February 17, 2023. The patient’s clinical information was collected from the hospital in Beijing, China, which the patient first visited on February 6, 2023. A standardized surveillance reporting form was used by field investigators and clinicians to gather epidemiological and clinical data. These data included demographics, housing environment, underlying medical comorbidities, exposure history, clinical symptoms, clinical laboratory test results, treatment, clinical complications, and outcomes.
Collection of clinical samples and detection
Clinical samples were collected from the patient’s bronchoalveolar lavage fluid, sputum, throat swab, anal swab, and blood and from the pigeons (cloacal swab and environmental smear specimen) and were processed for detection of pathogens. RNA was extracted from the samples using the QIAamp Viral RNA Mini Kit (Qiagen, Hilden, Germany) and tested for PPMV-1 virus and SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (RT-PCR) using commercial kits from NBGen and DAAN Biological Technology Co., Ltd. (Beijing, China), respectively. The above examinations were performed in strict accordance with the manufacturers’ instructions.
Staining and detection of immune-related cells
Blood was drawn from the patient via sterile venipuncture into EDTA vacutainers (Becton Dickinson, BD, Franklin Lakes, NJ, USA). Fresh blood was incubated with a 6-colour T-cell, B-cell, and natural killer (NK) cell panel of monoclonal antibodies specific for CD3 (BV510), CD56 (APC), CD45 (APC-Cy7), CD4 (PE), CD19 (BV421), and CD8 (FITC) in Trucount tubes. After cell surface staining for 15 min at room temperature in the dark, erythrocytes were lysed by incubation with lysis buffer (BD) for 10 min. Flow cytometry was performed on a BD FACSymphony™A5 system (BD) and analysed using FlowJo 10 software. BD CS&T beads were used for the flow cytometer set-up and control samples. Standardized fluorescence compensation for the FACSymphony flow cytometer was established using BD FC beads for all fluorochromes in conjunction with FlowJo 10 software and CS&T beads.
Next-generation sequencing and phylogenetic analysis
PPMV-1 genes were amplified by RT-PCR and library preparation using a Nextera XT DNA library preparation kit (Illumina, San Diego, CA, USA) for sequencing on the Illumina MiniSeq platform. Raw FastQ data for PPMV-1 were assembled using a CLC Genomics Workbench, version 21.0, and the BLAST sequence was searched against the NCBI database. MEGA 6.0 was used for sequence alignment and construction of a phylogenetic tree based on the F gene with PPMV-1 reference sequences downloaded from the NCBI. In the same way, SARS-CoV-2 RNA was amplified by RT-PCR using upstream and downstream primer combinations covering the entire genome and NEBNext Q5 hot start HiFi PCR master mix (New England Biolabs, Hitchin, UK). After library preparation, the genome was sequenced on the Illumina MiniSeq platform. Raw FastQ data for SARS-CoV-2 were assembled using the CLC Genomics Workbench, version 21.0, and the censuses sequence was uploaded to
https://pangolin.cog-uk.io/
for type identification.
Isolation of PPMV-1 and SARS-CoV-2
To isolate PPMV-1, Madin-Darby bovine kidney (MDBK) cells were inoculated with samples and the virus was detected by an immunofluorescence assay. Confluent MDBK cells were inoculated with approximately 200 μL of the patient’s sputum sample or 200 μL of a pigeon cloaca sample and grown in 6-well plates containing 800 μL of maintenance medium consisting of Dulbecco’s modified Eagle’s medium (Invitrogen, Carlsbad, CA, USA) and antibiotics (100 U/mL penicillin and 100 g/mL streptomycin, Invitrogen). After viral absorption for 2 h, the infection medium was replaced with maintenance medium and incubated at 37°C. Cytopathic effects (CPEs) were monitored after 1–2 days. The MDBK cells were fixed with 4% paraformaldehyde for 10 min, permeabilized with Triton X-100 for another 20 min, and incubated in blocking buffer for 10 min. The cells were then incubated with a mouse antibody against PPMV-1 nucleocapsid protein (1:1000, generated and kindly provided by Professor Honglei Sun, China Agricultural University) and then with an FITC-labelled secondary antibody (1:400, KPL Inc., Gaithersburg, MD, USA), both at 37°C for 60 min. The cells were then stained with 1 mg/mL DAPI. All images were acquired with a fluorescence microscope (Olympus, Tokyo, Japan).
For isolation of virus, Vero cells in six-well plates containing Dulbecco’s modified Eagle’s medium supplemented with 2% foetal bovine serum (Invitrogen) were inoculated with 1 mL of viral transport medium from the patient’s throat swab that was identified to be positive for SARS-CoV-2 and incubated in a CO
2
incubator at 37°C. The plates were observed daily for CPEs using an inverted microscope (Eclipse Ti; Nikon, Tokyo, Japan). After cultivation for 5 days, serial passages were carried out. After three passages, the virus was identified by real-time RT-PCR.
Neutralizing antibody assay
Microneutralization assays were performed. Starting at a 1:10 dilution, 50 μL of two-fold serial dilutions of antisera were pre-incubated 1:1 with 100 median tissue culture infective doses (TCID
50
) of the virus stocks at 37°C for 2 h. The mixture was then transferred to 96-well plates containing MDBK cells and incubated for a further 18–20 h at 37°C in a 5% CO
2
incubator. The end-point dilutions were assessed using an immunofluorescence assay.
Scanning and transmission electron microscopy
Scanning electron microscopy (SEM) was used to detect changes in the morphology of normal human bronchial epithelial (NHBE) cells following PPMV-1 inoculation to gain an understanding of the invasiveness of PPMV-1 in human respiratory epithelial cells. Virus isolated from the patient sputum specimen produced CPEs in monolayers of NHBE cells 48 h after inoculation. Briefly, NHBE cell cultures were inoculated with the virus at a multiplicity of infection (MOI) of 1. Forty-eight hours post-infection, infected and mock-infected NHBE cells were fixed with 2.5% glutaraldehyde (Soliabio, Beijing, China) at 4°C overnight, washed and dehydrated in an ethanol gradient, subjected to critical point drying, and vacuum-evaporated with platinum. The membrane supporting the NHBE cells was then cut from the Transwell rack and glued to a sample holder, and the samples were examined by SEM using a Hitachi SU8000 (Tokyo, Japan).
NHBE cells were infected with PPMV-1 at an MOI of 1, and cell culture supernatants were collected at 48, 72, and 96 h post-inoculation for virus titration. The titres of PPMV-1 in the cell supernatants at different time points were determined by TCID
50
assays as described elsewhere [
21
]. MDBK cells were seeded in 96-well plates at a density of 2 × 10
4
cells/well. After 24 h, the culture supernatants were serially diluted with Dulbecco’s modified Eagle’s medium, and MDBK cells were infected with 100 μL of 10-fold serial dilutions of harvested culture supernatants. The cells were incubated at 37°C for 96 h. The CPEs on cells in each well were observed using a light microscope (IX70; Olympus). TCID
50
values were calculated using the method devised by Reed and Muench [
22
].
Transmission electron microscopy (TEM) was used to observe the morphology of the virus particles with the aim of identifying the virus. Twenty hours after infection, MDBK cells infected with PPMV-1 at an MOI of 10 were fixed with 2.5% glutaraldehyde (Soliabio). After washing with phosphate-buffered saline, the samples were dehydrated with an alcohol gradient and embedded in Epon812 for 72 h at 60°C. Ultra-thin sections were cut, stained with uranium acetate and lead citrate, and then observed using a Hitachi HT7800 transmission electron microscope.
Results
Clinical information and pathogen detection
The patient first visited our hospital with a fever (38.5°C) on February 6, 2023 (day 1 of onset). Before this illness, the patient had experienced persistent physical weakness since being infected with SARS-CoV-2 on December 30, 2022. The patient also had a history of hypertension, coronary heart disease, and dyslipidaemia, for which he was prescribed aspirin and a statin. He complained of shivering, cough, palpitations, weakness, nausea, and continuous fever and had taken antipyretic agents at home. The patient was treated with moxifloxacin as an outpatient on February 6–9, 2023. On February 10 (day 5), his temperature increased to 39.7°C and was accompanied by cough, abdominal pain, and diarrhoea. Therefore, he was hospitalized for treatment. On February 16, 2023 (day 11), there had been no improvement and the patient was transferred to the intensive care unit. A computed tomography scan of the chest indicated bronchitis with thickening of the walls of the bronchial tubes in both lungs.
After the patient was admitted to hospital, relevant pathogens were sought. On February 17 (day 12), APMV-1 was suggested in bronchoalveolar lavage fluid by mNGS. Subsequently, sputum, throat swabs, and anal swabs were collected from the patient for detection of APMV-1, SARS-CoV-2, and other pathogens. The specific detection results are shown in
Figure 1
.
Epidemiological investigations
Epidemiological investigation showed that the patient lived with his wife in a single-family cottage in an alley in an urban district of Beijing. The property’s floor area was approximately 70 square metres and the building had poor ventilation. A neighbour opposite the residence had raised pigeons in their attic for a long time. The residence of the patient was close to that of this neighbour. When the patient left his home, he needed to pass the house where the pigeons lived. The patient had intensive contact with the pigeons kept by the neighbour before the onset of his illness. Pigeon cloacal swabs and environmental smear samples of the loft tested positive for PPMV-1. The sequences of PPMV-1 samples from the patient and pigeons were identical. Based on epidemiological and aetiological evidence, cross-species transmission from pigeons to a human was confirmed.
Serum samples from close contacts (the patient’s wife and neighbour) were tested for neutralizing antibodies using MDBK cells. The patient’s microneutralization antibody titres were 1:8 on day 18 and day 23 and 1:16 on day 28 and day 31 after onset of the illness, while the close contacts were negative for the serum antibody.
Immune-related cell count analysis
To better understand the immune status of the patient, 6-colour flow cytometric assays using the BD FACSymphony™A5 system were performed to determine immune-related cell counts. White blood cell, lymphocyte, monocyte, total T lymphocyte, total B lymphocyte, NK cell, helper/inducer T-cell, and suppressive/cytotoxic T-cell counts (
Table 1
) were significantly decreased in comparison with normal levels (
Figure 2
,
Table 1
).
Table 1.
Flow cytometry analysis of the patient’s peripheral blood.
Open in a new tab
*Arrows represent the high and low cell count values compared with normal levels.
Virus isolation and immunofluorescence assays
Virus was isolated from a sputum sample collected from the patient on February 18 (day 13 after illness onset) and from pigeon cloacal samples and was identified by immunofluorescence after inoculation with MDBK cells (
Figure 3
). Virus isolated from the sputum specimen produced CPEs on monolayers of MDBK cells after 72 h. After 4 days, CPEs and detached cells were evident over the entire monolayer area. Multiple subsequent passages and isolation of plaques yielded culture suspension and infected cells from a single plaque of the virus. The culture suspension and cells were used for identification of the virus by fluorescence electron microscopy. After confirming the virus as PPMV-1 by real-time RT-PCR and immunofluorescence assays, the virus was named PPMV-1-202302. Vero cells were inoculated with clinical specimens for isolation of SARS-CoV-2, produced no typical CPEs, and were confirmed to be negative for SARS-CoV-2 by real-time RT-PCR.
PPMV-1 and SARS-CoV-2 genome analysis
The sequences of the viruses isolated from the patient and the pigeons shared a nucleotide similarity of 100%. The full-length genome of the isolated virus displayed 99.45% nucleotide sequence identity with a PPMV-1 isolated from pigeons in eastern China (pigeon/Shandong/190610-2/2019, GenBank). Phylogenetic analysis clustered the virus within a group of pigeon viruses isolated in north China, including a strain isolated from the patient’s neighbour’s pigeons (
Figure 4
). This indicates the possibility of transmission from pigeons to humans. The virus had the VI.2.1.1.2.2 genotype, which in China exists mainly in pigeons. Moreover, the 112RRQKRF117 motif was observed in the cleavage site of the fusion protein, which indicates high virulence in poultry. Furthermore, the SARS-CoV-2 genome was obtained from the sputum sample collected on February 19, 2023 with 96.1% coverage, and was subtyped as Omicron variant BF.7.14 through the Pangolin COVID-19 Lineage Assigner Web application (
https://pangolin.cog-uk.io/
).
Virus identification and infectivity analysis
The virus isolation culture supernatants were collected for virus purification using discontinuous sucrose gradient centrifugation, and the purified virus was examined by TEM. The virus particles were polymorphic with a diameter of 100–400 nm, and the spines on the surface were approximately 12–15 nm long (
Figure 5
A).
The replication ability of the virus from the patient and pigeons was examined in NHBE cells, which form a ciliated-pseudostratified columnar epithelium at an air-liquid interface. SEM was used to investigate the CPEs of PPMV-1-infected NHBE cells in detail (
Figure 5
B). Shrinkage of cilia in the plaque region and beaded changes in the periphery of plaques were detected (
Figure 5
B). The cilia were disordered in virus-infected cells in the far periphery of the plaques. Extracellular viral particles were observed in infected NHBE cells by TEM. The virus titres (TCID
50
/ml) at 48, 72, and 96 h post-inoculation were 6.3 × 10
2
, 4.7 × 10
3
, and 1 × 10
5
, respectively. These findings indicate that epithelial cells in the human upper and lower respiratory tract are susceptible to PPMV-1 infection.
Discussion
PPMV-1 has long been prevalent among pigeons and leads to significant economic losses in the Chinese pigeon industry nationwide [
23–25
]. Human infection with PPMV-1 is rarely reported. This report describes a case of PPMV-1 infection and isolation of the virus in a sputum sample from a human patient and a pigeon cloaca sample. The patient was also SARS-CoV-2-positive, having been diagnosed with COVID-19 on December 30, 2022. Whole genome sequences of PPMV-1 from the case and the pigeons were obtained by next-generation sequencing. With the timely detection of pathogens that in part directed clinical treatment, the patient had recovered by April 8, 2023.
In this study, mNGS was used to identify the causative pathogen in the patient’s samples. The interval between onset of the patient’s illness and identification of the pathogen was 12 days. Compared with a previous report in which NDV was identified by mNGS, which took 23 days [
18
], this short detection time provided a valuable time window for effective clinical treatment. Ultimately, because of the early diagnosis by mNGS, the patient was successfully discharged from hospital 64 days after PPMV-1 infection. This report highlights the clinical benefit of early diagnosis by mNGS for patients with infections of unknown origin. The patient’s serum was positive for neutralizing antibody against PPMV-1, with a slight upward trend between days 18 and 31, indicating a recent infection. However, pathogen and serum antibody tests were negative for the patient’s wife and neighbour, indicating that the virus had limited transmission ability and that this was a case of cross-species infection rather than human-to-human transmission.
PPMV-1 is a common zoonotic pathogen that circulates in the pigeon reservoir and can occasionally spread to humans. Although the risk of infectious diseases originating from the human-animal interface is usually focused on the wild environment, close attention to interaction between domestic pets and humans in urbanized regions is also warranted. The comprehensive One Health strategy targeting both the wild environment and the human built environment is intended to prevent and control zoonotic pathogens [
26–27
]. Action can be taken to control the risk of spillover or transmission to humans by reduced contact with animals. Meanwhile, intensive surveillance to track the activity of pathogenic microorganisms is supposed to be in place in both wild and domesticated species. Furthermore, universal or targeted vaccination is an optional strategy that can be used to contain infection and transmission in animals as well as between animals and humans.
On May 5, 2023, the World Health Organization stated that COVID-19 is now an established and ongoing health issue but no longer constitutes a public health emergency of international concern
[
28
]
. However, it should be noted that the impact of long COVID is open-ended and involves extensive and diverse populations. During the period when COVID-19 was prevalent, the risk of severe infection caused by usually mild pathogens may have increased in individuals who had contracted COVID-19 to give rise to a population with underlying medical comorbidities, particularly in immunocompromised individuals. In late 2022, the BF.7.14 lineage was dominant in Beijing, and our patient was initially infected with SARS-CoV-2 during the same period. On February 18, 2023, residual SARS-CoV-2 was detected in respiratory samples from the patient and were also identified as BF.7.14 lineage. It seemed unlikely that the same variant was contracted in a such short period of time. Furthermore, on February 13, 2023 (week 7), the positive SARS-CoV-2 rate in virological surveillance was only 2.8% in Beijing, indicating that the virus activity was at a low level and the risk of infection with COVID-19 was minimal. The above-mentioned evidence indicates that the patient had since experienced symptoms of long COVID rather than reinfection. The case reported here, which met the above criteria, reflects this situation. Strengthening surveillance among at-risk groups with post-COVID-19 syndrome is important, especially for individuals having frequent contact with animals, including pets.
The patient described in this report had chronic underlying diseases with hypertension and coronary heart disease. He had experienced persistent physical weakness since being diagnosed with COVID-19 on December 30, 2022. The synergistic effect of the chronic underlying diseases and a previous infection with SARS-CoV-2 may have led to compromised immunity, which might have increased the severity of the PPMV-1 infection. It has not been reported and might be controversial whether a previous infection with SARS-CoV-2 increases the severity of the disease caused by PPMV-1 infection. However, it was previously reported that patients who were infected with COVID-19 and influenza had more severe symptoms and a higher risk of death than those who were infected with COVID-19 alone
[
29
]
. The patient has lived in the same region for many years but has never been infected with PPMV-1. Nevertheless, after contracting COVID-19 in late 2022, he did not recover fully and was diagnosed with long COVID. In this physiological context, he was subsequently infected with PPMV-1 in February 2023. This infection pattern indicates that there may be a potentially causal relationship between PPMV-1 and COVID-19 rather than occasional co-infection, but the mechanism affecting the change of susceptibility is still unknown.
This study has several limitations. The mechanism of pigeon-to-human PPMV-1 cross-species transmission warrants further study. It is crucial to study viral and host factors associated with cross-species transmission to help develop effective intervention measures. Moreover, PPMV-1 has not been rigorously investigated, and its epidemiology and variation in pigeons require further investigation.
In conclusion, cross-species transmission of PPMV-1 from pigeons to humans is a new public health concern. mNGS can play a significant role in discovery and early diagnosis of novel pathogens. Enhanced surveillance to detect an increased risk of severe disease after viral infection is warranted in the population with long COVID.
Acknowledgement
Health care workers who contributed to the epidemiological survey, sample collection, and transportation. We were grateful to Dr Xiaohui Zou, from China–Japan Friendship Hospital, for kindly providing support to our manuscript.
Funding Statement
This work was supported by National Key R&D Program of China [grant no 2021ZD0114103].
Disclosure statement
No potential conflict of interest was reported by the author(s). | 0 | [
"hypertension ",
"coronary heart disease ",
"dyslipidaemia ",
"aspirin ",
"statin ",
"persistent physical weakness ",
"COVID-19 ",
"SARS-CoV-2 ",
"exposure to domesticated pigeons ",
"fever ",
"shivering ",
"cough ",
"palpitations ",
"weakness ",
"nausea ",
"antipyretic agents ",
"moxifloxacin ",
"abdominal pain ",
"diarrhoea ",
"hospitalized ",
"computed tomography scan ",
"bronchitis ",
"thickening of the walls of the bronchial tubes ",
"APMV-1 ",
"mNGS ",
"sputum sample ",
"throat swab ",
"anal swab ",
"PPMV-1 ",
"SARS-CoV-2 ",
"virus isolation ",
"immunofluorescence assay ",
"66 years old ",
"male ",
"admitted to the hospital ",
"PPMV-1-202302 ",
"Vero cells ",
"SARS-CoV-2 genome ",
"Omicron variant BF.7.14 ",
"phylogenetic analysis ",
"genotype VI.2.1.1.2.2 ",
"112RRQKRF117 motif ",
"high virulence ",
"NHBE cells ",
"SEM ",
"TEM ",
"virus particles ",
"cytopathic effects ",
"CPEs ",
"virus titres ",
"TCID50 ",
"neutralizing antibody ",
"neutralizing antibody ",
"neutralizing antibody ",
"neutralizing antibody ",
"long COVID ",
"post-COVID-19 syndrome ",
"synergistic effect ",
"compromised immunity ",
"increased severity ",
"previous infection with SARS-CoV-2 ",
"potentially causal relationship ",
"cross-species transmission ",
"viral and host factors ",
"effective intervention measures ",
"epidemiology ",
"variation in pigeons ",
"discharged ",
"recovered ",
"enhanced surveillance ",
"increased risk of severe disease ",
"population with long COVID "
] | [
-672,
-672,
-672,
-672,
-672,
-38,
-38,
-38,
-14,
-12,
-12,
-12,
-12,
-12,
-12,
-12,
-10,
-6,
-6,
-6,
-5,
-5,
-5,
-4,
-4,
-3,
-3,
-3,
-2,
-2,
-1,
-1,
0,
0,
0,
13,
13,
14,
14,
14,
14,
14,
14,
15,
15,
15,
15,
15,
15,
15,
15,
16,
23,
28,
31,
38,
38,
38,
38,
38,
38,
38,
38,
38,
38,
38,
38,
64,
64,
64,
64,
64
] | 0 |
PMC10476922 | 2021
Rehabilitation course and functional outcome of acute disseminated encephalomyelitis related to SARS-CoV-2 infection
CASE DESCRIPTION
Acute hospitalisation
A 59-year-old Asian male migrant worker was diagnosed with acute disseminated encephalomyelitis (ADEM) 43 days after presentation with severe COVID-19, based on the combination of encephalopathy, generalised motor weakness and multifocal magnetic resonance (MR) imaging findings.[
1
] His acute neurological presentation had been described in a case series of COVID-19 patients with encephalitis.[
2
] He received four interval courses of intravenous immunoglobulin on Day 43, 67, 95 and 146 of illness, and his hospitalisation was further complicated by septic shock requiring inotropic support, acute kidney injury requiring haemodialysis, deranged liver function, provoked segmental pulmonary embolism and polyarticular gout flare. He had a history of polyarticular gout for ten years.
The patient was transferred out of intensive care on Day 50 of illness, with minimal neurological recovery and a Glasgow Coma Scale (GCS) score of E4VTM1. There was no consistent visual pursuit, vocalisations or functional communication. His encephalopathy gradually improved over time, and he scored 9/23 on the Coma Recovery Scale-Revised (CRS-R) on Day 70. He was able to follow instructions inconsistently on Day 72 of illness, and his CRS-R score improved to 10/23 on Day 83 of illness. In view of his generalised profound weakness, a nerve conduction study performed on Day 89 of the illness showed axonal sensorimotor polyneuropathy suggestive of critical illness polyneuropathy. Figures
1
and
2
show the patient's rehabilitation and neurocognitive progress across different care facilities.
Rehabilitation course
The patient was transferred to inpatient rehabilitation facility on Day 186 of illness with a GCS of E4V4M6. A physiatrist-led transdisciplinary rehabilitation programme was commenced with three hours per day of rehabilitation therapies, 5.5 days per week consisting of physiotherapy, occupational therapy, speech therapy, psychology reviews and fortnightly dietician reviews. Weekly multidisciplinary conferences were conducted for functional goal setting. Functional Independence Measure (FIM) was the primary instrument used to document improvements. The patient continued to make slow but considerable functional gains during his rehabilitative course. His rehabilitation problems are described below.
Cognitive and behavioural impairments
In this patient, global and severe cognitive deficits were noted upon his emergence from a minimally conscious state. On admission to rehabilitation, he showed sustained attention for 10–15 minutes each time, and was disoriented, with slow information processing speed. He was able to follow one-step commands only. Immediate information recall was impaired, and the Abbreviated Mental Test (AMT) score was 1/10. Participation was limited owing to attentional deficits, slow processing speed and impaired short-term memory. To address attention deficits, therapy was conducted in a quiet and visually bland environment to reduce distractions, and coaxing was frequently required to engage the patient in therapy sessions. In view of reduced information processing speed, cognitive demands were reduced through task simplification and increased time for information processing during therapy sessions. Occasional episodes of irritability and agitation, related to fatigue, pain or giddiness experienced during therapy, were de-escalated through time-out-on-the-spot techniques and redirection. The patient was unable to use cognitive remediation strategies such as errorless learning, repetition, visual memory aids or schedule reminders. Additionally, daily reality orientation, flexibility of therapy timings and sleep wake regulation were employed. His AMT improved to 3/10 on Day 258 of illness. Mini-Mental State Examination or Montreal Cognitive Assessment could not be performed throughout the stay due to the patient's limited attention span and fatigue.[
3
] The rehabilitation staff maintained a consistent, encouraging and empathetic stance, and the patient's motivation and cooperation improved slowly, aided by regular supportive counselling and mobile digital media tools.
Quadriparesis
Motor examination revealed disproportionate spastic weakness in the patient's lower limbs with a Medical Research Council (MRC) grade 2/5 (left) and 1/5 (right), compared to his upper limbs (MRC scale 3/5), corresponding to the location of his periventricular lesions visualised on MR imaging. This improved from his initial complete quadriparesis during his intensive care unit (ICU) stay.[
2
] In addition, his motor recovery was complicated by the concomitant diagnosis of critical illness polyneuropathy (CIP) and steroid myopathy. Functionally, the patient had dependent in bed mobility with poor sitting balance and required maximum assistance for activities of daily living (ADLs). Physical therapy focused on training his sitting balance, sitting tolerance and verticalisation via a tilt table. Task-specific training for ADLs was carried out by occupational therapists using mirror visual feedback during grooming tasks.
Orthostatic hypotension
During therapy, the patient experienced symptomatic postural hypotension related to severe deconditioning owing to prolonged immobilisation. His blood pressure dropped from 135/92 mmHg in the supine position to 112/87 mmHg on inclination to 50° on tilt table standing. He was scheduled to receive 2–2.5 L of fluids per day, with fluid boluses administered before therapy, and bilateral thigh-length elastic compression stockings with abdominal binders were used to passively increase venous return. On Day 266 of illness, the patient tolerated sitting at the edge of the bed and was mobilised in a tilt-in-space wheelchair for 60 minutes without postural hypotension.
Swallowing and communication
The patient suffered from mild oropharyngeal dysphagia, which was thought to be related to prolonged intubation and tracheostomy. Upon cessation of feeding through the nasogastric tube on Day 142 of illness, he tolerated a blended diet. Video fluoroscopic swallowing study on Day 189 of illness showed no aspiration with regular diet consistency and thin fluids with controlled cup drinking, after which the patient resumed a normal diet. In terms of communication, he had functional communicative ability for both expressive and receptive speech.
Nutritional/metabolic parameters
Eight months into admission, the patient lost 14.4 kg (body mass index [BMI] 21.6 kg/m
2
) from a premorbid weight of 84 kg (BMI 26.5 kg/m
2
). Nadir albumin level of 24 g/L on Day 108 of illness improved to 30 g/L during rehabilitation. A high caloric diet of 2,000 Kcal per day with 70 g of protein was encouraged, with oral nutritional supplements mandated whenever oral intake was poor. In addition, the nadir anaemia of 6.3 mg/L improved to 10.2 mg/L during rehabilitation. Initial mild immobilisation-related hypercalcemia, at the highest level of 2.78 mmol/L on Day 53 of illness, normalised during rehabilitation.
Decubitus ulceration
Owing to severe immobility and prolonged recumbency, the patient unfortunately developed a 6-cm × 4-cm Grade 3 sacral ulcer on Day 133 of illness. This significantly limited adjunctive mobilisation efforts to a sitting position, such as electromechanical training using automated body weight-supported treadmills (e.g. Lokomat
®
), which were contraindicated owing to the presence of the decubitus ulcer under the pelvis straps. After strict 2–3 hourly bed-turning, pressure relief mattresses, pressure offloading during tilt table exercises, and progressive increases in sitting duration over days with meticulous skin dressing and wound checks, wound healing was achieved on Day 258 of illness.
Urinary incontinence
In view of the patient's decubitus ulcer, an indwelling urinary catheter was required for skin hygiene. Upon catheter removal after decubitus healing, he regained spontaneous voiding but remained dependent on diapers owing to his high level of dependency.
Recurrent nosocomial infections
Therapy was hampered by three episodes of catheter-associated urinary tract infections and
Clostridium difficile
diarrhoea, all of which responded to appropriate antibiotics.
Recurrent polyarticular gout flares
Recurrent gout flares of the left hip, both knees and ankles, and the first metatarsal phalangeal joints hindered rehabilitation. Right knee and left hip aspiration performed on Days 46 and 174 of illness, respectively, yielded turbid straw-coloured fluid and confirmatory negatively birefringent crystals. There was no evidence of septic arthritis on cell counts and fluid cultures. The patient was treated with a tapering course of oral prednisolone and uric acid-lowering therapy with febuxostat in view of renal impairment. His serum uric acid levels decreased from a peak of 903 µM/L to 483 µM/L. The affected joints were mobilised gently during gout flares.
Acute and chronic lower body pain
The rehabilitation course of the patient was significantly interrupted by intermittent lower limb and back pain. The exact history, pain reporting and elucidation of the nature of pain were difficult to delineate owing to the patient's impaired sensory discrimination and severe cognitive deficits. We postulate that the pain was multifactorial, with acute pain flares on a background of chronic pain. Possible sources of acute pain flares included polyarticular gout flares and his decubitus ulcer, which later healed. Chronic pain could have resulted from joint stiffness from prolonged ICU immobilisation, axonal sensorimotor polyneuropathy (CIP), the primary neurological insult (ADEM) and central neuropathic pain, accounted for by widespread lesions visualised within the brain and spinal cord at C1, T9-T11 and conus medullaris, causing dysfunction of spinal-thalamic-cortical pathways.[
4
,
5
] Additionally, bilateral adductor spasticity (Grade 2 on the Modified Ashworth Scale[
6
]) with restricted hip abduction and flexion (passive range of motion of hip abduction was reduced to 20° and left hip flexion to 90°) may have likely contributed.[
6
] Pain was managed by simple analgesia (acetaminophen, NSAIDS) as well as gabapentin. Physical modalities such as superficial heat or electrical stimulation were contraindicated owing to the presence of insensate skin and cognitive impairment.
The patient's FIM data and that at admission are shown in
Table 1
, reflective of low FIM efficiency, slow progress and high dependency.
Table 1.
Summary of total and subset Functional Independence Measure (FIM) scores during inpatient rehabilitation course.
Open in a new tab
DISCUSSION
This case report illustrates the dilemmas and challenges faced during the rehabilitation of a patient with ADEM in critical COVID-19.
Diagnostic delays
Diagnostic delays have been described during severe COVID-19 encephalopathy.[
2
,
7
,
8
] In the current case, computed tomography imaging of the brain was normal on Day 16, and radiological evidence of brain pathology was only detected on diagnostic MR imaging, which could only be obtained upon safe de-isolation on Day 34.
Rehabilitation in ADEM related to SARS-CoV-2 infection
The complex interplay between multiple medical complications and treatments received for COVID-19 related ADEM resulted in several rehabilitation challenges. Initiating early rehabilitation often needs to take into consideration the medical stability of patients and existing infection control protocols. In particular, decubitus ulcerations secondary to motor weakness, dependency and steroid-induced skin atrophy substantially limited initial rehabilitation efforts and prolonged the length of stay in hospital. Thus, meticulous preventive nursing care and nutrition are vital care components even after the critical phase of severe COVID-19.
Furthermore, this case demonstrates that neurocognitive sequelae of COVID-19 persist beyond acute care. This is in accordance with emerging evidence showing persistent fatigue, anxiety and depression even after acute COVID-19.[
9
] In overstretched healthcare systems battling with pandemic surges, prolonged inpatient rehabilitation stays may not be feasible. However, remarkable, albeit slow, functional gains were evident at more than eight months after the initial presentation, implying the presence of delayed yet sustained neuroplastic mechanisms in the brain and spinal cord.
Indeterminate prognosis of COVID-19-related ADEM
Case series of post-viral ADEM have reported variable functional outcomes, with paediatric patients having better outcomes compared to adults.[
10
] Previous reports also highlighted persistent chronic impairments, especially in cognitive domains, and hampered societal participation with consequential vocational cessation.[
11
]
Specific therapeutics for recovery from COVID-19-related ADEM
Carda
et al
. reported on the role of initial stratification of rehabilitation needs and recommendations for rehabilitation in COVID-19 survivors, which was well illustrated in our case.[
3
] However, amantadine, which is deemed beneficial for recovery of conscious awareness following traumatic disorders of consciousness, could not be used acutely owing to severe orthostatic hypotension from severe deconditioning.[
12
,
13
] An empirical impairment-based approach with close clinical monitoring thus appears appropriate in view of the lack of evidence for specific therapies for disorders of consciousness in ADEM.
COVID-19 rehabilitation care and psychosocial challenges
Currently, recommendations for COVID-19 rehabilitation are still evolving; the general consensus argues against a specific COVID-19 rehabilitation service, which would increase service fragmentation and further stress healthcare systems.[
14
] Rather, emphasis should be placed on early detailed functional assessment with family engagement to decide on a suitable rehabilitation plan to maximise recovery and improve quality of life.[
15
] In our patient, the physical engagement of his immediate family who lived in a neighbouring country was not possible owing to prolonged pandemic-related cross-border restrictions. Videoconferencing and digital communication were essential to facilitate interactions between the patient, family and rehabilitation professionals.
Rehabilitation challenges of COVID-19 survivors may arise owing to the interactions of multiple organ dysfunction. In addition, we found that the combination of chronic pain, cognitive impairment and irritability impeded rehabilitation efforts, emphasising the need to incorporate psychological interventions as part of a holistic rehabilitation approach.
CONCLUSION
In conclusion, this report describes the neuro-medical course and rehabilitation challenges of a patient with severe ADEM after COVID-19. The rehabilitation and medical needs of these patients are highly dynamic and formidable, long after the initial neurological insult. This results in significant long-term morbidity, physical and cognitive disability, and long-term healthcare-related costs, compounding the socioeconomic burden of patients with neurologic and other long-term complications following infection with SARS-CoV-2, including long COVID-19.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | 1 | [
"history of polyarticular gout ",
"diagnosed with COVID-19 ",
"severe COVID-19 ",
"encephalopathy ",
"generalised motor weakness ",
"multifocal magnetic resonance imaging findings ",
"diagnosed with ADEM ",
"received intravenous immunoglobulin ",
"septic shock ",
"inotropic support ",
"acute kidney injury ",
"haemodialysis ",
"deranged liver function ",
"provoked segmental pulmonary embolism ",
"polyarticular gout flare ",
"transferred out of intensive care ",
"minimal neurological recovery ",
"Glasgow Coma Scale score of E4VTM1 ",
"no consistent visual pursuit ",
"vocalisations ",
"functional communication ",
"encephalopathy improved ",
"scored 9/23 on the Coma Recovery Scale-Revised ",
"followed instructions inconsistently ",
"score improved to 10/23 on the Coma Recovery Scale-Revised ",
"nerve conduction study ",
"axonal sensorimotor polyneuropathy ",
"critical illness polyneuropathy ",
"ceased feeding through the nasogastric tube ",
"tolerated a blended diet ",
"59 years old ",
"male ",
"Asian ",
"migrant worker ",
"admitted to the hospital ",
"transferred to inpatient rehabilitation facility ",
"physiatrist-led transdisciplinary rehabilitation programme ",
"three hours per day of rehabilitation therapies ",
"physiotherapy ",
"occupational therapy ",
"speech therapy ",
"psychology reviews ",
"fortnightly dietician reviews ",
"weekly multidisciplinary conferences ",
"functional goal setting ",
"Functional Independence Measure ",
"cognitive and behavioural impairments ",
"global and severe cognitive deficits ",
"sustained attention for 10–15 minutes ",
"disoriented ",
"slow information processing speed ",
"followed one-step commands only ",
"immediate information recall impaired ",
"Abbreviated Mental Test score of 1/10 ",
"participation limited ",
"attention deficits ",
"therapy conducted in a quiet environment ",
"coaxing required ",
"cognitive demands reduced ",
"task simplification ",
"increased time for information processing ",
"episodes of irritability and agitation ",
"time-out-on-the-spot techniques ",
"redirection ",
"daily reality orientation ",
"flexibility of therapy timings ",
"sleep wake regulation ",
"quadriparesis ",
"disproportionate spastic weakness ",
"lower limbs ",
"Medical Research Council grade 2/5 ",
"upper limbs ",
"Medical Research Council scale 3/5 ",
"periventricular lesions ",
"motor recovery complicated ",
"critical illness polyneuropathy ",
"steroid myopathy ",
"dependent in bed mobility ",
"poor sitting balance ",
"required maximum assistance for activities of daily living ",
"physical therapy ",
"sitting balance ",
"sitting tolerance ",
"verticalisation via a tilt table ",
"task-specific training ",
"mirror visual feedback ",
"orthostatic hypotension ",
"symptomatic postural hypotension ",
"severe deconditioning ",
"prolonged immobilisation ",
"blood pressure dropped ",
"fluid boluses administered ",
"bilateral thigh-length elastic compression stockings ",
"abdominal binders ",
"swallowing and communication ",
"mild oropharyngeal dysphagia ",
"prolonged intubation ",
"tracheostomy ",
"functional communicative ability ",
"expressive speech ",
"receptive speech ",
"nutritional/metabolic parameters ",
"high caloric diet ",
"oral nutritional supplements ",
"urinary incontinence ",
"recurrent nosocomial infections ",
"catheter-associated urinary tract infections ",
"Clostridium difficile diarrhoea ",
"recurrent polyarticular gout flares ",
"left hip ",
"both knees ",
"ankles ",
"first metatarsal phalangeal joints ",
"acute and chronic lower body pain ",
"intermittent lower limb pain ",
"back pain ",
"impaired sensory discrimination ",
"severe cognitive deficits ",
"multifactorial pain ",
"polyarticular gout flares ",
"joint stiffness ",
"axonal sensorimotor polyneuropathy ",
"primary neurological insult ",
"central neuropathic pain ",
"bilateral adductor spasticity ",
"restricted hip abduction ",
"restricted hip flexion ",
"pain managed with simple analgesia ",
"gabapentin ",
"physical modalities contraindicated ",
"insensate skin ",
"cognitive impairment ",
"video fluoroscopic swallowing study ",
"no aspiration ",
"resumed a normal diet ",
"turbid straw-coloured fluid ",
"negatively birefringent crystals ",
"treated with oral prednisolone ",
"uric acid-lowering therapy ",
"febuxostat ",
"renal impairment ",
"mild immobilisation-related hypercalcemia ",
"decubitus ulceration ",
"severe immobility ",
"prolonged recumbency ",
"6-cm × 4-cm Grade 3 sacral ulcer ",
"limited mobilisation efforts ",
"bed-turning ",
"pressure relief mattresses ",
"pressure offloading ",
"indwelling urinary catheter ",
"decubitus ulcer ",
"nadir albumin level of 24 g/L ",
"nadir anaemia of 6.3 mg/L ",
"AMT improved to 3/10 ",
"motivation and cooperation improved ",
"supportive counselling ",
"mobile digital media tools ",
"wound healing ",
"regained spontaneous voiding ",
"dependent on diapers ",
"tolerated sitting at the edge of the bed ",
"mobilised in a tilt-in-space wheelchair ",
"serum uric acid levels decreased ",
"lost 14.4 kg ",
"body mass index 21.6 kg/m2 ",
"improved to 30 g/L ",
"improved to 10.2 mg/L ",
"normalised during rehabilitation ",
"discharged "
] | [
-8760,
-336,
-336,
-336,
-336,
-336,
-288,
-288,
-288,
-288,
-288,
-288,
-288,
-288,
-288,
-216,
-216,
-216,
-216,
-216,
-216,
-168,
-168,
-156,
-105,
-99,
-99,
-99,
-24,
-24,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
3,
3,
3,
10,
10,
10,
10,
10,
10,
17,
47,
47,
47,
47,
47,
47,
47,
47,
47,
47,
48,
48,
72,
72,
72,
72,
72,
72,
72,
80,
80,
120,
216,
216,
216,
216,
216,
277
] | 1 |
PMC9514285 | 2022
Bilateral papilledema with vision loss due to post–COVID-19–induced thiamine deficiency: illustrative case
Abstract
BACKGROUND
Bilateral papilledema with vision loss is considered a neurosurgical emergency due to high intracranial pressure. However, it may not be the only cause of papilledema. The authors reported an association among coronavirus disease 2019 (COVID-19), bilateral papilledema, blindness, and Wernicke’s encephalopathy (WE).
OBSERVATIONS
An 18-year-old woman presented to the neurosurgery service with rapid profound vision loss and bilateral papilledema. She had COVID-19 3 months earlier with subsequent loss of smell (anosmia) and taste (ageusia), which resulted in hyperemesis and a 43-lb weight loss. Examination revealed ataxia, horizontal nystagmus, and blindness. Magnetic resonance imaging and magnetic resonance venography of her brain were normal. Presumptive diagnosis of WE was made, and she was treated with intravenous thiamine with restoration of vision within 48 hours. Patient’s thiamine level was less than half the normal value.
LESSONS
Neurosurgeons should be aware of this unique correlation between papilledema and vision loss and its association with WE due to post–COVID-19 hyperemesis and weight loss from anosmia and ageusia.
Keywords:
COVID-19, vision loss, papilledema, Wernicke’s encephalopathy, thiamine deficiency, hyperemesis
ABBREVIATIONS
:
CN = cranial nerve, COVID-19 = coronavirus disease 2019, CSF = cerebrospinal fluid, ED = emergency department, FLAIR = fluid-attenuated inversion recovery, ICU = intensive care unit, IIH = idiopathic intracranial hypertension, IV = intravenous, LP = lumbar puncture, MRI = magnetic resonance imaging, OP = opening pressure, WE = Wernicke’s encephalopathy
Bilateral papilledema with vision loss is usually a neurosurgical emergency due to optic disc swelling caused by high intracranial pressure. Although there are several causes of bilateral papilledema, idiopathic intracranial hypertension (IIH) is the most common in patients under the age of 50.
1
Clinical history and elevated opening pressure (OP) during lumbar puncture (LP) determined the diagnosis.
One of the rare presentations of bilateral papilledema can be seen in Wernicke’s encephalopathy (WE) with a reported incidence of 4%.
2
Although WE has been typically found in poorly nourished persons with alcohol use disorder, it also has been diagnosed in patients who do not have the disorder.
3
,
4
More recently, WE has been associated with coronavirus disease 2019 (COVID-19) and was described in patients recovering from acute respiratory failure managed on mechanical ventilation,
5
,
6
noncritically ill patients with COVID-19,
7
,
8
and in one patient who previously had COVID-19.
9
We present a unique case of a patient who had COVID-19 complicated by anosmia and ageusia who presented to the neurosurgery service with acute loss of vision, bilateral papilledema, nystagmus, and ataxia. The presumptive diagnosis of WE was made, and the patient was treated with thiamine replacement. She regained her vision within 48 hours. This is the first case report of a patient who had COVID-19 presenting with bilateral papilledema and vision loss due to thiamine deficiency with normal brain magnetic resonance imaging (MRI).
Illustrative Case
An 18-year-old woman with no significant past medical history except for COVID-19 infection 3 months prior presented to an outside hospital emergency department (ED) and stated she “was watching TV as usual, and suddenly noticed inability to see the people on the screen.” In the ED, her physical examination was significant for blunt affect, slow responses to conversation, and reddened lips. She had normal mentation. The patient was seen by an ophthalmologist in the ED; her pupils were equal and reactive to light with visual acuity in right eye (OD) 20/400; in left eye (OS) she was able to count fingers 3 ft away. Attempts to sustain horizontal or upward gaze resulted in slow nystagmus, and then eyes drifted to primary gaze. No primary position nystagmus was seen. Both fundi had diffusely blurred margins; the right fundus had grade III edema and large inferior disc hemorrhage, and the left had grade II edema without hemorrhage.
The patient was admitted to an outside hospital where MRI and magnetic resonance venography of the brain were performed. Both results were within normal limits. She received an LP with an initial OP of 35 cm H
2
O (sitting position). Four tubes of cerebrospinal fluid (CSF) were taken for analysis (approximately volume of 12 mL). The clinical diagnosis of IIH was made and the patient was started on acetazolamide. Overnight, the patient’s vision became worse: she only had light perception bilaterally. A repeat LP was performed (18 hours later) with an OP of 15 cm H
2
O (lateral decubitus). The patient was transferred to our facility for tertiary neurosurgery care.
At our facility, additional history revealed multiple hospital visits over the past 3 months for nausea, vomiting, and inability to tolerate oral intake. Ever since her diagnosis of COVID-19, she had lost her senses of smell and taste (“everything tasted gross”). She had only been eating popsicles and lost 43 lb (24% of her body weight) in the last 3 months. The patient’s mother also related unsteadiness in the patient’s gait that required help for the past several weeks. The patient denied history of headaches.
Another LP was performed, leading to the placement of a lumbar drain for a trial of CSF diversion due to a presumption of IIH; however, the OP was still low at 12 cm H
2
O (lateral decubitus). The lumbar drain was draining CSF at a rate of 10 to 12 mL/hr, but the patient’s vision continued to get worse. Because of conflicting information regarding the possibility of IIT and a suspicion of WE, thiamine level was obtained, and the lumbar drain was clamped. The patient was empirically started on intravenous (IV) thiamine 200 mg every 12 hours. Within 48 hours, her vision improved: OD 20/50; OS 20/40 (measured by Snellen chart 4 ft away) with minimal residual nystagmus. She continued to have some ataxia. The blunt affect had improved. The lumbar drain was removed, and the acetazolamide was discontinued. The patient was observed for 3 more days in the hospital and then discharged. Her thiamine level was 34 nmol/L (normal 70–180 nmol/L). Six months later, the patient had no evidence of papilledema or optic disc hemorrhages and had a thiamine level of 184 nmol/L.
Discussion
Observations
COVID-19 has affected millions of people worldwide, but its adverse post–COVID-19 health outcomes and potential long COVID-19–related effects are still evolving. Such adverse outcomes affect almost all organ systems.
10
Neurological manifestations were seen in approximately 36.4% of patients,
11
with ageusia and anosmia being the most common (35.8%–51% and 38.5%–53%, respectively).
12
,
13
The pathological basis is still unresolved but is believed to be due to neurotropic infection of the gustatory or olfactory systems.
14
The average duration of symptoms range from short term (average 8 days)
15
to several months.
16
Complications from anosmia and ageusia resulting in hyperemesis have not been well documented in the literature. Complications from hyperemesis, however, have been reported in pregnant women during their first trimester. When severe, hyperemesis gravidarum, as it is called, has been associated with thiamine deficiency resulting in WE.
3
,
4
The classic triad of WE, initially described in malnourished persons with alcohol use disorder, includes confusion, ataxia, and nystagmus; however, only a small percentage of patients experience all three symptoms.
17
,
18
Bilateral papilledema, although infrequent, has been reported in patients with WE.
2
,
19
,
20
De Wardener and Lennox, in their study of patients in a Singapore prisoner-of-war camp, found that 2 of 52 (4%) patients with WE had papilledema.
2
In 1989, Mumford
21
described a 24-year-old woman who presented in her 16th week of pregnancy, having had symptoms of vomiting for 8 weeks, with ataxia, vertical and horizontal nystagmus, inability to abduct both eyes with marked bilateral papilledema with capillary dilation, and peripapillary flame hemorrhages. The patient eventually became comatose. She was treated with high-dose IV thiamine; improvement in symptoms occurred within 6 hours of treatment.
It is postulated that optic disc edema in these patients represents a thiamine-induced mitochondrial dysfunction that results in obstruction of axoplasmic flow.
20
Disc hyperemia and retinal hemorrhages can also result from the obstruction. Reports have also shown that resolution of the disc edema occurs and visual function is restored if WE is treated in a timely manner; therefore, visual function is often preserved.
21
,
22
The association between COVID-19 and WE has been reported in several studies.
5–9
Branco de Oliveira et al. presented a retrospective case series involving 15 patients in the intensive care unit (ICU) with COVID-19 infections who developed WE and their response to treatment with IV thiamine. All patients had encephalopathy, with 67% displaying at least one other sign of the classic WE triad (ophthalmoparesis and ataxia). These patients developed WE from their lengthy stay in the ICU with poor nutritional status.
5
,
6
There have been four other cases of patients infected with COVID-19 who were not in the ICU who developed WE (
Table 1
).
7–9
All reported poor nutrition from emesis; all had brain MRI that indicated WE;
7–9
three had active COVID-19 infections
7
,
8
and one had post–COVID-19 status;
9
two had normal thiamine levels;
7
and three had cranial nerve (CN) involvement.
7
,
8
None of the patients had papilledema.
TABLE 1.
Comparison of our case report with four case reports of patients with COVID-19 and WE
Open in a new tab
Dx = diagnosed; NA = not applicable.
*
Normal level: 70–180 nmol/L.
The first two cases (
Table 1
) were reported by Pascual-Goñi et al.
7
The first patient was a 60-year-old woman hospitalized for COVID-19 with diplopia and a right-sided abducens palsy. Her MRI showed symmetrical hyperintensities in the mammillary bodies and hypothalamus typical of WE. The second patient was a 35-year-old woman with a 3-week history of vomiting with COVID-19 infection who had developed diplopia and bilateral abducens palsy, altered mental state, and encephalopathy. She also had MRI findings of symmetrical hyperintensities in the mamillary bodies and hypothalamus and demonstrated unusual involvement of the limbic system not typical of WE.
7
The third case involved a 24-year-old man with COVID-19 infection who presented with right-sided facial droop, mild left-sided extremity tingling and weakness, and the sensation of falling to the left when walking.
8
The patient had nausea and vomiting for a week prior to his diagnosis of COVID-19, with the only respiratory symptom being a dry cough. His brain MRI showed T2 fluid-attenuated inversion recovery (FLAIR) hyperintensity in the splenium of the corpus collosum, mammillary bodies, periaqueductal gray matter, tectum, and ventral and dorsal medulla, which was a pattern typically seen in WE.
23
This was the first COVID-19 case with CN VII palsy and WE. Finally, the fourth case involved a 36-year-old man diagnosed with COVID-19 infection 6 weeks earlier who presented with subacute onset of painless bilateral blindness.
9
He had multiple hospitalizations for severe nausea, diarrhea, and odynophagia, with the eventual diagnosis of oral thrush that limited his oral intake. He had unintentional weight loss since his COVID-19 diagnosis (52 lb, or 20% of body weight). His brain MRI showed FLAIR hyperintensity of the medial thalami, mammillary bodies and periaqueductal gray matter, and associated enhancement with restricted diffusion of the medial thalamus bilaterally consistent with WE. The patient was treated with IV thiamine and within 5 hours his vision improved. It should be noted in this case an LP was performed with a normal OP.
Finally, the association between elevated OP and papilledema in WE is elusive. Our patient had elevated OP initially and subsequent punctures yielded normal OP while her vision was deteriorating. Interestingly, Mumford described a comatose patient with WE who had bilateral papilledema and OP of 19 cm H
2
O.
21
The association between papilledema and normal OP is not a unique finding in ophthalmology. Half of patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome presented with bilateral papilledema with normal OP.
24
We believe that bilateral papilledema in the setting of WE after COVID-19 may also be associated with normal OP. However, more data are needed to fully support such a conclusion.
Lessons
The cases in the literature showing an association between COVID-19 and WE involve malnutrition resulting in thiamine efficiency. None of the patients had papilledema. Our report is the first case of a patient who had COVID-19 and had bilateral papilledema and blindness without typical MRI findings of WE with documented thiamine deficiency. The diagnosis was based on clinical presentation of hyperemesis, weight loss, ataxia, nystagmus, and bilateral papilledema. This case illustrates that the finding of papilledema and vision loss does not always require neurosurgical intervention and that patients who have had COVID-19 and have papilledema, vision loss, and hyperemesis should be evaluated for thiamine deficiency.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Guppy, Axelrod. Acquisition of data: all authors. Analysis and interpretation of data: Guppy. Drafting the article: Guppy, Axelrod. Critically revising the article: all authors. Reviewed submitted version of manuscript: Guppy, Kim. Approved the final version of the manuscript on behalf of all authors: Guppy. Study supervision: Guppy, Axelrod. | 1 | [
"anosmia ",
"ageusia ",
"COVID-19 infection ",
"nausea ",
"vomiting ",
"inability to tolerate oral intake ",
"weight loss 43 lb ",
"unsteadiness in gait ",
"18 years old ",
"female ",
"admitted to the hospital ",
"vision loss ",
"bilateral papilledema ",
"nystagmus ",
"ataxia ",
"blunt affect ",
"slow responses to conversation ",
"reddened lips ",
"normal mentation ",
"visual acuity in right eye (OD) 20/400 ",
"visual acuity in left eye (OS) count fingers 3 ft away ",
"slow nystagmus ",
"diffusely blurred margins ",
"grade III edema ",
"large inferior disc hemorrhage ",
"grade II edema ",
"no primary position nystagmus ",
"MRI of the brain ",
"magnetic resonance venography of the brain ",
"LP with an initial OP of 35 cm H2O ",
"cerebrospinal fluid (CSF) analysis ",
"clinical diagnosis of IIH ",
"acetazolamide ",
"denies history of headaches ",
"lumbar drain ",
"thiamine level ",
"IV thiamine 200 mg every 12 hours ",
"thiamine level 34 nmol/L ",
"vision became worse ",
"light perception bilaterally ",
"repeat LP ",
"OP of 15 cm H2O ",
"transferred to our facility ",
"vision improved ",
"OD 20/50 ",
"OS 20/40 ",
"minimal residual nystagmus ",
"ataxia ",
"blunt affect improved ",
"lumbar drain removed ",
"acetazolamide discontinued ",
"discharged ",
"thiamine level 184 nmol/L ",
"no evidence of papilledema or optic disc hemorrhages "
] | [
-2160,
-2160,
-2160,
-2160,
-2160,
-2160,
-2160,
-2160,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
18,
18,
18,
18,
18,
48,
48,
48,
48,
48,
48,
48,
48,
96,
4320,
4320
] | 2 |
PMC8511908 | 2021
SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long
COVID
Abstract
Over 10% of COVID-19 convalescents report post-COVID-19 complications, namely, ‘long
COVID’ or ‘post-COVID syndrome,’ including a number of neuro-psychiatric symptoms. The
pathophysiology of COVID-19 in the central nervous system is poorly understood but may
represent post-COVID injury, ongoing sterile maladaptive inflammation, or SARS-CoV-2
persistence. We describe a long COVID patient with SARS-CoV-2 RNA in the cerebrospinal
fluid, which seems important, specifically due to recent reports of gray matter volume
loss in COVID-19 patients. Further studies of SARS-CoV2 RNA, markers of inflammation, and
neuronal damage in the CSF of patients with long COVID would be useful and should address
whether the CNS can serve as a reservoir of SARS-CoV-2, clarify the pathway by which
COVID-19 contributes to CNS dysfunction, and how best to therapeutically address it.
Keywords:
cerebrospinal fluid, COVID-19, long COVID, post-acute sequelae of COVID-19 (PASC), SARS-CoV-2
Background
Neurological symptoms associated with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infections are common. SARS-CoV-2 may not always be present in the
cerebrospinal fluid (CSF) of patients with acute neurological manifestations,
1
although some reports of SARS-CoV-2 RNA in the CSF during acute COVID-19 exist.
2
Other studies report inflammatory response with cytokine release.
3
Long COVID is a term to describe the effects of acute coronavirus disease of 2019
(COVID-19) that continue for weeks or months beyond the initial illness. We report the case
of a woman with long COVID and SARS-CoV-2 RNA real-time reverse transcriptase polymerase
chain reaction (RT-PCR) detection in the CSF, which seems important given that at least two
separate recent reports describe gray matter volume loss in various regions of the brain
immediately, as well as within a few months after COVID-19.
4
,
5
Together, these two studies provide both a
comparison of patients with and without recent COVID-19, (4 – this should be a supersript
referring to reference number 4) and a comparison of brain scans before and after COVID-19.
(5 – this should be a supersript referring to reference number 5)
Case report
On 1 October 2020, a 42-year-old woman had a positive SARS-CoV-2 RT-PCR assay from her
nasopharyngeal swab. At the time, she reported only cough and diarrhea. After 10 days,
repeated nasopharyngeal RT-PCR test was negative and the patient was asymptomatic. On 23
November 2020, she had a recurrence of her previous mild viral illness–related symptoms and
also developed a loss of smell and taste: her nasopharyngeal antigen test for SARS-CoV-2 was
positive. Two weeks later, she became fatigued and developed anxiety, palpitations,
diarrhea, vertigo, and perioral tingling. On 27 January 2021, she was hospitalized with a
progressive headache, dizziness, anxiety, palpitations, diarrhea, and panic attacks.
Neurological examination revealed hyperreflexia in the lower limbs and malaise. Routine
blood tests, basic immunological and serological screening, and anti-neuronal antibodies
were all negative. Brain magnetic resonance and electroencephalography showed no
pathological changes. Psychological and psychiatric assessment revealed increased tension
and depression, which was not present before. A 24-h electrocardiography (ECG) monitoring
confirmed sinus tachycardia, and a transthoracic echocardiogram showed no abnormalities. Due
to the new-onset diarrhea, proctoscopy was performed to exclude colitis. Stool studies for
common viral (excluding SARS-CoV-2), bacterial, and parasitic pathogens were unrevealing and
fecal calprotectin was also negative. Her stool studies showed heavy growth of
Candida glabrata
susceptible to fluconazole.
Antigen and RT-PCR tests for SARS-CoV-2 from nasopharyngeal swabbing were negative at the
time of admission, but we confirmed detectable serum nucleocapsid immunoglobulin G (IgG)
antibodies against SARS-CoV-2 (the patient had not been previously vaccinated against
COVID-19 and anti-spike antibodies were not tested). Her CSF analysis showed mild elevation
of protein (0.505 g/l) and lactate dehydrogenase (LDH) (0.57 μkat/l), although other
parameters were in normal ranges (neutrophil count, 2 cells/μl; lymphocyte count, 0 cell/μl;
erythrocyte count, 10 cells/μl; lactate, 1.55 mmol/l; glucose, 3.75 mmol/l; chloride,
128 mmol/l). CSF studies for bacteria, mycobacteria, fungi, and common neurotropic viruses
were negative, as was an evaluation of oligoclonal bands.
RT-PCR for the detection of SARS-CoV-2 RNA in the CSF was performed with Charité/Berlin
primers and probes,
6
targeting E gene for the coronavirus screening and RdRp gene as the confirmatory
assay. Briefly, viral RNA was stabilized in CSF with equal volume of DNA/RNA Shield solution
(ZymoResearch, CA, USA) and aliquoted to prevent RNA degradation and contamination of the
original sample. Viral RNA was extracted from the CSF using Quick-RNA Viral Kit
(ZymoResearch, CA, USA), and RT-PCR assays were performed using Reliance One-Step Multiplex
RT-PCR Supermix (Bio-Rad Laboratories, CA, USA) in CFX96 Touch Real-Time detection system
(Bio-Rad). Thermal cycling ran at 55°C for 10 min for reverse transcription, followed by
denaturation for 10 min at 95°C and then 45 amplification cycles: 10 s at 95°C and 30 s at
58°C. The CSF was tested in three replicates for each gene and was considered clearly
positive at cycle threshold (Ct) of 38.94, 37.22, and 38.17, respectively, for the RdRp gene
(
Figure 1
). The time between the
first positive nasopharyngeal SARS-CoV-2 RT-PCR and the positive CSF was 114 days (from the
positivity in October) and was 62 days from the separate onset of symptoms on 23 November
(since we do not have genomic analysis to distinguish a relapse from a reinfection) –
(ZymoResearch: CA, USA), (Bio-Rad Laboratories: CA, USA).
Based on the disease course, the presumed diagnosis was long COVID associated with the
presence of viral RNA in the central nervous system (CNS). Due to the lack of scientific
evidence, we initiated pulse therapy with methylprednisolone (500 mg/day intravenously for
three consecutive days), suspecting an autoimmune post-viral reaction to COVID-19 affecting
the CNS. We also initiated fluconazole, symptomatic therapy with intravenous multivitamin
solutions, alprazolam, beta-blocker, physiotherapy, and psychological support. Eight days
later, we repeated the lumbar puncture which again showed mild elevation of proteins
(0.451 g/l) and LDH (0.62 μkat/l), and the other parameters remained in normal ranges
(neutrophil count, 0 cells/μl; lymphocyte count, 1 cell/μl; erythrocyte count, 4 cells/μl;
lactate, 1.51 mmol/l; glucose, 3.21 mmol/l; chloride, 127.6 mmol/l). Repeat RT-PCR for
SARS-CoV-2 from the CSF was negative. After the treatment, the patient’s symptoms were
mostly alleviated, but she continued to have attacks of headache and anxiety.
Discussion
SARS-CoV-2 exhibits neurotropism for CNS and peripheral nervous system.
7
,
8
The virus could enter the CNS by several
possible mechanisms. Two basic pathways responsible for CNS invasion are hematogenous and
neuronal spread.
7
The olfactory neuron dysfunction represents one of the neuronal and non-neuronal
pathways for SARS-CoV-2 entry into the brain.
7
In this mode, the unique anatomical organization of olfactory nerves and the
olfactory bulb in the nasal cavity and forebrain forms a ‘channel’ between the nasal
epithelium and the brain compartments, especially the brainstem, containing the respiratory
and cardiovascular centers. Several analyses indicate that the spike protein of SARS-CoV-2
binds to the angiotensin-converting enzyme 2 (ACE2) protein.
7
The ACE2 receptors have been detected in the glial cells and neurons, particularly in
the brainstem and the regions responsible for the regulation of cardiovascular function,
including the solitary nucleus, subfornical organ, paraventricular nucleus, and rostral
ventrolateral medulla. Other hypotheses of virus entry to the CNS also include peripheral
immune cell transmigration (the ‘Trojan horse’ mechanism).
9
The damage to the CNS and the involvement of neuroimmunological pathways could be
particularly relevant for many neurological and neuro-psychiatric symptoms, and these
effects do not seem to spare pediatric patients either.
9
–
11
Approximately 10% of recovered COVID-19 patients face persistent physical, cognitive, and
psychological symptoms well past the acute phase. However, the exact pathophysiology of long
COVID and particularly the effects within CNS are not yet understood. Probable mechanisms
described in the literature include maladaptive hyperinflammation of various tissues (e.g.
vascular endothelium), which may be due to an exaggerated cytokine release. Such response
may be triggered by the interaction between SARS-CoV-2 and the immune system, but also other
compartments (e.g. endothelium and other cell lines capable of interacting with the virus
via ACE2 receptors, prompting complex sequential physiological cascades). Viral reservoirs
or lingering fragments of viral RNA/proteins could also contribute to this maladaptive response.
12
Gaebler
et al.
13
discussed immune evolution and possible influence of immunofluorescence and
PCR-confirmed SARS-CoV-2 persistence in intestinal biopsies from asymptomatic individuals
4 months after the onset COVID-19. These reservoirs could repeatedly stimulate the immune
system and be responsible for the fluctuating course of symptoms in long COVID patients. Due
to numerous neurological symptoms in the long COVID patients, the question remains whether
the virus persists in the CNS, how such persistence contributes to the symptomatology, and
subsequently how best to address it.
Little is known about the role of CSF analysis in COVID-19 patients with neurological
symptoms. Several CSF studies have not found a consensus on how COVID-19 can be associated
with these neurological symptoms.
1
,
14
Some
investigators have found anti-SARS-CoV-2 spike IgG antibodies in several patients with encephalopathy.
15
SARS-CoV-2 antibodies may or may not represent an actual presence of SARS-CoV-2 in
the CNS at any point during or after COVID-19. Even if such antibodies cross the blood–brain
barrier hematogenously or are brought in via the Trojan horse mechanism, their presence may
signify certain capacity for spill-over of the systemic SARS-CoV-2 infection or inflammation
into the CNS, where such process may be able to contribute to potentially deleterious
processes. Other possible CNS damages could be due to the direct effect of SARS-CoV-2
binding to the ACE2 expressed in capillary endothelium of blood–brain barrier to gain access
to the CNS or by indirect effect of the cytokine storm on mitochondria or on the nerve fibers.
16
Other investigators reported inflammatory markers or signs of neuronal damage.
3
Currently, the paucity of available data mainly includes reports on the CSF analysis in
patients with neurological manifestations during acute COVID-19, and no study to our
knowledge has evaluated various pertinent parameters in the CSF of patients with long COVID.
Further input on possible pathways leading to dysfunction and how to counteract these
effects could also lead through studies of neuroglia (e.g. astrocytes), vascular pericytes,
and autoantibodies against cerebral structures and specific inflammatory patterns (also
found in children with long COVID).
17
–
20
The persistence of a replicable virus in the CNS is only one of the possible explanations
for our patient’s presentation, particularly since the typical COVID-19 symptoms (loss of
smell and taste) were accompanied by other, less specific symptoms of fatigue, anxiety,
headaches, and tingling. Furthermore, the relevance of SARS-CoV-2 presence in the CSF is
unclear also because the RNA was detected at relatively high Ct values. False-positive
results are possible with RT-PCR technology, although it is quite infrequent.
6
,
21
CSF sample was collected under standard
aseptic conditions and was without blood contamination. All the routine preventive measures
were taken to avoid possible laboratory cross-contamination of CSF. Moreover, the sample was
then aliquoted into three separate analyses (different RNA isolation and PCR runs) to
further minimize the possibility of a false-positive result. Although we cannot strictly
exclude the possibility of a false positive result, it is plausible to consider CNS viral
persistence as a possible mechanism of long-term symptoms at least in some patients.
Conclusion
To our knowledge, this is the first report to confirm the occurrence of SARS-COV-2 RNA in
the CSF of a patient with long COVID specifically. This case raises the possibility that
SARS-CoV-2 may persist in the central nervous system weeks after respiratory infection.
Further studies of SARS-CoV2 RNA, markers of inflammation, and neuronal damage in the CSF
of patients with long COVID would be useful and should address the following questions:
Is the CNS a possible reservoir of SARS-CoV-2 persistence, and if so, what are the
consequences to the overall and neuropsychiatric health?
With or without the contribution of viral persistence, what are the characteristics of
the inflammatory response in the CNS and how can it be therapeutically addressed?
Is there a clear clinical and physiological distinction between the post-COVID syndrome
(the damage caused by the CNS inflammation during acute COVID-19) and long COVID, or is
persistent inflammation with or without viral persistence necessary for long COVID to
develop?
Footnotes
Author contributions:
All authors reviewed and approved the final manuscript prior to submission. DV, MS, SS,
OB, MTJD, BB and ZB collected patient-level data. MS performed the PCR analysis and
evaluated the results. DV, SD and MK performed literature search and review. All authors’
writing contributed equally to the development of the manuscript.
Conflict of interest statement:
The authors declared no potential conflicts of interest with respect to the research,
authorship, and/or publication of this article.
Funding:
The authors received no financial support for the research, authorship, and/or
publication of this article.
Informed consent:
The patient provided verbal informed consent for the publication of this case report.
ORCID iDs:
Ondrej Bilec
https://orcid.org/0000-0002-3735-6356
Martin Kršák
https://orcid.org/0000-0002-1746-7462
Contributor Information
Daša Viszlayová, Department of Neurology, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia; Department of Neurology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic.
Martin Sojka, Regional Public Health Authority in Komárno, Komárno, Slovakia.
Silvia Dobrodenková, Travel Health Clinic Bratislava, Bratislava, Slovakia.
Szabolcs Szabó, Department of Neurology, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia.
Ondrej Bilec, Department of Neurology, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia.
Mária Turzová, Department of Neurology, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia.
Juraj Ďurina, Department of Internal medicine, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia.
Barbara Baloghová, Department of Internal medicine, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia.
Zoltán Borbély, Department of Internal medicine, Faculty Hospital Nové Zámky, Nové Zámky, Slovakia.
Martin Kršák, Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, 12700 East 19th Avenue Box 168, Aurora, CO 80045, USA. | 1 | [
"cough ",
"diarrhea ",
"SARS-CoV-2 RT-PCR assay positive ",
"nasopharyngeal swab ",
"repeated nasopharyngeal RT-PCR test negative ",
"asymptomatic ",
"recurrence of viral illness-related symptoms ",
"loss of smell ",
"loss of taste ",
"nasopharyngeal antigen test for SARS-CoV-2 positive ",
"fatigue ",
"anxiety ",
"palpitations ",
"diarrhea ",
"vertigo ",
"perioral tingling ",
"42 years old ",
"female ",
"admitted to the hospital ",
"hospitalized ",
"progressive headache ",
"dizziness ",
"anxiety ",
"palpitations ",
"diarrhea ",
"panic attacks ",
"neurological examination ",
"hyperreflexia in the lower limbs ",
"malaise ",
"routine blood tests ",
"basic immunological and serological screening ",
"anti-neuronal antibodies ",
"brain magnetic resonance ",
"electroencephalography ",
"psychological and psychiatric assessment ",
"increased tension ",
"depression ",
"24-h electrocardiography (ECG) monitoring ",
"sinus tachycardia ",
"transthoracic echocardiogram ",
"proctoscopy ",
"stool studies ",
"Candida glabrata ",
"fluconazole ",
"antigen and RT-PCR tests for SARS-CoV-2 negative ",
"detectable serum nucleocapsid immunoglobulin G (IgG) antibodies against SARS-CoV-2 ",
"CSF analysis ",
"mild elevation of protein ",
"mild elevation of lactate dehydrogenase (LDH) ",
"RT-PCR for SARS-CoV-2 RNA in the CSF positive ",
"pulse therapy with methylprednisolone ",
"symptomatic therapy ",
"intravenous multivitamin solutions ",
"alprazolam ",
"beta-blocker ",
"physiotherapy ",
"psychological support ",
"repeated lumbar puncture ",
"mild elevation of proteins ",
"mild elevation of LDH ",
"repeat RT-PCR for SARS-CoV-2 from the CSF negative ",
"symptoms alleviated ",
"headache ",
"anxiety "
] | [
-720,
-720,
-720,
-720,
-710,
-710,
-30,
-30,
-30,
-30,
-16,
-16,
-16,
-16,
-16,
-16,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
8,
8,
8,
8,
8,
8,
8
] | 3 |
PMC9066079 | 2022
Long-COVID severe refractory cough: discussion of a case with 6-week longitudinal cough characterization
Abstract
Long coronavirus disease (COVID) refers to an array of variable and fluctuating symptoms experienced after acute illness, with signs and symptoms that persist for 8–12 weeks and are not otherwise explicable. Cough is the most common symptom of acute COVID-19, but cough may persist in some individuals for weeks or months after recovery from acute phase. Long-COVID cough patients may get stigmatised because of the public fear of contagion and reinfection. However, clinical characteristics and longitudinal course of long-COVID cough have not been reported in detail, and evidence-based treatment is also lacking. In this paper, we describe a case of long-COVID severe refractory cough with features of laryngeal hypersensitivity and dysfunction. We characterized cough using patient-reported outcomes and engaged in continuous cough frequency monitoring. Through the case study, we discuss potential mechanisms, managements, and clinical implications of long-COVID refractory cough problems.
Keywords:
Cough, Coronavirus, Hypersensitivity
INTRODUCTION
Cough is the most common symptom of acute coronavirus disease-19 (COVID-19), but cough may persist in 10%–20% of the patients for weeks or months after recovery from acute phase [
1
]. Long COVID (post-COVID syndrome) refers to an array of variable and fluctuating symptoms experienced after acute illness, with signs and symptoms that persist for 8–12 weeks and are not otherwise explicable [
2
]. Cough is a frequent symptom of long COVID [
1
,
3
]; such patients may get stigmatised because of the public fear of contagion and reinfection [
4
]. Cough may thus limit social activity and impair quality of life seriously.
Despite the substantial impacts, the clinical characteristics and longitudinal course of long-COVID cough have not been reported in detail, and evidence-based treatment is also lacking. Here, we describe a case of long-COVID severe refractory cough. In diagnostic evaluations, he exhibited features of laryngeal hypersensitivity and dysfunction. For cough characterization, we recorded cough patient-reported outcomes (PROs) and engaged in continuous cough frequency monitoring for 6 weeks of treatments. Through the case study, we discuss potential mechanisms, managements, and clinical implications of long-COVID cough problems.
CASE REPORT
Baseline description
A 40-year-old man was referred to our cough clinic with persistent cough. He was a former smoker but had no previous history of chronic allergic or respiratory illness. He had suffered from severe COVID-19 pneumonia 4 months prior, requiring 1 month of hospitalisation and intensive care. At discharge, he exhibited a cough, blood-tinged sputum, dyspnea, and chest pain; however, the symptoms other than cough and dyspnea gradually resolved over time. When he visited our clinic, he was suffering from daily cough and intermittent breathlessness that had persisted for 3 months after discharge. The cough was mainly dry but was intermittently accompanied by a small amount of phlegm. The cough was severe during daytime, triggered or worsened by cold or dry air, motion, talking, eating, or deep breathing, but also occurred during sleep. He reported throat discomfort, and an urge-to-cough sensation. He had no symptoms suggesting asthma, a nasal disease, or gastroesophageal acid reflux. His cough severity numerical rating scale score was 9 (0–10; a higher score indicates a more severe cough) at baseline (day 1;
Fig. 1
). The Cough Hypersensitivity Questionnaire (CHQ) score was 16 (0–22; a higher score indicates more cough triggers and greater laryngeal sensation) [
5
], and the Leicester Cough Questionnaire (LCQ) score was 5.6 (3–21; a lower score indicates a higher impact of cough on the quality of life) [
6
]. That impact was profound in the social domain (LCQ social domain score: 1.0). The Medical Research Council (MRC) breathlessness scale score was 3.
Diagnostic investigations
On examination, the patient was alert and orientated. Physical examination of the respiratory, cardiovascular, and gastrointestinal systems was unremarkable. Chest computed tomography revealed no evidence of a residual lesion or lung fibrosis. The spirometric findings were within the normal ranges: forced expiratory volume in 1 second (FEV
1
) 93% of predicted, forced vital capacity (FVC) 83% of predicted, and FEV
1
/FVC 89%. Fractional exhaled nitric oxide test could not be performed due to the difficulty to maintain constant expiration. Blood tests, including a complete blood count, blood chemistry, and a coagulation panel, were unremarkable. Sputum microbiology, including acid-fast bacillus staining, was negative.
Treatments and follow-up
His cough was not accompanied by any evident pathologic diseases and had been unresponsive to first-generation antihistamines, codeine, and inhaled corticosteroids. As he was seriously troubled by coughing and experienced ineffective treatments for 3 months, we decided to commence high-intensity treatments including cough neuromodulators (gabapentin 100 mg twice a day [bid] and amitriptyline 10 mg once a day), azithromycin 250 mg every other day, and prednisolone 15 mg bid. A low-dose proton pump inhibitor was given for a gastroprotective purpose. He was also educated to try cough suppression techniques and improve vocal hygiene [
7
,
8
,
9
]. We started continuous cough monitoring using the Hyfe, a smartphone application-based cough tracker [
10
].
On day 8, challenge laryngoscopy was performed. No structural abnormality was found, but grade 1 glottic adduction and grade 2 supraglottic constriction [
11
] were observed during effort inspiration, indicating a comorbid mild-to-moderate laryngeal dysfunction (
Fig. 2
). Notably, he felt the relief from strong urge-to-cough sensation during the flexible laryngoscope was placed in the throat. The continuous cough monitoring revealed daily cough counts of about 500/day during the first week. The maximum daily cough count was 1,793 (on day 4;
Fig. 1
); his cough was particularly worsened by talking, motion, or physical activity. Based on the laryngeal hypersensitivity and dysfunction (high CHQ score and positive findings on challenge laryngoscopy), gabapentin was increased to 300 mg bid, while other drugs were gradually tapered.
On day 18, he still suffered from coughing, intermittently aggravated by physical stimuli such as exercise and talking, but the PRO measurements and objective cough counts revealed gradual reductions in cough severity scores and objective cough frequency. He experienced fatigue after the increased gabapentin dosing, but this was relatively well tolerated; the gabapentin dose was further increased to 300 mg 3 times a day. On day 35, further reductions in the objective cough frequency and subjective cough severity score were observed, but the LCQ and CHQ scores had not improved. Particularly, the LCQ social domain score was aggravated (1.5). The MRC breathlessness scale score was 2. He experienced severe fatigue, eyelid twitching, and peripheral tingling pain, and thus we decided to decrease the dose of gabapentin to 100 mg bid, and after 1 week, we observed that his cough was not aggravated (
Fig. 1
). We will continue to follow him up until his cough is resolved.
This case report was approved by the Institutional Review Board (IRB) of the Asan Medical Center (IRB No. 2022-0524). The presented data is a part of the Korean Chronic Cough registry, a prospective, observational cohort study (IRB No. 2019-0754). The patient agreed to participate in the prospective follow-up and case reporting. An informed consent was obtained.
DISCUSSION
In this paper, we described the case of a young man with long-COVID severe refractory cough. Although he remains under follow-up, we consider that an interim report may help to increase public and medical awareness of this refractory condition. We draw no generalisation but suggest that (1) post-COVID cough can be severe, persistent, and treatment-refractory in some patients; and (2) that the cough can be accompanied by laryngeal hypersensitivity and dysfunction. The LCQ data showed that the impact of long-COVID cough on quality of life may be substantial, especially in the social domain.
Neither the cough nor the breathlessness was explicable on spirometry or chest imaging, and therapies targeting asthma and upper airway disease, were ineffective. However, laryngeal hypersensitivity and dysfunction were evident, as revealed by a high CHQ score and positive findings on challenge laryngoscopy. Laryngeal hypersensitivity/dysfunction are common in patients with chronic cough, particularly refractory cough [
5
,
12
]. We thus suggest that functional aberrations of the larynx underlie the persistent cough and breathlessness in this case. Also, his urge-to-cough sensation was greatly relieved while the flexible laryngoscope was placed
in situ
(transiently causing pain and physical discomfort), suggesting neural gating mechanisms involved in his cough.
Although we observed that cough gradually improved with cough neuromodulators, we presume that the observed improvement may be attributable to regression to the mean effects or to benefits from behavioural cough suppression techniques and vocal hygiene, because his cough remained relatively stable after dose de-escalation of gabapentin (at day 35). This represents only a single case, and treatments for long-COVID cough should be investigated in controlled trials.
There is no consensus on the management of long-COVID cough patients. The clinical practice guidelines for chronic cough should perhaps be followed [
1
,
7
,
8
,
9
]. However, as the clinical presentations and symptoms of long COVID are variable [
1
,
13
], the approach should be individualised. Comorbidities that may potentially cause dyspnoea should be actively evaluated. Drugs such as gabapentin or amitriptyline may cause fatigue or compromise cognitive function [
8
]. Studies with more patients are required, followed by clinical trials. Novel antitussive drugs including P2X3 antagonists [
14
] might be trailed in severe refractory cough cases.
We found different utility of PROs and objective cough frequency in evaluating longitudinal changes of his cough status. The PROs, such as LCQ and CHQ, were helpful to understand the impact on quality of life, particularly in the social domain, and the hypersensitive nature of the cough. We utilized continuous cough frequency monitoring and found that it was more sensitive in evaluating cough variability and responses to the treatments in a short term. This gap between LCQ and cough frequency might be due to longer time scale of the PROs, but also indicate that the impact of long-COVID cough on quality of life persists longer than coughing itself.
Finally, we highlight the impact of cough in long-COVID patients. As shown in this case, the impact can be substantial particularly in the social aspect of life. As suggested in 6-month or longer prospective follow-up studies of post-COVID patients [
15
,
16
,
17
], physical symptoms including anosmia, chest tightness, or cough may improve over time, but psychological and social issues may persist for longer periods of time. Job loss is another frequent complication [
16
,
18
].
We hypothesize that active intervention to control midterm health issues (2–6 months) including cough will help to prevent or reduce long-term (>6–12 months) consequences in patients with long COVID, such as anxiety, depression, social isolation, or job loss. As uncertainty seems to trigger a vicious cycle of long COVID [
18
,
19
], objective tests should seek to identify any pathology of cough that requires treatment and reduce health concerns. It is also important to raise public awareness of the condition.
In conclusion, we report a case of long-COVID refractory cough comorbid with laryngeal dysfunction and hypersensitivity; we characterized the nature and longitudinal changes of cough using the PROs and continuous cough frequency monitoring for 6 weeks. Prospective cohort studies are warranted to understand the clinical characteristics of and identify optimal managements for patients with long-COVID refractory cough.
ACKNOWLEDGEMENTS
The work was supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp.. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.
Footnotes
Conflict of Interest:
The authors have no financial conflicts of interest.
Author Contributions:
Conceptualization:
Woo-Jung Song, Peter M. Small, Kian Fan Chung.
Formal analysis:
Yu Ri Kang, Woo-Jung Song.
Investigation:
Yu Ri Kang, Woo-Jung Song.
Methodology:
Yu Ri Kang, Ji-Yoon Oh, Ji-Hyang Lee, Woo-Jung Song.
Project administration:
Yu Ri Kang.
Writing - original draft:
Yu Ri Kang, Woo-Jung Song.
Writing - review & editing:
Ji-Yoon Oh, Ji-Hyang Lee, Peter M. Small, Kian Fan Chung. | 0 | [
"COVID-19 pneumonia ",
"hospitalisation ",
"intensive care ",
"cough ",
"blood-tinged sputum ",
"dyspnea ",
"chest pain ",
"informed consent ",
"Institutional Review Board approval ",
"discharge ",
"cough persisted ",
"dyspnea persisted ",
"other symptoms resolved ",
"treatment with antihistamines ",
"treatment with codeine ",
"treatment with inhaled corticosteroids ",
"40 years old ",
"male ",
"admitted to the hospital ",
"referred to cough clinic ",
"persistent cough ",
"daily cough ",
"intermittent breathlessness ",
"throat discomfort ",
"urge-to-cough sensation ",
"cough severity numerical rating scale score 9 ",
"Cough Hypersensitivity Questionnaire score 16 ",
"Leicester Cough Questionnaire score 5.6 ",
"Medical Research Council breathlessness scale score 3 ",
"physical examination ",
"chest computed tomography ",
"spirometric findings ",
"fractional exhaled nitric oxide test ",
"blood tests ",
"sputum microbiology ",
"treatment with gabapentin 100 mg bid ",
"treatment with amitriptyline 10 mg once a day ",
"treatment with azithromycin 250 mg every other day ",
"treatment with prednisolone 15 mg bid ",
"low-dose proton pump inhibitor ",
"cough suppression techniques ",
"vocal hygiene ",
"continuous cough monitoring ",
"challenge laryngoscopy ",
"grade 1 glottic adduction ",
"grade 2 supraglottic constriction ",
"laryngeal hypersensitivity ",
"laryngeal dysfunction ",
"gabapentin increased to 300 mg bid ",
"other drugs tapered ",
"cough counts about 500/day ",
"maximum daily cough count 1793 ",
"cough worsened by talking ",
"cough worsened by motion ",
"cough worsened by physical activity ",
"gabapentin increased to 300 mg 3 times a day ",
"fatigue ",
"eyelid twitching ",
"peripheral tingling pain ",
"gabapentin dose decreased to 100 mg bid ",
"cough not aggravated ",
"follow-up "
] | [
-672,
-672,
-672,
-672,
-672,
-672,
-672,
-672,
-672,
-96,
-96,
-96,
-96,
-72,
-72,
-72,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
8,
18,
18,
18,
18,
35,
35,
42
] | 4 |
PMC8606980 | 2021
Severe COVID-19 and long COVID in a 31-year-old woman with incontinentia pigmenti: A case report
Abstract
Incontinentia pigmenti is a rare genetic disease affecting the skin, microvasculature, and central nervous system, in which a hyperactive inflammatory response is observed. Due to the inflammatory phase of COVID-19 and associated cytokine storm, infection with SARS-CoV-2 in individuals with incontinentia pigmenti is a concern. Furthermore, type I interferon autoantibodies are found in life-threatening COVID-19 pneumonia and in 25% of individuals with incontinentia pigmenti. The present case report describes a 31-year-old Caucasian woman with incontinentia pigmenti and severe COVID-19. She was hospitalized for oxygen therapy, intravenous antibiotics, and corticosteroids. Eight months later, she is still symptomatic. To our knowledge, she is the first reported case of long COVID in incontinentia pigmenti. Increased autoimmunity may be implicated in both incontinentia pigmenti and long COVID. Pending evidence-based guidelines, COVID-protective measures including vaccination should be recommended to all patients with incontinentia pigmenti. Specific interferon therapy may be considered along with usual COVID treatment.
Keywords:
Infectious disease, incontinentia pigmenti, COVID-19, SARS-CoV-2, apoptosis, TNF-α, long COVID, type I interferon autoantibodies, autoantibodies, NEMO, inflammation
Introduction
Incontinentia pigmenti (IP) is a rare X-linked genetic disease affecting the skin, hair, teeth, microvasculature, and central nervous system. In the hemizygous male, the disease is usually lethal. In the heterozygous female, severity varies according to the random process of X inactivation.
IP is caused by a mutation in the
NEMO
gene (Xq28) encoding the nuclear factor-kappa-B (NF-κB) essential modulator (NEMO) protein. NEMO regulates cell proliferation and immune response by limiting apoptosis.
1
In 80% of IP cases, the mutation in the
NEMO
gene is a deletion of exons 4 to 10. The truncated NEMO molecule is devoid of activity, resulting in a complete lack of NF-κB activation and an acute sensitivity to tumour necrosis factor alpha (TNF-α)-induced apoptosis.
2
Varying degrees of immunodeficiency have been observed in IP. In 1972, Honig and Miller described a possibly related immunological disorder.
3
In 2017, unresponsiveness to lipopolysaccharide injection was noted in two women affected by IP with immunodeficiency.
4
The immune dysregulation in IP is classically linked to an exaggerated inflammatory response leading to increased apoptosis.
5
Coronavirus disease (COVID-19), a SARS-CoV-2 infection, is of concern to individuals with IP, as COVID-19 can induce TNF-α as well as the apoptosis to which these individuals are particularly vulnerable. The compound, synergistic effect of COVID-19 and IP is therefore troubling. The following case report describes the clinical evolution of COVID-19, including severe disease and long COVID, in a patient with IP.
In the general population, COVID-19 infection may induce a severe inflammatory phase, or cytokine storm showing high serum levels of interleukins 6 and 8 (IL-6 and IL-8) and TNF-α.
6
The post-mortem lung analysis of fatal COVID-19 cases revealed apoptosis, necroptosis, and massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis.
7
Anomalies related to type I interferons, including autoantibodies, have also been found in severe COVID
8
(10%)
9
and in fatal COVID (20%).
10
Furthermore, those autoantibodies are more prevalent in individuals with IP (25%) than in the healthy population (3%).
9
The concentration of autoantibodies against type I interferons α and ω was increased with age, whereas interferon-β autoantibodies were rarer (1.3% of critical patients and 0.9% of deceased patients) and were not age-dependent.
10
Case
Medical history
The patient is a 31-year-old Caucasian woman affected by IP. In May 2006, she was identified as having an
NEMO
gene deletion of exons 4 through 10.
She was born at term (weight 3.57 kg and APGAR
11
score 8-9-9). She had typical IP skin involvement and reports skin healing delays and scars for even minor injuries. In early adulthood, she had a cholecystectomy, from which she suffered complications including dehiscence of the wound. She had staples for approximately 2 years before closing of the wound. Healing time for a cervical sprain and ligament tear were also longer than expected.
She reports six to seven infections a year, mainly initially viral and progressing to bacterial involvement requiring antibiotic therapy. Community-acquired infections would last longer (a month as compared to 7–10 days for others). Prior to COVID-19, she was never hospitalized for an infection.
The patient reports normal vision but narrow visual field and no involvement of the retina. On physical examination, she has 16 pointed teeth, including three milk teeth. Her hair is sparse. Some nails have typical striae. She reports easy bruising but has no mottled rash. Her feet and lower legs have a purplish coloration. She has been taking metoprolol for an arrhythmia since April 2020. She never smoked and was not exposed to secondary smoke.
She does not have epilepsy or mental retardation. She reports learning difficulties in school, for which she needed special help. In high school, she repeated Grade 10. She had been working as a supervisor of a daycare service while studying for a second university certificate, when she was infected with SARS-CoV-2.
Evolution of SARS-CoV-2 infection
In Day 1, on 8 August 2020, she had fatigue and a sore throat. A nasopharyngeal swab on the same day tested positive for SARS-CoV-2 on polymerase chain reaction (PCR).
In Day 14, she consulted a COVID-19 clinic, complaining of fever (40.5°C), chills, myalgia, asthenia, headaches, anosmia, dysgeusia, pharyngitis, dry cough, dyspnea at speech, anorexia, dizziness, diarrhoea, and facial rash. Vital signs were blood pressure 102/79 mm Hg, pulse 112 bpm, saturation 93% in room air, respiratory rhythm 30 bpm, and oral temperature 38.2°C. Physical examination showed poor general state, increased work for breathing, with retractions and diffuse crackles. She was transferred to the Emergency Department and then hospitalized. She received oxygen supplementation by nasal cannula, intravenous corticotherapy, and antibiotics. She did not need intubation. She was diagnosed with bacterial pneumonia as per chest X-ray and discharged 4 days later with moxifloxacin for 7 days.
In Day 29, she consulted for relapsing cough and dyspnea. Vital signs were within normal range (blood pressure 139/88 mm Hg, pulse 98 bpm, saturation 100% in room air, respiratory rhythm 20 bpm, temperature 36.4°C). Pulmonary auscultation and physical examination were normal. The chest X-ray showed an overall decrease in alveolar consolidation but persistence in the pulmonary bases and accentuation in the left inferior lobe. Doxycycline was started for 7 days, as well as a budesonide/formoterol inhalator.
In Day 50, she was diagnosed with acute otitis media. She complained of earache, hearing loss, sore throat, nasal congestion, rhinorrhea, headache, myalgia, and dizziness. She was subfebrile. The cough had improved somewhat. She received intranasal corticosteroids and a prescription for cefprozil antibiotic, from which she later developed a rash. Intramuscular ceftriaxone was planned but levofloxacin was tried first, given the rhinosinusitis symptoms.
In Day 70, symptoms persisted but without fever. Refractory rhinosinusitis was suspected; a non-steroidal anti-inflammatory drug was prescribed while awaiting sinus imaging.
In Day 86, a computed tomography (CT) angiography was ordered for coughing and slowly worsening dyspnea, as increased fatigue interfered with her capacity to perform the activities of daily living. The CT angiography showed alveolitis but no pulmonary embolism. The patient was referred to a pulmonologist. A new course of corticotherapy and antibiotics helped relieve infectious (suspected bacterial superinfection) and inflammatory symptoms.
In Month 3, symptoms persisted and now included cognitive deficits. Unable to focus attention, she quit work; academic performance dropped. She had a normal cognitive screening including a score of 28/30 on the Montreal Cognitive Assessment
12
(MoCA).
In Month 8, side effects of a first COVID-19 vaccination on 21 April 2021 included 40°C fever and temporary exacerbation of long-haul symptoms (headaches, dizziness, nausea, chills, myalgia, cough, and dyspnea).
In Month 9, the patient is still unable to work, with persistent severe fatigue and multiple symptoms (
Table 1
). She now considers adapting her lifestyle for a return to work, as she does not expect symptom resolution anytime soon, although her health is slowly improving.
Table 1.
Persistent symptoms reported by patient – Month 9 post-infection.
Open in a new tab
She has enrolled in a clinical trial based on Nepotchatykh et al’.s
13
profiling of circulating microRNAs (miRNAs) in myalgic encephalomyelitis/chronic fatigue syndrome, a syndrome with symptoms common to long COVID. She was assessed for miRNA levels and underwent a post-exertional stress challenge. She was also referred to a research study on long COVID and will get the battery of tests planned by the
Biobanque québécoise de la COVID-19
(BQC19)
14
as well as an autoantibody panel, including autoantibodies against type 1 interferon. She will also be tested for primary immunodeficiency. Results are pending.
Discussion
The scientific literature indicates a severe episode of COVID-19 in a patient with IP.
9
Several hypotheses may be advanced. The COVID-19 cytokine storm triggers, among other things, a TNF-α increase and possible apoptosis. Individuals affected by IP are highly sensitive to both TNF-α and apoptosis. Although the serum level of TNF-α was not measured, the combination of COVID-19 and IP could result in an exaggerated inflammatory response and magnified apoptosis.
Second, autoantibodies have been suspected to contribute to the aetiology of COVID-19 and long COVID. Autoantibodies against type I interferon were not present in asymptomatic or mild COVID cases (0/663) but were detected in 10.2% of life-threatening COVID (101/987).
9
Type I interferon autoantibodies are also more common in individuals with IP than in the general population, and a possible association between IP and susceptibility to autoimmunity has been raised in the scientific literature.
9
A study of six patients with IP showed that three had autoimmunity.
15
Our patient’s autoantibody levels were not initially measured; detailed measures will be available as part of her current participation in two clinical trials. Other mechanisms may be involved as well, but more research is needed.
This suggests an interesting option for treatment; individuals with autoantibodies against some, but not all, interferons could potentially receive interferon-β injections.
10
One patient with IP and COVID showed good clinical results. She had antibodies against interferon-α and ω but not β. As proposed by Bastard et al.,
16
individuals with IP could conceivably be screened for autoantibodies before ever getting COVID-19. If infected with SARS-CoV-2, they could then receive personalized interferon therapy.
It is noteworthy that the present patient is female and have a body mass index 33 kg/m
2
(height 1.65 m and weight 90.9 kg), both of which are risk factors for long COVID in the general population,
17
in addition to hospitalization.
18
Long COVID may therefore not be specific to her IP status.
The patient also presented with arrhythmia at the young age of 30 years. Arrhythmia is not usually present in IP. Another underlying medical condition may therefore complicate the clinical picture.
Finally, there may be publication bias. It is highly imperative that healthcare professionals report all COVID-19 cases complicated by IP, no matter the outcome, so as to advance knowledge in this rare disease.
Conclusion
Considering TNF-α, apoptosis, and possible autoantibodies against type I interferon, it is biologically plausible that individuals with IP are at risk for severe COVID-19. More research is needed to understand the various contributory pathways and to develop specific treatment.
Furthermore, the present case shows symptoms compatible with long COVID. More case reports and research on physiopathology are needed to verify whether IP is indeed a risk factor for long COVID. To our knowledge, this is the first long COVID case report in a patient affected by IP.
While awaiting evidence-based guidelines, individuals with IP should rigorously adhere to preventive and protective measures against COVID-19, including vaccination. In addition to usual COVID treatments, specific interferon therapy should be considered in a research setting, as indicated.
Acknowledgments
The author wants to acknowledge the patient presented in this case report for her active contribution. The author is grateful to Danielle Buch, Medical Writer, Research, for critical revision and substantive editing of the manuscript.
Footnotes
Declaration of conflicting interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethics approval:
Our institution does not require ethical approval for reporting individual cases or case series.
Funding:
The author(s) received no financial support for the research, authorship, and/or publication of this article but acknowledges a Fonds de Recherche du Québec grant related to her work in neurocognitive disorders.
Informed consent:
Written informed consent was obtained from the patient for the publication of this article.
ORCID iD:
Sylvie Rheault
https://orcid.org/0000-0003-0227-1624 | 0 | [
"incontinentia pigmenti ",
"NEMO gene deletion ",
"skin involvement ",
"delayed skin healing ",
"cholecystectomy ",
"wound dehiscence ",
"prolonged wound healing ",
"cervical sprain ",
"prolonged healing time ",
"frequent infections ",
"antibiotic therapy ",
"learning difficulties ",
"special help in school ",
"repeated grade 10 ",
"arrhythmia ",
"metoprolol ",
"31 years old ",
"female ",
"normal vision ",
"narrow visual field ",
"no retinal involvement ",
"pointed teeth ",
"sparse hair ",
"nail striae ",
"easy bruising ",
"purplish coloration of feet and legs ",
"no smoking ",
"no secondary smoke exposure ",
"no epilepsy ",
"no mental retardation ",
"working as a supervisor ",
"studying for a second university certificate ",
"SARS-CoV-2 infection ",
"fatigue ",
"sore throat ",
"nasopharyngeal swab ",
"positive PCR ",
"fever ",
"chills ",
"myalgia ",
"asthenia ",
"headaches ",
"anosmia ",
"dysgeusia ",
"pharyngitis ",
"dry cough ",
"dyspnea ",
"anorexia ",
"dizziness ",
"diarrhea ",
"facial rash ",
"hospitalization ",
"oxygen supplementation ",
"corticotherapy ",
"antibiotics ",
"bacterial pneumonia ",
"discharge ",
"relapsing cough ",
"relapsing dyspnea ",
"moxifloxacin ",
"doxycycline ",
"budesonide/formoterol inhalator ",
"acute otitis media ",
"earache ",
"hearing loss ",
"sore throat ",
"nasal congestion ",
"rhinorrhea ",
"headache ",
"myalgia ",
"dizziness ",
"subfebrile ",
"cough improvement ",
"intranasal corticosteroids ",
"cefprozil ",
"rash ",
"levofloxacin ",
"refractory rhinosinusitis ",
"non-steroidal anti-inflammatory drug ",
"sinus imaging ",
"CT angiography ",
"alveolitis ",
"no pulmonary embolism ",
"pulmonologist referral ",
"corticotherapy ",
"antibiotics ",
"symptom persistence ",
"cognitive deficits ",
"inability to focus ",
"quit work ",
"academic performance drop ",
"normal cognitive screening ",
"MoCA score 28/30 ",
"COVID-19 vaccination ",
"fever ",
"exacerbation of long-haul symptoms ",
"headaches ",
"dizziness ",
"nausea ",
"chills ",
"myalgia ",
"cough ",
"dyspnea ",
"persistent symptoms ",
"incapacitating fatigue ",
"continuous headaches ",
"attention deficit ",
"memory deficits ",
"fluctuating dyspnea ",
"fluctuating cough ",
"chest pain ",
"discomfort ",
"arthralgia ",
"post-activity polypnea ",
"increased resting heart rate ",
"exacerbation of palpitations ",
"back pain ",
"leg pain ",
"dizziness ",
"hair loss ",
"diaphoresis ",
"sleep disorder ",
"intermittent chills ",
"intermittent red eyes ",
"intermittent flushing ",
"intermittent sore throat ",
"exacerbation of anxiety ",
"depression ",
"obsessive compulsive disorder ",
"post-traumatic stress disorder ",
"clinical trial enrollment ",
"miRNA profiling ",
"post-exertional stress challenge ",
"research study referral ",
"autoantibody panel ",
"primary immunodeficiency testing "
] | [
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-8760,
-720,
-720,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
336,
448,
672,
672,
672,
672,
672,
840,
840,
840,
840,
840,
840,
840,
840,
840,
840,
840,
840,
840,
840,
840,
1008,
1008,
1008,
1224,
1224,
1224,
1224,
1224,
1224,
2016,
2016,
2016,
2016,
2016,
2016,
2016,
2419,
2419,
2419,
2419,
2419,
2419,
2419,
2419,
2419,
2419,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024,
3024
] | 5 |
PMC8132077 | 2021
“Long COVID”: A case report of persistent symptoms in a patient with prolonged SARS-CoV-2 shedding for over 110 days
Abstract
Coronavirus disease 2019 is a novel disease currently ravaging the world as a pandemic. More emphasis has been focused on the acute disease, with less attention on the detection and management of long-term sequelae which develop in some patients, variously termed “Long COVID,” Post-coronavirus disease 2019 syndrome, or ongoing coronavirus disease. There are also various reports in the literature on the duration of viral shedding, with the longest known recorded being about 70 days, and whether this duration has an effect on prognosis or patients remaining infectious is still unknown. We report the case of a 22-year-old health care worker with prolonged multi-systemic features of coronavirus disease 2019 including cardiovascular, respiratory, central nervous system, and musculoskeletal symptoms lasting about 18 weeks from symptom onset, though never hospitalized, and persistent detection of severe acute respiratory syndrome coronavirus 2 attributed to viral shedding for over 110 days, which is the longest duration recorded to our knowledge.
Keywords:
COVID-19, “Long COVID”, prolonged viral shedding, SARS-CoV-2
Introduction
The median duration for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral shedding from onset of symptoms has been documented to be around 12–20 days,
1
,
2
although there are case reports of patients exceeding this,
3
,
4
with the longest known reported being 70 days in an elderly immunosuppressed woman.
5
A study carried out in Wuhan, China, revealed that prolonged viral shedding was not uncommon in patients with coronavirus disease 2019 (COVID-19) pneumonia, with a median duration of 53.5 days in 36 patients tested for SARS-CoV-2 using real-time reverse transcriptase polymerase chain reaction (RT-PCR) test.
6
,
7
Several risk factors including administration of corticosteroids and immunoglobulins, delayed admission to the hospital, severe illness at admission, male sex, as well as old age have been found to be responsible for prolonged viral shedding,
8
–
10
with some studies linking this prolonged shedding with poorer prognosis and increased severity of the disease.
8
Patients with COVID-19 can go on to develop long-term sequelae and complications, although the exact prevalence and risk factor for this is yet to be elucidated.
11
A large prospective study of 4182 COVID-19 patients found 558 (13.3%) had symptoms lasting ⩾4 weeks, 189 (4.5%) for ⩾8 weeks, and 95 (2.3%) for ⩾12 weeks.
11
This distinct pathway of ongoing effects has been termed ‘’Long-COVID,” ongoing COVID, or Post-COVID-19 syndrome.
12
According to the Chief Executive Officer of the National Health Service, “Long COVID is already having a very serious impact on many people’s lives and could well go on to affect hundreds of thousands.”
13
This has gone largely unnoticed by health care workers especially in our environment, and the lack of a working diagnosis prevents planning for necessary services and impedes access to care for these patients. The National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), as well as the Royal College of General Practitioners (RCGP) have now defined post-COVID syndrome as the following: “Signs and symptoms that develop during or following an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis.” These symptoms can be multi-systemic, often appear as clusters, fluctuate over time, and can have significant psychological and social impact on patients.
12
,
14
Patients with prolonged viral shedding can present with symptoms of “Long-COVID” according to the definition given above. We present the case of a 22-year-old health care worker with “Long-COVID” lasting about 18 weeks, and prolonged SARS-CoV-2 shedding for over 110 days, which is the longest recorded duration to our knowledge.
Case report
A 22-year-old health care worker presented to our medical outpatient clinic with low grade fever, generalized body weakness, sore throat, anosmia, and headache all of approximately 1-week duration. She had no pre-existing condition. Generalized physical examination revealed a young overweight (body mass index (BMI): 29.4 kg/m
2
) lady, with mild breathlessness on exertion. She was afebrile with a normal cardiovascular, pulmonary, and systemic examination. Ancillary investigations including complete blood count with differential, serum electrolytes, urea and creatinine, chest x-ray, and electrocardiography were essentially normal. Nasopharyngeal swab for SARS-CoV-2 using RT-PCR was first positive on 29 June 2020. For treatment of COVID-19, she received the following medication: azithromycin 500 mg orally daily for a week, chloroquine 250 mg BID for 6 days, zinc 50 mg BID for 2 weeks, vitamin C 500 mg daily, analgesics, and anti-histamines. Anosmia and sore throat resolved at the end of the second week, while recurrent fever and headache persisted, and patient also developed a mucoid, non-bloody diarrhea associated with nausea and generalized abdominal pain. The diarrhea lasted 5 days with patient receiving ciprofloxacin 500 mg orally BID for 5 days and oral rehydration solution. In the third week after her symptom onset, she developed a mild to moderate sub-sternal non-radiating chest pain with occasional exertional dyspnea and easy fatigability which recurred until week 8. She also noted insomnia, and poly-arthritis involving both small and large joints, including the neck, with associated mild joint stiffness, for which she initiated naproxen 250 mg orally as needed. Fatigue, insomnia, joint pains, and breathlessness worsened over Week 6–12, although patient was still able to carry out activities of daily living. For the treatment of COVID-19, she was initiated on ivermectin at week 12; 12 mg orally daily for 5 days, aspirin 75 mg orally daily, continued on multivitamins, with dexamethasone 2 mg BID for 3 days after completing ivermectin, and incentive spirometry. Laboratory investigations from week 12 revealed the following: erythrocyte sedimentation rate was 75 mm/h, urea was 70 mg/dL, and Cr was 3.8 mg/dL. She had no clinical features of renal impairment. Other laboratory investigations, chest x-ray, and electrocardiogram (ECG) results were essentially normal. Exertional dyspnea improved remarkably after the course of ivermectin (week 12), with some improvement in fatigue and joint pain. She continued to have neck pain, abdominal bloating, excessive flatus, and headache for which she eventually initiated topiramate 50 mg BID and propranolol 20 mg BID. Symptoms waxed and waned with significant resolution of all other symptoms by week 18, aside from occasional easy fatigability and exertional dyspnea which were still present as at last contact with the patient (February 2021). Nasopharyngeal swabs for PCR were positive for SARS-CoV-2 on 29 June, 7 July, 22 July, 21 August, 29 September, and 20 October, with the first negative test occurring on 3 November 2020.
Discussion
Wide ranging values have been given in the literature for the duration of SARS-CoV-2 viral shedding from onset of symptoms,
1
–
3
but the longest known documented duration is 70 days in an elderly immunocompromised woman.
5
In this particular case, the virus shed was noted to be still infective, in contrast to other studies that have shown non-infective viral particles.
15
Our patient had none of the risk factors defined earlier for prolonged viral shedding, and it is really not known why she shed virus for this long. A large prospective study comprising 4182 COVID-19 patients who prospectively entered their symptoms in the COVID Symptom Study app were examined by a group of researchers. The study demonstrated that 558 (13.3%) patients with COVID-19 had symptoms lasting >28 days, 189 (4.5%) for >8 weeks, and 95 (2.3%) for >12 weeks. Patients with long-COVID-19 had symptoms of fatigue, breathlessness, headache, and anosmia characterizing “long-COVID” and was more likely to occur in patients who were females, had increased age, and increased BMI.
11
Our patient had all of these characterizing symptoms as well as two of the risk factors: female gender and increased BMI. Having more than five symptoms during the first week had the most significant association with “long-COVID” in all age groups and gender. These predictive symptoms were fatigue, headache, dyspnea, hoarse voice, and myalgia.
11
Our patient had two of these predictive symptoms: fatigue and headache. In another population, dyspnea was found to be a significant predictor of long-term symptoms,
16
another prominent symptom in our patient. The only pre-existing condition with significant association with “long-COVID” in this study was asthma,
11
which was not present in our patient. The most common symptoms associated with “long-COVID” were fatigue and headache, followed by anosmia and lower respiratory symptoms. Two basic patterns of symptomatology were identified: patients with predominant symptoms of fatigue, headache, and upper respiratory complaints, and those with multi-system complaints.
11
Our patient fell into the latter with respiratory, cardiovascular, central nervous system, gastrointestinal, and musculoskeletal symptoms.
Conclusion
Risk factors for prolonged viral shedding such as immunosuppression and use of corticosteroids among others should be assessed in COVID-19 patients. In those with prolonged shedding, infectiousness should be ascertained through viral culture because of the implications for possible continued transmission. It is really not known why our patient shed virus for this long, as she had no immunocompromising condition or any of the earlier identified risk factors. This underscores the need for more research in understanding this condition. There is also an urgent need for greater awareness about “long-COVID” among the healthcare community, in-depth research for better understanding especially in our environment which could then pave way for specialized interventions and better quality of life for these patients. There have been anecdotal reports of improvement in “long-COVID” symptoms in patients who have received COVID-19 vaccination, and this should be looked at in more detail. On a wider scale, COVID-19 preventive measures such as strict adherence to use of facemasks, hand hygiene, and social distancing might be the best way to prevent “long-COVID” in the long run.
Footnotes
Declaration of conflicting interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval:
Our institution does not require ethical approval for reporting individual cases or case series.
Funding:
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent:
Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD:
Ayanfe Omololu
https://orcid.org/0000-0003-0052-7622 | 0 | [
"COVID-19 vaccination ",
"low grade fever ",
"generalized body weakness ",
"sore throat ",
"anosmia ",
"headache ",
"nasopharyngeal swab positive for SARS-CoV-2 ",
"azithromycin ",
"chloroquine ",
"zinc ",
"vitamin C ",
"analgesics ",
"anti-histamines ",
"anosmia resolved ",
"sore throat resolved ",
"recurrent fever ",
"headache persisted ",
"mucoid diarrhea ",
"nausea ",
"generalized abdominal pain ",
"ciprofloxacin ",
"oral rehydration solution ",
"mild to moderate sub-sternal chest pain ",
"exertional dyspnea ",
"easy fatigability ",
"insomnia ",
"poly-arthritis ",
"naproxen ",
"fatigue worsened ",
"insomnia worsened ",
"joint pains worsened ",
"breathlessness worsened ",
"22 years old ",
"female ",
"health care worker ",
"overweight ",
"mild breathlessness on exertion ",
"afebrile ",
"normal cardiovascular examination ",
"normal pulmonary examination ",
"normal systemic examination ",
"normal complete blood count ",
"normal serum electrolytes ",
"normal urea ",
"normal creatinine ",
"normal chest x-ray ",
"normal electrocardiography ",
"ivermectin ",
"aspirin ",
"multivitamins ",
"dexamethasone ",
"incentive spirometry ",
"erythrocyte sedimentation rate elevated ",
"urea elevated ",
"Cr elevated ",
"exertional dyspnea improved ",
"fatigue improved ",
"joint pain improved ",
"neck pain ",
"abdominal bloating ",
"excessive flatus ",
"headache ",
"topiramate ",
"propranolol ",
"symptoms waxed and waned ",
"easy fatigability ",
"exertional dyspnea ",
"nasopharyngeal swab negative for SARS-CoV-2 ",
"Note: The time is calculated based on the information provided in the case report. The admission event has a timestamp of 0. Events that occurred before admission have negative timestamps, and events that occurred after admission have positive timestamps. The timestamps are approximate and based on the information provided in the case report."
] | [
-504,
-168,
-168,
-168,
-168,
-168,
-168,
-168,
-168,
-168,
-168,
-168,
-168,
-112,
-112,
-112,
-112,
-112,
-112,
-112,
-112,
-112,
-84,
-84,
-84,
-84,
-84,
-84,
-42,
-42,
-42,
-42,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
504,
504,
504,
728,
null
] | 6 |
PMC8958594 | 2021
The Combined Use of Neuropsychiatric and Neuropsychological Assessment Tools to Make a Differential Dementia Diagnosis in the Presence of “Long-Haul” COVID-19
Abstract
The longer term neurocognitive/neuropsychiatric consequences of moderate/severe COVID-19 infection have not been explored. The case herein illustrates a complex web of differential diagnosis. The onset, clinical trajectory, treatment course/response, serial neuroimaging findings, and neuropsychological test data were taken into account when assessing a patient presenting 8 months post-COVID-19 (with premorbid attention-deficit hyperactivity disorder, diabetes mellitus, mood difficulties, and a positive family history of vascular dementia). Her acute COVID-19 infection was complicated by altered mental status associated with encephalopathy and bacterial pneumonia. After recovery from COVID-19, the patient continues to experience persisting cognitive and emotive difficulties despite an ongoing psychopharmacotherapy regimen (16 + years), psychotherapy (15 + sessions), and speech-language pathology SLP; 2 × week/for 12 weeks). The purpose of her most recent and comprehensive neuropsychological evaluation was to determine the presence/absence of neurocognitive disorder. The patient is a 62-year-old Caucasian woman. Cognitive screening was completed 3 months post-acute COVID-19 as part of an SLP evaluation, and a full neuropsychological evaluation was conducted 8 months post-COVID-19 recovery on an outpatient basis (in person). The patient had serial neuroimaging. Initial neurological evaluation during acute COVID-19 included unremarkable brain computed tomography (CT)/magnetic resonance imaging. However, follow-up CT (without contrast) revealed, in part, “asymmetric perisylvian atrophy on the left.” Full neuropsychological evaluation at 8 months post-COVID-19 recovery revealed a dysexecutive syndrome characterized by language dysfunction and affective theory-of-mind deficit, consistent with dementia. There is need for careful use of differential diagnosis in COVID-19 patients with multiple risk factors that make them more susceptible to long-term neurological complications post-COVID-19. Differential diagnosis should involve multidisciplinary assessment (e.g., neuropsychology, SLP, neurology, and psychiatry).
Keywords:
Corona virus disease-19 neurological manifestations, NeuroCOVID stage III, Dementia, Clinical neuropsychology, Dysexecutive syndrome, Social cognition
Introduction
Although it is known that acute and post-acute cognitive and emotive dysfunction can occur with COVID-19 [
1
], the longer term neuropsychological manifestations of COVID-19 have not been fully characterized. The National Institute of Health and Care Excellence (NICE) in the UK has defined “long-haul” COVID-19 − as it has come to be known − as occurring when signs and symptoms continue or develop after acute COVID-19. This definition includes both “ongoing symptomatic COVID-19” and “post-COVID-19 syndrome.” While “ongoing symptomatic COVID-19” refers to signs and symptoms of COVID-19 from 4 to 12 weeks, “post-COVID-19 syndrome” refers to signs and symptoms that develop during or after an infection consistent with COVID-19 that continue for more than 12 weeks (and are not explained by an alternative diagnosis). Long COVID-19 is thought to occur in approximately 10% of people infected. To better characterize long-haul COVID-19, the guidelines state the importance of multidisciplinary assessment by various professionals in different disciplines, including respiratory physicians, cardiologists, neurologists, general physicians (from primary care or rehabilitation medicine), neuropsychologists or neuropsychiatrists, occupational therapists, speech and language therapists, and dieticians.
Toward this aim of comprehensive assessment, Helms et al. [
2
] reported the neurological and neuropsychological characteristics of 58 consecutive COVID-19 patients and observed that 33% (15 of 45) of patients exhibited a dysexecutive syndrome at discharge, consisting of “inattention, disorientation, or disorganized movements in response to commands.” Unfortunately, they did not report what actual neuropsychological tests were performed with patients to reach this conclusion. In separate studies, integrating neuroimaging and psychiatric data, short-term psychiatric dysfunction − including depression and psychosis − were reported in patients with COVID-19 [
3
,
4
,
5
]. Similarly, in yet another separate study, 65% of severe COVID-19 patients hospitalized in an intensive care unit (ICU;
N
= 58) experienced confusion, and 69% experienced agitation [
6
]. Regarding the neurological basis for the former finding, all 11 patients in the study who underwent perfusion neuroimaging were found to have bilateral frontotemporal hypoperfusion [
2
]. Additionally, in a separate magnetic resonance imaging (MRI) study of COVID-19, Kandemirli et al. [
6
] reported that 37% showed signal intensity abnormality accompanied by subcortical and deep white-matter signal intensity abnormality. Abnormalities involved the frontal lobe in 4 patients, the parietal lobe in 3 patients, and the temporal lobe in 1 patient. Guedji et al. [
7
] found orbitofrontal and limbic/paralimbic hypometabolism in COVID-19 patients versus matched controls.
Although the underlying neural mechanism for the observed functional changes is unknown, it has been speculated that COVID-19 can trigger an acute immune-mediated encephalopathy, which leads patients to experience neurocognitive and/or neuropsychiatric symptoms [
5
,
7
,
8
]. Specifically, COVID-19 can activate cytokines at the cellular level that cause injury to the blood-brain barrier (BBB). Via breaks in the BBB, cytokines are thought to penetrate the brain parenchyma, especially within the temporal lobes where the BBB is weaker. An association between such an immune response and the development of Alzheimer's disease has already been put forth [
8
]. However, regarding COVID-19, it is thought that the activated inflammatory response − with entry of blood material into the parenchyma − can result in seizures and/or encephalopathy. This total process is referred to as the “COVID-19 cytokine storm hypothesis.”
Complicating matters in terms of isolating a causal link between COVID-19 infection and an onset of neurocognitive and/or neuropsychiatric symptomatology is the fact that it is also well known that critically ill patients in ICU settings in general (i.e., patients who suffer with multiple medical conditions and are on many medications) commonly develop delirium, memory loss, and slowed processing speed, and these symptoms can persist even after stabilization of their medical conditions [
9
]. As such, some researchers suggest that any decline in mentation among acutely ill patients with severe COVID-19 may not necessarily represent the action of a direct brain injury brought on by COVID-19 but could be attributable to the fact that these patients are critically ill. However, this reasoning is weakened by the finding that COVID-19 patients experience encephalopathy and delirium at a greater rate than would be otherwise expected for a patient in an ICU setting [
5
]. Furthermore, in a neuroimaging study, researchers [
10
] suggested that COVID-19 might disproportionately affect gray-matter volume in the frontal-temporal network in older adults infected, providing an anatomical and functional framework for understanding the expression of neuropsychiatric symptoms in COVID-19 patients.
Regardless of the exact underlying neurobiological cascade that may be triggered by COVID-19 acutely, infected patients that recover remain at increased risk for experiencing persistent cognitive difficulties, including a new onset or more rapidly progressing memory decline, inattention, and/or slowed processing speed [
5
]. Thus, some researchers suggest that such patients see a neurologist and/or undergo neurocognitive testing 6–8 months after recovery (i.e., if they are experiencing persistent cognitive issues, including slowness in processing information and/or poor attention) [
5
]. These researchers also hypothesized that patients with low scores in certain cognitive domains (e.g., processing speed vs. attention) may benefit from tailored cognitive rehabilitation services. Such treatment may maximize their chances of returning to their baseline level of cognitive capacity [
5
]. However, it is largely unknown whether engaging in cognitive rehabilitation would reduce risk for accelerated age-related cognitive decline later on.
There is already preliminary evidence that COVID-19 can result in longer term cognitive difficulties (i.e., up to 6 months post-COVID-19) [
11
]. For example, even mild COVID-19 patients can demonstrate persistent deficits in memory and heightened psychiatric symptomatology up to 6 months posttreatment [
12
,
13
]. In addition, general cognitive decay (as measured by the Mini-Mental State Exam [MMSE]) was present in patients with severe COVID-19 who were entering the post-acute phase of illness (i.e., defined as clinical stability and complete weaning from sedative and antipsychotic medications) − on average 30 days post-COVID-19 diagnosis [
14
]. Similarly, cognitive decline was still persistent at the 2-month follow-up in 58.7% (out of 179 COVID-19 positive patients) of mild-to-severe COVID-19 patients, with 39.1% of those patients also showing psychiatric comorbidity (i.e., also at the 2-month follow-up) [
15
]. In particular, cognitive deficits were noted in attention and calculation (i.e., during a counting backwards task), short-term memory (i.e., during recall of 3 familiar words), constructional apraxia (i.e., when asked to copy a drawing of 2 intersecting pentagons), and written language (i.e., composing/writing a complete sentence) [
15
]. Results utilizing the Montreal Cognitive Assessment (MoCA) have been similar [
13
].
Studies employing more comprehensive neuropsychological testing also suggest persistent cognitive difficulties in some COVID-19 patients. For example, Méndez et al. [
14
] followed COVID-19-positive patients up to 2 months posthospital discharge, assessing cognitive and neuropsychiatric symptomatology. Their telephone-based test battery included verbal learning and delayed recall, Animal Naming from the Controlled Oral Word Association Test, and Digit Span Backwards from the Wechsler Adult Intelligence Scale-III. They found that 58.7% of patients exhibited at least “moderate” neurocognitive decline, and 39.1% had psychiatric comorbidity. “Moderate” decline was defined as a score greater than two standard deviations below the population normative data in any single domain (i.e., verbal learning/memory, verbal fluency, or working memory) [
14
]. Furthermore, these researchers found that delirium during hospitalization and prior psychiatric diagnosis were associated with greater neurocognitive decline.
Further still, Zhou et al. [
16
] utilized an online iPad-based neuropsychological battery of tests that included the Trail Making Test, a symbol-digit transcription task, a continuous performance measure (Connors Continuous Performance Test [CPT]), and a forward and backward Digit Span Test. Comparing COVID-19-recovered patients (tested two to 3 weeks post-negative test) to age-, education-, and gender-matched controls, these researchers found that patients exhibited deficits in reaction time and sustained attention as assessed by the CPT. Finally, Whiteside et al. [
17
] utilized the most comprehensive neuropsychological battery to date in their case series based on their telephone-administered test battery. This group observed cognitive difficulties across 3 patients in the domains of verbal fluency and attention. This group proposed a three-stage model of cognitive dysfunction that corresponds to the three-stage NeuroCOVID model proposed by Fotuhi et al. [
5
].
Differential diagnosis is a major purpose for neuropsychological evaluation. The current case report centers on an individual with multiple premorbid risk factors (diabetes, attention-deficit hyperactivity disorder [ADHD], depression, and anxiety) who survived COVID-19 infection complicated by encephalopathy and an ICU stay. This patient reported persistent cognitive difficulties extending beyond the 6-month post-acute infection stage. The key concern for the neuropsychologist was to make a differential diagnosis between ongoing encephalopathy, onset of dementia (i.e., premorbid and independent of COVID-19 vs. perhaps being set in motion or hastened by COVID-19 infection), or exacerbation of preexisting neurocognitive (e.g., ADHD) and/or neuropsychiatric (anxiety/depression) and/or medical comorbidities (e.g., diabetes). Additionally, there was a question of whether the patient could return to work and general prognosis. This case describes a complex presentation of a constellation of cognitive and emotive symptoms that may increasingly represent what neuropsychologists will encounter in the outpatient neuropsychology clinic setting in the coming months/years.
Case Presentation
Patient Demographics
The patient is a 62-year-old Caucasian woman who completed four semesters of college (in a nursing program) but ultimately became a pharmacy technician. The patient has worked in the pharmacy field for 20 years total. The patient lives with her husband and has one adult daughter. Family neurological history is reportedly positive for dementia and stroke with associated aphasia. Current psychoactive medications include vitamin B12, Xanax/alprazolam, Neurontin/gabapentin, oxycodone and acetaminophen/Percocet, venlafaxine/Effexor XR, and melatonin. Prior diagnoses include high blood pressure, hyperlipidemia, sleep apnea, vitamin B12 deficiency, calcium deficiency, diabetes type 2, COVID-19 (recovered), depression, and anxiety.
Reason for Referral
A neuropsychological evaluation was conducted in order to clarify the patient's current level of cognitive functioning in the context of recovery from COVID-19-related encephalopathy, with persistence of cognitive-emotive symptoms 8 months posthospital discharge, with particularly worsening attention, poor short-term memory, and reduced executive functioning capacity. Cognitive screening with the Repeatable Battery for the Assessment of Neuropsychological Status Update® (RBANS Update) obtained while the patient was undergoing outpatient rehabilitation approximately 3 months prior to the full neuropsychological evaluation revealed extremely low immediate memory (SS = 69) but low average (SS = 89) delayed memory. The patient's spouse reported at that time: “She's always had bad attention, but it's much worse now. She repeats herself and does not realize it. She tells me the same story over and over.” The patient indicated: “I write everything down,” and “I can be talking to you and completely zone out.” She also acknowledged some personality change: “I've turned into a really hateful person. I used to laugh a lot.”
History of Presenting Concerns
The patient reported no significant cognitive issues before contracting COVID-19 in the spring of 2020, except for a prior diagnosis of ADHD identified in early adulthood (i.e., college-age). At the time of the full outpatient neuropsychological evaluation, the patient had no memory for the course of her COVID-19-related hospital stay. She reported that her first memory after falling ill with COVID-19 is of being in the rehabilitation facility in July 2020. Note that this symptom (i.e., lack of awareness/memory/insight) has been reported in other case studies of acute COVID-19 (e.g., 17). See Figure
1
for a summary of her symptom course.
The patient was in her normal state of health until she began to run an increasingly high fever several days prior to her hospital admission. She did experience ageusia and anosmia. Her family eventually took her to a rapid COVID-19 testing site due to worsening symptoms. The patient has a vague memory of being in the parking lot of the testing site, but she does not recall being transported to the ER from the testing site. Once at the hospital, the patient was noted to be extremely combative and did not want to be admitted. She eventually ended up in the COVID-19 ICU because her oxygen level was very low (i.e., hypoxia), and she was running such a high fever. She was intubated. She was found to have superimposed bacterial pneumonia, and she was diagnosed with COVID-19-related encephalopathy. She was eventually transferred to an inpatient rehabilitation hospital and then received rehabilitative services on an outpatient basis after that (she completed a brief cognitive screening as an outpatient during this time). She continued to carry the diagnosis of encephalopathy and was diagnosed with memory impairment, attention and concentration deficit, and cognitive communication deficit throughout the duration of rehabilitation services.
Medical records indicate that the patient experienced vague and then elaborate visual hallucinations while hospitalized, at first seeing a “white brick tunnel with light at the end,” which progressed to “people, cats, and dogs” that were not there. She further progressed to experiencing delusions along with visual hallucinations; e.g., she would save food to feed the imaginary animals. Further, she believed that her sister-in-law (who is childless in reality) had been in her hospital room with “her children” and that she, her sister-in-law, and the children, were all going on a trip to Disney. Psychiatry and neurology were consulted during her inpatient stay, and she was started on ZyPREXA/olanzapine (she discontinued use following discharge), and neuroimaging was obtained serially due to repeated concern for stroke.
Neuroimaging
Brain computed tomography (CT)/MRI in June 2020 during the acute stage of COVID-19 was interpreted as within normal limits. However, repeat CT testing in July in response to an abnormal neurological exam during the course of her inpatient stay revealed “mild parenchymal volume loss, particularly within the bilateral sylvian fissures. There is proportional dilation of the ventricles. No hydrocephalus.” Follow-up brain MRI 2 days later revealed “extensive patchy T2 FLAIR hyperintensities in the bilateral periventricular white matter.” Worsening encephalopathy led to repeat CT in mid-July and revealed “moderate diffuse cerebral atrophy with more prominent, asymmetric left perisylvian temporal and frontal lobe atrophy…background cerebral atrophy with asymmetric perisylvian atrophy on the left. Neurodegenerative disorder/dementia could be considered.”
Premorbid Conditions/Comorbidities
The patient has a history of back issues (with an onset before she contracted COVID-19) and a history of diabetes type 2. She suffered with lower back pain for approximately 10 years prior to her full outpatient neuropsychological evaluation, though without any surgery. However, her back pain was notable enough that it caused her to stop working approximately 10 years ago. At the time of the neuropsychological evaluation, the patient was walking with an assistive device. The patient also suffers with poorly controlled diabetes.
The patient had been treated for ADHD in the past with pharmacotherapy, though she was not taking any medication for this at the time of the neuropsychological evaluation. The patient indicated an “upset and irritable” mood. She indicated feeling overcome with anger at times, but at other times, her mood is “a lot better.” The patient had been participating in psychotherapy prior to contracting COVID-19 and had diagnoses of major depressive disorder and anxiety. She reported having a “hard time letting it out” in therapy initially but later gained from therapy as she indicated that her depression had gotten better, and she does not worry as much as she used to. She reported no recent change in her appetite. She does however experience significant daytime fatigue currently. She consumes up to two cans of caffeinated soda daily and has 1 cup of coffee daily. She denied alcohol use, and she quit smoking in 1985. She denied any other substance use.
The patient's neurological history is notable for at least one prior incident resulting in a head injury but without loss of consciousness. Additionally, the patient suffers from sleep apnea (diagnosed several years ago). She uses a continuous positive airway pressure machine and reported poor sleep quality without it. Sensory functioning is notable for slight cataracts diagnosed in the past year and reduced hearing. The patient had tubes placed in her ears approximately 20 years ago due to recurrent ear infections. The right tube has fallen out. The patient denied any recent change in her sense of taste or smell, though she did experience ageusia and anosmia during the acute phase of her illness.
Current Neurocognitive Functioning (8 Months Post-COVID-19)
The patient underwent cognitive rehabilitation with a speech and language pathologist and a physical therapist at a major research university-affiliated rehabilitation hospital on an outpatient basis. The patient reported at the time of neuropsychological evaluation that her memory for recent events remains compromised in that “I can't remember right now.” Specifically, she tends to forget her train of thought if she is interrupted. She cannot remember plans each day. She keeps a large wall calendar to note all appointments. The patient also continues to misplace items and sometimes places items in the wrong place, e.g., her spouse finds nonfood items in the refrigerator. Regarding attention, she reported that she forgets what she wants to say mid-sentence now. She also notices that she is tangential in conversation now. She also abandons tasks prematurely and forgets to complete them. She gets lost in the hospital when she has an appointment or when she is otherwise going somewhere new. However, her long-term memory remains intact. The patient is currently independent in terms of basic activities of daily living functions, but she requires help to accomplish most instrumental functions. For example, during the neurobehavioral status exam, the patient could not recall the names of her medications, but she was able to describe that she has to take 3–4 insulin shots per day.
Behavioral Observations the Day of Testing
The patient appeared alert, and spontaneous speech was fluent with normal prosody and rate, but word-finding difficulty was apparent. Receptive language was reduced; instructions were repeated on several tasks, and the patient appeared not to understand concepts at times. For example, she never figured out the concept of the Wisconsin Card Sorting Task, and it was discontinued after 30 min, and only one category sort. She also performed poorly on a sentence comprehension task, suggesting additional receptive language difficulties. Expressive language was also impacted as her single-word reading score was much lower than expected and notable for unusual pronunciations of words that she likely could easily sight-read in the past (e.g., “lamb” for “lame” and “trumpet” for “triumph”). Thought processes were coherent and of normal content, but she was quite tangential. Gross motor functions were very slow. Mood was euthymic and affect remained pleasant throughout the evaluation. The patient was cooperative with the interview and testing procedure. She appeared motivated to perform to the best of her abilities, and her score on one of two embedded performance validity measures was within expectation. Her performance on a standalone validity indicator was borderline (8/15 correct; when the cutoff for valid performance is 9 or above). When combined with her reliable Digit Span score, these results are suggestive of true difficulty in the domains of attention and learning, rather than suboptimal effort. Therefore, the present results were judged a valid reflection of her current level of cognitive-emotive functioning, with significant attentional and learning difficulties noted.
Test Data
Test data are presented in Table
1
.
Table 1.
Descriptors are based on normative data and professional consensus [
18
], and are adjusted based on clinical judgment
Open in a new tab
The term “within normal limits (WNL)” is used when performance is at or above the 16th percentile but a more specific level of functioning cannot be determined.
Tests administered: Apathy Evaluation Scale [
19
]; BAI [
20
]; BDI-II [
21
]; BVMT-R [
22
]; Bicycle Drawing Test [
23
,
24
,
25
]; BNT [
26
,
27
]; CVLT-3 [
28
]; Clock Drawing Test [
29
,
30
]; Complex Ideational Material from the BDAE [
31
,
32
]; CPT-3 [
33
]; COWAT [
34
]; Grooved Pegboard Test [
35
]; Reading the Mind in the Eyes Test [
36
]; Rey-15 [
37
]; SHAPS [
38
]; Trail Making Test (A and B) [
39
]; WASI-II (Verbal Comprehension Index and Matrix Reasoning subtest) [
40
]; WAIS-IV (Processing Speed Index and Working Memory Index) [
41
]; WRAT-5 (word reading and math computation) [
42
]; WCST (computerized) [
43
].
SD, standard deviation; BAI, Beck Anxiety Inventory; BDI-II, Beck Depression Inventory-2; BVMT-R, Brief Visuospatial Memory Test-Revised; BNT, Boston Naming Test; CVLT-3, California Verbal Learning Test, Third Edition; BDAE, Boston Diagnostic Aphasia Examination; CPT-3, Connors Continuous Performance Test − Third Edition; COWAT, Controlled Oral Word Association Test; SHAPS, Snaith-Hamilton Pleasure Scale; WASI-II, Wechsler Abbreviated Scale of Intelligence − Second Edition; WAIS-IV, Wechsler Adult Intelligence Scale − 4th Edition; WRAT-5, Wide Range Achievement Test-5th Edition; WCST, Wisconsin Card Sorting Test; RT, reaction time; ISI, inter-stimulus interval; WNL, within normal limits.
Testing Highlights
Intellectual Functioning
Taken together with demographic information (e.g., educational achievement and career trajectory), it is likely that the patient's intellectual functioning fell at least within the low average range at some point in the past. Her poor single-word reading test score (i.e., the WRAT-5) is unexpected and thus likely represents true language decline rather than being a genuine indicator of her baseline intellectual functioning. Consistent with this hypothesis, estimation of additional aspects of intellect most susceptible to cognitive decline revealed significantly reduced working memory and processing speed, providing further evidence of significant intellectual decline relative to her core verbal reasoning capacity.
Learning and Memory
Overall, her ability to accumulate (i.e., learn) new visual and verbal information was compromised (e.g., look at her scaled score trajectory across the learning trials of the CVLT-3 in Fig.
2
), but she did not show a rapid decay pattern after a delay. Recognition memory is adequate for visual information but is compromised for verbal information.
Attention, Processing Speed, and Executive Function
Basic attention is reduced, and her rote working memory is below average when no context is provided (i.e., Digit Span backward < Digit Span sequencing). These specific tests correlate with ability to manage finances [
44
]. Contextualized working memory in the form of rapid calculation via math word problems is below average. Processing speed is exceptionally low. She lost mental set across repeated trials of a complex problem-solving task (note that the WCST categories achieved significantly correlates with wages earned and hours worked) [
45
], and she struggled to represent time on a clock face (Fig.
3
), drew a bicycle lacking several important parts (Fig.
4
), she generated novel ideas very slowly, and performed below expectation in terms of rapid mental flexibility (see Fig.
5
). Indeed, Trail B performance is known to correlate with driving ability [
46
]. All of these tasks call upon utilization of more than one executive operation. Finally, her sustained attention capacity was poor on a CPT as her response speed was slow overall and slowed down even further (i.e., disproportionately) during later blocks of the task.
Language
Her performance across language measures suggests difficulty extracting meaning from verbal information presented in an auditory format.
Academic
The patient demonstrated below average calculation skill on a paper-and-pencil measure (WRAT-5 Math, Fig.
6
), which certainly represents decline for this patient given her career in a technical field where she had to use mathematics frequently. This test is also correlated with financial ability in Alzheimer's disease [
47
].
Mood, Social Cognitive Behavior, and Personality
On self-report mood measures, the patient's pattern of responses indicated moderate depression currently and mild anxiety. In addition, her social cognitive functioning on a behavioral task is compromised in terms of reduced affective theory of mind, with her performance falling within the exceptionally low range. Finally, the patient endorsed items on separate self-report measures to indicate the presence of clinically meaningful apathy but normal hedonic tone.
Diagnosis
The patient meets criteria for major neurocognitive disorder due to multiple etiologies with behavioral disturbance (i.e., apathy and reduced social cognition) (i.e., ICD 10: F02.81).
General Summary/Discussion of Neuropsychological Test Results
The patient's neuropsychological profile is aberrant relative to neurotypical individuals her age and education level. Intraindividual inspection of her scores revealed intellectual decline most notable in the following domains (in order of severity, high to low): processing speed, working memory, and perceptual reasoning. Vocabulary knowledge was roughly consistent with expectation. Basic attention on a rote Digit Span task was below average, and her learning curve across a list-learning task was flat, with essentially no growth across five trials (of the same list). The same pattern emerged on a visual learning task across three trials. However, she is not amnestic; she did not show a pattern of rapid decay across a delay period (for visual nor verbal information).
Her prominent learning difficulties provide evidence for the presence of an overall dysexecutive syndrome, a supposition that is also supported by her performance on a complex problem-solving task (i.e., the WCST). She only deduced one category, and she lost mental set twice (and the task was ultimately discontinued after 30 min for lack of achievement). Furthermore, she was very slow to respond on a CPT and showed a significant decrement in her speed of performance during later blocks of this task (relative to early blocks). Additional features of a dysexecutive syndrome include: poor working memory on the WAIS-IV (she could only keep track of 3–4 bits of information accurately) and poor phonemic fluency. Finally, her executive-based visuoconstructive ability was poor on the clock-drawing task (e.g., the size difference between the hour and minute hand was not represented) and on the bicycle drawing task (i.e., several key elements were missing), suggesting significant abstraction-motor planning difficulties. Research indicates that executive dysfunction and dysexecutive behavior − which compose the “dysexecutive syndrome” − have both separable and common neuroanatomical and functional correlates. The common correlate is rostral prefrontal cortex activity bilaterally [
48
]. Her executive functioning deficits on formal testing and the numerous dysexecutive behaviors reported by the patient's spouse and by the patient herself (e.g., worsened attention, losing her train of thought, being tangential in conversation, prospective memory difficulties, etc.) indicate anterior prefrontal cortex involvement.
Overall, then, these results indicate significant difficulty with learning, abstraction, attention, mental speed, and sustained focus, which is consistent with what the patient and her spouse reported (i.e., a dysexecutive presentation). However, importantly, language functioning was also an area of weakness. Both expressive (e.g., Complex Ideational Material) and receptive language (e.g., Animal Naming) were weaker than expected given her vocabulary knowledge. While her phonemic fluency difficulties implicate prefrontal pathology, her semantic language difficulties suggest some degree of temporal involvement. Specifically, moderately intense depressive symptoms, poor affective theory of mind, and clinically significant apathy (but normal hedonic tone) implicate primarily limbic structures, with spared functioning in certain reward-based striatal structures. Indeed, prior research indicates that affective theory-of-mind deficits in particular − which refer to a person's ability to understand the feelings, emotions, and affective states of others [
49
] − as quantified by accuracy score on the Reading the Mind in the Eyes Test [
50
] − relates to activity in the limbic-paralimbic region.
Possible Etiological Factors
Applying all of this information to the present case, the white-matter changes observed on imaging could relate to her diabetes and/or history of head injury and ADHD. It is also important to note the potential effects of pain medication (e.g., Percocet) use on her cognitive presentation, which may be expected to affect her processing speed most prominently and lead to a blunted/flat neurocognitive profile in general. Although she does demonstrate poor processing speed, this is not in isolation, and thus, pain medication is likely not the primary cause of her cognitive profile or the most parsimonious explanation for the peaks and valleys (variability) across her intraindividual neurocognitive pattern. Furthermore, although aspects of her test performance are consistent with premorbid ADHD, her attentional difficulties appear to be greater than that observed in this age-group with “typical” ADHD in isolation (i.e., a drastic worsening of attention over the course of weeks in an otherwise healthy adult ADHD patient is not expected). This finding is consistent with the budding research literature, e.g. [
17
].
Therefore, the nature of the onset of cognitive difficulties in tandem with the onset of COVID-19 symptoms and the fact that her cognitive functioning has not returned to baseline despite general recuperation/recovery from core respiratory and focal neurological symptoms (i.e., somnolence, hallucinations/delusions, and altered mental status) associated with the acute phase of COVID-19 suggest an ongoing process. A persistent low-level delirium due to encephalopathy versus an emergent neurodegenerative cause remained on the differential. Her cognitive pattern + serial neuroimaging implicate frontoparietal (i.e., given the presence of a dysexecutive syndrome, visuoconstructive, attentional, and mathematical difficulties), fronto-subcortical (i.e., given reduced processing speed, learning capacity, and ongoing emotive symptoms such as apathy and depression − with particular impact to limbic structures such as the amygdala and hippocampus but not the frontostriatal system given normal hedonic tone currently − a constellation that may be most associated with the onset and severity of COVID-19 infection) [
7
,
51
], and temporoparietal junction dysfunction (e.g., evidenced most prominently by social cognitive and reduced expressive and receptive language dysfunction).
Given that none of the above-discussed premorbid/confounding factors explains the fact that she experienced not only worsening attention but also a
new onset
and persisting cognitive difficulties following COVID-19 infection (i.e., new onset memory difficulties, mood and social cognitive difficulties, and language difficulties), an alternative explanation was required. Indeed, consistent with prior reports [
14
,
15
,
16
,
17
], the patient's neuropsychological exam confirms language, mathematical, socio-cognitive, and learning difficulties. The patient's most recent neuroimaging findings indicate progressive, and now, asymmetrical cerebral atrophy (i.e., affecting the left perisylvian region slightly > right), along with patchy white matter hyperintensities bilaterally. This largely excludes ongoing encephalopathy as an appropriate explanatory variable. Instead, an active neurodegenerative process (possibly ignited or hastened by the initial encephalopathy) appears more probable. Specifically, a frontotemporal or atypical AD pathology seems most plausible [
52
], given specific and notable decline in learning, language/single-word reading, and calculation skill. Indeed, recent research proposes the existence of a temporoparietal junction subtype of AD [
53
]. Her most recent neuroimaging findings may be the strongest harbinger for the presence of an independent neurodegenerative process [
54
]. Also, note that the patient has a positive family history of neurodegenerative disease following stroke (characterized by aphasia), and this likely increased her risk for cognitive decline even without COVID-19.
Regarding the specificity of COVID-19 in this patient's neuropsychological exam, the presence of a dysexecutive profile (which is strongly consistent with previous reports of the neuropsychological profile in COVID-19 patients) fits with what is known about the impact of COVID-19 on the brain. The idea that COVID-19 may alter fronto-subcortical circuitry in particular is supported by these data and other previous work, including neuroimaging studies that have consistently observed frontotemporal/fronto-subcortical dysfunction in COVID-19 patients. Specifically, in one study, all 11 COVID-19 patients who underwent perfusion neuroimaging were found to have bilateral frontotemporal hypoperfusion [
2
]. Additionally, in a separate MRI study of COVID-19 [
6
], researchers observed frontal-subcortical signal intensity abnormality in nearly 20% of COVID-19 patients. Guedji et al. [
7
] observed orbitofrontal and limbic/paralimbic hypometabolism in COVID-19 patients versus matched controls. Again, these results provide evidence to support the idea that fronto-limbic disruption is a characteristic of this virus.
Recommendations
What the patient perceived as a “memory problem” turned out to be more so a language, working memory/attentional, and dysexecutive problem based on the results of psychometric testing. Given her history of COVID-19, the presence of a dysexecutive syndrome (with notable language difficulties on neuropsychological testing) and neuroimaging findings suggestive of atypical AD versus frontotemporal pathology; PET brain imaging was recommended to further interrogate a neurodegenerative diagnosis (e.g., to confirm or rule out a straightforward frontal-temporal pattern of hypoactivation consistent with what has been reported in COVID-19 patients who have undergone PET imaging [
7
]) versus an atypical AD pattern of hypoactivation (which would include more temporoparietal involvement [
52
]). In addition, continued speech and language therapeutic services were encouraged, with more direct focus on addressing the patient's language difficulties (in addition to attentional, learning, and executive deficits). Referral to geriatric psychiatry or continued community-based psychotherapy was recommended to address ongoing mood symptoms in the context of her health issues. A behavioral approach to psychotherapy was recommended (as the most likely therapy orientation to be successful), given the patient's reduced executive functioning. A trial of a cognition-enhancing medication (i.e., a stimulant or atypical stimulant and/or an anticholinesterase inhibitor) to address ongoing attentional, learning, daytime fatigue, and executive symptoms was also recommended. The patient was strongly encouraged to reduce her intake of caffeine. Given reported driving difficulties, cognitive flexibility difficulties, and processing speed difficulties on testing (e.g., Trail B), a formal driving evaluation was recommended. Given the patient's pattern of difficulties, including math decline, attentional and executive difficulties, and the expected pattern of further decline, it was recommended that she refrain from returning to her job, at least not in a pharmacy technician role like the one she had in the past.
Conclusion
The strengths of this case report include the serial nature of cognitive and brain assessment (i.e., neuroimaging). The limitation of this case includes several premorbid conditions that each can affect brain health. Nevertheless, overall, these results provide further preliminary evidence for continuing to investigate the interaction between COVID-19 infection, detectability of cognitive decline, and emergent or accelerated progression of neurodegenerative disease. The timeline of neuropsychological evaluation of this patient, i.e., 8 months post-COVID-19 recovery, helps to solidify the hypothesis that COVID-19 may increase risk for neurodegeneration or increase manifestation/detectability of cognitive decline or actually speed up progression in neurodegenerative disease. The latter idea has been speculated on in the literature already [
7
,
15
].
The pattern of cognitive-emotive deficits observed in this patient includes a dysexecutive syndrome with attentional and social cognitive deficits. The former is consistent with previous reports of acute and post-acute COVID-19 patients [
17
], but the latter is a novel finding that deserves further inquiry. This case also illustrates the need for caution in interpreting neuropsychological data in the midst of several overlapping differentials and correlating neuropsychological findings with serial neuroimaging data (when available). Specifically, this patient (based on neuroimaging, and also based on the patient's pattern of symptom onset, and evolving cognitive and neuropsychiatric symptoms) demonstrated a traditionally accepted “neurodegenerative pattern” in addition to meeting the neuroCOVID stage III criteria [
5
]. However, this pattern may have been missed without a full neuropsychological evaluation and amidst the backdrop of her comorbid diagnoses, which otherwise “clouded” aspects of her neuropsychological profile and may have ultimately resulted in a less accurate conclusion (i.e., “inconclusive,” “primarily psychiatric-related,” “vascular-related,” etc. vs. major neurocognitive disorder).
In this vein, this case uniquely illustrates complex differential diagnosis and the potential confluence of several etiological risk factors contributing to the manifestation of a major neurocognitive disorder. It is this type of complex presentation (i.e., which calls for careful consideration of premorbid conditions and the differentiation between normal age-related cognitive change vs. cognitive decline, the neurobiology of COVID-19, and other factors such as vascular risk factors, premorbid psychiatric illness, and medication regimen) that is more likely to be observed in the outpatient neuropsychology clinic, and it will be essential to carefully evaluate/monitor these types of patients' neurocognitive and neuropsychiatric functioning over time. In fact, these results suggest that long-term follow-up of these patients may be necessary [
17
]. It is recommended that the neuropsychological battery used with these patients (at minimum) include executive, learning and memory, attention, processing speed, language, social cognitive, and mood measures to properly assess the patient's degree of vulnerability/increased risk for neurodegenerative disease associated with COVID-19 infection.
Statement of Ethics
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval was not required or obtained for this study. The paper is exempt from Ethical Committee approval because all information is de-identified.
Conflict of Interest Statement
The author has no conflicts of interest to declare.
Funding Sources
There is no funding source to disclose.
Author Contributions
S.N. Light was solely involved in the inception, writing, and interpretation of all data presented in this case study.
Data Availability Statement
All data generated and analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. | 0 | [
"quit smoking ",
"had tubes placed in ears ",
"diagnosed with diabetes type 2 ",
"experienced back issues ",
"diagnosed with ADHD ",
"experienced head injury ",
"admitted to hospital ",
"fever ",
"ageusia ",
"anosmia ",
"hospitalized ",
"intubated ",
"diagnosed with COVID-19-related encephalopathy ",
"diagnosed with superimposed bacterial pneumonia ",
"experienced vague visual hallucinations ",
"brain CT/MRI in June 2020 ",
"experienced elaborate visual hallucinations ",
"experienced delusions ",
"started on ZyPREXA/olanzapine ",
"diagnosed with depression ",
"diagnosed with anxiety ",
"experienced sleep apnea ",
"started taking vitamin B12 ",
"started taking Xanax/alprazolam ",
"started taking Neurontin/gabapentin ",
"started taking oxycodone and acetaminophen/Percocet ",
"started taking venlafaxine/Effexor XR ",
"started taking melatonin ",
"experienced reduced hearing ",
"brain CT in July 2020 ",
"brain MRI in July 2020 ",
"repeat CT in mid-July 2020 ",
"experienced cataracts ",
"transferred to inpatient rehabilitation hospital ",
"received rehabilitative services on an outpatient basis ",
"completed cognitive screening ",
"62 years old ",
"female ",
"discontinued use of ZyPREXA/olanzapine ",
"neuropsychological evaluation ",
"reported memory difficulties ",
"reported attention difficulties ",
"reported executive functioning difficulties ",
"reported language difficulties ",
"reported mood difficulties ",
"diagnosed with major neurocognitive disorder ",
"diagnosed with dysexecutive syndrome ",
"recommended PET brain imaging ",
"recommended speech and language therapeutic services ",
"recommended referral to geriatric psychiatry ",
"recommended trial of cognition-enhancing medication ",
"recommended formal driving evaluation ",
"discontinued use of medication ",
"experienced daytime fatigue ",
"consumed caffeinated soda ",
"consumed coffee ",
"denied alcohol use ",
"denied substance use ",
"completed neuropsychological testing ",
"performed poorly on Wisconsin Card Sorting Task ",
"performed poorly on sentence comprehension task ",
"performed poorly on single-word reading test ",
"performed poorly on math computation test ",
"performed poorly on Trail Making Test ",
"performed poorly on Clock Drawing Test ",
"performed poorly on Bicycle Drawing Test ",
"performed poorly on CPT-3 ",
"performed poorly on COWAT ",
"performed poorly on Grooved Pegboard Test ",
"performed poorly on Reading the Mind in the Eyes Test ",
"performed poorly on SHAPS ",
"performed poorly on BAI ",
"performed poorly on BDI-II ",
"performed poorly on Apathy Evaluation Scale "
] | [
-360,
-240,
-120,
-120,
-40,
-40,
-24,
-24,
-24,
-24,
-24,
-24,
-24,
-24,
-24,
-24,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-20,
-17,
-15,
-12,
-12,
-10,
-8,
-5,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | 7 |
PMC9633038 | 2022
Autoimmune Reaction Associated With Long COVID Syndrome and Cardiovascular Disease
Abstract
A 35-year-old woman with history of cardiovascular disease presented with shortness of breath, lightheadedness, fatigue, chest pain, and premature ventricular contractions 3 weeks after her second COVID-19 vaccine. Symptoms subsided following catheter ablation and ibuprofen except for chest pain and fatigue, which persisted following ablation and subsequent SARS-CoV-2 infection. The case suggests causal associations between COVID-19 vaccine/infection and recurrence of cardiovascular disease, including long-COVID–like symptoms. (
Level of Difficulty: Advanced.
)
Key Words:
arrhythmia, autoimmune disease, long COVID, pericarditis, SARS-CoV-2
Abbreviations and Acronyms:
ANA, antinuclear antibodies; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PVC, premature ventricular contraction; SLE, systemic lupus erythematosus
Central Illustration
History of Presentation
A 35-year-old Russian woman presented for evaluation with complaints of fatigue, chest and joint pain, and dyspnea. The patient had a history of cardiovascular disease (CVD), having been hospitalized for 3 days with palpitations and premature ventricular contractions (PVCs) at 1 year and 10 months before her first Pfizer SARS-CoV-2 vaccination. Symptoms resurfaced 3 weeks after patient’s second vaccination and worsened progressively, with multiple hospital admissions that included dual cardiac ablations over a 3-month period. Ibuprofen was prescribed for pericarditis 2 months after the second ablation, and 3 weeks later, the patient tested positive for SARS-CoV-2. The patient took only vitamin D to combat SARS-CoV-2 infection. Shortly after testing positive for SARS-CoV-2, the patient presented again with chest pain when moving or breathing, joint pain, and dermatitis, symptoms that persisted for 6 months.
Learning Objectives
•
To investigate medical history and test results to deduce possible causal relationships between COVID vaccine/infection and exacerbated CVD symptoms.
•
To examine CVD and genetic history as factors in determining sensitivity to long COVID.
•
To recognize possible causal roles of COVID vaccination/infection in cyclically exacerbated COVID, CVD, and autoimmune symptoms.
•
To recognize pericarditis and autoimmune reaction as symptoms of COVID vaccine or long COVID.
Past Medical History
CVD was first evident when the patient was hospitalized for 3 days with presyncope, palpitations, and high burden of PVCs, 1 year and 10 months before she was vaccinated for SARS-CoV-2. Three weeks after receiving her second vaccination, the patient experienced lightheadedness, fatigue, frequent presyncope, shortness of breath, and chest pain, and she was admitted to the hospital with high burden of PVCs. Cardiac magnetic resonance showed borderline cardiomegaly with left ventricle enlargement but no evidence of infarct, fibrosis, or amyloidosis. Ejection fraction was 62.3%. Catheter ablation procedures were performed on 2 consecutive days. Symptoms improved after the ablations, and echocardiogram showed trace mitral regurgitation, tricuspid regurgitation, and pericardial effusion (
Video 1
). Symptoms of chest pain and fatigue were still evident but subsided during 2 to 3 weeks treatment with Advil. GeneCompass genetic analyses exploring 100 genes for CVD and diabetes revealed mutations at 6 potential CVD/diabetes mellitus susceptibility loci—APOC1 (rs4420638), CETP (rs3764261), IL4 (rs2243250), AGT (rs5051), and AGT (rs699) for CVD and SLC30A8 (c.973C) for diabetes mellitus—suggesting moderate risk for developing CVD and/or diabetes mellitus, but no susceptibility genes for immune system disorders. Shortly after testing positive for COVID-19, the patient reported recurrent chest pain when moving or breathing as well as joint pain. The patient has a family history of diabetes, high blood pressure, and cardiac cirrhosis.
Differential Diagnosis
The differential diagnosis included long COVID-19, arthritis, and systemic lupus erythematosus (SLE).
Investigations
Antinuclear antibody (ANA) immunofluorescence assay screening was positive for autoimmune antibodies with a 1:80 titer and nuclear and homogenous pattern (
Table 1
). Taken together with the symptoms present at that time (limb/joint pain, dermatitis, fatigue, and shortness of breath) and in accordance with the international consensus for ANA patterns (ICAP), the results are consistent with 3 possible autoimmune-related diagnoses: SLE, chronic autoimmune hepatitis, and juvenile idiopathic arthritis. Based on a double-stranded DNA (dsDNA) antibody test (
Table 2
), which showed the absence of DS antibody, it can be concluded that the patient does not have SLE. She had normal levels of alkaline phosphatase (52 U/L), aspartate transaminase (20 U/L), and alanine transaminase (9 U/L), which indicate that she does not have autoimmune hepatitis. The patient tested negative for antineutrophil cytoplasmic antibodies, vasculitis proteinase 3, and myeloperoxidase (
Table 3
). She also tested negative for the following antibodies: cyclic citrullinated peptide (immunoglobulin G [IgG]), complements C3 and C4, B2 glycoprotein I (IgG, immunoglobulin A [IgA], immunoglobulin M [IgM]), phosphatidylserine (IgG, IgM), cardiolipin (IgA, IgG, IgM), Sjogren syndrome type A and B antigens, and Smith and Smith/Ribonucleoprotein antibodies (
Table 4
). Blood tests revealed normal hormonal and white blood cell levels, slightly elevated low-density lipoprotein cholesterol (LDL-C) (
Table 5
), and progressively reduced high-density lipoprotein cholesterol (HDL-C) levels over 1 year between 2019 to 2021 (from 79 to 65 mg/dL).
Table 1.
ANA Screening Results
Open in a new tab
ANA = antinuclear antibody.
Table 2.
Double-Stranded DNA Antibody Test Results
Open in a new tab
Table 3.
ANCA Antibody Test Results
Open in a new tab
AI = antibody index.
Table 4.
List of Antibodies Tested
Open in a new tab
AB = antibody; APL = IgA Phospholipid; GPL = IgG phospholipid; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; MPL = IgM phospholipid ; NEG = negative; RNP = ribonucleoprotein; SM = Smith.
Table 5.
Cholesterol Blood Test Results
Open in a new tab
calc = calculated; H = high; HDL = high-density lipoprotein; LDL = low-density lipoprotein.
Management
The patient is currently stable but still presents with severely restricted physical performance, chest pain, joint pain, and fatigue. She has switched from a vegetarian to nonvegetarian diet as a possible avenue to mitigate fatigue (she was tested for low iron and ferritin levels after COVID-19 infection) and continues to take a vitamin D supplement. The patient was prescribed statin medication for LDL-C and HDL-C but did not take it.
Discussion
The purpose is to alert physicians to the possibility that preexisting cardiovascular disease may sensitize some patients to COVID vaccines and/or infection, leading to recurrent and/or exacerbated CVD and/or long COVID symptoms, including autoimmune reaction. The case timeline is outlined in
Figure 1
. The reappearance of exacerbated CVD (PVCs), hospitalizations, and COVID-like symptoms coinciding with the patient’s COVID-19 vaccination schedule suggests a causal relationship. To our knowledge, the patient was not infected at the time of vaccination and had no history of COVID-19 infection. Rare cases of long-COVID-19–like symptoms associated with COVID-19 vaccination have been reported (reviewed by Couzin-Frankel and Vogel
1
), and autoimmune response stimulated by the spike protein antigen has been implicated as the possible culprit.
2
,
3
The presenting symptoms, as well as results of ANA screening of the patient’s blood that do not implicate other autoimmune disease, are consistent with the possibility that the symptoms are driven by the vaccine. Indeed, fatigue and shortness of breath, the major symptoms that were exacerbated after the second vaccination, are the 2 most common symptoms of long COVID. Similarly, exacerbation of chest and joint pain and difficulty breathing subsequent to COVID infection may be causally linked. Patients with preexisting CVD including arrhythmia are at increased risk for developing long COVID and have poorer prognoses.
4
,
5
The patient’s symptoms and presence of autoantibodies are consistent with long COVID.
6
Pericarditis and arrythmias, the 2 main cardiovascular conditions exhibited by the patient, have also been reported in association with long COVID and secondary to an immune reaction to the vaccine.
In addition to the confirmed arrhythmias, genetic analyses of the patient’s blood revealed the presence of mutations within several CVD-associated high-risk genes. In particular, the rs4420638 variant of
APOC1
is associated with higher LDL-C levels in plasma,
7
and the rs3764261 variant of
CETP
is associated with increased HDL-C and decreased blood pressure.
8
Low serum HDL-C and high LDL-C are established risk factors for coronary artery disease, whereas low HDL-C is associated with poor outcome of patients with COVID-19.
9
It seems possible that the significant decline of HDL-C in the patient’s blood that was evident immediately before severe vaccine/COVID-19 symptoms may contribute to enhanced transmission of the COVID spike protein, activation of autoimmune reactions, and long-COVID symptoms.
Genetic results also indicated an absence of gene mutations associated with autoimmune disorders, consistent with COVID-19–induced autoimmune disease symptoms independent of the patient’s susceptibility to immune disorders. Cytokine storm is just one of the multiple possible pathways through which the SARS-CoV-2 virus can exacerbate the autoimmune response. During cytokine storm, immune cells are hyperactivated by elevated circulating cytokines and target internal organs. SARS-CoV-2–mediated cytokine storm has been reported to propagate long COVID
10
and is a candidate mechanism for the symptoms described in this case report.
A strength of this case report is the recurrence of severe CVD and long-COVID–like symptoms with autoimmune reaction, coincident with 2 separate COVID-related events, vaccination and infection. The cause and effect are consistent with the known high-risk status of and poorer prognoses of CVD patients for COVID infection and the development of long COVID. Limitations of the study include the selective bias of case studies, which cannot represent entire populations with long COVID and preexisting CVD.
Follow-up
The patient remains under observation.
Conclusions
A long-COVID–like condition is supported by patient symptoms, gene analysis, ANA screening, and blood test in association with a CVD and lipid susceptibility profile. The mechanism may involve COVID-19 spike protein–mediated autoimmune activation. An implication of this study is that COVID vaccine, exacerbated CVD, and long COVID symptoms can be causally associated. Patients with preexisting CVD are at a higher risk of long-COVID–related symptoms relative to patients without preexisting CVD. For future direction, it will be important for doctors and patients to understand possible mechanisms causing long COVID symptoms, especially how the spike protein can instigate an inflammatory response and an autoimmune reaction. It will also be important to determine whether the significant decline of HDL-C in the patient’s blood seen before severe COVID-19 symptoms is causally linked to activation of autoimmune reactions and long COVID.
Funding Support and Author Disclosures
Dr Shehadeh is funded by grants from the National Institute of Health, Miami Heart Research Institute, and the American Heart Association. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the
Author Center
.
Appendix
For a supplemental video, please see the online version of this paper.
Appendix
Video 1
Echocardiogram Showing Pericardial Effusion
Download video file
(504.6KB, mp4) | 0 | [
"history of cardiovascular disease ",
"hospitalized for palpitations ",
"premature ventricular contractions ",
"first Pfizer SARS-CoV-2 vaccination ",
"cardiac magnetic resonance ",
"borderline cardiomegaly ",
"left ventricle enlargement ",
"ejection fraction ",
"catheter ablation procedures ",
"symptoms improved ",
"echocardiogram ",
"trace mitral regurgitation ",
"tricuspid regurgitation ",
"pericardial effusion ",
"GeneCompass genetic analyses ",
"mutations at potential CVD/diabetes mellitus susceptibility loci ",
"second vaccination ",
"symptoms resurfaced ",
"hospital admissions ",
"dual cardiac ablations ",
"Ibuprofen prescribed ",
"pericarditis ",
"tested positive for SARS-CoV-2 ",
"took vitamin D ",
"presented with chest pain ",
"joint pain ",
"dermatitis ",
"symptoms persisted ",
"35 years old ",
"female ",
"Russian ",
"admitted to the hospital ",
"fatigue ",
"chest pain ",
"joint pain ",
"dyspnea ",
"family history of diabetes ",
"high blood pressure ",
"cardiac cirrhosis ",
"differential diagnosis ",
"long COVID-19 ",
"arthritis ",
"systemic lupus erythematosus ",
"antinuclear antibody immunofluorescence assay screening ",
"autoimmune antibodies ",
"double-stranded DNA antibody test ",
"absence of DS antibody ",
"normal levels of alkaline phosphatase ",
"aspartate transaminase ",
"alanine transaminase ",
"tested negative for antineutrophil cytoplasmic antibodies ",
"vasculitis proteinase 3 ",
"myeloperoxidase ",
"normal hormonal and white blood cell levels ",
"elevated low-density lipoprotein cholesterol ",
"progressively reduced high-density lipoprotein cholesterol ",
"prescribed statin medication ",
"did not take statin medication ",
"switched to nonvegetarian diet ",
"takes vitamin D supplement ",
"remains under observation "
] | [
-630,
-630,
-630,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-570,
-546,
-546,
-546,
-546,
-474,
-474,
-462,
-462,
-462,
-462,
-462,
-462,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
0,
24
] | 8 |
PMC10284064 | "2023\nTransient constrictive pericarditis: A complication of COVID-19 infection or first presentati(...TRUNCATED) | 0 | ["SARS-CoV-2 infection ","history of SARS-CoV-2 infection ","positive real-time reverse transcriptas(...TRUNCATED) | [-504.0,-504.0,-504.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.0,0.(...TRUNCATED) | 9 |
End of preview. Expand
in Data Studio
Citation
If you find this dataset or our work useful in your research, please consider citing:
Jing Wang, Amar Sra, Jeremy C. Weiss. Active Learning for Forecasting Severity among Patients with Post Acute Sequelae of SARS-CoV-2. arXiv:2506.22444, 2025.
BibTeX:
@misc{longcovid,
title = {Active Learning for Forecasting Severity among Patients with Post Acute Sequelae of SARS-CoV-2},
author = {Jing Wang and Amar Sra and Jeremy C. Weiss},
year = {2025},
eprint = {2506.22444},
archivePrefix = {arXiv},
primaryClass = {cs.LG}
}
- Downloads last month
- 39