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By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Household Transmission of Influenza
Source: Ng S, et al. Effects of Oseltamivir treatment on duration of clinical illness and viral shedding and household transmission of Influenza virus. Clin Infect Dis. 2010;50:707-714.
These authors assessed the benefits of antiviral therapy of the index flu patient on reduced viral shedding and prevention of secondary household cases who did not receive chemoprophylaxis. They followed 384 patients with influenza during the 2007 and 2008 flu seasons (65% of whom had influenza A) and tracked 331 household contacts for up to 7-10 days using RT-PCR and viral culture of nose and throat specimens every 2-3 days. None of the household contacts received antiviral prophylaxis.
As anticipated, index cases who received oseltamivir within 24 hours of symptom onset had a statistically significant reduction in the duration of symptoms. However, while there was some reduction in the duration of viral shedding in these patients, the results were not statistically significant. The mean duration of viral shedding was six days (up to a maximum of 12 days). For patients receiving oseltamivir within 48 hours, the reductions in viral shedding were minimal (acceleration factor, 0.76 and 0.99 for 2007 and 2008, respectively, compared with index cases who did not receive antivirals). In such settings, shedding of virus has been well documented, and shedding of antiviral-resistant virus on therapy even been demonstrated.
The overall secondary attack rate in household contacts was 8.1%. Based on the initiation of oseltamivir within < 24 hrs., 24-48 hrs., or > 48 hrs of the index case, the secondary attack rate in their respective household members varied from 4.7% (95% CI, 1%-13%), 6.0 (CI 95%, 2.5%-12%), to 7% (95% CI, 1.5%-19%), compared with 8.7% (95% CI, 6.8-11.6%) in contacts of index cases who did not receive antiviral treatment (p < .01 for trend). The unadjusted protective effect of treatment of the index case began within 24 hours or > 24 hours of symptom onset was 46% and 31%, respectively. While the risk of secondary infection was lower if the household contact had been previously vaccinated, it was also lower if the index case was older or the household member was older. Household contact of index patients < 18 years of age had the highest risk of secondary infection. Thus, there appeared to be a modest reduction in infectivity of index cases who received oseltamivir, especially if they received prompt antiviral therapy.
Reintroduction of TB Meds following Hepatotoxicity
Source: Sharma SK, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis. 2010;50:833-839.
Drug-related hepatotoxicity during treatment for tuberculosis is a common barrier to initiation of antimycobacterial. While most hepatotoxicity results in minimal to no gastrointestinal complaints, some patients experience significant nausea, anorexia, vomiting, or abdominal pain. While there are several proposed methods for reintroducing TB therapy in these patients, there is no consensus as to how to proceed. Our local public health department strongly discourages the stepwise reintroduction of medications based on concerns about the potentiation of resistance, although this approach has been recommended by both the American Thoracic Society and the British Thoracic Society.
These investigators selected 237 consecutive patients with clinical and laboratory evidence of hepatotoxicity occurring during antimycobacterial treatment, and prospectively evaluated the risk of recurrent hepatotoxicity upon reintroduction of TB therapy over a three-month period. Hepatotoxicity was defined as ≥ 3 times the upper limit of normal transaminases on three consecutive occasions, ≥ 5 times the ULN transaminase on one occasion, or any elevation in transaminase associated with nausea, vomiting, anorexia, and jaundice. Patients were screened for other contributing causes of hepatotoxicity, such as hepatitis, HIV, and alcohol use; based on this, 58 patients were excluded from the analysis and four patients died.
Treatment was not reintroduced until normalization of liver function test results. The median time to normalization of liver test results was 18 days (range, 14 to 28 days), and the median time to reintroduction of medications was 23 days (range, 14 to 44 days).
Patients were randomly assigned to one of three retreatment strategies: the simultaneous reintroduction of all three meds (isoniazid, rifampin and pyrazinamide) at maximal dosages at day one; the stepwise reintroduction of medications at full dosages with rifampin at day one, INH at day eight, and PZA at day 15 (similar to the ATS recommendations); and the stepwise reintroduction of medications with dose-escalation beginning with INH 100 mg/day at day one, increasing to full dose by day four, then rifampin 150 mg/day at day eight, increasing to full dose by day 11, and finally PZA at 500 mg/day at day 15, increasing to maximal dose by day 18 (according to the BTS guidelines).
Nineteen (10.9%) patients had recurrent treatment-related hepatotoxicity. The frequency of recurrent hepatotoxicity was similar (13.8% vs. 10.2% vs. 8.6%), (p = .69), respectively, for each of the three groups outlined above. In addition, the peak bilirubin and transaminase values were similar between the three groups. The median number of days to recurrent of hepatotoxicity was similar (14 for group 1 vs. 21 days for the other two groups, with a maximum of 35 days). No deaths were observed. The only risk factor associated with recurrent hepatoxicity was lower pre-treatment albumin levels.
These data support the simultaneous reintroduction of full-dose TB medications in patients who have experienced hepatoxicity. The severity of the initial hepatotoxicity did not appear to predict the risk of recurrent hepatotoxicity, nor the severity of symptoms if recurrent hepatotoxicity occurred.
Chronic Fatigue Patients Banned from Blood Donation
Sources: Lombardi VC, et al. Detection of an infectious retrovirus, XMVR, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326:585-589; Erlwein O, et al. Failure to detect the novel retroviral XMVR in chronic fatigue syndrome. PLoS ONE. 2009;5:e8519.
The debate regarding the potential infectious cause for chronic fatigue syndrome (CFS) became more intense during the past year, with a report published in Science in October 2009, suggesting a link between CFS and a murine retrovirus called xenotrophic murine leukemia virus-related virus (XMRV). Lombardi et al at the National Cancer Institute and the Cleveland Clinic identified XMRV gag sequences by nested polymerase chain reaction (PCR) in 68 (67%) of 101 samples from patients with CFS, compared with only eight (3.7%) of 218 peripheral blood mononuclear cells from healthy controls. XMRV gag and env sequences were detected in seven of 11 CFS patients and one of 11 controls. Although only fragments of virus were detected by molecular means, and it was not clear whether viable or infectious XMRV was present in these patients, additional work suggested that patient-derived XMRV was able to infect culture cell lines.
While attracting lots of attention, a causative link between XMRV and CFS has not been established. And there has been criticism levied at this report based on the limited description of the CFS patients, who were not randomly selected, and how the controls were defined. Furthermore, two other studies from the United Kingdom and the Netherlands were unable to reproduce these findings. Erlwein et al examined PBMCs from 186 patients with CFS in the United Kingdom, none of whom had evidence of XMRV.
Nonetheless, the Canadian Blood Service has decided to ban blood donations from patients with CFS. Although I cannot imagine that too many patients with CFS actually pony up their blood products, the Canadians have decided to take a cautious approach until further information is available. The U.S. Blood Service is in the process of evaluating the data, as well. One wonders, with the availability of molecular techniques for identifying viral particles, how many of us don't have fragments of something drifting through our systems, or minimally detectable upregulation of various latent viruses simply during periods of stress? How safe is safe enough for utilization of this important resource?
Chilblains: A Medical Mystery?
Sources: Prakash, et al. Idiopathic Chilblains. 2009; 122:1152-5; Bohman KD, et al. Perniosis (chilblains) masquerading as CA-MRSA: A case report. Cases J. 2009;2:6500; Noaimi AA and Fadheel BM. Treatment of perniosis with oral pentoxifylline in comparison with oral prednisolone plus topical clobetasol ointment in Iraqi patients. Saudi Med J. 2008;29:1762-1764.
I was recently requested to evaluate an elderly Pakistani male with recurrent lower extremity ulcerations and bullae with intermittent and progressive violaceous blisters and ulcers at the ends of his toes, mostly on the pads but also at the base of the nail bed. The lesions on the shins would occur every several weeks, mostly in the winter and spring months. He also had onychomycosis involving several toes and, at first, was thought to maybe have an "ID" reaction, but he failed to respond to a four-month course of terbinafine. An extensive workup, including biopsies and cultures, blood and stool examination for parasites and evaluation for auto-immune etiology or vasculitis was unrevealing. He had no evidence of hepatitis B, C, or E, and cryoglobulins were negative. Skin biopsy of a bullous lesion showed supepidermal blisters with mild perivascular inflammation and eosinophils.
The working diagnosis? Chilblains also called perniosis. I remember my grandmother in Minnesota talking about chilblains, which is an old term for the vasospastic effect of cold exposure on the hands and feet. The lesions are characterized by blisters, ulcers, or even pustules are often accompanied by inflammation, burning, or itching. They resemble a vasculitic or thromboembolic lesion, but there is no evidence for either on biopsy. Interestingly, once it occurs, it apparently can continue for months after cold exposure has been removed. The treatment is conservative, although it's important to rule out a vasculitis or cryoglobulinemia, and includes avoiding cold or damp weather, and keeping the extremity warm. Calcium channel blockers, such as nifedipine, have been effective in many patients, and one Saudi study suggested that pentoxifylline may be beneficial.