key: cord-0805551-6jyog587
authors: MacLean, Emily L.; Villa-Castillo, Luz; Ruhwald, Morten; Ugarte-Gil, César; Pai, Madhukar
title: Integrated testing for TB and COVID-19
date: 2022-02-11
journal: Med (N Y)
DOI: 10.1016/j.medj.2022.02.002
sha: 16da1d148669739f41472473608c91ec62c07106
doc_id: 805551
cord_uid: 6jyog587

Integrated testing for TB and COVID-19 may help find those TB patients who are not accessing care in the context of the COVID-19 pandemic., Some molecular platforms with assays for both diseases are already commercially available; however, integrated testing approaches need to be systematically evaluated to ensure their appropriate implementation.

The COVID-19 pandemic is wreaking havoc on all realms of global health, and tuberculosis (TB) 2 care and services are no exception [1, 2] . After one year of the pandemic, high TB burden 3 countries were reporting drops in TB case notifications ranging from 16% to 41% (mean 23%) -4 levels not seen since 2008 [3] . Of the approximately 10 million people who developed TB in 2020, 5 only 5.8 million people were diagnosed and reported to national TB programs, an 18% decrease 6 compared to 2019 [1] . Reduced access to medical care and TB services as well as the 7 reallocation of existing public health tools, personnel, and infrastructure to COVID-19 efforts 8 could explain this reduction [4] . Predictably, the decline in people seeking TB care has led to an 9 increase in TB-related deaths: in 2020, at least 1.5 million people died of TB, a figure not seen 10 since 2017. Evidently, we are off track to meet many of the END TB goals, and without 11 redoubled efforts and innovative strategies to reach those who need testing and treatment, we 12 risk missing these milestones by even larger margins [1] . 13

Additionally, emerging data suggest that people with TB who develop COVID-19 are at a higher 14 risk of severe disease and mortality compared to those without COVID-19. As well, a recent 15 systematic review reported that COVID-19 patients with TB were at almost twice the risk of 16 mortality compared to individuals with COVID-19 alone [5] . Therefore, reaching people with TB 17 and ensuring they receive appropriate care is urgent. Increasing TB testing and case 18 notifications is a critical and pressing priority. 19

Proposed action: "Integrated testing" 20

More people with presumptive TB need to be reaching the second step of the TB care cascade, 21 namely, moving from (1) developing incident TB to (2) accessing testing [6] . One proposed catch-22 up intervention is integrating testing for TB and COVID-19. In the absence of World Health 23

Organization policy, other global stakeholders have proposed frameworks and guidelines for 24 integrated testing, although evidence to support these recommendations is limited. 25

In early 2021, USAID and Stop TB Partnership issued a brief document recommending that for 26 people presenting to healthcare facilities with respiratory symptoms, a "simultaneous, integrated 27 approach to testing for TB and COVID-19 should be implemented in countries with a high 28 burden of TB", namely, "diagnostic tests for both COVID-19 and TB should be done at the same 29 time (simultaneous testing) on a multiplex testing platform (integrated testing)" [7] . These 30 recommendations are broad and apply to anyone with presumptive TB or In late 2021, the Global Fund released a briefing note providing guidance regarding testing for 32 TB and COVID-19. In particular, they recommend that in communities with prevalent TB and 33 COVID-19, people whose clinical signs and symptoms meet case definitions for both TB and 34 COVID-19 should undergo "systematic testing for both pathogens". They also recommend 35 molecular testing in those who have had symptoms for longer than 7 days, and antigen rapid 36 testing for those with symptoms lasting 5-7 days ( Figure 1 ) [8] . 37

The Global Fund brief also suggests action in case people with TB are suspected to have 38 developed COVID-19 symptoms. Should this situation arise, TB must continue to be properly 39 managed, and then testing for SARS-CoV-2 infection should be performed if individuals "meet 40

the COVID-19 case definition or when there is persistence or worsening of their condition 41 despite appropriate treatment for the specific form of TB" [8] . 42

Certain countries have launched their own integrated testing efforts. In India, for example, this 43 approach is termed bi-directional screening for TB and COVID-19. The Indian Ministry of Health 44

and Family Welfare recommends that "COVID screening for all diagnosed TB patients and TB 45 screening for all COVID positive patients should be conducted"; TB screening should be 46 undertaken in all individuals with influenza-like illness; and all individuals with severe acute 47 respiratory illness should be screened for TB [9] . Recently, the Ministry also issued guidance that 48 all individuals undergoing COVID-19 treatment with a cough last longer than two weeks should 49 be tested for TB [10] . 50

The differences in these approaches demonstrate that there is not yet a clear consensus of who 51 exactly should be prioritized: the target population for integrated testing needs to be more well-52 defined. The Global Fund's testing algorithm ( Figure 1 ) is narrower than the catch-all approach 53

proposed by Stop TB Partnership and USAID. However, the two documents ultimately may not 54 lead to much difference in practice, as discerning between the two diseases based on clinical 55

picture alone can be difficult. Also, since COVID-19 has been impacting TB-endemic countries 56 in waves, the need for integrated testing changes over time. When COVID-19 incidence rates 57 are low, it is not completely obvious why TB programs would also need testing for And while this approach may assist in finding cases, the yield of integrated testing and its cost-59 effectiveness is unclear. 60

Despite this ambiguity, there are some products already available which may be utilized for 62 integrated testing. As countries have greatly scaled-up their testing capabilities to deal with the 63 large-scale demand COVID-19 testing, this infrastructure could be expanded to include more 64 testing for TB. In some cases, molecular testing for COVID-19 was originally possible due to 65 existing laboratory infrastructure and diagnostics networks used by national TB and HIV 66 programs [11] . Single cartridges that can detect multiple pathogens as well as non-PCR based 67 platforms for multi-disease testing are becoming commercially available. The work to create 68 'fast follower' assays has begun, with some TB tests that utilize the same platform or technical 69 basis as novel COVID-19 tests under development. Some products that may be considered for 70

integrated TB and COVID-19 testing are shown in Table 1 , including GeneXpert, a technology 71 that has been scaled-up in many high TB burden countries ( Figure 2 incorporating either of these user-friendly advances have the potential to reach people in remote 91 areas and may make obtaining good quality samples easier from people with all forms of 92 presumptive TB [11] . 93

Evidence describing the disruptions to TB programs and services since the beginning of the 95 COVID-19 pandemic is accumulating [4, 5] , and although it is well-recognised that there has been 96 a global decline in TB testing [4] , reports of interventions to recover these losses are very limited. 97

This is also true for integrated TB and COVID-19 testing. 98

One study in Madagascar reported that the Ministry of Public Health had decided to use existing 99

GeneXpert platforms for COVID-19 testing, which were in-place for TB testing. The authors 100 noted that automated platforms like GeneXpert require less trained staff than traditional PCR 101 due to the decreased number of hands-on steps, and because the network was already 102 existing, the country could quickly take advantage of its services [12] . 103

In high TB burden settings like South Africa, it has been suggested that community-based 104 screening networks deployed for COVID-19 could also support TB testing and lead to improved 105 linkage to care. For individuals who test positive for TB, there is an opportunity to test for 106 COVID-19 at the time of TB contact tracing [13] . 107 A publication of public health efforts in Kerala, India has shown that systematic integration of 108 COVID-19 and TB testing is possible [14] . When health authorities noted that their capacity was 109 entirely being directed to COVID-19 control efforts, they adopted strategies to incorporate those 110 efforts with other disease programs' work. Anyone who was eligible for COVID-19 testing was 111 screened for TB if they met any of the four conditions: (i) presence of influenza-like illness in an 112

individual with risk factors for developing TB (e.g., close contact, elderly, living with diabetes); 113

(ii) individuals testing negative for COVID-19 but whose symptoms lasted for >14 days; (iii) any 114 individual hospitalized for due to COVID-19; or (iv) positive for COVID-19 and four-symptom 115 (cough >2 weeks, fever >2 weeks, weight loss, night sweats) screen positive for TB. Those who 116 screened positive were offered molecular TB testing using new and existing Truenat and 117

GeneXpert platforms, with tests for TB and COVID-19 run on both systems. The authors 118

reported that their integrated testing efforts comprised 8% of total TB diagnoses made state-119 wide in a one-month period [14] . 120

Currently, we are recruiting adults with presumptive TB or Peru, to 121 investigate integrated TB and COVID-19 testing using the GeneXpert platform [15] . Each 122 participant is providing us with a sputum sample and an NP swab, which are then tested for 123

both TB and COVID-19. So far, we have observed that with a single sputum sample, we can 124 identify 98% of culture-confirmed TB cases and 84% of RT-PCR-confirmed COVID-19 cases. 125

Our in-study prevalence of concurrent TB and COVID-19 is around 2%, which does raise some 126 questions about the efficiency and cost-effectiveness of this approach on a large scale [15] . 127

Integrated testing for TB and COVID-19 has the potential to help recover a proportion of the 129 missing people who developed TB in the pandemic era, but many important unknowns remain 130 regarding its implementation. Implementing integrated testing within existing laboratory and 131 specimen collection workflows is likely feasible, but patient acceptability of introducing testing 132 for COVID-19 and TB, a disease that is typically accompanied by substantial social stigma, is 133 not known. 134

Evidence is urgently needed to understand who exactly should be tested for both TB and 135 COVID-19. Considering that COVID-19 is typified by acute but short-term symptoms, while TB 136 is characterised by longer-term clinical symptoms, who is the ideal target population for 137 integrated testing? As resources are not unlimited, an efficient strategy that can identify cases at 138 a relatively high rate would be desirable. Certain sub-populations, such as immunocompromised 139 people, will need particular attention to ensure integrated testing policies reach them. 140

Evaluations of integrated testing in large populations with diverse epidemiologic history, clinical 141 symptoms, and varied symptom duration distributions will help draw conclusions regarding who 142

should undergo integrated testing. 143

Examining integrated testing in a variety of settings is needed to understand where this 144 intervention should immediately be rolled-out. Example settings include urban locales with very 145 J o u r n a l P r e -p r o o f high TB prevalence where there are many shared risk factors for COVID-19; rural settings in 146 high TB burden countries where integrated disease testing could greatly improve quality of care; 147 or countries with a higher proportion of people who are immunocompromised. It is also 148 important to account for the fact that COVID-19 has been impacting countries in waves: in 149 countries with high TB prevalence, integrated testing may therefore be irrelevant when COVID-150 19 incidence is low, but may again become highly relevant during COVID-19 surges. Good 151 surveillance for both infections is necessary to make adjustments in testing policies. 152

Against the background of global supply chain issues, further investigation into alternative but 153 acceptable sampling strategies is warranted. Although NP swabs are considered the gold 154 standard for COVID-19 molecular testing, other samples may yield a sufficiently high proportion 155 of cases. Other sample types such as tongue swabs, nasal swabs, throat swabs, aerosol 156 collection in face masks, or conventional sputum could be candidates for testing of both 157

conditions, and strategies like sample batching and at-home sample collection should be 158

considered. More work is needed to understand these approaches in the context of integrated 159

testing. 160

Modeling studies to understand the cost and cost-effectiveness of integrated TB and COVID-19 161 testing will help aid decision-making and in setting priorities. Simulations should be run for 162 different iterations of testing strategies, target populations, incidence triggers, and settings. 163

Despite the calls for integrated disease testing, it is not yet known whether the yield will be 164 worth the additional costs. Molecular testing for Covid-19 is expensive for many low and middle-165 income countries. Adding a second molecular test for TB for all people with respiratory 166 symptoms might be prohibitively expensive in many settings unless the strategy is worth the 167 effort and costs. Understanding this piece will help countries plan and allocate resources, as 168 well as inform future policies. 169

Ostensibly, integrated testing for TB and COVID-19 seems to be a beneficial intervention, but it 171 has yet to be systematically evaluated and data are lacking. Available multiplex platforms can 172 facilitate this testing, with more products emerging. As new SARS-CoV-2 variants of concern 173 arise, integrated testing policies will need to be re-examined and updated as needed. Careful 174 design of studies and outcomes will need to be considered to ensure the real impact of 175 integrated testing can be identified and measured. MR is an employee of FIND. FIND is a non-for-profit foundation, whose mission is to find 185 diagnostic solutions to overcome diseases of poverty in LMICs. It works closely with the private 186 and public sectors and receives funding from some of its industry partners. It has organisational 187 firewalls to protect it against any undue influences in its work or the publication of its findings. All 188 industry partnerships are subject to review by an independent scientific advisory committee or 189 another independent review body, based on due diligence, TTPs and public sector 190 requirements. FIND catalyses product development, leads evaluations, takes positions and 191

accelerates access to tools identified as serving its mission. It provides indirect support to 192

industry (e.g. access to open specimen banks, a clinical trial platform, technical support, 193 expertise, laboratory capacity strengthening in LMICs) to facilitate the development and use of 194 products in these areas. FIND also supports the evaluation of publicly prioritised TB assays and 195 the implementation of WHO-approved (guidance and PQ) assays using donor grants. In order to 196 carry out test evaluations, FIND has product evaluation agreements with several private sector 197 companies for TB and other diseases, which strictly define its independence and neutrality vis-198 à-vis the companies whose products get evaluated and describes roles and responsibilities. 

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