Clinical Evidence: External Factors

Introduction

When the loss-of-function filaggrin gene mutation was first revealed in the medical literature as a strong link to patients affected with atopic dermatitis (AD), the general sentiment of the medical community was that of an excitement for possessing a key to point to external factors as the cause of AD since the skin barrier defect would naturally open doors for invading actors to enter and trigger the inflammatory process manifested in AD ( ). Combining with the clinical evidences that AD patients commonly have pathogenic bacterial colonization in their skin and frequent skin infections with bacterial, fungal, and viral microorganisms, there are strong data to support external causes for the development of AD. The principal goal of this chapter is therefore to examine and analyze those relevant clinical data to delineate the degree these external factors are contributing to the disease development. In discussing the external factors as the contributors for AD development, we must at the same time reason if external factors alone will be sufficient to cause the disease to develop.

Although clinical data are generally not considered as robust as those collected through laboratory investigations, it nevertheless provides a supporting documentation from a different angle. In a way, clinical evidence provides a sense of reality or a sense of living proof. Any medical theory or purely laboratory-based research result unsupported by clinical evidence will be called into question of whether the theory is correct or that data are relevant for the actual disease.

First, we define what is clinical evidence. According to the online 2019 Oxford Dictionary , the term clinical relates “to the observation and treatment of actual patients rather than theoretical or laboratory studies.” Another dictionary defines clinical as “(of a disease or condition) causing observable and recognizable symptoms.” Merriam-Webster Dictionary defines this way: “of, relating to, or conducted in or as if in a clinic: such as a: involving direct observation of the patient or b: based on or characterized by observable and diagnosable symptoms.” Clinical evidence therefore will be the collected data gathered from the clinical observations or studies.

Thus, to collect clinical evidence, we gather all the data relating to the symptoms and signs of what we can observe, obtain, measure about and from actual patient encounter, rather than by theoretic consideration, speculation, or purely laboratory investigation. However, laboratory data are also part of the supporting evaluation of clinical data and of documenting clinical evidence. One simple example is the clinical evaluation of early clinical failure of treatment of a gram-negative bacteria sepsis (bloodstream infection). To collect clinical evidence accurately and correctly, the clinical investigators first establish that all these patients indeed have bloodstream infection by gram-negative bacteria documented by results of blood culture, a laboratory method. Moreover, the clinical researchers have to measure many parameters to develop a set of criteria for determining the “predictors” for early clinical failure. These parameters would include some “purely clinical data” such as blood pressure, respiratory rate, altered mental status, but also include other “laboratory data” such as white blood cell count. Together, these collected data provide the valuable predictors for early clinical failure on treatment for gram-negative sepsis ( ). Similarly, to collect clinical data and to document clinical evidence in relation to development of AD, some laboratory-generated information, such as bacterial culture determinations, skin histopathology findings, genetic mutation information in skin barrier protein, immunologic status, and other clinically supportive laboratory data, is also included. The following discussions delineate clinical findings to suggest that external factors play a significant role in AD development.

Staphylococcus aureus colonization

Pathogenic bacterial species colonized in the skin of AD patients is a well-documented finding. Pathogenic Staphylococcus aureus species colonize in about 30% to 100% of AD patients’ skin. This kind of colonization displaced other commensal bacteria species beneficial to the human hosts, and this abnormal colonization is associated with increased disease severity ( ). Theoretically, several molecules expressed by S. aureus may contribute to the inflammation of AD:

• δ-toxin from these bacteria is capable of stimulating mast cells leading to inflammatory cytokine release.

• α-toxin from these bacteria can damage keratinocytes leading to damage-related inflammatory responses.

• Phenol-soluble modulins are stimulatory to keratinocytes for cytokine release.

• Protein A can trigger keratinocyte inflammatory responses and act as superantigens to generate B-lymphocyte immune activation ( ).

• Enterotoxin B from S. aureus is capable of triggering leukocyte expression of a pruritus-inducing cytokine interleukin 31 (IL31), and experimental overexpression of IL31 in mice actually triggers skin inflammation ( ).

In one study, bacterial culture survey points out that a S. aureus– predominant colonization is associated with a severe disease phenotype, and a Staphylococcus epidermidis– predominant colonization is linked to a milder disease phenotype of AD ( ). But a mere association of S. aureus colonization does not prove a contributing role of these bacteria in triggering the disease development. One of the best studies that links S. aureus colonization to AD development is a Switzerland-conducted prospective birth cohort study. In this study of 149 white, fully term healthy infants, the researchers obtained bacterial culture at birth and at seven time points over their first 2 years of life. These infants were examined and followed by the physicians to monitor the development of skin disease at birth; at age day 1, 3, and 7; and at age 1, 3, 6, 12, and 24 months. At age 3 months, the investigators found that S. aureus colonization was significantly more prevalent in those patients who developed AD later on, compared to those infants who did not develop the skin disease. Furthermore, the prevalence of colonization increased 2 months before the onset of AD and at the time of disease onset. In addition, the patients who had positive S. aureus colonization developed AD at a younger age than those patients without the bacterial colonization ( ). There were additional negative effects of S. aureus colonization. These colonized bacteria not only settled in the skin but also pushed away the commensal skin bacteria such as S. epidermidis , which normally provides their own antimicrobial peptides and enhances human-producing antimicrobial peptides for immune defenses of human skin ( ). A proposed mechanism of how S. aureus colonization would trigger AD development is depicted in Fig. 10.1 . More discussions on the role of S. aureus in AD are detailed in Chapter 6 .