European Journal of Clinical Microbiology & Infectious Diseases

, Volume 29, Issue 9, pp 1051–1054

Recurrent respiratory papillomatosis: an overview


  • Qingliang Xue
    • The Respiratory Diseases Department of the Chinese PLA General Hospital
  • Haitao Wang
    • The Third Hospital of the General Brigade of Armed Police
    • The Respiratory Diseases Department of the Chinese PLA General Hospital

DOI: 10.1007/s10096-010-0963-6

Cite this article as:
Xue, Q., Wang, H. & Wang, J. Eur J Clin Microbiol Infect Dis (2010) 29: 1051. doi:10.1007/s10096-010-0963-6


Recurrent respiratory papillomatosis (RRP) primarily caused by human papillomas virus is a rare and benign neoplasm, primarily involving the epithelium mucosae of the respiratory tract. RRP may occur anywhere in the respiratory tract with a predilection to the laryngeal area and may potentially threaten life. Because of the absence of specific clinical manifestations, the diagnosis of this disease is easily delayed. The high awareness of RRP and performing endoscopy as soon as possible in suspected patients are the prerequisites for early diagnosis. Surgical removal on endoscope is still a fundamental treatment. Adjuvant treatment is required only in some patients. Because of the potential of malignant transformation and recurrence, careful follow-up for RRP is required for early detection and treatment.


Respiratory papillomatosis is a benign neoplasm occurring in the respiratory tract and caused primarily by human papillomas virus (HPV) infection. Because of its recurrent nature, it is commonly named as recurrent respiratory papillomatosis (RRP) [1]. RRP is a rare disease with the incidence rate estimated ranging from four to 12 cases per 1,000,000 person-years [2]. Although benign, it may cause significant morbidity and mortality and often induces high medical cost due to repeated treatments [2]. RRP usually presents a variable and prolonged clinical course and has been divided into juvenile-onset and adult-onset types according to the onset age whether or not over 13-years old. The diagnosis and therapy of this disease is challenging due to the absence of specific clinical manifestations and its recurrent nature, respectively. This article summarizes the etiology, pathology, diagnosis and therapy of RRP and reviews the recent updates.


HPV is a small non-enveloped virus, about 55 nm in diameter. Its DNA is a double-strand circular structure including about 8 kb and coding 8–10 genes. The early genes E1 and E2 are associated with viral replication and transcription, E4 is associated with viral release from infected cells, and E6 and E7 are probably associated with viral transformation. The late genes L1 and L2 code viral capsid proteins. Viral capsid is primarily composed of L1 protein with a small portion of L2 protein embedding deeply. The L1 protein provides the dominant antigenic epitopes recognized by neutralizing antibodies. The mechanism of how HPV infects the host cell is unclear. Heparin sulphate and α6-integrin may be associated with HPV infection. After entering the host cell, HPV puts off capsid and translocates into nuclei to replicate. According to the DNA studies, over 118 types of HPV have been identified. RRP is primarily associated with HPV6, HPV11, HPV16 and HPV18, and HPV6 and HPV11 are responsible for approximately 90% of patients with RRP [3].

HPV is a commensal organism in humans. It tends to induce widespread latent infection due to the inhabitation of host immune function. HPV is the primary pathogen of human anogenital warts, and the anogenital site is the primary reservoir of HPV. The laryngeal area is not the fitting parasitic location for HPV [4]. It is well accepted that HPV could be transmitted from the mother’s anogenital site to the infant’s respiratory tract during delivery, and even before delivery through infected placenta and amniotic fluid, resulting in juvenile-onset RRP after months or years of latency. The identification of HPV DNA sequences from both the anogenital warts of mothers and the RRP of children confirms an etiological association between the two [5]. About 0.7% of infants with maternal anogenital warts in pregnancy would fall ill, an approximate 231 times higher risk than others [6]. These facts suggest the maternal anogenital warts in pregnancy should be a primary risk factor for juvenile-onset RRP. For adult-onset RRP, having multiple sexual partners and oral sex may be the high risk factors [7]. Additionally, extra-oesophageal acid reflux disease is a high risk factor for RRP [8]. Iatrogenic transmission also deserves attention because HPV can survive on cryoprobe, in liquid nitrogen and in the plume generated by laser ablation or electrocautery [9, 10].


RRP is a mucosal, exophytic and benign neoplasm, sessile or pedunculated, usually presenting irregular, multiple and cauliflower-like clusters. Factors affecting the severity degree of this disease are primarily HPV type and onset age. Patients with HPV11 infection and younger patients have higher risk for high severity score [11]. RRP may arise anywhere of the respiratory tract with a predilection to the so-called transformation area where squamous epithelia and ciliated columnar epithelia meet. The most common lesion site anatomically is the laryngeal area. The incidence rate of lower respiratory tract or lung involvement is low. The high risk factors for RRP to spread into the lower respiratory tract may include HPV11 infection, age below 3 years and tracheotomy preformed to avoid airway obstruction [12]. RRP arising in trachea without laryngeal lesions has been only reported in a few cases [13].

It is generally accepted that HPV infects its host cell, primarily keratinocyte, through the microtrauma or abrasions in the surface of epithelium. The HPV infection establishes a tumorigenic microenvironment by suppressing effective TH1-like immune responses to HPV, which, together with the altered expression of genes regulating cellular growth and differentiation, favors the disorder proliferation of infected host cells and the development of RRP [14]. The positive feedback between cyclooxygenase2 and prostaglandinE2 is a promoting agent to the development of RRP [15]. Host immune status also plays a significant role in the disease outcome. In some patients, RRP lesions have been seen to regress spontaneously, but prone to recur even after years of regression. In other patients such as pregnant women [16], RRP lesions are prone to aggravation. Under some conditions such as smoking, irradiation, cytotoxic drugs, p53 mutation, HPV11 infection, high severity score or high activity of 2′, 5′-oligoadenylate synthetase, RRP lesions may transform malignantly [17, 18]. Whether or not the high number of surgical treatments should be regarded as a high risk factor of malignant transformation is still controversial [19, 20].


The common clinical symptoms of RRP include hoarseness, cough, wheeze, voice change, chronic dyspnea, choking, syncope, and so on. Stridor or respiratory harshness is possibly audible on the auscultation of chest. Chest radiography is usually unremarkable. Because of its nonspecific clinical manifestations, RRP is easily mistaken for asthma, acute laryngitis, upper respiratory infection or bronchitis. But, asthma therapies and anti-infective treatments are inefficacious. High awareness of RRP and consideration in the right clinical context are prerequisites for early and correct diagnosis. Endoscopy should be performed as soon as possible in suspected patients, which would enable the diagnosis to be established early and correctly.

Endoscopy is the main method to make a definite diagnosis. Multiple cauliflower-like neoplasms with smooth and neat surface and without necrosis can be seen on endoscope. These neoplasms are prone to hemorrhage after touched because of their fragile nature. Histological findings of biopsy sample slices stained by hematoxylin and eosin reveal finger-like projections of neoplastic and nonkeratinized stratified squamous epithelium covering a fibrovascular stroma core. Parakeratosis, koilocytosis and acanthosis are often observed. Cellular differentiation appears abnormal and the atypia degree varies. Serological specific antibody detection is a useful tool for establishing the diagnosis of HPV infection. The detection of HPV DNA by PCR with consensus primers and subsequent restriction mapping or the hybridization methods using probes for each HPV type are available for the specific typing of HPV.

A staging system established by the University of Washington is licensed to the American Society of Pediatric Otolaryngology. This staging system utilizes the method of severity score primarily based on the clinical features and anatomical area of involvement. It is helpful to standardize the evaluation of patients and to select and evaluate treatment modalities.


The treatment goals of RRP mainly include curing lesions and preventing recurrence. Repeating treatment is usually required because recurrence is very common after cured or regressing spontaneously. Latent virus is the main cause of recurrence [21] because HPV may persist latently in the morphologically normal tissue adjacent to lesions, and eradication is usually impossible [22]. Whether or not the latent virus reactivates is possibly associated with such factors as host immune status, HPV type, extent and duration of disease. Up to now, many surgical and medical treatments have been tried, but none of them has been proven fully efficacious in all patients. When selecting a treatment, suffering, side effects and costs related to treatment are required to be considered in addition to curative effect [23].

Surgical removal on endoscope is still the fundamental treatment, and the most extensively used approaches in recent years are laser ablation and microdebrider removal. Other available approaches include electrocautery and cryotherapy. In patients with recalcitrant RRP, repeating surgical removal with variable intervals is required to secure an adequate airway. However, excessive surgical removal may injure the lamina propria leading to scarring and iatrogenic airway stenosis [24]. Surgical removal utilizing microdebrider might be helpful to reduce such complications [25, 26]. In some severe patients, tracheotomy is required because papillomatous lesions may obstruct the airway and threaten life. Approximately 14% of patients with RRP require tracheotomy to avoid life-threatening airway obstruction [27]. Under some conditions, such as papillomatous lesions spreading into distal bronchi or presenting signs of malignant transformation, patients maybe require chest surgery.

Adjuvant medical treatment is required in approximately 20% of patients with RRP. The most common criteria for adjuvant treatment include more than four surgical removals required per year, rapid regrowth of disease with airway compromise and distal multisite spread. The most commonly used adjuvant treatments are antiviral and immunoregulation drugs. Other available adjuvant drugs include anti-reflux drugs, mitomycinC, cyclooxygenase2 inhibitors, retinoids, zinc and indole-3-carbinol. Antiviral drugs are mainly nucleoside analogs and show variable success in different groups of patients [28]. The commonly used antiviral drugs include cidofovir, ribavirin, acyclovir and ganciclovir. Oral or vein administration is a common route. Intralesional injection of cidofovir has been suggested as a promising treatment in recent years [29, 30]. However, the evidence from clinical, randomized, blinded, placebo-controlled trials are still absent to confirm the efficacy of the intralesional injection of cidofovir [31]. Additionally, there are controversies about whether or not cidofovir increases the risk of the malignant transformation of RRP [32, 33]. Interferon-α is the most commonly used immunoregulation drug. It was reported safe and efficacious, especially in patients with HPV6 infection [34, 35].

The research and development of a multivalent HPV vaccine has progressed rapidly in recent years. The mechanism of the HPV vaccine is to design recombinant non-infectious HPV virus-like particles expressing the HPV L1 protein. These particles show high immunogenicity and are the active component of the HPV vaccine. The HPV vaccine has been proven efficacious in preventing HPV infection of the cervix [36, 37] and possibly reduces the incidence of RRP [38] and the medical cost [39]. However, the HPV vaccine is suggested to be less likely of therapeutic value [40]. It is also not known whether the HPV vaccine is efficacious in preventing HPV infection in men [41].


RRP primarily caused by HPV infection is a rare, epithelial, exophytic and benign neoplasm occurring in the respiratory tract with laryngeal predilection and potential mortality. The diagnosis of this disease is challenging due to its nonspecific clinical manifestations and unremarkable chest radiography. For early and correct diagnosis, high awareness of RRP and consideration in the right clinical context are prerequisites. Endoscopy should be performed as soon as possible in suspected patients. Once the diagnosis is established, a considerate treatment regimen is required to cure this disease and prevent recurrence. In addition, subsequent follow-up is required for early detection and treatment of malignant transformation and recurrence.

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© Springer-Verlag 2010