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Jaime E. Ollé-Goig¹, Israel Molina-Pinargote², Nuria Forcada², Joan-Pau Millet^{2, 3}

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Affiliations: 

(1). Asociación Catalana para el Control de la Tuberculosis en el Tercer Mundo (ACTMON), Barcelona, Spain. (2). Serveis Clinics. Centro de Tratamiento Directamente Observado para la Tuberculosis. Barcelona, Spain. (3). CIBER de Epidemiologíay Salud Pública (CIBERESP), Madrid, Spain.

Corresponding author: Jaime E. Ollé-Goig. Carretera de les Aigües, 181. 08017 Barcelona, Spain. Email: olleuganda@gmail.com

Citation:  Jaime E. Ollé-Goig, Israel Molina-Pinargote, Nuria Forcada, Joan-Pau Millet. Paradoxical reactions in a patient under treatment for multidrug-resistant tuberculosis. A case reports. Special Journal of Pathology, Immunology, and Cancer [SJ-PIC], 2020, 1 (1): 1-7

Case Report peer review history:

 Received-03-11-2020;     Accepted-13-11-2020 ;     Published-24-11-2020

Running title:  Paradoxical reactions in an MDR-TB patient

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Abstract   

Some patients with tuberculosis (TB), after starting treatment, may suffer an enlargement of their initial lesions (tuberculomas, adenopathy) or the development of new ones after some days or weeks of treatment. We describe a patient with primary resistance to several anti-TB medications (MDR-TB) and not infected with the human immunodeficiency virus (HIV). During the first weeks of treatment, he developed marked enlargement of the cervical adenopathy which remitted after some weeks.

Algunos pacientes con tuberculosis (TB), después de unos días o semanas de recibir tratamiento anti-TB, pueden desarrollar nuevas adenopatías o un aumento de tamaño de las lesiones (tuberculomas, adenopatías) detectadas al inicio. Describimos un enfermo con resistencia inicial a diversos medicamentos anti-TB (MDR-TB) que no estaba infectado por el virus de la inmunodeficiencia humana (VIH). Durante las primeras semanas desarrolló un aumento de tamaño importante de las adenopatías cervicales que remitieron semanas más tarde.

Keywords: Multidrug-resistant-tuberculosis, Paradoxical reaction, HIV

Introduction and Case description

A 26-year-old male from Nepal was referred to our TB Centre from a general public hospital in Barcelona with a diagnosis of bilateral cervical adenopathies. The patient had lived in Spain for the past three years and worked as a cook. There was no recent history of contact with a person with TB but his father, who remained in Nepal and had died from hemoptysis. His medical history was non-remarkable; he had never received anti-TB treatment. He suffered during some weeks before admission weakness, low-grade fever, and a non-productive cough.

He had noticed a progressive swelling in both sides of his neck. Vital signs on admission were within normal limits. Physical examination revealed multiple bilateral cervical and supraclavicular nodes soft and tender, some as large as 10 x 6 cm; there were no axillary or inguinal nodes; the chest was clear on auscultation and no abnormalities were detected in the chest X-ray. Results of basic laboratory investigations (AAFB smear of the pus for AAFB and culture) were normal, including the HIV test. Several sputum samples for acid and alcohol fast bacilli (AAFB) smears were all negative.

Case Management

The patient was started on isoniazid, rifampicin, ethambutol, and pyrazinamide. A polymerase chain reaction (PCR) and an AAFB smear of the pus were positive for AAFB. Subsequent cultures revealed AAFB resistance to isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin. The therapeutic regimen was changed to PAS, pyrazinamide, moxifloxacillin, and cycloserine orally and capreomycin by injection[1].

After a few days of treatment the right cervical mass had swollen and began to drain (Fig.1); steroids were added (30 mg of prednisone/day). Weeks later, new adenopathies appeared on the left side (Figure 2). The cervical nodes on both sides drained twice and eventually closed after a few weeks. The patient suffered from paresthesias in both legs which disappeared after a short course of oral pregabaline. After 22 months of such treatment, the patient was discharged; he had no further complaints and the cervical and supraclavicular nodes had disappeared. We were unable to follow his course as he returned to his home country. 

Case findings

Our patient was Nepalese, a country with few resources (Human Development Index: 149) and with a high annual incidence of TB (111 x 10⁵). He presented with MDR-TB; he had never received TB treatment and there was no known TB contact, although his father might have died of TB some years before in the patient’s country of origin. MDR-TB is a worldwide growing problem that poses serious therapeutical difficulties for achieving cure; about 153 000 cases were detected in 2017 (1). After knowing the results of the antibiogram the drug regimen, after a few days of treatment with anti-TB primary drugs, was changed to several second-line medications. In view of the undulant clinical course, steroids were added and administered for three months.

Case Discussions

An article before the HIV epidemic described seven immigrant patients in the United Kingdom with adenopathies, two patients developing them while on anti-TB treatment or having abandoned it; they also had pulmonary or pleural tuberculosis (2). A study from a TB hospital in Florida divided the patients into three groups: HIV-infected on anti-TB treatment and antiretroviral (ARV) drugs; HIV-infected patients only on anti-TB medications; and HIV-negative patients on anti-TB treatment. Paradoxical reactions were more frequent in the group of patients who were on treatment for both TB and HIV. The authors suggested that these reactions may represent an immune response enhanced by the ARV medications (3).

HIV-infected patients tend to develop paradoxical reactions during the early phase of TB treatment and some authors state that it is more frequent among those with more significant immune restitution and concomitant reduction of the viral load (4). The association between ARV treatment and anti-TB treatment has been reported by other authors. Breen et al. suggested postponing the initiation of ARVs, especially in the presence of disseminated TB (5).

A large study from South Korea found that among patients with peripheral lymph nodes TB paradoxical reactions were not unusual and occurred at a median of eight weeks after starting treatment (6); in a significant proportion, like in our patient, the nodes drained spontaneously and several patients developed new ones; younger age, male sex and local tenderness at diagnosis were all associated with reactions; more than half of the patients had a spontaneous resolution of the TB paradoxical reactions without the addition of steroids.

A case of a female patient from India was published by Kant (7). She presented with bilateral cervical adenopathies with multiple draining sinuses; she was HIV negative and resistant to the anti-TB primary drugs (MDR-TB). After 18 months of treatment with six-second line medications, the patient was declared cured. A woman from Bangladesh living in the United States for several months had a history of cervical nodes for two years which drained spontaneously while on TB treatment; she was HIV negative; prednisone was added and the patient improved.

No mention was made whether an antibiogram was obtained (8). A retrospective study from a group in South Korea determined that among 467 patients not HIV-infected 18 % suffered a paradoxical reaction. Paradoxical reactions were more frequent in patients with extra-pulmonary TB; 7 % had lymph node enlargement after completing anti-TB therapy (9). The authors felt it was not necessary to prolong treatment for these reactions to improve

Case Contribution to sustainable development  

These paradoxical reactions in an MDR-TB patient case report may have laid out the framework for clinical observations of the idiosyncratic response of first-line drugs used in the clinical management of diseases of a globally significant public health concern (8). This framework opens a new and basic research horizon for conventional full-length papers to ask relevant questions as they get engaged in designing similar researches in the same field. While providing a clinical advantage to disease management it will help improve recovery confidence of those affected with similar diseases today and in the foreseeable future

Case Limitations

This study has the normal general limitations usually attributed to all case reports. Like all case reports, this study had no rigorous scientific labor, had limited bases for generalization of the observations, difficult to replicate, authors’ bias could not be ignored. It was time-consuming and costly

Case Conclusions and recommendations

The etiology of these paradoxical reactions has not been completely clarified and several mechanisms have been proposed: host immune reactions such as a delayed hypersensitivity response to mycobacterial antigens, a decrease in immune suppression, and a change in the immune response to TB proteins (8). Recently, the administration of prophylactic steroids in HIV-infected patients has been proposed in order to prevent the immune reconstitution inflammatory syndrome (IRIS) in patients with TB initiating ART (10).

**[1]New anti-TB agents such as linezolid and bedaquiline were not easily available.

References

1. Lange C, Aarnoutse RE, Alffenaar  JWC, Bothamley G, Brinkmann F, Costa J, et al. Management of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2019; 23:645-662.

2. Silver CP, Steel SJ. Mediastinal lymphatic gland tuberculosis in Asian and coloured immigrants. Lancet 1961; 1:1251-1256.

3. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158:157-161.

4. Navas E, Martín-Dávila P, Moreno L, Pintado V, Casado JL, Fortún J, Pérez-Elías MJ, Gomez-Mampaso E, Moreno S. Paradoxical reactions of tuberculosis in patients with acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 2002; 162:97-99.

5. Breen RA, Smith CJ, Bettinson H, Dart S, Bannister B, Johnson MA, Lipman MC. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax. 2004 Aug;59(8):704-7.

6. Cho O-H, Cho OH, Park KH, Kim T, Song EH, Jang EY, Lee EJ, Chong YP, Choi SH, Lee SO, Woo JH, Kim YS, Kim SH. Paradoxical responses in non-HIV-infected patients with peripheral lymph node tuberculosis. J Infect 2009; 59:56-61.

7. Kant S, Saheer S, Hassan G, Parengal J. Extra-pulmonary primary multidrug-resistant tubercular lymphadenitis in an HIV negative patient. BMJ Case Rep. 2012 May 8;2012: bcr0620114337.

8. Uetrecht J, Naisbitt DJ. Idiosyncratic adverse drug reactions: current concepts. Pharmacol Rev. 2013 Mar 8;65(2):779-808.

9. Singh A, Rahman H, Kumar V, Anila F. An unusual case of paradoxical enlargement of lymph nodes during treatment of tuberculous lymphadenitis in immunocompetent patient and literature review. Am J Case Rep. 2013 Jun 14; 14:201-4.

10. Yu SN, Cho OH, Park KH, Jung J, Kim YK, Lee JY, Chong YP, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH. Late paradoxical lymph node enlargement during and after anti-tuberculosis treatment in non-HIV-infected patients. Int J Tuberc Lung Dis 2015; 19:1388-1394.

11. Meintjes G, Stek C, Blumenthal L, Thienemann F, Schutz C, Buyze J, Ravinetto R, van Loen H, Nair A, Jackson A, Colebunders R, Maartens G, Wilkinson RJ, Lynen L; PredART Trial Team.. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med 2018; 379:1915-1925.

Author contribution

JEO-G wrote the paper. All authors took care of the patient and revised the manuscript.

Funding

This work has not received any funding.

Conflict of interest

The authors declare no conflict of interest