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Upper airway. 3: Sinonasal involvement in chronicobstructive pulmonary disease

J R Hurst

Correspondence to:Dr J R Hurst, Academic Unit ofRespiratory Medicine, Royal FreeCampus, UCL Medical School,London NW3 2PF, UK; [email protected]

Received 27 April 2009Accepted 5 May 2009

ABSTRACT

This review presents the evidence that chronic obstructive

pulmonary disease (COPD) is associated with significantsinonasal symptoms, inflammation and airway obstruction.Upper airway symptoms in COPD cause impairment toquality of life. The severity of upper airway involvementrelates to that present in the lower airway, suggesting thatthe nose may be used to model the lung in COPD. Moreimportantly, relationships between upper and lower airwaybacteria and inflammation, and the association between

sinusitis and treatment failure at exacerbation raise thepossibility that nasal intervention in COPD may not onlyimprove health status but may also affect important clinicaloutcomes such as exacerbation frequency.

It is not widely appreciated that chronic obstruc-tive pulmonary disease (COPD) is associated withsinonasal (upper airway) involvement, a conceptthat might at first seem surprising given thatCOPD is defined by the presence of inflammationand airflow limitation in the lung.1 However,noxious stimuli to the lung must enter the lowerairways via the upper airways, and the airways arein continuity such that this distinction is itselfartificial. Additionally, as discussed elsewhere inthis series, there are recognised associationsbetween rhinitis and asthma, and these conditionsmay represent the upper and lower airwaymanifestations of a single allergic airways disease.This review summarises the evidence supportingsinonasal involvement in COPD, interactionsbetween the upper and lower airway, and themechanisms and implications that may result fromsuch interaction. Given that COPD is associatedwith lower airway symptoms, inflammation andairway obstruction, it would seem appropriate toassess whether these features are also present inthe upper airway. However, it is important first toconsider the effects of cigarette smoke on the nose.

CIGARETTE SMOKE AND THE NOSE

Unlike asthma-rhinitis, where the nasal airway isprobably exposed to a greater allergen load than thelung, most cigarette smoke bypasses the nose andreaches the lung via the mouth. The nasal airwaymay be exposed to a proportion of the sidestreamsmoke (which originates from the tip of the cigaretteand otherwise escapes to the atmosphere). Thiscontrasts with the lung which predominantlyreceives mainstream smoke, inhaled through thecigarette itself via the mouth. A proportion ofsmokers exhale smoke through the nose.

The strongest association between nasal pathol-

ogy and smoking is for malignant disease (thoughthese tumours are not common), and there is much

less evidence that cigarette smoking per se results in aspecific nasal inflammatory disease analogous toCOPD.2 Indeed, surprisingly little is known aboutnon-malignanthistological changes in the nose due tocigarette smoke exposure. Nasal pathology doesappear to be more common in smokers.3 Analysis oftheUS NHANES II data suggested that smokers havea higher prevalence of upper respiratory tract diag-noses than non-smokers,4 whilst in a study of 191men, current smoking was associated with a fivefoldincreased risk of chronic rhinitis in a dose-dependentmanner.5 Nasal mucociliary clearance is prolonged insmokers compared with non-smokers, and longest insmokers who regularly exhale through their nose.6

There is also evidence that cigarette smoking isassociated with increased nasal resistance.7

In summary, although the available data aresparse, it does appear that active cigarette smokingis associated with an increased prevalence of nasaldisease and therefore when assessing whether thereis sinonasal involvement in COPD appropriatecorrection for smoking status must be considered.

NASAL SYMPTOMS IN COPD

This was addressed by one of the first studies everto investigate the possibility of sinonasal involve-ment in COPD.8 Montnemery et al conducted a

large questionnaire-based study from a randomselection of a Swedish population in which infor-mation on the presence of chronic nasal symptomsand a self-reported diagnosis of COPD was availablefor 8469 subjects. Thirty-three percent of the totalpopulation reported recurrent or persistent nasalsymptoms, compared with 40% of the subjectsself-reporting COPD. Recurrent or persistent nasalsymptoms were also more prevalent in currentsmokers than in non-smokers. Although the studyis limited by the absence of spirometry to confirmthe presence of airflow obstruction, these were thefirst data to suggest a higher prevalence of nasal

symptoms in COPD than in the general population,and a higher prevalence in COPD than in smokers asa whole. In a recent follow-up to the original study,the presence of nasal discharge or nasal blockage inthe original survey approximately doubled the riskof a subsequent incident diagnosis of COPD over an8 year period.9 A second epidemiological survey, byvan Manen et al,10 investigated the prevalence ofself-reported comorbidities in 290 patients withirreversible airflow obstruction and in 421 controls.The prevalence of sinusitis in the controls was2.5%, compared with 12.4% in the subjects withairflow obstruction, equivalent to an adjustedodds ratio (OR) of 6. It is likely that a proportion

of the patients with airflow obstruction hadchronic asthma rather than COPD.

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Roberts et al11 were the first to assess the prevalence of

chronic nasal symptoms in a population with COPD confirmedat spirometry. In 61 patients with moderate to severe disease(mean forced expiratory volume in 1 s (FEV1) 0.98 litre, 37%predicted), 75% reported regularly experiencing nasal symptomswhen stable, the most common of which was rhinorrhoea(fig 1). Importantly, nasal symptoms were no less prevalent inthe ex-smokers, suggesting that nasal symptoms are not solelydue to active smoking and that they persist following smokingcessation. Nasal symptoms were also more common in patientswith chronic sputum production.

Not all investigators have found an increased prevalence ofnasal symptoms in subjects with COPD. A study from Greececompared the prevalence of rhinitis in subjects with andwithout COPD.12 COPD was confirmed with spirometry, andrhinitis was defined by the presence of nasal symptoms togetherwith objective evidence of reduced nasal airflow at rhinomano-metry. Of the 6112 subjects assessed, 6% had COPD and 25%had rhinitis. The prevalence of rhinitis was higher in smokersthan in both ex-smokers and never-smokers (30, 27 and 20%,respectively), but the prevalence of rhinitis in COPD (28%) was

not significantly different from the prevalence in subjectswithout COPD (25%). Notably, the patients with COPD inthis study were likely to have had milder disease than thosestudied by Robertset al.11

In conclusion, it seems likely that COPD is associated with ahigher prevalence of chronic nasal symptoms than found incontrol subjects, not solely attributable to active cigarettesmoking and which persist after smoking cessation. The

presence of chronic nasal symptoms suggests that COPD maybe associated with chronic rhinosinusitis. Difficulties in asses-sing sinonasal disease using symptoms alone has led national13

and international14 guideline committees additionally to requireobjective evidence of disease on physical examination orimaging studies. To date there are no reports of sinonasalimaging in COPD, but further evidence of sinonasal involve-ment has been provided by studies of nasal inflammation. Theseare discussed further in the following section.

NASAL INFLAMMATION IN COPD

A number of studies have now demonstrated that stable COPDis associated with increased nasal inflammation, and these are

summarised in table 1.The first study to assess nasal inflammation in COPD was

published in 2003. Nihlen et al15 performed nasal lavage beforeand after histamine challenge in 23 patients with COPD and 26controls, each group containing both current smokers andnever- or ex-smokers. Although there were no differences in theconcentrations of inflammatory markers between the subjectswith COPD and controls at baseline, prior to the histaminechallenge, this probably reflected the methodology employed inwhich initial nasal wash samples were discarded. Histaminechallenge resulted in a greater nasal neutrophil response in thesubjects with COPD compared with the controls (assessed usingmyeloperoxidase), greatest in the subjects with COPD reportingnasal symptoms who also had an increase in nasal fucoseconcentration (a marker of mucinous secretion). The authorsconcluded that individuals suffering from both COPD andnasal complaints exhibited greater nasal neutrophil activity andsecretory responsiveness than COPD patients without nasalsymptoms.15 Thestudyis open to criticism regarding the inclusionof current, ex-smokers and never-smokers (thus being unable to

Figure 1 Prevalence (%) of individual chronic nasal symptoms in 61patients with stable moderate and severe chronic obstructive pulmonarydisease (COPD). Data from Roberts et al,11 with permission.

Table 1 Studies investigating nasal inflammation in stable COPD

Author Year Subjects Smoking Method Results and comments

Nihlen 200315 26 Control Current, ex andnever

Nasal lavage before andafter nasal histaminechallenge

Prechallenge, no differences in nasal wash a2M, fucose, ECP or MPO between controlsand COPD. Significantly greater MPO response to histamine in subjects with COPD. InCOPD, the presence of nasal symptoms was associated with greater increases in MPO andfucose concentration. Any patients with COPD prescribed inhaled corticosteroids had these

withdrawn 2 weeks prior to challenge.

23 COPD, mean

FEV156%

Current and ex

Vachier 200419 14 Contro l Curr ent andnever

Matched nasal andendobronchial biopsy

Smoking associated with squamous metaplasia in nose and lung, and increased CD8 + cellscompared with control non-smokers. Eosinophils fewer, and neutrophils and macrophagesmore abundant in nasal and bronchial biopsies of smokers with COPD than controlsmokers. No patients with COPD were prescribed inhaled corticosteroids.

14 COPD,median FEV167%

Current

Hurst 200516 12 Control Ex and never Nasal lavage, with pairedsputum in COPD patients

Greater nasal wash IL8 (but not IL6 or total leucocytes) in ex-smoking COPD comparedwith matched controls. Significant relationship between sputum and nasal wash IL8 (butnot IL6 or total leucocytes) in COPD. Lower airway bacterial colonisation in COPDassociated with higher nasal bacterial load, and self-reported postnasal drip. Patients withCOPD were on treatment, including some on inhaled corticosteroids.

47 COPD, meanFEV139%

35 matched exand 12 current

Hens 200818 23 Contro l Ex and never Nasal sec ret io nscollected by absorption

Greater nasal eotaxin, G-CSF and IFNc (trend) in COPD. No differences in nasal IL1b, IL8,IP10, MIG, MCP-1 or VEGF. Patients with COPD were on treatment, including some oninhaled corticosteroids.31 COPD, mean

FEV159%Current and ex

COPD, chronic obstructive pulmonary disease; ECP, eosinophil cationic protein; FEV1, forced expiratory volume in 1 s; G-CSF, granulocyte colony-stimulating factor; IFNc, interferon

c; IL, interleukin; IP-10, interferon c-induced protein 10; a2M, a-2-macroglobulin; MIG, monokine-induced by IFNc; MCP-1, monocyte chemotactic protein-1;MPO, myeloperoxidase; VEGF, vascular endothelial growth factor.

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differentiate any inflammation caused by current smoking fromthat associated with COPD), and the experimental design whichprobably biased against detecting differences between subjects withCOPD and control subjects in the baseline state.

We developed this initial description of nasal inflammation inCOPD by performing a study that included a smoking-matchedcontrol group, and which additionally assessed relationshipsbetween nasal and bronchial inflammation.16 Even followingsmoking cessation, COPD was associated with greater nasalinflammation than that present in an ex-smoking or never-

smoking control group of similar age and sex distribution.Moreover, the degree of nasal inflammation reflected thatpresent in the lung, as evidenced by a significant correlationbetween the concentration of interleukin 8 (IL8) in matchednasal wash and sputum samples (fig 2). Bacterial colonisation isan important phenomenon in COPD, and patients with lowerairway colonisation both had a higher total nasal bacterial loadand were more likely to experience postnasal drip. Similaritiesbetween upper and lower airway inflammation in COPD aretherefore also associated with relationships between upper andlower airway bacterial carriage. Eradicating upper airwaypathogens in the critical care setting is associated with areduced risk of ventilator-associated pneumonia,17 and such an

approach deserves investigation in COPD.Hens et al recently reported a study enrolling fewer patients,but which assessed a greater number of nasal inflammatorymarkers.18 Patients with COPD had higher nasal concentrationsof eotaxin, granulocyte colony-stimulating factor (G-CSF), anda trend to higher interferon c concentrations than controlsubjects, without significant differences in IL1b, IL8, IP10(interferonc-inducible protein 10), MIG (monokine induced byinterferonc), MCP-1 (monocyte chemoattractant protein-1) or

VEGF (vascular endothelial growth factor). This study did notcontrol for the effects of active cigarette smoking, and withmultiple comparisons in a small group of subjects there is theattendant risk of type I and type II errors. However, this is alsothe only study to date that has reported nasendoscopy findings

in patients with COPD. There were more signs of nasalinflammation in the patients with COPD than in the controls,

though the assessor was not blinded to the presence or absenceof disease. As with the study by Hurstet al,16 the concentrationsof inflammatory markers in the nose were not significantlyrelated either to indices of airflow obstruction or to the severityof nasal symptoms.

Vachier et al19 took a different approach and assessed pairednasal and bronchial biopsies in smokers with and without COPD,and non-smoking controls. The patients with COPD had mild

disease with a median FEV1 of 67% predicted, none had nasalsymptoms and none was prescribed inhaled corticosteroids.Smoking was associated with squamous metaplasia and infiltra-tion of the nasal and bronchial mucosa with CD8+ cells. Therewere differences between the smokers with and without COPD inthe number of eosinophils (fewer in COPD), neutrophils andmacrophages (both more abundant in smokers with COPD),suggesting that COPD is associated with further increases in nasalinflammation over that due to smoking alone. The study did notreport on relationships between the relative severity of upper andlower airway inflammation in the subjects with COPD.

These four studies15 16 18 19 are the only reports to date that haveexaminedthe presenceof sinonasal inflammation in stable COPD.However, approaching the question from a rhinological perspec-tive, two studies by Ragabet alalso warrant discussion.20 21 Theseexamined lower airway involvement in a small number ofpatients with chronic rhinosinusitis who had failed medicaltreatment. Sixty percent were found to have lower airwaysymptoms or spirometric abnormalities (though the methodologydoes not permit a distinction between asthma and COPD).20

Moreover, patients who had asymptomatic airflow obstructionhad a higher proportion of neutrophils in sinus washings thanthose with normal spirometry, and the number of theseneutrophils correlated with the degree of airflow obstruction.21

This provides further evidence of relationships between the degreeof upper and lower airway involvement in these patients, thoughthe results are difficult to interpret with specific regard to COPD.

Exacerbations of COPD are important events resulting inconsiderable morbidity and mortality. Exacerbations are asso-ciated with further increases in both lower airway and systemicinflammation,22 and there are also data examining nasalinflammatory changes at exacerbation. In a small pilot studyof experimental rhinovirus-induced exacerbations, there was anincrease in nasal IL8 concentration over baseline which peakedon day 4 following inoculation, coinciding with the peak innasal viral load.23 Interestingly, patients with COPD needed avery low dose of virus to become infected, and it is tempting toattribute this to increased nasal inflammation. The majorsubtype of rhinovirus enters cells through association withintercellular adhesion molecule-1 (ICAM-1), a receptor that maybe upregulated in response to inflammation. In support of thishypothesis, patients prone to frequent COPD exacerbationshave greater airway inflammation in the stable state24 and arealso more susceptible to developing colds.25 Only one study hasinvestigated nasal inflammation in naturally occurring exacer-bations.22 We reported that markers of nasal inflammation werehigher in patients at exacerbation than at baseline, and (as atbaseline) there was a significant correlation between the degreeof upper and lower airway inflammation. The presence of nasalrhinovirus was associated with a higher nasal wash IL6concentration than that present in non-rhinoviral exacerbations,raising the possibility that nasal wash indices may prove usefulbiomarkers of exacerbation aetiology. In contrast to the baselinestate, at exacerbation there were significant correlations between

the severity of nasal symptoms and the nasal washconcentrationsof both IL6 and IL8.

Figure 2 The magnitude of the nasal inflammatory response in stablechronic obstructive pulmonary disease (COPD) relates to that occurring

in the lung: correlation between interleukin 8 (IL8) concentration in pairednasal wash and sputum samples from 47 patients with COPD (r = 0.30,p = 0.039). From Hurst et al,16 with permission.

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In summary, there is accumulating evidence that patientswith COPD have upregulated nasal inflammation comparedwith controls, additive to that associated with current cigarettesmoking. This inflammation persists after smoking cessation,and the magnitude correlates with that present in the lowerairway. There are also relationships between upper and lowerairway bacterial carriage. Nasal inflammation is furtherupregulated at exacerbation, and the magnitude of the nasal

inflammatory response at exacerbation relates to the severity ofnasal symptoms.

NASAL AIRWAY OBSTRUCTION IN COPD

COPD is defined by the presence of airflow obstruction in thelung1 and it is therefore plausible that sinonasal involvement inCOPD might result in obstruction to the nasal airway.

Although the mucosa of the nasal and pulmonary airways aresimilar, both formed of pseudostratified columnar ciliatedepithelium, there are significant differences in the submucosa,and this has important implications for the generation of airwaynarrowing. Airway obstruction in the nose is predominantlycaused by engorgement of venous sinusoids, in comparison with

the lung where smooth muscle tone, thickening of the airwaywall and excess mucus are major contributors.

We have assessed nasal airway obstruction in COPD usingacoustic rhinometry,26 a non-invasive technique in which areflected sound pulse is used to model nasal cross-sectional areaas a function of distance into the nose. It is important to remarkthat acoustic rhinometry measures nasal airway rather thanairflow obstruction, and that there are at present no reports ofchanges in nasal airflow in patients with COPD. The portion ofthe nasal airway most susceptible to inflammatory obstructioncan be recognised on a rhinometry trace as the second minimumcross-sectional area (MCA2). We have reported a significantlylower MCA2, reflecting a narrower nasal airway, in patients

with COPD experiencing chronic nasal symptoms comparedwith those without such symptoms.26 There was also asignificant correlation between the severity of nasal airwayand pulmonary airflow obstruction,26 the magnitude of whichwas similar to that described between upper and lower airwayIL8 concentrations.16 This therefore provides further evidencethat nasal involvement in COPD is similar in effect andmagnitude to that occurring in the lung.

MECHANISMS OF INTERACTION BETWEEN THE UPPER AND

LOWER AIRWAY IN COPD

Taken together, the evidence presented above demonstratesthat patients with COPD have more nasal symptoms than

controls, which persist after smoking cessation. There is also anasal inflammatory response in COPD, the severity of whichrelates to the severity of lower airway inflammation.Similarities in upper and lower airway involvement are furtherreflected by a relationship between the severity of pulmonaryairflow obstruction and obstruction to the nasal airway.Therefore, there seems little doubt that COPD is associatedwith the coexistence of nasal symptoms, airway obstructionand inflammation. However, an important point remains: doessinonasal involvement in COPD simply represent coexistentdisease or can the presence of inflammation at one site in theairway affect outcomes at another? If true, this would lead tothe hypothesis that nasal intervention in COPD could affect

important lower airway outcomes such as lung function declineor exacerbations.

How might nasal involvement in COPD affect the lowerairway? First, loss of the normal conditioning function of thenose will allow unfiltered, cold and dry air to reach the bronchi.Secondly, elegant work in asthma-rhinitis has demonstratedthat application of an inflammatory stimulus to the nasalmucosa results in lower airway inflammation,27 and vice versa,28

mechanisms that are likely to operate via the systemic (blood)compartment such that there may be homing of inflamma-

tory cells to the entire airway in response to inflammatorystimulation at any part of it. Thirdly, bronchoconstrictorneuronal responses may play a role, though the existence ofnasobronchial reflexes remains controversial.29 Finally, therelationship between postnasal drip and lower airway bacterialcolonisation16 suggests that direct passage of mediators orpathogens along the respiratory mucosa may be important.These concepts are summarised in fig 3.

CLINICAL IMPLICATIONS OF NASAL INVOLVEMENT IN COPDTwo studies, in different populations, have now reported thatthe presence of nasal symptoms in COPD is associated withimpairment to quality of life.18 30 Both employed variants of the

Sino-Nasal Outcome Test (SNOT) questionnaire, a validateddisease-specific health status tool. The study of Hens et al18

included a control population and showed that SNOT scoreswere significantly worse in the subjects with COPD. Weexamined relationships between the SNOT score and the St.Georges Respiratory Questionnaire,30 reporting a weak andstatistically non-significant correlation. One explanation forthis could be that the total health status burden in COPD is notfully reflected using tools that do not include an upper airwaycomponent.

The only current data relating clinically important outcomesin COPD to sinonasal involvement come from a studyinvestigating treatment failure at exacerbation.31 Treatmentfailure was defined as the need for a further physician visit with

persistent respiratory symptoms requiring a change in anti-biotics. A total of 232 exacerbations in 107 patients were studied

Figure 3 Potential mechanisms for interaction between the upper andlower airways in chronic obstructive pulmonary disease (COPD).(1)Lossof nasal conditioning function. (2) Direct passage of inflammatorymediators and/or microorganisms between the upper and lowerrespiratory tract. (3) Nasobronchial neuronal reflexes. (4) Stimulation at

one point of the respiratory mucosal surface results in a pan-airwayinflammatory response.

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and the failure rate was 15%. Intriguingly, a history of sinusitiswas significantly more likely to be present in the patients whoexperienced one or more treatment failures than in those whoseexacerbations always recovered (29% vs 9%, p = 0.009). Ahistory of sinusitis was not associated with the presence of anyof the other five variables that predicted treatment failure(exacerbation frequency, disease severity, the need for homeoxygen therapy, the prescription of maintenance oral corticos-

teroids or a prior history of pneumonia).These two findingsthat nasal symptoms are associated

with health status impairment and that the presence of sinusitisis associated with treatment failure at exacerbationraise thehypothesis that therapeutic nasal intervention might be a novelapproach to therapy in COPD. An effective nasal interventionmight not only reduce nasal symptoms, and thereby improvehealth status, but also affect clinically important lower airwayoutcomes such as exacerbation frequency. At present there areno trials reporting nasal interventions in COPD. Indeed, whilstthe nasal route is commonly used to deliver oxygen andadminister non-invasive ventilation, there are also no studiesinvestigating relationships between nasal inflammation and useof these treatments.

A final and attractive implication of pan-airway involvementin COPD is the opportunity to use the nose to study the lung.This is particularly important in patients with more severeCOPD where it becomes difficult to justify elective endobron-chial biopsy. Obtaining nasal biopsies is much less invasive, canbe repeated more readily, and similarities between thepathological findings in COPD nasal and bronchial biopsieshave been described above.19 A recent study has also demon-strated that cell surface marker expression and functionalresponses of matched, cultured nasal and bronchial cells aresimilar,32 and some of the subjects recruited to this study hadCOPD. This builds on earlier work demonstrating that nasaland bronchial epithelial cell cultures are of similar size and

shape, and have similar growth rates and ciliary beatfrequency.33 Gene expression alterations in relation to smokingare also similar in bronchial and nasal mucosa,34 though a smallstudy in 20 subjects examining the presence of sputum DNAmicrosatellite instability failed to find such changes simulta-neously in the nose.35

AREAS FOR FUTURE STUDY

Although there is now considerable evidence from multiplesources reporting nasal symptoms, and inflammatory andfunctional changes in COPD, the individual studies arerelatively small and there is still the need for a definitive,larger investigation of sinonasal involvement in COPD. This

should be performed across the spectrum of COPD diseaseseverity, and comprehensively assess nasal symptoms, exam-ination findings, inflammation, bacterial carriage, sinonasalimaging and function.

The second major unanswered question is whether it ispossible to affect sinonasal involvement in COPD with nasaltreatmentaiming to reduce nasal symptoms, improve qualityof life and affect important lower airway outcomes such asexacerbations.

CONCLUSIONS

COPD can be associated with upper airway (sinonasal)symptoms that affect quality of life, and a nasal inflammatory

process. This is not, at present, reflected in COPD guidelines.Practioners in otolaryngology might consider the diagnosis of

COPD in patients with chronic rhinosinusitits, and practionersin respiratory medicine should consider identifying those COPDpatients with chronic nasal symptoms. In the absence of specificintervention studies in COPD, nasal symptoms should currentlybe managed by reference to appropriate guidelines.13 For thoseconsidering intervention studies, guidelines exist for theconduct of such research,36 and it must be hoped that suchstudies are indeed performed given the urgent need for truly

novel treatment strategies to treat this prevalent and devastat-ing disease.

Competing interests:None.

Provenance and peer review: Commissioned; not externally peer reviewed.

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ANSWERFrom the question on page 56

The transbronchial biopsy showed large numbers of mono-nuclear cells in both bronchial and parenchymal tissue. Themononuclear cells were heavily parasitised with Leishmaniaamastigotes (figs 1 and 2). No granulomas were seen.Leishmaniaspp. were also identified in a parotid aspirate (Supplementaryfig 4). Stains and cultures were negative for bacteria, fungi,

mycobacteria,Pneumocystis jiroveciiand cytomegalovirus.Leishmaniasis is usually spread through sandfly bites,

although direct humanhuman transmission may occur vianeedle sharing.1 2 The Leishmania parasite resides free in thesandfly digestive tract in the proamastigote form. Uponentering the human host, the parasite is taken up bymacrophages where it transforms to the obligate intracellularamastigote stage. Depending on the leishmaniasis species,macrophage traffic patterns and host immunity, the infectionmay remain localised in the skin (cutaneous leishmaniasis) ormay disseminate systemically (visceral leishmaniasis or kala-azar as in this case). The typical systemic spread is throughoutthe reticuloendothelial system (bone marrow, spleen and liver)although any organ may be affected. Pulmonary involvement

with kala-azar is uncommon, with very few cases reported.3

Diagnosis is usually made by biopsy of the affected organs,

although microbiological, serological and PCR techniques exist.Visceral leishmaniasis is treated with pentavalent antimonycompounds or amphotericin B.4

Patients with advanced HIV disease frequently present withrespiratory illness, and the differential diagnosis is extremelywide.5 Asymptomatic hepatosplenomegaly is a common featurein patients with HIV, although in this clinical context its presencenarrows the differential somewhat to cytomegalovirus, toxoplas-

mosis, leishmaniasis, schistosomiasis, endemic mycoses, M aviumcomplex, miliary tuberculosis and HIV-associated lymphoma.The previous treatment for leishmaniasis was a red-herringsince the parasite is difficult to eradicate completely and mayrecur, especially in immunosuppressed patients.1

REFERENCES1. Piscopo TV, Mallia AC. Leishmaniasis. Postgrad Med J 2006;82:64957.2. Cruz I,Morales MA, Noguer I, et al. Leishmania in discarded syringes from

intravenous drug users. Lancet2002;359:11245.3. Sarker CB,Chowdhury KS, Siddiqui NI, et al. Clinical profile of Kala-azar in adults: as

seen in Mymensingh Medical College Hospital, Mymensingh, Bangladesh. MymensinghMed J 2003;12:414.

4. Alvar J,Aparicio P, Aseffa A,et al. The relationship between leishmaniasis and AIDS:the second 10 years. Clin Microbiol Rev2008;21:33459.

5. Huang L,Stansell J. Pulmonary complications of human immunodeficiency virusinfection. In: Mason RJ, Broaddus VC, Murray JF, et al, eds.Murray and Nadels textbookof respiratory medicine. 4th edn. Philadelphia, PA: Elsevier Saunders, 2005:211162.

Pulmonary puzzle

Review series

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