In the Literature Free

GETTING SEVERE COVID-19—IT IS IN YOUR GENES

Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2020 Dec 11. doi: 10.1038/s41586-020-03065-y. Epub ahead of print. PMID: 33307546.

Pairo-Castineira and colleagues participating in the Genetics of Mortality in Critical Care (GenOMICC) consortium performed genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) on 2244 critically ill patients with coronavirus disease 2019 (COVID-19) cared for in 208 intensive care units in the United Kingdom using Mendelian randomization. They compared the results to existing data from other studies of healthy volunteers and identified significant differences in 5 genes: IFNAR2, TYK2, OAS1, DPP9, and CCR2. Thus, they concluded that the development of critical illness in COVID-19 patients is related to genes affecting the early response to infection by the innate immune response (IFNAR2 and OAS genes) and to later stage responses affecting host-driven inflammatory lung injury (DDP9, TYK2, and CCR2).

The interferon receptor gene, IFNAR2, was associated with protection against severe disease, a finding consistent with previous observations that patients with rare loss of function mutations in this gene suffered from severe COVID-19. Variants in oligoadenylate synthase-like (OAS) genes were previously implicated in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV).

The role of interferons, which are critical to the initial response to viral infection has previously been examined [1]. It has been demonstrated that the SARS-CoV-2 gene, ORF3b, potently inhibits the activation of type I interferons. Autoantibodies to interferons have been associated with severe COVID-19 [2] as have been loss of function mutations in the TLR7 gene that result in reduced interferon (IFN) production in response to TLR7 agonists.

High expression of TYK2, which encodes a tryrosine kinase, was associated with a 1.3 increased odds ratio of developing severe COVID-19. This gene is a target for Janus kinase inhibitors, such as baracitinib. Another association was with dipeptidyl peptidase 9 (DPP9), part of a gene cluster that, among other things, enzymatically inactivate the chemokine ligand, CXCL10, which plays roles in antigen presentation and inflammasome activation. Also associated with severe COVID-19 was inferred CCR2 expression in lung tissue. CCR2 is a chemotactic receptor with a role in monocyte/macrophage chemotaxis.

Overall, it appears that severe disease resulting from SARS-CoV-2 infection may result from an initially impaired innate immune response followed by an excessive inflammatory response. The findings reported by Pairo-Castineira and colleagues may provide some useful insights into treatment. If interferon treatment is to be effective, it can be hypothesized that it must be administered very early in infection. The role of TYK2 is consistent with the beneficial, albeit modest, effect reported with the use of the Janus Kinase inhibitor, baracitinib, when given with remdesivir to COVID-19 patients. The association CCR2 with severe disease suggests the potential therapeutic role of antagonists or monoclonal antibodies directed against this chemokine.

References

PROSTATIC ABSCESS WITH ATTENTION TO STAPHYLOCOCCUS AUREUS

Wooster ME, Huang G, Sanders JW 3rd, Peacock JE Jr. Prostatic abscess: clinical features, management, and outcomes of a “stealth” infection: retrospective case series and review of the literature. Diagn Microbiol Infect Dis. 2020 Dec 5;99(4):115285. doi: 10.1016/j.diagmicrobio.2020.115285. Epub ahead of print. PMID: 33360491.

Wooster and colleagues reviewed the records of 22 adults over 5 years seen at a single center who had prostatic abscess confirmed by imaging. Their age range was 30–72 years, with a median of 57 years. Symptoms had been present for a median of 4 days (range 1–28 days), and 59% had fever (59% met sepsis criteria), 45% had dysuria, and 32% had urinary retention. Pain was common but variable in location and included perineal, scrotal, low back, and flank sites. Six had suprapubic tenderness, 5 had costovertebral tenderness, and only 7 (38.9%) of 18 who had a recorded examination had prostate tenderness. None had had an indwelling bladder catheter, and only one patient had undergone a urologic procedure (cystoscopy) in the previous 6 weeks.

The median peripheral white blood cell count on admission was 16 450 cells/µL. Five (22.7%) patients lacked pyuria. All 22 patients had abscesses demonstrated by computed tomography (CT) examination, with solitary and multiple lesions demonstrated in 13 (59.1%) and 9 (40.9%), respectively; 4 had extension outside the prostatic capsule. The median abscess size was 3.2 cm, and approximately three-fourths were >2 cm in diameter.

Only 18 patients had admission urine cultures, 11 (81.8%) of which were positive. These yielded in addition to Enterobacterales and Enterococcus faecalis, Staphylococcus aureus in 6 (54.5%), 3 of which were methicillin-resistant S. aureus (MRSA). Although 5 patients had a documented urinary tract infection for which antimicrobials had been prescribed in the previous 6 weeks, in no case was the same bacteria recovered at the time of presentation with prostatic abscess.

Blood cultures were obtained for 16 patients, 9 (56.5%) of which were positive. These yielded S. aureus (3 MRSA) in 7, along with Escherichia coli and E. faecalis in one each. Thirteen (59.1%) patients underwent a procedure for abscess drainage, and culture of abscess contents was positive in all 5 cases in which it was performed. The median duration of antibiotic administration was 34.5 days (range, 4–65 days). One patient died of E. coli sepsis during hospitalization. There were no documented relapses among survivors in the following 6 months.

At least one-half of the cases of prostatic abscess in this series by Wooster et al were caused by S. aureus, and the authors believed that these cases, in contrast to those caused by usual urine pathogens, were hematogenous in origin (of note is that one of the patients bacteremic with this organism had a mitral valve vegetation). S. aureus has been reported by others as a frequent cause of prostatic abscess, and some have provided further evidence of bloodstream infection as a source of prostatic abscess.

Thus, Walker and colleagues recently reviewed their experience with 21 patients with a discharge diagnosis of prostatic abscess due to S. aureus (57% due to MRSA) over 10 years at a single center in eastern Tennessee [1]. Four-fifths of the 21 patients were bacteremic. Only 67% presented with “genitourinary concerns,” and one-half had a history of genitourinary disease or instrumentation, whereas 11 (52%) had concurrent skin or soft tissue infection. A history of injection drug use or diabetes mellitus were each present in 38%.

A number of observations from these studies are of interest. From the study by Wooster and colleagues, these include the variable location of associated pain, the relatively low frequencies of dysuria and of prostatic tenderness, and the lack of pyuria and of bacteriuria in one-fifth of cases each. Of at least equal interest is the high proportion of cases due to S. aureus, together with evidence that those cases may have been hematogenous in origin. In the series by Walker et al of cases due to S. aureus, 81% of which were bacteremic (and often occurred in injection drug users), local symptoms were frequently absent. This suggests that prostatic abscess should be considered as a potential site of localized infection in patients with S. aureus bacteremia even in the absence of localizing signs or symptoms.

Reference