Successive infection and variability in disease

Chronic diseases manifest in patients and within patient populations with a high degree of variability. Some people have five chronic diseases, and others have one. Some patients experience symptoms of disease early in life while others not until they are very old. According to the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., this variability can be attributed to several factors.

Over the course of a lifetime, patients pick up the approximately 90 trillion bacteria to which they play host.¹ Each person's unique microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. is referred to as their “pea soup.” In everyday language, the term pea soup is otherwise used to refer to a dense fog – an apt metaphor for the human microbiotaThe bacterial community in the human body. Many species in the microbiota contribute to the development of chronic disease.. The promiscuity with which bacteria exchange DNA as well as the sheer number of bacteria to which any given person plays host are both factors which severely limit researchers' ability to accurately predict species-species and species-disease interactions.

The process by which a person accumulates the bacteria which drive disease is known as “successive infection.” Successive infection is the process by which an infectious cascade of pathogens slow the immune response and allow for subsequent infections to proliferate. In patients sick with the Th1 diseases, successive infection is ongoing and has additive properties: generally speaking, the more sick people are, the more sick they tend to become. Like a person's pea soup, the process by which a person accumulates additional bacteria via successive infection has an inherent variability to it.

Over the course of their lifetime, humans encounter and accumulate different pathogens and thus develop a unique infectious history. People acquire bacteria from the food they eat, from their mothers during gestation, from injectable medicines, from a family member or friend, etc. Some pathogens are relatively common across different people. For example, approximately half of the human population is infected with Chlamydia pneumoniae² while 50% of people are infected with H. pylori.³ However, each person's exact mix of microbes which represents thousands of species – known as their “pea soup” – is nothing if not unique.

Using high throughput sequencing, one research team found that of bacteria present on the hands of 51 undergraduate students leaving an exam room, there were 332,000 genetically distinct bacteria belonging to 4,742 different species. Each student carried on average 3,200 bacteria from 150 species on their hands. Only five species were found on all the students’ hands, while any two hands – even belonging to the same person – had only 13% of their bacterial species in common.⁴ According to the study's authors, each student’s bacterial “fingerprint” was totally unique.

However, variability in disease has more to do with how bacteria interact through processes like horizontal gene transferAny process in which a bacterium inserts genetic material into the genomes of other pathogens or into the genome of its host. than merely the sheer number of species present. Horizontal gene transfer is the process in which a bacterium inserts genetic material, usually circular strands of DNA called plasmids, into the genomes of other pathogens.

Given the frequency with which horizontal gene transfer occurs and the number of plasmids a given bacteria can contain – some bacteria have more than 20 plasmids – it is no surprise that the human microbiota is so diverse.

If you take the 21 plasmids of Borrelia, they can transfer DNA in 21! (21 factorial) combinations with other species, which is a very large number. Then you have to add in the DNA in the plasmids of the other key species - Staph, Rickettsia, Strep, Treponema, E.coli, Bacillus, and then add all of their chromosomes, add in the remaining non-plasmid bacterial species (like Mycobacteria), add the viruses, stir the soup together, accumulating new components for a few decades, and the number of combinations of pathogenic DNA in our cells becomes virtually infinite.

Trevor Marshall, PhD

There is broad support for the conclusion that early infections, especially acute infections, predispose a person to later onset of chronic diseases, diseases which are undoubtedly caused by chronic bacterial infections. The role beta-lactam antibiotics, which are often prescribed for acute infections, play in fostering the growth of L-form bacteriaDifficult-to-culture bacteria that lack a cell wall and are not detectable by traditional culturing processes. Sometimes referred to as cell wall deficient bacteria. is discussed elsewhere.

Successive infection is the process by which an infectious cascade of pathogens slow the immune response and allow for subsequent infections (and the diseases which they cause) to proliferate. In a 2004 Science paper, Finch and Crimmins proposed that early infection burdened survivors with a “cohort morbidity phenotype,” which they carry with them throughout their lives.⁵

Bacterial infections make the body a more hospitable environment for other infections via two primary means: affecting both human host-cell pathways and the expression of human genes. This effect has been documented in a range of clinical and laboratory-based studies. O'Connor and team at the Centers for Disease Control and Prevention state, “At least 13 of 39 recently described infectious agents induce chronic syndromes.”⁶ For example:

• Food poisoning and hemolytic uremic syndrome – According to a University of Utah team, fully 10% of people who suffered from E. coli food poisoning later developed a relatively infrequent life-threatening complication called hemolytic uremic syndrome (HUS) where their kidneys and other organs fail.⁷ According to the study, 10-20 years after patients recover, between 30-50% of E. coli survivors will have some kidney-caused problem, conditions which include high blood pressure caused by scarred kidneys, slowly failing kidneys, or even end-stage kidney failure that requires dialysis.
• Respiratory tract or gastrointestinal infection and Guillain-Barre syndrome (GBS) – Approximately two-thirds of patients with GBS, a suspected autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body syndrome, have a history of an antecedent respiratory tract or gastrointestinal infection.⁸ Campylobacter infection is the most commonly identified precipitant of GBS and can be demonstrated in as many as 30 percent of cases.⁹
• Prenatal infection and schizophrenia – According to Alan S. Brown of Columbia University, “Accumulating evidence suggests that prenatal exposure to infection contributes to the etiology of schizophrenia.” In a 2006 study, Brown showed that prenatal infections such as rubella, influenza, and toxoplasmosis are all associated with higher incidence of schizophrenia.¹⁰ Brown found a seven-fold increased risk of schizophrenia when mothers were exposed to influenza in the first trimester of gestation.
• Reactive arthritis following infection – Reactive arthritis (Reiter's syndrome) is classically seen following infection with enteric pathogens such as Yersinia, Salmonella, Campylobacter and Shigella.¹¹
• Cytomegalovirus and viral déjà vu – Nobel Laureate Rolf Zinkernagel and team injected cytomegalovirus (CMV) into the brains of mice that were only a few days old. The researchers found that the innate immune systems of the mice were able to eliminate CMV from most of the tissues except for those of the central nervous system. As a result, the virus persisted in the brains of the mice. Later in life, when the same mice were challenged by infection with a similar virus, they developed a condition resembling a type of autoimmune disease and died. The team referred to this concept as viral “déjà vu.”¹²
• Common infections and stroke – In a prospective cohort study, a composite measure of Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 1 and 2 infection, were associated with a higher risk of stroke and other vascular events.¹³
• SARS and mental health problems – In a 2009 study, many survivors of the severe acute respiratory syndrome (SARS) pandemic of 2003 suffer from persistent mental health problems and chronic fatigue years later.¹⁴ Over 40% of the respondents had active psychiatric illnesses, 40.3% reported a chronic fatigue problem, with 27.1% meeting the modified 1994 CDC criteria for chronic fatigue syndrome. Also, being a health care worker at the time of SARS infection more than tripled the risk of psychiatric morbidities at follow-up.
• Mortality and airborne infectious disease at birth – Using 150 years of demographics data from the period spanning 1766 to 1894, Bengtsson and Lindström showed that Swedish children severely exposed to airborne infectious diseases during their birth year had a much higher risk of dying of airborne infectious diseases at ages 55–80.¹⁵
• Infant diarrhea and cardiovascular disease – Diarrhea as infant (the primary cause of which is microbial pathogens) has been associated with cardiovascular disease later in life.¹⁶

Because chronic pathogens take lengthy periods of time to proliferate, these effects are sometimes experienced only decades later.

Long-term observation, especially of those who survive a severe episode [of E. coli food poisoning], is therefore necessary even when recovery appears complete.

Richard L. Siegler, et al. ¹⁷

It would be wrong to assume that there are no long-term effects of acute infections, especially given the fact that chronic pathogens are slow-growing and build up over the course of decades:

Folks often assume once you’re over the acute illness, that’s it, you’re back to normal and that’s the end of it. The long-term consequences are an important but relatively poorly documented, poorly studied area of foodborne illness.

Robert Tauxe, MD, Centers for Disease Control and Prevention, Associated Press interview

O’Connor and team at the Centers for Disease Control and Prevention have identified the time before and around birth as times when acute infections seem to have their most devastating impact.

A person’s age at the time of infection—from intrauterine [occurring within the uterus] or perinatal (the time period surrounding birth), through childhood and adolescence, to adulthood and the elder years—may further influence the risk for chronic outcome. For example, perinatal herpes virus infection dramatically increases the risk of developing adult or pediatric chronic liver disease. Recurrent infections or perhaps serial infections with certain agents might also determine a person’s risk for chronic outcome.

Siobháin O'Connor, et al. ¹⁸

There does not seem to be any reason why chronic pathogens do not cause disease just as easily as acute infections in the aforementioned examples. (One reason why L-form bacteria, for example, have not been more widely identified as the cause for chronic disease is that the fastidious organisms have difficult-to-master culturing requirements.)

Consider Alzheimer's disease, a condition which appears late in life, even though a person may be predisposed to the disease decades before a diagnosis. A 2010 NYU study using a PET scanner to examine the plaque in brains (which is the hallmark of Alzheimer's disease) found that a child's level of plaque was consistent with their fathers and especially their mothers – even years before a child has a diagnosis.¹⁹ The fact that amyloid-beta protein has recently been identified as an antimicrobial peptide²⁰ suggests that what is being passed between the generations isn't so much the propensity to produce plaque, but the need to produce plaque in response to slow-growing microbes.