Weekly Articles 5/9/2021

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Some interesting articles this time around. 

This is a pair of articles that came out in the recent Lancet ID issue and deals with the use of antiseptic mouthwash and its role in preventing STIs. 

Chow EPF, Williamson DA, Hocking JS, Law MG, Maddaford K, Bradshaw CS, McNulty A, Templeton DJ, Moore R, Murray GL, Danielewski JA, Wigan R, Chen MY, Guy RJ, Zhang L, Donovan B, Grulich AE, Kaldor JM, Whiley DM, Cornelisse VJ, Howden BP, Lewis DA, Read TRH, Fairley CK. Antiseptic mouthwash for gonorrhoea prevention (OMEGA): a randomised, double-blind, parallel-group, multicentre trial. Lancet Infect Dis. 2021 May;21(5):647-656. doi: 10.1016/S1473-3099(20)30704-0. Epub 2021 Mar 4. PMID: 33676595.

This was a randomized, double-blind, multi-center trial done over 12 weeks comparing the detection of oropharyngeal gonorrhea in MSM patients using either a Listerine mouthwash (which in-vitro, inhibited the growth of gonorrhea) and Biotene. Patients were randomized in a 1:1 fashion to either Listerine or Biotene, with primary end-point being the proportion of MSM patients diagnosed with oropharyngeal gonorrhea via NAAT. Patients were instructed to use the mouthwash once per day. 530 patients were randomized, with both groups being fairly well balanced. At 12 weeks, there was no statistical difference in the rate of gonorrhea detection in the oropharynx between groups (4% in the Biotene group vs 7% in the Listerine group, adjusted risk difference 3.1%, 95% CI -1.4 to 7.7):

Notably, there was less adherence in the Listerine group compared to the biotene group (46% vs 70%). There were no difference between groups in the development of anorectal gonorrhea, but those in the Listerine group were less likely to develop urethral gonorrhea (aRD -4.3%, 95% CI -7.4 to -1.3).

Van Dijck C, Tsoumanis A, Rotsaert A, Vuylsteke B, Van den Bossche D, Paeleman E, De Baetselier I, Brosius I, Laumen J, Buyze J, Wouters K, Lynen L, Van Esbroeck M, Herssens N, Abdellati S, Declercq S, Reyniers T, Van Herrewege Y, Florence E, Kenyon C. Antibacterial mouthwash to prevent sexually transmitted infections in men who have sex with men taking HIV pre-exposure prophylaxis (PReGo): a randomised, placebo-controlled, crossover trial. Lancet Infect Dis. 2021 May;21(5):657-667. doi: 10.1016/S1473-3099(20)30778-7. Epub 2021 Mar 4. PMID: 33676596.

A similar trial, this time  comparing Listerine with placebo in a MSM population using PrEP for HIV. This was a randomized, double-blind, placebo controlled cross-over trial (so one group started in the Listerine and at 3 months, switched to placebo, and vice-versa) assessing superiority of Listerine in preventing any bacterial STI (including gonorrhea, chlamydia, and syphilis). Patients were randomized in a 1:1 fashion to Listerine then placebo, or placebo then Listerine. Notably here, the participants were encouraged to not only use it once per day, but once before and then after any sexual encounters. They were also encouraged to ask their partners to use the mouthwash. Primary outcome was the combined incidence of all diagnosis of syphilis, gonorrhea, or chlamydia during the study period. Because this trial took place in the middle of the Pandemic, recruitment was halted and the trial was stopped as it was unethical to encourage mouthwash use during sexual activity (esp during quarantine). Despite this, the authors were able to recruit enough patients based on their power calculation. 343 patients were enrolled, with the rate of STI between groups being similar in both the Listerine and placebo periods:

Adherence to either mouthwash hoovered around 70% across the board with no significant adverse events reported. 

While the in-vitro data was encouraging, it seemed this effect was not as pronounced in vivo. Furthermore, it seemed Biotene may have some anti-microbial properties that were not accounted for prior to the first study. While adherence and appropriate duration of the use of antiseptic may be valid criticism here, if there was indeed an effect there would have been one seen across the two trials. There is also the concern about the potential for mouthwashes to harm the mucosa of the oropharynx, leading to a “depletion of the good bacteria” and “overgrowth of the bad bacteria” which would be suggestive of the increase in STI seen during the Listerine arm of the second trial. Just use condoms.

Polish LB, Pritt B, Barth TFE, Gottstein B, O’Connell EM, Gibson PC. First European Haplotype of Echinococcus multilocularis Identified in the United States: An Emerging Disease? Clin Infect Dis. 2021 Apr 8;72(7):1117-1123. doi: 10.1093/cid/ciaa245. PMID: 32198510; PMCID: PMC8028098.

A cool case report of Echinococcus multilocularis. Echinococcus granulosus is the more commonly one seen in the US. Here, a 36yo lady with history of Graves presented for follow up, where she was found to have elevated AST (45) and alk phos (357). A RUQ sonogram was done which revealed a 10cm heterogeneous area in the right lobe of the liver, and MRI subsequently a hepatic mass in both lobes of the liver with partial obstruction of the portal vein and dilated left upper quadrant veins. She was also found to have a left lung base mass of around 3x3x3cm. Biopsy of the mass revealed necrotic debris with surrounding fibroid wall with adjacent normal liver parenchyma. Lymphs, granulomas, and plasma cells were seen. Infectious work-up was positive for a Toxo IgG and Echinococcus IgG that were positive. Immunodiagnosis revealed the diagnosis of Echinococcus and gene sequencing revealed this was the first case of an european haplotype E. multilocularis seen in the US since 1977. She didn’t really have many risk factors; she had a healthy dog at home and has traveled to Costa Rica, Rome, and Montreal, but used to hunt foxes as a teenager.

Abate G, Stapleton JT, Rouphael N, Creech B, Stout JE, El Sahly HM, Jackson L, Leyva FJ, Tomashek KM, Tibbals M, Watson N, Miller A, Charbek E, Siegner J, Sokol-Anderson M, Nayak R, Dahlberg G, Winokur P, Alaaeddine G, Beydoun N, Sokolow K, Kown NP, Phillips S, Baker AW, Turner N, Walter E, Guy E, Frey S. Variability in the Management of Adults With Pulmonary Nontuberculous Mycobacterial Disease. Clin Infect Dis. 2021 Apr 8;72(7):1127-1137. doi: 10.1093/cid/ciaa252. PMID: 32198521; PMCID: PMC8028102.

This is a multicenter, epidemiological study that sought to determine the risk factors for pulmonary NTM and variability in management. 297 patients with negative HIV diagnosis were evaluated. The most commonly diagnosed NTM was MAC (247), followed by M, kansasii (23), and M. abscessus (12). The most common symptom was cough (86%), followed by dyspnea (51%). Those with cough were more likely to have a productive cough (65%). Most patients were likely to have multiple nodules, followed by multifocal bronchiectasis, and tree-in-bud opacities:

Interestingly, only 13% of patients were diagnosed with NTM after 2 or more sputum cultures were obtained. 40% were diagnosed with only one sputum culture, which is in contrast to the IDSA/ATS guidelines. While most patients (85%) received >3 drugs, only 33% of the studied population had therapy that adhered to the IDSA/ATS guidelines. Mortality overall was 16%. Adherence to treatment guidelines was associated with higher likelihood of microbiological cure (OR 4.58, 95% CI 2.0 to 10.4). In evaluating HIV-negative patients with MAC, adherence to guidelines was not associated with improved mortality, though female gender and tree-in-bud opacities were: 

This is a bit of a mess. While pulmonary NTM is quite rare (and colonizes several surfaces we interact with daily), it is even more difficult to accurately diagnose. While the results of therapy were not great overall, it begs to differ if all of those patients who were managed truly did have NTM and not something else (most likely). While difficult, it is reassuring that adhering to guidelines of a difficult disease to manage led to better outcomes, though the road for cure in these patients is a difficult one, as nearly 60% of patients had some sort of drug adverse event during their course of treatment (which had a mean duration of ~14 months). 

Murray DD, Zaunders J, Milliken ST, Mee Ling Munier C, Ford C, Orla Morrissey C, Visweswaran M, Avery S, Sasadeusz J, Kwan J, Desai S, Law M, Koelsch KK, Lewin SR, Moore J, Kelleher AD, Polizzotto MN. Altered Immune Reconstitution in Allogeneic Stem Cell Transplant Recipients With Human Immunodeficiency Virus (HIV). Clin Infect Dis. 2021 Apr 8;72(7):1141-1146. doi: 10.1093/cid/ciaa748. PMID: 32520987; PMCID: PMC8028103.

This was a study that evaluated immune reconstitution in patients with controlled HIV following allogeneic stem cell transplant in terms of CD4 and CD8 cells. 6 patients with HIV were evaluated, and these were compared to 21 non-HIV ASCT patients. There was zero post-transplant mortality, while CMV reactivation occurred in 2/6 in the HIV group while it only occurred in 1/21 in the non-HIV group. There was no difference between groups in terms of CD4 T-cell counts, however CD8 T-cell counts were higher post-transplant in the HIV positive group:

Most of the CD8 T-cells in the HIV group were CD45RO+, though subsets of these were different among the 3 patients evaluated. In 2 of the patients that had pre-transplant cells, the proportion of each subset was similar in both, pre and post transplant periods. 

Baker AW, Maziarz EK, Lewis SS, Stout JE, Anderson DJ, Smith PK, Schroder JN, Daneshmand MA, Alexander BD, Wallace RJ, Sexton DJ, Wolfe CR. Invasive Mycobacterium abscessus Complex Infection After Cardiac Surgery: Epidemiology, Management, and Clinical Outcomes. Clin Infect Dis. 2021 Apr 8;72(7):1232-1240. doi: 10.1093/cid/ciaa215. PMID: 32133489; PMCID: PMC8028101.

This was a case series of 10 patients who underwent cardiac surgery during an outbreak of M. abscessus due to exposure to heater-cooler units during surgery. Patients were excluded if they had a VAD or OHT, and a total of 10 patients were evaluated. All required cardiopulmonary bypass and the use of HCUs, with 7 undergoing valve surgery and 9 ending up with prosthetic material post-op. 6 patients developed disseminated disease, and all isolates were resistant to azithromycin/clarithromycin (erm-gene positive). The most commonly used regimen was amikacin, imipenem, and tigecycline, and median duration of therapy was 24 weeks. 7 patients had mediastinitis and underwent a total of 15 sternal debridements. Following the first 12 months of diagnosis, there were a total of 26 hospitalizations with 423 hospital days accumulated between the cohort. 8 patients died within 2 years and 4 of these were attributable to M. abcessus.

Marks M, Millat-Martinez P, Ouchi D, Roberts CH, Alemany A, Corbacho-Monné M, Ubals M, Tobias A, Tebé C, Ballana E, Bassat Q, Baro B, Vall-Mayans M, G-Beiras C, Prat N, Ara J, Clotet B, Mitjà O. Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study. Lancet Infect Dis. 2021 May;21(5):629-636. doi: 10.1016/S1473-3099(20)30985-3. Epub 2021 Feb 2. PMID: 33545090; PMCID: PMC7906723.

More COVID. This is a post-hoc analysis of a trial that evaluated the use of HCQ as PEP in close contacts. Here, though, the goal was to evaluate the impact that viral load in index cases had in terms of transmission to close contacts. 314 patients with COVID and available viral loads were evaluated, and 282 of these had at least one close contact, meaning 282 clusters were evaluated with contacts ranging from 2 to 19. Viral load in cases was associated with the presence of fever, but negatively associated with the presence of anosmia:

Multivariate analysis found that the viral load of the index case was strongly associated with the risk of transmission (aOR per log10 inc in viral load 1.3, 95% CI 1.1 to 1.5), with 90% of transmission occurring in those whose index case was >5.1 log 10:

Should be terribly surprising, as higher viral load is, well more virus to go around. Though how helpful this is going forward is unclear, as the higher the viral load the more symptomatic a patient is, which means others will stay away from them.

COVID and anticoagulation is still an issue that makes my head hurt. This is a multicenter, randomized trial evaluating intermediate dose anticoagulation (1mg/kg daily of lovenox) compared to standard dose prophylactic anticoagulation in a 1:1 fashion. Primary end-point was the composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality within 30 days of enrollment. Notably, this was part of a larger trial, which had a 2×2 factorial design with the other hypothesis evaluating statin and matchin placebo. 600 patients were randomized, with 45.7% of patients in the intermediate AC group and 44.1% of the standard AC group reaching the primary outcome: 

Risk of VTE was not statistically different between groups (risk difference -0.2%, 95% CI -3.2 to 2.6, OR 0.93, 95% CI 0.37 to 2.32) There was also no difference in all-cause mortality or other exploratory secondary outcomes. There is an interesting blog-post by Josh Farkas on heparin resistance and how this may play a role in our anticoagulation approach:

Bottom line, it may be that in some cases, we may be underdosing heparin in a lot of these critically ill patients and even an intermediate dose of anticoagulation may not be enough to overcome such resistance (which may be driven by low heparin concentration in setting of acute phase reactants). There is another blog that goes over the 3 trials and summarizes the salient points of these:https://emcrit.org/pulmcrit/therapeutic-anticoagulation-covid/. Again, it seems to be messy situation and seems that, for the foreseeable future, higher than prophylactic dose anticoagulation may not be recommended. 

Nagler AR, Goldberg ER, Aguero-Rosenfeld ME, Cangiarella J, Kalkut G, Monahan CR, Cerfolio RJ. Early Results from Severe Acute Respiratory Syndrome Coronavirus 2 Polymerase Chain Reaction Testing of Healthcare Workers at an Academic Medical Center in New York City. Clin Infect Dis. 2021 Apr 8;72(7):1241-1243. doi: 10.1093/cid/ciaa867. PMID: 32594114; PMCID: PMC7337722.

This is a COVID-19 testing program at a hospital in New York for employees. Patients were screened if they were symptomatic, asymptomatic with recent exposure, or if they were returning to work in services that had been suspended during the pandemic. Nearly 15,000 patients were screened, with positivity rates being 33% in symptomatic workers, 8% in asymptomatic but exposed workers, and 3% in returning workers. During this 8 week time-frame, the rate of positivity across the three groups decreased significantly, likely due to PPE and decreased community transmission:

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