Weekly Articles 8/1/2021

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Tons on COVID and a few interesting HIV articles.

Vafa Bayat, Russell Ryono, Steven Phelps, Eugene Geis, Farshid Sedghi, Payam Etminani, Mark Holodniy, Reduced Mortality With Ondansetron Use in SARS-CoV-2-Infected Inpatients, Open Forum Infectious Diseases, Volume 8, Issue 7, July 2021, ofab336, https://doi.org/10.1093/ofid/ofab336

Does zofran help with COVID-19 mortality? Maybe. This was a retrospective cohort study of VA patients who were hospitalized with COVID. Primary outcome was 30 day mortality, which was evaluated using cox proportional hazards model. 10741 patients were included, and were divided into 3 groups: one without zofran, one with up to 8mg of zofran, and the last with >8mg of zofran given in the first 48hrs post diagnosis. Patients who were given zofran were much younger, and less likely to have underlying respiratory comorbidities of hypertension. All cause mortality was lower in both zofran group (13.5% for group 2 and 10.6% for group 3 vs 17.5% for group 1, p=0.005 and <0.001). This was true for ICU and non-ICU patients (for group 3 vs group 1 15.0% vs 26.8%, p=0.26):

After controlling for variables like age, gender, cancer history, history of diabetes, comorbidities, and therapy with remdesivir or steroids, 30-day mortality was still lower for both zofran groups:

As you can see, overall zofran seems to have a mortality benefit when given at doses greater than 8mg. Further, older patients tend to have greatest benefit, and comorbidities do not seem to play a major role as confounders. The authors also analyzed mortality associated with metoclopramide, and found an elevated 30-day mortality (HR 1.74 95% CI 1.45-2.08). While these results seem promising, the overall imbalance between groups (i.e. I assume that those who had more CV history were less likely to receive zofran due to QTc prolongation concerns) and lack of standardization make me a bit weary about applying this as a COVID therapy. Either way, it does not harm COVID patients so that is something. 

Thompson MG, Burgess JL, Naleway AL, Tyner H, Yoon SK, Meece J, Olsho LEW, Caban-Martinez AJ, Fowlkes AL, Lutrick K, Groom HC, Dunnigan K, Odean MJ, Hegmann K, Stefanski E, Edwards LJ, Schaefer-Solle N, Grant L, Ellingson K, Kuntz JL, Zunie T, Thiese MS, Ivacic L, Wesley MG, Mayo Lamberte J, Sun X, Smith ME, Phillips AL, Groover KD, Yoo YM, Gerald J, Brown RT, Herring MK, Joseph G, Beitel S, Morrill TC, Mak J, Rivers P, Poe BP, Lynch B, Zhou Y, Zhang J, Kelleher A, Li Y, Dickerson M, Hanson E, Guenther K, Tong S, Bateman A, Reisdorf E, Barnes J, Azziz-Baumgartner E, Hunt DR, Arvay ML, Kutty P, Fry AM, Gaglani M. Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines. N Engl J Med. 2021 Jul 22;385(4):320-329. doi: 10.1056/NEJMoa2107058. Epub 2021 Jun 30. PMID: 34192428; PMCID: PMC8262622.

This was a prospective cohort study of healthcare workers vaccinated with either the Moderna or Pfizer vaccines and their impact in preventing COVID infection with partial or full vaccination, mean RNA load, and frequency of febrile illness duration. Primary outcome was time to RT-PCR positivity in vaccinated vs unvaccinated participants (both partially and fully vaccinated individuals were compared within the same group). 3975 patients were included, of which 80% had received at least one dose of the vaccine and 84% of those had both. 204 participants (5%) were infected, of which 5 were fully vaccinated, 11 were partially vaccinated, and 156 were unvaccinated. Vaccine effectiveness is summarized in the table below:

Overall adjusted efficacy of the vaccine in partially vaccinated individuals was 81% and 91% for those who were fully vaccinated. The Pfizer vaccine seemed to do better when compared to the Moderna vaccine (94% vs 84% for fully vaccinated individuals) but did about the same in partially vaccinated folks. Viral load, duration of viral shedding, and sick days were significantly lower in the vaccine group, regardless of partial or full vaccination:

This is, again, encouraging news for the vaccine and hopefully more people are willing to take it going forward. 

Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, Stowe J, Tessier E, Groves N, Dabrera G, Myers R, Campbell CNJ, Amirthalingam G, Edmunds M, Zambon M, Brown KE, Hopkins S, Chand M, Ramsay M. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021 Jul 21:NEJMoa2108891. doi: 10.1056/NEJMoa2108891. Epub ahead of print. PMID: 34289274; PMCID: PMC8314739.

This was an English study evaluating the effectiveness of the Pfizer vaccine and the AstraZeneca vaccine against the Delta (B.1.617.2) variant. The authors used a test negative case-control design to estimate the vaccine effectiveness against symptomatic disease caused by the delta variant as compared with the alpha variant. Vaccine effectiveness was measured 21 days after the first dose and 14 days after the second dose. 19109 sequenced cases were evaluated, of which 14837 were linked to the alpha variant and 4272 were linked to the delta variant. Vaccine effectiveness for any vaccine against the delta variant was lower than against the alpha variant:

Further, the Pfizer vaccine seems to perform better than the AstraZeneca one. They were unable to perform an analysis of effectiveness against severe disease or death, which I think are also important outcomes. Regardless, the effectiveness remains reasonable, and the lack of severe disease requiring hospitalization seen in other retrospective studies seems to suggest there is a benefit of the vaccine against the delta variant. We would have to wait and see for further data to come out. 

Liu Y, Liu J, Xia H, Zhang X, Zou J, Fontes-Garfias CR, Weaver SC, Swanson KA, Cai H, Sarkar R, Chen W, Cutler M, Cooper D, Muik A, Sahin U, Jansen KU, Xie X, Dormitzer PR, Shi PY. BNT162b2-Elicited Neutralization against New SARS-CoV-2 Spike Variants. N Engl J Med. 2021 Jul 29;385(5):472-474. doi: 10.1056/NEJMc2106083. Epub 2021 May 12. PMID: 33979486; PMCID: PMC8133696.

This is more of a basic science paper. Here, the authors engineered the complete S genes of the variant virus and evaluated serum from 15 patients who had received the Pfizer vaccine to measure neutralization activity. Three recombinant viruses were evaluated using 50% plaque reduction neutralization. In looking at the figure, the neutralization of the USA-WA 1/2020 (wild type) was similar to that of the 3 variants tested: 

Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, Mandelboim M, Gal Levin E, Rubin C, Indenbaum V, Tal I, Zavitan M, Zuckerman N, Bar-Chaim A, Kreiss Y, Regev-Yochay G. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med. 2021 Jul 28. doi: 10.1056/NEJMoa2109072. Epub ahead of print. PMID: 34320281.

This was a retrospective cohort study on healthcare workers who got 2 doses of the Pfizer vaccine evaluating vaccine effectiveness. The goal was to identify any and every breakthrough infection, including asymptomatic infections. Breakthrough infections were then matched with four or five uninfected controls to evaluate correlates of breakthrough infection. 11453 healthcare workers were fully vaccinated, of which 1497 underwent RT-PCR testing. 39 had breakthrough cases. 26 of these had mild symptoms, but none required hospitalization. Peri-infection neutralizing antibodies were available in 22 cases and these were matched with 104 controls. The peri-infection neutralizing antibody GMT was higher in the controls than in cases (530.4 vs 193). Peri-infection anti-S IgG was also higher in controls, with peak neutralizing antibodies reaching a GMT of 1028 vs 152.2 in cases.

Not surprisingly, lower neutralizing antibodies is correlated with higher occurrences of breakthrough infection, but reassuringly, none of the breakthrough infections were severe enough to warrant hospitalization. 

Caricchio R, Abbate A, Gordeev I, Meng J, Hsue PY, Neogi T, Arduino R, Fomina D, Bogdanov R, Stepanenko T, Ruiz-Seco P, Gónzalez-García A, Chen Y, Li Y, Whelan S, Noviello S; CAN-COVID Investigators. Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Jul 20;326(3):230-239. doi: 10.1001/jama.2021.9508. PMID: 34283183.

This is a randomized, double-blind, placebo controlled phase 3 trial evaluating the anti-IL-1 beta canakinumab. Patients with severe COVID-19 were randomized in a 1:1 ratio to either one dose of canakinumab or placebo. Those who were requiring mechanical ventilation were excluded. Doses were 450mg for those <60kg, 600mg for 60-80kg, and 750 for >80kg. Patients were allowed to use steroids, convalescent plasma, or other antivirals. Primary endpoint was the proportion of patients who survived without requiring mechanical ventilation from day 3 to day 29. The use of other immunomodulators was prohibited. 477 patients were randomized, and both groups were fairly well balanced. A higher number of patients in the canakinumab group received dexamethasone (41% vs 32%), while a higher number of patients in the placebo group received tocilizumab. Primary endpoint was 88.8% in the canakinumab group vs 85.7% in the placebo group (rate difference 3.1%, 95% CI -3.1 to 9.3; OR 1.39, 95% CI 0.76 to 2.54):

COVID related deaths was lower in the canakinumab group, but this did not reach statistical significance (rate difference -2.3, 95% CI -6.7 to 2.2, OR 0.67, 95% CI 0.3 to 1.5). Adding the use of anakinra or tocilizumab to the composite primary outcome, canakinumab had better outcomes:

By day 29, a lower proportion of patients in the canakinumab use required non-invasive mechanical ventilation, high flow oxygen, or mechanical ventilation compared to the placebo group:

While there was a trend towards improvement with canakinumab, I am not surprised the results were not statistically significant. Perhaps just inhibiting one component of the inflammatory cascade is not enough in cases of severe covid, hence these results. 

Kabir S, Rahman SMM, Ahmed S, Islam MS, Banu RS, Shewade HD, Thekkur P, Anwar S, Banu NA, Nasrin R, Uddin MKM, Choudhury S, Ahmed S, Paul KK, Khatun R, Chisti MJ, Banu S. Xpert Ultra Assay on Stool to Diagnose Pulmonary Tuberculosis in Children. Clin Infect Dis. 2021 Jul 15;73(2):226-234. doi: 10.1093/cid/ciaa583. PMID: 32421765.

I do not typically talk about pediatrics but I found this to be interesting nonetheless. This paper evaluated the utility of the Xpert Ultra on stool to diagnose pulmonary tuberculosis in children. Xpert Ultra has a lower LOD for TB compared to the Xpert. Children from 4 tertiary care hospitals in Bangladesh who had presumptive pulmonary TB were enrolled. Induced sputum and stool specimens were cultured and had both Xpert and Xpert Ultra performed. Pulmonary TB was diagnosed if there was TB detected on induced sputum or stool specimen. Bacteriologically confirmed TB was defined as positivity of any test on either stool or sputum specimen. 454 children were enrolled. Stool specimens were positive by culture in 2 cases, positive by Xpert in 11, and by Xpert ultra in 60. 13.4% of cases were diagnosed by stool Xpert Ultra, of which 49 were exclusively detected in this manner. When using bacteriologically confirmed TB on induced sputum as the standard, Xpert Ultra had a higher sensitivity than the Xpert, though at the cost of specificity. When using trace call as negative (i.e. lowest bacillary burden) the sensitivity decreases:

On confirmed sputum culture, the sensitivity for both assays increased which  is not surprising as MTB-PCR tends to increase in sensitivity with higher bacillary loads:

I think this is an interesting study, and while it applies mostly to children (who tend to swallow their sputum), there may be some utility in adults. Though I would assume the bacillary load would be lower in stool, limiting the utility of an Xpert assay. 

Le Maréchal M, Mailles A, Seigneurin A, Tattevin P, Stahl JP, Épaulard O. A Prospective Cohort Study to Identify Clinical, Biological, and Imaging Features That Predict the Etiology of Acute Encephalitis. Clin Infect Dis. 2021 Jul 15;73(2):264-270. doi: 10.1093/cid/ciaa598. PMID: 32433723.

This was a French cohort study evaluating patterns of patients presenting with acute encephalitis and attempting to see what type of pattern would be predictive of VZV and HSV encephalitis. 349 patients were included, with 25% being diagnosed with HSV and 11% with VZV. 34% had no etiology. Patients with viral encephalitis were older (65 vs 57) and were more likely to have supratentorial dysfunction (95% vs 87%), however rates of fever, CSF parameters, and lab values were overall similar between groups. CSF Lymphocytes were higher in the viral encephalitis group (80% vs 65%) and neutrophils were lower (12% vs 28%). Viral encephalitis patients were more likely to have hemorrhage (14.2% vs 2.3%, adjusted OR 11.85, 95% CI 2.69 to 52.29) and were more likely to have temporal lobe signal on imaging (AOR 18.62, 95% CI 5.85 to 59). So here, there was no real pattern that arose, however older patients, and CSF showing higher lymphocytes and temporal lobe signal were predictive of viral encephalitis. This was, of course, something we already knew. 

Atkinson A, Zwahlen M, Barger D, d’Arminio Monforte A, De Wit S, Ghosn J, Girardi E, Svedhem V, Morlat P, Mussini C, Noguera-Julian A, Stephan C, Touloumi G, Kirk O, Mocroft A, Reiss P, Miro JM, Carpenter JR, Furrer H; Opportunistic Infections Project Working Group of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE. Clin Infect Dis. 2021 Jul 15;73(2):195-202. doi: 10.1093/cid/ciaa615. PMID: 32448894.

This study sought to investigate if PJP prophylaxis could be withheld in patients who were virally suppressed, regardless of their CD4 status.The authors emulated a pragmatic, RCT using observational data and attempted to replicate a 2-arm, open label study comparing 2 strategies to starting and stopping PJP prophylaxis:

  1. Continue PJP prophylaxis if CD4 <200 and stop if their CD4 >200 for at least 3 months. 
  2. Stop PJP prophylaxis if Viral load is <400 for at least 2 consecutive measurements. Resume if >400. 

Patients were followed until they were diagnosed with PJP, died, had adverse events, dropped out, or were followed up to 5 years. The authors replicated all patients so that at time 0, each patient was on both arms (as they were eligible to be on both strategies). Patients were artificially censored if they did not comply with the stopping rules and the HR was used to compare stopping strategies by fitting a pooled logistic model, including IPW. 4813 patients were evaluated, with 52 PJP diagnosis. Follow up time was similar for both strategies (10,324 person years vs 10324 person years). After adjusting for baseline factors and fitting the pooled logistic regression model, HR for the first 5 years of follow up was 0.8 (95% CI 0.6 to 1.1). After adjusting for postbaseline ART adherence, aHR was 0.9 (95% CI 0.6 to 1.3):

Absolute risk difference between the two strategies at 5 years was 0 (95% CI -0.01 to 0.01). This suggests that stopping PJP prophylaxis after achieving viral suppression is as effective as stopping it after a CD4 of 200. Of course, there are limitations with using observational data and attempting to emulate a trial, but I think this adds to the idea that PJP prophylaxis can be safely stopped if there is viral suppression. 

Parienti JJ, Fournier AL, Cotte L, Schneider MP, Etienne M, Unal G, Perré P, Dutheil JJ, Morilland-Lecoq E, Chaillot F, Bangsberg DR, Gagneux-Brunon A, Prazuck T, Cavassini M, Verdon R, Hocqueloux L. Forgiveness of Dolutegravir-Based Triple Therapy Compared With Older Antiretroviral Regimens: A Prospective Multicenter Cohort of Adherence Patterns and HIV-RNA Replication. Open Forum Infect Dis. 2021 Jul 1;8(7):ofab316. doi: 10.1093/ofid/ofab316. PMID: 34307726; PMCID: PMC8297697.

This was a multicenter prospective cohort study that evaluated the use of DTG-based regimen and sought to investigate if low to moderate adherence would allow for high rate of virological suppression (i.e. if someone on DTG-based therapy could afford to be non-adherent and still achieve suppression.  Three different groups were identified: those who started on DTG-therapy, those who failed another therapy and then switched to DTG-therapy, and those who were switched from a prior regimen to DTG-therapy not due to failure. DTG was combined with ABC/3TC for the regimen in most instances. Electronic drug monitoring devices were used to evaluate the number of electronic pill cap opening events and to evaluate treatment interruption. Primary outcome was HIV viral load at 6 months. 399 patients were evaluated, 102 were on DTG, 90 on RAL, 107 were on boosted-PI, and 100 were on NNRTI based regimens. Patients on the DTG-group had higher treatment interruptions, tended to be older, and were more likely to have been switched to it due to failed therapy. Multivariate analysis found that therapy with raltegravir, low adherence, and having had prior failed therapy were associated with viral load >50 at 6 months:

Indeed, 8 patients had failure of viral suppression in the DTG group, compared to 18 in the RAL group, 12 in the NNRTI group, and 26 in the boosted-PI group. No mutations were detected in the DTG group, while 4 were detected in the RAL group.  In looking at surface forgiveness plot and linear regression models of adherence patterns, the plot for DTG was flat, suggesting that adherence was not as associated with failed viral suppression when compared to raltegravir (you can see that adherence of ~65% was associated with ~2.67 log10 copies with minimal treatment interruption):

Risk of virological detection was independently associated with other third-drugs when compared to Dolutegravir:

I have written about the favorability of DTG to raltegravir, and this seems to suggest that it is more “forgiving” when it comes to adherence. Hence, another reason to continue to pursue DTG or even BIC as first line therapy. 

Fabienne Caby, Marguerite Guiguet, Laurence Weiss, Alan Winston, Jose M Miro, Deborah Konopnicki, Vincent Le Moing, Fabrice Bonnet, Peter Reiss, Cristina Mussini, Isabelle Poizot-Martin, Ninon Taylor, Athanasios Skoutelis, Laurence Meyer, Cécile Goujard, Barbara Bartmeyer, Christoph Boesecke, Andrea Antinori, Eugenia Quiros-Roldan, Linda Wittkop, Casper Frederiksen, Antonella Castagna, Maria Christine Thurnheer, Veronica Svedhem, Sophie Jose, Dominique Costagliola, Murielle Mary-Krause, Sophie Grabar, (CD4/CD8 ratio and cancer risk) project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord, CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies, Clinical Infectious Diseases, Volume 73, Issue 1, 1 July 2021, Pages 50–59, https://doi.org/10.1093/cid/ciaa1137

This cohort study evaluated the impact of CD4/CD8 ratio restoration on the risk of Kaposi sarcoma and Non-Hodgkin’s lymphoma in people living with HIV. The idea here is that a low CD4/CD8 ratio (i.e. low CD4 and high CD8) are associated with T-cell activation, exhaustion, increased innate immune activation, and senescence. Patients who had achieved virological control within 9 months were eligible. Baseline was the CD4/CD8 ratio within 6 months after virological control, and then every 6 months for the first 3 years and every 12 months afterward. 56708 PLHW were included, with the median ratio being 0.43 and only 8% of the population having a CD4/CD8 ratio >1. The cumulative incidence of CD4/CD8 ratio restoration >1 was 28% in the first 2 years, and 45% at 5 years. 221 KS cases and 187 NHL cases were diagnosed after baseline (incidence rate 72,100,000 person years for KS and 61/100,000 person years for NHL). Using 3 models (1: adjusted for CD4/CD8 ratio, 2: adjusted for CD4 and CD8 independently, 3: adjusted for all 3), KS was associated with low ratio and low CD4/high CD8 independently by all 3 models:

The lower CD4 and higher the CD8, the stronger the association, which was gone by the time CD4 was 500. CD4 restoration was associated with decreased KS risk (HR 1.57 with CD4 350). In looking at the figure below, there was a strong inverse correlation between the risk of KS and ratio restoration:

For NHL, the ratio was not predictive of risk, however NHL risk was associated with high absolute CD8 count (HR 1.61 for CD 2000 up to 3.14 for CD8 3000 compared to CD8 of 1000). This was seen with CD4 >500, where higher CD8 count from baseline was associated with higher risk for NHL:

I think this suggests that HIV does something to the immunology of a person that is independent of the suppression of CD4. I still do not understand the increased susceptibility of some OIs in HIV/AIDS compared to transplant patients, as these seem to be very different (i.e high risk for HSCT for aspergillus or SOT in CMV, but toxo and MAC seem to be more prevalent in HIV patients). There are still a lot of things I do not understand with regards to HIV from an immunological point of view, but I think this can allow one to predict the risk of KS and NHL going forward.

Iroh Tam P, Arnold SLM, Barrett LK, Chen CR, Conrad TM, Douglas E, Gordon MA, Hebert D, Henrion M, Hermann D, Hollingsworth B, Houpt E, Jere KC, Lindblad R, Love MS, Makhaza L, McNamara CW, Nedi W, Nyirenda J, Operario DJ, Phulusa J, Quinnan GV, Sawyer LA, Thole H, Toto N, Winter A, Van Voorhis WC. Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial. Clin Infect Dis. 2021 Jul 15;73(2):183-191. doi: 10.1093/cid/ciaa421. PMID: 32277809; PMCID: PMC8282326.

What does one use for cryptosporidium diarrhea in PLWH? Nitazoxanide, but I do not find that it works that well. This is a single center, randomized, double-blind, placebo controlled study evaluating the use of clofazimine for cryptosporidium diarrhea. Patients were randomized in a 1:1 fashion to either CFZ (100mg TID if >50kg or 50mg TID if <50kg) or placebo for 5 days. Primary endpoint was efficacy in the reduction in the log number of Cryptosporidium shed in the first collected stool of each study day. 22 patients were randomized, though notably patients in the CFZ group had lower BMI, lower SBP, lower lymphocytes, and had shorter duration of diarrhea when compared to the placebo group. Coinfection with other pathogens was also prevalent, with most of them being infected with E. coli. Further, more patients in the Clofazaimnie group had higher mean number of pathogens, 8 vs 3. In the ITT and per protocol population, there was no difference in shedding between groups:

There was a trend towards increased change from baseline in Cryptosporidium shedding in the CFZ-treated group (2.17 log10) and in total crypto shedding (1.02 log10). Further, more patients in the CFZ group had AE such as diarrhea (75% vs 40%), abdominal pain  (67% VS &)%) and malaise (50% vs 30%). So it seems clofazimine does not seem to work, however there was a significant imbalance between groups and this, along with the small number of patients, makes the results difficult to interpret. A larger RCT may potentially be more suitable to answer this question. 

Camara M, Soumah AM, Ilboudo H, Travaillé C, Clucas C, Cooper A, Kuispond Swar NR, Camara O, Sadissou I, Calvo Alvarez E, Crouzols A, Bart JM, Jamonneau V, Camara M, MacLeod A, Bucheton B, Rotureau B. Extravascular Dermal Trypanosomes in Suspected and Confirmed Cases of gambiense Human African Trypanosomiasis. Clin Infect Dis. 2021 Jul 1;73(1):12-20. doi: 10.1093/cid/ciaa897. PMID: 32638003; PMCID: PMC8246823.

Here is one disease I do not talk about. African sleeping sickness. This disease is caused by T. brucei and diagnosis requires the microscopic evaluation of blood, lymph, or CSF to see extracellular trypanosomes and to confirm serology. Many times, however, extra-vascular parasites can exist in the skin. Therefore, there can exist situations where the blood is negative for parasites, but these are hanging out in the skin. This was a prospective observational study evaluating 5417 subjects who were serologically screened for gambiense human African trypanosomiasis (gHAT). 66 of these were included and underwent biopsy of the skin, which then underwent H&E staining as well as anti-ISG65 immunolabeling and anti-Hsp70. PCR was also performed on the biopsy specimens. 40 served as seronegative controls, 8 were unconfirmed seropositive (+ serology but no parasites on blood) and 18 were confirmed seropositive. Pruritus, dermatitis, asthenia, fever, and weight loss were more common in those who were seropositive or seropositive confirmed. When looking at skin biopsies, all 11/11 seronegative controls did not test positive, however all unconfirmed seropositive patients and confirmed seropositive were found to be positive for at least one T. brucei-specific anti-IGS65 antibody. They were also found to be positive with Giemsa staining, H&E staining, or labeling with anti-HSP70 antibody. 

PCR was negative in 11/11 seronegative controls for both blood and skin, however 18/18 of the confirmed seropositives tested positive by PCR in blood and 14/18 skin samples were positive by PCR. Further, PCR was positive in 6/8 patients with unconfirmed seropositive skin samples but all blood samples in this group were negative. At 20 months, the proportion of positive skin biopsies decreased overtime. This suggests that skin is a potential reservoir for parasites and a positive serological result in light of negative blood confirmation, the next step would be skin biopsy. 

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