Sinusitis is a common problem in people with human immunodeficiency virus (HIV) infection; in one retrospective review, 11% of hospitalised patients were affected by this disorder. Sinusitis is more common with immunodeficiency (CD4 T lymphocyte cell (CD4) count < 200/μL), and it is more likely to be extensive and chronic in very immunodeficient patients. Up to one-third of cases may be asymptomatic, although most have fever, headache and nasal discharge. A minority have facial pain and tenderness. Sinusitis should be considered in the differential diagnosis of headache and fever in people with HIV infection.
Most cases of sinusitis in people with HIV infection are caused by bacterial respiratory pathogens such as Streptococcus pneumoniae and Haemophilus influenzae, although Pseudomonas aeruginosa and Staphylococcus aureus may also be causative agents. Mycobacteria spp., cytomegalovirus (CMV), Encephalitozoon spp., Cryptococcus spp., Aspergillus spp., Acanthamoeba spp. Cryptosporidia spp. and Pneumocystis jirovecii have all been reported as pathogens in people with HIV infection (Table 1 Infectious cases of sinusitis). Non-Hodgkin’s lymphoma also may affect the sinuses.
|Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Pseudomonas aeruginosa Mycobacteria spp.||Aspergillus spp. Cryptococcus spp.||Encephalitozoon spp. Acanthamoeba spp. Cryptosporidium parvum Pneumocystis jirovecii||Cytomegalovirus|
Computed tomography (CT) scanning is the most sensitive imaging modality for diagnosing sinusitis. The presence of bony erosions on CT scan or ophthalmoplegia suggest possible infection with Aspergillus spp., and mandates the need for biopsy. Erosions may also be associated with Pseudomonas infection or lymphoma. Opportunistic pathogens need to be considered in the differential diagnosis, and a diagnostic aspirate should be performed in immunodeficient patients and in patients who have a poor response to therapy or severe disease. Samples should be examined for bacteria, fungi, mycobacteria and microsporidia and other microbes depending upon the level of immunosuppression of the patient.
Standard therapy with antibacterial agents (e.g. amoxicillin with clavulanic acid), decongestant and expectorant agents is appropriate in most cases. In severe cases where parenteral therapy is required, a third-generation cephalosporin (e.g. ceftriaxone) is recommended. In non-responsive disease, broadening of the antimicrobial spectrum to cover Ps. aeruginosa and S. aureus should be considered, pending results of sinus sampling. Surgery should be considered in the presence of ocular complications, systemic disease not responding to empirical antimicrobial therapy, and in conjunction with antifungal agents in fungal sinusitis. Surgical intervention for infective sinusitis is as effective in people with HIV as in those without HIV.
Bacterial pneumonia is a significant cause of morbidity and mortality in people with HIV infection. It is predominantly caused by S. pneumoniae. People with HIV are at much higher risk of invasive pneumococcal infection than the general population, with the incidence of pneumococcal bacteraemia 100 times that of age-matched populations, and pneumococcal pneumonia rates five to 17 times those of the general population. Children with HIV infection appear to be at even greater risk of invasive pneumococcal disease. Recurrent pneumococcal infection is more common in patients with HIV infection than in the general population.
Risk factors for pneumococcal infection in patients with HIV infection include cigarette smoking (both active and passive forms), injecting drug use, recent hospital admission, blood transfusion as the mode of HIV transmission, alcoholism, a previous acquired immune deficiency syndrome (AIDS)-defining illness and previous pneumococcal infection. The risk of pneumococcal infection is greater in individuals with CD4 cell counts < 500/μL compared with > 500/μL, and is greatest with CD4 cell counts < 200/μL. Infection with S. pneumoniae with reduced sensitivity to penicillin occurs at a similar frequency in people with HIV infection and the general population.
People with HIV infection who present with S. pneumoniae disease most commonly present with pneumonia. The major symptoms are fever (96%), cough (90%) and dyspnoea (72%). Bacterial pneumonia due to H. influenzae may be indistinguishable from that due to S. pneumoniae. In advanced immunosuppression, pneumonia secondary to P. aeruginosa and to S. aureus increases in frequency and may present with cavitatory infiltrates. Rare presentations of pneumococcal infection include mediastinitis, multiple brain abscesses, meningitis, pericarditis and endocarditis, cervical cellulitis, and testicular abscess.
The diagnosis of bacterial pneumonia is usually clinical. Nevertheless, blood should be sent for culture. Blood cultures are a sensitive diagnostic tool, with isolation of S. pneumoniae in 85% of patients. Additional testing to be considered should include urine antigen for pneumococcus and legionella as well as atypical pneumonia serology. Leukocytosis may not occur, but a left shift with band forms may be observed. Chest X-ray findings include segmental, lobar or multilobar consolidation, although interstitial infiltrates are found in some patients. Thoracentesis should be considered for patients with pleural effusions if there is clinical concern of empyema.
Decisions on treatment are based on the severity of the pneumonia. Treatment for bacterial pneumonia is the same for patients with HIV infection as for the general population. For cases of mild-to-moderate pneumonia, amoxicillin 1 g three times daily may be used, with or without a macrolide or doxycycline if atypical pneumonia is suspected. However, if parenteral therapy is required, intravenous benzyl penicillin (penicillin G) 1.2 g every 6 hours is recommended. In patients with penicillin allergy, roxithromycin 300 mg daily may be used, or for parenteral therapy, cephalothin 1 g every 6 hours. In severe pneumonia, intravenous ceftriaxone 1 g daily (or benzyl penicillin 1.2 g every 4 hours with gentamicin) plus azithromycin 500 mg daily or erythromycin 1 g 6 hourly are recommended. Specific recommendations exist for tropical areas of northern Australia.
The role of vaccination with the 23-valent pneumococcal unconjugated polysaccharide vaccine had been controversial. Its use has been recommended by authorities in the USA, Europe, Brazil and Australia. However, a randomised, placebo-controlled study in African adults showed no decrease in pneumococcal disease in the vaccinated group compared with the placebo group. Importantly, this study also showed an increased risk for all types of pneumonia in the vaccine arm. However, other studies have shown an overall benefit from vaccination, and both combination antiretroviral therapy (cART) and vaccination with pneumococcal vaccine had independent protective effects against pneumococcal infection regardless of CD4 cell count. A study of the 7-valent pneumococcal conjugate vaccine in Malawi showed adults with HIV-infection were protected from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A.  Most authorities would now therefore favour vaccination. Current guidelines generally suggest the use of the conjugated polysaccharide vaccine first followed by the unconjugated polysaccharide vaccine 8 weeks or more later.
Respiratory tract infections caused by uncommon organisms
Many different organisms have been demonstrated as causing infectious syndromes involving the respiratory tract in persons with HIV/AIDS. A list of common and important infections can be found in other sections. Tuberculosis, which is a very important infection globally in relation to HIV, is covered in mycobacterium tuberculosis. Three infections not covered elsewhere in this monograph are covered here.
Penicilliosis is a systemic mycotic infection, caused by Penicillium marnefei, a dimorphic fungus endemic in South-East Asia, Hong Kong and parts of southern China. P. marneffei was first isolated from a species of bamboo rat; however, the environmental source of infection remains unclear. Infection is thought to occur by the respiratory route. An increased risk is seen with recent occupational exposure to soil. Symptomatic infection occurs only rarely in the immunocompetent host. Clinical presentation may occur many years after exposure. The rapid explosion of HIV in the areas endemic for this fungus has led to a significant increase in cases of P. marneffei infection with more than 1000 cases reported in a 7-year period at one hospital in Thailand;. increased incidence occurs during the wet season (May to October).
P. marneffei infection is usually reported in late-stage HIV disease when the CD4 cell count is < 100/μL. The presentation is subacute with constitutional signs and symptoms. Fever and weight loss occur in 95% of patients. Cough and pulmonary symptoms occur in up to one-third of patients. On examination, lymphadenopathy and hepatomegaly are seen in 70% of patients, and concomitant oral candidiasis in 50%. Characteristic skin lesions, cutaneous papules with central necrotic umbilication resembling molluscum contagiosum are present in 70% of patients (Figure 1 Penicilliosis).
Figure 1 Penicilliosis Source: Stewart GJ, Kunanusont C, Phanuphak P, Hanvanich M, Wabitsch R. Managing HIV with limited medical resources.
Penicilliosis Source: Stewart GJ, Kunanusont C, Phanuphak P, Hanvanich M, Wabitsch R. Managing HIV with limited medical resources. Med J Aust 1996;165:499-503. Used with permission.
These lesions of penicilliosis are similar to those seen in histoplasmosis and cryptococcosis, but are distributed predominantly on the upper parts of the body (scalp, face, upper extremities and trunk). Disseminated disease is common at presentation, with possible lung, liver, spleen and bone involvement. In contradistinction to both histoplasmosis and cryptococcosis, dissemination to the central nervous system does not occur with P. marneffei. The reason for this lack of neurotropism is not clear. Anaemia and abnormal liver function tests are also frequently present. In patients with lung involvement, X-ray findings include nodules, interstitial infiltrates and pleural effusion. There has been a series of patients with hepatic disease who lacked skin manifestations, but whether this indicates a different form of the disease is not clear. An immune reconstitution inflammatory syndrome has not been described with P. marneffei infection.
Diagnosis is made by fungal culture or histopathology examination of a specimen obtained from a normally sterile site (i.e. blood, skin lesions, bone marrow, lymph node, liver). Isolation occurs most frequently from bone-marrow aspirates and lymph-node samples (100%), followed by skin biopsy (90%) and blood cultures (76%). Full identification of the organism may take up to 7 days. Galactomannan (GM) is a heteropolysaccharide in the cell walls of most Aspergillus and Penicillium species. The use of the GM antigen assay may facilitate earlier diagnosis of P. marneffei infection for patients with HIV in areas of endemicity, as 73% of patients have positive tests, particularly those with fungaemia. Research continues on a serological assay and polymerase chain reaction (PCR) assay to assist in diagnosis, but these tests are not generally currently available for clinical use.
Therapy for penicilliosis depends on severity of disease. Mild-to-moderate disease can be treated with itraconazole 200 mg per day. Severe disease requires treatment with amphotericin B (0.5-1.0 mg per kg per day) for induction therapy followed by itraconazole (400 mg per day) as maintenance therapy. Measurement of itraconazole levels is recommended. Relapse rates without maintenance therapy approach 50%. Maintenance therapy with itraconazole (200 mg daily) should be continued lifelong. Relapse occurs infrequently in the presence of maintenance therapy, although it is more likely in patients who remain in endemic areas. There have been recent reports of successful discontinuation of maintenance therapy in patients who have achieved immune reconstitution with antiretroviral therapy (CD4 cell count > 100/μL for 6 months). In patients with HIV infection and a CD4 cell count < 200/μL who live in an endemic area, primary prophylaxis with itraconazole at a dose of 200 mg per day is recommended.
Originally considered a fungus, Nocardia species are a group of ubiquitous actinomycetes. Nocardial taxonomy is complex and, of the nine species described, only seven have been associated with human disease, with N. asteroides the most commonly identified. Although distributed worldwide, disease is most common in men, and mainly occurs in severely immunocompromised people. A preponderance of cases occur in rural areas, probably reflecting exposure via contact with soil. Nocardia spp. may cause cutaneous, pulmonary or disseminated disease. Dissemination is thought to occur primarily from the lung, but in the case of injecting drug users with HIV infection the occurrence of mediastinal disease exclusive to this population suggests direct intravenous contamination as the portal of entry. Pulmonary and disseminated disease occur almost exclusively in association with defects in cell-mediated immunity, immunoglobulin production or leukocyte function. Prevalence in people with HIV infection is low, varying from 0.3-1.8%, although one West African autopsy study showed 4% of patients with pulmonary nocardial infection. Infection in people with HIV is strongly associated with injecting drug use and advanced immunosuppression with a CD4 cell count of < 200 cells/μL.
Cutaneous disease may present as one of four types: mycetoma; lymphocutaneous (sporotrichoid) infection; acute cutaneous infection; or systemic disease with cutaneous involvement. Multiple types may occur in the same person. Mycetoma is a chronic, indurated, granulomatous, subcutaneous infection consisting of nodules and draining sinus tracts, often localised to the site of inoculation. The discharge from these sinus tracts often contains small white granules consisting of masses of mycelia. Dissemination from mycetoma is rare, but local invasion from head and neck lesions may result in severe disability or death. Lymphocutaneous disease also develops as a nodule at the site of inoculation; however, central ulceration rather than draining sinus formation occurs, and as ulceration spreads to the lymph nodes, multiple subcutaneous nodules develop along the draining lymphatics (Figure 2 Localised nocardial infection). Acute cutaneous infection may manifest as a superficial skin infection with pustules, abscesses, cellulitis, granulomas and ulcers (Figure 2 Localised nocardial infection).
Pulmonary disease is the most common manifestation of nocardial infection in the immunocompromised patient, typically presenting as a subacute illness. Fever and cough with thick purulent sputum are usually present; other constitutional signs are variable. Chest X-ray findings are variable and may consist of a necrotising pneumonia with cavitation formation, infiltrates of varying size, single or multiple nodules which are highly suggestive of malignant tumours, and pneumonia-associated empyema. Pulmonary infections have a propensity for haematogenous spread with extrapulmonary dissemination occurring in half of all patients and seeding of the central nervous system (CNS) occurring in one third. Brain abscesses, usually supratentorial, are the most common CNS presentation; meningitis is rarely reported. Clinically silent CNS involvement is sufficiently common that cerebral-imaging studies are recommended, preferably magnetic resonance imaging (MRI), in all patients. An immune reconstitution inflammatory syndrome (IRIS) has not been reported in nocardial infection.
A high index of suspicion for Nocardia spp. infection may be the most useful aid in diagnosis. In all suspected cases, early notification to the microbiology laboratory is essential. Sputum or pus should be examined for weakly acid-fast, gram-positive filamentous bacteria. Sputum smears are often negative, and bronchoscopy or lung aspiration is usually necessary. Nocardia grow quite slowly, and colonies may take up to 4 weeks to develop. Thirty per cent of patients with Nocardia spp. infection detected in blood cultures also have concomitant bacteraemia with other pathogens. If cerebrospinal fluid or urine is used for culture, specimens should first be concentrated to optimise yield.
The treatment of nocardial infections may include both surgical and medical interventions; however, prospective, controlled, clinical trial data are lacking. Antibiotics should not be delayed as early administration has been shown to improve outcomes. Sulfonamides are the best studied drugs, with trimethoprim-sulfamethoxazole (cotrimoxazole) the most frequently used formulation, despite limited efficacy data and poor in vitro results. Minocycline generally has excellent in vitro activity, and has been successfully used at doses of 100-200 mg twice daily as an alternative agent in pulmonary and even cerebral infection. Other useful drugs in the management of nocardial infection include imipenem, meropenem, cefotaxime, ceftriaxone, amikacin, and amoxicillin/clavulanic acid. Therapy should be continued in the immunosuppressed person for at least 12 months, as shorter durations of therapy have been associated with relapse and increased mortality. In cases of disseminated infection, therapy should include at least two active agents. In CNS infections, cotrimoxazole is generally used in combination with imipenem, meropenem, amikacin or a third-generation cephalosporin. Different Nocardia species may differ in their in vitro susceptibility to antibiotics, and species identification is critical to guiding the selection of therapeutic agents.
Although it is often stated that cotrimoxazole reduces the risk of nocardiosis in people with HIV disease, there is no compelling clinical evidence to support this claim, especially at the doses used for Pneumocystis jirovecii pneumonia (PJP) prophylaxis. Indeed, there are numerous case reports of patients who develop nocardiosis despite receiving cotrimoxazole prophylaxis.
Rhodococcus equi infection
Rhodococcus equi (formerly called Corynebacterium equi) is an aerobic, gram-positive, weakly acid-fast, non-spore forming coccobacillus. R. equi was first isolated from horses and has been widely reported as a pathogen in domestic animals. However, contact with either farm environments or animals is rarely documented in people with HIV and R. equi infections. R. equi is usually acquired through the respiratory route in both animals and humans, although person-to-person and nosocomial transmissions have been described.
R. equi infection in people with HIV presents with pulmonary involvement, usually accompanied by bacteraemia and frequent dissemination to extrapulmonary sites. R. equi infection usually presents subacutely with fever and cough. Weight loss, pleuritic chest pain and haemoptysis are also frequently reported. R. equi infection in people with HIV infection usually occurs at CD4 cell counts < 200/μL, and concomitant infections with other opportunistic pathogens occur frequently. Radiological features consist of cavitating lesions with a strong predilection for involvement of the upper lobe (50-75% of cases). Consolidation is also frequently seen. However, in one case series normal chest X-ray findings were reported in one-quarter of patients. Both the clinical picture and X-ray findings may suggest infection with Mycobacterium tuberculosis or Nocardia spp. Histological examination demonstrates multiple microabscesses with dense infiltration by histiocytes and intracellular gram-positive coccobacilli. An immune reconstitution inflammatory syndrome has not been described.
R. equi can be cultured from blood, sputum, bronchoalveolar washings and biopsy material using standard media. R. equi resembles oropharyngeal commensal diphtheroids and is frequently regarded as a contaminant, leading to late diagnosis in many cases.
The optimal choice and duration of antibiotic therapy for R. equi infection remains to be determined. Based on in vitro susceptibility, R. equi is sensitive to erythromycin, rifampicin, vancomycin, gentamicin and ciprofloxacin. Initial therapy with erythromycin or imipenem plus rifampicin for at least 2 weeks is recommended. Ciprofloxacin is an alternative agent, but ciprofloxacin-resistant strains from South-East Asia have been reported. Surgical intervention is sometimes needed and lifelong, suppressive, oral therapy with a macrolide and rifampicin is recommended. Mortality in patients with HIV and R. equi infections is high, often with death resulting from other concomitant infections.
Non-infectious respiratory tract disease
Chronic airflow limitation
Abnormalities of pulmonary parenchyma, including emphysema, airways disease and reduced pulmonary diffusing capacity, occur at a higher incidence in the setting of HIV infection. There is an association between cigarette smoking and accelerated emphysema in people with HIV not receiving cART. Half of the smokers with HIV (with a smoking history of ≥ 25 pack-years) had radiological evidence of emphysema compared with none of the controls without HIV. Emphysema may be associated with CD8-- positive lymphocyte-mediated damage. Several studies have demonstrated a reduction in pulmonary diffusing capacity in people with HIV infection, and that these changes are not predictive of an opportunistic infection in asymptomatic people. It is possible that these changes are a marker of early emphysema. The relevance of these findings in the cART era is unclear, although smoking cessation is still recommended. Smoking is common in people living with HIV in many settings and difficult to reverse.There are no specific therapies for chronic airflow limitation in HIV infection. However, an awareness of drug interactions, particularly between ritonavir and inhaled steroids such as fluticasone and mometasone, is very important. In general, the principles related to smoking cessation for people with HIV infection are the same as for people without HIV infection, but the possibility of drug interactions must again be borne in mind, for example, bupropion and efavirenz are likely to interact.
Lymphocytic interstitial pneumonitis
Lymphocytic interstitial pneumonitis is a clinical condition characterised by cough, dyspnoea, hypoxaemia and a predominantly CD8-positive lymphocyte infiltrate in the lung. Physical examination reveals crackles. The condition is predominantly seen in children with HIV infection and is rare in adults. Radiographical findings include diffuse reticular or nodular pulmonary infiltrates. Pleural effusions or hilar masses occur infrequently. In some cases, this disorder is part of a multisystem condition known as diffuse infiltrative CD8 lymphocytosis syndrome, which features universal parotid involvement and possible muscle and liver involvement. Host genetics appear to play a role in the development of this syndrome, with HLA-DR5 being over represented. Although controlled trial data are lacking, corticosteroids benefit some patients.  One atypical case of lymphocytic interstitial pneumonitis (with clubbing) responded to a triple nucleoside antiretroviral regimen.
The incidence of Kaposi’s sarcoma (KS) has significantly declined since the introduction of cART. Patients with pulmonary KS usually have advanced immunodeficiency (CD4 cell counts < 50/μL) and present with dry cough and dyspnoea. Half complain of chest pain and one-third have haemoptysis, while a minority have fever. Most (85%) will have concomitant skin involvement. Chest X-ray findings consist of diffuse interstitial infiltrates (90%), pleural effusions (80%) and nodules (37%). Diagnosis is made by the characteristic appearance of purple nodules on bronchoscopy, or a bloody pleural effusion. Cytology of sputum is not helpful, but transbronchial biopsy may be. Open lung biopsy is often required for definitive diagnosis. Treatment with liposomal doxorubicin and effective cART has markedly improved the median survival for patients with pulmonary KS.
Non-Hodgkin’s lymphoma and Castleman’s disease can also present with respiratory symptoms and signs including cough and dyspnoea, pulmonary nodules and mediastinal and thoracic lymphadenopathy. Primary effusion lymphoma is related to human herpesvirus 8 (HHV8) (as are KS and Castleman’s disease). Severely immunodeficient patients usually present with dyspnoea and a pleural effusion, and diagnosis is made by cytology of pleural fluid or pleural biopsy. Prognosis is very poor, despite treatment with chemotherapy and cART.
Carcinoma of the lung
The risk of lung cancer is three-to six-fold higher in patients with HIV infection compared with the general population. It is unclear how much of this increased relative risk is due to the higher rates of smoking in HIV populations and what contribution HIV infection makes. Carcinoma of the lung occurs at any CD4 cell count, and the relationship between immune status and the incidence of non-AIDS-related malignancy is unclear. A trend towards a three-fold increased risk of lung cancer in the antiretroviral treatment interruption arm of the SMART study suggests control of HIV infection with cART may reduce the incidence of this malignancy; however the study was not powered for uncommon events and was stopped early by the study’s Data Safety Monitoring Board. Treatment for carcinoma of the lung in people with HIV infection is no different to that in the general population, though interactions between chemotherapy and antiretroviral therapy need to be borne in mind.