The FDA has announced plans to remove vasoactive intestinal polypeptide (VIP) from the list of drugs that may be compounded by licensed pharmacies in the United States. Since its first use as a nasal spray beginning in 2008, VIP given at a dose of 50 mcg per spray, usually 4-8 sprays a day, has been used with unmatched safety in over 10,000 patients with documentation of efficacy in a complex group of patients who have been found to meet a case definition for chronic inflammatory response syndrome (CIRS).


In robust literature that demonstrates safety and efficacy of use of VIP, we have seen (i) correction of proteomics refractory to all other therapies (1); (ii) correction of transcriptomics as part of molecular hypometabolism (2); and (iii) correction of excessive gray matter nuclear atrophy as shown by a study using before and after results of VIP with a patient as his own control (3).


One of the arguments posed opposing use of VIP is that CIRS has no ICD-10 code. That is true; CIRS is a chronic form of systemic inflammatory response syndrome (SIRS) which is an acute illness, generally thought to involve sepsis or pancreatitis.  SIRS has a ICD-10 code.


Notwithstanding the role of ICD-10 codes as an epidemiologic tool and not an encyclopedia of medicine, the argument to exclude CIRS as an entity is arbitrary. If we look at ICD-9, that version of disease classification has approximately 9000 entries. ICD-10 has more than 50,000. Did medicine grow by a factor of 5? Or was the coding simply deficient before ICD-10?  


We look at chronic fatigue syndrome (CFS) as an analogous entity of a chronic, multisystem, multi-symptom illness that has gone through an evolution of name, case criteria and use in medical practice. CFS became ME/CFS and is now recognized by all Federal agencies by its new name (4), Systemic Exertion Intolerance Disease (SEID).


A timeline of parallel evolution of CFS and CIRS may be of assistance in assessment of changes in nomenclature for CIRS and CFS.


1994:Fukuda et al, publishes a case definition for chronic fatigue syndrome (CFS) specifically stating that all other illnesses are ruled out.


1998: Pfiesteria Human Illness Syndrome is codified as possible estuary associated syndrome (PEAS) by the CDC. At that time, the absence of documentation of the unique toxin made by the dinoflagellate, Pfiesteria, to account for illness is noted. The analogy was made repeatedly of the similarity of PEAS to CFS. The case definition of PEAS specifically rules in symptoms such as are seen in SEID and rules out any other known alternative source for the illness.


2002: A presentation by Shoemaker to a CFS meeting in Chicago, Illinois, provides the first academic linkage of exposure to water-damaged buildings to CFS, with similarity in symptoms noted. CBAI replaces PEAS as the name, as the illness is not caused by exposure to estuaries.


2003: The case definition for chronic biotoxin associated illness (CBAI) was published by Shoemaker (exposure, symptoms, labs and response to treatment).


2004: At the IACFS meetings in Madison, Wisconsin, Shoemaker again presents an expanded comparison of similarity of CBAI to CFS.


2008: The US GAO codifies the case definition for illness acquired following the exposure to the interior environment of a water-damaged building that supersedes Shoemaker’s case definition. It includes exposure, symptoms, labs and response to treatment


2009: At the IACFS meetings in Reno, Nevada, Shoemaker presents 163 patients and 54 controls in the pediatric age group that meet the International CFS pediatric case definition. They were known CBAI patients, however. The match of symptoms combined with statistical significance of measurements of innate immune activation and resultant successful treatment were accepted by the conference leaders as evidence of mold exposure causing a CFS-like condition.


2010: The case definition for CBAI is reworked and combined with all 20 known biomarkers (then) to create an entity called chronic inflammatory response syndrome (CIRS). This case definition relies on exposure; symptoms the same or like those seen in published, peer-reviewed literature; laboratory abnormalities the same or like those seen in published, peer-reviewed literature and response to therapy.  It becomes the case definition for what had been called CBAI. The use of CIRS as a defining case definition is accepted in multiple US courts, both State and Federal.


2015: At the request of HHS, NIH, SSA, FDA and CDC, The Institute of Medicine developed an evidence-based, clinical diagnostic criteria for CFS for use by clinicians using a consensus building method. The new case definition employs a new term, “systemic exertion intolerance disease (SEID).” The diagnosis requires following three symptoms: (i) a substantial reduction or impairment to engage in pre-illness levels of occupational, education, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not life-long), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest; and (ii) post exertional malaise (found in at least 50% of the time following moderate or severe intensity of exercise); and (iii) unrefreshing sleep. These three elements are combined with one of the following two: 1. cognitive impairment. 2. Orthostatic intolerance.


Note there is no mention of differential diagnosis in 2015; note there is no requirement that all other diseases be ruled out as previously had been required.


Comparison of CIRS with SEID shows an exact match of symptoms in diagnostic elements used for SEID but with a far greater number of biomarkers published in peer-reviewed literature supporting CIRS. CIRS is a SEID. SEID is a CIRS.


In an evaluation of efficacy and safety of VIP created by polling health care providers, the patients shown to have CIRS were diagnosed before visiting a CIRS specialist as having CFS in over 50% of the cases. The difference is that CIRS patients respond to therapy with resolution and indeed, in some cases cure, when transcriptomic abnormalities that underly molecular hypometabolism are corrected, largely by VIP. Comparing the mandatory elements of the case definition for SEID, we find that element 1 is found in 98% of CIRS. Element 2 is found in 98% or higher in CIRS. Element 3 is found in essentially 99% of CIRS cases. Of the two additional conditions, cognitive impairment is found in over 95% of cases. Orthostatic intolerance is found in at least in 67% of the CIRS cases.


The fundamental difference between SEID and CIRS is that CIRS has a published 12-step protocol that shows marked improvement demonstrated for over 15 years with few dropouts. The last step in the protocol being use of VIP.


There is no delineation of volumetric central nervous system abnormalities of SEID as there are for CIRS. There is no transcriptomic basis to define SEID with differential gene activation like there is with CIRS. For those patients diagnosed with SEID who have anaerobic threshold elevation, seen in over 90% of CIRS patients, we find successful correction of these metabolic abnormalities with use of VIP.


The argument then is if CIRS patients meet Federal agency-endorsed guidelines for diagnosis worthy of an ICD-10 appellation and all these patients are CIRS patients, can we not identify CIRS as SEID?


We feel the answer to this question is yes. We feel this parallel approach provides a basis to use CIRS principles in treatment of SEID. 




1.Shoemaker R, House D, Ryan J. Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health 2013; 5(3): 396-401.

2..Ryan J, Shoemaker R. RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal polypeptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing. Med Res Arch 2016; 4(7): 1-11.

3.Shoemaker R, Katz D, McMahon S, Ryan J. Intranasal VIP safely restores atrophic grey matter nuclei in patients with CIRS. Internal Medicine Review 2017; 3(4): 1-14

4.Wright E. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An IOM report on redefining an illness. JAMA 2015; 313: 1101-2.

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