A comparison between HIV-Associated Neurocognitive Disorder

(HAND) and Long Covid: A systematic review

Group members:
1. Alexandra D. Álvarez Colón (#4739250)
2. Nabhya L. Moya Correa (#4740311)
3. Perla K. Irizarry Santiago (#4740005)
4. Estefanía Rivas-García (#4740548)
5. Javier Jacob Flores (#4766993)

Abstract : Recently HIV and Covid-19 infection are of more attention for the high
percentage of infected patients worldwide; from which some patients have developed
neurocognitive symptoms. HIV Associated Neurocognitive disorder (HAND) and Long
Covid both can affect the central and peripheral nervous system. During our
systematic review, we selected from a total of twenty-two articles to establish with the
literature the similarities and differences in which both pathologies affect the brain,
causing neurocognitive symptoms. HAND has symptoms more closely related to
dementia and affects the CNS primarily with a slower progression from early to late
stages. However, Long Covid can be developed within three months after the initial
infection with PNS symptomatology that quickly progresses to CNS symptoms
including parkinsonism. Between both pathophysiology, we see a similar route of
infection, the cytokine activation of the microglia that in turn triggers neuronal
apoptosis and demyelination. Based on the analysis, we found a strong correlation
between the mechanisms of activation and the amount of stimulus, on the CNS and
PNS, with the intensity of the clinical manifestations.

Key words: HAND, long covid, long covid neuropathogenesis, HAND

neuropathogenesis, HAND neurocognitive symptoms and long covid neurological
symptoms

Introduction

Neurocognitive disorders, according to the Diagnostic and Statistical Manual of

Mental Disorders, are a group of syndromes in which a significant clinical
characteristic is an acquired impairment in cognitive performance. This decrease in
mental function is caused by a medical disease other than psychiatric. Deterioration
from an earlier level of cognitive functioning is a feature of neurocognitive illnesses
such as delirium, moderate cognitive impairment, and dementia. The risk factors for
developing neurocognitive disorders are commonly related to age (people over 60
years old), cardiovascular disorders, diabetes, substance and alcohol abuse, and head
trauma. These illnesses are characterized by a wide range of clinical traits and
etiologies, with common causes including Alzheimer's disease, cerebrovascular
disease, Lewy body disease, frontotemporal degeneration, traumatic brain injury,
infections, and alcohol addiction. Viruses like HIV, Covid-19, Cytomegalovirus, Herpes
Simplex, Picornavirus and West Nile have, also, been associated with neurological
disorders. More recently HIV and Covid-19 infection are of more attention for the high
percentage of infected patients worldwide; from which some patients have developed
neurocognitive symptoms.

The HIV-associated neurocognitive disorder (HAND) is described as the spectrum of

neurocognitive dysfunction in patients with late stage of HIV infection. The most
common cognitive dysfunction reported in patients is the decreased speed of
information processing followed by other cognitive impairments such as attention and
memory deficits. The progression of HAND can range from asymptomatic
neurocognitive impairment (ANI) to minor neurocognitive disorder (MND) to the more
severe HIV-associated dementia (HAD). Highly active antiretroviral therapy (HAART)
has decreased the frequency of HAD, but HAND is still common: more than 50% of
HIV-infected persons receiving HAART demonstrate milder HAND syndromes (Heaton
et al., 2010). During the last 20 years, it is still estimated that HAND occurs in 30% to
60% of the patients infected with the virus. The virus is established in the central
nervous system (CNS) in the early stages and its persistence within the CNS can help
us to understand HIV-related brain injury even when highly active antiretroviral
therapy is effective (Sanmarti et al., 2014).

On the other hand , COVID-19 is caused mainly by severe acute respiratory

syndrome coronavirus 2 (SARS-CoV-2) and is characterized as a respiratory disease.
However, Long COVID-19 may be defined as patients who, four weeks after the
diagnosis of SARS-Cov-2 infection, continue to have signs and symptoms not
explainable by other causes (Sisó-Almirall et al.,2021). It is an infection that impacts
multiple systems including the CNS. For instance, at three-month post-discharge,
brain structural and metabolic abnormalities were reported among COVID-19
survivors, which correlated with persistent neurological symptoms such as memory
loss, anosmia, and fatigue (Yong, 2021). Recent studies have suggested loss of gray
matter in multiple regions being more prominent in the left hemisphere of the brain in
areas with high connectivity with the olfactory system. In patients with Long COVID,
cognitive problems have been commonly reported and affect approximately 70% of
cases. Studies of patients who have died of COVID-19 show evidence of ischemic
lesions and indications of neuroinflammation (Matschke et al., 2020).

In this project we aim to describe the mechanism that causes neurocognitive

disorders in patients with HAND and to retrospectively analyze data to find possible
similarities with neurocognitive deficits found in patients with Long COVID infections.
As we evaluate the data, our purpose is to improve our understanding of the viral
mechanism and pathophysiology of both HAND and Long COVID to possibly find
similarities in the disease process that can create new research avenues for treatment
and prevention of these neurocognitive deficits.

Objective

The objective of this research is to establish with the literature the similarities and
differences in which both pathologies affect the brain causing neurocognitive
symptoms.

Methodology

A systematic search was conducted without restrictions. Articles were selected

based on patients only presenting the pathologies without comorbidities. The data
was selected from a period that includes articles from 2015 till 2022. Twelve articles
were selected from a total of twenty-two; clinical manifestation, neuropathogenesis,
disease stages were used as inclusion criteria. Articles that presented HAND and
Long Covid in relation with other diseases were eliminated and the articles that were
not related to this Hand and Long Covid were excluded. The following databases
were used for the search: PubMed, ScienceDirect, Researchgate, NCBI and Semantic
scholar.

Key words: HAND, long covid, long covid neuropathogenesis, HAND

neuropathogenesis, HAND neurocognitive symptoms and long covid neurological
symptoms

Discussion

Neurocognitive symptoms have presented in patients with both infections and affect
the CNS and PNS. Literature shows that HAND has symptoms more closely related to
Dementia and affects the CNS primarily with a slower progression from early to late
stages. HAND develops during the advanced stage of HIV infection, even when
patients start presenting symptoms in the early stage of the infection. Currently, up to
30-50% of people living with HIV may suffer from HAND, the mild form. The etiology
of HAND is currently being studied by researchers, but may in part be caused by
residual injury from unsuppressed HIV viral replication in the brain in the time prior to
starting ART. Risk factors for developing HAND include lack of viral suppression, low
nadir CD4 count, and increasing age. (Vastag et al., 2022) HAND can present in three
categories: Asymptomatic neurocognitive impermeant (ANI), Mild neurocognitive
disorder (MND) and HIV associated dementia (HAD); this would depend on the
amount of cognitive deterioration the patient is presenting. These three categories
are made according to the Frascati criteria. Asymptomatic Neurocognitive Impairment
(ANI) a mild form of HAND, where people report independence in the performance of
everyday functions. The criteria for ANI, the patient must have a score ≤ 1 standard
deviation (SD) in at least two of five cognitive domains, where daily life is not
interfered. (Vally Z, 2017). Mild Neurocognitive Disorder (MND), the most common form
of HAND with a score of at least 1 SD, slightly interferes with the patient's day-to-day
functions.HIV-associated dementia (HAD), it is the most severe form.For the diagnosis,
a score of 2 SD below the normative data is required, in at least two cognitive areas,
daily activities are completely affected.(Vastag Z, 2022). This incapacitates the
person, preventing them from performing daily tasks independently. HAND has high
prevalence, specifically in its mildest form (ANI). Therefore, its early diagnosis of
HAND is important, and to reduce its progression from ANI and MND to HAD. (Vastag
Z, 2022­) During the course of primary infection, HIV enters the brain parenchyma via
infected lymphocytes and monocytes. This is the reason why inflammatory CSF
changes are already present in the asymptomatic stages of the infection in almost all
individuals. The basal ganglia and the frontal white matter are the most early and
intensely affected. (Eggers et al.,2017)

HIV enters the brain as a cell free virion by the mannose 6 phosphate receptor or
encased within infected monocytes or macrophages.(Figure 2). Once in the CNS it
targets microglia and astrocytes, causing the release of numerous inflammatory
markers and HIV viral proteins. This can also disrupt the glutamate homeostasis
causing toxicity and in a chronic secretion of these factors exacerbation of replication
and pathogenic immune signaling leads to neuronal injury.

According to this mechanism), HIV-infected patients begin to present cognitive

deficits. At this stage, the neurological symptoms of HAND begin to appear, among
the most common are problems with psychomotor skills, speed of information
processing, executive functions, memory, language and sensory perception. (Vally Z,
2017). The neurological symptoms in HAND will affect both the Central Nervous
System (CNS) and the Peripheral Nervous System (PNS). (Table 1) The neurological
symptoms associated with the CNS are cognitive deficit, irritability, depression, loss of
motivation, difficulty in attention and concentration, memory problems; and also
language problems where fluency is altered. On the other hand, SNP-associated
neurological symptoms are slow movements (bradykinesia), sensory and perceptual
problems, gait disturbance (loss of balance, stumbling), hyperreflexia, myelopathy and
neuropathy. (Vastag et al., 2022)

Long Covid can be developed within three months after the initial infection with PNS
symptomatology that quickly progresses to CNS symptoms including parkinsonism.
Long Covid can present in five categories: TYPE 1, 2, 3A and 3B, 4A and 4B and 5; this
would depend on the onset and duration of symptoms.(Batiha et al.,2022). The type 1
symptoms are related to the severity and complications of the SARS-CoV-2 infection.
In type 2, persistent symptoms for 6 weeks from the start of SARS-CoV-2 infection. In
type 3A the symptoms persist for 3 months, while in type 3B persist for 6 months. On
the other hand, type 4A becomes symptomatic within 1 to 3 months, while type 4B
after 3 months. Finally, type 5 patients are initially asymptomatic at time of diagnosis
and die within 12 months. (Batiha et al.,2022).
COVID-19 infected leukocyte enters within the CNS by hematogenous or direct
transsynaptic pathways using angiotensin converting enzyme 2 (ACE2) receptor.
(Figure 2). Then it induces cytokine storm causing a disruption of the tight junctions in
the endothelial lining of the blood–brain barrier, increasing its permeability allowing
transmigration of more virus-infected leukocytes into the CNS. The cytokine release
precipitates platelet activation and adhesion, which causes further endothelial
impairment and once cytokines and leukocytes crossed they activate microglias to
trigger apoptosis and demyelination of neurons.
 Long-COVID is a disease that develops regardless of the initial severity of the
disease. It has a clinical spectrum that includes a wide range of symptoms that, like
HAND, occur in both the CNS and PNS. (Guo et al., 2022)(Table 1)As part of the
sequelae due to SARS-CoV-2 exposure, the CNS is affected and presents
neurological and psychiatric symptoms. Neurological symptoms occur one year after
post Covid-19 and among the most important are memory and attention deficits,
inability to perform daily tasks, headaches and chronic fatigue. The peripheral
nervous system (PNS) is affected by Long-Covid infection and shows symptoms for
weeks or even months post-infection. The symptoms that occur in patients are
sensorimotor deficit (hypoesthesia, dysesthesia, tremor), muscle weakness, myalgias,
hyposmia, hypogeusia and hearing loss/tinnitus. (Stefanou ML, 2021)

Between both pathophysiology, we see a similar route of infection, the cytokine

activation of the microglia that in turn triggers neuronal apoptosis and demyelination.
However, HIV affects the brain more than COVID-19 since it has more routes to infect
the brain and can progress since the virus is always present, as in the case of
COVID-19 that affects it during the period present and later we see the
symptomatology. Both pathologies' main mechanism of injury is the chronic
inflammatory process developed in the brain. (Eggers et al.,2017) (Batiha et al.,2022)
(Omeragic, A, 2020)

Conclusion

HAND has three stages and presents neurocognitive symptoms in the later stages
of the disease, affecting mainly the CNS and presenting a more severe
neurocognitive presentation while Long Covid usually resolve on its own and present
neurocognitive symptoms in the early and late stages, but the severity depends on
the length of infection and the intensity of the clinical manifestations. Despite sharing
a similar mechanism of neuropathogenesis in the brain, HIV showed a more effective
route of infecting the brain. Based on the analysis, we found a strong correlation
between the mechanisms of activation and the amount of stimulus, on the CNS and
PNS, with the intensity of the clinical manifestations. Given the inherent differences in
both pathologies and the infancy of Long Covid research, we determined further
studies are required to determine a stronger link and possible treatment alternatives.
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