Needle in the haystack studies: Getting the bug leads to effective treatment

Photograph of a needle in a haystack.

Are there new pathogen-induced skin diseases that are not yet identified? If yes, how many such diseases might there be? And how to choose diseases for study, and what laboratory studies, intellectual analysis, and paradigms should be used to identify such diseases? Are there as yet undescribed pathogenic organisms?


If these questions resonate with you, please remember the past, of many organisms being proposed as the cause of morphea, psoriasis, and similar disorders, but not being proved. For the brave of heart, and the curious of mind, keep reading.


On June 4, the New England Journal of Medicine published the results of unbiased next-generation sequencing of the genomes found in the cerebral spinal fluid (CSF) of one patient; these explained and led to effective treatment of a very serious clinical conundrum. A patient with severe combined immunodeficiency had progressive neurological disease, fever, and progressive hydrocephalus. Massive supporting data, including brain biopsies, is detailed in the report. A tiny percentage(0.016%) of the DNA sequences in CSF corresponded to those of the leptospira genome; initially, the routine tests for leptospiral infection were negative. Based on these genomic studies, a targeted anti-leptospiral drug, intravenous penicillin G, led to clinical and microbial resolution.  Table 2 of the article shows a panel of leptospiral tests, including many that were negative.


What would Dr. Koch muse? Yes, leptospira causes CNS disease. Current tests for leptospira are orders and orders of magnitude more sensitive than what was previously available, but even those may have negatives related to methodological considerations.


The microbiome is of high current interest, bolstered by new genetic methodologies, and there may be patients and diseases that deserve the kind of genetic analysis described in this artcle. With a strong enough magnet, pulling the needle out of the haystack may be easier than previously contemplated.



Wilson MR. Naccache SN, Samayoa E, et al (2014) Actionable diagnosis of neuroleptospirosis by next generation sequencing by next generation sequencing. N Engl J Med 370:2408-2417 (doi:10.1056/NEJMoa1401268)