Introduction

Several chronic infections are widespread among human populations worldwide, when these pathogens avoid total elimination by the immune system by various host immune system evasions and manipulations; this is especially true for chronic viral pathogen infections [1]. Chronic infection strategies by pathogens can include one or a combination of the following: continuous pathogen replication, pathogen latency and reactivation, and in the case of viral pathogens, an invasion of the host genome to propagate itself from generation to generation [1]. The main focus herein will be on latent pathogen infections, where latency in the discussion below means cellular latency, not clinical latency as in the delay in the onset of symptoms caused by a pathogen infection. A latent pathogen infection is defined herein as a mostly asymptomatic pathogen infection that, during latency, can be detected by certain diagnostic tests, such as antibody tests. This paper proposes an immune system-based classification system for latent infections by viral, bacterial, fungal, and protozoan pathogens.

One of the most distinctive medical facts about any individual is their variety and number of latent pathogen infections. This is also essential information for many medical treatments, since some medical treatments can have immuno-suppressive consequences and reactivate certain latent pathogen infections with severe consequences [1, 2]. If a latent pathogen reactivates because of an intentional medically induced immune system suppression, such as after an organ transplant, or because of an incidental immune system suppression caused by other pathogen infections, malnutrition, stress, or drug side effects, it is likely to affect immune system defenses and assist other pathogen infections [2]. If a latent pathogen infection impairs the immune system, it will probably assist other pathogen infections, whether they are active or latent. However, if a latent pathogen infection is not reactivated and it does not significantly impair the immune system, it may or may not incidentally assist other pathogen infections.

A large percentage of humans are latently infected by several pathogens, and some latent viral infections are suspected of increasing the risk of bacterial and fungal co-infections [2]. Many humans carry latent infections of alpha, beta, and gamma herpesviruses, where alpha herpesviruses include herpes simplex virus 1 and 2 and varicella-zoster virus [1,2,3]. Beta herpesviruses include herpesvirus 6A, 6B, 7, and cytomegalovirus, and depending on the country, at least 60 to 80% of the human population of the developed world is estimated to be latently infected with cytomegalovirus [1,2,3]. Furthermore, it has been estimated that over 90% of the adult human population worldwide carries a latent infection of Epstein-Barr virus, a gamma herpesvirus [1, 3,4,5]. Latent infections by non-viral pathogens also infect billions of people; e.g., protozoan parasites capable of dangerous reactivations, such as Toxoplasma gondii, are estimated to infect 30 to 50% of the human population in various countries worldwide [6].

Furthermore, fungal pathogens or bacterial pathogens can cause latent infections, and billions of people have these latent infections [7]. Latent bacterial infections include Mycobacterium tuberculosis, in which in 2014, it was estimated that approximately 1.7 billion humans were infected, and in 2014 approximately 10 million tuberculosis cases reactivated worldwide [7].M. tuberculosis infections, particularly multi-drug resistant M. tuberculosis, are the most prevalent cause of death from an infectious disease worldwide, followed by human immunodeficiency virus (HIV) as the second most common cause of death [7, 8]. In fact, M. tuberculosis is the largest single pathogen cause of death in HIV-infected individuals [8].

A classification system for latent pathogen infections

Latent pathogen infections can be categorized on the basis of whether the latent pathogen infection by its evasion or manipulations significantly impairs or does not impair the host immune system. If either the adaptive or innate immune systems of the host are impaired, the latent pathogen infection will almost unavoidably assist some other pathogen infection, whether it is active or latent in the host. If there is no significant immune system impairment caused by the latent pathogen, the latent pathogen infection could possibly exist either with or without assisting other pathogen infections, depending on its cellular effects.

Type IV—latent infections that even during latency can impair some of the host’s immune system defenses and thereby assist other pathogen infections

The immune system damage can be theoretically reversible, such as in the case of T-cell exhaustion caused by hepatitis C viral infections [9]. In other infections, the immune system damage caused by some pathogens can be essentially irreversible, such as in the case of T-cell exhaustion caused by hepatitis B viral infections that release vast amounts of sub-viral particles [10]. In fact, irreversible immune system damage is possible by several paths, including population inflation of specifically targeted T-cells in the case of cytomegalovirus infections, T-cell senescence by telomere shortening in the case of cytomegalovirus or in the case of human immunodeficiency virus 1 (HIV-1), or by T-cell population declines caused by HIV [10]. For example, HIV during a latency period lasting several years irreversibly decimates the CD4+ T-cell population of an infected host, and this allows other infections by fungal pathogens (e.g., Candida albicans, Pneumocystis jirovecii, Histoplasma capsulatum), bacterial pathogens (e.g., Mycobacterium tuberculosis), viral pathogens (e.g., cytomegalovirus), and protozoan parasites (e.g., Toxoplasma gondii) to ultimately kill an immuno-suppressed host [11]. In some cases, a bi-directional synergy of assistance is possible with latent co-infections by other pathogens, such as the protozoan parasites Leishmania infantum and Leishmania donovani, that can accelerate HIV infections by causing overexpression of CCR5, a co-receptor for HIV entry into CD4+ T-cells [12].

Cytomegalovirus is another viral pathogen that, during a latent pathogen infection, will assist other pathogen infections, especially in causing specifically targeted T-cell inflation in elderly people [1, 13]. Kaposi’s sarcoma-associated herpesvirus 8 infection of B-cells and dendritic cells can cause immune system impairment regarding general dendritic cell presentation of pathogenic antigens to T-cells [14].

Type III—latent infections that do not significantly impair the host’s immune system defenses in themselves, but which can assist other pathogen infections

This type of latent pathogen infection is not only immune system evasive, but fundamentally immune system manipulative, with side effects that can assist other pathogen infections. Epstein-Barr virus can cause some cancers and autoimmune diseases, by itself or by co-infections with Kaposi’s sarcoma-associated herpesvirus 8, but it does not appear to significantly damage the immune system’s capabilities during latency, but it does appear to assist other pathogens, including Kaposi’s sarcoma-associated herpesvirus 8, and Helicobacter pylori [1, 5]. Human herpesvirus 6A (HHV-6A) infections can facilitate an increased incidence of human cytomegalovirus infections [2]. As previously noted, protozoan parasites, Leishmania infantum and Leishmania donovani, can accelerate HIV infections by causing overexpression of CCR5, a co-receptor for HIV entry into CD4+ T-cells, an unusual but dangerous host immune system manipulation which assists concurrent HIV infections [12].

Type II—latent infections that do not significantly impair the host’s immune system defenses and do not assist other pathogen infections

This type of latent pathogen infection is usually immune system evasive, but not broadly immune system manipulative to the extent of helping other pathogens. Varicella-zoster virus infection of a host initially causes chickenpox (varicella), then latently infects the host’s sensory neurons of the dorsal root ganglia of over 90% of the people in the world, and can reactivate and cause shingles [1,2,3, 15]. During its active phase, this virus can interfere with the host’s innate immune system’s targeting of varicella-zoster virus-infected cells and even manipulate monocytes, macrophages, NK cells, dendritic cells, and T-cells, but during latency, this virus does not appear to cause major impairments of the host’s immune system or assist other pathogen infections, so far as is known at this time [15]. Adeno-associated virus, used in gene therapy applications, may or may not help other pathogen infections during its latent infections; its effects will probably become more clearly understood in the near future [16]. Polyomavirus BK latently infects the renal urinary tract of most healthy individuals, and polyomavirus JC latently infects the kidneys of most healthy individuals, but they do not appear to help other pathogen infections during their latent infections, so far as is known at this time [17].

Type I—latent infections that potentially improve immune responses to a later pathogen

There was a study of 375 COVID-19 patients in Egypt and the relationship between their SARS-CoV-2 viral infection outcomes and the presence in almost 69% of the patients of various protozoan parasite infections, including T. gondii, Cryptosporidium, Giardia, and Entamoeba histolytica [18]. This study found that the protozoan parasite stimulation of T-cells significantly increased the levels of interferon-γ and that preexisting protozoan parasite infections with increased levels of interferon-γ resulted in a large majority of cases with more moderate COVID-19 symptoms [18]. This may have been a case where such patients had received drug treatments for their protozoan parasite infections that would have blocked later stage T-cell, NK-cell or B-cell exhaustion [18, 19]. Therefore, when some latent pathogen infections do not significantly impair the immune system, the immune response can possibly be improved against a later pathogen infection [18, 19]. This category will be less commonly applicable, but still possible for some latent pathogen infections that stimulate effective immune responses against a second pathogen.

Table 1 provides an illustrative example of one implementation of a latent pathogen infection classification system. This table is only one illustrative example, and it is not the conceptual idea itself. The conceptual idea is not limited only to the pathogens listed in Table 1. Clinical use of any implementation of any such table would require experimental validation of the pathogen effects by at least two, and preferably three, independent groups.

Table 1 Example table of latent pathogen infections and their classification types
Full size table

A few examples may illustrate how this table can be utilized. Reference to Table 1 indicates that an infection with HIV fits in the type IV category, since HIV infections even while latent damage the T-cells of the adaptive immune system. In a second example, an infection with varicella-zoster virus fits in the type II category, because this infection does not appear to substantially impair the immune system defenses during latency, and it does not materially assist other pathogen infections, so far as is known at present. It should be noted that some pathogen infections may cause immune system impairments only when they are active or reactivated, but not while they are latent pathogen infections, so this is an important distinction for implementations of this classification system. Future research information may also change the classification of a latent pathogen infection when all of its effects are more clearly understood and clarified.

What are the benefits of this classification system?

This system can enable medical care that is safer for patients and the medical care providers and can also enable a safer selection of tissue or organ transplant donors and recipients. Presently, any debilitating or lethal pathogen infection can potentially be transmitted to a tissue or organ transplant recipient, who will usually be medically immuno-suppressed to minimize immune system rejection of the transplant. Transmission of pathogens has been observed even in the most unlikely cases, for example, protozoan parasites, such as Toxoplasma gondii, were transmitted by bone marrow transplants, which could be very dangerous for immuno-suppressed recipients [20]. Clearly, type IV individuals with lethal latent pathogen infections should not be used as tissue or organ transplant donors, regardless of whether they are still alive or deceased from a recent accident. Type II individuals would probably be far safer choices as tissue or organ transplant donors. This classification system is also vitally important for recipients, since recipients are subjected to immune system suppression after transplants to minimize rejections, and this immune system suppression would very likely reactivate latent pathogen infections with potentially lethal consequences. This could be especially relevant for increasingly widespread multi-drug resistant pathogens, including M. tuberculosis. Such multi-drug resistant pathogens might be latent while an individual's immune system is strong, but then reactivate during intentional immune system suppression, creating virtually untreatable reactivated pathogen infections.

How could this classification system be implemented?

There are different approaches by which a latent pathogen classification system can be implemented. Testing individuals just before they receive emergency medical care or become tissue or organ transplant donors or recipients requires considerable time, which is limited and frequently not available, especially for emergency medical care or if the prospective tissue or organ donor is dying or is already deceased after an accident. One implementation to overcome an extreme time shortage for testing would be in periodically testing an individual for various latent pathogen infections when they apply for a driver’s license or a renewal of a driver’s license. Then, their driver’s license could be encrypted to confidentially indicate the type of latent pathogen classification that they have.

The mark can be encrypted in a bar code or another encoding only readable after decryption by emergency rooms, hospitals, ambulances, etc., so that bank tellers, post office workers, policemen, or other non-medical personnel cannot, by casual inspection, determine their classification. A driver with an extremely dangerous HIV infection or another type of type IV latent pathogen infection can have their driver’s license encrypted as a “Type IV” classification without indicating their specific latent pathogen infections. This would tell hospitals and medical care providers to be especially careful for their own safety and that this individual’s organs are hazardous for organ transplants, while maintaining some patient confidentiality. If an individual has a lower level latent pathogen classification, then, their driver’s license can be correspondingly encrypted. Of course, their latent infection category could worsen before their next driver’s license renewal and latent pathogen test, but such a change in latent pathogen classification is far more likely for young adults with more active and risky lifestyles.

In another implementation, instead of testing individuals when they renew their driver’s license, the testing can be done on a periodic basis when they are issued a new medical insurance card, or when they have a routine blood test before a medical visit to a hospital or doctor. Their latent pathogen infection classification can be updated and encrypted on their medical insurance card or some type of ID card, and again, their classification will preferably only be decrypted by essential medical care providers, emergency rooms, or hospitals and not readable by non-medical personnel. This is another way to implement a classification system to avoid a time shortage situation for testing individuals before providing emergency medical treatment. This will increase the safety of both medical care providers and patients and enable the safer selection of tissue or organ transplant donors and recipients.

Alternative classification systems

Each country will need to decide how many pathogens to include in any implementation, and what the optimum cost-benefit point will be in terms of antibody testing or other testing for latent pathogens and how much medical risk will be accepted with lethal pathogens not included in the classification system. Furthermore, some genetic strains of a pathogen can be much more dangerous than other genetic strains of the pathogen (T. gondii, for example), and their prevalence can vary by geography. There are alternative approaches for classifying latent patent infections, depending on the focus of greatest concern. One alternative is to classify latent pathogen infections on the basis of how dangerous or lethal they would be upon reactivation. Another alternative is to classify latent pathogen infections on the basis of how easy they are to reactivate, such as by various medical immune system suppressions. In either of these alternative approaches, a four category system, with the type IV category for the most dangerous or the easiest to reactivate latent pathogen infections, should be useful.

Conclusion

The latent pathogen infections in an individual can be classified and updated on a periodic basis in a four category system by whether or not an individual’s immune system is impaired and by whether or not these latent infections will assist other active or latent pathogen infections. Such a classification system for latent infections by viral, bacterial, fungal, and protozoan parasite pathogens will be practical and useful and indicate whether certain medical treatments will be dangerous for transmitting or reactivating an individual’s latent pathogen infections. It will also immediately provide additional pathogen infection status information necessary for providing emergency medical care and for quickly and safely selecting tissue or organ transplant donors and recipients. This classification system will increase the safety of medical care providers and also increase the safety of patients by immediately indicating vulnerabilities to certain medical treatments that can reactivate latent pathogen infections, many of which can be lethal for immuno-compromised or immuno-suppressed individuals. The reactivation of multi-drug resistant pathogens from latency would be particularly dangerous for immuno-compromised or immuno-suppressed individuals. In various implementations, this classification system can be encrypted and/or can also avoid naming specific pathogen infections that carry a detrimental social stigma.