In the Literature

Human Polyomavirus, Peacock Plumage, and Chronic Pruritic Dermatitis

Nguyen KD, Lee EE, Yue Y, Stork J, Pock L, North JP, et al. Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses. J Am Acad Dermatol. 2017 May; 76(5):932–940.e3. Smith SDB, Erdag G, Cuda JD, Rangwala S, Girardi N, Bibee K, et al. Treatment of human polyomavirus-7 associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review. Transpl Infect Dis. 2017 Oct 24. doi: 10.1111/tid.12793. [Epub ahead of print] PubMed PMID: 29064138.

In 2015, Ho and colleagues reported the cases of 2 lung transplant recipients who developed severely pruritic brown cutaneous eruptions on their extremities that were recalcitrant to topical and symptomatic therapies, including corticosteroids and antihistamines [1]. In one case the lesions were described as “multiple brownish pink, scaly, thin papules and plaques involving the gluteal cleft and back, with progression up to the neck and chest but sparing acral areas and the face,” whereas in the other the neck, back, chest, axillae, buttocks, and legs were affected by brown papules and plaques. Examination of biopsies revealed a pattern of parakeratosis characterized as “peacock plumage,” as well as viral capsids within keratinocytes; molecular and immunohistochemistry studies identified these as human polyomavirus 7 (HPyV7).

Nguyen et al. took this observation further by retrospectively screening archived skin biopsy specimens for evidence of “peacock plumage” and subjected them to polymerase chain reaction (PCR) for evidence of the presence of HPyV. Those that were positive for HPyV6 or HPyV7 underwent further analysis using electron microscopy (EM), immunofluorescence, qPCR, and finally, complete unbiased next generation sequencing (NGS). They identified 3 patients with clear evidence of infection with 1 of these HPyV, confirmed infection of keratinocytes, and demonstrated the presence of intact virions by EM and by NGS. The virus was present in significantly higher concentrations in the lesions than in adjacent normal appearing skin.

Each of the patients had a pruritic (severe in 1) rash for 12 to >24 months. The eruption was described as “generalized, scaly, hyperpigmented papules coalescing into plaques.” Two of the patients had known immunocompromise: human immunodeficiency virus (HIV)/AIDS in 1 and immunosuppressive therapy for prevention of rejection of renal and pancreatic transplantation the other. Nguyen and colleagues suggest that this dermatological disease be termed HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses.

At least 14 types of polyomavirus have been described, with the first 2 to be identified being the JC and BK polyomaviruses. JC polyomavirus is the etiologic agent of progressive multifocal leukoencephalopathy seen in immunocompromised patients, whereas BK polyomavirus is associated nephritis and hemorrhagic cystitis in renal and hematopoietic stem cell transplant recipients. Trichodysplasia spinulosa (TS), a rare condition manifest as flesh colored papules and keratin spines involving the face of transplant recipients, is caused by TS polyomavirus.

Although the evidence strongly indicates that HPyV-7 (and possibly HPyV-6) is the cause of these chronic pruritic skin eruptions occurring predominantly in immunocompromised patients, the virus can be found, albeit in low concentration, on the skin of approximately 12% of healthy individuals and an even higher proportion of HIV-infected subjects. The molecular findings described in these studies, as well as the apparent response to the topical application of cidofovir, nonetheless, make a strong case for a likely role in the pathogenesis of this skin disorder.

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Tedizolid, Linezolid, and Thrombocytopenia

Lee EY, Caffrey A. Thrombocytopenia with tedizolid and linezolid. Antimicrob Agents Chemother. 2017 Oct 16. pii: AAC.01453-17. doi: 10.1128/AAC.01453-17. [Epub ahead of print] PubMed PMID: 29038274.

A limiting factor in the prolonged administration of linezolid, often considered as >2 weeks of therapy, is myelotoxicity, most often manifested as leukopenia or anemia but also as thrombocytopenia. Tedizolid has been suggested to be a possibly less myelotoxic alternative to linezolid. Lee and Caffrey examined this question by interrogating the Food and Drug Administration (FDA) Adverse Event Reporting System, which receives voluntary reports. They examined reports of linezolid-associated thrombocytopenia for a 10-year period ending in June 2014, which is when tedizolid received FDA approval, as well for July 2014–December 2016.

In the latter period after the approval of tedizolid, 1468 (0.07%) of a total of almost 2 million adverse event (AE) reports were of thrombocytopenia, with 408 (0.02%) implicated linezolid and 41 (0.002%) implicated tedizolid. There was only 1 report of thrombocytopenia related to tedizolid use and 11 to linezolid, representing 2.44% and 2.70% of all AE reports for the 2 drugs, respectively. The reporting odds ratio (ROR), which reperesents the odds that an outcome occurs given a particular exposure when compared to the odds of that outcome occurring in the absence of that exposure, was 37.9 (95% confidence interval [CI], 20.78 to 69.17) for linezolid and 34.0 (95% CI, 4.67–247.30) for tedizolid. The ROR for linezolid in the pre-tedizolid period was 12.1 (95% CI, 11.19–12.96) consistent with prior observations that reporting adverse effects attributed to a drug may increase over time after it has become commercially available.

Overall, the results indicate that there is a significant and comparable risk of thrombocytopenia occurring in association with use of each of these oxazolidinone antibiotics. This lack of difference is consistent with the results of individual comparative trials, none of which detected a significant difference in the development of thrombocytopenia. However, the duration of antibiotic therapy in these trials was often relatively brief and unequal. Thus, in the ESTABLISH I and ESTABLISH II trials of treatment of acute bacterial skin and skin structure infections, tedizolid was administered for 6 days and linezolid for 10 days. Although there was no significant difference in development of thrombocytopenia in each trial, a post hoc pooled analysis identified modest and largely clinically unimportant greater reductions in platelet counts in linezolid recipients at days 11–13 [1].

The method used in this study has great shortcomings, especially because of the voluntary nature of the reporting. Placed in the context of other available evidence, however, it does suggest that, at least with short-term administration, any difference between linezolid and tedizolid is unlikely to have great clinical significance.

Reference

Rapid Diagnosis of Tuberculous Meningitis

Bahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV, Byamukama A, et al; ASTRO-CM Trial Team. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis. 2017 Sep 14. pii: S1473-3099(17)30474–7. doi: 10.1016/S1473-3099(17)30474–7. [Epub ahead of print] PubMed PMID: 28919338.

The sensitivity of the older Cepheid Xpert® MTB/RIF (Xpert) assay in the diagnosis of tuberculosis meningitis is variously reported at 55%–80% and thus has room for improvement. The Cepheid Xpert® MTB/RIF UltraA (Ultra) assay was developed to increase the sensitivity of the Xpert® MTB/RIF assay in the detection of Mycobacterium tuberculosis nucleic acid.

In a study of 1520 patients with suspected active pulmonary tuberculosis, the sensitivity of Ultra was 5% (95% confidence interval [CI], 2.7% to 7.8%) greater than that of the older assay. As expected, however, this was at the expense of specificity, which was 3.2% lower (95% CI, −2.1% to −4.7%) [1]. The major benefit of Ultra was seen in smear negative, culture positive patients in whom the sensitivity increase was 17% as well as in human immunodeficiency virus (HIV) infected patients for whom there was an increased specificity of 12%.

Baht and colleagues examined the accuracy of Ultra in 129 HIV-infected patients in Uganda with suspected tuberculous meningitis, comparing it to culture as well as to Xpert. They used 2 separate diagnostic definitions in their analysis. Excluding the Ultra result, 23 patients had evidence of definite or probable tuberculous meningitis and Ultra detected 16 of these, yielding a sensitivity of 70% (95% CI, 47% to 87%). This was greater than the sensitivity of both the older Xpert test (43%) and culture (43%).

Using a composite diagnostic standard in which positivity of any one of smear, culture, or commercialized polymerase chain reaction (PCR) (including both Xpert and Ultra), Ultra was positive in 21 of 22, yielding a sensitivity of 95%. The negative predictive value of Ultra was 99% (106 of 107), whereas that of Xpert was 90%, as was that of culture. Sufficient cerebrospinal fluid from 2 samples positive by Ultra (each at “trace” and “very low” levels, based on PCR cycle), but negative by both culture and Xpert, was available to perform next generation sequencing (NGS). NGS detected M. tuberculosis nucleic acid both.

The evaluation of the accuracy of laboratory tests that may be more sensitive than a “gold standard” is fraught with difficulty. In such a case, when is a “false positive” truly false? Nonetheless, there is value in a sensitive test that can provide a result within approximately 80 minutes compared to a culture that takes weeks. The value of rapid diagnostic testing in tuberculous meningitis can be seen by the fact that the median time to culture positivity was 16 days, and 7 of 10 patients with a positive cerebrospinal fluid culture died before the culture became positive.

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