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Inosine Pranobex Significantly Decreased the Case-Fatality Rate among PCR Positive Elderly with SARS-CoV-2 at Three Nursing Homes in the Czech Republic

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During the COVID-19 pandemic, the elderly population has been disproportionately affected, especially those in nursing homes (NH). Inosine pranobex (IP) has been previously demonstrated to be effective in treating acute viral respiratory infections. In three NH experiencing the SARS-CoV-2 virus epidemic, we started treatment with IP as soon as clients tested PCR+. In Litovel, CZ, the difference in case-fatality rate (CFR) for the PCR+ group using vs. not using IP was statistically significant, and the odds ratio (OR) was 7.2. When comparing all those taking IP in the three NH vs. the non-drug PCR+ group in Litovel, the odds ratio was lower for all three NH, but still significant at 2.9. The CFR in all three tested NHs, age range 75–84, compared to the CFR in all NHs in the Czech Republic, was significantly reduced (7.5% vs. 18%) (OR: 2.8); there was also a significant difference across all age groups (OR: 1.7). In our study with 301 residents, the CFR was significantly reduced (OR: 2.8) to 11.9% (17/142) in comparison to a study in Ireland with 27.6% (211/764). We think the effect of IP was significant in this reduction; nevertheless, these are preliminary results that need larger-scale trials on COVID-19 patients.
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pathogens
Communication
Inosine Pranobex Significantly Decreased
the Case-Fatality Rate among PCR Positive Elderly
with SARS-CoV-2 at Three Nursing Homes
in the Czech Republic
JiˇríBeran 1,* , Marian Špajdel 2, Vˇera Katzerová3, Alena Holoušová4, Jan Malyš 4,
Jana Finger Rousková5,6 and JiˇríSlíva 6
1Department for Tropical, Travel Medicine and Immunization, Institute of Postgraduate Health Education,
100 05 Prague, Czech Republic
2Department of Psychology, Faculty of Philosophy and Arts, Trnava University, 918 43 Trnava, Slovakia;
marian.spajdel@truni.sk
3Domov D˚uchodc ˚u Litovel, 784 01 Litovel, Czech Republic; katzerova@volny.cz
4Sanatorium Topas, 534 01 Holice, Czech Republic; alena.holousova@sanatorium-topas.cz (A.H.);
jan.malys@sanatorium-topas.cz (J.M.)
5Senior d˚um Beránek Úpice, 542 32 Úpice, Czech Republic; rouskova.jana@email.cz
6
Department of Pharmacology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic;
slivaj@seznam.cz
*Correspondence: jiri.beran@vakcinace.cz; Tel.: +420-603-113-867 or +420-495-541-584
Received: 12 November 2020; Accepted: 14 December 2020; Published: 16 December 2020


Abstract:
During the COVID-19 pandemic, the elderly population has been disproportionately aected,
especially those in nursing homes (NH). Inosine pranobex (IP) has been previously demonstrated to
be eective in treating acute viral respiratory infections. In three NH experiencing the SARS-CoV-2
virus epidemic, we started treatment with IP as soon as clients tested PCR+. In Litovel, CZ, the
dierence in case-fatality rate (CFR) for the PCR+group using vs. not using IP was statistically
significant, and the odds ratio (OR) was 7.2. When comparing all those taking IP in the three NH vs.
the non-drug PCR+group in Litovel, the odds ratio was lower for all three NH, but still significant at
2.9. The CFR in all three tested NHs, age range 75–84, compared to the CFR in all NHs in the Czech
Republic, was significantly reduced (7.5% vs. 18%) (OR: 2.8); there was also a significant dierence
across all age groups (OR: 1.7). In our study with 301 residents, the CFR was significantly reduced
(OR: 2.8) to 11.9% (17/142) in comparison to a study in Ireland with 27.6% (211/764). We think the
eect of IP was significant in this reduction; nevertheless, these are preliminary results that need
larger-scale trials on COVID-19 patients.
Keywords:
inosine pranobex; natural killer cells; acute respiratory viral infection; treatment;
COVID-19; nursing homes; case-fatality rate
1. Introduction
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first
detected in Wuhan in December 2019 and has since spread around the globe. Real-time PCR assays
are recommended for diagnosing the SARS-CoV-2 infection [
1
]. Clinical presentations include mild,
moderate, or severe cases, which are easily counted. However, asymptomatic infections are hidden
from statistics.
Viral dynamics, cellular immunity, and the antibody response in infected but asymptomatic
patients are still not fully understood [
2
,
3
]. The initial infectious dose significantly influences the length
Pathogens 2020,9, 1055; doi:10.3390/pathogens9121055 www.mdpi.com/journal/pathogens
Pathogens 2020,9, 1055 2 of 10
of the incubation period and the clinical presentation; as a result, we can see in any given population
coronavirus disease (COVID-19) cases ranging from mild to severe. Very low infectious doses can be a
reason for asymptomatic infections, but it is very dicult to demonstrate this at the population-level
with serological tests [2,3].
Any successful control of a viral infection involves the complex interplay between diverse cell
types associated with both innate and adaptive immunity. Natural killer (NK) cells are a type of innate
lymphoid cell that plays an important role in the first line of immune defense against any viral infection,
including COVID-19. They constitute the primary rapid, innate immune attack on virus-infected
cells [4] (Figure 1).
Pathogens 2020, 9, x FOR PEER REVIEW 2 of 10
Viral dynamics, cellular immunity, and the antibody response in infected but asymptomatic
patients are still not fully understood [2,3]. The initial infectious dose significantly influences the
length of the incubation period and the clinical presentation; as a result, we can see in any given
population coronavirus disease (COVID-19) cases ranging from mild to severe. Very low infectious
doses can be a reason for asymptomatic infections, but it is very difficult to demonstrate this at the
population-level with serological tests [2,3].
Any successful control of a viral infection involves the complex interplay between diverse cell
types associated with both innate and adaptive immunity. Natural killer (NK) cells are a type of
innate lymphoid cell that plays an important role in the first line of immune defense against any viral
infection, including COVID-19. They constitute the primary rapid, innate immune attack on virus-
infected cells [4] (Figure 1).
Figure 1. Three levels of antiviral immunity and the influence of specific COVID-19 treatment options.
Legend: red dotvirus SARS-CoV-2; IPinosine pranobex; NK cellsnatural killer cells; CTL
cytotoxic T-lymphocyte (CD8+); APCantigen presenting cell; Naïve Thnaïve helper T lymphocyte
(CD4+ cell); Th1type of helper cells that lead to an increased cell-mediated immunity; Th2type of
helper cells that lead to a humoral immune (antibody) response; T-Cella type of lymphocyte, which
differentiate into helper, regulatory, or cytotoxic T cells or become memory T cells; B-CellB cells are
involved in humoral immunity and differentiate into a plasma cell; plasma cellshort-lived antibody-
producing cell derived from B-Cell; IgA, IgM, IgGantibody classes of immunoglobulins; MF
macrophages, specialized cells involved in the detection, phagocytosis and destruction of SARS-CoV-
2 virus; convalescent plasmahigh titers of neutralizing antibodies against SARS-CoV-2 to
experimentally treat several critical COVID-19 patients; tocilizumaba humanized monoclonal
antibody against the interleukin-6 receptor (IL6); favipiraviran antiviral medication used to treat
influenza and experimentally also COVID-19; hydroxycholochin (hydroxychloroquine)suggested
Figure 1.
Three levels of antiviral immunity and the influence of specific COVID-19 treatment
options. Legend: red dot—virus SARS-CoV-2; IP—inosine pranobex; NK cells—natural killer
cells; CTL—cytotoxic T-lymphocyte (CD8+); APC—antigen presenting cell; Naïve Th—naïve helper
T lymphocyte (CD4+cell); Th1—type of helper cells that lead to an increased cell-mediated
immunity; Th2—type of helper cells that lead to a humoral immune (antibody) response; T-Cell—a
type of lymphocyte, which dierentiate into helper, regulatory, or cytotoxic T cells or become
memory T cells; B-Cell—B cells are involved in humoral immunity and dierentiate into a
plasma cell; plasma cell—short-lived antibody-producing cell derived from B-Cell; IgA, IgM,
IgG—antibody classes of immunoglobulins; MF—macrophages, specialized cells involved in the
detection, phagocytosis and destruction of SARS-CoV-2 virus; convalescent plasma—high titers
of neutralizing antibodies against SARS-CoV-2 to experimentally treat several critical COVID-19
patients; tocilizumab—a humanized monoclonal antibody against the interleukin-6 receptor (IL6);
favipiravir—an antiviral medication used to treat influenza and experimentally also COVID-19;
hydroxycholochin (hydroxychloroquine)—suggested early in the pandemic as prevention or treatment
method for COVID-19; remdesivir—a nucleotide analog prodrug indicated for treatment of COVID-19
disease in hospitalized patients.
Pathogens 2020,9, 1055 3 of 10
NK cells kill infected cells rapidly and directly, without antigen presentation or recognition. In
response to stimuli from diverse sources including infections, cytokines, stress, or other immune cells,
NK cells exert the following distinct actions: (1) secretion of perforin and granzyme to directly kill target
cells, (2) release of cytokines to regulate the immune response, and (3) coupling with death-inducing
receptors on target cells, which induce apoptosis [57].
Adaptive immunity is the second line of antiviral defense and is based on antigen presentation.
The virus is processed by antigen presentation cells (APC), and the most important antigens are
displayed on the APC surface together with molecules of the major histocompatibility complex
(MHC) [8].
In the immune system, there is an equilibrium between Th1 (T-helper 1) and Th2 (T-helper 2) cell
activity. When Th1 activity is increased, as part of cellular immunity, Th1 cytokines are produced that
suppress Th2 activity and vice versa. Immune system activity is similar to the pendulum of a clock
that swings from one side (Th1 stimulated by thymus-dependent intracellular antigen) to the other
(Th2—thymus dependent extracellular antigen) depending on the stimulus and type of antigen. You
cannot have both actions at the same time.
When a virus replicates inside a target cell, it is considered by the immune system as
a thymus-dependent intracellular antigen, and thus, adaptive immunity via Th1 and cytotoxic
T-lymphocytes (CTL) is employed as the second line of the body’s anti-viral immunity. Additionally,
cytokines IL-2, TNF-
α
, and INF-
γ
, which activate macrophages, T-cells, and dendritic cells, are released.
In terms of cytotoxic activity, CTLs have a role very similar to NK cells [8,9].
When these two lines of immunity are overwhelmed, the virus is released into the blood, which
leads to viremia. The virus is now mostly extracellular and thymus-dependent extracellular antigen
and Th2, in co-operation with T follicular helper cells (Tfh), begin to stimulate antibody production.
Antibodies then bind to extracellular antigens on the virus particles and mark them for destruction
by macrophages.
The elderly population has been particularly and severely aected by SARS-CoV-2 [
10
,
11
], which may be potentially explained by immunosenescence, malnutrition, comorbidities,
polypharmacotherapy, and inflammatory conditions in these patients [
12
,
13
]. As a result, SARS-CoV-2
has disproportionately aected the residents of nursing homes (NH). For instance, in Ireland, they
performed a survey of NHs. Surveys were returned from 62.2% (28/45) of the surveyed NHs (2043
residents, 2303 beds), and three-quarters (21/28) reported COVID-19 outbreaks (1741 residents, 1972
beds). The incidence among residents was 43.9% (764/1741): 40.8% (710/1741) laboratory-confirmed,
with 27.2% (193/710) asymptomatic, and 3.1% (54/1741) as clinically suspected cases. Case-fatalities
among residents were 27.6% (211/764). This study demonstrates the significant impact of COVID-19 on
the NH sector. Systematic point-prevalence testing was suggested to reduce the risk of transmission
from asymptomatic carriers and help manage outbreaks in NH settings [10].
Inosine pranobex (IP), also known as inosine acedoben dimepranol, inosine pranobex, and
methisoprinol, is a synthetic compound with immunomodulatory and antiviral properties. The drug
was initially authorized in 1971, and it is currently marketed in more than 70 countries for treating viral
diseases, including subacute sclerosing panencephalitis, acute viral respiratory infections, measles,
herpes simplex infections, varicella, human papillomavirus, cytomegalovirus, and Epstein–Barr
virus [14].
Clinical and immunological studies conducted over the past five years have confirmed the eect
of inosine pranobex (IP), via natural killer (NK) cells and cytotoxicity, for treating the majority of
investigated viral infections; this eciency will hopefully be transferrable to the currently spreading
acute viral respiratory infection COVID-19 [4].
Studies on IP have demonstrated that its immunomodulatory activity is characterized by enhancing
lymphocyte proliferation, cytokine production, and NK cell cytotoxicity [
14
,
15
]. The eects of IP at the
cellular level have been investigated in detail [
15
], and it was found that NK cells exposed to IP had
increased expression of multiple NKG2D ligands, leading to increased NKG2D-dependent target cell
Pathogens 2020,9, 1055 4 of 10
immunogenicity. In a recent study [
16
], IP administration was shown to elicit early and consistent
increases in NK cell levels within 1.5 h of receiving IP and with two-fold or higher level by the fifth day.
IP-induced NK populations contained granzyme A and perforin [16,17].
IP is a potent medication for treating or preventing viral infections under various conditions,
including patients who are elderly but otherwise healthy. This is particularly important since, in these
populations, NK performance is known to be compromised, and insucient performance may be a
key contributor to high rates of viral infections associated with immunosenescence [1820].
The aim of this prospective trial was to critically assess the possible benefits of IP in the prevention
and treatment of COVID-19 in nursing home settings.
2. Results
2.1. Patients Characteristics
Starting in June 2020, the COVID-19 epidemic began devastating the nursing home in Litovel,
CZ. Out of a total of 56 residents, 33 tested positive. Of these, 19 began to show clinical signs and
were started on inosine pranobex, at a dose of two tablets three times a day for 7 days. Patients with
uricemia or on dialysis took a dose of one tablet three times a day for 1 day only. Of the patients
taking inosine pranobex, five patients were hospitalized for pneumonia in the department of infectious
diseases. All but one patient received two treatments with anti-COVID plasma; no antiviral treatments
were administered while the patients were in the infectious disease department. They continued with
symptomatic treatment and started, when necessary, antibiotic treatment, mineral supplementation,
rehydration, and oxygenation.
The COVID-19 epidemic also hit a second NH in Sanatorium Topas Holice, CZ, during the second
week of September. At that time, the home had a capacity of 174 people. A total of 86 tested positive for
SARS-CoV-2 and began taking inosine pranobex at a dose of two tablets, three times a day for 7 days.
COVID negative residents (88) used inosine pranobex preventively two tablets once a day for 10 days.
The epidemic appeared in a third NH, in Ber
á
nek
Ú
pice, CZ, at the beginning of September. The
capacity of the home was 71 people, and 37 tested PCR+on four separate test dates spread over a 20
day period. These residents started taking inosine pranobex at a dose of two tablets, three times a day
for 7 days. Nothing was given to clients with a negative PCR test.
In Litovel, inosine pranobex was administered to PCR+residents only after they began to show
symptoms of COVID-19. In the other two nursing homes, they started giving inosine pranobex to all
clients immediately after testing positive (PCR); as such, there was no control group. Table 1shows the
data clearly.
Table 1.
Use of inosine pranobex in three nursing homes—Litovel, Sanatorium Topas Holice, and
Beránek Úpice.
Nursing
Homes Capacity PCR+
PCR+with
Inosine
Pranobex
PCR+with
Inosine
Pranobex
(Patient Died)
PCR+
without
Inosine
Pranobex
PCR+
without
Inosine
Pranobex,
(Patient Died)
PCR
without
Inosine
Pranobex
Litovel 56 33 19 1 14 4 23
Sanatorium
Topas Holice 174 86 86 11 0 0 88 *
Ber
á
nek
Ú
pice
71 37 37 5 0 0 34
Total 301 156 142 17 14 4 145
* All negative clients took inosine pranobex at a dose of 2 tablets once a day for 10 days when the epidemic first
occurred in the nursing home (none became positive).
Pathogens 2020,9, 1055 5 of 10
2.2. Recorded Case-Fatality Rate
In Litovel, none of the hospitalized patients died but one PCR+NH resident receiving inosine
pranobex died. It is noteworthy that he was not treated with inosine pranobex until 6 days after testing
positive. The patient was an otherwise healthy 95-year-old man who was PCR+for SARS-CoV-2, with
no symptoms of COVID-19 from the date of his PCR test until the sixth day. He then experienced
acute onset of weakness and developed diculty breathing (SpO
2
92%); treatment with 3 g of IP was
initiated; death came suddenly 5 days later.
In the other Litovel group, of the 14 positive patients not taking inosine pranobex, four patients
died. The dierence in the number of deaths was statistically significant, and the odds ratio (OR) was 7.2
(95% CI: 0.71–73.54; p=0.0324). This indicates that a PCR+nursing home client taking inosine pranobex
is seven times less likely die than one not taking IP. The dierence in the case-fatality rate (CFR) of
PCR+residents between the group using and not using inosine pranobex was statistically significant.
The patients who died were very old (73, 90, 92, and 93 years). They did not develop typical
respiratory symptoms of COVID-19. Instead, they typically experienced sudden onset weakness, low
oxygen saturation (SpO
2
), or suspected micro-embolization. Importantly, all were polymorbid and
none were treated with IP. Patient deaths were attributed to gastrointestinal problems (i.e., icterus,
ileus, and gastroenteritis with severe electrolyte imbalances).
In the Sanatorium Topas Holice NH, a total of 11 PCR+residents treated with inosine pranobex
died. Among these taking inosine pranobex prophylactically, there were no new PCR+diagnoses
among the residents.
In the Ber
á
nek
Ú
pice NH, a total of five (age 88–95) PCR+residents died while on inosine pranobex.
These results are shown in Figures 2and 3. Inosine pranobex had a significant eect on the course
of the disease in institutionalized patients older than 65 years of age. When comparing the CFR of
all those taking inosine pranobex in the three nursing homes with the non-IP PCR+group in Litovel,
the dierence was still statistically significant. The odds ratio (2.9) was lower for all three nursing
homes but still significant (95% CI: 0.8–10.3), i.e., the chances of survival were still three times higher
for residents taking inosine pranobex. The decrease in survival odds was also potentially due to the
heterogeneity of the residents in the three nursing homes. Two of the homes were Alzheimer’s centers
(Sanatorium Topas Holice and Ber
á
nek
Ú
pice), and the third (Litovel) was a very large, specialized
facility (174 residents), which had a building layout that facilitated the spread of COVID because it was
all but impossible to totally isolate positive residents from the rest of the nursing home’s population.
This was why IP was used prophylactically with the PCR negative residents in this NH.
The age cohort of 75–84 year-olds was significantly influenced in all three nursing homes, where
the reduced CFR compared to the CFR in other nursing homes in the Czech Republic was statistically
significant—there was a reduction in CFR from 18% to 7.5% in the specified age group within the
selected homes. The odds ratio was 2.8 (95% CI: 0.8–9.6; p=0.047). Nevertheless, there was also a
significant dierence across all age groups—OR: 1.7 (95% CI: 0.96–2.98; p=0.031).
Pathogens 2020,9, 1055 6 of 10
Pathogens 2020, 9, x FOR PEER REVIEW 6 of 10
Figure 2. Comparison of the case-fatality rate (CFR) for COVID-19 of residents at three nursing homes
(Litovel, Holice, and Úpice) that used IP, with the CFR for COVID-19 of the residents of the Litovel
nursing home, some of whom used IP and some of whom did not use IP.
Figure 3. Comparisons of the CFR for COVID-19 of the residents of three selected nursing homes
(Litovel, Holice, and Úpice) in the CZ (142 clients PCR+/17 died) that used IP, to the CFR for COVID-
19 patients from all nursing homes (NH) in the CZ (415/78) until 8/8/2020, and to the CFR of 21 NH
in Ireland (211/764).
Figure 2.
Comparison of the case-fatality rate (CFR) for COVID-19 of residents at three nursing homes
(Litovel, Holice, and
Ú
pice) that used IP, with the CFR for COVID-19 of the residents of the Litovel
nursing home, some of whom used IP and some of whom did not use IP.
Pathogens 2020, 9, x FOR PEER REVIEW 6 of 10
Figure 2. Comparison of the case-fatality rate (CFR) for COVID-19 of residents at three nursing homes
(Litovel, Holice, and Úpice) that used IP, with the CFR for COVID-19 of the residents of the Litovel
nursing home, some of whom used IP and some of whom did not use IP.
Figure 3. Comparisons of the CFR for COVID-19 of the residents of three selected nursing homes
(Litovel, Holice, and Úpice) in the CZ (142 clients PCR+/17 died) that used IP, to the CFR for COVID-
19 patients from all nursing homes (NH) in the CZ (415/78) until 8/8/2020, and to the CFR of 21 NH
in Ireland (211/764).
Figure 3.
Comparisons of the CFR for COVID-19 of the residents of three selected nursing homes
(Litovel, Holice, and
Ú
pice) in the CZ (142 clients PCR+/17 died) that used IP, to the CFR for COVID-19
patients from all nursing homes (NH) in the CZ (415/78) until 8/8/2020, and to the CFR of 21 NH in
Ireland (211/764).
Pathogens 2020,9, 1055 7 of 10
3. Discussion
Acute respiratory infections are globally the most common type of viral infections. Severe forms
are responsible for approximately 3.9 million deaths per year and are one of the leading causes of
morbidity and mortality worldwide [
21
]. This number is likely to increase considerably with the
current spread of COVID-19.
In view of the current COVID-19 pandemic, it is important to consider the results of studies
using clinical subjects with laboratory-confirmed acute viral respiratory infections, which have been
conducted to compare the ecacy and safety of specific treatments, in this case, IP, compared to
placebos [
22
]. In this study, the primary ecacy endpoint was considered the “time to resolution of
all influenza-like disease-associated symptoms.” IP 500 mg tablets or placebo were self-administered
orally for 7 days (i.e., two tablets, three times per day). The first dose was taken immediately after
case randomization at the clinic, and the remaining doses were self-administered at the nursing home.
The medication was taken at intervals of approximately 8 h but was adjusted to fit the patient’s
lifestyle so as not to interfere with normal sleeping patterns. Each patient received a kit containing
either IP or placebos sucient for 7 days of treatment [
22
]. In subjects less than 50 years of age and
without any associated on-going disease, statistically significant dierences in “time to resolution of all
influenza-like disease-associated symptoms” were observed between treatment groups, and patients
treated with IP showed faster improvement than those treated with placebo [22].
A dierent study investigated the breadth and kinetics of the immune response during a non-severe
case of COVID-19 [
23
]. The study provided valuable insights in that it paralleled the immunological
results and clinical conditions of the diseased in a previously healthy 45 year-old female patient from
Wuhan, China, who traveled to Melbourne, Australia. The patient did not experience respiratory
failure or acute respiratory distress syndrome; she did not require supplemental oxygenation and was
discharged after one week of hospitalization, which indicates she had a non-severe but symptomatic
course of the disease. Clinical findings in the lungs were observed on day five of hospitalization;
however, these resolved after 10 days. It is important to consider the time sequence of the body’s
immune response: first, the activity of minimally active NK cells is enhanced; however, when their
activity decreases, cytotoxic T lymphocytes (containing granzymes A and B and perforin) begin to
increase; the levels of helper T lymphocytes are maintained during this process, which is then followed
by an increase in antibody-secreting cells (ASCs) together with T follicular helper (Tfh) cells. This leads
to an increase in the production of antibodies, with maximum levels of IgG and IgM occurring on day
20. When lymphocyte cytotoxic activity is induced, the course of COVID-19 is often mild, and clinical
findings in the lungs disappear within a few days even without treatment. In such cases, it is probably
not necessary to stimulate the immune responses with IP [
23
]. Nevertheless, in elderly patients or
in those who are suering from pre-existing chronic diseases, IP treatments have the potential to
substantially increase the levels of NK cells, accelerate the resolution of symptoms, and can prevent a
potential decline into primary viral pneumonia.
The results of previous studies indicate that IP can boost the levels of phenotypically competent
NK cells in healthy individuals during conditions associated with acute viral respiratory infections,
which indicates that it can be used to improve potentially compromised immune functions [16,22].
In Ireland, in a large study involving 28 nursing homes (2043 residents, 2303 beds) during the
COVID-19 outbreak, 21 institutions were aected (1741 residents, 1972 beds) with 43.9% of the residents
infected with COVID-19. The resident case-fatality was 27.6% (211/764) [
10
]. Recently, data with
detailed demographics from five care homes in Northern Ireland were published [
24
]. In total, 388
individuals were tested (245 residents/87 positive, and 143 staff/10 positive). Most of the tested residents
were women (72%). Those testing positive had a mean age of 86.4 years (SD, 8.05) and CFR was 31%.
With regard to other international comparisons on NH COVID-19 infection rates and case-fatalities,
results are consistent with a report on eighty-nine residents in a US facility [
25
], with an infection rate
of 64% and a CFR of 26%, and a series from 394 residents in four UK NHs with an infection rate of 40%,
and a CFR of 26% [26].
Pathogens 2020,9, 1055 8 of 10
Our study consisted of three nursing homes with 301 residents, 156 of whom (51.8%) tested
positive for the SARS-CoV-2 virus (PCR test). This was a higher rate than in the nursing homes in
Ireland, but resident case-fatality was much lower (11.9% (17/142)), which can probably be attributed
to inosine pranobex. The average age of residents who tested PCR positive at the three NHs (Litovel,
Holice,
Ú
pice) was 82.7, 84.9, and 85.5 years with median age 83.5, 86.9, and 86.0 years, respectively.
Most of them were women (68.4%, 72.1%, 89.2%, and for all three NHs 76.1%). These demographic
data are very similar to other publications [24].
In our study, we demonstrated the positive eects of IP on nursing home residents, which is
clearly the population at the highest risk for a severe course of COVID-19. The CFR in all three nursing
homes, as of the end of the first epidemic wave, in those over 65 years of age, was lower than in the
residents of similar nursing homes elsewhere in the Czech Republic, and this dierence was statistically
significant OR: 1.7 (95% CI: 0.96–2.98; p=0.031). The CFR was also lower than in the residents of
similar types of nursing homes in Ireland (OR: 2.8 (95% CI: 1.6–4.8; p=0.00008). The benefit of IP was
also significant in the cohort of those 75–84 years of age. This is probably because, in this particular
group, while the immune system might be somewhat compromised, it is still capable of responding
positively to the eect of IP. It is critically important to start IP (after considering contraindications) in
those over 65 years, as soon as they test PCR+for COVID-19. Evidence suggests that the case-fatality
rate and the number of hospitalizations can be significantly reduced with this approach. Nevertheless,
these are preliminary results that need confirmation using larger-scale trials on COVID-19 patients.
To conclude, IP (as an o-label drug in some countries) can be used for treating COVID-19 in at
least some cases of infection and to potentially minimize the severity of the disease course.
In elderly patients who are immunosenescent (especially residents of nursing homes) and have
been exposed to SARS-CoV-2, initial treatments should be a maximum dosage of 1 g (two tablets) per
10 kg of body weight three or four times per day for 7–10 days or until 2 days after symptom resolution.
4. Materials and Methods
4.1. Subjects
This prospective clinical study was performed in three nursing homes in three towns (Litovel,
Sanatorium Topas Holice, and Ber
á
nek
Ú
pice) in the Czech Republic. The study ran from June 2020
until September 2020. While the first home was an unspecialized nursing home, the other two specialize
in caring for clients with Alzheimer’s disease. The number of clients, average age (AG), median age
(MA), and percentage of women (PW) of PCR positive residents for the three selected homes were
as follows (1) Litovel NH: 67, AG =82.7 years, MA =83.5 years, PW =68.4%, (2) Sanatorium Topas
Holice NH: 174, AG =84.9 years, MA =86.9 years, PW =72.1%, and (3) Beránek Úpice NH: 71 AG =
85.5 years, MA: 86.0 years, PW =91.2%, respectively. The PCR-testing for the SARS-CoV-2 virus was
performed on all clients.
4.2. Treatment
All PCR+clients for SARS-CoV-2 were treated with inosine pranobex as soon as a positive test was
recorded. Isoprinosine 500 mg tablets (each tablet contains 500 mg of inosine pranobex; Ewopharma
International, s.r.o., Prokopa Vel’k
é
ho 52, 811 04 Bratislava, Slovak Republic) was administered to
patients; however, it was not used precisely as it is currently described in the summary of product
characteristics (SmPC), i.e., based on the patient’s body weight and the nature and severity of the
disease. The dosage regimen was based on practical limitations, i.e., elderly patients 65 years and
older: received two tablets 3 times a day. The average duration of treatment was seven days.
Clients who were PCR negative for COVID (in Topas Holice) started taking isoprinosine 500 mg
tablets at a dose of 2 tablets once a day for 10 days as soon as the infection was detected within the
nursing home.
Pathogens 2020,9, 1055 9 of 10
At all three NHs, PCR+patients received symptomatic treatment and, if necessary, also mineral
supplementation, rehydration, and oxygenation. If residents developed signs of bacterial pneumonia
(i.e., C-reactive protein >70 mg/L, auscultation findings, fever, low SpO
2
), then antibiotic treatment
was initiated.
Altogether there were 21 patients hospitalized at various infectious diseases departments. Except
for one patient from the Litovel NH, none of them requested specific antiviral (anti-COVID-19)
treatment during hospitalization (i.e., remdesivir or anti-COVID plasma); however, intensive antibiotic
treatment, mineral supplementation, and rehydration was provided as needed.
4.3. Statistical Analysis
All analyses were conducted using SPSS
®
software version 20 (IBM, New York, NY, USA). The
chi-square test was used to study associations between two categorical variables (one-sided hypothesis)
with a 5% level of significance. No adjustments for multiplicity were made. The odds ratios were
calculated with 95% confidence intervals (CIs). All analyses grouped subjects according to the treatment
they actually received.
4.4. Ethical Statement
The study was conducted in accordance with the Declaration of Helsinki, and the project was
approved by the ethics committee of the University Hospital Hradec Kr
á
lov
é
on 19NOV2020 (project
identification code ISO-ELD-2020 and Ethics Committee (EC) approval no.: 202012 P05).
Author Contributions:
J.B. developed the concept for the study, data collection, data analysis, manuscript outline,
and manuscript development. M.Š. statistical analysis. V.K., A.H., J.M., and J.F.R. patient treatments, collection
of data, and data analysis. J.S. data analysis, outline, and manuscript development. All authors have read and
agreed to the published version of the manuscript.
Funding:
The study was performed under the supervision of the Institute for Postgraduate Medical Education
(IPVZ).
Conflicts of Interest:
In 2015, the author J.B. and M.Š. participated in a clinical study on the treatment of acute
respiratory viral infections using inosine pranobex.
References
1.
Pan, Y.; Zhang, D.; Yang, P.; Poon, L.L.M.; Wang, Q. Viral load of SARS-CoV-2 in clinical samples.
Lancet Infect. Dis. 2020,20, 411–412. [CrossRef]
2.
Woloshin, S.; Patel, N.; Kesselheim, A.S. False Negative Tests for SARS-CoV-2 Infection-Challenges and
Implications. N. Engl. J. Med. 2020,383, e38. [CrossRef] [PubMed]
3.
Weinstein, M.C.; Freedberg, K.A.; Hyle, E.P.; Paltiel, A.D. Waiting for Certainty on Covid-19 Antibody
Tests—At What Cost? N. Engl. J. Med. 2020,383, e37. [CrossRef] [PubMed]
4.
Waggoner, S.N.; Reighard, S.D.; Gyurova, I.E.; Cranert, S.A.; Mahl, S.E.; Karmele, E.P.; McNally, J.P.;
Moran, M.T.; Brooks, T.R.; Yaqoob, F.; et al. Roles of natural killer cells in antiviral immunity.
Curr. Opin. Virol.
2016,16, 15–23. [CrossRef] [PubMed]
5.
Smyth, M.J.; Cretney, E.; Kelly, J.M.; Westwood, J.A.; Street, S.E.; Yagita, H.; Takeda, K.; Van Dommelen, S.L.;
Degli-Esposti, M.A.; Hayakawa, Y. Activation of NK cell cytotoxicity. Mol. Immunol.
2005
,42, 501–510.
[CrossRef] [PubMed]
6.
Moretta, A.; Marcenaro, E.; Parolini, S.; Ferlazzo, G.; Moretta, L. NK cells at the interface between innate and
adaptive immunity. Cell Death Dier. 2008,15, 226–233. [CrossRef]
7. Ma, Y.; Li, X.; Kuang, E. Viral Evasion of Natural Killer Cell Activation. Viruses 2016,8, 95. [CrossRef]
8.
Laing, K.; Hutchinson, F. Immune Responses to Viruses. British Society for Immunology. Available
online: https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/
immune-responses-viruses (accessed on 5 June 2020).
9. Braciale, T.J.; Hahn, Y.S. Immunity to viruses. Immunol. Rev. 2013,255, 5–12. [CrossRef]
Pathogens 2020,9, 1055 10 of 10
10.
Kennelly, S.P.; Dyer, A.H.; Noonan, C.; Kennelly, S.M.; Martin, A.; O’Neill, D.; Fallon, A. Asymptomatic
carriage rates and case-fatality of SARS-CoV-2 infection in residents and stain Irish nursing homes.
Age Ageing 2020, in press. [CrossRef]
11.
Shahid, Z.; Kalayanamitra, R.; McClaerty, B.; Kepko, D.; Ramgobin, D.; Patel, R.; Aggarwal, C.S.; Vunnam, R.;
Sahu, N.; Bhatt, D.; et al. COVID-19 and Older Adults: What We Know. J. Am. Geriatr. Soc.
2020
,68, 926–929.
[CrossRef]
12.
Vellas, C.; Delobel, P.; de Souto, B.P.; Izopet, J. COVID-19, Virology and Geroscience: A Perspective. J. Nutr.
Health Aging 2020,24, 685–691. [CrossRef] [PubMed]
13.
Perrotta, F.; Corbi, G.; Mazzeo, G.; Boccia, M.; Aronne, L.; D’Agnano, V.; Komici, K.; Mazzarella, G.;
Parrella, R.; Bianco, A. COVID-19 and the elderly: Insights into pathogenesis and clinical decision-making.
Aging Clin. Exp. Res. 2020,32, 1599–1608. [CrossRef] [PubMed]
14.
Sliva, J.; Pantzartzi, C.N.; Votava, M. Inosine Pranobex: A Key Player in the Game against a Wide Range of
Viral Infections and Non-Infectious Diseases. Adv. Ther. 2019,36, 1878–1905. [CrossRef] [PubMed]
15.
McCarthy, M.T.; Lin, D.; Soga, T.; Adam, J.; O’Callaghan, C.A. Inosine pranobex enhances human NK cell
cytotoxicity by inducing metabolic activation and NKG2D ligand expression. Eur. J. Immunol.
2020
,50,
130–137. [CrossRef] [PubMed]
16.
Rumel, A.S.; Newman, A.S.; O’Daly, J.; Duy, S.; Grafton, G.; Brady, C.A.; Curnow, S.J.; Barnes, N.M.; Gordon, J.
Inosine Acedoben Dimepranol promotes an early and sustained increase in the natural killer cell component
of circulating lymphocytes: A clinical trial supporting anti-viral indications. Int. Immunopharmacol.
2017
,42,
108–114. [CrossRef] [PubMed]
17.
Hersey, P.; Edwards, A. Eect of isoprinosine on natural killer cell activity of blood mononuclear cells
in vitro
and in vivo. Int. J. Immunopharmacol. 1984,6, 315–320. [CrossRef]
18.
Gayoso, I.; Sanchez-Correa, B.; Campos, C.; Alonso, C.; Pera, A.; Casado, J.G.; Morgado, S.; Tarazona, R.;
Solana, R. Immunosenescence of human natural killer cells. J. Innate Immun.
2011
,3, 337–343. [CrossRef]
[PubMed]
19.
Hazeldine, J.; Lord, J.M. The impact of aging on natural killer cell function and potential consequences for
health in older adults. Ageing Res. Rev. 2013,12, 1069–1078. [CrossRef]
20.
Watzl, C.; Long, E.O. Signal transduction during activation and inhibition of natural killer cells.
Curr. Protoc. Immunol. 2010,90, 11.9B.1–11.9B.17.
21.
World Health Organization. Influenza: BRaVe Call to Action. Available online: http://www.who.int/
influenza/patient_care/clinical/call_to_action/en (accessed on 5 April 2020).
22.
Beran, J.; Salapova, E.; Spajdel, M. Inosine pranobex is safe and eective for the treatment of subjects with
confirmed acute respiratory viral infections: Analysis and subgroup analysis from a Phase 4, randomised,
placebo-controlled, double-blind study. BMC Infect. Dis. 2016,16, 648. [CrossRef] [PubMed]
23.
Thevarajan, I.; Nguyen, T.H.O.; Koutsakos, M.; Druce, J.; Caly, L.; van de Sandt, C.E.; Jia, X.; Nicholson, S.;
Catton, M.; Cowie, B.; et al. Breadth of concomitant immune responses prior to patient recovery: A case
report of non-severe COVID-19. Nat. Med. 2020,26, 453–455. [CrossRef] [PubMed]
24.
Neill, C.; Sartaj, M.; Holcroft, L.; Hasan, S.S.; Conway, B.R.; Aldeyab, M.A. Surveillance study of asymptomatic
and presymptomatic coronavirus disease 2019 (COVID-19) in care homes in Northern Ireland. Infect. Control
Hosp. Epidemiol. 2020, 1–3. [CrossRef] [PubMed]
25.
Arons, M.M.; Hatfield, K.M.; Reddy, S.C.; Kimball, A.; James, A.; Jacobs, J.R.; Taylor, J.; Spicer, K.;
Bardossy, A.C.; Oakley, L.P.; et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled
Nursing Facility. N. Engl. J. Med. 2020,382, 2081–2090. [CrossRef] [PubMed]
26.
Graham, N.S.N.; Junghans, C.; Downes, R.; Sendall, C.; Lai, H.; McKirdy, A.; Elliott, P.; Howard, R.;
Wingfield, D.; Priestman, M.; et al. SARS-CoV-2 infection, clinical features and outcome of COVID-19 in
United Kingdom nursing homes. J. Infect. 2020,81, 411–419. [CrossRef] [PubMed]
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... There was an error in the original article [1]. The authors wish to remove words "of this prospective trial" from the last paragraph of Section 1 (on Page 4, row 8) and delete "prospective clinical" from Section 4.1 (first sentence of this Section on Page 8). ...
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A new Coronavirus, called SARS-CoV-2, was identified in Wuhan, China, in December 2019. The SARS-CoV-2 spread very rapidly, causing a global pandemic, Coronavirus Disease 2019 (COVID-19). Older adults have higher peak of viral load and, especially those with comorbidities, had higher COVID-19-related fatality rates than younger adults. In this Perspective paper, we summarize current knowledge about SARS-CoV-2 and aging, in order to understand why older people are more affected by COVID-19. We discuss about the possibility that the so-called “immunosenescence” and “inflammaging” processes, already present in a fraction of frail older adults, could allow the immune escape of SARS-CoV-2 leading to COVID-19 serious complications. Finally, we propose to use geroscience approaches to the field of COVID-19.
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The elderly may represent a specific cluster of high-risk patients for developing COVID-19 with rapidly progressive clinical deterioration. Indeed, in older individuals, immunosenescence and comorbid disorders are more likely to promote viral-induced cytokine storm resulting in life-threatening respiratory failure and multisystemic involvement. Early diagnosis and individualized therapeutic management should be developed for elderly subjects based on personal medical history and polypharmacotherapy. Our review examines the pathogenesis and clinical implications of ageing in COVID-19 patients; finally, we discuss the evidence and controversies in the management in the long-stay residential care homes and aspects of end-of-life care for elderly patients with COVID-19.
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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents. Methods We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic. Results Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide. Conclusions Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.
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SARS-CoV-2, a novel virus that causes COVID-19 infection, has recently emerged and caused a deadly pandemic. Studies have shown that this virus causes worse outcomes and a higher mortality rate in older adults and those with comorbidities such as hypertension, cardiovascular disease, diabetes, chronic respiratory disease, and chronic kidney disease. A significant percentage of older American adults have these diseases, putting them at a higher risk of infection. Additionally, many adults with hypertension, diabetes, and chronic kidney disease are placed on angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Studies have shown that these medications upregulate the ACE-2 receptor, the very receptor which the SARS-CoV-2 virus uses to enter host cells, which puts older adults at a further increased risk of infection. In this review, we discuss the transmission, symptomatology, mortality, and possible treatments for this infection, as they relate to older adults.