Multidrug-resistant tuberculosis in rural China: lack of public awareness, unaffordable costs and poor clinical management

Abstract

China has the second highest global incidence and prevalence of multidrug-resistant tuberculosis (MDR-TB). We describe here the life experience of a rural Chinese farmer with complicated and aggressive TB. It is unclear if this patient contracted MDR-TB initially or developed MDR-TB during treatment because the initial laboratory results are dubious. The lack of public awareness of TB in rural China fuelled by a belief in toxicity of TB treatment, as mentioned by his brother, caused the patient to stop his TB treatment repeatedly long before completion. The cost of MDR-TB treatment in China is unaffordable for most Chinese, especially those in rural areas. He paid about ¥300 000 (almost US$50 000) for his TB treatment. He was discharged early twice for ‘financial difficulties’. This case highlights excessive costs, lack of public awareness, poor patient education, inadequate follow-up, lack of coordination between clinical services and the importance of treatment adherence.

Case presentation

A 62-year-old Chinese man came to Shenyang Chest Hospital in Liaoning Province in 2016 with pain in the left hip for 1.5 months. He was diagnosed with haematogenous disseminated pulmonary tuberculosis (TB) and sacroiliac joint TB. He started anti-TB treatment later with isoniazid, rifampicin, ethambutol and pyrazinamide. Ten days later, he received sacroiliac joint incision to clear the infected area (figure 1). The pus specimen was positive for both Mycobacterium tuberculosis (MTB) and rifampicin resistance with Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) shortly after, and his treatment was changed from rifampicin to rifapentine. Pus specimen for Lӧwenstein-Jensen (L-J) media was positive for MTB and rifampicin resistance. He was mainly attended by the surgical department that had limited knowledge of the importance of compliance, and the patient himself was not educated on the danger and consequences of self-termination of his treatment. A month later, he stopped his TB treatment on his own because he felt discomfort in his stomach and because he thought he was cured, his hip condition has improved. Another reason for his earlier self-termination was that his older brother told him that anti-TB treatment was very toxic and should not exceed 2 months.

Figure 1.

Left sacroiliac joint.

In late 2016, he returned to Shenyang Chest Hospital with left epididymal swelling and pain for 2 weeks. His epididymis specimen was tested positive for MTB with BACTEC MGIT 960 system liquid media test (Becton Dickinson, Sparks, Maryland, USA, referred as ’MGIT 960' hereafter), but drug sensitivity test (DST) was not performed because the patient did not pay for it. He was treated with left epididymis surgical resection and started anti-TB treatment again including isoniazid, rifampicin, ethambutol, pyrazinamide and levofloxacin. In early 2017, the patient stopped his TB treatment again, before it reached 2 months.

One month later, he came to Liaoyang Municipal Tuberculosis Hospital with symptoms including abdominal distension, fatigue, chest tightness after physical activities, shortness of breath, wheezing and occasional cough for 1 month. He had lost 5 kg over 6 months. Tuberculous peritonitis was suspected and peritoneal puncture was performed, with about 2000 mL yellowish ascitic fluid taken out. Though acid-fast bacilli result was negative with the fluid, his protein level, his lactate dehydrogenase (LDH), adenosine deaminase (ADA) and lymphocyte predominance were indicating TB. Anti-TB treatment was started again with isoniazid, rifampicin, ethambutol, pyrazinamide and levofloxacin, but his condition did not improve.

Another month passed and the patient came to Shenyang Chest Hospital with same symptoms as before. He was diagnosed with haematogenous disseminated pulmonary TB and tuberculous peritonitis and pleuritis. Nephrotuberculosis was also identified. Peritoneal puncture was performed, with about 1100 mL yellowish ascitic fluid taken out. Thoracic tube drainage produced a total of 700 mL fluid. Other infections and tumour were excluded through testing of the fluid. His radiological results and purified protein derivative (PPD) positive record were all supporting TB diagnosis. He was transferred to the surgical department shortly after due to abdominal pain, which could be an intestinal obstruction. Later, his urine was found positive for both MTB and rifampicin resistance with Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA). He received anti-TB treatment (isoniazid, ethambutol, pyrazinamide, levofloxacin and para-aminosalicylic acid), peritoneal and thoracic tube drainage of fluids during his hospitalisation. Left fistula was found later at the sacroiliac joint incision site, with yellow-white purulent fluid and necrotic tissue flowing out. Consultation with the orthopaedic department showed that the original operation area of ​​the drainage hole had formed fistula and pus, which could have been caused by drug-resistant TB. After topical application of medicine to the fistula, the patient was transferred to a drug-resistant ward (earlier than DST report). He was in poor health condition with weight loss and intermittent fever. He had an intermittent cough, with a small amount of yellow sputum, shortness of breath after activities, right chest pain and poor diet. His anti-TB treatment was changed to moxifloxacin, capreomycin, pyrazinamide, ethambutol, pasiniazid and prothionamide (though the MGIT 960 result was not out yet, give his previous rifampicin resistance record, the doctor changed the regimen). Based on the pus specimen from the fistula, the patient was found with multidrug-resistant (MDR)-TB according to MGIT 960 results (resistant to isoniazid, rifampicin and streptomycin, but his L-J solid culture results were only indicating rifampicin resistance). One month later, his peritoneal and thoracic fluid was decreasing. Another 10 days later, his fistula was healed. Later, his diet and general health conditions improved, with no more shortness of breath. However, in some days, the patient was found with extremities and trunk skin flaky red itchy herpes. Consultation with the dermatology department advised that drug eruption was highly likely. As a result, pyrazinamide, ethambutol, pasiniazid and prothionamide were stopped, with only moxifloxacin and capreomycin remained. Liver protection and antiallergy treatment were started. Later, as the skin condition worsened, moxifloxacin was also stopped, leaving only capreomycin. The allergy finally started fading and was completely gone. After that, other anti-TB drugs were tried to be added, but all were later stopped due to allergies such as itchiness, rash, a decrease of leucocyte and thrombocytopaenia. Capreomycin was also stopped eventually, due to persistent hypokalaemia. In the meantime, the patient self-reported improvements and was discharged due to financial difficulties. He has spent about ¥96 000 during this hospitalisation.

In late 2017, the patient came back to Shenyang Chest Hospital with a right scrotal mass with pain for a month. Tumour was excluded through blood-based and ascites-based markers, as well as postoperative pathology. Right scrotum tenderness associated with a lump in patient was found in the examination, and the border between epididymis and testicle was not clear. The colour ultrasound indicated a hypoechoic mass in the right scrotum in size of 3.5×2.0 cm, and 2.1 cm effusion in the right sheath cavity; enhanced MRI showed a round mass in the right scrotum. The diagnosis was made as right epididymis–testicular TB and right sheath effusion (figure 2). Later, right epididymis–testicle surgical resection was performed under general anaesthesia (figure 3). After the operation, the specimens were cut and milky pus and caseous material were observed, consistent with changes in TB. After the operation, the patient was of poor nutritional status, leucocyte had decreased to 2.0×10⁹/L. After 2 weeks, he was discharged due to financial difficulties. He has spent ¥300 000 since his health-seeking behaviour related to TB in 2016. The patient comes back for follow-up visits with stable health conditions. Though doctors had tried to add anti-TB treatment, due to severe side effects, it was never tolerated and the patient refused to take anti-TB treatment any more.

Figure 2.

Swollen right epididymis.

Figure 3.

Right epididymis and testicle.

Global health problem list

1. China has the second most MDR-TB/rifampicin-resistant TB (RR-TB) patients in the world.

2. Laboratory quality and costs could delay the detection of drug-resistant TB cases.

3. There are rumours going on about anti-TB drugs, so patient education is very necessary.

4. Drug resistance problem could be prevented through better patient education.

5. Treatment cost is a huge barrier for patients with TB, especially those with drug resistance.

Global health problem analysis

China is heavily affected by TB, ranking the second regarding MDR-TB/RR-TB.¹ It was estimated that among all patients with TB, about 10% had MDR-TB, and among those who had anti-TB treatment before, 25.6% (95% CI 21.5 to 29.8), had MDR-TB.² Though many researchers support that transmission of drug-resistant strains as the main reason for MDR-TB,^{2 3} others believe that inappropriate treatment was one of the major risk factors for MDR-TB⁴ and the main causes of not completing treatment include huge financial burden, limited knowledge and the side effects.⁴ It is a pity that MGIT 960 DST was not performed on the patient during the first treatment. Though L-J test was done, as the second L-J results were inconsistent with MGIT 960 and the clinical outcome, it may not be accurate. In the meantime, the laboratory did not store the patients’ bacteria samples so it was impossible to trace back if this patient had contracted an MDR-TB disease in the first place or developed the resistance during the treatment.

Laboratory quality and related costs could delay the detection of drug-resistant TB cases

The failed laboratory test with solid culture was only making things more complicated. In the first L-J culture, it indicated only resistant to rifampicin. However, in the second L-J solid culture, it was still reporting only resistant to rifampicin, while the MGIT 960 results indicated resistant to isoniazid, rifampicin and streptomycin. Two main reasons could explain the discrepancy. First, liquid culture is 10% more sensitive than solid media.⁵ Another possible explanation was that isoniazid concentration standard was set too high—the WHO guideline was 0.2 µg/mL,⁶ but the hospital has been using 1.0 µg/mL. As a result, both of the L-J DST results were sensitive against isoniazid.

Rumours going on around anti-TB drugs

One obvious pattern of the self-termination of the anti-TB treatment by the patient, in the beginning, was always within 2 months. It was due to the fear of his brother’s warning on the toxicity of anti-TB treatment, and it should not exceed 2 months. In the meantime, the patient also observed the side effects, proving his brother’s toxicity theory. Without enough knowledge about the side effects and the importance of adherence, the patient just quit the treatment due to the fear of toxicity. How common is the rumour among patients with TB and the general public should be further studied and if it is a common mistake, doctors should take actions to prevent this kind of hearsay.

Patient and medical system education on TB should be strengthened

The patient first encountered the medical staff from the surgical department. They might not have enough education or did not prioritise the importance of adherence and did not highlight this point to the patients. As a result, the patient did not fully understand the consequence of non-adherence.

Treatment cost is a huge barrier

One of the main reasons for not completing TB treatment among the Chinese was the financial burden.⁴ In China, TB first-line treatment is free of charge, but many tests and most of the second-line drugs are not covered and are of a huge burden to the patients. Although the Chinese social health insurance schemes have expanded rapidly and could cover most of the Chinese population,⁷ the increasing costs of payment not covered by the social health insurance are blocking patients from seeing the doctor.⁸ In this case, the patient has paid ¥300 000 for TB-related care which is enormous given the average per capita disposable income was only ¥23 821 in China in 2016 (with the rural per capita ¥12 363).⁹

Patient’s perspective.

I am an ordinary farmer and have been rather healthy. It all started in 2016. I began to feel some strange symptoms, such as difficulty to walk with the left leg and sore hip. I was very worried. I went to see many local doctors but they did not know what the problem was. Then, I was admitted to Shenyang Chest Hospital. There, they told me that I had TB in one of my butt joints and I needed a surgery. These tests and surgery fees are very expensive for me. Fortunately, about 50%–60% of the expenses can be reimbursed, but I had to pay all the expenses first. I used my family’s savings for the treatment.

The operation was very successful. I felt much better and I could walk as before. One and a half months later, the doctor advised me to return home and continue taking medicine. I felt very uncomfortable with oral anti-TB drugs. My brother told me that the drugs were toxic and not good for the body, so I did not dare to take them any more.

The nightmare began. I developed abdominal distension, coughing, shortness of breath, swollen genitals and pus at the waist. The doctor told me that I had TB in many parts of my body and I was rather scared. I came to this TB hospital again and conducted many tests and took many medications. I was admitted to the hospital six times. I heard that I had acquired drug-resistant TB, as a result, many medicines could not be reimbursed, and I had to do pleural effusion and ascites again and again. It costed my whole family about ¥300 000. Despite the serious skin rash that followed and the decline in white blood cells, my situation gradually improved. Although I was forced to leave the hospital due to financial difficulties, I was very grateful to the doctors. I hope that the doctors can summarise my case, and treat more patients like me. I also hope to get financial assistance to complete future treatment.

Learning points.

• Quality and cost of laboratory tests could delay the detection of drug-resistant tuberculosis (TB) cases, laboratory test-related costs should be subsidised by the government in order to control drug-resistant TB.

• There are rumours going on about anti-TB drugs, so patient education and public awareness needs to be improved.

• Treatment cost is a huge barrier for patients with TB in China, especially those with drug resistance. More financial support is needed for patients with TB, especially for those with multidrug-resistant.