Friday, June 20, 2014

Rare Diseases of Unknown Origin

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. This book builds the case that the best way to advance our understanding of the common diseases is to focus our attention on the rare diseases.

Here is a short excerpt from Chapter 6:

There are a number of rare diseases of unknown etiology. Some of these diseases may be caused by infectious agents.

6.4.1 Rule—A portion of human diseases of unknown etiology will eventually be shown to have an infectious etiology.

Brief Rationale—It is difficult to satisfy Koch’s postulates for every type of infectious disease (see Glossary item, Koch’s postulates). Nonetheless, if efforts to find a non-infectious cause of a disease fail, and if the temporal and geographic pattern of disease occurrences resembles the typical pattern of an infectious epidemic, then an infectious etiology is likely.

Here is an incomplete list of the rare or uncommon diseases whose etiologies are unknown:
Balanitis xerotica obliterans
Behçet disease
Benign fasciculation syndrome
Brainerd diarrhea
Cardiac syndrome X
Chronic fatigue syndrome
Chronic prostatitis/chronic pelvic pain syndrome
Chronic Kidney Disease of unknown causes (in Central America)
Cluster headache
Complex regional pain syndrome
Copenhagen disease
Cronkhite–Canada syndrome
Cyclic vomiting syndrome
Dancing mania
Dancing plague of 1518
Danubian endemic familial nephropathy
Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome)
Electromagnetic hypersensitivity
Encephalitis lethargica
Exploding head syndrome
Fields’ disease
Functional colonic disease
Giant cell (temporal) arteritis
Gluten-sensitive idiopathic neuropathies
Gorham vanishing bone disease
Granuloma annulare
Granulomatosis with polyangiitis (Wegener’s syndrome)
Gulf War syndrome
Hallermann–Streiff syndrome
Heavy legs
Henoch–Schönlein purpura
Interstitial cystitis
Irritable bowel syndrome
Kawasaki disease
Lichen sclerosus
Lytico–Bodig disease
Microscopic polyangiitis
Morgellons disease
Mortimer’s disease
Myofascial pain syndrome
New daily persistent headache
Nodding disease
Peruvian meteorite illness of 2007
Picardy sweat
Pigmented villonodular synovitis
Pityriasis rosea
Polyarteritis nodosa
Posterior cortical atrophy
Prurigo nodularis
SAPHO syndrome
Sick building syndrome
Sjögren’s syndrome
Spontaneous cerebrospinal fluid leak
Stiff person syndrome
Sudden unexpected death syndrome (some cases)
Sweating sickness
Synovial osteochondromatosis
Takayasu’s arteritis
Tolosa–Hunt syndrome
Trigger finger
Tropical sprue

Based on past experience, we can infer that some portion of the diseases of unknown etiology will have an infectious etiology. Whipple disease, previously a disease of unknown etiology, is characterized by organ infiltrations by foamy macrophages (i.e., scavenger cells that “eat” bacteria and debris). The organ most often compromised is the small intestine, where infiltration of infected macrophages in the lamina propria (i.e., a strip of connective tissue subjacent to the epithelial lining of the small intestine) causes malabsorption. Whipple disease is rare. It occurs most often in farmers and gardeners who work with soil. Whipple disease was first described in 1907 [35], but its cause was unknown until 1992, when researchers isolated and amplified, from Whipple disease tissues, a 16s ribosomal RNA sequence that could only have a bacterial origin [36]. Based on molecular features of the ribosomal RNA molecule, the researchers assigned it to Class Cellulomonadacea, and named the species Tropheryma whipplei, after the man who first described the disease, George Hoyt Whipple.

Particularly noteworthy in the case of Whipple disease is that Koch’s postulates were not satisfied. Koch’s postulates are a set of observations and experimental requirements proposed by Heinrich Hermann Robert Koch in the late 1800s, intended to prove that a particular organism causes a particular infectious disease. For the experimentalist, the most important of the Koch’s postulates require the extraction of the organism from a lesion (i.e., from diseased, infected tissue), the isolation and culture of the organism in the laboratory, and the consistent reproduction of the lesion in an animal injected with the organism. In the case of Whipple disease, the bacterial cause was determined without benefit of isolation or culture. The consistent extraction from Whipple disease tissue of a particular molecule, characteristic of a particular species of bacteria, was deemed sufficient to establish the infectious origin of the disease.

If it were possible to isolate and culture T. whipplei, it is highly unlikely that the disease could be experimentally transmitted to animals or humans; another opportunity to satisfy Koch’s postulates would fail. As a general rule, bacteria in the human body are eaten by macrophages, wherein they are degraded. In the case of Tropheryma whipplei, only a small population of susceptible individuals lacks the ability to destroy T. whipplei organisms. In susceptible individuals, the organisms multiply within macrophages. When organisms are released from dying macrophages, additional macrophages arrive to feed, but this only results in the local accumulation of macrophages bloated by bacteria. Whipple disease is a good example of a disease caused by an organism but dependent on a genetic predisposition, expressed as a defect in innate immunity, specifically a reduction of macrophages expressing CD11b (also known as macrophage-1 antigen) [37] (see Glossary item, Innate immunity).

Aside from our inability to culture and extract the T. whipplei organism, Whipple disease cannot be consistently reproduced in humans because it can only infect and grow in a small portion of the human population. In short, T. Whipplei fails to satisfy Koch’s postulates. As we learn more and more about the complexity of disease causation, formerly useful paradigms such as Koch’s postulates seem inadequate. When we encounter rare diseases of infectious cause, we might expect to find that the pathogenesis of disease (i.e., the biological steps that lead to a clinical phenotype) may require several independent causal events to occur in sequence. In the case of Whipple disease, the infected individual must be exposed to a soil organism, limiting the disease to farmers and gardeners. The organism, residing in the soil, must be ingested, perhaps by the inhalation of dust. The organism must evade degradation by gut macrophages, limiting disease to individuals with a specific type of defect in cell-mediated immunity, and the individual must have disease that is sufficiently active to produce clinical symptoms.

It has been proposed that Koch’s postulates be updated to accommodate modern molecular techniques, and to adjust for the complex ways that organisms interact with humans. The very meaning of biological causation has changed as we learn more and more about disease. We now know that there are many instances wherein the infectious agent cannot account for all of the cellular processes that culminate in disease [38]. The general subject of biological causation will be discussed in Section 9.1.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: infectious disease, microbiology, rare diseases, orphan diseases, orphan drugs, unknown etiology, idiopathic disease, mystery diseases, undetermined origin, unknown origin

Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.