The spectrum of pulmonary disease in patients with HIV infection

JSG MONTANER, L SPOUR, C ZALA. The spectrum of pulmonary disease in patients with lilV infection. Can J Infect Dis 1994;5(Suppl E):34E-39E. Pnewnocystis carinii pneumonia (PCP) and Kaposi's sarcoma were the harbingers of the 111v epidemic more lhan 10 years ago. Since lhen. the spectrum of pu lmonary disease associaled with 111v infecUon has become heller underslood . Although mosl of these condiUons a.re infecUous in nalure. neoplaslic and in!lammalory processes also occur with increased frequency. The mosl common infecUous pu lmonary diseases include PCP. Mycobacierium tuberculosis infccUon and pyogenic baclerial pneumonia secondary lo Sirepiococcus pneumoniae. Haemophilus injluenzae or Staphylococcus aureus. Among the noninfecUous causes of pulmonary disease. lhe mosl common a.i·e Kaposi's sarcoma. airways hyper-reaclive d isease (aslhma) and emphysema. Respiralory involvement in I 11v-infecled individuals is nol always re lated to the 111v infecUon. These palienls often present with pulmonary disorders that are common in the genernJ populalion. Differenlia.l diagnosis of respiratory condilions is significanUy facilitated by the prior knowledge of U1e degree of immunodeficiency present as measured by the CD4 count. In parUcu la.i·, most episodes of PCP occur in paUents with absolute CD4 counts below 200 cells/mm . On lhe other hand . baclerial pneumonias and tuberculosis tend to occur at any Lime during the nalural h istory of 11rv disease . History and physical examinalion ca.i1 help in the differenlial diagnosis; however. they are rclalively nonspecific in this setting. The same can be said of radiographic findings as well as laboratory and physiological abnormaliUes . Of note. lhe lactate dchydrogenase (LDII) serum level has proved lo be extremely useful in ru ling out PCP. Even mild PCP is usual ly accompanied by a significanl elevalion of LOIi. FurU1ermore. th e degree of LOIi elevalion generally correlales wilh lhe severity of the PCP episode. Also. changes in LDII parallel the clinical course of the underlying PCP. Often LOIi level has been useful in discriminaling worsening PCP following the iniliation of therapy from worsening respiratory symptoms due lo superimposed disease. It musl be emphasiZed, however. thal LDII level. a lthough a very sensilive marker for PCP. is also nonspecific. Of nole. hemolysis, lymphomas. pulmona.i-y embolism, liver disease and dapsonc therapy can be associated with elevated LOIi in the context of 111v disease. Given the high frequency of respiratory involvement in this palienl populalion. it is generally recommended lhal preventive lherapies be used whe never possible. Currenl recommendations stress lhe need for pneumococcal vaccine, yearly ·nu vaccinalion and routine screening with tuberculin skin lesl (PPD). 111v-infected individuals with a PPD skin lest reaction of 5 mm of induralion or greater using 5 tuberculin uni ls will be considered candidates for one year of isoniazid prophylaxis. PCP prophylaxis has been shown to be extremely useful in this selling either as primary or secondary prophylaxis . Recenlly. rifabulin al doses of 300 mg dai ly has been shown to decrease signi ficanUy the frequency of Mycobacierium avium complex infection in palienls with CD4 counts below 100/mm . (Pour resume. voir page 35E)

Mycobacler-ium tuberculosis and pyogenic bacterial pneumonia secondary lo Streptococcus pneumoniae. Haemophilus injluenzae or Staphylococcus aureus infection are lhe rnosl frequenlly encountered complications. Less frequenlly. a variely of fungi and viruses can give rise lo pulmonary infection . Cylomegalovirus pneumonilis. once felt lo be eJ\.1semely frequent in this population. is now rnosl oflen regarded as a conlaminanl in pulmonary secretions. Although Mycobacterium avium inlracellulare (MAI or MAC) is a frequent lale complicalion of AIDS. respiratory disease secondary lo MAI is dislinclly uncommon (2).
The noninfectious causes of pulmonary disease among 111v-infeclccl individuals are listed in Table 2.
Among lhem. Kaposi's sarcoma is particularly frequ ent (3). More recently, an increased frequency of airways hyperreactivity and emphysema has been described in AIDS patients (4,5). Less frequ ently, lymphocytic interstitial pneumonilis, nonspecific interstitial pneumonitis lymphoma and drug radialion-relaled pneumonitis can be seen (2). It is important to highlight that not all lung disease in patients with HIV infection or even AIDS is necessarily related to the 111v infection. These patients often present with pulmonary disorders that are common in the general popu lation. As mentioned above, asthma. emphysema and bacterial pneumonia are frequent non-HIV specific conditions in these patients.
The relative frequency of HIV-associated complications is continuously changing as new effective preventive and/or suppressive therapies and anliretrovirals continue to alter the natural history of the disease. As shown in Table 3. PCP represented the leading AIDS index diagnosis in Canada up to January 1987. Al that lime, PCP alone was the index disease in 52% of cases. As of January 1993, PCP alone represented 38% of the AIDS index diagnoses, while 33% were attributed to other opportunistic infections. Although the frequency of PCP as the AIDS index disease has decreased somewhat since the advent of PCP prophylaxis, PCP remains the single most frequent AIDS index disease (6 .7).

DIFFERENTIAL DIAGNOSIS
The differential diagnosis will be influenced by prior knowledge of the degree of immunosuppression present. In the absence of signs or symptoms, this can be readily assessed using the CD4 cell count. In general, AIDS-defining illnesses are uncommon if the CD4 count is above 300/mm 3 . In particular, most episodes of PCP occur in patients with absolute CD4 counts below 200/mm 3 . On the other hand, bacterial pneumonias or tuberculosis tend to occur at any time during the natural history of HIV disease (8).
Historical data or behavioural factors will also influence the differential diagnosis. As such. the frequency of bacterial pneumonias is particularly high among 111v-infected individuals who use intravenous  (11-14).
Although not frequent, respiratory disease in lhe context of IIIV infection can at times lead lo acule respiratory failure. This is in fact the leading cause of intensive care unit (1cu) admission an1ong 111v-infected individuals. Of the causes of 1cu admission related lo HIV infection, acute respiratory failure secondary lo PCP is by far the most important due to its high frequency and its potentially high mortality. In a recent review of the causes for admission to 1cu in 111v-infected individuals at St Pauls Hospital in Vancouver, between lhe years 1985 and 1990, PCP was diagnosed in 92% of the 1cu cases. cerebral toxoplasmosis in 3%, Kaposi's sarcoma in 3% and bacterial pneumonia, gastrointestinal bleeding, lymphoma and cardiomyopathy in 2% each of the cases (15). Note U1at more Ulan one condition could be present in a given patient.
lt is useful to keep in mind that the natural history of 111v I AIDS is continuously being altered by stateof-the-art therapy. Also, the so-called 'prophylaxis' against the various opportunistic infections encountered is usually not true prophylaxis but rather suppressive llierapy. It is important to consider that not all respiratory disease in 111V-infected individuals is necessai;ly an opportunistic infection or AIDS-related disease. but often these represent non-111v specific pathology.
Finally, contrary to most other ai·eas of medicine. the search for a single diagnosis when dealing with AIDS may be fruitless, since multiple pathological processes often occur simultaneously in lliis disease (16).

HISTORY AND PHYSICAL EXAMINATION
As in any other selling, pulmonary involvement in patients with HIV infection generally produces nonspecific signs and symptoms. Fever, malaise and weight loss for several weeks to months before the onset of pulmonary symptoms are not infrequent. In a group of patients with AIDS and pulmonaiy involvement. Slover et al (17) reported that cough was U1e most frequent symptom, present in 89% of patients. Dyspnea was present in 64%, productive cough in 39%, pleurilic pain in 20% and hemoptysis in 3% ofpalients. Acute symptoms were characteristically present among patients with bacterial pneumonias who were more likely lo present with shaking chills. Symptoms in patients with opportunistic infections such as PCP were usually more indolent, although in some instances they were also rapidly progressive (17).
Physical examination may be useful in establishing the diagnosis of AIDS or AIDS-related complex, but is not usually helpful in establishing the etiology of the pulmonary involvement. Pulmonary findings during physical examination are more useful in suggesting that the respiratory symptoms in a given high risk patient are not caused by an AIDS-related opportunistic infection. Diffuse wheezing would suggest the diagnosis of asthma; consolidation of the lung would be suggestive of an acute bacterial pneumonia; and a large pleural effusion. particularly if it is accompanied by characteristic skin or mucosa! lesions. would be suggestive of Kaposi's sarcoma.

RADIOGRAPHIC FINDINGS
The chest radiograph is usually the first tool in the assessment of an 1 -1rv-infected individual with respiratory symptoms. Only rarely does the chest x-ray yield a firm diagnostic clue; however, findings are often helpful in guiding the next steps in the evaluation.
A diffuse interstitial pattern is most commonly caused by PCP. It must be recognized, however. that PCP can present with a wide variety of radiological patterns, from a normal x-ray lo airspace disease, and from cavitary lesions lo pneumothoraces. The interstitial pattern may be limited to the upper lung fields, particularly among patients who develop PCP while receiving aerosolized pentamidine for PCP prophylaxis. A diffuse interstitial pattern may also occur with M tuberculosis, MAJ, histoplasmosis and coccidioidomycosis. Malignancies are infrequent causes of diffuse interstitial patterns. A diffuse airspace pattern can be essentially attributable to any of the infections described above. In addition, malignancies can also cause diffuse airspace consolidation. Such a radiological appearance, in the context of PCP, is often associated with significant respiratory distress. Focal airspace consolidation is most often attributable lo bacterial pneumonia, but may also be caused by Mycoplasma pneumoniae or viruses. PCP and mycobacterial infections have also led lo focal airspace consolidation in the past. Nodular lesions are often seen with Kaposi's sarcoma. They can also occur with mycobacterial and fungal infections as well as PCP. Cavitary lesions are relatively uncommon among patients with HTV disease. They have been described in the context of PCP. M tuberculosis, M avium, bacterial pneumonias and fungal infections.
Pleural effusions, particularly if they are large, are likely related to Kaposi's sarcoma. Smaller effusion can be seen in association with any of the above mentioned infectious processes. Intrathoracic adenopathy is frequently seen in the context of malignancies (Kaposi's sarcoma or lymphoma) or infectious processes, particularly tuberculosis. Pneumothoraces have been noted in association with PCP, particularly among those receiv- ing aerosol pentamidine for PCP prophylaxis. Finally, it must be emphasized that a normal chest film does not rule out significant pulmonary involvement by any of the above mentioned conditions in patients with HIV infection. Of note. it has been demonstrated tl1al a full two-thirds of 11rv-infected individuals with advanced immunodeficiency may have unsuspected lung lesions on exanlination with high resolution computed tomography of the chest. Destructive lung lesions, from isolated lung cysts lo widespread emphysema. were particularly frequent in these individuals (5.18).

OTHER LABORATORY TESTS
Numerous other laboratory tests are often useful in the assessment of 11rv-infected individuals presenting with respiratory complaints. Obviously. this greatly varies depending on the specific nature of their complaints. In general. the serum level of lactate dehydrogenase (LOH) has proven extremely useful in this setting lo rule out PCP. Even mild PCP is usually accompanied by a significant elevation of LOH, to one and a half Lo two Limes the upper limit of normal. The degree of LOH elevation generally correlates with the severity of the PCP episode. Furthermore, changes in LOI I parallel the clinical course of the underlying disease. This is a useful aid in discriminating worsening PCP following the initiation of therapy from worsening respiratory symptoms due to a superimposed process.
It must be emphasized, however. that LOH, although a very sensitive marker of PCP, is also nonspecific. Elevations in the level of LOI I can be seen in hemolytic processes, lymphomas. pulmonary embolisms and liver disease, among other conditions occurring not infrequently among HIV-infected individuals. Of particular note, in this context, is the fact that dapsone therapy can lead to the development of methemoglobinemia. which in tum leads lo hemolytic anemia and an elevation in LOH. Because this is a dose-related phenomenon. it is most likely to be encountered among patients who are receiving treatment with full doses of dapsone for an episode of PCP rather than those receiving low dose intermittent dapsone for PCP prophylaxis (19)(20)(21)(22)(23).
Numerous other tests have been used with various degrees of success in the assessment of patients with respiratory involvement in the context of Hrv infection. These include: pulmonary function test before and after bronchodilators; methacholine challenge; carbon monoxide diffusing capacity of the lungs; oxygen saturation while breathing air at rest and during exercise; and arterial blood gases. If pulmonary function tests are normal, a gallium Jung scan is often performed. Increased uptake in the lungs would suggest direct pulmonary involvement and would warrant further evaluation to establish a defmitive diagnosis (2).
All of the these tests, while very sensitive indicators of lung dysfunction, have a relatively low specificity. As such, etiological confirmation of pulmonary involve-37E menl must be obtained from pu lmonary secretions. as diclalecl by signs and symptoms. This is most often done using sputum. sputum induction or bronchoa lveolar lavage. In all instances. respiratory secretions s h ou ld be examined thoroughly, considering the wide variety or organisms lhal can lead to respiralo1-y involvement in these patients .

PREVENTION OF RESPIRATORY DISEASE AMONG HIV-INFECTED INDIVIDUALS
Given lhe ver-y high frequency of respiratory involvement in lhis patient population, il is generally recommenclecl lhal an aggressive preventive strategy be initialed immediately upon diagnosis or 111v infection. Al l HIV-in feclecl individuals should receive pneumococcal vaccine. ll has now been clemonslralecl that this is a cost effective inlervenlion that should be imp lemented as soon as possible fo llowing the diagnosis or 11rv to maximize the chances of an adequate humoral response. Yearly 'Ou vaccination during the appropriate time or the year is a lso recommended for all 111v-infectecl individuals. The cost effectiveness of this is less well clocumentecl (2).
A rro skin test will allow iclenlificalion or individuals at high r isk for the development of tuberculosis. A 5 mm or greater incluralion following a 5 tuberculin unit (TU) PPD will require one year or isonazicl (1N11) prophylaxis. PPD skin testing shou ld ideally be repealed on a yearly basis. The pred ictive value of this lest is likely lo be compromised as the immunodeficiency progresses (2,(11)(12)(13)(14). PCP prophylaxis should be initialed in all 111v-infccled individuals who have any of: CD4 count below 200/mm 3 ; fraction CD4 count below 15% : unexplained fever: oral candicliasis: or a prior episode of PCP. The preferred prophylactic regimen is trimclhoprim-su lfamethoxazole (TMP-SMX) 1 double-strength tablet once da ily. for life. Adverse reactions lo TMP-SMX arc frequent and at limes severe among 111v-infeclecl individuals . Palicnls should be warned that the drug must be discontinued if generalized rash or fever develops. Alternative prophylactic regimens include clapsone al a close or I 00 mg by mouth three limes weekly or aerosol penlamicl ine intermittently. Aerosol pentamicline can be laken in closes of 60 mg every second clay for five do e followed by one close every two weeks via a Fisoneb u ltrasonic ncbulizer {Fisons. New York): alternatively, 300 mg monthly can be cleliverecl via a Respirgarcl lube jet nebulizer (Marquest, Colorado). It shou ld be noted that the aerosol penlamicline closes are nebuUzer-specific (2 ,6,8) .
Recently it has been clemonstralecl that rifabulin at closes of 300 mg daily can sign ificantly decrease the frequency or MAJ in patients with aclvancecl immunodeficiency. This prophylactic intervention is recommcnclecl for patients who have CD4 counts be low 100/mm 3 (24).
Despite the availability or preventive therapies. we must recognize that U1ey are only partially effective. Furthermore, issues of acceptabil ity, to lerability and compliance, among others, will continue lo jeopardize our ability lo eradicate definitively some of the c often serious respirat01-y complications of 111v I AIDS (2)(3)(4)(5).