General therapy

Patients diagnosed with pertussis should be strictly isolated in compliance with respiratory infectious disease protocols to prevent the spread of the disease. Symptomatic supportive treatment is often necessary for managing severe paroxysmal cough and blockage of the respiratory tract by sputum. Nasal feeding may be employed to prevent aspiration and minimize the risk of aspiration pneumonia in infants. In cases with hypoxia, oxygen therapy should be promptly administered to ensure adequate oxygenation. For neonates and small infants, extra caution should be given during nebulization treatments, with close monitoring to ensure timely sputum inhalation post-nebulization and vigilance against the potential risk of asphyxia. Supportive treatment may include providing patients with nutrient-dense and easily digestible foods to maintain their nutritional status.

Antimicrobial therapy

Empirical antimicrobial therapy is crucial for children of all ages who are clinically or etiologically diagnosed with pertussis and are experiencing the disease's catarrhal stage or paroxysmal spasmodic cough stage. This treatment is essential for eradicating B. pertussis strains from the nasopharyngeal region and eliminating the source of infection. Even during the paroxysmal phase, targeted antibiotic therapy can effectively mitigate symptoms in most pediatric patients [21]. Typically, notable improvements are observed within 3–5 days following the completion of treatment [21]. Therefore, we should be alert when initiating antibacterial therapy for patients suspected of having pertussis within 3–4 weeks of onset, particularly those at high risk of developing severe complications. This decision should be made after thoroughly weighing the potential benefits and risks and ensuring adequate communication with the patient and their caregivers.

Macrolide antibiotics

Historically, erythromycin, azithromycin, and other macrolide antibiotics have been recommended as the primary antibiotics for treating pertussis [23, 33, 34]. The in vitro susceptibility testing outcomes for B. pertussis against various macrolide antibiotics exhibit a high degree of consistency [12, 21, 35, 36], facilitating the selection of macrolides on the basis of drug availability and pediatric patient compliance. Oral administration of azithromycin is generally preferred, with intravenous administration reserved for cases where oral administration is not tolerated [37]. The recommended dosage for azithromycin is 10 mg/kg per dose daily for 5 days, followed by a possible break of 3–4 days before resuming treatment for another 3 days [21, 35, 38]. When erythromycin is prescribed, the recommended dosage for children is 10–15 mg/kg per dose, which does not exceed the maximum daily dose of 2 g, and erythromycin is administered every 8 h for a treatment duration of 14 days. For clarithromycin (oral), the recommended dosage for children aged 1 month or older is 7.5 mg/kg per dose, with a maximum daily dose not exceeding 1 g, twice daily for a treatment duration of 7–14 days.

However, in recent years, clinical strains of B. pertussis in China have demonstrated a substantial resistance rate to macrolide antibiotics, as identified by antibiotic susceptibility tests in vitro[12, 21, 35, 36, 39]. Most B. pertussis isolates are ERBP strains with high MICs exceeding 256 mg/L [12, 21, 35, 36, 39]. Mi et al. [35] used erythromycin or azithromycin to treat 31 children with ERBP infection and 30 children with erythromycin-sensitive B. pertussis (ESBP) infection. They reported that the clearance rates of B. pertussis in the nasopharynx after 7 days and 14 days of treatment were 3.2% vs. 33.3% and 22.6% vs. 80.0%, respectively, indicating that ERBP is also resistant to macrolides in vivo and may cause treatment failure in eliminating ERBP strains from the nasopharynx. Consequently, these antibiotics are not recommended as preferred first-line antibiotics for treating pertussis in the Guidelines for Diagnosis and Management and Prevention of pertussis of China (2024 edition) [37]. Here, the experts who drafted this consensus agreed that macrolides should no longer be considered the preferred treatment option. However, if the initial therapeutic approach involves the use of macrolides and a significant deterioration in the patient's condition, if no significant reduction in the bacterial load is observed via PCR or culture during antimicrobial therapy, or if no appreciable improvement is observed after 4–5 days of treatment, it is advisable to switch to alternative antibiotics. Conversely, in cases where infection is confirmed to be ESBP or where empirical treatment with erythromycin, azithromycin, or clarithromycin has yielded positive outcomes, continuation of the same macrolide antibiotic therapy is recommended, typically for a duration of 2 weeks.

Notably, most of the existing data on pertussis resistance to macrolide antibiotics are based on in vitro antibiotic susceptibility tests. Currently, NGS techniques are widely used in clinical settings, and the erythromycin resistance gene may be detected when the B. pertussis bacterium is tested. Through the comparison of resistance genes and resistance phenotypes in hundreds of pertussis strains, the expert group behind this consensus has not found any inconsistent strains (data not published), suggesting that the results of erythromycin resistance gene detection are reliable for identifying erythromycin-resistant biological phenotypes.

Trimethoprim sulfamethoxazole

Trimethoprim sulfamethoxazole (TMP-SMX) demonstrate robust antibacterial activity against B. pertussis both in vivo and in vitro. Considering that ERBP is already widespread in China, alternative antibiotics [34, 37], such as TMP-SMX, are recommended as the preferred oral therapeutic option for children over 2 months of age. The recommended dosage regimen is 24–36 mg/kg per dose, not exceeding a maximum daily dose of 1.92 g, which is administered twice a day for a total duration of 14 days. It is advisable to monitor for potential kidney injury during medication, with an emphasis on maintaining adequate hydration and performing regular urine analysis. Renal function assessment should be conducted if necessary. Notably, TMP-SMX usage is associated with a common incidence of rashes, and treatment should be promptly discontinued in cases of severe anaphylaxis. Additionally, this antibacterial agent is contraindicated in individuals with severe G-6-PD enzyme deficiency, liver or kidney injury, or severe hypersensitivity to sulfamethoxazole.

Beta-lactam antibiotics

Beta-lactam antibiotics, including piperacillin, cefoperazone–sulbactam, ceftriaxone, amoxicillin, and ampicillin, exhibit varying degrees of antibacterial activity against B. pertussis in vitro [21, 35]. Among these antibiotics, piperacillin and cefoperazone–sulbactam could be cost-effective and readily available options. A study conducted at the Children's Hospital of Zhejiang University School of Medicine evaluated the in vitro drug susceptibility of nearly 1200 strains of B. pertussis. The results indicated that piperacillin had an MIC of less than 0.016 mg/L against virtually all strains (data not published). Piperacillin-tazobactam also exhibited remarkable bactericidal activity in eradicating bacteria from the nasopharynx in children [21, 35]. This medication is indicated for intravenous administration in severe cases of pertussis or for use in infants under 2 months of age. The recommended dosage of piperacillin is 40–50 mg/kg per dose, which is administered every 8 h. Piperacillin effectively treats bacterial coinfections, including those caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or other related pathogens. Typically, the treatment lasts for 1–2 weeks, with the possibility of subsequent TMP-SMX therapy being considered once the patient's condition improves or they reach the age of two months. The clinically proven cefoperazone–sulbactam is also an effective medication for treating pertussis infection [21, 35]. The recommended dosage of cefoperazone–sulbactam is 50–60 mg/kg per dose, which is administered every 12 h. Notably, the efficacy of other beta-lactam drugs has not been thoroughly evaluated. The fact that a beta-lactam antibiotic is not mentioned here does not mean that it is ineffective for pertussis treatment or is as effective as the antibiotics mentioned. Notably, the therapeutic regimens of these beta-lactam antibiotics are clinically effective, primarily on the basis of empirical evidence, and further rigorous clinical trials are necessary to obtain a high-quality, evidence-based evaluation.

B. pertussis is a slow-growing bacterium, and antimicrobial treatment requires a relatively long duration, usually about two weeks. Any premature discontinuation of medication may result in a relapse of pertussis symptoms. Therefore, unless the etiological test is negative after treatment, it is not recommended to interrupt antimicrobial treatment, even after 5–7 days, even if there are significant clinical improvements. Other antibiotics can replace antibiotics during treatment because of side effects or other reasons. It is advisable to conduct DNA testing or bacterial culture assessments at intervals of 5–7 days throughout the therapeutic process. Evidence of clinical symptom improvement, along with a reduction in the quantity of bacterial colonies as determined by culture or a decrease in nucleic acid copies measured by qPCR, indicates the effectiveness of the treatment. The duration of medication may be shortened once the results of the etiology test return negative.

Antimicrobial therapy for close contacts

In the management of newborn and infant patients, antimicrobial therapy should be duly considered for their close contacts. As a primary treatment modality, it is advisable to prescribe TMP-SMX orally to etiologically positive family members or caregivers. Fluoroquinolones may serve as a viable alternative for adults with high-TMP-SMX allergies. Infants who have had close contact with a person with pertussis and cannot wholly interrupt this contact should be promptly administered sensitive antibacterial agents for prophylactic purposes, adhering to the medication mentioned above and the treatment protocol. The targeted population includes (1) infants aged 3 months or younger, (2) children attending childcare facilities who have not received four doses of the pertussis vaccine, and (3) household members or healthcare workers responsible for providing care to infants younger than 3 months.

Antimicrobial therapy for “asymptomatic infections”

In individuals who have no obvious symptoms but are positive for pertussis, close observation, regular follow-up, and periodic retesting are advisable [40]. Furthermore, patients exhibiting recurrently positive etiological tests, especially those with positive bacterial culture results, indicating active infections, should receive antimicrobial therapy, particularly if they are in constant interaction with individuals who are at high risk of developing severe pertussis.

Intensive treatment for severe pertussis

Severe pertussis patients necessitate intensive treatment alongside antibiotic therapy. Nevertheless, a standardized approach to selecting and timing intensive treatment for pertussis remains elusive, and its impact on prognosis remains inconclusive across various studies. Consequently, the modalities of intensive treatment are currently in the exploratory phase.

(1)

Mechanical ventilation therapy is necessary when apnea and respiratory failure persist despite the administration of standard treatment measures.

(2)

Treatment of hyperleukemia is essential, as it poses a significant risk for severe pertussis and even death [24, 25, 27, 29]. Effectively reducing the total count of peripheral blood leukocytes can significantly improve the prognosis of patients. Currently, two primary treatment methods are leukapheresis and therapeutic plasma exchange. Among these, therapeutic plasma exchange is a more established, safer, and easier-to-perform approach than leukapheresis. In particular, therapeutic plasma exchange is highly recommended in the following scenarios, especially for infants younger than 60 days who are suffering from pertussis[24, 41]: (a) Whose WBC count exceeds 25 × 109/L and the lymphocyte count surpasses 12 × 109/L, complicated by conditions such as heart failure, pulmonary hypertension, or organ failure; (b) in cases where the WBC count increases above 48 × 109/L, the lymphocyte count exceeds 15 × 109/L; (c) whose the WBC count exceeds 30 × 109/L, it increases by more than 50% within a 24-h period, and the lymphocyte count also exceeds 15 × 109/L. By adhering to these recommendations, therapeutic plasma exchange can be effectively utilized to manage hyperleukemia and mitigate its associated risks.

(3)

The management of pulmonary hypertension involves targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors, which result in hemodynamic and functional improvements in children [42]. Inhaled NO (iNO) is commonly used in the acute management of pulmonary arterial hypertension, which presents with hemodynamic instability and right heart failure. The use of iNO in term and near-term infants for treating persistent pulmonary hypertension (PPHN) in newborns has been well studied and documented through several double-blinded placebo-controlled trials [43, 44]. Typically, the initial dose begins at 20 parts per million (ppm), which is promptly reduced to 5 ppm once the oxygenation status has improved. Following this, gradual tapering to 1 ppm precedes discontinuation [45]. It is generally advisable to limit the duration of treatment to no more than 5 days. However, the therapeutic effect of iNO on pertussis-induced pulmonary hypertension is still uncertain [24].

(4)

The optimal timing for initiating extracorporeal membrane oxygenation (ECMO) support in patients with severe pertussis remains a topic of ongoing debate, and the overall survival rate associated with this therapy remains low. It is advisable to initiate ECMO earlier, rather than as a late remedial measure, in pertussis patients with multiple risk factors that predict poor ECMO outcomes. These risk factors include young age, low ratios of partial pressure of oxygen to fraction of inspiration oxygen (PaO2/FiO2), the need for vasoactive medications, the presence of a neuronal system or infectious complications, pulmonary hypertension, and rapid disease progression (requiring intubation and ECMO support within 24 h of hospital admission) [46]. In particular, patients with severe pulmonary hypertension, where hemodynamic collapse may occur rapidly, are strong candidates for earlier ECMO initiation [47, 48].

(5)

Intravenous administration of pertussis immunoglobulin (P-IVIG) at a dosage of 15 mL/kg daily for 1–2 days.

Chinese medicine treatment

Traditional Chinese Medicine for treating pertussis principally focuses on purging the lungs, clearing heat, resolving phlegm, and reducing adverse flow. Clinically, pertussis was divided into the initial cough stage, paroxysmal cough stage, and recovery stage, advocating for lung-dispelling, lung-purging, and lung-nourishing treatments, respectively.

During the initial cough stage, the treatment principal is to disperse wind and promote lung ventilation, with the formula of choice being the modified Mulberry Leaf and Chrysanthemum Drink. Commonly used medicinal herbs include mulberry leaf, chrysanthemum flower, platycodon root, stemona root, bitter apricot seed, perilla leaf, loquat leaf, forsythia fruit, cowherb seed, mint, and licorice.

In the paroxysmal cough stage, the treatment principal is to purge the lungs and resolve phlegm, with the formula of choice being the combined Mulberry Bark Decoction and Tussilago and Jujube Lung-Draining Decoction. Commonly used medicinal herbs include mulberry bark, scutellaria root, fritillaria bulb, pinellia rhizome, stemona root, perilla seed, bitter apricot seed, scutellaria root, coptis rhizome, coicis seed, gardenia fruit, and jujube.

During the recovery stage, the treatment principal is to nourish yin and boost qi, with the formula of choice being the combined Ginseng and Schisandra Decoction and Ophiopogon and Oatstraw Decoction. Commonly used medicinal herbs include ophiopogon, codonopsis root, oatstraw, polygonatum root, poria, atractylodes macrocephala, mulberry leaf, and trichosanthes root.

Traditional Chinese Medicine emphasizes individualized treatment. Therefore, in this consensus guideline, we recommend herbal medicines without specifying dosages.

Criteria for the removal of quarantine

Respiratory isolation may be terminated when any of the following criteria are fulfilled: (1) The patient has completed a course of sensitive antibiotics for at least 5 days [34, 49], leading to a notable improvement in their clinical manifestations. (2) The patient has been experiencing paroxysmal cough for a duration exceeding 21 days [34]. (3) No positive results are obtained from nasopharyngeal swab cultures, nasopharyngeal or oropharyngeal swab testing for B. pertussis DNA. Children who meet criteria (1) and (2) for removal of quarantine but whose nasopharyngeal swab culture results are positive are advised to continue antimicrobial therapy. Additionally, it is strongly recommended that they wear masks upon resuming school attendance.