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Procalcitonin values in respiratory infections children under five years old viral infections versus bacterial infections

Paediatric respiratory tract infection is a major public health in Morocco. A study conducted reported that the aetiologies of respiratory infection in children less than five years old are mainly viral [1]. Furthermore, bacterial and viral respiratory children infections often present with similar symptoms. Infection misdiagnosis leads to an antibiotic overuse and thus increases resistance emergence [2-5]. Between 80 and 90% of all antibiotics are prescribed for tract respiratory infections despite the predominately viral origin of the infection [6]. The use of Procalcitonin (PCT) as reliable blood biomarker mirroring the host response to infection, and as a suitable guide differentiating bacterial from viral respiratory infection in children was evaluated in many studies [7]. Procalcitonin (PCT) is the prohormone of calcitonin produced by the thyroid gland in response to inflammation caused by bacterial infection [8]. In healthy individuals PCT is < 0, 05 ng/ml, and increases rapidly within 3 hours of the development of bacterial infection [9]. PCT levels peak within 6h to 12h and remain high until the infection declines either by the antibiotic therapy or by the host immune system [10]. Once the infection is managed the PCT value decreases half daily [11]. Inversely, in response to viral infections PCT levels stay normal, interferon Gama, a cytokine released in response to viral infections blocks the up regulation of PCT resulting in higher specify of PCT to-ward bacterial infections [12, 13].


Introduction
Paediatric respiratory tract infection is a major public health in Morocco. A study conducted reported that the aetiologies of respiratory infection in children less than five years old are mainly viral [1]. Furthermore, bacterial and viral respiratory children infections often present with similar symptoms. Infection misdiagnosis leads to an antibiotic overuse and thus increases resistance emergence [2][3][4][5]. Between 80 and 90% of all antibiotics are prescribed for tract respiratory infections despite the predominately viral origin of the infection [6]. The use of Procalcitonin (PCT) as reliable blood biomarker mirroring the host response to infection, and as a suitable guide differentiating bacterial from viral respiratory infection in children was evaluated in many studies [7]. Procalcitonin (PCT) is the prohormone of calcitonin produced by the thyroid gland in response to inflammation caused by bacterial infection [8]. In healthy individuals PCT is < 0, 05 ng/ml, and increases rapidly within 3 hours of the development of bacterial infection [9]. PCT levels peak within 6h to 12h and remain high until the infection declines either by the antibiotic therapy or by the host immune system [10]. Once the infection is managed the PCT value decreases half daily [11]. Inversely, in response to viral infections PCT levels stay normal, interferon Gama, a cytokine released in response to viral infections blocks the up regulation of PCT resulting in higher specify of PCT to-ward bacterial infections [12,13].
In this study, we aimed to evaluate the PCT usefulness in differentiating paediatric patients with viral from bacterial low respiratory infections.

Study setting and procedures for recruited children
Data was collected from a study, which was conducted from 2010 to 2011 in Morocco's capital at the "Hôpital d'Enfant de Rabat" to define the epidemiology and aetiology of respiratory distress at HER.
Inclusion criteria were children aged from 2-59 years old admitted to HER with respiratory symptomatology. Exclusion criteria were non-respiratory illness, or a condition not caused by respiratory illness, or in the event of evidence of a foreign body in the respiratory tract.
An antero-posterior chest X-ray, nasal and pharyngeal swabs for diagnosis of bacterial infection/carriage, and a nasopharyngeal aspirate (NPA) for diagnosis of respiratory viruses by molecular techniques were collected. Venous blood was also collected for blood culture, and biochemistry tests including Procalcitonin (PCT).

Laboratory tests
Blood samples are cultured using an automated blood culture system (BD Bactec ® , BD, USA). Bacterial isolates are identified by Phoenix Automated Microbiology System (PHX system, BD) or standard procedure [1]. The presence of Streptococcus pneumoniae in blood samples is investigated by real-time PCR. In addition, Respifinder test explored viral infection in NAP samples [1]. Levels of serum PCT are tested using a mini-Vidas ® apparatus [1].

Statistical analysis
Statistical analyses are performed with IBM SPSS version 19 (IBM Statistics 19). Demographic data, PCT level, and patient outcomes are compared between the viral infection and bacterial infection groups by Mann-Whitney U test. A probability of < 0, 05 was considered statistically significant. Medians and interquartile ranges (IQRs) are presented for non-normally distributed variables and means with corresponding standard deviations are presented for normally distributed variables.

Ethics
The protocol and informed consent documents were approved by the Ethics Committee of the Hospital Clinic (Barcelona, Spain) and by the Comité d'Ethique de la Recherche´ Biomédicale (Depart No1252-16 Dec 2009) of the Faculty of Medicine in Rabat.

Results
Six hundred and sixty-four (664) children responded to the inclusion criteria during the study period, including 248 (31, 9%) females and 416 (53, 5%) males. The median age of the study patients was 19 (IQR 10-33) months old. The population baseline characteristics are shown in table 1 ( Figure 2) and PCT serum concentrations test are shown in table 2.
In the same way, results found according to respiratory low infection probable diagnosis threshold were: no risk 235 (35, 4%), low risk 122 (18, 4%) and probable infection 307 (46, 2%). The thresholds used in this study are shown in figure 2 and figure 3.

Discussion
One of the main goals of this experiment was to show how PCT could distinguish between viral respiratory infection and bacterial ones, in a cohort of 664 children under 5 years old, whom were recruited from HER as part of wider research attempting to define epidemiology

Viral infection
Our results showed that the paediatric respiratory tract infections in 664 children less than five years old are in general viral infections. This reflect the low PCT levels which were mostly under 0,1 ng/ml serum concentration in 35,4% cases, and under the 0,5 ng/ml serum concentration in 72,6% cases. Several studies have reported that PCT levels remained low (< 0.5 ng/ml) in viral infections [14][15][16]. Both Patrick Joseph [16] and Toikka [17] have found low PCT levels which are respectively 0, 75 ng/m and 0, 56 ng/ml in viral pneumonia cases. In the other hand Guoji Zhu [18] has found a median of 0.25 ng/ml in a paediatric group of 50 children, with one case greater than or equal to 2 ng/ml and three cases which had been between 0,8 -1,5 ng/ml. Our finding concurs with other studies. In fact, our PCT median value reached 0.14 ng /ml in viral infection versus 0.13 ng / ml in no infection group. Unlike what was shown by Branch [19], 17% of viral infection were > 0, 25 ng/ml value, we found that PCT levels were < 0, 25 ng/ml in 18, 4% and > 0, 25 ng/ml in 46, 2%. This can be explained by down regulation due to cytokines release in response to viral infections, such as gamma interferon (INF)-γ. Hence Procalcitonin synthesis is not induced in most viral infections [13,[20][21][22], and thus the majority of PCT values were close to normal. These results showed higher specificity of PCT towards bacterial infection.

Bacterial infection
In the 39 cases of bacterial infection found, 52.7% were less than 0.5 ng/ml. According to the Hedlund study [23], PCT appears to rise more often when the bacterium is a pyogenic than when it is an atypical or intracellular organism. Indeed, some infections, especially due to intracellular bacteria, are not accompanied by a rise in PCT. This is consistent with our results: in the 39 bacterial infection founded, 7 cases had a Mycoplasma pneumonia with a PCT value that varies between 0.05 ng/ml and 0.5 ng/ml.
On the other hand, 7 cases took antibiotics 2 weeks before the PCT assay. Thus, 13 cases showed PCT values ranging from 0.05 to 0.5 ng/ml. This, according to Hausfater [24], may correspond to the circumstances in which sampling takes place, which coincides with either the early phase of the infection, that is to say before the 3 hours following the stimulation of the PCT, or it coincides with an antibiotic therapy phase, as well and given the kinetics of rapid decline of the marker, the PCT normalize.
The remaining 13 cases had a PCT value greater than 10 ng/ml with a difference between gram-negative 0.21 ng/ml (IQR: 0.82-10.73) and Gram-positive 0.15 ng/ml (IQR: 0.17-10.73). This is in line with what was reported by Kocazeybek [ 25].
In conclusion, this study showed that serum PCT levels could be used as a powerful biomarker in paediatrics respiratory infections for discrimination between bacterial and viral aetiologies and could reduce antibiotic prescribing rates in the era of multiples drug resistant bacterial strains.