Key words COVID-19 - environmental pollution - apheresis - chlorinated water
Introduction
The 2020 pandemic of SARS-CoV-2 infection did not respect any borders and did not
spare any regions of the world. Nevertheless, there are striking differences in the
mortality rates and the occurrence of severe courses of the disease in different
countries [1 ]
[2 ]. This had been attributed to obvious
differences of dissemination and efficiency of containment in different countries.
It had also been related to the lack of knowledge of truly SARS-CoV-2 positive
individuals versus the number of ill patients. Obviously, the availability and
capacity to test for the virus are completely inconsistent between and sometimes
even within different countries.
Finally, the different age profile, occurrence of comorbidities, quality of health
care systems and even genetic predispositions have been blamed for the striking
variations in the incidence of critical disease and lethal outcome [3 ]
[4 ]
[5 ]
[6 ]
[7 ]
[8 ].
Even if all these factors will play an important role they do not fully explain the
reality of what we are seeing now.
Why did so many more casualties occur in Italy, France, Spain, the UK, and the United
States than in other European countries like Germany, Austria, Switzerland or
Scandinavia?
Even if methods of containment and exposure as well as infection rates play a crucial
role, such drastic discrepancies remain currently inexplicable.
All these countries do have modern and efficient health care systems with more or
less similar shortcomings. In all these countries, there are similar elderly
populations with no major demographic differences. The same is true for the rate and
distribution of comorbidities that had been defined as risk factors for severe
COVID-19 disease such as diabetes, hypertension or heart disease [8 ]
[9 ]
[10 ]
[11 ]. There is currently no clear evidence for
major differences in genetic predisposition between the populations of these Western
countries.
Is There any Other Plausible Explanation?
Is There any Other Plausible Explanation?
Here we would like to open the discussion with a provocative hypothesis regarding
these enigmatic differences in incidence of severe COVID-19 disease. We suggest that
the use of chlorinated drinking water and/or other environmental pollutants
could play a key role in the variation of susceptibility to the contraction of
severe corona virus infection in these Western countries. Across Africa, South
America, and Asia, tap water is unsuitable for drinking due to contamination and
general hygienic conditions, which differ strongly from the Western world.
In contrast, in all countries of the Western world water can be used for drinking
from the tap. However, there is one crucial difference. Whereas in countries like
the US, UK, France, Spain, and Italy tap water is highly chlorinated, countries like
Germany, Austria, Switzerland, and Scandinavia refrain from chlorination of their
drinking water. In fact, we found an intriguing correlation of the rate of
chlorination of tap water in different countries with the incidence of severity of
COVID-19 disease ([Fig. 1 ]).
Fig. 1 Distribution of water quality and COVID-19 infection.
Those countries that have not been exposing their populations to high levels of
chlorinated water in the last decade exhibit a 2-20 fold lower death rate in the
current pandemic. This is a most striking observation, which may be a mere
coincidence but it should be worthwhile to seriously consider this conundrum.
Effects of Chlorinated Water on our Immune System
Effects of Chlorinated Water on our Immune System
There is indeed ample and substantial evidence that chlorinated water may affect
various functions of our immune system.
Chlorine gas is a formidable lung toxin [12 ].
Airway injury occurs due to oxidative damage, swarming of inflammatory cells, and
resultant airway hyper-responsiveness [13 ].
Lipid peroxidation is a major damage event in the lung, and may critically affect
the airway surface layer and its surfactant capacity [14 ]
[15 ]. There is limited data regarding the
availability of ingested or transdermally absorbed chlorine to partake in such
processes.
When water is disinfected with chlorine and ingested, chlorinated, and brominated,
mixed bromochloro acetates are formed [16 ].
Earlier studies in mice and rats exploring the potential of immunotoxicity of
bromochloromethane and other disinfection by-products (DBPs) did not reveal any
major effects on cellular or humoral immunity [17 ]
[18 ]. Other research using experimental
animals, however, reported a suppressive effect of chlorine-based drinking water on
macrophage function [19 ]
[20 ]. The intracellular redox status
experiences depletion of reduced glutathione (GSH) [12 ]. The haloacetates, trichloroacetate, dichloroacetate, and their
brominated analogues induce hepatic lipid peroxidation [16 ], and the liver is usually considered to be
the target for lipid peroxidation processes related to chlorinated water [21 ]. The release of lipid toxins may be
enhanced by SARS-CoV-2 driven liver disease [22 ], which is more prevalent in more severe systemic COVID-19 disease
[23 ].
However, the small amounts of chlorine used for water disinfection, or evaporating
from swimming pool surfaces may result in an attack of phospholipids by chlorine
species, inducing chlorinated phospholipids. This consideration brings lipid
peroxidation products into the center of attention [24 ]. Sodium chlorate (NaClO3 ) is a by-product during
disinfection of drinking water with chlorine dioxide. Human erythrocytes exhibit a
significant increase in protein and lipid peroxidation, and a concomitant decrease
in reduced glutathione [25 ]
[26 ]. They offer an attractive shuttle system
of peroxidated lipids, which come in indirect contact with the alveolar surface, as
it is separated from the bloodstream by a membrane as thin as
0.2 μM. Chlorine driven ROS-induced lipid transformations without
oxygen lead to formation 2-hexadecenal from sphingolipids. 2-Hexadecenal has a
potent adverse biological potential. 2-Chloro-, and 2-bromo-substituted fatty
aldehydes are produced by hypochlorous acid-induced endothelial damage, supposing a
perfect storm at the lung-blood endothelial interface [27 ]. Whilst the exact pathways are still
unknown it is plausible how ingested chlorine could via systemically released
hepatic lipid peroxidation products, and by-products of lipid peroxidation in
erythrocyte walls, be shuttled to the critical site of SARS-CoV-2 mediated disease:
the alveolar ductal system and its neighboring endothelial surface [28 ]
[29 ]
[30 ].
More recent work has elucidated the role of polychloroaminated biphenyls on
alterations of the innate immune response of marine mammals [31 ]. Interestingly, even swimming in a pool
with chlorinated water induces an acute change of serum immune markers in humans
[32 ]. Thus, in both males and females
there was a significant decrease in cytokines following 40 min swimming in a
chlorinated pool [32 ]. Likewise in the blood
of children with a high content of organochlorine compounds in drinking water an
imbalance of cellular components of innate and adaptive immunity was found [33 ]. This suggests both acute and chronic
effects of chlorinated water on the human innate immune response may interfere with
the capacity of an individual to fight a virus infection.
Finally, chlorinated water may alter microbiome composition, the immune-gut barrier,
and gene expression of intestinal cells [33 ].
Thus, numerous typical chlorinated disinfection by-products altered specifically
genes in intestinal cells associated with immune and inflammation pathway.
Therefore, these environmental aspects of the coronavirus pandemic need to be
explored to develop better strategies and protection of our populations for the
future.
Other Environmental Pollutants Impairing Immune Function
Other Environmental Pollutants Impairing Immune Function
Beyond the role of chlorination in drinking water there may be other environmental
pollutants playing a key role in causing a predisposition for viral infections such
as by SARS-CoV-2. One of the most devastating chemical accidents occurred in 1976 in
Northern Italy in Seveso, which also was an epicenter of the COVID-19 pandemic. The
exposure of the population to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD)
induced major medical problems including effects on the hormonal, metabolic, and
immune systems. TCDD triggers a wide range of immunotoxic effects on both the
humoral, cellular and also the innate immune response and interacts with the aryl
hydrocarbon receptor [34 ]
[35 ]
[36 ]
[37 ]
[38 ]
[39 ]. It alters type 3 innate lymphoid cells
in the colon and the entire intestinal tract [40 ]
[41 ]. These effects on the immune system may
even have been transferred to the next generation [42 ]
[43 ]. Thus, offspring of pregnant rats exposed
to TCDD exhibited an immunosuppression characterized by reduced thymus weight,
reduced virus-associated natural killer (NK) cell, and specific antibody responses
[42 ].
Furthermore, it has been shown that suppression of immune function led to an enhanced
susceptibility to viral infections including influenza [44 ]
[45 ]. In fact, even low levels of TCDD
exposure lead to enhanced mortality to the influenza virus [45 ]. In addition to TCDD, exposure to
pesticides may play an important role. Particularly, in Northern Italy more than 65
percent water samples from rivers and lakes exhibit high levels of pesticides
including p ,p ′-DDE or p ,p ′-DDT and
glyphosates.
These pesticides have been shown to exert a significant effect on the immune system.
Persistent organic pollutants including 16 polychlorinated biphenyls and
organochlorine factors increased pro-inflammatory cytokines, activated macrophages,
and enhanced immunosenescence [46 ]
[47 ]
[48 ].
In experimental settings, glyphosate exposure may cause toxic effects on intestinal
morphology, antioxidant capacity and barrier function [49 ].
PFAS, per- and polyfluorinated alkyl substances, are a huge class of non-classical
persistent organic pollutants (POPs), which have been produced since the 1940s.
Common use of these compounds, for example as surfactants, stain repellents, fire
containment and many more applications has caused widespread environmental
contamination. Human exposure occurs amongst other exposure pathways through air,
water and particularly through terrestrial and aquatic food chains, including
through food processing and packaging processes. Perfluorooctanesulfonic acid (PFOS)
and perfluorooctanoic acid (PFOA) represent the two most frequently studied members
of this large family of molecules. Although no geographical differences in the
exposure to these chemicals can be deduced, they have to be discussed in the light
of the COVID-19 pandemic.
In 2018, the European Food Safety Authority (EFSA) performed a risk assessment on
PFOS and PFOA on human health. Although the risk assessment was primarily based on
associations of the compounds to serum cholesterol levels, antibody response to
vaccination in children was also identified as a critical effect [50 ]. This risk assessment is currently updated
and the opinion is out for public consultation. In essence, it is confirmed for
humans and animals, that levels of PFOS and PFOA are inversely linked to
functionality of the immune system. The most significant concern regards the strong
inverse association of PFAS blood levels and antibody response for example,
following booster vaccinations to diphtheria and tetanus, particularly in children
as shown on the Faroe Islands [51 ] and in
Germany [52 ]. Supporting information from
animal studies is available [53 ]. Perhaps more
relevant to COVID-19 is a less pronounced inverse association with antibody titers
[54 ].
Finally, important data link nitrogen dioxide (NO2 ) levels to COVID-19
fatality rates [55 ]. Spatial analysis has been
performed on a regional scale and combined with the number of death cases taken from
66 administrative regions in Italy, Spain, France, and Germany. Results show that
out of the 4443 fatality cases, 3487 (78%) were in five regions located in
Northern Italy and central Spain. Interestingly, the same five regions exhibited the
highest NO2 concentrations combined with downwards airflow which prevents
an efficient dispersion of air pollution. These results suggest that the long-term
exposure to this pollutant may be an important contributor to fatality caused by the
SARS-CoV-2 virus in these regions [55 ].
An explanation for susceptibility to progress to severe Covid disease may be provided
by the observation that high levels of NO2 affect innate immunity in the
lung [56 ] and induce airway inflammation [57 ].
In summary, there is evidence that environmentally persistent compounds, particularly
perfluorinated compounds and nitrogen dioxide, may compromise the immune response.
Whilst no particular geographical association can be determined for perfluorinated
compounds, regional segregation of death rates with NO2 levels may
provide more direct clues.
Effect of Environmental Pollutants on Lipid Levels and Cardiometabolism
Effect of Environmental Pollutants on Lipid Levels and Cardiometabolism
All these environmental pollutants including dioxin-related chemicals as well as
pesticides induce significant hormonal and metabolic alterations. Thus, exposure to
DDT increases the incidence of diabetes in the NOD mouse model [58 ].
Acute dioxin exposure led to long-term metabolic consequences in mice [59 ]. Organochlorine pesticides may potentially
mediate insulin resistance [60 ].
Population-based studies demonstrated an association between polychlorinated
dibenzo-p -dioxin and polychlorinated biphenyls and the incidence of
diabetes and hyperlipidemia [61 ]. Given the
fact that diabetes, obesity and the metabolic syndrome are major risk factors for
severe COVID-19 infections, the role of these environmental factors is even more
prominent. Of course, the risk of microbial contamination has to be balanced with
the potential risk of disinfection by-products [62 ].
Environmental pollution has been correlated with severe dyslipidemia predisposing for
metabolic syndrome and cardiovascular disease [63 ]
[64 ]
[65 ]. Organochlorine pesticides significantly
aggravated disorders of fatty acid metabolism [66 ].
Similarly workers exposed to dioxin reportedly had elevated lipid levels [67 ]. Hyperlipidemia contributed to the higher
role of atherosclerotic plaques and ischemic heart disease in these individuals
[68 ].
Role of Lipids, Environmental Pollutants, and Therapeutic Apheresis
Role of Lipids, Environmental Pollutants, and Therapeutic Apheresis
Changes in the lipid metabolism have been described in survivors of SARS-CoV
infections [69 ]. Recovered SARS patients had
increased phosphatidylinositol and lysophosphatidylinositol levels after 12 years,
which might be also a result of treatment with high doses of methylprednisolone.
Therefore, long-term effects of therapeutic interventions on the lipid metabolism
should be considered in COVID-19 patients.
The impact of the lipoprotein metabolism on the clinical outcome in COVID-19 patients
is currently not well understood. Recently, the impact of underlying cardiovascular
disease (CVD) and myocardial injury on fatal outcomes in patients with COVID-19 has
been described [70 ]
[71 ]
[72 ]. This study compared 52 patients with and
135 patients without elevation of troponin T (TnT) levels. Total, high-density
lipoprotein, and low-density lipoprotein (LDL) cholesterol levels did not differ
between both groups, but patients with elevated TnT levels had higher triglyceride
levels. The inflammatory biomarkers high-sensitivity C-reactive protein and
procalcitonin were significantly increased in patients with elevated TnT levels.
Other strategies to lower lipoprotein levels might represent interesting novel
therapeutic approaches. In general, lowering LDL cholesterol and lipoprotein(a)
levels could have beneficial effects like upregulation of ACE2 and prevention of
cardiovascular complications during COVID-19 infection. Lipoprotein apheresis could
be an attractive alternative therapeutic approach to treat critically ill patients.
Apheresis has been shown to mediate lipid-lowering and anti-inflammatory effects
[73 ]. This might mediate beneficial
effects in COVID-19 patients with elevated CRP levels and inflammation.
Therefore, lipoprotein apheresis using rigidly implemented isolation measures might
be a novel protective strategy in the treatment of COVID-19 patients. The European
Group – International Society for Apheresis e.V. (E-ISFA) – has
recently joined the German Center for Infection Research, the ESCMID Emerging
Infections Task Force and a number of other institutions including the Robert Koch
Institute in the LEOSS (Lean European Open Survey on SRAS-CoV-s Infected Patients)
registry. This is an open, international and anonymous registry covering all aspects
of COVID-19 infections from diagnosis, laboratory measurements over medical
treatments to clinical outcomes (https://leoss.net). This initiative
will help defining the impact of apheresis therapy on COVID-19 patients.
Furthermore, therapeutic apheresis is an efficient biophysical method to remove
metabolic inflammatory immunological and environmental components from the blood of
patients. Many patients with severe COVID-19 infection exhibit lymphopaenia which
may lead to secretion of high amounts of inflammatory cytokines and cytokine storm
[74 ]
[75 ]
[76 ].
Specifically therapeutic environmental apheresis (INUSpherese®) may be
useful. We have previously shown that this method allows an effective removal of
lipoproteins, inflammatory cytokines as well as environmental pollutants. This
includes a reduction of heavy metals, but also a reduction of environmental
pesticides ([Fig. 2 ]). Environmental
apheresis® is therefore useful to improve parameters of metabolic
inflammation and hyperlipidemia, which have been shown to be major risk factors for
the development of severe Coronavirus disease 2019. Furthermore, it has been shown
to improve neuroinflammation and polyneuropathy [73 ]
[77 ]. Thus, the removal and reduction of
environmental pollutants together with the reduction of lipids and inflammatory
factors may provide a protective mechanism for prevention and mitigation of severe
corona virus infections.
Fig. 2 Level of environmental pesticides before and after therapeutic
apheresis (INUSpherese®).
