Flying and Blood Clots: Safety, Risks, Prevention, and More
Why Extra-pulmonary Tuberculosis Is The Most Dreaded Form Of TB
As the world marks tuberculosis (TB) day with the theme 'Wanted: Leaders for a TB-free world', it is important to address extra-pulmonary tuberculosis.
This is an adverse form of the disease which is prevalent especially in our immunocompromised patients from various causes.
The mention of tuberculosis conjures up images of a wasted person with a persistent cough, sometimes with sputum which may be bloody, chest pains, weight loss and fever with night sweats.
While these are the typical symptoms of a person suffering from pulmonary (lung) TB, there are other manifestations of TB, particularly extra-pulmonary TB, which few Kenyans are aware of.
According to the WHO report, tuberculosis is the leading cause of death, which ranks above HIV/AIDs
While pulmonary TB accounts for about 70 percent of TB cases, extra pulmonary TB accounts for 20 to 30 percent. This type of TB can affect any part of the body.
Doctors always look-out for patients who come with symptoms that might appear not connected to pulmonary TB but have been persistent for a while. More often than not, these patients have received treatment, but their illness has not improved.
Spinal TB is a potentially debilitating form of extra pulmonary TB as it can lead to paralysis. Any persistent back pain accompanied by fever and weight loss should trigger an alarm for spinal TB. The investigations needed to detect this form of TB are MRI, CT or ultrasound scans, X-rays, fine needle aspiration, or bone biopsy.
In Kenya, treatment for any TB both pulmonary and extra-pulmonary is provided free by the government. This consists of a combination therapy of four drugs taken for two months and two drugs taken for four months. This six-month treatment works for most cases of TB except for meningitis and bone TB which require more aggressive therapy which often takes at least nine months to even longer depending on the response to treatment.
Most people with TB are cured by strictly following a drug regimen that is provided to patients with support and supervision. Treatment of TB is sometimes complicated by resistance. This is a situation where the bacteria that causes TB does not respond to one or more of the drugs used in its treatment.
Resistance is caused by inappropriate, or incorrect use of antimicrobial drugs, or use of ineffective formulations of drugs (e.G. Use of single drugs, poor quality medicines, or those kept in bad storage conditions) and premature treatment interruption.
Detection is done using special laboratory tests which analyse the bacteria for sensitivity to the drugs, or detect resistance patterns.
Resistance can vary from one drug (mono resistance) to two drugs or more (multi-drug resistance (MDR) (which has to include at least isoniazid and rifampicin) of the most powerful anti-tubercular drugs available.
Extensive drug-resistant (XDR) tuberculosis occurs when the TB is resistant to the above two drugs as well as fluoroquinolones and any of the three injectable medications. This is an extremely difficult and expensive form to treat and most patients succumb to the disease.
Drug resistant TB is a big concern in Kenya and the only solution to controlling it is making sure that the TB patient gets cured the first time round by providing access to diagnosis, having adequate infection control in facilities where patients are treated and ensuring the appropriate use of recommended second-line drugs.
Ninety per cent of patients diagnosed with ordinary TB will be treated successfully with proper adherence to drugs. The cost of treating normal TB is approximately Sh7000 in a private hospital, while the cost of treating drug resistant TB can run to millions of shillings per patient. It is therefore critical that all measures are taken to ensure that the dosage schedule is followed to avoid developing resistance to these drugs.
Any patient who has been coughing for at least two weeks or more and has been experiencing fevers, weight loss, night sweats and has not felt any better despite taking antibiotics for the Community Acquired Pneumonia should try seek medical help to rule out tuberculosis.
Dr Salim Hassanali is a Consultant Pulmonologist/Intensivist at Aga Khan University Hospital, Nairobi
Related TopicsUAB Medicine Treats Underserved Patients In Non-Tuberculosis Mycobacterial (NTM) Program
Brian Garcia, M.D.
According to the American Lung Association, the number of people living with Non-tuberculosis Mycobacterial (NTM) lung disease is on the rise, especially among women and older age groups. This bacterial infection can be especially difficult to diagnose, requiring the expertise of a multidisciplinary team the UAB Medicine Non-tuberculosis Mycobacterial (NTM) Program.
NTM infections arise from organisms commonly found in soil and water, and typically affect those with underlying lung diseases such as COPD or a weakened immune system, causing chronic cough, fatigue, fever, and night sweats. While NMT infections most commonly arise in the lungs, they can also appear in skin or soft tissue infections, lymph nodes, or other organs.
"Some states require public health reporting of NTM infections, but Alabama is not one of them," said Brian Garcia, M.D., medical director of UAB's NTM clinic. "As a result, this is an under-represented infection at a clinical level and an epidemiologic level."
The NTM clinic team is comprised of Garcia, German Henostroza, M.D., and Angela Thomas, Nurse Coordinator.
"The number of NTM patients currently in the United States is around 80,000 patients," Garcia explained. "The more elderly patients we have living with chronic lung disease, the more that we will see this infection. Because the organism is so ubiquitous, I tell patients that they will encounter these bacteria no matter what. We see patients with these infections anywhere in their bodies, but 95% of our patients have pulmonary infections."
"There must be a lung infection confirmed either twice in sputum or once in bronchoscopy, radiographic evidence of the disease and symptoms attributed to the infection and that are significant enough that treatment is justified," said Garcia. "Treatment is difficult, typically multiple antibiotics every day for 18 months or longer. That means side effects and drug interactions that must be considered."
"The mycobacterium avium complex we call MAI accounts for about two-thirds of the cases that we encounter. We treat that infection with a prolonged course of three oral antibiotics," said George Solomon, M.D., associate professor of medicine.
"The second most encountered organism is mycobacterium obsessive complex. It requires an initial period of oral and intravenous antibiotics, followed by a prolonged period of oral and inhalation antibiotics," Solomon said. "It's a more complicated infection treatment regimen."
"If you have a patient in which you expect nontuberculous mycobacterial disease, you are not going to just stumble upon it. You are going to have to go searching," Solomon continued. "I recommend early and often thinking about referral because this can be a very challenging illness to diagnose."
Community physicians can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST. For more information on resources available at UAB Medicine, visit uabmedicine.Org/physician
Tuberculosis Vaccines — An Update
Tuberculosis (TB), a disease which is both curable and preventable, still kills 2–3 million people every year. After decades of neglect, the immense public health impact of TB is now widely recognized, and the development of new tools to combat and control the epidemic has become an international priority. The current strategy for TB control is based on reducing the spread of infection through effective treatment of individuals with active disease and vaccination of children. The WHO has initiated the directly observed therapy (DOTS) campaign in many regions, but so far this programme has not been able to control the global TB epidemic or prevent the increase in multidrug resistant (MDR) strains of Mycobacterium tuberculosis1.
The current TB vaccine Mycobacterium bovis bacillus Calmette–Guérin (BCG) is the most widely used vaccine worldwide. BCG provides efficient protection against TB in newborns, but does not prevent the establishment of latent TB or reactivation of pulmonary disease in adults. Being a viable organism, the activity of BCG depends on its initial replication, and it therefore cannot be used as a booster in an adult population that is already sensitized by prior BCG vaccination, exposure to environmental mycobacteria or latent TB2. A novel, effective vaccination strategy against adult pulmonary TB is therefore a crucial goal and an active field of research, development and clinical evaluation.
Global distribution and disease burden
In 2004, approximately 9 million people developed active TB. Although this places TB as one of the most important global health problems, active disease represents only the tip of the iceberg, as it has been estimated that one-third of the world's population is latently infected with M. Tuberculosis. Globally, the incidence of TB is growing, mainly owing to the spread of HIV in Africa, where it has been estimated that 13% of adults with newly diagnosed TB are also co-infected with HIV3. However, in recent years, the increasing TB problem in Eastern European countries has contributed to the worsening global epidemic. Africa has the highest estimated incidence (356 per 100,000 population per year), but major parts of Asia also have a significant TB problem1 (Fig. 1). In most of these regions, the incidence of TB has now reached such a magnitude that it is overwhelming the limited resources available to identify and treat active contagious pulmonary TB. Furthermore, by primarily targeting the working population, TB is a major roadblock to healthy economic development in many developing countries.
Figure 1: The distribution of tuberculosis in 2003.Immunity to M. Tuberculosis
M. Tuberculosis infection remains latent with no overt clinical symptoms throughout life in more than 90% of infected individuals. Progressive mycobacterial infection in patients with deficient interferon-γ (IFN-γ) and tumour necrosis factor (TNF) signalling provides convincing evidence for the importance of these cytokines in the control of TB. The major source of these cytokines are CD4+ T cells, the most important lymphocyte population in the protective immune response and the main target for most vaccination strategies4. The role of CD8+ T cells is less clear. They are induced during natural M. Tuberculosis infection, and although they do not seem to have a major role in the initial control of the infection, they might be more involved in the later, chronic stages of the disease5. To target this lymphocyte subset, some of the new vaccines are delivered through live carriers such as viral vectors or genetically modified strains of BCG. In the 5–10% of latently infected individuals who go on to develop active TB, the balance between the natural immunity of the host and the pathogen is thought to change, for example, following an immunosuppressive event, resulting in massive bacterial replication and reactivation of the disease.
All of the new TB vaccine candidates that are under clinical evaluation (Table 1) are designed as pre-exposure vaccines and, hence, are aimed at stimulating an immune response that controls subsequent infection more efficaciously than the immune response that is stimulated during natural infection, thereby delaying reactivation. It is not known whether post-exposure administration of these vaccines to already latently infected individuals would prolong host containment of latent TB and prevent reactivation, or whether this would require specially designed post-exposure vaccines based on antigens that are expressed by the bacteria during latency, as recently discussed elsewhere6.
Table 1 The leading tuberculosis vaccine candidates in clinical trialsVaccine concepts and clinical trials
Current attempts to develop improved TB vaccination strategies can be divided into two approaches — replacing or boosting BCG. The first strategy aims to replace BCG with a more effective vaccine. This is generally believed to demand an improved, attenuated mycobacterial vaccine strain, obtained either through the generation of gene-deletion mutants of M. Tuberculosis, or by re-introducing important antigens or other factors into the existing BCG vaccine strain. Viable, attenuated mycobacterial vaccines obviously present a broad variety of antigens and will potentially cover a combination of different T-cell populations, but such vaccines must be not only more potent than BCG, but also at least as safe, in order to be considered as candidates for clinical trials7.
The second strategy involves the development of a booster vaccine that takes advantage of BCG priming vaccination in childhood, and is given to increase the immune response and prolong immunity to also cover the adult population. It is generally agreed that such a vaccination strategy can be best accomplished with a subunit vaccine. Subunit vaccines are based on a restricted number of antigens and hence on a highly focused immune response for protection. In several of the leading vaccine candidates, the individual antigens are fused into polyproteins, something that both increases the immunogenicity of the individual antigens and has obvious advantages from a manufacturing point of view. The success of the booster strategy is underpinned by recent advances in adjuvant development. Until recently, the only adjuvants appropriate for use in TB vaccines were either ineffective at stimulating T-cell responses or were too toxic for human use. This situation has rapidly changed in recent years, and a number of novel, promising T-cell adjuvants such as the IC31 adjuvant, cationic liposomes, the AS2 formulation and LTK63 (for mucosal delivery) are now under late-preclinical or clinical development in TB vaccines (Table 1).
Eventually, the ultimate vaccine strategy could be based on a combination of both approaches, that is, a prime–boost vaccination regime that comprises priming with the best possible viable vaccine candidate and boosting with the best possible subunit vaccine candidate4.
BCG replacement vaccines
rBCG30. RBCG30 is a recombinant BCG vaccine in which the well-known and well-characterized antigen 85B (Ag85B) is overexpressed. This 30 kDa enzyme, which is involved in outer cell-wall synthesis, is a key component in several TB vaccines, and although Ag85B is already abundantly secreted by BCG, overexpression appears to increase responses to this important antigen8. RBCG30 has been tested in a Phase I trial in humans and was well tolerated.
rBCG ΔureC:Hly. To amplify the CD8+ T-cell response induced by BCG, a recombinant BCG mutant has been constructed that expresses listeriolysin (Hly), which can perforate the phagosome membrane. The gene (ureC) encoding the urease enzyme that increases the pH of the phagosome containing BCG was additionally deleted to avoid neutralizing the phagosome, as this would reduce the activity of Hly9. Surprisingly, apoptosis of infected macrophages and cross-priming of dendritic cells seems to be the major mechanisms responsible for the increased activity of this vaccine10. A clinical Phase I trial is planned to commence by the end of 2007.
BCG booster vaccines
Ag85B–ESAT6/TB10.4 fusion molecules. The Ag85B–ESAT6 fusion molecule (H1) is made up of the two secreted antigens Ag85B and ESAT6. These individual antigens both have an impressive track record of studies confirming their antigenicity in humans and their vaccine potential. H1 has shown promise both for parenteral (in IC31 or cationic liposomes) and mucosal (in LTK63) delivery11,12. In addition to being a valuable vaccine component, ESAT6 (the component of H1 localized in the region that was deleted during the original attenuation of BCG, and which is therefore absent from all BCG vaccine strains) is a key component in a new generation of diagnostic tests for M. Tuberculosis infection13. An alternative fusion construct, called H4, has been engineered and consists of Ag85B and the TB10.4 antigen, which is also from the ESAT family of small secreted antigens14. TB10.4 has similar immunological properties to ESAT6, but it is highly expressed and immunodominant in BCG. H4 is a powerful booster vaccine for BCG, whereas the H1 vaccine for comparison, in addition to boosting Ag85B responses, will supplement the BCG antigen repertoire with the important ESAT6 antigen component.
H1 is currently in clinical trials administered both parenterally and through the mucosal route. The first clinical trial in Leiden, Holland (Dissel and Ottenhoff, unpublished data) evaluated the vaccine in a conventional parenteral vaccination strategy, using the IC31 adjuvant. This trial was conducted in purified protein derivative (PPD)-negative individuals and the vaccine was shown to be both safe and strongly immunogenic. The H1/IC31 vaccine is currently being evaluated in PPD-positive BCG-vaccinated individuals at the same site. Another trial that has recently started will test the nasal administration of the H1 antigen, using the LTK63 adjuvant. The H4/IC31 vaccine will commence clinical trials in mid-2007 in Sweden.
MTB72f. The MTB72f vaccine is a fusion molecule consisting of two antigens that are strong targets for T helper 1 (TH1) cells in PPD-positive individuals. Rv1196 (MTB32) is inserted into the middle of the serine protease Rv0125 (MTB39), which is thus present as two fragments15. MTB72F in the AS02A adjuvant formulation has recently completed two Phase I trials in healthy PPD-negative adults in the United States and Belgium. The vaccine was well tolerated and safe, and could induce both antigen-specific humoral and cell-mediated immune responses.
MVA85A. MVA85A is a modified vaccine virus Ankara (MVA) strain expressing antigen 85A, another member of the Ag85 family of protective antigens. In Phase I studies in humans, MVA85A was found to be safe and well tolerated, and this vaccine has induced strong immune responses, particularly in previously BCG-vaccinated individuals16.
Conclusions
With increasing investment from public funds such as the European Union, National Institutes of Health and the Bill & Melinda Gates Foundation in recent years, TB vaccine research, development and evaluation has become an active area, with several vaccines in various stages of early clinical development. Most of this work is conducted by public research organizations and public–private partnerships, but a recent re-analysis and demonstration of the significant commercial value of a novel TB vaccine17 will probably result in a larger investment from private industry. This will promote streamlined development and the eventual global distribution of a novel vaccine. Although a new, improved vaccination strategy against TB is finally on the horizon, its eventual success will still depend on continued close integration with information from basic research. The identification of reliable correlates of protection, as well as the answers to more basic immunological questions relating to immunological memory and the relative importance of different T-cell subsets, will be important for the potential modification of the leading TB vaccines, the generation of second-generation products and the selection of which vaccines to move forward into expensive efficacy trials (Box 1). It will furthermore be a high priority for the clinical development programmes to evaluate whether the current vaccines, all of which have been designed for pre-infection administration, will also prevent reactivation of TB if administered post-exposure to the large proportion of the global population already latently infected with TB.
Box 1Key areas for tuberculosis (TB) vaccine developmentDetermine the correlates of vaccine induced protective immunity
Determine the requirements for post-exposure TB vaccines
Understand vaccine-induced T-cell memory to Mycobacterium tuberculosis
Determine the role of CD8+ T cells in M. Tuberculosis infection and immunity
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