Tuberculosis

by Kenneth Lyen

A WALK DOWN SINGAPORE’S MEMORY LANE

Many of us have forgotten that in the mid-20th century, Singapore was still a third world country, with poverty, malnutrition and infectious diseases. My father, a general practitioner would take me to the swamps of Jurong and the kampongs of Ang Mo Kio when he did his house calls. The patients were too poor, and they paid with vegetables and eggs.

I remember walking down Singapore’s Sago Lane in the 1950s, which was lined with “death houses” where people would spend their last days of their lives waiting to die (1).

I also remember the emaciated looks of the dying occupants, some of whom were suffering from terminal tuberculosis (TB).

Above is the funeral along Sago Lane.

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In the 1960s I would shadow Dr Hu Pin Ya (third from the right), a chest physician at Tan Tock Seng Hospital, watching him go through large numbers of miniature chest Xrays.

TB Tan Tock Seng Hosp 3 Mobile Xray.v1 c

These were taken by the mobile Xray vans that would visit the housing estates screening the residents for TB. In 25 years, the mobile vans took 1.6 million Xrays and diagnosed 46,864 patients with TB (2,3).

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Dr Hu would also take me on a tour around Tan Tock Seng Hospital where the TB Control Unit was situated (4).

TB Tan Tock Seng Hosp 1 Rotary Clinic 19

We passed the Rotary Centre, a clinic funded by the Rotary Club to cater for TB patients. Indeed, most of the cases of suspected TB were sent to Tan Tock Seng Hospital, which gained a nickname, the “TB Hospital”. Dr Hu would also make regular trips to St John’s Island, which was a quarantine station for TB among other infectious diseases (5).

I also had the privilege of meeting one of the most important figures in Singapore’s fight against TB, Dr Chew Chin Hin. He held several positions at Tan Tock Seng Hospital, including medical director (1965-1979), and later he was appointed Deputy Director of Medical Services, Ministry of Health (1981-1991). During his long career, Dr Chew introduced several strategies in the prevention and treatment of TB, including using combination antibiotics, and he also reduced the total duration of treatment from 24 to 6 months (6).

Because of the success of Tan Tock Seng Hospital as the centre for TB, when the incidence fell, the TB centre was amalgamated with another infectious diseases hospital, the Middleton Hospital, and they formed the Communicable Disease Centre (CDC) (7).

In 2003, the Severe Acute Respiratory Syndrome (SARS) caused by a coronavirus, spread to Singapore, and it woke up the unprepared health sector (8), resulting in the construction of a new building dedicated to handling future pandemics, the National Centre for Infectious Diseases (NCID) (9).

The Singapore Anti-Tuberculosis Association (SATA) was established in 1947 by a group of friends who survived the internment camp during the second world war. Subsequently many clinics were set up scattered throughout Singapore. Xrays were installed to diagnose TB, antibiotic treatment was given and its administration was supervised closely. BCG vaccination was also given at these clinics to prevent TB (2,3).

The incidence of TB in Singapore has declined over the past few decades. The preliminary data for 2019 shows that the total number of new cases of TB had fallen even further to 1329 (10-12).

The drop in the number of cases of TB in Singapore has led, in 2009, to the reassignment and rebranding of SATA as community health centres (SATA CommHealth Centres) (2,3). Patients are no longer restricted to those with infections such as TB. In fact they are currently being used for the management of the Covid-19 cases.

WORLDWIDE TB

According to the Institute of Health Metrics and Evaluation (IHME), in 2017 there were 1.18 million deaths from TB worldwide, making it the third commonest infectious disease killer, only ranking below lower respiratory infections and diarrheal diseases. TB has displaced HIV/AIDS which killed 954,000 people, and malaria which claimed 435,000 lives in 2017 (13).

The incidence of TB in Singapore is 47 per 100,000 population in 2018. The Philippines has an incidence of 554. The incidence for China has fallen over the past 2 decades. The distribution of TB is highest in South Asia (mainly India and Sri Lanka), followed by sub-Saharan Africa, then Southeast and East Asia. The countries affected would predominantly be the poorer ones.

CLINICAL MANIFESTATIONS: SYMPTOMS AND SIGNS

The exact clinical manifestation of TB depends upon which part of the body is mostly affected. Unfortunately, most patients may have a dormant form of TB and do not exhibit any symptoms initially, and this is known as latent TB. It is estimated that only about 10% of latent TB transforms into an active symptomatic form. Additionally, the onset of symptoms is often very slow and gradual, so the complaints like coughing may be dismissed as flu or an allergic cough (14).

a) Lungs

Pulomonary disease is the commonest manifestation of TB, and is classically characterized by a chronic cough.

There may also be nocturnal fever, which may be associated with night sweats.

In more severe cases, there could be spitting out of blood-stained phlegm.

Another observation is poor appetite, weight loss, and tiredness. These are the commonest symptoms of TB. (12)

When you listen with your stethoscope, you might hear some crackling sounds or crepitations.

b) Meningitis

Kernig Brudzinski sign meningitis.v1 cro

While the commonest part of the body affected are the lungs, TB it can spread to the brain and spinal cord, causing meningitis, an extremely serious complication that carries a high morbidity and mortality. There may be chronic headaches, dizziness, vomiting, and drowsiness leading to coma and death.

TB meningitis has to be suspected early, when the only symptom are cough and drowsiness. The classical signs of meningitis such as fever and neck stiffness may be absent, which makes clinical diagnosis very difficult. On examination, Kernig’s or Brudzinski’s signs may be present (14).

c) Bones and Joints

TB can also spread to the bones or joints, causing skeletal TB or TB arthritis. There may be bone or joint pains, backache or stiffness.

Skeletal or bone TB is suspected if there is backache, swelling of the bones or bone deformities, stiffness, on top of the other symptoms of TB such as fever and weight loss (14).

c) Kidneys

Another place that TB can spread to are the kidneys, leading to frequency of urination, pain on passing urine, and loin pain.

TB of the kidneys may cause the urine to turn cloudy due to pus, or red due to blood. Otherwise there are hardly any physical signs pointing to this diagnosis.

d) Lymph Nodes

When TB spreads to the lymph nodes, this is known as tuberculous lymphadenitis. The enlarged lymph nodes are often located in the neck or in the armpits area. The glands are usually not painful, and when you slide your fingers over the nodes, they can be irregular, and the overlying skin may be adherent to the underlying lymph glands.

MICROBIOLOGY OF MYCOBACTERIUM TUBERCULOSIS

Robert Koch 1843-1910 looking down micro

TB was first identified 138 years ago by Robert Koch (1843-1910) in 1882 (15). Antibiotics against the organism was discovered and administered since 1943, 77 years ago. There has even been a vaccine against the disease, that has been used since 1921, almost 100 years ago. The question we must ask is why has this disease not been wiped out from the face of the earth by now? What has been the delay?

To answer this question, we need to explore the issues a little bit more carefully.

Mycobacterium tuberculosis is a rod-shaped bacteria (bacillus) with a thick coating on its surface consisting of mycolic acid, wax and complex lipids, that makes it resistant to the conventional Gram stain. The cell wall resists decolorisation by the weak acids used for bacterial stains, which is referred to as being “acid-fast”. However, when you use a phenol-carbol fuchsin stain heated to enable the dye to penetrate the waxy mycobacterial cell wall, two German scientists, Franz Ziehl (1859–1926) and Friedrich Neelsen (1854–1898), were able to stain the Mycobacterium tuberculosis. The stain is known as the Ziehl-Neelsen stain (16).

The next step is to prove that the bacteria isolated from patients with clinical TB, is the correct one responsible for the disease. Robert Koch used the following scheme to prove his postulates that the bacteria he isolated does indeed cause TB (15):

The microorganism must be isolated from a diseased TB patient, and grown in pure culture.
The cultured microorganism should cause disease when introduced into a healthy animal, such as guinea pigs.
The microorganism must be re-isolated from the inoculated, diseased experimental guinea pig, and identified as being identical to the original specific causative agent found in the TB patient.

By proving that that the bacterium Mycobacterium tuberculosis causes TB, Robert Koch received the Nobel prize in 1905, and the bacillus is sometimes referred to as Koch’s bacillus, and his three postulates are known as Koch’s postulates (15).

DIAGNOSIS OF TB

Culturing TB is a protracted process because the bacterium is very slow-growing, taking some six weeks to get an adequate culture. Hence when TB is suspected clinically, the diagnosis needs to be confirmed accurately and quickly. Several new tests are now available.

a) Polymerase Chain Reaction (PCR) Test on sputum, nasal or gastric aspirate

The PCR test was introduced since 1996, but it is only in recent years that it has gained popularity. The test can be done on blood samples, sputum, nasal, bronchial, or gastric aspirates. It has a sensitivity of 80% and a specificity of close to 99%. In Singapore, the turnaround time for the test result is currently 1 to 2 days (17,18).

b) Interferon-gamma release assays (IGRAs) blood test

The interferon-gamma release assay is an alternative to the PCR test to diagnose suspected TB. It measures a person’s immune reactivity to the Mycobacterium tuberculosis. Two commercially available tests have been approved by the US Food and Drug Administration: the Quantiferon TB-Gold test and the T-test. The major advantages are that results come back within 24 hours, and prior BCG vaccination does not give rise to false positives, and patients only require a single visit for the test. The major disadvantages are that it cannot differentiate latent from active TB; nor can it predict which patient with latent TB are more likely to develop active TB. This test is not useful for immunocompromised patients because of false negative results. It is unable to monitor the efficacy of anti-tuberculous treatment, and there are inadequate data to determine whether or not it can be used for patients under 5 years of age. The sensitivity is around 87% and the specificity is about 90% (19-22).

c) Mantoux Purified Protein Derivative (PPD) Tuberculin Skin Test

Charles Mantoux (1877-1947) used a technique first described by Robert Koch where he employed glycerin to extract a protein from Mycobacterium tuberculosis, which he then sterilized; this protein was called tuberculin. In 1907 Mantoux injected the protein into the skin of patients, and showed that those who had TB reacted 48 hours later with redness and swelling at the injection site. Initially this test was unreliable, and it was not until 1940 when a more purified protein derivative (PPD) was used, and this gave better results (23).

The Mantoux Test was one of the commoner ways of diagnosing TB, but because of its inaccuracy, it is slowly losing popularity. It requires the careful injection of 0.1 ml of tuberculin purified protein derivative into the inner surface of the forearm intradermally. A positive diagnosis of TB is made when the induration measures more than 1 cm in diameter. The erythema (redness) is not considered in the diagnosis (24).

The problem with the Mantoux test is that a person who was previously vaccinated with BCG might sometimes have a positive result. Hence it may not definitively separate a person who was vaccinated versus someone who has active TB. Another problem is that even in unvaccinated subjects, there is a small percentage of persons with false positive or false negative readings. Some people develop an abscess or ulcer at the injection site, and others are unhappy that they have to return to the doctor 48 hours later to have the result read.

d) Chest Xray

The chest Xray on the left shows a white patch highlighted by the radiologist encircling it in red ink. This is a primary lesion found in early TB and is called a Ghon focus, named after Anton Ghon (1866–1936), an Austrian pathologist.

The central Xray shows a typical secondary lesion of TB affecting the upper lobe depicted by the white arrows. At the centre is a black area shown by the black arrows, and this is a cavity resulting from destruction of the lungs by Mycobacterium tuberculosis.

The far right Xray shows TB spreading to the entire lung, and the small white specks resemble millet seeds, and hence this form of TB is referred to as miliary TB.

FAMOUS PEOPLE WITH TB

There are several famous examples of TB including its presence in some Egyptian mummies dating back to several thousand years. The writers Jane Austen, Emily Bronte and John Keats also developed TB. South African president Mandela contracted TB while in prison, and Eleanor Rooselvelt caught it in Europe. Below are pictures of the artist Edvard Munch and his famous painting “The Scream".

Edvard Munch (1863-1944), the Norwegian expressionist artist, is best known for his work, "The Scream". It symbolises the anxieties and fears of the human condition, and may well have been his state of mind when he learnt that he had TB, which had already taken away both his mother and his elder sister. Edvard’s TB made his health rather fragile and he spat out blood when he was a boy. "My fear of life is necessary to me, as is my illness," Edvard wrote. "Without anxiety and illness, I am a ship without a rudder.... My sufferings are part of myself and my art. They are indistinguishable from me, and their destruction would destroy my art" (25).

PREVENTION OF TB

Prevention is better than cure, and this applies equally to TB. For the individual, prevention is through vaccination. For the general public, prevention is by social distancing, wearing of masks, and quarantine.

a) Vaccination

The above photos show two French doctors, Dr Albert Calmette (1863-1933) and Dr Camille Guerin (1972-1961). By culturing and re-culturing Mycobacterium tuberculosis some 200 times, they managed to weaken the bacterium so it became non-pathogenic. This live attenuated strain of mycobacterium TB was inoculated into research animals, and on discovering that the animals acquired immunity to TB, they successfully tried it out on human volunteers in 1921. The vaccine is named after them: the Bacille Calmette-Guerin (BCG) vaccine (26,27).

BCG Vaccine

In Singapore the BCG vaccine is compulsory for all Singaporeans. It is usually given intradermally at birth either in the buttocks or in the upper arm. Neonatal vaccination with BCG is partially protective against pulmonary TB. The effectiveness in preventing pulmonary TB is only about 50-70% (46,47). However, BCG gives better protection of 70-80% against the more severe forms of TB, such as TB meningitis and miliary TB (48). For that reason, 28 countries worldwide are giving universal BCG vaccination, including Singapore (26,27).

More recently, with the onset of Covid-19 pandemic, there has been an unconfirmed observation that countries that have universal BCG vaccination appear to have better survival statistics against the novel coronavirus. Careful analysis of data have shown that the BCG vaccine does not confer any significant benefits to Covid-19 patients (28,28a).

b) Contact Tracing

In the past, early detection of TB was made using chest Xrays. Once TB was diagnosed, it set into motion a team of people for contact tracing, and this became a tour de force for the TB Control Centre. Contact tracing is an important means of finding potential patients who were in close contact with a confirmed TB patient. These contacts were isolated and closely followed up (29).

c) Quarantine

Isolating a patient with TB prevents the spread, and this has been popular especially in Europe during the 19th century. Patients went up high mountains and spend the rest of their lives living in sanatoriums. It is believed that the relatively low oxygen pressure in these mountainous regions slowed down the replication of Mycobacterium tuberculosis so the patient lived longer (30,31).

St John’s Island

In the 19th Century, the British used St John’s island, off Singapore, as a quarantine station for patients with a variety of infectious diseases including cholera, leprosy, smallpox, and TB (32).

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I accompanied some physicians on their regular visits to St John’s Island where drug addicts were being rehabilitated and quarantined, and I was told that some of them had TB. I was not allowed to go near the quarantine facilities, but I had a great time swimming and playing on the beautiful beaches.

Tan Tock Seng Hospital

I remember the long rows of single-storied buildings which were the isolation wards of Tan Tock Seng Hospital in the 1940s to the 1960s. This is where TB and other infectious patients were quarantined (4). The photo on the right was taken on 10 May 2021.

Nowadays, quarantine and isolation beds are available in most hospitals including the National Centre for Infectious Diseases (photos above). Depending on circumstances, quarantine can now take place in other places. For the novel coronavirus, selected patients are quarantined in their own homes, or even in specially designated holiday chalets (33).

d) Wearing Face Masks

Both patient and doctor had to conscientiously wear a face mask if TB was suspected in a patient. Wearing face masks has been promoted for many decades, and it reduced the spread of TB (34).

TREATMENT

The good news is that there are many anti-TB antibiotics. The bad news is that the bacteria have become resistant to several of the older antibiotics. To counteract the resistance, combination antibiotics have been used, but gradually the bacteria have also become resistant to this multiple therapy.

Streptomycin

The first antibiotic effective against TB was streptomycin, discovered by Albert Schatz in 1943. This aminoglycoside kills Mycobacterium tuberculosis by interfering with its 30S subunit of the ribosome, thereby preventing the translation step of protein synthesis. Unfortunately, it had to be injected daily, and there were two serious side effects: deafness and renal failure (35).

Rifampicin

Rifampicin was discovered in 1965 and was an instant success because of its efficacy against TB and it shortened the hitherto treatment time from 2 years to about 9 months or less. The mechanism of action is to inhibit the bacterial RNA polymerase which prevents the transcription of DNA to messenger RNA which stops protein synthesis. The major side effects include hepatitis which may be transient, nausea, vomiting, breathlessness and occasional skin rash. Rifampicin is orange-red in color, and when excreted in the urine, the urine might turn a similar color, and can be mistaken by patients as blood. Hence the need to warn patients taking rifampicin to continue the medicine even if their urine turns reddish (36).

Isoniazid

Isoniazid was introduced in 1952 and has been widely used for the treatment of TB. It acts by inhibiting the synthesis of mycolic acid, a component of the mycobacterium cell wall. Early in its usage, about 20% of patients developed a peripheral neuropathy experienced as numbness, pin and needles of the fingers and toes. Other side effects include a transient hepatitis, nausea, vomiting, skin rash. It is sometimes associated with anemia, low white blood cells and low platelets. The peripheral neuropathy can be avoided by giving vitamin B6 or pyridoxine (37).

Pyrazinamide

Although pyrazinamide was discovered in 1936, it was not widely used until 1972. Its mechanism of action is unknown. Side effects include abnormal liver function, mild joint pains, and increased uric acid production that can result in gout (38).

Ethambutol

Discovered in 1961, ethambutol has been generally used for TB. It prevents the formation of the bacterial cell wall. One of its major side effects is an inflammation of the optic nerve (optic neuritis) and loss of color vision. This prevents its use on children under six years of age. It can also cause numbness and pins and needles due to a peripheral neuropathy (39).

Newer Drugs for Multiple Drug Resistant TB

Despite the CDC’s efforts to ensure that all patients adhered to the entire course of antibiotic treatment, unfortunately some patients did not complete the full course. Over the years, it is believed that the failure to complete the course of antibiotics, Mycobacterium tuberculosis has become resistant to most of the above drugs. Fortunately, newer drugs are now available which are effective.

Bedaquiline

One such antibiotic is bedaquiline which was originally discovered in 2004. The American Food and Drug Administration fast-tracked an accelerated approval, and the drug was approved in 2012. Bedaquiline is a bactericidal drug that blocks the proton pump ATP synthase. By doing so, it deprives the bacterial cell from deriving energy from ATP. The bacteria take several days to die, but after that, they continue to die consistently. Side effects include nausea, joint and chest pain, and headaches. It prolongs the electrocardiogram QT interval and can cause cardiac arrhythmias (40).

Linezolid

Linezolid was discovered in 1987 but was not approved for use until 2000. It inhibits the mycobacterium ribosomal translation in the manufacture of proteins. Side effects include diarrhea, nausea, vomiting, headaches and skin rash. Because of the multiple drug resistance to the older anti-TB drugs, linezolid is finding its way into the mainstream treatment of TB (41).

Pretomanid

The most recent drug to gain American Food and Drug Administration approval in 2019 is pretomanid, which was first identified in 2000. It is not a standalone medicine, and is used in combination with bedaquiline and linezolid for the treatment of multiple drug-resistant TB. Its mechanism of action appears similar to isoniazid in that it inhibits the cell wall mycolic acid biosynthesis (42).

SURGERY

Over the past few decades, the use of surgery in the treatment of TB has declined. But more recently, with the emergence of drug resistant TB, surgery has been employed to supplement drugs treatment of TB (43). If there is an enlarged lymph node suspected of being tuberculous, the surgeon is called to remove the gland, where it is sent for TB diagnostic tests. Bone and spinal TB is fortunately quite uncommon, but there are occasions when orthopedic surgery may be necessary for conditions such as managing spinal instability due to severe curvature of the spine (kyphoscoliosis).

CONCLUSIONS

TB is the third most common worldwide infectious diseases. In 2018 the World Health Organisation announced that there are 10 million new cases of TB resulting in 1.3 million deaths, and this trend continues unabated. It is a disease that has been around for many centuries, and unfortunately this has led to complacency and neglect. Luckily, Singapore has taken action to minimize its prevalence. The guidelines by the National Institute for Health and Care Excellence on the management of TB can be recommended (49).

What lessons has TB taught Singapore?

TB has been in Singapore for two centuries. It therefore had a lot of time to educate the health sector. Firstly, it established the operation centre at Tan Tock Seng Hospital, leading to the creation of the TB Control Unit, which was renamed the Communicable Disease Centre (CDC). So whenever any infectious disease outbreaks came to Singapore, the CDC becomes the natural focus for organizing the defence force. For example, when SARS came to Singapore in 2003, the CDC was the main control centre. Some deficiencies in handling SARS were uncovered by this pandemic, and prompted the construction of the National Centre for Infectious Diseases (NCID) building which was opened in September 2019, just in time to tackle the recent novel coronavirus pandemic.

Secondly, to address TB in the community, the Singapore Anti-Tuberculosis Association (SATA) was set up. This decentralized approach to tackling TB, led to the setting up of several SATA centres in the neighbourhood housing estates. These centres were later renamed SATA CommHealth, and recently, they became very useful to help detect and care for patients with Covid-19 infection.

Thirdly, control of TB required early diagnosis and so SATA organized mobile vans equipped with Xray machines to screen the general public in the housing estates.

Contact tracing was another important development in identifying potential persons who might have caught TB from a known case. This necessitated setting up an army of healthcare workers trained to carry out this activity, and it effectively minimized the spread of TB. Social isolation and quarantine of infected patients has been carried out over the years.

The current BCG vaccine may only be partially protective against pulmonary TB, but nevertheless, some protection is better than no protection. Currently this vaccine is given to all newborn babies in Singapore. There is some interesting controversy with regards to whether BCG protection extends beyond TB, and helps defend against other viral infections including Covid-19.

One must not forget that better hygiene, better sanitation, better nutrition, better housing, and a higher standard of living, have all played an important role in reducing the incidence of TB.

No doubt there are many more lessons that TB has taught us (44,45). The success and failure of handling current and future pandemics depends on how well we have learnt lessons from the past. But learning never stops. We now have to tackle the current crisis, the Covid-19 challenge. Undoubtedly we will make mistakes, but hopefully future generations will learn from them.

Written by Kenneth Lyen

27 April 2020, updated 11 May 2021