Sunday, February 28, 2016

Counting the Rare Diseases

"The beginnings and endings of all human undertakings are untidy."- John Galsworthy

In the U.S., as written in Public Law 107-280, the Rare Diseases Act of 2002, "Rare diseases and disorders are those which affect small patient populations, typically populations smaller than 200,000 individuals in the United States." (1). Since the population of the U.S. is about 314 million, in 2013, this comes to about 1 case for every 1,570 persons. This is not too far from the definition recommended by the European Commission on Public Health; fewer than 1 in 2,000 people. It is important to have numeric criteria for the rare diseases, because special laws exist in the U.S. and in Europe to stimulate research and drug development for diseases that meet the criteria for being "rare". Unfortunately, it is very difficult to know, with any certainty, the specific prevalence or incidence of any of the rare diseases. A certain percentage of the cases will go unreported, or undiagnosed, or misdiagnosed. Though it is impossible to obtain accurate and up-to-date prevalence data on every rare disease, the U.S. the National Institutes of Health has estimated that rare diseases affect, in aggregate, 25-30 million Americans (2).

There seems to be a growing consensus that there are about 7,000 rare diseases (3). Depending on how you choose to count diseases, this may be a gross underestimate.

There are several thousand inherited conditions with a Mendelian inheritance pattern (4). To the rare genetic diseases, we must add the different types of cancer. Every cancer other than the top five or ten most common cancers, occurs with an incidence much less than 200,000 and would qualify as a rare disease. There are more than 3,000 named types of cancer, and many of these cancers have well-defined subtypes, with their own morphologic, clinical or genetic characteristics. Including defined subtypes, there are well over 6,000 rare types of cancer (5), (6), (7), (8).

Regarding the infectious diseases, well over 1,400 different infectious organisms have been reported in the literature (9). I've looked at several popular microbiology textbooks, and each seems to cover at most 300 organisms, and many of the textbook organisms would be considered rare. Hence, it's reasonable to assume that there are well over 1000 well-documented infectious diseases. This number is growing all the time, as we uncover new species of pathogenic organisms.

If we focus our attention on just one type of infectious disease, the fungal infections, we can see immediately why it is impossible to get a meaningful count of the number of rare diseases produced by microorganisms.

As the number of immune-compromised patients increases, due to transplants, AIDS, cancer treatment, long-term steroid use; and with the proliferation of medical devices that provide potential entry points for fungi, the number of newly recognized fungal pathogens will increase. It is estimated that there are about 20 new fungal diseases reported each year (10). If the number of diseases caused by other types of organisms (i.e., bacteria, protists, animals, viruses and prions) remains steady, then it will not be long before the number of different fungal diseases exceeds the number of different diseases produced by all other organisms, combined.

The increase in newly recognized fungal pathogens is partly credited to technical advances. It is now possible to identify heretofore undiagnosed cases of pathogenic species (11). In the past, when clinical mycology laboratories had fewer available tests, it was common to lump fungal pathogens under a commonly encountered species or genus. For example, Aspergillus fumigatus is a common cause of severe pulmonary infections in immune-compromised patients. With advanced typing techniques, an additional 34 species of Aspergillus have been isolated from clinical specimens (10).

In the absence of advanced fungal typing techniques, it can be difficult to correctly assign a fungal species name to a clinical specimen. Pathogenic fungi grow within human tissues vegetatively, as an expanding colony of hyphae or yeasts. The vegetative growth phase observed in tissues lacks the characteristic morphologic traits observed in sexually or asexually fungal reproduction. The pathologist who observes fungal infections in human tissues reaches a diagnosis on clinical presentation and on the somewhat non-specific morphologic features of the fungus in biopsied tissue (i.e., length and thickness of hyphae, presence or absence of septations, angularity of branches, etc.). Adding to the general confusion, fungal specimens grown in culture may have a different morphology from that of the same fungus growing in human tissue. This situation is very different from that of bacterial infections, which have the same morphology in tissues as they have in the culture dish. Consequently, a rare type of fungal infection can be misdiagnosed as a common fungal infection; unless an adequate tissue specimen is delivered to a well-equipped microbiology laboratory.

Sometimes, one clinical disease can be produced by any number of different fungal organisms. Mycetoma, also known as Madura foot and as maduromycosis, occurs most often in India, Africa, and South America. It presents as a slowly growing, fungating mass arising in the subcutaneous tissues, usually on the foot. As the mass grows, draining sinuses discharge fluid and hard grains (white, white-yellow or black grains). The may become superinfected, making it very difficult to determine the primary pathogen that caused the disease. More than thirty different species of fungi, and several bacteria, have been grown from these lesions. It has been claimed that black grain mycetomas is caused by Leptosphaeria senegalensis, Madurella grisea, Madurella mycetomatis, or Pyrenochaeta romeroi. White grain mycetomas are reputedly caused by Acremonium species, Aspergillus nidulans, Neotestudina rosatii, or Pseudallescheria boydii. White-yellow grain mycetomas are said to be caused by: Actinomadura madurae, Nocardia asteroides, and Nocardia brasiliensis. Brown-red grain mycetomas are said to be caused by: Actinomadura pelletieri or Streptomcyes somaliensis. Taken at face value, these claims would indicate that many different organisms, both bacterial and fungal, can produce a disease of remarkably specific, even unique clinical features. Suffice it to say that clinical science has much to learn about mycetoma.

It is worthy to note that many fungal organisms are unknown; we simply do not know the full list of potential fungal pathogens that live on earth. Furthermore, many of the known fungal organisms are unnamed. Fungi are classified based on the morphologic features of sexual growth in culture. If a fungal organism cannot be cultured, or if it does not display sexual reproduction in culture, then it cannot be classified with certainty. A special pseudoclass of fungi, deuteromycetes (spelled with a lowercase "d", signifying its questionable validity as a true biologic class) has been created to hold these indeterminate organisms until definitive classes can be assigned. At present, there are several thousand such fungi sitting in a taxonomic limbo (10).

A fungal infection with a single organism may produce many different clinical presentations. One or more of the following clinical scenarios may unfold, when a human is exposed to a fungus. These scenarios are listed in order of increasing morbidity:

1. The fungus grows in the external environment, usually in soil or on plants, never interacting in any way with humans.

2. Spores and asexual reproductive forms are emitted into the air. In warm and tropical locations, fungal elements are the predominant particulate matter found in air samples. Humans are exposed constantly to a wide variety of fungi just by breathing (spores and conidia), by ingestion (fungi grow on the plants we eat), and by direct skin contact with fungal colonies in soil and airborne organisms.

3. After exposure, fungi may leave, without colonizing (e.g., you inhale them, and then you exhale them, and they're gone).

4. After exposure, fungi may transiently colonize a mucosal surface, such as the oral cavity, the nose, the gastrointestinal tract, the respiratory tract, or the skin. Once on a mucosal surface, an acute allergic response may occur (e.g. sneezing). After a time, the colony fails to thrive due to an inhospitable environment (e.g., insufficient food, poor ionic milieu, effective host immune response).

5. After exposure, fungi permanently colonize the mucosal surface, with no clinical effect. Candida species commonly colonize the mouth and the vagina. Aspergillus species may colonizes the respiratory surfaces (e.g. bronchi). In many cases, we simply carry fungal colonies as commensals (organisms that live within us, without causing disease).

6. Colonies persist, but the host reacts with an acute or chronic immune response. Chronic allergic aspergillosis of the bronchi is a good example. The patient may have a chronic cough. Microscopic examination of bronchial mucosa may reveal some inflammation, the presence of eosinophils, and the occasional hypha. Sometimes the host response is granulomatous, producing small nodules lining the bronchi, containing histiocytes and lymphocytes. A truce between the fungal colony and the host response is sometimes attained, in which the fungus colonies never leave, the inflammation never regresses, but the fungus does not invade into the underlying mucosa.

7. Fungi invade through the mucosa into the submucosa and underlying tissue. These locally invasive infections often manifest as a fungal ball, consisting of varying amounts of inflammatory tissue, necrosis, and fungal elements.

8. Fungal elements invade into lymphatics, traveling with the lymph fluid, and producing regional invasive fungal disease along the route of lymphatic drainage. The prototypical example of this process is found in infections with Sporothrix schenckii, which typically gains entrance to the skin, from the soil, through abrasions. Infection yields multiple skin papules, emanating from the point of primary infection (usually the hand or the foot), and following the line of lymphatic drainage.

9. Fungal elements invade into blood vessels.

10. Fungal elements grow in the blood and disseminate throughout the body.

11. Fungal elements spread throughout the body to produce invasive fungal infections in multiple organs.

A single species of fungus may manifest itself by any and all of these clinical manifestions (i.e., diseases). How shall we count the ways?

Likewise, many infectious organisms may manifest as several different named conditions, each with its own distinctive clinical features. For example, Leishmaniasis, an infectious disease that is common in Africa but rare in Europe, may present in one of four different forms (cutaneous, visceral, diffuse cutaneous, and mucocutaneous).

Now, if you are brash enough to think that all these "counting" issues could be resolved, with diligent effort, then please take a moment to consider the rare diseases caused by environmental agents. Depending on the toxin (which no doubt number in the thousands and greater), level of exposure, type of exposure, individual who is exposed (i.e., age, genetics, nutritional status), and admixture with other toxins (e.g., alcohol plus barbiturates, methamphetamine plus heroine), there are an uncountable number of rare diseases that may result.

Nonetheless, even the low-ball "7,000" number tells us that there are many rare diseases; way too many for any individual to fully comprehend.

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, number of rare diseases, how many rare diseasesjules j berman


[1] Rare Diseases Act of 2002, Public Law 107-280, 107th U.S. Congress, November 6, 2002.

[2] FAQ about rare diseases. National Center for Advancing Translational Sciences. National Institutes of Health., viewed on October 24, 2013.

[3] Field MJ, Boat T. Rare Diseases and Orphan Products: Accelerating Research and Development. Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development. 2010. The National Academics Press, Washington, D.C. Available from:

[4] Omim. Online Mendelian Inheritance in Man. Available from:, viewed June 20, 2013.

[5] Berman JJ. Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches. BMC Cancer 5:100, 2005. Available from:, viewed on Jan. 1, 2015.

[6] Berman JJ Tumor taxonomy for the developmental lineage classification of neoplasms. BMC Cancer 4:88, 2004., viewed Jan. 1, 2015.

[7] Berman JJ. Tumor classification: molecular analysis meets Aristotle. BMC Cancer 4:10, 2004. Available from:, viewed Jan. 1, 2015.

[8] Berman JJ. Neoplasms: principles of development and diversity. Jones & Bartlett, Sudbury, 2009.

[9] Berman JJ. Taxonomic Guide to Infectious Diseases: Understanding the Biologic Classes of Pathogenic Organisms. Academic Press, Waltham, 2012.

[10] Guarro J, Gene J, Stchigel AM. Developments in fungal taxonomy. Clinical Microbiology Reviews 12:454-500, 1999.

[11] Pounder JI, Simmon KE, Barton CA, Hohmann SL, Brandt ME. Petti CA. Discovering potential pathogens among fungi identified as nonsporulating molds. Journal of Clinical Microbiology 45:568-571, 2007.