Pertussis (whooping cough) is a highly contagious vaccine-preventable airborne bacterial infection which affected patients of all ages . The disease is characterized by paroxysmal cough, also known as a "100-days cough". The illness is caused by Gram-negative bacteria, named Bordetella pertussis (B. pertussis). Outbreaks occur periodically every three to five years . Pertussis is endemic worldwide, particularly in young children regardless of ethnicity, climate or geographic location .
The permanent sources of the infection are adults; consequently the etiologic agent is widespread in society . Unvaccinated or incompletely vaccinated babies are in a great risk of complications and even lethal outcome .
In spite of pertussis vaccination program in many countries around the world the disease continued to be a global problem of the present day .
The aim of this study is to show the epidemiological characteristics and clinical manifestations of whooping cough during an epidemic outbreak in Stara Zagora region, Bulgaria and to clear up its origin.
Materials and Methods
During the period of 20th August 2016 to 28th September 2016 thirty-three patients with whooping cough were hospitalized at the Department of Infectious Diseases, Stara Zagora University Hospital, Bulgaria. They were in age between 2 months and 19 years. The distribution by age and sex was showed in Figure 1. Clinical, laboratory, epidemiological, serological and molecular-genetic investigations were completed in all. Instrumental methods as X-ray and abdominal ultrasound were applied in some patients.
The medical procedures of this study were approved by the Local Ethics Committee of Stara Zagora University Hospital, Bulgaria (2 Stoletov Str., 6000 Stara Zagora). Statistical analysis was performed by Excel 2007 (Microsoft, Redmond, Washington, USA) and SPSS Statistics 19.0 (IBM Corp., Armonk, New York, USA).
Medical history and clinical manifestation
The beginning of the disease in our patients was gradual with symptoms similar to a common cold such as runny nose, mild dry
cough and low-grade temperature. Two of investigated patients had an acute start according to data of their parents. Temperature up to 38 degree C had only one patient. It is difficult to determine accurately the duration of the catarrhal period. It was between 8 and 14 days (Mean +/- SD: 10.8 +/- 3.4). The cough tended to come in short bursts - paroxysms - followed by racking gasps for air - whooping noise. A typical inspiratory whoop was marked in 88% of patients. Attacks could occur spontaneously, but usually they were provoked by yawning, eating or crying. They were more common at night. 21% of children (younger than 6 months) had a short catarrhal stage. In them the paroxysms were multiple and severe although they were not as clearly manifested as in older ones.
Gaggling and gasping appeared as early symptoms in all children. An apnoea was demonstrated in 9% of them. The number of coughing paroxysms varied from 5 to 25 (Mean +/- SD: 16.25 +/- 5.7). Paroxysms associated with vomiting at the end of coughing were seen in 73% of patients. Eyes' haemorrhages as a result of cough exertions were fixed in one child. During the hospital stay the patients were restless and irritable with poor appetite. Different signs of respiratory deficiency were registered in 18% of patients. All of them had tachydyspnea and cyanosis which was exacerbated by paroxysms. Clinical manifestations were presented in Figure 2. Physical signs of pneumonia which were radiologically proven had 18% of children, data for bronchitis were found in 3% of all patients.
The typical laboratory data - leukocytosis with lymphocytosis were observed in 82% of patients (Table 1). The leukocytes count varied from 18.6 to 46x109/L (mean 21,3 ± 6,4). The mean value of lymphocytosis was 69.08 +/- 3.8% (range: 62.2-72.2%). The diagnosis was first suspected based on the typical clinical manifestation and data from the epidemiological study. Laboratorial findings supported the diagnosis. A polymerase chain reaction (PCR) was applied. All, except three patients had PCR positive results. Enzyme-linked immunosorbent assay (ELISA) test showed positive results for Anti-B. pertussis IgM in 70% of patients. Those up to 3 months old had a negative result.
The mean hospital stay was 9.12 +/- 2.1 days (range: 6-15). All patients were followed up for one month. Approximately half of them had residual mild cough that was provoked by physical efforts.
The epidemiological study showed that 4 municipalities were affected in Stara Zagora region. The first 5 cases were hospitalized at the Department of Pediatrics of one Municipal Hospital by presumption of acute respiratory disease for 2 days. After that they were transferred to the Department of Infectious Diseases (Stara Zagora University Hospital) with suspicion of whooping cough. The verification of immunization status indicated that only 12% of patients had completed a vaccination regiment (Table 2).
Three of them without immunization were 2 months old. Almost all patients with their parents and relatives were attended to Roma wedding on 20th August 2016. The contact group consisted of 111 persons. Fifty-five of them were children. Extreme prophylaxis with macrolides was administered. The main source of infection was children or adults with an atypical course of the disease. Seventy children were epidemiologically studied. They were contact persons of the first 5 children with whooping cough who had been first hospitalized at the Department of Pediatrics (Municipal Hospital). It was found that they had a regular age-related immunization status. A meeting of Regional Health Inspection (Stara Zagora, Bulgaria) was held with all general practitioners (GPs) from the affected municipalities to learn about the epidemic situation in the region. They were instructed to take immediate extraordinary immunization in children with incomplete regiments. A letter has been prepared and sent to all GPs in the region about the emerging epidemic outbreak of whooping cough. The information on the site of the Regional Health Inspection (Stara Zagora) under heading "Whooping cough" and "Vaccines - a guarantor of your child's health" was published.
A specific etiological treatment was applied in all patients. The therapy was Ampicillin 100mg/kg four times a day for five days
or Sulbactam-Ampicillin in a dose of 150 mg/kg twice a day for 5 days. After the dehospitalization oral macrolides were prescribed for another 5 days. All patients had a favorable outcome.
All of our patients met the clinical, laboratory and epidemiological criteria for whooping cough according to the definition of Centers for Disease Control and Prevention, Atlanta, USA (CDC) .
They had paroxysms of coughing most of them with inspiratory whoop. Most of them had post-tussive emesis, some had cyanosis and 3 had apnea. Whooping cough in the infants younger than 6 months of age had atypical clinical course . Infants younger than one year old, and especially under six months may present with severe cough of any duration, poor feeding, apnea, or bradycardia without coughing paroxysms . In our study children in this age group had similar clinical manifestations. They often lacked the typical whooping noise.
Data from the literature search showed that the mean hospitalisation stay was 7.9 days (SD: 10.2) for all cases from 1998 to 2012 .
The duration of hospital stay of our patients was longer (P-value <0.001) in infants younger than 6 months (Mean +/- SD: 13.82 +/- 3.6) compare to those older than 1 year of age (Mean +/- SD: 6.2 +/- 3.1).
A PCR assay can confirm pertussis infection quickly (with in one or two days) and is not affected by antimicrobial therapy .
PCR data for pertussis were positive in almost all of our patients. Three children (< 3 months old) had negative results. It was assumed the influence of immature immune status. Patients who get the whole scheme of whooping cough vaccine and some of those with incomplete vaccination had a comparative mild clinical form. It was the most common - in 15 children. Six children without any vaccination (all of them were 11) had severe clinical form. According to the Bulgarian specialized medical materials the clinical forms of pertussis are determined by the number of cough paroxysms, the presence of cyanosis and apnea, as well as the degree of general malaise . Mild form occurs in vaccinated and older individuals with paroxysmal counts up to 10 times per day often without a typical whoop. Moderate form is characterized with 10-20, while severe one has up to 50 paroxysms with tachydyspnea, cyanosis and apnea. Complications such as pneumonia, bronchiolitis, encephalitis, seizures are most common in the severe form of the disease . We observed severe forms more often in children <1 year especially younger than 6 months old. Moderate clinical form had 12 patients.
In Bulgaria, the first registration of whooping cough was in 1897. For the first time whooping cough vaccine was introduced in 1957 .
It was replaced with an acellular vaccine in 2010. The National Immunization Calendar of Bulgaria consists of 5 obligatory acellular pertussis vaccine intakes. They are administered at 2,3,4,16 months and 6 years of age. Most of our patients are unvaccinated or incompletely vaccinated. They belonged to the Roma community. It is difficult to cover the immunizations among them because of their unwillingness and frequent migration.
Most of our patients were aged up to 3 years.
Although pertussis can affect any age, most serious cases and fatalities are observed in early infancy . The observed complications in our study are in children under 6 months of age who are not immunized. The secondary complications vary depending on patient's age .
Young infants are at the greatest risk of secondary bacterial pneumonia, the most common cause of pertussis-related deaths .
All our patients were fully recovered.
Our observation confirms that children who are completely vaccinated have shorter courses of illness than those with incomplete vaccination schedule .
Fatal cases had significantly higher peak White Blood Cell (WBC) and lymphocyte counts .
Culture assumed to be the gold standard for diagnosis because of its 100% specifity for identification. After the first 2 weeks, sensitivity decreases and the risk of false-negative result increases .
Almost all of our patients were hospitalized after this period. Serological and molecular-genetic methods for B. Pertussis detection were investigated in our study. A Polymerase Chain Reaction assay (PCR) is the most sensitive method. It is not influenced by antimicrobial therapy .
Macrolides are the first line treatment. Although antibiotics are effective in eliminating B. pertussis after the 5th day of application, they do not alter the subsequent clinical course of the illness [13-15].
Although Ampicillin has not been shown to reduce pertussis transmission or symptoms, we used it as parenteral treatment in cases with severe clinical course. Antibacterial duration of 3-5 days has the same therapeutic effect as the one with duration of
10-14 days .
The vaccine is sufficiently effective (71-85%), to prevent the disease . Despite the extensive scale of its conduct whooping cough persists. Nowadays it is one of the most common vaccinepreventable diseases. The revival of pertussis in the 21st century is a result of reduced immunogenicity of the vaccinated as well as the occurrence of mutations of B. pertussis .
Through them the etiological agent is able to avoid preventive role of the vaccine. Investigation of the intensity of postvaccination immunity indicates that the duration of protection lasts 4-12 years. It is a period of childhood when the contacts are the most common and most dense and the risk of spreading the infection is highest. Immunity after infection is also incomplete and perpetual. It provides protection within 7 to 20 years .
In the described epidemic outbreak of whooping cough the clinical presentations are typical for the disease. The main reason of the occurrence of the outbreak is the serious omissions in the vaccination schedule among children. All patients had a favorable outcome. The modern trend among parents to refuse vaccines for their children is the high risk for emergence of epidemic outbreaks of various vaccine-preventable diseases. Performing strict and proper immune prophylaxis according to the requirements of the immunization calendar of the Republic Bulgaria as well as recommending vaccines for adults expecting a child is of great importance to prevent the risk of spreading the infection.
We are grateful to all physicians, nursing, laboratory staff and patients who participated in this study. We thank the staff of the Department of Infectious Diseases, Stara Zagora University Hospital, Stara Zagora (Bulgaria) for the medical care and treatment of the patients.
Declaration Of Authorship
L.P. designed the study; L.P., P.P., V.T. and T.P. collected data; L.P. interpreted data; L.P. prepared the article; L.P., P.P., V.T. and T.P. performed the literature search; L.P. conducted statistical analysis. All authors approved the final version of the article.
All authors declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.