Alladi Mohan

Miliary tuberculosis: new insights into an old disease

Miliary tuberculosis is a potentially lethal form of tuberculosis resulting from massive lymphohaematogeneous dissemination of Mycobacterium tuberculosis bacilli. The emergence of the HIV/AIDS pandemic and widespread use of immunosuppressive drugs has changed the epidemiology of miliary tuberculosis. Impaired cell-mediated immunity underlies the diseases development. Clinical manifestations are non-specific and typical chest radiographic findings may not be seen until late in the course of the disease. Atypical presentations--eg, cryptic miliary tuberculosis and acute respiratory distress syndrome--often delay the diagnosis. Several laboratory abnormalities with prognostic and therapeutic implications have been described, including pulmonary function and gas exchange impairment. Isolation of M tuberculosis from sputum, body fluids, or biopsy specimens, application of molecular methods such as PCR, and histopathological examination of tissue biopsy specimens are useful for the confirmation of diagnosis. Although response to first-line antituberculosis drugs is good, evidence regarding optimum duration of treatment is lacking and the role of adjunctive corticosteroid treatment is unclear.

Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity

BACKGROUND Drug-induced hepatotoxicity (DIH) is the most common adverse drug reaction leading to interruption of antituberculosis treatment. Worldwide, different reintroduction regimens have been advocated, but no consensus guidelines are available. Reintroduction of antituberculosis drugs in patients with DIH has never been studied systematically. We aimed to compare the safety of 3 different reintroduction regimens of antituberculosis drugs in patients with antituberculosis DIH. METHODS A total of 175 patients with a diagnosis of antituberculosis DIH were randomized to receive 1 of 3 different predefined reintroduction regimens of antituberculosis drugs and were evaluated prospectively. Patients in arm I were given isoniazid, rifampicin, and pyrazinamide simultaneously at full dosage from day 1. In arm II, drugs were administered in a manner similar to that recommended in the American Thoracic Society guidelines for reintroduction. In arm III, drugs were administered in accordance with British Thoracic Society guidelines. RESULTS Nineteen patients (10.9%) had recurrence of DIH during follow-up. Eight, 6, and 5 patients had recurrence of hepatitis in arms I, II, and III, respectively (P = .69). Of all the clinical and laboratory parameters, pretreatment serum albumin level was the only statistically significant predictor of future recurrence of DIH on reintroduction of antituberculosis drugs (P < .01). CONCLUSIONS The recurrence rate of hepatotoxicity was not significantly different between the 3 groups. According to the findings of the present study, all 3 of the potentially hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) can be reintroduced simultaneously at full dosage safely from day 1, especially for patients with bilateral extensive pulmonary tuberculosis, to halt disease transmission or to treat patients with life-threatening tuberculosis. TRIAL REGISTRATION ClinicalTrials.gov identifier number: NCT00405301.

Epidemiology, clinical manifestations, and diagnosis of Chikungunya fever: lessons learned from the re-emerging epidemic.

Chikungunya fever, caused by “Chikungunya virus,” is an arbovirus disease transmitted by the bite of infected mosquitoes belonging to the genus Aedes. Chikungunya fever epidemics have been reported from several countries around the world. The disease that was silent for nearly 32 years re-emerged in the October 2005 outbreak in India that is still ongoing. The incubation period ranges from 3 to 12 days. The onset is usually abrupt and the acute stage is characterized by sudden onset with high-grade fever, severe arthralgias, myalgias, and skin rash. Swollen tender joints and crippling arthritis are usually evident. In the chronic stage, relapses that include sensation of fever, asthenia, exacerbation of arthralgias, inflammatory polyarthritis, and stiffness may be evident. Neurological, ocular, and mucocutaneous manifestations have also been described. Chronic arthritis may develop in about 15% of the patients. Viral culture is the gold standard for the diagnosis of Chikungunya fever. Reverse transcription polymerase chain reaction and real-time loop-mediated isothermal amplification have also been found to be useful. Serodiagnostic methods for the detection of immunoglobulin M and immunoglobulin G antibodies against Chikungunya virus are more frequently used. Chikungunya is a self-limiting disease; however, severe manifestations such as meningoencephalitis, fulminant hepatitis, and bleeding manifestations may sometimes be life-threatening. Treatment is symptomatic and supportive. Prevention by educating the community and public health officials, vector control measures appear to be the best approach at controlling Chikungunya fever as no commercially available vaccine is available for public use in India for this condition presently.

Lethal interaction: the colliding epidemics of tobacco and tuberculosis

Tobacco consumption ranks high among the leading health risks and tuberculosis (TB) is a major public health issue in countries where the smoking problem has reached epidemic proportions. Given that both smoking and TB are major health concerns and are widely prevalent in several countries, it is surprising that the association between smoking and TB is still a matter of debate and controversy. Although several studies have evaluated the effect of smoking on TB, the association has been largely overlooked by the TB and public health communities at large. Three recent reviews, including two meta-analyses, have summarized a large body of published literature on the association between smoking and various TB outcomes. These reviews show that there is considerable evidence that tobacco smoking is associated with TB. The evidence is strong for TB disease but less strong for TB infection and mortality. Even if the effect is relatively modest, the population-attributable risk is likely to be substantial due to the widespread nature of tobacco exposure. TB control programs must begin to address tobacco control as a potential preventive intervention. Since tobacco control will have multiple health benefits, it is likely to be a highly cost-effective intervention from a societal perspective.

Clinical presentation and predictors of outcome in patients with severe acute exacerbation of chronic obstructive pulmonary disease requiring admission to intensive care unit

BackgroundSevere acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) is a common reason for emergency room (ER) visit about which little has been documented from India.MethodsProspective study of the clinical presentation and predictors of outcome in 116 patients presenting with severe AE-COPD requiring admission to the medical intensive care unit between January 2000 and December 2004.ResultsTheir mean age was 62.1 ± 9.8 years. There were 102 males. Mean duration of COPD was 7.2 ± 5.8 years. All males were smokers (22.3 ± 11.2 pack years); 35.2% smoked cigarettes and 64.8% smoked bidis. All women were exposed to domestic fuel. Associated co-morbid illnesses were present in 81 patients (69.8%); 53(45.7%) had one co-morbid illness and the remaining 28 (54.3%) had two or more co-morbid illnesses. Evidence of past pulmonary tuberculosis (PTB) was present in 28.4% patients; 5 patients who also had type II diabetes mellitus had active PTB. Arterial blood gas analysis revealed respiratory failure in 40 (33.8%) patients (type I 17.5% and type II 82.5%). Invasive mechanical ventilation was required in 18 patients. Sixteen (13.7%) patients died. Stepwise multivariate logistic regression analysis revealed need for invasive ventilation (OR 45.809, 95%CI 607.46 to 3.009;p < 0.001); presence of co-morbid illness (OR 0.126, 95%CI 0.428 to 0.037;p < 0.01) and hypercapnia (OR 0.114, 95%CI 1.324 to 0.010;p < 0.05) were predictors of death.ConclusionCo-morbid conditions and metabolic abnormalities render the diagnosis of AE-COPD difficult and also contribute to mortality. High prevalence of past PTB and active PTB in patients with AE-COPD suggests an intriguing relationship between smoking, PTB and COPD which merits further study.

MYASTHENIC CRISIS-LIKE SYNDROME DUE TO CLEISTANTHUS COLLINUS POISONING

Poisoning with Cleistanthus collinus frequently causes cardiac manifestations such as rhythm disturbances and also results in other manifestations such as metabolic acidosis and hypokalemia. We present the case of a patient who presented with a rare myasthenic crisis-like syndrome requiring assisted ventilation due to Cleistanthus collinus poisoning, which responded to treatment with neostigmine.

Miliary tuberculosis: A new look at an old foe

Miliary tuberculosis (TB), is a fatal form of disseminated TB characterized by tiny tubercles evident on gross pathology similar to innumerable millet seeds in size and appearance. Global HIV/AIDS pandemic and increasing use of immunosuppressive drugs have altered the epidemiology of miliary TB. Keeping in mind its protean manifestations, clinicians should have a low threshold for suspecting miliary TB. Careful physical examination should focus on identifying organ system involvement early, particularly TB meningitis, as this has therapeutic significance. Fundus examination for detecting choroid tubercles can help in early diagnosis as their presence is pathognomonic of miliary TB. Imaging modalities help in recognizing the miliary pattern, define the extent of organ system involvement and facilitate image guided fine-needle aspiration cytology or biopsy from various organ sites. Sputum or BAL fluid examination, pleural, pericardial, peritoneal fluid and cerebrospinal fluid studies, fine needle aspiration cytology or biopsy of the lymph nodes, needle biopsy of the liver, bone marrow aspiration and biopsy, testing of body fluids must be carried out. GeneXpert MTB/RIF, line probe assay, mycobacterial culture and drug-susceptibility testing must be carried out as appropriate and feasible. Treatment of miliary TB should be started at the earliest as this can be life saving. Response to first-line anti-TB drugs is good. Screening and monitoring for complications like acute respiratory distress syndrome (ARDS), adverse drug reactions like drug-induced liver injury, drug-drug interactions, especially in patients co-infected with HIV/AIDS, are warranted. Sparse data are available from randomized controlled trials regarding optimum regimen and duration of anti-TB treatment.

Outcomes of Category III DOTS treatment in immunocompetent patients with tuberculosis pleural effusion.

OBJECTIVES To study the efficacy and safety of Category III DOTS treatment (intermittent thrice-weekly rifampicin [RMP], isoniazid [INH] and pyrazinamide for 2 months, followed by RMP and INH for 4 months) under Indias Revised National Tuberculosis Control Programme in patients with uncomplicated small unilateral pleural effusion (<1500 ml). DESIGN This prospective, multicentre, observational study recruited 351 patients between 2006 and 2010. Patients were regularly followed up clinically as well as with ultrasound examination of the chest. RESULTS Successful outcome (clinical response with complete resolution on ultrasound examination at 6 months) was seen in 274 patients (78.1%). Efficacy was 88.9% (excluding defaulters), and 94% among those completing follow-up as per protocol. None of the patients received corticosteroids. Other outcomes included treatment extension (n = 26, 7.4%), default (n = 43, 12.2%), treatment failure (n = 3, 0.9%) and death (n = 3, 0.9%). Seventy-nine mild/moderate adverse events and one treatment-related serious adverse event were noted; one patient developed recurrent drug-induced hepatotoxicity. Two patients (0.7%) had relapse/re-infection at 24 months follow-up. CONCLUSION Intermittent thrice-weekly treatment for 6 months with three drugs in the intensive phase is effective and safe for unilateral small pleural effusion in immunocompetent patients. Although Category III no longer exists in the programme, the results are reassuring for intermittent treatment in extra-pulmonary TB under programme conditions.

Index-TB guidelines: Guidelines on extrapulmonary tuberculosis for India.

Extrapulmonary tuberculosis (EPTB) is frequently a diagnostic and therapeutic challenge. It is a common opportunistic infection in people living with HIV/AIDS and other immunocompromised states such as diabetes mellitus and malnutrition. There is a paucity of data from clinical trials in EPTB and most of the information regarding diagnosis and management is extrapolated from pulmonary TB. Further, there are no formal national or international guidelines on EPTB. To address these concerns, Indian EPTB guidelines were developed under the auspices of Central TB Division and Directorate of Health Services, Ministry of Health and Family Welfare, Government of India. The objective was to provide guidance on uniform, evidence-informed practices for suspecting, diagnosing and managing EPTB at all levels of healthcare delivery. The guidelines describe agreed principles relevant to 10 key areas of EPTB which are complementary to the existing country standards of TB care and technical operational guidelines for pulmonary TB. These guidelines provide recommendations on three priority areas for EPTB: (i) use of Xpert MTB/RIF in diagnosis, (ii) use of adjunct corticosteroids in treatment, and (iii) duration of treatment. The guidelines were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, which were evidence based, and due consideration was given to various healthcare settings across India. Further, for those forms of EPTB in which evidence regarding best practice was lacking, clinical practice points were developed by consensus on accumulated knowledge and experience of specialists who participated in the working groups. This would also reflect the needs of healthcare providers and develop a platform for future research.

Biomarkers for the diagnosis of bacterial infections: in pursuit of the 'Holy Grail'

Fever is one of the most frequent causes for hospitalization in developing countries. While several aetiological causes result in a febrile illness, bacterial infections constitute an important “curable” cause of fever. Systemic bacterial infection, bacterial sepsis and related syndromes are life-threatening illnesses that need early initiation of appropriate antimicrobial therapy. In a systematic review and meta-analysis1 (22 eligible studies, 58296 patients), 2051 (13.5%) of 15166 adults and 3527 (8.2%) of 43130 children were found to have community acquired bloodstream infections in Africa. In another systematic review2 (17 eligible studies, 40644 patients), blood stream infections were evident in 1784 (12%) of 14386 adults and 1722 (7%) of 26258 children in South and South-East Asia. Inspite of availability of reliable diagnostic methods for detecting bacterial infections, these are not widely available or accessible in routine practice in developing countries and confirmation of diagnosis of bacterial infection is done mainly in referral hospitals or research facilities. An ideal biomarker for bacterial infections should facilitate early rapid diagnosis, predict the course and prognosis of the disease and guide therapeutic decisions (e.g. antibiotic stewardship). Leucocyte count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), pro-adrenomedullin (ProADM), serum procalcitonin (PCT), mid-regional pro-atrial natriuretic peptide (ANP), pancreatic stone protein (PSP)/regenerating protein (reg), interleukin-6 (IL-6), IL-8, IL-27, soluble urokinase-type plasminogen activator receptor (suPAR) among others, have been studied as potential biomarkers to facilitate diagnosis and aid prognostication in bacterial sepsis3,4,5,6. The study by Qu et al7 featured in this issue, is an attempt in the quest for defining the diagnostic value of PCT, CRP, IL-6 and serum amyloid A (SAA) for bacterial infection in febrile patients. The authors prospectively studied 326 adult patients admitted with fever in an infectious diseases department and measured serum PCT, CRP, IL-6 and SAA, within 24 h of admission, in these patients. Following in-hospital diagnostic work-up, the patients were categorized as having bacteraemia group (n=58, 17.8%; group1), bacterial infection with negative blood culture (n=218, 66.9%; group 2) and non-bacterial infection group (n=50, 15.3%; group 3). PCT at a cut-off value of 0.26 ng/ml was found to have a sensitivity and specificity of 64.5 and 84 per cent, respectively for detecting bacterial infection in febrile patients. In this study7, PCT with an area under the curve of 0.804, was found to be superior to CRP (P<0.05), IL-6 (P < 0.001) and SAA (P < 0.01) in the early identification of bacterial infection. PCT, a 116 amino acid polypeptide precursor of the hormone calcitonin, belongs to the class of molecules, called “hormokines” that can exhibit either classical hormonal expression, or upon stimulation due to inflammation manifest more cytokine-like behaviour3,6,8. PCT, following translation from calcitonin-messenger RNA (mRNA), is enzymatically cleaved into smaller peptides, to yield the 32-amino acid mature calcitonin. In microbial infections and in various forms of inflammation, circulating level of PCT has been found to increase several-fold. Microbial infection is thought to result in ubiquitous increase of first calcitonin (CALC-I) gene-expression and a constitutive release of PCT from all parenchymal tissues and differentiated cell types in the body9. PCT peptide release from parenchymal cells (including liver, lung, kidney, adipocytes and muscle) in comparison to circulating cells (e.g. leucocytes), suggests a tissue based, rather than a leucocyte based mechanism of host defense3,6,8. Hence, PCT has been assessed as a diagnostic marker for bacterial infection in febrile neutropenic patients also10. The inflammatory release of PCT is thought to be induced either directly via microbial toxins (e.g. endotoxin) or indirectly via a humoral or cell-mediated host immune response [e.g. IL-1β, tumour necrosis factor-alpha (TNF-α), IL-6]. PCT levels rarely increase in response to viral infections and this lack of viral response is thought to be due to the virus-stimulated synthesis of α-interferon by macrophages, which, in turn, inhibits TNF synthesis3,6,8. So, PCT has also been used to distinguish bacterial infections from viral infections. PCT with its wide biological range, short time of induction (2-4 h) following a bacterial stimulus, and long half-life (22-26 h) has been found to be a useful biomarker for identification of bacterial infection and antibiotic stewardship3,11. Some studies12,13 have suggested that elevated PCT levels are useful in predicting bacteraemia in febrile patients. Two meta-analyses published in 200614 and 200715 had yielded conflicting results regarding the diagnostic utility of PCT. In the meta-analysis14 published in 2006 (33 studies, 3,943 patients) that included predominantly surgery or trauma patients, PCT was found to be a useful diagnostic marker for sepsis, severe sepsis, or septic shock, in critically ill patients and was found to be superior to CRP. In the subsequent systematic review and meta-analysis15 that included 18 studies [14 phase 2 studies (group 1), 1602 patients; and 4 phase 3 studies (group 2), 495 patients], the authors report that PCT cannot reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients. In this meta-analysis15, studies where sites of infection typical in sepsis (e.g. abdominal sepsis, pancreatitis, or meningitis) were clearly evident and studies that assessed the ability of procalcitonin to diagnose septic shock were excluded. Therefore, selection bias and other methodological issues appear to be the reasons for the differences in these results. Further, in a more recent meta-analysis16, (30 studies, 3244 patients) that assessed the accuracy and clinical value of PCT for diagnosis of sepsis in critically ill patients, bivariate analysis yielded a mean sensitivity of 0·77 [95% confidence intervals (CI) 0·72-0·81] and specificity of 0·79 (95% CI 0·74-0·84) and an area under the curve (AUC) of 0·85 (95% CI 0·81-0·88) suggesting PCT as a useful biomarker. In the study by Qu et al7, median PCT levels were observed to be lower in patients with Gram-positive compared to Gram-negative bacterial infections [0.53 (0.18-2.90) vs 2.13 (0.46-10.12), P<0.01). Further research with adequately powered studies is required to delineate this issue in greater detail. Overall, PCT appears to hold promise as a useful biomarker for bacterial infection in patients presenting with fever. While interpreting test results of biomarkers for bacterial infections, sepsis and related syndromes as “rule-in” or “rule-out” tests, issues concerning false-positive and false-negative results must be kept in mind. Several common causes of falsely elevated serum PCT levels in the absence of bacterial infection, such as, acute respiratory distress syndrome (ARDS), severe complicated falciparum malaria, trauma, chemical pneumonitis, among others should be carefully considered3,8,11. It has also been reported that low PCT levels at presentation are useful in excluding bacterial infection as an aetiological cause17. Caution should be exercised in excluding bacterial infections based on a low PCT level because low levels of PCT are often seen early in the course of infection; in subacute bacterial endocarditis with bacteraemia; and in localized infections. Therefore, if the clinical evaluation suggests a possible diagnosis of bacterial sepsis, but serum PCT levels are not elevated at the time of initial presentation, patients should still be treated for sepsis initially. Clinical monitoring over the next 48 h with serial PCT measurements can help in clarifying whether the initial diagnosis of bacterial sepsis is correct and antibiotics can be discontinued early if sepsis is excluded and PCT remains low18,19. As on today, PCT is an expensive test as compared to other biomarkers (such as, CRP) and this may be a limiting factor to its wider use in developing countries. Cost-effectiveness analysis takes into account a variety of factors including cost of the PCT assay, the frequency of PCT measurement, and the cost and duration of antibiotic therapy among others4. This issue merits further study in the Indian context.