Infectious disease

Neurological complications of dengue virus infection.

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Dengue is the second most common mosquito-borne disease affecting human beings. In 2009, WHO endorsed new guidelines that, for the first time, consider neurological manifestations in the clinical case classification for severe dengue. Dengue can manifest with a wide range of neurological features, which have been noted—depending on the clinical setting—in 0·5—21% of patients with dengue admitted to hospital. Furthermore, dengue was identified in 4—47% of admissions with encephalitis-like illness in endemic areas. Neurological complications can be categorised into dengue encephalopathy (eg, caused by hepatic failure or metabolic disorders), encephalitis (caused by direct virus invasion), neuromuscular complications (eg, Guillain-Barré syndrome or transient muscle dysfunctions), and neuro-ophthalmic involvement. However, overlap of these categories is possible. In endemic countries and after travel to these regions, dengue should be considered in patients presenting with fever and acute neurological manifestations.

Diagnosis

Clinical suspicion is essential for diagnosis of dengue because many symptoms are non-specific. Various methods are available for laboratory confirmation. During the first days of infection, dengue virus is present in blood; thus, at that time, detection of NS1 antigen or RNA by RT-PCR and viral culture are appropriate diagnostic methods.1 Dengue virus-specific IgM antibodies are present in serum samples 3—10 days after disease onset.1 IgM capture (MAC)-ELISA is the most widely used serological test. Antibodies against other flaviviruses (eg, Japanese encephalitis, West Nile virus, yellow fever) might cross-react with dengue virus, leading to false-positive reactions.136

In endemic countries, or among travellers who recently (<14 days) returned from such regions, dengue should be ruled out in patients with fever and neurological features (panel 2). If possible, lumbar puncture should be done and CSF analysed for abnormalities and for dengue virus-specific antibodies, NS1 antigen, or dengue virus RNA, depending on available laboratory facilities. Differential diagnosis in patients with febrile encephalopathy includes malaria, tuberculosis, leptospirosis, rickettsial infection, and other bacterial or viral diseases (caused by, for example, Japanese encephalitis, West Nile virus, or herpes simplex virus [HSV]), depending on the local epidemiology. In a prospective hospital-based study in Vietnam, most children with acute encephalitis of presumed viral origin were infected with Japanese encephalitis (26%), followed by enteroviruses (9%) and dengue virus (5%).30 In adults and adolescents in Brazil, dengue was the leading cause of viral encephalitis (47%), followed by infections with HSV-1.31

To differentiate dengue encephalitis from encephalopathy, detection of dengue virus, NS1 antigen, or dengue virus-specific IgM antibodies in CSF is helpful. Nevertheless, sensitivity of serological techniques can be low. Dengue virus-specific IgM antibodies have been recorded in CSF of 22—33% of patients diagnosed with dengue encephalitis (Table 1, Table 2).90Detection of dengue virus in CSF could be hampered by low sensitivity of RT-PCR in CSF, compared with findings in serum, because of a lower viral load.137 Moreover, measurement of IgM antibodies in CSF might not be a reliable diagnostic marker of dengue CNS involvement, owing to low titres in CSF.138 Abnormalities in CSF—such as lymphocytic pleocytosis—support the diagnosis of dengue encephalitis, but they are not always present (Table 1, Table 2, Table 3). A mild increase in CSF protein has been recorded.28 In a series of patients with neurological complications of dengue, four of seven with encephalitis had no alterations in CSF.90 Therefore, normal CSF cellularity should not exclude dengue encephalitis.

The case definitions in panel 2 are designed to be used epidemiologically and clinically and to guide diagnosis and prognosis. Although we propose criteria for a classification scheme, a topic as challenging and as controversial as dengue encephalitis needs to be addressed in a standard way. Prospective studies are needed to assess the specificity and sensitivity of the proposed case definitions and to generate supporting evidence. Cases fulfilling neither the definition for encephalitis nor that for encephalopathy—eg, without CSF testing or when categories are overlapping—can be categorised as other or non-specified dengue CNS involvement.

Neuroimaging might provide additional clues in the diagnosis of neurological complications of dengue. In dengue encephalitis, brain MRI can be normal or show focal parenchymal abnormalities.22, 41 Nevertheless, no specific MRI findings suggestive of dengue encephalitis have been reported. Neuroimaging features of patients with dengue are diverse, with cerebral oedema the most commonly reported finding.77 Meningeal enhancement on post-contrast MRI has been reported occasionally as well.77

Finally, EEG abnormalities can be seen in dengue patients with neurological complications. In a study of 23 patients with dengue virus infection and neurological symptoms, EEG abnormalities were recorded in 12 people.139 Slowing on EEG can be seen, but this finding is unspecific and could be attributable to seizures, intracranial haemorrhage, and viral infection per se, besides encephalopathy.77

Management

Currently, no effective antiviral agents are available to treat symptomatic dengue virus infection.140 Therefore, management remains supportive. In mild cases, antipyretic drugs and oral fluids could be useful. Acetyl-salicylic derivatives and other non-steroidal anti-inflammatory drugs should be avoided. Management of haemorrhagic complications should be initially conservative. Precise management of intravenous fluids is needed, and blood or platelet transfusion is only necessary when severe bleeding takes place.1

In patients with severe dengue and signs of plasma leakage, prompt fluid resuscitation is imperative, with close monitoring of packed-cell volume to avoid fluid overload. Isotonic crystalloid solutions should be used, with isotonic colloid solutions reserved for patients presenting with profound shock or those who do not have a response to initial crystalloid treatment.140, 141 In a randomised controlled trial from Vietnam,142 use of oral prednisolone during the early acute phase of dengue infection was not associated with a reduction in the development of shock or other recognised complications of dengue virus infection.

For supportive management of patients with neurological manifestations, possible underlying causes such as intracranial bleeding, liver failure, hyponatraemia, hypokalaemia, or metabolic acidosis should be ruled out and—if possible—corrected. Management of dengue encephalitis remains supportive and should include adequate hydration, nutrition, monitoring of consciousness, and maintenance of airways.143 Symptomatic seizures should be treated with non-hepatotoxic anticonvulsants. Decompressive craniotomy and cerebral haematoma evacuation were done in two patients with dengue after correction of prothrombin time and platelet count.92 Nevertheless, prognosis is not good and, in one case series, two of five patients died.92 At this moment, haematoma surgery cannot be proposed as a routine treatment for dengue virus intracranial bleeding.

Some clinicians recommend treatment of immune-mediated dengue CNS involvement with pulses of intravenous methylprednisolone for several days.50, 69, 72 However, up to now, no randomised controlled trial has been undertaken to show the efficacy of this approach in patients with dengue myelitis or acute disseminated encephalomyelitis. High doses of intravenous immunoglobulin might be useful to treat post-dengue Guillain-Barré syndrome. Supportive treatment—including hydration and analgesic drugs—is used for myalgia and transitory muscle dysfunction. The effectiveness of corticosteroids in dengue myositis remains to be proven.

No treatment has been approved for neuro-ophthalmic manifestations of dengue. Steroids have been administered previously because of possible underlying immune mechanisms, although up to now no randomised trials have been done. Topical steroids have been used to treat anterior uveitis, whereas pulsed intravenous methylprednisolone or systemic oral steroids might be indicated for extensive retinal vasculitis.120

Currently, no vaccine is available for protection against dengue. However, several vaccine candidates are in development.

Conclusions and future research

Dengue should be included in the differential diagnosis of acute febrile disease with neurological manifestations in dengue-endemic countries and in patients with a recent travel history to an endemic region. Many neurological manifestations of dengue have been recorded, ranging—with substantial overlap—from encephalitis and encephalopathy to immune-mediated syndromes and muscle involvement. Recent evidence suggests that dengue virus has neuroinvasive capacity. In several studies in endemic areas, a large proportion of viral encephalitis was caused by dengue virus.26—32 However, even though CNS involvement is included now as a criterion for severe dengue in the 2009 WHO case classification,1 no standardised case definitions or diagnostic criteria for dengue encephalitis or encephalopathy have been agreed, which leads to inconsistent use of these terms in published work.

An updated WHO dengue guideline should include a case definition for dengue encephalitis and encephalopathy, to guide clinicians and clinical epidemiological researchers into this topic. A case classification—such as the one proposed in panel 2—could serve as a starting point, which could be reviewed by WHO, agreed by consensus and best available current evidence, and refined as additional data become available from prospective studies. For this reason, assessment of CSF in patients with suspected neurological manifestations of dengue should be standardised. Very few published reports present findings of CSF testing for dengue virus, dengue virus-specific IgM antibodies, or NS1 antigen combined with CSF cellularity and confirmation of dengue in serum samples in a consistent way. Further epidemiological and neuropathological studies are needed to ascertain the true incidence and burden of neurological complications of dengue, to elucidate the underlying pathophysiology, and to assess the sensitivity and specificity of diagnostic markers for dengue encephalitis.

Source: Lancet

Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial.

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Background

Southern Africa has had an unprecedented increase in the burden of tuberculosis, driven by the HIV epidemic. The Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial examined two public health interventions that aimed to reduce the burden of tuberculosis by facilitating either rapid sputum diagnosis or integrating tuberculosis and HIV services within the community.

Methods

ZAMSTAR was a community-randomised trial done in Zambia and the Western Cape province of South Africa. Two interventions, community-level enhanced tuberculosis case-finding (ECF) and household level tuberculosis—HIV care, were implemented between Aug 1, 2006, and July 31, 2009, and assessed in a 2×2 factorial design between Jan 9, 2010, and Dec 6, 2010. All communities had a strengthened tuberculosis—HIV programme implemented in participating health-care centres. 24 communities, selected according to population size and tuberculosis notification rate, were randomly allocated to one of four study groups using a randomisation schedule stratified by country and baseline prevalence of tuberculous infection: group 1 strengthened tuberculosis—HIV programme at the clinic alone; group 2, clinic plus ECF; group 3, clinic plus household intervention; and group 4, clinic plus ECF and household interventions. The primary outcome was the prevalence of culture-confirmed pulmonary tuberculosis in adults (≥18 years), defined as Mycobacterium tuberculosis isolated from one respiratory sample, measured 4 years after the start of interventions in a survey of 4000 randomly selected adults in each community in 2010. The secondary outcome was the incidence of tuberculous infection, measured using tuberculin skin testing in a cohort of schoolchildren, a median of 4 years after a baseline survey done before the start of interventions. This trial is registered, number ISRCTN36729271.

Findings

Prevalence of tuberculosis was evaluated in 64 463 individuals randomly selected from the 24 communities; 894 individuals had active tuberculosis. Averaging over the 24 communities, the geometric mean of tuberculosis prevalence was 832 per 100 000 population. The adjusted prevalence ratio for the comparison of ECF versus non-ECF intervention groups was 1·09 (95% CI 0·86—1·40) and of household versus non-household intervention groups was 0·82 (0·64—1·04). The incidence of tuberculous infection was measured in a cohort of 8809 children, followed up for a median of 4 years; the adjusted rate ratio for ECF versus non-ECF groups was 1·36 (95% CI 0·59—3·14) and for household versus non-household groups was 0·45 (0·20—1·05).

Interpretation

Although neither intervention led to a statistically significant reduction in tuberculosis, two independent indicators of burden provide some evidence of a reduction in tuberculosis among communities receiving the household intervention. By contrast the ECF intervention had no effect on either outcome.

Discussion

We assessed prevalence of tuberculosis in 24 communities in Zambia and South Africa, after 3 years of ECF or household interventions for tuberculosis control. Of 64 463 randomly selected individuals, 894 individuals had active tuberculosis. Averaging over 24 communities the geometric mean of tuberculosis prevalence was 832 per 100 000 population. We also measured the incidence of tuberculous infection in a cohort of 8809 children, followed up for a median of 4 years. The adjusted prevalence ratio for prevalence and the adjusted rate ratio for incidence did not differ significantly for the ECF versus non-ECF or for the household versus non household groups. However, for the household versus non-household groups the upper bounds of the CI for both prevalence ratio and incidence rate ratio were close to unity. The concordance of two robust outcome measures, measured in different population groups and with different methods suggests that the household intervention did have some effect on the burden of tuberculosis in these communities.

The convergence of HIV and tuberculosis has led to an urgent need for an evidence-based public health response to reduce the burden of tuberculosis at the community level. Cluster-randomised trials should provide the gold standard for evidence-based policy making.

A systematic review of published work identified five studies that provided evidence for the effect of interventions on the epidemiology of tuberculosis at community level . Apart from preliminary data from the ZAMSTAR trial, two were randomised trials—the DETECTB trial of enhanced case-finding strategies in Zimbabwe and a trial of a household-level intervention in Brazil. The ZAMSTAR trial is the only study to measure the effect of public health interventions on tuberculosis with a randomised design and direct measurements of the burden of disease as the endpoint. The ZAMSTAR trial covered a population of almost 1 million people and was designed to detect reductions in prevalence of tuberculosis, and incidence of tuberculous infection, of 30%. Our study identified no evidence that the ECF intervention had an effect on the burden of tuberculosis at community level. However, despite not reaching statistical significance, there is plausible evidence that the household intervention did reduce the burden of tuberculosis in these communities.

 

Source: Lancet

Bill & Melinda Gates Foundation.

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial.

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Abstract

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.

Design Double blind randomised trial.

Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.

Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.

Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).

Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.

Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.

Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.

Discussion

In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.

Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.4 5 6 32 33 34 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.35 36 37 38 39 40 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.

Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.

Possible reasons for findings

It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.42 43 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.

Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,32 41 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.40 41

The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm0911 36 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.16 17 18

What is already known on this topic

  • Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
  • Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
  • Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
  • In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
  • These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic

What this study adds

 

 

Source: BMJ

 

 

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial.

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Abstract

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.

Design Double blind randomised trial.

Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.

Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.

Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).

Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.

Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.

Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.

Discussion

In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.

Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.4 5 6 32 33 34 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.35 36 37 38 39 40 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.

Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.4 8 14 36 37 38 39 40 41

Possible reasons for findings

It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.42 43 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.

Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,32 41 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.40 41

The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm0911 36 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.16 17 18

What is already known on this topic

  • Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
  • Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
  • Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
  • In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
  • These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic

What this study adds

 

Source: BMJ

 

Double-Dose Tamiflu No Better Than Standard Dose for Severe Flu.

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A double dose of oseltamivir (Tamiflu) offers no advantage over single-dose therapy among children and adults with severe influenza, according to a BMJ study.

Some 325 patients (three-quarters children) hospitalized with severe flu in Southeast Asia were randomized to either double-dose oseltamivir (150 mg twice daily, or pediatric equivalent) or standard treatment (75 mg twice daily, or equivalent). Detected viruses included various subtypes of seasonal influenza, 2009 pandemic flu, and avian flu.

The proportion of patients with no detectable viral RNA on day 5 did not differ between the groups (roughly 70%). In addition, the groups did not differ with respect to clinical failure or in-hospital mortality. Findings generally were consistent regardless of patient age or flu type.

The authors say their results “do not support routine use” of double-dose therapy in severe flu. Editorialists agree, adding that the results “could help to preserve oseltamivir stocks during a future pandemic.”

Source: BMJ

Dengue deluge highlights need for vaccine.

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dengue

The global health burden of dengue could be much higher than previously thought. In modeling work published, a team led by Simon Hay, an epidemiologist at the University of Oxford, UK, estimated that 390 million people around the world were infected with the mosquito-borne virus in 2010, a figure more than three times greater than that given by the World Health Organization.

Only around a quarter of all the dengue cases were ‘apparent’—requiring medical treatment or making people miss work or school—so the findings are unlikely to greatly affect clinical practice. However, the large number of previously unrecognized people with mild or asymptomatic infections could have an impact on future mosquito control efforts or vaccination campaigns. “The bigger the problem, the more important become any efforts to prevent it,” says Donald Shepard, a health policy researcher at Brandeis University in Waltham, Massachusetts, who studies dengue.

Source: Nature

Oral Regimen Temporarily Suppresses Resistant Gut Bacteria.

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An oral regimen of colistin and neomycin suppresses extended-spectrum beta-lactamase in patients, but the effect of treatment disappeared within 7 days, according to a new study.

There have been attempts to eradicate these resistant bacteria, but most previous research has been uncontrolled or used case studies. “This is the first really methodologically sound and well-controlled study in this area. We tried to improve the evidence base,” Stephan Harbarth, MD, associate professor of infectious diseases and infection control at Geneva University Hospitals in Switzerland, told Medscape Medical News.

This regimen could be used to combat outbreaks and prepare patients for surgery, said Dr. Harbarth, who presented findings here at the 23rd European Congress of Clinical Microbiology and Infectious Diseases.

In the single-center, double-blind, placebo-controlled trial, adults with a rectal swab that tested positive for extended-spectrum beta-lactamase were randomized to 1 of 2 groups. A total 27 patients received colistin (50 mg 4 times daily) and neomycin (250 mg 4 times daily) for 10 days, plus nitrofurantoin (100 mg 3 times daily) for 5 days if they had a positive urine culture at baseline; and 27 patients received placebo.

The researchers conducted cultures (rectal, inguinal, urine) on day 6 of treatment, day 1 after the end of treatment, and day 7 after the end of treatment. The primary outcome was the detection of Enterobacteriaceae by rectal swab at 28 ± 7 days after the end of treatment. When primary outcome data were missing, they were imputed on the basis of the last observation.

There was no significant difference between the 2 groups at 28 ± 7 days after the end of treatment. However, there were differences during and soon after treatment.

Patients in the treatment group were more likely to experience liquid stool than those in the placebo group (25.9% vs 6.9%; P = .05). Inguinal Enterobacteriaceae colonization was present in 29 of 58 patients at baseline, whereas urinary colonization was present in 12 patients in the treatment group and 7 in the placebo group. There was no difference between the 2 groups for inguinal or urinary colonization at any point during the study.

In the treatment group, there was no significant change in minimum inhibitory concentration of colistin from baseline to 28 ± 7 days after the end of treatment.

Although the primary end point was not met and the regimen can’t be used for broad-scale control of infection, “it’s an infection-control measure that could be useful for suppression of this multiresistant carriage in the gut flora. In certain situations, like epidemics or prior to high-risk surgery, this could be a valuable intervention,” said Dr. Harbarth.

He pointed out that modifications to the regimen might be more successful. Different agents that are more active in the colon might improve outcome, probiotics could be used, and drug dosages could be refined. It could also be that one of the drugs used — neomycin — was underdosed in the study, Dr. Harbarth added.

“The results were interesting, but sadly disappointing,” session moderator Hilary Humphreys, MD, professor of clinical microbiology at the Royal College of Surgeons in Dublin, Ireland, told Medscape Medical News. This study confirms that “it’s very difficult with a temporary suppression regimen to see permanent eradication in the gastrointestinal tract, because there are huge numbers of bacteria and the physiology and the environment where those bacteria exist is very complex.”

Dr. Humphreys said he agrees that the regimen could be applied to outbreaks and during preparation for major surgery. “I think those are probably its major uses.”

Source: medscape.com

 

 

C difficile: 10% of Patients Are Carriers at Hospitalization.

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One in 10 (9.7%) patients has asymptomatic Clostridium difficile(CD) colonization at the time of hospitalization, according to a new study. The 3 main risk factors for colonization are recent hospitalization (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.02 – 5.84), chronic dialysis (OR, 8.12; 95% CI, 1.80 – 36.65), and corticosteroid use (OR, 3.09; 95% CI, 1.24 – 7.73).

Surbhi Leekha, MBBS, MPH, from the Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, and colleagues present their analysis of adults admitted to a tertiary care hospital in an article published in the May issue of the American Journal of Infection Control. Approximately half of admissions were enrolled in the study, but only 22% of admitted patients provided stool samples (n = 320).

Colonization rates were determined by polymerase chain reaction analysis of formed stool. This approach circumvented the problems associated with anaerobic cultures.

The data are consistent with a previous large, multicenter study in Canada, which demonstrated that recent hospitalization is a risk factor for CD colonization. A previous study has also demonstrated that individuals receiving chronic dialysis are at risk for CD infection. This is the first study, however, to demonstrate that corticosteroid use is a risk factor for CD colonization.

The authors note that although CD epidemiology has changed during the past decades, the risk factors for infection appear to be unchanged.

“We propose that elucidation of risk factors for CD colonization could help identify asymptomatic individuals for targeted surveillance in selected hospital settings such as high endemicity despite the use of other control measures or epidemic situations. Potential infection prevention measures to prevent CD transmission from asymptomatically colonized patients include contact precautions, hand hygiene with soap and water, and environmental cleaning with a sporicidal agent. In our population, by targeting those with identified risk factors, we would need to screen approximately half of those patients with anticipated stays >24 hours, to identify three-fourths of those colonized with C difficile,” the authors write.

Source: medscape.com

 

 

The Long-Term Effects of Childhood Bacterial Meningitis.

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Adult survivors of childhood bacterial meningitis have lower educational achievement and a lower likelihood of economic self-sufficiency than matched healthy controls.

 

The short-term sequelae of childhood bacterial meningitis can include hearing loss, motor deficits, seizures, and cognitive impairment. But what about functioning in adult life? In a recent cohort study, investigators used national patient registries in Denmark to compare the educational achievement and economic self-sufficiency of individuals with meningococcal, pneumococcal, or Haemophilus influenzae meningitis diagnosed between 1977 and 2007, before age 12 years, with those of age- and sex-matched controls who had not had meningitis. To assess for family-related cofactors, the researchers also evaluated the siblings and parents of these two cohorts.

Survivors of pneumococcal or H. influenzae meningitis were less likely than matched controls to complete high school or to obtain higher education by age 35. They also were less likely to attain these goals than their siblings, who performed similarly to the siblings of controls. In contrast, although meningococcal meningitis survivors were less likely than controls to complete high school or to obtain higher education by age 35, these survivors had educational achievement comparable to that of their siblings, who had lower achievement than the siblings of controls. Educational achievement was lower among parents of meningococcal meningitis survivors than among parents of controls; achievement among pneumococcal and H. influenzae meningitis survivor parents was comparable to that among controls. By 2010, fewer survivors than controls were economically self-sufficient (–3.8%, –10.6%, and –4.3%, respectively, for meningococcal, pneumococcal, and H. influenzae meningitis).

Comment: This large, well-designed study confirms sustained intellectual and economic sequelae of childhood bacterial meningitis but also suggests different routes to these long-term effects. Intellectual and economic impairments are likely direct consequences of the severity of pneumococcal and H. influenzae meningitis. However, family factors appear to predominate in the poorer intellectual and economic achievements of meningococcal meningitis survivors.

 

Source: Journal Watch Infectious Diseases

 

Novel Avian-Origin Influenza A (H7N9) Virus in China.

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130418094043-china-bird-flu-0418-horizontal-galleryTesting of throat-swab specimens from three patients who died of severe lower respiratory tract disease revealed infection with a novel reassortant H7N9 virus.

 

Because of the morbidity and mortality associated with H5N1 influenza, avian influenza virus infection in humans has garnered considerable attention. Now, investigators describe the clinical profile of three patients in China who died from complications of severe lower respiratory tract disease caused by a novel reassortant avian-origin influenza A (H7N9) virus.

Two of the patients (one residing in Shanghai, the other in Anhui Province) had been present at a chicken market within 7 days of illness onset; the third (also from Shanghai) had no known exposure to live birds within the preceding 2 weeks. All three patients had “high” fever, cough, and dyspnea, and all of them developed acute respiratory distress syndrome. All also had leukopenia, lymphocytopenia, and ground-glass opacities and consolidation on chest radiography, and two of them manifested rhabdomyolysis. Two patients died within 10 days of hospital admission, and the third one within 20 days.

Throat-swab specimens obtained from the patients were subjected to viral propagation in pathogen-free embryonated chicken eggs and RNA extraction. Real-time reverse-transcriptase polymerase chain reaction, genome sequencing, and phylogenetic analysis revealed that all three patients had been infected with a novel avian-origin influenza A (H7N9) virus.

Comment: On the basis of the findings from these patients, diagnostic tests for the novel reassortant H7N9 viruses have been developed. Public health officials around the world continue to closely monitor this outbreak, which serves as a reminder of influenza viruses’ unique capacity to evolve and cause respiratory tract infections in humans.

Source: Journal Watch Infectious Diseases