Significance of Mantoux Test and Its Correlation with Erythrocyte Sedimentation Rate in Pediatric Cleft Lip and Palate Patients: An Institutional Perspective

Abstract

Aims and Objective

This retrospective study evaluates the importance of Mantoux test and Erythrocyte Sedimentation Rate (ESR) levels in pediatric tuberculosis and also signifies the impact of this test in treatment planning and implementation in pediatric cleft lip and palate patients.

Methodology

Retrospective analyses of the records of 2010 pediatric cleft lip and palate patients below 5 years age were performed, and patients with elevated ESR subjected to Mantoux test were identified. The parameters included were age, sex, ESR levels, type of cleft, history of contact with TB & BCG vaccination, Mantoux conversion, chest X-ray findings, number of smear-positive pulmonary tuberculosis.

Results

Out of 2010 patients with cleft lip and palate, 180 patients were subjected to Mantoux test due to high ESR levels. Among these, 54 (30%) patients found as Mantoux positive, in which 45 patients were identified as smear-positive pulmonary tuberculosis patients; as a result, surgery was deferred and they underwent antituberculous therapy. Most of the Mantoux-positive cases were found in patients with ESR range of 20–30 mm, i.e., 38 patients (71%), and common age group was 6 months–1 year. The most commonly involved cleft type was: unilateral cleft lip and palate having 36 patients (66.7%). The overall incidence of tuberculosis was 2%.

Conclusion

Although the correlation of Mantoux test with elevated ESR was not significant in our study, it could be of value as a screening tool along with the Mantoux test, which is sensitive but nonspecific in the diagnosis of active tuberculosis. Together, they could be a valuable screening tool in any community or hospital for diagnosis of the disease.

Introduction

Cleft lip and/or palate constitutes a large fraction of all human birth defects and has a reported incidence of 1.08 in 100 live births in India [1]. In spite of having BCG vaccination and tuberculosis control program for the past 50 years, India has the highest tuberculosis (TB) burden in the world [2]. It accounts for 20% of 8.6 million global TB cases annually [2]. An estimated 28 lakh new cases occurred in India, and 4.8 lakh people died due to TB according to the WHO Global Report for the year 2015 [2]. It is estimated that the annual risk of tuberculosis infection in children is 5–7% [3]. The proportion of children among new TB patients in India was reported to be 6% in 2016 as per the annual report of RNTCP (Revised National Tuberculosis Control Program) 2017 [3].

Malnutrition is an important contributing factor for tuberculosis because cell-mediated immunity is the key host defense against tuberculosis [4]. As a result in malnourished children, the likelihood is increased of primary or latent infection progressing to active disease [4]. Considering the fact that cleft lip and/or palate patients are malnourished due to incorrect feeding techniques and quantity, this increases the chances of these children becoming susceptible to tuberculosis, so it is important to diagnose the disease in cleft lip and palate patients before surgery. A combination of factors including high costs, limited resources and poor performance of various diagnostic tests makes the diagnosis of tuberculosis difficult in developing countries. Moreover, most of the patients with cleft lip and palate come from poor socioeconomic status, from far places and are also associated with multiple health problems like chest infections, ear infections, and malnourishment [3]. In such cases, the patients have an elevated ESR (Erythrocyte Sedimentation Rate) level, and then Mantoux test could be used as a screening tool for tuberculosis infection. Thus, it plays a significant role in the management of these patients and also has an impact on the surgical intervention. The estimated lifetime risk of developing tuberculosis for a young child infected with Mycobacterium tuberculosis as indicated by a positive tuberculin test is about 10% [2].

This study correlates ESR levels with Mantoux test prediction and its impact on the surgical intervention of cleft patients and reflects its use as bedside screening cum diagnosing aid and allows vital decisions in the planning of cleft lip and palate surgery in pediatric patients.

Methodology

Retrospective analyses of the records of cleft lip and palate patients below 5 years age, reported to our unit from Jan 2013 to Dec 2016, were included in the study. Due to the retrospective nature, it was granted an exemption by the Institutional Review Board. As a standard protocol, all cleft patients reporting to our unit for surgery undergo a series of blood examination which includes ESR. Those patients with elevated ESR pertaining to infection further undergo a Mantoux test. All patients who underwent Mantoux test were identified and included in the study. Apart from Mantoux test, clinical presentations like fever, cough, dyspnoea and signs like decreased breath sounds, rales or wheezing were also taken into consideration. Since signs and symptoms can be often misleading in infants and children, Mantoux remained the primary criteria for patient selection for the study. The parameters included in the study were age, sex, ESR levels, type of cleft, history of contact with TB & BCG vaccination, Mantoux conversion, Chest X-Ray (CXR) findings, and number of smear-positive pulmonary tuberculosis. CXR evaluated for radiological lesions which strongly suggest tuberculosis like miliary, hilar, or paratracheal lymphadenopathy with or without parenchymal involvement, pleural effusion, and fibrocaseous cavitary lesions.

The technique of Mantoux test: A standard dose of five tuberculin units (TU) (0.1 ml) is injected intradermally on the volar aspect of the forearm and interpreted 48–72 h later. A discrete, pale elevation of the skin (a wheal) 6 mm in diameter should be produced when the injection is given correctly. The test should be read between 48 and 72 h after administration. Reading should be performed in bright light, with the forearm slightly flexed at the elbow. Mantoux test is considered positive if the induration is 10 mm or more in cases with no prior history of BCG vaccination and 15 mm or more with BCG vaccination.

Results

Of the total 2010 pediatric cleft lip and palate patients, 180 patients showed elevated ESR levels higher than 20 mm/1st h with positive clinical and radiographic finding suspicious of tuberculosis. Following Mantoux test 54 (30%), patients were found to be positive. There was no significant gender predilection in any of the groups. History of contact with tuberculosis, i.e., parental history of TB, was seen only in 6 patients (11%). History of BCG vaccination seen in Mantoux-positive group was 44 patients (Fig. 1). Most of the Mantoux-positive cases were found in patients with ESR range of 20–30 mm, i.e., 38 patients (Fig. 2). Common age group was 6 months–1 year with 24 patients (Fig. 3). The most commonly involved cleft type was: unilateral cleft lip and palate having 36 patients (Fig. 4). Number of patients found positive in the first admission was 33, i.e., 61% cases. Mantoux conversion observed in our study was 35% and 2% in the second and third admissions, respectively. The time gap observed from the first to third admission was within a 2-year period.

Fig. 1.

BCG correlation in Mantoux and smear test cases

Fig. 2.

ESR level and Mantoux-positive correlation

Fig. 3.

Age and Mantoux-positive correlation

Fig. 4.

Type of cleft and Mantoux-positive correlation

All the 54 Mantoux test positive patients were referred to a higher center for establishing bacteriological diagnosis using specimens like Gastric Lavage (GL)/Induced sputum (IS) or bronco alveolar lavage (BAL) depending on the facilities available. Among them, 45 patients identified as smear-positive pulmonary tuberculosis: total incidence 2%. Thus, the false-positive value for Mantoux test was 16.6% in our study. The positive predictive value for Mantoux test was 80% and negative predictive value 100%. The false-positive rate of Mantoux test in patients with prior BCG vaccination in our study stands at 13%. The patients who were diagnosed as smear-positive pulmonary tuberculosis were put on antituberculous therapy: 2 months of intense therapy with HRZE+4 months with HR. Initial 2 months of intense therapy was with isoniazid (5–10 mg/kg daily dosage), rifampicin (10 mg/kg daily dosage), pyrazinamide (30–35 mg/kg daily dosage), and ethambutol (20 mg/kg daily dosage). Then 4 months of maintenance therapy with isoniazid and rifampicin was continued. All cleft surgeries were postponed for 2 months, i.e., until the intense therapy was completed.

Discussion

Malnutrition is a problem of considerable magnitude in developing countries like India. It predisposes people to the development of chronic infections, e.g., Tuberculosis. Pediatric cleft patients in India have a higher rate of malnourishment due to functional disabilities like suctioning impairment and also due to poor social and economic status. A study carried out by RNTCP in 2007 revealed that social impact was the primary cause of tuberculosis in India followed by economic reasons [5]. These patients have higher chances of developing tuberculosis which makes it important in diagnosing the disease before the surgery. The diagnosis of tuberculosis in young children is challenging, especially in countries with limited health resources and weak national reporting system and also because the clinical features are vague and nonspecific [2]. Microbiological confirmation of such cases is rare due to primary health-care setups, lack of skilled professionals, patient non-compliance, poor economic and social background, and unawareness of such diseases among these population, thus making it difficult to perform extensive confirmatory tests like gastric lavage, bronchoscopy, PCR, and immunodiagnostics [6]. The general problem encountered is not only patient non-compliance but the family non-compliance. Since most of these people are daily wage workers, staying back in the hospital for long periods for such extensive tests is difficult for them. Although in our case we could possibly establish the bacteriological diagnosis, in many scenarios with a small setup it would not be feasible.

In such cases, determining the ESR acts as a valuable screening tool which has been used by physicians in a certain part of the world. ESR is an acute-phase reactant that reflects inflammation or disease activity and has been considered a useful marker of disease in patients with tuberculosis [7]. It acts as an alternative marker for infection, especially in children with tuberculosis as they rarely cough and produce sputum [7]. Most of the Mantoux-positive cases in our study were found in patients with ESR range of 20–30 mm which correlates with the study by Goyal et al. [8], but the percentage of true Mantoux positive in our study was 30%. Although elevated ESR may be expected in children with tuberculosis, it is not a specific marker for tuberculosis and it can be raised in conditions like otitis media too, but when a raised level is noted we can perform additional tuberculin test which then acts as a valuable screening tool to rule out tuberculosis. Tuberculin test was developed by Koch in 1890, but the intradermal technique currently in use was described in 1912 by Charles Mantoux, a French physician who developed on the work of Koch and Clemens von Pirquetto [9]. In spite of the long-standing history, it is surprising that the interpretation of the test remains controversial. The Mantoux test does not measure immunity to tuberculosis, instead gives the degree of hypersensitivity to tuberculin. There is no correlation between the size of induration and likelihood of current active tuberculosis, but the reaction size is correlated with the future risk of developing tuberculosis disease [6]. So with the help of such an economical screening tool, we can identify the patients with the potential risk of tuberculosis and isolate them so that it prevents the spread of such diseases to the surgeon, operation theater personnel, and other patients.

In our study, the incidence of Mantoux positive was 2.7% of the total pediatric cleft lip and palate cases and the actual incidence of TB following microbiological confirmation test was 2% which coincides with the worldwide pediatric tuberculosis incidence [10]. Even though the false-positive value of the Mantoux was 16.6% in our study, it could be still invaluable in the assessment of a child with suspected TB when correlated clinically with other factors. One of the main controversies in its use is due to its relative risk of false positive in patients who have received BCG vaccination. As per meta-analysis of 26 published papers on Mantoux test, false-positive risk was accounted to be as low as 2.12% and the general agreement is that a cutoff measurement of skin indurations of > 15 mm is more likely to be the result of tuberculosis infection than due to previous BCG vaccination [11]. Although the false-positive rate in patients with prior vaccination in our study stands to 13%, we agree that it could be successfully used for circumstantial evidence for the diagnosis of TB. Mantoux conversion is the development of new or enhanced hypersensitivity due to infection with tuberculous or non-tuberculous mycobacteria, including BCG vaccination and is defined as a change (within a 2-year period) of Mantoux reactivity which meets either of the following criteria: a change from a negative to a positive reaction, an increase of ≥ 10 mm [9]. The total incidence of Mantoux conversion observed in our study was 37%. One of the chief limitations of the tuberculin skin test is its complex administration and reading. Various factors influence the outcome, so also its interpretation like age, immunological status, co-existing illness, concurrent infection with environmental mycobacteria infections result in loss of usual bimodal distribution of skin test reaction size [7]. With all these limitations, Mantoux test is still being successfully used as a screening tool in high prevalence country to identify individuals (particularly children) infected with Mycobacterium tuberculosis. In addition, it can demonstrate the size of the problem of tuberculosis in an entire community [10]. With all the disadvantages related to the test, Mantoux test still serves as the single most accurate means of determining the trend in the tuberculosis situation in a given community.

Conclusion

Although the correlation of Mantoux test with elevated ESR was not significant in our study, it could be of value as a screening tool along with the Mantoux test. The interpretation of Mantoux needs to be correlated with the patient’s clinical context to confirm the diagnosis of active tuberculosis. Further, there is a paucity of literature supporting the use of Mantoux test as a screening tool in pediatric cleft patients in the developing countries with the increasing burden of the disease. Approximately, 1 million children develop TB each year and at least 14% die [3]. Thus, it is important to understand the scale of the problem so as to allow accurate diagnosis at the earliest and to target the mortality rate and transmission of the disease to its best.

Compliance with Ethical Standards

Conflict of interest

The authors declare that there is no conflict of interest.