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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 116-121

Predicting antitubercular drug-induced liver injury and its outcome and introducing a novel scoring system


1 Department of Internal Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Internal Medicine, Unit V, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Internal Medicine, St. Vincent Hospital, Worcester, MA, USA
4 Department of Preventive Medicine and Community Health, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
6 Department of Internal Medicine, Unit IV, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission31-Jan-2021
Date of Acceptance24-Feb-2021
Date of Web Publication14-Jun-2021

Correspondence Address:
Ajay Kumar Mishra
Department of Internal Medicine, St. Vincent Hospital, 123 Summer Street, Worcester 01545, MA
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_15_21

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  Abstract 


Background: Tuberculosis (TB) is a major global health problem, mainly in developing countries. Despite the availability of highly effective first-line antitubercular (ATT) drugs, ATT drug-induced liver injury (ATT DILI) leads to treatment interruption and consequently loss of therapeutic efficacy. Methods: In this prospective cohort study from India, all consecutive patients who met inclusion criteria and started on ATT were included. The incidence, risk factors, and outcome of ATT DILI were determined. A clinical prediction score for ATT DILI was derived. Results: A total of 393 patients were included. The incidence of ATT DILI was 9.7% (95% confidence interval 7%–13.2%). HIV infection, daily regimen, disseminated disease, and chronic liver disease were identified as significant risk factors (P < 0.05) for developing DILI. A prediction score derived from the risk factors showed that a score of >5 could predict DILI with a sensitivity of 74% and a specificity of 67%. All-cause mortality in DILI was 4.7%. Conclusion: The incidence of ATT DILI was 9.7% in our cohort with higher incidence among the patients on daily regimen. The study suggests that the combination of risk factors of extensive TB disease, HIV infection, chronic liver disease, and under nutrition increases the vulnerability to DILI, particularly with daily treatment regimen, emphasizing the role of acquired risk factors in the development of DILI.

Keywords: Drug-induced liver injury, outcome, scoring, tuberculosis


How to cite this article:
Raj Mani SS, Iyyadurai R, Mishra AK, Manjunath K, Prasad J, Lakshmanan J, Yadav B, Reginald A, Jasmine S, Hansdak SG, Zachariah A. Predicting antitubercular drug-induced liver injury and its outcome and introducing a novel scoring system. Int J Mycobacteriol 2021;10:116-21

How to cite this URL:
Raj Mani SS, Iyyadurai R, Mishra AK, Manjunath K, Prasad J, Lakshmanan J, Yadav B, Reginald A, Jasmine S, Hansdak SG, Zachariah A. Predicting antitubercular drug-induced liver injury and its outcome and introducing a novel scoring system. Int J Mycobacteriol [serial online] 2021 [cited 2021 Sep 17];10:116-21. Available from: https://www.ijmyco.org/text.asp?2021/10/2/116/318374




  Introduction Top


Tuberculosis (TB) remains as a major global health problem, being the second leading cause of death worldwide from an infectious disease. In India, there were 2.8 million new cases of TB and 0.517 million TB-related deaths in 2015.[1] This is despite the availability of effective treatment. A major reason for poor outcome is discontinuing treatment which is due to adverse drug reactions.[2] The first-line drugs used for the treatment of TB, namely isoniazid, rifampicin, and pyrazinamide, are hepatotoxic.

The incidence of antitubercular drug-induced liver injury (ATT DILI) varies from 3% to 28% in different studies, with higher incidence in Asian countries.[3] Several risk factors have been identified for DILI from previous studies, including age, female sex, abnormal baseline liver function test (LFT), malnutrition, underlying liver disease, HIV infection, extent of TB, and genetic polymorphisms, such as NAT2 and CYP2E1.[4],[5],[6],[7],[8] Despite adequate knowledge of risk factors, we are not yet able to predict which group of patients will develop ATT DILI before initiation of treatment. ATT DILI not only leads to interruption of treatment but also increases the risk of developing drug-resistant TB. It is, in this background, that this study was conducted to determine the incidence, risk factors, clinical profile, and outcomes of ATT DILI so that, in future, patients at risk can be identified early and the above-mentioned risks, serious hepatic complications, and death be prevented.


  Methods Top


Design

This is a prospective observational cohort study with patients recruited from the Department of General Medicine and Directly Observed Treatment Short Course (DOTS) Clinic (Community Health and Development Hospital) of Christian Medical College, Vellore, Tamil Nadu, India. The patients were started on either weight-based daily ATT regimen or intermittent thrice weekly DOTS regimen based on the place of recruitment. The study protocol was approved by the Institutional Ethics Review Board, Christian Medical College, Vellore. Informed consent was obtained from all the patients recruited in the study.

Case definition

In this study, ATT DILI was diagnosed according to the American Thoracic Society (ATS) definition:[9]

  1. Normalization of liver enzymes and resolution of signs and symptoms of hepatotoxicity after withdrawal of all anti-TB drugs
  2. Presence of at least one of the following: (a) Asymptomatic rise to more than 5 times the upper limit of normal (ULN) level of alanine transaminase (ALT) and/or aspartate transaminase (AST); (b) any increase in more than 3 times the ULN level of AST and/or ALT above pretreatment levels together with anorexia, nausea, vomiting, and jaundice; or (c) an absolute increase in the serum bilirubin more than 1.5 mg/dl.


Inclusion criteria

  1. All patients newly diagnosed to have TB, started on anti-TB, were eligible for this study
  2. All patients who were initiated on the treatment with documented baseline normal LFTs elsewhere and presented with ATT DILI to our hospital were also enrolled in the study.


Exclusion criteria

  1. Patients who had abnormal baseline LFT, patients on alternate hepatotoxic drugs other than antiretroviral treatment, pregnant patients, patients with malignancy on treatment, and patients who did not give informed consent were excluded from the study


Baseline investigations and follow-up

All patients enrolled had blood glucose, LFT, hepatitis B surface antigen, anti-hepatitis C antibody (HCV antibody), and HIV ELISA done at baseline. After initiation of ATT, all patients were clinically assessed for symptoms of hepatitis at every visit until completion of treatment either monthly or at intervals as advised by the treating physician.

Reintroduction of drugs after antitubercular drug-induced liver injury

Once the LFTs normalized, ATT drugs were reintroduced as per the treating physician's discretion. The order of the reintroduction of drugs was as decided by the treating physician. Once the drug was re-introduced, the patients were closely monitored for clinical features of worsening hepatitis and regular monitoring of LFT was done.

Sample size calculation and statistical methods

For the incidence of ATT DILI, the sample size was calculated based on a previous study from India from Parthasarathy et al. to provide 90% power with α error of 5%.[4] The calculated sample size was 400. Multivariate logistic regression was done according to the three models: patient-related background variables, disease, and treatment-related variables.[10],[11] Levels of significance were set at P = 0.05 and Z-value >1.96 at 95% confidence interval (CI).


  Results Top


All consecutive patients who were eligible and consented for the study from April 2013 to May 2014 were included. A total of 393 patients were recruited for the study [Figure 1]. The baseline characteristics of the patients on daily and DOTS regimen, mean age, and gender distribution were well matched [Table 1]. At baseline, the DOTS arm had lower rates of HIV infection and disseminated disease but had greater under nutrition compared to patients on daily regimen. Different sites of TB are summarized in [Table 2].
Table 1: Baseline characteristics of the patients

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Table 2: Distribution of tuberculosis according to anatomical site

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Figure 1: STROBE diagram

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Incidence of drug-induced liver injury

For calculation of incidence of ATT DILI, 38 patients out of 388 patients who developed DILI after starting ATT were included. Five patients who presented with DILI after starting treatment elsewhere were excluded. Therefore, the incidence of ATT DILI was calculated as 9.7% (95% CI 7%–13.2%). The incidence of DILI among patients on DOTS regimen was 3.5% (95% CI 2.4%–4.8%) when compared to daily regimen being 14% (95% CI 7.9%–22.4%).

Clinical profile of patients with drug-induced liver injury

Out of 43 patients who developed DILI, 23 patients (53%) were males and 24 patients (56%) had disseminated disease. Thirty-nine patients (90.7%) were on weight-based daily regimen, and only four patients on intermittent thrice weekly DOTS regimen. Vomiting was the most common symptom seen in 25 (58%) patients with DILI, followed by jaundice in 13 (30.2%) patients. However, 7 patients (16.3%) were asymptomatic and diagnosed solely by enzyme elevation more than five times. Clinically, icterus was observed in 28 (65%) patients and hepatomegaly in 2 (4.6%) patients. Signs of liver failure such as ascites or encephalopathy were seen in 4 (9.3%) patients.

LFTs showed that elevation of liver enzymes with elevated bilirubin was the most common abnormality, seen in 26 patients (60%) followed by cholestatic pattern in 11 (26%) and isolated liver enzyme elevation in 6 patients (14%). Fifteen patients (35%) had severe hepatitis according to the WHO Toxicity Standards. Presence of chronic liver disease was found to be significant risk factor for developing severe hepatitis.

Most of the patients (33, 76.7%) developed DILI within first 2 months [Figure 2]. Thus, we suggest careful clinical and biochemical monitoring during first 2 months in patients with clinical risk factors.
Figure 2: Study summary regarding antitubercular drug-induced liver injury

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Predictors of drug-induced liver injury

Using unadjusted and multivariate logistic regression analyses, HIV infection (odds ratio [OR] 2.84), daily regimen (OR 4.46), disseminated disease (unadjusted OR 1.769), hypoalbuminemia (OR 1.92), and chronic liver disease (OR 4.72) were identified as significant risk factors for the development of DILI [Table 3]. Other factors such as older age (age >60 years), chronic hepatitis B or C infection, or past history of jaundice were not significant in unadjusted analysis.
Table 3: Clinical predictors of antitubercular drug-induced liver injury

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Outcome of patients with antitubercular drug-induced liver injury

In our cohort, 39 patients (90.7%) required hospitalization for DILI. Four patients (9.3%) needed intensive care, out of which three improved and one expired. The mean time duration for normalization of liver function was 22 days (3–81 days).

Alternate regimen of amikacin, levofloxacin, and ethambutol was started after the development of DILI in 30 patients (69.8%). Four patients who had cholestasis were started on isoniazid, pyrazinamide, ethambutol, and levofloxacin (HZEL) regimen since the treating physician considered the cholestasis being secondary to rifampicin use. Four patients had acute hepatic failure out of which three patients recovered, and in these patients, the hepatotoxic ATT drugs were re-zintroduced successfully in full doses. All-cause mortality was 4.7% (2 patients). The causes of death were acute liver failure in one patient and pulmonary embolism in the other patient.

Drug-induced liver injury and antitubercular drug rechallenge

All three hepatotoxic drugs were successfully challenged in five patients. At least two drugs were challenged in other patients. Pyrazinamide rechallenge was successful in all six patients in whom pyrazinamide rechallenge was attempted. Seven patients developed rechallenge hepatitis [Table 1].


  Discussion Top


The incidence of DILI in our study was 9.7% (CI 7%–13.2%). A meta-analysis of 14 published studies from Western countries showed an incidence of 4.38%.[12] The incidence of ATT DILI from our study was comparable to the studies from Asian countries.[13],[14],[15] The reason for higher incidence of ATT-induced hepatitis in Asian countries is unknown. Presence of more clinical risk factors and predisposing genetic polymorphism may play a role in increased incidence of hepatotoxicity.

Predictors of liver injury

In our study, we identified disseminated disease, chronic liver disease, hypoalbuminemia, HIV infection, and daily regimen as the significant risk factors for developing DILI. Similar to previous studies, one of the significant predictors of DILI was hypoalbuminemia.[10],[16] However, this may be confounded by associated significant factors such as HIV infection, disseminated disease, and underlying chronic liver disease. In our cohort, patients with HIV infection had predisposition to disseminated disease (55.5% vs. 23%, OR 2.454), which is already known.[16],[17],[18]

Hence, did HIV infection confound the association between disseminated disease and drug-induced liver injury?

We did a subgroup analysis that showed HIV infection and disseminated TB being independent risk factors of DILI in patients with localized disease and without HIV infection, respectively. Disseminated tubercular disease had significant association with the development of DILI in univariate analysis (OR 1.77). Since disseminated TB, HIV infection, and hypoalbuminemia are closely interrelated, this may have diminished the influence of disseminated TB in the logistic regression analysis [Table 3]. Hence, disseminated disease must still be considered among the significant risk factors for DILI.

Type of regimen and risk of developing drug-induced liver injury

Majority of the patients who were on DOTS treatment in our study were from the community hospital. These patients had localized TB disease and lower rates of HIV infection. HIV-infected patients who have disseminated disease were mostly on daily regimen. These factors may have contributed to the lower incidence of DILI in the DOTS group. Despite this, subgroup analyses comparing both regimens showed that daily regimen was the significant risk factor for TB DILI when compared to thrice weekly regimen. Hence, we can conclude that HIV infection, disseminated disease, and daily regimen were the independent risk factors for developing ATT DILI.

The model of impact of DILI on TB treatment is shown in Figure 2. All these indicate the significant effect on patients' lives and public health importance of DILI on morbidity and mortality of TB. The only significant modifiable risk factor identified from our study was the daily regimen. From our study, DOTS regimen may be considered as a treatment option in patients with high risk of developing DILI.

However, from our study, we do not have long-term outcomes of TB including relapses and drug resistance which can aid in choosing either regimen. The WHO is currently advocating daily treatment regimen for TB because of more rapid sterilization (culture negativity) and lower rates of relapse.[19]

Predictive scoring system

Based on the results of our study, we propose a scoring system based on the significant risk factors for predicting DILI. Scores were assigned based on the OR obtained from univariate and multivariate logistic regression analyses. HIV infection, chronic liver disease, daily treatment regimen, extent of TB, hypoalbuminemia, and female gender were included in the scoring system [Table 4]. Significance of the scoring system was calculated using receiver operator characteristics curve. Area under the curve was 0.728 with standard error of 0.037 and CI of 0.65–0.80, which indicates that this predictive score is a fairly good score for predicting DILI. A total score of 5 and above predicts DILI with a sensitivity of 74% and a specificity of 67%. This score must be validated by a prospective study.
Table 4: Predictive scoring system based on risk factors for drug-induced liver injury (CMC Vellore DILI score)

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Rechallenge of antitubercular drugs

Isoniazid was the first drug rechallenged followed by rifampicin in most of the patients. Pyrazinamide was rechallenged only in six patients which was successful in all these patients. Hence, we suggest that whenever possible, rechallenging the patients with pyrazinamide may be attempted at escalating doses according to the British Thoracic Society (BTS) guidelines. Furthermore, we suggest that rechallenge of all three drugs, at the same time, can be attempted in patients with mild hepatitis in the absence of clinically significant risk factors. Recent studies published by Zuberi et al. from Karachi[20] and Sharma et al.[21] showed no significant difference between the ATS and the BTS guidelines.[20],[21] Our results are consistent with the published literature that there is a lack of difference in risk of rechallenge hepatitis between the two rechallenge regimens (13% vs. 13%).[22],[23]

Our study has merit of being a prospective study from a developing country with such a sample size covering all these aspects of DILI. The impact of DILI on TB treatment is well summarized in Figure 2. Our study has few limitations. The interaction between antiretroviral and ATT drugs for the risk of developing DILI was not studied. Our study does not have long-term follow-up, and hence, we could not assess relapse, default rate, and drug resistance in the long term.[24],[25],[26],[27]


  Conclusion Top


The incidence of ATT DILI from our study was 9.7% (95% CI 7%–13.2%) with higher incidence among the patients on daily regimen. The high incidence of ATT DILI emphasizes the public health importance of this side effect in India. The results emphasize the importance of acquired risk factors in the development of DILI and require careful monitoring in the first 2 months. A prediction score based on the above risk factors is suggested to identify patients who will develop DILI which needs further validation. Rechallenge by both the ATS and the BTS guidelines had similar successful rate.

Future directions

Genetic predisposition also seems to play a role in DILI apart from clinical risk factors, and the role of various genetic polymorphisms in the Indian setting needs further study so that we can derive a score based on both clinical and genetic risk factors that can predict DILI before initiation of treatment. The mechanism whereby the disseminated TB leads to hepatic vulnerability also needs further exploration.

Ethical clearance

The study was approved by the Institutional Ethics Review Board, Christian Medical College, Vellore (IRB Min No: 8157 dated 09.01.2013).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplementary File 1


  Definitions Top


  • Pulmonary tuberculosis was classified as follows:


    • Sputum positive if sputum smear showed acid-fast bacilli (AFB)
    • Sputum negative if AFB smears were negative, but symptoms and radiological features were suggestive of tuberculosis.


  • Tuberculosis meningitis was diagnosed as PRESUMPTIVE (based on duration of illness), CSF findings (lymphocytic pleocytosis with increased protein and low sugar and radiological features), or DEFINITE (also positive culture)
  • Pleural and peritoneal tuberculosis was diagnosed based on fluid analysis and/or caseating granulomas on histology or positive culture
  • Tuberculosis of the lymph node was diagnosed based on imaging, caseating granulomas on histology, or positive culture
  • Tuberculosis of the bone and spine was diagnosed based on histopathology/culture from the suspected area
  • Genitourinary tuberculosis was diagnosed based on positive urine AFB smear and/or culture
  • Disseminated tuberculosis was defined as radiological features of military or involvement of two or more different sites.



  Severity and Types of Hepatitis Top


The degree of severity of hepatotoxicity was assessed by the peak level of serum transaminases and classified according to the World Health Organization Toxicity Classification Standards.[9] Mild, moderate, and severe hepatitis were defined as elevations of Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) to 3–5 times the Upper limit of normal (ULN) (121– 200 UI/l), 5–10 times the ULN (201–400 UI/l), and 10 times the ULN (>400 UI/l), respectively.

Hepatitis was subclassified as follows: anicteric hepatitis was defined as elevation of liver enzymes without increase in bilirubin levels. Icteric hepatitis was defined as elevation of liver enzymes with increase in bilirubin levels. Drug-induced cholestasis was defined as direct hyperbilirubinemia without increase in liver enzymes. Drug-induced hepatitis with hepatic decompensation was defined as the presence of one or more of the following along with hepatitis: prolonged prothrombin time, ascites, or encephalopathy.



 
  References Top

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WHO | Global Tuberculosis Report 2016. WHO. Available from: http://www.who.int/tb/publications/global_report/en/. [Last accessed on 2016 Nov 11].  Back to cited text no. 1
    
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Park CK, Shin HJ, Kim YI, Lim SC, Yoon JS, Kim YS, et al. Predictors of default from treatment for tuberculosis: A single center case-control study in Korea. J Korean Med Sci 2016;31:254-60.  Back to cited text no. 2
    
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Kumar R, Shalimar, Bhatia V, Khanal S, Sreenivas V, Gupta SD, et al. Antituberculosis therapy-induced acute liver failure: Magnitude, profile, prognosis, and predictors of outcome. Hepatology 2010;51:1665-74.  Back to cited text no. 3
    
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Parthasarathy R, Sarma GR, Janardhanam B, Ramachandran P, Santha T, Sivasubramanian S, et al. Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99-108.  Back to cited text no. 4
    
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Shakya R, Rao BS, Shrestha B. Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors. Ann Pharmacother 2004;38:1074-9.  Back to cited text no. 5
    
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Lorent N, Sebatunzi O, Mukeshimana G, Van den Ende J, Clerinx J. Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: A prospective cohort study. PLoS One 2011;6:e19566.  Back to cited text no. 6
    
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An HR, Wu XQ, Wang ZY, Zhang JX, Liang Y. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin Exp Pharmacol Physiol 2012;39:535-43.  Back to cited text no. 7
    
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Cho HJ, Koh WJ, Ryu YJ, Ki CS, Nam MH, Kim JW, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb) 2007;87:551-6.  Back to cited text no. 8
    
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Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52.  Back to cited text no. 9
    
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World Health Organization. Conceptual Framework for Action on the Social Determinants of Health: Debates, Policy & Practice, Case Studies; 2010. Available from: http://apps.who.int/iris/bitstream/10665/44489/1/9789241500852_eng.pdf. [Last accessed on 2014 Sep 23].  Back to cited text no. 10
    
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Shidhaye R, Patel V. Association of socio-economic, gender and health factors with common mental disorders in women: A population-based study of 5703 married rural women in India. Int J Epidemiol 2010;39:1510-21.  Back to cited text no. 11
    
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Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465-71.  Back to cited text no. 12
    
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Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166:916-9.  Back to cited text no. 13
    
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Marzuki OA, Fauzi AR, Ayoub S, Kamarul Imran M. Prevalence and risk factors of anti-tuberculosis drug-induced hepatitis in Malaysia. Singapore Med J 2008;49:688-93.  Back to cited text no. 14
    
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Agal S, Baijal R, Pramanik S, Patel N, Gupte P, Kamani P, et al. Monitoring and management of antituberculosis drug induced hepatotoxicity. J Gastroenterol Hepatol 2005;20:1745-52.  Back to cited text no. 15
    
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Llibre JM, Tor J, Manterola JM, Carbonell C, Roset J. Risk stratification for dissemination of tuberculosis in HIV-infected patients. Q J Med 1992;82:149-57.  Back to cited text no. 16
    
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Gachot B, Wolff M, Clair B, Régnier B. Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med 1990;16:491-3.  Back to cited text no. 17
    
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del Arco C, García-Polo I, Santos I, Ortega O, Herraiz C, Quijano Y, et al. Tuberculosis in patients with HIV infection. An Med Interna 1989;6:633-4.  Back to cited text no. 18
    
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WHO | Treatment of Tuberculosis: Guidelines for National Programmes. WHO. Available from: http://www.who.int/tb/features_archive/new_treatment_guidelines_may2010/en/. [Last accessed on 2014 Sep 23].  Back to cited text no. 19
    
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Zuberi BF, Zuberi FF, Bader N, Alvi H, Salahuddin J. Comparison of British Thoracic Society and American Thoracic Society reintroduction guidelines for anti-tuberculous therapy induced liver injury. J Pak Med Assoc 2014;64:896-9.  Back to cited text no. 20
    
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Sharma SK, Singla R, Sarda P, Mohan A, Makharia G, Jayaswal A, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis 2010;50:833-9.  Back to cited text no. 21
    
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Sadanshiv M, George AA, Mishra AK, Kuriakose CK. Rifampicin-induced immune allergic reaction. Trop Doct 2018;48:156-9.  Back to cited text no. 22
    
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[PUBMED]  [Full text]  
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[PUBMED]  [Full text]  


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