J Harikrishna

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.

Infectious purpura fulminans

A 60 year old male patient was admitted to the medical intensive care unit (MICU) at the Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, in October 2013, with acute exacerbation of chronic obstructive pulmonary disease, acute respiratory failure requiring mechanical ventilatory support. While on treatment he developed new onset fever and evidence of septic shock. Pseudomonas bacteraemia was evident on blood culture. Laboratory work-up revealed a low platelet count (25,000/µl); prolonged prothrombin time (test = 18.4 sec, control = 13.2 sec) and activated partial thromboplastin time (test = 38 sec, control = 32 sec); decreased serum fibrinogen level (80 mg/dl) which was suggestive of overt disseminated intravascular coagulation (DIC) with a score of 5 as per the International Society for Thrombosis and Haemostasis (ISTH) Diagnostic Scoring System1,2. The patient developed characteristic skin lesions over the right lower limb (Figure) and succumbed to his illness within 48 hours of onset of these lesions. Fig Photograph showing non-blanchable, purple coloured skin lesions with well defined margins (arrow heads) along with bullae (arrows) containing clear fluid suggestive of infectious purpura fulminans. Purpura fulminans is an acute, often lethal syndrome characterized by DIC. It starts as well-demarcated erythematous macules that progress rapidly with haemorrhagic necrosis resulting in dark raised lesions, with vesicle or bulla formation3. It has been observed in severe acute bacterial infections caused by Neisseria meningitidis, Streptococcus pneumoniae, Group A and B streptococci, Staphylococcus aureus, Haemophilus influenzae, Plasmodium falciparum malaria and heritable protein C pathway defects4. Pseudomonas bacteraemia is an uncommon cause of purpura fulminans. It is important to recognize this uncommon cutaneous manifestation of systemic sepsis early and institute appropriate aggressive management as it is associated with a high mortality.

Provider-initiated HIV testing & counselling in incident tuberculosis cases under National TB Programme conditions at a tertiary care teaching hospital in Tirupati, south India

Background & objectives: As sparse published data are available regarding burden of human immunodeficiency virus (HIV) infection in incident tuberculosis (TB) cases at tertiary care teaching hospitals under National TB Programme conditions from India, the present study was designed to assess the proportion of referred registered TB patients who had actually undergone HIV testing and HIV-seropositivity in these. Methods: This was a study of provider-initiated HIV testing and counselling in patients registered for the treatment under Revised National TB Control Programme (RNTCP) of Government of India at a tertiary care teaching hospital in Tirupati, south India, during 2012-2013. Results: Between January 2012 and June 2013, 610 adult patients registered under RNTCP who were referred to Integrated Counselling and Testing Centre for HIV testing, were prospectively studied. Of these, 458 patients (75%) [mean age: 38.6±16.3 yr; 295 (64.4%) males] underwent HIV testing; HIV-co-infection was present in 21 (4.6%) patients. A significantly higher proportion of HIV co-infection was evident in PTB compared with EPTB [13/179 (7.2%) vs 8/279 (2.8%); respectively, P=0.038] and in previously treated patients compared to new patients [6/51 (11.8%) vs 15/407 (3.7%); respectively, P=0.009]. Interpretation & conclusions: The findings of this study showed that a higher proportion of TB patients underwent HIV testing (75%) compared to the national figure of 63 per cent in 2013-2014. HIV seropositivity (4.6%) in TB patients who underwent HIV testing was similar to the five per cent figure observed at national level during 2013-2014. The HIV status of 25 per cent of patients with incident TB still remained unknown, suggesting a need for better integration and co-ordination for effective management of HIV-TB co-infection.

Cleistanthus collinus poisoning: experience at a medical intensive care unit in a tertiary care hospital in south India.

Background & objectives: Ingestion of Cleistanthus collinus causes hypokalemia and cardiac arrhythmias leading to mortality in most cases. We undertook this retrospective study to evaluate the clinical presentation and predictors of outcome in critically ill patients admitted with C. collinus poisoning. Methods: The case records of 56 patients admitted to the medical intensive care unit (MICU) of a tertiary care teaching hospital in south India (2000-2014) with C. collinus poisoning were retrospectively analysed. Results: The mean age of patients was 36.7±13.3 yr; there were 30 males. Salient clinical manifestations included hypokalemia (58%), neutrophilic leucocytosis (48.2%), acute kidney injury (AKI) (42.9%), acute respiratory failure requiring mechanical ventilation (AcRFMv) (32.1%), shock (21.4%); cardiac arrhythmias and neuromuscular weakness (19.6% each); 21 patients (37.5%) had adverse outcome. Longer time-lapsed from consumption to reaching emergency room [median (interquartile range)] (hours) [49 (22-97) vs. 28 (7-56), P=0.038]; higher acute physiology and chronic health evaluation II (APACHE II) score at presentation [14 (8.25-14.75) vs. 2 (0-6) P<0.001]; and presence of the following [odds ratio (95% confidence intervals)] at initial presentation: shock [37.40 (4.29-325.98), P=0.001]; AcRFMv [26.67 (5.86-121.39), P<0.001]; elevated alanine aminotransferase [5.71 (1.30-25.03), P=0.021]; metabolic acidosis [5.48 (1.68-17.89), P=0.005]; acute kidney injury (AKI) [5 (1.55-16.06), P=0.007]; hyponatremia [4.67 (1.25-17.44), P=0.022]; and neutrophilic leucocytosis [3.80 (1.02-14.21), P=0.047] predicted death. A significant (P<0.001) increasing trend in mortality was observed with increasing International Program on Chemical Safety Poisoning Severity Score (IPCS-CSS) grade. Interpretation & conclusions: C. collinus is a lethal poison associated with high mortality for which there is no specific antidote. Careful search and meticulous monitoring of the predictors of death and initiating appropriate corrective measures can be life saving.

Trends in the presentation of acute exacerbation of chronic obstructive pulmonary disease requiring admission to ICU: Experience at a tertiary care teaching hospital in South India

Chronic obstructive pulmonary disease (COPD) is a common, and preventable disease. It is the third most common cause of death in the world 1. Acute exacerbation of COPD (AECOPD) is a common cause of hospital visits and leads to an increase in morbidity and mortality2. AE-COPD is characterized by acute deteriorations of the patient’s clinical status; worsening of health-related quality of life, lung function, and physical act ivity; disease progression; and an increased risk of death. Very little published data are available, especially from India, about the trends and seasonal variations of AE-COPD. This prompted us to undertake the present study.

Treatment of tuberculosis pericarditis

Tuberculosis (TB) is responsible for approximately 70% of the cases of large pericardial effusion and the most cases of constrictive pericarditis in developing countries. Early diagnosis and institution of appropriate therapy are critical to prevent mortality. Treatment of TB pericardial effusion consists of 4-drug therapy (isoniazid, rifampicin, pyrazinamide, and ethambutol) for 2 months followed by 2 drugs (isoniazid and rifampicin) for 4 months. Systematic reviews and meta-analyses suggest that although overall corticosteroids are associated with a beneficial effect on the variables analyzed, the wide confidence interval and a small number of events make it impossible to draw firm conclusions. Pericardiectomy is the definitive treatment for constrictive pericarditis, but is unwarranted either in very early constriction where it could be transitory.

Noninvasive ventilation as first-line treatment for acute respiratory distress syndrome: The time is not ripe yet!

Noninvasive ventilation (NIV) is a method of delivering mechanical ventilatory support via an upper airway mask without the need for tracheal intubation. Early reports of the applications of NIV in the treatment of acute respiratory failure date back to the mid-1940s when Motley et al.[1] used intermittent positive inspiratory pressure ventilation (IPPV) via an anesthesia mask in the treatment of acute respiratory failure caused by pneumonia, pulmonary edema, near-drowning, Guillain-Barre syndrome, and acute severe asthma.[1] However, with the emergence of invasive mechanical ventilation, the use of NIV took a back seat. The clinical application of NIV re-emerged in the 1980s when it was successfully used to treat obstructive sleep apnea,[2] and respiratory failure in patients with neuromuscular diseases.[3] Thereafter, the last two decades have witnessed a phenomenal increase in the clinical applications of NIV in the acute care setting.[4] NIV has emerged as a modality of choice in the management of severe acute exacerbation of chronic obstructive pulmonary disease (COPD) and cardiogenic pulmonary edema (Grade 1 [strong] recommendation).[5] Evidence is accumulating for use of NIV in patients with acute respiratory failure in the following settings: Immunosuppressed patients, following abdominal surgery and lung resection, for facilitating early extubation in patients with COPD, and as a transition to spontaneous breathing after planned extubation in patients at high risk for recurrent respiratory failure, such as, age >65 years, cardiac failure as the cause of intubation, Acute Physiology and Chronic Health Evaluation (APACHE) II score greater than 12 at the time of extubation (grade 2 [weak] recommendation).[5] NIV has many advantages compared to IPPV. It is easy to administer, avoids the need to secure an invasive airway, is associated with fewer complications, and a shorter hospital stay. Further, the cost of treatment and burden on health care system is also less with NIV.[5] Acute respiratory distress syndrome (ARDS), characterized by acute onset bilateral pulmonary infiltrates and refractory hypoxemia is associated with a high mortality. The standard care for patients with ARDS includes early IPPV with low tidal volume, high positive end-expiratory pressure, among others. The benefits and harms of NIV in ARDS have not been systematically evaluated. For conditions resulting in acute hypoxemic respiratory failure such as acute exacerbation of bronchial asthma, ARDS, severe community-acquired pneumonia (CAP), and chest trauma, NIV is not considered to be the modality of choice.[5,6] However, in these conditions, including ARDS, NIV has been tried when there were no contraindications. Evidence regarding the use of NIV in acute respiratory failure excluding COPD and cardiogenic pulmonary edema is limited to case series, observational studies and few randomized controlled trials (RCT) that included a heterogeneous, mixed population of patients with various etiological causes which had revealed conflicting results. One RCT[7] suggested that in patients with acute hypoxemic respiratory failure which included patients with ARDS, addition of NIV to standard medical management resulted in decreased rate of endotracheal intubation, length of Intensive Care Unit (ICU) stay, and mortality in a subset of patients with arterial partial pressure of carbon dioxide more than 45 mm of Hg compared to patients who received standard medical care and oxygen inhalation. Two other RCTs[8,9] also showed beneficial effects of addition of NIV to standard medical therapy compared to oxygen inhalation. Another RCT[10] showed NIV neither reduced need for intubation nor improved the clinical outcome. Further, an RCT[11] that compared NIV with IPPV concluded that NIV is as effective as IPPV in improving gas exchange and associated with fewer complications in ICU setting. A systematic review[12] that compared standard therapy alone with NIV along with standard therapy in patients with acute hypoxemic respiratory failure showed that NIV decreased the rate of endotracheal intubation, length of ICU stay and ICU mortality. In all these studies, the proportion of ARDS patients has been very small and significant heterogeneity observed in the results limits their extrapolation to patients with ARDS. In patients with moderate to severe ARDS, evidence comparing the use of NIV with IPPV head-on is sparse and is limited to few observational studies and no RCTs. In one observational study[13] in patients with acute lung injury (ALI)/ARDS who received a trial with NIV, tracheal intubation could be avoided in 40% of patients; however, a significantly higher mortality was observed in patients who had received NIV trial compared with patients who were intubated early. In patients with ARDS, while on one hand a substantial reduction in the need for tracheal intubation has been observed with the use of NIV, a substantial increase in mortality has been a cause for concern.[13] A meta-analysis[14] that evaluated on the role of NIV in ARDS showed no significant benefit of the addition of NIV to standard medical therapy. In another meta-analysis,[15] it was observed that NIV avoided intubation in 50% of patients; however, the authors concluded that in view of significant heterogeneity these results should be interpreted with caution. Further, a more recent meta-analysis[16] had also shown that, in patients with ALI/ARDS, while early use of NIV can decrease the endotracheal intubation rate, it did not change the mortality of these patients. Further, evidence is also available that failed NIV is associated with intubation-related complications and increased risk of death.[17] In this issue of the IJCCM, Sehgal et al.[18] reported their experience with NIV in patients with ARDS. In this prospective observational study[18] conducted in patients with mild to moderate ARDS, the authors reported that NIV has avoided intubation in 44% of subjects and univariate analysis has shown that baseline APACHE II score >17 and lack of improvement in the ratio of arterial oxygen tension (PaO2) to fraction of inspired oxygen (FIO2) >150 after 1 h of initiation predicted NIV failure. Further, significantly higher mortality in patients with NIV failure compared with no mortality observed in those with NIV success (19/23 vs. 0/18) is another cause for concern. Patients with NIV failure had more severe disease characterized by a higher median (interquartile range [IQR]) base line APACHE II score and PaO2/FIO2 ratio. The authors report that the median (IQR) time to intubation was 3 (1–4) h. This delay in initiating tracheal intubation and mechanical ventilation in patients with more severe disease could also have contributed to the higher mortality observed in the present study. While the observations from the present study[18] raise hope in terms of avoiding tracheal intubation, the results this study[15] should be interpreted with caution. This present study[15] where the authors have chosen a “sample of convenience” is underpowered as the sample studied (n = 41) is very small. As of now, NIV should be used with caution in patients with ARDS. Use of NIV is patients with ARDS should be considered only in ICUs equipped with facilities for round-the-clock monitoring and carrying out tracheal intubation as soon as it is required. Patients in whom NIV is being considered should be judiciously selected and carefully monitored for NIV failure with an intention to intubate as early as possible in case of NIV failure. At present, sufficient evidence is inadequate to make a strong recommendation to support the routine use on NIV as an initial mode of choice in patients with ARDS. Prospective, randomized, multicentric RCTs with an appropriate sample size are required to generate evidence regarding the role of NIV in patients with ARDS.