Identifying the irrationality of the diagnosis of “pertussis-like syndrome” to enhance diagnostic accuracy

TL;DR

This study shows that the diagnosis of 'pertussis-like syndrome' is often inaccurate and overlaps with actual pertussis, especially in infants, and suggests more precise pathogen testing to improve diagnosis and public health efforts.

Contribution

The study reveals the diagnostic ambiguity of 'pertussis-like syndrome' and advocates for replacing it with pathogen-specific diagnoses using modern detection methods.

Findings

Infants under 1 year old made up 69.73% of 'pertussis-like syndrome' cases, with severe outcomes concentrated in younger infants.

Only 4.37% of cases were exclusively diagnosed as 'pertussis-like syndrome,' with most having comorbidities like lower respiratory tract infections.

Common pathogens included respiratory syncytial virus, Mycoplasma pneumoniae, and parainfluenza virus, indicating the syndrome's overlap with other infections.

Abstract

The purpose of this study is to assess the rationale and epidemiological
patterns of "pertussis-like syndrome" diagnoses. A comprehensive analysis of
demographic, epidemiological, and etiological characteristics was conducted
on 10,561 diagnosed “pertussis-like syndrome” cases across 33
Chinese hospitals. Post-coronavirus disease 2019 pandemic, the incidence of
“pertussis-like syndrome” increased significantly. Infants
under 1 year old accounted for 69.73% of these cases, and severe outcomes
were particularly prevalent among younger infants. Among those admitted to
the intensive care unit, 83.03% were under 6 months of age, and 75.00% of
the four reported deaths occurring in infants were younger than 3 months.
While infants under 1 year consistently represented over half of annual
cases, their proportion declined from 82.93% in 2016 to 51.21% in 2022. In
contrast, there has been a notable rise in cases among children older than 3
years. It is important to highlight that only 4.37% of cases were
exclusively diagnosed as “pertussis-like syndrome,” with the
majority of patients presenting with comorbidities, particularly lower
respiratory tract infections (93.61%). The common pathogens identified in
the records included respiratory syncytial virus, Mycoplasma
pneumoniae, Haemophilus influenzae, and
parainfluenza virus. “Pertussis-like syndrome” exhibits a high
degree of overlap with pertussis in terms of the age distribution of
susceptible populations and epidemiological patterns. To improve diagnostic
accuracy, we recommend strengthening laboratory testing in suspected
“pertussis-like syndrome” cases to confirm or rule out
pertussis. For cases with identified pathogens that are not
Bordetella pertussis, a precise pathogen-specific
diagnosis should be established rather than relying on the ambiguous label
of “pertussis-like syndrome.”

This study highlights the critical importance of reevaluating the
diagnosis of “pertussis-like syndrome” to improve
diagnostic accuracy and patient outcomes. The global resurgence of
pertussis has underscored the need for precise identification of
respiratory infections, particularly in pediatric populations. Our
analysis of 10,561 cases across 33 hospitals in China revealed
significant overlaps between “pertussis-like syndrome” and
pertussis in terms of age distribution and epidemiological patterns.
Cases diagnosed as “pertussis-like syndrome” may include
undetected cases of pertussis. Moreover, the broad, ambiguous label of
“pertussis-like syndrome” often masks the true causative
pathogens. This imprecise diagnosis hinders targeted treatment and
public health surveillance. Given advancements in pathogen detection
technologies, we advocate for abandoning the “pertussis-like
syndrome” label in favor of precise, pathogen-specific diagnoses.
This shift may enhance diagnostic clarity, optimize clinical management,
and strengthen efforts to monitor and control respiratory infections
globally.

Figures

Distribution of the 10,561 cases by province. ArcGIS 10.7 (ESRI, Redlands, CA, USA) was used to visualize the geographical distribution.

Monthly distribution of cases diagnosed with “pertussis-like syndrome” in this study.

The proportion of children in different age groups in the annual cases.

The distribution of diagnoses other than “pertussis-like syndrome.”

The etiological distribution of the 1,385 cases with positive results.

Tables

TABLE 1. Basic information of the 10,561 cases

Variable	No. of cases	Proportion (%)
Age
0–<1 yr	7,364	69.73
0–<3 mo	2,918	27.63
3–<6 mo	3,028	28.67
6 mo–<1 yr	1,418	13.43
1–<3 yrs	1,070	10.13
3–<6 yrs	1,201	11.37
6–<12 yrs	898	8.50
≥12 yrs	28	0.27
Gender
Male	5,985	56.67
Female	4,576	43.33
Ethnicity
Han	10,363	98.13
Non-Han	198	1.87
Residence
Urban	5,035	47.67
Rural	5,521	52.28
Unknown	5	0.05
Region
Northeast	514	4.87
North	1,220	11.55
East	3,931	37.22
South	18	0.17
Central	4,152	39.32
Northwest	520	4.92
Southwest	206	1.95
Year of hospitalization
2016	820	7.77
2017	1,134	10.74
2018	470	4.45
2019	1,630	15.43
2020	952	9.01
2021	1,439	13.63
2022	4,116	38.97
Month of hospitalization
Spring	2,865	27.13
March	983	9.31
April	935	8.85
May	947	8.97
Summer	2,956	27.99
June	785	7.43
July	963	9.12
August	1,208	11.44
Autumn	2,452	23.22
September	980	9.28
October	800	7.58
November	672	6.36
Winter	2,288	21.66
December	712	6.74
January	820	7.76
February	756	7.16
ICU
Yes	271	2.57
Age distributiona
0–<1 yr	242	89.30
0–<3 mo	147	54.24
3–<6 mo	78	28.78
6 mo–<1 yr	17	6.27
1–<3 yrs	12	4.43
3–<6 yrs	9	3.32
6–<12 yrs	7	2.58
≥12 yrs	1	0.37
No	10,290	97.43
Discharge
Leave the hospital on doctor’s order	9,873	93.49
Discharged without a doctor’s advice	537	5.08
Transfer to another hospital as directed by the doctor	12	0.11
Death	4	0.04
Other	135	1.28

Full text

INTRODUCTION

The global resurgence of pertussis has emerged as a significant public health challenge in recent years. Since early 2023, the substantial rise in reported pertussis cases across multiple countries (1–3) has underscored the urgent need for improved detection, diagnostic protocols, and surveillance systems. In our epidemiological analysis of hospitalized pertussis cases in China, we identified a considerable proportion of patients diagnosed with “pertussis-like syndrome.”

“Pertussis-like syndrome” is clinically defined as a constellation of respiratory symptoms resembling those of pertussis but caused primarily by pathogens other than Bordetella pertussis (4). Affected children typically present with paroxysmal spasmodic coughing, facial flushing, and a characteristic high-pitched inspiratory “whooping” sound, which are hallmark features of classic pertussis. The etiological agents commonly associated with this syndrome include respiratory syncytial virus, adenovirus, Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae, among others (5, 6). However, in clinical practice, the diagnosis of “pertussis-like syndrome” is frequently established without prior laboratory confirmation to rule out Bordetella pertussis infection. Notably, the diagnosis of “pertussis-like syndrome” is no longer classified under the current International Classification of Diseases (ICD) (7).

With the advancement of pathogen detection technologies, the identification rates of these respiratory pathogens have significantly improved. This progress, however, raises critical questions. Are the current diagnostic criteria for “pertussis-like syndrome” sufficiently accurate? What are the distinctive epidemiological and clinical characteristics of these cases? Are the implicated pathogens being reliably detected? And, crucially, could these cases be better categorized within the existing ICD framework?

To address these questions, we conducted a comprehensive analysis of demographic and clinical data from pediatric patients diagnosed with “pertussis-like syndrome” across 33 hospitals in China. Our objectives were to clarify the clinical and etiological profiles of these cases and to improve diagnostic accuracy.

MATERIALS AND METHODS

Data source

This study conducted a retrospective review and analysis of discharge data for cases diagnosed with “pertussis-like syndrome” from the Futang Research Center of Pediatric Development (FRCPD), a leading non-profit organization dedicated to pediatric medical research in China. Established on 23 August 2016, with authorization from the Ministry of Civil Affairs of the People’s Republic of China, FRCPD comprises 69 provincial and municipal member hospitals. Additional details about FRCPD can be accessed through their official website (8).

The data for this study were collected from 11 provincial and 22 municipal hospitals spanning 25 provinces across all seven regions of China, from January 2016 to December 2022. The data were retrieved from the FUTang Updating Medical Records Database, and further specifics regarding data collection and cleaning methodologies are outlined in a prior publication (9). The data analyzed in this study were exclusively derived from hospitalized patients and did not include those who visited the emergency department but were not subsequently admitted.

Inclusion criteria

This study incorporated cases identified as “pertussis-like syndrome” while excluding those diagnosed with parapertussis or confirmed pertussis.

Variables and outcomes

Detailed sociodemographic data, including age, gender, ethnicity, and place of residence, as well as illness-related factors such as etiology, complications, comorbid diagnoses, and discharge status, were meticulously extracted from each patient’s medical record.

Statistical analysis

Continuous variables were summarized as means, while categorical variables were expressed as both frequencies and corresponding percentages. Statistical analyses were performed using JMP Pro 17.0 software, and graphical representations were created with Microsoft Excel 16.30 and GraphPad Prism 9.0.

RESULTS

Hospital and case distribution

This study included a total of 10,561 cases diagnosed with “pertussis-like syndrome,” collected from 33 research centers across 25 provinces in China. The geographical distribution of cases across provinces is illustrated in Fig. 1, while the hospital-specific case distribution is detailed in Table S1.

Distribution of the 10,561 cases by province. ArcGIS 10.7 (ESRI, Redlands, CA, USA) was used to visualize the geographical distribution.

Demographic and clinical characteristics

We conducted a comprehensive review and analysis of the demographic and clinical characteristics of the 10,561 cases diagnosed with “pertussis-like syndrome.” The baseline characteristics are summarized in Table 1. The majority of patients (69.73%, 7,364/10,561) were infants under 1 year of age. Among the 271 cases admitted to the intensive care unit (ICU), 89.30% (242/271) were infants younger than 1 year, and 83.03% (225/271) were under 6 months of age. Notably, all four recorded fatalities occurred in infants under 1 year, with 75.00% (3/4) being younger than 3 months. A gender disparity was observed among hospitalized children, with boys constituting 56.67% of cases compared to 43.33% for girls. Additionally, rural children accounted for a higher proportion of cases (52.28%) compared to their urban counterparts (47.76%).

Epidemiological characteristics

The temporal distribution of “pertussis-like syndrome” cases, as depicted in Fig. 2, demonstrates a significant escalation in case numbers following the coronavirus disease 2019 (COVID-19) pandemic. These findings reveal a notable upward trend in the incidence of “pertussis-like syndrome” post-pandemic, as illustrated in Fig. 2.

Monthly distribution of cases diagnosed with “pertussis-like syndrome” in this study.

As illustrated in Fig. 3, the annual distribution of “pertussis-like syndrome” cases stratified by age groups reveals notable epidemiological shifts. While infants under 1 year of age consistently represented the majority of cases, accounting for over half of the total cases annually, their proportional contribution exhibited a marked decline from 82.93% in 2016 to 51.21% in 2022. Conversely, the proportion of cases among children over 3 years old demonstrated a significant upward trend, increasing from 3.90% in 2016 to 40.30% in 2022, indicating a changing demographic pattern in disease distribution over the study period.

The proportion of children in different age groups in the annual cases.

Diagnosis and complications

Our analysis of diagnostic and complication profiles demonstrated that a mere 4.37% (462/10,561) of cases were diagnosed with “pertussis-like syndrome” as a standalone condition. The majority of cases presented with concomitant diagnoses, the distribution of which is depicted in Fig. 4.

The distribution of diagnoses other than “pertussis-like syndrome.”

Lower respiratory infection emerged as the most prevalent complication associated with “pertussis-like syndrome,” affecting 93.61% (9,886/10,561) of cases. This was followed by organ dysfunction, which was observed in 11.39% (1,203/10,561) of cases. A detailed breakdown of the 9,886 children diagnosed with lower respiratory infections revealed the following: bronchopneumonia accounted for 4,544 cases, pneumonia (including 844 severe cases) for 3,687 cases, and bronchitis for 1,655 cases.

Etiological distribution

Out of the 9,886 patients with lower respiratory infections, 1,385 cases (14.01%) had conclusive microbiological findings. Monomicrobial infections predominated, accounting for 79.49% (1,101/1,385) of positive cases, while polymicrobial infections were detected in 20.51% (284/1,385) of cases. Pathogen analysis revealed the following distribution among positive cases: viral agents were identified in 58.77% (814/1,385), bacterial pathogens in 36.25% (502/1,385), Mycoplasma species in 25.63% (355/1,385), and Chlamydia species in 5.85% (81/1,385). Figure 5 presents the comprehensive etiological distribution of pathogens among the 1,385 positive cases.

The etiological distribution of the 1,385 cases with positive results.

DISCUSSION

During the same study period and within the same database, we identified 21,107 cases of pertussis (10) and 10,561 cases of “pertussis-like syndrome,” indicating the widespread adoption of “pertussis-like syndrome” in the clinical work across various regions in China. Given its high prevalence, “pertussis-like syndrome” significantly compromises the diagnostic accuracy of true pertussis cases and confounds epidemiological surveillance.

Analysis of the age distribution of children diagnosed with “pertussis-like syndrome” revealed that the majority of cases occurred in infants under 1 year of age. Severe cases requiring intensive care or resulting in death were predominantly observed among infants, particularly those under 6 months of age. This epidemiological pattern mirrors that of pertussis (10), with both diseases predominantly affecting infants under 1 year of age, with younger infants at higher risk of severe outcomes and mortality.

Similar to other respiratory infections (11, 12), the incidence of “pertussis-like syndrome” declined during the COVID-19 pandemic, likely due to non-pharmaceutical interventions such as lockdowns, social distancing, and mask-wearing. However, cases rebounded significantly in the post-pandemic period, mirroring the resurgence of pertussis cases (10).

The age distribution of “pertussis-like syndrome” cases has evolved over time, paralleling trends observed in pertussis (10). While infants under 1 year of age consistently accounted for the majority of cases, their proportion gradually declined over time, while the proportion of cases among older children (over 3 years of age) steadily increased. This shift may reflect the impact of vaccination schedules, heightened awareness of pertussis in older children, and the emergence of more virulent or drug-resistant strains of Bordetella pertussis (13). The overlapping epidemiological patterns between “pertussis-like syndrome” and pertussis may also reflect the inclusion of undiagnosed pertussis cases within the “pertussis-like syndrome” category.

The diagnosis of “pertussis-like syndrome” highlights the challenges of reliably excluding pertussis through laboratory testing (14, 15). In many healthcare settings, limited access to advanced diagnostic tools often necessitates reliance on clinical criteria for diagnosis. In China, pertussis is classified as a notifiable infectious disease, which requires mandatory reporting to the national infectious disease surveillance system. However, the diagnostic process is complicated by the absence of reliable laboratory confirmation in many instances, resulting in underreporting and a preference for clinical diagnoses such as “pertussis-like syndrome” over confirmed cases of pertussis. Many clinicians refrain from diagnosing pertussis due to limited diagnostic capabilities or to avoid reporting to the national infectious disease surveillance system, choosing instead to initiate direct treatment for the condition.

In this study, the most common comorbidity associated with “pertussis-like syndrome” was lower respiratory tract infection, with respiratory syncytial virus identified as the most prevalent pathogen, followed by Mycoplasma pneumoniae, Haemophilus influenzae, parainfluenza virus, and Streptococcus pneumoniae. These findings are consistent with previous studies on the etiology of “pertussis-like syndrome” (4, 5). Notably, only 4.37% of cases were diagnosed solely as “pertussis-like syndrome,” significantly lower than the 9.58% of cases diagnosed solely as pertussis (10). This discrepancy may reflect the broader spectrum of pathogens associated with “pertussis-like syndrome,” which includes a wide range of bacterial and viral pathogens, in contrast to pertussis, which is caused exclusively by Bordetella pertussis.

As diagnostic methods for identifying common pathogens have become more sensitive and targeted, it is increasingly important to move away from the broad and ambiguous diagnosis of “pertussis-like syndrome” toward more precise pathogen-specific diagnoses. For cases where the causative pathogen remains unidentified, alternative diagnoses such as pneumonia, bronchitis, or bronchopneumonia—conditions listed in the ICD—should be considered. This approach not only facilitates more accurate diagnosis and treatment but also enhances our understanding of the epidemiology and etiology of respiratory infections.

Conclusions

The diagnosis of “pertussis-like syndrome” is predominantly reliant on clinical manifestations. Its widespread application in clinical practice may lead to an underestimation of the true prevalence of pertussis. Furthermore, the broad spectrum of pathogens implicated in “pertussis-like syndrome” limits its effectiveness in guiding precise therapeutic interventions. In light of significant advancements in pathogen detection technologies, it is advisable to discontinue the use of the “pertussis-like syndrome” diagnosis. Instead, clinical practice should prioritize specific pathogen identification, which would improve diagnostic precision.

Supplementary Material

Reviewer comments