AIDS-like illness reported in Asia - genetic and environmental factors suspected

[alert]

http://www.ctvnews.ca/sci-tech/new-disease-that-causes-aids-like-symptoms-found-in-asia-1.925646

New disease that causes AIDS-like symptoms found in Asia


Researchers have identified a mysterious new disease that has left scores of people in Asia and some in the United States with AIDS-like symptoms even though they are not infected with HIV.

The patients' immune systems become damaged, leaving them unable to fend off germs as healthy people do. What triggers this isn't known, but the disease does not seem to be contagious.

This is another kind of acquired immune deficiency that is not inherited and occurs in adults, but doesn't spread the way AIDS does through a virus, said Dr. Sarah Browne, a scientist at the National Institute of Allergy and Infectious Diseases.

She helped lead the study with researchers in Thailand and Taiwan where most of the cases have been found since 2004. Their report is in Thursday's New England Journal of Medicine.

"This is absolutely fascinating. I've seen probably at least three patients in the last 10 years or so" who might have had this, said Dr. Dennis Maki, an infectious disease specialist at the University of Wisconsin in Madison.

[snip]

[alert]

Re: AIDS-like illness reported in Asia

This sounds an awful lot like the illness reported in China for the past decade:

http://www.flutrackers.com/forum/showthread.php?p=423086

which is believed to have multiple causes. It would be interesting to know if Epstein-Barr virus has been tested for in the outbreak in the above post.

[alert]

Re: AIDS-like illness reported in Asia

The two outbreaks are unrelated. The inital article in this thread also contains the text:


The virus that causes AIDS -- HIV -- destroys T-cells, key soldiers of the immune system that fight germs. The new disease doesn't affect those cells, but causes a different kind of damage. Browne's study of more than 200 people in Taiwan and Thailand found that most of those with the disease make substances called autoantibodies that block interferon-gamma, a chemical signal that helps the body clear infections.



Read more: http://www.ctvnews.ca/sci-tech/new-d...#ixzz24Mo08iMS

Since the cases in China did not have this symptom (and some of them did have low T-cell counts), this is a different illness. Zhong Nanshan diagnosed about 80% of the Chinese cases with known infectious diseases, so it does remain possible that some of the Chinese cases had this illness, but it seems unlikely that this illness is caused by the pathogens in the Chinese outbreak. There is a phenomenon where in rare cases, Epstein-Barr, the virus identified in the largest number of the Chinese cases, can cause AIDS-like long-term progressive immune damage, but that lowers the T-cell counts as well, indicating that is not the situation here.

The article also implies that genetic factors may be involved in this illness.

[alert]

Re: AIDS-like illness reported in Asia

This would be the "reactive arthritis" phenomenon noted by Zhong Nanshan in some of the Chinese cases:

http://www.foxnews.com/health/2012/08/23/researchers-say-new-aids-like-disease-is-not-contagious/

[snip]

It's still possible that an infection of some sort could trigger the disease, even though the disease itself doesn't seem to spread person-to-person, he said.

[alert]

Re: AIDS-like illness reported in Asia

Hat-tip Mike Coston.

http://afludiary.blogspot.com/2012/08/nejm-adult-onset-immunodeficiency-in.html

Thursday, August 23, 2012
NEJM: Adult-Onset Immunodeficiency in Thailand and Taiwan


M. fortuitum a “rapidly-growing” Mycobacterium Credit CDC PHIL


# 6511





Investigators at the NIH have identified an antibody suspected to be the cause of a noninfectious AIDS-like syndrome observed in Asia in recent years, that can make people susceptible to opportunistic infections like those from nontuberculous mycobacteria (NTM).



Mycobacteria are slender, rod-shaped bacteria commonly found in the environment throughout the world.



Generally divided into three groups, the most famous are the bacilli that cause cause Tuberculosis and Leprosy (Hansen’s Disease) – while the third group - responsible for NTMs - are less well known.



Nontuberculous mycobacterial (NTMs) infections are rarely seen among non-HIV positive (or otherwise pulmonary or immune compromised) patients, but has been observed with increasing frequency over the past decade, particularly in Asia.



A couple of cites from the last decade include:

J Infect. 2006;53:77–84

Emergence of disseminated infections due to nontuberculous mycobacteria in non-HIV-infected patients, including immunocompetent and immunocompromised patients in a university hospital in Taiwan.

Lai CC, Lee LN, Ding LW, Yu CJ, Hsueh PR, Yang PC.



Clin Infect Dis. 2007 Aug 15;45(4):421-7. Epub 2007 Jul 5.

Disseminated nontuberculous mycobacterial infection in patients who are not infected with HIV in Thailand

Chetchotisakd P, Kiertiburanakul S, Mootsikapun P, Assanasen S, Chaiwarith R, Anunnatsiri S






While some sort of immune compromising condition has been associated with these opportunistic infections, until now the mechanism behind them has been a mystery.



Today, an NIH study appearing in the NEJM finds that high-titers of anti–interferon-γ autoantibodies (i.e. an antibody directed against the body’s own immune system) are associated with opportunistic infections -like NTM - in non-HIV positive patients.



Interferon-y (IFN-γ) – or type II interferon - is a cytokine that is a critical component of our body’s innate and adaptive immune system. Antibodies that inhibit or neutralize their function would be expected to greatly assist opportunistic infections in spreading.



First a link to the study, then more details from the NIH press release.





Adult-Onset Immunodeficiency in Thailand and Taiwan


Sarah K. Browne, M.D., Peter D. Burbelo, Ph.D., Ploenchan Chetchotisakd, M.D., Yupin Suputtamongkol, M.D., Sasisopin Kiertiburanakul, M.D., Pamela A. Shaw, Ph.D., Jennifer L. Kirk, B.A., Kamonwan Jutivorakool, M.D., Rifat Zaman, B.S., Li Ding, M.D., Amy P. Hsu, B.A., Smita Y. Patel, M.D., Kenneth N. Olivier, M.D., Viraphong Lulitanond, Ph.D., Piroon Mootsikapun, M.D., Siriluck Anunnatsiri, M.D., Nasikarn Angkasekwinai, M.D., Boonmee Sathapatayavongs, M.D., Po-Ren Hsueh, M.D., Chi-Chang Shieh, M.D., Ph.D., Margaret R. Brown, B.S., Wanna Thongnoppakhun, Ph.D., Reginald Claypool, R.N., Elizabeth P. Sampaio, M.D., Ph.D., Charin Thepthai, M.Sc., Duangdao Waywa, M.Sc., Camilla Dacombe, R.N., Yona Reizes, R.N., Adrian M. Zelazny, Ph.D., Paul Saleeb, M.D., Lindsey B. Rosen, B.S., Allen Mo, B.S., Michael Iadarola, Ph.D., and Steven M. Holland, M.D.

N Engl J Med 2012; 367:725-734 August 23, 2012


Conclusions
Neutralizing anti–interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection.



And more details from NIH/NIAID.



NIH Researchers Find Possible Cause Of Immune Deficiency Cases In Asia


Autoantibody May Cause Susceptibility to Opportunistic Infections

WHAT:




A clinical study led by National Institutes of Health investigators has identified an antibody that compromises the immune systems of HIV-negative people, making them susceptible to infections with opportunistic microbes such as nontuberculous mycobacteria (NTM). In this study conducted at hospitals in Thailand and Taiwan, the researchers found that the majority of study participants with opportunistic infections made an antibody against interferon-gamma (IFN-gamma), a cell-signaling molecule thought to play a major role in clearing harmful infections. The study findings will appear online in the August 23rd issue of the New England Journal of Medicine.


NTM are close relatives of the bacterium that causes tuberculosis and can cause severe lung disease. NTM and other opportunistic infections are common in people with immune deficiency diseases, such as AIDS, but they are rare in people with healthy immune systems. However, researchers in Southeast Asia have recently reported several cases of NTM infections in people with no known problems with their immune systems.



The study, led by Sarah Browne, M.D., of the National Institute of Allergy and Infectious Diseases, and Peter Burbelo, Ph.D., of the National Institute of Dental and Craniofacial Research, enrolled 203 people, ages 18 to 78 years old. Of these participants, 52 had NTM infections, 45 had other opportunistic infections with or without NTM co-infection, 58 had tuberculosis, and 48 were healthy volunteers. All participants were HIV-negative.
The investigators examined participant blood samples for antibodies to cell-signaling molecules such as IFN-gamma. Eighty-eight percent of the people with NTM or other opportunistic infections had antibodies that blocked their own IFN-gamma (called autoantibodies).



The autoantibodies inhibited IFN-gamma function, hindering the immune system’s ability to clear infection, causing a syndrome that made these study participants more vulnerable to opportunistic infections. More work is needed to determine why people in Southeast Asia appear to be predisposed to the development of this autoimmune condition.


Because the average age of the study participants with NTM or other opportunistic infections was 50 years, the investigators speculate that these antibodies develop over time as a result of combined genetic and environmental factors. Having identified the likely cause of this syndrome, the study authors say it may be possible to treat the underlying problem by targeting the cells that make the IFN-gamma autoantibodies.


ARTICLE:
SK Browne et al. Adult onset immunodeficiency in Thailand and Taiwan. New England Journal of Medicine. DOI: 10.1056/NEJMoa1111160 (2012).

Posted by Michael Coston at 7:12 AM

[Emily]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

This sounds like another emerging autoimmune disease.

The virus that causes AIDS -- HIV -- destroys T-cells, key soldiers of the immune system that fight germs. The new disease doesn't affect those cells, but causes a different kind of damage. Browne's study of more than 200 people in Taiwan and Thailand found that most of those with the disease make substances called autoantibodies that block interferon-gamma, a chemical signal that helps the body clear infections.

Read more: http://www.ctvnews.ca/sci-tech/new-d...#ixzz24MtzCNmY

I think this study was led by the NIH researcher, Dr. Browne, interviewed in your article, Alert:

http://bloodjournal.hematologylibrar.../17/3933.short

Anti-CD20 (rituximab) therapy for anti?IFN-γ autoantibody?associated nontuberculous mycobacterial infection

They are using rituximab to treat this, which is used in persistent cases of anti-NMDAR encephalitis. Both disease seem to have been recognized about the same time frame, and in Asia first.

Here's a study done in California:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773839/

Of the 20 cases tested, ten anti-NMDAR+ cases were identified; two patients were identified by retrospective testing and eight cases were identified prospectively. All ten patients were negative for viral studies, but four had a positive serum Mycoplasma IgM. The demographic, clinical, laboratory, and imaging findings of the ten cases are summarized in Table 1, while the frequencies are found in Table 2. The median age was 18.5 years (range 11?31 years), and none were of Caucasian descent, while there was a predilection for Asians/Pacific Islanders (50%).

But the targets of the autoimmune attacks are very different. It's a big mystery as to why these autoimmune diseases are emerging.

[Summerflower]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

It's a big mystery as to why these autoimmune diseases are emerging.

Also I'm thinking of Myalgic Encephalomyelitis / Chronic fatigue immune dysfunction syndrome. This emerged in the early 1930s and up to 20 Million people are now affected.

http://en.wikipedia.org/wiki/Chronic_fatigue_syndrome

[Emily]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

Also I'm thinking of Myalgic Encephalomyelitis / Chronic fatigue immune dysfunction syndrome. This emerged in the early 1930s and up to 20 Million people are now affected.

http://en.wikipedia.org/wiki/Chronic_fatigue_syndrome

http://www.plosone.org/article/info%...l.pone.0026358
Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

[Summerflower]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

Prof Ian Lipkin, from Columbia University, is looking at retroviruses and Chronic Fatigue Syndrome / Myalgic Encephalomyelitis.

http://cii.columbia.edu/blog.htm?cid=CalAzy&mid=565

[alert]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

Summerflower, we need to be VERY careful not to associate the various illnesses. One of the biggest sources of confusion, and the reason for the 2+ year delay in identifying the illness in the Chinese outbreak, was the association of unrelated CFS-like illnesses with the unknown "mystery illness".

A large number of individuals and sources were attempting to link the unknown illness to chronic fatigue syndrome, a link that ultimately turned out not to be warranted.

The cause of CFS remains completely unknown at this time.

[Summerflower]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

Hi Alert, Yes of course.

It's a big mystery as to why these autoimmune diseases are emerging.

I was just listing chronic fatigue syndrome as another autoimmune disease in response to Emily's comment above.
I agree with Emily that its a big mystery as to why these autoimmune diseases are emerging.

[alert]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

http://www.promedmail.org/direct.php?id=20120823.1259574

Published Date: 2012-08-23 18:21:18
Subject: PRO/EDR> Adult-onset immunodeficiency syndrome - Asian patients, not HIV
Archive Number: 20120823.1259574

ADULT-ONSET IMMUNODEFICIENCY SYNDROME - ASIAN PATIENTS, NOT HIV
************************************************** *************
A ProMED-mail post

http://www.promedmail.org

ProMED-mail is a program of the
International Society for Infectious Diseases

http://www.isid.org

Date: Thu 22 Aug 2012

Source: Associated Pres [edited]

[The entire original post from the AP is reproduced here. A summary of the NEJM paper by the ProMED moderator follows - alert]

Communicated by:

ProMED-mail

<promed@promedmail.org>

[It is assumed the preceding press statement is based on the paper titled: Adult-Onset Immunodeficiency in Thailand and Taiwan. By Sarah K. Browne and other, published in the current issue of the New England Journal of Medicine (N Engl J Med 2012; 367:725-734 August 23, 2012; http://www.nejm.org/doi/full/10.1056/NEJMoa1111160). The authors' summary follows.



Background


----------


Autoantibodies against interferon-gamma are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown.

Methods


-----------


We enrolled 203 persons from sites in Thailand and Taiwan in 5 groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained.

Results


------


Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-gamma in normal cells. High-titer anti-interferon-gamma autoantibodies were detected in 81 percent of patients in group 1, 96 percent of patients in group 2, 11 percent of patients in group 3, 2 percent of patients in group 4, and 2 percent of controls (group 5). 40 other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering.

Conclusions


----------


Neutralizing anti-interferon-gamma autoantibodies were detected in 88 percent of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection.



The adult-onset immunodeficiency syndrome, mediated by the production of anti gamma-interferon antibodies, does not appear to be contagious and the condition develops around age 50 on average but does not run in families, which makes it unlikely that a single gene is responsible, The prevalence of this condition in Asian people, though not necessarily resident in Asia, implies a genetic origin rather than a cryptic infectious agent. But anything is possible. - Mod.CP]


.................................................d k/sb/cp/ejp/ml

[Emily]

Re: AIDS-like illness reported in Asia - genetic and environmental factors suspected

http://www.ncbi.nlm.nih.gov/pubmed/2500007

J Biol Regul Homeost Agents. 1989 Jan-Mar;3(1):8-12.
Anti-interferon-gamma antibodies in sera from HIV infected patients.
Caruso A, Foresti I, Gribaudo G, Bonfanti C, Pollara P, Dolei A, Landolfo S, Turano A.
Source

Institute of Microbiology, University of Brescia, Italy.
Abstract

High serum levels of antibodies to interferon-gamma (IFN-gamma) have been found in patients infected with human immunodeficiency virus (HIV). A radioimmunoassay (RIA) with a recombinant IFN-gamma protein or an affinity purified IFN-gamma preparation as antigens, was developed to detect the specific anti-IFN-gamma antibodies. Reactivity of sera to IFN-gamma was confirmed by Western blot analysis. These antibodies, however, do not seem to recognize the active site of the molecule, since they do not neutralize the antiviral IFN-gamma activity in a biological assay. These results enforce the hypothesis of the role of autoimmunization during the course of the disease.

PMID:
2500007
[PubMed - indexed for MEDLINE]

http://arthritis-research.com/content/15/1/105

Adult-onset immunodeficiency - why is it important in rheumatology?
Hans-Hartmut Peter

Arthritis Research & Therapy 2012, 15:105 doi:10.1186/ar4121
[snip]
Why present adult-onset immunodeficiency to a readership of rheumatologists? The answer is simple. First, immunodeficiency is a booming field of translational immunology that should not be ignored by the rheumatologist. Second, there are increasing numbers of patients with symptoms of immunodeficiency being seen in rheumatology clinics. Rheumatologists are often confronted with patients suffering from either systemic autoimmune diseases plus drug-induced increased susceptibility to infections or with alarming symptoms or with unusual laboratory values all indicative of a primary dysfunction of the immune system. Alarming symptoms include recurrent bouts of fever, frequent and prolonged infections, unusual pathogens, hepatosplenomegaly, lymphadenopathy, recurrent mucocutaneous candidiasis, spontaneous bone fractures, lung abscesses and noncaseating granulomas. Typical laboratory findings are leukopenia, lymphopenia, low CD4 counts, myelodysplasia, autoimmune hemolytic anemia and thrombocytopenia as well as low concentrations of serum immunoglobulins or high IgE or IgM serum levels...