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To evaluate the efficacy of chemoprophylactic dose of oseltamivir in preventing H1N1 by comparing the rates of acute respiratory illness and H1N1 positivity of respiratory specimens between HCP with and without consumption of oseltamivir working in swine flu ICU.
The study was conducted on HCP posted in “Swine Flu Intensive Care Unit” from October 2009 to March 2010. Data on infection control measures, chemoprophylactic use of oseltamivir, flu-like illness, ADRs to oseltamivir, and contact history in family and neighborhood were collected by face-to-face interview conducted by investigator using a set of prespecified items in a questionnaire.
All HCP used infection control measures like using long-sleeved cuffed gown, gloves, cap, shoe cover, and N95 mask, and frequent hand washing. There was no history of any unprotected contact with an H1N1-positive case. Out of 100 HCP, 69% took chemoprophylaxis. There was no significant difference in incidence of flu-like illness between HCP who took chemoprophylaxis (48%) and those who did not (29%, P = 0.18). H1N1 testing was done on 17 HCP, but all tested negative. Incidence of adverse effects to chemoprophylactic dose of oseltamivir was high (57%). The most commonly reported adverse effects were nausea (54%), gastritis (51%), and headache (38%).
Chemoprophylaxis with oseltamivir is not recommended for HCP working in areas of high aerosol generation like ICU if infection control measures are adopted as there is no significant difference in the incidence of flu-like illness in HCP with and without intake of oseltamivir. This protects HCP from various adverse effects of the drugs, like nausea, gastritis, and headache.
Healthcare personnel (HCP) are at an increased risk of acquiring infectious diseases like H1N1 due to their occupational exposure and infection control measures need to be undertaken to prevent them. In a study of 328 HCP infected with H1N1 virus in Korea, 77.3% had not used an N95 mask during contact with the patients. Intermittent use of surgical masks was done by 46.9%, whereas only 29.4% of the HCP made proper use of surgical mask. In contrast, study of 66 HCP working in a hospital in Amsterdam with high standards of hygiene demonstrated a low incidence rate (incidence rate in the high-risk group was 5.7/1000 person weeks) of influenza A (H1N1) infection during the 2009 pandemic. None of the HCP belonging to intermediate- and low-risk groups tested positive for H1N1 by reverse transcriptase polymerase chain reaction (RT-PCR). However, studies describing the incidence rates of nosocomially acquired H1N1 infection among HCP in India are lacking.
During 2009 H1N1 pandemic, Ministry of Health and Family Welfare, Government of India, issued guidelines on use of personal protective equipment (PPE), antiviral prophylaxis, isolation, and management strategies for HCP in contact with suspected, probable, or confirmed cases of H1N1 infection. One of the most controversial guidelines for HCP was regarding chemoprophylaxis with oseltamivir.
This study was conducted to evaluate the effectiveness of oseltamivir when used for chemoprophylaxis against H1N1. Information on the incidence of suspected and confirmed cases of H1N1 infection among HCP directly involved in management of infected patients was collected and the incidence of adverse effects noted.
The study was conducted in a tertiary care hospital in New Delhi with a seven-bedded dedicated “Swine Flu Intensive Care Unit,” from October 2009 to March 2010. Infection control guidelines adopted in the intensive care unit (ICU) and by the HCP in the study were based on those recommended by the Ministry of Health and Family Welfare, Government of India, and were approved by the hospital administration. It was mandatory for all HCP working in the ICU to wear PPEs which consisted of N95 mask, long-sleeved cuffed gown, gloves, cap, and shoe cover, with emphasis on frequent hand washing every time contact was made to any object or patient in the ICU. All HCP had got training on infection control measures regarding H1N1. No personal belongings were allowed in the ICU, not even mobile phones, pen, etc. Regarding chemoprophylactic intake of oseltamivir, the hospital administration provided the drug to all HCP but ultimate decision on its intake was left on the HCP. Ethics committee approval was waived off as the study was observational and retrospective and dealing with H1N1 pandemic.
Written informed consent was taken from all HCP included in the study. Data were collected by face-to-face interview of the HCP by trained staff using a set of prespecified items in a detailed questionnaire shown in Appendix. Demographic data, data on use of infection control measures, use of oseltamivir for chemoprophylaxis, adverse effects of oseltamivir, flu-like illness, H1N1 testing, and history of any unprotected contact were recorded. HCP (doctors and nurses) included in the study were those with fixed duration of exposure in Swine Flu ICU for 14 days. All interviews were conducted within 15–30 days after last exposure in the ICU.
Dose of oseltamivir used for chemoprophylaxis was 75 mg and was administered on a daily basis during the entire period of exposure in the ICU, i.e. 14 days. Thus, HCP in our ICU took chemoprophylaxis in addition to using PPE and infection control measures. Monitoring for clinical features suggestive of flu-like illness was done for 7 days after last exposure in ICU. Testing for H1N1 was done using real-time RT-PCR in nasal and oropharyngeal specimens for patients with high-grade fever and severe cough and rhinitis.
Adverse drug reactions (ADRs) were defined as an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product. The severity of the reaction was determined based on the lines of that mentioned by Hartwig et al. as given below:
Incidence of flu-like symptoms in HCP with and without chemoprophylactic intake of oseltamivir was expressed as percentage and analyzed with Chi-square test. Odds ratio (OR) with 95% confidence interval (CI) were also calculated. P values <0.05 were considered significant. Adverse effects of oseltamivir with grades of severity were also expressed as percentage. Student's t-test was used to analyze demographic data.
One hundred and fifty HCP were interviewed, of which 100 were included in the study. 70% were doctors and 30% were nurses. None of them had any co-morbidities. 60% were aged less than 30 and the remaining 40% were less than 40 years. Demographic data were comparable between the two groups, with almost equal sex distribution. None of them had received any prior influenza vaccine. Reasons for exclusion of 50 HCP from the study were extended duration of chemoprophylaxis (10 days after last exposure in ICU: 15 HCP), increase of dosage of oseltamivir to 75 mg BD on appearance of flu-like illness (23 HCP), and noncompliance with chemoprophylaxis, missed dosing (12 HCP).
Of the 69 HCP who took chemoprophylaxis, 48% developed flu-like illness. Thirty-one HCP did not take any chemoprophylaxis and flu-like illness was reported in 29% (OR: 1.994; 95% CI: 0.803–4.950; P = 0.186). Incidence of various signs and symptoms reported by HCP in each group was compared [Table 1].
Nasal and oropharyngeal swabs for RT-PCR were collected from 17 patients. Nine were not taking oseltamivir, whereas eight were on chemoprophylaxis. None of the HCP tested positive for H1N1.
Sixty-three HCP were married or cohabiting; The number of contacts per HCP is depicted in Figure 1. Sixteen percent of contacts of HCP who did not take chemoprophylaxis reported flu-like illness, whereas 13% of contacts of HCP who took chemoprophylaxis reported of influenza-like illness (P = 0.39).
Percentage of HCP taking oseltamivir and reporting an adverse effect was 57%. Commonly reported side effects of drug oseltamivir include nausea, gastritis, and headache of mild, moderate, and mild severity, respectively [Table 2, Figure 2].
Treatment with oseltamivir in Influenza like illness reduces lower respiratory tract complications by 55%, antibiotic use by 26%, and hospitalization by 59%. Thus, use of neuraminidase inhibitors for treatment of H1N1 patients with risk factors such as extremes of age, pregnancy, immune suppression, and co-morbid conditions is non-controversial. But US Food and Drug Administration (FDA) and World Health Organization (WHO) guidelines do not support the use of neuraminidase inhibitors for therapeutic use in healthy adults with mild disease.
Post-exposure prophylaxis entails giving oseltamivir to exposed persons before the symptoms develop, and the effectiveness of oseltamivir in preventing influenza in household contacts has been proved.
Systematic review and meta-analysis by Acute Respiratory Infections Group, Cochrane Collaboration, Rome, evaluated two studies[11,12] in which oseltamivir (75 mg daily) was used for chemoprophylaxis. No conclusion could be drawn as evidence was insufficient to support or refute the use of oseltamivir for chemoprophylaxis against flu-like illness.
The meta-analysis also highlighted the safety data of neuraminidase inhibitors. Nausea was the most commonly reported adverse effect of oseltamivir (OR: 1.79; 95% CI: 1.1–2.93) and was higher with the dose of 150 mg given daily. Evidence for possibility of oseltamivir to induce sudden behavioral changes in recipients (hallucination, suicidal tendencies, and sudden death while asleep) came after a review was ordered by the Japanese government, triggered by the 567 serious neuropsychiatric cases received since the launch of the drug. Thereafter, prospective clinical trials have reported neuropsychiatric events at a rate of 0.5% with use of oseltamivir, whereas retrospective studies have mentioned an incidence of 20–27 neuropsychiatric adverse events per 1000 adults at 14 days and 30–40 neuropsychiatric adverse events per 1000 adults at 30 days.
Most of the studies evaluating the role of neuraminidase inhibitors have been conducted during seasonal influenza outbreaks. In pandemics, large population of healthy adults are at risk of acquiring influenza, but with a low incidence of severe respiratory tract complications. Neuraminidase inhibitors do not prevent infection or stop nasal viral excretion and are thus a suboptimal means of interrupting viral spread in a pandemic.
Novel influenza viruses are very efficient agents causing rapid spread and transmission of disease, and thus lead to outbreaks in healthcare settings. But evidence-based data available to guide infection control measures during pandemics are scarce. The use of N95 respirators instead of surgical masks for all close contacts during a pandemic is recommended based on evidence-based studies. A study conducted in Hong Kong during 2009 H1N1 epidemic also concluded that not wearing a surgical mask either by the exposed persons during contact with the index cases (4/4 vs. 264/832, P = 0.010) or vice versa (4/4 vs. 300/832, P = 0.017, Fisher's exact test) was one of the most significant risk factors for nosocomial acquisition of H1N1.
Incidence rates of H1N1 infection among HCP during 2009 pandemic have been described in two previous studies.[1,2] Attack rates were high when infection control measures were not followed, but low when proper measures were undertaken. Till date, no study compares the incidence rates in HCP with and without chemoprophylactic intake of neuraminidase inhibitors. We, in our study, attempt to highlight the advantages and disadvantages of chemoprophylactic intake of oseltamivir by HCP following infection control measures in places of high aerosol generation – Swine Flu ICU.
The results of our study report no significant difference in the incidence of flu-like illness and H1N1 infection among those who took chemoprophylaxis in comparison to those who did not. There was no significant difference in the incidence of flu-like illness among close contacts of HCP in the two groups. Instead, 57% of HCP who took oseltamivir reported an ADR – nausea, gastritis, and headache in decreasing order of frequency. But none reported any severe or life-threatening complication. Thus, we conclude that chemoprophylaxis with oseltamivir is not required by healthy HCP using PPE in areas of high aerosol generation like ICU. There is no clinically significant advantage in terms of protective efficacy. In contrast, incidence of adverse effects is high.
ADRs of therapeutic and prophylactic doses of oseltamivir were also studied during the 2009 H1N1 pandemic by Anovadiya et al. Causality, severity, and preventability assessments were also done. Frequency of ADRs in therapeutic and prophylactic groups was compared with phase III trial of oseltamivir. Therapeutic group reported significantly higher incidence (62%) and severity of ADRs in comparison to prophylactic group (41%). Common ADRs in both the groups were gastritis, nausea, vomiting, diarrhea weakness, sedation, loneliness, sadness, headache, and abdominal pain. Results of our study also report an incidence of 57% of ADRs among HCP. Though nausea and gastritis were the most common similar to the previous study, headache was reported as the third most frequently reported ADR, which is in contrast to the previous study.
Limitations of our study include its retrospective design and recall bias of HCP interviewed. However, the recall period did not extend beyond 15 days, and thus likelihood of this limitation is low. Another possible bias may be regarding exposure to H1N1 infection from external sources, e.g. community, neighborhood. To prevent this, we did inquire all HCP for any contact with a suspected H1N1-positive patient outside the hospital, but none of them reported any such exposure. Testing for H1N1 was not done in all HCP and we identified “flu-like illness” based on clinical features. Testing was limited to HCP with severe manifestations only. This could probably underestimate the number of HCP infected as the subclinical forms and those with mild illness could be missed out. Use of neuraminidase inhibitors for therapeutic use in healthy adults with mild disease is not recommended, and thus we did not attempt to identify or treat these mild forms which are self-limiting in nature and without any adverse sequel.
Indiscriminate use of oseltamivir increases the risk of development of oseltamivir-resistant H1N1 virus and is discouraged. During influenza pandemics, emphasis should be laid on infection control procedures, use of PPE, and hand washing. There is a paucity of clinical trials on the use of oseltamivir during pandemics, as highlighted by Gupta et al. Our study makes an attempt to describe the protective efficacy and safety of oseltamivir when used for chemoprophylaxis for HCP in contact with H1N1 infected patients. Further research is needed in the form of randomized controlled trials with a large sample size.
Source of Support: Nil.
Conflicts of interest: None declared.