MBBS, DNB, Resident, General Medicine, Aster Medcity

Dr Aswathy Krishna

MBBS, MD LeadConsultant, General Medicine Aster Medcity

Dr Geetha Mary Philips

MBBS, MD, Consultant, Microbiology, Aster Medcity

Dr Sonya Joy

MBBS, DNB, Consultant, Infectious diseases, Aster Medcity

Dr Anup P Warrier

Tuberculosis (TB) is still considered a major health disease leading to mortality specifically in India and worldwide. Rapid and early diagnosis can play a very important role in prevention of transmission and mortality. Various guidelines have proposed usage of different diagnostic tests to arrive and confirm the diagnosis of TB. Current study was a prospective, observational study in MTB patients with a positive result on at least one of the three modalities (CB NAAT, TB Culture, AFB Microscopy). The objective was to evaluate the clinical and diagnostic utility of CB NAAT and TB culture in patients with various clinical syndromes of MTB. A total of 156 subjects, of which majority were in the age group of > 50 years (53.2%), followed by 21 to 30 years (17.94%) and 41to 50 years (14.7%) were included. 35 patients were found to be only culture positive, with the other 2 tests being negative. The incremental yield of adding culture was found to be 22.43%. 20 patients out of the total 156 cases (12.8 %) were either smear or CB NAAT positive, but culture negative. 1 patient (0.64%) had Rifampicin resistant Multi-Drug Resistant (MDR) TB. The present study showed a sensitivity and specificity of CB NAAT like PPV and NPV but there may be a positive association between CB NAAT and TB culture.

Tuberculosis (TB) is a major public health disease that ranks as the second most leading cause of death worldwide. From a public health perspective, early and rapid diagnosis of TB is important because of its potential for transmission. [1] In 2018, incidence of TB in India was 2.69 million with mortality rate of 32 per lakh population. India constitutes 24% of total TB burden. A great majority of the cases are fully preventable and treatable. [2] The Revised National Tuberculosis Control Program (RNTCP) recommends the use of sputum smear microscopy for acid fast bacilli (AFB), nucleic acid amplification test (Gene Xpert) and Mycobacterium Culture, for the diagnosis of pulmonary tuberculosis (PTB). [3] Sputum microscopy is relatively inexpensive and quick but has poor sensitivity as compared to other two modalities [4] After the introduction of broth-based media drug susceptibility testing (DST), the results time reduced to weeks. However, the contamination rate limits its utility in a resource limited setting. To overcome these limitations, in 2008, the World Health Organization (WHO) certified and endorsed the line probe assay as a molecular method for the rapid diagnosis of TB and simultaneous detection of rifampicin (RMP) and isoniazid (INH) resistance. [5]

CB NAAT is an example of RT-PCR. It can detect Mycobacterium tuberculosis (MTB) and their DST patterns for the first line drug RMP in smear positive (including scanty), smear negative and culture positive samples. Gene Xpert provides accurate and rapid diagnosis, while culture is the most sensitive, but takes between 2 to 8 weeks to yield results and is not useful in rapid diagnostics. [3]

The published CB NAAT detection threshold is approximately 100- 130 colony forming units (cfu)/ml of sample. In comparison, the detection threshold is <10 cfu/ml for mycobacterial liquid culture and is >5000 cfu/ml for Ziehl Neilson staining for acid fast bacilli (AFB) via standard microscopy in sputum. [6]. The results of CB NAAT can help to speed up the decision-making process involved in the diagnosis of tuberculosis, so that early anti-tuberculosis treatment can be initiated, and it also reduces infectious periods. These can lead to cost savings. The current study was carried out to evaluate the clinical and diagnostic utility of CB NAAT and TB culture in patients with various clinical syndromes of MTB. 

which had been tested by less than or equal to 2 of the following tests were excluded from the study: 1. CB NAAT, 2. TB Culture, 3. AFB Microscopy. Primary objective of the study was to identify the diagnostic gain in simultaneous testing with AFB smear, CB NAAT and MTB culture in diagnosis of tuberculosis. Evaluation of the correlation between positivity of CB NAAT and TB culture and assessment of the sensitivity of CB NAAT in diagnosis of MTB from various specimens were the secondary objectives. Data from electronic medical records as well as lab records are used to fill the proforma for the respective patients. Diagnostic gain is calculated as the net difference in number or percentage of patients diagnosed by simultaneous testing with each specific tests. For calculating sensitivity of CB- NAAT, TB culture is taken as gold standard.

The statistical analysis is performed by IBM SPSS Statistics 20 version. All categorical variables are described as frequency and percentage. All Continues variable are described as mean ± SD. Normality is checked by Kolmogrov-smirnove test. Independent samples t-test is used to compare the mean values between two groups, Mann Whitney u test is used to test the significance among the non-parametric data. Pearson Chi-square test is used to find the association between categorical variables. P value of <0.05 was considered statistically significant. Sensitivity and Specificity are used to check diagnostic accuracy of the test.

The study included a total of 156 subjects, of which majority were in the age group of > 50 years (53.2%), followed by 21 to 30 years (17.94%) and 41to 50 years (14.7%). Hence majority of subjects were in the older age group. Majority of subjects were males 51% and 49% were females 

Most common symptoms among the subjects were fever in 78.8%, loss of appetite in 44.2%, loss of weight in 34.3%, 29.4% with breathlessness, 16.6% hard cough with expectoration, 19.2%with lymph node swelling, 13.4% with abdominal pain and 5.7% with haemoptysis.

Most common clinical finding was lymphadenopathy in 25% of patients followed by abdominal tenderness (17.3%) and reduced breath sounds. 9.61% patients have bronchial breath sounds, 8.9% had dull note on percussion and pallor, 7.6% had clubbing and 3.2 % of patients had shifting dullness.

Most common clinical diagnosis on presentation among subjects was Tuberculosis in 52% of patients (including pulmonary, extra pulmonary and disseminated TB). 16% of patients were diagnosed as pneumonia, 9% as pyrexia of unknown origin, 7% as lymphoma, 6.4% as lung malignancy, 3.8% as intestinal malignancy, 3.3% as chronic liver disease and 2.5% as inflammatory bowel disease
60% of patients were diagnosed to have Pulmonary TB, 38% Extra pulmonary TB and 2% with Disseminated TB.1312 patients fitting into the clinical criteria for Tuberculosis underwent the bundled TB diagnostic testing in our centre in the last 17 months. 156 patients were bundle positive, i.e., had at least one test positive. 

64 patients were smear positive. 121 patients were CB NAAT positive. 136 patients were Culture positive. The combined approach of smear plus CB NAAT yielded 121 patients, out of which 101 were also culture positive. 

For AFB microscopy, the sensitivity was found to be 43.38%, Specificity of 98.7%, PPV of 79.72% and NPV of 93.7%, calculated against the gold standard of Mycobacterium culture. The accuracy of AFB microscopy is calculated as 93%.  [Table 3] 

For CB NAAT, the sensitivity was found to be 74.34%, Specificity of 98.29%, PPV of 
83.47% and NPV of 97.06%, calculated against the gold standard of Mycobacterium culture. The accuracy of CB NAAT was calculated as 96%. Table 4] 


35 patients were found to be only culture positive, with the other 2 tests being negative. The incremental yield of adding culture was found to be 22.43%.  

20 patients out of the total 156 cases (12.8 %) were either smear or CB NAAT positive, but culture negative. 1 patient (0.64%) had Rifampicin resistant Multi-Drug Resistant (MDR) TB.  

25 out of 36 samples interpreted as ‘very low’ in CBNAAT were positive for TB culture. i.e; 69.4% of patients. 89.5% of patients with CB NAAT interpretation ‘low’, 96.6% of patient with ‘medium’ and 100% of patients with ‘high’ were culture positive for Mycobacterium Tuberculosis.

Sensitivity of CB NAAT in diagnosing Mycobacterium tuberculosis from various clinical specimens were calculated with TB Culture as gold standard. Highest sensitivity was for pus (100%), followed by lymph node (85%), BAL (81.8%), sputum (78.26%), Tissue (60.50%) and least sensitivity for body fluids (30%).

One of the most convenient ways of detecting pulmonary TB is by sputum examination with 2 samples as per RNTCP. The sensitivity of this test depends on several factors such as sample quality, the load of bacilli and the immune status of the patient and hence it is variable. Based on different studies, the sensitivity of sputum examination is around 40-80% because of which significant number of patients can be missed on routine sputum examination This contributes to open cases in community, facilitating spread of bacilli to susceptible hosts [7]. Thus, there is a need for a test with higher sensitivity to pick up the false negatives in high clinical suspicion of TB. Following the availability of CB NAAT for the detection of TB which has higher sensitivity, it has been efficiently utilized to detect sputum negative case of TB. This contributes to increase in the TB detection in patients.

In the National TB plan, three tests are recommended for diagnosis of TB. These are AFB microscopy, CB NAAT, and chest X ray [2]. In our study, we have evaluated the contribution of CB NAAT in case detection of tuberculosis to reinforce the significance of CB NAAT and to identify the diagnostic gain in simultaneous testing with AFB smear, CB NAAT and MTB culture in diagnosis of tuberculosis. The present study showed a sensitivity of 74.34% and specificity of 98.29% for CB NAAT. PPV and NPV were 83.47% and 97.06%, respectively. AFB smear had a sensitivity of 43.38%, specificity of 98%, PPV of 9.72% and NPV of 93.%. The accuracy of AFB Microscopy and CB NAAT was 93% and 96% respectively. 

We recommend a combined approach of smear microscopy with concurrent GeneXpert and culture for diagnosis of tuberculosis. The threshold for detection is high for smear (>5,000 cfu/ml) and GeneXpert (100-130 cfu/ml) while that for culture is low (<10 cfu/ml). A combined approach confers the advantage of smear and GeneXpert giving a quick diagnosis of TB along with detection of possible Rifampicin resistance, as well as culture for identifying cases with low bacterial load, thus increasing the yield.  

Several other studies also have shown similar findings. A study was conducted by D. Pragati Raoand K. Lakshmi Sowjanya for 2 months from February to March 2016. Out of 231 HIV positive patients, 59 cases (25.54%) had tuberculosis. Sputum smear for AFB negative and GeneXpert positive were 45 (76.27%). 8 (13.55%) cases were Rifampicin resistance and 51 (86.44%) were sensitive out of all tuberculosis patients [8]. A study conducted by Bansal D et al. for a period of 1 year where a total of 3033 pulmonary specimens were included in the study undergoing Gene Xpert; out of which 604 specimens were from HIV positive patients. In 85 (14.07%) HIV positive patients (out of 604) MTB was detected and RIF was sensitive (14.07%). In 06 (0.99%) HIV positive patients MTB, was detected and RIF resistance was found [9]. 

In a study by Kumari et al. GeneXpert MTB/RIF test showed a sensitivity of 60% and specificity of 97.9% for diagnosing TB Meningitis, the NPV was 95.9% and PPV was 75%. Singh et al. [10] showed that LJ culture had sensitivity, specificity, PPV and NPV of 8%, 100%, 100%, and 33.01%, respectively, and overall, nested Solomons et al., culture, Genotype and Xpert combined performed best with 56% sensitivity and 98% specificity.  

The results of CB NAAT are reported as high, medium, low or very low depending upon the Ct value (number of cycles required for the fluorescent signal to cross the threshold) of the MTB target present in the sample.  According to our study, CB NAAT has a lower sensitivity in body fluids (30%) and higher sensitivity in pus (100%). Sensitivity of lymph node sample was 85%, BAL (81.8%), sputum (78.26%) and tissue (60.5%).  The prevalence of extrapulmonary TB (EPTB) is showing a rising trend. The heterogenous clinical presentations, paucibacillary nature and difficulty in obtaining specimens (often requiring invasive procedures) make the diagnosis of EPTB, a challenging task and hence the requirement for a rapid, simplified, and cost-effective diagnostic tool arises. This is where CBNAAT plays an important role leading to early initiation of appropriate therapy, improved treatment outcomes, minimizing morbidity and mortality [7]. 

Previous studies of the MTB/RIF assay have reported a sensitivity of 100% for smear-positive respiratory and non-respiratory samples. Sensitivity for smear-negative samples was 57% and 37%, respectively. Another study conducted by Zeka et al. showed an improved sensitivity of 100% for smear-positive extrapulmonary tuberculosis and 63% for smear-negative EPTB [11]. A study conducted by S B Rufai assessed the sensitivity of the MTB/RIF assay for the diagnosis of tuberculosis by using ascitic fluid samples, keeping MGIT-960 as the gold standard. Out of 67 patients, the MTB/RIF assay was positive in only 12 (17.9%) cases while 82.1% was negative. The study showed that the diagnostic yield of the MTN/RIF assay was low even in culture-positive specimens (70.5%), indicating that in highly proteinaceous body fluids, such as ascitic fluid, Xpert MTB/RIF negative cases must be investigated further using other phenotypic methods. Xpert MTB/RIF has, however, a high positive predictive value (PPV), meaning that if GeneXpert is positive, the ATT can be started without waiting for other investigations [12]. 

A study conducted by Grant Theron on the determinants of PCR performance concluded a low mycobacillary load in extrapulmonary samples as compared to pulmonary specimens is primarily responsible for the low sensitivity of the MTB/RIF assay in the diagnosis of extrapulmonary tuberculosis [13]. According to a meta-analysis finding of Denkinger et al [14], sensitivity among pleural fluid was 46% and sensitivity among lymph node specimens was 83%.  Another meta-analysis finding of Penz et al [15], suggested sensitivity among pleural fluid was 37% and lymph node specimen was 87%.  A recently published study by Sharma et al [16], regarding the utility of GeneXpert in diagnosing EPTB has shown an overall sensitivity of 71% and PPV ranging from 98 to 100%.  

Major limitations of our study are smaller sample size and single centre study. Moreover, the incidence and prevalence of disease in different geographical areas might affect the conclusion. Since the CB NAAT is a constant, the statistical association between positivity of CB NAAT and TB culture was not done, only descriptive study was possible.

The present study showed a sensitivity and specificity of CB NAAT like PPV and NPV. AFB smear had a lower sensitivity and specificity like other tests. There may be a positive association between CB NAAT and TB culture. As the Ct value decreases, the probability for detection of Mycobacterium tuberculosis by TB culture increases. i.e., the samples with low CT value (interpreted as ‘high’) had higher percentage of positive cases compared to those with high Ct value (interpreted as ‘very low’). According to our study, CB NAAT has a lower sensitivity in body fluids and higher sensitivity in pus.

World Health Organisation. Global Tuberculosis Report. WHO, Geneva, Switzerland, 2016 

TB Statistics India/ National treatment outcome and state statistics TB facts.org/tb-statistics India/last updated in October 2019.

Prem Prakash Gupta: Association of Physicians of India, Medicine Update. Volume 28, 2018. Pg 577

Mathew P, KuoYH, Vazirani B, Eng RH, Weinstein MP. Are three sputum acid fast bacilli smear necessary for discontinuing tuberculosis isolation? J Clin Microbiol.2002;40(9):3482-4.

World Health Organisation, Molecular line probe assays for the rapid screening of patients at risk of multi drug resistant tuberculosis (MDR-TB). Policy statement. WHO, Geneva, Switzerland. 2008 

James H Jorgenson, Michael A Pfaller,Karen C Carroll, Guido Funke, Marie Lousie Landry, Sandra S Ritcher, David W Warnock : Manual of clinical microbiology. 11th ed. Pg 54-55 

TB India 2017: RNTCP-Annual Status Report – 9. 

Rao P, Sowjanya KL. Role of CBNAAT in rapid detection of mycobacterium tuberculosis in  PLHIV in a highly prevalent state. Journal of Evidence Based Medicine and Healthcare 2016;39(3):1896-1898. 

Bansal D, Avashia S, Karothiya M. A study of gene xpert in screening of sputum in HIV positive patients presenting to tertiary care centre. National Journal of Community Medicine 2016;7(8):657-660. 

Singh UB, Bhanu NV, Suresh VN, Arora J, Rana T, Seth PT. Utility of polymerase chain reaction in diagnosis of tuberculosis from samples of bone marrow aspirate. Am J Trop Med Hyg. 2006;75(5):960-63. 

Zeka AN, Tasbakan S, Cavusoglu C. Evaluation of the GeneXpert MTB/RIF assay for rapid diagnosis of tuberculosis and detection of rifampin resistance in pulmonary and extrapulmonary specimens. J Clin Microbiol. 2011;49: 4138–4141. 

Rufai SB, Singh S, Singh A, Kumar P, Singh J, Vishal A. Performance of Xpert MTB/RIF on ascitic fluid samples for detection of abdominal tuberculosis. J Lab Physicians. 2017; 9:47–52 

Theron, G., Peter, J., Calligaro, G. et al. Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments. Sci Rep 2015; 4, 5658.

Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2014;44(2):435-46 

Penz E, Boffa J, Roberts DJ, Fisher D, Cooper R, Ronksley PE, James MT. Diagnostic accuracy of the Xpert MTB/RIF assay for extra-pulmonary tuberculosis: a meta-analysis. Int J Tuber Lung Dis. 2015 Mar;19(3):278-84. 14. 

Sharma SK, Kohli M, Chaubey J, Yadav RN, Sharma R, Singh BK, et al. Evaluation of Xpert MTB/RIF assay performance in diagnosing extrapulmonary tuberculosis among adults in a tertiary care centre in India. Eur Respir J. 2014 Oct;44(4):1090-3. 

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Clinical Utility of Cartridge-based Nucleic Acid Amplification Test and Tuberculosis Culture in Diagnosing Mycobacterium Tuberculosis in Various Clinical Syndromes

#111827

Dr. Shabana T

Senior Consultant- Internal Medicine, Aster Medicity

Dr. Anil NX

Consultant Hematology and Hemato Oncology, Aster Medcity

Dr Deepak Charles

Fever, Thrombocytopenia, Intensive Care Unit and Tertiary Care Centre

Fever is a pervasive and ubiquitous concept in human myth and science. Fever as an illness has inflicted human civilization since ages, which was later recognized as a common manifestation of varied diseases. Many times prolong fever is accompanied by thrombocytopenia. The differential diagnosis of the clinical entity includes viral infections and haematological diseases. Fever with thrombocytopenia is most frequently caused by infections (50–70%) eg. viral infections, bacteremia, or fungaemia and frequently associated with patients suffering with septic shock.

The present study aim is to understand the etiology of febrile thrombocytopenia in a medical intensive care unit (MICU) of a tertiary care center, various bleeding manifestations at different platelet levels and outcome in these patients.

The study was carried out at Aster Medcity, Kuttisahib Road, Cheranelloor, Kochi – 682027, Kerala, India in a MICU from 6th June 2018 to 29th February 2020. This was a prospective, non-randomized study to identify cases of fever with thrombocytopenia in MICU. This study was conducted after the institutional ethics committee’s approval. The participants (>18 years age) having history of fever with thrombocytopenia (platelet<1.5 lac/micro Liter or µL) who were hospitalized in ‘ICU of Department of Medicine’ were recruited after written informed consent. 

Out of the 250 cases, 231 patients (92.4%) had good recovery and 19 patients (7.6%) expired during their stay at the intensive care unit.

This was the first of its kind study of this region. In our analysis, infectious etiologies were found associated with majority of patients with febrile thrombocytopenia and the most prevalent among them was Dengue. In 30% of patients, bleeding manifestations took place. Purpura and petechiae were the most frequent symptoms. Only a small number of individuals needed platelet transfusions because of severe thrombocytopenia (10,000/ µL) or life-threatening hemorrhagic symptoms. Of the 250 patients, 231 patients (92.4%) survived ICU stay and were ultimately discharged, while 19 patients (7.6%) expired.

In human myth and science, fever is a universal issue. Ancient cultures believed fever as a disease, but later medical research revealed it ‘a common symptom’ of many diseases.1 Fever  epidemics had always dragged attention of the mankind since ages, , which can be traced in the historical records of every race and nation. 

The average body temperature is 37.0°C (98.9°F). Fever is affected variably by the measurement site, tidal variation, vigorous activity, hormonal and menstrual status, individual variations, and environmental influences.2 It is a common practice to estimate a patient's body temperature by oral readings. However, mouth breathing, breathing rate, and recently consumed hot or cold liquids can affect the results3 and certain modern thermometers can accurately measure temperatures in the ear canal, which is unaffected by these effects.4 The core body temperature reflected by rectal temperature, is typically 0.3 to 0.60 °C higher than oral temperature. Normal body temperature follows a diurnal rhythm, rising in the afternoon and falling in the early morning. Normal ranges fall between 96.5 and 98.9 °F and 35.8 to 37.2 °C.5

Fever is defined as an increase in body temperature above the typical circadian range as a result of a disturbance in the anterior hypothalamic thermoregulatory region. Fever is also defined by morning temperature of more than 37.2°C (98.9°F) or by night time temperature of more than 37.7°C (99.9°F).6,7 The first thermometer was made by a Dutch ‘Gabriel Daniel Fahrenheit’ in the early eighteenth century.

Since the time of Hippocrates and the Roman Empire, medical fraternity had given detailed description of fever and its various patterns of presentations. Fever is generated by endogenous pyrogens, secreted from host inflammatory cells, such as lymphocyte activating factor, mononuclear cell factor, and interleukin-1. Dr. Paul Beeson in 1948 discovered Interleukin 1(IL-1), which is now known to play a significant role in fever and thermoregulation. 

Platelet count less than 1.5 lac/ μL  is called as thrombocytopenia.5 This is caused  by a decrease production in bone marrow, increase  destruction, or an increase in sequestration in an enlarged spleen.8,9 Petechiae on the skin and hemorrhages from the mucosa of the gastrointestinal and genitourinary tracts are the two cardinal signs of thrombocytopenia. In thrombocytopenic patients, intracranial bleeding is a rare event but may cause serious complications.

History, physical examination, complete blood count (CBC) results, and peripheral blood smear examination are important factors in the initial evaluation of thrombocytopenic patients and ruling out false thrombocytopenia.11 When there is prolong fever, it is often accompanied by thrombocytopenia. The differential diagnosis of the clinical entity includes viral infections and haematological diseases. Fever and thrombocytopenia is most frequently caused by infections (50–70%) eg. viral infections, bacteremia, or fungaemia, and frequently associated with patients suffering with septic shock.

Most common infections causing febrile thrombocytopenia are:

Arbovirus- Dengue, Yellow fever; Rodent borne virus- Hanta, Lassa virus; others- HIV, CMV, Parvo virus B19, HSV.

Viral infections

Gram positive and Gram negative septicemia, Typhoid, Leptospirosis, Miliary Tuberculosis, Borreliosis, Rickettsial infections.

Bacterial infections

Protozoal infections

Hematological causes-leukemia, lymphoma, Auto immune diseases, post chemotherapy, CLD patients with portal hypertension, drug induced thrombocytopenia.

Others

Most cases of fever and thrombocytopenia are treated outside the realm of an ICU. When patients with fever and thrombocytopenia are admitted to MICU with additional issues such as hemodynamic instability or multiple organ system involvement, there is a significant risk of morbidity and mortality.

The main objectives of the study is to a) identify cases of fever with thrombocytopenia in MICU as per laid out criteria b) evaluate etiologies of febrile thrombocytopenia, c) evaluate bleeding manifestations and platelet count at the time of the bleeding manifestations and d) follow up the outcome of patients admitted with fever and thrombocytopenia.

The study was carried out at Aster Medcity, Kuttisahib Road, Cheranelloor, Kochi – 682027, Kerala, India in MICU from 6th June 2018 to 29th February 2020. This was a prospective, non-randomized study to identify cases of fever with thrombocytopenia. This study was conducted after the institutional ethics committee’s approval. The participants (>18 years age) having history of fever with thrombocytopenia (platelet<1.5 lac/micro Liter or μL) who were hospitalized in ‘ICU of Department of Medicine’ were recruited after written informed consent. 

The duration of the study was twenty months. The patients (>18 years age) having history of fever with thrombocytopenia were recruited in the study based on the following selection criteria:

Platelet count less than 1.5 lac/ μL  (confirmed by peripheral blood smear )

Known case of immune thrombocytopenic purpura, malignancy, post chemotherapy, chronic liver disease with portal hypertension, and known case of auto immune diseases.

A total 250 patients were enrolled in the study. The study protocol was approved by institutional scientific and ethical committee of Aster Medcity, Cochin. During the study period, all patients admitted in MICU with fever and thrombocytopenia were screened according to the inclusion and exclusion criteria. The investigation reports were followed up regularly to identify the etiology, and the patients were closely monitored for bleeding manifestations. Once a definitive diagnosis was made, targeted therapy was offered along with symptomatic and supportive measures. Platelet counts were monitored on a daily basis throughout the period of stay in the ICU. Platelet transfusions were administered in case of severe bleeding manifestations or a platelet count less than 10,000/ μL. All the patients included in the study were followed up till the patient was discharged from the MICU.

Data was analyzed using the Microsoft excel spreadsheet. 

Of the total 250 patients enrolled in the study, 51 (20.4%) were between 18- 30 years age group, 67 (26.8%) were between 31-45 years age group, 89 (35.6%) were between 46-60 years age group and 43 (17.2%) were above 60 years as shown in Fig. 1. Among 250 subjects 173 (69.2%) were males and 77 (30.8%) were females.

Of the total 250 cases of fever with thrombocytopenia, infection was found to be the major cause, attributed to 246 cases out of 250 (98.4%). Among the type of infection, predominant was viral amounting to 156 cases (63.41%), followed by bacterial with 82 patients (33.33%). Among the etiological subgroups, dengue fever was the most common cause amounting to 98 cases (39.2%).  Other viral causes were attributed in 50 patients (20%),  leptospirosis in 19 patients (7.6%),tuberculosis in 6 patients (2.4%), varicella and enteric fever in 4 patients (1.6%), scrub typhus in 3 patients (1.2%), malaria in 2 patients (0.8%), fungal infection (invasive candidiasis) in 1 patient (0.4%) as shown in Fig. 2. Platelet count distribution among patients with febrile thrombocytopenia shown in Table 1.

Petechiae /purpura were the most common bleeding manifestations encountered in 36 cases (48%). Gastro Intestinal (GI) bleeding was found in 27 cases (36%),  ecchymosis in 19 cases (25.33%), Genito urinary (GU) bleeding in 13 cases (17.33%), nose bleeding in 4 cases (5.3%) and ICH (intracranial haemorrhage) in 1 patient (1.33%) as shown in Fig. 3.

Distribution According to Etiology and Bleeding Manifestations

Out of 98 cases of dengue, 49 cases (50%) had bleeding manifestations. Out of 82 cases of bacterial infections, 16 cases (19.5%) had bleeding manifestations. In 19 cases of leptospirosis, 7 patients (36.84%) had bleeding manifestations. 1 patient each, with malaria (50%), Scrub typhus (33%) and varicella encephalitis (25%) had bleeding manifestations as shown in Fig. 4.

In the study, 19 cases (7.6%) suffered mortality,  out of which 11 cases (57.89%) died due to bacterial infections (non-leptospirosis), 3 cases (15.78%) died due to viral infections and dengue was the cause of death in one patient (5.2%). 16.7% patients with severe thrombocytopenia i.e, Platelet count< 10,000/ μL  suffered mortality. However there was no statistical significant association between severity of thrombocytopenia and mortality (Fishers exact test -P value = 0.275) as shown in Table 2.

Out of the 250 cases, 231 patients (92.4%) recovered and 19 patients (7.6%) died in the ICU.

Febrile thrombocytopenia syndrome is frequently caused by infections, especially septicemia and dengue fever. In Kerala, dengue is commonly prevalent in rainy season from June to September. Febrile thrombocytopenia syndrome initially presents as flu without any bleeding tendency. Early detection and treatment of underlying cause leads to rapid clinical recovery and thrombocytopenia correction. The mortality seen in febrile thrombocytopenia is strongly associated with co-morbid conditions and is not associated with the degree of thrombocytopenia. 

Nair et al.16 carried out a similar study over a span of 1.5 years at St. Stephens Hospital, New Delhi. Total 109 patients were enrolled for the study, out of which 76 (69.7%) were male and 33 (30.3%) were female. These were recruited using selection criteria identical to our study. In Gondhali et al.17 study, 26% patients were found to be in the age group 21-40 years. The maximum number of fever with thrombocytopenia cases (35.6%) were found in the age group 46-60 years. As this study was conducted in an ICU, majority of the patients were middle-aged or older and had several co-morbidities. The adult population with robust immunity and no co-morbidities, suffering with febrile thrombocytopenia did not require ICU care and showed rapid recovery with minimum supportive treatment.

In Nair et al.16 study, 29 cases were of septicemia were reported, which was the leading cause of fever with thrombocytopenia. Second most common cause was enteric fever (16 cases), followed by dengue (15 cases), megaloblastic anemia (13 cases), malaria (10 cases) and hematologic malignancies (4 cases) respectively. 

In another similar study by Srinivas et al.18 41 cases of malaria were reported, which was the leading cause of fever with thrombocytopenia. Second common cause was enteric fever followed by septicemia, dengue, and leptospirosis.

Etiologies of fever with thrombocytopenia in the above studies differed due to regional and seasonal variations as shown in Table 3. In our study, 98 cases were of dengue, which was the leading cause of fever with thrombocytopenia. There were 82 cases of bacterial infections after excluding leptospirosis, enteric fever and scrub typhus. There were 19 cases of Leptospirosis, 6 cases of tuberculosis, 4 cases of enteric fever, 3 cases of scrub typhus, and 2 cases of malaria. On account of floods in Kerala during the study period, number of leptospirosis cases were high.

In our study, infections contributed 98.4% of the 250 cases, with 1.6 % cases of non- infectious etiology whereas in the Nair et al.16 study infections amounted to 68% of the cases, and hematological conditions contributed to 15% of the cases. 

In our study, 134 patients (53.6%) had platelet counts greater than 50,000/micro L, compared to 62 patients (56.8%) in Nair et al.16 study. In our study, 81 (32.4%) patients had a platelet count between 21,000 and 50,000/micro L, compared to 28(25.7%) in Nair et al.16 study. In our study, 13 (5.2%) patients had platelet count 10,000/micro L, compared to 19 patients (17.5%) in Nair et al.16 study. 

In Nair et al.16 study, spontaneous bleeding accounted for 31 cases (68%) of bleeding manifestations, followed by 10 cases (22.22%) of petechiae/purpura,and other cases (4.88%) as shown in Table 4. 

Petechiae/purpura was the most frequent presentation in a research by Gondhali et al.17, with 14 (14%) cases, followed by GI bleed (melena and hematemesis) in 5 (5%), GU bleed in 2 (2%), and sub conjunctival haemorrhage with epistaxis in 1 (1%). 

The most frequent bleeding manifestation in our analysis was petechiae/purpura, which had 36 cases (48%) followed by GI bleeding (27 cases, 36%), ecchymosis (19 cases, 25.33%), GU bleeding (13 cases, 17.33%), nasal bleeding (4 cases, 5.3%), and ICH in one patient (1.33%) as shown in Table 5.

In our study of 250 cases, 231 patients recovered and 19 patients died. 57.89% of mortality (11 cases) had bacterial infections other than leptospirosis, enteric fever, scrub typhus. 15.78% (3 cases) had other viral infection, 10.52% (2 cases) each of leptospirosis and varicella encephalitis and 5.2% (1 case) had dengue associated with cause of death.

In 19 cases of mortality, 3 cases had a platelet count below 10,000 /μL, 2 cases had platelet count in between 11-20,000/ μL  and 5 cases had platelet count between 20,000 & 50,000/ μL. In 9 cases platelet counts were above 100,000 /μL.

Our study throws light on different causes of febrile thrombocytopenia and its accompanied bleeding manifestations, and patient outcomes. The etiology of febrile thrombocytopenia was assessed, and it was the first study of its type, conducted in this region. In our analysis, infectious etiologies accounted for majority of cases of febrile thrombocytopenia. The most prevalent infectious etiology was dengue. In 30% of patients, bleeding manifestations were reported. Purpura and petechiae were the most frequent bleeding tendencies. Only few patients needed platelet transfusions owing to severe thrombocytopenia (10,000/ μL) or life-threatening haemorrhagic symptoms. Of the 250 patients, 231 patients (92.4%) survived and discharged from ICU, while 19 patients (7.6%) died. Early diagnosis and prompt supportive care contributed to patient’s survival. The patients in which mortality occurred, confounding factors like co-morbid conditions, coagulation abnormalities, etc. need to be evaluated in addition to the severity of thrombocytopenia.

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Fever with Thrombocytopenia in an Intensive Care Unit of a Tertiary Care Centre: A Prospective Study

 MD Psychiatry, Consultant Psychiatrist at Aster Aadhar Hospital,Kolhapur, Maharashtra, India

Dr. Behere Nilam S

On the context of increasing burden of mental disorders, it is important to note that mental disorders are heavily comorbid with many physical disorders. Not only do they exercise influence on pathogenesis of each other but also treatment plans and overall patient outcomes. Treatment of mental disorders can positively affect outcome of physical disorders.  A thorough understanding of comorbidity models between these two categories of disorders can guide to better disease prevention and management plans.

COVID-19 pandemic has not only brought on the table, the challenges of an infectious disease management and prevention but has also raised a few critical questions about approaches to medicine. While managing COVID-19 pneumonias with an intention to treat a ‘disease’, the pandemic had us revisiting the dictum of “treat the patient and not the disease”. These instances reminded that multiple illnesses do co-exist and exercise complex dynamic interplay in management and prognosis of each other. Further, it is not only a patient as a unit, but a patient, in-situ of his environment, socio-cultural setting, financial and occupational background has to be a target of intervention. 

Mental illnesses have been a staggering example of how a patient’s biological/medical, psychological and social functioning exercise influence on an illness. This is also an example of how comorbidity of multiple illnesses can remarkably impact the overall patient outcomes.

While WHO affirmatively states that there is “no health without mental health”, mental health still remains largely unattended, worldwide. Common mental disorders, which include depression and anxiety disorders, has been found to be highly prevalent across the globe. Depression, most prevalent all mental disorders, is the 3rd leading cause of disease burden globally (>300 million; 4.4% of world population). Anxiety follows depression closely in global disease burden (around 250 m; 3.6% of world population)1,2.

In India, approximately 1 in 40 people have had suffered depression in their lifetimes and 1 in 20 people are currently depressed. What’s remarkable to note is that, the two most vulnerable age groups i.e. adolescent and geriatric populations, account for more than half of the total burden of mental illness3. With suicide being the leading cause of death for Indians from age group 15—39 years, the mental health scenario in India is all the more concerning. 

With mental disorders being a significant inclusion of Non-communicable group of diseases, the UN declaration of sustainable developmental goals has laid emphasis on mental health specific targets4. While it is important to scale up interventions for mental wellbeing, dearth of mental health professionals in India and worldwide has been a major impediment. There are only 0.3 psychiatrists per 100,000 populations in India, against the WHO recommendation of 1 psychiatrist per 100,000 populations3. Inclusion of mental health in Comprehensive Primary Healthcare Package in Ayushman Bharat Yojana is a welcome step by Ministry of Health and Family Welfare and reinforces the necessity of treating mental illnesses on priority basis5. 

Treatment of common mental disorders is now a primary healthcare imperative. A strategy to address the huge mental health burden is by complementing treatment of other physical illnesses with screening and management of mental illness. This seems to be an effective and tangible strategy, as mental disorders are heavily comorbid with most other communicable and non-communicable diseases.  

With the specific objectives of treating comorbidity of physical and mental disorders, it is important to understand how comorbidities exercise effects on each other.

Dr Norman Sartorius, formerly the Director of the Division of Mental Health of WHO, urged the need to accept the fact that comorbidity of mental and physical disorders is the rule rather than an exception6. Comorbidity, in the most simplified terms means presence of two distinct disorders. Comorbidity further could be a co-occurrence or co-variance. Figure 1a. shows co-occurrence where distinct additional clinical entity has existed or occurs during the clinical course of the index disease. The etiological factors are usually different for each of them although the outcomes can follow a common pathway. Psychosis and cancer could be an example of this, where the final outcome could still be same i.e. impaired social functioning. 

Covariance, as shown in Figure 1b, could however have common underlying pathologies, or can influence course of each other. Depression, diabetes, hypertension, cardiovascular disorders usually follow covariance models. 

1. Mental disorders as a cause of Physical disorders

Times, as old as that of Galen and Hippocrates, have raised speculations about psychological factors leading to physical illness. More recently, seminal work by Friedman and Rosenman7 in 1974 and Matthews et al8 in 1977 and a few others with accurate epidemiological methods, suggested that type A personality, with achievement- striving, irritable, angry characteristics had more probability of developing cardiovascular disorders. Unfavourable balance of LDL and HDL, elevated blood glucose levels, smoking and obesity, which are seen commonly in depression have been found to be causative of cardiovascular risk9. Excessive consumption of alcohol, similarly, can be causative of hepatic failure10. 

2. Mental disorders as consequence of  physical disorders

Depression in hypothyroidism could be an example of how physical illness can consequently result into mental illness11. Higher prevalence of Depression and Anxiety disorders is seen in communicable diseases like HIV, Tuberculosis, Leprosy and most other diseases with chronic course. 

3. Mental disorders and physical disorders with common etiological pathways

Vascular depression is a remarkable example of how common pathways can lead to differently presenting set of conditions. Krishnan et al12 were the first to propose vascular changes that present as depression. The same vascular changes were found in pathogenesis of vascular dementias. In a few systematized epigenetic studies, polymorphisms of 5-Hydroxytryptamine by substitution of specific amino-acids have been found to be a common pathway of causation of depression as well as platelet aggregation abnormalities leading to vascular pathologies13. Figure 2 shows bidirectional factors causing depression and cerbro-vascular disorders like stroke.  
With modern modalities of brain imaging, it is a growing consensus that most of the comorbid physical illness share common pathways of causation with mental illnesses. Furthermore, as the knowledge about neurobiology of mental illness is deepening, the compartments of cause and consequences of comorbidities are progressively blurring.


4. Mental illness as a medication adverse effect

A list of medications used to treat physical illness can be causative for mental illnesses. The converse also holds true for many psychotropic medications like anti-psychotics, anti-depressants, mood stabilizers and others. A few anti-tubercular drugs like Isoniazid, Rifampicin are known to cause psychosis. Corticosteroids are also causative of drug-induced psychosis. Certain anti-epileptic drugs like Levitiracetam are known to cause behavioural disturbances in children which include extroverted behaviours like irritability, agitation and aggressiveness. 

Many first generation antipsychotics like Haloperidol and Trifluperazine result in extra-pyramidal side-effects and drug induced parkinsonism. Most of the second generation anti-psychotics like Olanzapine, Resperidone, Aripiprazole and Clozapine, on prolonged use, are known to cause metabolic syndrome, diabetes mellitus, weight gain, hypercholesterolemia and other cardio-vascular diseases. Mood stabilizers like Sodium Valproate can cause hepatic toxicity and thereby hepatic failure. While the list is long, it is important that all the drugs are used rationally and judiciously.

COMORBIDITY OF MENTAL DISORDERS WITH NON-COMMUNICABLE AND COMMUNICABLE DISEASES

A. Mental disorders and Cardio-vascular Diseases 

Several common well-recognized risk factors for cardiovascular disorders have been found in people with mental disorders. Patients are more likely to be overweight, more likely to smoke, more likely to have diabetes and dyslipidaemia.14,15 Several meta-analyses of longitudinal studies have found depression to be a consistent predictor of subsequent first onset coronary artery disease16, Stroke17 and Myocardial infarction18. Figure 3 shows complex dynamics of risks and causation of cardiovascular disorders and depression.

The relation between diabetes and depression is bidirectional: people with diabetes are more likely to develop depression, and depression is a risk factor for diabetes.19,20 Diabetes is more common among people with psychosis and schizophrenia, because of the effects of atypical antipsychotic medications, links between diabetes and schizophrenia and cultural and lifestyle factors.

About 25% of people with cancer have anxiety and/or depression.21 Anxiety and/or depression in people with cancer is associated with a poorer quality of life, poorer compliance with treatment, longer hospitalization and a higher risk for suicide.22 The lifestyle often associated with severe mental disorder increases the risk for cancer. For example, the rate of smoking among people with schizophrenia is as high as 80%, which increases their risk for lung cancer or pneumonia.

One in three of all cigarettes smoked is smoked by a person with a mental disorder. People with long-term mental health problems face difficulty in quitting smoking than general population23. Nicotine increases the rate at which some antipsychotic drugs are metabolized, so that smokers require higher doses of the medication to achieve the same response 

E. Mental disorders and communicable diseases

Communicable diseases with chronic course have been found to have heavy comorbidity with common mental illnesses like depression. 39% of HIV patients are reported to suffer from depression24. Prevalence of depressive symptoms in tuberculosis, in a study in India25, was found to be as high as 84%. Similarly, higher prevalence of depression and anxiety disorders is also found in leprosy and many other diseases with chronic course. Adherence to medication regime was also found be inadequate in patients with chronic course of illness. 

IMPORTANCE OF MANAGEMENT OF MENTAL HEALTH COMORBIDITIES

Treatment of mental disorders can prevent physical disorders

Techniques like behavioural activation, meditation and yoga, regular eating and sleeping habits are commonly recommended for treatment of depression and anxiety disorders. These healthy lifestyle methods have been found to prevent occurrence of NCDs.

Treatment of mental disorders improves adherence to treatment of physical disorders

Patients with mental wellbeing possess favourable attitudes towards long course management of communicable and non-communicable diseases. 

Studies have shown that high positive mood states (measured in terms of happiness, joy, contentment, and enthusiasm) lower morbidity, increased longevity, and reduced health symptoms.26 Not only this but better endocrine function (lower levels of cortisol, epinephrine, norepinephrine) and better immune response (higher antibody production, greater resistance to illness) was found to be related to positive emotional style27. Positive mood states lower inflammatory response and lower blood pressure. Higher levels of purpose in life, personal growth, and positive relationships lower cardiovascular risk (lower glycosylated haemoglobin, lower weight, lower waist-hip ratios, higher HDL cholesterol) and better neuroendocrine regulation (lower salivary cortisol throughout the day).

It is very important to screen all patients with non-communicable diseases and long standing communicable diseases for common mental disorders like depression and anxiety disorder. Annexure 1 and 2 contain PHQ-9 and GAD scales for respective disorders.

It is also very important to obtain history of substance use in every patient presenting to a physician. Alcohol, tobacco and cannabis dependence is more common in population than presumed.

Simultaneous attention is warranted to both mental and physical illness.

Management of mild severity of depression and anxiety can be done by simple psychological interventions.

Management of moderate to severe variety of mental illness may require complex interventions and referral to a mental health professional.

Rational use of drugs is important to prevent complications and comorbidity. 

Inversely, in patients with primary mental illness, physical symptoms are often neglected. Regular physical check-ups are recommended for patients with mental illness. 

When a patient is the unit of treatment, effective management of all comorbidities may lead to greater patient satisfaction and better patient outcomes. After all, regaining of physical, occupational and social functionality should be the final goal of any health intervention.

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Ayushman Bharat Yojana. Retrieved on 27/09/2021 from  https://pmjay.gov.in/

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february-2023

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