Correlation between leukocytosis and infection in patients with diabetic ketoacidosis

doi:10.21203/rs.3.rs-3606143/v1

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Research Article

Correlation between leukocytosis and infection in patients with diabetic ketoacidosis

https://doi.org/10.21203/rs.3.rs-3606143/v1

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Background

Diabetic Ketoacidosis, a fatal complication of diabetes, presents in patients with type 1 and type 2 diabetes mellitus. Psychological stress or any acute medical condition, such as infections and surgeries, can trigger and alleviate diabetic ketoacidosis. Like infections, diabetic ketoacidosis can result in leukocytosis, making it harder to distinguish between the two conditions, resulting in the overuse of antimicrobial agents to blindly treat infections, and increasing the rate of antimicrobial resistance, a global threat to humanity.

Methods

A retrospective cross-sectional study was conducted on the correlation between infection and leukocytosis in patients referring to Imam Khomeini Hospital Complex, Tehran, Iran, from September 2018 to September 2022. Comorbidities, clinical findings at admission, acidosis severity, hospitalization duration, laboratory data, and radiologic findings were retrieved using the Hospital Information System and then compared and analyzed.

Results

Of the 129 evaluated patients, 84 showed leukocytosis, while 45 did not. The mean age of participants was 38.17 ± 21.30 years. The total population included 52 males and 77 females; 92 were diagnosed with type 1 diabetes, and 37 had type 2 diabetes, with a mean duration of diabetes of 8.07 ± 6.99. We evaluated the correlation between leukocytosis due to infection in patients with diabetic ketoacidosis and their age, sex, diabetes type, and duration, PH levels, hospitalization duration, erythrocyte sedimentation rate and C-reactive protein levels, chest X-ray findings, blood and urine culture results, patients' prognosis, and presence of an infectious process in general. We found no correlation between leukocytosis and sex, diabetes type, PH levels, and blood cultures. However, there were significant correlations between leukocytosis and infection presence, urine cultures, radiologic findings, patients' age, diabetes and hospitalization duration, and ESR and CRP levels. We also found a white blood cell count threshold of 14.96 as a sign of infection in patients with DKA.

Conclusion

Our findings suggested that a total WBC count of, 14000/mm³ or higher can indicate the presence of infection in patients with DKA, which could indicate the start of antibiotic therapy in such patients.

Trial registration

Not applicable. This study is not a clinical trial.

Diabetic ketoacidosis

leukocytosis

infection

diabetes

Diabetic ketoacidosis (DKA) is one of the life-threatening complications of diabetes. It can occur in type 1 diabetes mellitus (T1DM) and type 2; however, it commonly affects younger adults with type 1 diabetes, with a peak age range of 10 to 14 years. The decrease in effective circulating insulin and the increase in counter-regulatory hormones (growth hormone, glucagon, epinephrine, norepinephrine, and cortisol) are the primary factors that promote glycogen degradation, glucose production, and ketone accumulation, which can lead to this fatal condition.(1, 2) The following biochemistry criteria are required to establish the diagnosis of DKA: blood glucose levels exceeding 11 mmol/L [200 mg/dl], a pH of less than 7.3 or serum bicarbonate 18 mEq/L or less, and ketonemia or ketonuria.(3, 4) Studies have reported a recent surge of DKA at the time of type 1 diabetes mellitus diagnosis, which holds significant clinical importance.(5–7) However, some have shown decreasing trends in DKA incidence at the time of type 1 diabetes diagnosis.(8–11) In 2018, the lowest rate of DKA prevalence in newly diagnosed T1DM was in Denmark (14.7), and Saudi Arabia had the highest prevalence (79.8%). Interestingly, countries with a higher prevalence of type 1 diabetes showed a lower incidence of DKA.(3)

DKA mortality rate in developed and developing countries was < 1% and 3–13%, respectively, primarily due to cerebral edema in children under 12.(11–15) Acute medical conditions, psychological stress, or surgical procedures can precipitate DKA. The most common culprits are infections, such as urinary tract and respiratory infections or gastroenteritis.(16–18)

Numerous studies have discussed leukocytosis in DKA, irrespective of the presence of an infectious process.(19, 20) However, determining whether leukocytosis is attributed to DKA or infections can pose a challenge as they share similar symptoms, such as lethargy, nausea, vomiting, tachycardia, elevated C-reactive protein (CRP), elevated procalcitonin, and leukocytosis and infections are proven to increase mortality rates and hospitalization complications.(21–23) The misuse of antibiotics for blindly treating infections in patients with DKA can devastate anti-microbial resistance (AMR) and financial implications, as The World Health Organization (WHO) has now declared AMR a significant threat to humankind.(24, 25) Therefore, determining whether leukocytosis is attributed to infections or DKA is essential and can significantly reduce mortality and morbidity in patients with DKA and AMR.

Given the limited number of studies conducted on this subject and the significance of distinguishing between DKA and infections, our study was conducted on the correlation between leukocytosis and infection in patients with DKA referring to Imam Khomeini Hospital Complex in Tehran, Iran.

In a retrospective cross-sectional study, we evaluated the correlation between leukocytosis and infection in patients with diabetic ketoacidosis referring to this center from the beginning of September 2018 to September 2022 in a tertiary hospital in Tehran, Iran.

Data collection

Utilizing the Hospital Information System (HIS), we retrieved demographics, comorbidities, characteristics of diabetes, clinical findings at admission (including symptoms, review of systems, vital signs, and physical examination), acidosis severity, hospitalization duration, laboratory data, including erythrocyte sedimentation rate (ESR), CRP, complete blood count with differential (CBC diff), blood culture (B/C), and urine culture (U/C), and radiologic findings.

DKA diagnosis was established based on blood glucose levels exceeding 250 mg/dl, venous PH less than 7.3 or serum bicarbonate less than 15 mEq/L, and the presence of ketonemia or ketonuria. The diagnosis of infection was determined either through clinical examination or the combination of laboratory data and clinical symptoms, including positive B/Cs, positive U/Cs, increased ESR, increased CRP, and abnormal chest X-rays (CXR) and was then categorized into ten groups; urinary tract infections (frequency, urgency, dysuria), meningitis (headache, stupor, vomiting), peritonitis (nausea and vomiting, severe stomach pain, swollen stomach), pelvic inflammatory disease (low back pain, nausea and vomiting, unusual discharge, intermittent bleeding), respiratory infections (tachypnea, cough, chest pain, dyspnea, respiratory distress, crackles), soft tissue infections (redness, warmth, swelling, and discharge), endocarditis (chills, headache, muscle pain, splinter hemorrhage, Osler's nodes, chest pain), gastroenteritis (diarrhea, bloating, nausea and vomiting, abdominal cramps), surgical site infections (redness, warmth, swelling, pruritic discharge of the site of surgery), and COVID-19 (shortness of breath, chest pain, fever, tachycardia, muscle and joint pain, respiratory distress). Leukocytosis was defined as elevated white blood cells (WBCs) over 11.0x10^9/L.

The inclusion criteria were all patients with DKA admitted to the hospital from September 2018 to September 2022. Patients with burns, immune system disorders such as lupus and rheumatoid arthritis, hematologic malignancies, systematic steroid use within the past 30 days, patients with moderate-to-severe COVID-19 pneumonia treated with corticosteroids, and thyroid-related disorders were excluded from this study.

Statistical Analysis

The extracted data was compiled in an Excel spreadsheet, and then the SPSS statistics software was employed to examine the data. (Version 26.0 IBM Corp. Armonk, NY, USA) For quantitative variables, the mean and standard deviation were reported; for qualitative variables, frequency and percentage were reported. Pearson’s correlation coefficient, independent samples T-test, and ANOVA test were used to examine the correlation between variables.

Ethical consideration

The Research Ethics Committee of Tehran University of Medical Sciences approved this study, and patient confidentiality was maintained by coding. (Approval number: IR.TUMS.IKHC.REC.1400.268)

From the beginning of September 2018 to September 2022, we evaluated 129 patients with DKA recruited from a tertiary hospital center in Tehran, Iran. The total population contained 84 individuals with and 45 without leukocytosis. Out of the total of 84, 53 individuals had an infection, while 31 exhibited no signs or symptoms. (Fig. 1)

[Insert Fig. 1 here]

Characteristics of the study population are summarized in Table 1.

Table 1

The characteristics of study participants
Characteristics	Mean	SD	Number	Percentage
Age	38.17	21.30
Male			52	40.3
Female			77	59.6
Diabetes type I			92	71.3
Diabetes type II			37	28.6
Diabetes duration	10.24	8.20
Hospitalization duration	10.25	8.20
PH	7.170	0.12
ESR^a	26.25	36.14
CRP^b	29.46	28.86
Normal CXR^c			80	62.01
Abnormal CXR			49	37.98
Normal B/Cs^d			122	94.57
Abnormal B/Cs			7	5.42
Normal U/Cs^e			109	84.49
Abnormal U/Cs			20	15.50
Infected	14.96	8.16
Uninfected	13.29	7.66
Death			4	3.10
Discharge			125	96.89
^{a Erythrocyte sedimentation rate, b C−reactive protein, c Chest X−Ray, d Blood culture, e Urine culture}

Table 2 displays the mean and standard deviation of the participant's age. Participants of a higher age group exhibited a higher leukocytosis count and infection rate than younger participants, which is statistically significant. (P value = 0.0001)

Table 2

Correlation between leukocytosis due to infection and age
Leukocytosis	Infection	Mean	SD^a	P value
Yes	No	42.67	22.887	0.0001
	Yes	52.17	25.145
	Total	47.85	24.251
No	No	30.28	16.749
	Yes	33.00	12.871
	Total	31.07	15.633
	No	34.23	19.558
Total	Yes	44.13	22.737
Total	Total	38.17	21.3000
^{a Standard Deviation}

Table 3 shows no statistically meaningful correlation between sex and leukocytosis. (P value = 0.070)

Table 3

Correlation between leukocytosis due to infection and sex
Leukocytosis	Infection		Sex		Total	P value
Leukocytosis	Infection		Male	Female	Total	P value
Yes	No	Number	14	17	31	0.393
	No	%	40.0%	34.7%	36.9%
	Yes	Number	21	32	53
	Yes	%	60.0%	65.3%	63.1%
	Total	Number	35	49	84
	Total	%	100.0%	100.0%	100.0%
No	No	Number	16	16	32	0.008
	No	%	94.1%	57.1%	71.1%
	Yes	Number	1	12	13
	Yes	%	5.9%	42.9%	28.9%
	Total	Number	17	28	45
	Total	%	100.0%	100.0%	100.0%
Total	No	Number	30	33	63	0.070
	No	%	57.7%	42.9%	48.8%
	Yes	Number	22	44	66
	Yes	%	42.3%	57.1%	51.2%
	Total	Number	52	77	129
	Total	%	100.0%	100.0%	100.0%

The number of patients diagnosed with either type 1 or type 2 diabetes is shown in Table 4. There was no statistically significant correlation between leukocytosis due to infection and diabetes type. (P value > 0.05)

Table 4

Correlation between leukocytosis due to infection and diabetes type
Leukocytosis	Infection		Diabetes		Total	P value
Leukocytosis	Infection		I	II	Total	P value
Yes	No	Number	22	9	31	0.393
	No	%	40.74%	30.0%	36.9%
	Yes	Number	32	21	53
	Yes	%	59.2%	70.0%	63.0%
	Total	Number	54	30	84
	Total	%	100.0%	100.0%	100.0%
No	No	Number	26	6	32	0.008
	No	%	68.4%	85.7%	71.1%%
	Yes	Number	12	1	13
	Yes	%	31.6%	14.3%	28.9%
	Total	Number	38	7	45
	Total	%	100.0%	100.0%	100.0%
Total	No	Number	48	15	63	0.070
	No	%	57.7%	40.5%	49.2%
	Yes	Number	44	22	66
	Yes	%	47.3%	59.5%	51.2%
	Total	Number	92	37	129
	Total	%	100.0%	100.0%	100.0%

Table 5 depicts the relationship between diabetes and hospitalization duration and leukocytosis due to an infectious process. As demonstrated, a statistically robust correlation existed between leukocytosis, infection presence, and diabetes duration. Patients with more extended periods of diabetes exhibited signs and symptoms of infection more than others. (P value = 0.006) In addition, Patients with more extended hospital stays were diagnosed with infection more than patients with shorter periods of hospitalization, which was statistically significant. (P value = 0.008) Table 4. Correlation between leukocytosis due to infection and diabetes and hospitalization duration

Table 5

Correlation between leukocytosis due to infection, hospitalization, and diabetes duration
Leukocytosis	Infection	Duration of diabetes		P value	Hospitalization duration		P value
Leukocytosis	Infection	Mean	SD^a		Mean	SD^a	P value
Yes	No	11.6667	11.58612	0.006	8.1333	8.08762	0.008
	Yes	14.5000	5.84355		11.4444	6.82747
	Total	13.2121	8.88383		9.9394	7.49558
No	No	7.3250	7.25832		9.5313	4.62800
	Yes	9.9231	6.17065		12.5385	14.80774
	Total	8.0756	6.99432		10.4000	8.76304
Total	No	8.7106	8.97463		9.0851	5.89705
	Yes	12.5806	6.31281		11.9032	10.69690
	Total	10.2487	8.20226		10.2051	8.20256
^{a Standard Deviation}

Table 6 shows the correlation between leukocytosis caused by infection and PH levels. The mean acidosis in infected patients with leukocytosis was 7.17, and in non-infected patients with leukocytosis was 7.17. As per the statistical analysis, we found no significant correlation between these two variables. (P value > 0.05)

Table 6

Correlation between leukocytosis due to infection and PH
Leukocytosis	Infection	PH		P value
Leukocytosis	Infection	Mean	SD^a	P value
Yes	No	7.177	0.133	0.805
	Yes	7.173	0.113
	Total	7.175	0.119
No	No	7.188	0.119
	Yes	7.116	0.164
	Total	7.167	0.136
Total	No	7.184	0.122
	Yes	7.149	0.136
	Total	7.170	0.128
^{a Standard Deviation}

Table 7 displays the ESR and CRP levels in infected and uninfected patients, with and without leukocytosis. The infection rate among patients with higher ESR levels was higher than that of patients with lower levels of ESR. There was a statistically valid correlation between the two variables. (P value = 0.013) The mean levels of CRP in infected patients were higher than those in uninfected patients, and our analysis showed a statistically significant relationship between the two variables. (P value = 0.002)

Table 7

Correlation between leukocytosis due to infection and ESR and CRP levels
Leukocytosis	Infection	ESR		P value	CRP		P value
Leukocytosis	Infection	Mean	SD^a	P value	Mean	SD^a
Yes	No	11.2000	15.11007	0.013	21.9333	22.19545	0.002
	Yes	56.2000	42.11752		45.4467	35.66501
	Total	33.7000	38.60423		33.6900	31.54166
No	No	11.6897	19.36142		17.8276	13.23434
	Yes	42.8333	49.19319		47.0000	38.61465
	Total	20.8049	33.67062		26.3659	26.70651
Total	No	11.5227	17.84623		19.2273	16.68290
	Yes	50.2593	44.99794		46.1370	36.28201
	Total	26.2535	36.14404		29.4606	28.86180
^{a Standard Deviation}

Table 8 exhibits the number of patients with abnormal chest X-rays (CXR). There were no abnormalities in 28 infected patients, and 25 showed abnormalities in CXRs. Among non-infected patients, 21 showed normal CXRs, and 10 had abnormalities, which was statistically significant. (P value = 0.002)

Table 8

Correlation between leukocytosis due to infection and CXR findings
Leukocytosis	Infection		CXR^a		Total	P value
Leukocytosis	Infection		Normal	Abnormal	Total	P value
Yes	No	Number	21	10	31	0.223
	No	%	42.8%	28.5%	36.9%
	Yes	Number	28	25	53
	Yes	%	57.1%	71.4%	63.0%
	Total	Number	49	35	84
	Total	%	100.0%	100.0%	100.0%
No	No	Number	29	3	32	0.001
	No	%	93.5%	21.4%	71.1%
	Yes	Number	2	11	13
	Yes	%	6.4%	78.5%	28.8%
	Total	Number	31	14	45
	Total	%	100.0%	100.0%	100.0%
Total	No	Number	50	13	63	0.002
	No	%	62.5%	26.5%	48.8%
	Yes	Number	30	36	66
	Yes	%	37.5%	73.4%	51.1%
	Total	Number	80	49	129
	Total	%	100.0%	100.0%	100.0%
^{a Chest X−Ray}

The data presented in Table 9 reveals no statistically significant correlation between the type of infection as determined by blood culture and leukocytosis. Two infected and four non-infected patients with leukocytosis blood cultures showed infections with the methicillin-resistant staphylococcus aureus species. (P value = 1)

Table 9

Correlation between leukocytosis due to infection and blood cultures
Leukocytosis	Infection		B/C^a			Total	P value
Leukocytosis	Infection		Normal	MSSA	MRSA	Total	P value
Yes	No	Number	27	4	0	31	1.0
	No	%	34.6%	100.0%	0.0%	36.9%
	Yes	Number	51	0	2	53
	Yes	%	65.3%	0.0%	100.0%	63.1%
	Total	Number	78	4	2	84
	Total	%	100.0%	100.0%	100.0%	100.0%
No	No	Number	31	1	-	32	1.0
	No	%	70.4%	100.0%	-	71.1%
	Yes	Number	13	0	-	13
	Yes	%	29.5%	0.0%	-	28.8%
	Total	Number	44	1	-	45
	Total	%	100.0%	100.0%	-	100.0%
Total	No	Number	58	5	0	63	1.0
	No	%	47.5%	100.0%	0.0%	48.8%
	Yes	Number	64	0	2	66
	Yes	%	52.4%	0.0%	100.0%	51.2%
	Total	Number	122	5	2	129
	Total	%	100.0%	100.0%	100.0%	100.0%
^{a Blood culture}

The contents of Table 10 indicate the correlation between leukocytosis and positive urine cultures. Infected patients with leukocytosis had 43 negative urine cultures and 10 positive urine cultures. Uninfected patients with leukocytosis had 30 negative and one positive urine culture, which is statistically meaningful. (P value = 0.005)

Among uninfected patients without leukocytosis, 29 had negative, and 3 had positive urine cultures. (P value = 0021) Infected patients without leukocytosis had seven normal and six positive urine cultures. (P value = 0.021) The correlation between leukocytosis and positive urine cultures was statistically significant. (P value < 0.05)

Table 10

Correlation between leukocytosis due to infection in patients with DKA and urine cultures
Leukocytosis	Infection		U/C^a		Total	P value
Leukocytosis	Infection		Normal	Klebsiella	Total	P value
Yes	No	Number	30	1	31	0.005
	No	%	41.0%	9.0%	36.9%
	Yes	Number	43	10	53
	Yes	%	58.9%	90.9%	63.1%
	Total	Number	73	11	84
	Total	%	100.0%	100.0%	100.0%
No	No	Number	29	3	32	0.021
	No	%	69.04%	33.3%	71.1%
	Yes	Number	7	6	13
	Yes	%	30.95%	66.6%	28.88%
	Total	Number	36	9	45
	Total	%	100.0%	100.0%	100.0%
Total	No	Number	59	4	63	0.0001
	No	%	43.96%	100.0%	48.8%
	Yes	Number	50	16	66
	Yes	%	56.03%	0.0%	51.2%
	Total	Number	109	20	129
	Total	%	100.0%	100.0%	100.0%
^{a Urine culture}

As shown in Table 11, out of a total of 84 patients with leukocytosis, 31 (36.9%) had no apparent infectious source; 17 (20/2%) were diagnosed with respiratory infections; 10 (11/9%) were diagnosed with urine infections; and 6 (7/1%) had soft tissue infections; 5 (6/0%) had pelvic inflammatory disease; 4 (4/8%) were diagnosed with peritonitis; and 4 (4/8%) had COVID-19; 2 (2/4%) had meningitis; 2 (2/4%) had gastroenteritis; 2 (2/4%) had surgical site infections; and 1 (1/2%) was diagnosed with endocarditis. We found a significant correlation between leukocytosis and infection in patients with DKA. (P value = 0.034) The frequency of infections in patients with DKA, with or without leukocytosis, is shown in Fig. 2.

Table 11

Correlation between leukocytosis due to infection and infection type
Source		Leukocytosis		Total	P value
Source		Yes	No	Total	P value
No infection	Number	31	32	63	0.034
No infection	%	36.9%	71.1%	48.8%
UTI	Number	10	6	16
UTI	%	11.9%	13.3%	12.4%
Meningitis	Number	2	0	2
Meningitis	%	2.4%	0.0%	1.6%
Peritonitis	Number	4	0	4
Peritonitis	%	4.8%	0.0%	3.1%
PID	Number	5	0	5
PID	%	6.0%	0.0%	3.9%
Respiratory	Number	17	5	22
Respiratory	%	20.2%	11.1%	17.1%
Soft tissue and abscess	Number	6	2	8
Soft tissue and abscess	%	7.1%	4.4%	6.2%
Endocarditis	Number	1	0	1
Endocarditis	%	1.2%	0.0%	0.8%
Gastroenteritis	Number	2	0	2
Gastroenteritis	%	2.4%	0.0%	1.6%
SSI^a	Number	2	0	2
SSI^a	%	2.4%	0.0%	1.6%
COVID-19	Number	4	0	4
COVID-19	%	4.8%	0.0%	3.1%
Total	Number	84	45	129
Total	%	100.0%	100.0%	100.0%
^{a Surgical Site Infection}

[Insert Fig. 2 here]

By examining Table 12, we can ascertain that the mean and standard deviation of the WBC count in infected and uninfected patients were 14/96 ± 8.16 and 11/53 ± 6/73, respectively.

Table 12

Leukocytosis levels in patients with and without infection
Infection	Mean	SD
No	11.5381	6.73811
Yes	14.9670	8.16414
Total	13.2924	7.66809

Among all 129 patients, four patients with leukocytosis died, Including two with infections and two without any evident infection. However, there was no significant correlation between leukocytosis and the prognosis of patients, as shown in Table 13. (P value = 0.181)

Table 13

Correlation between leukocytosis due to infection in patients with DKA and prognosis
Infection	Leukocytosis		Outcome		Total	P value
Infection	Leukocytosis		Death	Discharge	Total	P value
Yes	Yes	Number	2	29	31	0.246
	Yes	%	100.0%	47.5%	49.2%
	No	Number	0	32	32
	No	%	0.0%	52.4%	50.7%
	Total	Number	2	61	63
	Total	%	100.0%	100.0%	100.0%
No	Yes	Number	2	51	53	0.642
	Yes	%	100.0%	79.7%	80.3%
	No	Number	0	13	13
	No	%	0.0%	20.3%	19.7%
	Total	Number	2	64	66
	Total	%	100.0%	100.0%	100.0%
Total	Yes	Number	4	80	84	0.181
	Yes	%	100.0%	64.5%	65.6%
	No	Number	0	45	45
	No	%	0.0%	36.5%	34.8%
	Total	Number	4	125	129
	Total	%	100.0%	100.0%	100.0%

This study investigated the correlation between leukocytosis and infection in patients with DKA. Our findings revealed that leukocytosis is a sign of infection in patients with DKA, with a threshold of 14.96, and is a crucial factor in distinguishing between infection and DKA. We also observed a significant increase in ESR and CRP in infected DKA patients compared to uninfected patients with DKA. We found no meaningful correlation between leukocytosis and sex, diabetes type, the severity of acidosis, and overall prognosis. However, a statistically significant relationship existed between diabetes, hospitalization duration, older age, and leukocyte count.

Although patients with DKA have higher leukocyte counts than the general population due to ketoacidosis, it has always been challenging to identify new-onset infections in these patients. Karavanaki et al. conducted a study on hs-CRP, leukocyte, and cytokine level fluctuations during the inflammatory process of DKA. They found that the WBC count in moderate/severe DKA was much higher than in mild DKA (15.2*102/mm3), which decreased rapidly over time.(19) Huang et al. Conducted a similar study on leukocytosis and procalcitonin levels. In this study, the leukocytosis threshold to differentiate between early stages of infection and DKA within one hour of admission was 10*10⁹/L, compared to the threshold of 14.96 in our study. They also reported that procalcitonin to lactic acid ratio (PLR) had a high diagnostic efficacy for infections.(20)

Xu et al. found that infection was the leading cause of higher leukocyte count in infected patients with DKA (16910 mm³) compared to non-infected patients with DKA (10310 mm³), which is consistent with our findings. Similar to our study, a higher WBC count was reported in patients with DKA compared to patients without DKA, and the lymphocyte count in the DKA group (1654/mm³) was lower than in the non-DKA group (1940 /mm³).(26)

Wasif et al. evaluated 967 patients for three years, including 112 non-infected patients, 679 bacterial infections, and 671 viral infections. They found a mean WBC count of 9431 in all patients and statistically significant differences between the three age groups.(27)

Firouz et al. reported that acidosis in DKA can exacerbate the severity of leukocytosis, irrespective of an infectious process. However, we found no significant correlation between PH levels and leukocytosis. They reported that more extended periods of leukocytosis were associated with a longer time for acidosis correction.(28)

In this study, we reported that leukocytosis, with a threshold of 14000/mm³ or greater, indicates infection in patients with DKA and may be a factor in determining whether DKA causes leukocytosis or if infections are involved. However, further studies with larger populations are needed to confirm our findings.

Our study has some potential limitations, as the period during which it was conducted coincided with the COVID-19 pandemic, which may have affected the number of patients referred to our hospital. Additionally, we were unable to retrieve some variables, such as procalcitonin, which may have affected the accuracy of our study.

It can be challenging to distinguish the cause of leukocytosis in patients with DKA, as both ketoacidosis and infections play a role. Only a few studies have been conducted on this matter. Our study demonstrated that a total WBC count of, 14000/mm³ or higher can indicate the presence of infection, whether major or occult, in patients with DKA. Our findings revealed a significant correlation between infection in patients with DKA and U/C, CXR findings, duration of diabetes, age, hospitalization period, ESR, and CRP. Furthermore, we identified ESR and CRP as other indicators of infection. This new data suggests that leukocytosis of 14000/mm³or higher, ESR, and CRP are indicators of infection, which could prompt the start of adequate antibiotic therapy in patients with DKA, reducing mortality rates caused by infections in these individuals.

DKA: diabetic Ketoacidosis

T1DM: Type 1 Diabetes Mellitus

CRP: C-reactive Protein

AMR: Anti-microbial Resistance

WHO: World Health Organization

ESR: Erythrocyte Sedimentation Rate

COVID-19: Coronavirus disease 2019

Acknowledgments

Not applicable.

Authors' Contribution

SG contributed to conceptualization, interpretation, and project administration and supervision. MH, SG, and MD contributed to reviewing and editing. ER, KF contributed to writing the original draft, data validation, data analysis, and editing. PMA contributed to data gathering and writing the original draft. ER, as the corresponding author, had full access to all parts of the study and had the responsibility of submitting the manuscript for publication.

Funding

The authors received no funding or ﬁnancial support for this study.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

This study was approved by the ethics committee of Tehran University of Medical Sciences, Tehran, Iran (Approval number: IR.TUMS.IKHC.REC.1400.268). All methods were carried out in accordance with relevant guidelines and regulations. This study was conducted in an academic teaching/research hospital (Imam Khomeini Hospital Complex aﬃliated to Tehran University of Medical Sciences). In this academic center, all patients or their legal guardians are initially explained that their information and possible samples will be anonymously collected, reviewed, and reported in educational and research projects. The patients who give written consent to this issue will be included in the mentioned studies (like our study). Patients are allowed to freely choose whether or not their data be used in an anonymized database. Informed consent was obtained from all the patients and/or their legal guardian(s) for this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors' information

^a Assistant Professor of Infectious Disease, Department of Infectious Disease and Tropical Medicine, School of Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences

^b Infectious Diseases Department, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

^c Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences

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No competing interests reported.

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Correlation between leukocytosis and infection in patients with diabetic ketoacidosis

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