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Immunology and Host Response

Burden of Tuberculosis in South African Children During Treatment for Underlying Malignancies

A Single-center Experience in Johannesburg

Naidu, Gita MD, PhD*; Izu, Alane PhD*; Madimabe, Metsekae Richard MSc*; Poyiadjis, Stelios MD; MacKinnon, Diane MD; Rowe, Biance MD; Madhi, Shabir Ahmed MD, PhD*

Author Information
The Pediatric Infectious Disease Journal: December 2020 - Volume 39 - Issue 12 - p 1111-1115
doi: 10.1097/INF.0000000000002873

Abstract

Young and immunocompromised children are at high risk of Mycobacterium tuberculosis infection progressing to tuberculosis (TB) disease.1 The relationship between M. tuberculosis infection and active TB depends on the balance between the immune system and M. tuberculosis, which may be influenced by HIV infection and other immunodeficiency states.2 Individuals with cancer are immunodeficient, due to the disease and treatment, with an increased risk for infections,3,4 including susceptibility of latent M. tuberculosis infection progressing to TB.5 TB has been reported in children with cancer in countries with high and low burdens of TB.6–8 South Africa has a high incidence of TB; that is 301 per 100,000 population in 2018.9 In a previous South African study (1991–2005), the incidence of TB in children treated for cancer (9117 per 100,000 years) was 22-fold greater than the general population.10

Tests used to diagnose M. tuberculosis infection include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs).11 In very young and immunocompromised children, TST has poor sensitivity.12,13 IGRA may have a role in diagnosing M. tuberculosis infection in immunocompromised children.1 The GeneXpert M. tuberculosis/resistance to rifampicin test was unavailable in South Africa during the study period.

The aim of this study was to evaluate the prevalence of M. tuberculosis infection using TST and IGRA enzyme-linked immune absorbent spot (T-SPOT.TB Test; Oxford Immunotec Ltd, Oxford, United Kingdom) assay (T-Spot) in a cohort of children being initiated on cancer treatment and to describe the epidemiology of TB in these children.

MATERIALS AND METHODS

All children admitted to the Paediatric Oncology Unit, Chris Hani Baragwanath Academic Hospital (CHBAH), Soweto, South Africa from 2011 to 2013 and diagnosed with cancer were enrolled and followed up until 2015. The hospital is a tertiary care center with 2 in-patient wards (total beds n = 45), an out-patient clinic and 2 community-residential facilities and a referral center for hospitals in the surrounding areas.

At enrollment, all children were screened for M. tuberculosis infection using the TST Mantoux method and the T-Spot test. For the Mantoux method, 0.1 mL of purified protein derivative RTS-2TU (TUBERSOL; Sanofi Pasteur, Toronto, ON, Canada) was intradermally injected on the volar aspect of the left forearm. The reactivity to the TST was measured within 48–72 hours14; a transverse diameter of ≥5 millimeters induration was indicative of underlying M. tuberculosis infection (all children were immunocompromised).

Five milliliters of blood was also obtained from all participants for the T-Spot test using a commercial kit (T-SPOT.TB).15 These tests were performed at the Respiratory and Meningeal Pathogens Research Unit, CHBAH using methods described by the manufacturer.

During treatment, the standard of care for investigation of TB in children with pneumonia or clinical signs and symptoms of TB was collection of 2–3 early morning induced-sputum samples or gastric washings in those unable to expectorate, for M. tuberculosis culture. Identification of M. tuberculosis was undertaken by the National Health Laboratory Service, which used the World Health Organization recommendation of specimen processing for M. tuberculosis culture. Samples were incubated in the Mycobacterium Growth Indicator Tube 960 TB System (Becton Dickinson, Sparks, MD)16; phenotypic drug susceptibility testing of M. tuberculosis complex to first-line and second-line anti-TB drugs was performed.

A diagnosis of probable TB was made by the attending physician based on criteria in the National Childhood Tuberculosis Guidelines of South Africa, which are based on a combination of history of exposure, clinical signs, the TST reading and chest radiography.17

Definitions

  1. Absolute neutrophil, lymphocyte and monocyte counts:
    • a. <1000 cells/µL: moderate suppression;
    • b. <500 cells/µL: severe suppression and
    • c. <100 cells/µL: profound suppression.
  2. Prolonged neutropenia, lymphopenia and monocytopenia is defined as absolute counts of <1000 cells/µL for ≥7 days.18
  3. Malnutrition is described for arm muscle area, mid-upper arm circumference and triceps skinfold thickness.19,20
  4. Treatment is categorized as:
    • a. Category 1: Stage 1 and 2 Hodgkin lymphoma (HL), localized solid tumors (STs), standard-risk (SR) acute lymphoblastic leukemia (ALL);
    • b. Category 2: Medium-risk ALL, stage 1 and 2 non-Hodgkin lymphoma (NHL), stage 3 and 4 HL, metastatic ST and
    • c. Category 3: High-risk (HR) ALL, stage 3 and 4 NHL, acute myeloid leukemia (AML).

Statistical Analysis

Descriptive statistics were used to calculate counts, proportions, means and medians. Chi square tests, t test and Wilcoxon rank-sum tests were performed to assess differences between those with hematologic malignancies (HMs) and ST. Follow-up time in years was calculated for each child from the time of presentation to TB infection, death and end of study or abandonment of treatment. Incidence per 100 person-years was calculated as the number of events divided by the total person-years multiplied by 100. Exact CIs are reported for all incidence rates and comparisons are made using the χ2 test. Stepwise Poisson regression was used to assess the incidence of TB and various risk factors. Children with a reactive TST at time of enrollment were excluded from analyses.

Ethics Considerations

Approval was obtained from the Human Research Ethics Committee, University of the Witwatersrand for the study (HREC: M080304). Parents of children provided informed consent for participation in the study; assent was obtained from those 7 years and older.

RESULTS

We enrolled 169 children, 82 (48.5%) with HM and 87 (51.5%) with ST. The median age of presentation was 68.5 months (interquartile range: 36–121 months), children with HM were older (89 months) than those with a ST (48 months; P = 0.001). Eighteen of the 169 children (10.7%) were living with HIV, of whom 17 (94.4%) were antiretroviral therapy naïve; 15.9% (13/82) had HM and 5.7% (5/87) had ST. Twenty-five of 87 children (28.7%) with ST and 10 of 21 (47.6%) with HL presented with stage 4 disease, 17 of 19 children (73.9%) with NHL had stage 3 and 4 disease and 25 of 32 (78.1%) with ALL had HR disease. Most of the cohort had severe malnutrition, 72% (121/169) based on mid-upper arm circumference, 64.6% (109/169) by triceps skinfold thickness and 74.2% (125/169) by arm muscle area.

Five children (2.9% of 169; 4 HM and 1 ST) had a reactive TST at enrollment, all of whom were empirically treated for TB, none subsequently were diagnosed with TB and were excluded from further analyses. Three children (1.8% of 169) had known contact with a TB source case. The T-Spot assay yielded indeterminate or negative results in the first 100 children tested (including the 5 with a reactive TST), and further T-Spot testing was terminated.

Thirty-four children (20.7% of 164) were diagnosed with TB following initiation of cancer treatment. Of these, 70.6% children (24/34) were diagnosed with HM and 29.4% (10/34) with ST (Table 1). Fourteen of the 34 children (41.2%) had an indeterminate and 20.5% (7/34), a negative T-Spot result at screening. Twelve of the 34 TB cases (35.3%) were culture-confirmed, 10 with pulmonary and 2 with extrapulmonary (M. tuberculosis cultured from lymph nodes) TB. All M. tuberculosis isolates were pan susceptible to first-line TB drugs. The overall mean time from initiation of cancer treatment to diagnosis of TB was 5.5 months, which was sooner in children with HM (3.7 months) than ST (9.60 months; P = 0.029). The time to TB diagnosis from presentation of malignant disease was 6.6 and 4.9 months for culture-confirmed and probable TB, respectively (Table 1). The spectrum of types of cancer in children with TB is described in Table 1. Of the total cohort, 42.1% (8/19; 7 living with HIV) with NHL, 40% (4/10) with AML and 37.5% (12/32) with ALL, developed TB.

TABLE 1. - Cancer Diagnosis, HIV Status and Time to Diagnosis in Children Diagnosed With Culture-confirmed and Probable Tuberculosis
Variable Overall, n = 34* Culture-confirmed Tuberculosis, n = 12 Probable Tuberculosis, n = 22
Number of children with tuberculosis 34 12 22
Hematologic malignancy; n (%) 24/34 (70.5) 6/12 (50) 18/22 (81.8)
 Acute lymphoblastic leukemia 12/24 (50) 3/6 (50) 9/18 (50)
 Acute myeloid leukemia 4/24 (16.7) 1/6 (16.7) 3/18 (16.7)
 Non-Hodgkin lymphoma 8/24 (33.3) 2/6 (33.3) 6/18 (33.3)
Solid tumors; n (%) 10/34 (29.4) 6/12 (50) 4/22 (18.2)
 Wilms tumor 5/10 (50) 2/6 (33.3) 3/4 (75)
 Osteogenic sarcoma 1/10 (10) 1/6 (16.7) 0/4
 Brain tumor 1/10 (10) 1/6 (16.7) 0/4
 Adrenocorticoid carcinoma 1/10 (10) 1/6 (16.7) 0/4
 Kaposi sarcoma 1/10 (10) 1/6 (16.7) 0/4
HIV positive; n (%) 8/34 (23.5) 3/12 (25) 5/22 (22.7)
Time from presentation to tuberculosis diagnosis (mo) 5.5 (6.3) 6.58 (5.85) 4.86 (6.61)
*n = number.

The overall incidence (per 100 child-years) rate of TB in our study was 7.6 (95% CI: 5.3–10.7), including 11.3 (95% CI: 7.2–16.8) and 4.3 (95% CI: 2.1–7.9) in children with HM and ST, respectively. Although children living with HIV trended to have a higher incidence of TB (19.3; 95% CI: 8.3–38) than those without HIV (6.4; 95% CI: 4.2–9.4; Table 2), this was not significant after adjusting for other risk factors (Table 2). Children with HR-ALL, stage 3 and 4 NHL and AML had a TB incidence of 20.4 (95% CI: 12.8–30.9) compared with 2.4 (95% CI: 0.8–5.6) in children with localized ST, stage 1 and 2 HL and SR-ALL. There was no identifiable association between nutritional status at enrollment and the risk of developing with TB.

TABLE 2. - Risk Factors Associated With Developing Tuberculosis
Variable Total Person-years Incidence of Tuberculosis Adjusted P Incidence of Culture-confirmed Tuberculosis Adjusted P Incidence of Probable Tuberculosis
Overall 445 7.6 (5.3–10.7); n = 34 2.7 (1.4–4.7); n = 12 4.9 (3.1–7.5); n = 22
Type of cancer
 Hematologic malignancy 212 11.3 (7.2–16.8); n = 24 Reference group 2.8 (1–6.2); n = 6 Reference group 8.5 (5–13.4); n = 18
 Solid tumor 233 4.3 (2.1–7.9); n = 10 0.169 2.6 (0.9–5.6); n = 6 0.338 1.7 (0.5–4.4); n = 4
HIV status
 HIV negative 403 6.4 (4.2–9.4); n = 26 Reference group 2.2 (1–4.2); n = 9 Reference group 4.2 (2.5–6.7); n = 17
 HIV positive 42 19.3 (8.3–38); n = 8 0.134 7.2 (1.5–21.1); n = 3 0.076 12 (3.9–28.1); n = 5
Age at presentation, yr
 <5 188 6.9 (3.7–11.8); n = 13 Reference group 2.7 (0.9–6.2); n = 5 Reference group 4.2 (1.8–8.4); n = 8
 5 to <10 145 5.5 (2.4–10.9); n = 8 0.626 3.4 (1.1–8); n = 5 0.594 2.1 (0.4–6); n = 3
 ≥10 106 12.2 (6.5–20.9); n = 13 0.103 1.9 (0.2–6.8); n = 2 0.427 10.4 (5.2–18.5); n = 11
Treatment category*
 Category 1 207 2.4 (0.8–5.6); n = 5 Reference group 1.9 (0.5–4.9); n = 4 Reference group 0.5 (0–2.7); n = 1
 Category 2 130 5.4 (2.2–11.1); n = 7 0.177 2.3 (0.5–6.8); n = 3 0.833 3.1 (0.8–7.9); n = 4
 Category 3 108 20.4 (12.8–30.9); n = 22 0.009 4.6 (1.5–10.8); n = 5 0.685 15.8 (9.2–25.2); n = 17
*Treatment category: category 1 = localized solid tumor, stage 1 and 2 Hodgkin lymphoma, standard-risk acute lymphoblastic leukemia; category 2 = medium-risk acute lymphoblastic leukemia, stage 3 and 4 Hodgkin lymphoma, stage 1 and 2 non-Hodgkin lymphoma, metastatic solid tumor and category 3 = high-risk acute lymphoblastic leukemia and stage 3 and 4 non-Hodgkin lymphoma and acute myeloid leukemia.
Incidence refers to incidence per 100 child-years as defined in the main manuscript.
Adjusted P were obtained from a Poisson regression model adjusted for the following covariates: having at least one suspected septic episode, type of cancer, HIV status and age at presentation.
— indicates not applicable.

Children who developed TB were exposed to a higher number of high-dose corticosteroids (HDCS) courses (350 per 100 child-years) before the diagnosis of TB than those who did not develop TB (29.4 courses per 100 child-years; P < 0.001; Table 3). In addition, those who developed TB were more likely to have been treated for septic episodes (rate per 100 child-years) associated with profound neutropenia (322.2. vs. 31.3; P < 0.001), profound lymphopenia (288.9 vs. 27.2; P < 0.001) and profound monocytopenia (416.7 vs. 43.0; P < 0.001) before diagnosis of TB than those who did not develop TB (Table 3). Furthermore, following the diagnosis of TB, these children had a higher incidence of septic episodes compared with before developing TB, with prolonged neutropenia (366.7 vs. 33.7; P < 0.001), prolonged lymphopenia (394.4 vs. 39.4; P < 0.001) and prolonged monocytopenia (477.8 vs. 47.0; P < 0.001). Similar associations were found when restricting to culture-confirmed cases (Table 1, Supplemental Digital Content, http://links.lww.com/INF/E92).

TABLE 3. - Incidence of Low White Cell Counts and High-dose Corticosteroid Exposure Before the Diagnosis of Tuberculosis in Patients With and Without Tuberculosis
Event Patients With Tuberculosis (Total Person-years = 18) Patients With No Tuberculosis (Total Person-years = 419) P
Incidence* of cycles of high-dose corticosteroids before TB diagnosis (95% CI); n 350 (268.9–447.8); 63 29.4 (24.4–35); 123 <0.001
Incidence of SE with prolonged neutropenia before TB diagnosis (95% CI); n 366.7 (283.6–466.5); 66 33.7 (28.3–39.7); 141 <0.001
Incidence of SE with profound neutropenia before TB diagnosis (95% CI); n 322.2 (244.7–416.5); 58 31.3 (26.1–37.1); 131 <0.001
Incidence of SE prolonged§ lymphopenia before TB diagnosis (95% CI); n 394.4 (308.1–497.5); 71 39.4 (33.6–45.9); 165 <0.001
Incidence of SE with profound lymphopenia before TB diagnosis (95% CI); n 288.9 (215.8–378.8); 52 27.2 (22.4–32.7); 114 <0.001
Incidence of SE with prolonged monocytopenia before TB diagnosis (95% CI); n 477.8 (382.2–590.1); 86 47 (40.7–54.1); 197 <0.001
Incidence of SE with profound monocytopenia before TB diagnosis (95% CI); n 416.7 (327.7–522.3); 75 43 (36.9–49.7); 180 <0.001
*Incidence = incidence per 100 child-years where incidence is defined as the number of events divided by the total person-years multiplied by 100.
n = number of events.
Profound neutropenia, lymphopenia and monocytopenia = absolute cell counts <100 cells/µL.
§Prolonged neutropenia, lymphopenia and monocytopenia = absolute counts of <1000 cells/µL for ≥7 days.
P when comparing children who developed TB to those that did not.
SE indicates septic episode.

There were 26 deaths (76.5%) among the 34 children with TB (7 were culture-confirmed TB). The deaths among the TB cases included eleven with HR-ALL, 8 with stage 3 or 4 NHL (7 living with HIV), 3 with AML and 1 each with HIV-related Kaposi sarcoma, Wilms tumor, osteogenic sarcoma and adrenocortical carcinoma. At the time of death, multiple pathogens were isolated from these children, including multidrug-resistant bacteria, fungi and respiratory viruses (Table 2, Supplemental Digital Content, http://links.lww.com/INF/E92).

DISCUSSION

The overall incidence (per 100 child-years) for TB in our study cohort was 7.6, 11.3 in children with HM and 4.3 in children with ST, with 35.3% of TB cases being culture-confirmed. Notably, all the TB cases in our study tested negative using the TST and negative or indeterminate using the T-Spot (in those tested) at diagnosis of the malignancy, indicating the limited value for screening for latent M. tuberculosis infection in this immunocompromised population.

In our study cohort, the T-Spot testing was abandoned after yielding either an intermediate or a negative result in the first 100 children tested. This is consistent with other studies that demonstrate very low sensitivity of IGRAs in immunocompromised children and in children from low-middle income countries where IGRAs’ performance is equivalent or inferior to TST.21 A study, undertaken in the Western Cape, South Africa, in children with cancer, found that TST and IGRA results were discordant (8.8% and 17.6% were positive for the TST and IGRA, respectively), with fewer positive results than expected, and concluded that neither test could be used in isolation to exclude M. tuberculosis infection.22 The World Health Organization guidelines state “there is no gold standard” for diagnosing latent TB, and both TST and IGRAs are “imperfect tests.”23,24

TST was also a suboptimal test for screening for TB in our immunocompromised population. The population M. tuberculosis infection rate in South Africa is 3% year-on-year.25 Our study cohort, who presented with a median age of 5.7 years, the expected TST positivity rate would have been approximately 17.1% instead of the 2.9% detected. Therefore, caution must be exercised in the interpretation of the TST (and IGRA) test when screening for M. tuberculosis infection in children with underlying cancer in high burden HIV and TB areas. Nevertheless, we identified 5 children with a positive TST on admission who were treated empirically for TB (standard of care for immunocompromised children); none of whom subsequently developed TB or died. This suggests some role for ongoing screening using the TST in populations like ours, to select out those who should possibly be empirically treated with a full course of TB treatment, considering the high risk of developing TB in children with cancer in settings such as ours. It is recommended the TST be the first test in immunocompromised children, and if positive, the child should be considered to have TB.26

The incidence of TB observed in our study (7.6 per 100 child-years) was similar to that reported in an earlier South African study in children with cancer (9.1 per 100 years)10 done from January 1991 to December 2005, even though the overall reported burden of TB in South Africa was much higher (300 per 100,000 in 1991 to 900 per 100,000 in 2005)27 compared with 762 and 520 per 100,000 for periods 2011 and 2015,28 respectively.

Stefan et al10 reported that 53% of children with cancer who developed TB had a HM of which ALL was most common (22.8%), the time from initiation of cancer treatment to diagnoses of TB was 7.6 months and none of the deaths in the latter study was attributed to TB. In our study, 66.7% of the children with TB had a HM, with ALL (35.3%) the most common cancer, followed by NHL (33%) and Wilm's tumor (14.7%). The time to diagnosis of TB relative to presentation with cancer was shorter in our study (5.5 months) and 76.5% of children with TB died in our study. Children treated for HR-ALL, stage 3 or 4 NHL and AML, all HM, had a higher incidence of TB compared with those with localized ST, stage 1 or 2 HL and SR-ALL. Similarly, a meta-analysis to estimate the relative incidence of TB in children with cancer reported a 16.8 times higher incidence rate-ratio in those with HM than ST.29

In low-burden TB areas, the risk of developing TB in patients with cancer is also increased. In the United States, it was documented that adults with HM who were treated with hemopoietic stem cell transplantation were 40 times more at risk of developing TB than the general population.30 Likewise, in high burden TB countries like India, adults with leukemia, especially AML, had a 13.8-fold increased risk of developing TB than the general population.31

The diagnosis of TB is often delayed among immunocompromised children, due to a low index of suspicion and unavailability of diagnostic tests for TB.32 Additionally, young and immunocompromised children are more likely to have a negative TST, and less likely to have positive sputum staining for acid-fast bacilli.7 Bronchoalveolar lavage is an effective procedure for the microbiologic diagnosis of TB in adult patients with HM,33 but in our setting, this technique is not readily available. Many children with cancer may have an increased risk for bleeding, due to complications of the disease or treatment, therefore are unsuitable candidates for invasive procedures such as bronchoalveolar lavage.

All children in our study diagnosed with TB experienced septic episodes with prolonged and profound pancytopenia before the diagnosis of TB. Other than 1 study in adults from Taiwan, there are no published reports on the hematologic parameters in individuals with cancer and TB. This study reported that TB in AML patients was associated with significant neutropenic septic episodes compared with non-AML patients. The risk of developing TB correlated partly with the absolute neutrophil count.34 Recent research on neutrophil peptides documented that neutrophils are bactericidal against TB, which suggests that neutrophils are important in the defense against TB. In an adult noncancer TB cohort diagnosed with TB, the risk of TB was inversely and independently associated with neutrophil counts on enrollment into the study.35 Our study findings were consistent with this result, supporting the important role of neutrophils in the defense against TB.

Our study also demonstrated that the children who developed TB were treated with more courses of HDCS than those who did not develop TB. This indicates that treatment with HDCS, a mainstay of treatment for HM, may be a risk factor for developing TB. This supports the findings of Silva et al36 who too reported that pretreatment with HDCS was a risk factor for the development of TB in adult cancer patients. Moreover, a study conducted in Saudi Arabia found that 68.75% of adult patients with both cancer and TB had received HDCS before the diagnosis of TB.5 HDCS has also been linked to increased disease severity of TB at presentation, increased risk for miliary TB and higher case fatality rates from TB.8 Corticosteroids reduce the production of interleukin-1 and tumor necrosis factor alpha by inhibiting monocyte chemotaxis, inhibits T-cell activation and cytokine production and causes lymphocytopenia. These mechanisms increase the risk of TB.37

We had a high mortality in children diagnosed with TB (76.5%). All of those who died also had concurrent respiratory viral, bacterial and fungal infections and 8 were living with HIV. This suggests a complex disease process at the time of death. However, it is difficult to delineate the role of the pathogens identified as the direct cause of death, as we did not conduct postmortem studies. Studies in adult cancer patients with TB have recorded mortality figures ranging from 10%38 to 62%.36 To our knowledge, there are no recent studies documenting mortality from TB in children with cancer, and there were no deaths recorded in the study from the Western Cape, South Africa.10

Cancer-induced and chemotherapy-induced immunosuppression increase the risk of TB,39 and diagnosis is impeded by the low sensitivity of TST and IGRA. Consequently, a high index of suspicion for TB has to be maintained in children with cancer, especially children with HR-ALL, advanced stage NHL and AML, living with HIV, being treated with chemotherapy protocols containing HDCS and causing prolonged and profound pancytopenia as these have been identified as notable risk factors for developing TB. The limitations of the study are patients were not aggressively followed-up for history of positive TB contact and not retested for TB infection. However, as this was a longitudinal study, patients were regularly followed up and investigated for TB on clinical suspicion. Given the poor performance of tests for TB infection in our study population, the concurrent initiation of cancer therapy together with TB treatment in children with cancer in high TB-endemic settings, or at least for those presenting with identified risk factors for developing TB, should be further investigated.

ACKNOWLEDGMENTS

The authors thank Dr. Vaughan for her assistance with the retrieval of missing data from the National Health Laboratory Services, South Africa. The authors also thank Ms. Senna, Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, South Africa for her assistance with the collection and sampling of specimens.

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Keywords:

tuberculosis; infections; South Africa; children; cancer

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