Symptom screening for active tuberculosis in pregnant women living with HIV
Appendices
Appendix 1. Search strategy
We will include search terms to capture clinical tuberculosis symptoms among HIV‐infected pregnant women. We will utilize both MeSH terms and free text terms to identify phrases of our search. In order to increase the sensitivity of our findings, we will search “All fields” when possible rather than only title and abstracts. We will include the following search terms.
1 exp HIV Infections/
2 HIV/ or HIV‐2/ or HIV‐1/
3 (HIV or hiv‐1* or hiv‐2* or hiv1 or hiv2 or hiv‐I* or hiv‐II* or hivI* ).tiab
4 "HIV infect*".tiab
5 ("human immunodeficiency virus" or "human immunedeficiency virus" or "human immuno‐deficiency virus" or "human immune‐deficiency virus" or (human immun* and deficiency virus)).tiab
6 ("acquired immunodeficiency syndrome" or "acquired immunedeficiency syndrome" or AIDS).tiab
7 ("acquired immuno‐deficiency syndrome" or "acquired immune‐deficiency syndrome").tiab
8 or/1‐7
9 exp Tuberculosis/
10 (tuberculosis or TB or tuberculoses or tuberculous).tiab
11 Mycobacterium tuberculosis/
12 9 or 10 or 11
13 8 and 12
14 (pregnant adj3 wom?n).mp.
15 Pregnant Women/
16 Pregnancy/
17 pregnan*.tiab
18 14 or 15 or 16 or 17
19 13 and 18
20 mass screening.mp. or Mass Screening/
21 physical examination.mp. or Physical Examination/
22 Cough/
23 Weight Loss/
24 Fever/ or Fatigue/
25 Prenatal Diagnosis/ or ((prenatal* or pre natal* or antenatal* or ante natal*) adj2 screen*).tiab.
26 clinical algorith*.mp.
27 (cough* or "weight loss*" or "weight reduction*" or fever* or pyrexia* or "night sweat*" or fatigue*).tiab
28 ("four‐symptom screen*" or "four‐symptoms screen*").tiab
29 triag*.mp. or Triage/
30 case finding.mp.
31 symptom* adj2 screen* .mp.
32 or/20‐31
33 19 and 32
This is the preliminary search strategy for MEDLINE. It will be adapted for other electronic databases. All search strategies will be reported in full in the final version of the review.
Appendix 2. Data extraction form
| Symptom screen for active tuberculosis in pregnant women living with HIV: data extraction form | ||||
| Study ID | ||||
| Name of data extractor | 1 – SL 2 – JM 3 – Other (Specify ________________________) | |||
| First Author | ||||
| Corresponding author and email | ||||
| Was an author contacted? | 1 – Yes Contact Date:______________ □ YES Response Result: □ NO Response 2 – No | |||
| Title of study | ||||
| Year of publication | ||||
| Year(s) study conducted | ||||
| Language | 1 ‐ English 2 ‐ French 3 ‐ Spanish 4 ‐ Other:__________________ | |||
| Journal | ||||
| Publication status of study | 1 – Published 2 – Unpublished What is the anticipated study completion date? | |||
| Country or countries where study was conducted (list all) | ||||
| World Bank Classification | 1 – Middle/Low 2 – High 3 – Study includes both middle/low & high | |||
| For the diagnosis of active TB, what reference standard was used to identify TB and not TB? Circle all that apply. NAAT – nucleic acid amplification test LJ – Lowenstein‐Jensen ZN – Ziehl‐Neelsen stain FM – Fluorescence microscopy | 1 – Sputum: Solid Culture (circle method) LJ 7H10 7H11 2 – Sputum: Liquid Culture (circle method) MGIT Bactec460 3 – Sputum: Both Solid and Liquid Culture (specify above) 4 – Sputum: NAAT (circle method) GeneXpert Other (specify): _____________ 5 – Sputum: Smear (circle method) ZN FM 6 – Sputum: Other, specify: _________________________ 7 – Non‐sputum: specify: ___________________________ 9 – Unknown/not reported | |||
| Were patients unable to produce sputa included in this study? | 1 – Yes 2 – No 9 – Unknown/not reported | |||
| How many sputum specimens per patient were obtained for the diagnosis of active TB? | 1 – One 2 ‐ Two 3 ‐ Other (specify):______________ 9 ‐ Unknown/not reported | |||
| What was the clinical setting of the study? | 1 – Outpatient, Maternal/child health clinic 2 – Outpatient, HIV clinic or other general medicine clinic 3 – Inpatient 4 – Both out‐patient and in‐patient 5 – Community‐based 6 ‐ Other, describe:________________________ 9 – Unknown/not reported | |||
| Study design | 1 – Randomized trial 2 – Cross‐sectional 3 – Cohort 4 ‐ Case‐control 5 – Other (specify):_________________________ 9 – Unknown/not reported | |||
| What was the manner of patient selection into the study? | 1 – Consecutive 2 – Random 3 – Convenience 4 – Other, specify 9 – Unclear/not reported | |||
| Direction of study data collection | 1 – Prospective 2 – Retrospective 9 – Unknown/not reported | |||
| Comments about study design | ||||
| Index tests: What symptoms were evaluated as screens for TB? Indicate all that apply. | 1 – Cough 2 – Fever 3 – Night sweats 4 – Weight loss 5 – Cough > 2 week duration 6 – Failure to gain weight 7 – Other, specify: _______________________ | |||
| Please select the statement that best describes the purpose of screening as described in the study. | 1‐ Pregnant PLHIV with signs or symptoms suggestive of active TB were screened for TB only 2 ‐ Pregnant PLHIV with and without TB signs or symptoms were screened for TB 3 ‐ Neither 1 nor 2. 4 ‐ Other, specify: _______________________ | |||
| Number after screening by exclusion & inclusion criteria (Total for study) | _____ 9 – Unknown/not reported | |||
| Number included in analysis (# screened ‐ # withdrawals) (Total for study) | _____ 9 – Unknown/not reported | |||
| HIV status of participants (Total for study) | 1 – HIV‐positive 9 – Unknown/not reported | |||
| Percentage of HIV‐negative and HIV‐positive | _____ % of participants were HIV‐negative _____ % of participants were HIV‐positive Specify numerator/denominator | |||
| Pregnancy status of participants | 1 – Pregnant 2 – Postpartum 3 – Pregnant and postpartum 9 – Unknown/not reported | |||
| Percentage of pregnant and postpartum | _____ % of participants were pregnant _____ % of participants were postpartum Specify numerator/denominator | |||
| Gestational or Postpartum age | Pregnant: Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | Postpartum: Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | ||
| Percentage of pregnant and/or postpartum and HIV‐positive | _____ % of participants were pregnant or postpartum, and HIV‐positive Specify numerator/denominator | |||
| Age of participants | All Study Participants: Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | Pregnant PLHIV: Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | ||
| Reported AFB‐smear status | All Study Participants: _____ % of participants have AFB‐smear positive pulmonary TB Specify numerator/denominator______ 9 – Unknown/not reported | Pregnant PLHIV: _____ % of participants have AFB‐smear positive pulmonary TB Specify numerator/denominator______ 9 – Unknown/not reported | ||
| Participant engagement in medical care (indicate all that apply) | All Study Participants: 1 – Previously engaged in HIV care 2 – Never before received HIV care 3 – Both 4 – Other, specify: ________________ 9 – Unknown/not reported | Pregnant PLHIV: 1 – Previously engaged in HIV care 2 – Never before received HIV care 3 – Both 4 – Other, specify: ________________ 9 – Unknown/not reported | ||
| Proportion of participants with HIV never before engaged in care (i.e. enrolling into HIV care) | PLHIV: _____ % of participants previously engaged in care _____ % of participants never before engaged in care Specify numerator/denominator__________ 9 – Unknown/not reported | Pregnant PLHIV: _____ % of participants previously engaged in care _____ % of participants never before engaged in care Specify numerator/denominator__________ 9 – Unknown/not reported | ||
| ART status of PLHIV | PLHIV: 1 – No ART 2 – Combined ART 3 – ART for PMTCT only 9 – Unknown/not reported | Pregnant PLHIV: 1 – No ART 2 – Combined ART 3 – ART for PMTCT only 9 – Unknown/not reported | ||
| Proportion of PLHIV participants receiving combination ART (i.e. not only treated for PMTCT) | _______% of participants were on no ART _______% of participants were on combined ART _______% of participants were on ART for PMTCT only 9 – Unknown/not reported | |||
| What was the CD4‐cell count of included patients? | PLHIV: Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | Pregnant PLHIV: Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | ||
| What was the HIV viral load of included patients? | PLHIV: __________% with undetectable viral load Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | Pregnant PLHIV: __________% with undetectable viral load Range:____________ Mean (SD):_________________ Median (IQR):____________ 9 – Unknown/not reported | ||
| Did the study include patients with previous TB history? | All Study Participants: 1 – Yes ___________% of participants had a prior history of TB Specify numerator/denominator______ 2 – No 9 – Unknown/not reported | Pregnant PLHIV: 1 – Yes ___________% of participants had a prior history of TB Specify numerator/denominator______ 2 – No 9 – Unknown/not reported | ||
| WHO four‐symptom screen | Reference Test: Xpert or culture | |||
| TB Disease | Not TB | Total | ||
| Positive | ||||
| Negative | ||||
| Total | ||||
| Pregnant PLHIV on ART | Reference Test: Xpert or culture | |||
| WHO four‐symptom screen | TB Disease | Not TB | Total | |
| Positive | ||||
| Negative | ||||
| Total | ||||
| Pregnant PLHIV not on ART | Reference Test: Xpert or culture | |||
| WHO four‐symptom screen | TB Disease | Not TB | Total | |
| Positive | ||||
| Negative | ||||
| Total | ||||
| Symptom (specify symptom): | Reference Test: Xpert or Culture | |||
| TB Disease | Not TB | Total | ||
| Positive | ||||
| Negative | ||||
| Total | ||||
Appendix 3. QUADAS‐2
Domain 1: patient selection
Risk of bias: could the selection of patients have introduced bias?
Signalling question 1: Was a consecutive or random sample of patients enrolled?
We will score 'yes' if the study enrolled a consecutive or random sample of eligible participants (i.e., pregnant PLHIV); 'no' if the study selected participants by convenience; and 'unclear' if the study did not report the manner of participant selection or we could not tell.
Signalling question 2: Was a case‐control design avoided?
Case control study design may overestimate sensitivity and specificity for screening and diagnostic tests (Lijmer 1999). We will score 'yes' to studies which are not case‐control studies. We will score 'no' to studies which are case‐control studies. We will score 'unclear' if we could not tell.
Signalling question 3: Did the study avoid inappropriate exclusions?
We will score 'yes' to studies, which included: a) all pregnant PLHIV regardless of symptoms and b) pregnant PLHIV who were unable to produce sputum (expectorated or induced). We will score 'no' if studies excluded pregnant PLHIV on the basis of no symptoms or the inability to produce sputum (no attempts at sputum induction). We will also score 'no' if studies excluded pregnant PLHIV presumed to have extrapulmonary TB. We will score 'unclear' if we could not tell.
Applicability: Are there concerns that the included patients and setting do not match the review question?
We are interested in how the four‐symptom TB screen performs in pregnant PLHIV who would be screened in routine practice. We have defined 'screening' for active TB in accordance with WHO guidance, as "the systematic identification of people with suspected active TB, in a predetermined target group, using tests, examinations or other procedures that can be applied rapidly”(WHO 2013). We will score 'low concern' for studies in which the four‐symptom TB screen was performed uniformly within the predetermined study target population of pregnant PLHIV, 'high concern' if the four‐symptom TB screen was not performed uniformly within the predetermined study target population of pregnant PLHIV, and 'unclear concern' if we could not tell.
Domain 2: index test
Risk of bias: could the conduct or interpretation of the index test have introduced bias?
Signalling question 1: were the index test results interpreted without knowledge of the results of the reference standard?
We will score 'yes' if the study interpreted the result of the four‐symptom TB screen blinded to the result of the reference standard or if it is clear that the results of the index test were available before the results of the reference standard were known; we will score 'no' if the study did not interpret the result of the four‐symptom TB screen blinded to the result of the reference standard. We will score 'unclear' if we could not tell if the index test results were interpreted without knowledge of the reference standard results. We will also answer yes if the tests (index test and reference standard) were carried out in different places.
Signalling question 2: if a threshold was used to define positivity, was it prespecified?
This question is not applicable for our review.
Applicability: are there concerns that the index test, its conduct, or its interpretation differ from the review question?
If index test methods vary from those specified in the review question, concerns about applicability may exist. We will score 'high concern' if the four‐symptom TB screen was applied for the purpose of TB diagnosis, rather than as a TB screening tool; 'low concern' if the four‐symptom TB screen was applied as a screening tool, and 'unclear concern' if we could not tell.
Domain 3: reference standard
Risk of bias: could the reference standard, its conduct, or its interpretation have introduced bias?
Signalling question 1: is the reference standard likely to correctly classify the target condition?
Microbiological reference standard
Mycobacterial culture (liquid or solid) or nucleic acid amplification tests (e.g., Xpert) are considered the best reference standards to identify active TB in PLHIV. Due to the difficulties in diagnosing HIV‐associated TB, it is recommended that multiple cultures from sputum be evaluated.
We will answer 'no' if a consistent approach was not followed for all patients (for example, some but not all patients were asked to provide sputum for Xpert or culture testing). We will answer 'unclear' if we could not tell.
Signalling question 2: were the reference standard results interpreted without knowledge of the results of the index test?
We will answer 'yes' if the study interpreted the result of the reference standard blinded to the result of the four‐symptom TB screen, or if the reference standard result was reported on an automated instrument; 'no' if the study did not interpret the result of the reference standard blinded to the result of the four‐symptom TB screen, and 'unclear' if we could not tell. We will also answer yes if the tests carried out in different places.
Applicability: are there concerns that the target condition as defined by the reference standard does not match the question?
In general, we think there will be low concern for almost included studies based on the current definition of the reference standard. We will judge 'high concern' if the included studies did not speciate mycobacteria isolated in culture, 'low concern' if speciation was performed, and 'unclear' if we could not tell.
Domain 4: Flow and timing
Risk of bias: could the patient flow have introduced bias?
Signalling question 1: was there an appropriate interval between the index test and reference standard?
We will answer 'yes' if the index test and reference standard(s) are collected on the same patients at the same time or within seven days. We chose seven days as a time period during which either treatment of TB or natural progression of TB without treatment could impact test results. We will answer 'no' if specimens were collected for index and reference standard tests greater than seven days apart, and 'unclear' if we could not tell.
Signalling question 2: did all patients receive the same reference standard?
We will answer 'yes' if all participants in the study received the same reference standard to confirm TB; 'no' if not all patients received the reference standard to confirm TB, and 'unclear' if we could not tell.
Signalling question 3: were all patients included in the analysis?
We will determine the answer to this question by comparing the number of participants enrolled in the study with the number of participants included in the two‐by‐two tables. We will answer 'yes' if the number of participants in the two‐by‐two tables match the number of participants recruited into the study, or if these numbers do not match, then sufficient explanation is provided for any discrepancy. We will answer 'no' if the number of participants in the two‐by‐two tables do not match the number of participants recruited into the study and insufficient explanation is provided for any discrepancy, and 'unclear' if we could not tell.
Judgments for overall 'Risk of bias' assessments for domains
If we answer:
-
all signalling questions for a domain “yes,” then we will judge risk of bias “low”;
-
all or most signalling questions for a domain “no,” then we will judge risk of bias “high”;
-
one signalling question for a domain “no,” we will discuss with a third author the 'Risk of bias' judgement;
-
all or most signalling questions for a domain “unclear,” then we will judge risk of bias “unclear”;
-
only one signalling question for a domain “unclear,” we will discuss with a third author the 'Risk of bias' judgement for the domain.
Algorithm for TB screening in adults and adolescents living with HIV in HIV‐prevalent and resource‐constrained settings. Reprinted from: Guidelines for intensified tuberculosis case‐finding and isoniazid preventive therapy for people living with HIV in resource‐constrained settings. Copyright: WHO 2011a.
