key: cord-0786372-hmdmkf2c
authors: Twahirwa Rwema, Jean Olivier; Diouf, Daouda; Phaswana-Mafuya, Nancy; Rusatira, Jean Christophe; Manouan, Alain; Uwizeye, Emelyne; Drame, Fatou M.; Tamoufe, Ubald; Baral, Stefan David
title: COVID-19 Across Africa: Epidemiologic Heterogeneity and Necessity of Contextually Relevant Transmission Models and Intervention Strategies
date: 2020-06-18
journal: Ann Intern Med
DOI: 10.7326/m20-2628
sha: 372542218379e03573dae45d87a5e21806ed0c4d
doc_id: 786372
cord_uid: hmdmkf2c

This commentary discusses the COVID-19 pandemic on the African continent. The authors describe why the international community should be hesitant in developing forecasts and prevention strategies for COVID-19 in the absence of integration of African data and leadership by African institutions.

N ephrogenic systemic fibrosis (NSF) is a debilitating and often fatal condition caused by collagen deposition in soft tissues and internal organs, such as the heart, liver, and lungs (1) . Nephrogenic systemic fibrosis is associated with exposure to gadolinium-based contrast agents (GBCAs) administered during magnetic resonance imaging or angiography scans (2) and has no definitive treatment. Because these scans gain diagnostic effectiveness in many clinical situations when administered with GBCAs (3), patient exposure to these agents has become ubiquitous. In 2007, the U.S. Food and Drug Administration (FDA) released warnings about the use of GBCAs in recognition of the substantial risk for NSF with their use (4) .

Two important variables that seem to account for much of the NSF risk are the degree of stability of the linkage of gadolinium to its chelate ligand and the host's degree of kidney impairment (5) . Dissociation of the gadolinium-ligand complex releases the toxic unbound gadolinium ion that, in a subset of patients, triggers a cascade of events culminating in the histologic manifestations of NSF (5) (6) (7) . Newer GBCAs have relatively greater stability in their gadolinium-ligand bond compared with older GBCAs (8) and so are thought to carry markedly lower NSF risk (3) . Kidney impairment is an additional risk factor for NSF, probably because of the kidney's role in clearing most GBCAs, and almost all cases of NSF have occurred in patients with advanced kidney disease (5) . However, uncertainties remain about the relative safety of newer GBCAs compared with older agents, and the degree and chronicity of kidney dysfunction that portends NSF risk (2, 9) .

Uncertainties about NSF risk are reflected in the divergent positions of advisory boards, some of which recommend liberal use of the newer GBCAs, whereas others recommend against use of both older and newer GBCAs in patients with impaired kidney function (5, 10) . Thus, we sought to synthesize the evidence about the safety of newer versus older GBCAs across the spectrum of kidney function. Our review addressed 2 key questions. First, with exposure to newer GBCAs, what is the occurrence of NSF per index GBCA expo-sure among all patients, regardless of kidney function; patients with key risk factors for chronic kidney disease (CKD), such as diabetes and hypertension; and patients with any degree of kidney impairment, including acute kidney injury and CKD? Second, compared with older GBCAs, what is the occurrence of NSF per index GBCA exposure for newer GBCAs among all patients, regardless of kidney function; patients with key risk factors for CKD; and patients with any degree of kidney dysfunction?

This review was conducted as a project for the Veterans Affairs (VA) Evidence Synthesis Program. The original technical report is available at www.hsrd .research.va.gov/publications/esp. The protocol was registered a priori (PROSPERO: CRD42019135783), and each step was pilot tested to train and calibrate the study team.

We searched MEDLINE (PubMed), EMBASE (Elsevier), Cochrane Central Register of Controlled Trials (Wiley), and Web of Science (Clarivate) for Englishlanguage references from inception to 5 March 2020 by using a combination of database-specific subject headings and keywords related to NSF and gadolinium (Supplement Table 1 , available at Annals.org). We handsearched key references to identify citations not captured in the electronic database searches (5, 10 -27) .

Consistent with the classification system of the American College of Radiology (ACR) for GBCAs (Table  1) , we hereafter refer to newer GBCAs as ACR group II or III agents and older GBCAs as ACR group I agents (10) . We included studies that documented exposure to ACR group II or III GBCAs; assessed NSF occurrence after GBCA exposure; and had 1 of the following study designs: randomized controlled trials, cohort studies, case-control studies, case series, and case reports. We excluded studies that did not report the number of patients exposed to GBCAs; those not published in English; and, for longitudinal studies, those with a follow-up shorter than 2 weeks between GBCA exposure and occurrence of NSF cases (Supplement Table 2 , available at Annals.org).

We screened titles and abstracts initially by using DistillerAI (Evidence Partners), an artificial intelligence technology (28). Two authors (K.M.G. and J.L.) reviewed titles and abstracts of a subset of articles (n = 100) to train the DistillerAI program to perform study selection on the remaining titles and abstracts by using the eligibility criteria described earlier. The DistillerAI program identified eligible titles and abstracts by assigning a prediction score of relevance to the study questions, with citations scoring 0.5 and above automatically advancing to full-text screening. Human investigators reviewed articles with a prediction score below 0.5. At the full-text screening stage, authors dual-screened all fulltext articles for inclusion. Any disagreements between author pairs were resolved by joint review or by conferring with a third team member. Articles that met inclusion criteria underwent data abstraction and quality assessment.

One investigator abstracted relevant data from each study into a customized DistillerSR (Evidence Partners) database, and this information was verified by a second investigator. If disagreement about data abstraction arose between investigators, a third investigator provided a majority decision. Key elements for data abstraction were patient descriptors, GBCA exposure, comparator (if any), confirmed or suspected NSF cases, and source of funding. We defined NSF cases as "confounded" if evidence was clear that a patient had been exposed to several GBCAs before NSF developed.

Author pairs conducted quality assessment of each study, with arbitration by a third author whenever disagreements arose. We used the Cochrane Effective Practice and Organization of Care Risk of Bias (ROB) 

Tool to assess randomized, nonrandomized, and controlled before-after studies for quality (29) . For observational studies, we assessed quality by using an adapted version of the Newcastle-Ottawa scale (from the version modified by Guyatt and Busse [30] ). We then assigned a summary ROB score of low, unclear, or high to each study.

We summarized key characteristics of included studies (such as patient descriptors, GBCA exposure, and NSF outcome) overall and by ACR GBCA subgroup. Because of heterogeneity in methodology, patient population, and length of follow-up across included studies, quantitative data synthesis using metaanalytic techniques was not feasible. Instead, we reported NSF cases per index GBCA exposure from individual studies grouped by our key questions, and calculated an exact 95% CI around estimates by using the method described by Clopper and Pearson (31). We did not calculate 95% CIs for studies with a sample size less than 26 or those reporting NSF as a secondary outcome. Analyses were performed with the R statistical package, version 3.5.3 (R Foundation for Statistical Computing).

We followed the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of evidence of the collated data (32) . In brief, this assessment focused on 4 domains that might limit the certainty of evidence: ROB, consistency, directness, and precision. Additional domains, whenever applicable, included coherence, dose-response association, impact of plausible residual confounders, strength of association or magnitude of effect, and publication bias. Two authors (K.M.G. and A.M.G.) assigned a summary rating of high, moderate, low, or very low for the certainty of evidence in each study.

The U.S. Department of Veterans Affairs, which funded this review, was not involved in the design, conduct, or analysis of the study.

We identified 3084 studies through the primary literature search and 170 additional articles through hand-searches of relevant publications, totaling 3254 retrieved articles. After removing duplicates, 1269 articles remained. Of these, we identified 329 potentially eligible articles after screening titles and abstracts and retained 34 articles reporting on 32 studies after fulltext review ( Figure 1 ) (7, . Most of the studies were conducted in North America, Europe, or Asia. Supplement Table 3 (available at Annals.org) provides detailed study characteristics.

Twenty studies met inclusion criteria for key question 1. Nine were prospective cohort studies, 10 were retrospective cohort studies, and 1 was a nonrandomized trial. Most index GBCA exposures in the 19 cohort studies were to ACR group II agents; only 2 cohort studies reported exposures to the ACR group III agent gadoxetic acid (of note, 1 cohort study had exposures to gadobenate dimeglumine and gadoteridol). Five studies reported exposures to several gadolinium agents (35, 41, 45, 50, 53) , 12 reported exposures to the same agents (7, 36, 37, 43-47, 49, 50, 53, 54) , and 2 reported several exposures to unknown agents (42, 51) . Only 12 studies reported the approach to diagnosing NSF, which varied and included review of patient medical records (n = 4), clinical symptoms and examination of skin lesions or biopsy (n = 5), and the Girardi criteria (n = 3) (66) . Eight studies were postmarketing surveillance studies funded by GBCA manufacturers (33, 42, 44, 45, 47, 50, 51, 53) . The nonrandomized controlled trial enrolled patients with CKD stage 3 or 4; all patients in the exposure group received the ACR group II agent gadoterate meglumine. Follow-up for NSF incidence was 3 months, with the diagnostic approach for ascertaining NSF cases unclear (33) . Four studies featured all patients, regardless of kidney function; no studies included patients with CKD risk factors; and 15 included patients with CKD ( Table 2 ). 

Three of the 5 studies in this subgroup were prospective cohort studies that were phase 4 postmarketing surveillance studies funded by GBCA manufacturers (47, 51, 53) . Together, they comprised 3 of the 4 largest studies (n > 1000) for this key question. These 3 studies had a pooled patient population of 62 544, of whom only 1045 had an estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 . Among their 27 045 patients with index exposures to gadobutrol and 35 499 with index exposures to gadoterate meglumine, no cases of NSF occurred (upper limit of the exact 95% CI, 0.0001 to 0.0011 case) ( Figure 2 ). The other 2 studies reported no cases of NSF among 901 patients with chronic liver disease (39, 49) .

No studies specifically targeted patients with CKD risk factors, nor were CKD risk factors consistently assessed in studies that enrolled patients regardless of kidney function.

For this subgroup, we further divided studies into those that enrolled patients across the spectrum of CKD, those that enrolled patients with stage 3 to 5 CKD, and those that enrolled patients with end-stage renal disease (ESRD) or receiving dialysis. Overall, no cases of NSF were reported (upper limit of the exact CI, 0.0002 to 0.0258 case [0.0002 to 0.002 case in the largest study]).

Across the Spectrum of CKD. Three studies included patients with CKD of any stage. One study followed 15 377 patients with no CKD or CKD stage 1 to 5 for a mean of 6 years after exposure to gadoterate meglumine (54) . A second study followed 908 patients with CKD ranging from moderate to severe after index exposure to gadobutrol (45) . The third study was a prospective cohort trial conducted as a phase 4 observational study to evaluate NSF risk after gadoxetic acid exposure in 186 patients with moderate to severe CKD undergoing liver imaging (n = 186) (42) . No cases of NSF were reported in any of these 3 studies ( Figure 2 ). CKD Stages 3 to 5. Eight studies examined NSF risk after gadolinium exposure specifically in patients with CKD stage 3 to 5. Primary index exposures were to gadoteridol and gadobenate dimeglumine in 1 study, gadobenate dimeglumine only in 4 studies, gadoterate meglumine in 2 studies, and gadoxetic acid in 1 study. Nephrogenic systemic fibrosis was the primary outcome in 5 studies, with a pooled patient population of 2350 (35, 37, 41, 44, 50) , and a secondary outcome in the remaining 3 studies, with a combined population of 126 patients (33, 38, 43) . None of these studies reported any NSF cases (Figure 2) .

ESRD or Receiving Dialysis. Four studies investigated NSF risk in patients with ESRD (7, 36, 40, 46) . Across the 4 studies, no cases of NSF were reported among the 896 combined patients after exposure to the ACR group II agents gadoteridol (n = 141), gadobenate dimeglumine (n = 401), or gadoterate meglumine (n = 354) (Figure 2 ).

Among the cohort studies, ROB was high in 11 (58%) (7, 38, 40 -44, 47, 49 -51) and unclear in 8 (42%) (Supplement Figure, graphs A the nonrandomized prospective trial was high (Supplement Figure, graph C, available at Annals.org) (33) . Major factors contributing to high ROB were inadequate or unclear exposure characterization (such as not considering coexisting exposure to GBCAs outside that of the study), inadequate outcome identification (such as not using standard diagnostic criteria for NSF or limiting NSF assessment to a subpopulation of patients), and clinically significant rates of missing data. Table 3 summarizes the certainty of evidence for the occur- 

Twelve studies had data for key question 2. Of these, 1 was a nested case-control study and 11 were cohort studies (9 retrospective and 2 prospective) (34, [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] . The primary index exposure to ACR group I agents in the studies was to gadopentetate dimeglumine (n = 9) or gadodiamide (n = 8). Group II agents included gadoterate meglumine (n = 4), gadobutrol (n = 5), gadobenate dimeglumine (n = 6), gadofosveset trisodium (n = 1), gadoteridol (n = 2), and gadoversetamide (n = 1). Ten studies reported their approach for diagnosing NSF, which varied and consisted of review of patient medical records (n = 1), clinical symptoms and examination of skin or biopsy (n = 8), or use of Cowper criteria (67) (n = 1) (55-62, 64, 65) . Follow-up for ascertainment of NSF cases after index GBCA exposure ranged from 60 days to 15 years, with a median of 28 months ( Table 2) .

Across the 12 studies in this subsection, 8499 patients had an index exposure to ACR group II agents and 110 345 patients had an index exposure to ACR group I agents; no patient had an index exposure to the ACR group III agent gadoxetic acid. Thirty-seven NSF cases developed after index exposure to ACR group I agents (upper limit of exact CI, 0.001 to 0.0672 case [0.0001 to 0.0003 case for the 2 studies with n > 20 000 patients]), and 4 NSF cases occurred after index exposure to ACR group II agents (upper limit of exact CI, 0.0018 to 0.0204 case [0.0018 to 0.0026 case for the 3 studies with n > 1000 patients]).

Three retrospective cohort studies included patients in this subgroup (62, 64, 65) . Fourteen cases of NSF developed in 109 096 pooled patients with index exposures to ACR group I agents (upper limit of the exact CI, 0.0001 to 0.0120 case) and 1 NSF case occurred in 4321 pooled patients with index exposures to ACR group II agents (upper limit of the exact CI, 0.0018 to 0.0058 case). All 15 NSF cases occurred in patients with impaired kidney function at the time of GBCA exposure ( Figure 2 ).

No study assessed NSF risk in this subpopulation of patients.

Nine studies specifically included patients with CKD. Across 4 studies with at least 30 participants (total n = 1173), 14 cases of NSF occurred after index exposure to ACR group I agents (upper limit of the exact CI, 0.0065 to 0.067 case); no cases occurred across 5 studies (total n = 4152) with index exposures to ACR group II agents (upper limit of the exact CI, 0.0025 to 0.0204 case). Eight additional NSF cases developed after ACR group I exposure and 3 after ACR group II exposure in 2 studies in which NSF was a secondary outcome.

Across the Spectrum of CKD. Three studies-2 retrospective cohort and 1 case-control-included patients with CKD of any stage (34, 58, 60) . No NSF cases were reported in the cohort studies. However, in the case-control study, 7 NSF cases occurred after index exposure to ACR group I agents and 3 after index exposure to ACR group II agents ( Table 3) . § Includes 2 cohort studies and 1 nonrandomized controlled study that are not included in the upper-limit 95% CI ranges. ͉͉ All 10 cases were from 1 case-control study (34) and thus are not included in the upper-limit 95% CI ranges. ¶ Studies were excluded if they had a study population of <26. Only the upper 95% CI is shown where there is only 1 study in the category. ** One case of NSF was reported in a cohort study in which NSF was not a primary outcome, which is not included in the upper-limit 95% CI ranges.

CKD Stages 3 to 5. Two retrospective cohort studies reported GBCA exposures specifically among patients with CKD stage 3 to 5 (57, 59) . Six NSF cases developed among 246 patients with index exposure to ACR group I and no cases among 1423 patients exposed to ACR group II agents in 1 study (57) . In the second study, 1 NSF case occurred among 26 patients with index exposure to ACR group I agents; NSF did not develop in 1 patient with index exposure to ACR group II agents (59) .

ESRD or Receiving Dialysis. Four studies-2 prospective (55, 63) and 2 retrospective (56, 61)-included patients receiving dialysis. Across the studies, 9 NSF cases developed in 348 patients with index exposure to ACR group I agents and no cases developed in 1079 patients with index exposure to ACR group II agents.

Risk of bias was low in 1 study (59) , unclear in 4 studies (34, 55, 62, 63) , and high in 7 studies (Supplement Figure, graphs D to F, available at Annals.org) (56 -58, 60, 61, 64, 65) . Similar to key question 1, the most common methodologic issues that led to high ROB included inadequate or unclear exposure characterization (n = 5), inadequate outcome identification (n = 9), and higher rates of missing data (n = 7). See Table 3 for a summary of the certainty of evidence for the occurrence of NSF after exposure to ACR group II versus ACR group I GBCAs.

We reviewed 20 studies with patients who were exposed only to newer GBCAs (ACR groups II and III) and 12 studies that assessed the occurrence of NSF among patients after index exposure to newer GBCAs compared with older linear GBCAs (ACR group I). We found that NSF occurs very rarely after exposure to newer linear or macrocyclic GBCAs. However, the upper exact 95% CIs around NSF cases per index exposure to newer GBCAs (that is, ACR group II and III) are similar to those for older GBCAs (ACR group I): specifically, 0.0018 to 0.0204 case for newer versus 0.0001 to 0.0672 case for older GBCAs. In addition, data are relatively scarce for patients with CKD, those with acute kidney injury, those at risk for CKD, and those exposed to ACR group III agents, which limits conclusions about safety among these populations.

Our findings are generally consistent with 2 recent reviews of NSF risk after GBCA exposure that we retrieved from our database search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and Web of Science on 5 March 2020. The review by Woolen and colleagues (2019) (68) examined the risk for NSF among patients with stage 4 or 5 CKD after exposure to ACR group II GBCAs and found no cases of NSF among 4931 patients across 16 studies (upper exact CI, 0.07 case). Our analysis included all studies in that review, except for 2 that did not meet inclusion criteria. In addition, we included 14 studies that were not part of Woolen and colleagues' review. The other review, by Attari and colleagues (2019) (69), examined clinical features and risk factors of confirmed NSF cases in addition to comparing the incidence of NSF before and after 2008 (when the FDA issued the boxed warning). The authors derived the denominator for incidence rate calculations from assumptions about market share for GBCAs by ACR group and found an NSF rate of 1.52 cases per million exposures (CI, 1.37 to 1.68 cases) for ACR group I agents and 0.008 case (CI, 0.001 to 0.032 case) for ACR group II agents.

Our review builds on the recent reviews by Woolen and colleagues (68) and Attari and colleagues (69) in several ways. First, we prioritized studies that provided a specific denominator for patient exposure by GBCA and those that included a comparison with ACR group I GBCAs. A reliable exposure denominator and control group are critical for application of data to clinical decision making (70) . Second, we included patient populations across the spectrum of kidney function and specifically sought to identify data that would elucidate the risk for NSF among key patient subpopulations, such as those at risk for CKD and those with acute kidney injury. Establishing risk heterogeneity by clinical condition would support a more nuanced and patient-centered approach to radiologic imaging decisions. Examining the literature on subpopulation risk also allowed us to identify gaps in the evidence base, which may guide future NSF risk evaluation, especially as clinical practice evolves. Finally, our review included data across ACR group II and III agents. This inclusive approach found additional evidence gaps given the particularly limited data on ACR group III agents, which is probably a consequence of the restricted indications for their use (5) .

The evidence base reported in this review has a few limitations. First, most included studies were of a less rigorous, observational design. Second, assessment of gadolinium exposure was frequently incomplete because study authors did not account for GBCA exposures outside the health care settings evaluated. As a consequence, this exposure misclassification bias might have inflated estimations of NSF risk after gadolinium exposure by shrinking the exposure denominator for calculations of NSF risk. Third, many studies had substantial missing data, which is particularly relevant in situations of a rare adverse event and which may have led to underreporting of NSF cases. Fourth, a potential for conflict of interest was present, because many of the larger, single-agent observational studies included in this review were conducted by the GBCA manufacturers (42, 45, 47, 50, 51, 53) . In fact, most of these studies were conducted in response to an FDA mandate for postmarketing surveillance and were powered on the basis of expected incidence rates that turned out to be greater than observed. Underpowering was complicated further by the FDA's removal of the postmarketing surveillance requirement in the midst of some study periods, and recruitment subsequently was stopped early. Finally, notable heterogeneity existed in patient populations, methodology, and timeframe, which drove our decision not to conduct meta-analyses or calculate risk ratios. Despite these study-level differences, our findings were consistent across included studies, with no or very few cases of NSF reported.

Despite this review's rigorous design, our approach has some potential limitations. To be specific, this work is not a comprehensive review of all potential Risk for Nephrogenic Systemic Fibrosis After Exposure to Gadolinium Agents REVIEW Annals.org Annals of Internal Medicine harms associated with gadolinium exposure. Awareness and concern are growing about the long-term deposition of gadolinium in brain and other tissues among patients with normal kidney function (1, 3) . In addition, we focused our review on higher-order evidence that could provide risk calculations. However, in doing so, we may have excluded studies that reported information about NSF cases potentially linked to gadolinium exposure, but those from which we could not identify a clear numerator or denominator. We attempted to mitigate methodologic limitations by using an a priori publicly registered protocol, conducting a comprehensive literature search, and performing a thorough quality assessment.

In conclusion, the occurrence of NSF after exposure to newer linear or macrocyclic GBCAs was very rare. Limited evidence suggests that additional studies in patient populations with mild kidney disease would substantially change these conclusions. However, considering the scarcity of data about the use of newer and seemingly safer GBCAs among patients with advanced CKD, CKD risk factors, or acute kidney injury, further investigations in these populations are warranted and will require particular attention to comprehensive exposure and outcome assessment (such as documentation of all GBCA exposures and use of standardized diagnostic criteria for NSF). Meanwhile, caution in the use of GBCAs in patients with severely impaired kidney function and acute kidney injury remains prudent, because the exact clinical factors contributing to NSF risk in these subpopulations are still unknown. 

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Provision of study materials or patients: S. Cantrell, B. Ear. Statistical expertise: A.S. Kosinski. Obtaining of funding