A Clinical Analysis of the 2024 Pertussis Outbreak Among Pediatric Patients in an Infectious Diseases Hospital in Bucharest, Romania

Abstract

Introduction: The objective of this study was to identify and analyze cases of pertussis hospitalized in 2024 that met the clinical criteria, epidemiological context, and laboratory confirmation through polymerase chain reaction (PCR) or serological testing for Bordetella pertussis. This study aimed to assess the age distribution of cases, vaccination rates, identify severe cases, and associated complications such as apnea, acute respiratory failure, and acute pneumonia. The findings aim to provide valuable data to enhance diagnostic and therapeutic strategies for managing pertussis in the pediatric population. Methods: We conducted a retrospective study from January to November 2024, involving pediatric patients admitted to the Pediatric Departments of the National Institute of Infectious Diseases “Prof. Dr. Matei Balş,” Bucharest, Romania, diagnosed with pertussis. The diagnosis was established based on epidemiological and clinical criteria and confirmed through laboratory tests, including serology or PCR testing. The selection criteria focused on hospitalized patients presenting clinical signs suggestive of pertussis, with laboratory confirmation. Results: Among the hospitalized patients, a significant proportion, 56.9%, were unvaccinated, while 12.5% had incomplete vaccination status. Common comorbidities contributing to increased hospitalization risk included prematurity, malnutrition, and asthma. Co-infections were identified in 32% of cases, with common pathogens such as measles, SARS-CoV-2, rhinovirus, and adenovirus. Respiratory complications were frequent, with apnea occurring in 51% of cases, pneumonia in 60%, and respiratory failure in 13.2%. Despite these complications, no fatalities were reported. Conclusions: This study highlights significant concerns related to low vaccination coverage in the pediatric population, emphasizing the importance of improving vaccination rates to prevent severe pertussis cases. The study also identifies the frequent occurrence of severe complications, including respiratory failure, apnea, and pneumonia, underlining the need for early intervention and effective management. Co-infections with respiratory pathogens further complicate diagnosis and treatment, underscoring the importance of comprehensive clinical evaluation in suspected cases of pertussis.

Introduction

Pertussis is a highly contagious acute respiratory disease. It is caused by the bacterium Bordetella pertussis, which is a fastidious, gram-negative, pleomorphic bacterium [1]. Humans are the only known hosts for B. pertussis. Transmission occurs through close contact with infected individuals via aerosolized droplets [2,3]. Pertussis follows a cyclical pattern, with outbreaks typically occurring every 2-5 years, often peaking during late summer and autumn [2,3]. Before vaccination programs were established, pertussis affected almost all children. Infants remain at the greatest risk of severe illness, though the disease imposes a significant health burden across all age groups. Pertussis is endemic worldwide, particularly in regions with low vaccination coverage. Decreasing maternal immunity and reduced transplacental antibody transfer in mothers who did not receive the tetanus, diphtheria, and acellular pertussis vaccine during pregnancy have contributed to an increase in pertussis cases among very young infants during outbreaks [3]. The restrictions implemented during the COVID-19 pandemic, including mask-wearing and physical distancing measures, disrupted the usual circulation patterns of common respiratory pathogens such as influenza and RSV. Similarly, strategies aimed at mitigating the spread of COVID-19 caused a marked decline in B. pertussis transmission, possibly compromising population immunity [4]. These disruptions also influenced the epidemiology of other pediatric infectious diseases. Prolonged reductions in exposure to numerous viruses and bacteria diminished immune stimulation against community-acquired pathogens. This led to an expansion of the population "naive” to these infections and a reduction in collective immunity, increasing the vulnerability of children to such illnesses [5].

Pertussis has an incubation period of 7 to 10 days, with a clinical course divided into catarrhal and paroxysmal stages, each lasting approximately two weeks, though the cough may persist for months [1,3]. The catarrhal stage resembles a common cold, while the paroxysmal stage is characterized by violent, uninterrupted coughing episodes, often followed by a distinctive whooping sound as the patient gasps for air; in severe cases, apnea, cyanosis, may occur [1,3]. Complications include apnea, secondary bacterial infections (e.g., pneumonia, otitis media), respiratory failure, pulmonary hypertension, and neurological manifestations such as seizures or brain hemorrhages due to hypoxia. Diagnosis primarily relies on bacterial culture, but due to its limited sensitivity, polymerase chain reaction (PCR) is preferred, especially within the first three weeks of cough onset; serology can support the diagnosis, particularly in unvaccinated individuals, while extreme leukocytosis with absolute lymphocytosis suggests pertussis in young children and correlates with poor prognosis in infants [1,4,6].

Treatment consists of macrolide antibiotics with trimethoprim-sulfamethoxazole (TMP-SMX) as an alternative for those intolerant to macrolides [1,7,8].

The aim of our study was to identify and analyze cases of pertussis hospitalized in 2024 that met the clinical criteria, epidemiological context, and laboratory confirmation through polymerase chain reaction (PCR) or serological testing for Bordetella pertussis. This study aims to assess the age distribution of cases, identify severe cases and associated complications, and provide valuable data to improve diagnostic and therapeutic strategies. Additionally, it intends to highlight major issues related to low vaccination coverage.

Methods

We conducted a retrospective study on a cohort of 288 pediatric patients diagnosed with pertussis who were hospitalized at the National Institute of Infectious Diseases "Prof. Dr. Matei Balș”, Bucharest, Romania, between January and November 2024. The diagnosis of whooping cough was established based on epidemiological and clinical criteria confirmed by laboratory tests (IgM ELISA test from blood and PCR from nasopharyngeal secretions – identification of Bordetella pertussis).

The patients' ages ranged from 17 days to 16 years. The criteria for hospitalization included: respiratory distress, evidence of pneumonia, inability to feed, episodes of apnea with or without coughing, and seizures.

The study included hospitalized patients with a clinical presentation suggestive of pertussis, confirmed through serology or PCR testing. The patients excluded from the study were those who, despite presenting with characteristic symptoms and an epidemiological link to outbreaks, did not have laboratory confirmation; additionally, patients in convalescence from pertussis were also excluded.

Patient data included demographic characteristics (distribution by sex and age), vaccination status, comorbidities, laboratory findings, complications (e.g., apnea, respiratory failure, pneumonia), and antimicrobial treatments.

Data collection was performed using an MS Excel database, ensuring the confidentiality of the study participants by protecting their personal data. Upon admission, all legal caregivers signed a consent form for the publication and the use of patient data for the study. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the National Institute of Infectious Diseases "Prof. Dr. Matei Balș.” with identification number C02923. For the statistical analysis, R software, version 4.4.2, was used. Copyright (C) 2024 The R Foundation for Statistical Computing, R Core Team (2024). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.

Results

The study included 288 hospitalized patients over an 11-month period who were diagnosed with whooping cough. The patients presented moderate or severe forms of the disease, with associated complications and infections, but no deaths were recorded.

A slight delay in the outbreak compared to the rest of Europe is observed: 2 sporadic cases in February and April (9 cases), followed by a gradual increase in May and June, peaking in July (69 cases) and August (65 cases), and a decline in September (50 cases) and October (31 cases).

The patients' ages ranged from 17 days to 16 years. The average age was 2 years and 9 months. It is noteworthy that 41% (n=119) of patients were under 1 year old, and 31% (n=88) were between 1 and 3 years. Regarding the distribution by sex, no significant difference was noted: females accounted for 51% (n=148) and males for 49% (n=140),

Table 1. Characteristics of our cohort.

. The average number of days from the onset of symptoms was 13.6 days.

Of the total 288 hospitalized patients, 56.9% (n=164) were unvaccinated, 12.5% (n=36) were incompletely vaccinated, 3.1% (n=9) were ineligible for vaccination (infants under 2 months of age), and 6.2% (n=18) could not specify their vaccination status

Among the hospitalized patient, 37.5% (n=108) had associated underlying pathologies. A significant number of children born prematurely were hospitalized (n=38). Other associated pathologies included neurological disorders in 11 patients (e.g., global developmental delay, epilepsy, history of febrile seizures), cardiac conditions in 15 patients (including congenital heart defects, which may lead to pulmonary hypertension), renal pathologies in 3 patients, and gastroesophageal reflux disease in 4 patients, 10 patients had asthma or recurrent wheezing. Regarding the diagnostic methods, 79.2% (n=228) were diagnosed based on validated IgM serology during hospitalization, and 20.8% (n=60) were diagnosed through PCR testing.

In patients under 1 year of age, we considered leukocytosis significant when it exceeded 25,000 leukocytes/mm³ (22.7%, n=27), with lymphocytosis greater than 20,000/mm³ (10.1%, n=12), and monocytosis higher than 1,000/mm³ (68.9%, n=82) – characteristic changes associated with Bordetella pertussis infection. In 5.04% (n=6) of patients, neutrophilia greater than 10,000/mm³ was noted. Additionally, 0.6% (n=2) of patients exhibited a leukemoid reaction, characterized by a WBC count greater than 50,000/mm³.

In patients over 1 year of age, leukocytosis exceeding 15,000/mm³ was observed in 48.5% (n=82), significant lymphocytosis greater than 12,000/mm³ in 24.9% (n=42), and monocytosis above 1,000/mm³ in 52.1% (n=88). Neutrophilia greater than10,000/mm³ was noted in 16.6% (n=28). One case presented a leukemoid reaction, characterized by a white blood cell (WBC) count exceeding 50,000/mm³. Hematological changes, such as leukocytosis with lympho-monocytosis, have been frequently described in pertussis over time. In our study, we correlated leukocyte values with respiratory failure in pertussis. We highlight the relevant findings of our research (

Table 2. Hematological changes.

and

Table 3. Characteristics in patients with or without acute respiratory failure.

¹ Welch Two Sample t-test; Pearson’s Chi-squared test. SD – standard deviation.

). Considering the inflammatory syndrome, fibrinogen levels exceeding 400 mg/dL were observed in only 3.5% (n=10) of cases, while 24.4% (n=65) had CRP levels greater than 3 mg/L. The average length of hospitalization was 6.7 days. We observed that a higher number of hospitalization days significantly correlated with the status of respiratory failure.

The most significant complications were apnea episodes, reported in 51.04% (n=147) of cases, and acute respiratory failure in 13.2% (n=38). Pneumonias with radiologically described consolidation were noted in 4.5% (n=13). Other complications included epistaxis (n=5), neurological manifestations such as seizures or syncope (n=5), and acute otitis media (n=4),

Table 4. Characteristics of our cohort

. Out of the total 288 hospitalized patients, 44% (n=126) were diagnosed and treated for co-infections. Noted cases included measles (n=22), rhinovirus (n=30), SARS-CoV-2 (n=15), adenovirus (n=14), and enterocolitis with or without an identified etiologic agent.

It is important to mention that not all patients were tested for co-infections; investigations were conducted only when the clinical presentation warranted further evaluation. Diagnostic methods included PCR, cultures, and serology testing. In our study, we investigated the correlation between co-infections and respiratory failure in pertussis. We highlight the relevant findings of our research (Table 4).

Clarithromycin was the first-line treatment in 84.7% (n=244) of cases. In 2 cases, where macrolide tolerance was not achieved, trimethoprim/sulfamethoxazole was used.

In patients presenting with respiratory failure or co-infections, the treatment was complex, involving a combination of antibiotics or antivirals and non-specific human immunoglobulin. In 28.9% (n=101) cases, macrolides were used in combination with amoxicillin-clavulanate or a second/third-generation cephalosporin due to complications. In cases of SARS-CoV-2 co-infection, remdesivir was administered to selected patients in 1.1% (n=4) of cases. In 1.1% of cases (n=4), the administration of human immunoglobulin was necessary (

Table 5. Characteristics of our cohort.

).

Discussion

The vaccination rate among children treated in our hospital remains critically low, with 72.6% being unvaccinated, partially vaccinated, or unable to specify their vaccination status. This trend is largely attributed to parental skepticism, limited educational background, and personal beliefs regarding vaccination.

We also observed a substantial number of ex-premature infants hospitalized in our clinic (n=44), highlighting their vulnerability to severe forms of the disease. Notably, none of the mothers had received the pertussis vaccine during pregnancy. The management of ex-premature infants can be particularly challenging, especially in cases with persistent complications related to prematurity.

We also anticipate cases with a significantly elevated lymphomonocyte count. Our observations indicate that a higher lympho-monocyte count is strongly associated with respiratory failure. In pertussis, it is well established that an excessive accumulation of leukocytes, along with elevated levels of pertussis toxin, contributes to disease pathology. The pertussis toxin can lead to pulmonary vessel obstruction due to leukocyte infiltration, which may result in pulmonary hypertension and acute pulmonary vasoconstriction. The most frequent clinical manifestation is persistent airway spasm [9].

However, we expect that respiratory failure will primarily occur in individuals with a history of asthma or recurrent wheezing, as neutrophil count does not necessarily serve as a negative predictive factor. In our cohort, respiratory failure shows a strong correlation with high neutrophil count, most likely due to bacterial superinfection and/or a pronounced inflammatory response associated with pertussis, which may drive an increase in neutrophil count [10].

The overlap of the pertussis epidemic with the measles epidemic in unvaccinated children posed challenges in the management of cases, complications, and isolation protocols. Co-infections, such as rhinovirus-enterovirus, SARS-CoV-2, and adenovirus, have also been described in studies from Italy and may explain some of the more complex cases [11]. Coinfections are strongly correlated with the rate of respiratory failure in our cohort.

Among the hospitalized children, 13.2% experienced acute respiratory failure and required oxygen support via low-flow support. We did not resort to other ventilation methods, and no child required intubation. In contrast, data from Italy indicated that among patients under 1 year of age, five patients (4.6%) required intubation, four patients (3.7%) needed non-invasive ventilation, and 14 patients (13%) received high-flow oxygen therapy [11]. In Romania, during the period from January 1, 2024, to December 31, 2024, a total of 2,862 cases of pertussis were reported, including five deaths (all infants under 4 months of age) The majority of cases were reported in unvaccinated individuals, most of whom (77%) were infants (under 1 year of age) and children aged 1-4 years [12]. In Romania, the pertussis vaccination schedule consists of doses at 2, 4, and 11 months, with booster doses at 6 years and 14 years [13]. Additionally, our study found that the largest group consisted of patients under 3 years of age.

In Romania the wave of infections was delayed compared to the rest of Europe, beginning in May and peaking in the summer of 2024 [12]. In Denmark, the number of cases showed an upward trend starting in August 2023, peaking in the fall of 2023, and subsequently declining in January-February 2024 [14]. In Catalonia, the seasonal pattern changed during the current outbreak: the number of cases began to rise in January 2024, peaking in February and March, a trend also observed in Italy [11,15] a phenomenon that may have multiple causal explanations, including epidemiological factors, demographic structure, seasonality, and others.

In Denmark, most cases were observed in adolescents aged 10-19 years, likely due to the absence of a booster dose for this age group [14]. In Catalonia, the incidence during the ongoing outbreak was higher among children and adolescents aged 10-14 years compared to previous outbreaks, with fewer cases in children under 1 year of age. This has led to considerations for introducing a booster dose in preadolescents, preferably at the age of 10-11 years [15]. In Italy, the wave of infections primarily affected neonates and unvaccinated infants, who were at high risk for severe complications and mortality [11].

The vaccination rate among children, in general, declined during the COVID-19 pandemic in many countries [16]. Comparatively, in Denmark, approximately 85% of pregnant women were vaccinated at the onset of the epidemic (August 2023). Vaccination is recommended in the late second or early third trimester (during week 25 or 32 gestational age). The proportion of newborns and infants aged 0-2 months affected by pertussis has decreased compared to previous outbreaks. This decline may reflect the protective effect of maternal vaccination against severe forms of pertussis. On 1 January 2024, pertussis immunization during pregnancy was officially endorsed by the Danish Health Authority as a permanent program [14].

A study conducted in Catalonia following the 2023-2024 pertussis outbreak revealed that the severity of cases among young children has decreased, resulting in a reduction in hospitalizations among infants under 1 year of age. This improvement reflects the benefits of the vaccination programme for pregnant women in Catalonia [15].

In this region, maternal vaccination has been implemented since 2014, making it the first area, along with Ireland, to introduce a vaccination programme for pregnant women. This initiative has led to noticeable changes in the incidence of cases across different age groups [15].

Italy experienced a pertussis outbreak similar to that of Romania beginning in January 2024. The outbreak primarily affected neonates and unvaccinated infants at high risk of severe complications and mortality [11].

The limitations of this study include the inability to confirm an etiological diagnosis in some patients who met the clinical and epidemiological case definition for pertussis. Additionally, although several cases of co-infection were suspected, comprehensive testing for all patients was not feasible. Furthermore, the number of respiratory failure cases was too small to allow for an extensive statistical analysis.

Conclusions

In light of the recent measles outbreak, a critical concern has emerged regarding the low vaccination rates within the pediatric population. In both Romania and our study, the pertussis outbreak has primarily affected infants and unvaccinated young children. Severe forms of the disease have been observed, with a significant rate of complications, including respiratory failure, apnea, and pneumonia. Co-infections involving respiratory pathogens (e.g., measles, SARS-CoV-2, rhinovirus) may complicate diagnosis and management. In response to such outbreaks, it is crucial for pediatricians, infectious disease specialists, and family physicians to actively engage in screening individuals presenting with respiratory symptoms. This proactive approach is essential for minimizing exposure and effectively controlling the spread of infection. A range of preventive strategies should be implemented, including vaccinating pregnant women - particularly those with pregnancies at risk for preterm birth - to protect newborns, especially those born prematurely. Additionally, vaccinating infants as early as possible and providing antibiotic prophylaxis to close contacts are vital measures. Most importantly, efforts should prioritize vaccinating children at higher risk of severe disease, including infants under 6 months of age and children with associated underlying medical conditions.