Introduction
Recent epidemiological studies, such as the Gutenberg Long-COVID study in Germany
(https://www.unimedizin-mainz.de/gcs/),
show the immense consequences that long-COVID could have for our health system.
According to this, up to 40% of those affected stated that they still had
residual symptoms of COVID-19 six months after the infection. Every third person
with a SARS-CoV-2 infection complained that after six months they were not as
productive as before the illness. The list of possible symptoms is very extensive
and ranges from exhaustion, shortness of breath, headaches, sleep disorders, lack of
concentration to cognitive problems, skin rashes, diarrhea, and tinnitus [1]
[2]
[3]. Recently, an S1 guideline on
post/long-COVID was drawn up by various German and Austrian medical
societies [4]. According to the Cochrane
Rehabilitation Review [5], a
post/long-COVID diagnosis can be assumed if one of four criteria is present:
1) Symptoms that persist from the acute COVID-19 phase or its treatment, 2) Symptoms
that have led to a new health restriction, 3) New symptoms that have occurred after
the end of the acute phase but are understood to be a consequence of COVID-19, or 4)
Worsening of a pre-existing underlying condition. Based on an extensive literature
review, a new guideline for the long-term effects of COVID-19 was also drawn up by
the British health authority (National Institute for Health and Care Excellence
(NICE) in December 2021. Here, long-COVID was defined as signs and symptoms that
develop during or after infection with COVID-19 and last longer than 12 weeks and
cannot be explained by any other diagnosis [6].
A study from King’s College London, in which 4000 patients with COVID-19
prospectively documented their symptoms in an app, identified criteria for early
prediction of their risk to develop long-COVID. Across countries and ethnic
backgrounds, obese, older and female patients, and those requiring hospitalization
were most at risk of developing long-COVID [7]. Another study from Norway showed that even patients with a milder form of
COVID-19, who had isolated themselves at home, often developed symptoms of
long-COVID. It showed that 52% of young adults between the ages of 16 and 30
who were self-isolated still had symptoms after 6 months; 28% continued to
have a disturbance of taste and smell, 21% still felt tired and exhausted,
13% had dyspnea, 13% had difficulty concentrating, and 11%
had difficulty remembering [8].
What is the relationship between long-COVID and diabetes?
An infection with SARS-CoV-2 can induce or aggravate clinical diabetes mellitus
type 1 (T1DM) and type 2 (T2DM) [9]
[10]
[11]
[12]. After infection with
SARS-CoV-1, it was shown that metabolic derangement was still detected in fully
recovered patients up to 12 years after the infection [13]. Compared to healthy controls, there
were significant differences in the metabolome in these patients. In particular,
there were significant changes in lipid metabolism [13]. On the other hand, it was striking
that after the SARS-CoV-1 infection, diabetes that had evolved during the acute
illness completely regressed in many patients.
We have set up an international registry CoviDIAB
(https://covidiab.e-dendrite.com) to follow up on patients with
diabetes who have emerged during the current pandemic [14]. This registry will provide evidence if
and to what extent T1DM or T2DM presenting in the framework of acute SARS-CoV-2
infection may regress in the post-infectious observation interval. Intriguingly,
some patients may develop diabetes for the first time in the long-COVID
phase.
Infection and inflammation are potent drivers of diabetes. Moreover, steroid
administration deserves our attention. An 8–10 days course of
dexamethasone is routinely administered to patients with severe COVID-19, and
many patients with long-term damage to the lung parenchyma continue to receive
steroid treatments over a protracted period of time. Therefore, steroid-induced
metabolic deterioration and steroid-induced diabetes in these patients is not
unexpected. This has been also observed in our clinic. After extensive use of
steroids for several weeks to treat COVID-19, the administration is abruptly
stopped, which in some cases have led to acute adrenal insufficiency.
Following COVID-19, many patients exhibit autoimmune disorders resulting in the
prolonged therapeutic use of steroids, enhancing risks of metabolic side
effects. This situation could get even worse in the coming months and years, as
the new drugs that are now approved for the treatment and prevention of a severe
course of COVID-19 might increase the steroid-related metabolic adverse effects.
A notable example is protease inhibitors that prevent serine protease-mediated
proteolysis of spike glycoproteins of the SARS-CoV-2 virus [15]. One drug of this class, Nirmatrelvir
is combined with the long-known generic HIV drug Ritonavir, which is supposed to
increase the therapeutic effect. Similar to steroids, these drugs are
metabolized in the liver by the cytochrome P450 (CYP3A4) enzyme system [16]. When steroids are administered
concurrently to Nirmatrelvir/Ritonavir, this may lead to Cushing-like
changes and, under certain circumstances, to the occurrence of adrenal
insufficiency after discontinuation of the steroids as previously observed in
patients with HIV [17].
Patients with metabolic syndrome receiving other medications that are broken down
via the CYP3A4 enzyme system, for example antihypertensive agents, such as
calcium channel antagonists, or anti-dyslipidemic agents, such as statins,
should expect an increased effect in the acute phase and must be closely
monitored. On the other hand, accumulating evidence suggest that SARS-CoV-2
mediated reprograming of cholesterol metabolism results in the upregulation of
the expression of several lipid synthesis modulators (including
SREBP1/2, CD36, PPARγ or DGAT-1) leading to the production of
cholesterol and lipid droplets. A reduction in cholesterol synthesis through the
blockade of this pathway can decrease both the viral replication and the
inflammatory response induced by SARS-CoV-2 [18]. Also, the enzyme cholesterol 25-hydroxylase that depletes
cholesterol from plasma membrane is upregulated during SARS-CoV-2 infection
which is believed to restrict viral internalization to the cell [19].
Since we were recently able to show that SARS-CoV-2 could be detected in the
adrenals of patients that died due to COVID-19 and that the virus is able to
infect adrenal cells in vitro, it must be assumed that the adrenal glands can be
damaged in the context of COVID-19 [20].
If patients now receive these new antiviral substances in the acute phase
together with repeated doses of steroids, this may lead, after steroid
withdrawal, to a new form of secondary adrenal insufficiency with symptoms
similar to those of long-COVID, such as fatigue, exhaustion, blood pressure
dysregulation, lack of concentration and depression [21].
Do patients with diabetes have a higher risk of long-COVID?
So far, the course of the pandemic has shown very clearly that patients with
obesity, diabetes, and metabolic syndrome belong to the main risk groups for the
development of a severe course including a fatal outcome of COVID-19. A
significant number of people that died from COVID-19 suffered from pre-existing
diabetes with or without obesity and hypertension [12]. Recent data demonstrated that the same
group of patients are at an increased risk of long-COVID symptoms. Studies have
shown, for example, that type 2 diabetics in particular have a high prevalence
of post-COVID fatigue [22]. One scenario
can be attributed to the increased glycolytic activity in inflammatory cells
such as macrophages which exacerbate viral load and increase proinflammatory
cytokine production resulting in more epithelial damage, lung fibrosis and T
helper lymphocyte dampening [23].
Post-COVID fatigue syndrome in patients with pre-existing diabetes is also
associated with reduced muscle strength [24]. The reduced muscle strength may indicate the presence of
sarcopenia, which is, of course, more common in patients with poorly controlled
diabetes. This shows that, especially for patients with diabetes in the
post-COVID phase, appropriate glycemic control and an adequate nutritional
status are of great importance to ensure rapid recovery. In addition to fatigue,
these patients with T2DM and long-COVID also experienced weight loss and
significantly reduced physical activity. On the other hand, there are also
reports of excessive food intake and weight gain in patients with long-COVID
[24]. Yet, an other case control study
of hospitalized patients showed no difference between the occurrence of
long-COVID symptoms and the presence of diabetes. In this study, it was pointed
out that a diabetic metabolic status plays a more important role in the acute
phase of the COVID-19 than in the post-COVID phase. Nevertheless, the authors
emphasize that further longitudinal studies are needed to confirm these
assumptions [25]. Another international
study showed both acute and long-lasting glycemic disorders in patients after
SARS-CoV-2 infection [26].
Long-term metabolic changes must therefore also be assumed in the post-acute
phase of COVID-19 [27]. The relationship
between COVID-19 and diabetes-related metabolic derangement is certainly a
mutually reinforcing vicious circle. On one hand, the inflammation in acute
COVID-19 disease leads to a lasting deterioration in the metabolic situation; on
the other hand, diabetes is a state of chronic inflammation with changes in the
innate and adaptive immune system that enhance and accentuate symptoms of
long-COVID. It is therefore not surprising that poorly controlled diabetes has
been described as a risk factor for post-COVID lung fibrosis [28].
What can we do?
Overall, it can be assumed that poorly controlled diabetes mellitus is not only a
significant risk factor in the acute phase of COVID-19 and vaccination failure,
but also for symptoms and complications in the post-COVID phase. Therefore,
patients in the post-COVID phase must be early monitored and optimally managed,
focusing on appropriate glycemic and lipid profile control [29]. An adequate metabolic adjustment not
only leads to a positive influence on long-term complications, such as pulmonary
fibrosis, but also minimizes the development of tiredness, exhaustion and
fatigue syndromes. Checking and monitoring the metabolic status must therefore
be an integral part of any clinical monitoring of a post-COVID outpatient
clinic.
Since patients with diabetes mellitus often have established cardiometabolic
disorders such as atrial fibrillation, sarcopenia, muscle fatigue and
microvascular endothelial disorders, the deterioration of these complications of
diabetes in the acute and post-acute phase of COVID-19 is to be expected.
Therefore, strict control of diabetes and its comorbidities with structured
rehabilitation, physical activity and an optimal dietary adjustment are crucial
for the management of the post-COVID phase ([Fig. 1]).
Fig. 1 Management of long-COVID.
A healthy diet in the post-COVID phase can also help to alleviate it. Many
experimental studies have shown that an unhealthy, high-fat diet increases
susceptibility to various infectious diseases [30]. For example, experimental animals on a high-fat diet had a
two-fold increase in mortality with increases in lung changes and inflammatory
cytokines in influenza infection compared to animals on a normal diet. The
proportion of fat in the diet can therefore influence the course of viral
diseases. Diets rich in omega-3 fatty acids promote the formation of
anti-inflammatory proteins, which can have a positive effect on lung and organ
damage. Numerous studies have shown that dietary supplementation with the
short-chain fatty acids propionate and butyrate, supplementation with vitamins
and minerals such as zinc, and administration of acetyl-CoA carboxylase
isoforms, such as ACC1 and carnitine palmitoyl transferase 1 inhibitors, reduce
the long-term damage caused by viral-induced inflammation [30]. Thus, long-term consequences caused by
COVID-19 could be positively affected by a targeted change of our own metabolism
through microbiota and dietary strategies. Dietary supplementation with
tryptophan or glutamine supplementation has been suggested for the long-COVID
phase [25]
[31]
[32]
[33]
[34]
[35]. Such approaches need
to be further investigated in larger, controlled studies. Further promising
impacts on treatment, especially for fatigue in post-COVID patients, are based
on a new active ingredient BC 007 from the Berlin start-up company Berlin Cures,
which is currently being tested in clinical studies at the University of
Erlangen. This is an unmodified DNA aptamer, which was initially developed
without reference to long-COVID. This aptamer acts as a binding partner for
autoimmune antibodies directed against G protein-coupled receptors. Since BC 007
also binds antibodies directed against α1-adrenoceptor,
β1-adrenoceptor, β2-adrenoceptor, and endothelin A receptors,
this drug was tested for the therapy of cardiomyopathies. Patients with chronic
fatigue syndrome often have high antibody titers against these receptors, which
could explain symptoms of chronic fatigue up to and including postural
hypertension. Thus, BC 007 is now in phase II clinical trials for fatigue
syndrome. It is not yet known how the metabolism is influenced by this
approach.
Interestingly, many patients with the classic symptoms of long-COVID including
chronic fatigue report an improvement in their condition after the use of
therapeutic apheresis. In Germany, therapeutic apheresis is mainly used in
specialized centers for severe lipid disorders [36]. These are patients with very high LDL and LPa levels that cannot
be treated as effectively with any other therapeutic approach. The mechanism of
action by which an extracorporeal apheresis procedure could have a positive
impact on the course of long-COVID syndrome has not yet been fully elucidated.
It is clear that after therapeutic apheresis, metabolic parameters, in
particular the lipid values, can be significantly improved and reduced by up to
80%. In addition, an anti-inflammatory effect is achieved by a
significant reduction in C-reactive proteins and other pro-inflammatory peptides
and cytokines [37]
[38]. Finally, extracorporeal apheresis
achieves a significant reduction in immunoglobulins and autoantibodies. Another
effect could be an improvement in blood circulation and the function of the red
blood cells, whereby the oxygen content of the blood carriers is also optimized
in the brain, with an improvement on “brain fog”, a classic
symptom reported by patients with post-COVID. The effects of therapeutic
apheresis on the autoimmune process, anti-inflammatory and rheological changes
in post-COVID patients are currently being investigated in various clinical
studies.
