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Paradoxical reactions (PR) to tuberculosis (TB) treatment are common during treatment, but have also been described after treatment. A presentation with recurrent signs or symptoms of TB after cure or completion of prior treatment needs to be differentiated between microbiological relapse and a paradoxical reaction. We searched all published literature on post-treatment PR, and present a synthesis of 30 studies, focusing on the epidemiology, diagnosis and management of this phenomenon. We report an additional case vignette. The majority of studies were of lymph node TB (LN-TB), followed by central nervous system TB (CNS-TB). A total of 112 confirmed and 42 possible post-treatment PR cases were reported. The incidence ranged between 3 and 14% in LN-TB and was more frequent than relapses, and between 0 and 2% in all TB. We found four reports of pulmonary or pleural TB post-treatment PR cases. The incidence did not differ by length of treatment, but was associated with younger age at initial diagnosis, and having had a PR (later) during treatment. Post-treatment PR developed mainly within the first 6 months after the end of TB treatment but has been reported many years later (longest report 10 years). The mainstays of diagnosis and management are negative mycobacterial cultures and anti-inflammatory treatment, respectively. Due to the favourable prognosis in LN-TB recurrent symptoms, a short period of observation is warranted to assess for spontaneous regression. In CNS-TB with recurrent symptoms, immediate investigation and anti-inflammatory treatment with the possibility of TB retreatment should be undertaken.

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Objective To investigate the causes and management of cranial magnetic resonance imaging(MRI)lesion progression during anti-tuberculosis treatment of tuberculous meningitis(TBM)in children.Methods The medical records of 17 children with TBM from February 2011 to May 2022 in this hospital were analyzed retrospectively,including the occurrence time,duration,clinical symptoms,cerebrospinal fluid re-sults,imaging characteristics,causes and treatment schemes.Results The mean duration of cranial MRI le-sion progression in 17 children with TBM after anti-tuberculosis treatment was(33.59±19.50)days;11 cases(64.71％)had no clinical symptoms.The progression of cranial MRI lesions was manifested as thickening of the original meningeal lesion compared with the previous one in 11 cases(64.71％),enlarging of the original lesion in the brain parenchyma in nine cases(52.94％),the original lesion disappeared in six cases(35.29％),and the appearance of a fresh lesion in one case(5.88％).The reasons identified were paradoxical response(PR)in 14 cases(82.35％),diagnosis of drug-resistant tuberculosis in one case(5.88％),association with i-soniazid metabolism type of rapid acetylation in one case(5.88％),and increase in foci due to unregulated an-ti-tuberculosis treatment in one case(5.88％).The treatment regimens for the 14 cases of conflicting reac-tions were:HRZE(H:isoniazid;R:rifampicin;E:ethambutol;Z:pyrazinamide)or HRZ in combination with or without linezolid,extended or additional glucocorticoids in nine cases,addition of levofloxacin in three cases,no specific therapy in five cases;The metabolic type of fast acetylated isoniazid was adjusted to 15 mg/kg in chil-dren.The children with drug-resistant tuberculosis were changed to drug-resistant regimen;Children with poor dependence did not change the treatment plan.Conclusion PR is the common reason for the progress of brain MRI lesions after TBM anti-tuberculosis treatment in children,and glucocorticoid treatment can promote the lesion absorption.

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OBJECTIVE: A paradoxical GH rise after the glucose load (GH-Par) is described in about one-third of acromegalic patients. Here, we evaluated the GH profile in subjects with and without acromegaly aiming to refine the definition of GH-Par. DESIGN: Observational case-control study. METHODS: Our cohort consisted of 60 acromegalic patients, and two groups of subjects presenting suppressed GH (< 0.4 µg/L) and high (non-acro↑IGF-1, n = 116) or normal IGF-1 levels (non-acro, n = 55). The distribution of GH peaks ≥ 120% from baseline, insulin, and glucose levels were evaluated over a 180-min time interval after glucose intake. RESULTS: A similar proportion of subjects in all three groups shows a GH ratio of ≥ 120% starting from 120 min. Re-considering the definition of paradoxical increase of GH within 90 min, we observed that the prevalence of GH peaks ≥ 120% was higher in acromegaly than in non-acro↑IGF-1 and non-acro (respectively 42%, 16%, and 7%, both p < 0.001). In patients without GH-Par, a late GH rebound was observed in the second part of the curve. Higher glucose peak (p = 0.038), slower decline after load, 20% higher glucose exposure (p = 0.015), and a higher prevalence of diabetes (p = 0.003) characterized acromegalic patients with GH-Par (with respect to those without). CONCLUSIONS: GH-Par response may be defined as a 20% increase in the first 90 min after glucose challenge. GH-Par, common in acromegaly and associated with an increased prevalence of glucose metabolism abnormalities, is found also in a subset of non-acromegalic subjects with high IGF-1 levels, suggesting its possible involvement in the early phase of the disease.

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BACKGROUND: Paradoxical responses (PR) occur more frequently in lymph node tuberculosis (LNTB) than in pulmonary tuberculosis and present difficulties in differential diagnosis of drug resistance, new infection, poor patient compliance, and adverse drug reactions. Although diagnosis of mediastinal LNTB has become much easier with the development of endosonography, limited information is available. The aim of this study was to investigate the clinical course of mediastinal LNTB and the risk factors associated with PR. METHODS: Patients diagnosed with mediastinal LNTB via endosonography were evaluated retrospectively between October 2009 and December 2019. Multivariable logistic regression was applied to evaluate the risk factors associated with PR. RESULTS: Of 9,052 patients who underwent endosonography during the study period, 158 were diagnosed with mediastinal LNTB. Of these, 55 (35%) and 41 (26%) concurrently had pulmonary tuberculosis and extrapulmonary tuberculosis other than mediastinal LNTB, respectively. Of 125 patients who completed anti-tuberculosis treatment, 21 (17%) developed PR at a median of 4.4 months after initiation of anti-tuberculosis treatment. The median duration of anti-tuberculosis treatment was 6.3 and 10.4 months in patients without and with PR, respectively. Development of PR was independently associated with age < 55 years (adjusted odds ratio [aOR], 5.72; 95% confidence interval [CI], 1.81-18.14; P = 0.003), lymphocyte count < 800/µL (aOR, 8.59; 95% CI, 1.60-46.20; P = 0.012), and short axis diameter of the largest lymph node (LN) ≥ 16 mm (aOR, 5.22; 95% CI, 1.70-16.00; P = 0.004) at the time of diagnosis of mediastinal LNTB. CONCLUSION: As PR occurred in one of six patients with mediastinal LNTB during anti-tuberculosis treatment, physicians should pay attention to patients with risk factors (younger age, lymphocytopenia, and larger LN) at the time of diagnosis.

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Amikacin liposome inhalation suspension (ALIS) is a key drug for the treatment of refractory Mycobacterium avium complex pulmonary disease (MAC-PD). Although cases of drug-induced interstitial lung disease (DIILD) by ALIS have been reported, its diagnosis is challenging due to overlapping existing pulmonary shadows, airway bleeding, exacerbation of underlying conditions, and the potential for various concurrent infections. A 72-year-old woman started treatment with ALIS for refractory MAC-PD. Three weeks later, she had a fever, cough, and appetite loss. She was hospitalized because multiple infiltrative opacities were observed on chest X-ray and chest computed tomography. Because the opacities worsened after empiric antibiotic therapy with broad-spectrum antibiotics, we initiated corticosteroid therapy, suspecting DIILD caused by ALIS, although drug lymphocyte stimulation tests for ALIS and amikacin were negative. Three days later, we found signs of improvement and quickly tapered the corticosteroids. After obtaining informed consent, we performed a drug provocation test of ALIS. Seven days later, she exhibited fever, an increased peripheral white blood cell count, and elevated serum C-reactive protein level, all of which returned to baseline 4 days after stopping ALIS, leading to a diagnosis of DIILD caused by ALIS in this patient. DIILD caused by ALIS is rare but should be carefully diagnosed to ensure that patients with refractory MAC-PD do not miss the opportunity to receive ALIS treatment.

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Strong inhibitory recurrent connections can reduce the tendency for a neural network to become unstable. This is known as inhibitory stabilization; networks that are unstable in the absence of strong inhibitory feedback because of their unstable excitatory recurrent connections are known as Inhibition Stabilized Networks (ISNs). One of the characteristics of ISNs is their "paradoxical response", where perturbing the inhibitory neurons with additional excitatory input results in a decrease in their activity after a temporal delay instead of increasing their activity. Here, we develop a model of populations of neurons across different layers of cortex. Within each layer, there is one population of inhibitory neurons and one population of excitatory neurons. The connectivity weights across different populations in the model are derived from a synaptic physiology database provided by the Allen Institute. The model shows a gradient of excitation-inhibition balance across different layers in the cortex, where superficial layers are more inhibitory dominated compared to deeper layers. To investigate the presence of ISNs across different layers, we measured the membrane potentials of neural populations in the model after perturbing inhibitory populations. The results show that layer 2/3 in the model does not operate in the ISN regime but layers 4 and 5 do operate in the ISN regime. These results accord with neurophysiological findings that explored the presence of ISNs across different layers in the cortex. The results show that there may be a systematic macroscopic gradient of inhibitory stabilization across different layers in the cortex that depends on the level of excitation-inhibition balance, and that the strength of the paradoxical response increases as the model moves closer to bifurcation points.

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BACKGROUND: Patients with pulmonary tuberculosis may present with deterioration of pleural effusion during anti-tuberculosis therapy, referred to as a paradoxical response (PR), with some patients requiring additional intervention. However, PR may be confused with other differential diagnoses, and the predictive factors for recommending additional therapies are unknown. Therefore, this study aimed to reveal useful information for the diagnosis and intervention of PR. METHODS: Data from human immunodeficiency virus-negative patients with tuberculous pleurisy (n = 210), including 184 patients with pre-existing pleural effusion and 26 patients with PR at Fukujuji Hospital, were retrospectively collected from January 2012 to December 2022 and compared. Furthermore, patients with PR were divided into the intervention group (n = 9) and the no intervention group (n = 17) and were compared. RESULTS: Patients in the PR group had lower pleural lactate dehydrogenase (LDH) (median 177 IU/L vs. 383 IU/L, p < 0.001) and higher pleural glucose (median 122 mg/dL vs. 93 mg/dL, p < 0.001) levels than those in the preexisting pleural effusion group. Other pleural fluid data were not significantly different. Patients in the intervention group had a shorter duration from the initiation of anti-tuberculosis therapy to the development of PR than patients in the no intervention group (median 19.0 days [interquartile range (IQR): 18.0-22.0] vs. median 37.0 days [IQR: 28.0-58.0], p = 0.012). CONCLUSION: This study demonstrates that, apart from lower pleural LDH and elevated pleural glucose levels, PR presents with similar features to preexisting pleural effusion and that patients who develop PR faster tend to require intervention.

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BACKGROUND: Prostatic specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration-resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti-androgens (SGA) post-chemotherapy using combined conventional imaging, and new generation imaging in the form of C-11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan. METHODS: We retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3-6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C-11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging. RESULTS: We identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75-21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group-A), whereas 39.6% displayed a paradoxical response (PR) (Group-B), defined as increased choline avidity combined with stable or down-trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group-A, 4.6 for Group-B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group-A versus Group-B, respectively (Log-Rank = 0.0063). CONCLUSION: Nearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C-11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

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BACKGROUND: Paradoxical inflammatory responses can occur during microbiologically successful antituberculous therapy. Optimal treatment is unknown, but corticosteroids are used most often. It is likely that interleukin-1 (IL-1) plays a central role in the development of these paradoxical responses, and if corticosteroids fail or are undesirable because of adverse effects, anti-IL-1 therapy may therefore be a rational choice. METHODS: We present seven HIV-negative tuberculosis patients with paradoxical responses, two with exclusively pulmonary and five with extrapulmonary tuberculosis. All had received corticosteroids, with unsatisfactory effect. Patients were treated with the IL-1 receptor antagonist anakinra and monitored for reduction of fever and inflammatory markers, imaging evidence of stabilization or regression of lesions, and respiratory improvement. FINDINGS: Six patients had anemia and four patients had lymphopenia at the start of the antituberculosis treatment. Fever was present in six patients at the moment of paradoxical response. Anakinra resulted in the decrease of fever within days, followed by resolution of symptoms and radiological improvement in five patients. Anakinra induced neutropenia, necessitating its cessation in two patients, who recovered quickly afterward. CONCLUSION: Anakinra can be considered in HIV-negative tuberculosis patients with paradoxical responses when steroids fail or are undesired. Given its favorable safety profile and reversible side effects, it is conceivable that anakinra might also be used as first-line adjuvant treatment for paradoxical responses. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781).

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Background and Purpose: Intraspinal tuberculoma is a rare disease in children, and its imaging findings have been described in only a few case reports. This study aimed to investigate the magnetic resonance imaging (MRI) features of pediatric intraspinal tuberculoma and to explore the possible pathogenesis of the disease. Materials and Methods: The clinical and MRI data of 24 child patients with intraspinal tuberculoma (such as 6 cases of intramedullary tuberculoma, 8 cases of intradural extramedullary tuberculoma, and 10 cases of epidural tuberculoma) were retrospectively analyzed. All patients underwent plain and contrast-enhanced MR scans. The diagnosis was confirmed by surgical pathology or by antituberculous treatment and follow-up data. Results: Intramedullary tuberculoma had a round shape, while intradural extramedullary tuberculoma and epidural tuberculoma presented long-fusiform or en plaque shapes. Regarding MRI signals, intramedullary tuberculoma and extramedullary tuberculoma were mainly isointense on T1-weighted imaging (T1WI) and hypointense or isointense on T2WI. Rim enhancement was observed in intramedullary tuberculoma, and marked homogeneous enhancement was dominant in extramedullary tuberculoma. Ten (10/24) tuberculomas occurred during antituberculous therapy, with intradural extramedullary tuberculoma accounting for 7 cases (7/8), which was significantly more frequent than intramedullary tuberculoma (1/6) or epidural tuberculoma (2/10). Conclusion: MRI is important in the diagnosis of intraspinal tuberculoma, which is characterized by isointensity on T1WI, isointensity, or hypointensity on T2WI, and rim or obvious homogeneous enhancement. Some intraspinal tuberculomas, especially intradural extramedullary tuberculomas, might be associated with the "paradoxical response" mechanism during the tuberculosis treatment.

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Emerging anti-tumor necrosis factor (TNF)-α antibodies therapy changed treatment strategy to inflammatory bowel diseases because of the efficacy. However, TNF-α inhibitor can be associated with an increased risk of infectious complications, especially tuberculosis. A 71-year-old female with steroid-dependent ulcerative colitis (UC) was admitted due to relapse of UC with endoscopically severe active. Golimumab and adjunctive prednisolone started with 30 mg daily resulted in clinical remission. However, she had general fatigue and fever at the time of seventh injection of golimumab without abdominal symptoms. Based on positive interferon-gamma release assay, polymerase chain reaction positive for tuberculosis (TB) in pleural fluid, and chest computed tomography, she was diagnosed as tuberculous pleuritis. Standard anti-TB treatment (isoniazid, rifampicin, ethambutol, and pyrazinamide) was started without cessation of golimumab, because cessation of TNF-α inhibitors during anti-TB treatment could cause the paradoxical response by skewing from regulatory to inflammatory immune responses. However, four weeks after initiation of anti-TB treatment, she got fever-up and pleural effusion increased. We then started prednisolone 30 mg daily as diagnosis of paradoxical response, resulting in improving the symptoms. This is a suggestive case of paradoxical response during anti-TB treatment despite continuous TNF-α inhibitors.

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Antitumor necrosis factor-associated nontuberculous mycobacteria-immune reconstitution inflammatory syndrome (IRIS) has rarely been reported. An 84-year-old woman with a history of rheumatoid arthritis treated with etanercept was diagnosed with Mycobacterium avium complex (MAC) pulmonary disease six years before admission. Etanercept was discontinued two years ago because of MAC pulmonary disease progression and restarted nine months before admission because of worsening arthritis, again resulting in MAC pulmonary disease progression. Etanercept was discontinued again; however, the pulmonary disease progressed more rapidly. The condition was considered paradoxical worsening caused by IRIS due to etanercept discontinuation. The disease resolved quickly with chemotherapy for MAC.

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We describe seven proned patients with coronavirus disease 2019-related acute respiratory distress syndrome in whom a paradoxical decrease in driving pressure reversibly occurred during passive, volume-controlled ventilation when compressing the lower back by a sustained "dorsal push." We offer a potential explanation for these unexpected observations and suggest the possible importance of eliciting this response for lung-protective ventilation of similar patients. DESIGN/SETTING: Case series at a single teaching hospital affiliated with the University of Minnesota. Measurements were recorded from continuously monitored airway pressure and flow data. PATIENTS: Nonconsecutive and nonrandomized sample of coronavirus disease 2019 acute respiratory distress syndrome patients who were already prone and paralyzed for optimized lung protective clinical management while inhaling pure oxygen. INTERVENTIONS: Sustained, firm manual pressure applied over the lower back in all patients, followed by abdominal binding in a subset of these. MEASUREMENTS AND MAIN RESULTS: Respiratory system driving pressure declined and respiratory system compliance improved in seven patients with the dorsal push maneuver. In a subset of four of these, abdominal binding sustained those improvements over >3 hours. CONCLUSIONS: Sustained compressive force applied to the dorsum of the passive and prone patient with severe respiratory failure due to coronavirus disease pneumonia may elicit a paradoxical response characterized by improved compliance and for a given tidal volume, lower plateau, and driving pressures. Such findings, which suggest end-tidal overinflation within the aerated part of the diseased lung despite the already compressed anterior chest wall of prone positioning, complement and extend those observations recently described for the supine position in coronavirus disease 2019 acute respiratory distress syndrome.

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BACKGROUND: Paradoxical response (PR) is defined as a clinical or radiological worsening in patients receiving adequate anti-tuberculosis treatment, with the exclusion of documented relapse or of other disease presentations. Although most patients with PR show spontaneous improvement, some cases presenting with diffuse alveolar damage have also been reported. METHODS: Retrospective clinical and laboratory data were collected on 89 patients of pulmonary tuberculosis who were treated at our hospital between April 2013 and January 2019. RESULTS: PR occurred in 21 patients (24%), and the median onset time after anti-tuberculosis treatment was 22 days. The time to onset of PR was shorter in diffuse pulmonary infiltrates group than in local pulmonary infiltrates group or in pleural effusion group. Low serum albumin, elevated lactate dehydrogenase (LDH), high Creactive protein (CRP) and chest radiographic appearance exceeding one-lung area were associated with PR incidence. There was no difference in sputum smear grading and pulmonary cavitation. Six out of the ten patients died, developing PR with diffuse pulmonary infiltrates. CONCLUSION: Low albumin and chest radiographic appearance exceeding one-lung area were risk factors for developing PR. Diffuse pulmonary infiltrates in early phase of anti-tuberculosis treatment was related with Inhospital mortality.

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Background: Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy. Material and Methods: We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing. Results: We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1, one in CLN3 and another in NR2E3. All patients were followed for at least three years (range 39-63 months). None had systemic abnormalities. Conclusions: Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.

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Immune reconstitution inflammatory syndrome (IRIS) is an immune reaction that occurs along with the recovery of the patient's immunity. Tuberculosis-related IRIS (TB-IRIS) upon tumor necrosis factor (TNF)-α inhibitor treatment has been reported in non-human immunodeficiency virus (HIV) patients. However, the importance of biological treatment, as a risk factor of IRIS, has not yet been established. In this study, we examined TB-IRIS in non-HIV patients to explore the role of TNF-α inhibitor treatment. Out of 188 patients with pulmonary TB, seven patients had IRIS. We examined univariate logistic and multivariate analysis to elucidate risk factors of TB-IRIS. Univariate analysis indicated that usage of immunosuppressive drugs, TNF-α inhibitors, and history of food or drug allergy were significantly related with TB-IRIS. On initial treatment, the values of serological markers such as serum albumin and serum calcium were significantly related with TB-IRIS. There was a higher mortality rate in patients with TB-IRIS. Furthermore, multivariate analysis revealed that usage of TNF-α inhibitors, history of allergy, and serum hypercalcemia were related to TB-IRIS. Usage of TNF-α inhibitors, history of allergy, and serum hypercalcemia may be independent predictors of TB-IRIS in non-HIV patients. Since higher mortality has been reported for TB-IRIS, we should pay attention to TB patients with these risk factors.

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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.

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Anti-programmed cell death-1 (PD-1) agents enhance the antitumor immunoresponse. A number of reports have indicated that patients with malignancies who receive anti-PD-1 agents are at risk for tuberculosis (TB) infection. In this report, we present a patient with non-small cell lung cancer who developed pulmonary tuberculosis while receiving the anti-PD-1 agent nivolumab, and who subsequently demonstrated a paradoxical response (PR) 10 days after initiation of anti-MTB treatment. We suggest that anti-PD-1 agents not only induce the development of pulmonary TB, but also development of PR after anti-MTB treatment, through upregulation of the immune response. Furthermore, based on their radiological and immunological similarity, we speculate that the schema of development of PR closely resembles that of pseudoprogression in non-small cell lung cancer patients after anti-PD-1 treatment.

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