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 Pathogenesis, 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⁾ While some researchers refer to each person's unique microbiota as an individual's “pathogen burden” and other terms,^{2) 3)} we have referred to it as a person's “pea soupThe unique combination of bacterial pathogens (and co-mingling of bacterial genes) which accounts for each individual’s disease presentation..” In everyday language, the term pea soup is otherwise used to refer to a dense fog – an apt metaphor for the human microbiota. 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.” In successive infection, an infectious cascade of pathogens slow the immune response and allow for subsequent infections to proliferate, resulting in dysbiosis (microbial imbalances). In patients sick with chronic inflammatory 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 pneumoniae⁴⁾ while 50% of people are infected with H. pylori.⁵⁾ 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.⁶⁾ 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 transfer than merely the sheer number of species present. Horizontal gene transfer is the process by 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 likely caused by chronic microbial infections. The role of beta-lactam antibiotics, which are often prescribed for acute infections, play in fostering the growth of L-form bacteria is discussed elsewhere.

One of the more straightforward examples of successive infection is the process by which infections of the teeth and gums (odontogenic infections) disseminate through the bloodstream to the body at large and “seed” native or prosthetic heart valves, joint replacements, or other prosthetic devices.⁷⁾ For this reason, many physicians have recommended antibiotic prophylaxis as essential prior to any invasive dental procedure⁸⁾ and routine examination of the oral cavity prior to elective prosthetic heart valve implantation or artificial joint replacement. It is precisely this type of infectious process, that the Marshall Pathogenesis points to as an early (and ongoing) driver of chronic disease.

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.⁹⁾

Microbial 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.”¹⁰⁾ 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.¹¹⁾ 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 autoimmune syndrome, have a history of an antecedent respiratory tract or gastrointestinal infection.¹²⁾ Campylobacter infection is the most commonly identified precipitant of GBS and can be demonstrated in as many as 30 percent of cases.¹³⁾
• 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.¹⁴⁾ Brown found a seven-fold increased risk of schizophrenia when mothers were exposed to influenza in the first trimester of gestation. This work was echoed by a 2009 paper by Sørensen et al. who showed that bacterial infections (upper respiratory tract and gonococcal infections) were associated with elevated risk of the disease.¹⁵⁾
• Reactive arthritis following infection – Reactive arthritis (Reiter's syndrome) is classically seen following infection with enteric pathogens such as Yersinia, Salmonella, Campylobacter and Shigella.¹⁶⁾
• 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.”¹⁷⁾
• 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.¹⁸⁾
• prenatal exposure to influenza and cardiovascular disease – Prenatal exposure to the 1918 influenza pandemic (Influenza A, H1N1 subtype) is associated with >/=20% excess cardiovascular disease at 60 to 82 years of age, relative to cohorts born without exposure to the influenza epidemic, either prenatally or postnatally. These findings suggest novel roles for maternal infections in the fetal programming of cardiovascular risk factors that are independent of maternal malnutrition.¹⁹⁾
• 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.²⁰⁾ 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. This may be because corticoteroids were used heavily during the recent SARS outbreak.²¹⁾
• 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 55–80.²²⁾
• 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.²³⁾
• Chronic pharyngotonsillitis and chronic bacteria – A 2008 Berlin study used fluorescence in situ hybridization (FISH) with group and species-specific 15/23S RNA based probes to search for invasive bacteria in 90 patients who were surgically treated for recurrent inflammation of the pharynx and tonsils. Abundant foci of invasive bacteria were found in 86% of the resected tonsils, despite previous treatment with antibiotics and absent symptoms of ongoing infection. All of the foci were polymicrobial and contained up to 10 different species or groups of bacteria. The local concentrations of invasive bacteria were up to 1012 bacteria/ml.²⁴⁾
• Obsessive compulsive disorder and childhood infections like strep – A 2010 team of researchers developed a new animal model to show how exposure to strep affects the brain and leads to a number of physical and mental ailments. According to one of the collaborators, Daphna Joel, “It's almost impossible to show how strep can lead to OCD in humans ― almost all of us, even very young children, have been exposed to the bacterium at one time or another. But childhood seems to provide a distinct window of opportunity for the disorder to take root through strep infection. This work was presented at a 2010 meeting and is expected to be published at the beginning of 2011.
• Mice exposed to an airborne pathogen develop sub-chronic lung inflammation – Repeated low dose aerosol exposures to Bacillus thuringiensis (a commercial pesticide) can induce sub-chronic lung inflammation in mice, which may be the first step in the development of chronic lung diseases.²⁵⁾
• Bacterial infection causes stress-induced memory dysfunction in mice. – Mice were infected with the non-invasive intestinal pathogen, Citrobacter rodentium in both C57BL/6 mice and “germ-free” Swiss-Webster mice, in the presence or absence of acute stress. No behavioural abnormalities were observed, either at the height of infection or following bacterial clearance. After infection clearance, however, when infected Swiss-Webster mice were exposed to acute stress, however, memory dysfunction was apparent. Conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota did not develop memory problems.²⁶⁾
• Bacterial vaginosis and HIV – Bacterial vaginosis is associated with a greater than three-fold risk of female-to-male transmission of HIV.²⁷⁾
• Prenatal infection and autism – A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.²⁸⁾
• Childhood infections and asthma – Children who experience repeated rhinovirus-induced wheezing episodes in infancy have a significantly increased risk of developing asthma.²⁹⁾ Neonates colonized in the hypopharyngeal region with S. pneumoniae, H. influenzae, or M. catarrhalis, or with a combination of these organisms, are at increased risk for recurrent wheeze and asthma early in life.³⁰⁾
• Enterovirus and type I diabetes – A 2010 Norwegian paper showed that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection, characterized by the presence of viral RNA in blood.³¹⁾

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. ³²⁾

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 (radio 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. ³³⁾

There does not seem to be any reason why chronic pathogens do not cause disease just as easily as acute infections. (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.³⁴⁾ The fact that amyloid-beta protein has recently been identified as an antimicrobial peptide³⁵⁾ 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.

In at least one respect, chronic forms of infections have an advantage over acute forms. Virulence factors required for acute infection are often repressed during chronic infections for species capable of causing both types of infection. Acute virulence factors can stimulate the host immune system and cause damage to host tissues, while establishing chronic infection necessitates avoiding the host immune response and maintaining a stalemate with the host, where invasive tissue damage is minimized.³⁶⁾

…because the women are all healthy when they enroll [then any disease can be detected as they continue sampling from that time].

Claire Fraser-Liggett, Director of the Institute for Genome Sciences at the University of Maryland, BBC Radio 4 program about the Human Microbiome

It is common practice to assign one group of patients participating in a controlled trial to be the “healthy control group.” While researchers are apt to make a hard distinction between health and disease, this dichotomy is contrary to what we know about successive infection.

The process of successive infection does not just occur in sick people or people who are symptomatic. In healthy subjects, subclinical infection is not the exception, but the rule. For example:

• 30% of healthy people are carriers of the pathogen Staphylococcus aureus.³⁸⁾
• A 2011 pyrosequencing study looked at 16S rDNA amplicons of eight culture-negative healthy female urine specimens.³⁹⁾ The study found a significant amount of sequences belonging to bacteria with a known pathogenic potential.

From even before birth, every human is constantly acquiring new microbes as demonstrated in several studies⁴⁰⁾ by Rob Knight and Jeffrey Gordon's team. After sequencing the microbiome of two individuals at four body sites over 396 timepoints, the group essentially concluded that the notion of a “core microbiome” is overblown.

We find that despite stable differences between body sites and individuals, there is pronounced variability in an individual's microbiota across months, weeks and even days. Additionally, only a small fraction of the total taxa found within a single body site appear to be present across all time points, suggesting that no core temporal microbiome exists at high abundance (although some microbes may be present but drop below the detection threshold). Many more taxa appear to be persistent but non-permanent community members.

J. Gregory Caporaso et al. ⁴¹⁾

Clearly, the microbiota can be affected in any number of ways that are not picked up by the relatively crude tests that we use to measure “health.” Further, patients will carry pathogenic elements of their microbiota without symptoms to show for it – at least initially.

The variability of patients' responses – both between control and experimental groups, and among an experimental group (some subjects get a side effect, some don't) – may ultimately be a testament to the unique nature of each person's microbiota.

Because everyone person's microbiota is unique, it may be overly simplistic, if not naive, to say there is such a thing as a person who is truly healthy.