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Capacity and use of diagnostics and treatment for patients with severe acute respiratory infections in the pre-COVID-19 era in district and provincial hospitals in Viet Nam

Objective To describe the burden of severe acute respiratory infection (SARI) and the infrastructure and current practices of SARI management in hospitals in Viet Nam. Methods We conducted a short observational study at critical care units (CCUs) in 32 district hospitals and 16 provincial hospitals in five provinces in Viet Nam from March to July 2019. We collected data on hospital equipment and medicines used in SARI management. At the patient level, data were collected for 14 consecutive days on all patients presenting to CCUs, including information on demographics, intervention and treatment within 24 hours of CCU admission and 7-day outcome. Results There were significant differences between district and provincial hospitals in the availability of microbial culture, rapid influenza diagnostic tests, inflammatory markers and mechanical ventilation. Among 1722 eligible patients admitted to CCUs, there were 395 (22.9%) patients with SARI. The median age of SARI patients was 74 (interquartile range: 58–84) years; 49.1% were male. Although systemic antibiotics were available in all hospitals and were empirically given to 93.4% of patients, oseltamivir was available in 25% of hospitals, and only 0.5% of patients received empiric oseltamivir within 24 hours of admission. The 7-day mortality was 6.6% (26/395). Independent factors associated with 7-day mortality were septic shock and requiring respiratory support within 24 hours of admission. Discussion SARI is a major burden on CCUs in Viet Nam. Barriers to delivering quality care include the limited availability of diagnostics and medication and non-protocolized management of SARI in CCUs.


Data collection
SARI cases were defined as: 1) a history of fever or measured fever ≥38 °C, 2) cough, 3) symptom onset within the past 10 days and 4) requiring hospitalization. 20 Patient outcomes were evaluated at 7 days after admission to the CCU, or when the patient was discharged or transferred to another hospital, whichever came first.
We collected data related to clinical management of SARI in the CCUs from hospital administration records and the patients' medical records. Data from hospital administration records included information on the availability or use of laboratory tests and medication given to the patients to manage SARI and sepsis that follow international and national guidelines. 21, 22 Demographic characteristics, onset of symptoms and medical history were collected using a modified standardized questionnaire on arrival to the CCU. 23 Relevant comorbidities included chronic cardiac disease, chronic renal disease, chronic liver disease and chronic respiratory disease, according to World Health Organization definitions of pre-existing conditions associated with increased risk of severe influenza or death. 24 We calculated the quick sequential organ failure assessment (qSOFA) score within the first 24 hours of admission, giving one point for each of three criteria: respiratory rate ≥22 breaths/ minute, altered mentation and systolic blood pressure ≤100 mmHg. 22 For each patient, information on relevant treatments and interventions during the first 24 hours of admission and early mortality (within 7 days of CCU admission) was also extracted from patients' medical records.

Ethics
This study was approved by the Institutional Review Board of Hanoi Medical University (approval number 59/GCN-DDNCYSH-DHYHN). All participants or legal guardians were informed about the study's purpose and gave their verbal consent for use of their data. The need for written consent was waived by the Institutional Review Board because the data collected were extracted from medical records as part of routine clinical care, with minimal risk of harm to the participants.
(CCUs) in LMICs is challenged by a relative lack of epidemiologic data, context-specific effective interventions and resources. 6-8 In addition, during outbreaks, health care systems and CCUs are under a greater burden. 9,10 However, protocolization of critical care in LMICs is limited, and the use of available diagnostics and treatment in this setting is not well known. 11 Viet Nam is an LMIC that has experienced many outbreaks of emerging infectious respiratory diseases such as SARS-CoV, avian influenza A(H5N1) and SARS-CoV-2. 12-14 Most of the SARI studies in Viet Nam mainly describe clinical and pathological characteristics but give little information about the concordance between clinical management capacity and the availability of medical supplies in association with patient outcome. 15-17 Our previous assessment of health care infrastructure capacity to respond to SARI indicated enormous limitations on relevant structural and human resources in selected district and provincial hospitals in Viet Nam. 18 This study describes current practices in SARI case management and the burden to CCUs on medical resources in district and provincial hospitals in Viet Nam in the months leading up to the COVID-19 pandemic.

Study design
This was a multi-centre, prospective, observational study to evaluate the management and outcomes of patients with SARI who were admitted to CCUs in Viet Nam. As of 2019, Viet Nam had 63 provinces divided into six administrative regions, with a population of 96.5 million. 19 Per 10 000 inhabitants, Viet Nam had 28.5 hospital beds and 8.8 medical doctors. 19 In this study, we used convenience sampling to select five provinces from different administrative regions. In each province, we invited all hospitals at the provincial and district levels to participate in the study. In each participating hospital, we excluded surgical CCUs and paediatric CCUs. Between March and July 2019, all participating hospitals underwent a 14-day observational period. During the first 7 days, all patients aged ≥18 years admitted to the eligible CCUs were enrolled in the study, and all were observed for outcomes for 7 days from their enrolment.  Table 1). However, the duration from symptom onset to hospitalization was higher in patients with SARI presenting to district CCUs than in those presenting to provincial CCUs (median, 2 days vs 1 day, respectively).
Most district and provincial hospitals had the essential supplies and equipment to conduct diagnostic testing (e.g. chest X-ray and complete blood count) and to treat patients with SARI and sepsis. However, specific laboratory testing capacity was more available in provincial hospitals than in district hospitals, for example, for blood and sputum culture, inflammatory markers (C-reactive protein and procalcitonin), lactate, arterial blood gas and influenza A and B antigen detection ( Table 2).
To further elucidate the impact of testing deficiency on the frequency of indicated investigations, we evaluated the association between the percentage of test availability and the proportion of SARI patients who received the corresponding test at each hospital level (Fig. 1a). In district hospitals, the frequency of patients who received each specific laboratory test was limited in terms of testing capacity, expressed by a significantly positive correlation (r = 0.96, P < 0.001). Meanwhile, in provincial hospitals, the relationship between testing capacity and frequency of testing displayed a positive trend (r = 0.36, P = 0.09) (Fig. 1a). Noticeably, among patients with SARI, 95.5% of patients in district and 62.8% of patients in provincial hospitals had no microbiological testing for etiology (Fig. 1c).
Among the 395 patients who met the case definition of SARI, 340 (86.1%) underwent chest X-ray, of whom 225 (66.2%) had X-ray confirmed pneumonia. However, only 8/395 patients (2%) received rapid influenza diagnostic tests, 32/395 (8.1%) received blood cultures and 44/395 (11.1%) received sputum cultures to identify the etiology of SARI. No patients were tested via polymerase chain reaction (PCR) assay for respiratory viruses, including influenza, which could be due to a deficiency of PCR machines in the participating hospitals: only three of 48 hospitals (6.3%) had the capacity to perform on-site PCR testing. In all patients with SARI diagnosis on admission, 88.4% (349/395) received empiric intravenous antibiotics within 24 hours of admission, whereas only

Statistical analysis
Data collected on paper case report forms were entered into an electronic database (EpiData, Odense, Denmark). The proportion of patients who received laboratory tests was calculated as the number of patients who received a test divided by the total patients admitted to all CCUs in which the test was available. Statistical analysis was performed using R software version 3.6.1. All categorical data were calculated as frequencies and compared using chisquared or Fisher's exact test, as appropriate. Continuous variables were given as medians with interquartile range (IQR), and comparisons between groups were performed using the Mann-Whitney U test or Kruskal-Wallis test, as appropriate. Cox proportional hazards regression was used to identify variables that predicted 7-day mortality. P values <0.05 were considered statistically significant.

RESULTS
Of the 51 hospitals invited to participate in the study, 48 responded (94% response rate). A total of 1759 patients were admitted to the 48 participating CCUs between March and July 2019 (Appendix Fig. 1 Table 4).

DISCUSSION
Our study shows that SARI remains a burden on the Vietnamese health care system. A considerable proportion of SARI cases (22.9%) were admitted to CCUs, and 7-day mortality (6.6%) was not negligible in the pre-COVID-19 era. Laboratory testing for SARI was severely limited in the district hospitals and underused in the provincial hospitals included in this study.
Previous studies in developing countries demonstrated that SARI was common among patients admitted to emergency departments (range of about 20-30%). 25, 26 In a surveillance study of 15 sites in Viet Nam during 2006-2010, the hospital admission rates in outpatients presenting with influenza-like illness (ILI) -defined as a measured temperature of 38 °C or more and cough and/ or sore throat -was 9.3%. Of 6516 outpatients with ILI tested for influenza by PCR, 22% were positive. 27 In a study of hospital admissions in a tertiary paediatric hospital in Hanoi during 2007-2014, pneumonia and bronchitis were the leading causes and accounted for 24.5% and 19.1% of all emergency visits, respectively. 28 In 2016, SARI surveillance on 4003 specimens revealed 0.5% (2/395) received empiric oseltamivir treatment. The proportions of patients with SARI requiring oxygen therapy, invasive mechanical ventilation or vasopressors were 73.2% (289/395), 7.3% (29/395) and 4.8% (19/395), respectively, and the proportions were higher in provincial CCUs than in district CCUs ( Table 3). The median age of patients receiving oxygen therapy and mechanical ventilation within 24 hours of admission was 76 (IQR: 63-85) and 77 (IQR: 65-88), respectively. Use of corticosteroids was common in patients with SARI (238/395 [60.3%]), particularly in district CCUs ( Table  3). The overall rate of corticosteroid use in patients needing supplementary oxygen or invasive mechanical ventilation was 63.3% (183/289) and 65.5% (19/29), respectively, compared with 50% (51/102) in patients without respiratory support.
The overall 7-day mortality in patients presenting to CCUs was 6.6% (26/395) (Appendix Fig. 1). The 7-day mortalities in patients initially admitted to district and provincial CCUs were 10/247 (4%) and 16  rate was lower at 6.6%. This may be due to the greater number of patients in district hospitals, where the clinical severity of cases tends to be milder, and to early mortality being assessed at day 7 after admission, which can lead to underestimation of the mortality rate in CCUs and hospitals.
In our study, SARI cases tended to be older and had more chronic cardiovascular and respiratory comorbidities than the general population. This is concordant with previous studies in which SARI cases tended to be associated with risk factors including older age and underlying heart and pulmonary diseases. 29,30 that 20.2% were positive for influenza virus and 41.8% were positive for at least one non-influenza respiratory virus (including 16.2% respiratory syncytial virus, 13.4% rhinovirus, and 9.6% adenovirus and other viruses). 15 During the study period, the participating hospitals were not actively involved in SARI sentinel surveillance, and no data were reported.
One study conducted at a provincial hospital in Viet Nam in 2009-2010 demonstrated a case mortality rate of 9.8% among hospitalized patients with communityacquired pneumonia. 17 In our study, the number of SARI cases admitted to CCUs was higher, but the mortality Dat  surveillance study in Egypt demonstrated that patients for whom pathogens were identified had a significantly lower rate of intensive care unit admission, length of hospital stay and overall mortality than those with unknown etiology. 33 Although the predominant pathogens in SARI cases are presumably viruses, especially influenza (up to 50% of tested respiratory samples from previous surveillance in Viet Nam), 15,27,34 strengthening laboratory We found an apparent disparity in laboratory testing capacity between district and provincial hospitals in Viet Nam. Although the diagnosis of respiratory infections is more commonly based on physical examination, chest imaging and identification of pathogens are key to clinical management, especially in critically ill patients. Laboratory testing also contributes to identifying and preventing issues with antimicrobial resistance. 31,32 A SARI Fig. 1.

B. C.
ABG: arterial blood gas; CBC: complete blood count; CRP: C-reactive protein; CXR: chest X-ray; PCT: procalcitonin; RIDT: rapid influenza diagnostic tests. We found that 93.4% of patients in our study were given empiric antibiotics within the first 24 hours of admission, but only a small number of patients received antiviral drugs. For patients with SARI presenting to CCUs, the use of empiric antimicrobials on admission is reasonable and recommended. 31 Corticosteroids were more commonly used in district hospitals than in provincial hospitals, although international guidelines advise against routinely using corticosteroid therapy in patients with community-acquired pneumonia. 31 In our 2017 survey, we noted a shortage of supplies and equipment in the district hospitals compared with provincial hospitals and a lack of ventilators at both hospital levels. 18 In this study, we reaffirmed that -in addition capacity in order to identify causal pathogens is critically important for the management of not only SARI but also of other emerging and re-emerging diseases, considering the current burden of SARI cases in CCUs in Viet Nam. In regards to laboratory testing, in addition to microbiological identification tests (blood culture, sputum culture or viral PCR for respiratory tract specimens), other investigations recommended for severity assessment, antibiotic de-escalation and mortality prediction in SARI include blood gas analysis or inflammatory and sepsis markers (C-reactive protein, procalcitonin and lactate). [35][36][37][38][39] The shortage and underuse of these tests in our study reinforces the need to develop a care bundle for SARI management to further improve the quality of care in LMICs.
to the availability of equipment -supply of and access to laboratory tests for critical care in district hospitals were still insufficient for SARI management. The current SARS-CoV-2 pandemic has highlighted vulnerabilities of the critical care system for SARI management caused by a shortage of supplies, especially ventilators, even in developed countries. 40 Under the current situation of COVID-19, accurate diagnosis of SARS-CoV-2 is solely based on nucleic acid amplification tests, which have major capacity constraints in almost all CCUs in district hospitals. Hence, both the limitations of laboratory and supply capacities are major obstacles for CCUs in district hospitals in Viet Nam to cope with COVID-19.
There were several limitations in our study. First, because the study hospitals were selected by convenience sampling, the findings were not representative of the capacity of the health care system nationwide, although we believe it reflected the general situation in Viet Nam. Second, for the purposes of this study, SARI was defined using clinical symptoms. Without a doctor's justification, there may have been bias in actual diagnosis and indications for investigations (i.e. the hospital doctors may have another differential diagnosis that indicated different practices for laboratory test orders).
In conclusion, our study reported a high rate of CCU admission among SARI patients in selected district and provincial hospitals in Viet Nam. With the current insufficiencies in diagnostic and treatment capacity in district hospitals and underuse in provincial hospitals, it is recommended that a standardized protocol for SARI management in resource-constrained settings be developed to improve quality of care.