Extrathoracic airway dysfunction

COMMENTARY

A

new

human

herpesvirus: KSHV or HHV8?

See page 799

Herpes virology has enjoyed the spotlight for the past decade, during which three new herpesvirus types have been discovered. Evidence for the most recent putative human herpesvirus (although not yet isolated in culture or definitively demonstrated by electronmicroscopy) was found using molecular techniques in Kaposi’s sarcoma (KS) lesions and in B-cell lymphomas of the abdominal cavity. 1,2 Not since isolation of hepatitis C3 has a new human virus been detected solely by molecular procedures. Some researchers have designated this presumed eighth human herpesvirus Kaposi sarcoma associated herpesvirus (KSHV) because of its detection in both HIV positive and negative individuals with all forms of KS.’ Whether this agent is oncogenic, however, requires further evaluation since it is absent in many KS lesions and KS-derived cell lines-eg, in the SLK line which induces KS-like lesions in nude mice.’ Moreover, the recent detection of similar sequences in squamous cell carcinomas in immunocompromised individuals8 makes the role of this agent in any specific cancer unclear. Whenever a new human virus is discovered, identification of its potential pathogenic role becomes an exciting challenge. By genomic analysis’1 and by its presence in B cells,6 this putative eighth human herpesvirus (HHV8) resembles Epstein-Barr virus (EBV). Finding HHV8 DNA sequences in peripheral blood mononuclear cells and B lymphocytes of KS patients6 suggests that the virus is widespread but, as with EBV, HHV8 is probably undetectable in many individuals. Perhaps immune compromise permits increased expression of the agent. Serological studies should resolve the issue of prevalence. Whitby et al now report that polymerase chain reaction studies showing KSHV sequences in peripheral blood mononuclear cells might reflect the propensity of an individual to develop KS. Although these noteworthy findings require confirmation, similar observations suggest that the presence of KSHV sequences presages development of B-cell lymphomas. HHV8 could cause malignant conditions such as KS or B-cell lymphomas or an acute human illness, as do many human herpesviruses, or be a benign agent. HHV7, for example, is still in search of a disease. HHV8 may not be oncogenic but rather infect a specific B-cell subset that proliferates in response to a developing cancer. In this case one might be able to detect anti-KS antibodies produced by HHV8-infected B cells. Alternatively, the HHV8-infected B cells could have an indirect role in malignancies by enhancing the spontaneous or induced transforming event. A similar promoting role of EBV in some B-cell lymphomas has been proposed, since many B-cell lymphomas do not contain EBV.9 Another possibility is that the HHV8-infected B cells produce cytokines that increase the proliferation of endothelial cells involved in KS,’° epithelial cells that lead to squamous cell carcinomas, or certain B cells that evolve into lymphomas (see figure). Analysis of cytokines released by HHV8-infected B cells could provide insight into these possibilities. Moreover, whether the finding of HHV8 in peripheral blood can be a prognostic sign or pose a problem in blood transfusions requires additional evaluation. However, KS has not been frequently

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Figure: Potential

role of HHV8 in induction of

malignant

disease

associated with transfusions." Meanwhile, without any pathogenic role defined, designating this agent HHV8 seems most

appropriate.

Jay A Levy Cancer Research Institute, and Department of Medicine, University of California, San Francisco, CA, USA

Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesviruslike DNA sequences in AIDS-associated Kaposi’s sarcoma. Science

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1994; 266: 1865-69. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995; 332: 1186-91. 3 Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-62. 4 Su IJ, Hsu YS, Chang YC, Wang IW. Herpesvirus-like DNA sequence in Kaposi’s sarcoma from AIDS and non-AIDS patients in Taiwan. Lancet 1995; 345: 722-23. 5 Huang YQ, Li JJ, Kaplan MH, et al. Human herpesvirus-like nucleic acid in various forms of Kaposi’s sarcoma. Lancet 1995; 345: 759-61. 6 Ambroziak JA, Blackbourn DJ, Herndier B, et al. Herpesvirus-like sequences in HIV-infected and uninfected Kaposi’s sarcoma patients. Science 1995; 268: 582-83. 7 Herndier BG, Werner A, Arnstein P, et al. Characterization of a human Kaposi’s sarcoma cell line that induces angiogenic tumors in animals. AIDS 1994; 8: 575-81. 8 Rady PL, Yen A, Rollefson JL, et al. Herpesvirus-like DNA sequences in non-Kaposi’s sarcoma skin lesions of transplant patients. Lancet

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1995; 345: 1339-40. Miller G. Epstein-Barr virus: biology, pathogenesis and medical aspects. In: Fields BN, et al, eds. Virology, 2nd ed. New York: Raven, 1990: 1921-50. 10 Levy JA, Ziegler JL. Acquired immune deficiency syndrome (AIDS) is an opportunistic infection and Kaposi’s sarcoma results from secondary immune stimulation. Lancet 1983; ii: 78-81. 11 Peterman TA, Jaffe HW, Beral V. Epidemiologic clues to the etiology of Kaposi’s sarcoma. AIDS 1993; 7: 605-11.

9

Extrathoracic airway

dysfunction

See page 791 In respiratory outpatient clinics, doctors often encounter patients with chronic cough and asthma-like symptoms but no evidence of asthma. In such cases, finding the cause and effective treatment is difficult once other diseases of the lower respiratory tract-eg, chronic or endobronchial tumour-have been excluded. Some patients respond to treatment for gastro-oesophageal reflux or to the discontinuation of an angiotensin converting enzyme inhibitor, but many continue to have symptoms. The extent to which symptoms are related to extrathoracic rather than intrathoracic airway abnormalities is unknown. Far less attention has been paid to extrathoracic airway

bronchitis, infection,

to functioning of the lower This discrepancy may partly be a "territorial" airways. fall between respiratory issue (extrathoracic airways medicine and otolaryngology) but also relates to the difficulty of differentiating upper from the much commoner lower airways obstruction. Conventional lung function tests are poor at separating the two and lack sensitivity in detecting extrathoracic airway narrowing. The maximum flow volume curve is the most useful 1 physiological test for upper airway narrowing.’ The characteristic features are a global reduction in inspiratory flow and/or an expiratory flow volume curve showing a "flat top" that represents constant rather than diminishing flow through much of the lung volume. Whether expiratory or inspiratory flow is most affected depends on whether the obstruction is intrathoracic or extrathoracic and on the extent to which it responds to dynamic pressure changes. Both expiratory and inspiratory flow are reduced with a relatively rigid extrathoracic airway obstruction whereas inspiratory flow is predominantly impaired if the affected airway is both extrathoracic and floppy since the airway wall is then sucked in by the

function and dysfunction than

negative intra-airway pressures generated during inspiration. Maximum mid-inspiratory flow correlated with mid-inspiratory glottal on area measured histamine bronchoscopy during challenge. Bucca et al have now exploited the different effect of lower (bronchial) and upper (extrathoracic) airway 2

obstruction on the maximum flow volume curve to determine the site of airway hyperreactivity in 441 patients with the asthma-like symptoms of non-productive cough, episodic dyspnoea, and wheeze lasting for at least 2 months, but with no evidence of asthma or airways obstruction. Subjects inhaled increasing doses of histamine and carried out a maximum flow volume manoeuvre after each dose, from which the forced expiratory volume in one second (FEV) and maximum mid-inspiratory flow (MMIF) were measured. Bronchial and extrathoracic airway hyperreactivity were judged to be present when less than 8 mg/mL histamine was needed to cause a fall in FEVj and MMIF of 20% (PD2) and 25% (PD25)’ respectively. Only two of 75 normal subjects showed extrathoracic hyperreactivity by these criteria. Extrathoracic hyperreactivity was found in 67% of subjects and was the sole abnormality in 25%. The 151 patients with cough as their only symptom were more likely to have extrathoracic hyperreactivity and less likely to have bronchial hyperreactivity than were subjects in other symptom groups. When cough was associated with wheeze and/or dyspnoea, subjects were more likely to have both upper and lower airway hyperresponsiveness. The researchers also related the reactivity measurements to four extrathoracic diseases diagnosed from a symptom questionnaire (pharyngitis, post-nasal drip, laryngitis, and sinusitis). Extrathoracic hyperreactivity alone or combined with bronchial hyperreactivity was associated with all four disorders, by comparison with subjects without hyperreactivity and in contrast to subjects with bronchial hyperreactivity alone. Most subjects had a normal MMIF before histamine challenge, unlike many patients with vocal cord dysfunction.’J Thus chronic cough and upper airways disorders such as post-nasal drip, pharyngitis, and sinusitis seem to be associated with upper airway hyperreactivity to histamine

patients without asthma. The nature of the relation is uncertain, however, and it is not clear to what extent the in

disease labels such as pharyngitis indicate an allergic or infective disorder. Does pharyngitis or post-nasal drip cause extrathoracic hyperreactivity, which in turn causes cough, or does the underlying disease process cause symptoms and upper airway hyperresponsiveness? Extrathoracic hyperreactivity was found in 76 of 106 patients with chronic sinusitis and resolved in most cases after treatment with antibiotics and nasal steroids.’ Measurement of extrathoracic airway reactivity, as done in this study, is not easy and it will suffer from the problems inherent in measurements of airway responsiveness.5 Upper and lower airway hyperreactivity are not independent. Diseases such as asthma may be associated with extrathoracic airways dysfunction3,6 whereas patients with upper airway abnormalities are more likely to have bronchial hyperreactivity3,7 (although the extent to which this is due to the upper airway problem or concomitant lower airway disease is uncertain). The repeatability of PD 25 MMIF is not given but is probably worse than that for PD20 FEV1 since it is more effort dependent. Measurement of extrathoracic reactivity is unlikely to become a routine test but it seems to be a useful research tool and may help to open up a neglected area associated with considerable morbidity. The combination of functional studies with biopsy of the upper airways could pave the way for more focused therapy. T W Harrison, A E Tattersfield Respiratory Medicine, City Hospital, Nottingham, UK

Division of

Miller RD, Hyatt RE. Obstructing lesions of the larynx and trachea: clinical and psychologic characteristics. Mayo Clin Proc 1969; 44: 145-61. 2 Bucca C, Rolla G, Scappaticci E, Baldi S, Caria E, Oliva A. Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms. Allergy 1991; 46: 147-53. 3 Goldman J, Muers M. Vocal cord dysfunction and wheezing. Thorax 1991; 46: 401-04. 4 Bucca C, Giovanni R, Scappaticci E, et al. Extrathoracic and intrathoracic airway responsiveness in sinusitis. J Allergy Clin Immunol 1

1995; 95: 52-59. 5

6

7

Britton J, Tattersfield AE. Does measurement of bronchial hyperreactivity help in the clinical diagnosis of asthma? Eur J Respir Dis 1986; 68: 233-38. Lisboa C, Jardim J, Angus E, Macklem P. Is extrathoracic airway obstruction important in asthma? Am Rev Respir Dis 1989; 122: 115-21. Annesi I, Oryszczyn M-P, Neukirch F, Orvoen-Frija E, Korobaeff M, Kauffmann F. Relationship of upper airways disorders to FEV1 and bronchial hyperresponsiveness in an epidemiological study. Eur Respir J 1992; 5: 1104-10.

Disinfection in

endoscopy

Decontamination of flexible and other heat-sensitive endoscopes after each patient is standard practice, but which disinfectant is best? The disinfecting agent should kill microorganisms rapidly and thus allow speedy patient turnaround, be bactericidal against typical and atypical mycobacteria, and be virucidal. The ideal agent should not damage equipment and should be safe. Glutaraldehyde fulfils all of the above requirements except the last: it is irritant and sensitising to the skin and respiratory tract.’1 Furthermore, despite modern processing equipment in endoscopy suites, environmental contamination can take placet and endoscopy nurses who become sensitised to glutaraldehyde may have to pursue

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