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  Table of Contents  
Year : 2019  |  Volume : 37  |  Issue : 3  |  Page : 450-453

Paradoxical upgradation response in non-HIV tuberculosis: Report of two cases

Department of Internal Medicine, Batra Hospital and Medical Research Centre, New Delhi, India

Date of Submission09-Jul-2018
Date of Decision24-Jul-2019
Date of Acceptance01-Nov-2019
Date of Web Publication28-Nov-2019

Correspondence Address:
Dr. Thrinadh Kunapareddy
Department of Internal Medicine, Batra Hospital, New Delhi - 110 062
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_18_242

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 ~ Abstract 

A paradoxical upgradation response in tuberculosis (TB) is defined as the worsening of a pre-existing tubercular lesion or the appearance of a new lesion in a patient whose clinical symptoms initially improved with anti-TB treatment. A paradoxical response is common in HIV patients in the form of immune reconstitution inflammatory syndrome. A similar kind of response can also be seen in immunocompetent patients. Here, we present two cases of non-HIV TB who initially improved with antitubercular therapy (ATT) but worsened thereafter. After excluding possibilities such as multidrug-resistant TB, treatment failure or a superadded infection, a paradoxical upgradation response was diagnosed. Both the cases improved after treatment with corticosteroids in addition to ATT.

Keywords: Antitubercular therapy, non-HIV, paradoxical reaction, paradoxical response

How to cite this article:
Kabra MN, Kunapareddy T. Paradoxical upgradation response in non-HIV tuberculosis: Report of two cases. Indian J Med Microbiol 2019;37:450-3

How to cite this URL:
Kabra MN, Kunapareddy T. Paradoxical upgradation response in non-HIV tuberculosis: Report of two cases. Indian J Med Microbiol [serial online] 2019 [cited 2020 Oct 28];37:450-3. Available from:

 ~ Introduction Top

A patient on antitubercular therapy (ATT) can have worsening of his condition after an initial improvement termed as a paradoxical upgradation response. These reactions may be wrongly diagnosed as drug resistance, treatment failure or a superadded infection. Less is known about the exact mechanism of paradoxical upgradation responses. The development of paradoxical response in pulmonary tuberculosis (PTB) is rare compared to extrapulmonary TB (EPTB). In PTB, paradoxical reaction develops on the ipsilateral side of lung lesion and it is rare on the contralateral side. We report two unusual cases of paradoxical reactions: one in PTB and the other in EPTB.

 ~ Case Reports Top

Case 1

A 34-year-old male, medical professional, presented with complaints of fever with sore throat for 6 days and cough for 3 days with generalised weakness. The patient was given symptomatic treatment, but he had persistent cough so was advised chest X-ray (CXR), sputum gram stain, acid-fast bacillus (AFB) stain and culture. CXR showed prominent left hilum with a possibility of enlarged lymph nodes, so contrast-enhanced computed tomography (CECT) chest was done which showed multiple discrete and confluent necrotic lymph nodes in the right paratracheal, bilateral tracheobronchial, subcarinal, left para-aortic and left hilar regions. The largest confluent lymph node was seen in the left hilar region measuring nearly 3.4 cm × 2.4 cm, multiple opacities noted in the apical segment of the left lung lower lobe likely tubercular aetiology [Figure 1]a, [Figure 1]d, [Figure 1]g and [Figure 1]j. Sputum AFB was positive, and he was started on ATT with four drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E). GeneXpert for Mycobacterium tuberculosis (MTB) revealed MTB (detected very low), and rifampicin resistance was not detected. The patient clinically improved after initiation of ATT. AFB culture and sensitivity revealed MTB sensitive to first-line drugs.
Figure 1: (a-l) Serial chest computed tomography scan images of a 34-year-old male with pulmonary tuberculosis. Pre- and paratracheal lymphadenopathy at the time of diagnosis (a), worsened after treatment (b) and it resolved with the addition of steroids (c). In the same way hilar lymphadenopathy (d-f). Consolidation in the apical segment of the left lower lobe (g and h) resolved with the addition of steroids (i). Newly developed consolidation at the right apical zone (k as compared to j) disappeared after treatment with steroids (l)

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After 2 months, the patient again presented with worsening cough, sore throat and anorexia. The patient's compliance with ATT was good and HIV status was negative. A repeat sputum sample was sent for AFB stain and culture, and he was advised to continue four-drug ATT (HRZE). Repeat sputum AFB stain was negative. As symptoms persisted, the patient was advised for CECT chest which revealed multiple enlarged conglomerated centrally necrotic lymph nodes in the right upper paratracheal, bilateral lower paratracheal, bilateral hilar, aortopulmonary window, prevascular and para-aortic regions, the largest one in the right paratracheal region measuring 4.2 cm × 2.7 cm × 2.5 cm. Multiple subcentimetric size soft-tissue density nodules are seen in bilateral lung parenchyma. A small patchy area of ground-glass opacity was noted in the right upper lobe abutting the mediastinal lymph nodes [Figure 1]b, [Figure 1]e, [Figure 1]h and [Figure 1]k. There is a small tiny hypodense lesion in IV-A segment of the liver with multiple hypodensities in splenic parenchyma suggestive of infective granuloma. As compared to the previous CECT, there is an increase in the number of nodal stations and lung nodular lesions with hepatosplenic involvement. Endobronchial ultrasound was done, and fine-needle aspiration cytology (FNAC) was taken from the right paratracheal and left hilar lymph nodes. Pus aspirated was AFB smear positive, MTB detected high in GeneXpert and rifampicin resistance was not detected. Subsequent AFB culture was, however, negative. Hence, a paradoxical upgradation response was thought of and the patient was given oral prednisolone and the first-line ATT continued. The steroid was gradually tapered over 8 weeks. Repeat CT showed a decrease in number and size of mediastinal lymphadenopathy with interval resolution of lung parenchymal nodules [Figure 1]c, [Figure 1]f, [Figure 1]i and [Figure 1]l. The patient completed first-line ATT and recovered without any further complications.

Case 2

A 63-year-old male, non-smoker, non-alcoholic, driver by profession, with a history of diabetes mellitus, hypertension and psoriasis presented with complaints of high-grade fever associated with a cough, chest pain and dyspnoea for 1 week. Chest X-ray was done, and it revealed an increased cardiothoracic ratio. Two-dimensional (2D) echo revealed moderate concentric left ventricular hypertrophy. The patient was started on conservative management with IV antipyretics, antibiotics and other supportive treatments. As there was no improvement, a CT thorax and abdomen was done which revealed loculated fluid density in the anterior mediastinum with enlarged partially necrotic lymph nodes and increased vascularity with a possibility of TB or neoplasia and bilateral pleural effusion present (left >right) [Figure 2] a and d]. A CT-guided FNAC was done, and mediastinal fluid aspirated was sent for AFB stain and culture and found to be AFB stain positive. Hence, the patient was started on weight-based ATT (HRZE) and was discharged as he improved.
Figure 2: (a-f) Serial chest computed tomography scan images of a 63-year-old male with tuberculosis. There is a loculated fluid density in the anterior mediastinum at the time of diagnosis (a), worsened after treatment (b and c). There is bilateral pleural effusion present (left > right) (d) which although showed an interval resolution (e) worsened to moderate pleural effusion (left > right) (f). Note that there is no pericardial effusion initially (d and e) and the patient developed moderate to significant pericardial effusion and pericarditis (f) with treatment

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He was on regular follow-up with improving symptoms. However, at 2 months post-ATT, the patient again presented with chest heaviness, shortness of breath, cough and fever. A repeat CT chest was done on an outpatient basis which upon comparison with the earlier CT showed an interval increase in size and extent of the mediastinal loculated collection; however, there was an interval resolution of pleural effusion [Figure 2]b and [Figure 2]e. As the AFB culture sensitivity report was awaited, considering a possibility of multidrug-resistant TB moxifloxacin and amikacin were added to four-drug ATT. However, the patient continued to be symptomatic with persisting frequent episodes of nausea, vomiting, chest discomfort and worsening breathlessness, so he was admitted for further management. A repeat CT thorax and abdomen was done, and it revealed bilateral moderate pleural effusion (left > right) with underlying passive partial collapse, moderate to significant pericardial effusion with pericardial thickening and enhancement likely pericarditis, heterogeneous-enhancing inflammatory changes in anterior mediastinum prevascular space in retrosternal location-likely infective or inflammatory changes with no significant mediastinal adenopathy [Figure 2]c and [Figure 2]f. The liver was found to be grossly enlarged with no evidence of focal lesion/intrahepatic biliary radical dilatation. 2D echo was repeated, and it showed early effusive constrictive pericarditis with mild pericardial effusion [Figure 3]a. Subsequently, his AFB culture sensitivity test revealed MTB sensitive to all first-line drugs. In view of documented sensitive MTB and history of regular intake of ATT by the patient, a possibility of paradoxical upgradation reaction was thought, and the patient was started on oral corticosteroid. In view of echo findings and significant symptoms, opinion was taken from a cardiologist and cardiothoracic surgeon, and the patient was advised pericardiectomy. However, the patient refused for the same, so the patient was discharged after stabilisation on oral steroids with a plan for surgery in case of further worsening. His clinical condition improved gradually, and steroids were tapered over time. Repeat echo revealed minimal pericardial effusion with no evidence of constrictive pericarditis [Figure 3]b. The patient recovered without any further complications after completing first-line ATT.
Figure 3: (a and b) Two-dimensional echocardiography images of the same patient showing early effusive constrictive pericarditis with mild pericardial effusion (a) which resolved to minimal effusion without any evidence of constrictive pericarditis with the addition of steroids to antitubercular therapy (b)

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 ~ Discussion Top

Paradoxical reactions were first identified by Choremis et al.[1] Paradoxical reactions can be clinical or radiological.[2] Pornsuriyasak and Suwatanapongched proposed a diagnostic criteria which include (1) initial clinical/radiological improvement with adequate ATT, (2) paradoxical clinical/radiological deterioration, (3) no conditions interfering with efficacy of ATT should be present (compliance, malabsorption or side effects) and (4) absence of other explanations for deterioration.[3] Paradoxical reaction is common and may affect up to 25% of patients being treated for TB.[4] They have unpredictable timing, clinical course and severity.[5],[6] The time to onset is mostly from 28 to 50 days and could be 9 months also.[2] For paradoxical reaction to be diagnosed, the clinical or radiological worsening should occur at least 1 month of receiving ATT according to Carvalho et al.[7] The worsening of patient condition seen in 2 weeks to <1-month period might be attributed to delayed treatment response.[2] Evidence suggests that latency of paradoxical response is more in EPTB compared to PTB. Contributing factors or predictors of paradoxical upgradation reaction are young age, HIV-positive status, short duration of illness, high lymphocyte count, highly positive tuberculin skin sensitivity test, recipient of Vitamin D at start of therapy, AFB culture-positive diagnostic sample, disseminated TB and EPTB.[2],[3],[8],[9],[10],[11],[12] Paradoxical upgradation response is attributed to hypersensitivity to the tubercular proteins and cell wall products released by the dying mycobacteria in response to ATT.[5],[13] It is said that culture-positive patients have more potential for paradoxical upgradation response since they have a higher mycobacterial load. Moreover, enhanced Toll-like receptor signalling is responsible for paradoxical reactions in the patient supplemented with Vitamin D at the start of therapy.[12]

The AFB stain of a repeat sample could be positive, but the AFB culture should be negative to label it as a paradoxical reaction.[3] Paradoxical reactions are more commonly seen as worsening of the original lesions as compared to the development of new lesions. However, in both our cases, we have development of new lesions. Central nervous system (CNS) is the common site of paradoxical reaction whether it may be worsening or development of new lesions. After CNS, new lesions may develop as new pleural effusion or new lymph nodes.[4] However, in our cases, one had development of new lesions in the liver and spleen and the other developed pericardial effusion. Paradoxical reaction presenting as a case of splenic rupture is also reported.[4] Usually, a paradoxical reaction is self-limited, but it can also lead to respiratory failure and death.[3],[5] Paradoxical response may reappear in one-third of patients after discontinuation of corticosteroids.[3] In case of treatment failure, corticosteroids will worsen the condition.[6] Hence, there is a need for a clinician to have a high index of suspicion for paradoxical reactions in non-HIV TB as they are not uncommon and should be aptly managed.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

Choremis CB, Padiatellis C, Zou Mbou Lakis D, Yannakos D. Transitory exacerbation of fever and roentgenographic findings during treatment of tuberculosis in children. Am Rev Tuberc 1955;72:527-36.  Back to cited text no. 1
Tai ML, Nor HM, Kadir KA, Viswanathan S, Rahmat K, Zain NR, et al. Paradoxical manifestation is common in HIV-negative tuberculous meningitis. Medicine (Baltimore) 2016;95:e1997.  Back to cited text no. 2
Pornsuriyasak P, Suwatanapongched T. Thoracic manifestations of paradoxical immune reconstitution inflammatory syndrome during or after antituberculous therapy in HIV-negative patients. Diagn Interv Radiol 2015;21:134-9.  Back to cited text no. 3
Bloch S, Wickremasinghe M, Wright A, Rice A, Thompson M, Kon OM, et al. Paradoxical reactions in non-HIV tuberculosis presenting as endobronchial obstruction. Eur Respir Rev 2009;18:295-9.  Back to cited text no. 4
Breen RA, Smith CJ, Bettinson H, Dart S, Bannister B, Johnson MA, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704-7.  Back to cited text no. 5
Goel N. Paradoxical response to anti-tuberculous therapy presenting as choroiditis. Clin Exp Optom 2015;98:183-5.  Back to cited text no. 6
Carvalho AC, De Iaco G, Saleri N, Pini A, Capone S, Manfrin M, et al. Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients. Clin Infect Dis 2006;42:893-5.  Back to cited text no. 7
Brown CS, Smith CJ, Breen RA, Ormerod LP, Mittal R, Fisk M, et al. Determinants of treatment-related paradoxical reactions during anti-tuberculosis therapy: A case control study. BMC Infect Dis 2016;16:479.  Back to cited text no. 8
Singh AK, Malhotra HS, Garg RK, Jain A, Kumar N, Kohli N, et al. Paradoxical reaction in tuberculous meningitis: Presentation, predictors and impact on prognosis. BMC Infect Dis 2016;16:306.  Back to cited text no. 9
Cheng VC, Ho PL, Lee RA, Chan KS, Chan KK, Woo PC, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21:803-9.  Back to cited text no. 10
Lee YJ, Jung SH, Hyun WJ, Kim SH, Lee HIe, Yang HW, et al. Acase of obstructive jaundice caused by paradoxical reaction during antituberculous chemotherapy for abdominal tuberculosis. Gut Liver 2009;3:338-42.  Back to cited text no. 11
Barr DA, Coussens AK, Irvine S, Ritchie ND, Herbert K, Choo-Kang B, et al. Paradoxical upgrading reaction in extra-pulmonary tuberculosis: Association with vitamin D therapy. Int J Tuberc Lung Dis 2017;21:677-83.  Back to cited text no. 12
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;14:201-4.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]


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