http://www.nccn.net/~wwithin/TBtest.doc
(nice formatted Word Doc)

The Rationale for TB Screening of Healthcare Workers (HCWs) and Other Low-risk Populations:

A Critical Review of CDC Policy or
The Emperor Has No Clothes, Cough or Fever

Summary:
1) Healthcare workers(HCWs) are identified by the CDC as a high risk group for development of TB; however, no current clinical data exists that supports that contention. The overwhelming majority of TB, as with most infectious diseases, occur in individuals with compromised immune systems.

2) Targeted TB testing in HCWs is only recommended by the CDC; however, local facilities have often initiated mandatory testing policies amongst employees, subject to employment termination for refusal.

3) According to the CDC, initiation of chemoprophylaxis in the TB positive HCW is not mandatory in circumstances of negative health exam, negative chest radiograph and absence of additional risk factors. The overwhelming majority of HCWs who test positive have normal clinical exams and radiographs.

4) Current randomized studies of chemoprophylaxis in the TB skin test positive, healthy HCWs do not exist. Some randomized studies in AIDS patients show TB disease occurs with higher incidence in those receiving therapy for latent TB compared with those receiving no therapy.

5) One analysis showed no benefit to treatment of LTBI in all non disease states despite risk factors. Risks associated with chemoprophylaxis for TB may outweigh potential benefits.

6) TB skin test is inaccurate but yet is considered the gold standard to diagnose infection. Because there is no better method to diagnose infection, its actual test accuracy is unknown.

7) Phenol, a component of Tubersol, is a highly toxic industrial chemical with numerous known health risks yet this is a component of Tubersol.

8) The CDC claims that the TB skin test is safe, yet the manufacturer states that NO known carcinogenicity studies have been performed. In fact, phenol, when injected intradermally, is associated with skin cancer development in test animals.

9) The CDC states that TB skin testing is safe in pregnant women yet manufacturers have NOT performed mutagenicity testing. This is alarming in consideration that phenol, a component of Tubersol, is a known mutagen.

Summary: TB skin testing should not be required of otherwise healthy HCWs unless safety and efficacy studies have proven a benefit in this low risk population. The FDA should halt the use of Tubersol pending the standard and usual safety testing has been performed, including carcinogenicity and mutagenicity testing.

INTRODUCTION
The following document is a review of current TB screening policies for HCWs. This includes an analysis of two published documents. First, "The Core Curriculum on Tuberculosis" (4th edition, 2000), published by the U.S. Department of Health and Human Services and The Centers for Disease Control. The second, a joint statement published in the MMWR, June 2000, represents the works of the American Thoracic Society and the CDC.

After anti-TB medications became available in the 1940's, a gradual decline of the number of TB cases were reported from 1953 until about the mid 1980's when there was a 20% increase from 1985 through 1992 (1, p. 16). According to the CDC, the major factors for this rise were 1) a deterioration of TB public health infrastructure, 2) HIV/AIDS epidemic, 3) immigration and 4) transmissions in congregate settings. (It would seem most logical that, since HIV increases the risk of TB by as much as 100-fold, and AIDS was an entirely new disease entity coinciding with this period of TB resurgence, that HIV would be the most likely contributing factor for rising cases of TB.) The CDC  claims that the deterioration of the TB public health infrastructure was a major factor for TB resurgence, yet, the CDC publication offers no supportive evidence of this conclusion. If this were true, there would be an increase in the incidence of TB amongst healthy HCWs. Data to this effect is absent. In fact, I have not discovered any published data that proves the hypothesis that the neglect in screening programs resulted in more cases of TB during this era.

It is interesting to note that the incidence of TB in the US has declined steadily since the 1900's. This decline was noted in spite of the fact that pharmaceutical therapies were unavailable for nearly five decades. How did the incidence of TB decline in the absence of TB screening programs and
chemoprophylaxis? The CDC's contention that the small TB spike occurring in the late 1980's was the result of deteriorating TB control infrastructure seems very questionable.

The unrealistic goals of the CDC
In 1989, the CDC announced the goal of eliminating tuberculosis from the US by 2010. Plans and task forces were then established to accomplish this goal. To apparently help achieve this goal, the CDC now concludes that healthcare workers are part of a "targeted" population of individuals who
are at high risk for developing the infection  (TB skin tested positive) and developing subsequent clinical disease of tuberculosis. Institutional TB skin testing is recommended for the staff of healthcare facilities (1, p. 25;90-91).

Elimination of TB is unachievable and unrealistic. First, our government's open door immigration policy allows countless high risk individuals into the US undetected on a daily basis. How can those individuals be screened when our government refuses to identify illegal aliens and allows them access to the healthcare system? Secondly, since the majority of TB occurs in the immune compromised host, how will the disease be irradicated unless the coexisting conditions are eliminated. AIDS, cancer and chemotherapy populations grow each year. Thirdly, false negative skin testing alone will bypass significant numbers of infected individuals (even one case missed in screening is significant when the goals are 100% eradication and the CDC claims a 23% transmission rate!) .

CURRENT POLICIES

Risk analysis for TB and the rationale to screen HCWs There are an alleged 10-15 million infected (skin test positive) persons in the US (1, p20:no source given).  Of these, if not detected and no preventative treatment is initiated, the CDC states that 10% will develop TB at some point, 5% within the first 1-2 years, in spite of normal immune system (1, page 7; (2) page 8). The  primary source of this data is not referenced in the CDC publications. Accurate natural historical data is critically important in order to support screening of asymptomatic HCWs. A study recently published in JAMA (3) challenges the CDC report and showed that of the estimated worldwide TB infection (TB test positive) rate of 32%, only 7.96 million cases of disease were reported in 1997, or a TB disease incidence of less than  0.2% amongst infected individuals (assuming a 6 billion world population). This is far less than the 5-10% rates quoted in the CDC publications and are consistent with the general concept that TB is a disease of opportunity, generally harmless to the immune competent
host. This data alone should challenge the wisdom in screening otherwise
healthy populations.

In addition, the CDC quotes a transmission rate of 21-23% (ref 1, page 6): this seems alarmingly high (referenced from "CDC Program Management Report"-unavailable). This implies that 21-23% of all contacts with a TB patient will develop the infection or disease! Demographic data simply does
not support this alarmingly high rate.
Summary of CDC's High Risk Groups for Developing TB (modified from 1, p 8)

HIV/AIDS
Silicosis
Substance abuse
Hematological and reticuloendothelial disease 
Chronic malabsorption and malnutrition
Diabetes Mellitus
Prolonged steroid therapy
Solid organ transplantation
Cancer of head and neck
Chronic renal failure
Low body weight
Healthcare workers

Table 3 in Ref 2 (p 9) assigns relative risk values for many of these groups; however, missing in this table are relative risk data of HCWs with healthy immune systems! 

DISEASE Relative Risk
Silicosis  30
Diabetes mellitus 2-4.1
Chronic renal failure/hemodialysis 10-25.3
Gastrectomy 2-5
Jejunoileal bypass 27-63
Solid organ transplant
 renal 37
 cardiac 20-74
Carcinoma of head or neck 16

The HCWs receiving mandatory yearly testing should be informed of his relative risk to develop TB disease. With the sole exception of the HCWs, all individuals designated  in the CDC publications as high risk are those with abnormal systemic or pulmonary immune defenses. But is this proven? Is it possible that, as with many other diseases, the integrity of the host immune response system is of far greater importance than the presence of mere exposure to microorganisms?  In fact, if HCWs were not at higher risk than the general population, unless they had additional medical risk factors, screening of HCWs would be no more valid than screening 100% of the population.

Although historical studies showed higher infection and disease rates in HCWs in an era when the prevalence of TB was higher, modern era data suggests this is no longer the case. McKenna, et al (4) concluded that the "overall case rate of tuberculosis in healthcare workers was slightly lower than the natural rate....most healthcare workers do not appear to have a risk of clinically active tuberculosis greater than the general population".  This conclusion has been confirmed in other recent studies (5).

TESTING AND THERAPY

The TB skin test
Tubersol, manufactured  by Aventis, is comprised of a purified protein derivative of the organism M. tuberculosis. Its efficacy as a screening test is derived from the delayed hypersensitivity response in the infected host after intradermal injection. The exact number of doses sold in the US annually is apparently a guarded secret (personal communication, Aventis Pasteur, Sept 12, 2003).

False negatives are thought to occur frequently. Listed causes (6) include anergy, recency of exposure, viral infections, various vaccinations, overwhelming infection, various drugs(steroids) and malignancies and any condition that can impair the cell mediated immune response (sarcoid, malnutrition) . False positives include nontuberculous infections and BCG vaccine state. In spite of these inaccuracies, the CDC states that for persons with latent TB infection who have a normal immune system, test sensitivity approaches 100% ( 2, p 11). This statement is ridiculous for several reasons. First, the TB skin test is the gold standard, so it is not possible to accurately gauge the incidence of false negative exams. The sensitivity of this test , in actuality, remains unknown. Secondly, false negative exams occur in the groups who are at the very highest risk for disease in the first place, meaning that the false negative tests weigh heavily against the efficacy of screening in the most important risk groups-the one's most likely to develop disease in the first place!

Compounding the inaccuracies of the TB skin test is the revelation that only one in three positive reactions are correctly classified as positive by screen test interpreters (7).

Serious untoward reactions to the Tuberculin substance have been reported. Adverse reactions include local skin reactions (vesicles, ulcers, necrosis, scarring), rashes, and  anaphylaxis. Shockingly, in spite of its widespread use, the manufacturer's insert 6)  states that Tubersol has not been evaluated for its carcinogenic or mutagenic potentials or influence on fertility. This is surprising
considering the widespread use and frequent repetition intervals of administration, particularly to the long term HCWs employee. It is also irresponsible for the CDC to  state that tuberculin is safe and reliable throughout the course of pregnancy (1, p. 29). This is in direct opposition with the manufacturers statement that Tubersol is NOT tested for mutagenicity. It is a fact that a declaration of safety without testing is a declaration of assumed safety, not a proven scientific fact.

What can we gather from the toxicology of its components? Tubersol contains 0.28% phenol(5), which is known to be highly toxic to humans (8). The 1969 American Heritage Dictionary defines phenol as a "caustic, poisonous, white, crystalline compound...derived from benzene and used in various resins, plastics, disinfectants, and pharmaceuticals. Phenol is also known as 'carbolic acid.'" Amongst the known adverse reactions to phenol are:

-irritating to skin, eyes, mucous membranes in humans
-ingestion in humans may cause death, paralysis, weakness, seizures, coma, respiratory collapse
-animal testing has shown severe toxicity
-limited data available on the chronic effects in humans, but in humans has caused dermal inflammation and necrosis, arrhythmia's, hepatic enlargement and dysfunction.
-animal studies have shown chronic exposure effects the CNS, respiratory, renal and cardiovascular systems
-no human development and reproduction studies have been performed BUT...-animal studies have shown reduced weight, growth retardation, abnormal development, increased maternal mortality and decreased maternal weight gain.
-no studies have been done in humans with regards to carcinogenicity BUT...- animal studies show phenol applied to skin is a skin carcinogen in mice!

These findings should be embarrassing to the FDA and shocking to recipients of the TB skin test. The CDC has no supportive data to state unequivocally that this test  agent "is both safe and reliable throughout the course of pregnancy" (1, p 29) when animal studies exist to the contrary and
demonstrate that one of its constituents is a skin carcinogen! How did the FDA approve this agent for use in the tuberculin skin test? Without testing, no conclusions can be made as to the safety of Tubersol, regardless of what comments critics might offer such as, for example, "....but it is such a small dose". Has Aventis proven that Tubersol is safe? The FDA, CDC and Aventis simply cannot answer that question with available scientific data.

The myth of screening and prophylactic therapy for the skin test positive HCWs- is there any proof of benefit?

With regards HCWs, a 1992 survey of 210 hospitals in the U.S. calculates the tuberculin reactivity rate of only 0.64% (9). This rate would even be expected to be  lower today with falling prevalence of TB. Is it really worth screening 156 health HCWs in order to discover one positive convertor? In turn that convertor invariably will have a negative clinical exam and radiograph.

Cost benefit analysis was studied at a time when the tuberculin agent was $10. The costs of screening was $4,500 per person eligible for treatment and and $350,000 per case of TB prevented (10).  The current cost of tuberculin is $18. It is particularly disappointing that as few as 25% of treated individuals actually are able to complete therapy.

Do local TB statistics support screening studies? Illinois Department of Public Health Statistics (11) compiling TB disease in all counties between 1990-2001 reveals that 86% of 104 counties reported on average fewer than two TB cases per year and 67% as few as one case annually! How can screening healthy HCWs in those counties with such low disease prevalence be justified? It simply cannot.

Inconsistencies within the CDC guidelines are easily found.  First, the CDC publications do not  support blanket chemoprophylaxis for all TB skin positive individuals with normal health exams and radiographs, yet one wonders how the CDC could NOT suggest therapy if the CDC believes their own statistic that 10% of these individuals really were destined to developed disease. If a subsequent TB positive test results in a negative clinical exam and chest radiograph and a decision NOT to treat, why not replace the risky, inaccurate TB test with a clinical exam and an employee radiograph? The decision to test SHOULD be a decision to treat.

Secondly, in order to justify chemoprophylaxis, outcomes studies must show proven safety, efficacy and long term benefit. If there were no proven benefits to the treatment group over non treated individuals, then the screening program would be without merit. Are there studies that support better outcomes in the treated group vs. untreated group in healthy HCWs? This author has discovered no such literature. Other studies challenge the supposition of beneficial chemoprophylaxis.

In Ref 2 (pg. 12), there is an allusion to seven trials in the 1950's -60's which demonstrated reduction of TB disease in the 25-92% range with chemoprophylaxis. Since these studies were done in the decades when TB was significantly more prevalent, approximately 50 years ago, they are no longer valid. Secondly, these studies almost exclusively involved non-US participants in countries where environmental and health issues were substantially different than in the US. This is not applicable to the current issue of treatment outcomes in healthy US HCWs treated for LTBI. The MMWR report  (2, p 13) also refers to the IUAT trial which indicated a reduction of LTBI by 65-75%. Unfortunately, this trial was also performed in non-US individuals, all of whom had abnormal chest radiographs. This is a significantly different population than the typical US HCW who rarely displays an abnormal radiograph (2, pg. 11, and personal experience). The MMWR report attempts to further inflate these success statistics by quoting a 69-93% efficacy in "compliant" participants, a statistic that has little significance in real-life clinical outcomes. A closer look at the success rates shows they are quoted in meaningless percentages (if i bought three lottery tickets instead of one, does the 200% improved chance of winning mean anything in the real world?) Where is the statistical proof (for CDC authors, that would be the "p" values)? For the group with fibrotic lesions < 2 cm (the group closest to the most typical HCWs), there was NO STATISTICALLY SIGNIFICANT DIFFERENCE in placebo treatment and 12 week, 24 week and 52 week regimens. In addition, these trials were conducted from 1969-1977, over 30 years ago when TB rates were generally higher than today.

The MMWR report reviewed randomized treatment of LTBI in HIV positive individuals in seven studies from 1980-1997, although only one was strictly in the US (2,p  16). These results were decisively mixed, with some studies actually demonstrating higher TB rates in groups receiving isoniazid than nontreated groups! If benefit of prophylaxis is at best equivocal in high risk individuals, on what basis does the CDC use to justify prophylaxis in the healthy HCWs?

In a more recent study involving a New York area population of HIV-positive patients with anergy, there was a no significant difference in TB rates in those receiving anti-TB prophylaxis with INH compared with placebo (12). Once again, if efficacy of therapy for LTBI in the highest risk group is
unproved, how can we justify prophylaxis in low risk HCWs with an intact immune system?

In order to answer these questions more completely with regards to the low risk HCWs, Tsetat et. al. (13)  performed a decision analysis of screening test positive adults and concluded that "from the perspective of the individual adult with a positive skin test for TB, we cannot make a case for INH therapy". Furthermore these authors distinguished TB mortality rates from individuals dying with their disease rather than because of their disease and calculated lower TB mortality rates than earlier authors. With this factored into the risk-benefit analysis they further concluded that "it does not matter how high the rate of developing TB is-the preferred strategy is always "NO INH". These authors do not recommend therapy unless active TB disease is detected.

The FDA safety record with anti-tuberculous drugs The 2000 MMWR report states:

"In 1965, when Isoniazid was first recommended in the United States for treatment of LTBI , it was not thought to cause severe toxicity. However studies in the late 1960's suggested that isoniazid did cause hepatitis....It was not until the 1970's that when several persons receiving isoniazid for LTBI died from hepatitis that the likelihood of isoniazid hepatitis was understood" (2, p 15-16).

Most clinicians are now very aware of the dangers of INH therapy and the need for careful clinical evaluation of all patients receiving therapy for LTBI. Unfortunately, this  failure of the CDC/FDA to detect toxicity in recommended drug therapies prior to their widespread use and acceptance was not an isolated incidence.

The CDC manual published in 2000 (1, pg. 78) did not discuss potential hepatotoxicity of two additional anti-TB drugs, rifampin and pyrazinamide. In 2003, the CDC published a retraction of the recommendation of these drugs for LTBI based on the discovery of 48 cases of severe liver injury and 11 related deaths (14). An alarming 5% of patients who started this therapy did not complete the regimen due to hepatic toxicity. With these high percentages of complications it is difficult to comprehend how such severe adverse reaction rates were not discovered in pilot studies before the CDC issued widespread recommendations for their use in LTBI. Understandably, the FDA's and CDC's track record in TB drug safety testing would leave one even more concerned of their widely held opinion of the untested but assumed safety of the phenol containing skin testing agent Tubersol.

When recommendations become mandatory
According to the CDC, the "risk assessment should identify which HCWs have the potential for exposure and the frequency with which the exposure may occur. This information can then be used to determine which HCWs to include in the skin testing program and the frequency with which they should be tested" (1, p 91). This site or occupation-specific risk assessment of all HCWs is a targeted testing program. It is uncertain how individual institutions implement targeted testing. Radiology technicians currently undergo mandatory yearly testing at Memorial Medical Center and Springfield Clinic. It is my understanding that employment can be terminated in HCWs refusing to be tested.

The FDA and CDC: conflicts of interest

The following was published in the Washington Free Press as the results of an UPI investigation(15).

In the year 2000, the U.S. House of Representatives Committee on Government Reform held hearings to examine conflicts of interest in the two official panels that control vaccine policy in the U.S. (there is one panel at the Centers for Disease Control and one at the FDA). Among the committee's findings were widespread conflicts of interest among panel members in the form of financial ties to pharmaceutical companies who manufacture vaccines that the panels oversee. Following is a summary of the committee findings, assembled by Dr Joseph Mercola.

    * The CDC routinely grants waivers from conflict of interest rules to every member of its advisory committee.

    * CDC advisory committee members who are not allowed to vote on certain recommendations due to financial conflicts of interest are allowed to actively participate in committee deliberations and advocate specific positions.

    * The chairman of the CDC's advisory committee until recently owned 600 shares of stock in Merck, a pharmaceutical company with an active vaccine division.

    * Members of the CDC's advisory committee often leave key details out of their financial disclosure statements, and are not required to provide the missing information by CDC ethics officials.

    * Three out of the five FDA advisory committee members who voted to approve the rotavirus vaccine in December 1997 had financial ties to the pharmaceutical companies that were developing different versions of the vaccine. The vaccine was recalled a few years later after numerous public
complaints of serious bowel obstruction due to the vaccine.

* Four out of the eight CDC advisory committee members who voted to approve guidelines for the rotavirus vaccine in June 1998 had similar financial ties.

In a USA Today report of conflicts of interest on the 18 advisory committees established by the FDA, the following was reported (16).

* 54% of the experts hired to advise the government on safety and efficacy policies had financial relationships with the pharmaceutical companies that would be directly affected by their opinions

* since 1988, the FDA has waived on more than 800 occasions the federal law that would have other wise prohibited use of experts with financial conflicts

* 92% of FDA advisory meetings had at least one member with a conflict of interest

* 55% of FDA advisory meetings were held when at least half of the committee members had conflicts

*  in 102 FDA advisory meetings dealing with the fate of a specific drug, 33% of the experts had a financial conflict.

The pharmaceutical industry enjoys the benefits of increased revenue when government regulatory bodies pass favorable legislature promoting use of its products. The influential power of this industry has been subject to much criticism. According to Public Citizen's report (17)

Drug industry lobbying ranks include 26 former members of Congress. All told, 342 lobbyists (51 percent of those employed by the industry) have "revolving door" connections between K Street and the federal government.

The Pharmaceutical Research & Manufacturers of America (PhRMA), which represents more than 100 brand-name prescription drug companies, shelled out $14.3 million last year, a 26 percent increase from 2001 and nearly double what the group spent in 2000. PhRMA hired 112 lobbyists in 2002, 30 more than the year before.

Brand-name drug manufacturers spent more than 20 times as much on lobbying as generic drug-makers - $76 million versus $3.4 million. And they employed seven lobbyists for every one hired by their generic counterparts. Biotechnology companies spent $12 million on lobbying.

Since Public Citizen began tracking the drug industry's lobbying activities in 1997, the industry has spent nearly $478 million lobbying the federal government. In that same period, the top 25 pharmaceutical companies and trade groups gave $48.6 million to federal campaigns. Well over $100 million more went to paying for issue ads, hiring academics, funding non profits and other activities to promote the industry's agenda in Washington. All told, the drug industry has spent nearly $650 million on political influence since 1997.

Drug company profits have been staggering.

*By comparison, all companies in the Fortune 500 suffered a combined loss of 66.3 percent in profits from 2001 to 2002. The pharmaceutical industry soared past other business sectors - raking in profits five-and-a-half times greater than the median for all industries represented in the Fortune
500.

*17% profit (as a percent of revenue) far outpaces the 3.1% median value for all other Fortune 500 industries.

*Profits registered by the 10 drug companies on the list were equal to more than half the $69.6 billion in profits netted by the entire roster of Fortune 500 companies - when all losses are subtracted from all gains.

The dollars available to the drug companies for influencing industry agencies are staggering. There is no question that the CDC's policy of widespread use of Tubersol for testing HCWs has widely increased the market for their product. National advisory committees have been an essential and necessary part of healthcare policy in this country but has been also linked to significant conflicts of interest, as reported in JAMA (18). In a review of of doctors involved in establishing national guidelines on disease treatment, they found that :

85% of guideline authors have some sort of relationships with drug companies, and they are often not disclosed

38% of respondents said they had served as employees or consultants for drug companies; 58% received research money

59% had links with drug companies whose medications were considered in the particular guidelines they authored, almost all cases predating the guideline creation process

These numbers may be even greater, as only 52% of authors responded

These are disturbing revelations. Questions must be asked regarding the establishment of national TB skin testing policies for healthy HCWs. First, to what degree has Aventis benefited from the expansion of mandatory testing to healthy HCWs in the United States? Secondly, did advisory committee members who established TB skin testing policies have financial ties with Aventis?

Conclusions

There is no clinical scientific  evidence that the healthy HCW is at higher risk than the general population. Furthermore, even in positive TB reactors, there is no modern scientific evidence that would support benefit of chemoprophylaxis for LTBI in healthy HCWs. The Tubersol agent in use has not been adequately tested for safety and its accuracy is questionable and unproveable. The TB skin testing policy for LTBI in the typical HCW is of doubtful efficacy and benefit and of unknown risk to the individual HCW. Mandatory testing is unsupported. Most tragically, our government health
agencies have a tract record of errors in drug safety testing and these same agencies have conflicts of interest that raise serious questions of the mechanisms that healthcare policies are established.

Recommendations
Immediate suspension of mandatory TB skin testing policies of HCWs is reasonable considering the lack of clinical efficacy of testing or subsequent treatment of LTBI. A review of current local and state public health records could be undertaken to determine a) the incidence of TB skin test reactivity amongst HCWs, b) the true risk of TB disease in the skin reactive HCWs who fails to receive prophylaxis for LTBI and c) the outcome analysis of the HCWs placed on preventative drug therapy and finally d) the review or performance of pertinent toxicology studies on Tubersol that establishes this agent as  safe.

References

1) Core Curriculum on Tuberculosis. What Every Clinician Should Know. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Fourth Ed. 2000

2) Targeted tuberculin testing and treatment of latent TB infection. MMWR; 49, June 9, 2000

3)JAMA 1999;282:677-686

4) McKenna, MT, et. al., The association between occupation and tuberculosis. A population-based study. Am. J. Resp. Crit Care Med.154: 587-93, 1996.

5) Kwan, SYL, et. al., Nosocomial tuberculosis in hospital staff in a Hong Kong chest hospital. Chinese Med J. 103, 909-914, 1990.

6) Tubersol PDR, 2003

7) Underreading of the tuberculin skin test reaction. Kendig, et.al., Chest,113,1175,1998

8) http://www.lakes-environmental.com/toxic/PHENOL.HTML

9) Fridkin, SK, et. al., SHEA-CDC Tuberculosis survey, Part 1. Status of tuberculosis infection control programs at member hospitals. Infect. Control Hosp Epidemiol. 16: 129-134, 1992

10) Raad, I. et. al., Annual tuberculin skin testing of employees at a university hospital: a cost-benefit analysis. Inf. Control Hosp Epidemiol; 10, 465-9, 1989.

11) http://www.idph.state.il.us/health/infect/tb90-01.htm

12) F. Gordin, et. al., NEJM; 337(5), 315-320, 1997.

13) Tsevat, J, et. al., Isoniazid for the tuberculin reactor: take it or leave it. Am Rev. Respir. Dis., 137: 215-220, 1988.  

14) Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection---United States, 2003. MMWR; 52(31), 735-39, 2003.

15) http://www.washingtonfreepress.org/61/conflictsOfInterest.htm

16) http://www.mercola.com/2000/oct1/fda_drug_approvals.htm

17) http://www.citizen.org/pressroom/release.cfm?ID=1469-profit margins by
drung companies

18) N.K. Choudhry, et. al. Relationships between authors of clinical practice guidelines and the pharmaceutical industry JAMA; 287,612-617, 2002.

http://www.indystar.com/articles/6/156065-8596-052.html

Outbreak of TB concerns agencies
Fort Wayne cases may signal new strain of disease that spreads easily, health official reports.
By Andy Gammill
andy.gammill@indystar.com
June 19, 2004

Federal and state health workers have been dispatched to Fort Wayne to help control a growing tuberculosis outbreak that may represent a new strain of the disease. The disease has alarmed local doctors because the Fort Wayne patients appear to have contracted it from casual social contact, said Allen County Health Commissioner Dr. Deborah McMahan.

Tuberculosis traditionally has spread among people in prolonged contact with one another, such as family members or refugees in camps. In Fort Wayne, people seem to be catching the airborne bacteria from their friends and developing the disease, McMahan said.

One person has died, and at least 17 cases over a three-year span have been definitively connected. As many as 28 cases may be tied to the outbreak, the Fort Wayne-Allen County Health Department said. Allen County, about 120 miles northeast of Indianapolis, usually reports about eight tuberculosis cases a year, but 13 cases already have been reported this year. Federal officials have described this outbreak as a crisis.

Laboratory tests from the Fort Wayne patients do not match samples taken during any other U.S. outbreak of tuberculosis, McMahan said. "The real significance to having identified a new strain is it tells you it originated here in Fort Wayne," she said. Health Department officials noticed late last year that they were seeing more cases than usual and began testing older cases to see if they were related.

The Indiana State Department of Health isn´t ready to conclude that there´s a new strain of tuberculosis or that it´s more easily spread, spokeswoman Margaret Joseph said. State and federal health officials are concerned about the outbreak mainly because of its size and the fact that it´s still growing, she said. Everyone who suspects they came into contact with a tuberculosis patient in Fort Wayne should seek treatment and consult with a doctor, Joseph said. Testing and preventing further spread of the disease are essential, she added. A spokeswoman for the federal Centers for Disease Control and Prevention confirmed that the agency has two staffers in Fort Wayne tohelp the local Health Department.

The State Department of Health has two nurses assigned to the case as well. The outbreak has taxed the resources of the state's tuberculosis division, Joseph said. Indiana sees cases of tuberculosis every year, but rarely in such significant clusters, she said. It's also putting a strain on the Fort Wayne-Allen County Health Department, administrator Loren Robertson said.

The department operates a small tuberculosis clinic but doesn't have the staff  to complete the exhaustive investigations required with tuberculosis cases, he said. Public health workers quiz patients about everyone they came in contact with and then track down those people for testing.

One of the recent tuberculosis patients had 590 contacts, Robertson said. Plus, medicine must be delivered to patients daily, taking more staff time, he said. "We had the nurses and an office person, but we didn't have the office staff to do the extent we needed," he said. "We're going off the charts here. We´re running out of space at the clinic." It's unclear how much more the outbreak will grow, but healthworkers say they hope that by getting the word out, they can make sure people are tested if they were exposed.


Tuberculosis
• Cause: Tuberculosis is caused by bacteria that can invade any part of the body but usually attack the lungs. The bacteria are spread through the air from one person to another, mostly through coughing or sneezing. Usually long-term contact is required before one can catch it.

• Symptoms: Symptoms include a severe cough, pain in the chest, coughing up blood or phlegm, weakness, fatigue, weight loss, chills, fever and night sweats.
 
• Diagnosis: Doctors can determine whether the disease is present from a skin prick test, but further tests are required to detect whether a person has an active case of the disease.

Source: Centers for Disease Control and Prevention
 

Hmmm, wonder if they are working on a BCG vaccine in the US? Anyone  know?

Yes, in deed.  See below.

"http://www.vidyya.com/vol6/v6i50_2.htm

Clinical trial of a new TB vaccine in the U.S. begins; New vaccine may prove more potent than 100-year-old current vaccine

The Aeras Global TB Vaccine Foundation and the David Geffen School of Medicine at UCLA announced on 17 February 2004 that they have begun the first clinical trial of a live recombinant tuberculosis vaccine in the U.S. Six volunteers were inoculated today with the new vaccine at the Center for Vaccine Development, St. Louis University, Missouri, under the direction of Dr. Daniel F. Hoft. Volunteers are also being recruited at another trial site in Winston-Salem, North Carolina, by
Piedmont Medical Research Associates under the direction of Dr. Thomas W. Littlejohn III.

The vaccine, known as rBCG30, was constructed by Dr. Marcus Horwitz and his research team at the David Geffen School of Medicine at UCLA. The live vaccine, which uses the current vaccine called BCG (Bacille Calmette-Guerin) as a delivery vehicle, over-expresses the major protein secreted by the TB organism. The Aeras Global TB Vaccine Foundation, the world's only organization dedicated solely to developing and distributing new TB vaccines, conducted the preclinical development and regulatory activities required to begin the study to test the vaccine in humans, in collaboration with Dr. Horwitz.

"The development of the vaccine required a decade-long effort, and we are gratified to see the vaccine progress to clinical trials," said Dr. Horwitz, professor of medicine and microbiology, immunology and molecular genetics at UCLA.

Each year 8 million people develop new cases of TB, and 2 million people die of the disease -- nearly all of them in the developing world. The current TB vaccine used throughout most of the world, BCG,
is almost a century old and has limited efficacy. In conjunction with drug therapy, a more effective vaccine would greatly reduce the TB disease burden around the world.

First developed and tested in TB-susceptible guinea pigs, the new vaccine was found to be more potent than the commercially available BCG vaccine. Funding for basic research, animal testing and vaccine characterization at UCLA was provided by The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

"We are within reach of new vaccines that could not only save millions of lives, but achieve the longstanding goal of bringing TB under control in the developing world," said Dr. Jerald Sadoff, President & CEO of Aeras Global TB Vaccine Foundation, which is sponsoring the human trial with support from the Bill & Melinda Gates Foundation. "This is the first step in using modern vaccines to defeat this global pandemic."

The bacterium that causes tuberculosis -- Mycobacterium tuberculosis -- currently infects 2 billion people worldwide, and is the leading killer of people infected with HIV. TB is an airborne bacterial disease that can spread through the lungs to the bones and the brain. Most forms of TB can be treated with drugs, but the complex regimen takes at least six months to complete, and medicine is not always available in developing countries.

The current clinical trial will enroll 30 healthy adults in the U.S. to test the safety of the vaccine and the immune response it provokes. After the trial has been completed, a similar study will be conducted in South Africa, where Aeras has developed a clinical trial site for TB vaccine studies."

Thank You! How the public cannot see through all of this is beyond me! Fear, fear, and more fear, that is the motto! Not only do people have to be aware of vaccine dangers, but they have to be made aware of how many vaccines are going to be added through scare tactics.
 

 
 
May 25, 2004
The Times
http://www.timesonline.co.uk/printFriendly/0,,1-369-1121662,00.html
 
 
Does your child really need that TB vaccination?
By Juliet Rix
Some experts argue that the vaccination scheme is unnecessary and that resources would be better employed helping high-risk groups
 
 
TUBERCULOSIS (TB) kills more people than any other infectious disease: every year two million people die of it worldwide. Here, after decades of decline, the number of cases has risen by 27 per cent over the past ten years, and London is now statistically a high-risk area.

In the face of all this, parents are naturally keen for their 10 to 14-year-olds to receive the BCG vaccine in the routine schools immunisation programme. But the situation may not be as it first appears. Indeed, thousands of children are being vaccinated unnecessarily, and using up valuable resources that could be better employed elsewhere.

Certainly in some inner-city communities the incidence of TB is now several times higher than the World Health Organisation’s “high-risk” threshold, and rising, but the number of cases among white Britons is still falling, says Peter Ormerod, professor of respiratory medicine at Blackburn Royal Infirmary. “Many of the cases that do occur,” he adds, “are in people aged over 50 who became infected decades ago but have only now developed the disease.”

The fact is that TB is concentrated in certain identifiable sectors of the population: the homeless and communities with close links to parts of the world where TB is rife — particularly Africa and the Indian sub-continent.

What is more, contrary to popular belief, you do not catch TB by sitting next to someone on the bus — or even from a child spitting in the playground. According to the Department of Health (DoH), TB is not highly infectious.

To catch the disease you usually need prolonged close contact — for example, living in the same household — with an adult with active TB, says Dr Delane Shingadia, a senior lecturer in paediatric infectious diseases at St Bartholomew’s Hospital, London. Children with active TB are rarely infectious. Nor do people who are infected but have not developed the  disease (about a third of the world’s population) pass on the infection.

Government policy already recognises the patchy nature of TB by offering BCG vaccination selectively to newborns from high-risk groups. But if “high-risk” children are to be vaccinated at birth, why do we have a schools programme vaccinating predominantly low-risk teenagers? The DoH says the reasons are “historical”.

So has the time come to stop vaccinating thousands of children, most of whom gain nothing from it (a small number of whom suffer adverse reactions) and refocus the resources on those who really need it?

BCG is not an effective vaccine. Studies suggest that it offers about 70 per cent protection for 15 years (there is no revaccination). The BCG is not used in the Netherlands, Denmark or the US, where it is regarded as muddying the waters for quick diagnosis (the skin test used to detect exposure to TB comes up positive in vaccinated people). Scrapping the schools programme would lead to “no more than about 25 additional cases of active TB a year”, says Paul Sommerfeld, chair of the respected independent charity TB Alert.

It is a figure with which Dr John Moore-Gillon, president of the British Lung Foundation, concurs. He says that all those cases should be curable. The number of cases avoided is smaller than the number of significant adverse reactions expected from the vaccine, some of which (although not full-blown cases of the disease) require treatment with anti-TB drugs.

Dr John Innes, consultant in respiratory medicine and infectious diseases in Birmingham, says there is a case for stopping the schools programme and using the resources in other TB services. Ormerod, who is working on new TB guidelines for the National Institute for Clinical Excellence (Nice), says: “The BCG is one of the least important aspects of our fight against TB. The front line is early diagnosis and effective treatment.”

TB is eminently curable. A six-month course of antibiotics results in full recovery, except when diagnosis has been long delayed or in rare cases of multi-drug resistance. “Given that 55 per cent of TB cases are in people from non-English speaking communities, there is a desperate need for knowledgeable nurses to help ensure completion of appropriate treatment,”  says Dr Ian Campbell, chairman of the joint committee on TB of the British Thoracic Society.

There is a need for more research, too. “We are fighting this world disease with antediluvian technology,” says Sommerfeld. “We have a vaccine that was developed in the 1920s, we have not had a significant new drug since the 1930s, and there has not been nearly enough done to reduce treatment time. We don’t even have good diagnostic tools.”

Moore-Gillon says: “There has been a failure of attention to TB.” Two years ago the Government agreed — officially — that urgent action was required. In January 2003 a TB Action Plan was circulated by the DoH for urgent consultation. “Since then there has been a deafening silence,” says Moore-Gillon. The plan has been “about to be published for so long that it has become known as the TB Inaction Plan”.


Health Protection Agency TB factsheet

 

As far as TB goes, the lowered immune system due to mercury fillings is more likely to cause serious TB. My mother worked in a TB hospice where they pulled mercury fillings to cure TB.
 

New Anti-Inflammatory Drugs Increase TB Risk

Thu Aug 5, 3:21 PM ET

NEW YORK (Reuters Health) - Recently developed drugs called TNF-blockers have brought relief to many people with inflammatory conditions such as rheumatoid arthritis or the intestinal disorder, Crohn's disease. However, the drugs do carry a risk.

In a report released on Thursday, federal health officials at the Centers for Disease Control and Prevention (news - web sites) in Atlanta point out that patients taking TNF-alpha antagonists, such as Remicade (infliximab), Enbrel (etanercept), and Humira (adalimumab) have an increased risk of tuberculosis.  As of January 2004, "several hundred reports" of active TB disease in patients taking drugs in this class had been received by the U.S. Food and Drug Administration (news - web sites)'s adverse-event reporting system, according to an article in the Morbidity and Mortality Weekly Report.

While most of these cases occurred outside the U.S., where the risk of TB infection is higher, the report describes 12 instances of active tuberculosis diagnosed among Californians who were being treated with TNF-blockers.  Eleven patients had TB disease after taking Remicade and one while on Enbrel therapy. Most of the cases probably represent progression of latent TB infection to active TB disease, according to CDC, because all but one patient had at least one risk factor for having latent TB.

In some of these cases, patients had not been screened for TB prior to starting TNF-blocker therapy.

Testing for TB involves measuring the reaction to a tuberculin skin test, but the CDC notes that many patients who need TNF-blockers may also be less sensitive to tuberculin because of their underlying condition or its treatment. Therefore, "tuberculin skin test results at the time of initiating TNF-alpha antagonist therapy might be falsely negative."  The CDC recommends that doctors consider treating latent TB in patients with negative tuberculin test results whose circumstances "suggest a probability" of latent TB. Postponing TNF-blocker therapy, when possible, until treatment of TB is complete, should also be considered.


SOURCE: Morbidity and Mortality Weekly Report, August 6, 2004.


Vaccine Pkg Insert - TB test - Tubersol® -Tuberculin Purified Protein Derivative (Mantoux)

http://www.vaccineshoppe.com/US_PDF/752-22_4611.pdf


 

From: "Robert Cohen" <notmilk@earthlink.net>
Subject: Milk & Tuberculiosis


Milk and Tuberculosis

According to Virgil Hulse, M.D. (Author of Mad Cows and Milkgate), half of the dairy herds in America have cows testing positive for bovine tuberculosis. One cow infects another cow with tuberculosis.

Last week (January 10, 2005), America became aware of the Michigan hunter who caught bovine tuberculosis from a deer. The deer most likely ran out of the woods onto the cow's turf and became infected. This story should act as a warning to both hunter and dairy consumer. Eat body parts or drink body fluids from diseased animals and suffer the consequences. See:

<http://glrc.org/story.php3?story_id=2524 >

Some say that half the dairy herds in America are infected with bovine tuberculosis. Others promote the consumption of raw milk. Neither thought should be comforting to milk and dairy consumers.

Milk & Tuberculosis

"Infected raw milk is the chief means by which milk-borne tuberculosis is transmitted to man."
Journal of Dairy Science, 19:435, 1936

"Many diseases such as tuberculosis are transmissible by milk products."

Journal of Dairy Science 1988; 71

"Some strains of mycobacteria, similar to those that are associated with tuberculosis, have been found to survive pasteurization."

The National Mastitis Council, Inc. 1970 Washington, D.C.

"A Mycobacterium bovis-infected dairy herd of 369 Holstein cows with lactation duration between 200 and 360 days was tested... 170 cows had positive tuberculin test results, and 199 had negative results." Journal of the American Veterinary Medical Association, 1998 Sep, 213:6

Robert Cohen
http://www.notmilk.com
 

Tuberculosis From Cows to People

Nine years ago, I first reported that cow's milk can be the infectious agent that carries tuberculosis to humans. I am surprised that America's raw milk movement continues to grow, when so many various types of virus and bacteria can be found in raw milk. Many (but not all) of these microscopic creatures are killed by pasteurization.  This week, the British Broadcasting Corporation (BBC) reported that a cluster of tuberculosis cases have been traced to an infected dairy herd. The number of humans now identified as having been infected by the same genetic strain of mycobacterium tuberculosis is now up to twenty. More than 50,000 new cases of tuberculosis cases are recorded in England each year. Five percent of those infected die annually in England.

I reported the following in a 1998 Notmilk letter:

"According to Virgil Hulse, M.D. (Author of Mad Cows and Milkgate), half of the dairy herds in America have cows testing positive for bovine tuberculosis." One cow infects another cow with tuberculosis, and humans are infected by drinking unpasteurized milk from infected cows. More than seventy years ago, the Journal of Dairy Science (19:435, 1936) revealed:  "Infected raw milk is the chief means by which milk-borne tuberculosis is transmitted to man."

That same journal reported that tuberculosis infections from milk continued fifty years later, despite modern technology's attempts to make milk safer or cleaner. In 1998, the Journal of Dairy Science (vol.71) revealed: "Many diseases such as tuberculosis are transmissible by milk products." Can live tuberculosis bacteria be found in pasteurized milk? In 1970, the National Mastitis Council admitted:

"Some strains of mycobacteria, similar to those that are associated with tuberculosis, have been found to survive pasteurization."  How bad is the problem? The Journal of the American Veterinary Medical Association (1998 Sep, 213:6) published a 1998 study in which milk consumers learned: "A Mycobacterium bovis-infected dairy herd of 369 Holstein cows with lactation duration between 200 and 360 days was tested... 170 cows had positive tuberculin test results, and 199 had negative results."

It can't happen here, right?

Robert Cohen
http://www.notmilk.com
i4crob@earthlink.net
 

"Infected raw milk is the chief means by which milk-borne tuberculosis is transmitted to man."
--Journal of Dairy Science, 1936, 19:435

"Many diseases such as tuberculosis are transmissible by milk products."
--Journal of Dairy Science 1988; 71

"The causative (tuberculosis) organism in cattle, called Mycobacterium bovis, is one of the most heat-resistant of the non-spore forming pathogenic
bacteria, but fortunately it is destroyed by pasteurization."
--Modern Dairy Products, by Lincoln Lampert

 

For up-to-date news and information, visit the Paratuberculosis Awareness & Research Association

Introduction.
Since Crohn's disease was first recognised in the early part of the twentieth century, it has been theorised that the disease is caused by a bacterial infection, with the principal suspect being mycobacteria, and more specifically in recent times, Mycobacterium paratuberculosis. Recently, research is making advances in understanding this organism, and is indicating more and more that at least some cases of Crohn's disease, if not all, are caused by paratuberculosis infection. Most importantly, the majority of Crohn's patients treated with antibiotic treatment which has activity against Mycobacterium paratuberculosis go into clinical remission.

This is important information for sufferers of Crohn's disease, because Mycobacterium paratuberculosis is endemic in foods derived from cattle in most areas of the western world. Mycobacterium paratuberculosis causes a chronic Inflammatory Bowel Disease in cattle, and many other species, which is similar to Crohn's disease. In some countries, the percentage of cattle herds infected with Mycobacterium paratuberculosis is extremely high. In the United States, 40% of large dairy herds are infected with Mycobacterium paratuberculosis.

Mycobacterium paratuberculosis is present in the milk, faeces, and meat of infected cattle. There is a large body of evidence which indicates that Mycobacterium paratuberculosis is not killed by the standard food processing techniques that we rely on to protect us from disease-causing bacteria, such as pasteurization and cooking. Mycobacterium paratuberculosis may also be present in water supplies in areas where the faeces of infected cattle wash into the water supply, and standard water treatment methods do not kill it. 

Up to now, the beef and dairy industries have preferred to defer action on removing Mycobacterium paratuberculosis from herds of food animals until it is proven that Mycobacterium paratuberculosis causes disease in humans. That proof has now arrived. In February 1998, a paper was published in the British Medical Journal which documented the first proven case of M. paratuberculosis causing disease in a human being. The patient, a seven year old boy, developed a M. paratuberculosis infection in the lymph nodes of his neck. This was followed, after a five year incubation period, by an intestinal disease that was indistinguishable from Crohn's disease. See Mycobacterium paratuberculosis Cervical Lymphadenitis followed five years later by terminal  ileitis similar to Crohn's Disease for more details.

In order to facilitate self-education about this important subject, I have put together this web site, which contains either the full-text or abstracts of most of the relevant medical research. The information is broken down into various sections, as listed in "Contents", along the left hand side of this screen. All of the medical references have been taken from the Medline database. There is also an Index of the research papers which are available in full-text.

For information about the methods/author of this web site, see site information. For a summary of the contents of the site, see the page "Summary of main points". For a list of links to important sites for Crohn's disease sufferers and for medical professionals, see the page "Links to other information resources on the Web". For a list of changes/updates that have been made to this site, see the page "Changes".

For a description of Crohn's disease, see the page What is Crohn's disease?.

For further information about the situation with Crohn's disease and Mycobacterium paratuberculosis in the United States, please visit the Paratuberculosis Awareness & Research Association, an organization of sufferers of Crohn's disease that has been formed to address important questions about research into the connection between Mycobacterium paratuberculosis and Crohn's disease and the presence of Mycobacterium paratuberculosis in food derived from cattle.

www.crohns.org
 

http://www.datamonitor.com/~b8bb8d96cd3149228acff5fb50faa8a7~/healthcare/rep
orts/product_summary.asp?pid=BFHC0500
 

July 2005 12:45
http://news.independent.co.uk/uk/health_medical/article297165.ece

'Ineffective' tuberculosis vaccinations in schools to be dropped

By Jeremy Laurance
Published: 06 July 2005

The Government is to abandon the schools vaccination programme against tuberculosis despite the growth in cases of the disease.

Professor Liam Donaldson, the Government's chief medical officer, will announce today that the BCG vaccination offered to all children between the ages of 10 and 14 is to be dropped because it is ineffective. Evidence shows that tuberculosis is falling among the white population and that schoolchildren are at lowest risk, but it remains a risk among immigrant groups. The vaccination will continue to be offered to babies from high-risk groups whose parents were born abroad.

The move has the backing of specialists in the field who are lobbying for the £10m cost of the vaccination scheme to be ploughed back into services to improve TB control. Cases of tuberculosis have grown from 5,000 in 1987 to almost 7,000 last year, but they are concentrated among the homeless and communities with close links to parts of the world where tuberculosis is rife, especially in Africa and the Indian subcontinent.

Professor Peter Ormerod, of the British Thoracic Society, said: "All the scientific evidence shows that the schools BCG programme is given to people at extremely low risk of TB. Children born abroad or with parents born abroad are at higher risk and they are offered vaccination at birth, which will continue. If you are not in one of those groups, the chances of getting TB are one in 100,000." Professor Ormerod, professor of respiratory medicine at Blackburn Royal Infirmary, said the BCG vaccine was only 75 per cent effective and gave protection for 10 to 15 years. For every 5,000 children vaccinated, one case of TB would be prevented over the following 15 years.

Some children suffered adverse reactions, including a BCG abscess which required treatment with anti- tuberculosis drugs, or a keloid scar - an unsightly disfigurement at the site of the injection. Professor Ormerod said: "It is hugely cost-ineffective. If you are having to give 5,000 injections to prevent one case of disease, that is madness. The British Thoracic Society fully supports the decision to stop the school BCG programme, but we will lobby to have the money saved invested in TB services." Tuberculosis is a global killer, claiming more than two million lives a year. In Britain, after decades of decline, the number of cases started to rise again in the mid-1980s. Although it is curable with drugs, the development of drug-resistant strains of TB in recent years has caused alarm. These cases are extremely difficult and costly to treat.

TB is not easy to catch, and in most cases requires prolonged close contact with an infected person. Once infected, the disease can lie dormant and may not emerge until years or decades later.

Professor Ormerod said most white victims of the disease were in their fifties or older who became infected decades ago. The proportion of the white population infected had fallen year on year. The Government is to abandon the schools vaccination programme against tuberculosis despite the growth in cases of the disease.

Professor Liam Donaldson, the Government's chief medical officer, will announce today that the BCG vaccination offered to all children between the ages of 10 and 14 is to be dropped because it is ineffective. Evidence shows that tuberculosis is falling among the white population and that schoolchildren are at lowest risk, but it remains a risk among immigrant groups. The vaccination will continue to be offered to babies from high-risk groups whose parents were born abroad.

The move has the backing of specialists in the field who are lobbying for the £10m cost of the vaccination scheme to be ploughed back into services to improve TB control. Cases of tuberculosis have grown from 5,000 in 1987 to almost 7,000 last year, but they are concentrated among the homeless and communities with close links to parts of the world where tuberculosis is rife, especially in Africa and the Indian subcontinent. Professor Peter Ormerod, of the British Thoracic Society, said: "All the scientific evidence shows that the schools BCG programme is given to people at extremely low risk of TB. Children born abroad or with parents born abroad are at higher risk and they are offered vaccination at birth, which
will continue. If you are not in one of those groups, the chances of getting TB are one in 100,000."

Professor Ormerod, professor of respiratory medicine at Blackburn Royal Infirmary, said the BCG vaccine was only 75 per cent effective and gave protection for 10 to 15 years. For every 5,000 children vaccinated, one case of TB would be prevented over the following 15 years. Some children suffered adverse reactions, including a BCG abscess which required treatment with anti- tuberculosis drugs, or a keloid scar - an unsightly disfigurement at the site of the injection.

Professor Ormerod said: "It is hugely cost-ineffective. If you are having to give 5,000 injections to prevent one case of disease, that is madness. The British Thoracic Society fully supports the decision to stop the school BCG programme, but we will lobby to have the money saved invested in TB services." Tuberculosis is a global killer, claiming more than two million lives a year. In Britain, after decades of decline, the number of cases started to rise again in the mid-1980s. Although it is curable with drugs, the development of drug-resistant strains of TB in recent years has caused alarm. These cases are extremely difficult and costly to treat.

TB is not easy to catch, and in most cases requires prolonged close contact with an infected person. Once infected, the disease can lie dormant and may not emerge until years or decades later. Professor Ormerod said most white victims of the disease were in their fifties or older who became infected decades ago. The proportion of the white population infected had fallen year on year.
 

Alternatives to TB Testing – Reasons to avoid the Mantoux skin test

By Vaccination Liberation

Over the past six months Vaccination Liberation has received many requests for information on the TB skin test due to the fact that their college or place of employment is now requiring such a test be performed. Wondering why this was all of a sudden a huge issue, VacLib co-director Wendy Callahan sent an email about the availability of a book for a whopping $1500 entitled Tuberculosis: Extracting Value from a Stagnant Marketplace that was published in September 2002. In their sales plug for this overpriced “report”, the reasons to purchase it are as follows: (1.) Identify the areas of the TB market which offer the highest potential for new market entrants, (2.) Understand the changing competitive dynamics in the TB market, and (3.) Identify the key epidemiological trends for TB in the major markets. So the old adage “follow the money” certainly applies to the latest big Pharma/public health assault to our bodies. It is interesting to note that Dr. David Ayoub attempted to find out from Aventis exactly how many doses of Tubersol® are sold in the U.S. annually. Aventis refused to reveal this information so one can only imagine the incredible profits Aventis is making off this one product.

Many employers and colleges are now requiring TB testing while claiming that TB testing bypasses vaccine exemption laws (afterall, it is just a “test”). However, we have found that in every case where a person challenged the TB testing on constitutional grounds (our first amendment right to religious freedom), claiming the state’s religious exemption, or demanding that the employer or bureaucrat guarantee that the “test” is free of dead or live pathogens, the mandatory nature of the TB test was waived for them. In each of these cases, a letter was written to their supervisor, or the main person responsible for the TB policy, citing the multitude of reasons the TB test was a violation of their strongly held religious convictions. Since we are “told” that the TB test or Mantoux skin test is benign and not a “big deal”, it is important to review exactly what is in this seemingly innocuous test and why accepting these ingredients into your body is akin to medical experimentation.

Tubersol ingredients
The most commonly used Mantoux skin test is Tubersol® manufactured by Aventis Pasteur. The package insert claims that “Tubersol® is prepared from a large batch Master Batch, Connaught Tuberculin (CT68) and is a cell-free purified protein fraction obtained from a human strain of Mycobacterium tuberculosis grown on a protein-free synthetic medium, and inactivated. Tubersol® is a sterile isotonic solution of Tuberculin in phosphate buffered saline containing Tween 80 as a stabilizer. Phenol 0.28% is added as a preservative.”

The 1972 edition of Encyclopedia and Dictionary of Medicine and Nursing defines phenol as “an extremely poisonous antiseptic, germicidal and disinfectant.” The Oxford Universal Dictionary (1955) defines phenol as “A hydroxyl derivative of benzene, commonly known as carbolic acid.”

The current research on the stabilizer Tween 80 reveals the following:
“Neonatal female rats were injected ip (0.1 ml/rat) with Tween 80 in 1, 5 or 10% aqueous solution on days 4-7 after birth. Treatment with Tween 80 accelerated maturation, prolonged the oestrus cycle, and induced persistent vaginal oestrus. The relative weight of the uterus and ovaries was decreased relative to the untreated controls. Squamous cell metaplasia of the epithelial lining of the uterus and cytological changes in the uterus were indicative of chronic oestrogenic stimulation. Ovaries were without corpora lutea, and had degenerative follicles.” ~ PMID: 8473002 [PubMed - indexed for MEDLINE]
This test is also composed of a protein fraction derived from a human strain of tuberculosis. Aside from the shedding of RNA and DNA into the lymphatic system from this test, the presence of foreign proteins in one’s blood has been associated with the development of allergies.

How Safe is it?
According to the Tubersol® package insert, this product has never been tested for carcinogenic or mutagenic potentials or impairment of fertility. Even so, the Aventis asserts that this product is safe to administer to pregnant women. And this is noted despite the fact that phenol is a known mutagen and associated with skin cancer development in animals that were injected intradermally.

How does it “work”?
A negative reaction, meaning that the person does not have tuberculosis, is determined if induration (hardening of tissue as in a spider bite) at the test site is less than 15 mm. If induration is greater than 15 mm, it is assumed that the person has active tuberculosis and is then “requested” to have a chest x-ray to rule out the possibility of a false-negative reaction.

“False negatives are thought to occur frequently. Listed causes include anergy, recency of exposure, viral infections, various vaccinations, overwhelming infection, various drugs(steroids) and malignancies and any condition that can impair the cell mediated immune response (sarcoid, malnutrition). False positives include non-tuberculous infections and BCG vaccine state. In spite of these inaccuracies, the CDC states that for persons with latent TB infection who have a normal immune system, test sensitivity approaches 100% ( 2, p 11). This statement is ridiculous for several reasons. First, the TB skin test is the gold standard, so it is not possible to accurately gauge the incidence of false negative exams. The sensitivity of this test, in actuality, remains unknown. Secondly, false negative exams occur in the groups who are at the very highest risk for disease in the first place, meaning that the false negative tests weigh heavily against the efficacy of screening in the most important risk groups─ the one's most likely to develop disease in the first place!

“Compounding the inaccuracies of the TB skin test is the revelation that only one in three positive reactions are correctly classified as positive by screen test interpreters.” (1)
Although there is substantial proof that the Mantoux skin test is an inaccurate method for detecting the presence of tuberculosis infection, it is still considered the “gold standard” for diagnosing tuberculosis.

Alternative Testing for TB

We know of three methods of testing for tuberculosis that are non-invasive.
The first method is through the Best BioMeridian System, which happens to be approved by the FDA. It is also referred to as the Meridian Stress Assessment.
The Best BioMeridian is run through a PC, and has additional hardware to hook up to the computer. There are stainless steel handholds that you hold in your hands with a damp paper towel while the practitioner tests you via a series of meridian points on your hands and feet. It can scan for active and latent viruses, bacteria, fungi and other pathogens. To find out more about this testing method and to find a practitioner in your area, go to http://www.biomeridian.com

The second alternative is through the F Scan. The F Scan device is similar to a Rife machine. It detects any virus, bacteria, fungi, and more. The newer ones have frequencies for zapping the BX-cancer virus. The F Scan scans the body like a virus-scan on a computer, looking for hidden viruses, bacteria, fungi parasites and other pathogens.
It's also run thru a computer with peripheral hardware similar to the Best BioMeridian.
You may be able to find a practitioner on the Royal Rife website http://www.royalrife.com
This machine is not FDA approved, but a professional looking printout may be accepted in lieu of regular TB test.

The third alternative is through the EPFX / QXCI that is run through a regular PC.
From their website:
“The EPFX / QXCI is a state of the art evoked potential bio-feedback system for stress detection and stress reduction, designed by a Complementary Health Practitioner, Professor Bill Nelson.
“During testing, the EPFX / QXCI device resonates with thousands of tissues, organs, nutrients, toxins and allergens for one hundredth of a second each, and records the degree to which your body reacts. This type of rapid testing is known as the Xrroid process.
The EPFX / QXCI scans the patient's body like a virus-scan on a computer, looking for everything from viruses, deficiencies, weaknesses, allergies, abnormalities and food sensitivities. It reports on the biological reactivity and resonance in your body and indicates needs, dysfunctions and vulnerabilities. The information provided is fundamentally different from X-rays, blood tests, etc., as it tells us about the energetic state of your body and the direction in which the body is focusing its energy.”
Their websites are http://www.theqxci.com and http://www.qxciscio.com
These two links will get you to maps to find a practitioner in your area. This list is not comprehensive and only lists practitioners that want to be listed.
Although the medical profession does not tell people about non-invasive TB screening methods either due to the lack of revenue these methods generate, or ignorance of their availability, it is important to educate more employers and schools about them and their reliability as compared with the Mantoux test.

Vaccination Liberation has assisted many Americans in taking the necessary steps to assure their most fundamental of human rights – the right to decide what will or will not be injected subcutaneously into their bodies. If you believe as we do that your right to abstain from state, college or employer coerced medical experimentation is an important one, consider joining Vaccination Liberation and making sure your state is well-networked with other conscientious objectors.

References:
1. “The Rationale for TB Screening of Healthcare Workers and Other Low-risk Populations: A Critical Review of CDC Policy” by David Ayoub, MD
http://www.vaclib.org/basic/tbtest.htm
2. “Hidden Facts about Tuberculosis, the TB Test and the BCG Vaccine” by Ingri Cassel
http://www.proliberty.com/observer/20030723.htm
3. More on Tuberculosis from Vaccination Liberation
http://www.vaclib.org/basic/tb.htm

 

Article Last Updated: Saturday, December 27, 2003 - 2:58:58 AM
PSTwww.oaklandtribune.com

Berkeley scientists create tuberculosis 'superbug'
Virulent bacteria results from attempt to render TB harmless By Ian Hoffman, STAFF WRITER

In trying to make tuberculosis less infectious, Berkeley scientists created a superbug that killed every lab mouse it touched. Scientists say their mutant could be a guide to the strange pathogenicity of TB, which can live dormant in humans for decades before triggering disease. What wakes the bug up in some people, not others, is a maddening puzzle for researchers. Infectious disease professor Lee W. Riley and his post-doctoral students set out to find a solution by rendering TB harmless. Working inside an airlocked and highly filtered chamber at the University of California, they disabled a collection of genes associated with the bacteria's invasion of healthy cells. They ended up with one of the world's few "hypervirulent" organisms: A bug so lethal to its host population that it leaves itself nowhere to run, endangering its chances of survival. "We thought that by disrupting that gene we would make the bacteria less virulent and what happened was the opposite," Riley said. "It all made sense. This is a bacteria where it's more important for it to become latent." Former Berkeley post- docs Nobuyuki Shimono of Kyushu University and Lisa Morici of TulaneUniversity reported the synthetic bug in this week's edition of the Proceedings of the National Academy of Sciences.

TB infects almost a third of the world's population, primarily in Southern Africa, South America, the Middle East and Asia. It's among the deadliest infectious diseases, killing more than 2 million a year. Yet the details of its life cycle -- and the path to a vaccine -- have eluded scientists for decades. Riley said Berkeley's mutant was so deadly for mice because their immune system didn't perceive it as a threat and so never mounted much of a defense. The mutant meanwhile copied itself until it killed all the mice within 10 months. Wild or natural tuberculosis germs are more cleverly evolved. "It's a very smart bug and it sort of learned to live with the host when the host's immune system is at its best," Riley said. "If it killed everybody right away, it would never transmit itself to others." He plans on bombarding the germ with antigens in search of one that might be promising for a vaccine. Contact Ian Hoffman at ihoffman@angnewspapers.com .
 

Author: Vandana Batra, MD, Consulting Staff, Baybees Pediatrics
Coauthor(s): Jocelyn Y Ang, MD, Assistant Professor, Department of Pediatrics, Division of Infectious Diseases, Children's Hospital of Michigan and Wayne State University


Vandana Batra, MD, is a member of the following medical societies: American Academy of Pediatrics

Editor(s): Robert W Tolan, Jr, MD, Chief of Allergy, Immunology and Infectious Diseases, The Children's Hospital at St Peter's University Hospital, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leslie L Barton, MD, Professor, Program Director, Department of Pediatrics, University of Arizona School of Medicine; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Russell W Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center

Disclosure





INTRODUCTION Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography



Background: Tuberculosis (TB) is the most common cause of infection-related death worldwide. In 1993, the World Health Organization (WHO) declared TB to be a global public health emergency. Mycobacterium tuberculosis is the most common cause of TB. Very rare causes are Mycobacterium bovis and Mycobacterium africanum. Tubercle bacilli belong to the family Mycobacteriaceae and the order Actinomycetales. The acid-fast characteristic of the mycobacteria is their unique feature. M tuberculosis is an aerobic, non–spore-forming, nonmotile, and slow-growing bacillus with a curved and beaded rod-shaped morphology. It is a very hardy bacillus that can survive under adverse environmental conditions. Humans are the only known reservoirs for M tuberculosis.


Pathophysiology: TB occurs when individuals inhale bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses. Among the several virulence factors in the mycobacterial cell wall are the cord factor, lipoarabinomannan (LAM), and a highly immunogenic 65-kd M tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro. LAM is a heteropolysaccharide that inhibits macrophage activation by interferon-gamma and induces macrophages to secrete tumor necrosis factor-alpha, which causes fever, weight loss, and tissue damage.

The infective droplet nucleus is very small, measuring 5 micrometers or less, and may contain approximately 1-10 bacilli. Although a single organism may cause disease, 5-200 inhaled bacilli are usually necessary for infection. The small size of the droplets allows them to remain suspended in the air for a prolonged period of time. Primary infection of the respiratory tract occurs as a result of inhalation of these aerosols. The risk of infection is increased in small enclosed areas and in areas with poor ventilation. Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli. However, these naïve macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.

Thereafter, transportation of the infected macrophages to the regional lymph nodes occurs. Lymphohematogenous dissemination of the mycobacteria to other lymph nodes, the kidney, epiphyses of long bones, vertebral bodies, juxtaependymal meninges adjacent to the subarachnoid space, and apical posterior areas of the lungs sometimes occurs. In addition, chemotactic factors released by the macrophages attract circulating monocytes to the site of infection, leading to differentiation of the monocytes into macrophages and ingestion of free bacilli. Logarithmic multiplication of the mycobacteria occurs within the macrophage at the primary site of infection.

A cell-mediated immune (CMI) response terminates the unimpeded growth of the M tuberculosis 2-3 weeks after initial infection. CD4 helper T cells activate the macrophages to kill the intracellular bacteria with resultant epithelioid granuloma formation. CD8 suppressor T cells lyse the macrophages infected with the mycobacteria, resulting in the formation of caseating granulomas. Mycobacteria cannot continue to grow in the acidic extracellular environment, so most infections are controlled. The only evidence of infection is a positive tuberculin skin test (TST) result. However, the initial pulmonary site of infection and its adjacent lymph nodes (ie, primary complex or Ghon focus) sometimes reach sufficient size to develop necrosis and subsequent radiographic calcification.

Most persons infected with M tuberculosis do not develop active disease. In individuals who are immunocompetent, the lifetime risk of developing disease is 5-10%. In certain instances, such as extremes of age or defects in CMI (eg, human immunodeficiency virus [HIV] infection, malnutrition, administration of chemotherapy, prolonged steroid use), TB may result. For patients with HIV, the risk of developing TB is 7-10% per year.

Progression of the primary complex may lead to enlargement of hilar and mediastinal nodes with resultant bronchial collapse. Progressive primary TB may develop when the primary focus cavitates and organisms spread through contiguous bronchi. Lymphohematogenous dissemination, especially in young patients, may lead to miliary TB when caseous material reaches the bloodstream from a primary focus or a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus). Tubercular meningitis also may result from hematogenous dissemination. Bacilli may remain dormant in the apical posterior areas of the lung for several months or years. Progression of disease because of multiplication of these bacilli may lead to the development of reactivation-type TB (ie, endogenous re-infection TB).


Frequency:


In the US: Approximately 15 million people are infected with M tuberculosis in the United States. The number of TB cases reported annually in the United States dropped 74% (ie, 84,304 to 22,201) between 1953 and 1985. Subsequently, a resurgence in the number of TB cases was reported, with a peak of 26,673 cases in 1992. While the incidence increased by approximately 13% in all ages from 1985-1994, the rate among children younger than 15 years increased by 33%. This resurgence was attributed to the HIV epidemic, which increased the risk of developing active TB among persons with latent TB infection. Other contributory factors were emigration from developing countries and transmission in settings such as endemic hospitals and prisons.
Development of multidrug-resistant (MDR) organisms and deterioration of the public health infrastructure for TB services further contributed to the rise in the number of cases. The decline in case number since 1992 has been attributed to increased awareness of the disease, institution of more aggressive preventive measures, improvement in health care strategies (eg, prompt identification and treatment of patients with TB), and highly active antiretroviral therapy for HIV-positive patients. Although the case rate has declined since 1992, a huge reservoir of individuals who are infected with M tuberculosis remains.

Internationally: According to the WHO, more than 8 million new cases of TB occur each year. Currently, 19-43.5% of the world's population is infected with M tuberculosis. TB occurs disproportionately among disadvantaged populations, such as homeless individuals, malnourished individuals, and those living in crowded areas. According to the WHO, developing countries including India, China, Pakistan, Philippines, Thailand, Indonesia, Bangladesh, and the Democratic Republic of Congo account for nearly 75% of all cases of TB.
Mortality/Morbidity: The mortality rate from TB in the United States is currently 0.6 deaths per 100,000 individuals, which represents approximately 1,700 deaths per year and an annual mortality rate of approximately 7% per newly identified case. In 1953, the mortality rate was 12.5 per 100,000 individuals. This decrease in mortality is attributed to improved health care and prompt initiation of therapy. MDR-TB cases have a reported fatality rate of greater than 70%. Worldwide, deaths due to TB are estimated at 3 million per year.

Race: According to the Centers for Disease Control and Prevention (CDC), rates of TB are 10 times higher among Asians and Pacific Islanders, 8 times higher among non-Hispanic blacks, and 5 times higher among Hispanics, Native Americans, and Native Alaskans compared to non-Hispanic whites. However, race may not be an independent risk factor, and risk is best defined on the basis of social, economic, and medical factors as well.

Sex: TB equally affects females and males.

Age: An increased risk of mortality from TB exists at the extremes of age.




CLINICAL Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography



History:

While the natural history of TB in children follows a continuum, the American Thoracic Society (ATS) definition of stages is useful:
Stage 1: Exposure has occurred, implying that the child has had recent contact with an adult who has contagious TB. The child has no physical signs or symptoms and has a negative TST result. The chest radiograph (CXR) does not show any changes at this stage. Not all patients who are exposed become infected, and it may take 3 months for the TST result to become positive. Unfortunately, children younger than 5 years may develop disseminated TB in the form of miliary disease or tubercular meningitis before the TST result becomes positive. Thus, a very high index of suspicion is required when a young patient has a history of contact.

Stage 2: This stage is heralded by a positive TST result. No signs and symptoms occur, although an incidental CXR may show the primary complex.

Stage 3: Tuberculous disease occurs and is characterized by the appearance of signs and symptoms depending on the location of the disease. Radiographic abnormalities also may be seen.

Stage 4: This stage is defined as TB with no current disease. This implies that the patient has a history of previous episodes of TB or abnormal, stable radiographic findings with a significant reaction to the TST and negative bacteriologic studies. No clinical findings suggesting current disease are present.

Stage 5: TB is suspected, and the diagnosis is pending.
Asymptomatic infection: Patients with asymptomatic infection have a positive TST result but do not have any clinical or radiographic manifestations. Children with asymptomatic infection may be identified on a routine well-child physical examination, or they may be identified subsequent to TB diagnosis in household or other contacts (eg, children who recently have immigrated, adopted children).
Disease evaluation: Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard antibacterial therapy should be evaluated for TB. Also, patients with fever of unknown origin, failure to thrive, significant weight loss, or unexplained lymphadenopathy should be evaluated for TB.
Pulmonary TB may manifest itself in several forms, including endobronchial TB with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease. Symptoms of primary pulmonary disease in the pediatric population often are meager. Symptoms are more likely to occur in infants. Fever, night sweats, anorexia, nonproductive cough, failure to thrive, and difficulty gaining weight may occur.
Endobronchial TB with enlargement of lymph nodes: This is the most common variety of pulmonary TB. Symptoms are the result of impingement on various structures by the enlarged lymph nodes. Persistent cough may be indicative of bronchial obstruction, while difficulty in swallowing may result from esophageal compression. Vocal cord paralysis may be suggested by hoarseness or difficulty breathing.
Tubercular pleural effusion: Pleural effusions due to TB usually occur in older children rather than in infants and rarely are associated with miliary disease. Typical history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath. Fever usually persists for 14-21 days.
Progressive primary TB: Progression of the pulmonary parenchymal component leads to enlargement of the caseous area and may lead to pneumonia, atelectasis, and air trapping. This is more likely to occur in young children than in adolescents. The child usually appears ill with symptoms of fever, cough, malaise, and weight loss.
Reactivation TB: This condition usually has a subacute presentation with weight loss, fever, cough, and, rarely, hemoptysis. Reactivation TB typically occurs in older children and adolescents. The condition is more common in patients who acquire TB when older than 7 years.
Extrapulmonary TB includes peripheral lymphadenopathy, tubercular meningitis, miliary TB, skeletal TB, and other organ involvement.
Lymphadenopathy: Patients with lymphadenopathy (ie, scrofula) may have a history of enlarged nodes. Fever, weight loss, fatigue, and malaise are either absent or minimal. Lymph node involvement typically occurs 6-9 months following infection by the tubercle bacilli. More superficial nodes commonly are involved. Frequent sites of involvement are the anterior cervical, submandibular, and supraclavicular nodes. TB of the skeletal system may lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes.
Tubercular meningitis: One of the most severe complications of TB is tubercular meningitis. Tubercular meningitis develops in 5-10% of children who become infected when younger than 2 years; thereafter, the frequency drops to less than 1%. A very high index of suspicion is required to make a timely diagnosis because of the insidious onset of the disease. A subacute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss, and fever may be present. After 1-2 weeks, patients may experience vomiting and seizures or alteration in the sensorium. Deterioration of mental status, coma, and death may occur despite prompt diagnosis and early intervention.
Miliary TB: This is a complication of primary TB in young children. It may manifest subacutely with low-grade fever, malaise, weight loss, and fatigue. A rapid onset of fever and associated symptoms also may be observed. History of cough and respiratory distress may be obtained.
Bone or joint TB: This may present acutely or subacutely. Vertebral TB may go unrecognized for months to years because of its indolent nature.
Additional sites: Other unusual sites for TB include the middle ear, gastrointestinal tract, skin, kidneys, and ocular structures.
Congenital TB is a rare entity. Symptoms typically develop during the second or third week of life and include poor feeding and poor weight gain, cough, lethargy, and irritability. Other possible symptoms include fever, ear discharge, and skin lesions. To make a diagnosis of congenital TB, the infant should have proven TB lesions and at least one of the following:
Lesions in the first week of life
Documentation of TB infection of the placenta or the maternal genital tract
Presence of a primary complex in the liver
Exclusion of the possibility of postnatal transmission
Physical:

Primary TB is characterized by the absence of any signs on clinical evaluation. These patients are identified by a positive TST result. Tuberculin hypersensitivity may be associated with erythema nodosum and phlyctenular conjunctivitis.
Signs of disease are dependent on the site involved (pulmonary or extrapulmonary).
Pulmonary disease may manifest itself in several forms, including endobronchial TB with focal lymphadenopathy, progressive pulmonary disease, pleural involvement, and reactivated pulmonary disease.
Endobronchial disease: Enlargement of lymph nodes may result in signs suggestive of bronchial obstruction or hemidiaphragmatic paralysis. Vocal cord paralysis may occur as a result of local nerve compression. Dysphagia due to esophageal compression also may be observed.
Progressive primary pulmonary TB: This condition presents with classic signs of pneumonia, including tachypnea, nasal flaring, grunting, dullness to percussion, egophony, decreased breath sounds, and crackles.
Pleural effusion: Signs include tachypnea, respiratory distress, dullness to percussion, decreased breath sounds, and, occasionally, features of mediastinal shift.
Reactivation TB: Physical examination results may be normal or may reveal posttussive crackles.
Extrapulmonary TB: Manifestations include peripheral lymphadenopathy, tubercular meningitis, miliary TB, skeletal TB, and other organ involvement.
Lymphadenopathy: This usually involves anterior or posterior cervical and supraclavicular nodes. Less commonly, submandibular, submental, axillary, and inguinal lymph nodes are involved. Typically, nodes are firm and nontender with nonerythematous overlying skin. The nodes are initially nonfluctuant. Suppuration and spontaneous drainage of the lymph nodes may occur with caseation and the development of necrosis.
Tubercular meningitis: Three stages of tubercular meningitis have been identified.

Stage 1: No focal or generalized neurologic signs are present. Possibly, only nonspecific behavioral abnormalities are found.

Stage 2: This stage is characterized by the presence of nuchal rigidity, altered deep tendon reflexes, lethargy, and/or cranial nerve palsies. Tubercular meningitis most often affects the sixth cranial nerve, resulting in lateral rectus palsy. This is due to the pressure of the thick basilar inflammatory exudates on the cranial nerves or to hydrocephalus. The third, fourth, and seventh cranial nerves also may be affected. Funduscopic changes may include papilledema and the presence of choroid tubercles, which should be sought carefully.

Stage 3: This final stage comprises major neurologic defects, including coma, seizures, and abnormal movements (eg, choreoathetosis, paresis, paralysis of one or more extremities). In the terminal phase, decerebrate or decorticate posturing, opisthotonus, and/or death may occur. Patients with tuberculomas or tubercular brain abscesses may present with focal neurologic signs. Spinal cord disease may result in the acute development of spinal block or a transverse myelitis–like syndrome. A slowly ascending paralysis may develop over several months to years.
Miliary TB: Physical examination includes lymphadenopathy, hepatosplenomegaly, and systemic signs including fever. Respiratory signs may evolve to include tachypnea, cyanosis, and respiratory distress. Other signs, which are subtle and should be sought carefully in the physical examination, are papular, necrotic, or purpuric lesions on the skin or choroidal tubercles in the retina.
Bone TB: Common sites involved are the large weightbearing bones or joints including the vertebrae (50%), hip (15%), and knee (15%). Destruction of the bones with deformity is a late sign of TB. Manifestations may include angulation of the spine (gibbus deformity) and/or Pott disease (severe kyphosis with destruction of the vertebral bodies). Cervical spine involvement may result in atlantoaxial subluxation, which may lead to paraplegia or quadriplegia.
Congenital TB: Signs of congenital TB include failure to thrive, icterus, hepatosplenomegaly, tachypnea, and lymphadenopathy.
Causes: Risk factors for the acquisition of TB are usually exogenous to the patient. Thus, likelihood of being infected depends on the environment and the features of the index case. However, the development of TB disease depends on host factors including immunocompetence.

Infection
The number of bacilli in the inoculum and the relative virulence of the organism are the major factors determining transmission of the disease. TB is transmitted by inhaling the tubercle bacilli.
The infectiousness of the source case is of vital importance in determining likelihood of transmission. Bacillary population of TB lesions varies and depends on the morphology of the lesion. Nodular lesions have 100-10,000 organisms, whereas cavitary lesions have 10 million to 1 billion bacilli. Thus, persons with cavitary lesions have the potential for being highly infectious. Also, contacts of persons with sputum-positive smears have an increased prevalence of infection as opposed to contacts of those with sputum-negative smears.
Persons who have received anti-TB drugs are much less infectious than those who have not received any treatment. This decline in infectiousness is due primarily to reduction in the bacillary population in the lungs.
Environmental factors also contribute to the likelihood of acquiring the infection. The concentration of bacilli depends on the ventilation of the surroundings and exposure to ultraviolet light. Thus, overcrowding, congregation in prison settings, poor housing, and inadequate ventilation predispose individuals to the development of TB.
Disease
Defects in cell-mediated immunity and level of immunocompetence are major determinants for development of disease.
HIV is one of the most significant risk factors for TB infection. Case rates for persons who are dually infected with HIV and M tuberculosis exceed the lifetime risk of persons with TB infection who are not infected with HIV.
Steroid therapy, cancer chemotherapy, and hematologic malignancies increase the risk of TB.
Malnutrition interferes with the CMI response and therefore accounts for much of the increased frequency of TB in impoverished patients.
Non-TB infections, such as measles, varicella, and pertussis, may activate quiescent TB.
Individuals with certain human leukocyte antigen (HLA) types have a predisposition to TB. Hereditary factors, including the presence of a Bcg gene, have been implicated in susceptibility to acquisition of TB.
DIFFERENTIALS Section 4 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Actinomycosis
Arthritis, Septic
Aspergillosis
Bronchiectasis
Bronchopulmonary Dysplasia
Brucellosis
Chronic Granulomatous Disease
Coccidioidomycosis
Cysticercosis
Failure to Thrive
Fever Without a Focus
Histoplasmosis
Infections of the Lung, Pleura and Mediastinum
Legionella Infection
Lymphadenopathy
Meningitis, Aseptic
Meningitis, Bacterial
Nocardiosis
Osteomyelitis
Pericarditis, Constrictive
Pleural Effusion
Pneumonia

WORKUP Section 5 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab Studies:


Making the diagnosis of TB in children is extremely challenging because of difficulty in isolating M tuberculosis. Definitive diagnosis of TB depends upon isolation of the organism from secretions or biopsy specimens.

Despite innovations in rapid diagnosis, many of the classic diagnostic tools remain useful and continue to be involved in the evaluation of patients with TB.

Detection and isolation of the mycobacterium are accomplished as follows:
The initial step is to obtain appropriate specimens for bacteriologic examination. Examination of sputum, gastric lavage, bronchoalveolar lavage, lung tissue, lymph node tissue, bone marrow, blood, liver, cerebrospinal fluid (CSF), urine, and stool may be useful, depending on the location of the disease.

Gastric aspirates are used in lieu of sputum in very young children (<6 y) who usually do not have a cough deep enough to produce sputum for analysis.

Using the correct technique for obtaining the gastric lavage is important because of the scarcity of the organisms in children compared to adults. An early morning sample should be obtained, before the child has had a chance to eat or ambulate, as these activities dilute the bronchial secretions accumulated during the night.

Initially, the stomach contents should be aspirated, and then a small amount of sterile water should be injected through the orogastric tube. This aspirate also should be added to the specimen.

Since gastric acidity is poorly tolerated by the tubercle bacilli, neutralization of the specimen should be performed immediately with 10% sodium carbonate or 40% anhydrous sodium phosphate. Even with careful attention to detail and meticulous technique, the tubercle bacilli can be detected in only 70% of infants and in 30-40% of children with disease.

Sputum specimens may be used in older children. Nasopharyngeal secretions and saliva are not acceptable. In older children, bronchial secretions may be obtained by the stimulation of cough by an aerosol solution of propylene glycol in 10% sodium chloride.

Bronchoalveolar lavage also may be used to provide bronchial secretions for detection of tubercle bacilli.

Decontamination of the specimens obtained may be performed by the addition of sodium hydroxide, usually in combination with N-acetyl-L-cysteine. Other body fluids (eg, CSF, pleural fluid, peritoneal fluid) also can be centrifuged so the sediment can be stained and evaluated for presence of acid-fast bacilli (AFB). Smears of CSF are positive in fewer than 10% of patients in some series. Enhancement of the yield may be possible by staining the clot that may form in standing CSF and using the sediment of a centrifuged specimen. Increased yield also may be obtained from cisternal or ventricular fluid.

Obtain overnight urine specimens in the early morning. Send immediately for analysis since the tubercle bacilli tolerate the acidic pH of urine poorly.
Staining of the specimen is as follows:
Since M tuberculosis is an AFB, staining of AFB provides preliminary confirmation of the diagnosis.

Staining also can give a quantitative assessment of the number of bacilli being excreted (eg, 1+, 2+, 3+). This can be of clinical and epidemiologic importance in estimating the infectiousness of the patient and in determining the discontinuation of respiratory isolation. However, for reliably producing a positive result, smears require approximately 10,000 organisms per milliliter. Therefore, in early stages of the disease or in children in whom the bacilli in the respiratory secretions are sparse, the results may be negative. A single organism on a slide is highly suggestive and warrants further investigation.

A significant drawback of AFB smears is that they cannot be used to differentiate M tuberculosis from other acid-fast organisms such as other mycobacterial organisms or Nocardia species.

Conventional methods include the Ziehl-Neelsen staining method. The Kinyoun stain is modified to make heating unnecessary. Fluorochrome stains, such as auramine and rhodamine, are variations of the traditional stains. The major advantage of these is that slides can be screened faster because the acid-fast material stands out against the dark, nonfluorescent background. However, fluorochrome-positive smears must be confirmed by Ziehl-Neelsen staining.
Conventional growth techniques are as follows:
Culture of mycobacterium is the definitive method to detect bacilli. It is also more sensitive than examination of the smear. Approximately 10 AFB per millimeter of a digested concentrated specimen are sufficient to detect the organisms by culture.

Another advantage of culture is that it allows specific species identification and testing for recognition of drug susceptibility patterns. However, since M tuberculosis is a slow-growing organism, a period of 6-8 weeks is required for colonies to appear on conventional culture media.

Conventional solid media include the Löwenstein-Jensen medium, which is an egg-based medium, and the Middlebrook 7H10 and the 7H11 media, which are agar-based media. Liquid media (eg, Dubos oleic-albumin media) also are available, and they require incubation in 5-10% carbon dioxide for 3-8 weeks. These media usually have antibacterial antibiotics, which are slightly inhibitory for tubercle bacilli.
Modern approaches in diagnosis are as follows:
Since mycobacteria require 6-8 weeks for isolation from conventional media, automated radiometric culture methods (eg, BACTEC) are increasingly being used for the rapid growth of mycobacteria. The methodology employs a liquid Middlebrook 7H12 medium containing radiometric palmitic acid labeled with radioactive carbon 14 (14C). Several antimicrobial agents are added to this medium to prevent the growth of nonmycobacterial contaminants. Production of 14CO2 by the metabolizing organisms provides a growth index for the mycobacteria. Growth generally is detected within 9-16 days.

Another rapid method for isolation of mycobacteria is SEPTICHEK. This nonradiometric approach has a biphasic broth-based system that decreases the mean recovery time versus conventional methods.

Mycobacterial growth indicator tubes (MGITs), which presently are used as a research tool, have round-bottom tubes with oxygen-sensitive sensors at the bottom. MGITs indicate microbial growth and provide a quantitative index of M tuberculosis growth.
Identification of species is as follows:

M tuberculosis can be reliably differentiated from other species on the basis of culture characteristics, growth parameters, and other empiric tests. M tuberculosis produces heat-sensitive catalase, reduces nitrates, produces niacin, and grows slowly. Serpentine cording is demonstrated on smears prepared from the BACTEC system.

Addition of p-nitro-acetyl-amino-hydroxy-propiophenone (NAP) inhibits the growth of M tuberculosis complex (including M bovis and M africanum) but does not inhibit growth of other mycobacteria. This provides the basis for the NAP differentiation test.

Chromatographic analysis of mycobacterial cell wall lipids can provide further speciation. The most useful approaches include gas-liquid chromatography and high-performance liquid chromatography (HPLC). The unique mycolic acid pattern associated with the species can be detected by the chromatographic separation of the ester. A significant drawback of these methods is the requirement of bacterial colonies grown in conventional solid media, a process that takes at least 3 weeks. However, the recent combination of HPLC with fluorescence detection has made the method more sensitive, thus BACTEC broth culture can be used instead of conventional solid media. This may make the method comparable to the NAP and AccuProbe tests. The expense of the initial equipment limits the availability of HPLC.

Nucleic acid probes are used as follows:
Since biochemical methods are time-consuming and laborious, nucleic acid hybridization using molecular probes has become widely accepted. Commercially available probes, including the AccuProbe technology, help advance identification of the M tuberculosis complex. Sensitivity and specificity approach 100% when at least 100,000 organisms are present.

The basic principle is the utilization of a chemiluminescent, ester-labeled, single-strand DNA probe. A luminometer is used to assess the chemiluminescence.

Positive test results should be reported as M tuberculosis complex because the probe does not reliably differentiate between M tuberculosis and other members of the complex (eg, M bovis). Final identification to species level is required because pyrazinamide should not be included in the treatment regimen if the isolate is M bovis.

Niacin production, nitrate reduction, pyrazinamidase, and susceptibility to thiophene-2-carboxylic acid hydrazide can help differentiate between M bovis and M tuberculosis.
Polymerase chain reaction (PCR) and other amplification tests are used as follows:
Nucleic acid amplification allows the direct identification of M tuberculosis in clinical specimens, unlike the nucleic acid probes, which require substantial time for bacterial accumulation in broth culture.
The US Food and Drug Administration has approved 2 tests, the amplified M tuberculosis direct test and the AMPLICOR M tuberculosis test. The AMPLICLOR test targets the DNA. The most commonly used target sequence for the detection of M tuberculosis has been the insertion sequence IS6110. The amplified M tuberculosis direct test is an isothermal transcription-mediated amplification that targets RNA.
Although amplification techniques are promising tools for the rapid diagnosis of TB, several caveats remain. Contamination of samples by products of previous amplification and the presence of inhibitors in the sample may lead to false-positive or false-negative results.
Although the sensitivity and specificity of the nucleic acid techniques in smear-positive cases exceed 95%, the sensitivity of smear-negative cases varies from 40-70%. Thus, discordance between the acid-fast smear result and the nucleic acid amplification techniques requires careful clinical appraisal and judgment.
M tuberculosis drug susceptibility is determined as follows:
Because of the emergence of MDR organisms, determination of the drug susceptibility panel of an isolate is important so that appropriate treatment can be ensured.
Numerous chromosomal mutations are associated with drug resistance. Genotypic methods now being evaluated to identify these mutations include DNA sequencing, solid phase hybridization, and PCR–single-strand combination polymorphism analysis.

Mutations of the catalase peroxidase gene katG, the inhA gene involved in fatty acid biosynthesis, the ahpc gene, and the oxyR gene have been identified as major determinants for isoniazid (INH) resistance.

Resistance to rifampin is determined by mutations in the rpoB gene encoding the beta subunit of the RNA polymeras