Impact of Infection on Glycemic Control in Diabetic Patients; a Hospital-based Cohort Study in Pakistan

58.3%) had poor-control. The mean pre-infection HbA1c in good-control diabetic patients was 6.2% while in poor-control was 8.5% (p: 0.000). While the mean post-infection HbA1c in the good-control was 6.9% and in the poor-control was 8.3% (p: 0.010). The poor-control group had a higher infection-related death rate (62.5% vs. 37.5%, p: 0.72), and multiple sites of infection (65.2% vs. 34.8%, p: 0.47). In the poor-control group, there was a higher rate of re-infection (52.8 vs. 47.2%, p: 0.45), whereas the rate of septic shock was similar (50%, p: 0.42). Conclusion: Based on our study, we conclude that infection had variable effect on glycemic control . Moreover, diabetes per se had a major effect on infection risk, its severity, and mortality, regardless of glycemic control.


INTRODUCTION
Diabetes is described as a metabolic disorder that elevates blood glucose levels.In 2017, the prevalence of diabetes worldwide was estimated at around 8.4%, and it is expected to rise further in the coming decades [1].Infections had a significant impact and are associated with increased morbidity and mortality in diabetes patients [2].Not only this, it had also been identified that diabetic patients had an increased risk of acquiring infection [3].

Uncontrolled
diabetes had a catastrophic relationship with infections.Diabetic patients with higher glysated hemoglobin A1c (HbA1c) had an elevated long term risk of infection [4].One study of the Danish population reveals that there is a hazard ratio of 1.64 of infections in individuals with an HbA1c of 10.5% [5].On the other hand, there is insufficient evidence that controlling blood sugars has any positive impact on risk of infection and its prevention [6].
For a developing country with high prevalence of diabetes, it is of the utmost importance to recognize the effect of infection on glycemic control.The rationale to conduct this study was to identify the impact of infection on glycemic control i.e.HbA1c in diabetic patients.
It will provide us useful information about the role of glycemic variation and its impact on infection.Secondary objectives were to compare the outcomes (infection related mortality, reinfection, multiple sites of infection, septic shock and length of hospital stay among patients with good and poor glycemic control.

Study setting and duration
It is a cohort study conducted at the Aga Khan University Hospital (AKUH), Karachi, Pakistan.Aga Khan University Hospital is a tertiary care hospital with 650 beds.It is one of the few hospitals in the country which has Joint Commission International Accreditation (JCIA).
The study duration was one year from July 2019 to June 2020.

Study design
This cohort study was conducted on patients admitted to the Department of Internal Medicine at the Aga Khan University Hospital.Patients with diabetes aged 18 or older were selected.The presence of diabetes in patients is identified by HbA1c > 6.5% and/or the use of oral hypoglycemic agents and/or insulin [7].Their record was reviewed and infections were identified on the basis of the following three criteria: a) laboratory parameters that favors infection like cultures growing micro-organisms, high white cell counts and increase inflammatory markers All the patients who had newly diagnosed diabetes were excluded.

HbA1c and Glycemic groups
Patients whose HbA1c was checked within three months prior to the infection were termed as preinfection HbA1c.The records of the patients were followed after three months.All those individuals whose HbA1c was evaluated after three months of infection were labelled as postinfection HbA1c.
All pre-infection HbA1c were subcategorized into two groups that include poor and good glycemic control.The study defined poor glycemic control as HbA1c ≥ 7% and good glycemic control as HbA1c ≤ 6.9% [11].
Comparative analysis was done between patients with infections and poor glycemic control and those with good glycemic control.

Definition of the outcomes
Primary outcome was to identify the level of pre and post infection HbA1c.Secondary outcomes were infection-related mortality, multiple sites of infection, re-infection, septic shock and length of the hospital stay.Infection related mortality was defined as mortality due to the severity of infection and septic shock.Multiple sites of infection means presence of infection in two or more areas of the body.Re-infection was characterized as patients who recovered from infection and became infected again within 6 months.Septic shock was defined as those individuals who had evidence of infection with hemodynamic compromise.Length of hospital stay was the duration of hospitalization of patients

Recruitment of data
Demographics including age, gender, type of diabetes and other co-morbidities were recorded.Glycemic groups were identified on the basis of HbA1c.Different types of infections that were diagnosed were documented.The outcomes of patients were also noted.Clinical presentations on the initial hospital encounter were documented.Radiological features, laboratory parameters and microbiological cultures were also recorded in the study.

Data Analysis
Data analysis was done using IBM Statistical Package for the Social Sciences (SPSS) Version 26.Categorical variables were reported as frequency and percentage while quantitative variables were reported with mean and standard deviation.The continuous and categorical variables were compared using independent sample t-test with level of significance of 0.05.The proportions were compared between groups with chi square with a level of significance of 95%.

Inclusion of the patients
A total of 428 patients were admitted with various infections from July 2019 to June 2020 at the Aga Khan University Hospital, Karachi.Out of these, 228 patients (53.2%) were found to have diabetes.Sixty patients (26.4%) were excluded because of the presence of newly diagnosed diabetes.A total of 168 patients (73.6%) met the inclusion criteria and were included in the study.

Demographics and outcomes of the patients
The mean age of the patients was 67.  1 shows the detailed features of these patients.

Diagnostic evidence of infections
The presence of an infection was identified via three different processes.

Comparison of Pre-& Post-infection HbA1c
The mean pre-infection HbA1c in diabetic patients with good control was 6.2% while in poor control groups it was 8.5% (p = 0.000).After 3 months of recovery from the infection, the mean post-infection HbA1c in the good control group was 6.9% and in the poor control group was 8.3% respectively (p = 0.010).

Glycemic control and outcomes
While comparing the outcomes between good and poor glycemic control, we didn't find any statistically significant difference.The poor glycemic control group had a higher infectionrelated mortality (62.5%), and multiple sites of infection were more common in that group (65.2%).A higher risk of re-infection (52.8%) was observed in the poor glycemic control group, whereas the risk of septic shock was similar in both (50%) groups.Table 3 shows the comparative analysis between the two groups.
The mean length of hospital stay in patients with good glycemic control was 7.3 days.In contrast, the mean length of hospital stay in patients with poor glycemic control was 7.0 days.(Figure 1)

DISCUSSION
Diabetes is highly prevalent in our sub-continent region as almost half of the patients admitted to our tertiary care hospital had diabetes.Majority of the patients had poor glycemic control.Pneumonia and urinary tract infections were the most common infections encountered in our diabetic population.Our cohort study indicates that infections can increase HbA1c levels in patients with well-controlled diabetes, but not significantly in patients with poorly controlled diabetes.We also didn't observe any significant association between glycemic control and infection-related mortality, septic shock, multiple sites of infections, re-infections and length of hospital stay.
There are various hypotheses that chronic hyperglycemia can suppress the immunity of patients and make them more vulnerable to infections.The most common sites of infection in diabetic patients are the urinary tract, skin and soft tissues and respiratory tract [12].Similar to this, pneumonia, urinary tract infection and osteomyelitis were common in our study population.Pulmonary infections tend to have a higher prevalence in the diabetes population  To evaluate this, we compare HbA1c levels before and after infections.We identified that patients with good glycemic control had a mean HbA1c level of 6.2% which increased to 6.9% postinfection (after 3 months).On the other hand, in poor glycemic control patients had a mean HbA1c level of 8.5% pre-infection and 8.3% post-infection.This could be due to the fact that our patients with poorly controlled diabetes were treated aggressively with higher doses of insulin.
A cohort study identified that poor glycemic control is associated with a 3 fold increase risk of infection-related mortality In our study, the mean duration of hospital stay was 7.1 days.Additionally, we noted that patients with well-controlled diabetes stayed longer than those with poorly controlled diabetes but this difference did not reach statistical significance.
There are certain limitations in our study which we need to acknowledge.Firstly, it's a single centered study with a small sample size, so the data cannot be generalized to the whole population.Secondly, we had used HbA1c as a marker for glycemic control and hadn't compared fasting and post-prandial sugars in the diabetic individuals.
To our knowledge, it is the first study that has compared the variation in HbA1c after infections.Though this study had a small sample size, it has provided us with valuable and useful information.Acute infections had a potential to elevate HbA1c levels even after recovery from infection.It is widely known that uncontrolled diabetes can increase the risk and severity of infection.But the data on well-controlled diabetes is scarce.
In our study, we found that there was no difference in infection related outcomes between patients with good and poorly controlled diabetes but infections can disturb glycemic control and required rigorous monitoring of blood glucose for any alteration or adjustment of anti-diabetic medications.

CONCLUSION
We conclude from our study that infection had variable effect on glycemic control.Beside this, diabetes per se had a major influence on risk of infection, its severity and mortality irrespective of glycemic control.The diabetic patient is more vulnerable, so any infection they develop requires urgent medical attention.

[ 8 ]
b) radiological imaging that suggests presence of infection that includes ultrasound or cross section images showing collection or inflammation [9] c) clinical presentation like fever, productive cough, dysuria, purulent discharge that indicate presence of infection [10].

Figure 1 :
Figure 1: Length of hospital stay in good versus poor glycemic control patients.

[ 13 ] 14 .
. Respiratory tract infections are more severe in diabetics when compared with non-diabetics [We also observed that 50.6% of our diabetic patients admitted with pneumonia.The prevalence of urinary tract infection in diabetic patients is 10-12% in the African population[15].Interestingly, the Pakistani population had a higher prevalence of 52.7%[16].In our study, 36.9% of patients with diabetes had urinary tract infection.

Table 1 : Demographic Features and Characteristics of the diabetic patients.
a Other diagnosis includes cellulitis, acute cholecystitis, fungal infections and abdominal sepsis.

Table 3 : Comparison of glycemic control and outcomes.
Ikeda et al. report that hepatitis C patients had pre-treatment HbA1c of 5.85% and post-treatment HbA1c of 5.65% [21].
[19].The impact of intensive glycemic control on risk and severity of infections is not evaluated [20].Mor et al. states that strict glycemic control can prevent infection in type 2 diabetes mellitus patients.5